THIAZOLE DERIVATIVES FOR THE TREATMENT OF ANIMAL TRYPANOSOMIASIS

Field of the Invention

5 The present invention relates to a new class of compounds, to their use in human and veterinary medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. In particular, the present invention provides compounds for use in medicine, and particularly in the treatment of animal trypanosomiasis.

10

Background

Animal trypanosomiasis is also known as animal African trypanosomiasis (AAT), and is a disease of vertebrate non-human animals. Human African trypanosomiasis (HAT) is

15 commonly known as sleeping sickness. Animal trypanosomiasis is caused by various parasite species and sub-species of the Trypanosoma genus, trypanosomes which are pathogenic to animals, including Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and Trypanosoma evansi. It is thought that there are likely further, un-identified

20 trypanosome species or sub-species that are pathogenic to animals and also cause animal trypanosomiasis. HAT is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.

Trypanosomes are protozoan parasites in the family Trypanosomatidae and most 25 trypanosomes are transmitted by tsetse flies with the trypanosomes infecting the blood of the animal. As such, an infected animal can act as a disease reservoir with resultant potential for further disease spread in areas affected by the tsetse fly. In Africa, the disease is most common in areas affected by tsetse flies and is spread by the bite of an infected tsetse or other infected flies. Many different animals can be infected by animal 30 trypanosomiasis, including domestic livestock, such as cattle, goats, pigs, sheep and camels. Wild animals, including elephants and leopards have also been found to have trypanosomiasis. Different parasites affect different ranges of organism.

Animals are primarily at risk from this disease wherever trypanosomes and the tsetse fly 35 vector exist, and in Africa this "tsetse belt" is between latitude 15° N and 29° S, from the southern edge of the Sahara Desert to Zimbabwe, Angola and Mozambique. Although AAT is most commonly found in the "tsetse belt" region of Africa there is now evidence that trypanosomes can spread beyond this area, and therefore the potential for spread of the disease with the associated risks to domesticated and wild animals extends beyond Africa. This risk of disease spread beyond the tsetse belt is particularly associated with Trypanosoma vivax (T vivax), which does not appear to require the tsetse fly for transmission. As reported by Spickler, "African Animal Trypanosomiasis" http://www.cfsph.iastate.edu/Diseaselnfo/factsheets.php, T. vivax is also found in South and Central America and in the Caribbean with the associated potential risk of transmission to animals via mechanical vectors in these regions.

Thus it would be desirable to provide a treatment for animal trypanosomiasis which is effective against the Trypanosoma vivax and/ or Trypanosoma congolense forms of the disease in particular. In cattle the disease is frequently fatal unless treated. The symptoms include loss of condition, severe weight loss / emaciation, anaemia and fever. Current treatments for animal trypanosomiasis were introduced more than 50 years ago with isometamidium chloride, ethidium bromide and diminazene acetate forming the main treatments at present. However, as discussed by Chitanga et al, in recent years there have been increasing problems due to resistance to the presently available treatments, Chitanga et al., "High Prevalence of Drug Resistance in Animal Trypanosomes with a History of Drug Exposure". PLoS Neglected Tropical Diseases, 201 1 , 5, e1454.

Thus it would be desirable to provide a treatment for animal trypanosomiasis having improved activities versus current therapies and not cross-resistant to current therapies.

This disease is a major restraint to livestock industry in affected parts of Africa, with those areas with reliance on cattle being particularly at risk. In 2010 the annua! losses have been reported to be in excess of US $ 1 billion. The socio-economic impact of animal trypanosomiasis has been found to disorient the way of life for communities where the disease is prevalent. In some cases it has been reported that the number of animals a family would have reared is reduced, with up to a 50% reduction in beef and dairy production in AAT endemic areas being observed. Where farmers have reduced healthy livestock to rear, and sell or utilise the assets from the animals (milk, meat) this not only has an immediate impact on their own lives, but in a community reliant on livestock this disease can have a devastating impact. The disease is a particular problem in sub-Saharan Africa, where it is commonly referred to as AAT, nagana, or nagana pest, and has a major effect on agriculture. In regions where herds are affected, not only are meat and milk production significantly reduced, but also the use of infected animals for vital tasks such as ploughing are compromised. This is confirmed in Bouyer et al. "Community- and farmer-based management of animal African trypanosomiasis in cattle". Trends in Parasitology, 2013, 29, 519-522.

Thus it would be of great economic benefit to cattle farmers in regions affected by animal trypanosomiasis, and particularly farmers in sub-Saharan Africa to provide an improved treatment for AAT, an improved AAT treatment suitable for intramuscular injection, an improved AAT treatment suitable for intramuscular injections formulated as a single-dose for direct action (treatment of an infected animal) and/or prophylactic utility (uninfected animal). Thus there is a need for new and effective anti-animal trypanosomiasis agents. In particular there is a need for new anti-animal trypanosomiasis agents which: are effective against Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and/or Trypanosoma evansi infections; are effective against drug-resistant Trypanosoma congolense and/or Trypanosoma vivax; have transmission-blocking potential; which can be formulated for pharmaceutical or veterinary use, such as for intramuscular or oral administration; which can be formulated for subcutaneous injection; which can be used for single-dose treatment; and/or which can be used for prophylactic treatment. The present invention provides a novel class of compounds which are trypanosome inhibitors having potential as anti-animal trypanosomiasis agents. The novel class of compounds according to the present invention have potential for the treatment of Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and/or Trypanosoma evansi infections. In particular the novel class of class of compounds according to the present invention have potential for the treatment of: Trypanosoma congolense infections; Trypanosoma congolense and Trypanosoma vivax infections; Trypanosoma vivax infections; Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei , Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and Trypanosoma evansi infections. Desirable properties of compounds of formula (I) according to the present invention include: potency against Trypanosoma congolense; potency against Trypanosoma vivax; potency against Trypanosoma congolense and Trypanosoma vivax; non-mutagenicity; both potency against Trypanosoma congolense and low mutagenicity; both potency against Trypanosoma vivax and low mutagenicity; potency against Trypanosoma congolense and Trypanosoma vivax and low mutagenicity; desirable potency, low mutagenicity and desirable intravenous and intramuscular pharmacokinetics.

Summary of the Invention

According to a first aspect the present invention provides compounds of general formula (I)

wherein X is a -(CH ₂ ) _n - group, wherein Y is a -(CH)- group or N, wherein n is 0 or 1 , wherein R ¹ is a -(CH ₂ ) _m R ⁸ group and wherein m = 0, 1 , 2 or 3, wherein R ² is H, CI, F, a -(CrC ₃ ) alkyl group, or a phenyl group, wherein R ³ and R ⁴ are independently selected from: H; -(CrC ₃ ) alkyl; and combinations thereof, wherein R ⁵ , R ⁶ , and R ⁷ are independently of each other selected from: H; CN, halogen; a -(C C ₆ ) alkyl group; a -(C C ₆ ) alkoxy group; a -(C C ₆ ) alkyl NR ¹² R ¹³ alkylamine group; a -(C C ₆ ) alkyl NR ¹² R ¹³ group wherein the R ¹² and R 13 together with the N to which they are attached form a 4- or 5-membered ring heterocyclic group having a single heteroatom, wherein R is H, a -C-bonded 5 or 6 membered aryl or heteroaryl group, a -C- bonded 4, 5 or 6 membered heterocyclic group, a -(C C ₆ ) alkyl group optionally substituted by one or more hydroxyl or halogen groups, or R ⁸ is an -OR ⁹ group wherein R ⁹ is H, a -(C C ₆ ) alkyl group, a -C(0)R ¹⁰ group, or a -C(0)OR ¹ ° group; wherein when R ⁸ is an aryl, heteroaryl, heterocyclic, alkyl or haloalkyl group, R ⁸ may be independently substituted by one or more R ¹¹ groups, wherein R ¹⁰ is a -(C C ₆ ) alkyl group optionally substituted by one or more halogens, wherein R ¹¹ is a halogen, or a -(C C ₆ ) alkyl group and wherein R ¹² and R ¹³ are independently selected from: H; -(CrC ₃ ) alkyl; and combinations thereof; or where together with the -N atom of the amine group, the N, R ¹² and/or R ¹³ groups form an -N or -C-linked 4-, 5- or 6-membered ring heterocyclic group, or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof.

According to a further aspect, the present invention provides compounds of formula (I) wherein X is -CH ₂ -, n is 1 and Y is -CH- which include the isomeric formulae (IA) and (IB):

NHS(0) ₂ R ₁

IA

IB wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined hereinbefore,

In a yet further aspect, the present invention provides, compounds of formula (IA) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined hereinbefore.

There is also provided compounds of formula I:

wherein X is a -(CH ₂ ) _n - group, wherein Y is a -(CH)- group or N, wherein n is 0 or 1 , wherein R ¹ is a -(CH ₂ ) _m R ⁸ group and wherein m = 0, 1 , 2 or 3, wherein R ² is H, CI, F, a -(C1-C3) alkyl group, or a phenyl group, wherein R ³ and R ⁴ are independently selected from: H; an optionally substituted - (C1-C ₃ ) alkyl; and combinations thereof, wherein R ⁵ , R ⁶ , and R ⁷ are independently of each other selected from: H; CN, halogen; a -(C C ₆ ) alkyl group; a -(C C ₆ ) alkoxy group; a -(C C ₆ ) alkyl NR ¹² R ¹³ alkylamine group; a -NR ¹² R ¹³ alkylamine group; a -(C C ₆ ) alkoxy NR ¹² R ¹³ alkoxyamine group; wherein the alkyl, alkoxy and alkylamine groups are independently of each other optionally substituted by one or more halogens or methyl groups; and combinations thereof, 4-, 5- or 6-membered ring heterocyclic group, wherein R ¹² and R ¹³ are independently selected from: H; -(C1-C ₃ ) alkyl; and combinations thereof; or where together with the -N atom of the amine group, the N, R ¹² and/or R ¹³ groups form an -N or -C-linked 5- or 6-membered ring heterocyclic group, wherein R ⁸ is H, a -C-bonded 5 or 6 membered aryl or heteroaryl group, a -C- bonded 4, 5 or 6 membered heterocyclic group, a -(C C ₆ ) alkyl group optionally substituted by one or more hydroxyl or halogen groups, or R ⁸ is an -OR ⁹ group wherein R ⁹ is H, a -(C C ₆ ) alkyl group or -C(0)R ¹⁰ , wherein when R ⁸ is an aryl, heteroaryl, heterocyclic, alkyl or haloalkyl group, R ⁸ may be independently substituted by one or more R ¹¹ groups, wherein R ¹⁰ is a -(C C ₆ ) alkyl group optionally substituted by one or more halogens, and wherein R ¹¹ is a halogen, or a -(C C ₆ ) alkyl group or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof.

These and additional aspects provided by the present invention are detailed in the description hereinafter. Description For the avoidance of doubt, all definitions provided herein apply equally to general formula (I), (IA) and (IB) as detailed hereinbefore. As such, reference to compounds of formula (I) includes compounds of formula (IA) and (IB). Scientific and technical terms used herein have the meanings with which they are commonly understood in the art unless specifically defined alternatively herein.

Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.

In the above definitions, unless otherwise indicated, alkyl groups having two or more carbon atoms, may be unsaturated or saturated, and are preferably saturated. Alkyl groups having three or more carbon atoms, may be straight chain, branched chain, or cyclic and are preferably saturated. For the avoidance of doubt, this definition equally applies to other functional groups as detailed herein which include an alkyl group having two or more carbon atoms, or three or more carbon atoms, such as, for example, alkoxy groups, or alkylamine groups. For example, a saturated C ₃ alkyl substituent can be in the form of normal-propyl (n-propyl), or iso-propyl (/-propyl), or cyclopropyl, similarly a saturated C ₄ alkyl substituent can be in the form of normal-butyl (n-butyl), secondary butyl (sec-butyl) also known as 1-methylpropyl, iso-butyl (/-butyl) also known as 2- methylpropyl, tertiary butyl (t-, or te/f-butyl) also known as 1 , 1-dimethylethyl, cyclobutyl, or 1-methylcyclopropyl. Similarly a saturated C ₄ alkoxy substituent can be n-butoxy, sec- butoxy, i-butoxy, t-butoxy, cyclobutoxy, methoxycyclopropyl, or 1-methylcyclopropoxy.

Preferred R ¹ alkyl substituents when m = 1 are saturated Ci , C ₂ or C ₃ alkyl substituents, or saturated 4- or 5-membered heterocyclic rings, particularly 4- or 5-membered rings containing one heteroatom, and especially tetrahydrofuranyl rings.

Particularly preferred R ¹ alkyl substituents when m = 1 are saturated C ₃ alkyl substituents, and especially iso-propyl.

Preferred R ¹ alkyl substituents when m = 0 are saturated C ₄ alkyl substituents, or saturated 4- or 5-membered heterocyclic rings, particularly 4- or 5-membered rings containing one O, S or N heteroatom, and especially tetrahydrofuranyl, tetrahydrothiophenyl or oxytyl rings. Particularly preferred R ¹ alkyl substituents when m = 0 are saturated C ₄ alkyl substituents, and in particular iso-butyl.

For the avoidance of doubt where a group herein is optionally substituted by an alkyl group said alkyl group(s) may not be further substituted by a further (unsubstituted) alkyl group.

The term optionally substituted as used herein indicates that the particular group or groups may have one or more non-hydrogen substituents. The total number of such substituents which may be present is equal to the number of H atoms present on the unsubstituted form of the particular group. For example, the aryl, heteroaryl, heterocyclic or alkyl R ⁸ groups in compounds of formula (I), (IA) and (IB) may have one or more substituents. Preferably the R ⁸ groups in compounds of formula (I), (IA) and/or (IB) are unsubstituted.

The terms heteroaryl, heterocyclic and heteroalkyl as used herein indicates that the particular group or groups has/have one or more non-hydrogen groups, so-called heteroatoms selected from N, O and S and mixtures thereof. Preferred heteroatoms for use herein are N and O. Examples of suitable heteroatom containing groups for use herein include: oxetyl; oxet-1-yl; oxet-2-yl; tetrahydrofuranyl; tetrahydrofuran-1-yl; tetrahydrofuran-2-yl; tetrahydrofuran-3-yl; tetrahydropyranyl; tetrahydropyran-4-yl; isoxazolyl; isozazol-3-yl; dioxolyl; diolol-2,2-yl; 1 ,2-dioxalyl; tetrahydrothiophenyl.

The term "veterinarily acceptable" as used herein includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

For the avoidance of doubt the term "veterinarily acceptable" as used herein includes acceptability for both veterinary and human (pharmaceutically acceptable) purposes.

Compounds

The present invention provides compounds of formula (I): or a veterinarily acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and Y are as defined hereinbefore.

Various aspects of the invention, compounds of formula (I), are described below. The features specified in each aspect may be combined with other specified features, from one or more other aspects to provide further aspects. For the avoidance of doubt, such further combined aspects comprise additional aspects of the present invention.

According to another aspect the invention provides compounds of formula (I) wherein R ² is H.

Where one or both of R ³ and/or R ⁴ are optionally substituted alkyl groups, the one or more optional substituents are independently selected from: -OH; -CH ₃ ; halogen and combinations thereof. According to an aspect the invention provides compounds of formula (I) wherein: R ³ and R ⁴ are both H; wherein one of R ³ or R ⁴ is H and one is -CH ₃ ; where both R ³ and R ⁴ are -CH ₃ groups; wherein one of R ³ or R ⁴ is H and one is a C ₃ alkyl group, preferably an iso-propyl group; or where one of R ³ or R ⁴ is H and one is a - CH ₂ CH ₂ OH group.

Thus the invention additionally provides compounds of formula (I) wherein R ² is H and , R ³ and R ⁴ are independently selected from: -OH; -CH ₃ ; halogen and combinations thereof and wherein R ¹ , R ⁵ , R ⁶ , R ⁷ , X and Y are as defined hereinbefore.

According to a preferred aspect the invention provides compounds of formula (I) wherein Thus the invention additionally provides compounds of formula (I) wherein R ² , R ³ and R ⁴ are H and wherein R ¹ , R ⁵ , R ⁶ , R ⁷ , X and Y are as defined hereinbefore.

According to another aspect the invention provides compounds of formula (I) wherein n = 1 , Y is -(CH)- and the -NHS(0) ₂ R ¹ group is at the 4 -position on the cyclohexyl ring.

Thus the invention additionally provides compounds of formula (I) n = 1 , Y is -(CH)- and the -NHS(0) ₂ R ¹ group is at the 4 -position on the cyclohexyl ring wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and Y are as defined in hereinbefore, and particularly wherein R ² , R ³ and R ⁴ are H.

Where n = 1 , Y is -(CH)- and the -NHS(0) ₂ R ¹ group is at the 4-position on the cyclohexyl ring the invention additionally provides compounds of formula (I) having the isomeric forms (IA) and (IB):

NHS(0) ₂ R ₁

IA

IB or veterinarily or pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs or polymorphs thereof wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined hereinbefore for compounds of Formula (I). According to a further aspect the invention provides compounds of formula (IA):

NHS(0) ₂ R ₁

or a veterinarily or pharmaceutically acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined hereinbefore for compounds of formula (I), and particularly wherein R ² , R ³ and R ⁴ are H.

The invention provides compounds of formula (I), (IA) and/or (IB) as defined hereinbefore, and specifically including the features of any or all of the various aspects as previously indicated, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is at the ortho-position on the aryl ring and is a halogen, a saturated -(CrC ₃ ) alkyl group or a saturated -(CrC ₃ ) alkoxy group wherein the alkyl and alkoxy groups are independently optionally substituted by one or more halogens.

According to a further aspect still the invention provides compounds of Formula (I), (IA) and/or (IB) as defined hereinbefore, and specifically including the features of any or all of the various aspects as previously indicated, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a halogen at the ortho-position on the aryl ring.

Preferred alkyl, alkyloxy and alkylamine R ⁵ , R ⁶ or R ⁷ substituent groups for use herein are -(C C ₃ ) alkyl, (C C ₃ )alkyloxy, and (C C ₃ ) alkyl NR ¹² R ¹³ alkylamine groups. Particular R ⁵ , R ⁶ , and R ⁷ groups for use in the compounds of Formula (I), (IA) and/or (IB) are independently of each other selected from: H; F; CI; Br; -CN, -CH ₃ ; -OCH ₃ ; -OCF ₃ ; - CF ₃ ; -CH ₂ N(CH ₃ ) ₂ ;-CH ₂ N(CH ₃ ) ₂ ; -CH ₂ N(CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N(CH ₃ ) ₂ ; CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ ; pyrrolidine-1-ylmethyl; azetidine-1-ylmethyl and combinations thereof. In accordance with a yet further aspect at least one of R ⁵ , R ⁶ , and R ⁷ is at the ortho-position on the aryl ring and is selected from F, CI or CH ₃ .

The present invention additionally provides compounds of formula (I), (IA), and/or (IB) as defined hereinbefore, and including the features or any or all of the previously indicated aspects, wherein there are two ortho substituents on the aryl ring and optionally a meta or para substituent.

According to a yet further aspect the invention provides compounds according to formula (I), (IA) and/or (IB) wherein two of R ⁵ , R ⁶ , and R ⁷ are ortho-groups on the aryl ring each of which is independently selected from: halogen groups or a -(C C ₃ ) alkyl group which is optionally substituted by one or more halogens.

The invention also provides compounds of Formula (I), (IA) and/or (IB) as defined hereinbefore, wherein R ¹ is -(CH ₂ ) _m R ⁸ wherein m = 1 and R ⁸ is a saturated -(C C ₄ ) alkyl group or a phenyl group each of which are independently optionally substituted by one of more halogen, or CF ₃ groups, and wherein the alkyl group may be independently optionally substituted by an -C(0)R ¹⁰ group, and wherein when R ¹ is -(CH ₂ ) _m R ⁸ , m = 1 and R ⁸ is a phenyl group, the phenyl group is preferably substituted at the ortho- position by a halogen.

Further compounds according to the present invention of formula (I), (IA), and/or (IB) are compounds wherein at least one of R ⁵ , R ⁶ , and R ⁷ is an ortho-group on the aryl ring, and is a halogen group or a -(C C ₃ ) alkyl group which is optionally substituted by one or more halogens, and wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a meta- or para-group on the aryl ring.

According to an aspect the invention provides compounds according to formula (I), (IA) and/or (IB) wherein at least one of the R ⁵ , R ⁶ , and R ⁷ is an ortho-group on the aryl ring and is independently selected from: halogen groups or a -(C C ₃ ) alkyl group which is optionally substituted by one or more halogens and wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a meta- or para-group on the aryl ring and is independently selected from: halogen groups; -CN; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N(CH ₃ ) ₂ ; -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ ; - CH ₂ -N-linked 4, 5 or 6 membered heterocyclic group, preferably a 5 or 6 membered heterocyclic group.

According to an aspect the invention provides compounds according to Formula (I), (IA) and/or (IB) wherein two of R ⁵ , R ⁶ , and R ⁷ are ortho-groups on the aryl ring each independently selected from: F; CI; or a -CH ₃ group which is optionally substituted by one or more halogens and wherein the remaining R ⁵ , R ⁶ , or R ⁷ group is a meta- or para- group on the aryl ring and is independently selected from: -CN; -CH ₂ N(CH ₃ )2, - CH ₂ N(CH ₂ CH3)2; -CH ₂ CH ₂ N(CH3)2; -CH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ ; an azetidine group, a pyrrolidine group; a piperidine group; or a morpholine group.

According to a yet further aspect still the invention provides compounds of Formula (I), (IA) and/or (IB) as defined hereinbefore, and specifically including the features of any or all of the various aspects as previously indicated, wherein R ² , R ³ and R ⁴ are H, and R ¹ is a Ci to C ₄ alkyl group, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a halogen at the ortho- position on the aryl ring and wherein at least one of the R ⁵ , R ⁶ or R ⁷ substituent groups is a (C1-C3) alkyl NR ¹² R ¹³ alkylamine group at the ortho or para-position on the aryl ring.

Suitable (C C ₃ )alkyl NR ¹² R ¹³ and NR ¹² R ¹³ alkylamine groups for use herein include: -C- linked azetidin-2-yl (trimethlyleneiminyl); -C-linked N-methyl azetidin-2-yl; -N-linked methyl-N-azetidinyl; -C-linked N-methyl azetidin-1-yl; ethyldimethylamine; methyldimethylamine.

A group of compounds of Formula (I), (IA), and/or (IB) wherein at least one of R ⁵ , R ⁶ , and R ⁷ (C1-C3) alkyl NR ¹² R ¹³ alkylamine group.

According to another aspect still the invention provides compounds of Formula (I), (IA) and/or (IB) as defined hereinbefore, and specifically including the features of any or all of the various aspects as previously indicated, wherein R ² , R ³ and R ⁴ are H, at least one of R ⁵ , R ⁶ , and R ⁷ is a halogen at the ortho-position on the aryl ring and wherein R ¹ is a - (CrC ₃ )alkyl R ⁸ group wherein R ⁸ is a -C-bonded 4, 5 or 6 membered heterocyclic group, or a -(C1-C3) group substituted by one or more hydroxyl groups.

As detailed hereinafter various compounds have been prepared in accordance with Formula 1. The present invention provides compounds according to the first aspect independently selected from: N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-ci s-cyclohexyl]-2-methyl- propane-1 -sulfonamide;

[(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]am ino]-trans- cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate;

[(2S)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl ]amino]-trans- cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate;

[3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amin o]-trans- cyclohexyl]sulfamoyl]-2,2-dimethyl-propyl] acetate;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-3- hydroxy-2,2-dimethyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2,2,2- trifluoro-ethanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-1- tetrahydrofuran-2-yl-methanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-1- tetrahydrofuran-3-yl-methanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino] -trans- cyclohexyl]tetrahydropyran-4-sulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-1- isoxazol-3-yl-methanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-1-(5- methylisoxazol-3-yl)methanesulfonamide;

N-[4-[(4-amino-5-benzoyl-thiazol-2-yl)amino]-trans-cyclohexy l]-2-methyl-propane- 1-sulfonamide;

N-[4-[[4-amino-5-(2-chlorobenzoyl)thiazol-2-yl]amino]-trans- cyclohexyl]-2-methyl- propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,4-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(pyridine-3-carbonyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(3-fluorobenzoyl)thiazol-2-yl]amino]-trans- cyclohexyl]-2-methyl- propane-1 -sulfonamide;

N-[4-[[4-amino-5-[4-fluoro-2-(trifluoromethyl)benzoyl]thiazo l-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide; N-[4-[[4-amino-5-(2-methoxybenzoyl)thiazol-2-yl]amino]-trans -cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,4-dichlorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-[2-(trifluoromethoxy)benzoyl]thiazol-2-yl]a mino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,4-dimethylbenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(4-methylbenzoyl)thiazol-2-yl]amino]-trans- cyclohexyl]-2-methyl- propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,5-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-3,3,3- trifluoro-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-cy clohexyl]-1-phenyl- methanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]- cyclohexyl]benzenesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-cy clohexyl]-1-(2- chlorophenyl)methanesulfonamide;

N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl]-2- methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(4-cyano-2,6-difluoro-benzoyl)thiazol-2-yl] amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-[3-(dimethylaminomethyl)-2,6-difluoro-benzo yl]thiazol-2- yl]amino]cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6-difluoro-be nzoyl]thiazol-2- yl]amino]-trans-cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride;

N-[4-[[4-amino-5-[2,6-difluoro-4-(pyrrolidin-1-ylmethyl)b enzoyl]thiazol-2-yl]amino]- trans-cyclohexyl]- 2-methyl-propane-1 -sulfonamide hydrochloride;

N-[4-[[4-amino-5-[2-chloro-4-[(dimethylamino) methyl]benzoyl]thiazol-2-yl]amino]- trans-cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride;

N-[4-[[4-amino-5-[2-chloro-5-[(dimethylamino)methyl]benzo yl]thiazol-2-yl]amino]- trans-cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride;

N-[4-[[4-amino-5-(2-chloropyridine-3-carbonyl)thiazol-2-y l]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide; N-[4-[[4-amino-5-[2-(trifluoromethyl)pyridine-3-carbonyl]thi azol-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2-bromopyridine-3-carbonyl)thiazol-2-yl]am ino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-(2-iodobenzoyl)thiazol-2-yl]amino]-trans-cy clohexyl]-2-methyl- propane-1 -sulfonamide;

N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6-difluorobenzoy l)thiazol-2- yl]amino]-trans-cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-y l)amino)cyclohexyl)-1- (tetrahydrofuran-3-yl)methanesulphonamide;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-yl)a mino)cyclohexyl)-2- methoxyethanesulphonamide;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cyclohexyl)oxetane-3-sulphonamide;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cyclohexyl)tetrahydrofuran-3-sulphonamide;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cyclohexyl)tetrahydrothiophene-3-sulphonamide-1 , 1 -dioxide;

(R)-3-N-((trans)-4-((4-amino-5-(2,6-ichlorobenzoyl)thiazol-2 - yl)amino)cyclohexyl)sulphamoyl)-2-methylpropyl acetate;

N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-yl)a mino)cyclohexyl)-3- hydroxy-2-methylpropane-1-sulphonamide;

N-((4-amino-5-(4-(azetidine-1-ylmethyl)-2,6-difluorobenzoyl) thiazol-2- yl)amino)cyclohexyl)-2-methylpropoane-1-sulphonamide hydrochloride;

N-trans-((4-amino-5-(2,6-dichloro-4-((dimethylamino)methy l)benzoyl)thiazol-2- yl)amino)cyclohexyl)-2-methylpropane-1-sulphonamide hydrochloride;

N-trans-((4-amino-5-(4-(2-(dimethylamino)ethyl)-2,6-diflu orobenzoyl)thiazol-2- yl)amino)cyclohexyl)-2-methylpropane-1-sulphonamide hydrochloride;

N-trans-4-((4-amino-5-(4-(azetidine-1-ylmethyl)-2,6-dichl orobenzoyl)thiazol-2- yl)amino)cyclohexyl)-2-methylpropane-1-sulphonamide hydrochloride;

N-trans-4-((4-amino-5-(4-((dimethylamino)methyl-2,6-diflu orobenzoyl)thiazol-2- yl)amino)cyclohexyl)tetrahydrofuran-3-sulphoanamide hydrochloride;

N-trans-4-((4-amino-5-(2,6-difluoro-4-((methylamino)methy l)benzoyl)thiazol-2- yl)amino)cyclohexyl)-2-methylpropane-1-sulphonamide;

N-trans-4-((4-amino-5-(4-aminomethyl)-2,6-difluorobenzoyl )thiazol-2- yl)amino)cyclohexyl)-2-methylpropane-1-sulphonamide hydrochloride; N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6-difluorobenz oyl)-4-

(methylamino)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1-sulphonamid hydrochloride;

N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6-difluorobenz oyl)-4- (dimethylamino)thiazol-2-yl)amino)cyclohexyl)-2-methylpropan e-1-sulphonamide; N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6-difluorobenz oyl)-4- (isopropylamino)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1-sulphonarnide formate; and

N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6-difluorobenz oyl)-4- ((hydroxyethyl)amino)thiazol-2-yl)amino)cyclohexyl)-2-methyl propane-1- sulphonamide hydrochloride;

or a veterinarily acceptable, salt, hydrate, solvate, isomer, prodrug or polymorph thereof. Preferred compounds according to the present invention of Formula (IA) wherein R ² , R ³ and R ⁴ are H, at least one of R ⁵ , R ⁶ and R ⁷ is an ortho-group and R ¹ is as defined hereinbefore include the compounds of Examples 29 and 32 and veterinarily acceptable, salts, solvates and hydrates thereof. Where alkyl groups are included in the compounds of Formula (I), (IA), and/or (IA) as defined hereinbefore such groups are preferably saturated alkyl groups.

Particularly preferred individual compounds according to the present invention are independently selected from:

N-[4-[[4-amino-5-[3-(dimethylaminomethyl)-2,6-difluoro-be nzoyl]thiazol-2- yl]amino]cyclohexyl]-2-methyl-propane-1 -sulfonamide;

N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6-difluorobenzoy l)thiazol-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride; and

N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6-difluoroben zoyl)thiazol-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide; and veterinarily acceptable, acid salts, hydrates, solvates, isomers, prodrugs or polymorphs thereof and for the avoidance of doubt, where said compounds are listed as salts, then alternative veterinarily acceptable, acid salts, hydrates, solvates, isomers, prodrugs or polymorphs thereof are considered to be included. Veterinarily acceptable acid addition salts of certain compounds of the formula (I) may be readily prepared in a conventional manner by mixing together solutions of a compound of the formula (I) and the desired acid, as appropriate. For example, a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration or by evaporation under reduced pressure of the reaction solvent. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties Selection, and Use" by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002). Suitable acid addition salts for use herein include: fumarate, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, 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, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, and trifluoroacetate.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' as used herein describes a molecular complex comprising the compound of the invention and one or more pharmaceutically or veterinarily acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co- crystals. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975). Hereinafter all references to compounds of formula (I) include references to salts, solvates, and multi-component complexes. The compounds of the invention include compounds of formula (I) as hereinbefore defined, and polymorphs and crystal habits thereof.

Isomers of compounds of formula (I) as used herein, and included in the present invention include optical, geometric and tautomeric isomers and in particular compounds of formulae (IA) and (IB), with compounds of formula (IA) being a preferred group of compounds. Stereoisomers such as enantiomers and diastereomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof are included in the present invention. Also included are acid addition salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, ^/-tartrate or d/-arginine. Geometric isomers may be separated by conventional techniques well known to those skilled in the art, for example, by chromatography and fractional crystallisation. Stereoisomers may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). As indicated, so-called 'prodrugs' of the present compounds are also within the scope of the invention. Thus certain derivatives of compounds of formula (I), which may have little or no pharmacological activity themselves, can, when administered into or onto the body of a mammal, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. In addition some compounds of formula (I) can be pro-drugs for other compounds of formula(l). Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula I, that is, compounds formed in vivo upon administration of the drug. An example of a metabolite in accordance with the invention is a phenol derivative of a compound of formula I (-Ph -> -PhOH).

The present invention includes all veterinarily acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagent in place of the non- labelled reagent previously employed.

It is to be appreciated that references to treatment as used herein includes prophylaxis as well as treatment via the alleviation of established symptoms of a condition i.e. prevention or control. "Treating" or "treatment" of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

Prophylactic treatment of animal trypanosomiasis as defined herein included includes the treatment of a subject with a prophylaxis-effective amount of compound of formula (I) wherein said prophylaxis-effective amount is an amount of compound that is effective in inhibiting, decreasing the likelihood of the disease by animal trypanosomiasis parasites, or preventing animal trypanosomiasis infection or preventing the delayed onset of the disease by animal trypanosomiasis parasites, when administered before infection, i.e. before, during and/or slightly after the exposure period to animal trypanosomiasis parasites Treatment of animal trypanosomiasis as defined herein includes: treatment of Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and/or Trypanosoma evansi infections; treatment of: Trypanosoma congolense infections; treatment of Trypanosoma congolense and Trypanosoma vivax infections; treatment of Trypanosoma vivax infections.

Regarding the use of the compounds of the invention in animals, there is provided: a veterinary composition comprising a compound of formula (I), (IA) or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, together with one or more veterinarily acceptable, carrier, diluent or excipient; a compound of formula (I), (IA) or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a veterinary composition containing any of the foregoing, for use as a medicament; a compound of formula (I), (IA), or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a veterinary composition containing any of the foregoing, for use in the prophylactic treatment of animal trypanosomiasis; a compound of formula (I), (IA) or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a veterinary composition containing any of the foregoing, for use in the treatment of animal trypanosomiasis; use of compound of formula (I), (IA), or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof for the preparation of a veterinary formulation for the treatment of animal trypanosomiasis; a compound of formula (I), (IA), or (IB) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a veterinary composition containing any of the foregoing, for use in the treatment of drug-resistant animal trypanosomiasis;

Regarding the use of the compounds of the invention in humans, there is provided: a pharmaceutical composition comprising a compound of formula (I), (IA), or (IB) or an acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, together with one or more acceptable carrier, diluent or excipient; a compound of formula (I), (IA) or (IB) or an acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a pharmaceutical composition containing any of the foregoing, for use as a medicament.

Further diseases, disorders or conditions affecting animals or humans which may be treatable with the compounds of the present invention include, but are not limited to: HAT. Thus according to a further aspect the present invention provides a compound of formula (I), (IA), or (IB) or an acceptable, salt, solvate, hydrate, isomer, prodrug or polymorph thereof, or a pharmaceutical composition containing any of the foregoing, for use in the treatment of HAT.

PROCESS FOR PREPARATION The following routes illustrate methods of synthesising compounds of formula (I), (IA) and (IB). Scheme 1 illustrates a general route of the preparation of the compounds of formula (I) from intermediates (II) and (III).

SCHEME 1

R5R6R7

In respect of compounds (I), (II), and (III) in Scheme 1 the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and X are as defined hereinbefore for compounds of formula (I) unless stated otherwise. Exemplary compounds prepared in accordance with the process of Scheme 1 are detailed hereinafter. For the avoidance of doubt, although Scheme 1 illustrates a group of compounds of general formula (I) wherein Y is -CH- the general route is equally applicable to compounds having Y = N, with a corresponding heterocyclic intermediate (ll)-HET, as detailed hereinafter for the preparation of Example compounds 36, 37 and 38 from corresponding (ll)-HET intermediate compounds.

For the avoidance of doubt the cyanamide in Scheme 1 has general formula R ³ R ⁴ NCN wherein R ³ and R ⁴ are as defined hereinbefore. Thus according to a further embodiment the present invention provides a process for the preparation of compounds of general formula (I) comprising coupling of a isothiocyantocyclohexyl intermediate compound of general formula (II) with a 2- bromophenylethanone intermediate compound of general formula (III).

In a preferred group of compounds according to the present invention X is -CH ₂ -. Thus according to a further embodiment the present invention provides a general process for the preparation of compounds of general formula (I) comprising coupling of a isothiocyantocyclohexyl intermediate compound of general formula (II) wherein X = CH ₂ with a 2-bromophenylethanone intermediate compound of general formula (III). Exemplary compounds wherein X is -CH ₂ -, prepared in accordance with the process of Scheme 1 include the compounds of Examples 12 to 25, and 29 to 39 hereinafter.

Scheme 2 illustrates a process for the preparation of intermediate compounds of general formula (II) examples of preparative compounds corresponding to general formula (II) prepared in accordance with the process of Scheme 2 are detailed herein after and includes preparative compound 18 as prepared from preparative compound 17 and commercially available sulphonyl chloride.

Scheme 2 also illustrates suitable reagents and reaction conditions for the preparation of the compound of Example 1 hereinafter. As will be appreciated by the skilled chemist the reagents and conditions employed in the transformations in Scheme 2 may be utilised, modified and/or substituted for alternatives as necessary in order to furnish various alternative compounds of general formula (I), (IA) and/or (IB) via the general processes in Scheme 1.

SCHEME 2

II

In respect of compounds (II) in Scheme 2 the definitions of R ¹ , R ² , and X are as defined hereinbefore for compounds of formula (I) unless stated otherwise. Scheme 3 illustrates an alternative route for the preparation of the compounds of general formula (I) from intermediate compounds of general formulae (IV) and (V). As will be appreciated some sulphonyl chlorides of formula (V) are available from commercial sources whilst others required synthesis. Exemplary compounds prepared in accordance with the methods of Scheme 3 are detailed hereinafter and include the compounds of Examples 1 to 5.

Further compounds prepared using a variation of the methodology in Scheme 3 from intermediate compounds of general formula (IV) and alternative commercially available sulphonyl chlorides general formula (V) include the compounds of Examples 1 , 6, 7, 8, 9, 10, 11 , 26, 27 and 28.

KSCN S02CI2

Ri-Br R ₁ -s^≡N R -S0 ₂ CI Triethylamine

In respect of compounds (I), (IV) and (V) in Scheme 3 the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as defined hereinbefore for compounds of formula (I) unless stated otherwise. For the avoidance of doubt the cyanamide in Scheme 3 has general formula R ³ R ⁴ NCN wherein R ³ and R ⁴ are as defined hereinbefore.

In Scheme 3 compounds of general formula (I) are provided via direct coupling of amine intermediate (IV) and sulphonyl chloride intermediate (V). Intermediate (IV) can be prepared by reactions detailed in Scheme 3 using preparative intermediates 3, 6, 9, 12 and 15 to give Example compounds 2, 3, 4 and 5. As indicated hereinbefore, additional compounds were made from commercially available sulfonyl chloride intermediates, these include the compounds of Examples 1 to 11 , and 26-28.

Scheme 4 illustrates suitable reagents and reaction conditions for the preparation of a compound of general formula (IA), the compound of Example 32, from intermediate compounds of general formulae (II) and (III), preparative compounds 18 and 34. As will be appreciated by the skilled chemist the particular reagents and conditions employed in the transformations in Scheme 4 may be utilised, modified and/or substituted for alternatives as necessary in order to furnish various alternative compounds of general formula (IA) via the general processes in Schemes, 1 , and 2 as detailed hereinbefore.

i.KOtBu

As detailed in Scheme 4, the intermediate compound of preparation 18, can be made from the compounds of preparations, 17 and 16 respectively starting from tert-butyl N- (frans-4-aminocyclohexyl)carbamate, and the intermediate compound of preparation 34 can be made from the compounds of preparations 19, 30, 31 , 32, 33, 34 and 59, starting from 3, 5 difluorobenzonitrile. According to a further aspect there is provided a method for the preparation compounds of formula (IA) comprising coupling of a isothiocyantocyclohexyl intermediate compound of formula (II) having corresponding a frans-configuration to the final product with a 2- bromophenylethanone intermediate compound of general formula (III).

Further exemplary compounds of general formula (IA) prepared in accordance with the process of Scheme 4 are detailed hereinafter. For the avoidance of doubt, although Scheme 4 illustrates a process for the preparation of specific compounds of general formula (IA) wherein Y is -CH- the route is equally applicable to alternative compounds having Y = N, from a corresponding heterocyclic intermediate (ll)-HET, as detailed hereinbefore in relation to the process of Scheme 1.

Thus according to a further aspect the present invention provides a process for the preparation of the compound of Example 32, and in particular the hydrochloride salt thereof, comprising reaction of the hydrobromide salt of the 2,6-difluoro-phenylethanone intermediate of preparation 34 with the isothiocyanatocyclohexyl intermediate of preparation 18.

Schemes 5 and 6 illustrate suitable reagents and reaction conditions for the preparation of intermediate compounds of general formula (VI) from commercially available starting materials via two alternative routes including either a Dess Martin reaction or a reductive animation step respectively. Compounds of general formula (VI) are suitable for use in the preparation of compounds of general formula (I) or (IA) wherein R ⁷ is a -CH ₂ NR ¹² R ¹³ group. As will be readily appreciated the R' and R" in intermediate compounds of general formula (VI) are selected to correspond to the desired CH ₂ NR ¹² R ¹³ groups in the final compound.

SCHEME 5

In Scheme 6 the reductive amination step employs an intermediate compound of general formula HNR'R" in which the R' and R" groups are selected to correspond to the desired NR ¹² R ¹³ groups in intermediate compounds of general formula (VI), and thereafter in final compounds of general formulae (I) or (IA).

As will be appreciated by the skilled chemist the particular reagents and conditions employed in the transformations in Schemes 5 or 6 may be utilised, modified and/or substituted for alternatives as necessary in order to furnish various alternative compounds of general formulae (I) or (IA).

SCHEME 6

Scheme 7 illustrates suitable reagents and reaction conditions for the preparation of compounds of general formulae (I) or (IA) from commercially available starting materials in an alternative route employing intermediate compounds of general formulae (VII) and (VIII). In Scheme 7 the reductive animation step employs an intermediate compound of general formula (VII) in which the R' and R" groups are selected to correspond to the desired NR ¹² R ¹³ groups in intermediate compounds of general formula (VIII), and thereafter in final compounds of general formulae (I) or (IA). In the final step illustrated in Scheme 7, intermediate compounds of general formulae (VII) and compounds of general formula HNR"'R"" are reacted to provide final compounds of general formulae (I) or (IA). The R'" and R"" groups are selected to correspond to the desired NR ³ R ⁴ groups in final compounds of general formulae (I) or (IA).

As will be appreciated by the skilled chemist the particular reagents and conditions employed in the transformations in Scheme 7 may be utilised, modified and/or substituted for alternatives as necessary in order to furnish various alternative compounds of general formulae (I) or (IA).

SCHEME 7

The general reaction mechanisms described hereinbefore for the preparation of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.

It will also be appreciated by a person skilled in the art that the compounds of the invention could be made by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley- VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide. It will also be apparent to a person skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. According to a further aspect the present invention provides processes for the preparation of compounds of general formula (IA) using analogous methods to those provided for the preparation of the compound of Example 32 via preparations 34 and 18 as detailed hereinbefore in relation to Scheme 4. The compounds of the present invention may be delivered in combination with one or more auxiliary active agents for the treatment of animal trypanosomiasis. Suitable auxiliary active agents for use in the combinations of the present invention include: isometamidium chloride (3-[N'-[(3-amino-5-ethyl-6-phenyl-8-phenanthridin-5- iumyl)imino]hydrazino]benzamidine chloride); ethidium bromide (3,8-Diamino-5-ethyl-6- phenylphenanthridinium bromide); diminazene acetate (4,4'-diamidino- diazoaminobenzene-di-acetamidoacetate); and derivatives thereof.

The suitability of a potential combination of two or more, anti-animal trypanosomiasis drugs can be assessed on the basis of their in vitro or in vivo drug interactions. For the assessment of in vitro interactions, the interactions of the two, or more, selected anti- animal trypanosomiasis drugs are investigated in vitro using standard dose-response assays over a range of individualised concentrations. Similarly the assessment of selected anti-animal trypanosomiasis drugs are investigated in vivo by analysing for levels of parasitaemia in the animal at different concentrations of the different drugs. The selection of suitable conditions and concentrations for carrying out such investigations would be within the remit of the skilled practitioner.

According to a further aspect the present invention provides a pharmaceutical composition comprising: a compound of formula (I) or a veterinarily acceptable, salt, solvate, hydrate, isomer, prodrug, or polymorph thereof; one or more additional anti- animal trypanosomiasis agents; and one or more veterinarily acceptable, carriers, diluents or excipients.

Examples of suitable combinations herein include a compound of the present invention and one or more additional therapeutic agents independently selected from: isometamidium chloride; ethidium bromide; diminazene acetate; and derivatives thereof; and mixtures or combinations thereof.

If a combination of active agents is administered, then the composition comprising a compound of formula (I) as detailed hereinbefore may be administered to an individual prior to, simultaneously, separately or sequentially with other therapeutic regiments or co-agents useful in the treatment of animal trypanosomiasis. If a combination of active agents is administered, then the different actives may be formulated for the same or different delivery, for example one active formulated for immediate and another for sustained release. If a combined therapy is to be administered the active agents may be formulated for the same or different routes of administration as desired.

Administration and Dose Ranges In order to select the most appropriate dosage forms and routes of administration considered appropriate for the treatment of the desired indication, compounds of formula (I) should be assessed for their biopharmaceutical properties, such as for example, solubility, solution stability (across a range of pHs), likely dose level and permeability. Initial biopharmaceutical testing for potential as anti-animal trypanosomiasis treatment has provided positive results.

Compounds of the invention intended for veterinary or pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze- drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more veterinarily acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Veterinarily and pharmaceutically acceptable excipients include one or more of: lubricants, binding agents, diluents, surface-active agents, anti-oxidants, colorants, flavouring agents, preservatives, flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti- foaming agents, surfactants and taste-masking agents.

Veterinary and pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Gregory E. Hardee and J. Desmond Baggo, "Development and Formulation of Veterinary Dosage Forms", 2 ^nd Edition (CRC Press, 1998) and/or in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). Formulations suitable for oral administration include solids, semi-solids or liquids such as tablets; soft or hard capsules; bolus; powders; lozenges (including liquid-filled); chews; multi and nano-particulates; gels; solid solutions; fast-dispersing dosage forms; fast- dissolving dosage forms; fast-disintegrating dosage forms; films; ovules; sprays; buccal/mucoadhesive patches; and liquid formulations. Liquid formulations include suspensions, solutions, elixirs and syrups. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual or sublingual administration by which the compound enters the blood stream directly from the mouth. Liquid formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

Formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N. Y., N.Y., 1980 (ISBN 0-8247-6918-X).

The compounds of the invention may also be administered parenterally, or by injection directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. A preferred parenteral administration route is intramuscular. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

The present invention provides a veterinary or pharmaceutical composition formulated for parenteral delivery comprising a compound of formula (I) or a veterinarily acceptable, salt, solvate or hydrate thereof, according to any preceding claim, together with one or more veterinarily acceptable excipients. The present invention further provides said composition formulated for parenteral delivery as an immediate release, or as a modified release formulation suitable for intramuscular or intravenous administration.

Thus, according to a further aspect still the present invention provides a veterinary composition formulated for intramuscular delivery comprising a compound of formula (I) or a veterinarily acceptable, salt, solvate or hydrate thereof, according to any preceding claim, together with one or more veterinarily acceptable excipients. The present invention further provides said composition formulated for delivery as an immediate release, slow release or as a modified release formulation.

According to an aspect the present invention provides a veterinary composition formulated for oral, topical, intramuscular, rectal, subcutaneous or intravenous delivery comprising a compound of formula (I) or a veterinarily acceptable, salt, solvate or hydrate thereof, according to any preceding claim, together with one or more veterinarily acceptable excipients. The present invention further provides said composition formulated for delivery as an immediate release, slow release or as a modified release formulation.

The compounds of the invention may also be administered topically, (intra)dermally, or transdermal^ to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations containing compounds of the invention may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

DOSAGES

Typically, a veterinarian or livestock owner will determine the actual dosage which will be most suitable for an individual mammal. The specific dose level and frequency of dosage for any particular animal may be varied and will depend upon a variety of factors including the condition being treated, the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the animal to be treated. Clearly a physician considering human use will utilise comparable determinations. In general however a suitable dose will be in the range of from about 0.01 to about 50 mg/kg of body weight per day,

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as one, two, three, four or more doses per day. If the compounds are administered transdermal^ or in extended release form the compounds could be dosed once a day or less.

The compound is conveniently administered in unit dosage form; for example, containing 0.01 to 50 mg/kg of active ingredient.

These dosages are based on an average cow having a weight of about 20kg to 1500kg, and more particularly 600kg to 800kg. The veterinarian or livestock owner will readily be able to determine doses for animals whose weight falls outside this range, such as calves and bulls.

The present invention provides a veterinary composition formulated as a solution suitable for intramuscular delivery comprising a compound of formula (I) or a veterinarily acceptable, salt, solvate or hydrate thereof, together with one or more pharmaceutically acceptable excipients. The present invention further provides said composition formulated for intramuscular delivery as an immediate release, or as a modified release formulation. In as much as it may be desirable to administer a combination of active compounds, as detailed hereinbefore, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more veterinary compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separate veterinary compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. Another example of such a kit is a plurality of vials or other container, each vial containing a liquid formulation comprising a specific dosage of the composition of formula (I) for a different weight of animal, or for the same weight of animal, such that the liquid formulation in each vial may be ready for direct injection into an animal.

For the avoidance of doubt, references herein to "treatment" include references to curative and prophylactic treatment.

Animal Trypanosomiasis

Compounds of the present invention are useful in the treatment of animal trypanosomiasis. Compounds according to the present invention have potential for the treatment of Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei, Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and/or Trypanosoma evansi infections. In particular the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of infections independently selected from: Trypanosoma congolense infections; Trypanosoma congolense and Trypanosoma vivax infections; Trypanosoma vivax infections; Trypanosoma congolense, Trypanosoma vivax, Trypanosoma brucei , Trypanosoma simiae, Trypanosoma godfreyi, Trypanosoma suis, and Trypanosoma evansi infections.

In particular, the novel class of class of trypanosome inhibitor I compounds according to the present invention have potential for the treatment of African trypanosomiasis attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense.

Animals can be infected with more than one strain of trypanosomes. For example, animals infected with Trypanosoma brucei rhodesiense can also have co-existing mixtures of pathogenic trypanosomes (T congolense, T vivax and T b. brucei). Animals infected with Trypanosoma brucei rhodesiense can act as reservoirs for the acute rhodesiense form of human African trypanosomiasis (HAT), also known as zoonotic sleeping sickness.

As indicated hereinbefore, insects are most commonly involved in the natural transmission of the pathogenic trypanosomes which lead to ATT. The disease life cycle has two phases, one in the insect vector and the other in the mammalian host. Transmission by insects may be cyclical by tsetse flies, Glossina species, or mechanical by other biting flies such as horse flies (Tabanidae) and stable flies (Muscidae). In addition, tsetse flies can also act as mechanical transmission vectors, latriogenic transmission can also occur, for example during multiple animal treatments such as castration or vaccination programmes where needles or surgical instruments are not changed or disinfected properly between animals and/or where the infected blood on the needle or instrument has not dried between interventions. Congenital transmission of T vivax has been reported, and carnivores may be infected with T evansi and T brucei by ingesting meat or organs from infected animals.

According to a further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, cattle, camels, horses, dogs, sheep, goats or pigs, and in particular cattle attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma congolense. According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, cattle, sheep, goats, domestic buffalo or horses attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma vivax.

According to a further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis attributable to infection from the life-threatening form of trypanosomiasis independently selected from: Trypanosoma duttonella; Trypanosoma nannomonas; Trypanosoma trypanozoon. According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of AAT and HAT attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma trypanozoon. According to a further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in pigs attributable to infection from the life-threatening form of trypanosomiasis independently selected from: Trypanosoma simiae; Trypanosoma godfreyi.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, cattle, sheep, or goats attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma uniforme.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, horses, camels, dogs, cattle, sheep, goats, pigs, attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma brucei.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of trypanosomiasis based diseases in domestic animals, horses, camels, dogs, cattle, sheep, goats, pigs, attributable to infection from the life-threatening form of trypanosomiasis independently selected from: Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, camels, horses, dogs, domestic buffalo, cattle, attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma evansi.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in equine animals, horses, donkeys and/or mules, attributable to infection from the life-threatening form of trypanosomiasis, Trypanosoma equiperdum.

According to a still further aspect the novel class of class of trypanosome inhibitor compounds according to the present invention have potential for the treatment of African trypanosomiasis in domestic animals, cattle, and domestic buffalo, attributable to infection from the life-threatening forms of trypanosomiasis, Trypanosoma theileris evansi and Trypanosoma ingens (subgenus megatrypanum). Once infected, tsetse flies remain infected for life. Tsetse flies become infected by feeding on parasitemic animal, i.e. an animal with blood infected with trypanosomes. The trypanosomes develop and multiply within the flies digestive tracts to produce infected metacyclic trypanosomes (metatrypanosomes). In the second stage, when an infected tsetse fly bites the skin and feeds on the blood of a mammalian host, metacyclic trypanosomes are injected into the host skin tissue. These infected metatrypanosomes (parasites) develop and multiply at the site of infection in the lymphatic system. This initial infection may be detected as a swelling or chancre in the skin. The disease spreads throughout the host when mature blood trypanosomes (or trypomastigotes) are released via lymph vessels and lymph nodes into the blood circulatory system as bloodstream trypomastigotes, which are carried throughout the body, and reach other body fluids (e.g., lymph, spinal fluid), and continue to replicate by binary fission. According to a further aspect the present invention provides compounds of formula (I) for use as anti-animal trypanosomiasis medicaments.

According to another aspect the present invention provides compounds of formula (I) for use in the reduction of disease progression in an AAT-infected mammal. According to a yet further aspect the present invention provides compounds of formula (I) for use in the reduction of disease progression in an AAT-infected mammal by reduction of, or knock- back, of the parasite levels in an AAT-infected mammal and thereby impact upon disease progression in said mammal. For the avoidance of doubt such impact upon disease progression includes: slowing down of the degree disease progression; and/or prevention of further progression of the disease; and/or delaying the time at which aspects of the disease are presented in an infected mammal.

In the search for new drugs with anti-animal trypanosomiasis activity, compounds which can treat AAT with a single administration of compound are particularly desirable. A further object of the invention is to provide compounds having potential for use in single dose treatments for AAT.

Whilst it is clearly desirable to provide compounds suitable for use in single dose treatments for AAT the present invention also provides compounds for use in the treatment of AAT via multiple-dosing i.e. dosing via "one or more treatments" with a compound of Formula (I).

A further need for new drugs with anti-AAT activity is for compounds which are active against drug-resistant AAT strains. Drug resistance to AAT is an increasing issue. There is a need for new classes of compound which are active against drug resistant strains of AAT found in the sub-Saharan Africa.

As demonstrated in the hereinafter, preliminary testing has demonstrated activity of a compound of formula (I) against a diminazine resistant strain of T. congolense.

Thus according to a further aspect the present invention provides compounds of formula (I) for use in the treatment of drug-resistant AAT.

For enhanced effectiveness of compounds suitable for intramuscular delivery, in addition to anti-AAT potential compounds also need to be sufficiently soluble to be formulated. Compounds of the invention have been demonstrated to display: desirable in vitro inhibitory activity against T. brucei; desirable Ames profiles (negative mutagenicity); good intravenous and intramuscular pharmacokinetics; desirable in vivo potency in T. congolense and T. vivax mouse models; desirable solubilities.

Trypanosoma brucei in vitro screening and results Compounds of general formula (I) according to the present invention have been shown to have desirable inhibitory activity, expressed as an IC ₅₀ , against Trypanosoma brucei (T brucei) strain Tb bsf 427 VSG 221 (standard). In the results provided in Experiment 1 , compounds of formula (I) demonstrate desirable inhibitory activity against 7 brucei.

7 brucei in vitro method: The method of Rycker et al, "A Static-cidal Assay form Trypanosoma brucei to Aid Hit Prioritisation for progression into drug Discovery Programmes" as published in PLOS, November 2012, Vol 6, Issue 1 1 , e1932 used to determine the inhibitory potential of compounds of formula (I) against 7 brucei. In these experiments, the 7 brucei was the bloodstream form and was prepared in accordance with the culture procedure of Rycker et al. procedure. In this method the dose-response curves were determined from a minimum of 3 independent experiments.

Compound bioactivity was expressed as EC ₅₀ , where EC ₅₀ is the concentration of test compound/inhibitor, the inhibitory concentration, at which the response (or binding) is reduced by half in vitro. The EC ₅₀ is a measure of how effective a druggable compound is and is one measure used herein to determine the potential of compound of the present invention for the treatment of animal trypanosomiasis. Experiments have confirmed that compounds of formula (I) exhibit desirable inhibitory profiles against 7 brucei strain Tb bsf 427 VSG 221. Preferably the present compounds exhibit inhibitory effectiveness against 7 brucei expressed as an EC ₅₀ , of less than about 0.010 micromolar (μΜ), more preferably less than about 0.003 micromolar (μΜ), yet more preferably between about 0.0001 and about 0.003 micromolar (μΜ), more preferably still between about 0.0002 and about 0.0025 micromolar (μΜ) wherein said EC ₅₀ measurement can be carried out using the methodology described hereinbefore. Compounds according to the present invention, including compounds of the Examples 1 to 39, have been tested and found to demonstrate inhibitory effectiveness of between about 0.0001 and about 0.005 micromolar (μΜ).

For the avoidance of doubt, the skilled person will understand that a first compound with a lower EC ₅₀ will have a higher inhibitory effectiveness than a second compound with a higher EC ₅₀ , and therefore, the first compound will have a greater potency than the second compound.

Thus according to a further embodiment the present invention provides compounds of formula (I) having inhibitory potential of less than about 0.005 micromolar (μΜ) more preferably lower than about 0.003 micromolar (μΜ), yet more preferably between about 0.0001 and about 0.003 micromolar (μΜ), more preferably still between about 0.0001 and about 0.0005, and in particular about 0.0002 micromolar (μΜ) against T. brucei expressed as an EC ₅₀ .

Bovine hepatic microsome intrinsic clearance

Compounds of general formula (I) have been demonstrated to exhibit desirable intrinsic clearance profiles when incubated with bovine hepatic microsomes.

Bovine microsome clearance method:

Test compound (0.5μΜ) was incubated with mixed gender, mixed breed bovine liver microsomes, obtained from Xenotech LLC™ (0.5mg/mL, buffered with 50mM potassium phosphate buffer, to provide a pH of 7.4) and the reaction started with addition of excess nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) (8mg/mL, buffered with 50mM potassium phosphate buffer, provided a pH of 7.4). Immediately, at time zero, then at 3, 6, 9, 15 and 30 minutes an aliquot (50μΙ_) of the incubation mixture was removed and mixed with acetonitrile (100μΙ_) to stop the reaction. Internal standard was added to all samples, the samples centrifuged to sediment precipitated protein and the plates then sealed prior to ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS-MS) analysis using a Quattro Premier XE (Waters corporation, USA).

XLfit curve fitting software (available from I DBS, UK) was used to calculate the exponential decay and consequently the rate constant (k) from the ratio of peak area of test compound to internal standard at each time point. The rate of intrinsic clearance (CLi) of each test compound was then calculated using the following calculation:

CLi (mL/min/g liver) = k x V x Microsomal protein yield

Where V (mL/mg protein) is the incubation volume/mg protein added and microsomal protein yield is taken as 52.5mg protein/ g liver. The L-type calcium channel blocker, Verapamil (0.5μΜ), (f?S)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl) ethyl]-(methyl)amino}-2-prop-2-ylpentanenitrile, commercially available as Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Calaptin, and Covera-HS was used as a positive control to confirm acceptable assay performance. Compound clearance is expressed as CLi where CLi is the intrinsic clearance. In the results provided in Experiment 2, compounds of formula (I) demonstrate desirable intrinsic clearance when incubated with bovine hepatic microsomes. Preferably the present compounds intrinsic clearance levels, expressed as CLi, of less than about 2.5, more preferably between about 0.5 and about 2.5, more preferably between about 0.5 and about 2, and yet more preferably between about 0.5 and about 1.5 wherein said mean CLi value can be determined using the methodology described hereinbefore. Compounds according to the present invention, including compounds of the Examples 1 to 39, have been tested and found to demonstrate mean CLi of between about 0.5 and about 2.5.

Additional pharmacokinetic testing for compounds of general formula (I) has been carried out, and in the results presented hereinafter at Experiment 4 the desirable pharmacokinetic profiles of compounds herein are demonstrated.

T. congolense and T. vivax in vivo anti-AAT results

Compounds of general formula (I) according to the present invention have been shown to have desirable activity in mouse models of T. congolense and T. vivax. In the results provided in Experiment 3, compounds of formula (I) demonstrate desirable anti-AAT activity against T. congolense and T. vivax in mice models of infection.

Rodent models as anti-AAT drug discovery efficacy models for compound screening have been extensively used and validated for use through the identification of several anti-AAT drugs such as isometamidium chloride, ethidium bromide and diminazene acetate. Such mouse models, including the Trypanosoma congolense mouse model are an integral part of the drug discovery and development pathway. In vivo data for the potential anti-AAT efficacy of compounds of general formula (I) has been demonstrated using T. congolense and T. vivax mouse models of the disease. In particular, and as illustrated in the results of Experiment 3 hereinafter, compounds of formula (I) can provide a full cure / ED ₁₀ o in these mouse models at doses of 10mg/kg within 4 days post-treatment. These improved potencies, versus current therapies, expressed as ED ₁₀ o, the dose required to eradicate 100% of the target infection [ED ₁₀ o of 10mg/kg mg/kg], via intramuscular dosing once daily for 4 days. Methodology

As will be appreciated any standard method for such in vivo testing can be used, such as for example the T. congolense method of Feyera et al. BMC Complementary and Alternative Medicine 2014, 14: 1 17 [http://www.biomedcentral.com/content/pdf/1472- 6882-14-1 17.pdf], or the 7. vivax method of D'Archivio et al. PLOS Neglected Troplical Diseases, January 3 ^rd 2013, DOI: 10 1371

http://www.plosntds.org/article/info%3Adoi%2F10.1371 ⁰ /o2Fioumal.pntd.0001978.

Pharmacokinetics were investigated in male Holstein-Fresian calves (130-220Kg) following intravenous administration at 2mg free base/Kg or singular muscular dose at 10mg/Kg free base as a formulation prepared at 50mg/ml_. Animals treated intravenously were administered by IV infusion via jugular vein while animals treated via intramuscular (IM) received up to 4 10ml_ maximum volume deep muscle injections at different sites. For IV administration, blood samples were taken at 3, 15, 30 minutes, 1 , 2, 3, 4, 6, 12, 24, 48, 72 and 96 hours post injection. For IM administration, blood samples were taken at 15, 30 minutes, 1 , 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post injection. All blood samples were then added to 2 volumes sterile water and stored and frozen down until bioanalysis by UPLCMSMS.

Parasites: 7. congolense:

The trypanosomes used in this experiment were of the cloned stabilate 7. congolense (IL3000), originally derived from trypanosomes isolated from a bovine in 1966 in Transmara, Kenya.

Experimental design:

All animal procedures were performed in accordance with the Animal (Scientific Procedures) Act 1986 and Specified Animal Pathogens Order 1998. Infected animals had access to food and water ad libitum and were housed under a 12-hour light/dark photoperiod.

Trypanosoma infection was completed following the standard protocol for Trypanosoma experiments. Briefly, 1 ml_ of cryopreserved stabilate in 10 % glycerol was diluted with Hanks Balanced Salt Solution plus 20mM Glucose (HBSS+G) to 4 x 104 trypomastigotes/mL. Female mice (NMRI) were intraperitoneally injected with 0.2 mL/animal (~1 x 104) on day 0. The level of parasitaemia was inspected microscopically on day 3 and further monitored using tail blood smears, counting 20 high powered fields (x 400 magnification). All animals exceeding 50 parasites/field were cell counted using a haemocytometer; mice with a parasite burden over 1 x 108 were promptly and humanely terminated. From our experience (unpublished data) the mice will not survive for a further 24 hours.

Parasite suppression:

On day 3 post infection animals were randomly allocated to 3 mice per group. Infected animals were dosed with one of the following: diminazene diaceturate (I. P.) - 40mg/kg once only as a control (early-stage trypanocide to clear the parasites in the systemic circulation and in tissues other than CNS), or compound (subcutaneously) 10mg free base/kg once daily for 4 days, one group of 3 mice was an untreated control group. The dose solutions were prepared daily, using 5% DMSO : 40% PEG400 : 55% MilliQ H ₂ 0 for compound and 10% DMSO : 90% peanut oil for diminazene diaceturate. To measure the response to treatment parasitaemia is monitored twice per week until day 21. After day 21 the mice will be checked only once per week until day 63 post treatment. Mice surviving to the end of experiment and blood smear aparasitaemic are considered cured. Results:

Example compound 32 was well tolerated by mice and proved to be effective with four single daily doses of 10 mg/kg supressing infection in all 3 treated mice.

Parasites T. vivax:

The trypanosomes used in this experiment were of the cloned stabilate T. vivax (ILRAD V34), originally derived from trypanosomes isolated from a bovine in 1976 in Zaria, Nigeria.

Experimental design:

All animal procedures were performed in accordance with the Animal (Scientific Procedures) Act 1986 and Specified Animal Pathogens Order 1998. Infected animals had access to food and water ad libitum and were housed under a 12-hour light/dark photoperiod.

Trypanosoma infection was completed following the standard protocol for trypanosoma experiments. Briefly, Trypanosoma vivax strain ILRAD V34 was grown from stabilates in donor Balb/c mouse (Harlan, United Kingdom). Parasites were harvested from mice by terminal exsanguination and subsequent blood was diluted with Hanks Balanced Salt Solution plus 20mM Glucose (HBSS+G) to 5 x 104 trypomastigotes/mL. Female mice (NMRI) were intraperitoneal^ injected with 0.2 mL/animal (~ 1 x 104) on day 0. The level of parasitaemia was inspected microscopically on day 3 and further monitored using tail blood smears, counting 20 high powered fields (x 400 magnification). All animals exceeding 50 parasites/field were cell counted using a haemocy to meter; mice with a parasite burden over 1 x 108 were promptly and humanely terminated. From our experience (unpublished data) the mice will not survive for a further 24 hours. Parasite suppression:

On day 3 post infection animals were randomly allocated to 3 mice per group. Infected animals were dosed with one of the following: diminazene diaceturate (I. P.) - 40mg/kg once only as a control (early-stage trypanocide to clear the parasites in the systemic circulation and in tissues other than CNS), or compound (subcutaneously) 10mg free base/kg once daily for 4 days, one group of 3 mice was an untreated control group. The dose solutions were prepared daily, using 5% DMSO : 40%PEG400 : 55% MilliQ H ₂ 0 for compound and 10%DMSO : 90% peanut oil for diminazene diaceturate. To measure the response to treatment parasitaemia is monitored twice per week until day 21. After day 21 the mice will be checked only once per week until day 63 post treatment. Mice surviving to the end of experiment and blood smear aparasitaemic are considered cured.

Results:

Example compound 32 was well tolerated by mice and proved to be effective with two single daily doses of 10 mg/kg supressing infection in all 3 treated mice.

Trypanosome inhibitor compounds of formula (I) exhibited desirable in vivo behaviour in the 7 congolense and 7 vivax mouse models They were curative in mouse models of 7 congolense and 7 vivax with a 10mg/kg dose, once a day for 4 days (7. congolense) or 2 days (7 vivax), given subcutaneously in IL3000 and ILRAD V34 strains respectively. Preliminary results indicate that compounds of the invention have desirable levels of efficacy in this model versus current anti-AAT therapies. Compounds of formula (I) have been demonstrated to have comparable potency to current anti-AAT therapies (diminazene, which shows cure when dosed at 40 mg/kg ip, single dose).

As demonstrated by the results presented in Experiment 3 below, and particularly the results shown in Tables 6 and 8 compounds of the invention provided desirable efficacy when dosed subcutaneously in the above mouse models to mice infected either with T. congolense or both T. congolense and T. vivax.

Compounds identified as being active in such four-day assays can subsequently be progressed through several secondary tests as follows. In the 'dose ranging, full four- day test', compounds are tested at a minimum of four different doses, by subcutaneous and/or oral routes, to determine ED ₅₀ and ED ₉₀ values. This test also provides useful information on relative potency and oral bioavailability. In the Onset/recrudescence' test, mice are administered a single dose (by subcutaneous or oral route) on day 3 post- infection and followed daily to monitor parasitaemia. Results are expressed as the rapidity of onset of activity (disappearance of parasitaemia), time to onset of recrudescence, increase of parasitaemia and survival in number of days. Compounds can also be tested for prophylactic activity by administering the compound prior to infection, followed by daily examination of smears.

Genotoxicity Studies / Ames test ln-vitro genotoxicity studies can be carried out using a variety of methods. As detailed hereinafter, Ames in vitro genotoxicity testing was carried out on compounds of formula (I). In the results provided in Experiment 5, compounds of formula (I) have been shown to demonstrate negative mutagenicity in the Ames assay. The OECD Guideline for Testing of Chemicals: 471 - Bacterial Reverse Mutation Test, as adopted on July 21 ^st 1997, [http://www.oecd.org/chemicalsafety/risk-assessment/1948418. pdf] the contents of which are incorporated herein by reference provide a standard method for measuring reverse mutations at selected loci of strains of Salmonella typhimurium and at the tryptophan locus of Escherichia coli (E. coli) WP2 uvrA may be used to carry out testing in accordance with Experiment 3 below.

Initial results obtained using the Ames in-vitro genotoxicity assay methodology in the presence and absence of exogenous (S9) metabolic activation, indicate that compounds of the present invention have no mutagenic potential at selected loci of strains of Salmonella typhimurium and at the tryptophan locus of Escherichia Coli (E. Coli) WP2 uvrA. Trypanosome inhibitor compounds of formula (I) exhibited no genotoxicity in the Ames test. Preferred compounds of formula (I) have a desirable in vivo T. congolense and T. vivax potencies, such as having an EC ₅₀ of less than 0.005, for example. Thus according to a further aspect the present invention provides compounds of formula (I) having desirable in vivo T. congolense and T. vivax potencies and no genotoxicity in the Ames assay. Preferably, the compounds of formula (I) have in vivo potency in cattle against T. congolense and T. vivax of less than 50 mg/kg.

Compounds tested for cytotoxicity via HepG2 assay with compounds plated in 384 well plates in increasing concentration to obtain a dose response (top concentration of 50μΜ). 25μΙ_ of media containing 1x10 ⁵ HepG2 cells/mL is added to each well and plate incubated at 37°C for 72 hours. 5μΙ_ of resazurin (25mM) is then added to each well and incubated for 1.5 hours at 37°C. Plate is then read in plate reader at an excitation wavelength of 550nm and emission wave length of 595nm

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

Abbreviations

APCI atmospheric pressure chemical ionisation mass spectrum

δ chemical shift

br broad

d doublet

Dd double doublet

DCM Dichloromethane

DMP Dess-Martin periodinane, 1 , 1 , 1-Triacetoxy-1 , 1-dihydro-

1 ,2-benziodoxol-3(1 H)-one

DIPEA Ν,Ν-diisopropylethylamine (or Hunig's base)

DMF dimethylformamide

DMSO dimethyl sulfoxide

ES low resolution electro spray mass spectroscopy

EtOAc ethyl acetate

HPLC high performance liquid chromatography

HRMS high resolution mass spectrum

hr hours

J coupling constant

LCMS liquid chromatography mass spectrometry M multiplet

Min minutes

m/z mass spectrum peak

NMR nuclear magnetic resonance

Ppm parts per million

Q quartet

R.T. room temperature

s singlet

sec seconds

T triplet

TMEDA tetramethylethylenediamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Equipment

Reactions using microwave irradiation were carried out in a Biotage Initiator microwave. Normal phase TLCs were carried out on pre-coated silica plates (Kieselgel 60 F254, BDH) with visualisation via U.V. light (UV254/365 nm) and/or ninhydrin and potassium permanganate solution. Flash chromatography was performed using Combiflash Companion and Combiflash Rf (Teledyne ISCO) and prepacked RediSep Rf silica gel columns purchased from Teledyne ISCO. Mass-directed preparative HPLC separations were performed using a Waters HPLC (2545 binary gradient pumps, 515 HPLC make up pump, 2767 sample manager) connected to a Waters 2998 photodiode array and a Waters 3100 mass detector. Preparative HPLC separations were performed with a Gilson HPLC (321 pumps, 819 injection module, and 215 liquid handler/injector) connected to a Gilson 155 UV/vis detector. On both instruments, HPLC chromatographic separations were conducted using Waters XBridge C18 columns, 19 x 100 mm, 5 μηι particle size; using 0.1 % ammonia in water or 0.1 % formic acid in water (solvent A) and acetonitrile (solvent B) as mobile phase. ¹ H NMR, ¹⁹ F NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer ( ¹ H at 500.1 MHz, ¹³ C at 125 MHz ¹⁹ F at 470.5 MHz), or a Bruker Avance DPX 300 ( ¹ H at 300 MHz). Chemical shifts (δ) are expressed in ppm recorded using the residual solvent as the internal reference in all cases. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), doublet of doublets (dd) or a combination thereof. Coupling constants (J) are quoted to the nearest 0.5 Hz. Low resolution electrospray (ES) mass spectra were recorded on a Bruker MicroTof mass spectrometer, run in positive or negative mode. High resolution mass spectroscopy (HRMS) was performed using a Bruker MicroTof mass spectrometer. LC-MS analysis and chromatographic separation were conducted with a Brucker MicrOTOf mass spectrometer or an Agilent Technologies 1200 series HPLC connected to an Agilent Technologies 6130 quadrupole LC/MS, where both instruments were connected to an Agilent diode array detector. The column used was a Waters XBridge column (50 mm ^χ 2.1 mm, 3.5 μηι particle size,) and the compounds were eluted with a gradient of 5 to 95% acetonitrile/water +0.1 % Ammonia.

Unless otherwise stated herein reactions have not been optimised. Solvents and reagents were purchased from commercial suppliers and used without further purification. Dry solvents were purchased in sure sealed bottles stored over molecular sieves.

The preparations and compounds have been named using the ChemDraw Ultra 12.0 naming application.

Preparative Compound 1 : Tert-butyl N-(trans-4-isothiocvanatocvclohexyl) carbamate

Tert-butyl N-(trans-4-aminocyclohexyl)carbamate (supplied from Apollo Scientific, CAS no. 177906-48-8), (5g, 23.332mmol) was dissolved in DCM (100ml_) at room temp. Di(imidazol-1-yl)methanethione (4.5g,25.665mmol) was then added in one portion and reaction mixture stirred overnight at R.T. Deionized water (50ml_) was added and DCM separated and dried using Magnesium Sulphate. Product was purified by silica column chromatography using Combiflash RF ^® automated purification system (Hexane - 10%- 60% EtOAc gradient elution) to give a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.78 (1 H, br, d, J = 7.3 Hz, NH), 3.76 (1 H, m, J = 10.6 Hz, CHN), 3.27 (1 H, br, m, J =7.6 Hz, CHNCS), 2.04 (2 H, br, dd, J = 13 Hz, 3.2 Hz, cyclohexyl CH), 1.75 (2 H, br dd, J = 12.9 Hz, cyclohexyl CH), 1.53 (2 H, qd, J = 13.1 Hz, 7.9 Hz, cyclohexyl CH), 1.37 (9 H, s, lBu), 1.22 (2 H, qd, J = 13.2 Hz, 8.5 Hz, cyclohexyl CH). reparative Compound 2: Tert-butyl N-(cis-4-isothiocvanatocvclohexyl)carbamate

Tert-butyl N-(cis-4-aminocyclohexyl)carbamate (supplied from Biofine International CAS no. 247570-24-7), (1 g, 4.66mmol) was dissolved in DMF (25ml_) at R.T. Di(imidazol-1- yl)methanethione (0.998g, 5.6mmol) was then added in one portion and reaction mixture stirred overnight at R.T. DMF was removed under reduced pressure then crude residue dissolved in DCM (50ml_). The organics were washed with saturated sodium chloride (3 x 20ml_), dried using magnesium sulphate and concentrated under reduced pressure to give a solid. The solid was confirmed as desired product by ¹ H NMR (500 MHz, DMSO- cf _e ) δ 6.74 (1 H, br, d, J = 6.8 Hz, NH), 3.73-3.79 (1 H, m, J = 7.9, 10.6, 13.3 Hz, CHN), 3.3 (1 H, br, m, J =7.8 Hz, CHNCS), 2.0 (2 H, br, dd, J = 13.4 Hz, 12.9 Hz, cyclohexyl CH), 1.8 (2 H, br dd, J = 3.4 Hz, cyclohexyl CH), 1.5 (2 H, qd, J = 13.1 Hz, 8.0 Hz, cyclohexyl CH), 1.37 (9 H, s, ^l Bu), 1.25 (2 H, qd, J = 13.2 Hz, cyclohexyl CH).

Preparative Compound 3: Tert-butyl N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-

Cyanamide (9.74g, 23.171 mmol) was dissolved in MeCN (30ml_). Potassium tertiary butoxide (1 M in THF) (2.6g, 23.171 mmol) was added in one portion. Reaction mixture was stirred at R.T. for 10 minutes. 2-bromo-1-(2,6-difluorophenyl)ethanone (4.54g, 19.309mmol) was then added in one portion as a solution in MeCN (20ml_) and tert- butanol (20ml_) and reaction stirred for a further 15 minutes at R.T. Tert-butyl N-(trans-4- isothiocyanatocyclohexyl)carbamate (4.95g, 19.309mmol) was then added in one portion and reaction stirred overnight at R.T. The resulting solid present was filtered and dried by suction filtration. Product confirmed by LCMS M+H 453 and ¹ H NMR (DMSO- cf _e ) δ 8.63 (1 H, br d, NH), 8.10 (2H, br s, NH ₂ ), 7.51 (1 H, m, J = 7.4 Hz, ArH), 7.12 - 7.20 (2 H, m, J = 7.7 Hz ArH, NH), 6.74 (1 H, d, J = 7.7 ArH), 3.64 (1 H, br m, CHN), 1.71 - 2.0 (4 H, br m, cyclohexyl CH), 1.13 - 1.31 (4 H, br m, cyclohexyl CH), 1.37 (9H, s, ^l Bu).

Preparative Compound 4: Tert-butyl N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-

2-vnaminol-cis-cyclohexyncarbamate

Tert-butyl N-(cis-4-isothiocyanatocyclohexyl)carbamate (0.99g, 3.87mmol) was dissolved in DMF (30ml_) with DIPEA (0.8ml_, 4.59mmol) and benzylsulfanylmethanimidamide hydrobromide (CAS no. 55796-74-2), (0.953g, 3.87mmol) then reaction mixture stirred at R.T. for 18 hrs. 2-bromo-1-(2,6-difluorophenyl)ethanone (1.09g, 4.64mmol) was then added in one portion as a solution in DMF (10ml_) and reaction stirred again overnight at R.T. 2M HCI (10ml_) was added and reaction mixture extracted with EtOAc (2 x 20ml_). The organics were combined and washed with saturated sodium chloride (3 x 10ml_), dried using magnesium sulphate and concentrated under reduced pressure to give a solid. The crude product was used without further purification in synthesis of preparative compound 5.

Preparative Compound 5: r4-amino-2-r(cis-4-aminocvclohexyl)amino1thiazol-5-yl1-

(2,6-difluorophenyl)methanone

Tert-butyl N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl] carbamate (0.530g, 1.17mmol) was dissolved in DCM (20ml_) with TFA (1.33g, 1 1.7mmol) at R.T. and the reaction mixture at R.T. for 3 hrs. The reaction mixture was concentrated under reduced pressure to give crude product as the TFA salt. The crude product was purified using Phenomenex® Strata SCX ion exchange resin chromatography (2M ammonia in MeOH eluent) to give title compound as the free base solid. The crude product was used without further purification in the synthesis of example compound 1.

Preparative Compound 6: r4-amino-2-r(trans-4-aminocvclohexyl)amino1thiazol-5- vn-(2,6-difluorophenyl)methanone

Tert-butyl N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]-tr ans-cyclohexyl] carbamate (1.500g,3.3148mmol) was dissolved in DCM (50ml_) with TFA (3.92g,34.364mmol). The reaction mixture was stirred overnight at R.T. 2M NaOH was then added in portions until reaction mixture was basic then extracted with DCM (3 x 50ml_). The organic extracts were combined and dried using magnesium sulphate then concentrated under reduced pressure to give a solid. The solid was confirmed as desired product by LCMS M+H 353 (R _t = 1.2 min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.53 (1 H, br, s, NH), 8.07 (2H, br, s, NH ₂ ), 7.49 (1 H, m, J = 6.7 Hz, 16.7 Hz, ArH), 7.16 (2 H, m, J = 15.6 Hz, ArH), 3.65 (1 H, br, s, CHN), 3.34 (2 H, br, s, NH ₂ ), 1.84 - 1.9 (2 H, br, m, J = 13.5 Hz, cyclohexyl CH), 1.68 - 1.81 (2 H, br, m, J = 1 1.4 Hz, cyclohexyl CH), 1.16 - 1.29 (2 H, br, m, J = 3.05 Hz, cyclohexyl CH), 1.0 - 1.09 (2 H, br m, J = 13.4 Hz, cyclohexyl CH).

Preparative Compound 7: (R)-3-bromo-2-methylpropyl acetate

(R)-3-bromo-2-methypropanol (supplied by Aldrich CAS no. 93381-28-3), (1.7g, 1 1.1 1 mmol) was dissolved in DCM (20ml_) with triethylamine (2.25g, 22.22mmol) at R.T. Acetic anhydride (2.27g, 22.22mmol) was then added in one portion and reaction stirred at R.T. for 2 hrs. Saturated sodium bicarbonate (50ml_) was added and DCM separated. Saturated sodium bicarbonate was washed with DCM (2 x 50m L) and organics combined, washed with saturated sodium chloride (20ml_) and dried using magnesium sulphate. DCM was then concentrated under reduced pressure to give a clear liquid. The liquid was confirmed as desired product by ¹ H NMR (300MHz CDCI ₃ ) δ 3.98 (2 H, m, CH ₂ 0), 3.37, (2 H, d, J = 5.3 Hz, CH ₂ Br), 2.64 - 2.72 (1 H, m J = 7.2 Hz, CH), 2.02 (3 H, s, COMe), 2.01 (3 H, d, 6.8 Hz, Me). Preparative Compound 8: (R)-2-methyl-3-thiocvanatopropyl acetate

[(2R)-3-bromo-2-methyl-propyl] acetate (1 g, 5.1269mmol) was dissolved in ethanol (10ml_) with potassium thiocyanate (5.48g, 5.64mmol) in a sealed 20ml_ microwave vial and heated under microwave conditions at 120°C for 2.5hrs Reaction diluted with DCM (50ml_) and washed with deionized water (20ml_) and dried using magnesium sulphate. Product was purified by silica column chromatography using Combiflash RF ^® automated purification system with DCM as eluent to give a clear liquid. The clear liquid was confirmed as desired product by ¹ H NMR (300MHz) CDCI ₃ ) δ 3.96 - 4.15 (2 H, dd, dd J = 4.9 Hz, 6.5 Hz, CH ₂ 0), 2.85 - 3.13 (2 H, dd, dd J = 6.0 Hz, 7.1 Hz, CH ₂ SCN), 2.20 - 2.33 (1 H, m, J = 6.7 Hz, 12.8 Hz, CH), 2.06 (3 H, s, COMe), 1.1 1 (3 H, d, J = 6.7 Hz, Me).

Preparative Compound 9: (R)-3-(chlorosulphonyl)-2-methylpropyl acetate

(R)-2-methyl-3-thiocyanatopropyl acetate (0.67g, 4.14mmol) was added to deionized water (0.15ml_) and acetic acid (1.7g, 20.68mmol). Reaction was then heated to 55°C and sulfuryl chloride (0.59g, 41 mmol) then added drop wise. Reaction stirred at 55 °C for 5 hrs. Reaction was cooled to R.T. and diluted with ether (50ml_). Deionized water (10ml_) was then added drop wise and reaction mixture extracted with ether (2 x 25ml_) and concentrated under reduced pressure. DCM (50ml_) was added and washed with deionized water (5 x 10ml_), dried using magnesium sulphate and concentrated under reduced pressure to give a liquid. The liquid was confirmed as desired product by ¹ H NMR (500MHz CDCIs) 5 4.18 - 4.21 (1 H, dd, J = 4.7 Hz, 11.3 Hz, CH), 3.99 - 4.03 (1 H, dd, J = 6.7 Hz, CH), 3.90 - 3.94 (1 H, dd, J = 4.8 Hz, CH), 3.59 - 3.64 (1 H, dd, J = 7.5 Hz, CH), 2.69 - 2.74 (1 H, m, J = 4.8 Hz, 4.8 Hz, CHMe), 2.10 (3 H, s, COMe), 1.26 (3 H, d, J = 6.9 Hz, Me).

Preparative Compound 10: (S)-3-bromc-2-methylpropyl acetate

The method of preparative compound 7, (R)-3-bromo-2-methylpropyl acetate was used using (S)-3bromo-2-methylpropanol (supplied by Aldrich CAS no. 98244-48-5), (5g, 32.67mmol), triethylamine (6.61g, 65.37mmol) and Acetic Anhydride (6.67g, 65.37mmol) as starting materials to give the title compound as a clear liquid. The liquid was confirmed as the desired product by ¹ H NMR (300MHz, CDCI ₃ ) δ 3.94 - 4.08 (2 H, dd, J = 5.5 Hz, 1 1 Hz, OCH ₂ ), 3.38 - 3.41 (2 H, dd, J = 1.7 Hz, 5.3 Hz, BrCH ₂ ), 2.1 1 - 2.19 (1 H, q, J = 5.5 Hz, 12.3 Hz, CHMe), 2.04 (3 H, s, COMe), 1.04 (3 H, d, J = 6.8 Hz, Me).

Preparative Compound 11 : (S)-2-methyl-3-thiocvanatopropyl acetate The method of preparative compound 8, (R)-2-methyl-3-thiocyanatopropyl acetate was used using [(2S)-3-bromo-2-methyl-propyl] acetate (2.0g, 10.25mmol) and potassium thiocyanate (1.09g, 11.21 mmol) as starting materials to give a clear liquid. The liquid was confirmed as desired product by ¹ H NMR (500MHz, CDCI ₃ ) δ 4.09 - 4.12 (1 H, dd, J = 4.9 Hz, 11.3 Hz, CH), 3.98 - 4.01 (1 H, dd, J = 6.6 Hz, 11.3 Hz, CH), 3.07 - 3.1 1 (1 H, dd, J = 6 Hz, 13.2 Hz, CH), 2.86 - 2.90 (1 H, dd, J = 7.5 Hz, 13.2 Hz, CH), 2.23 - 2.28 (1 H, q, J = 6.8 Hz, 13.5 Hz, CHMe), 2.06 (3 H, s, COMe), 1.1 1 (3 H, d, J = 6.8 Hz, Me).

Preparative Compound 12: (S)-3-(chlorosulphonyl)-2-methylpropyl acetate

The method of preparative compound 9, R)-3-(chlorosulphonyl)-2-methylpropyl acetate was used using (S)-2-methyl-3-thiocyanatopropyl acetate (1.15g, 6.58mmol), acetic acid (1.97g, 32.9mmol) and sulfuryl chloride (8.88g, 65.8mmol) as starting materials to give a clear liquid. The liquid was confirmed as desired product by ¹ H NMR (300MHz CDCI ₃ ) δ 4.13 - 4.19 (1 H, dd, J = 4.8 Hz, 11.3 Hz, CH), 3.95 - 4.02 (1 H, dd, J = 6.6 Hz, 1 1.2 Hz, CH), 3.88 - 3.93 (1 H, dd, 4.8 Hz, 14.2 Hz, CH), 2.65 - 2.73 (1 H, q, J = 7 Hz, 14 Hz, CHMe), 2.07 (3 H, s, COMe), 1.23 (3 H, d, J = 6.9 Hz, Me).

Preparative Compound 13: 3-bromo-2,2-dimethylpropyl acetate The method of preparative compound 7, (R)-3-bromo-2-methylpropyl acetate was used using 3-bromo-2,2-dimethylpropanol (6.4g, 38.43mmol), triethylamine (7.78g, 76.87mmol) and acetic anhydride (7.85g, 76.87mmol) as starting materials. Product was purified by column chromatography on silica using Combiflash RF ^® automated purification system and DCM as eluent to give an orange liquid. The liquid was confirmed as desired product by ¹ H NMR (500MHz, CDCI ₃ ) δ 3.94 (2 H, s, OCH ₂ ), 3.35 (2 H, s, BrCH ₂ ), 2.09 (3 H, s, COMe), 1.08 (6 H, s, Me ₂ ).

Preparative Compound 14: 2,2-dimethyl-3-thiocvanatopropyl acetate

The method of preparative compound 8, (R)-2-methyl-3-thiocyanatopropyl acetate using 3-bromo-2,2-dimethylpropyl acetate (2g, 9.57mmol) and potassium thiocyanate (1.02g, 10.52mmol) as starting materials. Product purified by column chromatography on silica (Hexane - 20%EtOAc eluent) using Combiflash RF® automated purification system to give a liquid. The liquid was confirmed as desired product by ¹ H NMR (300MHz CDCIs) δ 3.92 (2 H, s, OCH ₂ ), 3.04 (2 H, s, NSCH ₂ ), 1.09 (6 H, Me ₂ ). Preparative Compound 15: 3-(chlorosulphonyl)-2,2-dimethylpropyl acetate

Prepared in the same manner as preparative compound 9, (R)-3-(chlorosulphonyl)-2- methylpropyl acetate using 2,2-dimethyl-3-thiocyanatopropyl acetate (1.03g, 5.52mmol), acetic acid (2.32g, 27.63mmol), deionized water (0.199g, 11.05mmol) and sulfuryl chloride (7.46g, 55.27mmol) as starting materials to give a clear liquid. The liquid was confirmed as desired product by ¹ H NMR (300MHz CDCI ₃ ) δ 3.99 (2 H, d, OCH ₂ ), 3.89 (2 H, d, S0 ₂ CH ₂ ), 2.11 (3 H, s, COMe), 1.26 (6 H, s, Me ₂ ).

Preparative Compound 16: tert-butyl N-rtrans-4-(isobutylsulfonylamino)

Tert-butyl N-(trans-4-aminocyclohexyl)carbamate (4g, 18.67mmol) was dissolved in DMF (50mL) with triethylamine (2.08g, 20.53mmol) at R.T. A solution of 2-methylpropane-1- sulfonyl chloride (4.39g, 27.99mmol) in DMF (10ml_) was then added drop wise and the reaction mixture stirred overnight at RT. DMF was removed under reduced pressure and EtOAc (100ml_) added. Deionized water (50ml_) was added and organics separated, dried using magnesium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Hexane - 20% - 100% EtOAc gradient elution) using Combiflash RF® automated purification system to give a white solid. The solid was confirmed as desired product by 1 H NMR. (500 MHz, CDCI ₃ ) δ 4.39 (1 H, br, d, J = 7 Hz, NH), 4.22 (1 H, d, J = 7.7 Hz, NH), 3.40 (1 H, br, m, CHN), 3.21 - 3.33 (1 H, br, m, J = 7.6 Hz, 14.7 Hz, CHN), 2.93 (2H, d, J = 6.4 Hz, CH ₂ S0 ₂ ), 2.29 (1 H, m, J = 13.1 Hz, CHMe ₂ ), 2.20 (4 H, br, m, cyclohexyl CH), 1.24 - 1.45 (4 H, br, m, cyclohexyl CH), 1.45 (9 H, s, ^l Bu) 1.10 (6 H, d, J = 6.7 Hz, CHMe ₂ ).

Preparative Compound 17: N-(trans-4-aminocvclohexyl)-2-methyl-propane-1 - sulfonamide

Tert-butyl N-[trans-4-(isobutylsulfonylamino)cyclohexyl]carbamate (2.1 g,6.2786mmol) was dissolved in DCM (200MI) with TFA (8.94g, 78.421 mmol) at R.T. and reaction mixture stirred for 24 hrs. 2M NaOH was then added until reaction was basic then reaction mixture was extracted with DCM (3 x 50ml_). Organics were combined and dried using magnesium sulphate and concentrated under reduced pressure to give a gum. The solid was confirmed as desired product by ¹ H NMR. (500 MHz, DMSO-d ₆ ) δ 8.20 (2 H br, s, NH2), 7.09 (1 H, d, J = 7.5 Hz, NH), 2.97 - 3.10 (1 H, br, m, J = 14.6 Hz, 7.3 Hz, CHN), 2.89 (3 H, d, J = 6.4 Hz, CHN, CH ₂ S0 ₂ N), 2.02 - 2.13 (1 H, m, J = 13.2 Hz, CHMe ₂ ), 2.08 (4 H, br, m, cyclohexyl CH), 1.25 - 1.48 (4 H, m, J = 2.5 Hz, 4.5 Hz, 11.6 Hz, cyclohexyl CH), 1.03 (6 H, d, J = 6.7 Hz, CH/We ₂ ).

Preparative Compound 18: N-(trans-4-isothiocvanatocvclohexyl)-2-methyl- propane-1 -sulfonamide

N-(trans-4-arninocyclohexyl)-2-methyl-propane-1-sulfonamide (1.35g, 5.7604mmol) was dissolved in DCM (50ml_) at R.T. Di(imidazol-1-yl)methanethione (1.13g,6.3364mmol) was then added and reaction mixture stirred overnight at R.T. Deionized water (50ml_) was added and DCM separated and dried over magnesium sulphate. Product was purified by silica column chromatography (Hexane - 10%-60% EtOAc gradient elution) using Combiflash RF® automated purification system to give a white solid. The solid was confirmed as desired product by ¹ H NMR. (500 MHz, DMSO-d ₆ ) δ 7.05 (1 H d, J = 7.3 Hz, NH), 3.7 - 3.8 (1 H, m, J = 10.3 Hz, CHN), 3.13 - 3.21 (1 H, m, J = 7.1 Hz, 14.2 Hz, CHN), 2.88 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ ), 2.01 - 2.12 (3 H, m, J = 13.2 Hz, CHMe _2, cyclohexyl CH), 1.54 - 1.63 (2 H, m, J = 1.5 Hz, 13.2 Hz, cyclohexyl CH), 1.26 - 1.36 (2 H, m, J = 3.4 Hz, 12.2 Hz, cyclohexyl CH), 1.02 (6 H, d, CH/We ₂ ).

Preparative Compound 19: 4-cyano-2,6-difluoro-benzoic acid

To a cooled (-78 °C) stirring solution of 3,5-difluorobenzonitrile (3.059g, 21.991 mmol) in THF (90ml_) was added drop wise 2.5M n-butyl lithium in hexanes (9.0 ml, 22.5 mmol) maintaining temperature below -65° throughout and resulting in a red-orange solution. The reaction mixture was returned to -78 °C and stirred for 45 minutes at this temperature. Carbon dioxide (sublimation of dry-ice, passed through 4A molecular sieves), was bubbled through the reaction for ca. 50 minutes to give a thick white suspension. 2M HCI was then added until pH was ca.1 and reaction mixture allowed to warm to R.T. The phases were separated and the aqueous phase was extracted with EtOAc (2 x 100ml_). The combined organic phases were concentrated under reduced to give a white solid. The crude residue was partitioned between 1 M NaOH (90 ml) and EtOAc (150 ml). The aqueous layer was further extracted with 1 M NaOH (3 x 50 ml). The combined aqueous layers were acidified to about pH 1 with concentrated HCI and extracted with EtOAc (3 x 300 ml). The combined organic phases were dried using sodium sulphate and concentrated under reduced pressure to give title compound as a white solid. The solid was confirmed as desired product by NMR. ¹ H NMR (500 MHz, DMSO-de) δ 14.60 (1 H, br s, C0 ₂ H), 7.96 (2 H, d, J = 7.4 Hz, ArH). Preparative Compound 20: 4-cvano-2,6-difluoro-N-methoxy-N-methyl-benzamide

A suspension of 4-cyano-2,6-difluoro-benzoic acid (0.995g, 5.4339mmol) and N- methoxymethanamine hydrochloride (0.7g, 6.5571 mmol) in DCM (55ml_) at room temperature was treated with diisopropylethylamine (2.14g, 16.524mmol) in one portion and stirred at R.T. to give a colourless solution. A 50% solution of propyl phosphonic anhydride in EtOAc (4.8ml_) was added drop wise and the reaction was stirred at room temperature overnight. The mixture was treated with aqueous NaHC0 ₃ (100 mL) and vigorously stirred for 30 minutes. The phases were separated and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with water, dried using magnesium sulphate and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash RF® automated purification system (10-100% EtOAc - DCM gradient elution) to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 227 (R _t = 4.2 min) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.31 (2 H, d, J = 6.2 Hz ArH), 3.59 (3 H, s, OMe), 4.43 (3 H, s, NMe).

Preparative Compound 21 : 4-acetyl-3,5-difluorobenzonitrile

A solution of 4-cyano-2,6-difluoro-N-methoxy-N-methyl-benzamide (0.136g, 0.5266mmol) in THF (1.5mL) was cooled in an ice bath to about 0°C. A 3 M solution of methyl magnesium bromide in diethyl ether (0.53ml_, 1.59mmol) was added drop wise over about 5 minutes. The reaction mixture was then stirred in the cooling bath for 45 min, then allowed to warm to room temperature and stirred for further 4 hours. The reaction mixture was then quenched with pH 7 buffer (15 ml_, prepared with 825ml_ of 0.2M K ₂ HP0 ₄ and 175ml_ of 0.1 M citric acid solutions), extracted with EtOAc (3 x 25ml_), dried using sodium sulphate and concentrated under reduced pressure to give title compound as a pale yellow gum. The gum was confirmed as the desired product by LCMS M+H 214 (R _t = 1.8 min) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.31 (2 H, d, J = 6.8 Hz, ArH), 2.65 (3 H, t, J = 1.5 Hz, COMe).

Preparative Compound 22: 4-(2-bromoacetyl)-3,5-difluoro-benzonitrile

A solution of 4-acetyl-3,5-difluoro-benzonitrile (0.087g, 0.4819mmol) in THF (2ml_) was treated with trimethylphenylammonium tribromide (0.181g, 0.4819mmol) in small portions over 10 min. at R.T. with stirring. The resulting brown solution was stirred at R.T. for a further 2.5 hours. A white precipitate formed. The mixture was filtered and washed with THF. The filtrate and THF wash were combined and concentrated under reduced pressure. The crude product was purified by silica column chromatography using Combiflash RF® automated purification system (0-100% EtOAc-hexane gradient elution) to give title compound as a pale yellow solid. The solid was confirmed as desired product by NMR. ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.36 (2 H, d, J = 6.9 Hz), 4.34 (2 H, s, CH ₂ Br). Preparative Compou -cyano-2,6-difluoro-benzoic acid

The method of preparative compound 19, 4-cyano-2,6-difluoro-benzoic acid was used using 2,4-difluorobenzonitrile (5.07g,36.449mmol) in THF (150ml_) to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 182 (R _t 0.5 min) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 14.52 (1 H, br s, C0 ₂ H), 8.20 (1 H, m, ArH), 7.50 (1 H, dt, J = 9.0, 1.0 Hz, ArH).

Preparative compound 24: Methyl 3-cyano-2,6-difluoro-benzoate

A solution of 3-cyano-2,6-difluoro-benzoic acid (2.538g, 13.861 mmol) in methanol (50ml_) at 0° C was treated drop wise with thionyl chloride (1.65g, 13.861 mmol) at R.T. The mixture was heated under reflux for 6hrs. A further portion of thionyl chloride (1.65g, 13.861 mmol) was added drop wise to the heating reaction mixture and heating was continued overnight. Reaction mix was concentrated under reduced pressure. The residue was partitioned between EtOAc (3 x 50 ml_) and aqueous. NaHC0 ₃ (50 ml_). The organic phases were combined and washed with further portions of aqueous NaHC0 ₃ and saturated NaCI solution, dried over magnesium sulphate and concentrated under reduced pressure to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 198 (R _t = 4.6 min.) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.78 (1 H, m, ArH), 7.14 (1 H, dt, J = 8.7 Hz, 1.4 Hz, ArH), 4.02 (3 H, s, OMe). Preparative compound 25: Methyl 3-(aminomethyl)-2,6-difluoro-benzoate

A solution of methyl 3-cyano-2,6-difluoro-benzoate (0.50g, 2.5464mmol) in ethanol (25ml_) was purged with argon (x3). 20% palladium hydroxide on carbon (0.096g) was added and the mixture was purged again, firstly with argon (x3) and then hydrogen at atmospheric pressure. The reaction mixture was stirred at R.T. under hydrogen atmosphere for 36hrs. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to give the crude product. The product was purified by silica column chromatography using Combiflash RF® automated purification system (0-20% MeOH/NH ₃ -DCM gradient elution) to give title compound as colourless oil. The oil was confirmed as desired product by LCMS M+H 202 (R _t 0.2 min)and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.47 (1 H, m, ArH), 6.95 (1 H, dt, J = 8.8 Hz, 1.3 Hz, ArH), 3.97 (3 H, s, OMe), 3.91 (2 H, s, CH ₂ N), 1.47 (2 H, s, NH ₂ ).

Preparative Compound 26: Methyl 3-(dimethylaminomethyl)-2,6-difluoro-benzoate

A solution of methyl 3-(aminomethyl)-2,6-difluoro-benzoate (0.195g, 0.9693mmol) in formic acid (1 ml_) was treated with formaldehyde (37% solution in water, 7 mmol) and the resulting yellow solution was heated at 80 °C for 4.5 hours with stirring. The reaction was cooled to R.T. and concentrated under reduced pressure. 10% K ₂ C0 ₃ was then added until reaction mixture basic and extracted with DCM (4 x 50ml_). The combined organic phases were concentrated under reduced pressure to give colourless oil. The oil was confirmed as desired product by LCMS M+H 230 (R _t 4.6 min) and ¹ H NMR (500 MHz, CDCIs) δ 7.49 (1 H, m, ArH), 6.96 (1 H, dt, J = 8.8 Hz, 1.3 Hz, ArH), 3.98 (3 H, s, OMe), 3.49 (2 H, s, CH ₂ N), 2.28 (6 H, s, NMe ₂ ).

Preparative Compound 27: 3-(dimethylaminomethyl)-2,6-difluoro-N-methoxy-N- methyl-benzamide

A suspension of methyl 3-(dimethylaminomethyl)-2,6-difluoro-benzoate (0.4g, 1.745mmol) and N-methoxymethanamine hydrochloride (0.264g, 2.7048mmol) in THF (4ml_) was cooled in an ice-salt bath (<-15 °C) with stirring. A 2M solution isopropyl magnesium chloride in ether, (1.5ml_, 3mmol) was added drop wise over 5 min. The resulting yellow solution was stirred in the cooling bath for a further 70 min. The reaction was quenched with pH 7 buffer (20ml_; prepared with 825ml_ of 0.2M K ₂ HP0 ₄ and 175ml_ of 0.1 M citric acid solutions), extracted with EtOAc (5 x 25ml_), dried using magnesium sulphate and concentrated under reduced pressure. The crude product was purified via silica column chromatography using Combiflash RF® automated purification system (0-10% MeOH/NH3-DCM gradient elution) to give title compound as a pale yellow oil. The oil was confirmed as desired product by LCMS M+H 259 (R _t = 4.1 min) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.43 (1 H, m, ArH), 6.95 (1 H, t, J = 8.4 Hz, ArH), 3.55 (3 H, s, OMe), 3.50 (2 H, d, J = 4 Hz, CH ₂ N), 3.42 (3H, s, NMe), 2.27 (6 H, s, NMe ₂ ).

Preparative Compound 28j 1 -r3-(dimethylaminomethyl)-2,6-difluoro- phenyllethanone

The method of preparative compound 21 , 4-acetyl-3,5-difluorobenzonitrile was used using 3-(dimethylaminomethyl)-2,6-difluoro-N-methoxy-N-methyl-benz amide (0.3g , 1.1616mmol) in THF (3.5ml_) and a 3 M solution of methyl magnesium bromide in diethyl ether (0. 53ml_, 1.59mmol) giving title compound as a yellow gum. The gum was confirmed as desired product by LCMS 214 (R _t = 4.2 min) and ¹ H NMR (500 MHz, CDCIs) δ 7.45 (1 H, m, ArH), 6.93 (1 H, dt, J = 8.8 Hz, 1.4 Hz, ArH), 3.47 (2 H, s, CH ₂ N), 2.61 (3 H, t, J = 1.7 Hz, COMe), 2.27 (6 H, s, NMe ₂ ).

Preparative Compound 29: 2-bromo-1 -r3-(dimethylaminomethyl)-2,6-difluoro- phenyllethanone hvdrobromide

1-[3-(Dimethylaminomethyl)-2,6-difluoro-phenyl]ethanone (0.05g, 0.2345mmol) was treated with a solution of molecular bromine (0.042g, 0.2596mmol) in hydrogen bromide, 33wt% in acetic acid (2.05g,8.3674mmol)and heated with stirring at 60 °C for 1.5h. Reaction mixture was allowed to cool to R.T. and diluted with ether (20ml_) & stirred for a further 2hrs. The resulting precipitate was collected by filtration, washed with ether and dried by suction filtration to give the title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 292/294 (R _t = 1.1 min) and ¹ H NMR (500 MHz, DMSO-de) δ 9.80 (1 H, br s, NH ⁺ ), 7.89 (1 H, m, ArH), 7.45 (1 H, t, J = 9.1 Hz, ArH), 4.78 (2 H, s, CH ₂ Br), 4.39 (2 H, d, J = 4.5 Hz, CH ₂ NH), 2.79 (6 H, d, J = 4.3 Hz, NMe ₂ ).

Preparative Compound 30: Methyl 4-(aminomethyl)-2,6-difluoro-benzoate

The method of preparative compound 25, methyl 3-(aminomethyl)-2,6-difluoro-benzoate using methyl 4-cyano-2,6-difluoro-benzoate (1 g, 5.0725mmol) and 20% palladium hydroxide on carbon (0.192g) in ethanol (250ml_) to give title compound as an oil. The oil was confirmed as desired product by NMR and LCMS M+H 530 (R _t = 3.8 min). ¹ H NMR (500 MHz, CDCIs) δ 6.96 (2 H, d, J = 9.0 Hz, 2 ArH), 3.95 (3 H, s, OMe), 3.94 (2 H, s, CH ₂ N), 1.44 (2 H, s, NH ₂ ).

Preparative Compound 31 : Methyl 4-(dimethylaminomethyl)-2,6-difluoro-benzoate

The method of preparative compound 26, 3-(dimethylaminomethyl)-2,6-difluoro-benzoate was used using methyl 4-(aminomethyl)-2,6-difluoro-benzoate (0.479g, 2.381 1 mmol), formic acid (2 ml_) and formaldehyde (37% solution in water 15mmol) to give title compound as a colourless oil. The oil was confirmed as desired product by LCMS M+H 230 (R _t = 4.7 min) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.96 (2 H, d, J = 8.9 Hz, 2 ArH), 3.95 (3 H, s, OMe), 3.42 (2 H, s, CH ₂ N), 2.25 (6 H, s, NMe ₂ ).

Preparative Compound 32: 4-(dimethylaminomethyl)-2,6-difluoro-N-methoxy-N- methyl-benzamide

The method of preparative compound 27, 3-(dimethylaminomethyl)-2,6-difluoro-N- methoxy-N-methyl-benzamide was used using methyl 4-(dimethylaminomethyl)-2,6- difluoro-benzoate (0.616g,2.6874mmol), N-methoxymethanamine hydrochloride (0.924g, 4.057mmol) in THF (10ml_) and 2M isopropyl magnesium chloride in ether, (2.3ml_, 4.57mmol) as starting materials to give title compound as an orange oil. The oil was confirmed as desired product by LCMS 259 (R _t = 4.3 min) and ¹ H NMR (500 MHz, CDCIs) δ 6.97 (2 H, d, J = 8.1 Hz, 2 ArH), 3.56 (3 H, s, OMe), 3.44 (2 H, s, CH ₂ N), 3.42 (3 H, s, NMe), 2.28 (6 H, s, NMe ₂ ).

Preparative Compound 33: 4-(dimethylaminomethyl)-2,6-difluoro-N-methoxy-N- methyl-benzamide

The method of preparative compound 21 , 4-acetyl-3,5-difluorobenzonitrile was used using 4-(dimethylaminomethyl)-2,6-difluoro-N-methoxy-N-methyl-benz amide (0.613g, 2.3736mmol) and 3M solution of methyl magnesium bromide in diethyl ether (1.02ml_, 3.09mmol) as starting materials to give title compound as a yellow gum. The gum was confirmed as desired product by LCMS M+H 214 (R _t = 4.5 min) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.97 (2 H, d, J = 9.1 Hz, 2 ArH), 3.43 (2 H, s, CH ₂ N), 2.61 (3 H, t, J = 1.9 Hz, COMe), 2.27 (6 H, s, NMe ₂ ).

Preparative Compound 34: 2-bromo-1 -r4-(dimethylaminomethyl)-2,6-difluoro- phenyllethanone hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-[4-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone (0.1g, 0.4690mmol), molecular bromine (0.084g, 0.519mmol) in hydrogen bromide, 33wt% in acetic acid (4.1 g, 16.73mmol) to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 292/294 (R _t = 0.2 min) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.86 (1 H, br s, NH ⁺ ), 7.49 (2 H, d, J = 9.0 Hz, 2 ArH), 4.77 (2 H, s, CH ₂ Br), 4.38 (2 H, s, CH ₂ N), 2.78 (6 H, d, J = 4.3 Hz, NMe ₂ ).

Preparative Compound 35: 2,6-difluoro-4-formyl-benzonitrile

4-bromo-2,6-difluoro-benzonitrile (5.3g, 20.27mmol) was dissolved in THF (40ml_) under nitrogen and cooled to 0°C. A solution of isopropyl magnesium chloride 2M in THF (2.50g, 24.33mmol) was then added drop wise and reaction stirred for 1 hr at about 0°C. Piperidine-1-carbaldehyde (3.3g, 29.17mmol) was then added and reaction stirred for a further 1 hr at 0° C. 1 M HCI (10ml_) was added and reaction extracted with DCM (2 x 50m L). Organics were dried using magnesium sulphate and concentrated under reduced pressure to give a liquid. The crude product was purified by silica column chromatography using Combiflash RF® automated purification system (EtOAc 1 %-30% - hexane gradient elution) to give title compound as a yellow liquid. The liquid was confirmed as desired product by ¹ H NMR. (500 MHz, CDCI ₃ ) δ 10.02 (1 H, s, CHO), 7.55 (2 H, d, J = 7.1 Hz, ArH).

Preparative Compound 36: 4-((dimethylamino)methyl)-2,6-difluorobenzonitrile

2,6-Difluoro-4-formyl-benzonitrile (2g, 12.21 mmol) and N-methylmethanamine as a 2M solution in THF (2.08g, 46.24mmol) were added to DCM (100ml_) at R.T. and stirred for 45 min. under nitrogen. Sodium triacetoxyborohydride (5.174g, 24.42mmol) was then added in portions and reaction stirred over night at R.T. Deionized water (50ml_) was then added and organics separated and dried using magnesium sulphate and concentrated under reduced pressure to give a solid. The crude product was purified by silica column chromatography using Combiflash RF® automated purification system (MeOH 1 % - 5% - DCM gradient elution) to give title compound as a yellow liquid. The liquid was confirmed as desired product ¹ H NMR. (500 MHz, CDCI ₃ ) δ 7.09 (2 H, d, ArH), 3.47 (2 H, CH ₂ N), 2.28 (6 H, N(CH ₃ ) ₂ ).

Preparative Compound 37: 2,6-difluoro-4-(pyrrolidin-1 -ylmethyl)benzonitrile

The method of preparative compound 36, 4-((dimethylamino)methyl)-2,6- difluorobenzonitrile was used using 2,6-difluoro-4-formyl-benzonitrile (1.04g,6.21 mmol), pyrrolidine (0.397g, 5.59mmol) and sodium triacetoxyborohydride (1.97g, 9.3082mmol) to give title compound as a clear oil. The oil was confirmed as desired product by ¹ H NMR. (500 MHz, CDCI ₃ ) δ 7.09 (2 H, d, J = 8.2 Hz, ArH), 3.67 (2 H, s, CH ₂ N), 2.51 - 2.54 (4 H, m, J = 2.5 Hz, 13.4 Hz, pyrrolidine CH), 1.83 (4 H, m, J = 3.6 Hz, 13.4 Hz, pyrrolidine CH).

Preparative Compound 38: 1 -r2,6-difluoro-4-(pyrrolidin-1 -ylmethyl)phenvn ethanone

A 3M solution of methyl magnesium bromide in diethyl ether (2.97ml_, 8.91 mmol) was added to toluene (40ml_) at R.T. The system was then sealed, purged with nitrogen and evacuated. This was repeated 3 times. 2,6-difluoro-4-(pyrrolidin-1-ylmethyl)benzonitrile (0.66g, 2.9699mmol) was then added drop wise to the sealed system and the mixture then heated to reflux (100-110°C) overnight (unsealed) under positive pressure of nitrogen. The mixture was then cooled to R.T. and adjusted to pH 2 with 2M HCI. The mixture was then heated to reflux again for 45min. The mixture was then basified with 2M NaOH to pH 1 1 , extracted with EtOAc (100 mL), dried using magnesium sulphate and concentrated under reduced pressure to give an amber oil. The oil was confirmed as desired product LCMS M+H 240 (R _t = 4.9 min.) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.95 (2 H, d, J = 9.2 Hz, ArH), 3.60 (2 H s, CH ₂ N), 2.59 (3 H, s, CH ₃ ), 2.49 - 2.54 (4 H, m, J = 4.9 Hz, 6.2 Hz, 9.4 Hz, pyrrolidine CH), 1.78 - 1.83 (4 H, m, J = 3.6 Hz, 1 1.7 Hz, pyrrolidine CH).

Preparative Compound 39: 1 -(4-(dimethylamino)-2,6-difluorophenyl)ethanone

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 4-[(dimethylamino)methyl]-2,6-difluoro- benzonitrile (1.5g, 7.65mmol) and a 3M solution of methyl magnesium bromide (5.1 ml_), 15.29mmol) to give title compound as an oil. The oil was confirmed as desired product by ¹ H NMR (500MHz, CDCI ₃ ) δ 6.97 (2 H, d, J = 18Hz, ArH), 3.43 (2 H, s, CH ₂ N), 2.62 (3 H, s, CH3CO), 2.27 (6 H, s, N(CH ₃ ) ₂ ). Preparative Compound 40: 2-bromo-1 -r2,6-difluoro-4-(pyrrolidin-1 -ylmethyl)phenvn ethanone hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone (0.240g, LOmmol), molecular bromine (0.176g, 1.1 mmol) and hydrogen bromide as a solution in 33% acetic acid (7.38g, 30mmol to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 318/320 (R _t = 0.2 min.) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.12 (1 H, s, NH ⁺ ) 6.94 (2H, m, J = 3.0 Hz, 15.3 Hz, ArH), 4.22 (2H, s, CH ₂ N), 3.55 (2H, s, CH ₂ Br), 2.45 (4 H br, m, J = 5.1 Hz, pyrrolidine CH), 1.71 (4 H, m, J = 4.8 Hz, pyrrolidine CH). Preparative Compound 41 : 2-chloro-5-formyl-benzonitrile

The method of preparative compound 35, 2,6-difluoro-4-formyl-benzonitrile was used using 5-bromo-2-chloro-benzonitrile (5.12g, 23.59mmol), piperidine-1-carbaldehyde (3.2g, 28.3mmol) and a 1 M solution of isopropyl magnesium chloride in THF (14.15ml_) as starting materials . Product was triturated from hexane to give title compound as an orange solid. The solid was confirmed as desired product by ¹ H NMR. (500 MHz, CDCI ₃ ) δ 10.01 (1 H, s, CHO), 8.20 (1 H, s, J = 1.9 Hz, ArH), 8.07 (1 H, d, J = 6.3 Hz, 10.3 Hz, ArH), 7.73 (1 H, d, J = 8.3 Hz, ArH).

Preparative Compound 42: 2-chloro-5-r(dimethylamino)methyl1 benzonitrile

The method of preparative compound 36, 4-((dimethylamino)methyl)-2,6- difluorobenzonitrile was used using 2-chloro-5-formyl-benzonitrile (1 g, 6.04mmol) and a 2M solution of N-methylmethanamine in THF (6.04ml_, 12.08mmol) and sodium triacetoxy borohydride (2.56g, 12.08mmol) as starting materials to give title compound as an amber liquid. The liquid was confirmed as desired product by LCMS M+H 195 (R _t 0.25 min.) and ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.61 (1 H s, J = 1.9 Hz, ArH), 7.50 (2 H, m, J = 1.9 Hz, 5.5 Hz, ArH), 3.42 (2 H, s, CH ₂ N), 2.25 (6 H, s, NMe ₂ ).

Preparative Compound 43: 1 -r2-chloro-5-r(dimethylamino)methvnphenvnethanone

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 2-chloro-5-[(dimethylamino)methyl]benzonitrile (0.652g,3.35mmol) and a 3M solution of methyl magnesium bromide in diethyl ether (3.35ml_, 10.05mmol) to give title compound as a brown liquid. The liquid was confirmed as desired product by ¹ H NMR. (500 MHz, CDCI ₃ ) δ 7.49 (1 H, s, ArH), 7.36 (2 H d, J = 7.3 Hz, ArH), 3.40 (2 H, s, CH ₂ N), 2.61 (3 H, s, COMe), 2.23 (6 H, s, NMe ₂ ).

Preparative Compound 44: 2-bromo-1 -r2-chloro-5-r(dimethylamino)methvn phenyllethanone hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-[2-chloro-5- [(dimethylamino)methyl]phenyl]ethanone (0.552mg,2.6076mmol), molecular bromine (0.458g, 2.87mmol) and hydrogen bromide 33wt% in acetic acid (1.92g, 78.23mmol) as starting materials to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 290/292 (R _t = 0.24 min.) and ¹ H NMR (500 MHz, DMSO- cf _e ) δ 9.81 (1 H, br, s, NH ⁺ ), 8.0 (1 H, s ArH), 7.73 (2H d, ArH), 4.89 (2H, s, CH ₂ N), 4.35 (2 H, s, CH ₂ Br), 2.51 (6 H, s, NMe ₂ ).

Preparative Compound 45: 2-chloro-4-formyl-benzonitrile

The method of preparative compound 35, 2,6-difluoro-4-formyl-benzonitrile was used using 4-bromo-2-chloro-benzonitrile (5.106g, 23.59mmol), piperidine-1-carbaldehyde (3.20g, 28.30mmol) and a solution of 2M isopropyl magnesium chloride in THF (14.1 ml_, 28.3mmol) as starting materials. The crude product was triturated with hexane to give title compound as an orange solid. The solid was confirmed as desired product by ¹ H NMR (500 MHz, CDCI ₃ ) δ 10.07 (1 H, s, CHO), 8.02 (1 H, s, ArH), 7.90 (2 H, s, ArH).

Preparative Compound 46: 2-chloro-4-r(dimethylamino)methvnbenzonitrile

The method of preparative compound 36, 4-((dimethylamino)methyl)-2,6- difluorobenzonitrile was used using 2-chloro-4-formyl-benzonitrile (1.36g, 8.24mmol), a 2M solution of N-methylmethanamine in THF (12.36ml_, 24.71 mmol) and sodium triacetoxyborohydride (3.49, 16.48mmol) as starting materials to give title compound as a liquid. The liquid was confirmed as desired product by ¹ H NMR. (500 MHz, CDCI ₃ ) δ 7.61 (1 H, d, J = 7.9 Hz, ArH), 7.53 (1 H, s, ArH), 7.33 (1 H, d, J = 8 Hz, ArH), 3.46 (2 H, s, CH ₂ N), 2.25 (6 H, s, NMe ₂ ).

Preparative Compound 47: 1 -r2-chloro-4-r(dimethylamino)methyllphenyl1ethanone

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 2-chloro-4-[(dimethylamino)methyl]benzonitrile (0.8g, 4.1 1 mmol) and a 3M solution of methyl magnesium bromide in diethyl ether (4.11 ml_, 12.33mmol) as starting materials to give title compound as a yellow oil. The oil was confirmed as desired product by LCMS M+H 212 (R _t 0.22 min.) and ¹ H NMR (500 MHz, CDCIs) δ 7.54 (1 H, d, J = 7.9 Hz, ArH), 7.41 (1 H, s, J = 1.3 Hz, ArH), 7.28 (1 H, d, J = 7.1 Hz, ArH), 3.43 (2 H, s, CH ₂ N), 2.65 (3 H, s, CH ₃ CO) 2.25 (6 H, s, NMe ₂ ).

Preparative Compound 48: 2-bromo-1 -r2-chloro-5-r(dimethylamino)methvn phenyl] ethanone hydrobromide

Hydrogen bromide 33wt% in acetic acid (3ml_, 1.41 mmol) was added to 1-[2-chloro-5- [(dimethylamino)methyl]phenyl]ethanone (0.30g, 1.41 mmol) followed by molecular bromine (0.073ml_, 1.41 mmol) at R.T. The reaction mixture was stirred for 20 min. at R.T. then concentrated under reduced pressure to give a black gum. Acetone (5ml_) and diethyl ether (5ml_) were added. After 5 minutes the resulting black solid was filtered and dried by suction filtration to give title compound. The solid was confirmed as desired product by M+H 290/292 (R _t = 0.23 min.) and ¹ H NMR (500MHz, DMSO-cfe) δ 9.95 (1 H, s, NH ⁺ ), 7.84 (2 H, br, d, ArH), 7.67 (1 H, br, s, ArH), 4.89 (2 H br, s, CH ₂ N), 4.41 (2 H, br, s, CH ₂ Br), 2.76 (6 H, br, s, NMe ₂ ).

Preparative Compound 49: 2-chloro-N-methoxy-N-methyl-pyridine-3-carboxamide

A suspension of N-methoxymethanamine hydrochloride (0.743g, 7.62mmol) and 2- chloropyridine-3-carboxylic acid (1 g, 6.35mmol) in DCM (10ml_) was treated with DIPEA at R.T. (2.46g, 19.042mmol). A 50% solution of propyl phosphonic anhydride in EtOAc (6.0ml_, 10mmol) was then added drop wise and the reaction stirred at R.T. overnight. The mixture was treated with aqueous sodium bicarbonate solution and vigorously stirred for 30 min. The phases were separated and the aqueous layer was extracted with DCM (2 x 50ml_)). The combined organic layers were washed with deionized water (40ml_), dried using magnesium sulphate and concentrated under reduced pressure to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 201 (R _t 1.8 min.) and ¹ H NMR (500MHz CDCI ₃₎ δ 8.21 (1 H, d, J = 7.1 Hz, ArH), 7.47 (1 H, d, J = 3.3 Hz, ArH), 7.10 (1 H, m, J = 5.1 Hz, ArH), 3.26 (3 H, s, OMe), 3.17 (3 H, s, NMe).

Preparative Compound 50: 1 -(2-chloro-3-pyridyl)ethanone

A solution of preparative compound 49, 2-chloro-N-methoxy-N-methyl-pyridine-3- carboxamide (1.27g, 6.31 mmol) in THF (10ml_) was cooled in an ice/salt bath to about - 10°C. A 3M solution of methyl magnesium bromide in diethyl ether (1.13g, 9.47mmol) was then added drop wise to the cooled reaction over 5 minutes. The reaction mixture was allowed to warm to R.T. and stirred for 12hrs. The reaction mixture was then quenched with 3 M HCI (20ml_), and stirred for 30 minutes at R.T. Reaction mixture was then partitioned between diethyl ether (50ml_) and 3M HCI (10ml_). The organic phase was washed with aqueous sodium bicarbonate and saturated sodium chloride, dried using magnesium sulphate and concentrated under reduced pressure to give title compound. The product was confirmed by LCMS M+H 156 (R _t 2.5 min.) and ¹ H NMR (500MHz MeOD) δ 8.47 (1 H, dd, J = 4.8 Hz, ArH), 8.05 (1 H, dd, J = 7.6 Hz, ArH), (1 H, dd, J = 4.8 Hz, ArH), 2.64 (3 H, s, Me). Preparative Compound 51 : 2-bromo-1 -(2-chloro-3-pyridyl)ethanone

Molecular bromine (0.61 mL, 11.92mmol) and hydrogen bromide 33wt% in acetic acid (10ml_) were added to 1-(2-chloro-3-pyridyl)ethanone (1.68g, 10.84mmol) at R.T. with stirring. The reaction mixture was then heated to 60°C for 2hrs. The reaction mixture was allowed to cool to R.T. then diethyl ether (40ml_) was added and reaction mixture stirred at R.T. for 1 hr resulting in the formation of a white precipitate. The solid was filtered, washed with diethyl ether and dried by suction filtration to give title compound as a white solid. The solid was confirmed as desired product by LCMS 235 (R _t 4.3 min.) and ¹ H NMR (500MHz MeOD) δ 8.51 (1 H, dd, J = 4.8 Hz, ArH), 8.14 (1 H, dd, J = 7.7 Hz, ArH), 7.54 (1 H, dd, J = 2.8 Hz, 12.5 Hz, ArH), 4.67 (2 H, s, CH ₂ Br). Preparative Compound 52: N-methoxy-N-methyl-2-(trifluoromethyl)pyridine-3- carboxamide

The method of preparative compound 49, 2-chloro-N-methoxy-N-methyl-pyridine-3- carboxamide was used using 2-(trifluoromethyl) pyridine-3-carboxylic acid (1g, 5.23mmol), N-methoxymethanamine hydrochloride (0.612g, 6.28mmol), DIPEA (2.73ml_, 15.70mmol) and propyl phosphonic anhydride 50% in EtOAc (9.34ml_, 15.68mmol) as starting materials to give title compound as a brown oil. The oil was confirmed as desired product by LCMS M+H 235 (R _t 4.6 min.) and ¹ H NMR (500MHz CDCI ₃ ) δ 8.67 (1 H, d, J = 4.3 Hz, ArH), 7.74 (1 H, d, J = 7.8 Hz, ArH), 7.50 (1 H, dd, J = 4.7, 7.8 Hz, ArH), 3.32 (3 H, s, OMe), 3.27 (3 H, s, NMe).

Preparative Compound 53: 1 -r2-(trifluoromethyl)-3-pyridvnethanone

The method of preparative compound 50, 1-(2-chloro-3-pyridyl)ethanone was used using N-methoxy-N-methyl-2-(trifluoromethyl)pyridine-3-carboxamide (1.2g, 5.1 1 mmol) and a 3M solution of methyl magnesium bromide (2.55ml_, 7.66mmol)as starting materials to give title compound as a brown oil. The oil was confirmed as desired product by LCMS M+H 190 (R _t = 4.0 min.) and ¹ H NMR (500MHz CDCI ₃ ) δ 8.67 (1 H, d, J = 4.3 Hz, ArH), 7.75 (1 H, d, J = 7.7 Hz, ArH), 7.51 (1 H, dd, J = 7.7 Hz, ArH), 2.50 (3H, s, Me). Preparative Compound 54: 2-bromo-1 -r2-(trifluoromethyl)-3-pyridvnethanone

The method of preparative compound 51 , 1-(2-chloro-3-pyridyl)ethanone was used using 1-[2-(trifluoromethyl)-3-pyridyl] ethanone (0.803g,4.2458mmol), molecular bromine (0.239ml_, 4.67mmol) and hydrogen bromide 33wt% in acetic acid (10ml_) as starting materials to give title compound as white solid. The solid was confirmed as desired product by LCMS M+H 269 (R _t = 4.75 min.) ¹ H NMR (500MHz MeOD) δ 8.83 (1 H, d, ArH), 8.21 (1 H, d, J = 7.9 Hz, ArH), 7.78 (1 H, dd, J = 4.8 Hz, ArH), 4.66 (2 H, s, CH ₂ Br).

Preparative Compound 55: 2-bromo-N-methoxy-N-methyl-pyridine-3-carboxamide

The method of preparative compound 49: 2-chloro-N-methoxy-N-methyl-pyridine-3- carboxamide was used using 2-bromopyridine-3-carboxylic acid (1 g, 4.95mmol), N- methoxymethanamine hydrochloride (0.579g, 5.94mmol), DIPEA (2.59mL, 14.85mmol) and propyl phosphonic acid 50% in EtOAc (8.84mL, 14.85mmol) as starting materials to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 245/247 (R _t 3.85 min.) and ¹ H NMR (500MHz CDCI ₃ ) δ 8.34 (1 H, d, J = 4.4 Hz, ArH), 7.55 (1 H, d, ArH), 7.28 (1 H, dd, J = 3.0, 7.3 Hz, ArH), 3.42 (3 H, s, OMe), 3.32 (3 H, s, NMe).

Preparative Compound 56: 1 -(2-bromo-3-pyridyl)ethanone

The method of preparative compound 50, 1-(2-chloro-3-pyridyl)ethanone was used using 2-bromo-N-methoxy-N-methyl-pyridine-3-carboxamide (1.16g, 4.7374mmol) and a 3M solution of methyl magnesium bromide in diethyl ether (2.37ml_, 7.1 mmol) as starting materials to give title compound as a yellow oil. The oil was confirmed as desired product by LCMS M+H 199/201 (R _t = 3.15 min.) and ¹ H NMR (500MHz MeOD) δ 8.42 (1 H, dd, J = 4.8 Hz, ArH), 7.95 (1 H, dd, J = 7.6 Hz, ArH), 7.50 (1 H, dd, J = 4.8 Hz, ArH), 2.64 (3 H, s, Me).

Preparative Compound 57: 2-bromo-1 -(2-bromo-3-pyridyl) ethanone

The method of preparative compound 51 , 1-(2-chloro-3-pyridyl)ethanone was used using 1-(2-bromo-3-pyridyl)ethanone (0.608g, 3.04mmol), molecular bromine (0.171 ml_, 3.34mmol) and hydrogen bromide 33wt% in acetic acid (10ml_) as starting materials to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 279 (R _t 4.25 min.) and ¹ H NMR (500MHz MeOD) δ 8.50 (1 H, dd, J = 1.9 Hz, ArH), 8.04 (1 H, dd, J = 5.7 Hz, 9.6 Hz, ArH), 7.57 (1 H, dd, J = 4.8 Hz, ArH), 4.67 (2 H, s, CH ₂ Br).

Preparative Compound 58: 2-bromo-1 -(2-iodophenyl)ethanone

A solution of 1-(2-iodophenyl)ethanone (0.86g, 3.49mmol) in THF (15ml_) was treated with tnmethylphenylammonium tribromide (1.31g, 3.49mmol) in small portions over 10 minutes at R.T. The resulting yellow suspension was stirred at R.T. for 2 hours. A white precipitate formed and was filtered, washed with diethyl ether and the filtrate was concentrated under reduced pressure to give the crude product. The product was purified by silica column chromatography using Combiflash RF® automated purification system (0-100% EtOAc - hexane gradient elution) to give title compound as a yellow oil. The oil was confirmed as desired product by ¹ H NMR (500MHz CDCI ₃ ) δ 7.97 (1 H, d, J = 1 1 Hz, ArH), 7.47 (2 H, d, J = 8 Hz, ArH), 7.18 - 7.22 (1 H, m, J = 4, 12Hz, ArH), 4.47 (2 H, s, CH ₂ Br).

Preparative compound 59: Methyl 3-cyano-2,6-difluoro-benzoate

A solution of 4-cyano-2,6-difluoro-benzoic acid (1.765g, 9.639mmol) in methanol (40ml_) at 0° C was treated drop wise with thionyl chloride (1.147g, 9.639mmol) at R.T. The mixture was heated under reflux for 12hrs. A further portion of thionyl chloride (1.0ml_) was added drop wise to the heating reaction mixture and heating was continued for a further 5hrs. The reaction mix was concentrated under reduced pressure. The residue was partitioned between EtOAc (3 x 50 ml_) and aqueous. NaHC0 ₃ (50 ml_). The organic phases were combined and washed with further portions of aqueous NaHC0 ₃ and saturated NaCI solution, dried over magnesium sulphate and concentrated under reduced pressure to give crude product. The product was purified by silica column chromatography using Combiflash RF® automated purification system (0-50% EtOAc - hexane gradient elution) to give title compound as white solid. The solid was confirmed as desired product by ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.31 (2 H, dd, J =17.8 Hz, 13.7 Hz, 6.8 Hz, ArH), 4.02 (3 H, s, OMe).

Preparative Compound 60: Tert-butyl N-r4-rr4-amino-5-(2,6-dichlorobenzoyl) thiazol-2-vnaminol-trans-cyclohexyncarbamate

The method of preparative compound 3 Tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using cyanamide (0.930g, 22.12mmol), potassium tertiary butoxide (1 M in THF) (2.48g, 22.12mmol), N-(trans-4-isothiocyanatocyclohexyl) carbamate (4.73g, 18.44 mmol) and 2-bromo-1-(2,6-dichlorophenyl)ethanone (4.94g, 18.44 mmol) to give title compound. Product confirmed by LCMS M+H 486 and ¹ H NMR 400MHz (DMSO-d6) δ 8.65 (1 H, br, s, NH), 8.02 (2 H, br, s, NH ₂ ), 7.54 (1 H, d, J = 1.2 Hz, ArH), 7.42 (1 H, d ArH), 7.46 - 7.42 (1 H, dd, J = 9,7.1 , ArH), 6.71 (1 H, d, J = 8.1 , NH), 3.62 (1 H, br, CHN), 3.19 (1 H, br, CHN), 1.92 (2 H, m, cyclohexyl CH ₂ ), 1.78 (2 H, m, cyclohexyl CH ₂ ), 1.39 (9H, s, ^l Bu), 1.14 - 1.32 (4H, m, cyclohexyl CH ₂ ). Preparative Compound 61 : r4-amino-2-r(trans-4-aminocvclohexyl)amino1thiazol-5- vn-(2,6-dichlorophenyl)methanone

Tert-butyl-N-[4-[[4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-y l]amino]cyclohexyl]carbamate (8.38g, 17.26mmol) was added to DCM (100 mL) at room temperature with stirring. 4M HCI in dioxane (6.29g, 172.65mmol) was then added and the reaction was stirred at room temperature for 12 hours resulting in a white precipitate. This was filtered and washed with DCM (50 mL). The solid was added to 5% sodium carbonate solution (200 mL) and DCM (250 mL) and stirred until dissolved. DCM was separated then aqueous solution extracted with DCM (4 x 100 mL). DCM extracts were combined and washed with brine (50 mL) and dried over sodium sulphate and concentrated under reduced pressure to give title compound as a beige solid. Product confirmed by LCMS M+H 386 and ¹ H NMR 400MHz (DMSO-d6) δ 8.50 (1 H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.51 (1 H, d, J = 1.2 Hz, ArH), 7.49 (1 H, d, ArH), 7.41 (1 H, dd, J = 7.1 , 8.9 Hz, ArH), 3.64 (1 H, br, CHN), 1.88 (2 H, m, cyclohexyl CH ₂ ), 1.75 (2 H, m, cyclohexyl CH ₂ ), 1.23 (2 H, m, cyclohexyl CH ₂ ), 1.05 (2 H, m, cyclohexyl CH ₂ ).

Preparative Compound 62: 4-(Azetin-1 -ylmethyl)-2,6-difluorobenzonitrile

The method of preparative compound 36, 4-((dimethylamino)methyl)-2,6- difluorobenzonitrile was used using 2,6-difluoro-4-formyl-benzonitrile (4.57g, 27.37mmol), azetidine (5.0g, 87.58mmol) and sodium triacetoxyborohydride (13.68g, 57.74mmol) to give title compound as a yellow liquid. Product confirmed by NMR 500MHz (CDCIs) δ 10.7 (1 H, br, CHO), 7.03 (2 H, d, ArH), 3.71 (2 H, s, benzyl CH ₂ N), 3.36 (4 H, t, J = 7.3 Hz, azetidine CH ₂ N), 2.18 (2 H, tt, J = 7.1 , 7.1 Hz azetidine CH ₂ ). Preparative Compound 63: 4-(Azetin-1 -ylmethyl)-2,6-difluorophenyl)ethanone

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 4-(azetin-1-ylmethyl)-2,6-difluorobenzonitrile (1.06g, 5.08mmol) and a 3M solution of methyl magnesium bromide (3.38mL, 10.15mmol). Product was purified by silica column chromatography using Combiflash® RF automated purification system to give title compound as an oil. Product was confirmed by LCMS M+H 226 (R _t 0.21 min.) and ¹ H NMR 400MHz, (CDCI ₃ ) δ 6.93 (2 H, d, ArH), 3.57 (2 H, s, CH ₂ N), 3.25 (4 H, t, J = 7.1 Hz, azetidine CH ₂ ), 2.60 (3 H, s, COMe), 2.13 (2 H, tt, J = 7.04, azetidine CH ₂ ).

Preparative Compound 64: 1 -(4-(azetidine-1 -ylmethyl)-2,6-difluorophenyl-2- bromoethan-1 -one hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 4-(azetin-1-ylmethyl)-2,6- difluorophenyl)ethanone (0.220g, 0.98mmol), molecular bromine (0.171g, 1.07mmol) and hydrogen bromide as a solution in 33% acetic acid (5.99g, 24.42mmol) to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 307 (R _t = 0.32 min.).

Preparative Compound 65: 1 -(3,5-dichlorophenyl)-N, N-dimethylmethanamine

1 ,3-Dichloro-5-(chloromethyl)benzene (5g, 20.46mmol) was dissolved in 33% dimethylamine in EtOH (20ml_, 1 12mmol) and heated under microwave conditions at 100°C for 20min. Reaction was concentrated under reduced pressure and DCM (100ml_) added. DCM was washed with 5% sodium carbonate (20ml_) and DCM dried over MgS0 ₄ and concentrated under reduced pressure to give a brown liquid. Title compound confirmed by ¹ H NMR 500 MHz (CDCI ₃ ) δ 7.26 (1 H, s, ArH), 7.23 (2 H, s, ArH), 3.37 (2 H, s, benzyl CH ₂ N), 2.25 (6 H, s, NMe ₂ ). Preparative Compound 66: 2,6-dichloro-4-((dimethylamino)methyl) benzaldehyde

1-(3,5-dichlorophenyl)-N,N-dimethyl-methanamine (5.15g, 25.22mmol) was dissolved in THF (50ml_) under N ₂ and cooled to -78°C with stirring. N-butyl lithium (1.6M in hexanes) (10m L, 25.22mmol) was then added dropwise and reaction stirred at -78°C for 30min. DMF (5.8ml_, 75.65mmol) was then added and reaction stirred for a further 30 min. at -78°C. Water (50ml_) was added and extracted with DCM (100ml_). DCM was dried over MgS0 ₄ and concentrated under reduced pressure. Product was purified by silica column chromatography on silica using Combiflash® RF automated purification system to give title compound as a liquid. Product confirmed by ¹ H NMR 500 MHz (CDCIa) δ 10.46 (1 H, s, CHO), 7.37 (2 H, s, ArH), 3.41 (1 H, s, benzyl CH ₂ N), 2.24 (6 H, s, NMe ₂ ).

Preparative Compound 67: 1 -(2,6-dichloro-4-((dimethylamino)methyl)phenyl)ethan -I -0I

2,6-Dichloro-4-[(dimethylamino)methyl]benzaldehyde (1.38g, 5.92mmol) was dissolved in THF (10ml_) under N ₂ and cooled to 0°C. 3M Methyl magnesium bromide (2.37ml_, 7.1 mmol) was then added dropwise and reaction stirred at 0°C for 30min. 1 M HCI (5ml_) was then added and reaction extracted with DCM (50ml_) and dried over MgS0 ₄ and concentrated under reduced pressure to give title compound as a solid. Product confirmed by 1 H NMR 400 MHz (CDCI ₃ ) δ 7.28 (2 H, s, ArH), 5.58 (1 H, q, J = 6.6Hz, CHMeOH), 3.36 (2 H, s CH ₂ N), 3.05 (1 H, br, s, OH), 2.25 (6 H, s, NMe ₂ ), 1.66 (3 H, d, J = 6.8Hz, CH/WeOH). Preparative Compound 68: 1 -(2,6-dichloro-4-((dimethylamino)methyl) phenvPethan -1 -one

1-[2,6-Dichloro-4-[(dimethylamino)methyl]phenyl]ethan-1-o l (2.5g, 10.05mmol) was dissolved in DCM (100ml_) at room temperature then Dess-Martin periodinane (DMP) (4.69g, 11.06mmol) added and reaction stirred for 12 hours. Reaction was diluted with DCM (50ml_) and washed with 5% sodium carbonate (30ml_) then dried over MgS0 ₄ and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash® automated purification system to give title compound as an oil. Product was confirmed by LCMS M+H 248 (R _t 0.63) and ¹ H NMR 500MHz (CDCIa) δ 7.32 (2 H, s, ArH), 3.40 (2 H, s, CH ₂ N), 2.60 (3 H, s, COMe), 2.27 (6 H, NMe ₂ ).

Preparative compound 69: 2-Bromo-1 -(2,6-dichloro-4-((dimethylamino)methyl) phenyl)ethan-1 -one hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-(2,6-di-chloro-4- ((dimethylamino)methyl)phenyl)ethan-1-one (0.610g, 2.48mmol), molecular bromine (0.140ml_, 2.73mmol) and hydrogen bromide as a solution in 33% acetic acid (10ml_, 150mmol) to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 326 (R _t = 0.59 min.). Preparative compound 70: Tert-butyl-(4-cvano-3,5-diflurophenethyl)carbamate

4-Bromo-2,6,-diflurobenzonitrile (0.537g, 2.46mmol), [1 , 1 -bis(diphenylphosphino) ferrocene]palladium(ll) dichloride (0.1g, 0.12mmol), caesium carbonate (2.4g, 7.39mmol) and potassium tert-butyl-N-[2-(trifluoroboranuidyl)ethyl] carbamate (0.68g, 2.71 mmol) were added to toluene (15ml_) and water (2ml_) and heated at 80°C for 12 hours. Reaction was cooled and washed with saturated ammonium chloride (20ml_), extracted with DCM (100ml_) and dried over MgS0 ₄ and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash® automated purification system to give title compound as a white solid. Product was confirmed by ¹ H NMR 400MHz, (CDCI ₃ ) δ 6.93 (2 H, d, ArH), 4.60 (1 H, br, NH), 3.40 (2 H, m, CH ₂ N), 2.89 (2 H, t, benzyl CH ₂ ), 1.46 (9 H, s, tert-butyl).

Preparative compound 71 : 4-(2-aminoethyl)-2,6-difluorobenzonitrile

Tert-butyl-(4-cyano-3,5-diflurophenethyl)carbamate 0.40g, 1.42mmol) was added to DCM (100ml_) with 4 M HCI in dioxane (3.5ml_, 14.14mmol) and resulting suspension stirred for 12 hours at room temperature. The resulting white precipitate was filtered and washed with DCM (20ml_). The solid was added to 5% sodium carbonate (200ml_) then DCM (200ml_) added. This was stirred until solid fully dissolved. DCM was then separated and the aqueous layer was further extracted with DCM (200ml_). All DCM extracts were combined, dried over MgS0 ₄ and concentrated under reduced pressure to give title compound as a solid. Product was confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 6.93 (2 H, d, ArH), 3.01 (2 H, t, J = 6.8Hz, CH ₂ N), 2.81 (2 H, J = 6.8Hz, benzyl CH ₂ ), 1.24 (2 H, br, NH ₂ ).

Preparative compound 72: 4-(2-(dimethylamino)ethyl-2,6-difluorobenzonitrile

4-(2-Aminoethyl)-2,6-difluorobenzonitrile (0.45g, 2.47mmol) was added to formic acid (5ml_, 132mmol) with para-formaldehyde powder (0.371 g, 12.35mmol) and heated under N ₂ at 100°C for 12 hours. Reaction was basified with 2M NaOH then extracted with ethyl acetate (100ml_). Extracts were then washed with brine (50ml_), dried over MgS0 ₄ and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash® automated purification system to give title compound as an orange oil. Product was confirmed by LCMS M+H 21 1 (R _t = 0.15min.) and ¹ H NMR 500MHz, (CDCI ₃ ) δ 6.94 (2 H, d, ArH), 2.84 (2 H, t, J = 7.4Hz, CH ₂ N), 2.56 (2 H, t, J = 7.5Hz, benzylCH ₂ ), 2.28 (6 H, s, NMe ₂ ). Preparative compound 73: 1 -(4-(2-(dimethylamino)ethyl-2-6-difluorophenyl)ethan-

1 -one

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 4-(2-(dimethylamino)ethyl)-2,6- difluorobenzonitrile (0.27g, 1.28mmol) and a 3M solution of methyl magnesium bromide (0.856ml_, 2.26mmol). Product was purified by silica column chromatography using Combiflash® RF automated purification system to give title compound as an oil. Product was confirmed by ¹ H NMR 500MHz, (CDCI ₃ ) δ 6.82 (2 H, d, ArH), 2.77 (2 H, t, J = 7.6Hz, CH ₂ N), 2.57 (3 H, m, COMe), 2.54 (2 H, t, J = 7.7Hz benzyl CH ₂ ), 2.28 (6 H, s, NMe ₂ ).

Preparative Compound 74: 2-bromo-1 -(4-(2-(dimenthylamino)ethyl-2,6- difluorophenyl)ethan-1 -one hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-(4-(2-(dimethylamino)ethyl-2- 6-difluorophenyl)ethan-1-one (0.130g, 0.57mmol), molecular bromine (0.10g, 0.63mmol) and hydrogen bromide as a solution in 33% acetic acid (3ml_, 34.67mmol to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 308 (R _t = 0.78 min.).

Preparative compound 75: 1 -(3,5-dichlorobenzyl)azetidine

1 ,3-Dichloro-5-(chloromethyl)benzene (5.25g, 26.84mmol) and azetidine (5.08g, 89.02mmol) were dissolved in DMF (10ml_) and stirred at room temperature for 12 hours. DMF was removed under reduced pressure and DCM (100ml_) added. DCM was washed with 5% sodium carbonate and brine then DCM dried via hydrophobic filter and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash® automated purification system to give title compound as a clear liquid. Product was confirmed by LCMS M+H 217 (R _t = 0.41 min.) and ¹ H NMR 400MHz (CDCI ₃ ) δ 7.19 (2 H, s, ArH), 3.52 (2 H, s, benzyl CH ₂ N), 3.23 (4 H, t, J = 7.0Hz, azetidine CH ₂ N), 2.1 1 (2 H, tt, J = 7.0, 6.96Hz, azetidine CH ₂ ).

Preparative Compound 76: 4-(azetidine-1 -ylmethyl)-2,6-dichlorobenzaldehyde

The method of preparative compound 66, 2,6-dichloro-4-((dimethylamino)methyl) benzaldehyde was used using 1-(3,5-dichlorobenzyl)azetidine (2.76g, 12.75mmol), n- butyl lithium (5.6ml_, 14.03mmol) and DMF (2.96ml_, 38.26mmol) to give title compound as a clear liquid. Product conformed by ¹ H NMR 500MHz (CDCI ₃ ) δ 10.48 (1 H, s, CHO), 7.34 (2 H, s, ArH), 3.58 (2 H, s, benzyl CH ₂ N), 3.27 (4 H, t, J = 7.1 Hz, azetidine CH ₂ N), 2.14 (2 H, tt, J = 7.0, 7.0Hz, azetidine CH ₂ ), Preparative Compound 77: 1 -(4-(azetidine-1 -ylmethyl)-2,6-dichlorophenyl)ethan-1 - ol

The method of preparative compound 67, 1-(2,6-dichloro-4-((dimethylamino)methyl) phenyl)ethan-1-one was used using 4-(azetidine-1-ylmethyl)-2,6-dichlorobenzaldehyde (2.45g, 10.05mmol) and 3M methyl magnesium bromide (3.69ml_, 11.06mmol) to give title compound as an oil. Product was confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 7.23 (2 H, s, ArH), 5.57 (1 H, q, J = 6.7Hz, CHMeOH), 3.50 (2 H, s, benzylic CH ₂ N), 3.23 (4 H, t, J = 7.03Hz, azetidine CH ₂ N), 2.12 (2 H, tt, J = 7.0, 6.9Hz, azetidine CH ₂ ), 1.64 (3 H, d, J = 6.6Hz, CH/WeOH). Preparative Compound 78: 1 -(4-(azetidine-1 -ylmethyl-2,6-dichlorophenyl)ethan-1 - one

The method of preparative compound 68, 1-(2,6-dichloro-4-((dimethylamino)methyl) phenyl)ethan-1-one was used using 1-(4-(azetidine-1-ylmethyl)-2,6-dichlorophenyl) ethan-1-ol (1.58g, 6.08mmol) and Dess Martin periodinane (DMP) (2.84g, 6.69mmol) to give title compound. Product confirmed ¹ H NMR 400MHz (CDCI ₃ ) δ 7.23 (2 H, s, ArH), 3.51 (2 H, s, benzyl CH ₂ N), 3.21 (4 H, t, J = 6.8Hz, azetidine CH ₂ N), 2.54 (3 H, s, COMe), 2.09 (2 H, tt, J = 7.0, 6.9Hz, azetidine CH ₂ ).

Preparative Compound 79: 1 -(4-(azetidine-1 -ylmethyl)-2,6-dichlorophenyl-2- bromoethan-1 -one hydrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-(4-(azetidine-1-ylmethyl-2,6- dichlorophenyl)ethan-1-one (0.177g, 0.69mmol), molecular bromine (0.035mL, 0.69mmol) and hydrogen bromide as a solution in 33% acetic acid (0.840g, 3.34mmol) to give title compound as a brown solid. The solid was confirmed as desired product by LCMS M+H 338 (R _t = 1.07 min.). Preparative Compound 80: N-trans-(4-aminocvclohexyl)tetrahydrofuran-3- sulphonamide

Cyclohexane-1 ,4-diamine (1.0g, 8.75mmol) was added to DCM (50ml_) with triethylamine (2.44mL, 17.52mmol) at room temperature. A solution of tetrahydrofuran-3-sulphonyl chloride (0.747g, 4.37mmol) in DCM (10ml_) was added dropwise and reaction stirred for 12 hours. Reaction was diluted with DCM and washed with water (20ml_) DCM dried via hydrophobic filter and concentrated under reduced pressure. Product was purified by silica column chromatography using Combiflash® automated purification system to give the title compound as a solid. Product confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 3.99 (2 H, m, tetrahydrofuran CH ₂ ), 3.90 (1 H, m, tetrahydrofuran CH ₂ ), 3.77 (1 H, m, tetrahydrofuran CH ₂ ), 3.68 (1 H, m, CHN), 3.19 (1 H, m, CHN), 2.59 (1 H, m, tetrahydrofuran CH), 2.22 (2 H, m, tetrahydrofuran CH ₂ ), 1.97 (2 H, m, cyclohexyl CH ₂ ), 1.82 (2 H, m, cyclohexyl CH ₂ ), 1.62 (2 H, br, NH ₂ ), 1.18 (4 H, m, cyclohexyl CH ₂ ). Preparative Compound 81 : N-trans-(4-isothiocvanatocvclohexyl) tetrahydrofuran-

3-sulphonamide

The method of preparative compound 1 tert-butyl-N-trans-(4-isiothiocyanatocyclohexyl) carbamate was used using N-trans-(4-aminocyclohexyl) tetrahydrofuran-3-sulphonamide (0.450g, 1.81 mmol), di-(imidazole-1-yl)methanethione (0.355g, 1.99mmol) to give title compound as a solid. Product confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 4.14 (1 H, d, NH), 4.08 (2 H, m, tetrahydrofuran CH ₂ ), 4.0 (1 H, m, tetrahydrofuran CH), 3.87 (1 H, m, tetrahydrofuran CH), 3.77 (1 H, tetrahydrofuran CH), 3.60 (1 H, m, CHN), 3.41 (1 H, m, CHN), 2.31 (2 H, m, tetrahydrofuran CH ₂ ), 2.15 (4 H, m, cyclohexyl CH ₂ ), 1.69 (2 H, m, cyclohexyl CH ₂ ), 1.37 (2 H, cyclohexyl CH ₂ ). Preparative Compound 82: 2,6-difluoro-4-(((4-methoxybenzyl)(methyl)amino) methvPbenzonitrile

The method of preparative compound 36, 4-(dimethylamino)methyl)-2,6- difluorobenzonitrile was used using 2,6-difluoro-4-formyl-benzonitrile (2.0g, 11.97mmol), 1-(4-methoxyphenyl)-N-methyl methanamine (3.62g, 23.94mmol) and sodium triacetoxyborohydride (6.34g, 29.92mmol) to give title compound as a yellow oil. Product confirmed by LCMS M+H 303 (R _t = 1.33min.) and ¹ H NMR 400MHz (CDCI ₃ ) δ 7.27 (2 H, d, J = 8.4Hz, ArH), 7.12 (2 H, d, J = 8.4Hz, ArH), 6.89 (2 H, d, J = 7.8Hz, ArH), 3.83 (3 H, s, OMe), 3.52 (4 H, s, benzyl CH ₂ ), 2.22 (3 H, s, NMe). Preparative Compound 83: 1 -(2,6-difluoro-4-(((4-mehtoxybenzyl)(methyl)amino) methyl)phenyl)ethane-1 -one

The method of preparative compound 38, 1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone was used using 2,6-difluoro-4-(((4-methoxybenzyl) (methyl)amino)methyl)benzonitrile (2.25g, 7.44mmol) and a 3M solution of methyl magnesium bromide (3.73ml_, 1 1.17mmol). Product was purified by silica column chromatography using Combiflash® RF automated purification system to give title compound as an oil. The product was confirmed LCMS M+H 320 (R _t =1.51 min.) and ¹ H NMR 400MHz, (CDCI ₃ ) δ 7.28 (2 H, d, J = 7.0Hz ArH), 7.0 (2 H, d, J = 9.3Hz, ArH), 6.90 (2 H, d, J = 7.5Hz, ArH), 3.83 (3 H, s, OMe), 3.51 (2 H, s, benzyl CH ₂ ), 3.48 (2 H, s, benzyl CH ₂ ), 2.61 (3 H, s, COMe), 2.20 (3 H, s, NMe).

Preparative Compound 84: 2-bromo-1 -(2,6-difluoro-4-(((4-methoxybenzyl)methyl) amino)methyl)phenyl)ethan-1 -one hvdrobromide

The method of preparative compound 29, 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide was used using 1-(2,6-difluoro-4-(((4- methoxybenzyl)(methyl)amino)methyl)phenyl)ethane-1-one (0.555g, 1.74mmol), molecular bromine (0.089ml_, 1.74mmol) in hydrogen bromide, 33wt% in acetic acid (2.13g, 8.69mmol) to give title compound as an orange gum. The product was confirmed by LCMS M+H 400 (R _t = 1.68 min).

Preparative Compound 85: N-trans-4-((4-amino5-(2,6-difluoro-4-(((4-methoxy benzyl)methyl)amino)methyl)benzoyl)thiazol-2-yl)amino)cvcloh exyl)-2-methyl propane-1 -sulphonamide

The method of Preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.450g, 1.74mmol), cyanamide (0.088g, 2.08mmol), 1 M potassium tertiary butoxide 1 M solution in THF (2.25ml_, 2.25mmol) and 2-bromo-1-(2,6-difluoro-4-(((4-methoxybenzyl)methyl) amino)methyl)phenyl)ethan-1-one hydrobromide (0.832g, 1.74mmol) to give title compound as a yellow solid. Product was confirmed by LCMS M+H 636 (R _t = 1.71 min.) and ¹ H NMR 400MHz, (CDCI ₃ ) δ 7.29 (2 H, d, J = 6.5Hz, ArH), 6.98 (2 H, s, J = 7.6Hz, ArH),6.90 (2 H, d, J = 8.1 Hz, ArH), 5.54 (1 H, d, J = 7.9Hz, NH), 4.09 (1 H, br, CHN), 3.84 (3 H, s, OMe), 3.51 (2 H, s, benzyl CH ₂ ), 3.48 (2 H, s, benzyl CH ₂ ), 3.29 (2 H, br, NH ₂ ), 2.51 (1 H, m, azetidine CH ₂ ) 2.20 (1 H, m, CHMe ₂ ), 2.08 (4 H, br m, cyclohexyl CH), 2.92 (2 H, d, J = 6.5Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.22 (3 H, s, NMe), 2.15 (4 H, m, cyclohexyl CH ₂ ) 1.36 (4 H, m, cyclohexyl CH ₂ ), 1.12 (6 H, d, J = 6.8Hz, CH/We ₂ ).

Preparative compound 86: tert-butyl (3,5-difluorobenzyl)carbamate

To a solution of 3,5-difluorobenzaldehyde (20.00 g, 140.75 mmol, 15.38 mL) in CH ₃ CN (400ml_) was added Et ₃ SiH (49.10 g, 422.24 mmol) and TFA (32.10 g, 281.49 mmol). The reaction was stirred at 75 °C for 16 h. Saturated sodium bicarbonate solution (250ml_) was added then the CH ₃ CN was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate (300ml_). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by silica column chromatography to give the title compound as a white solid. Product was confirmed by ¹ H NMR 300MHz (CDCI ₃ ) δ 6.79 (2 H, d, ArH), 6.71 (1 H, m, ArH), 4.94 (1 H, br, NH), 4.30 (2 H, d, benzyl CH ₂ N), 1.47 (9 H, s, tert-butyl). Preparative Compound 87: 2,4-dichlorothiaqzole-5-carbaldehyde

To a solution of thiazolidine-2,4-dione (100g, 853.75 mmol) in POCI ₃ (876.24 g, 5.71 mol) was added DMF (124.80 g, 1.71 mol) in one portion at 0°C. Then degassed and purged with N ₂ for 3 times. The mixture was stirred at 60°C for 1 hr, and then stirred at 110°C for 4 hrs. The mixture was cooled to 20°C and concentrated under reduced pressure. The residue was poured into water (3 L) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (6L). The combined organic phase was washed with brine (2 L), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The product was purified by silica column chromatography to give title compound as a yellow solid. Product was confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 9.97 (1 H, s, CHO).

Preparative Compound 88: tert-butyl-(4-((2,4-dichlorothiazol5-yl)(hvdroxy)methyl)-

3,5-difluorobenzyl)carbamate

To a solution of tert-butyl N-[(3,5-difluorophenyl)methyl]carbamate (0.300g, 1.23 mmol) in THF (5m L) was added tetramethylethylenediamine (TMEDA) (0.357g, 3.08 mmol). The mixture was stirred at -78°C for 30 min. To the reaction was added n-Butyl lithium (2.5 M, 1.23 ml_, 6.16mmol) dropwise. The mixture was stirred at -78°C for 1 h. Then 2,4-dichlorothiazole-5-carbaldehyde (0.269g, 1.48 mmol) dissolved in THF (3m L) was added and reaction stirred at 0°C for i hr. Saturated NH ₄ CI (10ml_) was added mixture extracted with EtOAc (20 ml_). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The product was purified by silica column chromatography to give title compound as a yellow solid. Product was confirmed by ¹ H NMR 400MHz (DMSO-d6) δ 7.49 (1 H, t, NH), 7.12 (1 H, d, OH), 6.94 (2 H, d, ArH), 6.14 (1 H, d, CHOH), 4.12 (2 H, d, benzyl CH ₂ N), 1.36 (9 H, s, tert-butyl). Preparative compound 89: tert-butyl(4-(2,4-dichlorothiazole-5-carbonyl)-3,5- difluorobenzvDcarbamate

To a solution of tert-butyl-(4-((2,4-dichlorothiazol5-yl)(hydroxy)methyl)-3,5 -difluorobenzyl) carbamate (0.570g, 1.34 mmol) in CHCI ₃ (12ml_) was added Dess-Martin Periodinane (DMP) (1.14 g, 2.68 mmol). The mixture was stirred at 15°C for 30min. Saturated Na ₂ S0 ₃ (10mL) was added then extracted with DCM (60 ml_), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Product purified by silica column chromatograph to give title compound as a yellow solid. Product was confirmed by ¹ H NMR 400MHz (DMSO-d6) δ 7.55 (1 H, t, NH), 7.17 (2 H, d, ArH), 4.23 (2 H, d, benzyl CH ₂ N), 1.40 (9 H, s, tert-butyl).

Preparative Compound 90: tert-butyl-(4-(4-chloro-2-trans-((2-methylpropyl) sulphonamido)cvclohexyl)amino)thiazole-5-carbonyl)-3,5- difluorobenzvPcarbamate

To a solution of tert-butyl(4-(2,4-dichlorothiazole-5-carbonyl)-3,5-difluorob enzyl) carbamate (0.350g, 0.83 mmol) in dioxane (10ml_) was added N-(4-aminocyclohexyl)-2- methyl-propane-1 -sulfonamide (0.349g, 1.49 mmol). The mixture was stirred at 100 °C for 16 hr. Dioxane was removed under reduced pressure and residue purified by silica column chromatograph to give title compound as a yellow solid. Product was confirmed by LCMS M+H 622 (R _t = 0.91 min.) and ¹ H NMR 300MHz (DMSO-d6) δ 9.31 (1 H, br, NHS0 ₂ ), 7.52 (1 H, d, NHBoc), 7.06 (2 H, d, ArH), 4.17 (2 H, d, benzyl CH ₂ N), 2.89 (1 H, br, CHN), 2.50 (2 H, d, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 1.96 (4 H, m, cyclohexyl CH ₂ ), 1.39 (9 H, s, tert-butyl), 1.33 (4 H, cyclohexyl CH ₂ ), 1.02 (6 H, d, CH/We ₂ ).

Preparative Compound 91 : tert-butyl-(4-amino-2-(((trans)-4-((2-methylpropyl) sulphonamido)cvclohexyl)amino)thiazole-5-carbonyl)-3,5- difluorobenzvPcarbamate

To a solution of tert-butyl-(4-(4-chloro-2-trans-((2-methylpropyl)sulphonamid o) cyclohexyl)amino)thiazole-5-carbonyl)-3,5-difluorobenzyl)car bamate (0.280 mg, 0.45mmol) in EtOH (3.00 ml_) was added NH ₃ .H ₂ 0 (1.90 g, 13.52 mmol). The reaction was stirred at 85°C for 16 hr. The mixture was washed with water (10 ml_), and extracted with EtOAc (30ml_). The combined extracts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure to give title compound as a yellow solid. Product was confirmed by LCMS M+H 602 (R _t = 0.84min).

Preparative Compound 92: 1 -(3,5-difluorophenyl)-N.N-dimethylmethanamine

To the solution of triethylamine (42.73 g, 422.24 mmol) in EtOH (300ml_) was added dimethylamine hydrochloride (34.43 g, 422.24 mmol) and titanium isopropoxide (120g, 422.24 mmol) followed by 3,5-difluorobenzaldehyde (30.00 g, 211.12 mmol) and the resulting mixture stirred for 18h at 25-35°C. Sodium triacetoxyborohydride (67.12 g, 316.68 mmol) then was added and reaction stirred for 18h at 25-35°C. The reaction mixture was poured into aq. sodium bicarbonate solution (1 L) then extracted with DCM (1.5L). The organic extracts were combined and concentrated under reduced pressure. 1 M HCI (200ml_) was added and washed with methyl tert-butyl ether (400ml_), the aq. layer was based to pH=8~9 with sodium bicarbonate and extracted with DCM (500ml_). Combined organic extracts were dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give title compound as a yellow liquid. Product was confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 6.87 (2 H, dd, = 2.1 , 8.2 Hz, ArH), 6.76 - 6.64 (1 H, m, ArH), 3.40 (2 H, s, benzyl CH ₂ N), 2.25 (6 H, s, NMe ₂ ).

Preparative compound 93: (2,4-dichlorothiazol-5-yl)(4-((dimethylamino)methyl)-2,6- difluorophenvPmethanol

The method of preparative compound 88 tert-butyl-(4-((2,4-dichlorothiazol-5- yl)(hydroxy)methyl)-3,5-difluorobenzyl)carbamate was used using 2,4-dichlorothiazole-5- carbaldehyde (5.0g, 29.21 mmol), TMEDA (6.79g, 58.42mmol), n-butyl lithium 2.5 M (23.37ml_, 56.42mmol) and 1-(3,5-difluorophenyl)-N.N-dimethylmethanamine (5.32g, 29.21 mmol) to give title compound as a yellow solid. Product confirmed by LCMS M+H 353 (R _t = 0.58min.). Preparative compound 94: N-trans-4-((4-chloro-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cvclohexyl)-2-methylpropa ne-1 -sulphonamide

To the solution of (2,4-dichlorothiazol-5-yl)(4-((dimethylamino)methyl)-2,6-dif luorophenyl) methanol (2.70 g, 7.64 mmol) in DCM (54ml_) and THF (13ml_) was added DMP (6.48 g, 15.28 mmol). The resulting mixture was stirred for 1 h at 25-35 °C. The reaction mixture was washed with aq. sodium bicarbonate solution (30ml_). Dioxane (25 ml_) and N-((trans)-4-aminocyclohexyl)-2-methylpropane-1-sulphonamide (3.34 g, 14.24 mmol) were added to the organic layer then the reaction mixture was heated to 100-1 10 °C for 2h. The reaction mixture was diluted with EtOAc (100ml_) and washed with aq. sodium bicarbonate solution (40ml_). The EtOAc was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Product was purified by silica column chromatography to give title compound as a yellow solid. Product was confirmed by ¹ H NMR 400MHz (CDCI ₃ ) δ 7.02 - 6.84 (2 H, m, ArH), 4.42 - 4.26 (1 H, m, CHN), 3.68 (2 H, t, J = 6.5 Hz, benzyl CH ₂ N), 3.24 (1 H, m, CHN), 2.85 (2 H, d, J = 6.5 Hz, CH ₂ S0 ₂ N), 2.23 - 2.18 (6 H, s, NMe ₂ ), 2.15 - 1.95 (5 H, m, CHMe ₂ , cyclohexyl CH ₂ ), 1.43 - 1.28 (4 H, m, cyclohexyl CH ₂ ), 1.06 - 1.03 (6 H, d, J = 6.8Hz, CH/We ₂ ).

Example Compound 1 : N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- cis-cyclohexyn-2-methyl-propane-1 -sulfonamide

[4-Amino-2-[(cis-4-aminocyclohexyl)amino]thiazol-5-yl]-(2 ,6-difluorophenyl)methanone (0.352g, 1 mmol) was dissolved in DMF (20ml_) with isobutylsulphonyl chloride (0.172g, 1.1 mmol) and caesium carbonate (0.489g, 1.5mmol) and heated at 65°C for 12 hrs. Reaction was diluted with DCM then washed with 1 M HCI and sat. Sodium chloride. DCM was dried over magnesium sulphate and concentrated under reduced pressure. Product was purified by silica column chromatography (DCM - 15% MeOH gradient elution) to give title compound as a solid. Product confirmed by LCMS M+H 473 (R _t =5.05min.) and ¹ H NMR (500 MHz DMSO-d ₆ ) δ 8.62 (1 H, br s, NH), 8.07 (2 H, s, NH ₂ ), 7.50 (1 H, m, J = 15Hz, ArH), 7.16 (2 H, m, J = 7.8Hz, ArH), 7.01 (1 H, d, J = 6.2Hz, NH), 3.64 (1 H, br, CHN), 3.07 (1 H, br, CHN) 2.90 (2 H, d, CH ₂ S0 ₂ N), 2.08 (1 H, m, CH(CH ₃ ) ₂ ), 1.91 (4 H, cyclohexyl CH), 1.31 (4 H, cyclohexyl CH), 1.03 (6 H, d, CH(CH ₃ ) ₂ ).

Example Compound 2: r(2R)-3-rr4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2- vnaminol-trans-cvclohexynsulfamovn-2-methyl-propyn acetate

[4-Amino-2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]- (2,6-difluorophenyl) methanone (0.4g, 1.1351 mmol) was dissolved in a mixture of DCM (8ml_) and DMF (2ml_) with DIPEA (0.220g,1.7026mmol) at R.T. [(2R)-3-chlorosulfonyl-2-methyl-propyl] acetate (0.366, 1.7026mmol) was then added drop wise and reaction stirred overnight at R.T. Deionized water (10ml_) was added and reaction mixture extracted with DCM (2 x 25ml_ and dried using magnesium sulphate. Product was purified by silica column chromatography using Combiflash RF ^® automated purification system (Hexane - 10%- 100% EtOAc gradient elution) to give a gum. The solid was confirmed as desired product by LCMS M+H 531 (R _t = 2.41 min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.62 (1 H, br, s, NH), 8.06 (2 H, br, s, NH2), 7.49 (1 H, m, J = 6.7 Hz, 16.8 Hz, ArH), 7.15 - 7.18 (3 H, m, J = 7.5 Hz, ArH, NH), 3.96 (2 H, m, J = 6.2 Hz, 6.3 Hz, OCH ₂ ), 3.64 (1 H , br, s, CHN), 3.08 - 3.17 (2 H, m, J = 5.05 Hz, 4.9 Hz, CHN, CHMe), 2.89 (2 H, dd, J = 7.5 Hz, CH ₂ S0 ₂ HN), 2.26 (1 H, m, J = 18.6 Hz, 5.7 Hz, CHMe ₂ ), 2.02 (3 H, s, CH ₃ C0 ₂ ), 1.90 (4 H, m, cyclohexyl CH), 1.29 (4 H, m, J = 4.9 Hz, cyclohexyl CH), 1.05 (3 H, d, J = 6.8 Hz, CH/We). Aqueous solubility 100μg/mL. Example Compound 3: r(2S)-3-rr4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2- vnaminol-trans-cvclohexynsulfamovn-2-methyl-propyn acetate

The method of Example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]-trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone

(0.2g,0.5675mmol) and [(2S)-3-chlorosulfonyl-2-methyl-propyl] acetate (0.122g,0.5675mmol) as starting materials with DCM (8m L) and DMF (2ml_) and DIPEA (0.073g, 0.5675mmol) to give a yellow solid. The solid was confirmed as desired product by LCMS M+H 531 (R _t = 4.10 min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.62 (1 H, br, s, NH), 8.06 (2 H, br, s, NH2), 7.49 (1 H, m, J = 6.7 Hz, 16.8 Hz, ArH), 7.15 - 7.18 (3 H, m, J = 7.6 Hz, ArH, NH), 3.96 (2 H, m, J = 6.2 Hz, 6.3 Hz, OCH ₂ ), 3.64 (1 H, br, s, CHN), 3.08 - 3.12 (2 H, m, J = 4.9 Hz, 5 Hz, CHN, CHMe), 2.89 (2 H, dd, J = 7.4 Hz, CH ₂ S0 ₂ NH), 2.26 (1 H, m, J = 5.6 Hz, 18.8 Hz, CHMe ₂ ), 2.02 (3H, s, CH ₃ C0 ₂ ), 1.90 (4 H, m, cyclohexyl CH), 1.29 (4 H, m, cyclohexyl CH), 1.05 (3 H, d, J = 6.8 Hz, CH/We). Aqueous solubility 132μg/mL.

Example Compound 4: r3-rr4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cvclohexynsulfamovn-2,2-dimethyl-propyn acetate

The method of Example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]-trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone

(0.2g,0.5675mmol), (3-chlorosulfonyl-2,2-dimethyl-propyl) acetate (0.260g, 1.1351 mmol) and triethylamine (0.1 15g, 1.13mmol) in DCM (5mL) and DMF (1 ml_). Product was purified using Waters® automated mass directed preparative purification system to give a white solid. The solid was confirmed as desired product by LCMS M+H 545 (R _t = 4.19min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.62 (1 H, br, s, NH), 8.06 (2 H, br, s, NH ₂ ) 7.48 (1 H, m, J = 1.6 Hz, ArH), 7.18 (2 H, m, J = 15.7 Hz, ArH), 7.09 (1 H, d, NH), 3.92 (2 H, s, OCH ₂ ), 3.60 (1 H, br, m, CHN), 3.09 (1 H, br, m, CHN), 3.04 (2 H, s, CH ₂ S0 ₂ NH), 2.03 (3 H, s, MeC0 ₂ ), 1.92 (4 H, br, m, J = 1 1.5 Hz, cyclohexyl CH), 1.29 (4 H, br, m, J = 3.4 Hz, 7.5 Hz cyclohexyl CH), 1.09 (6 H, s, Me ₂ ). Aqueous solubility 136μg/mL.

Example Compound 5: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cvclohexyn-3-hvdroxy-2,2-dimethyl-propane-1 -sulfonamide.

[3-[[4-[[4-Amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amin o]-trans-cyclohexyl]sulfamoyl]- 2,2-dimethyl-propyl] acetate (0.04g,0.0734mmol) was dissolved in methanol (5ml_) at R.T. Sodium hydroxide (0.006g,0.1469mmol) was added in one portion and reaction stirred overnight at R.T. Reaction was diluted with DCM (20ml_) washed with deionized water, dried using magnesium sulphate and organics concentrated under reduced pressure to give a solid. The solid was confirmed as desired product by LCMS M+H 503 (R _t = 3.83min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.63 (1 H, br, s, NH), 8.06 (2 H, br, s, NH ₂ ), 7.47 (1 H, m, J = 1.5 Hz, ArH), 7.16 (2 H, m, J = 15.7 Hz, ArH), 6.99 (1 H, d, J = 7.3 Hz, NH), 4.70 (1 H, q, J = 5.4 Hz, OH), 3.64 (1 H, br, m, CHN), 3.17 - 3.20 (2 H, dd, J = 5.35 Hz, CH ₂ OH), 3.08 (1 H, br, m, CHN), 2.96 (2 H, s, CH ₂ S0 ₂ NH), 1.92 (4 H, br, m, J = 13.8 Hz, cyclohexyl CH), 1.26 (4 H, br, m, J = 9.9 Hz, cyclohexyl CH), 1.02 (6 H, s, Me ₂ ). Aqueous solubility 126μg/mL. Example Compound 6: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2,2,2-trifluoro-ethanesulfonamide

The method of Example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone (0.1g, 0.2838mmol), 2,2,2-trifluoroethanesulfonyl chloride (103.6mg,0.5675mmol) triethylamine (57.43g, 0.56mmol) in DCM (5ml_) and DMF (1 ml_). Product was purified using Waters® automated mass directed preparative purification system to give a yellow solid. Product confirmed by LCMS M+H 499 (R _t = 4.85min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.65 (1 H, br, m, NH), 8.06 (1 H, br, s, NH ₂ ), 7.78 (1 H, d, J = 7.6 Hz, ArH), 7.50 (1 H, m, J = 6.8 Hz, 16.7 Hz, ArH), 7.17 (2 H, t, J = 15.7 Hz, ArH, NH), 4.40 (2 H, q, J = 9.9 Hz, CH ₂ CF ₃ ), 3.64 (1 H, br, m, CHN), 3.19 (1 H, br, m, CHN), 1.74 - 2.05 (4 H, br, m, cyclohexyl CH), 1.18 - 1.40 (4 H, br, m, J = 9.2 Hz, cyclohexyl CH). Aqueous solubility 125 g/mL.

Example Compound 7: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-1 -tetrahvdrofuran-2-yl-methanesulfonamide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone

(0.118g,0.3348mmol), with DIPEA (0.065g,0.5023mmol)and tetrahydrofuran-2- ylmethanesulfonyl chloride (0.093g,0.5023mmol) in DCM (5m L) and DMF (2m L). Product was purified using Waters® automated mass directed preparative purification system to give a white solid. The solid was confirmed as desired product by LCMS M+H 501 (R _t = 4.65min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.65 (1 H, br, m, NH), 8.07 (2H, br, s, NH ₂ ), 7.50 (1 H, m, J = 6.7 Hz, 16.8 Hz, ArH), 7.13 - 7.20 (2H, m, J = 7.5 Hz, ArH), 7.02, (1 H, d, J = 7.3 Hz, NH), 4.12 (1 H, m, J = 12.9 Hz, CHN), 3.58 - 3.79 (2H, m, J = 3.6 Hz, 13.5.7 Hz, CHN, THF CH),3.12 - 3.28 (4 H, m, J = 5.9 Hz, 6.2Hz, CH ₂ S0 ₂ N, THF CH), 1.99 - 2.10 (1 H, m, THF.CH), 1.77 - 1.98 (6 H. br m, THF, CH, cyclohexyl CH), 1.59 - 1.74 (1 H, m, THF CH), 1.22 - 1.35 (4 H, m, J = 8.7 Hz, cyclohexyl CH). Aqueous solubility 125μg/mL.

Example Compound 8: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-1 -tetrahvdrofuran-3-yl-methanesulfonamide.

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2 yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone (0.1g,0.2838mmol), tetrahydrofuran-3-ylmethanesulfonyl chloride (0.105g,0.5675mmol) and triethylamine (54.43g, 0.567mmol) in DCM (5mL) and DMF (1 ml_). Product was purified using Waters® automated mass directed preparative purification system to give a solid. The solid was confirmed as desired product LCMS M+H 501 (R _t = 3.79min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.67 (1 H, br m, NH), 8.07 (2H, br s, NH ₂ ), 7.44 - 7.55 (1 H, m, , J = 6.7 Hz, 16.7 Hz, ArH), 7.10 - 7.21 (3H, m, J = 8.42 Hz, ArH, NH), 3.81 - 3.88 (1 H, m, = 1.0 Hz, 15.7 Hz, CHN), 3.58 - 3.77 (3 H, m, J = 1.0 Hz, 15.7 Hz, CHN, THF CH) 3.35 - 3.43(2 H, m, J = 15.8 Hz, THF CH), 3.04 - 3.18 (3 H, m, J = 6.4 Hz, 7.35 Hz, CH ₂ S0 ₂ N, THF CH), 2.03 - 2.15 (1 H, m, J = 7.5 Hz, 12.4 Hz, THF CH), 1.82 - 2.00 (4H, br m, cyclohexyl CH), 1.59 - 1.72 (1 H, m, 7.8 Hz, 19.1 Hz, THF CH), 1.21 - 1.39 (4 H, m, J = 8.7 Hz, cyclohexyl CH). Aqueous solubility 125μg/mL.

Example Compound 9: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cvclohexyntetrahvdropyran-4-sulfonamide

[4-Amino-2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]- (2,6-difluorophenyl) methanone (0.150g,0.4257mmol) was added to DCM (3m L) and DMF (1 ml_) with triethylamine (0.064g, 0.638mmol) at R.T. Tetrahydropyran-4-sulfonyl chloride (0.1 18g, 0.6385mmol) was then added drop wise and reaction mixture stirred overnight at R.T. Reaction mixture was then heated in a sealed (5m L) microwave vessel under microwave conditions at 70°C for 1 hr. Deionized water (5ml_) was added, organics separated and dried using Magnesium Sulphate and organics concentrated under reduced pressure. Product was purified using Waters® automated mass directed preparative purification system to give a solid. The solid was confirmed as desired product by LCMS M+H 501 (R _t = 3.55min.) and ¹ H NMR (500MHz DMSO-d ₆ ), 8.66 (1 H, br s, NH), 8.07 (2 H, br s, NH ₂ ), 7.49 (1 H, m, J = 6.8 Hz, 16.7Hz, ArH), 7.13 - 7.21 (2 H, J = 15.7 Hz, ArH, NH), 7.08 - 7.12 (1 H, d, J = 7.9 Hz, NH) 3.86 - 3.98 (2 H, m, J = 3.5 Hz, CHN, THP CH), 3.20 - 3.49 (4 H, m, THP CH), 3.08 (1 H, br m, CHN), 1.80 - 1.92 (6 H, br m, THP CH, cyclohexyl CH), 1.49 - 1.66 (2H, m, J = 12.1 Hz, THP CH), 1.20 - 1.39 (4 H br m, THP CH, cyclohexyl CH).

Example Compound 10: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-1 -isoxazol-3-yl-methanesulfonamide.

The method of Example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone

(0.150g,0.4257mmol), isoxazol-3-ylmethanesulfonyl chloride (0.1 16g,0.6385mmol) and triethylamine (0.065g, 0.638mmol) in DCM (3m L) and DMF (1 ml_). Product was purified using Waters® automated mass directed preparative purification system to give a yellow solid. The solid was confirmed as desired product by LCMS M+H 498 (R _t = 4.5min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.95 (1 H, d, J = 1.6 Hz, isoxazole CH), 8.65 (1 H, br d, NH), 8.08 (2 H, br s, NH ₂ ), 7.51 (1 H, m, J = 6.8 Hz, 16.8 Hz, ArH), 7.38 (1 H, br d, J = 7.5 Hz, NH), 7.12 - 7.21 (2 H, br m, J = 7.5Hz, ArH), 6.62 (1 H, d, J = 1.6 Hz, isoxazole CH), 4.54 (2 H, s, CH ₂ S0 ₂ N), 3.61 (1 H, br m, CHN), 3.1 1 (1 H, br m, CHN), 1.81 - 2.03 (4 H, br m, cyclohexyl CH), 1.19 - 1.37 (4 H, br m, J = 8.5 Hz, cyclohexyl CH).

Example Compound 11 : N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl1amino1- trans-cvclohexyn-1 -(5-methylisoxazol-3-yl)methanesulfonamide.

The method of Example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using [4-amino- 2-[(trans-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluor ophenyl)methanone

(0.150g,0.4257mmol), (5-methylisoxazol-3-yl)methanesulfonyl chloride (0.125g,0.6385mmol) and triethylamine (0.065g, 0.638mmol) in DCM (3m L) and DMF (1 ml_). Product was purified using Waters® automated mass directed preparative purification system to give a yellow solid. The solid was confirmed as desired product by LCMS M+H 512 (R _t = 4.6min.) and ¹ H NMR (500MHz DMSO-cfe) δ 8.67 (1 H, br d, NH), 8.07 (2 H, br s, NH ₂ ), 7.49 (1 H, m, J = 6.7 Hz, 16.8 Hz, ArH), 7.35 (1 H, d, J = 7.4 Hz, NH), 7.16 (2 H, m, J = 15.7 Hz, ArH), 6.28 (1 H, s, isoxazole CH), 4.44 (2 H, s, CH ₂ S0 ₂ N), 3.65 (1 H, br m, CHN), 3.13 (1 H, br m, CHN), 2.42 (3 H, s, Me), 1.82 - 2.03 (4 H, br m, cyclohexyl CH), 1.15 - 1.39 (4 H, br m, cyclohexyl CH).

Example Compound 12: N-r4-r(4-amino-5-benzoyl-thiazol-2-yl)amino1-trans- cyclohexyn- -methyl-propane-1 -sulfonamide

N-(Trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.050g, 0.18mmol) was dissolved in DCM (4ml_) at R.T. 3,5-dimethylpyrazol-1-yl formamidinium nitrate (0.037g, 0.18mmol) was then added with DIPEA (0.023g, 0.18mmol) in one portion. Reaction was stirred overnight at R.T. Phenylacyl bromide (0.043g, 0.216mmol) was added and reaction stirred at R.T. for 24 hrs. Deionized water (10ml_) was added and organics separated, dried using magnesium sulphate and concentrated under reduced pressure. The crude product was purified by silica column chromatography (EtOAc: Hexane 3:1 as eluent) using Combiflash RF® automated purification system to give a solid. The solid was confirmed as desired product by LCMS M+H 437.1 (R _t = 4.09) and ¹ H NMR (500MHz, CDCI ₃ )□ 7.75 (2 H, m, ArH), 7.42 - 7.48 (3 H, m, ArH), 3.32 (2 H, br m, CHN), 2.95 (2 H, d, J = 6 Hz, CH ₂ S0 ₂ N), 2.28 (1 H, m, CHMe ₂ ), 2.17 (4 H, br m, cyclohexyl CH), 1.38 (4 H, br m, cyclohexyl CH), 1.13 (6 H, d, J = 7, CH/We ₂ ). Aqueous solubility 5μg/mL. Example Compound 13: N-r4-rr4-amino-5-(2-chlorobenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide.

The method of Preparative Compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1g, 0.36mmol), cyanamide (0.018g, 0.43mmol), 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) 2-chlorophenylacyl bromide (0.093g, 0.4mmol) as starting materials to give a yellow solid. The solid was confirmed as desired product by LCMS M+H 471.1 (R _t = 4.13) and ¹ H NMR (500MHz, DMSO-d ₆ ) 51 1.98 (1 H, br s, NH), 8.54 (1 H, br s, NH), 8.04 (2 H, br s, NH ₂ ), 7.49 (1 H, d, J = 7.3 Hz, ArH), 7.35-7.43 (2 H, m ArH), 7.04 (1 H, d, J = 7.3, ArH), 3.63 (1 H, br s, CHN), 3.07 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.5, CH ₂ S0 ₂ N), 2.07 (1 H, m, CHMe ₂ ), 1.90 (4 H, br m, cyclohexyl CH), 1.29 (4 H, br m, cyclohexyl CH) 1.01 (6 H, d, J = 6.6 Hz, CH/We ₂ ). Aqueous solubility 59 μg/mL.

Example Compound 14: N-r4-rr4-amino-5-(2,4-difluorobenzoyl)thiazol-2-vnamino1-

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(- trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2,4-difluorophenylacyl bromide (0.085g, 0.36mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a yellow solid. The solid was confirmed as desired product by LCMS M+H 473.1 (R _t = 4.16) and ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.60 (1 H, br s, NH), 8.13 (2 H, br s, NH ₂ ), 7.50 (1 H, q, J = 7.5 Hz, ArH), 7.32 (1 H, td, J = 9.6 Hz, 2.2 Hz, ArH), 7.14 (1 H, td, J = 8.3 Hz, 1.8 Hz, ArH), 7.04 (1 H, d, J = 7.4 Hz, NH), 3.64 (1 H, br s, CHN), 3.08 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.07 (1 H, m, CHMe ₂ ), 1.82- 1.97 (4 H, br m, cyclohexyl CH), 1.23-1.36 (4 H, br m, cyclohexyl CH), 1 .01 (6 H, d, J = 6.7 Hz, C Me ₂ ). Aqueous solubility 72μg/mL.

Example Compound 15: N-r4-rr4-amino-5-(pyridine-3-carbonyl)thiazol-2-vnamino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol) and 2- bromo-1-(3-pyridyl)ethanone hydrobromide (0.114g, 0.36mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol)as starting materials to give a yellow solid as a precipitate. The solid was confirmed as desired product by LCMS M+H 438.1 (R _t = 4.41) and ¹ H NMR (500MHz, DMSO-de) δ 8.79 (1 H, s, ArH), 8.65 (1 H, dd, J = 4.8 Hz, 1.6 Hz, ArH), 8.50 (1 H, br s, NH), 7.98 (1 H, d, J = 8.1 Hz, ArH), 7.49 (1 H, m, ArH), 7.05 (1 H, d, J = 7 Hz, NH), 3.65 (1 H, br s, CHN), 3.10 (1 H, br s, CHN), 2.90 (2 H, d, J = 6.6 Hz, CH ₂ S0 ₂ N), 2.07 (1 H, m, CHMe ₂ ), 1.93 (4 H, br m, cyclohexyl CH), 1.31 (4 H, br m, cyclohexyl CH), 1.02 (6 H, d, J = 6.7 Hz, C Me ₂ ). Aqueous solubility 5μg/mL.

Example Compound 16: N-r4-rr4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2,6- dichlorophenylacyl bromide (0.096g, 0.36mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a solid. The solid was confirmed as desired product by LCMS M+H 505 (R _t = 4.15) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.36 (1 H, d, J = 1.1 Hz, ArH), 7.35 (1 H, s, ArH), 7.27 (1 H, d, J = 1.5Hz, ArH), 5.55 (1 H, br d, J = 6.7 Hz, NH), 4.07 (1 H, d, J = 8.2 Hz, NH), 3.30 (2 H, br s, 2x CHN), 2.93 (2 H, d, J = 6.3 Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.15 (4 H, br d, J = 14.9 Hz, cyclohexyl CH), 1.36 (4 H, br m, cyclohexyl CH), 1.12 (6 H, d, J = 6.4 Hz, CH/We ₂ ). Aqueous solubility 53μg/mL. Example Compound 17: N-r4-rr4-amino-5-(3-fluorobenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 3- fluorophenylacyl bromide (0.078g, 0.36mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a solid. The solid was confirmed as desired product by LCMS M+H 455.1 (R _t = 4.25) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.72 (1 H, dt, J = 1.1 Hz, 1.2 Hz, ArH), 7.58-7.65 (2 H, m, ArH), 7.35 (td, J = 8.4 Hz, 1 Hz, ArH), 5.94 (1 H, br s, NH), 4.46 (1 H, d, J = 7.4 Hz, NH), 3.53 (2 H, br m, 2 x CHN), 3.13 (2 H, d, J = 6.5 Hz, CH ₂ S0 ₂ N), 2.47 (1 H, m, CHMe ₂ ), 2.32 - 2.41 (4 H, br m, cyclohexyl CH), 1.58 (4 H, m, cyclohexyl CH), 1.31 (6 H, d, J = 6.8 Hz, CH/We ₂ ).

Example Compound 18: N-r4-rr4-amino-5-r4-fluoro-2-(trifluoromethyl)benzovn thiazol-2-vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1g, 0.36mmol), 4-fluoro- 2-trifluoromethylphenylacyl bromide (0.124g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 523.1 (R _t 4.47) ¹ H NMR (500MHz, CDCI ₃ ) δ 7.51 (1 H, m, ArH), 7.44 (1 H, dd, J = 8.8 Hz, 2.6 Hz, ArH), 7.29 (1 H, td, J = 8.3 Hz, 2.6 Hz, ArH), 5.34 (1 H, br d, J = 7.5 Hz, NH), 4.02 (1 H, d, J = 1.1 Hz, NH), 3.30 (2 H, br s, 2 x CHN), 2.93 (2 H, d, J = 6.7 Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.16 (4 H, m, cyclohexyl CH), 1.36 (4 H, m, cyclohexyl CH), 1.12 (6 H, d, J = 6.8 Hz, CH/We ₂ ).

Example Compound 19: N-r4-rr4-amino-5-(2-methoxybenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2- methoxyphenylacyl bromide (0.099g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 467.1 (R _t = 4.17) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.53 - 7.58 (2 H, m, ArH), 7.13 - 7.19 (2 H, m, ArH), 5.66 (1 H, d, J = 7.7 Hz, NH), 4.32 (1 H, d, J = 7.8 Hz, NH), 4.04 (3 H, s, OMe), 3.68 (2 H, d, J = 5.1 Hz, CHN), 3.46 (2 H, br s, CHN), 3.10 (2 H, d, J = 6.6, CH ₂ S0 ₂ N), 2.44 (1 H, m, CHMe ₂ ), 2.30 (4 H, m, cyclohexyl CH), 1.51 (4 H, m, cyclohexyl CH), 1.29 (6 H, d, J = 6.9 Hz, CH/We ₂ ). Aqueous solubility 76μg/mL Example compound 20: N-r4-rr4-amino-5-(2,4-dichlorobenzoyl)thiazol-2-yllaminol- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(- trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2,4-dichlorophenylacyl bromide (0.116g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 505.1 (R _t = 4.51) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.46 (1 H, d, J = 1.9 Hz, ArH), 7.35 (1 H, d, J = 8.3 Hz, ArH), 7.31 (1 H, dd, J = 8.2 Hz, 2.1 Hz, ArH), 5.45 (1 H, br d, J = 7.3 Hz, NH), 4.01 (1 H, d, J = 7.6 Hz, NH), 3.30 (2 H, br s, 2 x CHN), 2.93 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.16 (4 H, br m, cyclohexyl CH), 1.37 (4 H, m, cyclohexyl CH), 1.12 (6 H, d, J = 6.7 Hz, CH/We ₂ ). Aqueous solubility 22μg/mL.

Example Compound 21 : N-r4-rr4-amino-5-r2-(trifluoromethoxy)benzovnthiazol-2- vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2- tnfluoromethoxylphenylacyl bromide (0.123g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 521.1 (R _t = 4.44) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.27 (2 H, m, ArH), 7.14 (2 H, m, ArH), 5.23 (1 H, br d, J = 7.5 Hz, NH), 3.84 (1 H, d, J = 7.9 Hz, NH), 3.10 (2 H, br s, 2 x CHN), 2.72 (2 H, d, J = 6.3 Hz, CH ₂ S0 ₂ N), 2.06 (1 H, m, CHMe ₂ ), 1.95 (4 H, br m, cyclohexyl CH), 1.15 (4 H, m, cyclohexyl CH), 0.91 (6 H, d, J = 6.8 Hz, CHMe ₂ ). Aqueous solubility 65μg/mL.

Example Compound 22: N-r4-rr4-amino-5-(2,4-dimethylbenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2,4- dimethylphenylacyl bromide (0.098g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 465.1 (R _t = 4.38)and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.27 (1 H, d, J = 7.7 Hz, ArH), 7.07 (1 H, s, ArH), 7.03 (1 H, d, J = 7.8 Hz, ArH), 5.38 (1 H, br d, J = 8 Hz, NH), 4.04 (1 H, d, J = 7.6 Hz, NH), 3.29 (2 H, br s, 2 x CHN), 2.92 (2 H, d, J = 6 Hz, CH ₂ S0 ₂ N), 2.38 (3 H, s, Me), 2.36 (3 H, s, Me), 2.27 (1 H, m, CHMe ₂ ), 2.15 (4 H, br m, cyclohexyl CH), 1.35 (4 H, m, cyclohexyl CH), 1.12 (6 H, d, J = 6.8 Hz, CH/We ₂ ). Aqueous solubility 44μg/mL. Example Compound 23: N-r4-rr4-amino-5-(4-methylbenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1g, 0.36mmol), 4- methylphenylacyl bromide (0.092g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a white solid. The solid was confirmed as desired product by LCMS M+H 451.1 (R _t = 4.31) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.67 (2 H, d, J = 7.9 Hz, ArH), 7.25 (2 H, d, J = 7.3, ArH), 5.41 (1 H, d, J = 8.3, NH), 4.07 (1 H, d, J = 7.8, NH), 3.34 (2 H, br m, 2 x CHN), 2.94 (2 H, d, J = 6.4, CH ₂ S0 ₂ N), 2.43 (3 H, s, Me), 2.28 (1 H, m, CHMe ₂ ), 2.18 (4 H, br m, cyclohexyl CH), 1.39 (4 H, m, cyclohexyl), 1.13 (6 H, d, J = 6.8 Hz, CH/We ₂ ).

Example compound 24: N-r4-rr4-amino-5-(2,5-difluorobenzoyl)thiazol-2-yl1amino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.1 g, 0.36mmol), 2,5- difluorophenylacyl bromide (0.101 g, 0.43mmol), cyanamide (0.018g, 0.43mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.43ml_, 0.43mmol) as starting materials to give a solid. The solid was confirmed as desired product LCMS M+H 473 (Rt = 4.34) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.2 (1 H, m, ArH), 7.1 (2 H, t, J = 6.2 Hz, ArH), 5.56 (1 H, br d, J = 6.9 Hz, NH), 4.12 (1 H, d, J = 9 Hz, NH), 3.32 (2 H, br s, 2 x CHN), 2.93 (2 H, d, J = 6.5 Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.17 (4 H, br m, cyclohexyl CH), 1.38 (4 H, m, cyclohexyl CH), 1.12 (6 H, d, J = 6.7 Hz, CH/We ₂ ).

Example Compound 25: N-r4-rr4-amino-5-(2,6-dichlorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-3, 3, 3-trifluoro-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using 3,3,3- trifluoro-N-(trans-4-isothiocyanatocyclohexyl)propane-1-sulp homamide (0.133g, 0.42mmol), 2,6-dichlorophenylacyl bromide (0.133g, 0.5mmol) cyanamide (0.021g, 0.5mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.5ml_, 0.5mmol) as starting materials to give a solid. The solid was confirmed as desired product by LCMS M+H 545.0 (R _t = 4.34) and ¹ H NMR (500MHz, CDCI ₃ ) δ 7.12 (1 H, d, J = 1.1 , Hz, ArH), 7.1 1 (1 H, s, ArH), 7.03 (1 H, d, J = 1.6 Hz, ArH), 5.29 (1 H, br s NH), 4.00 (1 H, m, NH), 3.09 (2 H, br s, 2 x CHN), 3.00 (2 H, m, CF ₃ CH ₂ CH ₂ ), 2.41 (2 H, m, CF ₃ CH ₂ CH ₂ ), 1.97 (2

H, br m, cyclohexyl CH), 1.90 (2 H, br m, cyclohexyl CH), 1.14 (2 H, m, cyclohexyl CH),

I .06 (2 H, m, cyclohexyl CH). Aqueous solubility 44μg/mL.

Example Compound 26: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl1amino1- cvclohexyll-l -phenyl-methanesulfonamide

[4-Amino-2-[(-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6- difluorophenyl)methanone (0.186g, 0.53mmol) was prepared as a racemate using the method previously described in synthesis of preparative compound 6 and dissolved in DMF (5ml_) with caesium carbonate (0.326g, 1 mmol) at R.T. with stirring. Phenylmethanesulfonyl chloride (0.084g, 0.44mmol) was then added drop wise and reaction heated with stirring at 65°C for 5 hrs. The solvent was removed under reduced pressure then DCM (50ml_) added and washed with deionized water (20ml_). The organics were dried using magnesium sulphate and concentrated under reduced pressure to give title compound as a solid. The solid was confirmed as desired product as cis/tans mixture by LCMS M+H 507 and ¹ H NMR (500 MHz, DMSO-de) 58.63 (1 H, br, d, NH), 8.09 (2 H, br s, NH ₂ ), 8.01 (1 H, d, NH), 7.50 (1 H, m, ArH), 7.14 - 7.32 (7 H, m, ArH), 4.12 (1 H, q, CHN), 3.47 (1 H, br m, CHN), 3.36 (2H, s, CH ₂ S0 ₂ N), 1.72 - 2.03 (4 H, br m, cyclohexyl CH), 1.15 - 1.35 (4 H, br m, cyclohexyl CH).

Example Compound 27: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- cyclohexyllbenzenesulfonamide

[4-Amino-2-[(-4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6- difluorophenyl)methan

(0.08g, 0.227mmol) was prepared as a racemate using the method as previously described in the synthesis of preparative compound 6 and dissolved in DCM (5ml_) with triethylamine (0.041 g, 0.405mmol) at R.T. Benzenesulphonyl chloride (0.031g, 0.194mmol) was then added drop wise and reaction mixture stirred at R.T. for 4 hrs. Deionized water (10ml_) was added and organics separated, dried using magnesium sulphate and concentrated under reduced pressure to give title compound as a solid. The solid was confirmed as desired product as a cis/trans mixture by LCMS M+H 493 (R _t = 4.19 min.) and ¹ H NMR (500 MHz, DMSO-d ₆ ) 58.57 (1 H, br s, NH), 8.05 (2 H, br s, NH ₂ ), 7.82 (2 H, d, J= 7.1 Hz, ArH), 7.71 (1 H, d, J = 7.2 Hz, NH), 7.65 - 7.58 ( 3H, m, ArH), 7.49 (1 H, m, ArH ), 7.16 (2 H, t, J = 7.9 Hz, ArH ), 3.59 (1 H, br s, CHN), 2.94 (1 H, br s, CHN), 1.85 (2 H, br m, cyclohexyl CH), 1.63 (2 H, br m, cyclohexyl CH), 1.20 (4 H, br m, cyclohexyl CH).

Example Compound 28: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl1amino1- cyclohexyn-1 -(2-chlorophenyl)methanesulfonamide

The method of Example 26, N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]- - cyclohexyl]-1-phenyl-methanesulfonamide was used using [4-amino-2-[(4- aminocyclohexyl)amino]thiazol-5-yl]-(2,6-difluorophenyl)meth anone (0.07g, 0.2mmol), (2- chlorophenyl)methanesulfonyl chloride (0.067g, 0.3mmol) and caesium carbonate (0.130g, 0.4mmol) as starting materials to give title compound as a solid. The solid was confirmed as desired product as a cis/trans mixture by LCMS M+H 542 (R _t = 4.35 min) and ¹ H NMR (500 MHz, DMSO-d ₆ ) 58.62 (1 H, br s, NH), 8.08 (2 H, br s, NH ₂ ), 7.51 (3 H, m, ArH), 7.39 (2 H, m ,ArH), 7.32 (1 H, d, J= 7.4 Hz, NH), 7.15 (2 H, m, ArH), 4.49 (2 H, s, CH ₂ ), 3.66 (1 H, br s, CHN), 3.04 (1 H, br s, CHN), 1.92 (4 H, br m, cyclohexyl CH), 1.27 (4 H, br m, cyclohexyl CH).

Example Compound 29: N-r4-rr4-amino-5-(2,6-difluorobenzoyl)thiazol-2-vnamino1- trans-cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.276g, 1 mmol), 2,6- difluorophenylacyl bromide (0.282g, 1.2mmol) cyanamide (0.05g, 1.2mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (1.2ml_, 1.2mmol) as starting materials to give title compound as a solid. The solid was confirmed as desired product by LCMS M+H 473 and ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.63 (1 H, br s, NH), 8.07 (2 H, br s, NH ₂ ), 7.50 (1 H, m, J = 5.01 Hz, ArH), 7.17 (2 H, m, J = 7.8 Hz, ArH), 7.03 (1 H, d, J = 7.5 Hz, NH), 3.62 (1 H, br s, CHN), 3.07 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.07 (1 H, m, J = 6.6 Hz, CHMe ₂ ), 1.82 - 1.99 (4 H, br m, cyclohexyl CH), 1.20 - 1.37 (4 H, br m, cyclohexyl CH), 1.01 (6 H, d, J = 6.7 Hz, CH/We ₂ ). Aqueous solubility 46μ9/ηιί.

Example Compound 30: N-r4-rr4-amino-5-(4-cvano-2,6-difluoro-benzoyl)thiazol-2- vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.109g, 0.395mmol), 4-(2- bromoacetyl)-3,5-difluoro-benzonitrile (0.103g, 0.395mmol), cyanamide (0.017g, 0.395mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.4ml_, 0.4mmol) as starting materials. Crude product was purified via silica column chromatography using Combiflash RF® automated purification system (0-10% MeOH - DCM gradient elution) to give title compound as a bright yellow solid. The solid was confirmed as desired product by LCMS M+H 497.7 (R _t 4.1 min) and ¹ H NMR (500 MHz, DMSO-d ₆ ) 58.78 (1 H, br s, NH), 8.34 (1 H, br s, NH), 8.10 (1 H, br s, NH), 7.92 (2 H, d, J = 6.7 Hz, 2 ArH), 7.04 (1 H, d, J = 7.4 Hz, NH), 3.66 (1 H, br s, CHN), 3.09 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ ), 2.07 (1 H, m, CHMe ₂ ), 1.92 (4 H, br m, 4 cyclohexyl H), 1.26 (4 H, br m, 4 cyclohexyl H), 1.02 (6 H, d, J = 6.7 Hz, CH/We ₂ ). Aqueous solubility 46μg/mL. Example Compound 31 : N-r4-rr4-amino-5-r3-(dimethylaminomethyl)-2,6-difluoro- benzovnthiazol-2-vnamino1cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]cyclohexyl]carbamate was used using N-(4-isothiocyanatocyclohexyl)-2-methyl- propane-1 -sulfonamide (0.039g, 0.14mmol), 2-bromo-1-[3-(dimethylaminomethyl)-2,6- difluoro-phenyl]ethanone hydrobromide (0.052g, 0.1399mmol), cyanamide (0.007g, 0.14mmol) and 1 M potassium tertiary butoxide 1 M solution in THF (0.14ml_, 0.14mmol) as starting materials. Product was purified via silica column chromatography using Combiflash RF® automated purification system (0-1-%MeOH-DCM gradient elution) to give title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 530 (R _t = 4.7 min) and ¹ H NMR (500 MHz, DMSO-d ₆ ) 58.61 (1 H, br s, NH), 8.05 (2 H, br s, NH ₂ ), 7.45 (1 H, dd, J = 15.1 Hz, 8.3 Hz, ArH), 7.13 (1 H, t, J = 8.5 Hz, ArH), 7.01 (1 H, d, J = 7.6, NH), 3.64 (1 H, br s, CHN), 3.45 (2 H, s, CH ₂ N), 3.08 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ ), 2.16 (6 H, s, NMe ₂ ), 2.07 (1 H, m, CHMe ₂ ), 1.92 (4 H, br m, 4 cyclohexyl H), 1.29 (4 H, br m, 4 cyclohexyl H), 1.02 (6 H, d, J = 6.7 Hz, CH/We ₂ ). Aqueous solubility 132μg/mL.

Example Compound 32: N-r4-rr4-amino-5-r4-(dimethylaminomethyl)-2,6-difluoro- benzovnthiazol-2-vnamino1-trans-cvclohexyn-2-methyl-propane- 1 -sulfonamide hydrochloride.

Cyanamide (0.566.g, 13.471 mmol) was added to MeCN (2ml_) at R.T. then a solution of Potassium tertiary-butoxide 1 M in THF (1.89g, 16.84mmol) was added in one portion. The reaction mixture was stirred for 15 min. at R.T. N-(4-isothiocyanatocyclohexyl)-2- methyl-propane-1 -sulfonamide (3.13g, 11.23mmol) was then added as a solution in MeCN (2ml_) and tert-butanol (1 mL) and stirred for a further 15min. at R.T. 2-bromo-1-[4- [(dimethylamino)methyl]-2,6-difluoro-phenyl]ethanone hydrobromide (4.19g, 11.23mmol) was then added in one portion and reaction stirred overnight at R.T. Reaction was diluted with DCM (50ml_) and washed with deionized water (20ml_) and concentrated under reduced pressure. The crude product was then purified by silica column chromatography using CombiFlash RF® automated purification system (DCM - 1 %-20%MeOH gradient elution) to give a solid. Methanol (5ml_) was added with 1 M HCI in ether (2ml_) and reaction concentrated under reduced pressure to give a solid. Ether was then added and reaction mixture triturated to give a solid which was filtered and dried by suction filtration to give the title compound as an HCI salt. The solid was confirmed as desired product by LCMS M+H 530 (R _t = 4.9 min) and ¹ H NMR (500 MHz, DMSO-de) 58.71 (1 H, br s, NH), 8.08 (2 H, br s, NH ₂ ), 7.31 (1 H, br s, 2 ArH), 7.01 (1 H, d, J = 7.6 Hz, NH), 3.65 (1 H, br m, CHN), 3.33 (2 H, s, CH ₂ N), 3.08 (1 H, br s, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ ), 2.55 (6 H, br s, NMe ₂ ), 2.07 (1 H, m, CHMe ₂ ), 1.90 (4 H, br m, 4 cyclohexyl H), 1.29 (4 H, br m, 4 cyclohexyl H), 1.02 (6 H, d, J = 6.8 Hz, CH/We ₂ ). Aqueous solubility 132μg/mL.

Example Compound 33: N-r4-rr4-amino-5-r2,6-difluoro-4-(pyrrolidin-1 -ylmethyl) benzovnthiazol-2-vnaminol-trans-cyclohexyn- 2-methyl-propane-1 -sulfonamide hydrochloride

The method of Example compound 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6- difluoro-benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-met hyl-propane-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.094g, 0.34mmol), 2-bromo-1-[2,6-difluoro-4-(pyrrolidin-1- ylmethyl)phenyl]ethanone hydrobromide (0.135g,0.34mmol), cyanamide (0.017g, 0.41 mmol) and 1 M potassium tertiary butoxide in THF (0.677ml_, 0.677mmol) as starting materials to give desired compound as the freebase. This was dissolved in methanol (5ml_) and 1 M HCI (2ml_) in diethyl ether added. Solvent was then removed under reduced pressure to give title compound as the hydrochloride salt. The orange solid was confirmed as desired product by LCMS M+H 556. (R _t = 4.03 min.) and ¹ H NMR (500MHz, DMSO-de) δ 7.89 - 8.39 (2 H, br s, NH ₂ ), 7.49 (2 H, d, J = 7.6 Hz, ArH), 7.06, (1 H, d, J = 7.4 Hz, NH), 4.39 (2 H, d, J = 5.7 Hz, CH ₂ N), 3.35 - 3.43 (3 H, m, J = 13.9 Hz, CHN, pyrrolidine CH), 3.01 - 3.1 1 (3 H, m, CHN, pyrrolidine CH), 2.89 (2 H, d, J = 6.3, CH ₂ S0 ₂ N), 1.98 - 2.1 (4 H, m, CHMe ₂ pyrrolidine CH), 1.81 - 1.98 (5 H, m, pyrrolidine CH, cyclohexyl CH), 1.22 - 1.38 (4 H, m, cyclohexyl CH), 1.02 (6 H, d, J = 6.7 Hz, C Me ₂ ). Aqueous solubility 148μg/mL.

Example Compound 34: N-r4-rr4-amino-5-r2-chloro-5-r(dimethylamino) methvnbenzovnthiazol-2-vnamino1-trans-cvclohexyn-2-methyl-pr opane-1 - sulfonamide hydrochloride

The method of Example compound 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6- difluoro-benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-met hyl-propane-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.226g, 0.818mmol), 2-bromo-1-[2-chloro-5-[(dimethylamino) methyl]phenyl]ethanone hydrobromide (0.304g,0.818mmol), cyanamide (0.041 g, 0.982mmol), and a solution of 1 M potassium tertiary butoxide in THF (1.64ml_, 1.64mmol) as starting materials to give desired compound as the free base. The hydrochloride salt was prepared in the same manner as example compound 32, N-[4-[[4- amino-5-[2,6-difluoro-4-(pyrrolidin-1-ylmethyl)benzoyl]thiaz ol-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride, to give title compound as a beige solid. The solid was confirmed as desired product by LCMS M+H 528 (R _t = 0.23 min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 10.94 (1 H, br s, NH ⁺ ), 8.67 (1 H, br s, NH), 8.05 (2 H, br s, NH ₂ ), 7.60 (2 H, br m, ArH), 7.58 (1 H, br s, ArH), 7.01 (1 H, d, J = 7.4 Hz, NH), 4.30 (2 H, d, J = 6.4 Hz, CH ₂ N), 3.62 (1 H, br m, CHN), 3.08 (1 H, br m, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.70 (6 H, s, NMe ₂ ), 2.04 - 2.10 (1 H, m, J = 6.6 Hz, CHMe ₂ ), 1.85 - 1.96 (4H, br m, cyclohexyl CH), 1.25 - 1.35 (4 H, br m, J = 7.4 Hz, cyclohexyl CH), 1.02 (6 H, d, CH/We ₂ ). Aqueous solubility 132μ9/ηιΙ_.

Example Compound 35: N-r4-rr4-amino-5-r2-chloro-4-r(dimethylamino)methvn benzovnthiazol-2-vnamino1-trans-cvclohexyn-2-methyl-propane- 1 -sulfonamide hydrochloride

The method of Example compound 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6- difluoro-benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-met hyl-propane-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.297g, 1.08mmol), 2-bromo-1-[2-chloro-4- [(dimethylamino)methyl]phenyl]ethanone hydrobromide (0.40g, 1.08mmol), cyanamide (0.054g, 1.29mmol) and a solution of 1 M potassium tertiary butoxide in THF (2.15ml_, 2.15mmol) as starting materials to give desired compound as the free base. The hydrochloride salt was prepared in the same manner as example compound 32, N-[4-[[4- amino-5-[2,6-difluoro-4-(pyrrolidin-1-ylmethyl)benzoyl]thiaz ol-2-yl]amino]-trans- cyclohexyl]-2-methyl-propane-1 -sulfonamide hydrochloride, to give title compound as a beige solid. Product confirmed by LCMS M+H 528 (R _t 0.58 min.) and ¹ H NMR (500MHz, DMSO-de) δ 10.54 (1 H, br s, NH ⁺ ), 8.66 (1 H, br NH), 8.04 (1 H, br s, NH ₂ ), 7.75 (1 H, s, ArH), 7.56 (1 H. d, ArH), 7.47 (1 H, d, J = 7.7 Hz, ArH), 7.0 (1 H, d, J = 7.6 Hz, NH), 4.30 (2 H, d, J = 5.3 Hz, CH ₂ N), 3.61 (1 H, br, CHN), 3.08 (1 H, br, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.73 (6 H, s, NMe ₂ ), 2.03 - 2.1 (1 H, m, J = 13.2 Hz, CHMe ₂ ), 1.84 - 1.96 (4H, br m, cyclohexyl CH), 1.23 - 1.35 (4 H, br m, cyclohexyl CH), 1.01 (6 H, d, CH/We ₂ ). Aqueous solubility 132μg/mL.

Example Compound 36: N-r4-rr4-amino-5-(2-chloropyridine-3-carbonyl)thiazol-2- vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of Example compound 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6- difluoro-benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-met hyl-propane-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.20g, 0.724mmol), 2-bromo-1-(2-chloro-3-pyridyl)ethanone (0.204g, 0.87mmol), cyanamide (0.037g, 0.87mmol) and a solution of 1 M potassium tertiary butoxide in THF (0.87ml_, 0.87mmol) as starting materials. The crude product was purified using Gilson® preparative HPLC automated purification system (MeCN - 0.1 % formic in water gradient elution) to give the title compound as a white solid. The solid was confirmed as desired product by LCMS M+H 473 (R _t 4.4 min.) and ¹ H NMR (500MHz DMSO-de) δ 8.63 (1 H, br, s, NH), 8.47 (1 H, dd, J = 4.8 Hz, ArH), 8.08 (2 H, br, s, NH ₂ ), 7.87 (1 H, d, J = 7.4 Hz, ArH), 7.49 (1 H, dd, J = 4.8 Hz, 7.5 Hz, ArH), 7.01 (1 H, d, J = 7.5 Hz, NH) 3.64 (1 H, br, m, CHN), 3.08 (1 H, br, m, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.02 - 2.11 (1 H, m, J = 13.2 Hz, CH(CH ₃ ) ₂ ), 1.89 - 1.92 (4 H, br, m, cyclohexyl CH), 1.21 - 1.37 (4 H, br, m, cyclohexyl CH), 1.02 (6 H, d, J = 6.7 Hz, CH/We ₂ ). Aqueous solubility 1 18μg/mL.

Example Compound 37: N-r4-rr4-amino-5-r2-(trifluoromethyl)pyridine-3-carbonvn thiazol-2-vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of Example 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6-difl benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-methyl-propa ne-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.20g, 0.724mmol), 2-bromo-1-[2-(trifluoromethyl)-3-pyridyl]ethanone (0.233g, 0.87mmol), cyanamide (0.036g, 0.87mmol) and a solution of 1 M potassium tertiary butoxide in THF (0.87ml_, 0.87mmol) as starting materials. The crude product was purified using Gilson® preparative HPLC automated purification system (MeCN - 0.1 % ammonium hydroxide in water gradient elution) to give title compound as a yellow solid. The solid was confirmed as desired product by LCMS M+H 506 (R _t = 4.8 min.) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.78 (1 H, d, J = 4.7 Hz, ArH), 8.60 (1 H, br, NH), 8.05 (2 H, br, s, NH ₂ ), 8.01 (1 H d, J = 7.7 Hz, ArH), 7.77 (1 H, dd, J = 7.8 Hz, ArH), 7.02 (1 H, d, J = 7.6 Hz, NH), 3.64 (1 H, br, CHN), 3.08, (1 H, br, CHN), 2.88 (1 H, d, J = 6.4 Hz, CH- ₂ S0 ₂ N), 2.07 (1 H, m, J = 13.2 Hz, CHMe ₂ ), 1.81 - 1.97 (4 H, br, m, cyclohexyl CH), 1.21 - 1.37 (4 H, br, m, cyclohexyl CH), 1.01 (6 H, d, J = 6.7 Hz, C Me ₂ ). Aqueous solubility 127μg/mL. Example Compound 38: N-r4-rr4-amino-5-(2-bromopyridine-3-carbonyl)thiazol-2- vnamino1-trans-cvclohexyn-2-methyl-propane-1 -sulfonamide

The method of Example compound 32, N-[4-[[4-amino-5-[4-(dimethylaminomethyl)-2,6- difluoro-benzoyl]thiazol-2-yl]amino]-trans-cyclohexyl]-2-met hyl-propane-1 -sulfonamide hydrochloride was used using N-(trans-4-isothiocyanatocyclohexyl)-2-methyl-propane-1- sulfonamide (0.2g, 0.724mmol), 2-bromo-1-(2-bromo-3-pyridyl)ethanone (0.242g, 0.87mmol), cyanamide (0.037g, 0.87mmol), and a 1 M solution of potassium tertiary butoxide in THF (0.87ml_, 0.87mmol) as starting materials. The crude product was purified by Gilson® preparative HPLC automated purification system (MeCN - 0.1 % ammonium hydroxide in water gradient elution) to give title compound as a yellow solid. The solid was confirmed as desired product LCMS M+H 515/517 (R _t = 4.6 min) and ¹ H NMR (500MHz DMSO-d ₆ ) δ 8.61 (1 H, br, NH), 8.41 (1 H, dd, J = 4.7 Hz, 8.4 Hz, ArH), 8.06 (2 H, br, NH ₂ ), 7.80 (1 H, dd, J = 7.4 Hz, ArH), 7.51 (1 H, dd, J = 4.8 Hz, ArH), 7.01 (1 H, d, J = 7.5 Hz, NH), 3.64 (1 H, br, m, CHN), 3.08 (1 H, br, m, CHN), 2.89 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.07 (1 H, m, J = 13.2 Hz, CHMe ₂ ), 1.83 - 1.99 (4 H, br, m, cyclohexyl CH), 1.22 - 1.39 (4 H, br, m, cyclohexyl CH), 1.01 (6 H, d, J = 6.7 Hz,CH/We ₂ ). Aqueous solubility 129μ9/ηιΙ_. Example Compound 39: N-r4-rr4-amino-5-(2-iodobenzoyl)thiazol-2-yl1amino1-trans- cyclohexyn-2-methyl-propane-1 -sulfonamide

The method of preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.579g, 2.09mmol), 2- bromo-1-(2-iodophenyl)ethanone (0.953g, 2.93mmol), cyanamide (0.105g, 2.51 mmol) and a 1 M solution of potassium tertiary butoxide in THF (2.51 ml_, 2.51 mmol) as starting materials. The reaction mixture contained a white solid which was filtered and washed with MeCN. The filtrate was concentrated under reduced pressure to give the crude product. The product was purified by silica column chromatography using Combiflash RF® automated purification system (1 % - 10% MeOH - DCM gradient elution)to give title compound as a solid. The solid was confirmed as desired product by LCMS M+H 563 (R _t = 2.47 min.) and ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.52 (1 H, b, NH), 7.91 - 8.10 (2 H, b, NH ₂ ), 7.86 (1 H, d, J = 8Hz, NH), 7.41 - 7.45 (1 H, t, J = 7, 14 Hz, ArH), 7.28 (1 H, d, J = 7 Hz, ArH), 7.1 1 - 7.15 (1 H, td, J = 7, 17 Hz, ArH), 7.01 (1 H, d, J = 7 Hz, ArH), 3.61 (1 H, br, CHN), 3.07 (1 H, br, CHN), 2.89 (2 H, d, J = 6 Hz, CH ₂ S0 ₂ N), 2.04 - 2.11 (1 H, m, J = 7, 14, 27 Hz, CHMe ₂ ), 1.83 - 1.95 (4 H, br m, cyclohexyl CH), 1.23 - 1.34 (4 H, br m, cyclohexyl CH), 1.02 (6 H, d, J = 7 Hz, CH/We ₂ ).

Example Compound 40: N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)-1 -(tetrahydrofuran-3-yl)methanesulphonamide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl) amino]thiazol-5-yl]-(2,6-dichlorophenyl)methanone (0.2g, 0.52mmol), triethylamine (0.105g, 1.04mmol) and tetrahydrofuran-3-yl methanesulphonyl chloride (0.144g, 0.79mmol) in DCM (5ml_) / DMF (1 ml_). Product was purified via prep. HPLC to give title compound as a solid. Product confirmed by LCMS M+H 534 (R _t 2.0 min.) and ¹ H NMR 400MHz (DMSO-d6) δ 8.59 (1 H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.51 (1 H, br, ArH), 7.49 (1 H, br, ArH), 7.42 (1 H, d, ArH), 7.02 (1 H, d, NH), 4.1 1 (1 H, m, CHS), 3.75 (1 H, m, CHS), 3.63 (1 H, m, CHN), 3.23 (1 H, m, furan CH), 3.16 (1 H, m, furan CH), 3.11 (1 H, br, CHN), 2.04 (1 H, m, furan CH), 1.9 (4H, m, cyclohexyl CH ₂ ), 1.83 (2H, m, furan CH ₂ ), 1.66 (1 H, m, furan CH), 1.29 (4 H, m, cyclohexyl CH ₂ ). Example Compound 41 : N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)-2-methoxyethanesulphonamide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-dichlorophenyl) methanone (0.2g, 0.52mmol), triethylamine (0.105g,1.04mmol) and 2-methoxyethane sulphonyl chloride (0.124g, 1.04mmol) in DCM (5ml_) / DMF (1 ml_). Product was purified via silica column chromatography using Combiflash RF® to give title compound as a solid. Product confirmed by LCMS M+H 508 (R _t 1.97 min.) and ¹ H NMR 400MHz (DMSO-d6) δ 8.58 (1 H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.51 (1 H, d, J = 0.9 Hz, ArH), 7.50 (1 H, d, ArH), 7.42 (1 H, dd, J = 8.7, 7.4 Hz, ArH), 7.08 (1 H, d, J = 7.3Hz, NH), 3.64 (2 H, t, CH ₂ 0), 3.28 (2 H, t, CH ₂ S), 3.26 (3 H, s, OMe), 3.09 (1 H, br, CHN), 1.90 (4 H, m, cyclohexyl CH ₂ ), 1.29 (4 H, m, cyclohexyl CH ₂ ).

Example Compound 42: N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)oxetane-3-sulphonamide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-dichlorophenyl) methanone (0.2g, 0.52mmol), triethylamine (0.105g, 1.04mmol) and oxetane-3-sulphonyl chloride (0.163g, 1.04mmol) in pyridine (3 mL). Product was purified via silica column chromatography using Combiflash RF® to give title compound as a solid. Product confirmed by LCMS M+H 506 (R _t 1.90 min.) and ¹ H NMR 400MHz (DMSO-d6) δ 8.60 (1 H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.51 (1 H, d, J = 0.9 Hz, ArH), 7.50 (1 H, d, ArH), 7.42 (2 H, dd, J = 8.8, 7.4 Hz, ArH, NH), 4.77 (2 H, m, oxetane CH ₂ ), 4.63 (2 H, m, oxetane CH ₂ ), 3.63 (1 H, br, CHN), 3.10 (1 H, br, CHN), 1.87 (4 H, m, cyclohexyl CH ₂ ), 1.29 (4 H, m, cyclohexyl CH ₂ ).

Example Compound 43: N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)tetrahydrofuran-3-sulphonamide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-dichlorophenyl) methanone (0.2g, 0.52mmol), triethylamine (0.105g,1.04mmol) and tetrahydrofuran-3-sulphonyl chloride (0.13g, 0.80 mmol) in DCM (5 mL) / DMF (1 mL). Product was purified via silica column chromatography using Combiflash RF® to give title compound as a solid. Product confirmed by LCMS M+H 520 (R _t 1.92 min.) and ¹ H NMR 400MHz (DMSO-d6) δ 8.60 (1 H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.51 (1 H, d, J = 0.9 Hz, ArH), 7.49 (1 H, d, ArH), 7.42 (1 H, dd, J = 8.8, 7.3 Hz, ArH), 7.27 (1 H, d, J = 7.7 Hz, NH), 4.77 (2 H, m, furan CH), 3.91 (3 H, m, furan CH), 3.80 (1 H, m, furan CH), 3.68 (1 H, m, furan CH), 3.12 (1 H, br, CHN), 2.12 (2 H, m, furan CH) 1.91 (4 H, m, cyclohexyl CH ₂ ), 1.30 (4 H, m, cyclohexyl CH ₂ ).

Example Compound 44: N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)tetrahydrothiophene-3-sulphonamide-1 ,1 -dioxide

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-dichlorophenyl) methanone (0.2g, 0.52mmol), triethylamine (0.105g, 1.04mmol) and 1 , 1-dioxothiolane-3-sulphonyl chloride (0.17g, 0.80 mmol) in DCM (5 mL) / DMF (1 mL). Product was purified via silica column chromatography using Combiflash RF® to give title compound as a solid. Product confirmed by LCMS M+H 568 (R _t 2.02 min.) and ¹ H NMR 400MHz (DMSO-d6) δ 8.60 (1

H, br, NH), 7.99 (2 H, br, NH ₂ ), 7.57 (1 H, br, d, ArH), 7.50 (2 H, br, ArH, NH), 7.42 (1 H, br, ArH), 4.17 (1 H, br, thiolane CH), 3.64 (1 H, br, CHN), 3.17 (4 H, br, thiolane CH),

2.44 (1 H, br, thiolane CH), 2.29 (1 H, br, thiolane CH), 1.91 (4 H, m, cyclohexyl CH ₂ ),

I .30 (4 H, m, cyclohexyl CH ₂ ).

Example Compound 45: (R)-3-N-((trans)-4-((4-amino-5-(2,6-ichlorobenzoyl)thiazol- 2-yl)amino)cvclohexyl)sulphamoyl)-2-methylpropyl acetate

The method of example 2, [(2R)-3-[[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2- yl]amino]trans-cyclohexyl]sulfamoyl]-2-methyl-propyl] acetate was used using 4-amino-2- [(4-aminocyclohexyl)amino]thiazol-5-yl]-(2,6-dichlorophenyl) methanone (0.208g, 0.54mmol), DIPEA (0.105g, 0.81 mmol) and [(2R)-3-chlorosulphonyl-2-methyl- propyl]acetate (0.139g, 0.65 mmol) in DCM (10 mL) / DMF (3 mL). Product was purified via silica column chromatography using Combiflash RF® to give title compound as a solid. Product confirmed by LCMS M+H 564 (R _t 2.14 min.) and ¹ H NMR 400MHz (CDCI ₃ ) δ 8.03 (1 H, br, NH), 7.35 (1 H, br, ArH), 7.33 (1 H, br, ArH), 7.28 (1 H, br, ArH, ), 7.26 (1 H, br, NH), 6.14 (1 H, br, NH), 4.61 (1 H, d, CHN), 4.06 (2 H, br, CH20), 3.28 (2 H, br, CHN), 3.17 (1 H, m, CHS02), 2.98 (3H, s, MeC02), 2.90 (1 H, m, CHS02), 2.12 (4 H, m, cyclohexyl CH ₂ ), 1.35 (4 H, m, cyclohexyl CH ₂ ), 1.18 (3 H, d, Me).

Example Compound 46: N-((trans)-4-((4-amino-5-(2,6-dichlorobenzoyl)thiazol-2- yl)amino)cvclohexyl)-3-hvdroxy-2-methylpropane-1 -sulphonamide

The method of example 2, N-[4-[[4-amino-5-(2,6-difluorobenzoyl)thiazol-2-yl]amino]- trans-cyclohexyl]-3-hydroxy-2,2-dimethyl-propane-1 -sulfonamide was used using (R)-3- N-((trans)-4-((4-amino-5-(2,6-ichlorobenzoyl)thiazol-2-yl)am ino) cyclohexyl)sulphamoyl) 2-methylpropyl acetate (0.059g, O. IOmmol) and sodium hydroxide (0.008g, 0.21 mmol) in MeOH (5ml_). Product was purified using Waters® mass directed auto-prep, to give a solid. Product confirmed by LCMS M+H 522 (R _t 1.92min.) and NMR 500MHz (MeOD) δ 7.42 (1 H, d, J = 6.5, 10.8Hz, ArH), 7.34 (2 H, dd, J = 7.0, 8.9Hz, ArH), 3.53 (1 H, dd, J = 5.5, 10.7Hz, CH ₂ OH), 3.43 (1 H, dd, J = 6.5, 10.8 Hz CH ₂ OH), 3.25 (1 H, dd, J = 4.7, 14.3 Hz, CH ₂ S0 ₂ ), 3.91 (1 H, br, CHN), 2.81 (1 H, dd, J = 8.0, 14.3 Hz, CH ₂ S0 ₂ ), 2.17 (1 H, m, CHMe), 2.07 (4 H, m, cyclohexyl CH ₂ ), 1.39 (4 H, m, cyclohexyl CH ₂ ), 1.1 1 (3H, d, J = 6.8 Hz, Me). Example Compound 47: N-((4-amino-5-(4-(azetidine-1 -ylmethyl)-2,6- difluorobenzoyl)thiazol-2-yl)amino)cvclohexyl)-2-methylpropo ane-1 -sulphonamide hydrochloride

The method of Preparative Compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.220g, 0.79mmol), cyanamide (0.040g, 0.96mmol), 1 M potassium tertiary butoxide 1 M solution in THF (1.19ml_, 1.19mmol) and 1-[4-(azetidine-1-ylmethyl)-2,6-difluoro-phenyl]-2-bromo ethanone hydrobromide (0.301 g, 1.19mmol). Product was purified by prep. HPLC then converted to an HCI salt to give a yellow solid. Product was confirmed by LCMS M+H 452 (R _t = 1.58min.) and ¹ H NMR 400MHz, (MeOD) δ 7.01 (1 H, d, ArH), 6.98 (1 H, d, ArH), 3.66 (2 H, s, NCH ₂ ), 3.35 (4H, m, azetidine CH ₂ ) 3.20 (1 H, br CHN), 2.94 (2 H, d, CH ₂ S0 ₂ N), 2.18 (1 H, m, CHMe ₂ ), 2.18 (2 H m, azetidine CH ₂ ) 2.08 (2 H, m, (4 H, br m, cyclohexyl CH ₂ ), 1.41 (4 H, br m, cyclohexyl CH ₂ ) 1.11 (6 H, d, CH/We ₂ ).

Example compound 48j N-trans-((4-amino-5-(2,6-dichloro-4- ((dimethylamino)methyl)benzoyl)thiazol-2-yl)amino)cvclohexyl )-2-methylpropane- 1 -sulphonamide hydrochloride

The method of Preparative Compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.495g, 1.79mmol), cyanamide (0.090g, 2.15mmol), 1 M potassium tertiary butoxide 1 M solution in THF (2.32mL, 2.32mmol) and 2-bromo-1-(2,6-dichloro-4-((dimethylamino)methyl) phenyl)ethan-1-one hydrobromide (0.727g, 1.79mmol). Product was purified by silica column chromatography using Combiflash® then HCI salt prepared to give a solid. Product was confirmed by LCMS M+H 563 (R _t = 1.53min.) and ¹ H NMR 400MHz, (DMSO-de) δ 10.68(1 H, br, NH), 8.76 (1 H, br, NH), 8.03 (2 H, s, NH ₂ ), 7.79 (2 H, s, ArH) 7.03 (1 H, d, NH), 4.3 (2 H, s, CH ₂ N), 3.65 (1 H, br, CHN), 3.07 (1 H, br, CHN) 2.89 (2 H, d, CH ₂ S0 ₂ N), 2.73 (6 H, s, NMe ₂ ), 2.07 (1 H, m, CHMe ₂ ) 1.89 (4 H, br m, cyclohexyl CH ₂ ), 1.29 (4 H, br m, cyclohexyl CH ₂ ) 1.02 (6 H, d, CH/We ₂ ).

Example Compound 49: N-trans-((4-amino-5-(4-(2-(dimethylamino)ethyl)-2,6- difluorobenzoyl)thiazol-2-yl)amino)cvclohexyl)-2-methylpropa ne-1 -sulphonamide hydrochloride

The method of Preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.234g, 0.85mmol), cyanamide (0.043g, 1.02mmol), 1 M potassium tertiary butoxide 1 M solution in THF (1.1 mL, 1.1 mmol) and 2-bromo-1-(4-(2-(dimenthylamino)ethyl-2,6-difluorophenyl)eth an- 1-one hydrobromide (0.328g, 0.85mmol). Reaction resulted in solid which was filtered and washed with dried. An HCI salt was prepared to give title compound as a solid. Product was confirmed by LCMS M+H 544 (R _t = 1.38min.) and ¹ H NMR 400MHz, (DMSO-de) δ 10.20(1 H, br, NH), 8.74 (1 H, br, NH), 8.08 (2 H, s, NH ₂ ), 7.16 (2 H, d, ArH), 7.03 (1 H, d, J = 7.5Hz, NH), 4.3 (2 H, s, CH ₂ N), 3.65 (1 H, br, CHN), 3.36 (2 H, m, benzylCH ₂ ), 3.07 (1 H br, CHN), 3.07, (2 H, t, J = 8.32Hz, CH ₂ N), 2.89 (2 H, d, J = 6.4Hz, CH ₂ S0 ₂ N), 2.81 (6 H, d, J = 4.9Hz, NMe ₂ ), 2.07 (1 H, m, CHMe ₂ ) 1.89 (4 H, m, cyclohexyl CH ₂ ), 1.29 (4 H, m, cyclohexyl CH ₂ ) 1.02 (6 H, d, J = 6.7Hz, CH/We ₂ ).

Example Compound 50: N-trans-4-((4-amino-5-(4-(azetidine-1 -ylmethyl)-2,6- dichlorobenzoyl)thiazol-2-yl)amino)cvclohexyl)-2-methylpropa ne-1 -sulphonamide hydrochloride

The method of Preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-(trans- 4-isothiocyanatocyclohexyl)-2-methyl-propane-1 -sulfonamide (0.177g, 0.42mmol), cyanamide (0.021 g, 0.51 mmol), 1 M potassium tertiary butoxide 1 M solution in THF (0.55ml_, 0.55mmol) and 1-(4-(azetidine-1-ylmethyl)-2,6-dichlorophenyl-2-bromoethan- 1- one hydrobromide (0.177g, 0.42mmol) to give title compound as a solid. Product was confirmed by LCMS M+H 574 (R _t = 3.8min.) and ¹ H NMR 400MHz, (MeOD) δ 7.68 (2 H, d, ArH), 4.45 (2 H, s, benzyl CH ₂ N), 4.23 (1 H, br, CHN), 4.23 (4 H, m, azetidine CH ₂ N), 3.21 (1 H, br, CHN), 2.95 (2 H, d, J = 6.4Hz, CH ₂ S0 ₂ N), 2.62 (1 H, azetidine CH ₂ ), 2.51 (1 H, m, azetidine CH ₂ ) 2.20 (1 H, m, CHMe ₂ ), 2.08 (4 H, br m, cyclohexyl CH ₂ ), 1.43 (4 H, br m, cyclohexyl CH ₂ ), 1.1 1 (6 H, d, J = 6.7Hz, CH/We ₂ ).

Example compound 51 : N-trans-4-((4-amino-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cvclohexyl)tetrahydrofura n-3-sulphoanamide hydrochloride

The method of Preparative compound 3, tert-butyl N-[4-[[4-amino-5-(2,6- difluorobenzoyl)thiazol-2-yl]amino]-trans-cyclohexyl]carbama te was used using N-trans- (4-isothiocyanatocyclohexyl)tetrahydrofuran-3-sulphonamide (0.144g, 0.50mmol), cyanamide (0.025g, 0.50mmol), 1 M potassium tertiary butoxide 1 M solution in THF (0.496ml_, 0.50mmol) and 2-bromo-1-[4-(dimethylaminomethyl)-2,6-difluoro- phenyl]ethanone hydrobromide (0.185g, 0.50mmol) to give title compound as a solid. Product was confirmed by LCMS M+H 544 (R _t = 1.51 min.) and ¹ H NMR 400MHz, (MeOD) δ 7.45 (2 H, d, ArH), 4.45 (2 H, s, benzyl CH ₂ N), 3.87 - 4.08 (5 H, m, tetrahydrofuran CH), 3.80 (1 H, m, CHN), 3.27 (1 H, m, CHN), 2.94 (6 H, s, NMe ₂ ), 2.26 (2 H, d, tetrahydrofuran CH), 2.09 (4 H, m, cyclohexyl CH ₂ ), 1.46 (4 H, m, cyclohexyl CH ₂ ). Example Compound 52j N-trans-4-((4-amino-5-(2,6-difluoro-4-

((methylamino)methyl)benzoyl)thiazol-2-yl)amino)cvclohexy l)-2-methylpropane-1 - sulphonamide

N-7rans-((4-amino5-(2,6-difluoro-4-(((4-methoxybenzyl)met hyl)amino)methyl) benzoyl) thiazol-2-yl)amino)cyclohexyl)-2-methylpropane-1 -sulphonamide (0.102g, 0.160mmol) was added to DCM (5ml_) with potassium carbonate (0.044g, 0.321 mmol). 1-Chloroethyl chloroformate (0.028g, 0.193mmol) was then added and reaction stirred for 12 hours at room temperature. DCM was removed under reduced pressure then MeOH (5ml_) added and reaction heated under reflux for 2 hours. Reaction was diluted with DCM washed with water (20ml_), dried via hydrophobic filter and concentrated under reduced pressure. Product was purified using Waters® mass directed automated purification system to give title compound as a solid. Product was confirmed by LCMS M+H 516 (R _t = 1.51 min.) and ¹ H NMR 400MHz (MeOD) δ 7.05 (2 H, d, J = 7.6Hz, ArH), 3.76 (2 H, s, benzyl CH ₂ N), 3.20 (1 H, br, CHN), 2.94 (2 H, d, J = 6.4Hz, CH ₂ S0 ₂ N), 2.40 (3 H, s, NMe), 2.20 (1 H, m, CHMe ₂ ), 2.07 (4 H, m, cyclohexyl CH ₂ ), 1.41 (4 H, m, cyclohexyl CH ₂ ), 1.1 1 (6 H, d, J = 6.6Hz, CH/We ₂ ).

Example compound 53j N-trans-4-((4-amino-5-(4-aminomethyl)-2,6- difluorobenzoyl)thiazol-2-yl)amino)cvclohexyl)-2-methylpropa ne-1 -sulphonamide hydrochloride

To a solution of tert-butyl-(4-amino-2-(((trans)-4-((2-methylpropyl)sulphonam ido) cyclohexyl)amino)thiazole-5-carbonyl)-3,5-difluorobenzyl)car bamate (0.250g, 0.42mmol in DCM (15mL) was added TFA (2.94 g, 25.76 mmol. The reaction was stirred at 16 °C for 2 hr. The reaction was concentrated under reduced pressure and residue was washed with saturated sodium bicarbonate solution (15 ml_), and extracted with a solution of MeOH: DCM (1 : 10) (100 ml_). The combined extracts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The product was purified by Prep- HPLC (acidic modifier) then dried by lyophilisation. To give title compound as the HCI salt. Product was confirmed by LCMS M+H 502 (R _t = 1.92min.) and ¹ H NMR 400MHz (MeOD) δ 7.38 (2 H, d, ArH), 4.25 (2 H, s, benzyl CH ₂ N), 3.98 (1 H, br, CHN), 3.20 (1 H, br, CHN), 2.93 (2 H, d, CH ₂ S0 ₂ N), 2.20 (1 H, m, CHMe ₂ ), 2.15 (4 H, m, cyclohexyl CH ₂ ), 1.43 (4 H, cyclohexyl CH ₂ ), 1.09 (6 H, d, CH/We ₂ ).

Example compound 54: N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(methylamino)thiazol-2-yl)amino)cvclohexy l)-2-methylpropane- 1 -sulphonamide hydrochloride

To a solution of N-trans-4-((4-chloro-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1-sulphonamide (0.100g, 0.18mmol) in THF (1.00 mL) was added 2 M methylamine (0.46ml_, 0.9mmol). The reaction mixture was stirred at 50-60 °C for 16h in a sealed tube. The reaction was then concentrated under reduced pressure. The product was purified by pre-HPLC (HCI modifier) to give title compound as a yellow solid. Product was confirmed by LCMS M+H 544 (R _t = 2.89 min) and ¹ H NMR 400MHz (CDCI ₃ ) δ 8.88 (1 H, d, J = 5.0 Hz, NH), 6.94 (2 H, d, J = 7.9 Hz, ArH), 5.69 (1 H, br, NH), 4.07 (1 H, br, CHN), 3.43 (2 H, s, benzyl CH ₂ N), 3.29 (2 H, br, NH, CHN ), 3.14 (3 H, d, J = 5.1 Hz, NH/We), 2.93 (2 H, d, J = 6.5 Hz, CH ₂ S0 ₂ N), 2.33 - 2.23 ( 7 H, m, CHMe, NMe ₂ ), 2.16 (4 H, d J = 9.2 Hz, cyclohexyl CH ₂ ), 1.46 -1.26 (4 H, m, cyclohexyl CH ₂ ), 1.12 (6 H, d, J = 6.8 Hz, CH/We ₂ ).

Example compound 55: N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(dimethylamino)thiazol-2-yl)amino)cvclohe xyl)-2- methylpropane-1 -sulphonamide

The method of example compound 54, N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(methylamino)thiazol-2-yl)amino)cyclohexy l)-2-methylpropane-1- sulphonamide was used using N-trans-4-((4-chloro-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1 -sulphonamide

(0.100g, 0.18mmol) in THF (1.00 mL) and 2 M Dimethylamine (0.455mL, 0.91 mmol). Product was purified by prep. HPLC (basic modifier) to give title compound as a yellow solid. Product was confirmed by LCMS M+H 558 (R _t = 2.1 min.) and ¹ H NMR 400MHz (CDCI ₃ ) δ 6.92 (2 H, d, J = 7.9 Hz, ArH), 5.41 ( 1 H, m, NH), 4.0 (1 H, d, J = 7.9 Hz, NH), 3.43 (2 H, s, benzyl CH ₂ N), 3.20 (8 H, br, CHN, thiazoleNMe ₂ ), 2.92 (2 H, d, J = 6.4 Hz, CH ₂ S0 ₂ N), 2.27 (1 H, m, CHMe ₂ ), 2.28 (6 H, s, NMe ₂ ) 2.15 (4 H, m, cyclohexyl CH ₂ ), 1.36 (4 H, m, cyclohexyl CH ₂ ), 1.12 (6 H, d, J = 6.8 Hz, CH/We ₂ ). Example compound 56: N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(isopropylamino)thiazol-2-yl)amino)cvcloh exyl)-2- methylpropane-1 -sulphonamide formate

The method of example compound 54, N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(methylamino)thiazol-2-yl)amino)cyclohexy l)-2-methylpropane-1- sulphonamide was used using N-trans-4-((4-chloro-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1 -sulphonamide

(0.100g, 0.18mmol) in THF (0.5 ml_) and isopropyl amine (0.031 ml_, 0.36mmol) and di- isopropyl ethylamine (0.127ml_, 0.73mmol). Product was purified by HPLC (formic acid modifier) to give title compound as a yellow solid. Product was confirmed by LCMS M+H 572 (R _t = 2.29min.) and ¹ H NMR 400MHz (CDCI ₃ ) δ 8.74 (1 H, d, NH), 8.30 (1 H, s formate) 6.99 (2 H, d, J = 7.7 Hz, ArH), 5.77 (1 H, m, NH), 4.20 (2 H, m, NHCHMe ₂ , NHCHMe ₂ )), 3.61 (2 H, s, benzyl CH ₂ N), 3.29 (2 H, br, CHN), 2.93 (2 H, d, J = 6.5 Hz, CH ₂ S0 ₂ N), 2.40 (6 H, s, NMe ₂ ), 2.33 - 2.23 (5 H, m, CHMe ₂ , cyclohexyl CH ₂ ), 1.35 (10 H, m, NHCHMe _2, cyclohexyl CH ₂ ), 1.12 (6 H, d, J = 6.8 Hz, CH/We ₂ ). Example compound 57: N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-((hvdroxyethyl)amino)thiazol-2-yl)amino)c vclohexyl)-2- methylpropane-1 -sulphonamide hydrochloride

The method of example compound 54, N-((trans)-4-((5-(4-((dimethylamino)methyl)-2,6- difluorobenzoyl)-4-(methylamino)thiazol-2-yl)amino)cyclohexy l)-2-methylpropane-1- sulphonamide was used using N-trans-4-((4-chloro-5-(4-((dimethylamino)methyl-2,6- difluorobenzoyl)thiazol-2-yl)amino)cyclohexyl)-2-methylpropa ne-1-sulphonamide

(0.250g, 0.46mmol) in THF (0.5 mL) and 2-amino ethanol (0.110mL, 1.82mmol) and di- isopropyl ethylamine (0.795mL, 4.55mmol). EtOAc (10mL) was then added and washed with brine (5ml_) then EtOAc dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give a yellow oil. Tert-butyl methyl ether (20ml_) and EtOAc (1 ml_) were added to residue and then filtered. Petroleum ether (20ml_) was then added to the filtrate and resulting yellow solid collected by filtration. The solid was further purified by prep. HPLC (HCI modifier) to give title compound as a yellow solid. Product was confirmed by LCMS M+H 574 (R _t = 1.97min.) and ¹ H NMR 400MHz (DMSO cB) δ 1 1.10 (1 H, d, NH), 9.30 (1 H, NH), 8.90 (1 H, br, NH), 7.49 (2 H, d, J = 1.1 Hz, ArH), 7.04 (1 H, d, NH), 4.33 (2 H, s, benzyl CH ₂ N), 3.68 (1 H, br, CHN), 3.58 (4 H, m, NH(CH ₂ ) ₂ OH), 3.07 (1 H, br, CHN), 2.89 (2 H, d, J = 6.3 Hz, CH ₂ S0 ₂ N), 2.72 (6 H, s, NMe ₂ ), 2.06 (1 H, m, CHMe ₂ ), 1.88 (4H, m, cyclohexyl CH ₂ ), 1.31 (4H, m, cyclohexyl CH ₂ ), 1.01 (6 H, d, J = 6.8 Hz, CH/We ₂ ).

As stated hereinbefore, these are examples of compounds in accordance with the present invention. The skilled chemist will readily appreciate that by selection of alternative starting materials, reagents or intermediate preparative compounds, further example compounds of formula (I), (IA) or (IB) can be provided.

For example, compounds of Formula (IA) wherein R ² , R ³ and R ⁴ are H, R ¹ is a C ₄ alkyl group, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a fluorine at the ortho-position on the aryl ring and one of the R ⁵ , R ⁶ or R ⁷ substituent groups is a (CrC ₃ ) alkyl NR ¹² R ¹³ alkylamine group at the ortho or para-position on the aryl ring can be prepared in line with the methodology provided herein for Example 32 with use of an appropriate starting material to furnish the desired alternative compounds of Formula (IA) having: 2,6,-difluoro, 4- azetidin-2-yl; 2,6,-difluoro, 4-N-methyl azetidin-2-yl; 2,6,-difluoro, 4- methyl-N-azetidinyl; 2,6,-difluoro, 4-C-linked N-methyl azetidin-1-yl; 2,6,-difluoro, ethyldimethylamine; 2- fluoro, 2- methyldimethylamine; 2-fluoro, 2-azetidin-1-yl; 2- fluoro, 2-N-methyl-azetidin-1- yl; 2-fluoro, 2-azetidin-2-yl; 2- fluoro, 2-methylazetidinyl; 2-fluoro-2-C-linked N-methyl azetidin-2-y; 2-fluoro, 2-ethyl-2-dimethylamine groups.

For example, compounds of Formula (IA) wherein R ² , R ³ and R ⁴ are H, at least one of R ⁵ , R ⁶ , and R ⁷ is a chlorine at the ortho-position on the aryl ring and R ¹ is C ₄ alkyl one of the R ⁵ , R ⁶ or R ⁷ substituent groups is a (C C ₃ ) alkyl NR ¹² R ¹³ alkylamine group at the ortho or para-position on the aryl ring can be prepared in line with the methodology provided herein for Example 32 with use of an appropriate starting material to furnish the desired alternative compounds of Formula (IA) having: having: 2,6,-dichloro, 4-azetidin- 2-yl; 2,6,-dichloro, 4-azetidin-1-yl; 2,6,-dichloro, 4-N-methyl azetidin-2-yl; 2,6,-dichloro, 4-C-linked N-methyl azetidin-1-yl; 2,6,-dicloro, 4-methyldimethylamine; 2- chloro, 2- methyldimethylamine; 2- chloro, 2-azetidin-1-yl; 2- chloro, 2-N-methyl-azetidin-1-yl groups. For example, compounds of Formula (IA) wherein R ¹ is C ₄ alkyl, R ² , R ³ and R ⁴ are H, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a H, CI or F at the ortho-position on the aryl ring and wherein at least one of R ⁵ , R ⁶ , and R ⁷ is an NH ₂ containing group can be prepared in line with the methodology provided herein for Example 32 with use of an appropriate starting material to furnish the desired alternative compounds of Formula (IA) having: methylcyclopropylamine, 1-methyl, 1-aminoethyl, or a 1-amino-2-oxetyl groups

For example, compounds of Formula (IA) wherein R ² , R ³ and R ⁴ are H, wherein at least one of R ⁵ , R ⁶ , and R ⁷ is a chlorine at the ortho-position on the aryl ring and wherein R ¹ is a -(Ci-C ₃ )R ⁸ group wherein R ⁸ is a -C-bonded 4, 5 or 6 membered heterocyclic group, or a -(C C ₃ ) group substituted by one or more hydroxyl groups, can be prepared in line with the methodology provided herein for Example 2 with use of an appropriate starting material to furnish the desired alternative compounds of Formula (IA) having: oxetyl; oxet-1-yl; oxet-2-yl; tetrahydrofuranyl; tetrahydrofuran-1-yl; tetrahydrofuran-2-yl; tetrahydrofuran-3-yl; dioxolanyl; 1 , 3, dioxolanyl; 2,3,dimethyl-1 , 3- dioxolanyl; pyranyl; pyaran-4-yl; 1 H-1 ,3-dioxanyl; 2, 3, dihydroxypropanyl; 3-hydroxy, 2,2,-dimethylpropanyl substituents as R ¹ groups. Experimental Results

Experiments have been conducted to confirm: the inhibitory potential of compounds of general formula (I) against T brucei, against T congolense and against T vivax; the bovine hepatic clearance of compounds of general formula (I); the in-vivo efficacy of compounds of formula (I) in mice; the post infection survival rates of mice treated with compounds of general formula (I); the suitability of compounds of general formula (I) for use in anti-AAT therapies for intramuscular delivery via pharmacokinetic tests in calves; as well as to determine their mutagenic potential.

For the avoidance of doubt, whilst the results for a selection of the exemplified compound are provided and discussed hereinafter, similar results have been observed in corresponding experiments relating to other compounds of general formula (I) as exemplified hereinbefore.

Trypanosoma congolense

The trypanosomes used in the experiments herein were of the cloned stabilate T. congolense (IL3000), originally derived from trypanosomes isolated from a bovine in 1966 in Transmara, Kenya. Originally stabilates were received from Dr Liam Morrison at the University of Glasgow and were used once passed through immunosuppressed Balb/c (Cyclophosphamide 200 mg/kg I. P. 24h prior infection).

For the avoidance of doubt alternative sources of trypanosomes can be used, or they can be prepared in accordance with known methodologies such as are detailed in Gibson, "The origins of the trypanosome genome strains Trypanosoma brucei brucei TREU 927, T. b. gambiense DAL 972, T. vivax Y486 and T. congolense IL3000" in Parasites & Vectors, 2012, Vol 5, page 71.

Trypanosoma vivax

The trypanosomes used in experiments were of the cloned stabilate T vivax (ILRAD V34), originally derived from trypanosomes isolated from a bovine in 1976 in Zaria, Nigeria. The stabilates utilised herein were originally received from Annette MacLeod, Ph.D. Wellcome Trust Senior Fellow, University of Glasgow, and passed through immunosuppressed Balb/c (Cyclophosphamide 200 mg/kg I. P. 24h prior infection).

Trypanosoma brucei

T. brucei strain Tb bsf 427 VSG 221 is thought to originate from an infected sheep in 1960 in Uganda, as detailed in Cross and Manning "Cultivation of Trypanosoma brucei sspp. in semi-defined and defined media" in Parasitology, 1973, Volume 67, pages 315- 31. The 7. brucei strain Tb bsf 427 VSG 221 used in the experiments herein was subsequently passaged in Hirumi's medium and isolated as the predominant variant 221 in accordance with the methodology of Johnson and Cross "Selective cleavage of variant surface glycoproteins from Trypanosoma brucei" Biochem J, 1979; 178: 689-97.

Experiment 1 : Results of Trypanosoma brucei in vitro screen

Table 1 (a) illustrates the relative inhibitory potential of Example compounds of formula (I) against 7. brucei expressed as their EC ₅₀ values.

Table 1 (a)

Further experiments have been carried out to determine the relative inhibitory potential of Example compounds of formula (I) against 7. congolense and the relative inhibitory potential of Example compounds of formula (I) against 7. vivax again expressed as their EC ₅₀ values in μΜ. For example the relative EC ₅₀ values in μΜ against T. congolense and T. vivax respectively for some compounds of general formula (I) are illustrated in Table 1 (b).

Table Kb)

Experiment 2: Results of bovine hepatic clearance testing Table 2 illustrates the mean bovine hepatic microsome intrinsic clearance re; obtained for test compounds of general formula (I) expressed as (CLi). For avoidance of doubt the term CIH as used herein can be called CI.

Table 2

Experiment 3: in vivo efficacy testing and results As detailed hereinbefore, in-vivo efficacy of test compounds of general formula (I) was measured by assessing survival rates in mice post infection with T. congolense after dosing at 10mg/kg subcutaneous once daily for 4 days.

3.1 : Table 3 illustrates the relative survival rates obtained from testing Example compounds 16, 19, 25 and 52 of general formula (I) in mice post infection with T. congolense (strain IL3000 isolated from bovine in Transmara, Kenya, 1966) after dosing at 10mg/kg subcutaneous once daily for 4 days. Table 3

3.2: Table 4 illustrates the relative survival rates obtained from testing Example compounds 29, 31 and 32 of general formula (I) in mice post infection with 7 congolense and 7 vivax (strain ILRADv34 variant of Y486 isolated from bovine in Zairia, Nigeria 1976) after dosing at 10mg/kg subcutaneous once daily for 4 days.

Table 4

Experiment 4: Pharmacokinetic testing

As discussed hereinbefore the suitability of compounds of general formula (I) for use in anti-AAT therapies for intramuscular delivery were confirmed by pharmacokinetic testing of test compounds 29 and 32 in calves.

4.1 : Table 5 illustrates the intravenous data obtained for Ex 32 at a 2mg/kg dose level.

Table 5

wherein Clb is the blood clearance level as defined hereinbefore, VDss is the steady- state volume of distribution, half-life also known as t _{1 2} , and AUC is the total drug concentration over time and is provided by the area under the curve.

4.2: Table 6 illustrates the intramuscular data for Ex 32 at a 10mg/kg dose level. Table 6

Animal ID Calf 1 Calf 2 Calf 3 Mean (n = 3)

Cmax (ng/mL) 950 1674 2599 1723

Tmax (hours) 2 1 1 1

F(%) 78 75 66 74

AUC(0-°°) 529128 506693 460826 498595

(ng/min/mL wherein Cmax is the maximum concentration (of drug absorbed), Tmax is the time taken to reach Cmax, T ½ (half-life) is the time taken for the Cmax to drop in half, F (%) is a relative measurement drug bioavailability, in terms of the rate and extent to which it reaches the systemic circulation.

4.3: Table 7 illustrates the intramuscular data for Ex 29 at a 2.5mg/kg dose level.

Table 7

4.4: Table 8 illustrates the intramuscular data for Ex 29 at a 5mg/kg dose level.

Table 8

Experiment 5: ln-vitro Ames test results Example compound 29 was negative in the AMES assay for evaluation of mutagenic potential by measuring its ability to induce reverse mutations at selected loci of four strains of Salmonella typhimurium (TA98, TA100, TA1535 and TA1537) and at the tryptophan locus of Escherichia coli WP2 uvrA in the presence and absence of exogenous metabolic activation (Aroclor 1254 induced rat liver S9).

Example compound 32 was negative in the AMES assay for evaluation of mutagenic potential by measuring its ability to induce reverse mutations at selected loci of four strains of Salmonella typhimurium (TA98, TA100, TA1535 and TA1537) and at the tryptophan locus of Escherichia coli WP2 uvrA in the presence and absence of exogenous metabolic activation (Aroclor 1254 induced rat liver S9).