HETEROCYCLIC COMPOUNDS AND USE OF SAME

FIELD OF THE INVENTION

[0001 ] The invention relates to the field of medical treatment. More particularly, this invention relates to novel heterocyclic compounds and their use in treating a disease or condition caused by a trypanosomatid.

BACKGROUND TO THE INVENTION

[0002] Any reference to background art herein is not to be construed as an admission that such art constitutes common general knowledge in Australia or elsewhere.

[0003] Protozoa of the genus Trypanosoma are known to cause a number of diseases in humans. The majority of trypanosomes are transmitted by blood- feeding invertebrates and are responsible for a number of diseases falling under the banner of 'trypanosomiasis'. Human African Trypanosomiasis (HAT, African sleeping sickness) and Chagas' disease (American Trypanosomiasis) are such parasitic diseases causing significant morbidity and mortality in sub- Saharan Africa and South America, respectively.

[0004] HAT is caused by the protozoans Trypanosoma brucei rhodesiense and T. b. gambiense, transmitted by the bite of the Tsetse fly. In the 2004 World Health Report, HAT was estimated to cause 48,000 deaths and a disease burden of 1 .5 million disability-adjusted life years (DALYs) annually. T. cruzi, spread by the bite of the kissing bug, is the causative agent of Chagas' disease, and is endemic in 18 countries in Latin America, affecting as many as 8-10 million people. It is responsible for approximately 14,000 deaths and a disease burden of 0.7 million DALYs, annually.

[0005] Treatment of HAT is difficult, especially in its advanced stage (stage II), when the parasite infects the central nervous system. Only a few treatments are available: suramin and pentamidine for the disease in its early stage (stage I), and eflornithine and melarsoprol for stage II. These treatments are difficult to administer, and they are toxic and expensive. Treatments in clinical trials include pafuramidine and nifurtimox-eflornithine combination therapy. Two therapies are currently used for Chagas disease: nifurtimox and benznidazole, but these also have adverse side-effects, and neither prevents the development of, nor can treat, chronic Chagas' disease.

[0006] There is, therefore, a need for alternative compounds for the treatment of diseases caused by trypanosomes.

OBJECT OF THE INVENTION

[0007] It is an aim of this invention to provide for a heterocyclic compound suitable for treating a disease caused by trypanosomes which overcomes or ameliorates one or more of the disadvantages or problems described above, or which at least provides a useful alternative.

[0008] Other preferred objects of the present invention will become apparent from the following description.

SUMMARY OF INVENTION i9] According to a first aspect of the invention, there is provided pound of formula (I), or a pharmaceutically acceptable salt thereof:

Formula (I) wherein, Het is an unsaturated heterocycle selected from the group consisting of thiazole, pyrazole, imidazole, oxazole, isoxazole, triazole, tetrazole, pyrimidine, pyridine and pyrazine; R-ι is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, amine, amino, amido, all of which may be substituted or unsubstituted, nitro and halo;

R ₂ is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted;

R ₃ and R ₄ are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, oxo, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino;

W is selected in each instance from the group consisting of carbon, nitrogen and oxygen; m is 1 , 2 or 3;

R ₅ is one or more substituents independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino; with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4-triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[0010] In one embodiment, there is provided a compound selected from the group consisting of compounds of formula (II) to formula (XXIV), or a pharmaceutically acceptable salt thereof: wherein R _{1 ;} R ₂ and R ₅ are as described in any one or more of the above embodiments; with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4- triazole, Ri is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[001 1] According to a second aspect of the invention there is provided a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

[0012] Suitably, the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a trypanosomatid.

[0013] A third aspect of the invention resides in a method of treating a disease, disorder or condition caused by a trypanosomatid in a patient including the step of administering an effective amount of a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect to the patient, to thereby treat the disease, disorder or condition caused by the trypanosomatid.

[0014] A fourth aspect of the invention provides for a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect for use in the treatment of a disease, disorder or condition caused by a trypanosomatid in a patient.

[0015] A fifth aspect of the invention provides for use of a compound of the first aspect, or a pharmaceutically effective salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition caused by a trypanosomatid. [0016] In one embodiment of the third, fourth or fifth aspects, the disease, disorder or condition is trypanosomiasis.

[0017] The trypanosomiasis may be HAT or Chagas disease.

[0018] The trypanosome selected from the group consisting of Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi.

[0019] In one embodiment the disease, disorder or condition being treated may caused by a protozoa from the trypanosoma genus or the Leishmania genus.

[0020] Preferably, the patient is a domestic or livestock animal or a human.

[0021 ] The various features and embodiments of the present invention, referred to in individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently features specified in one section may be combined with features specified in other sections as appropriate.

[0022] Further features and advantages of the present invention will become apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order that the invention may be readily understood and put into practical effect, preferred embodiments will now be described by way of example with reference to the accompanying figures wherein:

[0024] FIG 1 is a reaction scheme for the synthesis of certain substituted thiazoles;

[0025] FIG 2 is a further reaction pathway for the synthesis of certain substituted thiazoles;

[0026] FIG 3 is another reaction scheme for the synthesis of certain substituted thiazoles; [0027] FIG 4 is a reaction scheme for the synthesis of certain substituted pyrazoles;

[0028] FIG 5 is a further reaction scheme for the synthesis of certain substituted pyrazoles;

[0029] FIG 6 is an alternative reaction scheme for the synthesis of certain substituted thiazoles;

[0030] FIG 7 is yet a further synthetic pathway for the synthesis of substituted thiazoles;

[0031 ] FIG 8 is a procedure which may be used to synthesise 3-phenyl pyrazoles;

[0032] FIG 9 is a further reaction pathway for the synthesis of 3-phenyl pyrazoles using a Michael addition approach;

[0033] FIG 10 is reaction scheme for the synthesis of certain substituted pyridyls;

[0034] FIG 1 1 shows a route by which 2-aryl- and 2-hetercyclo thiazoles can be assembled;

[0035] FIG 12 is an alternative approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles;

[0036] FIG 13 is another approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles;

[0037] FIG 14 is yet a further approach to the synthesis of 2-aryl- and 2- heterocyclo thiazoles;

[0038] FIG 15 is a reaction scheme to vary placement of the amide containing chain on a thiazole; and

[0039] FIG 16 is a reaction scheme to vary placement of the amide containing chain on a pyrazole. DETAILED DESCRIPTION

[0040] The present invention is predicated, at least in part, on the finding that certain unsaturated heterocyclic compounds display useful efficacy in the treatment of diseases caused by trypanosomatids. Particularly, the compounds of the invention are useful in the treatment of HAT and/or Chagas disease and/or Animal African trypanosomiasis (AAT).

Definitions

[0041] In this patent specification, the terms 'comprises', 'comprising', 'includes', 'including', or similar terms are intended to mean a non-exclusive inclusion, such that a method or composition that comprises a list of elements does not include those elements solely, but may well include other elements not listed.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as would be commonly understood by those of ordinary skill in the art to which this invention belongs.

[0043] As used herein, "trypanosomatid" refers to a protozoan of the order Trypsanomatida. Particularly preferred protozoa within this order are those of the genus Trypanosoma and Leishmania.

[0044] The term "trypanosome", as used herein, refers to a protozoan of the genus Trypanosoma and including a number of species known to cause trypanosomiasis including, but not limited to, Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi, Trypanosoma vivax, Trypanosoma congolense, Trypanosoma equiperdum and Trypanosoma brucei evansi.

[0045] In Africa, key trypanosome species pathogenic to cattle are T.vivax and T.congolense that are largely associated with the blood compartment and cause severe anemia (Nagana). Tequiperdum is transmitted venereally in horses and donkeys. T.brucei evansi (Surra) is transmitted mechanically by biting flies in horses, cattle and camels in Africa and in cattle, horses, camels, elephants, etc. in Asia. In South America, trypanosomes are only transmitted mechanically by biting flies and in this region T.vivax mainly affects cattle and sheep and T.evansi mainly affects horses and dogs but also cattle.

[0046] As used herein, "Leishmania" is a genus of the protist order Trypanosomatida and includes species such as Leishmania major, Leishmania tropica, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, Leishmania aethiopica, Leishmania chagasi and Leishmania mexicana, although without limitation thereto.

[0047] As used herein, "Leishmaniasis" is any disease or condition caused by, or otherwise associated with, parasitic protists of the genus Lesihmania. Primary hosts are mammals such as hyraxes, canids, rodents and humans. Typically, Leishmaniasis results from Leishmania transmission by the bite of certain species of sand fly (e.g. Phlebotominae and Lutzomyi). Most human disease is zoonotic (i.e transmissible only from non-human animals), but some can be spread between humans. The symptoms of Leishmaniasis include skin sores which erupt weeks to months after the person is bitten by sand flies, fever, damage to the spleen (which may result in an enlarged, palpable spleen) and liver, and anemia. Cutaneous Leishmaniasis is the most common form (typically caused by L. major, L. tropica, L. aethiopica and L. mexicana), which causes a sore at the bite site, healing in a few months to a year, leaving a permanent scar. This can progress to diffuse cutaneous Leishmaniasis characterized by widespread "leprous" skin lesions, mucocutaneous Leishmaniasis characterized by skin ulcers which spread particularly to the nose and mouth, and/or visceral Leishmaniasis in which the Leishmania parasites migrate to the vital organs. The most well known form of visceral Leishmaniasis is "Kala-Azar" typically caused by L. donovani.

[0048] As used herein, "effective amount" refers to the administration of an amount of the relevant active agent sufficient to prevent the occurrence of symptoms of the condition being treated, or to bring about a halt in the worsening of symptoms or to treat and alleviate or at least reduce the severity of the symptoms. The effective amount will vary in a manner which would be understood by a person of skill in the art with patient age, sex, weight etc. An appropriate dosage or dosage regime can be ascertained through routine trial.

[0049] The term "pharmaceutically acceptable salt", as used herein, refers to salts which are toxicologically safe for systemic or localised administration such as salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. The pharmaceutically acceptable salts may be selected from the group including alkali and alkali earth, ammonium, aluminium, iron, amine, glucosamine, chloride, sulphate, sulphonate, bisulphate, nitrate, citrate, tartrate, bitarate, phosphate, carbonate, bicarbonate, malate, maleate, napsylate, fumarate, succinate, acetate, benzoate, terephthalate, palmoate, piperazine, pectinate and S-methyl methionine salts and the like.

[0050] The term "alkyf refers to a straight-chain or branched alkyl substituent containing from, for example, 1 to about 12 carbon atoms, preferably 1 to about 9 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, still yet more preferably from 1 to 2 carbon atoms. Examples of such substituents may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, te/t-butyl, pentyl, isoamyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3- ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents, for example the carbon atoms of an alkoxy substituent branching off the main carbon chain . Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br, and I); halogenated alkyl {e.g., CF ₃ , 2-Br-ethyl, CH ₂ F, CF ₂ H, CH ₂ CI, CH ₂ CF ₃ , or CF ₂ CF ₃ ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonyl, sulphonamide, sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.

[0051] The term "alkenyf refers to optionally substituted unsaturated linear or branched hydrocarbon groups, having 2 to 12 carbon atoms, preferably 2 to 9 carbon atoms, more preferably 2 to 6 carbon atoms and having at least one carbon-carbon double bond. Where appropriate, the alkenyl group may have a specified number of carbon atoms, for example, C ₂ -C ₆ alkenyl which includes alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Examples of such substituents may be selected from the group consisting of ethenyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, hept-l,3-diene, hex-l,3-diene, non-l,3,5-triene and the like. Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br, and I); halogenated alkyl {e.g., CF ₃ , 2-Br-ethyl, CH ₂ F, CF ₂ H, CH ₂ CI, CH ₂ CF ₃ , or CF ₂ CF ₃ ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonyl, sulphonamide, sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.

[0052] The term " carboalkoxy" refers to an alkyl ester of a carboxylic acid, wherein alkyl has the same definition as found above. Examples include carbomethoxy, carboethoxy, carboisopropoxy and the like.

[0053] The term "alkoxy" as used herein means straight or branched chain alkyl groups linked by an oxygen atom (i.e., -O-alkyl), wherein alkyl is as described above. In particular embodiments, alkoxy refers to oxygen-linked groups comprising 1 to 10 carbon atoms ("C1 -10 alkoxy"). In further embodiments, alkoxy refers to oxygen-linked groups comprising 1 to 8 carbon atoms ("C1 -8 alkoxy"), 1 to 6 carbon atoms ("C1 -6 alkoxy"), 1 to 4 carbon atoms ("C1 -4 alkoxy") or 1 to 3 carbon atoms ("C1 -3 alkoxy").

[0054] The terms "cycloalkyi" and "cycloalkenyl" refers to optionally substituted saturated and unsaturated mono-cyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyi or cycloalkenyl group may have a specified number of carbon atoms, for example, C ₃ -C ₆ cycloalkyi or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms. C ₄ -C ₇ cycloalkyi or cycloalkenyl may be preferred in embodiments. C ₅ -C ₆ cycloalkyi or cycloalkenyl may be preferred in certain embodiments. Examples of such substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Substituted cycloalkyi or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br, and I); halogenated alkyl {e.g., CF ₃ , 2-Br-ethyl, CH ₂ F,

CH ₂ CI, CH ₂ CF ₃ , or CF ₂ CF ₃ ); hydroxyl; sulfonyl, sulphonamide, amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.

[0055] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 π electrons, according to Huckel's Rule.

[0056] The term "heteroaryl" refers to an aryl group containing from one or more (particularly one to four) non-carbon atom(s) (particularly N, O or S) or a combination thereof, which heteroaryl group is optionally substituted at one or more carbon or nitrogen atom(s). It may be a 4, 5, 6 or 7-membered ring, preferably 5 or 6-membered. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5 membered heteroaryls having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6- membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heretoaryls with three heteroatoms (e.g., 1 ,3,5- triazine); and 6-membered heteroaryls with four heteroatoms. "Substituted heteroaryl" means a heteroaryl having one or more non-interfering groups as substituents.

[0057] "Heterocyclyl" as used herein specifically in relation to certain 'R' groups refers to a non-aromatic ring having 5 to 7 atoms in the ring and of those atoms 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring wherein said heteroatoms are independently selected from O, N and S. 5 to 6 ring atoms may be preferred. Heterocyclic includes partially and fully saturated heterocyclic groups. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Non-limiting examples of heterocyclic include pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl and thiapinyl, imidazolinyl, thiomorpholinyl, and the like.

[0058] Whenever a range of the number of atoms in a structure is indicated (e.g., a C1-C12, C1-C10, C1-C9, C1-C6, Ci-C ₄ , or C2-C20, C2-C12, C2-C10, C2-C9, C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C ₄ alkyl, alkenyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1 -12 carbon atoms (e.g., C C ₂ ), 1 -9 carbon atoms (e.g., CrC ₉ ), 1 -6 carbon atoms (e.g., Ci-C ₆ ), 1 -4 carbon atoms (e.g., C C ₄ ), 1 -3 carbon atoms (e.g., C1-C3) , or 2-8 carbon atoms (e.g., C ₂ -C ₈ ) as used with respect to any chemical group (e.g., alkyi, etc.) referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1 -2 carbon atoms, 1 -3 carbon atoms, 1 -4 carbon atoms, 1 -5 carbon atoms, 1 -6 carbon atoms, 1 -7 carbon atoms, 1 -8 carbon atoms, 1 -9 carbon atoms, 1 -10 carbon atoms, 1 -1 1 carbon atoms, 1 -12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-1 1 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-1 1 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-1 1 carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).

[0059] "Substituted" or "Optionally substituted" in reference to a substituent group refers to substituent groups optionally substituted with one or more moieties, for example, those selected from the group consisting of optionally substituted C1 -10 alkyi {e.g., optionally substituted C1 -6 alkyi); optionally substituted C1 -10 alkoxy {e.g., optionally substituted C1 -6 alkoxy); optionally substituted C2-10 alkenyl; optionally substituted C2-10 alkynyl; optionally substituted C6-C12 aryl; aryloxy; optionally substituted heteroaryl; optionally substituted heterocycle; halo {e.g., CI, F, Br, and I); hydroxyl; halogenated alkyi {e.g., CF ₃ , 2-Br-ethyl, CH ₂ F, CF ₂ H, CH ₂ CF ₃ , and CF ₂ CF ₃ ); amino (e.g., NH ₂ , NR ₁₂ H, and NR ₁₂ R ₁₃ ); alkylamino; arylamino; acyl; amido; CN; NO ₂ ; N ₃ ; CH ₂ OH; CONH ₂ ; CONR ₁₂ R ₁₃ ; CO ₂ R ₁₂ ; CH ₂ OR ₁₂ ; NHCOR ₁₂ ; NHCO ₂ R ₁₂ ; C1 -3 alkylthio; sulfonyl, sulphonamide, sulfate; sulfonic acid; sulfonate esters such as alkyi or aralkyl sulfonyl, including methanesulfonyl; phosphonic acid; phosphate; and phosphonate.

[0060] As used herein, the terms "subject" or "individual" or "patient" may refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy is desired. Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes). A preferred subject is a human in need of treatment for a disease or condition caused by a trypanosome. However, it will be understood that the aforementioned terms do not imply that symptoms are necessarily present.

[0061 ] According to a first aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof:

Formula (I) wherein, Het is an unsaturated heterocycle selected from the group consisting of thiazole, pyrazole, imidazole, triazole, tetrazole, pyrimidine, pyridine and pyrazine;

Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, amine, amino, amido, all of which may be substituted or unsubstituted, nitro and halo;

R ₂ is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted;

R ₃ and R ₄ are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyl, alkyl hydroxyl and alkylamino; W is selected in each instance from the group consisting of carbon, nitrogen and oxygen; m is 1 , 2 or 3;

R ₅ is one or more substituents independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy, amino, amido, halo, alkoxyalkyi, alkyl hydroxyl and alkylamino; with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4- triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[0062] In one embodiment, Het is selected from the group consisting of thiazole, pyrazole, imidazole, oxazole, isoxazole, pyrimidine, pyridine and pyrazine.

[0063] In one embodiment, Het is selected from thiazole, pyrazole or pyridine.

[0064] In an embodiment, Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, O-alkyl, O-aryl, amine, amino and amido, all of which may be substituted or unsubstituted.

[0065] In any embodiment described herein, R-, is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidinyl, all of which may be substituted or unsubstituted.

[0066] In any embodiment described herein, R-i is optionally substituted phenyl or pyridyl. [0067] In any embodiment described herein, R ₂ is selected from the group consisting of alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkenyl, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.

[0068] In any embodiment described herein, R ₂ is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole, all of which may be substituted or unsubstituted, and NR ₂ Ri3 wherein R ₂ and Ri ₃ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or R ₂ and Ri ₃ join to form a ring.

[0069] In any embodiment described herein, R ₂ is pyrrolidinyl, piperidinyl, azepane, furanyl, phenyl, morpholinyl, all of which may be substituted or unsubstituted, and NR ₁₂ R ₁₃ wherein R ₁₂ and R ₃ are as previously described.

[0070] In embodiments, R ₃ and R ₄ are independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, carboalkoxy and amino.

[0071 ] In any embodiment described herein, R ₃ and R ₄ are independently selected from the group consisting of hydrogen, alkyl, hydroxyl and amino.

[0072] In any embodiment, W is selected from carbon or nitrogen.

[0073] In certain embodiments, m is 2.

[0074] In any embodiment described herein, R ₅ is one or more substituents independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cyano, carboxy, halo and amino.

[0075] In any embodiment described herein, R ₅ may be selected from hydrogen, d-C ₆ alkyl, chlorine and fluorine.

[0076] In any embodiment described herein, the compound is not either of the following compounds:

[0077] In one embodiment, there is provided a compound selected from the group consisting of compounds of formula (II) to formula (XXIV), or a pharmaceutically acceptable salt thereof:

wherein R _{1 ;} R ₂ and R ₅ are as described in any one or more of the above embodiments; and with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4- triazole, Ri is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[0078] In one embodiment, R-, is selected from the group consisting of phenyl, pyridyl, thiophene, piperidine and amine, each of which may be substituted or unsubstituted.

[0079] In embodiments, R ₂ is selected from the group consisting of CrC ₆ alkyl, C C ₆ alkoxy, phenyl, pyridyl, thiophene, piperidine, furanyl, C ₅ -C ₆ cyclyl, benzyl, thiazole, pyrazine, oxazole, pyrrolidinyl, morpholinyl, amine, azepane, pyrrole and isoxazole, each of which may be substituted or unsubstituted.

[0080] In one embodiment, R ₂ is piperidine independently substituted at one or more points on the ring with a moiety selected from the group consisting of fluoro, oxo, cyano and hydroxyl.

[0081 ] In certain embodiments, R ₅ is selected from hydrogen, fluorine, chlorine and C C ₆ alkyl.

[0082] In one embodiment, there is provided a compound of formula (XXV), or a pharmaceutically acceptable salt thereof:

Formula (XXV) wherein A and B are independently selected from carbon, nitrogen or sulphur atoms; dashed lines may represent a bond;

R-i and R ₂ may be as described in any one or more of the above embodiments; and with the proviso that when Het is 1 , 3-thiazole, R-, is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4- triazole, R-, is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[0083] In one embodiment of the compound of formula (XXV), Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, amino, all of which may be substituted or unsubstituted, and halo.

[0084] In embodiments, R-, is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidine, all of which may be substituted or unsubstituted

[0085] In one embodiment of the compound of formula (XXV), R ₂ is selected from alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.

[0086] In embodiments, R ₂ is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole and NR ₁₂ R ₁₃ , all of which may be substituted or unsubstituted, wherein R ₂ and Ri ₃ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or Ri ₂ and Ri ₃ join to form a ring. [0087] In one embodiment, there is provided a compound of formula (XI), or a pharmaceutically acceptable salt thereof:

formula (XI) wherein R _; R ₂ and R ₅ may be as described in any one or more of the above embodiments; with the proviso that when Het is 1 , 3-thiazole, Ri is 3-fluorophenyl at the 2-position of the thiazole ring, R ₅ is hydrogen and an ethylamide chain extends from the 4- position of the thiazole ring then R ₂ is not terf-butyl; and when Het is 1 ,2,4- triazole, Ri is 3-fluorophenyl at the 3-position of the ring, R ₅ is hydrogen and an ethylamide chain extends from the 5-position of the triazole ring then R ₂ is not 3-fluorophenyl.

[0088] In one embodiment of the compound of formula (XI), Ri is selected from the group consisting of alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyi, amino, all of which may be substituted or unsubstituted, and halo.

[0089] In embodiments, R-, is selected from the group consisting of phenyl, benzyl, pyridyl, thiophene, amido, amine, amino, and piperidine, all of which may be substituted or unsubstituted.

[0090] In one embodiment of the compound of formula (XI), R ₂ is selected from alkyl, aryl, alkylaryl, heterocyclyl, heteroaryl, cycloalkyi, O-alkyl and O-aryl, all of which may be substituted or unsubstituted.

[0091 ] In embodiments, R ₂ is selected from the group consisting of alkyl, phenyl, cyclohexyl, cyclopentyl, thiophene, pyridinyl, benzyl, thiazole, tetrahydropyranyl, furanyl, pyrazinyl, piperidinyl, thiophene, alkoxybutyl, pyrrolidinyl, morpholinyl, azepane, isoxazole and NR ₂ R ₃ , all of which may be substituted or unsubstituted, wherein R ₁₂ and R ₃ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and hexyl or R ₂ and R ₃ join to form a ring.

[0092] Suitably, in any one of the embodiments described above, substitution may be substitution selected from the group consisting of CrC ₆ alkyl, halo, C C ₆ alkoxy, cyano and hydroxyl.

[0093] In one embodiment, the compound of the first aspect is a trypanocidal compound.

[0094] In a preferred embodiment, the compound of the above formula is selected from the group consisting of:

wherein, R-, and R ₂ are as described for any one or more of the above embodiments.

[0095] In one embodiment, Ri is phenyl and R ₂ is selected from the group consisting of pyrrolidinyl, piperidinyl and azepane.

[0096] In one embodiment, the compound is selected from the group consisting of:

[0097] In one embodiment, the compound of any of the above formulae is a trypanocidal compound.

[0098] Suitably, in any one of the embodiments described above, substitution may be substitution selected from the group consisting of C C ₆ alkyl, d-C ₆ alkoxy, CrC ₆ aryl, CrC ₆ cycloalkyl, cyano, halo and hydroxyl.

[0099] In any one or more of the aforementioned embodiments, the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns. The combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to F) attached at the relevant point:

cyano, CrC ₆ alkyi, d-C ₆ haloalkyi CrC ₆ alkoxy, carboxyl, carboxy-CrC ₆ alkyi and amino and n is 1 , 2 or 3.

[00100] In any one or more of the aforementioned embodiments, the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns. The combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to F) attached at the relevant point:

and wherein each instance of R may be selected from hydrogen, fluoro, chloro and C C ₆ alkyl.

[00101 ] In any one or more of the aforementioned embodiments, the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged for 'R' are shown in the adjacent columns. The combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties (A to E) attached at the relevant point:

[00102] In any one or more of the aforementioned embodiments, the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged for 'R' are shown in the adjacent columns. The combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the adjacent moieties attached at the relevant point:

[00103] In any one or more of the aforementioned embodiments, the compound may be selected from those recited in the table below, wherein the core chemical structure with a right hand side moiety missing is shown in the left hand column and the possible replacements envisaged are shown in the adjacent columns. The combined structures are considered to have been disclosed as if each and every structure had been drawn with each of the ad acent moieties (A to F) attached at the relevant point:

[00104] In an embodiment, the compound of formula (I) to formula (XXV), as appropriate, is selected from the group consisting of:

wherein, for the purposes of this embodiment only, R ¹ to R ⁸ are independently selected from the group consisting of H, CH ₃ , CH ₂ CH ₃ , (CH ₂ ) ₂ CH ₃ , CH(CH ₃ ) ₂ , C(CH ₃ ) ₃ , OH, OCH ₃ ,O(CH ₂ CH ₃ ), CN, CO ₂ H, CO ₂ Me, CONH ₂ , C(O)NH(CH ₃ ), C(O)N(CH ₃ ) ₂ , F, CI, Br, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ NH ₂ , CH ₂ NH(CH ₃ ) and CH ₂ N(CH ₃ ) ₂ .

[00105] While the heterocyclic compounds shown all show interesting activities, in one embodiment, it is preferred that the heterocyclic ring of the compounds of the invention be selected from the group consisting of thiazole, pyrazole and pyridine.

[00106] In one embodiment, the compound is selected from the group consisting of:

[00107] The compounds can be synthesised by approaches which are known in the art. Such approaches can be found in reference texts and journal articles including the following: Eriiks, J.; Vandergoot, H.; Sterk, G.; Timmerman, H. J. Med. Chem, 1992, 35, 3239-3246; Walczynski, K.; Timmerman, H.; Zuiderveld, O.; Zhang, M.; Glinka, R. II Farmaco, 1999, 54, 533-541 ; Ahangar, N.; Ayatti, A.; Alipour, E.; Pashapour, A.; Formadi, A.; Emmami, S. Chem Biol Drug Des. 2011 , 78, 844-852; Caddick. S,; Judd. D.; Lewis. A,; Reich. M,; Williams.; M. Tetrahedron, 2003, 59, 5417-5423; Han, M.; Nam, K,; Shin, D.; Jeong, N.; Hahn, H. J. Comb. Chem.; 2010, 12, 518-530; Song, H; Wang, W.; Qin, Y. Synthetic Communications, 2005, 35, 2735-2748; and Duspara, P. A., et al. JOCS. 2012. 77, 10362-10368.

[00108] A number of synthetic pathways to one or more of the compounds of formula (I) to formula (XXV) are shown in FIGs 1 to 16. FIG 1 shows a synthetic scheme to access certain substituted thiazoles (J. Med. Chem, 1992, 35, 3239- 3246; and // Farmaco, 1999, 54, 533-541 ). FIG 2 {Chem Biol Drug Des. 2011 , 78, 844-852; Caddick. S; Judd. D.; Lewis. A,; Reich. M,; Williams.; M. Tetrahedron, 2003, 59, 5417-5423) shows a synthetic scheme yielding thiazoles with a differing substitution pattern from that in FIG 1 . FIG 3 shows a route to achieve a range of thiazole compounds which can then be further modified to either provide a urea linkage or offer a substituted amino group (Duspara, P. A., et al. JOCS. 2012. 77, 10362-10368). FIG 4 shows a synthesis to achieve a range of substituted pyrazole compounds. The final step shown leaves an ammonium moiety which is easily subsequently converted into a range of desirable functionalities in the manner already shown in FIG 2. FIG 5 presents a varying route to the same intermediate product as seen in FIG 4. FIG 6 then indicates another pathway by which the R-, and R ₂ moiety of the compounds can be manipulated. FIG 7 relates to modifications of the Ri and R ₂ positions of a thiazole heterocycle, once again indicating the flexibility in placing a range of functional groups at these positions.

[00109] FIG 8 shows a typical procedure used to synthesise 3-phenyl pyrazoles. This is applicable to a wide variation in the 3-position moieties as would be understood by those skilled in the art. Also, as shown, the RHS amine can be diversified to form ureas or amides. Derivatising to other amides and ureas is available to those skilled in the art. Additionally, the bromo ethyl warhead in the phthalimide could be replaced by an alkene, and the same reaction undertaken via Michael addition. These Michael acceptor principles are shown in FIG 9 wherein the synthetic utility is exemplified by showing how, in addition to the phthalimide-type approach of FIG 8, it is possible to utilize a Curtius rearrangement in order to introduce a variety of RHS (right hand side, as the compounds are drawn) groups.

[001 10] FIG 10 indicates, for a pyridyl core, similar synthetic principles, with options including Curtius rearrangement and Hofmann rearrangement routes. The main difference between this system and others, where instead of a nitrogen atom to join to in the core, there is a carbon, is the first step, where carbon-carbon bond-forming chemistry is possible, such as Suzuki, Heck or Sonogashira. In the particular scheme shown in FIG 10 a Heck reaction has been used. The chemistry shown is equally applicable to other heterocyclic cores such as the pyrimidines.

[001 1 1 ] FIG 1 1 shows a route by which 2-aryl- and 2-heterocyclo thiazoles can be assembled as is demonstrated specifically for 2-phenylthiazole compounds. It will be appreciated by a skilled artisan that manipulation of the 2- bromo moiety can be undertaken to give many variations and this is common to all cores where there is an intermediate aryl halide. Alternatives to this approach to achieve a similar class of end product are shown in FIGs 12, 13 and 14.

[001 12] A thiazole, or like heterocyclic, showing a different substitution pattern in that the ethylamide arm extends from the 2-position as opposed to the 4-position can be synthesized as demonstrated in FIG 15. A similar reversal of the positioning of the and R ₂ moieties is seen to be achieved for the pyrazole core in FIG 16.

[001 13] A very wide range of synthetic approaches have therefore been provided to allow access to the compounds of the invention. Such a large number of synthetic routes provides for maximum flexibility in synthesizing the compounds of the invention and should one particular route prove suboptimal then one of the specified alternatives may represent an improved position. It will be appreciated that while the synthetic schemes shown employ specific reactants to achieve a functional group transformation a wide range of similar commercially available reactants could be substituted in for those shown to provide the desired variability at each of the 'R' group positions.

[001 14] Further details of the synthetic approach to a range of compounds of the present invention is provided in the experimental section. [001 15] An important advantage presented by the compounds of the invention is that, as demonstrated by those with strong efficacy against both Trypanosoma brucei brucei and Trypanosoma cruzi, they are trypanosomacidal and not just trypanosomastatic.

[001 16] According to a second aspect of the invention there is provided a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

[001 17] Suitably, the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a trypanosomatid, preferably by a trypanosome.

[001 18] The pharmaceutical composition may include more than one compound of the first aspect. When the composition includes more than one compound then the compounds may be in any ratio. The composition may further comprise known co-actives, delivery vehicles or adjuvants.

[001 19] The compound of the first aspect is present in the pharmaceutical composition in an amount sufficient to inhibit or ameliorate the disease, disorder or condition which is the subject of treatment. Suitable dosage forms and rates of the compounds and the pharmaceutical compositions containing such may be readily determined by those skilled in the art.

[00120] Dosage forms may include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules and the like. These dosage forms may also include injecting or implanting devices designed specifically for, or modified to, ensure placement at the site of connective tissue degradation. A hydrogel is a preferred delivery form.

[00121 ] A third aspect of the invention resides in a method of treating a disease, disorder or condition caused by a trypanosomatid in a patient including the step of administering an effective amount of a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect to the patient, to thereby treat the disease, disorder or condition caused by the trypanosomatid.

[00122] A fourth aspect of the invention provides for a compound of the first aspect, or a pharmaceutically effective salt thereof, or the pharmaceutical composition of the second aspect for use in the treatment of a disease, disorder or condition caused by a trypanosomatid in a patient.

[00123] A fifth aspect of the invention provides for use of a compound of the first aspect, or a pharmaceutically effective salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition caused by a trypanosomatid.

[00124] In one embodiment of the third, fourth or fifth aspects, the disease, disorder or condition is caused by a trypanosome. In one embodiment, the disease, disorder or condition is trypanosomiasis.

[00125] The trypanosomiasis may be HAT or Chagas disease.

[00126] The trypanosome selected from the group consisting of Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma brucei brucei and Trypanosoma cruzi.

[00127] Preferably, the patient is a domestic or livestock animal or a human.

[00128] In one embodiment of the third, fourth or fifth aspects, the compound of the first aspect may be selected from any one or more compounds of formula I to formula XXV or any compound disclosed herein by way of a generic structure or exact chemical structure.

[00129] The following experimental section describes in more detail the characterisation of certain of the compounds of the invention and their efficacy against trypanosome species. The selectivity of certain of the compounds, given as their IC ₅₀ against human embryonic kidney (HEK) cells divided by their IC ₅ o against a specified trypanosome species, is also indicated and is an important indicatory of likely toxicity. The intention is to illustrate certain specific embodiments of the compounds of the invention and their efficacy without limiting the invention in any way.

EXPERIMENTAL General Synthetic Procedures and Characterisation Michael Addition

[00130] 3-Phenyl-1 H-pyrazole (1 .73 mmol), acrylate (5.20 mmol) and DBU (130 μΙ, 0.87 mmol) were combined in acetonitrile (3.5 ml), under nitrogen. The reaction was stirred at 50 °C for 18 h and monitored by TLC. Once complete all of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting with 15-25% ethyl acetate/petroleum spirits to obtain the desired product.

Curtius rearrangement

[00131 ] The carboxylic acid (0.87 mmol), diphenylphosphoryl azide (1 .04 mmol) and triethylamine (1 .04 mmol) were combined in anhydrous te/t-butanol (2 ml). The reaction mixture was heated to reflux for and the reaction progress was monitored by TLC and LRMS. Once complete a saturated aqueous solution of sodium bicarbonate was added and the product was extracted with ethyl acetate (three times). The organic layers were combined and washed once with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting with 0-15% ethyl acetate/petroleum spirit to obtain the desired product. tAmide coupling EDCI/DMAP

[00132] To a solution of the amine (0.39 mmol) in DMF (0.5 M final concentration) was added the benzoic acid (0.47 mmol), EDCI (0.47 mmol) and DMAP (0.04 mmol). The reaction mixture was stirred at 45 °C for 18 h. Water (approximately 2 ml) was added to the reaction mixture and the product extracted with ethyl acetate (three times). The organic layers were combined and dried with magnesium sulphate. All of the volatiles were remove in vacuo and the crude material was purified by column chromatography, eluting with 10% ethyl acetate/petroleum spirit to obtain the desired product.

Urea formation

[00133] The amine (0.30 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (2.97 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (0.45 mmol) was dissolved in anhydrous dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h, the secondary amine (0.60 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting with 40-60% ethyl acetate/dichloromethane. This gave the desired product.

Ester hydrolysis UOH/H20

[00134] The ester (1 .23 mmol) was dissolved in tetrahydrofuran (1 ml) and lithium hydroxide (59 mg, 2.46 mmol) dissolved in water (2.6 ml). The ester solution was added dropwise to the aqueous lithium hydroxide solution. The reaction mixture was stirred at ambient temperature and monitored by TLC and LRMS. Once complete, the reaction mixture was quenched by addition of an aqueous 1 M hydrochloric acid solution to acidic pH. The product was extracted with ethyl acetate (three times) and the subsequent organic layers were combined, washed one with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All volatiles were removed to yield the desired product.

Boc-deprotection with 4-toluenesulfonic acid [00135] To a solution of carbonate (0.5 mmol) in acetonitrile (2 imL) was added 4-toluenesulfonic acid hydrate (0.55 mmol). The suspension was refluxed until completion by TLC. The solution was then cooled to 0C in an ice bath. The precipitate was filtered, washed with cold acetonitrile (2 imL) and diethylether (2 x 10 imL) and finally dried in a vacuum oven at 50°C for 4h. The material was obtained as an aminium tosylate salt and used in the next step without further purification.

Boc-deprotection with TFA/DCM

[00136] The carbamate (0.1 7 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml) mixture. The reaction mixture was stirred at ambient temperature for 2 h and monitored by TLC. Once complete all of the volatiles were removed and the residue was washed with toluene three times to obtain the desired product which was used directly in the next step.

Suzuki coupling

[00137] Relevant arylbromide (1 .0 eq), potassium carbonate (4.0 eq), Arylboronic acid (1 .2 eq), TBAB (0.1 eq), PdCI ₂ (0.05 eq) and dppf (0.055 eq) were combined in a microwave reactor vessel with 4:1 dioxane and water (0.5 M final concentration) were added. The reaction mixture was irradiated in a CEM microwave at 130 °C for the time specified. The reaction was diluted with ethyl acetate and filtered through celite and the filtrate collected. The solvent was removed to give the crude product which was purified by column chromatography, eluting with ethyl acetate/petroleum benzine to give the desired product.

2-(2-(3-nitro-1H-pyrazol-1 -yl)ethyl)isoindoline-1 ,3-dione

[00138] To a solution of 3-nitropyrazole (10 g, 88.44 mmol) in dimethyl formamide (100 mL) was added potassium carbonate (24.62 g, 176.9 mmol, 2 eq) and N-(2-Bromoethyl)phthalimide (29.21 g, 1 14.97 mmol, 1 .3 eq). The mixture was then warmed to 50°C. After 3h, 300 mL of ice cold water was added and the precipitate collected by filtration. The solid was then recrystallised from ethanol to give the desired product (85%, 21 .5 g). The structure of the final product was confirmed by NMR and MS analyses.

2-(3-nitro- 1 H -pyrazol- 1 -yljethan- 1 -amine

[00139] To a solution of 2-(2-(3-nitro-1 H-pyrazol-1 -yl)ethyl)isoindoline-1 ,3- dione (5 g, 17.47 mmol) in ethanol (20 mL) was added hydrazine monohydrate (943 μί, 19.2 mmol, 1 .1 eq). The resulting mixture was stirred at 40°C. After completion of the reaction by TLC, the reaction mixture was filtered, dried over Na ₂ SO ₄ and concentrated under vacuum. The crude mixture was then taken up into toluene and evaporated under vacuum to remove the residue of hydrazine (3 times). The product (2.49 g, 91 %) was used in the next step without further purification. The structure of the final product was confirmed by NMR and MS analyses.

N-(2-(3-nitro-1H-pyrazol- 1 -yl)ethyl)piperidine- 1 -carboxamide

[00140] To a solution of the previously described crude amine (2 g, 12.8 mmol) and triethylamine (3.57 imL, 25.6 mmol, 2.0 eq) in tetrahydrofuran / dichloromethane 1 :1 (25 imL) at 0°C, a solution of 4-nitrophenyl chloroformate (5.16 g, 25.62 mmol, 2 eq) was added dropwise over 30 min. After 2hr, the resulting mixture was allowed to warm to room temperature and piperidine (6.3 imL, 64.0 mmol, 5 eq) was added. The solution was left at room temperature overnight and water was added. Water (50 imL) was added to the solution. The aqueous layer was then extracted with dichloromethane (3 x 70 imL). The combined organic layers was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude material was finally purified by column chromatography (eluent: DCM / MeOH gradient 99:1 to 95:5) to afford the desired material (2.39 g, 70%). The structure of the final product was confirmed by NMR and MS analyses.

N - (2-(3-amino- 1 H -pyrazol- 1 -yl)ethyl)pipehdine- 1 -carboxamide

[00141 ] To a solution of N-(2-(3-nitro-1 H-pyrazol-1 -yl)ethyl)piperidine-1 - carboxamide (1 g, 3.74 mmol) in MeOH (15 imL) was added ammonium formate (2.36 g, 37.4 mmol, 10 eq) and 10% Palladium on carbon (398 mg, 0.37 mmol, 10 mol%). The reaction mixture was refluxed 2hr. The solution was then filtered and dried over Na ₂ SO ₄ and concentrated under vacuum. The product (850 mg, 95%) was used without further purification. The structure of the final product was confirmed by NMR and MS analyses. -(2-(3-bromo-1W-pyrazoi- 1 -yl)ethyl)piperidine- 1 -carboxamide

[00142] To a solution of the N-(2-(3-amino-1 H-pyrazol-1 -yl)ethyl)piperidine-1 - carboxamide (100 mg, 0.42 mmol) in acetonitrile (5 imL) at 0°C was added a 48% aqueous solution of tetrafluoroboric acid (60 μΙ_, 0.46 mmol, 1 .1 eq) followed by terf-butylnitrite (61 μΙ_, 0.46 mmol, 1 .1 eq). The corresponding mixture was stirred at 0°C. After 1 hr, copper(ll) bromide (94 mg, 0.42 mmol, 1 .1 eq) was added and the resulting suspension heated at 50°C. After completion of the reaction by TLC, the suspension was diluted with a saturated solution of ammonium chloride (5 imL) and extracted with dichloromethane (3 x 10 imL). The organic layer were combined, dried over Na ₂ SO ₄ and concentrated under vacuum. The crude mixture was then purified by column chromatography over silica to afford the desired product (46 mg, 36%). The structure of the final product was confirmed by NMR and MS analyses.

N-(2-(3-aryl-1H-pyrazol- 1 -yl)ethyl)piperidine- 1 -carboxamide

[00143] Synthesised using the general procedure for Suzuki coupling.

Ethyl 2-(2-phenylthiazol-4-yl)acetate.

[00144] To a suspension of thiobenzamide (10 g, 72.89 mmol) in ethanol (100 mL) was added ethyl chloroacetoacetate (1 1 .53 mL, 80.17 mmol, 1 .1 eq), and the reaction mixture was heated to reflux for 8 h. The ethanol was evaporated under vacuum and the residue dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (60 mL), saturated solution of sodium bicarbonate (75 mL) and brine (50 mL). The organic layer was dried over MgSO ₄ , and concentrated under vacuum. The crude residue was then purified by column chromatography on silica (petroleum spirit / ethyl acetate gradient) to afford the desired product (15.9 g, 88%). The structure of the final product was confirmed by NMR and MS analyses.

2-(2-phenylthiazol-4-yl)ethan- 1 -ol

[00145] To a solution of ethyl 2-(2-phenylthiazol-4-yl)acetate (1 g, 4.04 mmol) in dry THF (15 mL) was cooled to -78°C, was added lithium aluminum hydride (306 mg, 8.09 mmol, 2 eq ). The mixture was stirred at -78°C for 1 hr and then allowed to warm to room temperature. After completion of the reaction by TLC, 1 M aqueous HCI (10 mL) was carefully added to reaction mixture followed by ethyl acetate (15 mL). The organic layer was collected and the aqueous layer washed with ethyl acetate (2 x 15 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The resulting material was purified by column chromatography on silica to afford the desired compound (759 mg, 91 %). The structure of the final product was confirmed by NMR and MS analyses.

2-(2-phenylthiazol-4-yl)ethyl methanesulfonate

[00146] To a solution of 2-(2-phenylthiazol-4-yl)ethan-1 -ol (100 mg, 0.49 mmol) and triethylamine (81 μΙ_, .584 mmol, 1 .2 eq) in CH ₂ CI ₂ (1 mL) at 0°C was added dropwise methanesulfonyl chloride (45 μί, 0.59 mmol, 1 .2 eq). The reaction was stirred at RT until completion by TLC. The solution was partitioned between CH ₂ CI ₂ (5 mL) and aqueous 1 M HCI (5 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuum. This crude material (1 12 mg, 81 %) was used in the next step without further purification. The structure of the final product was confirmed by NMR and MS analyses.

4 - (2-azidoethyl) -2-phenylthiazole

[00147] To a solution of 2-(2-phenylthiazol-4-yl)ethyl methanesulfonate (100 mg, 0.353 mmol) in dry DMF (1 imL) was added sodium azide (31 .1 mg, 0.494 mmol). The mixture was heated to 60°C. After completion of the reaction by TLC, the mixture was cooled to room temperature and diluted with ethyl acetate (10 imL). The solution was washed with water (3 x 10 imL) and brine (10 imL). The combined organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuum. The crude material was purified by column chromatography on silica to afford the desired material (71 mg, 87%). The structure of the final product was confirmed by NMR and MS analyses.

4-(2-aminoethyl)-2-phenylthiazole

[00148] To a solution of 4-(2-azidoethyl)-2-phenylthiazole (100 mg, 0.434 mmol) in methanol (3 imL) was added 10% Palladium on carbon (46 mg, 0.043 mmol, 10 mol%). The suspension was placed under a hydrogen atmosphere and left stirring for 5hr. The mixture was then filtered and the solvents removed under vacuum. The resulting amine was used in the next step without further purification. The structure of the final product was confirmed by NMR and MS analyses.

Amide formation

[00149] Amide were synthesised using the general procedure for amide synthesis

Urea formation

[00150] Ureas were synthesised using the general procedure for urea synthesis.

Methyl 3-(3-phenyl- 1 H -pyrazol- 1 -yljpropanoate

[00151] Synthesised using the general procedure for Michael addition.

3- (3-phenyl- 1 H -pyrazol- 1 -yljpropanoic acid

[00152] Synthesised using the general procedure for ester hydrolysis. ieri-butyl (2-(3-phenyl-1 -pyrazol-1-yl)ethyl)carbamate [00153] Synthesised using the general procedure for Curtius rearrangement. 2-(3-phenyl- 1 H -pyrazol- 1 -yljethan- 1 -aminium tosylate

[00154] Synthesised using the general procedure for boc-deprotection using

4- toluenesulfonic acid.

N-(2-(2-Phenylthiazol-4-yl)ethyl)isoxazole-3-carboxamide

[00155] To a solution of the 2-(2-phenylthiazol-4-yl)ethan-1 -amine (80 mg, 0.39 mmol) in DMF (1 ml) was added the 1 ,2-oxazole-3-carboxylic acid (53 mg, 0.47 mmol), EDCI (91 mg, 0.47 mmol) and DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred at 45 °C for 18 h. Water (approximately 2 ml) was added to the reaction mixture and the product extracted with ethyl acetate (three times). The organic layers were combined and dried with magnesium sulphate. All of the volatiles were remove in vacuo and the crude material was purified by column chromatography, eluting with 10% ethyl acetate/petroleum spirit to obtain the desired product as a pale-orange oil (17 mg, 15%). LRMS [M+H] ⁺ 300.1 m/z; HRMS [M+H] ⁺ 300.0801 m/z, found 300.0802 m/z; ¹ H NMR (400 MHz, DMSO) δ 9.08 (d, J = 1 .7 Hz, 1 H), 8.94 (t, J = 5.6 Hz, 1 H), 8.06 - 7.81 (m, 2H), 7.58 - 7.45 (m, 3H), 7.44 (s, 1 H), 6.88 (d, J = 1 .7 Hz, 1 H), 3.63 (dd, J = 13.1 , 7.2 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H).

4-Bromo-N-(2-(2-phenylthiazol-4-yl)ethyl)furan-2-carboxam ide

[00156] To a solution of the 2-(2-phenylthiazol-4-yl)ethan-1 -amine (80 mg, 0.39 mmol) in DMF (1 ml) was added the 4-bromo-2-furoic acid (90 mg, 0.47 mmol), EDCI (91 mg, 0.47 mmol) and DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred at 45 °C for 18 h. Water (approximately 2 ml) was added to the reaction mixture and the product extracted with ethyl acetate (three times). The organic layers were combined and dried with magnesium sulphate. All of the volatiles were remove in vacuo and the crude material was purified by column chromatography, eluting with 10% ethyl acetate/petroleum spirit to obtain the desired product as a colourless solid (13 mg, 9%). LRMS [M+H] ⁺ 377.1 m/z (Br ⁷⁹ ), 379.1 m/z (Br ⁸¹ ); HRMS [M+H] ⁺ 376.9954 m/z, found 376.9960 m/z (Br ⁷⁹ ), 378.9934 m/z, found 378.9940 m/z (Br ⁸¹ ); ¹ H NMR (400 MHz, DMSO) δ 8.62 (t, J= 5.7 Hz, 1 H), 8.1 1 (d, J= 0.8 Hz, 1 H), 7.99 - 7.81 (m, 2H), 7.59 - 7.45 (m, 3H), 7.42 (s, 1 H), 7.24 (d, J = 0.8 Hz, 1 H), 3.58 (dd, J = 13.1 , 7.1 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H).

Methyl 2-methyl-3-(3-phenyl-1H-pyrazol- 1 -yljpropanoate [00157] 3-Phenyl-1 H-pyrazole (250 mg, 1 .73 mmol), methyl methacrylate (280 μΙ, 2.60 mmol) and DBU (130 μΙ, 0.87 mmol) were combined in acetonitrile (3.5 ml), under nitrogen. The reaction was stirred at 50 °C for 18 h, though by TLC there was only a 50% conversion of the starting material to product. Additional methyl methacrylate (280 μΙ, 2.60 mmol) added to the reaction, and returned to heat at 50 °C for an additional 2 h. By TLC the reaction was complete and all volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 15-25% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless oil (342 mg, 81 %). LRMS [M+H] ⁺ 245.2 m/z; HRMS [M+H] ⁺ 245.1285 m/z, found 245.1284 m/z; ¹ H NMR (400 MHz, DMSO) δ 7.76 (ddd, J= 9.8, 6.3, 1 .8 Hz, 3H), 7.44 - 7.33 (m, 2H), 7.29 (dt, J = 9.3, 4.3 Hz, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 4.37 (dd, J = 13.6, 7.1 Hz, 1 H), 4.25 (dd, J= 13.6, 6.4 Hz, 1 H), 3.61 (s, 3H), 3.06 (dd, J= 13.7, 7.0 Hz, 1 H), 1 .06 (d, J = 7.1 Hz, 3H).

2-Methyl-3-(3-phenyl- 1 H -pyrazol- 1 -yljpropanoic acid

[00158] Methyl 2-methyl-3-(3-phenyl-1 H-pyrazol-1 -yl)propanoate (300 mg, 1 .23 mmol) dissolved in tetrahydrofuran (1 ml) and lithium hydroxide (59 mg, 2.46 mmol) dissolved in water (2.6 ml). The ester solution was added dropwise to the aqueous lithium hydroxide solution. The reaction mixture was stirred for 90 min and LRMS showed complete hydrolysis. The reaction mixture was quenched by addition of an aqueous 1 M hydrochloric acid solution to acidic pH. The product was extracted with ethyl acetate (three times) and the subsequent organic layers were combined, washed one with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All volatiles were removed to yield the title compound as a pale-yellow oil (249 mg, 88%). LRMS [M+H] ⁺ 231 .1 m/z; HRMS [M+H] ⁺ 231 .1 128 m/z, found 231 .1 127 m/z; ¹ H NMR (400 MHz, DMSO) δ 12.47 (s, 1 H), 7.88 - 7.65 (m, 3H), 7.45 - 7.33 (m, 2H), 7.33 - 7.17 (m, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 4.38 (dd, = 13.6, 7.0 Hz, 1 H), 4.17 (dd, J = 13.6, 7.0 Hz, 1 H), 2.98 (h, J = 7.1 Hz, 1 H), 1 .06 (d, J = 7.1 Hz, 3H). Teri-butyl ( 1 -(3-phenyl-1H-pyrazol- 1 -yl)propan-2-yl)carbamate

[00159] 2-Methyl-3-(3-phenyl-1 H-pyrazol-1 -yl)propanoic acid (200 mg, 0.87 mmol), diphenylphosphoryl azide (225 μΙ, 1 .04 mmol) and triethylamine (140 μΙ, 1 .04 mmol) were combined in anhydrous terf-butanol (2 ml). The reaction mixture was heated to reflux for 4 h and the reaction progress was monitored by LRMS. A saturated aqueous solution of sodium bicarbonate was added and the product was extracted with ethyl acetate (three times). The organic layers were combined and washed one with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-15% ethyl acetate/petroleum spirit. The title compound was obtained as a colourless solid (1 13 mg, 43%). LRMS [M+H] ⁺ 302.2 m/z, [M- ^t Bu] ⁺ 246.2 m/z; ¹ H NMR (400 MHz, DMSO) δ 7.86 - 7.73 (m, 2H), 7.69 (d, J= 1 .9 Hz, 1 H), 7.39 (dd, J = 10.5, 4.7 Hz, 2H), 7.33 - 7.21 (m, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 4.09 (qd, J = 13.9, 7.2 Hz, 2H), 3.91 (dt, J = 14.1 , 6.9 Hz, 1 H), 1 .35 (s, 9H), 1 .01 (d, J = 6.6 Hz, 3H).

1-(3-Phenyl- 1 H -pyrazol- 1 -yl)propan-2-amine

[00160] Teri-butyl (1 -(3-phenyl-1 H-pyrazol-1 -yl)propan-2-yl)carbamate (50 mg, 0.17 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 2 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a colourless solid which was used directly. LRMS [M+H] ⁺ 202.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.77 - 7.62 (m, 2H), 7.41 - 7.32 (m, 3H), 7.30 (dt, J = 9.6, 4.3 Hz, 1 H), 6.52 (d, J = 2.4 Hz, 1 H), 5.10 (s, 2H), 4.25 (qd, J = 14.6, 5.1 Hz, 2H), 3.82 (s, 1 H), 1 .27 (d, J = 6.7 Hz, 3H).

N -( 1-(3-Phenyl-1H-pyrazol- 1 -yl)propan-2-yl)pipehdine- 1 -carboxamide

[00161] 1 -(3-Phenyl-1 H-pyrazol-1 -yl)propan-2-amine (60 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (420 μΙ, 2.97 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (90 mg, 0.45 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (60 μΙ, 0.60 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 40-60% ethyl acetate/dichloromethane. This yielded the title compound with contaminants so the material was further purified by column chromatography, eluting 25-50% ethyl acetate/petroleum spirits to 40% ethyl acetate/dichloromethane. This gave the title compound as a colourless oil (27 mg, 29%). LRMS [M+H] ⁺ 313.3 m/z; HRMS [M+H] ⁺ 313.2023 m/z, found 313.2027 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.77 (dd, J = 5.2, 3.2 Hz, 2H), 7.41 (d, J = 2.3 Hz, 1 H), 7.39 - 7.32 (m, 2H), 7.30 - 7.24 (m, 1 H), 6.52 (d, J = 2.3 Hz, 1 H), 5.35 (t, J = 4.9 Hz, 1 H), 4.62 - 4.37 (m, 1 H), 3.72 (dd, J = 6.1 , 3.6 Hz, 1 H), 3.46 (ddd, J = 13.7, 8.5, 5.1 Hz, 1 H), 1 .53 (d, J = 6.8 Hz, 6H), 1 .45 (d, J = 4.4 Hz, 4H), 1 .20 (t, J = 7.0 Hz, 3H).

Methyl 3-(3-phenyl- 1 H -pyrazol- 1 -yl)butanoate

[00162] 3-Phenyl-1 H-pyrazole (250 mg, 1 .73 mmol), methyl crotonate (275 μΙ, 2.60 mmol) and DBU (130 μΙ, 0.87 mmol) were combined in acetonitrile (3.5 ml), under nitrogen. The reaction was stirred at 50 °C for 18 h and by TLC the reaction was complete. All of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 15-25% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless oil

[32] mg, 76%). HPLC - rt 7.48 min > 98% purity at 254 nm; LRMS [M+H] ⁺ 245.2 m/z; HRMS [M+H] ⁺ 245.1285 m/z, found 245.1284 m/z; ¹ H NMR (400 MHz, DMSO) δ 7.87 - 7.70 (m, 3H), 7.44 - 7.33 (m, 2H), 7.33 - 7.19 (m, 1 H), 6.66 (d, J = 2.3 Hz, 1 H), 4.93 - 4.62 (m, 1 H), 3.56 (s, 3H), 2.93 (ddd, J= 22.0, 16.0, 7.0 Hz, 2H), 1 .48 (d, J = 6.8 Hz, 3H); ¹³ C NMR (101 MHz, DMSO) δ 170.8, 149.7, 133.5, 130.3, 128.6 (2C), 127.3, 125.0 (2C), 102.2, 54.0, 51 .5, 40.5, 20.9.

3-(3-Phenyl-1H-pyrazol- 1 -yljbutanoic acid

[00163] Methyl 3-(3-phenyl-1 H-pyrazol-1 -yl)butanoate (300 mg, 1 .23 mmol) dissolved in tetrahydrofuran (1 ml) and lithium hydroxide (59 mg, 2.46 mmol) dissolved in water (2.6 ml). The ester solution was added dropwise to the aqueous lithium hydroxide solution. The reaction mixture was stirred for 90 min and LRMS showed complete hydrolysis. The reaction mixture was quenched by addition of an aqueous 1 M hydrochloric acid solution to acidic pH. The product was extracted with ethyl acetate (three times) and the subsequent organic layers were combined, washed one with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All volatiles were removed to yield the title compound as a pale-yellow oil (251 mg, 87%). LRMS [M+H] ⁺ 231 .2 m/z; HRMS [M+H] ⁺ 231 .1 128 m/z, found 231 .1 128 m/z; ¹ H NMR (400 MHz, DMSO) δ 7.95 - 7.64 (m, 3H), 7.38 (t, J= 7.6 Hz, 2H), 7.27 (t, J= 7.3 Hz, 1 H), 6.66 (d, J= 2.3 Hz, 1 H), 4.75 (dd, J= 14.1 , 6.7 Hz, 1 H), 2.92 (dd, J= 16.2, 7.9 Hz, 1 H), 2.77 (dd, J = 16.2, 6.2 Hz, 1 H), 1 .46 (d, J = 6.7 Hz, 3H).

Jett-butyl (2-(3-phenyl-1 -pyrazol-1-yl)propyl)carbamate

[00164] 3-(3-Phenyl-1 H-pyrazol-1 -yl)butanoic acid (100 mg, 0.43 mmol), diphenylphosphoryl azide (1 15 μΙ, 0.52 mmol) and triethylamine (70 μΙ, 0.52 mmol) were combined in anhydrous terf-butanol (1 ml). The reaction mixture was heated to reflux for 12 h and the reaction progress was monitored by LRMS. A saturated aqueous solution of sodium bicarbonate was added and the product was extracted with ethyl acetate (three times). The organic layers were combined and washed one with a saturated aqueous solution of sodium chloride and dried with magnesium sulphate. All of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-15% ethyl acetate/petroleum spirit. The title compound was obtained as a colourless solid (42 mg, 32%). LRMS [M+H] ⁺ 302.2 m/z, [M- ^t Bu] ⁺ 246.1 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.88 - 7.75 (m, 2H), 7.46 - 7.35 (m, 3H), 7.30 (ddd, J = 7.4, 3.9, 1 .3 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 5.00 - 4.75 (m, 1 H), 4.59 - 4.38 (m, J = 10.8, 7.9 Hz, 1 H), 3.72 - 3.56 (m, 1 H), 3.50 (ddd, J = 14.1 , 8.4, 5.6 Hz, 1 H), 1 .53 (d, J = 6.8 Hz, 3H), 1 .42 (s, 9H).

2-(3-Phenyl- 1 H -pyrazol- 1 -yljpropan- 1 -amine

[00165] Terf-butyl (2-(3-phenyl-1 H-pyrazol-1 -yl)propyl)carbamate (50 mg, 0.17 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 2 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a colourless solid which was used directly. LRMS [M+H] ⁺ 202.2 m/z; ¹ H NMR (400 MHz, DMSO) δ 8.37 (d, J = 0.8 Hz, 2H), 8.33 (d, J = 2.4 Hz, 1 H), 8.29 (dd, J= 8.3, 1 .2 Hz, 2H), 7.96 - 7.82 (m, 2H), 7.82 - 7.71 (m, 1 H), 5.1 9 - 5.02 (m, 1 H), 3.92 - 3.62 (m, 2H), 2.96 (dt, J = 3.6, 1 .8 Hz, 3H). ^* Note: there is one aromatic proton missing from the proton spectrum.

N-(2-(3-Phenyl-1H-pyrazol- 1 -yl)propyl)pipehdine- 1 -carboxamide

[00166] 1 -(3-Phenyl-1 H-pyrazol-1 -yl)propan-2-amine (80 mg, 0.40 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (555 μΙ, 3.97 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (120 mg, 0.60 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (80 μΙ, 0.80 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 40-60% ethyl acetate/dichloromethane. This yielded the title compound with contaminants so the material was further purified by column chromatography, eluting 25-50% ethyl acetate/petroleum spirits to 40% ethyl acetate/dichloromethane. This gave the title compound as a colourless oil (16 mg, 13%). LRMS [M+H] ⁺ 313.3 m/z; HRMS [M+H] ⁺ 313.2023 m/z, found 313.2028 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.89 - 7.65 (m, 2H), 7.49 - 7.31 (m, 3H), 7.31 - 7.25 (m, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 5.88 (d, J = 7.1 Hz, 1 H), 4.32 (dd, J = 13.7, 3.6 Hz, 1 H), 4.29 - 4.17 (m, 1 H), 4.10 (dd, J = 13.7, 4.8 Hz, 1 H), 3.31 (h, J = 8.6 Hz, 4H), 1 .67 - 1 .41 (m, 6H), 1 .08 (d, J = 6.6 Hz, 3H).

Tert-butyl (S)-(1 -(3-phenyl-1H-pyrazol- 1 -yl)propan-2-yl)carbamate

[00167] 3-Phenyl-1 H-pyrazole (200 mg, 1 .39 mmol), cesium carbonate (4.52 g, 13.90 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (704 mg, 2.78 mmol) were combined in anhydrous A/,A/-dimethylformamide (4 ml). The resulting suspension was heated to 50 °C and the progress of the reaction was monitored by TLC. Once the reaction was complete (~ 3 h) the reaction mixture was quenched by addition of water and the product was extracted with ethyl acetate three times. The organic layers were combined and washed with a saturated aqueous solution of sodium chloride. The crude material was purified by column chromatography, eluting 20% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (183 mg, 44%). LRMS [M+H] ⁺ 302.2 m/z; HRMS [M+H] ⁺ 302.1863 m/z, found 302.1867 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.87 - 7.70 (m, 2H), 7.41 - 7.34 (m, 3H), 7.31 - 7.25 (m, 1 H), 6.54 (d, J= 2.3 Hz, 1 H), 5.06 (d, J= 1 .1 Hz, 1 H), 4.25 (dd, J = 13.8, 4.5 Hz, 1 H), 4.20 - 4.10 (m, 1 H), 4.04 (dt, J = 12.4, 6.0 Hz, 1 H), 1 .41 (s, 10H), 1 .12 (d, J = 6.8 Hz, 3H).

(S)-1-(3-Phenyl-1H-pyrazol- 1 -yl)propan-2-amine

[00168] Terf-butyl (S)-(1 -(3-phenyl-1 H-pyrazol-1 -yl)propan-2-yl)carbamate (50 mg, 0.17 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 2 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a colourless solid which was used directly. LRMS [M+H] ⁺ 202.1 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.71 (d, J= 8.0 Hz, 2H), 7.37 (dddd, J = 12.8, 1 1 .3, 5.7, 3.0 Hz, 3H), 7.19 - 7.10 (m, 1 H), 6.64 - 6.51 (m, 1 H), 4.46 - 4.31 (m, 1 H), 4.26 (ddd, J = 1 1 .9, 6.6, 4.8 Hz, 1 H), 2.99 (s, 2H), 2.34 (s, 1 H), 1 .34 (dd, J = 12.6, 6.4 Hz, 3H).

(S)-N -( 1-(3-Phenyl-1 -pyrazol- 1 -yl)propan-2-yl)pipehdine- 1 -carboxamide

[00169] (S)-1 -(3-Phenyl-1 H-pyrazol-1 -yl)propan-2-amine (67 mg, 0.33 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (464 μΙ, 3.33 mmol) added (solution 1 ). In a separate flask para- nitrophenylchloroformate (100 mg, 0.50 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (65 μΙ, 0.66 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 5% ethyl acetate/dichloromethane. This yielded the title compound as a pale-yellow oil (27 mg, 26%). LRMS [M+H] ⁺ 313.3 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.87 - 7.67 (m, 2H), 7.41 - 7.33 (m, 3H), 7.31 - 7.25 (m, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 6.06 - 5.90 (m, 1 H), 4.32 (dd, J = 13.7, 3.6 Hz, 1 H), 4.28 - 4.19 (m, 1 H), 4.12 - 4.02 (m, 1 H), 3.32 (dd, J = 9.0, 4.4 Hz, 4H), 1 .64 - 1 .42 (m, 6H), 1 .09 (t, J = 6.2 Hz, 3H).

Jert-butyl (H)-( 1 -(3-phenyl-1H-pyrazol- 1 -yl)propan-2-yl)carbamate

[00170] 3-Phenyl-1 H-pyrazole (200 mg, 1 .39 mmol), cesium carbonate (4.52 g, 13.90 mmol) and (fi)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (704 mg, 2.78 mmol) were combined in anhydrous A/,A/-dimethylformamide (4 ml). The resulting suspension was heated to 50 °C and the progress of the reaction was monitored by TLC. Once the reaction was complete (~ 3 h) the reaction mixture was quenched by addition of water and the product was extracted with ethyl acetate three times. The organic layers were combined and washed with a saturated aqueous solution of sodium chloride. The crude material was purified by column chromatography, eluting 20% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (177 mg, 42%). LRMS [M+H] ⁺ 302.2 m/z; HRMS [M+H] ⁺ 302.1863 m/z found 302.1864 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.86 - 7.73 (m, 2H), 7.43 - 7.35 (m, 3H), 7.33 - 7.27 (m, 1 H), 6.55 (d, J= 2.3 Hz, 1 H), 5.08 (s, 1 H), 4.27 (dd, J = 13.7, 4.5 Hz, 1 H), 4.23 - 4.13 (m, 1 H), 4.05 (dd, J= 12.7, 5.8 Hz, 1 H), 1 .43 (s, 9H), 1 .14 (d, J = 6.8 Hz, 3H).

(R)-1 -(3-Phenyl- 1 H -pyrazol- 1 -yl)propan-2-amine

[00171] Terf-butyl (fl)-(1 -(3-phenyl-1 H-pyrazol-1 -yl)propan-2-yl)carbamate (239 mg, 0.79 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 18 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a yellow oil which was used directly. LRMS [M+H] ⁺ 202.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.70 (d, J= 8.0 Hz, 2H), 7.37 (dddd, J= 12.8, 1 1 .3, 5.7, 3.0 Hz, 3H), 7.17 - 7. 09 (m, 1 H), 6.64 - 6.51 (m, 1 H), 4.46 - 4.31 (m, 1 H), 4.26 (ddd, J = 1 1 .9, 6.6, 4.8 Hz, 1 H), 2.99 (s, 2H), 2.35 (s, 1 H), 1 .30 (dd, J = 12.6, 6.4 Hz, 3H).

(R)-N -( 1 -(3-Phenyl- 1 H -pyrazol- 1 -yl)propan-2-yl)piperidine- 1 -carboxamide

[00172] (ft)-1 -(3-Phenyl-1 H-pyrazol-1 -yl)propan-2-amine (159 mg, 0.79 mmol) was dissolved in a 50:50 solution of anhydrous dichloromethane and tetrahydrofuran (2 ml) and triethylamine (1 .1 ml, 7.90 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (796 mg, 3.95 mmol) was dissolved in dichloromethane (1 ml) and tetrahydrofuran (2 ml) with stirring (solution 2). Solution 2 was cooled to 0 °C prior to dropwise addition of solution 1 . The reaction was allowed to warm to ambient temperature and stirred for 2 h. After 2 h piperidine (160 μΙ, 1 .58 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-30% ethyl acetate/dichloromethane. This yielded the title compound as a pale-yellow oil (135 mg, 55%). LRMS [M+H] ⁺ 313.2 m/z; HRMS [M+H] ⁺ 313.2023 m/z, found 313.2027 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.86 - 7.67 (m, 2H), 7.48 - 7.34 (m, 3H), 7.29 (dt, J= 9.4, 4.3 Hz, 1 H), 6.56 (d, J = 2.3 Hz, 1 H), 5.99 (s, 1 H), 4.34 (dd, J = 13.8, 3.5 Hz, 1 H), 4.30 - 4.19 (m, 1 H), 4.10 (dd, J = 13.8, 4.8 Hz, 1 H), 3.42 - 3.22 (m, 4H), 1 .53 (ddd, J = 16.0, 9.0, 4.4 Hz, 6H), 1 .09 (d, J = 6.6 Hz, 3H).

Teri-butyl (R )-(2-(3-phenyl-1H-pyrazol- 1 -yl)propyl)carbamate

[00173] 3-Phenyl-1 H-pyrazole (250 mg, 1 .73 mmol), cesium carbonate (5.65 g, 17.30 mmol) and (S)-1 -((ieri-butoxycarbonyl)amino)propan-2-yl methanesulfonate (876 mg, 3.46 mmol) were combined in anhydrous N,N- dimethylformamide (10 ml). The resulting suspension was heated to 50 °C and the progress of the reaction was monitored by TLC. Once the reaction was complete (~ 18 h) the reaction mixture was quenched by addition of water and the product was extracted with ethyl acetate three times. The organic layers were combined and washed with a saturated aqueous solution of sodium chloride. All of the volatiles were removed in vacuo. The crude material was purified by column chromatography, eluting 5-10% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (60 mg, 12%). LRMS [M+H] ⁺ 302.2 m/z; HRMS [M+H] ⁺ 302.1863 m/z, found 302.1867 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.85 - 7.72 (m, 2H), 7.41 - 7.33 (m, 3H), 7.31 - 7.25 (m, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 5.05 (d, J = 1 .1 Hz, 1 H), 4.26 (dd, J = 13.8, 4.5 Hz, 1 H), 4.21 - 4.10 (m, 1 H), 4.05 (dd, J= 12.6, 6.7 Hz, 1 H), 1 .41 (s, 9H), 1 .12 (d, J = 6.8 Hz, 3H).

(Ή )-2-(3-Phenyl- 1 H -pyrazol- 1 -yljpropan- 1 -amine

[00174] Terf-butyl (ft)-(2-(3-phenyl-1 H-pyrazol-1 -yl)propyl)carbamate (239 mg, 0.79 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 18 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a brown oil which was used directly. LRMS [M+H] ⁺ 202.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.79 - 7.63 (m, 2H), 7.48 (d, J= 2.4 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 2H), 7.34 - 7.26 (m, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 4.65 (dd, J = 12.3, 6.1 Hz, 1 H), 3.40 (d, J = 5.7 Hz, 2H), 2.66 (s, 2H), 1 .58 (d, J = 6.8 Hz, 3H).

(R)-N -(2-(3-Phenyl- 1 H -pyrazol- 1 -yl)propyl)piperidine- 1 -carboxamide

[00175] (ft)-2-(3-Phenyl-1 H-pyrazol-1 -yl)propan-1 -amine (35 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (0.5 ml) and triethylamine (125 μΙ, 1 .70 mmol) added (solution 1 ). In a separate flask para- nitrophenylchloroformate (69 mg, 0.34 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (35 μΙ, 0.34 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 10-50% ethyl acetate/dichloromethane (32 mg, 60%). A portion of the material was further purified by chiral HPLC using a ChiralPAX column and eluting with 10% ethanol/petroleum spirits to ensure > 99.9% e.e.. This yielded the title compound as a clear oil. cHPLC - 8.63 min, >99.9% ee; LRMS [M+H] ⁺ 313.3 m/z; HRMS [M+H] ⁺ 313.2023 m/z, found 313.2025 m/z; ¹ H NMR (400 MHz, CDCIs) δ 7.85 - 7.71 (m, 2H), 7.41 (d, J = 2.3 Hz, 1 H), 7.40 - 7.32 (m, 2H), 7.31 - 7.24 (m, 1 H), 6.53 (d, J = 2.3 Hz, 1 H), 5.32 (s, 1 H), 4.50 (dqd, J = 8.3, 6.8, 3.5 Hz, 1 H), 3.71 (d, J= 13.7 Hz, 1 H), 3.47 (dd, J= 13.5, 8.6 Hz, 1 H), 3.33 - 3.19 (m, 4H), 1 .51 (t, J = 15.5 Hz, 6H).

Tert-butyl (S)-(2-(3-phenyl-1H-pyrazol- 1 -yl)propyl)carbamate

[00176] 3-Phenyl-1 H-pyrazole (250 mg, 1 .73 mmol), cesium carbonate (5.65 g, 17.30 mmol) and (H)-1 -((ieri-butoxycarbonyl)amino)propan-2-yl methanesulfonate (876 mg, 3.46 mmol) were combined in anhydrous N,N- dimethylformamide (10 ml). The resulting suspension was heated to 50 °C and the progress of the reaction was monitored by TLC. Once the reaction was complete (~ 18 h) the reaction mixture was quenched by addition of water and the product was extracted with ethyl acetate three times. The organic layers were combined and washed with a saturated aqueous solution of sodium chloride. All of the volatiles were removed in vacuo. The crude material was purified by column chromatography, eluting 5-10% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (97 mg, 19%). LRMS [M+H] ⁺ 302.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.87 - 7.71 (m, 2H), 7.38 (dd, J = 13.0, 5.1 Hz, 3H), 7.31 - 7.25 (m, 1 H), 6.53 (d, J = 2.3 Hz, 1 H), 4.87 (s, 1 H), 4.56 - 4.37 (m, 1 H), 3.60 (ddd, J = 13.6, 6.6, 4.1 Hz, 1 H), 3.47 (ddd, J = 14.1 , 8.5, 5.6 Hz, 1 H), 1 .51 (d, J = 6.8 Hz, 3H), 1 .40 (s, 9H).

(S)-2-(3-Phenyl-1H-pyrazol- 1 -yljpropan- 1 -amine

[00177] Terf-butyl (S)-(2-(3-phenyl-1 H-pyrazol-1 -yl)propyl)carbamate (239 mg, 0.79 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (1 ml). The reaction mixture was stirred at ambient temperature for 18 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a brown oil which was used directly. LRMS [M+H] ⁺ 202.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.78 - 7.62 (m, 2H), 7.49 (d, J= 2.4 Hz, 1 H), 7.41

- 7.34 (m, 2H), 7.31 (dt, J= 9.6, 4.3 Hz, 1 H), 6.58 (d, J= 2.4 Hz, 1 H), 4.64 (dd, J= 12.7, 6.2 Hz, 1 H), 4.48 (s, 2H), 3.41 (d, J= 5.7 Hz, 2H), 1 .58 (d, J= 6.9 Hz, 3H).

(S)-N-(2-(3-Phenyl-1H-pyrazol- 1 -yl)propyl)piperidine- 1 -carboxamide

[00178] (S)-2-(3-Phenyl-1 H-pyrazol-1 -yl)propan-1 -amine (35 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (0.5 ml) and triethylamine (125 μΙ, 1 .70 mmol) added (solution 1 ). In a separate flask para- nitrophenylchloroformate (69 mg, 0.34 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (35 μΙ, 0.34 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 10-50% ethyl acetate/dichloromethane (40 mg, 75%). A portion of the material was further purified by chiral HPLC using a ChiralPAX column and eluting with 10% ethanol/petroleum spirits to ensure > 99.9% e.e.. This yielded the title compound as a clear oil. cHPLC - rt 9.84 min, >99.9% ee; LRMS [M+H] ⁺ 313.2 m/z; HRMS [M+H] ⁺ 313.2023 m/z, found 313.2025 m/z; ¹ H NMR (400 MHz, CDCIs) δ 7.87 - 7.70 (m, 2H), 7.41 (d, J = 2.3 Hz, 1 H), 7.40 - 7.33 (m, 2H), 7.30 - 7.25 (m, 1 H), 6.53 (d, J = 2.3 Hz, 1 H), 5.34 (s, 1 H), 4.50 (dqd, J = 8.4, 6.8, 3.5 Hz, 1 H), 3.71 (d, J= 13.6 Hz, 1 H), 3.47 (dd, J= 13.6, 8.5 Hz, 1 H), 3.32

- 3.15 (m, 4H), 1 .50 (dd, J = 29.9, 5.6 Hz, 6H).

22%

2-Bromo-6-phenylpyridine

[00179] 2,6-Dibromopyridine (2 g, 8.44 mmol), phenylboronic acid (1 .03 g, 8.44 mmol), potassium carbonate (4.67 g, 33.77 mmol) and TBAB (271 mg, 0.84 mmol) were combined in a mixture of 1 ,4-dioxane (16 ml) and water (4 ml). The reaction mixture was degassed by bubbling nitrogen through for 30 min prior to the addition of PdCI ₂ (dppf) (62 mg, 0.084 mmol). The reaction mixture was stirred at 40 °C for 1 h before being filtered through celite. The filtrate was collected and the solvent removed. The crude material was then purified by column chromatography, eluting 100% petroleum spirits to give the title compound as a colourless solid (1 .85 g, 93%). ¹ H NMR (400 MHz, DMSO) δ 8.56 (dd, J= 6.3, 2.4 Hz, 1 H), 8.36 - 8.18 (m, 2H), 8.16 - 8.00 (m, 2H), 7.61 - 7.53 (m, 2H), 7.53 - 7.45 (m, 1 H).

2-Phenyl-6-vinylpyridine ² [00180] 2-Bromo-6-phenylpyridine (959 mg, 4.10 mmol), tributyl(vinyl) tin (2.40 ml, 8.20 mmol), palladium acetate (138 mg, 0.62 mmol) and triphenylphosphine (323 mg, 1 .23 mmol) were combined in tetrahydrofuran (8.2 ml) and the reaction mixture was thoroughly degassed. The reaction mixture was refluxed for 48 h and monitored for completion. Once complete, the reaction mixture was filtered through celite and the filtrate concentrated. The crude material was purified by column chromatography, eluting 0-5% ethyl acetate/petroleum spirits to give the title compound as a clear oil (713 mg, 96%). ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.08 - 8.01 (m, 2H), 7.69 (t, J= 7.8 Hz, 1 H), 7.63 - 7.55 (m, 1 H), 7.51 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1 H), 6.88 (dd, J = 17.4, 10.7 Hz, 1 H), 6.34 (dd, J = 17.4, 1 .4 Hz, 1 H), 5.48 (td, J = 10.9, 1 .4 Hz, 2H).

Ethyl ( 1 R,2R)-2-(6-phenylpyridin-2-yl)cyclopropane- 1 -carboxylate

[00181 ] 2-Phenyl-6-vinylpyridine (710 mg, 3.92 mmol) was added to ethyl diazoacetate (8 ml) and the reaction mixture was refluxed for 18 h. The reaction mixture was then concentrated in vacuo and the crude material was purified by column chromatography, eluting 0-10% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless solid (310 mg, 30%). LRMS [M+H] ⁺ 268.2 m/z; HRMS [M+H] ⁺ 268.1332 m/z, found 268.1334 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.06 - 7.97 (m, 2H), 7.65 (t, J = 7.7 Hz, 1 H), 7.60 - 7.55 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.44 - 7.38 (m, 1 H), 7.20 (dt, J = 4.0, 3.3 Hz, 1 H), 4.20 (qd, J = 7.1 , 1 .2 Hz, 2H), 2.67 (ddd, J = 8.0, 4.0 Hz, 1 H), 2.43 (ddd, J = 8.5, 5.5, 3.9 Hz, 1 H), 1 .77 (ddd, J = 8.5, 6.0, 3.6 Hz, 1 H), 1 .64 (ddd, J = 8.9, 5.5, 3.6 Hz, 1 H), 1 .30 (t, J = 8.0 Hz, 3H).

Ethyl ( 1 R,2S )-2-(6-phenylpyridin-2-yl)cyclopropane- 1 -carboxylate

[00182] The title compound was isolated as a product of the previous reaction as a colourless oil which crystallised on standing (137 mg, 13%). LRMS [M+H] ⁺ 268.2 m/z; HRMS [M+H] ⁺ 268.1332 m/z, found 268.1334 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.96 (ddd, J = 4.2, 3.5, 1 .8 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1 H), 7.53 (dd, J = 7.8, 0.5 Hz, 1 H), 7.47 - 7.40 (m, 2H), 7.39 - 7.34 (m, 1 H), 7.20 (d, J= 7.6 Hz, 1 H), 3.87 (q, J= 7.1 Hz, 2H), 2.77 (q, J= 16.5, 8.8 Hz, 1 H), 2.20 (ddd, J = 9.3, 8.0, 6.0 Hz, 1 H), 1 .91 (ddd, J = 7.3, 6.0, 5.0 Hz, 1 H), 1 .42 (ddd, J = 8.6, 8.0, 5.0 Hz, 1 H), 0.95 (t, J = 7.1 Hz, 3H).

(1 R,2R )-2-(6-Phenylpyridin-2-yl)cyclopropane- 1 -carboxylic acid

[00183] Ethyl (1 ft,2ft)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (310 mg, 1 .16 mmol) was dissolved in tetrahydrofuran (0.8 ml) and this solution was added dropwise to an solution of lithium hydroxide (56 mg, 2.32 mmol) in water (1 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete (~ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid. The product could then be extracted with ethyl acetate to give the title compound as an off-white solid (141 mg, 51 %). LRMS [M+H] ⁺ 240.2 m/z; HRMS [M+H] ⁺ 240.1019 m/z, found 240.1019 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.00 - 7.94 (m, 2H), 7.62 (t, J= 7.7 Hz, 1 H), 7.54 (dd, J= 7.9, 1 .0 Hz, 1 H), 7.47 - 7.35 (m, 3H), 7.1 7 (dd, J = 7.5, 0.9 Hz, 1 H), 2.71 (ddd, J = 8.9, 6.2, 3.8 Hz, 1 H), 2.39 (ddd, J= 8.5, 5.4, 3.8 Hz, 1 H), 1 .83 (ddd, J= 8.4, 6.2, 3.7 Hz, 1 H), 1 .66 (ddd, J = 9.0, 5.4, 3.7 Hz, 1 H).

(1R,2S)-2-(6-Phenylpyridin-2-yl)cyclopropane-1 -carboxylic acid

[00184] Ethyl (1 ft,2S)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (137 mg, 0.51 mmol) was dissolved in tetrahydrofuran (0.3 ml) and this solution was added dropwise to a solution of lithium hydroxide (25 mg, 1 .02 mmol) in water (0.5 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete (~ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid. The product was extracted with ethyl acetate to give the title compound as an off- white solid (43 mg, 35%). LRMS [M+H] ⁺ 240.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.85 (t, J= 7.9 Hz, 1 H), 7.78 (ddd, J= 5.8, 4.2, 2.4 Hz, 2H), 7.60 (dd, J= 8.0, 0.9 Hz, 1 H), 7.52 - 7.44 (m, 3H), 7.41 (dd, J = 7.8, 0.9 Hz, 1 H), 2.54 (dd, J = 16.1 , 8.4 Hz, 1 H), 2.38 (ddd, J= 15.7, 8.4, 7.3 Hz, 1 H), 1 .85 (dt, J= 9.1 , 4.6 Hz, 1 H), 1 .77 (td, J = 7.3, 5.1 Hz, 1 H).

Teri-butyl ((1R,2R)-2-(6-phenylpyhdin-2-yl)cyclopropyl)carbamate

[00185] (1 ft,2ft)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylic acid (141 mg, 0.59 mmol), diphenylphosphoryl azide (150 μΙ, 0.71 mmol), and triethylamine (99 μΙ, 0.71 mmol) were combined in anhydrous terf-butanol (2 ml). The reaction mixture was heated to reflux for 5 h and the progress monitored by TLC. Once complete, all volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-25% ethyl acetate/petroleum spirits. The title compound was obtained as an off-white solid (75 mg, 41 %). LRMS [M+H] ⁺ 31 1 .2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.01 - 7.93 (m, 2H), 7.58 (t, J= 7.7 Hz, 1 H), 7.48 (dd, J= 7.8, 0.8 Hz, 1 H), 7.45 - 7.38 (m, 2H), 7.38 - 7.32 (m, 1 H), 7.14 (d, J= 7.5 Hz, 1 H), 4.88 (s, 1 H), 3.15 (s, 1 H), 2.18 (s, 1 H), 1 .64 (ddd, J = 7.4, 5.8, 5.0 Hz, 2H), 1 .42 (s, 9H).

16%

2-Chloro-4-phenylpyrimidine

[00186] 2,4-Dichloropyrimidine (5 g, 33.57 mmol) was dissolved in acetonitrile (60 ml) prior to the addition of water (15 ml). To this was added phenylboronic acid (4.09 g, 33.57 mmol) and sodium carbonate (14.23 g, 134.28 mmol). The reaction mixture was degassed for 10 min by bubbling nitrogen through it before addition of Pd(PPh ₃ ) ₄ (354 mg, 0.34 mmol). The reaction mixture was stirred under nitrogen at 90 °C for 18 h. The reaction mixture was then filtered through celite and the filtrate collected. The solvent was removed in vacuo and the crude material was purified by column chromatography, eluting 10-15% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (2.98 g, 47%). LRMS [M+H] ⁺ 191 .1 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.62 (d, J= 5.3 Hz, 1 H), 8.16 - 7.99 (m, 2H), 7.63 (d, J = 5.3 Hz, 1 H), 7.50 (qdd, J = 6.0, 3.2, 1 .4 Hz, 3H).

4-Phenyl-2-vinylpyrimidine

[00187] 2-Chloro-4-phenylpyrimidine (400 mg, 2.1 0 mmol), tri butyl ( i ny l)ti n (1 .3 ml, 4.62 mmol), palladium acetate (71 mg, 0.32 mmol) and triphenylphosphine (165 mg, 0.63 mmol) were combined in tetrahydrofuran (4 ml) and the reaction mixture was heated to reflux for 18 h. The reaction mixture was filtered through celite and filtrate collected. All volatiles were removed in vacuo and the crude material purified by column chromatography, eluting 50- 75% ethyl acetate/petroleum spirits. The title compound was obtained as an orange oil (316 mg, 83%). LRMS [M+H] ⁺ 183.2 m/z; HRMS [M+H] ⁺ 183.0917 m/z, found 183.0919 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.71 (d, J= 5.3 Hz, 1 H), 8.18 - 8.02 (m, 2H), 7.60 - 7.42 (m, 4H), 6.95 (dd, J= 17.3, 10.5 Hz, 1 H), 6.72 (dd, J = 17.3, 1 .8 Hz, 1 H), 5.75 (dd, J = 10.5, 1 .8 Hz, 1 H).

2-(4-Phenylpyrimidin-2-yl)ethan- 1 -amine

[00188] 4-Phenyl-2-vinylpyrimidine (86 mg, 0.47 mmol) was added to a solution of ammonium hydroxide (3 ml) and ethanol (3 ml) in a sealed tube. The resulting reaction mixture was heated to 70 °C and monitored by LRMS. After 48 h there was minimal starting material remaining and mostly the desired product present. The reaction mixture was diluted with ethyl acetate and washed with an aqueous 2M solution of hydrochloric acid. Any precipitate was filtered off at this stage. The aqueous phase was then collected and basified with an aqueous 5M solution of sodium hydroxide and the product was then extracted with ethyl acetate three times. The organic layers were combined and dried with magnesium sulfate to yield the title compound as a brown oil (71 mg, 76%) which was used without further purification. LRMS [M+H] ⁺ 200.1 m/z; ¹ H NMR (400 MHz, DMSO) δ 8.74 (dd, J= 25.6, 5.3 Hz, 1 H), 8.23 - 8.13 (m, 2H), 7.85 (dd, J = 27.7, 5.4 Hz, 1 H), 7.61 - 7.46 (m, 3H), 3.33 (s, 3H), 3.20 - 2.93 (m, 4H).

N-(2-(4-Phenylpyrimidin-2-yl)ethyl)cyclopentanecarboxamid e

[00189] 2-(4-Phenylpyrimidin-2-yl)ethan-1 -amine (20 mg, 0.10 mmol), cyclopentanecarboxylic acid (13 μΙ, 0.12 mmol), EDCI (19 mg, 0.12 mmol) and DMAP (1 mg, 0.01 mmol) were combined in DMF (500 μΙ). The reaction mixture was heated to 40 °C and monitored by TLC and LRMS analysis. After 18 h the reaction was complete and all of the volatiles were removed. The crude material was purified by column chromatography, eluting 10% ethyl acetate/petroleum spirits to give the title compound as an off-white solid (8 mg, 27%). LRMS [M+H] ⁺ 296.2 m/z; HRMS [M+H] ⁺ 296.1757 m/z, found 296.1758 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.69 (d, J = 5.4 Hz, 1 H), 8.15 - 7.98 (m, 2H), 7.56 (d, J = 5.4 Hz, 1 H), 7.53 - 7.43 (m, 3H), 6.60 (s, 1 H), 3.80 (dd, J = 12.0, 5.8 Hz, 2H), 3.28 - 3.14 (m, 2H), 2.56 - 2.39 (m, 1 H), 1 .86 - 1 .53 (m, 8H).

N-(2-(4-Phenylpyrimidin-2-yl)ethyl)cyclohexanecarboxamide

[00190] 2-(4-Phenylpyrimidin-2-yl)ethan-1 -amine (20 mg, 0.10 mmol), cyclohexanecarboxylic acid (15 μΙ, 0.12 mmol), EDCI (19 mg, 0.12 mmol) and DMAP (1 mg, 0.01 mmol) were combined in DMF (500 μΙ). The reaction mixture was heated to 40 °C and monitored by TLC and LRMS analysis. After 18 h the reaction was complete and all of the volatiles were removed. The crude material was purified by column chromatography, eluting 10% ethyl acetate/petroleum spirits to give the title compound as an off-white solid (5 mg, 16%). LRMS [M+H] ⁺ 310.1 m/z; HRMS [M+H] ⁺ 310.1914 m/z, found 310.1916 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.70 (d, J = 5.4 Hz, 1 H), 8.14 - 7.96 (m, 2H), 7.56 (d, J = 5.4 Hz, 1 H), 7.54 - 7.47 (m, 3H), 6.75 - 6.56 (m, 1 H), 3.88 - 3.69 (m, 2H), 3.28 - 3.13 (m, 2H), 2.08 - 1 .97 (m, 1 H), 1 .85 - 1 .53 (m, 7H), 1 .47 - 1 .28 (m, 3H).

5-Bromo-2-phenylpyridine

[00191] 2,5-Dibromopyridine (2 g, 8.44 mmol), phenyl boronic acid (1 .03 g, 8.44 mmol) and sodium carbonate (1 .79 g, 16.88 mmol) were added to a mixture of tetrahydrofuran (12 ml) and water (12 ml). The reaction mixture was degassed by bubbling nitrogen through it for 10 min prior to the addition of Pd(PPh ₃ ) ₄ (178 mg, 0.17 mmol). The reaction mixture was heated to 75 °C for 18 h. The reaction mixture was then filtered through celite and the filtrate was collected and all volatiles were removed. The residue was dissolved in a mixture of water and dichloromethane. The dichloromethane layer was isolated and the aqueous phase was then re-extracted with dichloromethane. The organic layers were combined and dried with magnesium sulphate. All of the volatiles were removed and the crude material was purified by column chromatography, eluting 10-20% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless solid (446 mg, 48%). LRMS [M+H] ⁺ 234.1 m/z (Br ⁷⁹ ), 236.1 m/z (Br ⁸¹ ); ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.72 (dd, J = 2.4, 0.7 Hz, 1 H), 8.02 - 7.89 (m, 2H), 7.85 (dd, J = 8.5, 2.4 Hz, 1 H), 7.61 (dd, J = 8.5, 0.7 Hz, 1 H), 7.54 - 7.32 (m, 3H).

Benzyl (E)-3-(6-phenylpyridin-3-yl)acrylate

[00192] 5-Bromo-2-phenylpyridine (1 g, 4.27 mmol), benzyl acrylate (785 μΙ, 5.13 mmol), tri(o-tolyl)phosphine (131 mg, 0.43 mmol) and triethylamine (2.25 ml, 17.09 mmol) were combined in acetonitrile (8 ml). The reaction mixture was thoroughly degassed by bubbling nitrogen through for 5 min prior to the addition of palladium acetate (97 mg, 0.43 mmol). The reaction mixture was transferred to the CEM microwave for 3 h at 90 °C. The reaction mixture was filtered through celite and the filtrate was collected and all volatiles were removed. The crude material was purified by column chromatography, eluting 5-10% ethyl acetate/petroleum spirits to yield the title compound as a colourless solid (756 mg, 56%). LRMS [M+H] ⁺ 316.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.78 (d, J = 2.1 Hz, 1 H), 8.12 - 7.95 (m, 2H), 7.88 (dd, J= 8.3, 2.3 Hz, 1 H), 7.82 - 7.66 (m, 2H), 7.54 - 7.28 (m, 8H), 6.56 (d, J = 16.1 Hz, 1 H), 5.26 (s, 2H).

3-(6-Phenylpyridin-3-yl)propanoic acid

[00193] Benzyl (£)-3-(6-phenylpyridin-3-yl)acrylate (1 g, 3.17 mmol) which is dissolved in ethanol (25 ml) and 5% Pd/C (17 mg, 0.16 mmol) was added prior to the reaction being flushed with hydrogen gas. The reaction mixture was stirred at 50 °C and monitored by TLC and LRMS. Once completed, the reaction mixture was filtered through celite and the solvent removed in vacuo. The crude material was purified by column chromatography, eluting 25-40% ethyl acetate/petroleum spirits + 1 % acetic acid. The appropriate fractions were collected and washed three times with an aqueous saturated sodium bicarbonate solution. All of the volatiles were removed in vacuo to give the title compound as a cloudy oil (462 mg, 64%). LRMS [M+H] ⁺ 228.2 m/z; HRMS [M+H] ⁺ 228.1019 m/z, found 228.1019 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.60 (s, 1 H), 8.00 - 7.81 (m, 2H), 7.65 (dd, J= 3.9, 1 .9 Hz, 2H), 7.53 - 7.31 (m, 3H),

3.00 (t, J = 7.4 Hz, 2H), 2.71 (dd, J = 8.6, 6.2 Hz, 2H) ^* Note: carboxylic acid proton not visible by NMR.

Teri-butyl (2-(6-phenylpyridin-3-yl)ethyl)carbamate

[00194] 3-(6-Phenylpyridin-3-yl)propanoic acid (462 mg, 2.03 mmol), diphenylphosphoryl azide (525 μΙ, 2.44 mmol) and triethylamine (325 μΙ, 2.44 mmol) were combined in anhydrous terf-butanol (5 ml) and the reaction mixture was heated to reflux for 18 h. A saturated aqueous solution of sodium bicarbonate was added and the product was extracted with ethyl acetate (twice). The organic layers were combined and washed once with a saturated aqueous solution of sodium chloride. The organic phase was then dried with magnesium sulphate before the solvent was removed and the crude material purified by column chromatography, eluting 5-10% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless solid (205 mg, 34%). LRMS [M+H] ⁺ 299.2 m/z; HRMS [M+H] ⁺ 299.1754 m/z, found 299.1715 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.50 (d, J = 1 .8 Hz, 1 H), 8.06 - 7.86 (m, 2H), 7.66 (dd, J = 8.1 , 0.5 Hz, 1 H), 7.57 (dd, J = 8.0, 1 .6 Hz, 1 H), 7.49 - 7.41 (m, 2H), 7.41 - 7.34 (m, 1 H), 4.63 (s, 1 H), 3.51 - 3.22 (m, 2H), 2.82 (t, J= 6.9 Hz, 2H), 1 .41 (s, 9H).

2-(6-Phenylpyridin-3-yl)ethan- 1 -amine

[00195] Teri-butyl (2-(6-phenylpyridin-3-yl)ethyl)carbamate (205 mg, 0.69 mmol) was added to a 50:50 trifluoroacetic acid:dichloromethane (4 ml). The reaction mixture was stirred at ambient temperature for 18 h and TLC showed complete disappearance of starting material. All of the volatiles were removed and the residue was washed with toluene three times. This gave the title compound as a dark yellow oil which was used directly. LRMS [M+H] ⁺ 199.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.83 (s, 1 H), 8.34 (dd, J = 8.4, 1 .8 Hz, 1 H),

8.01 (d, J = 8.4 Hz, 2H), 7.91 - 7.73 (m, 2H), 7.71 - 7.45 (m, 2H), 3.42 (d, J = 1 .3 Hz, 2H), 3.28 - 3.19 (m, 2H), 3.1 3 (d, J = 25.1 Hz, 2H).

N-(2-(6-Phenylpyridin-3-yl)ethyl)pyrrolidine- 1 -carboxamide

[00196] 2-(6-Phenylpyridin-3-yl)ethan-1 -amine (35 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (0.5 ml) and triethylamine (125 μΙ, 1 .70 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (69 mg, 0.34 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h pyrrolidine (30 μΙ, 0.34 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-60% ethyl acetate/dichloromethane. The title compound was obtained as a colourless solid (13 mg, 26%). LRMS [M+H] ⁺ 296.2 m/z; HRMS [M+H] ⁺ 296.1757 m/z, found 296.1761 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.51 (d, J= 1 .7 Hz, 1 H), 8.04 - 7.83 (m, 2H), 7.73 - 7.53 (m, 2H), 7.51 - 7.30 (m, 3H), 4.27 (s, 1 H), 3.50 (dd, J = 12.9, 6.8 Hz, 2H), 3.26 (t, J = 6.3 Hz, 4H), 2.86 (t, J = 6.9 Hz, 2H), 1 .93 - 1 .75 (m, 4H).

N-(2-(6-Phenylpyridin-3-yl)ethyl)piperidine- 1 -carboxamide

[00197] 2-(6-Phenylpyridin-3-yl)ethan-1 -amine (35 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (0.5 ml) and triethylamine (125 μΙ, 1 .70 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (69 mg, 0.34 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (35 μΙ, 0.34 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-60% ethyl acetate/dichloromethane. The title compound was obtained as a colourless solid (13 mg, 26%). LRMS [M+H] ⁺ 310.2 m/z; HRMS [M+H] ⁺ 310.1914 m/z, found 310.1913 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.51 (d, J= 1 .7 Hz, 1 H), 8.03

- 7.88 (m, 2H), 7.67 (dd, J = 8.1 , 0.6 Hz, 1 H), 7.60 (dd, J = 8.1 , 2.3 Hz, 1 H), 7.49 - 7.42 (m, 2H), 7.41 - 7.35 (m, 1 H), 4.51 (s, 1 H), 3.49 (dd, J = 12.8, 6.9 Hz, 2H), 3.33 - 3.22 (m, 4H), 2.86 (t, J = 6.9 Hz, 2H), 1 .68 - 1 .42 (m, 6H).

N-(2-(6-Phenylpyridin-3-yl)ethyl)cyclopentanecarboxamide

[00198] 2-(6-Phenylpyridin-3-yl)ethan-1 -amine (35 mg, 0.17 mmol) and triethylamine (125 μΙ, 1 .70 mmol) were combined in DMF (500 μΙ) and pre- stirred for 2 mins. The cyclopentanecarboxylic acid (25 μΙ, 0.20 mmol), EDCI (32 mg, 0.20 mmol), and DMAP (2 mg, 0.02 mmol) were then added. The reaction mixture was heated to 40 °C and monitored by TLC and LRMS analysis. After 18 h the reaction was complete and all of the volatiles were removed. The crude material was purified by column chromatography, eluting 0-15% ethyl acetate/dichloromethane to give the title compound as a colourless solid (29 mg, 58%). LRMS [M+H] ⁺ 295.2 m/z; HRMS [M+H] ⁺ 295.1805 m/z, found 295.1803 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.51 (d, J= 1 .7 Hz, 1 H), 8.03

- 7.87 (m, 2H), 7.69 (dd, J = 8.1 , 0.6 Hz, 1 H), 7.62 (dd, J = 8.1 , 2.2 Hz, 1 H), 7.51 - 7.43 (m, 2H), 7.41 (dt, J= 9.6, 4.3 Hz, 1 H), 5.53 (s, 1 H), 3.53 (q, J= 6.8 Hz, 2H), 2.86 (t, J= 6.9 Hz, 2H), 2.55 - 2.31 (m, 1 H), 1 .99 - 1 .61 (m, 6H), 1 .53 (tdd, J = 6.9, 4.2, 1 .7 Hz, 2H).

N-(2-(6-Phenylpyridin-3-yl)ethyl)cyclohexanecarboxamide

[00199] 2-(6-Phenylpyridin-3-yl)ethan-1 -amine (35 mg, 0.17 mmol) and triethylamine (125 μΙ, 1 .70 mmol) were combined in DMF (500 μΙ) and pre- stirred for 2 mins. The cyclohexanecarboxylic acid (25 μΙ, 0.20 mmol), EDCI (32 mg, 0.20 mmol), and DMAP (2 mg, 0.02 mmol) were then added. The reaction mixture was heated to 40 °C and monitored by TLC and LRMS analysis. After 18 h the reaction was complete and all of the volatiles were removed. The crude material was purified by column chromatography, eluting 0-15% ethyl acetate/dichloromethane to give the title compound as a colourless solid (1 1 mg, 21 %). LRMS [M+H] ⁺ 309.2 m/z; HRMS [M+H] ⁺ 309.1961 m/z, found 309.1961 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.50 (d, J = 1 .7 Hz, 1 H), 8.03 - 7.87 (m, 2H), 7.69 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 8.1 , 2.2 Hz, 1 H), 7.53 - 7.35 (m, 3H), 5.52 (s, 1 H), 3.52 (q, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.09 - 1 .94 (m, 1 H), 1 .94 - 1 .68 (m, 5H), 1 .48 - 1 .28 (m, 2H), 1 .28 - 1 .06 (m, 3H).

2-Bromo-6-phenylpyridine

[00200] 2,6-Dibromopyridine (2 g, 8.44 mmol), phenylboronic acid (1 .03 g, 8.44 mmol), potassium carbonate (4.67 g, 33.77 mmol) and TBAB (271 mg, 0.84 mmol) were combined in a mixture of 1 ,4-dioxane (16 ml) and water (4 ml). The reaction mixture was degassed by bubbling nitrogen through for 30 min prior to the addition of PdCI ₂ (dppf) (62 mg, 0.084 mmol). The reaction mixture was stirred at 40 °C for 1 h before being filtered through celite. The filtrate was collected and the solvent removed. The crude material was then purified by column chromatography, eluting 100% petroleum spirits to give the title compound as a colourless solid (1 .85 g, 93%). ¹ H NMR (400 MHz, DMSO) δ 8.56 (dd, J= 6.3, 2.4 Hz, 1 H), 8.36 - 8.18 (m, 2H), 8.16 - 8.00 (m, 2H), 7.61 - 7.53 (m, 2H), 7.53 - 7.45 (m, 1 H).

Benzyl (E)-3-(6-phenylpyridin-2-yl)acrylate

[00201] 2-Bromo-6-phenylpyridine (1 .69 g, 7.22 mmol), benzyl acrylate (1 .35 ml, 8.66 mmol), tri(o-tolyl)phosphine (220 mg, 0.72 mmol) and triethylamine (3.85 ml, 28.88 mmol) were all combined in acetonitrile (5 ml). The reaction mixture was degassed by bubbling nitrogen through it for 2 min prior to the addition of palladium acetate (162 mg, 0.72 mmol). The reaction mixture was transferred to the CEM microwave for 3 h at 90 °C. The reaction was complete by TLC and the reaction mixture was filtered through celite and the filtrate collected. All of the volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 0-10% ethyl acetate/petroleum spirits to yield the title compound as a yellow oil (1 .13 g, 50%). LRMS [M+H] ⁺ 316.2 m/z; HRMS [M+H] ⁺ 316.1332 m/z, found 316.1336 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.09 - 8.01 (m, 2H), 7.81 - 7.68 (m, 3H), 7.52 - 7.27 (m, 9H), 7.15 (d, J = 15.6 Hz, 1 H), 5.27 (s, 2H).

3-(6-Phenylpyridin-2-yl)propanoic acid

[00202] The title compound can be prepared from from benzyl (£)-3-(6- phenylpyridin-2-yl)acrylate (495 mg, 1 .57 mmol) which is dissolved in ethanol (12 ml) and 5% Pd/C (8 mg, .0.8 mmol) was added prior to the reaction being flushed with hydrogen gas. The recation mixture was stirred at 60 °C for 18 h, at which point both TLC and LRMS confirmed that the reaction was complete. The reaction mixture was then filtered through celite and the solvent removed in vacuo. The crude material was then purified by column chromatography, eluting 40-50% ethyl acetate/petroleum spirits to give the title compound as a colourless solid (248 mg, 70%). LRMS [M+H] ⁺ 228.2 m/z; HRMS [M+H] ⁺ 228.1019 m/z, found 228.1020 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.87 - 7.76 (m, 3H), 7.67 - 7.60 (m, 1 H), 7.52 - 7.41 (m, 3H), 7.21 (d, J = 7.5 Hz, 1 H), 3.32 - 3.14 (m, 2H), 2.97 - 2.82 (m, 2H).

Teri-butyl (2-(6-phenylpyridin-2-yl)ethyl)carbamate

[00203] 3-(6-Phenylpyridin-2-yl)propanoic acid (100 mg, 0.44 mmol), diphenylphosphoryl azide (1 15 μΙ, 0.53 mmol) and triethylamine (70 μΙ, 0.53 mmol) were combined in anhydrous terf-butanol (1 ml) and the reaction mixture was heated to reflux for 5 h. A saturated aqueous solution of sodium bicarbonate was added and the reaction mixture turned cloudy. The product was extracted with ethyl acetate (three times) and the organic layers combined and washing once with a saturated aqueous solution of sodium chloride. The organic phase was then dried with magnesium sulphate before the solvent was removed and the crude material purified by column chromatography, eluting 5- 15% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless oil (34 mg, 26%). LRMS [M+H] ⁺ 299.2 m/z; HRMS [M+H] ⁺ 299.1754 m/z, found 299.1756 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.99 (dd, J = 5.2, 3.3 Hz, 2H), 7.66 (t, J = 7.7 Hz, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.49 - 7.42 (m, 2H), 7.42 - 7.36 (m, 1 H), 7.08 (d, J = 7.5 Hz, 1 H), 5.50 (s, 1 H), 3.60 (dd, J = 12.2, 6.0 Hz, 2H), 3.02 (t, J = 6.3 Hz, 2H), 1 .42 (s, 9H).

2-(2-Ammonioethyl)-6-phenylpyridin- 1 -ium 4-methylbenzenesulfonate

[00204] Teri-butyl (2-(6-phenylpyridin-2-yl)ethyl)carbamate (34 mg, 0.1 1 mmol) was dissolved in acetonitrile (220 μΙ) and para-toluenesulfonic acid (65 mg, 0.34 mmol) was added. The reaction mixture was heated to reflux and the progress of the reaction was monitored by LRMS. After ~ 2 h the reaction was complete by LRMS and the reaction mixture was transferred to the fridge. The resultant precipitate was filtered and washed with ether to give the title compound as a colourless solid (41 mg, 73%). LRMS [M+H] ⁺ 199.1 m/z; ¹ H NMR (400 MHz, DMSO) δ 8.08 (dd, J = 8.2, 1 .2 Hz, 2H), 7.94 - 7.85 (m, 2H), 7.85 - 7.73 (m, 2H), 7.61 - 7.39 (m, 6H), 7.32 (dd, J= 6.3, 1 .9 Hz, 1 H), 7.1 1 (d, J= 7.8 Hz, 4H), 3.32 (dd, J= 12.9, 6.8 Hz, 2H), 3.12 (t, J= 7.3 Hz, 2H), 2.29 (s, 6H).

N-(2-(6-Phenylpyridin-2-yl)ethyl)piperidine- 1 -carboxamide

[00205] 2-(2-Ammonioethyl)-6-phenylpyridin-1 -ium 4- methylbenzenesulfonate (41 mg, 0.08 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (40 μΙ, 0.26 mmol) added (solution 1 ). In a separate flask para-nitrophenylchloroformate (24 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml) with stirring (solution 2). Solution 1 was then added dropwise to solution 2 and the reaction mixture was stirred for 2 h at ambient temperature. After 2 h piperidine (20 μΙ, 0.16 mmol) was added to the reaction mixture which was allowed to stir at ambient temperature for 18 h. All volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting 30% ethyl acetate/dichloromethane. This yielded the title compound with contaminants as such, the material was further purified by column chromatography, eluting 25% ethyl acetate/petroleum spirits. This gave the title compound as a colourless oil (10 mg, 40%). LRMS [M+H] ⁺ 310.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.07 - 7.85 (m, 2H), 7.67 (t, J= 7.7 Hz, 1 H), 7.61 - 7.51 (m, 1 H), 7.51 - 7.32 (m, 3H), 7.10 (d, J= 7.0 Hz, 1 H), 6.1 1 (s, 1 H), 3.64 (dt, J = 6.0, 5.0 Hz, 2H), 3.27 - 3.12 (m, 4H), 3.12 - 2.95 (m, 2H), 1 .53 - 1 .43 (m, 2H), 1 .43 - 1 .29 (m, 4H).

N-(2-(6-Phenylpyridin-2-yl)ethyl)cyclohexanecarboxamide

[00206] 2-(2-Ammonioethyl)-6-phenylpyridin-1 -ium 4- methylbenzenesulfonate (21 mg, 0.1 1 mmol) was dissolved in anhydrous N,N- dimethylformamide (0.5 ml) and cyclohexanecarboxylic acid (15 μΙ, 0.13 mmol), triethylamine (150 μΙ, 1 .06 mmol), EDCI (20 mg, 0.13 mmol) and DMAP (2 mg, 0.01 mmol) were added. The resulting mixture was then heated to 40 °C for 18 h. The reaction mixture was concentrated in vacuo and the crude material purified by coloumn chromatography, eluting 0-15% ethyl acetate/dichloromethane. The title compound was obtained as an off-white solid (22 mg, 67%). LRMS [M+H] ⁺ 309.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.99 - 7.93 (m, 2H), 7.68 (t, J= 7.7 Hz, 1 H), 7.58 (dd, J= 7.9, 0.8 Hz, 1 H), 7.50 - 7.36 (m, 3H), 7.10 (d, J= 7.6 Hz, 1 H), 6.95 (s, 1 H), 3.75 - 3.64 (m, 2H), 3.07 - 2.98 (m, 2H), 2.02 (tt, J = 1 1 .8, 3.5 Hz, 1 H), 1 .92 - 1 .86 (m, 1 H), 1 .84 - 1 .53 (m, 7H), 1 .50 - 1 .34 (m, 2H).

N-(2-(6-Phenylpyridin-2-yl)ethyl)cyclopentanecarboxamide

[00207] 2-(2-Ammonioethyl)-6-phenylpyridin-1 -ium 4- methylbenzenesulfonate (21 mg, 0.1 1 mmol) was dissolved in anhydrous N,N- dimethylformamide (0.5 ml) and cyclopentanecarboxylic acid (14 μΙ, 0.13 mmol), triethylamine (150 μΙ, 1 .06 mmol), EDCI (20 mg, 0.13 mmol) and DMAP (2 mg, 0.01 mmol) were added. The resulting mixture was then heated to 40 °C for 18 h. The reaction mixture was concentrated in vacuo and the crude material purified by column chromatography, eluting 0-15% ethyl acetate/dichloromethane. The title compound was obtained as a colourless solid (29 mg, 94%). LRMS [M+H] ⁺ 295.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.05 - 7.91 (m, 2H), 7.69 (t, J = 7.7 Hz, 1 H), 7.63 - 7.55 (m, 1 H), 7.51 - 7.37 (m, 3H), 7.1 1 (d, J = 7.5 Hz, 1 H), 6.78 (s, 1 H), 3.81 - 3.64 (m, 2H), 3.14 - 3.01 (m, 2H), 2.55 - 2.37 (m, 1 H), 1 .87 - 1 .53 (m, 8H).

Amides, Carbamates, Ureas

4-(Chloromethyl)-2-phenylthiazole. [00208] Thiobenzamide (13.4 g, 0.097 mol) was added to a stirred solution of 1 ,3-dichloroacetone (16.6 g, 0.130 mol) in acetone (250 mL) under argon, and the suspension was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature and the white suspension was vacuum- filtered. The white solid was washed with acetone (3 ^χ 100 mL), then air-dried. The solid was dissolved in sulfuric acid (80 mL) and the solution was stirred under argon for 30 min. It was then poured onto ice and cold water was added until no more solid precipitated. The precipitate was collected by vacuum filtration, washed with water (3 ^χ 100 mL) and air-dried to yield the title thiazole as a white solid (3.1 g, 85 %), m.p.: 41 -43 °C. ¹ H NMR (CDCI ₃ ): 7.95 (m, 2H, H27H6'), 7.45 (m, 3H, H37H47H5'), 7.30 (s, 1 H, H5), 4.75 (s, 2H, CH ₂ ). The ¹ H NMR data matched those reported.

2-(2-Phenylthiazol-4-yl)acetonitrile

[00209] KCN (5.0 g, 0.08 mol) of was added to a solution of 4-(chloromethyl)- 2-phenyl thiazole (14.8 g, 0.070 mol) in DMF (80 mL) under argon. The solution was heated at 70°C overnight, then allowed to cool, poured onto water (600 mL) and extracted with EtOAc (3 ^χ 300mL). The organic layer was washed with brine (3 ^χ 100 mL), dried and evaporated to yield the title nitrile as a yellow solid (14 g, 67 mmol, 80 %). m.p.: 34-38 °C. IR (thin film) cm ^"1 : 2253 (CN). ¹ H NMR (CDCI3): 7.92 (m, 2H, H2', H6'), 7.45 (m, 3H, H3', H4', H5'), 7.29 (s, 1 H, H5), 3.95 (s, 2H, CH ₂ ). The ¹ H NMR data matched those reported. ieri-Butyl (2-(2-phenylthiazol-4-yl)ethyl)carbamate

[00210] Di-terf-butyl dicarbonate (5.9 g, 27 mmol) and nickel (II) chloride hexahydrate (0.30 g, 1 .3 mmol) were added to a stirred solution of 2-(2- phenylthiazol-4-yl)acetonitrile (2.6 g, 13 mmol) of in dry MeOH (100 mL), under argon. The reaction mixture was placed in an ice-bath then treated portionwise (over 30 min) with sodium borohydride (3.6 g, 94 mmol). The resulting solution was allowed to stir at room temperature for 1 .5 h. Triethylamine (2.0 mL) was added and the solution was stirred for 30 min. The volatiles were evaporated and the residue was extracted with EtOAc (3 ^χ 300 mL). The extract was washed with water (3 ^χ 300 mL) and saturated ammonium chloride solution (3 ^χ 300 mL), dried and evaporated to yield the title carbamate as an orange oil (0.57 g, 1 .9 mmol, 82 %). Rf: 0.50 (40 % EtOAC/Hexanes + NEt ₃ ). IR (thin film) cm ^"1 : 1693 (C=O), 3337 (NH). ¹ H NMR (CDCI ₃ ): 7.93 (dd, 2H, H2", H6"), 7.43 (m, 3H, H3", H4", H5"), 6.96 (s, 1 H, H5'), 5.14 (br s, 1 H, NH), 3.54 (dt (app q), J _{1 =} 6.4 Hz, 2H, H1 ), 2.99 (t, Ji = 6.4 Hz, 2H, H2), 1 .44 (s, 9H, t-butyl). ¹³ C NMR (CDCIs): 168.2 (C2'), 156.1 (C=O), 155.6 (C4'), 133.8 (C1 "), 130.1 (C4"), 129.0 (C2", C6"), 126.6 (C3", C5"), 1 14.4 (C5'), 40.1 (C1 ), 31 .9 (C2), 28.6 (f-butyl), 28.4 (f-butyl). HRMS (ESI): Observed: 305.1305, C ₁₆ H ₂₁ N ₂ O ₂ S ⁺ requires 305.1318.

2-(2-phenylthiazol-4-yl)ethanaminium chloride

[0021 1 ] The carbamate was deprotected using standard literature procedure using HCI in dioxane at reflux, m.p.: 140-142 °C. IR: 2443-3986 (NH). ¹ H NMR (MeOD): 8.02 (m, 2H, H2", H6", 7.60 (s, 1 H, H5'), 7.56 (m, 3H, H3", H4", H5"), 3.16 (t, J _{1 =} 7.2 Hz, 2H, H1 ), 3.26 (t, J _{1 =} 7.2 Hz, 2H, H2). ¹³ C NMR (DMSO): 28.3 (C2), 39.6 (C1 ), 1 19.7 (C5'), 128.4 (C3", C5"), 130.7 (C2", C6"), 133.5 (C4"), 149.8 (C4'), 172.3 (C2'). One pair of signals is isochronous or too broad to be observed. HRMS (ESI): Observed: 205.0802, Cn H ₁₃ N ₂ S ⁺ requires 205.0799

Representative example of amide coupling using an acid chloride

4-Fluoro-N-(2-(2-phenylthiazol-4-yl)ethyl)benzamide

[00212] Triethylamine (0.35 mL, 2.5 mmol) was added to a suspension of 2- (4-phenyl)thiazol-2-yl ethylamine dihydrochloride (0.24 g, 1 .2 mmol) of in DCM (10 mL) under argon. The reaction mixture was cooled in an ice-bath, then carefully treated with 4-fluorobenzoylchloride (0.17 mL, 1 .5 mmol). The resulting solution was allowed to warm to room temperature and stirring was continued overnight. The solvent was evaporated and the residue was purified using column chromatography. Elution with 25% EtOAc/hexanes yielded the title benzamide as a white solid (0.20 g, 0.65 mmol, 53 %), m.p: 123-124°C. Rf: 0.22 (25% EtOAc/hexanes). IR (thin film) cm ^"1 : 1651 (C=O), 3333 (NH). ¹ H NMR (CDCI ₃ ): 7.90 (m, 2H, C2"\ C6'"), 7.83 (m, 3H, NH, C2, C6), 7.42 (m, 3H, C3'", C4"\ C5'"), 7.03 (m, = 8.6 Hz, J = 1 .6 Hz, 2H, C3, C5), 7.03 (s, 1 H, C5"), 3.78 (dt (app q), = 5.6 Hz, J ₂ = 5.2 Hz, 2H, C1 '), 3.08 (t, J ₁ = 6.0 Hz, 2H, C2'). ¹³ C NMR (CDCI ₃ ): 30.5 (C2'), 39.8 (C1 '), 1 14.7 (C3, C5), 1 15.4 (C5"), 1 15.6 (C3, C5), 126.4 (C3'", C5'"), 129.0 (C2"\ C6'"), 129.3 (C2, C6), 129.4 (C2, C6), 130.3pm (C4'"), 131 .0 (C1 ), 131 .1 (C1 ), 133.5 (C1 '"), 155.6 (C4"), 163.4 (C4), 165.9 (C4), 166.4 (C=O), 168.5 (C2"). HRMS (ESI): Observed: 326.0880, C ₁₈ H ₁₅ N ₂ OSF requires 326.0889.

Representative example of an amide coupling using DCC

2-Methoxy-N-(2-(2-phenylthiazol-4-yl)ethyl)benzamide

[00213] 1 -Hydroxybenzotriazole hydrate (HOBT) (0.12 g, 0.83 mmol) and (0.17 g, 0.83 mmol) of 1 ,3-dicyclohexylcarbodiimide (DCC) were added to a solution of 2-methoxybenzoic (0.1 1 g, 0.75 mmol) of in DCM (10 mL) under argon. The solution was allowed to warm to room temperature and stirring was continued for 1 h. 2-(Phenethyl-4-phenyl)thiazole dihydrochloride (0.20 g, 0.75 mmol) was then added to the reaction mixture and the solution was stirred for 24 h or until TLC showed the consumption of starting material. The reaction misture was diluted with water (20 mL) The solution was extracted with ethyl acetate (3 ^χ 50 ml). The organic layer was washed with brine (3 ^χ 100 ml), dried and evaporated. The residue was subjected to column chromatography. Elution with 10% EtOAc/hexanes and then 40 % EtOAc/hexanes yielded the title benzamide an orange oil (0.10 g, 0.38 mmol, 71 %). Rf: 0.32 (30 % EtOAc/Hexanes). IR (thin film) cm ^"1 : 1638 (C=O), 3341 (NH). ¹ H NMR (CDCI ₃ ): 8.21 (m, = 5.2 Hz, 1 H, C6), 8.17 (br s, 1 H, NH), 7.96 (m, 2H, C2"\ C6'"), 7.42 (m, 4H, C4, C3"\ C4"\ C5'"), 7.07 (t of t, = 7.2 Hz, J ₂ = 1 .2 Hz, 1 H, C5), 7.01 (s, 1 H, C5"), 6.91 (d, = 8.4 Hz, 1 H, C3), 3.75 (s, 3H, Methoxy), 3.14 (t, J = 6.4 Hz, 2H, C2'). ¹³ C NMR (CDCI ₃ ): 168.1 (C2"), 165.4 (C=O), 157.6 (C2), 1 55.9 (C4"), 1 33.9 (C1 "'), 1 32.7 (C4), 1 32.3 (C6), 1 30.1 (C4'"), 1 29.1 (C2"\ C6'"), 1 26.6 (C3'", C5'"), 1 21 .9 (C1 ), 1 21 .4 (C5), 1 14.6 (C5"), 1 1 1 .4 (C3), 55.9 (OMe), 39.2 (C1 '), 31 .6 (C2'). H RMS (ESI): Observed: 339.1 165, C ₁₉ H ₁₉ N ₂ O ₂ S ⁺ requires 339.1 1 67.

Representative example of an amide coupling using HBTU

N-(2-(2-Phenylthiazol-4-yl)ethyl)cyclohexanecarboxamide

[00214] Cyclohexanecarboxylic acid (0.51 g, 1 .2 mmol) and DIPEA (1 .9 ml, 10 mmol) were added to a stirred solution of HBTU (0.40 g, 1 .0 mmol) in DMF/DCM (1 :1 , 1 0 mL) under argon. After 5 min, 2-(2-phenylthiazol-4- yl)ethanamine dihydochloride (0.25 g, 0.92 mmol) was added and stirring was continued for 24 h or until TLC showed the disappearance of starting material. The reaction was diluted with water(50 mL.) The solution was extracted with EtOAc (3 x 50 ml). The organic layer was washed with brine (3 ^χ 1 00 ml), dried and evaporated. The residue was subjected to column chromatography. Elution with 40% EtOAc/hexanes yielded the title amide as a white solid (0.1 0 g, 0.55 mmol, 75 %), m.p: 128-1 30 °C. Rf: 0.28 (25 % EtOAc/hexanes). IR (thin film) cm ^"1 : 1 637 (C=O), 3293 (NH). ¹ H NMR (CDCI ₃ ): 7.93 (m, 2H, C2"\ C6'"), 7.43 (m, 3H, C3"\ C4"\ C5'"), 6.95 (s, 1 H, C5"), 6.55 (br s, 1 H, NH), 3.62 (dt (app q), Ji = 6.0 Hz, J ₂ = 6.4 Hz, 2H, C1 '), 2.99 (t, Ji = 6.0 Hz, 2H, C2'), 2.08 (m, 1 H, C1 ), 1 .87 (m, 2H, C2, C6), 1 .75 (m, 2H, C2, C6), 1 .64 (m, 1 H, C4), 1 .39 (m, 2H, C3, C5), 1 .22 (m, 3H, C3, C4, C5). ¹³ C NMR (CDCI ₃ ): 1 76.2 (C2"), 1 68.3 (C=O), 1 55.8 (C4"), 1 33.7 (C1 '"), 1 30.2 (C4'"), 1 29.1 (C2"\ C6'"), 1 26.5 (C3"\ C5'"), 1 14.5 (C5"), 45.6 (CV), 38.8 (C2'), 30.9 (C4), 29.8 (C2, C6), 25.9 (C3, C5). HRMS (ESI): Observed: 315.1 533, Ci ₈ H23N ₂ OS ⁺ requires 31 5.1 531 .

N-(2-(2-Phenylthiazol-4-yl)ethyl)-1H-imidazole- 1 -carboxamide

[00215] 1 ,1 -Carbonyldiimidazole (0.40 g, 2.4 mmol) was added to a stirred solution of 2-(2-phenylthiazol-4-yl)ethane dihydrochloride (0.52 g, 1 .9 mmol) in DMF (3 mL) and acetonitrile (9 mL) under argon. After 24 h or when TLC showed the disappearance of starting material, the acetonitrile was evaporated and the residue was diluted with EtOAc (3 ^χ 50 imL), then washed with brine (3 x 50 imL), dried and evaporated. The residue was subjected to column chromatography. Elution with 50% EtOAc/hexanes and then 70% EtOAc/hexanes yielded the title urea an orange oil (0.63 g, 2.1 mmol, 69 %). R.f.: 0.1 6 (50 % EtOAc/Hexanes). IR (ATR) cm ^"1 : 1712 (C=O), 3219 (NH). ¹ H NMR (CDCI ₃ ): 3.04 (t, J _{1 =} 6.5 Hz, 2H, H2'), 3.71 (dt (app q), J _{1 =} 6.5 Hz, J ₂ = 5.5 Hz, 2H, H1 '), 6.94 (s, 1 H, H4), 6.95 (s, 1 H, H5"), 7.37 (m, 3H, H3"\ H4"\ H5'"), 7.40 (s, 1 H, H5), 7.81 (m, 2H, H2"\ H6'"), 8.14 (s, 1 H, H2), 8.29 (br t, 1 H, NH). ¹³ C NMR (CDCI ₃ ): 168.6 (C2"), 154.8 (C=O), 149.0 (C4"), 135.9 (C2), 133.2 (C1 '"), 130.2 (C4'"), 129.7 (C4), 129.0 (C2"\ C6'"), 126.3 (C3"\ C5'"), 1 16.2 (C5), 1 14.5 (C5"), 40.5 (CV), 30.5 (C2'). HRMS (ESI): Observed: 299.0971 , Ci ₅ H ₁₅ N ₄ OS ⁺ requires 299.0967.

Representative urea synthesis

N-(2-(2-Phenylthiazol-4-yl)ethyl)azepane- 1 -carboxamide

[00216] Triethylamine (0.08 imL, 0.59 mmol) was added to a stirred solution of A/-(2-(2-phenylthiazol-4-yl)ethyl)-1 -/-imidazole-1 -carboxamide (0.16 g, 0.54 mmol) and azepane (0.06 imL, 0.54 mmol) in DCM (6 imL) under argon. After 18 h, the solvent was evaporated and the residue was diluted with EtOAc (150 imL), then washed with brine (3 ^χ 50 ml), dried and the solvent was evaporated. The residue was subjected to column chromatography. Elution with 50 % EtOAc/hexanes and then 70 % EtOAc/hexanes to yield the title compounds as a yellow oil (0.12 g, 0.36 mmol, 68 %). R.f.: 0.34 (50 % EtOAc/Hexanes). IR (ATR) cm ^"1 : 1627 (C=O), 2931 (NH). ¹ H NMR (CDCI ₃ ): 7.90 (m, 2H, H2"\ H6'"), 7.40 (m, 3H, H3"\ H4"\ H5'"), 6.95 (s, 1 H, H5"), 5.50 (br t, 1 H, NH), 3.61 (dt (app q), Ji= 6.4 Hz, J ₂ = 5.6 Hz, 2H, H1 '), 2.99 (t, Ji= 6.4 Hz, 2H, H2'), 3.37 (t, Ji= 6.0 Hz, 4H, H2, H7), 2.99 (t, Ji= 6.4 Hz, 2H, H2'), 3.37 (t, Ji= 6.0 Hz, 4H, H2, H7), 1 .64 (m, 4H, H4, H5), 1 .50 (m, 4H, H3, H6). ¹³ C NMR (CDCI ₃ ): 168.2 (C2"), 158.0 (C=O), 156.4 (C4"), 133.7 (C1 '"), 130.1 (C4'"), 129.0 (C2"\ C6'"), 126.4 (C3"\ C5'"), 1 14.4 (C5"), 46.4 (C2, C7), 40.6 (C1 '), 31 .6 (C2'), 28.6 (C4, C5), 27.3 (C3, C6). HRMS (ESI): Observed: 330.1635, C ₁₈ H ₂₄ N ₃ OS ⁺ requires: 330.1640.

Representative carbamate synthesis

Isopropyl (2-(2-phenylthiazol-4-yl)ethyl)carbamate

[00217] Sodium hydride (60% dispersion in oil, 0.03 g, 1 .2 mmol) was added to a stirred solution of A/-(2-(2-phenylthiazol-4-yl)ethyl)-1 H-imidazole-1 - carboxamide (0.32 g, 1 .1 mmol) and isopropanol (0.08 ml, 1 .1 mmol) in DMF (10 mL) under argon. After 18 h, water was added and the mixture was extracted with EtOAc (3 χ 50 ml). The extract was washed with brine (3 χ 50 ml), dried and evaporated. The residue was subjected to column chromatography. Elution with 20% EtOAc/hexanes gave the title carbamate as a white solid (0.10 g, 0.34 mmol, 32 %), m.p.: 55-57 °C. R.f.: 0.30 (20 % EtOAc/Hexanes). IR (ATR) cm ^"1 : 1690 (C=O), 3330 (NH). ¹ H NMR (CDCI ₃ ): 7.91 (m, 2H, H2", H6"), 7.41 (m, 3H, H3", H4", H5"), 6.94 (s, 1 H, H5'), 5.20 (br s, 1 H, NH), 4.90 (m, J _{1 =} 6.0 Hz, 1 H, H1 "'), 3.58 (dt (app q), J ₁ = 6.5 Hz, J ₂ = 6.0 Hz, 2H, H2), 2.99 (t, J _{1 =} 6.5 Hz, 2H, H1 ), 1 .21 (d, J _{1 =} 6.0 Hz, 6H, Η1'''). ¹³ C NMR (CDCI ₃ ): 168.2 (C2'), 156.4 (C=O), 155.4 (C4'), 133.7 (C1 "), 130.0 (C4"), 129.0 (C2", C6"), 126.5 (C3", C5"), 1 14.4 (C5'), 68.0 (C1 '"), 40.3 (C2), 31 .8 (C1 ), 22.2 (C2'"). HRMS (ESI): Observed: 291 .1 168, C ₁₅ H ₁₉ N ₂ O ₂ S ⁺ requires 291 .1 167.

2-Phenyl-6-vinylpyridiner

[00218] 2-Bromo-6-phenylpyridine (959 mg, 4.10 mmol), tributyl(vinyl) tin (2.40 ml, 8.20 mmol), palladium acetate (138 mg, 0.62 mmol) and triphenylphosphine (323 mg, 1 .23 mmol) were combined in tetrahydrofuran (8.2 ml) and the reaction mixture was thoroughly degassed. The reaction mixture was refluxed for 48 h and monitored for completion. Once complete, the reaction mixture was filtered through celite and the filtrate concentrated. The crude material was purified by column chromatography, eluting 0-5% ethyl acetate/petroleum spirits to give the title compound as a clear oil (713 mg, 96%). LRMS [M+H] ⁺ 182.1 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.08 - 8.01 (m, 2H), 7.69 (t, J = 7.8 Hz, 1 H), 7.63 - 7.55 (m, 1 H), 7.51 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1 H), 6.88 (dd, J = 17.4, 10.7 Hz, 1 H), 6.34 (dd, J = 17.4, 1 .4 Hz, 1 H), 5.48 (td, J = 10.9, 1 .4 Hz, 2H).

Ethyl ( 1 R,2R)-2-(6-phenylpyridin-2-yl)cyclopropane- 1 -carboxylate

[00219] 2-Phenyl-6-vinylpyridine (710 mg, 3.92 mmol) was added to ethyl diazoacetate (8 ml) and the reaction mixture was refluxed for 18 h. The reaction mixture was then concentrated in vacuo and the crude material was purified by column chromatography, eluting 0-10% ethyl acetate/petroleum spirits. The title compound was obtained as a colourless solid (310 mg, 30%). LRMS [M+H] ⁺ 268.2 m/z; HRMS [M+H] ⁺ 268.1332 m/z, found 268.1334 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.06 - 7.97 (m, 2H), 7.65 (t, J = 7.7 Hz, 1 H), 7.60 - 7.55 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.44 - 7.38 (m, 1 H), 7.20 (dt, J = 4.0, 3.3 Hz, 1 H), 4.20 (qd, J = 7.1 , 1 .2 Hz, 2H), 2.67 (ddd, J = 8.0, 4.0 Hz, 1 H), 2.43 (ddd, J = 8.5, 5.5, 3.9 Hz, 1 H), 1 .77 (ddd, J = 8.5, 6.0, 3.6 Hz, 1 H), 1 .64 (ddd, J = 8.9, 5.5, 3.6 Hz, 1 H), 1 .30 (t, J = 8.0 Hz, 3H).

Ethyl ( 1 R,2S )-2-(6-phenylpyridin-2-yl)cyclopropane- 1 -carboxylate

[00220] The title compound was isolated as a product of the previous reaction as a colourless oil which crystallised on standing (137 mg, 13%). LRMS [M+H] ⁺ 268.2 m/z; HRMS [M+H] ⁺ 268.1332 m/z, found 268.1334 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.96 (ddd, J = 4.2, 3.5, 1 .8 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1 H), 7.53 (dd, J = 7.8, 0.5 Hz, 1 H), 7.47 - 7.40 (m, 2H), 7.39 - 7.34 (m, 1 H), 7.20 (d, J= 7.6 Hz, 1 H), 3.87 (q, J= 7.1 Hz, 2H), 2.77 (q, J= 16.5, 8.8 Hz, 1 H), 2.20 (ddd, J = 9.3, 8.0, 6.0 Hz, 1 H), 1 .91 (ddd, J = 7.3, 6.0, 5.0 Hz, 1 H), 1 .42 (ddd, J = 8.6, 8.0, 5.0 Hz, 1 H), 0.95 (t, J = 7.1 Hz, 3H) .

(1 R,2R )-2-(6-Phenylpyhdin-2-yl)cyclopropane- 1 -carboxylic acid

[00221 ] Ethyl (1 ft,2ft)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (310 mg, 1 .16 mmol) was dissolved in tetrahydrofuran (0.8 ml) and this solution was added dropwise to an solution of lithium hydroxide (56 mg, 2.32 mmol) in water (1 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete (~ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid. The product could then be extracted with ethyl acetate to give the title compound as an off-white solid (141 mg, 51 %). LRMS [M+H] ⁺ 240.2 m/z; HRMS [M+H] ⁺ 240.1019 m/z, found 240.1019 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.00 - 7.94 (m, 2H), 7.62 (t, J= 7.7 Hz, 1 H), 7.54 (dd, J= 7.9, 1 .0 Hz, 1 H), 7.47 - 7.35 (m, 3H), 7.1 7 (dd, J = 7.5, 0.9 Hz, 1 H), 2.71 (ddd, J = 8.9, 6.2, 3.8 Hz, 1 H), 2.39 (ddd, J= 8.5, 5.4, 3.8 Hz, 1 H), 1 .83 (ddd, J= 8.4, 6.2, 3.7 Hz, 1 H), 1 .66 (ddd, J = 9.0, 5.4, 3.7 Hz, 1 H).

(1R,2S)-2-(6-Phenylpyridin-2-yl)cyclopropane-1-carboxylic acid

[00222] Ethyl (1 ft,2S)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylate (137 mg, 0.51 mmol) was dissolved in tetrahydrofuran (0.3 ml) and this solution was added dropwise to a solution of lithium hydroxide (25 mg, 1 .02 mmol) in water (0.5 ml). The reaction mixture was stirred at 50 °C and monitored by LRMS and TLC for completion. Once complete (~ 2 h) the reaction mixture was neutralised by addition of an aqueous solution of 1 M hydrochloric acid. The product was extracted with ethyl acetate to give the title compound as an off- white solid (43 mg, 35%). LRMS [M+H] ⁺ 240.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.85 (t, J = 7.9 Hz, 1 H), 7.78 (ddd, J = 5.8, 4.2, 2.4 Hz, 2H), 7.60 (dd, J = 8.0, 0.9 Hz, 1 H), 7.52 - 7.44 (m, 3H), 7.41 (dd, J = 7.8, 0.9 Hz, 1 H), 2.54 (dd, J = 16.1 , 8.4 Hz, 1 H), 2.38 (ddd, J = 15.7, 8.4, 7.3 Hz, 1 H), 1 .85 (dt, J = 9.1 , 4.6 Hz, 1 H), 1 .77 (td, J = 7.3, 5.1 Hz, 1 H).

Isopropyl ((1R,2S)-2-(6-phenylpyridin-2-yl)cyclopropyl)carbamate LF-^'\3-' 72- 02

[00223] (1 ft,2S)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylic acid (75 mg, 0.31 mmol), diphenylphosphoryl azide (81 μΙ, 0.38 mmol), and triethylamine (52 μΙ, 0.38 mmol) were combined in anhydrous isopropanol (5 ml). The reaction mixture was heated to reflux for 2 h and the progress monitored by TLC. Once complete, all volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting with 0-25% ethyl acetate/petroleum spirits. This gave the title compound as a pale-yellow solid (53 mg, 58%) though further purification was required. A small amount of material (-12 mg) was purified by preparative TLC with 10% ethyl acetate/petroleum spirits as the eluent. This gave the title compound as a colourless solid. This led to the isolation of the title compound as an off-white solid. LRMS [M+H] ⁺ 297.2 m/z; HRMS [M+H] ⁺ 297.1598 m/z, found 297.1600 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.08 - 7.87 (m, 2H), 7.61 (t, J= 7.7 Hz, 1 H), 7.52 (dd, J = 7.8, 0.7 Hz, 1 H), 7.48 - 7.31 (m, 3H), 7.17 (d, J = 7.5 Hz, 1 H), 4.93 (dp, J= 12.4, 6.2 Hz, 2H), 3.16 (s, 1 H), 2.22 (s, 1 H), 1 .23 (dd, J= 6.2, 3.4 Hz, 6H).

Isopropyl ((1 R,2R )-2-(6-phenylpyridin-2-yl)cyclopropyl)carbamate

[00224] (1 ft,2ft)-2-(6-phenylpyridin-2-yl)cyclopropane-1 -carboxylic acid (75 mg, 0.31 mmol), diphenylphosphoryl azide (81 μΙ, 0.38 mmol), and triethylamine (52 μΙ, 0.38 mmol) were combined in anhydrous isopropanol (5 ml). The reaction mixture was heated to reflux for 2 h and the progress monitored by TLC. Once complete, all volatiles were removed in vacuo and the crude material was purified by column chromatography, eluting with 0-25% ethyl acetate/petroleum spirits. This gave the title compound as a pale-yellow solid (58 mg, 63%) though further purification was required. A small amount of material (-12 mg) was purified by preparative TLC with 10% ethyl acetate/petroleum spirits as the eluent. This gave the title compound as a colourless. This led to the isolation of the title compound as an off-white solid. LRMS [M+H] ⁺ 297.2 m/z; ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.01 - 7.92 (m, 2H), 7.59 (t, J = 7.7 Hz, 1 H), 7.52 - 7.47 (m, 1 H), 7.45 - 7.39 (m, 2H), 7.36 (dt, J = 9.7, 4.3 Hz, 1 H), 7.15 (d, J = 7.4 Hz, 1 H), 4.90 (dt, J = 12.5, 6.3 Hz, 2H), 3.14 (s, 1 H), 2.20 (s, 1 H), 1 .68 (ddd, J = 7.3, 5.8, 5.1 Hz, 1 H), 1 .21 (dd, J = 6.2, 3.4 Hz, 6H).

1 -phenyl- 1 H -pyrazol-3-amine

[00225] 3-Amino-pyrazole (1 .0 g, 12.03 mmol), Cs ₂ CO ₃ (3.92 g, 12.03 mmol), iodobenzene (3.68 g, 18.05 mmol), CuBr ₂ (0.268 g, 0.1 mmol), and DMF (4 ml_) were added to a 10-mL microwave vial. The vial was sealed and heated to 190 °C for 20 min (monitored by TLC). After cooling, the reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 imL x 3). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 0-40% ethyl acetate and petroleum benzine, afforded the desired product, 1 -phenyl-1 -/-pyrazol-3-amine, as a brown solid (1 .53 g, 80%).

3-iodo- 1 -phenyl- 1 H -pyrazole

[00226] To a stirred solution of 1 -phenyl-1 H-pyrazol-3-amine (1 .0 g, 6.28 mmol) in THF (20 imL) was added 4M aqueous HCI (15.0 imL), and the solution was cooled in an ice water bath. A solution of NaNO ₂ (0.52g, 7.54 mmol) in H ₂ O (10 imL) was added dropwise. After 20 min, a solution of Kl (2.61 g, 15.7 mmol) in H ₂ O (10 imL) was added, and stirred for 10 min in the ice water bath. Then the solution was slowly warmed up to room temperature and stirred for 1 h before 1 M aqueous Na ₂ S ₂ O ₃ was added until the colour of the mixture did not change. The phases were separated, and the aqueous phase extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with H ₂ O (5 mL x 2) and brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 0-10% ethyl acetate and petroleum benzine, afforded the desired product, 3-iodo-1 -phenyl-1 H-pyrazole, as a colourless oil (1 .39 g, 82% yield).

Benzyl (E)-3-(1 -phenyl-1 -pyrazol-3-yl)acrylate

[00227] 3-lodo-1 -phenyl-1 H-pyrazole (0.8 g, 2.9 mmol) was dissolved in a mixture of DMF:H ₂ OEt ₃ N (5:0.8:8 mL). To this solution were added benzyl acrylate (4.80 g, 29.62 mmol.), {PdCI ₂ (dppf)} (54 mg, 0.592 mmol) and tetrabutylammonium iodide (2.19 g, 5.92 mmol). The resulting mixture was heated at 50°C for 2 h. After cooling to room temperature, H ₂ O (300 mL) was added and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 0-35% ethyl acetate and petroleum benzine, afforded the desired product, benzyl (£)-3-(1 -phenyl-1 -/-pyrazol-3-yl)acrylate, as a yellow solid (0.558 g, 62%).

3- (1 -phenyl- 1 H -pyrazol-3-yl)propanoic acid

[00228] Benzyl (£)-3-(1 -phenyl- 1 H-pyrazol-3-yl)acrylate (0.5 g, 3.17 mmol) was dissolved in ethanol (25 ml) and 5% Pd/C (17 mg, 0.16 mmol) was added prior to the reaction being flushed with hydrogen gas. The reaction mixture was stirred at 50 °C (monitored by TLC and LCMS). Once completed, the reaction mixture was filtered through celite and the solvent removed in vacuo. The crude product was purified by flash column chromatography, eluting with 0-40% ethyl acetate/petroleum spirits + 1 % acetic acid, afforded the desired product, 3-(1 - phenyl-1 -/-pyrazol-3-yl)propanoic acid, as a white solid (0.301 g, 85%). ieri-butyl (2-(1-phenyl-1H-pyrazol-3-yl)ethyl)carbamate

[00229] 3-(1 -Phenyl-1 H-pyrazol-3-yl)propanoic acid (0.250 g, 1 .16 mmol), diphenylphosphoryl azide (0.382 g, 1 .39 mmol) and A/,A/-diisopropylethylamine (0.179 g, 1 .39 mmol) were combined in anhydrous terf-butanol (3 ml). The reaction mixture was heated to reflux for 3 h and the reaction progress was monitored by TLC and LRMS. Once complete a saturated aqueous solution of sodium bicarbonate was added and the product was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed once with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 0-15% ethyl acetate and petroleum benzine, afforded the desired product, tert-butyl (2-(1 -phenyl-1 H-pyrazol-3- yl)ethyl)carbamate, as a white solid (0.165 g, 50% yield).

2-(1 -phenyl- 1 H -pyrazol-3-yl)ethan- 1 -amine tosylate

[00230] Following general Boc-deprotection with p-toluensulfonic acid monohydrate, 2-(1 -phenyl-1 H-pyrazol-3-yl)ethan-1 -aminium 4- methylbenzenesulfonate was obtained as a white solid (0.053g, 60% yield).

N - (2- (1 -phenyl- 1 H -pyrazol-3-yl)ethyl)pipehdine- 1 -carboxamide

[00231 ] Following general urea formation, A/-(2-(1 -phenyl-1 H-pyrazol-3- yl)ethyl)piperidine-1 -carboxamide was obtained as a white solid (0.06 g, 72% yield).

2-(4-phenylthiazol-2-yl)acetonitrile

[00232] A mixture of 2-bromoacetophenone (1 .0 g, 5 mmol) and 2- cyanothioacetamide (0.5 g, 10 mmol) in ethanol (25 mL) was heated to 80°C for 4 h. The reaction mixture was cooled to room temperature and poured into an aqueous ammonia solution (final pH was >7). The mixture was then extracted with ethyl acetate (100 mL x 3) and the organic layers were washed with H ₂ O and brine. The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrate in vacuo. The crude product was purified by flash column chromatography, eluting with 0-30% ethyl acetate and petroleum benzene, afforded 2-(4-phenylthiazol-2-yl)acetonitrile (0.69 g, yield 70%) as a yellow solid. tert-butyl (2-(4-pheny!thiazQi-2-yl)ethy1)carbamate

[00233] To a stirred solution of 2-(4-phenylthiazol-2-yl)acetonitrile (0.5 g, 2.50 mmo!) in dry methanol (15 mL), cooled to 0°C, were added di-terf-butyl dicarbonate (1 .09 g, 4,99 mmol) and nickel (II) chloride hexahydrate (0.059 g,

0.25 mmoB. Sodium borohydride (0.881 g, 17,5 mmol) was then added in small portions over 30 min. The reaction was exothermic and effervescent. The resulting reaction mixture containing a finely divided black precipitate was allowed to warm to room temperature and left to stir for a further 1 h, at which point diethylenetriamine (0,257 g, 2.50 mmol) was added. The mixture was allowed to stir for 30 min before solvent evaporation. The purple residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (50 mL x 2), The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 0-35% ethyl acetate/petroleum benzine, afforded the desired product, terf-butyl-[2-(2- phenylthiazol-4-yl)ethyl] carbamate, as a brown oil (0.72 g, 95%).

2-(4-phenylthiazol-2-yl)ethan- 1 -amine dihydrochloride

[00234] 4 M HCI in dioxane (3 mL) was slowly added to terf-butyl-[2-(2- phenylthiazol-4-yl)ethyl] carbamate (0.3 g, 0.985 mmol) under nitrogen atmosphere. The solution was allowed to stir at room temperature for 2 h. The resulting precipitate was filtered and air-dried, used directly in the next step due to the nature of hydroscopic of the hydrochloride salt.

N-(2-(4-phenylthiazol-2-yl)ethyl)piperidine- 1 -carboxamide

[00235] Following general urea formation method, A/-(2-(4-phenylthiazol-2- yl)ethyl)piperidine-1 -carboxamide was obtained as an off-white solid (34 mg, 45% yield).

2- (3-oxobutyl)isoindoline- 1 ,3-dione

[00236] To a well-stirred suspension of phthalimide (5.0 g, 33.98 mol) and of

3- buten-2-one (2.38 g, 33.98 mmol in ethyl acetate (280 ml_) was added sodium ethoxide (0.1 15 g, 1 .70 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h, and further refluxed until an almost clear solution was obtained and refluxing was continued for an additional 2 h. The reaction mixture was cooled to room temperature and water (300 imL) was added. The precipitated solid was filtered off and washed with water (3 x 100 imL) and dried in vacuum oven, afforded the desired product, 2-(3-oxobutyl) isoindole-1 ,3-dione, as a white solid (3.62 g, 50 %).

2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione

[00237] To a solution of 2-(3-oxobutyl) isoindole-1 ,3-dione (3.0 g, 13.81 mmol) in methanol (100 imL) was added bromine (2.43 g, 15.19 mmol) dropwise at 0°C. The reaction mixture was stirred at the same temperature for 30 min and then at room temperature for 15 h. To the resulting clear solution was added concentrated sulfuric acid (10 M, 20 mL) and the resulting mixture was stirred at room temperature for 24 h. The precipitated solid was filtered and air- dried, afforded the desired product, 2-(4-bromo-3-oxobutyl)isoindoline-1 ,3- dione, as a white solid, (1 .85 g, 46% yield).

2-(3-oxo-4-thiocyanatobutyl)isoindoline-1,3-dione

[00238] To a hot solution (50°C) of 2-(4-bromo-3-oxobutyl)isoindoline-1 ,3- dione (1 .5 g, 5.07 mmol) in ethanol (10 mL), a solution (in 5 mL water) potassium thiocyanide (0.49 g, 5.07 mol) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into ice/water cold hydrochloric acid (to pH 6), the resulting white precipitated was filtered and washed with H ₂ O to give the desired product, 2-(3- oxo-4-thiocyanatobutyl)isoindoline-1 ,3-dione, as white solid (0.903 g, 65% yield).

2-(2-(2-bromothiazol-4-yl)ethyl)isoindoline-1,3-dione

[00239] To a solution of 2-(3-oxo-4-thiocyanatobutyl)isoindoline-1 ,3-dione (0.8 g, 2.92 mmol) in dichloromethane (20 mL) was added 33% HBr in acetic acid (20 mL) at room temperature. The mixture was stirred for 2 h at this temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 0-30% ethyl acetate and petroleum benzine, afforded the desired product, 2-(2-(4-bromothiazol-2-yl)ethyl)isoindoline-1 ,3- dione.

2-(2-bromothiazol-4-yl)ethan- 1 -amine

[00240] To a solution of 2-(2-(4-bromothiazol-2-yl)ethyl)isoindoline-1 ,3-dione (0.3 g, 0.889 mmol ) in ethanol (20 mL) was added hydrazine monohydrate (4 mL). The resulting mixture was refluxed for 4-5 h, the white precipitated was filtered and the precipitated was further washed with ether (3x). The combined filtrates were concentrated in vacuo to give the desired product, 2-(4- bromothiazol-2-yl)ethan-1 -amine, as light yellow solid.

Following general urea formation, A/-(thiazol-2-yl)ethyl)piperidine-1 -carboxamide derivatives were was obtained.

Biological Assays

[00241 ] All in vitro assays were carried out at least twice independently in singleton. The IC ₅₀ values are the means of two independent assays and vary by less than ±50%.

[00242] P. falciparum assay: In vitro activity against erythrocytic stages of P. falciparum was determined using a 3H-hypoxanthine incorporation assay, ^6,7 using the chloroquine and pyrimethamine resistant K1 strain ⁸ and the standard drug chloroquine (Sigma C6628). Compounds were dissolved in DMSO at 10 img/mL and added to parasite cultures in 96 well plates incubated in RPM1 1640 medium without hypoxanthine, supplemented with HEPES (5.94 g/L), NaHCO ₃ (2.1 g/L), neomycin (100 U/mL), AlbumaxR (5 g/L) and washed human red cells (type A+) at 2.5% haematocrit (0.3% parasitaemia). Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL were prepared. The plates were incubated in a humidified atmosphere at 37 °C; 4% CO ₂ , 3% O ₂ , 93% N ₂ . After 48 h, 50 μί of 3H-hypoxanthine (0.5 μθί) was added to each well of the plate. The plates were incubated for a further 24 h under the same conditions. The plates were then harvested with a Betaplate™ cell harvester (Wallac, Zurich, Switzerland), and the red blood cells transferred onto a glass fibre filter and washed with distilled water. The dried filters were inserted into a plastic foil with 10 mL of scintillation fluid, and counted in a Betaplate™ liquid scintillation counter (Wallac, Zurich, Switzerland). IC ₅ o values were calculated from sigmoidal inhibition curves by linear regression ⁹ using Microsoft Excel. Chloroquine and artemisinin we used as controls. [00243] L. donovani axenic amastigotes assay: Amastigotes of L. dono vani strain MHOM/ET/67/L82 were grown in axenic culture at 37 °C in SM medium ¹⁰ at pH 5.4 supplemented with 10% heat-inactivated fetal bovine serum under an atmosphere of 5% CO ₂ in air. 100 μΙ_ of culture medium with 10 ⁵ amastigotes from axenic culture with or without a serial drug dilution were seeded in 96-well microtitre plates. Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL were prepared. After 70 h of incubation the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions. 10 μΙ_ of Alamar Blue (12.5 mg resazurin dissolved in 100 imL distilled water) ¹¹ were then added to each well and the plates incubated for another 2 h. The plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. Data were analyzed using the software Softmax Pro (Molecular Devices Cooperation, Sunnyvale, CA, USA). Decrease of fluorescence (i.e. inhibition) was expressed as percentage of the fluorescence of control cultures and plotted against the compound concentrations. From the sigmoidal inhibition curves the IC ₅₀ values were calculated by linear regression. ⁹ Miltefosine was used as a positive control.

[00244] T. cruzi assay: Rat skeletal myoblasts (L-6 cells) were seeded in 96- well microtitre plates at 2000 cells/well in 100 μΙ_ RPM1 1640 medium with 10% FBS and 2 imM l-glutamine. After 24 h at 37°C/5% CO ₂ , the medium was removed and replaced by 100 pl_ per well containing 5000 trypomastigote forms of T. craz/Tulahuen strain C2C4 containing the β-galactosidase (Lac Z) gene. ¹² After 48 h the medium was removed from the wells and replaced by 100 pl_ fresh medium with or without a serial compound dilution of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL. After 96 h incubation at 37°C/5% CO ₂ the plates were inspected under an inverted microscope to assure growth of the controls and sterility and the substrate CPRG/Nonidet (50 pl_) was added to all wells. A color reaction developed within 2-6 h and could be read photometrically at 540 nm. Data were analyzed with the graphic program Softmax Pro (Molecular Devices), which calculated IC ₅ o values by linear regression ⁹ from the sigmoidal dose inhibition curves. Benznidazole was used as a positive control.

[00245] T. brucei rhodesiense assay: This parasite stock was isolated in 1982 from a human patient in Tanzania and after several mouse passages cloned and adapted to axenic culture conditions. ¹³ Minimum Essential Medium (50 μΙ_) supplemented with 25 imM HEPES, 1 g/L additional glucose, 1 % MEM non-essential amino acids (100x), 0.2 imM 2-mercaptoethanol, 1 imM Na- pyruvate and 15% heat inactivated horse serum was added to each well of a 96-well microtiter plate. Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/mL were prepared. Then 4x10 ³ bloodstream forms of T. b. rhodesiense STIB 900 in 50 μΙ_ was added to each well and the plate incubated at 37°C under a 5% CO ₂ atmosphere for 70 h. 10 μΙ_ Alamar Blue (resazurin, 12.5 mg in 100 imL double-distilled water) was then added to each well and incubation continued for a further 2-4 h. ¹⁴ Then the plates were read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. The IC ₅₀ values were calculated by linear regression ⁹ from the sigmoidal dose inhibition curves using SoftmaxPro software (Molecular Devices Cooperation, Sunnyvale, CA, USA). Melarsoprol was used as a control.

[00246] Rat skeletal myoblast cytotoxicity assay: Assays were performed in 96-well microtiter plates, each well containing 100 μΙ_ of RPM1 1640 medium supplemented with 1 % L-glutamine (200 imM) and 10% fetal bovine serum, and 4000 L-6 cells (a primary cell line derived from rat skeletal myoblasts). ^{15, 16} Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 g/mL were prepared. After 70 h of incubation at 37°C/5% CO ₂ the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions. 10 μΙ_ of Alamar Blue was then added to each well and the plates incubated for another 2 h. The plates were then read with a Spectramax Gemini XS microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) using an excitation wavelength of 536 nm and an emission wavelength of 588 nm. The IC ₅₀ values were calculated by linear regression ⁹ from the sigmoidal dose inhibition curves using SoftmaxPro software (Molecular Devices Cooperation, Sunnyvale, CA, USA). Podophyllotoxine was used as a positive control.

[00247] T. b. brucei assay: Compound activity against T. b. brucei was assessed using a modification of the Alamar blue® viability assay as previously described by Sykes and Avery. ¹⁷ in which resazurin was used instead of Alamar Blue (which is made up of resazurin dye ¹⁸ ). Briefly, 55 μΙ_ of HMI-9 media +10% FCS ¹⁹ containing 1200 cells/mL of logarithmic phase T. b. brucei 427 bloodstream parasites were added to a 384-well microtiter plate (Greiner, Monroe, NC, USA) and incubated for 24 h at 37°C/5% CO ₂ . Serial compound concentrations were prepared in 100% DMSO and diluted 1 :21 in DMEM media. 5 μΙ_ of this dilution was subsequently added to assay plates to give final compound concentrations ranging from 41 .67 to 0.0004 μΜ. Plates were incubated for 48 h at 37°C/5% CO ₂ . 10 μΙ_ of 0.49 imM resazurin prepared in HMI-9 media +10% FCS was added to assay plates and plates incubated for a further 2 h at 37 °C/5% CO ₂ followed by 22 h at room temperature. Assay plates were read at 535 nm excitation/590 nm emission on an Envision® multiplate reader (PerkinElmer, Massachusetts, USA). Data was analysed and IC ₅ o values calculated using the software GraphPad Prism 5. Pentamidine and suramin were used as controls.

[00248] HEK293 cytotoxicity assay: 55 μΙ_ of DMEM +10% FCS media (Gibco, Waltham, MA, USA) containing 72727 cells/mL of HEK293 cells was added to a 384-well microtiter plate (Greiner) and incubated for 24 h at 37°C/5% CO2. Serial compound concentrations were prepared in 100% DMSO and diluted 1 :21 in DMEM media. 5 μΙ_ of this dilution was subsequently added to assay plates to give final compound concentrations ranging from 83.34 to 0.0004 μΜ. Plates were incubated for 48 h at 37°C/5% CO ₂ . 10 μΙ_ of 0.49mM resazurin prepared in DMEM media +10% FCS was added to assay plates and plates incubated for a further 5 h at 37°C/5% CO ₂ followed by 19 h at room temperature. Assay plates were read at 535 nm excitation/590 nm emission on an Envision® multiplate reader (PerkinElmer, Massachusetts, USA). Data was analysed and IC ₅₀ values were calculated using the software Graph Pad Prism 5. Puromycin wasused as a positive control.

[00249] Note that in any representations of the activity data which follows below the compound label 'inactive' simply means that the associated compound did not have an IC ₅₀ value against T. brucei brucei of better than 10μΜ but activity was still observed. Thus, the label 'inactive' should be read as IC ₅₀ > 10μΜ.

[00250] The below results indicate efficacy of certain thiazole compounds against T. brucei brucei. The compounds conform to the generic structure below and the table following indicating the efficacy by comparison to the varying 'R' group (which equates to R ₂ in formula (I) to formula (XXV).

109

[0025] ] The following results indicate efficacy of certain thiazole compounds against T. brucei brucei. The compounds conform to the generic structure below with the table following indicating the efficacy by comparison to the varying 'R' group (which equates to R ₂ in formula (I) to formula (XXV) inclusive, this time, of the amide linkage).

[00252] The following results indicate efficacy of certain pyrazole compounds against T. brucei brucei. The compounds conform to the generic structure below with the table following indicating the efficacy by comparison to the varying 'R' group (which equates to R ₂ in formula (I) to formula (XXV) inclusive, this time, of the amide linkage).

0

[00253] The following results indicate efficacy of certain thiazole compounds against T. brucei brucei. The compounds conform to the two generic structures below with the table following indicating the efficacy by comparison to the particular structure shown above the results and varying an 'R' group (which equates to Ri in formula (I) to formula (XXV).

[00254] The table following indicates the efficacy of the compounds of the invention against a range of trypanosome and other genera of kinetoplastids including Leishmania.

7. ?. rhodesiense is a human pathogenic strain; /.. donovani causes leishmaniasis; P. falciparum causes malaria. MRK8 observed activity against 7. b. rhodesiense (HAT, 0.024[ig/mL), T cruzi (Chagas, 0. 169μg/mL), L donovani (Leishmania 7.7μg/mL) and P. falciparum (Malaria, 10.0 ug/mL).

[00255] Further select compounds of the invention will now be shown with IC ₅₀ values against T. brucei brucei indicated. For certain compounds the 'selectivity index' (SI), representing the IC ₅₀ value against HEK cells divided by the IC ₅₀ value against T. brucei brucei. The results indicate a number of trends including significantly improved activity being observable in the thiazole series when the RHS amide substituent is replaced by a urea. The thiazoles and pyrazoles appear to be favoured over triazoles and tetrazoles.

[00256] The following table demonstrates certain key properties of some of the particularly efficacious compounds.

[00257] The following table demonstrates the activity of two selected compounds, already shown to be highly active against T. brucei brucei, against T. cruzi.

[00258] The following tables provide activity data against T. brucei brucei and selectivity index information where it was felt the activity warranted further investigation of selectivity.

[00259] The tables which follow provide a summary of biological data (assume EC50 in uM unless otherwise indicated and any accompanying figure in parentheses represents the standard deviation) obtained for a range of compounds of the invention. Where a figure is provided without indication of the species against which it was tested then the species was T. brucei brucei. Otherwise Tbr = T. brucei rhodesiense; Tc = T. cruzi; leish = Leishmania donavani; L6 =rat skeletal myoblasts as a measure of mammalian cytotoxicity and hence the SI is the selectivity index of the ratio of toxicity of parasite to mammalian cells; EH = hepatic extraction ratio.

[00260] The data presented in this experimental section shows that the compounds of the invention are active, at least to a degree, against the subspecies T.b.brucei. This finding is further relevant as a surrogate to the disease causing subspecies T.b.rhodesiense and, by association, T.b.gambiense and of especial interest another species of particular concern due to Chagas disease, T.cruzi.

[00261 ] Certain trends are observable from the activity data and so some general SAR comments can be made. It is postulated from the results that the capacity to increase the steric bulk of the acyl substituent is limited and that para-substitution on ring structures in this position was deleterious apart from very small substituents, such as fluorine. Increasing polarity of the heterocyclic core appears to result in a drop off in efficacy and so tetrazoles, for example, are less preferred. Finally, the amide NH is observed to be important for improved activity and urea groups at the right hand side of the molecules, as drawn, further assists in improving efficacy.

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