Azetidin derivatives as potassium chanel inhibitors

Abstract

The invention relates to azetidinyl derivatives and their use in the treatment and prophylaxis of a disease or condition mediated by potassium channel inhibition, such as inhibition of Kv7, and to compositions containing said derivatives and processes for their preparation.

Description

[0001] CLI-C-P3879PCT

[0002] NOVEL COMPOUNDS

[0003] FIELD OF THE INVENTION

[0004] The invention relates to azetidinyl derivatives and their use in the treatment and prophylaxis of a disease or condition mediated by potassium channel inhibition, such as inhibition of Kv7, and to compositions containing said derivatives and processes for their preparation.

[0005] BACKGROUND OF THE INVENTION

[0006] Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane

[0007] potential, shaping action potentials and other electrical signals by gating the flow

[0008] of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

[0009] Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

[0010] The voltage-gated potassium channel family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following action potentials. The a subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel.

[0011] KCQN genes encode family members of the Kv7 potassium channel family. These include Kv7.1 (KCNQ1 - KvLQTI), Kv7.2 (KCNQ2), Kv7.3 (KCNQ3), Kv7.4 (KCNQ4), and Kv7.5 (KCNQ5). Four of these (KCNQ2-5) are expressed in the nervous system. They constitute a group of low-threshold voltage-gated K+channels originally termed the ‘M-channel’.

[0012] KCQN has been linked with a number of disorders, such as diseases associated with changes in motor neuron excitability, neurodevelopmental diseases, pain, psychiatric disorders, neuropathies and hearing disorders. Therefore, there is a great need to identify modulators of the KCQN ion channel.

[0013] SUMMARY OF THE INVENTION

[0014] According to a first aspect of the invention, there is provided a compound of formula (I):CLI-C-P3879PCT

[0015]

[0016] or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt, cocrystal or a solvate thereof, wherein:

[0017] R1represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-8 cycloalkyl, -C1-6 alkyl-C3-8 cycloalkyl, wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R1agroups;

[0018] R1arepresents C1-6 alkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or-SO2Ra;

[0019] Raand Rbindependently represent hydrogen or C1-6 alkyl;

[0020] R2represents aryl or heteroaryl, wherein said aryl or heteroaryl groups may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R2agroups;

[0021] R2arepresents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or -SO2Ra;

[0022] X and Y are both -N=, or X and Y are both -C(R5)=, or one of X represents -N= and the other represents -C(R5)=;

[0023] R5represents hydrogen or halogen;

[0024] n represents an integer selected from 0 to 2;

[0025] R3represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or -SO2Ra; p represents an integer selected from 0 to 4; and

[0026] R4represents C1-6 alkyl, halogen, haloCi-6 alkyl or oxo.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] Definitions

[0029] The term ‘halo’ or ‘halogen’ as used herein refers to fluorine, chlorine, bromine or iodine.

[0030] The term ‘cyano’ as used herein refers to a group where a carbon atom is triple bonded to a nitrogen atom.CLI-C-P3879PCT

[0031] The term ‘C1-6 alkyl’ as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, / so-propyl, butyl, / so-butyl, tert- butyl, pentyl, hexyl and the like.

[0032] The term ‘C1-6 alkoxy’ as used herein as a group or part of a group refers to a C1-6 alkyl group which contains one or more oxygen atoms wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy or propoxy.

[0033] The term ‘haloCi-6 alkyl’ as used herein as a group or part of a group refers to a C1-6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term ‘haloCi-6 alkyl’ therefore includes monohaloCi-6 alkyl and also polyhaloCi-6 alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-6 alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.

[0034] The term ‘oxo’ as used herein refers to the group =0.

[0035] The term ‘nitro’ as used herein refers to the group -N(=O)2.

[0036] The term ‘hydroxy’ or ‘hydroxyl’ as used herein refers to the group OH.

[0037] The term “C3-8 cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0038] The term ‘aryl’ as used herein refers to a carbocyclic monocyclic or bicyclic aromatic, unsaturated ring system containing for example 3 to 12 ring members. Examples of aryl rings include phenyl and naphthyl.

[0039] The term ‘heteroaryl’ as used herein refers to a monocyclic or bicyclic aromatic, unsaturated ring system containing for example 3 to 12 ring members. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.CLI-C-P3879PCT

[0040] Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.

[0041] Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

[0042] A bicyclic heteroaryl group may be, for example, a group selected from:

[0043] a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

[0044] b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms;

[0045] c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0046] d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms;

[0047] e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0048] f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0049] g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0050] h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0051] i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0052] j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0053] k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0054] l) a furan ring fused to a 5- or 6-membered ring containing 0, 1 , 2 or 3 ring heteroatoms;

[0055] m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; and

[0056] n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring

[0057] heteroatoms.CLI-C-P3879PCT

[0058] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-bjthiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).

[0059] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1 ,5-a] pyrimidine), triazolopyrimidine (e.g. [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine and pyrazolopyridine (e.g. pyrazolo[1 ,5-a]pyridine) groups.

[0060] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, quinolizine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

[0061] Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole, 4, 5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-ajpyrazine), chroman, thiochroman, isochroman, chromene, isochromene, benzodioxan, benzoxazine, benzodiazepine, and indoline groups.

[0062] The term ‘optionally substituted’ as used herein refers to a group which may be substituted or unsubstituted by a substituent as herein defined.

[0063] Embodiments

[0064] In one embodiment, R1represents C1-6 alkyl (such as -CH2-(CH3)3), C1-6 alkoxy (such as -O-CH2-CH3), C3-8 cycloalkyl (such as cyclobutyl) or -C1-6 alkyl-Cs-s cycloalkyl (such as -CH2-cyclopropyl or -CH2-cyclobutyl) wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by one or more (e.g. 1 or 2) R1agroups.

[0065] In one embodiment, R1arepresents halogen (such as fluorine) or hydroxy.

[0066] In a further embodiment, R1represents optionally substituted C1-6 alkyl (such as -CH2-(CHs)3 or -CH2-(CH3)(CH3)(OH)), C1-6 alkoxy (such as -O-CH2-CH3), optionally substituted C3-8CLI-C-P3879PCT

[0067] cycloalkyl (such as difluorocyclobutyl) or optionally substituted -C1-6 alkyl-C3-8 cycloalkyl (such as -CH2-cyclopropyl or -CH2-difluorocyclobutyl).

[0068] In one embodiment, R2represents phenyl or a 5 or 6 membered monocyclic heteroaryl group, wherein said phenyl or heteroaryl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups.

[0069] In a further embodiment, R2represents phenyl or a 6 membered monocyclic heteroaryl group, wherein said phenyl or heteroaryl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups.

[0070] In a yet further embodiment, R2represents phenyl, pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl), thiophenyl (such as thiophen-2-yl) or thiazolyl (such as thiazol-2-yl) wherein said phenyl, pyridyl, thiophenyl or thiazolyl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups.

[0071] In a yet further embodiment, R2represents phenyl or pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl) wherein said phenyl or pyridyl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups.

[0072] In a yet further embodiment, R2represents phenyl or pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl) wherein said phenyl or pyridyl group are substituted by 1 or 2 R2agroups.

[0073] In one embodiment, R2arepresents halogen (such as fluorine or chlorine), Ci-6 alkyl (such as methyl), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SO2Ra(such as -SO2-Me).

[0074] In a further embodiment, R2arepresents halogen (such as fluorine), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SO2Ra(such as -SO2-Me).

[0075] In a further embodiment, R2represents:

[0076] phenyl substituted by one or two halogen (such as fluorine), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SO2Ra(such as -SO2-Me) groups; or

[0077] pyridyl substituted by one halogen (such as fluorine) group; or

[0078] thiophenyl substituted by a cyano group; or

[0079] unsubstituted thiazolyl.CLI-C-P3879PCT

[0080] In a further embodiment, either R2represents phenyl substituted by one or two halogen (such as fluorine), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SO2Ra(such as -SO2-Me) groups or R2represents pyridyl substituted by one halogen (such as fluorine) group.

[0081] In a further embodiment, R2represents 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 3-fluoropyridin-4-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 3,5-difluoropyridin-2-yl, 5-fluoro-6-methylpyridin-2-yl, 5-cyanothiophen-2-yl or thiazol-2-yl.

[0082] In a further embodiment, R2represents 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 3-fluoropyridin-4-yl, 5-fluoropyridin-2-yl or 5-fluoropyridin-3-yl.

[0083] In one embodiment, X and Y are both -N=, or X and Y are both -C(H)=, or one of X is -C(H)= and the other is -C(F)=, or one of X is -N= and the other is -C(F)=, or one of X is -N= and the other is -C(H)=.

[0084] In one embodiment, R3represents C1-6 alkyl (such as methyl), halogen (such as chlorine or fluorine), C1-6 alkoxy (such as methoxy), haloCi-6 alkoxy (such as trifluoromethoxy or difluoromethoxy), cyano or -NRaRb(such as -NH2).

[0085] In one embodiment, n represents 1. In a further embodiment, n represents 1 and:

[0086] R3represents C1-6 alkoxy (such as methoxy); or

[0087] R3represents haloCi-6 alkoxy (such as trifluoromethoxy or difluoromethoxy); or

[0088] R3represents cyano; or

[0089] R3represents-NRaRb(such as -NH2).

[0090] In one embodiment, n represents 2. In a further embodiment, n represents 2 and:

[0091] both R3groups represent C1-6 alkyl (such as methyl); or

[0092] both R3groups represent C1-6 alkoxy (such as methoxy); or

[0093] one of R3represents C1-6 alkyl (such as methyl or ethyl) and the other represents C1-6 alkoxy (such as methoxy); or

[0094] one of R3represents C1-6 alkyl (such as methyl) and the other represents cyano; orCLI-C-P3879PCT

[0095] one of R3represents C1-6 alkoxy (such as methoxy) and the other represents halogen (such as fluorine or chlorine); or

[0096] one of R3represents C1-6 alkoxy (such as methoxy) and the other represents cyano; or one of R3represents C1-6 alkyl (such as methyl) and the other represents haloCi-6 alkoxy (such as difluoromethoxy).

[0097] In a further embodiment, n represents 2. In a further embodiment, n represents 2 and: both R3groups represent C1-6 alkyl (such as methyl); or

[0098] both R3groups represent C1-6 alkoxy (such as methoxy); or

[0099] one of R3represents C1-6 alkyl (such as methyl) and the other represents C1-6 alkoxy (such as methoxy); or

[0100] one of R3represents C1-6 alkyl (such as methyl) and the other represents cyano; or one of R3represents C1-6 alkoxy (such as methoxy) and the other represents halogen (such as fluorine or chlorine); or

[0101] one of R3represents C1-6 alkoxy (such as methoxy) and the other represents cyano; or one of R3represents C1-6 alkyl (such as methyl) and the other represents haloCi-6 alkoxy (such as difluoromethoxy).

[0102] In one embodiment, p represents an integer selected from 0 to 3.

[0103] In one embodiment, R4represents C1-6 alkyl (such as methyl), halogen (such as fluorine) or oxo.

[0104] In one embodiment, p represents 0.

[0105] In an alternative embodiment, p represents 1. In a further embodiment, p represents 1 and R4represents C1-6 alkyl (such as methyl) or oxo.

[0106] In an alternative embodiment, p represents 2. In a further embodiment, p represents 2 and both R4groups represent Ci-e alkyl (such as methyl) or both R4groups represent halogen (such as fluorine).

[0107] In an alternative embodiment, p represents 3. In a further embodiment, p represents 3 and one R4group represents C1-6 alkyl (such as methyl) and the other two R4groups represent halogen (such as fluorine).

[0108] In one embodiment, R5represents hydrogen or fluorine.CLI-C-P3879PCT

[0109] In one embodiment, Raand Rbindependently represent hydrogen or methyl. In a further embodiment, Raand Rbboth represent hydrogen. In an alternative embodiment, one of Raand Rbrepresents hydrogen and the other represents methyl. In an alternative embodiment, Raand Rbboth represent methyl. In a further embodiment, Rarepresents hydrogen or methyl. In a further embodiment, Rarepresents methyl.

[0110] In one embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-127 or a pharmaceutically acceptable salt, co-crystal or solvate thereof.

[0111] In one embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-127 or a pharmaceutically acceptable salt, co-crystal or solvate thereof.

[0112] A reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof. Hereinafter, compounds and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof as defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

[0113] Salts

[0114] Certain compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.

[0115] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts; Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of theseCLI-C-P3879PCT

[0116] compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0117] Acid addition salts (mono- or d / -salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or / -salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0118] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt.

[0119] Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

[0120] The compounds of the invention may exist as mono- or d / -salts depending upon the pKa of the acid from which the salt is formed.

[0121] It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include thoseCLI-C-P3879PCT

[0122] described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0123] Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0124] Solvates

[0125] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.

[0126] It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

[0127] As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0128] N-Oxides

[0129] Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.CLI-C-P3879PCT

[0130] Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0131] N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Commun. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0132] Prodrugs

[0133] It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, 19, 9, 1983, 499-538 and in Topics in Chemistry, Chapter 31, pp. 306-316 and in “Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.

[0134] Also included within the scope of the compound and various salts of the invention are polymorphs thereof.

[0135] Enantiomers

[0136] The compounds of formula (I) may be achiral or contain one or more R or S chiral centres. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventionalCLI-C-P3879PCT

[0137] synthetic methods or by stereospecific or asymmetric syntheses. The invention also extends to any tautomeric forms or mixtures thereof.

[0138] Isotopes

[0139] The subject invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0140] Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l,125l and131l, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0141] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase) etc. The radioactive isotopes tritium, i.e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0142] Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0143] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0144] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.CLI-C-P3879PCT

[0145] Purity

[0146] Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

[0147] Processes

[0148] According to a further aspect of the present invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes are examples of synthetic schemes that may be used to synthesise the compounds of the invention. In the following schemes reactive groups can be protected with protecting groups and de-protected according to well established techniques.

[0149] According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as herein defined which comprises:

[0150] (a) reacting a compound of formula (II):

[0151]

[0152] wherein R1, R3, n, X and Y are as defined in claim 1 and L1represents a suitable leaving group, such as a halogen atom (e.g. bromine) or iodide, with a compound of formula (III):

[0153]

[0154] wherein R4, p and R2are as defined in claim 1;CLI-C-P3879PCT

[0155] (b) reacting a compound of formula (IV):

[0156]

[0157] wherein R3, n, X, Y, R4, p and R2are as defined in claim 1, with a compound of formula R1-C(=O)-L2, wherein R1is as defined in claim 1 and L2represents OH, or L2is a suitable leaving group, such as a halogen atom (e.g. chlorine);

[0158] (c) deprotection of a protected derivative of a compound of formula (I);

[0159] (d) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and

[0160] (e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

[0161] Process (a) typically comprises reacting the compounds of formulae (II) and (III) under copper (I) iodide catalysis or alternatively under conditions of palladium catalysis in the presence of specific ligands such as RuPhos or CPhos.

[0162] Process (b) typically comprises reacting the compounds of formulae (IV) and R1-C(=O)-L2under conditions suitable for an acylation reaction, such as in the presence of a coupling agent such as EDC, or reacted with an activated chloroformate such as ethyl chloroformate.

[0163] Compounds of formulae (II), (III) and (IV) may be prepared in accordance with the below mentioned Schemes and experimental procedures provided in the Examples herein.

[0164] Compounds of formula R1-C(=O)-L2are either known or may be prepared in accordance with known procedures.

[0165] A wide range of well-known functional group interconversions for process (d) are known by a person skilled in the art for converting a precursor compound to a compound of formula (I)CLI-C-P3879PCT

[0166] and are described in Advanced Organic Chemistry by Jerry March, 4thEdition, John Wiley & Sons, 1992. For example, possible metal catalysed functionalisations such as using organotin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in ‘Palladium Reagents and Catalysts’ [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

[0167] If appropriate, the reactions described herein are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions on R1, R2, R3and R4defined herein to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include:

[0168] protection of reactive functions,

[0169] deprotection of reactive functions,

[0170] halogenation,

[0171] dehalogenation,

[0172] dealkylation,

[0173] alkylation of amine, aniline, alcohol and phenol,

[0174] Mitsunobu reaction on hydroxyl groups,

[0175] cycloaddition reactions on appropriate groups,

[0176] reduction of nitro, esters, cyano, aldehydes,

[0177] transition metal-catalyzed coupling reactions,

[0178] acylation,

[0179] sulfonylation / introduction of sulfonyl groups,

[0180] saponification / hydrolysis of esters groups,

[0181] amidification or transesterification of ester groups,

[0182] esterification or amidification of carboxylic groups,

[0183] halogen exchange,

[0184] nucleophilic substitution with amine, thiol or alcohol,

[0185] reductive amination,

[0186] oxime formation on carbonyl and hydroxylamine groups,

[0187] S-oxidation,

[0188] N-oxidation,

[0189] saltifi cation.CLI-C-P3879PCT

[0190] It is recognised that the sequence of reactions involving aryl coupling and reduction may be varied. It is also recognised that a wide range of palladium-based catalysts are suitable for conducting aryl coupling reactions.

[0191] It may also be recognised that isomer separation may occur at any suitable stage in the synthetic sequence. It should be stressed that such chiral separation forms a key aspect of the invention and that such separation may be conducted in accordance with the methodology described herein or may be conducted in accordance with known methodology. It is also recognised that it may be beneficial to temporarily form a protected derivative of an intermediate in the synthesis, for example, a Boc-protected amine, or SEM-protected amide, in order to facilitate chromatographic separation, chiral resolution or to give improved solubility or yields in particular steps.

[0192] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and de-protecting functional groups, can be found in Protective Groups in Organic Synthesis (P. G. M. Wuts and T. W. Greene; 4th Edition; John Wiley and Sons, 2007).

[0193] A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: a tert-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3).

[0194] An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as a tert-butyl carbamate (-NHCOOC(CH3)3, NH-Boc); a 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6H5, NH-Boc), as a 9-fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0195] Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.CLI-C-P3879PCT

[0196] A carboxylic acid group may be protected as an ester for example, as: an C1-7 alkyl ester (e.g. a methyl ester; a tert-butyl ester); a C1-7 haloalkyl ester (e.g. a C1-7 trihaloalkyl ester); a triC-1-7 alkylsilyl-C-1-7 alkyl ester; or a C5-20 aryl-Ci-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester.

[0197] It will be understood by those skilled in the art that certain compounds of the invention can be converted into other compounds of the invention according to standard chemical methods.

[0198] Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

[0199] Compounds of the claim of formula (I) may be prepared according to the following overall process described in Scheme 1 :

[0200] Scheme 1:

[0201] Overall routes to compounds of the claim

[0202]

[0203] For the above mentioned compounds within Scheme 1 the definitions of each variable is as follows:

[0204] A1-2 = functional group for interconversion, or R9-10

[0205] A3 = functional group for interconversion, H or C(=0)Ri3CLI-C-P3879PCT

[0206] A4 = H or a leaving group LG2

[0207] J and K are independently either a carbon atom connected to a functional group for interconversion, or Q and P respectively

[0208] Bi is either R1 or a group that can be transformed into R1 through functional group transformations.

[0209] B2 is a group capable of being transformed into a carbon chain through functionalisation. B4 is either H, CC^Me or R4

[0210] Pn is a nitrogen protecting group or H

[0211] Pr2 is an H, O' or OH group

[0212] LG1 is an O-activating group, H or, in the case where Re and R7 together form a carbonyl, an O-alkyl group

[0213] LG2 is a leaving group such as halogen

[0214] Nxindicates 0, 1 or 2 ring nitrogen atoms

[0215] R1-R3 are as defined for R2ain claim 1

[0216] x = 0, 1 or 2

[0217] R4, Re and R7 are as defined for R4in claim 1

[0218] R9 are as defined for R3in claim 1

[0219] P and Q are as defined for X and Y in claim 1

[0220] R13 is as defined for R1in claim 1.

[0221] Scheme 2 shows general methods for forming 2-aryl-azetidine precursors. Aromatic carbonyl compounds of formula (i)acan be transformed into chiral sulfinimines of formula (i)bby reaction with an appropriate chiral Ellman imine - either R- or S-tert-butyl-sulfinamide - in a suitable solvent such as THF or dichloromethane, in the presence of a dehydrating agent such as magnesium sulfate or titanium tetraethoxide. Chiral imine (i)bcan be reacted with the enolate derivative of an amide (e.g. Mi = morpholine) or ester (e.g. Mi = OEt) to give an adduct of formula (i)c. The enolate may be formed from the parent carbonyl species by any of the general methods known in the art, for example by deprotonation with a base such as lithium diisopropylamide, where Xi = H, or by fluoro-desilylation of the corresponding silyl derivative where Xi = a trialkylsilyl group using for example tetrabutylammonium fluoride or TBAT. Alternatively, where Xi = a halogen such as Br or I, it may be treated with zinc and copper salts in THF to generate a zinc enolate to act as a nucleophile. In the case of (i)cwhere Mi is a coordinating nitrogen species such as Weinreb amine or morpholine (i)d, reaction with an alkyl Grignard or alkyl lithium species, in a suitable solvent such as THF or diethyl ether, give a ketone of formula (i)e. Such a ketone may be reduced to an alcohol using a hydride reducing agent, such as sodium borohydride in a suitable solvent such asCLI-C-P3879PCT

[0222] ethanol, or lithium triethylborohydride in an aprotic solvent, or a chiral hydride source may be utilised, such as S- or R-Selectride® in THF, to give a compound of formula (ii)a.

[0223] Scheme 2:

[0224]

[0225] chiral sulfinamide diastereoisomers

[0226]

[0227] In the case of (i)cwhere Mi is an O-alkyl group such as OEt (i)f, (Scheme 3) treatment with acid such as HCI or TFA in a suitable solvent such as diethylether, 1 ,4-dioxane, ethyl acetate or dichloromethane leads to removal of the sulfinyl protecting group to give an amine of formula (ii)b. This amine may be cyclised to a beta-lactam by treatment with a strong base such as lithium diisopropylamide or potassium hexamethyldisilazide, a compound of formula (iv)awhere Rs and R? in (iv) together form a carbonyl group. Alternatively compound (ii)cmay be reacted with a hydride source such as lithium aluminium hydride in a solvent such as THF to form an alcohol (iv)b. Treatment of this alcohol with Mitsunobu cyclisation conditions such as (tributylphosphoranylidene)acetonitrile in toluene effects cyclisation to sulfinyl azetidine (iv)b.CLI-C-P3879PCT

[0228] Scheme 3:

[0229]

[0230] Intermediate alcohol (ii)amay be oxidised to an aldehyde using for example an iodonium reagent such as Dess-Martin periodinane in dichloromethane, to give a ketone (i)g. Reaction of (i)9with an alkyl Grignard or alkyl lithium species in a solvent such as THF affords alcohol (ii)dwhich may be cyclised under Mitsunobu conditions as before to sulfinyl azetidine (iv)c(Scheme 4).

[0231] Scheme 4:

[0232]

[0233] CLI-C-P3879PCT

[0234] Cleavage of the sulfinyl group on (iv)dcan be effected with acid to give the N-H azetidine (iv)f. Alternatively, a functional group interconversion can be performed at this stage, such as the conversion of an aromatic halide group to a nitrile to form an alternatively substituted aromatic (iv)eusing, for example, potassium hexacyanoferrate in the presence of a catalyst such as 1,T-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride in a solvent such as 1 ,4-dioxane prior to removal of the sulfinyl group (Scheme 5).

[0235] Scheme 5:

[0236]

[0237] Sulfinimides of formula (i)bmay also be reacted with silyl enol ethers in the presence of a suitable Lewis acid to form carbonyl species of formula (i)g(Scheme 6).

[0238] Scheme 6:

[0239]

[0240] A further strategy employed for the construction of aryl azetidines is to utilise a known azetidine of formula (viii)a. This may be oxidised to the corresponding imine N-oxide using an oxidant such as sodium tungstate dihydrate and hydrogen peroxide, which will react with an aryl Grignard or aryl lithium species (M2 = Li, Mg etc.) to give an N-hydroxy azetidine ofCLI-C-P3879PCT

[0241] formula (iv)9which may then be reduced with, for example, zinc in acetic acid, to an N-H azetidine of formula (iv)f(Scheme 7).

[0242] Scheme 7:

[0243]

[0244] Sulfinimines of formula (i)' may be reacted with propenyl anions, for example generated by treatment of allyl species, where X3 is a halogen, with zinc and copper salts to give alkene adducts of formula (i)L Following acid cleavage of the sulfinyl group to (i)k, the nitrogen can be protected with a protecting group Pi stable to oxidative cleavage - such as TMS-ethyl-sulfonyl - to give a protected amine which can be subjected to cleavage by use of an osmium VIII agent with sodium periodate, to give a carbonyl species of formula (i)1.

[0245] Cyclisation under Mitsunobu conditions to compound (iv)hfollowed by protecting group removal using a fluoride source such as tris(dimethylamino)sulphonium difluoro(trimethyl)silicate affords an azetidine of formula (iv)' (Scheme 8).

[0246] Scheme 8:

[0247]

[0248]

[0249] chiralCLI-C-P3879PCT

[0250] Sulfinimides of formula (i)mmay be deprotonated with base and condensed with carbonyl species such as aldehydes or ketones to form alcohols of formula (i)n. Reduction of the imine using a hydride agent forms the azetidine precursor (ii)d(Scheme 9).

[0251] Scheme 9:

[0252]

[0253] chiral diastereomer

[0254] Protected azetidine intermediates of formula (iv)cmay also be formed by an alternative cyclisation strategy. Carbonyl compounds of formula (i)acan be reacted with enols to form hydroxy species of formula (i)°. These can be converted into Ellman imines by reaction with an appropriate sulfinamide in the presence of a dehydrating agent such as titanium tetraisopropoxide to give compounds of formula (i)p. This imine may be reduced to the corresponding sulfinamide (iii)ausing a hydride source such as sodium borohydride. The hydroxy group can be activated to form a leaving group, for example by reaction with nosyl chloride in the presence of a base such as silver carbonate in the presence of silver triflate to from a compound (iii)band this may be cyclised to (iv)cusing a further base such as caesium carbonate (Scheme 10).CLI-C-P3879PCT

[0255] Scheme 10:

[0256]

[0257] diastereoisomers

[0258] Aryl azetidines intermediates of the invention may also be formed by the reaction of the enolates of azetidine carboxylates of formula (viii)cwhere P2 is a suitable protecting group such as a Boc group, with an aryl halide (i)qwhere X2 is a halide such as fluoride under conditions of nucleophilic aromatic substitution to afford the adduct (iv)L Decarboxylation of the saponified ester with, by for example treatment with acetic acid in NMP, gives protected azetidine (iv)kwhich can be subjected is to stronger acid to afford the N-H azetidine (iv)1(Scheme 11).

[0259] Scheme 11:

[0260]

[0261] CLI-C-P3879PCT

[0262] Nitroaromatic compounds of formula (v)awhere A2 is a leaving group such as a chlorine or a fluorine may be converted to analogue (v)bwhen R9 is an alkoxy group, by nucleophilic aromatic substitution. If both A1 and A2 are leaving groups then both positions may be substituted to form (v)c. Alternatively, halogen leaving groups, particularly bromine or iodine at A2or both A1 and A2 may be substituted by alkyl groups using palladium catalysed coupling of aryl boronates. If the steps are conducted sequentially then compound (v)bis formed first, then converted to compound (v)c. Alternatively, a halogen may be retained as an R10 or R9 substituent. Nitroaromatics of formula (v)bor (v)cmay be reduced to the corresponding amino-aromatic (v)dusing a variety of standard conditions such as zinc in aq. ammonium chloride. In some cases it may be preferable to reduce the nitro group of an intermediate (v)bto the amino-aromatic (v)eprior to halogen substitution of group A1 to give the same intermediate (v)d. Aromatic compounds in which A3 is a halogen (v)fcan be converted to Boc-protected amino-aromatic of formula (v)gby reaction with the corresponding tertiary butyl carbamate under palladium coupling conditions. Such materials can be deprotected to afford aminoaromatics (v)dby treatment with acid. (Scheme 12).

[0263] Scheme 12:

[0264]

[0265] CLI-C-P3879PCT

[0266] Aminoaromatics of formula (v) where A4 is H, (v)dmay be halogenated for example with bromine or iodine or an agent such as N-halosuccinimide, to form a compound of formula (vi)b. Alternatively compounds of formula (vi) in which the R10 substituent is H (vi)amay be halogenated at the R10 position to afford (vi)c. In some cases this compound represents an intermediate for a second step with alkyl or alkoxy substitution performed under palladium coupling or SNAr conditions respectively, to give (vi)b. The amino group of (vi)bor (vi)cmay be acylated with an appropriate activated carboxylic acid such as an acid chloride or an acid in the presence of a coupling agent such EDC, or reacted with an activated chloroformate such as ethyl chloroformate to give compounds of formula (vi)d(Scheme 13).

[0267] Scheme 13:

[0268]

[0269] Compounds of formula (vi)dwhere the R9 substituent is a nitro group (vi)e, can be coupled with azetidines of formula (iv)funder conditions of palladium catalysis to give a compound of formula (vii)awhich can be reduced using, for example, dissolving metal conditions, to give R9 amino containing Examples of formula (l)a(Scheme 14).CLI-C-P3879PCT

[0270] Scheme 14:

[0271]

[0272] Beta-lactams of formula (iv)amay be reacted with compounds of formula (vi)fwhere LG2 is a halide using copper (I) iodide catalysis to form lactam containing Examples of formula (l)b(Scheme 15).

[0273] Scheme 15:

[0274]

[0275] Compounds of formula (vi)gin which the A3 group is nitro and LG2 represents a leaving group such as chloride or fluoride, may be reacted with azetidines of formula (iv)funder conditions of nucleophilic aromatic substitution to give compounds of formula (vii)b. These may be reduced to amino aromatics of formula (vii)cusing for example, dissolving metal conditions. The amino group of (vii)cmay be acylated with an appropriate activated carboxylic acid such as an acid chloride or an acid in the presence of a coupling agent such as EDC, or reacted with an activated chloroformate such as ethyl chloroformate to give compounds of formula (I). A subset of (v), phenols of formula (v)hmay be converted to fluoroalkoxy analogues (v)i by treatment with phosphonic acid, (bromodifluoromethyl)diethyl ester and strong base such as KOH (Scheme 16).

[0276] Scheme 16:CLI-C-P3879PCT

[0277]

[0278] Azetidines of general formula (iv)fmay be reacted with compounds of formula (vi)fwhere LG2 is a leaving group such as bromide or iodide, under conditions of palladium catalysis in the presence of specific ligands such as RuPhos or CPhos to form compounds of formula (I) (Scheme 17).

[0279] Scheme 17:

[0280]

[0281] A further route to compounds of formula (I) utilises the reaction of an azetidine of formula (iv)fwith a compound of formula (vi)' to form an N-arylazetidine (vii)d. Halogenation of this material for example with bromine to form (vii)eallows conversion to the amino-aryl intermediate (vii)cusing palladium catalysed amination conditions (Scheme 18).CLI-C-P3879PCT

[0282] Scheme 18:

[0283]

[0284] Compounds of formula (I) where R2is a five membered ring such as (x), may be formed by the route described in Scheme 19 where E is selected from N-R-| , S or O and F, G and H are independently selected from N, CR2, CR3. An Ellman imine of formula (x)amay be condensed with an alpha silyl morpholine amide in the presence of a fluoride source to give a sulfinamide of formula (x)b. Reaction with an appropriate Grignard or aryl lithium species furnishes a ketone of formula (x)c. Alternatively, the imine of formula (x)amay be condensed with a reformatsky agent, made by reacting an alpha bromoester of formula (x)1with zinc, to from an ester of formula (x)m. Direct reaction of this ester with a Grignard agent under low temperature conditions can afford ketone (x)c. Compounds of formula (x)cmay be reduced to an alcohol of formula (x)dwith a suitable reducing agent, such as sodium borohydride or a chiral ruthenium complex such as RuCI(p-cymene)[(S,S)-Ts-DPEN], together with a coreductant such as formic acid. Removal of the acid protecting sulfinyl group with an acid, such as TFA, gives an hydroxyamine of general formula (x)fwhich may be reductively aminated with 2,4-dimethoxybenzaldehyde and a reducing agent such as sodium acetoxyborohydride to provide the secondary amine (x)g. Ring closure may then be effected under Mitsunobo conditions, for example using triphenylphosphine and carbon tetrabromide, to provide protected azetidine (x)h. N-deprotection may be achieved with mild acid to provide (x)' which can undergo the same sequence of transformations as outlined for compound (iv)fdescribed in Scheme 16 with sequential nucleophilic aromatic substation onto a heterocycle of formula (vi)9, followed by nitro reduction and amidation to provide compounds of formula (x).CLI-C-P3879PCT

[0285] Scheme 19:

[0286] "

[0287]

[0288] Protected azetidines of formula (viii)cin which Rs, and Re are hydrogen, and the nitrogen protecting group is Boc (viii)d, may be formed by the route described in Scheme 20.CLI-C-P3879PCT

[0289] An amino alcohol of formula (xi)amay be reductively aminated with a paramethoxybenzaldehyde in the presence of a reducing agent such as sodium borohydride to form a monoprotected amine (xi)b. This may be alkylated on nitrogen with bromoacetonitrile, in the presence of a base such as potassium carbonate to form an aminonitrile of formula (xi)c. Ring closure to the azetidine (xi)dcan then be effected using an O-activating reagent such as diethylchloroformate in the presence of a non-nucleophilic strong base such as potassium hexamethyldisilazide. Hydrolysis of this nitrile to acid (xi)emay be achieved by treatment with a strong base such as sodium hydroxide, followed by acidification with, for example, hydrochloride acid. Methyl esterification of the carboxyl group to form (xi)fcan be achieved using methanol in the presence of an acid catalyst, and the nitrogen protecting group can be exchanged to Boc by hydrogenation of the benzyl group with hydrogen and a palladium catalyst in the presence of di-tert-butyl decarbonate, to provide (viii)d.

[0290] Scheme 20

[0291]

[0292] Pharmaceutical Compositions

[0293] While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). In one embodiment this is a sterile pharmaceutical composition.

[0294] Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising (e.g. admixing) at least one compound of formula (I) (and sub-groups thereof as defined herein), together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents, as described herein.CLI-C-P3879PCT

[0295] The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

[0296] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0297] Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0298] The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.

[0299] Pharmaceutical formulations adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-CLI-C-P3879PCT

[0300] aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickley, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p 201-230).

[0301] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution using an appropriate diluent.

[0302] The pharmaceutical formulation can be prepared by lyophilising a compound of formula (I), or sub-groups thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze-drying and lyophilisation are therefore used herein as synonyms.

[0303] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0304] Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.

[0305] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening or coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0306] The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be broughtCLI-C-P3879PCT

[0307] about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatin.

[0308] In one particular embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.

[0309] In another particular embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

[0310] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0311] Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0312] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

[0313] Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.CLI-C-P3879PCT

[0314] The solid dosage forms (e.g.; tablets, capsules etc.) can be coated or un-coated. Coatings may act either as a protective film (e.g. a polymer, wax or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. The coating (e.g. a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum, duodenum, jejunum or colon.

[0315] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented in a polymer coating e.g. a polymethacrylate polymer coating, which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the gut. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (for example formulations based on ion exchange resins) may be prepared in accordance with methods well known to those skilled in the art.

[0316] The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption. In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B. Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13thMarch 2006. Nanoparticles for drug delivery are also described in J. Williams et al., J. Control. Release, 2003, 91(1-2), 167-172, and in R. Sinha et al., Mol. Cancer Ther.

[0317] 2006, 5(8), 1909-1917.

[0318] The pharmaceutical compositions typically comprise from approximately 1 % (w / w) to approximately 95% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Particularly, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient orCLI-C-P3879PCT

[0319] combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, particularly from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

[0320] The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g. solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and cosolvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.

[0321] The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0322] Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried).

[0323] Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0324] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into a polymer or waxy matrix that allow the active ingredients to diffuse or be released in measured amounts.

[0325] The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see W. L. Chiou and S. Riegelman, J. Pharm. Sci., 1971,CLI-C-P3879PCT

[0326] 60 (9), 1281-1302) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

[0327] This invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition, a capsule can contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours. Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non-pareils’). These beads can subsequently be filled into capsules or compressed into tablets.

[0328] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions.

[0329] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

[0330] Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0331] Compositions for administration by inhalation may take the form of inhalable powder compositions, or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. ForCLI-C-P3879PCT

[0332] administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0333] The compounds of the formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

[0334] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

[0335] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[0336] Methods of Treatment

[0337] The compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by potassium channel inhibition, in particular inhibition of the potassium channel Kv7. Thus, according to a further aspect of the invention there is provided a method of treating a disease state or condition mediated by potassium channel inhibition (e.g. Kv7) which comprises administering to a subject in need thereof a compound of formula (I) as described herein. Examples of such disease states and conditions are set out above, and in particular include:

[0338] diseases associated with changes in motor neuron excitability, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, pseudobulbar palsy, progressive bulbar palsy, epilepsy and progressive muscular atrophy;

[0339] neurodevelopmental diseases, such as Angelman syndrome, neonatal abstinence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorders, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, West syndrome, SCN8A-related epilepsy with encephalopathy (EIEE13), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doose syndrome, adrenoleukodystrophy (ALD), ATP6V1A encephalopathy, atypical childhood epilepsy withCLI-C-P3879PCT

[0340] centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), CDKL5 encephalopathy, childhood epilepsy with centrotemporal spikes (CECTS), epileptic encephalopathy with continuous spike-and-wave during sleep syndrome (ECSWS), GRIN 1 encephalopathy, GRIN2A epilepsy-aphasia syndrome, GRIN2B encephalopathy, intermediate epilepsy-aphasia disorder (IEAD), KCNT1 epilepsy of infancy with migrating focal seizures, neuronal ceroid lipofuscinoses (NCL), non-syndromic developmental and epileptic encephalopathy, PTPN23 encephalopathy, Rasmussen syndrome, SCN2A-related neonatal epilepsies, STXBP1 encephalopathy, tuberous sclerosis (TS) / tuberous sclerosis complex (TSC);

[0341] pain, such as neuropathic and inflammatory pain;

[0342] psychiatric disorders such as depression, anxiety, sleep disorders, substance abuse, addiction, schizophrenia, mania and autism;

[0343] neuropathies; and

[0344] hearing disorders, such as tinnitus.

[0345] The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, particularly a human.

[0346] The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life-threatening diseases), the benefits of administering a compound of the formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

[0347] The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).

[0348] Atypical daily dose of the compound of formula (I) can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required.CLI-C-P3879PCT

[0349] The compound of the formula (I) can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days, for example.

[0350] The compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg. The compound may be administered once or more than once each day. The compound can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen). Alternatively, the compound can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen). Examples of treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles.

[0351] In one particular dosing schedule, a patient will be given an infusion of a compound of the formula (I) for periods of one hour daily for up to ten days, in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

[0352] More particularly, a patient may be given an infusion of a compound of the formula (I) for periods of one hour daily for 5 days and the treatment repeated every three weeks.

[0353] In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.

[0354] In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, an in particular a continuous infusion of 24 hours to 72 hours.

[0355] In another particular dosing schedule, a patient is given the compound orally once a week.

[0356] In another particular dosing schedule, a patient is given the compound orally once-daily for between 7 and 28 days such as 7, 14 or 28 days.CLI-C-P3879PCT

[0357] In another particular dosing schedule, a patient is given the compound orally once-daily for 1 day, 2 days, 3 days, 5 days or 1 week followed by the required amount of days off to complete a one or two week cycle.

[0358] In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 2 weeks off.

[0359] In another particular dosing schedule, a patient is given the compound orally once-daily for 2 weeks followed by 1 week off.

[0360] In another particular dosing schedule, a patient is given the compound orally once-daily for 1 week followed by 1 week off.

[0361] Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0362] It will be appreciated that potassium channel inhibitors can be used as a single agent or in combination with other therapeutically active agents. Combination experiments can be performed, for example, as described in T.-C. Chou-and P. Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regulat. 1984, 22: 27-55.

[0363] The compounds as defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds (or therapies) for treatment of a particular disease state, for example autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal, and metabolic mediated diseases. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other therapeutically agents which support the therapy of the disease being treated.

[0364] Each of the compounds present in the combinations of the invention may be given in individually varying dose schedules and via different routes. As such, the posology of each of the two or more agents may differ: each may be administered at the same time or at different times. A person skilled in the art would know through his or her common general knowledge the dosing regimens and combination therapies to use. For example, theCLI-C-P3879PCT

[0365] compound of the invention may be using in combination with one or more other agents which are administered according to their existing combination regimen.

[0366] Where the compound of the formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one), the compounds can be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). These dosages may be administered for example once, twice, or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

[0367] In one embodiment is provided a compound of formula (I) for the manufacture of a medicament for use in therapy wherein said compound is used in combination with one, two, three, or four other therapeutic agents. In another embodiment is provided a medicament for treating autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases which comprises a compound of formula (I) wherein said medicament is used in combination with one, two, three, or four other therapeutic agents.

[0368] It will be appreciated that the particular method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0369] The weight ratio of the compound according to the present invention and the one or more other therapeutic agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other therapeutic agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration, and general physical condition of the particular patient, the mode of administration as well as other medication the individual mayCLI-C-P3879PCT

[0370] be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of formula (I) and another therapeutic agent may range from 1 / 10 to 10 / 1, more in particular from 1 / 5 to 5 / 1 , even more in particular from 1 / 3 to 3 / 1.

[0371] In one embodiment the pharmaceutical composition comprises a compound of formula (I) together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agent(s).

[0372] In another embodiment the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for preventing or treating autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal, and metabolic mediated diseases.

[0373] In a further embodiment the invention relates to a product containing a compound of formula (I) and one or more additional therapeutic agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal, and metabolic mediated diseases.

[0374] Examples of suitable additional therapeutic agents include: methotrexate, corticosteroids such as prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, cortisone and the like; mycophenolate mofetil, tacrolimus, leflunomide or teriflunomide, cyclosporine A, cyclophosphamide, mitoxantrone, fingolimod, azathioprine, glatiramer acetate, dimethyl fumarate, an IK-1 inhibitor such as TRAM-34, a JAK-inhibitor such as tofacitinib or braticinib, a SYK-inhibitor such as fostamatinib and interferon-beta (IFN-P).

[0375] EXAMPLES

[0376] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

[0377] Abbreviations

[0378] CAS Index number from Chemical Abstract Service of the American Chemical Society

[0379] CPhos 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl Cryo-EM Cryoelectron microscopyCLI-C-P3879PCT

[0380] cv Column volumes

[0381] DCM Dichloromethane

[0382] DIAD Diisopropyl azodicarboxylate

[0383] DIPEA Diisopropylethylamine

[0384] DMF Dimethyl formamide

[0385] DMSO-ofe Dimethylsulfoxide - hexadeuterated

[0386] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0387] DR Diastereomeric purity

[0388] ES+ Electrospray mass spectrometry positive ionisation mode ES- Electrospray mass spectrometry negative ionisation mode EtOAc Ethyl acetate

[0389] HLPC High performance liquid chromatography

[0390] KHMDS Potassium hexamethyldisilazide

[0391] LDA Lithium diisopropylamide

[0392] LCMS Liquid Chromatography - mass spectrometery LiHMDS Lithium hexamethyldisilazide

[0393] MTBE or TBME Methyl tert-butyl ether

[0394] MS Mass Spectroscopy

[0395] NCS N-Chlorosuccinimide

[0396] NIS N-lodosuccinimide

[0397] NMP N-Methylpyrrolidinone

[0398] NMR Nuclear magnetic resonance

[0399] Ns 4-Nitrophenylsulfonyl, Nosyl

[0400] RB(F) Round bottomed (flask)

[0401] RP Reversed Phase

[0402] RT Room Temperature

[0403] SCX Strong cation exchange

[0404] SFC Supercritical fluid chromatography

[0405] TBAT Tetrabutylammonium Difluorotriphenylsilicate

[0406] TFA T rifluoroacetic acid

[0407] THF Tetrahydrofuran

[0408] TMEDA N,N,N',N'-Tetramethylethylenediamine

[0409] TMS Trimethylsilyl

[0410] uPLC ultraHigh performance liquid chromatography

[0411] NBS N-BromosuccinimideCLI-C-P3879PCT

[0412] General Methods

[0413] NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer fitted with a Bruker 5mm BBFO probe, or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe™ Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at 298 K unless otherwise indicated.

[0414] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system, equipped with ACQUITY PDA Detector and ACQUITY QDa Mass Detector, running one of the analytical methods described below.

[0415] Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below.

[0416] Analytical Methods

[0417] Method 1 - UPLC Acidic

[0418] Column: Waters ACQUITY UPLC® CSH C18, 1.7 pm, 2.1x30 mm at 40 °C Detection: UV at 210-400 nm, MS by electrospray ionisation

[0419] Solvents: A: 0.1% v / v Formic acid in water, B: 0.1% v / v Formic acid in MeCN

[0420] Method 2 - UPLC Basic

[0421] Column: Waters ACQUITY UPLC® BEH C18, 1.7 pm, 2.1x30 mm at 40 °C Solvents: A O mM ammonium bicarbonate(aq), B: MeCN

[0422] (other parameters the same as Method 1 )

[0423] Method 3 - LCMS Acidic

[0424] Column: Waters X-Select CSH C18, 2.5 pm, 4.6x30 mm at 40 °C

[0425] Detection: UV at 254 nm, MS by electrospray ionisation

[0426] Solvents: A: 0.1% v / v Formic acid in water, B: 0.1% v / v Formic acid in MeCN

[0427] Method 4 - LCMS Basic

[0428] Column: Waters X-Bridge BEH C18, 2.5 pm, 4.6x30 mm at 40 °C

[0429] Solvents: A O mM ammonium bicarbonate(aq), B: MeCN

[0430] (other parameters the same as Method 3)

[0431] Description 1CLI-C-P3879PCT

[0432] (R,E)-N-(4-Bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) (CAS 1429182-39-7)

[0433] Prepared by the route of Description 100 but using 4-bromo-2-fluorobenzaldehyde in place of 2-fluorobenzaldeyde.

[0434] Description 2

[0435] Ethyl (S)-3-(4-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (D2) To a 250 mL RBF containing copper(l) chloride (938 mg, 9.47 mmol) and zinc (4.95 g, 75.8 mmol) was added THF (30 mL). The mixture was heated to 75 °C for 30 minutes. The reaction mixture was cooled down to RT and ethyl 2-bromoacetate (5.25 mL, 47.4 mmol) was added dropwise and then stirred at 50 °C for 30 minutes. The reaction mixture was cooled to 0 °C and then (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) (2.90 g, 9.47 mmol) in THF (30 mL) was added dropwise over 10 minutes, then stirred at 0 °C for 2 hours. The reaction mixture was quenched at 0 °C by addition of sat. aq. NH4CI solution (100 mL), the suspension was filtered, and the filtrate was diluted with water (100 mL). The product was extracted with EtOAc (3 x 100 mL), the combined organic extracts were washed with brine (200 mL), dried (MgSC ) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% iso-hexanes / MTBE) to afford ethyl (S)-3-(4-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)-amino)propanoate (D2) (3.25 g, 78%) as a colourless oil.

[0436] 1H NMR (500 MHz, DMSO-cfe) 57.50 (dd, J = 9.9, 1.7 Hz, 1 H), 7.48 - 7.40 (m, 2H), 5.72 (d, J = 6.6 Hz, 1H), 4.90 (q, J = 7.1 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.00 (dd, J = 15.6, 7.1 Hz, 1H), 2.83 (dd, J = 15.6, 7.7 Hz, 1H), 1.13 - 1.08 (m, 3H), 1.04 (s, 9H). UPLC-MS m / z 394.6 / 396.6 (M+H)+(ES+).

[0437] Compounds D2, D101 and derived materials D3-D6 had their stereochemistry assigned according to the procedure described in Tet. Lett. 55, (2014), 7219-7221, which provides rationalisation for the selectivity based on the choice of Ellman auxiliary. These assignments correspond with the modelling from the Cryo EM structure. Assignments are based on observing a single diastereomer by NMR / HPLC when the chiral Ellman auxiliary is still attached (i.e. DR >95%). This method of assignment was also used for analogous sulfinamides and their subsequently derived azetidines. In certain cases X-ray crystallography was used to confirm absolute stereochemical assignments.

[0438] Description 3

[0439] (R)-N-((S)-1-(4-Bromo-2-fluorophenyl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (D3)CLI-C-P3879PCT

[0440] To a solution of ethyl (S)-3-(4-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (D2) (2.00 g, 5.07 mmol) in THF (30 mL) at 0 °C was added dropwise lithium aluminium hydride (1 M in THF) (5.07 mL, 5.07 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched by addition of solid sodium sulfate decahydrate until effervescence ceased, the reaction mixture was filtered through a pad of sodium sulfate (EtOAc wash, 250 mL), passed through a phase separator and concentrated in vacuo to give (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (D3) (1.66 g, 74%) as a yellow oil.

[0441] 1H NMR (500 MHz, DMSO-d6) 67.53 - 7.46 (m, 1 H), 7.46 - 7.37 (m, 2H), 5.65 (d, J = 5.6 Hz, 1 H), 4.71 - 4.58 (m, 2H), 3.52 (dd, J = 10.4, 4.9 Hz, 1 H), 3.43 - 3.37 (m, 1 H), 2.07 - 1.96 (m, 1H), 1.86- 1.73 (m, 1H), 1.06 (s, 9H). UPLC-MS m / z 352.2 / 354.5 (M+H)+(ES+).

[0442] Description 4

[0443] (S)-2-(4-Bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)azetidine (D4)

[0444] To a solution of (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (D3) (1.66 g, 4.71 mmol) in toluene (40 mL) was added cyanomethylene)-tributylphosphorane (1.51 mL, 5.65 mmol). The reaction mixture was heated to 110 °C for 18 hours. The reaction mixture was cooled to RT and concentrated onto silica. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% heptane / MTBE) to afford (S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)azetidine (D4) (663 mg, 41%) as a yellow oil.

[0445] 1H NMR (500 MHz, DMSO-d6) 57.65 - 7.58 (m, 1H), 7.57 - 7.47 (m, 2H), 5.18 (t, J = 8.4 Hz, 1H), 4.15 -4.07 (m, 1H), 3.30 - 3.24 (m, 1H), 2.59 - 2.51 (m, 1H), 2.38 -2.27 (m, 1H), 1.10 (s, 9H). UPLC-MS m / z 334.5 / 336.5 (M+H)+(ES+).

[0446] Description 5

[0447] 4-((S)-1-((R)-tert-Butylsulfinyl)azetidin-2-yl)-3-fluorobenzonitrile (D5)

[0448] To a mixture of (S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)azetidine (D4) (200 mg, 598 pmol), potassium hexacyanoferrate(ll), trihydrate (126 mg, 299 pmol), potassium acetate (29.4 mg, 299 pmol) (oxydi-2,1-phenylene)bis(diphenylphosphine) (CAS 166330-10-5) (32.2 mg, 59.8 pmol) was added [Pd(cinnamyl)CI]2 (15.5 mg, 29.9 pmol) followed by dioxane (2 mL) and water (2 mL). The reaction mixture was degassed (evacuated and backfilled, N2 x 3), then heated to 85 °C for 18 hours. The reaction mixture was cooled to RT, diluted with brine (10 mL) and EtOAc (10 mL). The phases were separated and the aqueous was extracted using further EtOAc (2 x 20 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatographyCLI-C-P3879PCT

[0449] on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 4-((S)-1-((R)-tert-butylsulfinyl)-azetidin-2-yl)-3-fluorobenzonitrile (D5) (144 mg, 84%) as a brown oil.

[0450] 1H NMR (500 MHz, DMSO-d6) 67.89 - 7.81 (m, 2H), 7.78 (dd, J = 8.0, 1.5 Hz, 1 H), 5.27 (t, J = 8.5 Hz, 1 H), 4.20 - 4.11 (m,1H), 3.35 - 3.27 (m, 1 H), 2.63 - 2.55 (m, 1 H), 2.37 - 2.28 (m, 1H), 1.13 (s, 9H). LCMS: m / z281.2 (M+H)+(ES+).

[0451] Description 6

[0452] (S)-4-(Azetidin-2-yl)-3-fluorobenzonitrile, HCI (D6)

[0453] To a 40 mL vial containing 4-((S)-1-((R)-tert-butylsulfinyl)azetidin-2-yl)-3-fluorobenzonitrile (D5) (70 mg, 0.25 mmol) in ethyl acetate (2 mL) was added HCI (1 M in EtOAc) (1.2 mL, 1.2 mmol). The reaction mixture was stirred for 20 minutes at room temperature. The reaction mixture was blown down to dryness under a stream of nitrogen. To the crude product was added MTBE, the suspension was sonicated and then the supernatant removed by pipette, this was repeated three times, the resulting solid was concentrated in vacuo to give (S)-4-(azetidin-2-yl)-3-fluorobenzonitrile, HCI (D6) (56 mg, 100%) as a cream solid.

[0454] 1H NMR (500 MHz, D2O) 57.78 - 7.72 (m, 1 H), 7.72 - 7.65 (m, 2H), 5.94 (t, J = 9.2 Hz, 1 H), 4.37 - 4.28 (m, 1H), 4.06 - 3.97 (m, 1H), 3.19 - 3.07 (m, 1H), 2.95 - 2.85 (m, 1H). Two exchangeable protons not observed.

[0455] Description 7

[0456] (R)-N-((S)-1-(5-Fluoropyridin-3-yl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (D7) To a 500 mL RBF containing (R)-N-((S)-1-(5-fluoropyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (3.45 g, 95% Wt, 11.9 mmol) (prepared by the route of Description 3 but using 5-fluoronicotinaldehyde (CAS 39891-04-8) in place of 4-bromo-2-fluorobenzaldehyde in Description 1) in DCM (50 mL), was added Dess-Martin periodinane (6.08 g, 14.3 mmol). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched by addition of 1:1 saturated aq. sodium thiosulphate and NaHCOa (200 mL), the product was extracted with DCM (3 x 100 mL), the combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((S)-1-(5-fluoropyridin-3-yl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (D7) (2.66 g, 74%) as a yellow oil. UPLC-MS m / z 272.9 (M+H)+(ES+).

[0457] Description 8

[0458] (R)-N-((1S)-1-(5-Fluoropyridin-3-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D8)CLI-C-P3879PCT

[0459] To a 250 mL RBF containing (R)-N-((S)-1-(5-fluoropyridin-3-yl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (D7) (2.66 g, 90 Wt%, 8.79 mmol) in THF (30 mL) was added methylmagnesium bromide (3M in Et2<3) (8.79 mL, 26.4 mmol) at 0 °C. for 30 minutes. Additional methylmagnesium bromide (3M in Et20) (8.79 mL, 26.4 mmol) was added to the mixture and then stirred for 30 minutes. The reaction mixture was quenched by addition of sat. NH4CI (100 mL), the product was extracted with EtOAc (3 x 75 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((1S)-1-(5-fluoropyridin-3-yl)-3-hydroxybutyl)-2-methylpropane- 2-sulfinamide (D8) (1.50 g, 53%, ca. 7:3 mixture of diastereomers) as a yellow gum. UPLC-MS m / z 289.2 (M+H)+(ES+).

[0460] Description 9

[0461] 3-((2S,4S)-1-((R)-tert-Butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9a) 3-((2S,4R)-1-((R)-tert-Butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9b) To a 250 mL RBF containing (R)-N-((1S)-1-(5-fluoropyridin-3-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D8) (1.50 g, 95 Wt% 4.94 mmol) in toluene (20 mL) was added cyanomethylene)-tributyl-phosphorane (2.64 mL, 9.88 mmol). The solution was stirred at 110 °C for 18 hours. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g Redisep gold cartridge, 50-100% MTBE / isohexane followed by 0-70% EtOAc / isohexane) to afford 3-((2S,4S)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9a) (0.141 g, 10%) as a brown oil.1H NMR (500 MHz, DMSO-de) 68.56 - 8.50 (m, 2H), 7.82 (ddd, J= 9.8, 2.8, 1.8 Hz, 1H), 4.97 (t, J= 8.4 Hz, 1H), 4.29 (tq, J = 8.2, 6.2 Hz, 1 H), 2.79 (dt, J = 10.8, 8.7 Hz, 1 H), 2.03 - 1.84 (m, 1 H), 1.36 (d, J = 6.3 Hz, 3H), 1.05 (s, 9H). LCMS m / z 271.2 (M+H)+(ES+).

[0462] Further elution afforded 3-((2S,4R)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9b) (0.341 g, 23%,) as a brown oil.1H NMR (500 MHz, DMSO-de) 58.55 -8.47 (m, 2H), 7.91 - 7.85 (m, 1 H), 5.59 - 5.45 (m, 1 H), 4.60 (ddd, J = 8.2, 6.4, 3.4 Hz, 1 H), 2.57 -2.52 (m, 1H), 2.24 (ddd, J= 10.6, 8.3, 3.4 Hz, 1H), 1.61 (d, J= 6.4 Hz, 3H), 1.15 (s, 9H). LCMS m / z 271.2 (M+H)+(ES+).

[0463] Description 10

[0464] 3-Fluoro-5-((2S,4S)-4-methylazetidin-2-yl)pyridine, 2HCI (D10)

[0465] To a 40 mL vial containing 3-((2S,4S)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9a) (141 mg, 98 Wt%, 511 pmol) in EtOAc (2 mL)was added HCI (1 M in EtOAc) (2.56 mL, 2.56 mmol). The reaction mixture was stirred for 20 minutes. The reaction mixture was blown down to dryness and the residue suspended in MTBE, sonicated and thenCLI-C-P3879PCT

[0466] the supernatant was removed by pipette. This was repeated three times. The material was concentrated in vacuo to give3-fluoro-5-((2S,4S)-4-methylazetidin-2-yl)pyridine, 2HCI (D10) (130 mg) as a brown gum.

[0467] 1H NMR (500 MHz, DMSO-d6) 58.66 (d, J= 2.7 Hz, 1H), 8.56 (t, 1H), 8.03 (dt, J= 9.8, 2.3 Hz, 1H), 5.48 (p, J= 7.9 Hz, 1H), 4.49 (dq,J= 14.2, 7.0 Hz, 1H), 2.87-2.74 (m, 1H), 2.74-2.61 (m, 1H), 1.47 (d, J= 6.6 Hz, 3H). Exchangeable protons not observed.

[0468] Description 11

[0469] 3-Fluoro-5-((2S,4R)-4-methylazetidin-2-yl)pyridine, 2HCI (D11)

[0470] To a 40 mL vial containing 3-((2S,4R)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-5-fluoropyridine (D9b) (340 mg, 90 Wt%, 1.13 mmol) in EtOAc (2 mL)was added HCI (1 M in EtOAc) (5.66 mL, 5.66 mmol). The reaction mixture was stirred at RT for 20 minutes. The reaction mixture was blown down, and the residue suspended in MTBE, sonicated and then the supernatant was removed by pipette. This was repeated three times. The material was concentrated in vacuo to give3-fluoro-5-((2S,4R)-4-methylazetidin-2-yl)pyridine, 2HCI (D11) (0.290 g) as a tan solid.

[0471] 1H NMR (500 MHz, DMSO-d6) 58.66 (t, 1H), 8.60 (d, J= 1.8 Hz, 1H), 8.14 (dt, J= 10.0, 2.4 Hz, 1H), 5.66 (p, J= 7.1 Hz, 1H), 4.55-4.48 (m, 1H), 3.03-2.92 (m, 1H), 2.47-2.36 (m, 1H), 1.60 (d, J= 6.8 Hz, 3H). Exchangeable protons not observed.

[0472] Description 12

[0473] (S)-3-(4-Bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)-N-methoxy-N-methylpropanamide (D12)

[0474] N-Methoxy-N-methylacetamide (5.2 mL, 49 mmol) was added to a solution of KHMDS (1 M in THF) (53 mL, 53 mmol) in diethyl ether (100 mL) at -78 °C and the reaction stirred for 1 hour. A solution of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) (10 g, 33 mmol) in THF (10 mL) was added slowly over 30 minutes not allowing the internal temperature to raise above -65 °C. After the addition reaction stirred for 30 minutes at -78 °C. The reaction was quenched with sat. NH4CI(aq) (50 mL) and allowed to warm to RT. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography three times on silica gel (330 g gold cartridge, 50-100% EtOAc / DCM then 220 g gold cartridge DCM / MeOH 0-15%, followed by 120 g cartridge, 50-95% EtOAc / DCM) to afford (S)-3-(4-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)-N-methoxy-N-methylpropanamide (D12) (5.12 g, 35%) as a white solid.CLI-C-P3879PCT

[0475] 1H NMR (500 MHz, DMSO-cfe) 57.56 - 7.36 (m, 3H), 5.64 (d, J= 6.0 Hz, 1H), 4.93 (q, J = 6.6 Hz, 1 H), 3.58 - 3.64 (s, 4H), 3.11 - 2.99 (m, 4H), 1.05 (s, 9H). UPLC-MS m / z 409.3 / 411.2 (M+H)+(ES+).

[0476] Description 13

[0477] (R)-N-((S)-1-(4-Bromo-2-fluorophenyl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D13)

[0478] Methylmagnesium chloride (3M in THF) (20.8 mL, 62.4 mmol) was added to a solution of (S)-3-(4-bromo-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)-N-methoxy-N-methylpropanamide (D12) (5.11 g, 12.5 mmol) in THF (100 mL) at -78 °C and the reaction was stirred at -78 °C for 1 hour. The reaction was allowed to warm to RT and stirred for 30 minutes. The reaction mixture was then cooled to -78 °C and quenched with sat. NH4CI(aq) (10 mL) and warmed to RT. The mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 150 mL). The combined organics were dried over Na2SC>4 to afford (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D13) (4.55 g, 92%) as a colourless oil.

[0479] 1H NMR (500 MHz, DMSO-d6) 57.52 - 7.46 (m, 1H), 7.45 - 7.37 (m, 2H), 5.52 (d, J= 5.9 Hz, 1H), 4.91 (q, J= 6.6 Hz, 1H), 3.16 (dd, J = 17.4, 6.8 Hz, 1H), 3.01 (dd,J= 17.4, 7.0 Hz, 1H), 2.08 (s, 3H), 1.03 (s, 9H). UPLC-MS m / z 364.2 / 366.2 (M+H)+(ES+).

[0480] Description 14

[0481] (R)-N-((1S)-1-(4-Bromo-2-fluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D14)

[0482] To a stirred solution of (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D13) (4.55 g, 12.5 mmol) in THF (40 mL)and MeOH (10 mL)was slowly added NaBH4(1.00 g, 26.4 mmol) at 40 °C. The reaction mixture was cooled to RT and stirred for 16 hours. The reaction mixture was poured into ice / water (c.a. 250 mL), extracted with EtOAc (2 x 100 mL), the combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((1S)-1-(4-bromo-2-fluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D14) (3.86 g, 76%, ca. 6:4 mixture of diastereomers) as a colourless oil.

[0483] UPLC-MS m / z 366.2 / 368.2 (M+H)+(ES+)

[0484] Descriptions 15 and 16

[0485] (2S,4S)-2-(4-Bromo-2-fluorophenyl)-1 -((R)-tert-butylsulfinyl)-4-methylazetidine (D15) (2S,4R)-2-(4-Bromo-2-fluorophenyl)-1 -((R)-tert-butylsulfinyl)-4-methylazetidine (D16)CLI-C-P3879PCT

[0486] To a stirred solution of (R)-N-((1S)-1-(4-bromo-2-fluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D14) (3.86 g, 10.5 mmol) in toluene (100 mL) was added (tributylphosphoranylidene)acetonitrile (6.19 mL, 23.2 mmol). The reaction mixture was heated at 90 °C and stirred for 72 hours. Upon cooling, the mixture was evaporated in vacuo and purified by chromatography on silica gel (80 g cartridge, 10-50% MTBE / isohexane) to afford a mixture effractions. The material was recrystalized with MTBE (c.a. 5 mL) and the resulting crystals collected by filtration and set aside. The filtrate was concentrated in vacuo and re-purified by chromatography on silica gel (40 g cartridge, 10-50% MTBE / isohexane) to afford (2S,4S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-4-methylazetidine (D15) (1.21 g, 31%) as a dark brown oil.1H NMR (500 MHz, DMSO-de) 67.62 (t, J = 8.1 Hz, 1 H), 7.56 - 7.46 (m, 2H), 5.09 - 4.95 (m, 1 H), 4.30 (ddt, J = 14.4, 8.2, 6.2 Hz, 1H), 2.81 (dt, J = 10.8, 8.8 Hz, 1H), 1.89 (dt, J = 10.8, 7.8 Hz, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.07 (s, 9H).UPLC m / z 348.5 / 350.4 (M+H)+(ES+).

[0487] Further elution afforded additional fractions that were combined with the previously obtained crystals to give (2S,4R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-4-methylazetidine (D16) (1.2 g, 31%) as a light tan solid.1H NMR (500 MHz, DMSO-ds) 57.59 (t, J= 8.2 Hz, 1H), 7.52 (dd, J= 10.1, 1.9 Hz, 1H), 7.46 (dd, J= 8.3, 1.9 Hz, 1H), 5.59 (t, J = 7.9 Hz, 1 H), 4.60 - 4.51 (m, 1 H), 2.52 (s, 1 H), 2.24 (ddd, J = 10.5, 8.3, 3.4 Hz, 1 H), 1.61 (d, J = 6.4 Hz, 3H), 1.16 (s, 9H). UPLC-MS m / z 348.5 / 350.5 (M+H)+(ES+).

[0488] Description 17

[0489] 4-((2S,4S)-1-((R)-tert-Butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D17) To a 40 mL vial containing (2S,4S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-4-methylazetidine (D15) (1.20 g, 95% Wt, 3.27 mmol), potassium hexacyanoferrate(ll), trihydrate (691 mg, 1.64 mmol) and 1,T-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride (240 mg, 327 pmol) in dioxane (2 mL)was added potassium acetate (161 mg, 1.64 mmol) in water (1 mL). The mixture was stirred for 1 hour at 90 °C. The reaction mixture was diluted with brine (10 mL) and then product was extracted with EtOAc (3 x 10 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 5-75% MTBE / isohexane) to afford 4-((2S,4S)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D17) (0.659 g, 65%) as an orange oil.

[0490] 1H NMR (500 MHz, DMSO-d6) 57.91 - 7.80 (m, 2H), 7.78 (dd, J= 7.9, 1.6 Hz, 1 H), 5.12 (dd, J = 9.3, 7.6 Hz, 1 H), 4.39 - 4.30 (m, 1 H), 2.87 (dt, J = 10.9, 8.9 Hz, 1 H), 1.90 (dt, J = 11.3, 7.6 Hz, 1 H), 1.35 (d, J = 6.3 Hz, 3H), 1.10 (s, 9H). UPLC-MS m / z 295.2 (M+H)+(ES+).

[0491] Description 18CLI-C-P3879PCT

[0492] 4-((2S,4R)-1-((R)-tert-Butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D18) To a 40 mL vial containing (2S,4R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-4-methylazetidine (D16) (1.21 g, 93% Wt, 3.23 mmol), potassium hexacyanoferrate(ll), trihydrate (682 mg, 1.62 mmol) and Pd-117 (CAS 205319-06-8) (231 mg, 323 pmol)in 1,4-dioxane (2 mL)was added potassium acetate (159 mg, 1.62 mmol) in water (0.5 mL). The reaction mixture was stirred for 2 hours at 90 °C. The reaction mixture was blown down to dryness then purified by chromatography on silica gel (24 g cartridge, 5-50% MTBE / isohexane) to give4-((2S,4R)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D18) (0.709 g, 71%) as a yellow solid.1H NMR (500 MHz, DMSO-C / B) 5 7.88 - 7.81 (m, 2H), 7.74 (dd, J = 8.0, 1.6 Hz, 1 H), 5.68 (t, J = 7.9 Hz, 1 H), 4.64 - 4.54 (m, 1H), 2.56-2.51 (m, 1H), 2.30 (ddd, J= 10.6, 8.4, 3.6 Hz, 1H), 1.61 (d, J= 6.4 Hz, 3H), 1.17 (s, 9H). UPLC-MS m / z 295.2 (M+H)+(ES+).

[0493] Description 19

[0494] 3-Fluoro-4-((2S,4S)-4-methylazetidin-2-yl)benzonitrile (D19)

[0495] To a 40 mL vial containing 4-((2S,4S)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D17) (659 mg, 95% Wt, 2.13 mmol) in EtOAc (2 mL)was added HCI (1 M in EtOAc) (6.38 mL, 6.38 mmol). The reaction mixture was stirred at RT for 20 minutes. The material was concentrated in vacuo and loaded onto a column of SCX(10 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford 3-fluoro-4-((2S,4S)-4-methylazetidin-2-yl)benzonitrile (D19) (401 mg, 89%) as a yellow oil.

[0496] 1H NMR (500 MHz, DMSO-cfe) 57.85 (td, J= 7.9, 0.7 Hz, 1H), 7.77 - 7.62 (m, 2H), 4.86 (t,J= 8.2 Hz, 1H), 3.98-3.81 (m, 1H), 2.75-2.61 (m, 1H), 1.68- 1.54 (m, 1H), 1.11 (d, J = 6.1 Hz, 3H). Exchangeable proton missing.

[0497] Description 20

[0498] 3-Fluoro-4-((2S,4R)-4-methylazetidin-2-yl)benzonitrile HCI (D20)

[0499] To a 40 mL vial containing 4-((2S,4R)-1-((R)-tert-butylsulfinyl)-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D18) (709 mg, 95% Wt, 2.29 mmol) in EtOAc (2 mL)was added HCI (1 M in EtOAc) (6.86 mL, 6.86 mmol). The reaction mixture was stirred at RT for 20 minutes. The material was concentrated in vacuo and triturated with TBME followed by filtration to afford 3-fluoro-4-((2S,4R)-4-methylazetidin-2-yl)benzonitrile, HCI (D20) (437 mg, 80%) as

[0500] a colourless solid.

[0501] 1H NMR (500 MHz, DMSO-cfe) 59.86 (s, 1H), 7.98 (d, J= 10.2 Hz, 1H), 7.86 (d, J= 6.2 Hz, 2H), 5.79 (t, J= 8.8 Hz, 1H), 4.51 -4.23 (m, 1H), 2.99 (dt, J= 12.2, 8.7 Hz, 1H), 1.60 (d, J = 6.8 Hz, 3H). Exchangeable protons missing.CLI-C-P3879PCT

[0502] Description 21

[0503] Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluorophenyl)-2,2-dimethylpropanoate (D21)

[0504] To a stirred solution of diisopropylamine (1.90 mL, 13.45 mmol) in THF (60 mL) at 0 °C was added butyllithium (2.5 M in hexanes) (5.137 mL, 12.84 mmol). After 30 min, the mixture was cooled to -78 °C and ethyl isobutyrate (1.64 mL, 12.23 mmol) in THF (2 mL) was added. After a further 30 min, triisopropoxytitanium(IV) chloride (1 M in hexanes) (25.68 mL, 25.68 mmol) was added. After another 30 min, (R,E)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide (CAS 1397715-14-8) (1.500 g, 6.115 mmol) in THF (2 mL) was added. Stirring at -78 °C was continued for 3 hours, then the reaction mixture was diluted with sat. aq. ammonium chloride solution (50 mL) and allowed to warm to RT. The mixture was then diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% MTBE / isohexane) to afford ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluorophenyl)-2,2-dimethylpropanoate (D21) (1.873 g, 75%) as a pale-yellow oil. No ionisation was observed by mass spectrometry and the material was used directly in next step.

[0505] Description 22

[0506] (R)-N-((S)-1-(2,4-Difluorophenyl)-3-hydroxy-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (D22)

[0507] To a stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluorophenyl)-2,2-dimethylpropanoate (D21) (1.873 g, 88% Wt, 4.560 mmol) in THF (40 mL) at 0 °C was slowly added lithium aluminium hydride (1 M in THF) (5.02 mL, 5.016 mmol). After 10 minutes, the reaction mixture was allowed to warm to RT and stirred for a further hour. The reaction was then quenched by addition of sodium sulfate decahydrate until effervesce ceased. The mixture was filtered through a pad of sodium sulfate, rinsing with EtOAc (100 mL) and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((S)-1-(2,4-difluorophenyl)-3-hydroxy-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (D22) (0.744 g, 43%) as a paleyellowoil. LCMS m / z 320.2 (M+H)+(ES+).

[0508] Description 23

[0509] (S)-1-((R)-tert-Butylsulfinyl)-2-(2,4-difluorophenyl)-3,3-dimethylazetidine (D23)

[0510] To a stirred solution of (R)-N-((S)-1-(2,4-difluorophenyl)-3-hydroxy-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (D22) (0.744 g, 2.33 mmol) in toluene (20 mL)wasCLI-C-P3879PCT

[0511] added (tributylphosphoranylidene)acetonitrile (1.24 mL, 4.66 mmol). The reaction mixture was heated to reflux and stirred for 18 hours. Upon cooling, mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g cartridge, 5-50% MTBE / isohexane). The material was then suspended in heptane and heated to reflux for 10 minutes, then allowed to cool. The resulting white precipitate was collected by filtration to afford (S)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-3,3-dimethylazetidine (D23) (0.150 g, 20%) as a white solid.

[0512] 1H NMR (500 MHz, DMSO-ofe) 67.58 (td, J = 8.6, 6.6 Hz, 1 H), 7.26 (ddd, J = 11.2, 9.2, 2.6 Hz, 1H), 7.16 (td, = 8.6, 2.6 Hz, 1H), 4.84 (s, 1H), 3.87 (d, J = 7.4 Hz, 1H), 2.99 (d, J = 7.4 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 9H), 0.83 (s, 3H). UPLC-MS m / z301.7 (M+H)+(ES+>.

[0513] Description 24

[0514] (S)-2-(2,4-Difluorophenyl)-3,3-dimethylazetidine, HCI (D24)

[0515] To a stirred solution of (S)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-3,3-dimethylazetidine (D23) (0.150 g, 498 pmol) in ethyl acetate (2 mL) was added HCI (1 M in EtOAc) (2.49 mL, 2.49 mmol). The reaction was stirred at RT for 30 minutes, then the solvent was removed under a stream of compressed air. The residue was slurried in MTBE (ca. 3 mL) and collected by filtration to afford (S)-2-(2,4-difluorophenyl)-3,3-dimethylazetidine, HCI (D24) (0.113 g, 92%) as a crystalline white solid.

[0516] 1H NMR (500 MHz, D2O) 57.49 - 7.34 (m, 1 H), 7.18 - 7.01 (m, 2H), 5.56 (s, 1 H), 4.04 (d, J = 10.2 Hz, 1H), 3.74 (d, J = 10.2 Hz, 1H), 1.46 (d, J = 1.2 Hz, 3H), 1.11 (s, 3H). Two exchangeable protons missing.

[0517] Description 25

[0518] (R)-N-((S)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25)

[0519] To a stirred solution of (R,E)-N-((5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (CAS 1149752-50-0) (6.00 g, 95% Wt, 25.0 mmol) in dry THF (120 mL) under a nitrogen atmosphere was added 2,2-difluoro-1-morpholino-2-(trimethylsilyl)ethan-1-one (CAS 1630100-64-9) (6.86 g, 95% Wt, 27.5 mmol) and TBAT (1.35 g, 2.50 mmol). The reaction mixture was stirred for 18 hours. Additional TBAT (1.35 g, 2.50 mmol) was added and stirred for a further 3 hours before quenching with NH4CI (100 mL) and extracting with EtOAc (250mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((S)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25) (3.13 g, 27%) as

[0520] a yellow gum.CLI-C-P3879PCT

[0521] 1H NMR (500 MHz, DMSO-cfe) 58.59 (d, J= 2.9 Hz, 1H), 7.85 (td, J= 8.7, 2.9 Hz, 1H), 7.80 (dd, J = 8.8, 4.5 Hz, 1 H), 6.03 (d, J = 9.3 Hz, 1 H), 5.27 (dt, J = 18.2, 9.3 Hz, 1 H), 3.70 (d, J = 4.4 Hz, 2H), 3.63 (dt, J= 10.1, 5.2 Hz, 4H), 3.53 -3.42 (m, 2H), 1.11 (s, 9H). UPLC-MS m / z 394.4 (M+H)+(ES+).

[0522] Description 25a

[0523] (S)-N-((R)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25a)

[0524] To a stirred solution of (S,E)-N-((5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (CAS 1079275-52-7) (2.25 g, 95% Wt, 9.36 mmol) in dry THF (50.0 mL) under a nitrogen atmosphere was added 2,2-difluoro-1-morpholino-2-(trimethylsilyl)ethan-1-one (CAS 1630100-64-9) (2.72 g, 90% Wt, 10.3 mmol) and TBAT (505 mg, 936 pmol). The reaction mixture was stirred for 20 hours before quenching with sat. aq. NH4CI (10mL) and extracting with EtOAc (50mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford (S)-N-((R)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25a) (0.837 g, 20 %) as a yellow gum.

[0525] 1H NMR (500 MHz, DMSO-d6) 58.59 (d, J = 2.9 Hz, 1H), 7.85 (td, J = 8.7, 2.9 Hz, 1H), 7.80 (dd, J = 8.8, 4.5 Hz, 1 H), 6.03 (d, J = 9.3 Hz, 1 H), 5.27 (dt, J = 18.2, 9.3 Hz, 1 H), 3.70 (d, J = 4.4 Hz, 2H), 3.63 (dt, J = 10.1 , 5.2 Hz, 4H), 3.53 - 3.42 (m, 2H), 1.11 (s, 9H).

[0526] UPLC-MS m / z 394.4 (M+H)+(ES+).

[0527] Description 26

[0528] (R)-N-((S)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26)

[0529] Methylmagnesium chloride (3M in THF) (12.3 mL, 36.9 mmol) was added to a solution of (R)-N-((S)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25) (3.58 g, 90% Wt, 8.19 mmol) in THF (30.0 mL) at -78 °C and the reaction was stirred at -78 °C for 1 hour. The reaction was allowed to warm to RT and stirred for 1 hour. The mixture was then cooled to 0 °C and further methylmagnesium chloride (3M in THF) (12.3 mL, 36.9 mmol) was added. The reaction mixture was stirred at RT for a further 16 hours. The solution was cooled to 0 °C and quenched with ice-water (30mL) before adding sat. NH4CI(aq) (20 mL) and warmed to RT. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to afford (R)-N-((S)-CLI-C-P3879PCT

[0530] 2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26) (1.36 g, 42%) as a brown oil.

[0531] 1H NMR (500 MHz, DMSO-d6) 58.55 (d, J= 2.9 Hz, 1H), 7.88 (td, J= 8.7, 2.9 Hz, 1H), 7.82 (dd, J= 8.8, 4.5 Hz, 1H), 6.21 (d, J= 9.7 Hz, 1H), 5.30 (td, J= 14.0, 9.6 Hz, 1H), 2.45 - 2.27 (m, 3H), 1.16 (s, 9H). UPLC-MS m / z 323.3 (M+H)+(ES+).

[0532] Description 26a

[0533] (S)-N-((R)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26a)

[0534] Methylmagnesium chloride (2.87 mL, 3M in THF, 8.62 mmol) was added to a solution of (S)-N-((R)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D25a) (0.837 g, 90% Wt, 1.91 mmol) in THF (20.0 mL) at -78 °C and the reaction was stirred at this temperature for 1 hour, then allowed to warm to room temperature and stirred for a further 1 hour. The mixture was cooled to 0 °C and

[0535] further methylmagnesium chloride (2.87 mL, 3M in THF, 8.62 mmol) was added. Stirring was continued overnight. The mixture was then cooled to 0 °C and quenched with sat. NH4CI(aq) (20 mL) and allowed to warm to room temperature. Water (200 mL) was added and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to afford (S)-N-((R)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26a) (505 mg, 57 %) as a brown oil.

[0536] 1H NMR (500 MHz, DMSO-cfe) 58.55 (d, J = 2.9 Hz, 1H), 7.88 (td, J = 8.7, 2.9 Hz, 1H), 7.82 (dd, J = 8.8, 4.5 Hz, 1 H), 6.21 (d, J = 9.7 Hz, 1 H), 5.30 (td, J = 14.0, 9.6 Hz, 1 H), 2.45 - 2.27 (m, 3H), 1.16 (s, 9H). UPLC-MS m / z 323.3 (M+H)+(ES+).

[0537] Description 27

[0538] (R)-N-((1S)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D27)

[0539] Sodium borohydride (196 mg, 5.19 mmol) was added to a solution of (R)-N-((S)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26) (1.36 g, 82% Wt, 3.46 mmol) in MeOH (10.0 mL) and the reaction stirred for 1 hour. The reaction was quenched with NH4CI solution (200 mL), the volatiles removed in vacuo, and water (100 mL) was added. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g gold cartridge, 0-3% (0.7 M ammonia / MeOH) / DCM) to afford (R)-N-((1S)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-CLI-C-P3879PCT

[0540] hydroxybutyl)-2-methylpropane-2-sulfinamide (D27) (1.22 g, 100%) as a brown oil (1:1 mixture of diastereomers). UPLC-MS m / z 325.3 (M+H)+(ES+).

[0541] Description 27a

[0542] (S)-N-((1R)-2,2-Difluoro-1-(5-fluoropyridin-2-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D27a)

[0543] Sodium borohydride (62.2 mg, 1.64 mmol) was added to a solution of (S)-N-((R)-2,2-difluoro- 1-(5-fluoropyridin-2-yl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D26a) (0.505 g, 70% Wt, 1.10 mmol) in MeOH (10.0 mL) and the reaction stirred at room temperature for 1 hour. The reaction was quenched with sat. NH4CI (200 mL) and the volatiles removed in vacuo. Water (100 mL) was added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g gold cartridge, 0-3% (0.7 M Ammonia / MeOH) / DCM) to afford (S)-N-((1R)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D27a) (330 mg, 88 %) as a yellow oil (1:1 mixture of diastereomers). UPLC-MS m / z 325.3 (M+H)+(ES+).

[0544] Descriptions 28 and 29

[0545] 2-((2S,4R)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28)

[0546] 2-((2S,4S)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29)

[0547] To a 250 mL RB flask containing (R)-N-((1S)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D27) (1.22 g, 95% Wt, 3.57 mmol) in THF (10.0 mL) was added triphenylphosphine (937 mg, 3.57 mmol) followed by DIAD (695 pL, 3.57 mmol). The solution was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g gold cartridge, 0-30% EtOAc / isohexane) to afford 2-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28) (486 mg, 41%) as a pale-yellow solid.1H NMR (500 MHz, DMSO-de) 68.64 (d, J = 2.9 Hz, 1 H), 7.86 (td, J = 8.7, 3.0 Hz, 1 H), 7.76 (dd, J = 8.7, 4.6 Hz, 1 H), 5.47 (dd, J = 16.4, 8.3 Hz, 1 H), 4.63 - 4.45 (m, 1 H), 1.40 (dd, = 6.7, 1.0 Hz, 3H), 0.86 (s, 9H). UPLC-MS m / z 307.3 (M+H)+(ES+).

[0548] Further elution afforded 2-((2S,4S)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29) (815 mg, 37 %) as a brown oil.

[0549] 1H NMR (500 MHz, DMSO-d6) 58.48 (s, 1H), 7.88 (td, J= 8.6, 2.9 Hz, 1H), 7.82 (dd, J= 8.7, 4.5 Hz, 1H), 5.77-5.46 (m, 1H), 5.05 - 4.90 (m, 1H), 1.53 (dd, J = 6.8, 1.0 Hz, 3H), 0.88 (s, 9H). UPLC-MS m / z 307.3 (M+H)+(ES+).CLI-C-P3879PCT

[0550] Descriptions 28a and 29a

[0551] 2-((2R,4S)-1-((S)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28a)

[0552] 2-((2R,4R)-1-((S)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29a)

[0553] To a 40 mL vial containing N-((1R)-2,2-difluoro-1-(5-fluoropyridin-2-yl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D27a) (0.33 g, 95% Wt, 0.97 mmol) in THF (5.00 mL) was added triphenylphosphine (0.30 g, 1.2 mmol) followed by DIAD (0.23 mL, 1.2 mmol). The solution was stirred at room temperature overnight, then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g Gold cartridge, 0-30% EtOAc / isohexane) to afford: 2-((2R,4S)-1-((S)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28a) (0.13 g, 42 %) as a colourless solid.1H NMR (500 MHz, DMSO-de) 68.64 (d, J = 2.9 Hz, 1 H), 7.86 (td, J = 8.7, 3.0 Hz, 1 H), 7.76 (dd, J = 8.7, 4.6 Hz, 1 H), 5.47 (dd, J = 16.4, 8.3 Hz, 1 H), 4.63 - 4.45 (m, 1 H), 1.40 (dd, J = 6.7, 1.0 Hz, 3H), 0.86 (s, 9H). UPLC-MS m / z 307.2 (M+H)+(ES+).

[0554] Further elution afforded 2-((2R,4R)-1-((S)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29a) (0.35 g, 53 %) as a colourless solid.1H NMR (500 MHz, DMSO-de) 68.48 (s, 1 H), 7.88 (td, J = 8.6, 2.9 Hz, 1 H), 7.82 (dd, J = 8.7, 4.5 Hz, 1 H), 5.77 - 5.46 (m, 1 H), 5.05 - 4.90 (m, 1 H), 1.53 (dd, J = 6.8, 1.0 Hz, 3H), 0.88 (s, 9H). UPLC-MS m / z 307.5 (M+H)+(ES+).

[0555] Description 30

[0556] 2-((2S,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D30)

[0557] To a 40 mL vial containing 2-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28) (D28) (486 mg, 92% Wt, 1.46 mmol) in EtOAc (2 mL) was added HCI (1 M in EtOAc) (4.38 mL, 4.38 mmol). The reaction mixture was stirred for 16 hours. The material was concentrated in vacuo and slurried in TBME (5mL) for 2 hours. The white suspension was filtered under suction to afford 2-((2S,4R)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D30) (209 mg, 50%) as a white solid.

[0558] 1H NMR (500 MHz, DMSO-d6) 58.77 (d, J= 2.9 Hz, 1H), 7.96 (td, J= 8.7, 2.9 Hz, 1H), 7.80 (dd,J= 8.7, 4.4 Hz, 1H), 6.16 (t, J= 10.6 Hz, 1H), 5.03 (q,J= 10.6 Hz, 1H), 1.50 (d,J= 7.0 Hz, 3H). Exchangeable protons missing UPLC-MS m / z 203.2 (M+H)+(ES+).

[0559] Description 30a

[0560] 2-((2R,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D30a)

[0561] To a 40 mL vial containing 2-((2R,4S)-1-((S)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D28a) (130 mg, 95% Wt, 403 pmol) in EtOAc (2 mL) was added HCICLI-C-P3879PCT

[0562] (1.21 mL, 1M in EtOAc, 1.21 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was slurried in MTBE (5 mL) for 2 hours and the resulting white suspension was filtered under suction to afford 2-((2R,4S)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D30a) (82.0 mg, 70 %) as a white solid.

[0563] 1H NMR (500 MHz, DMSO-cfe) 58.77 (d, J = 2.9 Hz, 1 H), 7.96 (td, J = 8.7, 2.9 Hz, 1 H), 7.80 (dd, J = 8.7, 4.4 Hz, 1 H), 6.16 (t, J = 10.6 Hz, 1 H), 5.03 (q, J = 10.6 Hz, 1 H), 1.50 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 203.2 (M+H)+(ES+).

[0564] Description 31

[0565] 2-((2S,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31)

[0566] To a 40 mL vial containing 2-((2R,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29) (815 mg, 50% Wt, 1.33 mmol) in EtOAc (2 mL)was added HCI (1 M in EtOAc) (3.99 mL, 3.99 mmol). The reaction mixture was left to stir for 16 hours. The material was concentrated in vacuo and slurried in TBME (5 mL) for 2 hours. The white suspension was filtered under suction to afford 2-((2R,4R)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31) (508 mg, 69%) as an off-white solid.

[0567] 1H NMR (500 MHz, DMSO-d6) 58.78 (d, J= 2.9 Hz, 1H), 7.97 (td, J= 8.7, 2.9 Hz, 1H), 7.80 (dd, J= 8.7, 4.4 Hz, 1H), 6.17 (dd, J= 12.1, 6.9 Hz, 1H), 5.04 (q, J= 10.9 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H). Exchangeable protons missing. UPLC-MS m / z 203.2 (M+H)+(ES+).

[0568] Description 31a

[0569] 2-((2R,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31 a)

[0570] To a 40 mL vial containing 2-((2R,4R)-1-((S)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D29a) (350 mg, 50% Wt, 571 pmol) in EtOAc (2 mL) was added HCI (1.71 mL, 1M in EtOAc, 1.71 mmol). The reaction mixture was stirred for 1 hour at room temperature, then concentrated in vacuo. The residue was slurried in MTBE (5 mL) over 1 hour. The white suspension was filtered under suction to afford 2-((2R,4R)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31a) (212 mg, 64 %) as a white solid.

[0571] 1H NMR (500 MHz, DMSO-d6) 58.49 (s, 1H), 7.97 (td, J = 8.7, 2.9 Hz, 1H), 7.80 (dd, J = 8.7, 4.4 Hz, 1H), 6.17 (dd, J = 12.1, 6.9 Hz, 1H), 5.04 (q, J = 10.9 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 203.2 (M+H)+(ES+).

[0572] Description 32

[0573] 3,3-Difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-one (D32)

[0574] To a stirred solution of trimethyl(trifluoromethyl)silane (7.09 mL, 48.0 mmol) in dry THF (60.0 mL) under a nitrogen atmosphere at -40 °C was added 1-(trimethylsilyl)ethan-1-one (6.87 mL, 48.0 mmol) and TBAT (1.29 g, 2.40 mmol). The reaction mixture was stirred for 30CLI-C-P3879PCT

[0575] minutes before adding a solution of 5-fluoropicolinaldehyde (3.00 g, 24.0 mmol) in THF (10.0 mL). The mixture was stirred at -40 °C for 90 minutes then quenched with sat. aq. NH4CI (60 mL) and extracted with MTBE (2 x 60 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The residue was dissolved in MeOH (60 mL) and treated with 1 M HCI (60.0 mL, 60.0 mmol) at 0 °C and stirred for 20 minutes. Additional MeOH (60 mL) and 1 M HCI (60.0 mL, 60.0 mmol) were added, and the mixture stirred for a further 50 minutes. The solution was neutralised with sat. aq. NaHCOs (300 mL) and extracted with MTBE (2 x 200 mL). The organic extracts were combined, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-30 % EtOAc / isohexane) to afford 3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-one (D32) (3.11 g, 53%) as a white solid.

[0576] 1H NMR (500 MHz, DMSO-cfe) 68.52 (d, J= 2.9 Hz, 1H), 7.81 (td, J= 8.8, 2.9 Hz, 1H), 7.64 (dd, J= 8.8, 4.6 Hz, 1H), 6.84 (d, = 6.2 Hz, 1H), 5.19 (td, J= 12.9, 6.1 Hz, 1H), 2.37 (d, J = 1.6 Hz, 3H). UPLC-MS m / z 220.0 (M+H)+(ES+).

[0577] Descriptions 33, 34 and 35

[0578] (R)-N-((2R,4R)-3,3-Difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D33)

[0579] (R)-N-((2R,4S)-3,3-Difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D34)

[0580] (R)-N-((2S,4R)-3,3-Difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D35)

[0581] To a solution of 3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-one (D32) (3.11 g, 90% Wt, 12.8 mmol) and (R)-2-methylpropane-2-sulfinamide (4.64 g, 8.3 mmol) in THF (150 mL), was added titanium(IV) ethanolate (12.2 mL, 66% Wt, 38.3 mmol) and the reaction was stirred at 60 °C for 18 hours. The reaction mixture was cooled to -40 °C, then sodium borohydride (1.93 g, 51.1 mmol) was added, and the reaction mixture was stirred at -40 °C for 1 hour. The reaction was quenched by dropwise addition of MeOH (200 mL). Once effervescence ceased, brine (200 mL) was added, and the mixture was stirred for 5 min. The mixture was then filtered and washed through with EtOAc (3 x 100 mL). The filtrate was extracted with further EtOAc (2 x 100 mL). Organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((2R,4R)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D33) (634 mg, 14%).1H NMR (500 MHz, DMSO-cfe) 68.52 (d, J = 2.9 Hz, 1H), 7.77 (td, J = 8.8, 3.0 Hz, 1H), 7.61 (dd, J = 8.8, 4.6 Hz, 1H), 6.44 (d, J = 5.5 Hz, 1H), 5.74CLI-C-P3879PCT

[0582] (d, J = 8.9 Hz, 1 H), 5.23 (dt, J = 19.8, 5.4 Hz, 1 H), 3.88 (dq, J = 21.2, 7.3 Hz, 1 H), 1.25 (dd, J = 7.0, 1.4 Hz, 3H), 1.14 (s, 9H). UPLC-MS m / z 325.2 (M+H)+(ES+).

[0583] (R)-N-((2R,4S)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D34) (1.23 g, 27%).1H NMR (500 MHz, DMSO-cfe) 58.53 (d, J= 3.0 Hz, 1H), 7.79 (td, J = 8.8, 2.9 Hz, 1 H), 7.63 (dd, = 8.8, 4.6 Hz, 1 H), 6.48 (d, J = 5.9 Hz, 1 H), 5.59 (d, J = 8.4 Hz, 1 H), 5.00 (dt, J = 18.6, 6.5 Hz, 1 H), 3.85 (dq, J = 16.8, 8.4 Hz, 1 H), 1.32 (d, J = 7.0 Hz, 3H), 1.11 (s, 9H). UPLC-MS m / z 325.3 (M+H)+(ES+).

[0584] (R)-N-((2S,4R)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D35) (593 mg, 11%).1H NMR (500 MHz, DMSO-cfe) 58.52 (d, J= 3.0 Hz, 1H), 7.77 (td, J= 8.7, 2.9 Hz, 1H), 7.62 (td, J= 9.5, 4.6 Hz, 1H), 6.43 (d, J= 5.9 Hz, 1H), 5.22 (d, J = 8.3 Hz, 1 H), 4.99 (ddd, J = 15.4, 8.9, 5.9 Hz, 1 H), 3.76 (dq, J = 15.9, 7.8 Hz, 1 H), 1.35 (dd, J= 20.2, 7.0 Hz, 3H), 1.12 (d, J = 5.5 Hz, 9H). UPLC-MS m / z 325.3 (M+H)+(ES+).

[0585] Description 36

[0586] (1 R,3R)-3-(((R)-tert-Butylsulfinyl)amino)-2,2-difluoro-1 -(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D36)

[0587] To a stirred solution of (R)-N-((2R,4R)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D33) (0.55 g, 92% Wt, 1.6 mmol) and 2-nitrobenzenesulfonyl chloride (0.38 g, 1.7 mmol) in MeCN (25.0 mL) under a nitrogen atmosphere atO °C was added silver carbonate (0.47 g, 1.7 mmol) followed by silver trifluoromethanesulfonate (40 mg, 0.16 mmol). The reaction mixture was slowly warmed to RT and stirred in the dark for 22 hours. The reaction was diluted with sat. aq. NaHCOs (25 mL) and extracted into EtOAc (3 x 25 mL). Combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to afford (1 R,3R)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D36) (0.796 g, 87%) as a sticky white gum.

[0588] 1H NMR (500 MHz, DMSO-cfe) 58.56 (d, J = 2.9 Hz, 1H), 8.08 (dd, = 8.0, 1.2 Hz, 1H), 7.96 (td, J = 7.8, 1.4 Hz, 1 H), 7.93 (dd, = 8.0, 1.3 Hz, 1 H), 7.78 (td, J = 7.7, 1.3 Hz, 1 H), 7.72 (td, J = 8.7, 3.0 Hz, 1H), 7.56 (dd, J = 8.8, 4.3 Hz, 1H), 6.15 (t, J = 11.0 Hz, 1H), 5.83 (d, J = 8.8 Hz, 1H), 3.62 (dd, J= 14.4, 7.3 Hz, 1H), 1.32 (d, J= 7.0 Hz, 3H), 1.06 (s, 9H). UPLC-MS m / z 510.5 (M+H)+(ES+).

[0589] Description 37

[0590] (1S,3R)-3-(((R)-tert-Butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D37)CLI-C-P3879PCT

[0591] To a stirred solution of (R)-N-((2R,4S)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D34) (1.23 g, 92% Wt, 3.49 mmol) and 2-nitrobenzenesulfonyl chloride (850 mg, 3.84 mmol) in dry MeCN (60.0 mL) under a nitrogen atmosphere at 0 °C was added silver carbonate (1.06 g, 3.84 mmol) followed by silver trifluoromethanesulfonate (89.6 mg, 0.1 eq., 349 pmol). The reaction mixture was slowly warmed to RT and stirred in the dark for 48 hours. The reaction was diluted with sat. aq. NaHCOs (50 mL) and filtered. The precipitate was washed with EtOAc (50 mL) and the aqueous layer extracted with EtOAc (3 x 50 mL). Combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (1S,3R)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D37) (0.60 g, 27 %) as a sticky colourless gum.

[0592] 1H NMR (400 MHz, DMSO-cfe) 68.54 (d, J = 2.9 Hz, 1H), 8.08 (dd, J = 7.9, 1.2 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.85 - 7.69 (m, 2H), 7.62 (dd, J = 8.8, 4.4 Hz, 1H), 6.21 (dd, J= 12.6, 9.8 Hz, 1H), 5.73 (d, J= 8.6 Hz, 1H), 3.73 -3.58 (m, 1H), 1.25 (d, J= 7.0 Hz, 3H), 1.11 (s, 9H).

[0593] UPLC-MS m / z510.6 (M+H)+(ES+).

[0594] Description 38

[0595] (1R,3S)-3-(((R)-tert-Butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D38)

[0596] To a stirred solution of (R)-N-((2S,4R)-3,3-difluoro-4-(5-fluoropyridin-2-yl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (D35) (553 mg, 77% Wt, 1.31 mmol) and 2-nitrobenzenesulfonyl chloride (320 mg, 1.44 mmol) in dry MeCN (25.0 mL) under a nitrogen atmosphere at 0 °C was added silver carbonate (398 mg, 1.44 mmol) followed by silver trifluoromethanesulfonate (33.7 mg, 131 pmol). The reaction mixture was slowly warmed to RT and stirred in the dark for 6 days. The reaction was diluted with sat. aq. NaHCCh (25 mL), filtered and the precipitate washed with EtOAc (25 mL). The filtrate was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to afford (1 R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D38) (73.0 mg, 6.5%) as a colourless gum. UPLC-MS m / z510.6 (M+H)+(ES+).

[0597] Description 39

[0598] 2-((2S,4R)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D39)CLI-C-P3879PCT

[0599] To a stirred solution of(1R,3R)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D36) (796 mg, 87% Wt, 1.36 mmol) in dry DMF (15.0 mL) under a nitrogen atmosphere was added caesium carbonate (2.66 g, 8.15 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane) to afford 2-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D39) (380 mg, 87 %)as a white solid.

[0600] 1H NMR (500 MHz, DMSO-ofe) 68.64 (d, J= 2.9 Hz, 1H), 7.86 (td, J= 8.7, 2.9 Hz, 1H), 7.79 -7.73 (m, 1 H), 5.47 (dd, J = 16.3, 8.3 Hz, 1 H), 4.61 - 4.49 (m, 1 H), 1.40 (dd, J = 6.6, 1.0 Hz, 3H), 0.86 (s, 9H). UPLC m / z 307.2 (M+H)+(ES+). The absolute stereochemistry of D39 was determined by single crystal X-ray crystallography.

[0601] Description 40

[0602] 2-((2R,4R)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D40)

[0603] The material was prepared from (1S,3R)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D37) (320 mg, 41% Wt, 257 pmol) in the same manner as Description 39 (reaction time: 72 hours) to afford 2-((2R,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D40) (53.0 mg, 93%) as a white solid.

[0604] 1H NMR (500 MHz, DMSO-cfe) 58.62 (d, J= 2.9 Hz, 1H), 7.84 (td, J= 8.7, 2.9 Hz, 1H), 7.64 (dd, = 8.7, 4.5 Hz, 1 H), 5.85 - 5.77 (m, 1 H), 5.02 (dt, J = 19.6, 6.5 Hz, 1 H), 1.62 (dd, J = 6.8, 1.5 Hz, 3H), 1.25 (s, 9H). UPLC m / z 307.3 (M+H)+(ES+). The absolute stereochemistry of D40 was determined by single crystal X-ray crystallography.

[0605] Description 41

[0606] 2-((2S,4S)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D41)

[0607] The material was prepared from (1R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2,2-difluoro-1-(5-fluoropyridin-2-yl)butyl 2-nitrobenzenesulfonate (D38) (73.0 mg, 60% Wt, 86.0 pmol) in the same manner as Description 39 (reaction time: 18 hours) to afford 2-((2S,4S)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D41) (16.0 mg, 66%) as a yellow oil.CLI-C-P3879PCT

[0608] 1H NMR (500 MHz, DMSO-cfe) 58.65 (d, J= 2.9 Hz, 1H), 7.88 (td, J= 8.6, 2.9 Hz, 1H), 7.82 (dd, J = 8.7, 4.5 Hz, 1 H), 5.69 - 5.60 (m, 1 H), 5.05 - 4.92 (m, 1 H), 1.53 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H). UPLC m / z 307.3 (M+H)+(ES+).

[0609] Description 42

[0610] 4-(4-Fluorophenyl)-2,2-dimethylazetidin-1-ol (D42)

[0611] To a 40 mL vial containing 2,2-dimethylazetidine (510 mg, 5.99 mmol) and sodium tungstate dihydrate (593 mg, 1.80 mmol) in water (5.00 mL) was added hydrogen peroxide (1.36 mL, 30% Wt, 13.2 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 2.5 hours. The solution was extracted with DCM (3 x 5 mL), the combined organic extracts were passed through a phase separator and blown down to give a green oil. The material was transferred to a 40 mL vial, dissolved in THF (10 mL) then 4-fluorophenylmagnesium bromide (1 M in THF) (7.49 mL, 7.49 mmol) was added at 0 °C. The resulting solution was stirred at 0 °C for 1 hour. The reaction mixture was quenched by addition of sat. aq. NH4CI (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), passed through a phase separator, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to afford 4-(4-fluorophenyl)-2,2-dimethylazetidin-1-ol (D42) (87.0 mg, 7.1%) as a white solid.

[0612] 1H NMR (500 MHz, DMSO-cfe) 57.61 (s, 1H), 7.51 - 7.31 (m, 2H), 7.14 (t, J= 8.9 Hz, 2H), 4.24 (t, J = 8.9 Hz, 1H), 2.11 (dd, J= 9.9, 8.9 Hz, 1H), 1.46 (t, J = 9.4 Hz, 1H), 1.26 (s, 3H), 1.18 (s, 3H). UPLC-MS m / z 196.3 (M+H)+(ES+).

[0613] Description 43

[0614] 4-(4-Fluorophenyl)-2,2-dimethylazetidine (D43)

[0615] To a 40 mL vial containing 4-(4-fluorophenyl)-2,2-dimethylazetidin-1-ol (D42) (75.0 mg, 78% Wt, 300 pmol) and zinc (196 mg, 3.00 mmol) was added EtOH (3.00 mL) and then AcOH (1.00 mL). The reaction mixture was heated to 60 °C and stirred for 3 hours. Additional zinc (196 mg, 3.00 mmol) was added and the reaction mixture was stirred for a further 1 hour at 60 °C. The reaction mixture was cooled to RT and the solids were removed by filtration. The supernatant was concentrated in vacuo, dissolved in MeOH and loaded onto a 5g SCX-2 cartridge. The resin was washed with MeOH (3 x CV) and the combined eluents were set aside. The product was eluted with 2N NH3 in MeOH to give 4-(4-fluorophenyl)-2,2-dimethylazetidine (D43) (51.0 mg, 74%) as a colourless oil. UPLC-MS m / z 180.1 (M+H)+(ES+).

[0616] Description 44CLI-C-P3879PCT

[0617] 1 -Bromo-4-fluoro-3-methoxy-2-nitrobenzene (D44)

[0618] In a 500 mL 3-neck RBF 1-bromo-3,4-difluoro-2-nitrobenzene (CAS 884495-47-0) (4.90 g, 21 mmol) was dissolved in MeOH (100 mL) and the solution was cooled down to 0

[0619] °C. Sodium methoxide (5.4 M solution in MeOH) (5.0 mL, 27 mmol) was added dropwise and the reaction mixture stirred for 5 minutes at 0 °C. The ice bath was removed, and the reaction mixture stirred at RT for 18 hours. The reaction was quenched with water (30 mL) and concentrated in vacuo. The resulting aqueous mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried overMgSO4, filtered and concentrated in vacuo to give 1-bromo-4-fluoro-3-methoxy-2-nitrobenzene (D44) (4.94 g, 91%) as a paleyellowsolid.

[0620] 1H NMR (500 MHz, DMSO-ofe) 67.68 - 7.53 (m, 2H), 4.01 (d, J= 2.5 Hz, 3H).

[0621] Description 45

[0622] 1 -Fluoro-2-methoxy-4-methyl-3-nitrobenzene (D45)

[0623] A stirred mixture of 1-bromo-4-fluoro-3-methoxy-2-nitrobenzene (D44) (10.20 g, 40.80 mmol) and caesium carbonate (39.88 g, 122.39 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was purged with nitrogen for 10 minutes.2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (11.4 mL, 81.59 mmol) and [1,1 -bis(diphenylphosphino)ferrocene]-dichloropalladium(ll), dichloromethane adduct (CAS 95464-05-4) (1.666 g, 2.04 mmol) were added and purging was continued for a further 5 min. The reaction mixture was then heated to 90 °C and stirred under a nitrogen atmosphere for 3 hours. Upon cooling, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, dry load, 0- 50% EtOAc / isohexane) to afford 1-fluoro-2-methoxy-4-methyl-3-nitrobenzene (D45) (5.845 g, 74 %) as a clear yellow oil.

[0624] 1H NMR (500 MHz, DMSO-cfe) 57.52 - 7.45 (m, 1H), 7.21 - 7.16 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.22 (s, 3H).

[0625] Description 46

[0626] 3-Fluoro-2-methoxy-6-methylaniline (D46)

[0627] To a stirred solution of 1-fluoro-2-methoxy-4-methyl-3-nitrobenzene (D45) (5.840 g, 31.54 mmol) in THF (75 mL) and water (25 mL) at 0 °C was added ammonium chloride (10.12 g, 189.3 mmol) and zinc (12.37 g, 189.3 mmol). After 1 hour, the reaction mixture was allowed to warm to RT and stirred for a further 16 hours. The mixture was then filtered over Celite and the solid was rinsed with EtOAc. The mixture was diluted with sat. aq. sodium bicarbonate (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layersCLI-C-P3879PCT

[0628] were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-fluoro-2-methoxy-6-methylaniline (D46) (4.612 g, 90%) as a pale orange oil.

[0629] 1H NMR (500 MHz, DMSO-cfe) 56.66 (dd, J = 8.4, 6.0 Hz, 1 H), 6.30 (dd, J = 11.0, 8.4 Hz, 1 H), 4.85 (s, 2H), 3.73 (d, J = 0.9 Hz, 3H), 2.10 - 2.01 (m, 3H).

[0630] Description 47

[0631] 4-Bromo-3-fluoro-2-methoxy-6-methylaniline (D47)

[0632] To a solution of 3-fluoro-2-methoxy-6-methylaniline (D46) (4.612 g, 95% Wt, 28.24 mmol) in DMF (80 mL)at 0 °C was added N-bromosuccinimide (5.026 g, 28.24 mmol). The reaction mixture was stirred at 0 °C for 1.5 hours. The mixture was partitioned between MTBE (50 mL) and brine (50 mL). The two layers were separated and the organic phase was washed with citric acid (50 mL, 10% aq.), NaHCOs (50 mL, sat. aq.) and brine (50 mL), dried over gSO4 and concentrated in vacuo. The crude material was dissolved in MTBE (100 mL) and washed with a brine and water mixture (100 mL brine and 100 mL water) and then a 10% solution of LiCI (100 mL). The organic layer was collected, passed through a phase separator and concentrated to give 4-bromo-3-fluoro-2-methoxy-6-methylaniline (D47) (5.981 g, 86%) as brown oil.

[0633] 1H NMR (500 MHz, DMSO-cfe) 56.96 (d, J= 7.3, 0.9 Hz, 1H), 5.08 (s, 2H), 3.74 (d, J= 0.9 Hz, 3H), 2.04 (s, 3H). UPLC-MS m / z 234.5 / 236.4 (M+H)+(ES+).

[0634] Description 48

[0635] N-(4-Bromo-3-fluoro-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (D48)

[0636] In a 40 mL vial4-bromo-3-fluoro-2-methoxy-6-methylaniline (D47) (500 mg, 80% Wt, 1.71 mmol) was dissolved in DCM (10.00 mL)and the mixture cooled toO °C.3,3-Dimethylbutanoyl chloride (262 pL, 1.88 mmol) and triethylamine (476 pL, 3.42 mmol) were then added. The mixture stirred for 1 hour. The reaction mixture was diluted with brine (25 mL) and transferred into a separating funnel. The mixture was extracted with EtOAc (3x25 mL). The combined organic layers were collected, passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (D48) (577 mg, 97%) as a pale-yellow solid.

[0637] 1H NMR (500 MHz, DMSO-ofe) 59.24 (s, 1H), 7.33 (d, J= 7.1 Hz, 1H), 3.79 (d, J= 1.2 Hz, 3H), 2.21 (s, 2H), 2.10 (s, 3H), 1.05 (s, 9H). UPLC-MS m / z 331.7 / 332.8 (M+H)+(ES+).

[0638] Description 49

[0639] 4-Bromo-6-chloro-3-fluoro-2-methoxyaniline (D49)CLI-C-P3879PCT

[0640] To a stirred solution of4-bromo-3-fluoro-2-methoxyaniline (CAS 1137869-95-4) (1.01 g, 4.59 mmol) in MeCN (20 mL) was added NCS (644 mg, 4.82 mmol). The reaction mixture was heated at 70 °C for 16 hours. The mixture was cooled to room temperature, poured into water (100 mL) and filtered. The residue was washed with water (100 mL) after which it was dried under suction to afford 4-bromo-6-chloro-3-fluoro-2-methoxyaniline (D49) (880 mg, 72 %) as a black solid.

[0641] 1H NMR (500 MHz, DMSO-ofe) 57.32 (d, J = 6.6 Hz, 1H), 5.59 (s, 2H), 3.79 (s, 3H). LCMS m / z 254.0 / 255.8 (M+H)+(ES+).

[0642] Description 50

[0643] N-(4-Bromo-6-chloro-3-fluoro-2-methoxyphenyl)-3,3-dimethylbutanamide (D50) To a stirred solution of 4-bromo-6-chloro-3-fluoro-2-methoxyaniline (D49) (0.864 g, 3.40 mmol) in pyridine (10 mL, 0.12 mol) at 0 °C was added 3,3-dimethylbutanoyl chloride (520 pL, 3.73 mmol). The reaction mixture was stirred at 0 °C for 1 hour, then for 18 hours at RT. The reaction mixture was diluted with EtOAc (50 mL), then washed with 1 M HCI (100 mL) and sat. sodium bicarbonate (100 mL). The organic layer was dried over MgSC filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50%) to afford a purple / dark red solid. The material was slurried in isohexane (50 mL) and the resulting white solid was collected by filtration, rinsing with hexane, to afford N-(4-bromo-6-chloro-3-fluoro-2-methoxyphenyl)-3,3-dimethylbutanamide (D50) (0.530 g, 42%) as a white solid.

[0644] 1H NMR (500 MHz, DMSO-cfe) 59.52 (s, 1H), 7.70 (d, J = 6.5 Hz, 1H), 3.84 (d, J = 1.5 Hz, 3H), 2.22 (s, 2H), 1.05 (s, 9H). LCMS m / z 352.0 / 354.0 (M+H)+(ES+).

[0645] Description 51

[0646] 4-Bromo-3-fluoro-6-iodo-2-methoxyaniline (D51)

[0647] To a solution of4-bromo-3-fluoro-2-methoxyaniline (120 mg, 545 pmol) in AcOH (2.5 mL) was added NIS (135 mg, 600 pmol). The reaction was stirred at RT for 3 hours. The reaction mixture was poured into saturated aq. NaHCOs solution (30 mL) and once the effervescence subsided, the product was extracted with EtOAc (3 x 15 mL). The combined organic layers were and washed with brine (2 x 15 mL), dried over Na2SO4, and filtered. The solvent was evaporated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford 4-bromo-3-fluoro-6-iodo-2-methoxyaniline (D51) (163 mg, 82%) as an off-white solid.

[0648] 1H NMR (500 MHz, DMSO-cfe) 57.58 (d, J= 7.1 Hz, 1H), 5.34 (s, 2H), 3.78 (d, J = 1.0 Hz, 3H). UPLC-MS m / z 346.1 (M+H)+(ES+).CLI-C-P3879PCT

[0649] Description 52

[0650] 2-Amino-5-bromo-4-fluoro-3-methoxybenzonitrile (D52)

[0651] A 40 mL vial was charged with 4-bromo-3-fluoro-6-iodo-2-methoxyaniline (D51) (130 mg, 95% Wt, 357 pmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (CAS 72287-26-4) (26.1 mg, 35.7 pmol), and zinc cyanide (21.0 mg, 178 pmol). The vial was evacuated and back-filled with nitrogen (3 times). DMF (2 mL) and water (0.05 mL) were added, and the reaction was stirred at 120 °C for 2 hours. The reaction mixture was poured into brine (30 mL) and the product was extracted with EtOAc (3 x 20 mL). Organic phases were collected and washed with brine (2 x 20 mL) and dried over Na2SO4 and filtered. The solvent was evaporated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 2-amino-5-bromo-4-fluoro-3-methoxybenzonitrile (D52) (73 mg, 76%) as a white solid.

[0652] 1H NMR (500 MHz, DMSO-cfe) 67.60 (d, J= 7.0 Hz, 1H), 6.37 (s, 2H), 3.79 (d, J = 1.1 Hz, 3H).

[0653] Description 53

[0654] N-(4-Bromo-6-cyano-3-fluoro-2-methoxyphenyl)-3,3-dimethylbutanamide (D53) To a solution of 2-amino-5-bromo-4-fluoro-3-methoxybenzonitrile (D52) (507 mg, 75% Wt, 1.55 mmol) in pyridine (6 mL) was added 3,3-dimethylbutanoylchloride (281 pL, 2.02 mmol) at RT, and the reaction was stirred for 18 hours. The solvent was evaporated in vacuo and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford N-(4-bromo-6-cyano-3-fluoro-2-methoxyphenyl)-3,3-dimethylbutanamide (D53) (297 mg, 53 %) as a tan solid.

[0655] 1H NMR (500 MHz, DMSO-cfe) 59.96 (s, 1H), 8.08 (d, J= 6.7 Hz, 1H), 3.88 (d, J = 1.6 Hz, 3H), 2.27 (s, 2H), 1.06 (s, 9H). UPLC-MS m / z 342.8, 343.5 (M+H)+(ES+).

[0656] Description 54

[0657] 2-Amino-5-bromo-6-fluoro-3-iodobenzonitrile (D54)

[0658] To a 40 mL vial containing 6-amino-3-bromo-2-fluorobenzonitrile (1.00 g, 4.65

[0659] mmol) and AcOH (15 mL)was added NIS (1.151 g, 5.12 mmol). The reaction mixture was stirred for 3 hours, then quenched by addition of sat. aq. NaHCOs (100 mL). The resulting precipitate was collected by filtration, rinsing with water. The material was slurried in MeOH and collected by filtration to give2-amino-5-bromo-6-fluoro-3-iodobenzonitrile (D54) (1.13 g, 68%) as a cream solid.

[0660] 1H NMR (500 MHz, DMSO-cfe) 58.15 (d, J= 7.9 Hz, 1H), 6.47 (s, 2H).

[0661] Description 55CLI-C-P3879PCT

[0662] 2-Amino-5-bromo-6-fluoro-3-methylbenzonitrile (D55)

[0663] A 40 mL vial was charged with 2-amino-5-bromo-6-fluoro-3-iodobenzonitrile (D54) (400 mg, 95% Wt, 1.11 mmol), methylboronic acid (73.4 mg, 1.23 mmol), [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(ll) (CAS 72287-26-4) (45.5 mg, 55.7 pmol), and caesium carbonate (1.09 g, 3.34 mmol). The vial was sealed, evacuated and back-filled with N2 (3 times), and a degassed 1 ,4-dioxane (7.5 mL) and water (2.5 mL) mixture was added. The reaction was heated to 70 °C for 18 hours. The reaction mixture was cooled to RT, diluted with water (30 mL) and EtOAc (30 mL). The phases were separated, and the aqueous phase was extracted with further EtOAc (2 x 30 mL). The combined organics were washed with brine (50 mL) and dried over Na2SO4 and concentrated onto silica. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / hexane) to afford 2-amino-5-bromo-6-fluoro-3-methylbenzonitrile (D55) (133 mg, 45%) as an off-white solid.

[0664] 1H NMR (500 MHz, DMSO-flfe) 57.47 (dd, J= 8.1, 1.0 Hz, 1H), 6.38 (s, 2H), 2.07 (t,J= 1.0 Hz, 3H).

[0665] Description 56

[0666] N-(4-Bromo-2-cyano-3-fluoro-6-methylphenyl)-3,3-dimethylbutanamide (D56)

[0667] To a stirred solution of 2-amino-5-bromo-6-fluoro-3-methylbenzonitrile (D55) (560 mg, 87% Wt, 2.13 mmol) in pyridine (3.44 mL, 42.5 mmol) at 0 °C was added 3,3-dimethylbutanoyl chloride (385 pL, 2.77 mmol). The reaction mixture was stirred at 0 °C for 1 h, then diluted with 1 M HCI (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane). There material was further purified by chromatography on RP Flash C18 (40 g cartridge, 15-75% (0.1 % formic acid in MeCN) / (0.1% formic acid in water)) to afford N-(4-bromo-2-cyano-3-fluoro-6-methylphenyl)-3,3-dimethylbutanamide (D56) (360 mg, 49 %)as a white solid.

[0668] 1H NMR (500 MHz, DMSO-ofe) 510.00 (s, 1H), 8.03 (dd, J= 7.9, 0.8 Hz, 1H), 2.27 (s, 2H), 2.20 (d, J= 0.9 Hz, 3H), 1.07 (s, 9H). m / z 326.6 / 327.5 (M)+(ES+).

[0669] Description 57

[0670] 2-Bromo-5-fluoro-4-methoxy-3-nitropyridine (D57)

[0671] To a stirred solution of2,4-dibromo-5-fluoro-3-nitropyridine (CAS 884494-91-1) (1.10 g, 3.66 mmol) in THF (15 mL) at 0 °C was added sodium methoxide (0.5M in methanol) (7.310 mL, 3.655 mmol). The reaction mixture was allowed to warm to RT and stirred for 1 hour. The mixture was diluted with water (30 mL) and EtOAc (50 mL) followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated inCLI-C-P3879PCT

[0672] vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 2-bromo-5-fluoro-4-methoxy-3-nitropyridine (D57) (655 mg, 71%) as a white solid.

[0673] 1H NMR (500 MHz, DMSO-cfe) 58.67 (d, J = 4.2 Hz, 1H), 4.25 (d, J = 5.2 Hz, 3H). LCMS m / z 251.0 / 253.0 (M+H)+(ES+).

[0674] Description 58

[0675] 5-Fluoro-4-methoxy-2-methyl-3-nitropyridine (D58)

[0676] To a stirred solution of 2-bromo-5-fluoro-4-methoxy-3-nitropyridine (D57) (650 mg, 2.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (CAS 72287-26-4) (106 mg, 129 pmol) and caesium carbonate (2.53 g, 7.77 mmol) in 1 ,4-dioxane (21 mL) / water (5 mL) under a nitrogen atmosphere, was added trimethylboroxine ( (50% in THF) (1.81 mL, 6.47 mmol). The reaction mixture was heated at 100 °C and stirred for 16 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 5-fluoro-4-methoxy-2-methyl-3-nitropyridine (D58) (356 mg, 70%) as a colourless oil.

[0677] 1H NMR (500 MHz, DMSO-cfe) 58.66 (app. t, J = 3.9 Hz, 1H), 4.19 (d, = 4.8 Hz, 3H), 2.40 (app. t, J = 1.5 Hz, 3H). LCMS m / z 187.0 (M+H)+(ES+).

[0678] Description 59

[0679] 5-Fluoro-4-methoxy-2-methylpyridin-3-amine (D59)

[0680] A mixture of 5-fluoro-4-methoxy-2-methyl-3-nitropyridine (D58) (320 mg, 95% Wt, 1.63 mmol), zinc (641 mg, 9.80 mmol) and ammonium chloride (524 mg, 9.80 mmol) in THF (6 mL) / water (2 mL) was stirred at RT for 16 hours. The reaction mixture was filtered, rinsing with MeOH (100 mL). The filtrate was concentrated in vacuo and the resulting residue was taken up in sat. aq. Na2CO3 (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to give 5-fluoro-4-methoxy-2-methylpyridin-3-amine (D59) (280 mg, 100%).

[0681] 1H NMR (500 MHz, DMSO-cfe) 57.62 (d, J = 2.4 Hz, 1H), 5.03 (s, 2H), 3.88 (d, J = 2.3 Hz, 3H), 2.24 (d, J = 1.1 Hz, 3H). LCMS m / z 157.0 (M+H)+(ES+).

[0682] Description 60

[0683] 6-Bromo-5-fluoro-4-methoxy-2-methylpyridin-3-amine (D60)

[0684] To a stirred solution of 5-fluoro-4-methoxy-2-methylpyridin-3-amine (D59) (264 mg, 95% Wt, 1.61 mmol) in MeCN (7 mL)at0 °C was added N-bromosuccinimide (286 mg, 1.61 mmol).CLI-C-P3879PCT

[0685] The reaction mixture was stirred at 0 °C for 75 minutes. The mixture was then diluted with brine (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 6-bromo-5-fluoro-4-methoxy-2-methylpyridin-3-amine (D60) (307 mg, 81%) as a tan oil.

[0686] 1H NMR (500 MHz, DMSO-ofe) 55.25 (s, 2H), 3.92 (d, J = 2.6 Hz, 3H), 2.22 (d, J = 1.0 Hz, 3H). LCMS m / z 235.0 / 237.0 (M+H)+(ES+).

[0687] Description 61

[0688] N-(6-Bromo-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-2-(3,3-difluorocyclobutyl)acetamide (D61)

[0689] To a stirred solution of2-(3,3-difluorocyclobutyl)acetic acid (CAS 1373503-48-0) (149 mg, 994 pmol) in dry DCM (5 mL) under a nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1 -amine (96 pL, 729 pmol). The reaction mixture was stirred at RT for 45 minutes. A solution of 6-bromo-5-fluoro-4-methoxy-2-methylpyridin-3-amine (D60) (164 mg, 95% Wt, 663 pmol) in anhydrous pyridine (2 mL) was then added and the mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (4 x 25 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc / isohexane) to afford N-(6-bromo-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-2-(3,3-difluorocyclobutyl)acetamide (D61) (215 mg, 84%) as a white solid.

[0690] 1H NMR (500 MHz, DMSO-cfe) 59.62 (s, 1 H), 4.00 (d, J = 3.6 Hz, 3H), 2.78 - 2.67 (m, 2H), 2.57 (br.d, J = 7.4 Hz, 2H), 2.48 - 2.30 (m, 3H), 2.24 (s, 3H). LCMS m / z 367.0 / 369.0 (M+H)+(ES+).

[0691] Description 62

[0692] 2,4-Dibromo-5-fluoropyridin-3-amine (D62)

[0693] To a stirred solution of2,4-dibromo-5-fluoro-3-nitropyridine (CAS 884494-91-1) (1.00 g, 3.33 mmol) in AcOH (12.0 mL) under a nitrogen atmosphere was added iron (991 mg, 17.7 mmol). The reaction mixture was stirred at 60 °C for 40 minutes. The reaction mixture was cooled to RT and diluted with EtOAc(100 mL)and transferred into a separating funnel. The layer was washed with sat. aq. NaHCO3(150 mL) until basic. The aqueous layer was extracted with EtOAc (2 x 50 mL) and washed with brine (50 mL). The combined organic layers were dried overMgSO4, filtered and concentrated in vacuo to afford 2, 4-dibromo-5-fluoropyridin-3-amine (D62) (0.78 g, 82%) as an off-white solid.

[0694] 1H NMR (500 MHz, DMSO-cfe) 57.72 (s, 1H), 6.01 (s, 2H). UPLC-MS m / z 268.5 / 270.5 / 272.6 (1:2:1) (M+H)+(ES+).CLI-C-P3879PCT

[0695] Description 63

[0696] 5-Fluoro-2,4-dimethylpyridin-3-amine (D63)

[0697] 2,4-dibromo-5-fluoropyridin-3-amine (D62) (0.580 g, 2.15 mmol), methylboronic acid (283 mg, 4.73 mmol) and degassed aqueous CS2CO3 (3.95 mL, 2.50 molar, 9.89 mmol) were dissolved in 1,4-dioxane (7.80 mL) and purged with nitrogen before addition of [1,1 -bis-(diphenylphosphino)ferrocene]dichloropalladium(ll) (CAS 72287-26-4) (157 mg, 215 pmol). The reaction was stirred at 90 °C for 21 hours. The reaction mixture was cooled to RT, purged with nitrogen and additional methylboronic acid (283 mg, 4.73 mmol) and [1,1 -bis(diphenyl-phosphino)ferrocene]dichloropalladium(ll) (157 mg, 215 pmol) were added. The reaction mixture was stirred at 90 °C for a further 24 hours. The reaction mixture was cooled to RT, filtered over Celite and washed through with EtOAc (100 mL). The organic filtrate was collected and washed with sat. aq. NaHCO3(50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH / DCM) to afford 5-fluoro-2,4-dimethylpyridin-3-amine (D63) (0.243 g, 72 %) as a brown solid.

[0698] 1H NMR (500 MHz, DMSO-cfe) 57.56 (s, 1H), 5.10 (s, 2H), 2.25 (d, J= 1.1 Hz, 3H), 2.01 (d, J = 1.7 Hz, 3H). UPLC-MS m / z 141.5 (M+H)+(ES+).

[0699] Description 64

[0700] 6-Bromo-5-fluoro-2,4-dimethylpyridin-3-amine (D64)

[0701] To a stirred solution of5-fluoro-2,4-dimethylpyridin-3-amine (D63) (0.24 g, 89% Wt, 1.5 mmol) in MeCN (10 mL) atO °C was added N-bromosuccinimide (0.33 g, 1.8 mmol) in MeCN (5 mL). The reaction mixture was stirred for 20 minutes atO °C. The reaction was quenched by addition of brine (50 mL) and extracted into DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford 6-bromo-5-fluoro-2,4-dimethylpyridin-3-amine (D64) (0.29 g, 83 %) as a pale brown solid.1H NMR (500 MHz, DMSO-ofe) 55.33 (s, 2H), 2.24 (d, J= 1.1 Hz, 3H), 2.07 (d, J = 1.9 Hz, 3H). UPLC-MS m / z 219.0 / 221.1 (M+H)+(ES+).

[0702] Description 65

[0703] N-(6-Bromo-5-fluoro-2,4-dimethylpyridin-3-yl)-2-(3,3-difluorocyclobutyl)acetamide (D65)

[0704] To a stirred solution of6-bromo-5-fluoro-2,4-dimethylpyridin-3-amine (D64) (0.10 g, 0.46 mmol) and pyridine (0.59 mL, 7.3 mmol) in dry DCM (3 mL) under a nitrogen atmosphere at 0 °C was added 2-(3,3-difluorocyclobutyl)acetyl chloride (5.0 mL, 0.10 M in DCM, 0.50CLI-C-P3879PCT

[0705] mmol). The reaction mixture was stirred atO °C for 1 hour. The reaction was quenched with sat. aq. NaHCOa (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100 % EtOAc / isohexane) and allowed to crystallise overnight, before washing with hexane to afford N-(6-bromo-5-fluoro-2,4-dimethylpyridin-3-yl)-2-(3,3-difluorocyclobutyl)acetamide (D65) (0.088 g, 52 %) as a white crystalline solid.

[0706] 1H NMR (400 MHz, DMSO-ofe) 69.76 (s, 1H), 2.80-2.68 (m, 2H), 2.62 (d, J= 7.4 Hz, 2H), 2.47 -2.30 (m, 1H), 2.29 (d, J= 1.2 Hz, 3H), 2.12 (d, J = 2.3 Hz, 3H). Two protons obscured by residual solvent peak. UPLC-MS m / z 351.1 / 353.1 (M+H)+(ES+).

[0707] Description 66

[0708] (R)-3-(1-(4,6-Dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D66)

[0709] To a vial containing 2-chloro-4,6-dimethoxy-5-nitropyrimidine (CAS 478010-54-7) (43 mg, 0.19 mmol) and (R)-3-(3,3-difluoroazetidin-2-yl)benzonitrile HCI (D133), (43 mg, 95% Wt, 0.18 mmol) was added THF (5 mL) and DIPEA (0.15 mL, 0.89 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc / isohexane) to afford (R)-3-(1-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D66) (66 mg, 94%) as a pale-yellow gum.

[0710] 1H NMR (500 MHz, DMSO-cfe) 58.01 (d, J= 1.8 Hz, 1H), 7.89 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 5.98 (dd, J = 14.0, 7.4 Hz, 1 H), 4.75 (t, J = 12.1 Hz, 2H), 4.00 (s, 3H), 3.57 (s, 3H). UPLC-MS m / z 378.20 (M+H)+(ES+).

[0711] Description 67

[0712] (R)-3-(1-(5-Amino-4,6-dimethoxypyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D67)

[0713] To a 20 mL vial containing (R)-3-(1-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D66) (66 mg, 95% Wt, 0.17 mmol) in THF (4 mL) and water (2 mL)was added zinc (65 mg, 1.0 mmol) and then NH4CI (53 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of sat. aq. NaHCOa (20 mL) and the solution was extracted with EtOAc (3 x 10 mL). The combined organic extracts were passed through a phase separator and concentrated inCLI-C-P3879PCT

[0714] vacuo to give (R)-3-(1-(5-amino-4,6-dimethoxypyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D67) (44 mg, 72%) as a brown solid. UPLC-MS m / z 348.2 (M+H)+(ES+).

[0715] Description 68

[0716] (S)-2-(2-(2,4-Difluorophenyl)azetidine-1-yl)-3-fluoro-4-methoxypyridine (D68)

[0717] A stirred solution ofdicyclohexyl(2’-isopropoxy-6’-isopropyl-[1,1’-biphenyl]-2-yl)phosphane (12.6 mg, 27.9 pmol), (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139) (121 mg, 586 pmol) and 2-bromo-3-fluoro-4-methoxypyridine (CAS 109613-98-1) (0.115 g, 558 pmol) in THF (2 mL) was purged with nitrogen for 10 minutes. RuPhos G3 Precatalyst (CAS 1445085-77-7) (23.3 mg, 27.9 pmol)and LiHMDS (1 M in THF) (2.23 mL, 2.23 mmol) were then added. The reaction mixture was then heated to 65 °C and stirred under nitrogen for 1 hour. Upon cooling, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford (S)-2-(2-(2,4-difluorophenyl)azetidine-1-yl)-3-fluoro-4-methoxypyridine (D68) (0.092 g, 53%) as a thick colourless gum.

[0718] 1H NMR (500 MHz, DMSO-cfe) 57.76 (d, J= 5.7 Hz, 1H), 7.51 (td, J= 8.7, 6.7 Hz, 1H), 7.20 (ddd, J = 10.8, 9.3, 2.6 Hz, 1 H), 7.05 (td, = 8.6, 2.6 Hz, 1 H), 6.66 (t, J = 5.7 Hz, 1 H), 5.52 (t,J= 8.1 Hz, 1H), 4.20 -4.10 (m, 1H), 4.03 (qd, J= 8.3, 2.6 Hz, 1H), 3.84 (s, 3H), 2.77 -2.65 (m, 1H), 2.22 (dq, J = 10.5, 8.2 Hz, 1H). LCMS m / z 294.8 (M+H)+(ES+).

[0719] Description 69

[0720] (S)-5-Bromo-2-(2-(2,4-difluorophenyl)azetidine-1-yl)-3-fluoro-4-methoxypyridine (D69) To a solution of (S)-2-(2-(2,4-difluorophenyl)azetidine-1-yl)-3-fluoro-4-methoxypyridine (D68) (92 mg, 95% Wt, 0.30 mmol) in DMF (2 mL) at 0 °C was added N-bromosuccinimide (58 mg, 0.33 mmol). The reaction mixture was stirred at 0 °C for 1 hour then diluted with brine (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 50% brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford (S)-5-bromo-2-(2-(2,4-difluorophenyl)azetidine-1-yl)-3-fluoro-4-methoxypyridine (D69) (99 mg, 85%) as a thick yellow oil.

[0721] 1H NMR (500 MHz, DMSO-ofe) 57.94 (s, 1H), 7.54 - 7.46 (m, 1H), 7.25- 7.17 (m, 1H), 7.09 - 7.02 (m, 1 H), 5.55 (t, J = 8.0 Hz, 1 H), 4.23 - 4.08 (m, 2H), 4.02 (d, J = 3.7 Hz, 3H), 2.81 -2.71 (m, 1H), 2.30 -2.19 (m, 1H). LCMS m / z 372.8, 374.8 (M+H)+(ES+).

[0722] Description 70

[0723] (S)-6-(2-(2,4-Difluorophenyl)azetidine-1-yl)-5-fluoro-4-methoxypyridin-3-amine (D70)CLI-C-P3879PCT

[0724] To a stirred mixture of (S)-5-bromo-2-(2-(2,4-difluorophenyl)77zetidine-1-yl)-3-fluoro-4-methoxypyridine (D69) (99 mg, 95% Wt, 0.25 mmol), (R,S)-pyrrolidine-2-carboxylic acid (12 mg, 0.10 mmol) and copper (I) iodide (9.6 mg, 50 pmol) and potassium carbonate (52 mg, 0.38 mmol) in DMSO (4 mL) under a nitrogen atmosphere at RT was added aq. ammonium hydroxide (0.29 mL, 35% Wt, 2.5 mmol). The reaction mixture was stirred for 18 hours at 100 °C. Water (40 mL) was added and the compound was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over MgSC filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / heptane) to afford (S)-6-(2-(2,4-difluorophenyl)azetidine-1-yl)-5-fluoro-4-methoxypyridin-3-amine (D70) (8 mg, 9%) as a sticky brown gum.

[0725] 1H NMR (500 MHz, DMSO-ofe) 67.56 - 7.40 (m, 1H), 7.38 - 7.30 (m, 1H), 7.24 - 7.12 (m, 1 H), 7.07 - 6.96 (m, 1 H), 5.37 (t, J = 8.3 Hz, 1 H), 4.59 (s, 2H), 4.06 - 3.93 (m, 1 H), 3.88 (s, 3H), 3.84 - 3.77 (m, 1H), 2.25 - 2.13 (m, 1H). One proton obscured by residual solvent peak. LCMS m / z 309.8 (M+H)+(ES+).

[0726] Description 71

[0727] N-(4-Bromo-2-fluoro-6-methoxyphenyl)-3,3-dimethylbutanamide (D71)

[0728] To a stirred solution of4-bromo-2-fluoro-6-methoxyaniline (CAS 1261216-27-6) (300 mg, 1.36 mmol) and triethylamine (0.380 mL, 2.73 mmol) in dryDCM (15 mL) under a nitrogen atmosphere atO °C was added 3,3-dimethylbutanoyl chloride (0.209 mL, 1.50 mmol). The reaction mixture was stirred for 1 hour. It was then diluted with sat. aq. NaHCOs (20 mL), extracted with DCM (3 X 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford N-(4-bromo-2-fluoro-6-methoxyphenyl)-3,3-dimethylbutanamide (D71) (393 mg, 89%) as a brown solid.

[0729] 1H NMR (500 MHz, DMSO-cfe) 59.12 (s, 1H), 7.16 (dd, J = 9.0, 2.0 Hz, 1H), 7.12 (t, J = 1.8 Hz, 1H), 3.81 (s, 3H), 2.16 (s, 2H), 1.01 (s, 9H). UPLC-MS m / z 317.9 / 320.5 (M+H)+(ES+).

[0730] Description 72

[0731] 4-Chloro-6-methyl-5-nitropyridin-2-amine (D72)

[0732] To a mixture of4-chloro-6-methylpyridin-2-amine (CAS 36340-61-1) (1500 mg, 95% Wt, 9.99 mmol) suspended in cone, sulfuric acid (15.0 mL, 279 mmol) was added nitric acid (500 pL, 12.0 mmol) slowly atO °C. The resulting suspension was stirred at this temperature for 30 minutes. The mixture was poured into ice water (50 mL). The solution was then basified using 2 M aq. NaOH solution to ca. pH 8-10. The product was extracted using EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified byCLI-C-P3879PCT

[0733] chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 4-chloro-6-methyl-5-nitropyridin-2-amine (D72) (480 mg, 24%) as a yellow solid.

[0734] 1H NMR (500 MHz, DMSO-cfe) 67.16 (s, 2H), 6.48 (s, 1H), 2.33 (s, 3H).

[0735] Description 73

[0736] 4-Methoxy-6-methyl-5-nitropyridin-2-amine (D73)

[0737] In a microwave reaction vial (2.0-5.0 mL), 4-chloro-6-methyl-5-nitropyridin-2-amine (D72) (465 mg, 2.48 mmol), dry MeOH (10 mL) and sodium methoxide (5.4 M solution in MeOH) (1.38 mL, 7.44 mmol) were added. The vial was sealed, and the reaction was performed in a microwave reactor at 100 °C for 1 hour. The reaction was quenched with water (2 mL) and solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated in vacuo to give 4-methoxy-6-methyl-5-nitropyridin-2-amine (D73) (437 mg, 91%) as a yellow solid.

[0738] 1H NMR (500 MHz, DMSO-cfe) 56.73 (s, 2H), 5.98 (s, 1H), 3.80 (s, 3H), 2.24 (s, 3H). LCMS m / z 183.8 (M+H)+(ES+).

[0739] Description 74

[0740] 6-Chloro-4-methoxy-2-methyl-3-nitropyridine (D74)

[0741] 4-Methoxy-6-methyl-5-nitropyridin-2-amine (D73) (386 mg, 95% Wt, 2.00 mmol) was suspended in sulfuric acid (320 pL, 6.01 mmol) and water (1.2 mL) at 0 °C. A solution of sodium nitrite (152 mg, 2.20 mmol) in water (2.00 mL) was added dropwise with vigorous stirring at 0 °C. Stirring was continued for further 20 minutes then the mixture was allowed to warm to RT and stirred for a further 1 hour. The product was then extracted into EtOAc (4 x 30 mL). The combined organic layers were washed with brine (50 mL) dried over Na2SO4, filtered, and concentrated in vacuo. The residue was combined with pentachloro-15-phosphane (417 mg, 2.00 mmol). To this was added phosphoryl trichloride (2.25 mL, 24.0 mmol) and the reaction was stirred for 3 hours at 100°C. The reaction mixture was transferred in a 250 mL RBF. POOL was evaporated in vacuo and the residue was suspended in water (20 mL). The solution was basified to pH 7-8 using 2 M aq. NaOH solution. The product was extracted into EtOAc (4 x 20 mL). The combined organic layers were concentrated in vacuo to give 6-chloro-4-methoxy-2-methyl-3-nitropyridine (D74) (300 mg, 55.8%) as a brown wax.

[0742] 1H NMR (500 MHz, DMSO-cfe) 57.48 (s, 1H), 4.00 (s, 3H), 2.40 (s, 3H). UPLC-MS m / z 202.9 (M+H)+(ES+).

[0743] Description 75CLI-C-P3879PCT

[0744] 6-Chloro-4-methoxy-2-methylpyridin-3-amine (D75)

[0745] To a solution of6-chloro-4-methoxy-2-methyl-3-nitropyridine (D74) (100 mg, 95% Wt, 469 pmol) in EtOH (2 mL) was added a solution of NH4CI (50.2 mg, 938 pmol) in water (1 mL) and iron (131 mg, 2.34 mmol). The reaction mixture was heated to 70 °C for 18 hours, cooled to RT and filtered through Celite, washing with MeOH (3 x 10 mL). The filtrate was concentrated in vacuo and the resulting aqueous solution was basified using sat. aq.

[0746] NaHCCh (10 mL). The product was extracted into EtOAc (3 x 10 mL). the combined organics were dried (Na2SO4) filtered and concentrated in vacuo to give 6-chloro-4-methoxy-2-methylpyridin-3-amine (D75) (72 mg, 75%) as a brown oil.

[0747] 1H NMR (500 MHz, DMSO-ofe) 66.81 (s, 1H), 4.68 (s, 2H), 3.84 (d, J= 1.1 Hz, 3H), 2.22 (s, 3H).

[0748] Description 76

[0749] N-(6-Chloro-4-methoxy-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (D76)

[0750] To a solution of 6-chloro-4-methoxy-2-methylpyridin-3-amine (D75) (72 mg, 84% Wt, 0.35 mmol) in DCM (2 mL) was added triethylamine (0.15 mL, 1.1 mmol) and 3,3-dimethylbutanoylchloride (49 pL, 0.35 mmol) at 0 °C. The reaction was stirred atO °Cfor2 hours. Further 3, 3-dimethylbutanoylchloride (49 pL, 0.35 mmol) and triethylamine (98 pL, 0.70 mmol) were added and the reaction was stirred for an additional 2 hours atO °C. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford N-(6-chloro-4-methoxy-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (D76) (58 mg, 58%) as a pale-yellow solid.

[0751] 1H NMR (500 MHz, DMSO-cfe) 59.16 (s, 1H), 7.08 (s, 1H), 3.84 (s, 3H), 2.24 (s, 3H), 2.18 (s, 2H), 1.03 (s, 9H).

[0752] Description 77

[0753] tert-Butyl (3-fluoro-2-(trifluoromethoxy)phenyl)carbamate (D77)

[0754] To a stirred solution of 1-bromo-3-fluoro-2-(trifluoromethoxy)benzene (CAS 1242258-31-6) (0.550 g, 2.12 mmol) in dry 1,4-dioxane (10 mL) under a nitrogen atmosphere was added tert-butyl carbamate (498 mg, 4.25 mmol), CS2CO3 (1.38 g, 4.25 mmol)

[0755] and dicyclohexyl(2’,4’,6’-triisopropyl-[1,T-biphenyl]-2-yl)phosphane (202 mg, 425 pmol). The mixture was degassed for 5 minutes and then Pd-170 (CAS 1798782-02-1) (143 mg, 212 pmol) was added and the reaction heated to 70 °C and stirred for 3 hours. The reaction was then cooled to RT and partitioned between MTBE (30 mL) and sat. NaHCOs (20 mL) The two layers were separated, and the aqueous phase was extracted with MTBE (20 mL). The combined organics were washed with brine (25 mL), dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (24CLI-C-P3879PCT

[0756] g cartridge, 0-10% EtOAc / heptane, product eluted with ca. 4% EtOAc) to afford tert-butyl (3-fluoro-2-(trifluoromethoxy) phenyl)carbamate (D77) (0.751 g, 96%) as a yellow gum.

[0757] 1H NMR (500 MHz, DMSO-d6) 59.27 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 -7.33 (m, 1H), 7.23 - 7.15 (m, 1H), 1.45 (s, 9H). LCMS m / z 294.0 (M-H)' (ES‘).

[0758] Description 78

[0759] 3-Fluoro-2-(trifluoromethoxy)aniline (D78)

[0760] To a solution of tert-butyl (3-fluoro-2-(trifluoromethoxy)phenyl)carbamate (D77) (0.050 g, 0.17 mmol) in DCM (1 mL) was added TFA (0.30 mL, 3.9 mmol). The reaction mixture was stirred at RT for 1 hour, diluted with DCM (5 mL) then poured into sat. aq. NaHCOs (20 mL). The phases were separated and the aqueous was extracted with further DCM (3 x 10 mL). The combined organics were dried (MgSOzi) and concentrated in vacuo to give 3-fluoro-2-(trifluoromethoxy)aniline (D78) (25 mg, 68%) as a pale-yellow solid.

[0761] 1H NMR (500 MHz, DMSO-cfe) 57.10 - 6.94 (m, 1H), 6.62 - 6.53 (m, 1H), 6.47 - 6.37 (m, 1H), 5.72 (s, 2H).

[0762] Description 79

[0763] 4-Bromo-3-fluoro-2-(trifluoromethoxy)aniline (D79)

[0764] To a solution of3-fluoro-2-(trifluoromethoxy)aniline (D78) (308 mg, 1.58 mmol) in DMF (10 mL) at 0 °C was added N-bromosuccinimide (281 mg, 1.58 mmol). The reaction mixture was stirred at RT for 30 minutes, then diluted with brine (20 mL). The product was extracted using EtOAc (3 x 20 mL). The combined organics were washed with 50% brine (2 x 20 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% DCM / iso-hexanes) to afford 4-bromo-3-fluoro-2-(trifluoromethoxy)aniline (D79) (327 mg, 57%) as a yellow oil.

[0765] 1H NMR (500 MHz, DMSO-cfe) 57.30 (dd, J = 9.0, 7.5 Hz, 1 H), 6.60 (dd, J = 9.1 , 1.9 Hz, 1H), 5.97 (d, J = 5.9 Hz, 2H).

[0766] Description 80

[0767] N-(4-Bromo-3-fluoro-2-(trifluoromethoxy)phenyl)-3,3-dimethylbutanamide (D80) To a solution of4-bromo-3-fluoro-2-(trifluoromethoxy)aniline (D79) (200 mg, 75% Wt, 547 pmol)in DCM (5 mL) was added triethylamine (0.15 mL, 1.09 mmol) and 3,3-dimethylbutanoyl chloride (57.1 pL, 602 pmol)at 0 °C The reaction was stirred for 1 hour at 0 °C, then warmed to RT and stirred for 18 hours. The reaction mixture was cooled to 0 °C, further 3, 3-dimethylbutanoyl chloride (41.5 pL, 438 pmol)was added and the reaction mixture was stirred for 1 hour at 0 °C. Additional triethylamine (0.15 mL, 1.09 mmol) and 3,3-dimethylbutanoyl chloride (0.080 mL, 0.84 mmol) were added and the solution was stirred forCLI-C-P3879PCT

[0768] 1 hour at 0 °C. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford N-(4-bromo-3-fluoro-2-(trifluoromethoxy)-phenyl)-3,3-dimethylbutanamide (D80) (221 mg, 100%) as a colourless solid.

[0769] 1H NMR (500 MHz, DMSO-ofe) 59.89 (s, 1H), 7.76 - 7.69 (m, 2H), 2.30 (s, 2H), 1.01 (s, 9H). LCMS m / z 371.8 / 373.8 (M+H)+(ES+).

[0770] Description 81

[0771] N-(4-Bromo-3-fluoro-2-hydroxy-6-methylphenyl)-3,3-dimethylbutanamide (D81) To a solution of N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (D48) (0.350 g, 1.05 mmol) in DCM (10 mL) at -78 °C was added BBrs (1 M solution in DCM) (4.0 mL, 4.0 mmol) dropwise. The reaction was stirred for 1 hour and then allowed to slowly warm to RT. After 4 hours the reaction was cooled to 0 °C and quenched using sat. aq. NH4CI (3 mL) The mixture was partitioned between sat. aq. NH4CI (20 mL) and DCM (10 mL). The two layers were separated and the aqueous phase extracted with DCM (2 x 15 mL). The combined organics were washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in ~10 mL 9:1 DCM / MeOH and triturated with isohexane (25 mL), the resultant precipitate was filtered and washed with isohexane (20 mL) to give N-(4-bromo-3-fluoro-2-hydroxy-6-methylphenyl)-3,3-dimethylbutanamide (D81) (0.272 g, 81%) as a colourless powder.

[0772] 1H NMR (500 MHz, DMSO-d6) 59.76 (s, 1H), 9.16 (s, 1H), 6.99 (d, J= 6.9 Hz, 1H), 2.22 (s, 2H), 2.09 (s, 3H), 1.04 (s, 9H). UPLC-MS m / z 318.2 / 320.2 (M+H)+(ES+).

[0773] Description 82

[0774] N-(4-Bromo-2-(difluoromethoxy)-3-fluoro-6-methylphenyl)-3,3-dimethylbutanamide (D82)

[0775] To a 40 mL vial containing N-(4-bromo-3-fluoro-2-hydroxy-6-methylphenyl)-3,3-dimethylbutanamide (D81) (115 mg, 361 pmol)and KOH (304 mg, 5.42 mmol) in MeCN / H2O (4 mL)was added phosphonic acid, (bromodifluoromethyl)diethyl ester (128 pL, 723 pmol), dropwise. The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was acidified to pH 1 by addition of 1N HCI and then diluted with water (10 mL). The product was extracted into DCM (3 x5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-50% MTBE / heptane) to afford N-(4-bromo-2-(difluoromethoxy)-3-fluoro-6-methylphenyl)-3,3-dimethylbutanamide (D82) (42 mg, 30%) as a colourless solid.CLI-C-P3879PCT

[0776] 1H NMR (500 MHz, DMSO-cfe) 59.45 (s, 1H), 7.60 (d, J= 7.1 Hz, 1H), 6.98 (t, J= 72.7 Hz, 1H), 2.22 (s, 2H), 2.15 (s, 3H), 1.04 (s, 9H). UPLC-MS m / z 368.1 / 370.1 (M+H)+(ES+).

[0777] Description 83

[0778] 6-Bromo-3-fluoro-2-methylaniline (D83)

[0779] To a solution of 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (CAS 1286734-82-4) (0.32 g, 1.4 mmol) in methanol (5 mL) was added ammonium chloride (0.37 g, 6.9 mmol) and zinc (0.45 g, 6.9 mmol). The reaction mixture was stirred at RT for 20 hours. Further zinc (0.45 g, 6.9 mmol) and ammonium chloride (0.37 g, 6.9 mmol) were added and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered through Celite, washing with EtOAc (3 x 20 mL). The filtrate was diluted with sat. aq. NaHCOs (50 mL) and the phases were separated. The aqueous was extracted using EtOAc (2 x 20 mL). The combined organics were dried (MgSO4) and concentrated in vacuo to give 6-bromo-3-fluoro-2-methylaniline (D83) (336 mg, 100%) as a pale brown oil.

[0780] 1H NMR (500 MHz, DMSO-cfe) 57.23 (dd, J = 8.8, 6.0 Hz, 1H), 6.42 - 6.32 (m, 1H), 5.29 (s, 2H), 2.05 (d, J = 2.0 Hz, 3H). UPLC-MS m / z 204.1 / 206.2 (M+H)+(ES+).

[0781] Description 84

[0782] 3-Fluoro-6-methoxy-2-methylaniline (D84)

[0783] To a solution of6-bromo-3-fluoro-2-methylaniline (D83) (336 mg, 85% Wt, 1.40

[0784] mmol) and copper (I) iodide (320 mg, 1.68 mmol) in methanol (4 mL) was added sodium methoxide (478 mg, 95% Wt, 8.40 mmol). The reaction vial was sealed and heated by microwave (Biotage) at 100 °C for 40 minutes followed by a further 1 hour at 120 °C. Finally, the mixture was heated using a hot plate at 100 °C for 24 h. The reaction mixture was cooled to RT, filtered through Celite, rinsed with water (20 mL) and extracted into EtOAc (20 mL). The phases of the filtrate were separated and the aqueous was extracted using further EtOAc (2 x 10 mL). The combined organics were dried and concentrated in vacuo. The residue was redissolved in DMF (2.5 mL)then copper(l) iodide (320 mg, 1.68 mmol) was added followed by sodium methoxide in methanol (1.56 mL, 5.4 molar, 8.40 mmol). The reaction mixture was heated by microwave (Biotage) at 120 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted using further EtOAc (2 x 10 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a silica gel (12 g cartridge, 0-100% MTBE / iso-hexanes) to afford 3-fluoro-6-methoxy-2-methylaniline (D84) (65 mg, 29%) as a yellow oil.1H NMR (500 MHz, DMSO-cfe) 56.63 (dd, J = 8.8, 5.1 Hz, 1H), 6.33 - 6.26 (m, 1H), 4.74 (s, 2H), 3.73 (s, 3H), 1.98 (d, J = 1.8 Hz, 3H). UPLC-MS m / z 156.2 (M+H)+(ES+).CLI-C-P3879PCT

[0785] Description 85

[0786] 4-Bromo-3-fluoro-6-methoxy-2-methylaniline (D85)

[0787] To a solution of 3-fluoro-6-methoxy-2-methylaniline (D84) (65 mg, 0.42 mmol) in MeCN (1 mL) at 0 °C was added N-bromosuccinimide (75 mg, 0.42 mmol). The reaction mixture was stirred atO °C for 1.5 hours. The reaction mixture was diluted with water (10 mL) and EtOAc (10 mL). The phases were separated and the aqueous was extracted with further EtOAc (2 x 10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% MTBE / lso-hexanes) to afford 4-bromo-3-fluoro-6-methoxy-2-methylaniline (D85) (97 mg, 97%) as a dark purple solid.

[0788] 1H NMR (500 MHz, DMSO-ofe) 66.87 (d, J = 6.4 Hz, 1H), 4.93 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H), 2.03 (d, J = 2.1 Hz, 3H). UPLC-MS m / z 234.1 / 236.1 (M+H)+(ES+).

[0789] Description 86

[0790] N-(4-Bromo-3-fluoro-6-methoxy-2-methylphenyl)-3,3-dimethylbutanamide (D86) To a solution of 3,3-dimethylbutanoic acid (67 pL, 0.54 mmol) in DCM (2 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.070 mL, 0.53 mmol). The reaction mixture was stirred at RT for 1 hour, then a mixture of 4-bromo-3-fluoro-6-methoxy-2-methylaniline (D85) (98 mg, 0.42 mmol) and pyridine (0.30 mL, 3.70 mmol) in DCM (3 mL)was added dropwise. The reaction mixture was diluted with 1 M HCI (5 mL) and DCM (10 mL), the phases were separated, and the aqueous phase was extracted with further DCM (2x 10 mL). The combined organics were washed with sat. aq. NaHCOs (10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80% MTBE / lso-hexanes) to afford N-(4-bromo-3-fluoro-6-methoxy-2-methylphenyl)-3,3-dimethylbutanamide (D86) (64 mg, 45%) as a pale brown solid.

[0791] 1H NMR (500 MHz, DMSO-cfe) 59.16 (s, 1H), 7.18 (d, J = 6.4 Hz, 1 H), 3.75 (s, 3H), 2.19 (s, 2H), 2.07 (d, J = 2.5 Hz, 3H), 1.03 (s, 9H). UPLC-MS m / z 331.4 / 334.5 (M+H)+(ES+).

[0792] Description 87

[0793] N-(4-Bromo-3-fluoro-2-methoxy-6-methylphenyl)-3-hydroxy-3-methylbutanamide (D87) To a 40 mL vial containing 3-hydroxy-3-methylbutanoic acid (0.35 mL, 3.23 mmol) in THF (3 mL) was added 4-methylmorpholine (0.36 mL, 3.23 mmol) and then Isobutyl chloroformate (421 pL, 3.23 mmol). The mixture was stirred for 45 minutes at RT. To the reaction mixture was then added 4-bromo-3-fluoro-2-methoxy-6-methylaniline (252 mg, 1.08 mmol) and THF (3 mL) and the mixture stirred at 60 °C for 18 h. The reaction mixture was blown down to dryness and the crude product was purified by chromatography on silica gel (12 g cartridge,CLI-C-P3879PCT

[0794] 0-100% MTBE / Heptane) to afford N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-3-hydroxy-3-methylbutanamide (D87) (199 mg, 44 %) as a dark green oil.

[0795] 1H NMR (500 MHz, DMSO-cfe) 59.34 (s, 1H), 7.33 (d, J = 7.1 Hz, 1H), 4.78 (s, 1H), 3.79 (s, 3H), 2.45 (s, 2H), 2.11 (s, 3H), 1.25 (s, 6H). m / z 333.8 / 335.8 (M+H)+(ES+).

[0796] Description 88

[0797] (R)-N-((S)-1-(2,4-Difluorophenyl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D88a), (R)-N-((1S)-1-(2,4-Difluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D88b), (2S,4S)-1-((R)-tert-Butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88c) and (2S,4R)-1 -((R)-tert-Butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88d)

[0798] To a 40 mL vial containing (R)-N-((S)-1-(2,4-difluorophenyl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (D113) (1.50 g, 93% Wt, 4.63 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added potassium tetrahydroxydioxidoosmium, monohydrate (93.6 mg, 231 pmol) and sodium periodate (2.97 g, 13.9 mmol). The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was diluted with water (200 mL), the product was extracted into EtOAc (3 x 50 mL), the combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((S)-1-(2,4-difluorophenyl)-3-oxobutyl)-2-methylpropane-2-sulfinamide (D88a) (756 mg, 51 %) as a black oil.1H NMR (500 MHz, DMSO-cfe) 57.54 - 7.44 (m, 1H), 7.20 - 7.14 (m, 1H), 7.07 (td, J = 8.6, 2.6 Hz, 1 H), 5.48 (d, J = 5.8 Hz, 1 H), 4.92 (q, J = 6.6 Hz, 1 H), 3.21 - 3.11 (m, 1 H), 3.01 (dd, J = 17.3, 6.9 Hz, 1H), 2.08 (s, 3H), 1.03 (s, 9H). LCMS m / z 326.3 (M+Na)+(ES+). To this material in a 100 mL RBF was added MeOH (15 mL) and NaBH4 (134 mg, 3.55 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched by dropwise addition of 1 M HCI until effervescence ceased and then concentrated to ca. 25% volume. The solution was diluted with water (10 mL) and the product was extracted into EtOAc (3 x 15 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to afford (R)-N-((1S)-1-(2,4-difluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D88b) (626 mg, 74 %) as a black oil. m / z 306.3 (M+H)+(ES+).

[0799] To a solution of (D88b) in a 100 mL RBF in toluene (10 mL) was added cyanomethylene)-tributylphosphorane (810 pL, 3.03 mmol) and then the solution was heated to 110 °C for 18 hours. The reaction mixture was concentrated in vacuo and then the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to afford: (2S,4S)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88c) (221 mg, 48CLI-C-P3879PCT

[0800] %) as a yellow oil:1H NMR (500 MHz, DMSO-cfe)) 57.75 - 7.65 (m, 1H), 7.27 - 7.19 (m, 1H), 7.15 (td, J = 8.6, 2.6 Hz, 1H), 5.02 (t, J = 8.4 Hz, 1H), 4.28 (ddt, J = 14.5, 8.2, 6.2 Hz, 1H), 2.80 (dt, J = 10.8, 8.8 Hz, 1H), 1.91 (dt, J = 10.8, 7.9 Hz, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.06 (s, 9H). m / z 288.3 (M+H)+(ES+).

[0801] Also isolated was (2S,4R)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88d) (63 mg, 14 %) as a yellow oil.1H NMR (500 MHz, DMSO-d6)) 57.73 - 7.63 (m, 1H), 7.24- 7.16 (m, 1H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 5.60 (t, J = 7.9 Hz, 1H), 4.60-4.49 (m, 1H), 2.54 (dd, J = 10.5, 7.9 Hz, 1H), 2.23 (ddd, J = 11.1, 8.3, 3.3 Hz, 1H), 1.61 (d, J = 6.4 Hz, 3H), 1.16 (s, 9H). m / z 288.3 (M+H)+(ES+).

[0802] Description 89

[0803] 1 -Fluoro-2,4-dimethoxy-3-nitrobenzene (D89)

[0804] In a 40 mL vial 1 ,2,4-trifluoro-3-nitrobenzene (CAS 42096-74-2) (300 mg, 1.69 mmol) was dissolved in MeOH (7 mL) and the solution was cooled to 0 °C. Sodium methoxide (5.4M in MeOH) (753 pL, 4.07 mmol) was added dropwise. The mixture was stirred at 0 °C for 5 minutes and then allowed to warm to RT and stirred for 24 hours. The reaction was quenched with water (20 mL) and concentrated under reduced pressure. The solution was diluted with EtOAc (10 mL) and transferred into a separating funnel and the layers separated. The aqueous phase was extracted with EtOAc (2x 10 mL). The

[0805] combined organic layers were collected, passed through a phase separator, and concentrated in vacuo. The residue was dissolved in MeOH (7 mL) and sodium methoxide (5.4M in MeOH) (627 pL, 3.39 mmol) was added dropwise at RT. The mixture was heated to 40 °C and stirred for 24 hours. The reaction was quenched with water (20 mL) and concentrated under reduced pressure. The resulting aqueous solution

[0806] was extracted with EtOAc (3x 10 mL). The combined organic layers were collected, passed through a phase separator, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 1-fluoro-2,4-dimethoxy-3-nitrobenzene (D89) (114 mg, 30%) as a clear colourless oil.

[0807] 1H NMR (500 MHz, DMSO-ofe) 57.54 (dd, = 11.8, 9.5 Hz, 1H), 7.03 (dd, J = 9.5, 3.5 Hz, 1H), 3.97 (d, J = 2.4 Hz, 3H), 3.86 (s, 3H).

[0808] Description 90

[0809] 3-Fluoro-2,6-dimethoxyaniline (D90)

[0810] A mixture of 1-fluoro-2,4-dimethoxy-3-nitrobenzene (D89) (114 mg, 90% Wt, 510 pmol), zinc (200 mg, 3.06 mmol) and NH4CI (164 mg, 3.06 mmol) in THF (3 mL) and water (1 mL) was stirred at RT for 24 hours. The reaction mixture was heated to 50 °C for an additional 24 hours. The mixture was filtered through Celite, and the precipitate washed with EtOAc (25CLI-C-P3879PCT

[0811] mL). The filtrate was diluted with sat. aq. NaHCOs (20 mL) and the two layers separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organics were washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 3-fluoro-2,6-dimethoxyaniline (D90) (35 mg, 40%) as a colourless oil. UPLC-MS m / z 172.3 (M+H)+(ES+).

[0812] Description 91

[0813] 4-Bromo-3-fluoro-2,6-dimethoxyaniline (D91)

[0814] To a solution of 3-fluoro-2,6-dimethoxyaniline (D90) (39 mg, 0.23 mmol) in DMF (1 mL) at 0 °C was added NBS (41 mg, 0.23 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The mixture was partitioned between EtOAc (5 mL) and brine (5 mL) and separated. The organic phase was washed with 10% aq. LiCI solution (5 mL), collected, passed through a phase separator and concentrated in vacuo to give 4-bromo-3-fluoro-2,6-dimethoxyaniline (D91) (35 mg, 57%) as a dark brown oil. UPLC-MS m / z 250.1 / 252.1 (M+H)+(ES+).

[0815] Description 92

[0816] N-(4-Bromo-3-fluoro-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide (D92)

[0817] In a 40 mL vial 4-bromo-3-fluoro-2,6-dimethoxyaniline (D91) (35 mg, 0.14 mmol) was dissolved in DCM (1.00 mL) and the mixture cooled to 0 °C. 3,3-Dimethylbutanoyl chloride (21 pL, 0.15 mmol) and triethylamine (39 pL, 0.28 mmol) were then added. The reaction mixture was allowed to warm to RT and stirred for 18 hours. Additional 3,3-dimethylbutanoyl chloride (9.7 pL, 70 pmol) and triethylamine (20 pL, 0.14 mmol) were added and stirring was continued for a further 2 hours. Additional 3,3-dimethylbutanoyl chloride (9.7 pL, 70 pmol) and triethylamine (20 pL, 0.14 mmol) were added and stirring was continued for a further 18 hours. The reaction mixture was diluted with brine (5 mL) and transferred into a separating funnel. The mixture was extracted with EtOAc (3x 5 mL). The combined organic layers were collected, passed through a phase separator, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford N-(4-bromo-3-fluoro-2,6-dimethoxyphenyl)-3,3-dimethylbutanamide (D92) (31 mg, 49%) as a tan solid.

[0818] 1H NMR (500 MHz, DMSO-ofe) 56.78 (d, J = 5.6 Hz, 1H), 3.99 - 3.96 (m, 3H), 3.79 (s, 3H), 2.26 (s, 2H), 1.12 (s, 9H). Exchangeable proton not observed. UPLC-MS m / z 47.4 / 349.5 (M+H)+(ES+).

[0819] Description 93

[0820] (S)-3-Amino-3-(4-fluorophenyl)propanoic acid, HCI (D93)CLI-C-P3879PCT

[0821] To a stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluorophenyl)-propanoate (D101) (262 mg, 831 pmol) in EtOAc (2 mL) was added HCI (in ethyl acetate) (4.15 mL, 1.0 molar, 4.15 mmol). The reaction mixture was stirred for 1 hour and evaporated in vacuo. The mixture was diluted with MTBE (3 x 20 mL), sonicated and decanted each time to afford ethyl (S)-3-amino-3-(4-fluorophenyl)-propanoic acid, HCI (D93) (154 mg, 71%) as a sticky off-white solid.

[0822] 1H NMR (500 MHz, DMSO-ofe) 58.72 (br.s, 3H), 7.64 - 7.58 (m, 2H), 7.29 - 7.23 (m, 2H), 4.61 (br.s, 1H), 4.05-3.93 (m, 2H), 3.18 (dd, J = 16.1, 5.8 Hz, 1H), 2.98 (dd, J = 16.1, 9.1 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H). LCMS m / z 212.2 (M+H)+(ES+).

[0823] Description 94

[0824] (S)-4-(4-Fluorophenyl)azetidine-2-one (D94)

[0825] To a stirred solution of diisopropylamine (0.083 mL, 0.59 mmol) in dry THF (2 mL) under a nitrogen atmosphere at -78 °C was added 2.5M butyllithium in hexane (0.19 mL, 0.48 mmol). The reaction mixture was stirred for 1 hour and ethyl (S)-3-amino-3-(4-fluorophenyl)propanoic acid, HCI (D93) (50 mg, 95% Wt, 0.19 mmol) in THF (2 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 16 hours. The reaction was quenched with sat. aq. NaHCOs (40 mL). The mixture was extracted with DCM (3 X 40 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and evaporated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% MeOH / DCM) to afford (S)-4-(4-fluorophenyl)azetidine-2-one (D94) (14 mg, 42%) as a tan solid.

[0826] 1H NMR (500 MHz, CDCI3) 57.38 - 7.32 (m, 2H), 7.10 - 7.04 (m, 2H), 6.06 (s, 1 H), 4.72 (dd, J = 5.4, 2.6 Hz, 1 H), 3.45 (ddd, J = 14.9, 5.4, 2.6 Hz, 1 H), 2.86 (ddd, J = 14.9, 2.6, 1.0 Hz, 1H). LCMS m / z 166.2 (M+H)+(ES+).

[0827] Description 95

[0828] Ethyl (4-bromo-2-nitrophenyl)carbamate (D95)

[0829] To a solution of 4-bromo-2-nitroaniline (CAS 875-51-4) (1.00 g, 4.61 mmol) in 1,4-dioxane (50 mL) was added DIPEA (1.20 mL, 6.91 mmol) followed by dropwise addition of ethyl chloroformate (0.49 mL, 5.1 mmol). The reaction mixture was heated to 65 °C for 18 hours, cooled to RT, then further ethyl chloroformate (0.33 mL, 3.4 mmol) was added and the reaction was heated to 90 °C for 24 hours. The reaction mixture was cooled to RT, and then partitioned between water (100 mL) and EtOAc (100 mL). The phases were separated and the aqueous was extracted using further EtOAc (2 x 50 mL). The combined organics were washed with 1 M HCI (100 mL), then sat. aq. NaHCOa (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 gCLI-C-P3879PCT

[0830] cartridge, 0-100% EtOAc / isohexane) to afford ethyl (4-bromo-2-nitrophenyl)carbamate (D95) (722 mg, 29%) as a bright orange solid.

[0831] 1H NMR (500 MHz, DMSO-cfe) 69.89 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 4.12 (q, = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). UPLC-MS m / z 288.9 (M-H)-(ES').

[0832] Description 96

[0833] Ethyl (S)-(4-(2-(2,4-difluorophenyl)azetidine-1-yl)-2-nitrophenyl)carbamate (D96)

[0834] A stirred mixture of (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139) (156 mg, 761 pmol) and ethyl (4-bromo-2-nitrophenyl)carbamate (D95) (0.200 g, 692 pmol) in THF (3 mL) was purged with nitrogen for 10 minutes, feu Xphos Pd G3 (CAS 1447963-75-8) (55.0 mg, 69.2 pmol) and phosphazene base P2 Et, (CAS 165535-45-5) (460 pL, 1.38 mmol) were then added and purging was continued for a further 5 minutes. The reaction mixture was then stirred under nitrogen at RT for 3 hours. The mixture was diluted with sat. aq. NH4CI (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc / isohexane) to afford ethyl (S)-(4-(2-(2,4-difluorophenyl)azetidine-1-yl)-2-nitrophenyl)carbamate (D96) (0.140 g, 0.26 mmol, 38 %) as a thick purple oil.

[0835] LCMS m / z 378.2 (M+H)+(ES+); 376.0 (M-H)'(ES').

[0836] Description 97

[0837] (R)-N-((R,E)-1-(2,4-Difluorophenyl)-3-hydroxybutylidene)-2-methylpropane-2-sulfinamide (D97)

[0838] To a 500 mL RBF containing (R,E)-N-(1-(2,4-difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (CAS 1585971-57-8 ) (990 mg, 95% Wt, 3.63 mmol) in THF (40 mL) was added LDA (1 M in THF / hexanes) (3.99 mL, 3.99 mmol) at -78 °C. The reaction mixture was stirred for 30 minutes at -78 °C. To the reaction mixture was added magnesium bromide (1.34 g, 7.25 mmol), the solution was stirred for a further 15 minutes. Acetaldehyde (264 pL, 4.72 mmol) was then added and stirring was continued for 2 hours. The reaction mixture was quenched with 9:1 THF:AcOH and then diluted further with brine (200 mL). The product was extracted into EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 50-100% MTBE / isohexane) to afford (R)-N-((R,E)-1-(2,4-difluorophenyl)-3-hydroxybutylidene)-2-methylpropane-2-sulfinamide (D97) (408 mg, 35%) as a pale yellow oil. UPLC-MS m / z 304.6 (M+H)+(ES+).CLI-C-P3879PCT

[0839] Description 98

[0840] (R)-N-((1S,3R)-1-(2,4-Difluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D98)

[0841] To a 40 ml_ vial containing (R)-N-((R,E)-1-(2,4-difluorophenyl)-3-hydroxybutylidene)-2-methylpropane-2-sulfinamide (D97) (408 mg, 95% Wt, 1.28 mmol) in THF (3 mL) was added lithium triethylborohydride (1 M in THF) (3.19 mL, 3.19 mmol), dropwise, at -78 °C. The reaction mixture was stirred for 1 hour then quenched by addition of sat. aq. NH4CI (20 mL). The product was extracted with EtOAc (3x 10 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 50-100% MTBE / isohexane then 0-50% MeOH / MTBE) to afford (R)-N-((1S,3R)-1-(2,4-difluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D98) (291 mg, 55%) as a colourless oil. UPLC-MS m / z 306.3 (M+H)+(ES+); 304.1 (M-H)' (ES‘).

[0842] Description 99

[0843] (2S,4S)-1-((R)-tert-Butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D99) To a 100 mL RBF containing (R)-N-((1S,3R)-1-(2,4-difluorophenyl)-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D98) (291 mg, 74% Wt, 705 pmol) in toluene (10 mL) was added cyanomethylene)-tributylphosphorane (377 pL, 1.41 mmol) and then the solution was stirred at 110 °C for 18 hours. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (12 g cartridge, 0-50% MTBE / isohexane) to afford (2S,4S)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D99) (96 mg, 43%) as a colourless gum.

[0844] 1H NMR (500 MHz, DMSO-cfe) 59.15 (td, J = 8.6, 6.6 Hz, 1H), 8.69 - 8.53 (m, 2H), 6.46 (t, J = 8.4 Hz, 1H), 5.72 (ddt, J = 14.4, 8.3, 6.3 Hz, 1H), 4.29-4.17 (m, 1H), 3.35 (dt, J = 10.8, 7.9 Hz, 1H), 2.78 (d, J = 6.2 Hz, 3H), 2.50 (s, 9H). UPLC-MS 288.3 (M+H)+(ES+).

[0845] Description 100

[0846] (R,E)-N-(2-Fluorobenzylidene)-2-methylpropane-2-sulfinamide (D100)

[0847] To a solution of 2-fluorobenzaldehyde (2.12 mL, 97% Wt, 19.5 mmol) and (R)-2-methylpropane-2-sulfinamide (2.84 g, 23.4 mmol) in THF (60 mL) was added titanium ethoxide (8.13 mL, 39.1 mmol), and the reaction mixture was stirred at 65 °C for 18 hours. The mixture was cooled to RT and poured into sat. brine solution (100 mL). The resulting precipitate was filtered washing with water (75 mL) and EtOAc (3 x 75 mL). The phases of the filtrate were separated and the aqueous was extracted with further EtOAc (2 x 100 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / heptane) toCLI-C-P3879PCT

[0848] afford (R,E)-N-(2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D100) (4.12 g, 87%) as a colourless oil. (CAS 1187081-50-0).

[0849] 1H NMR (500 MHz, DMSO-d6) 58.71 (s, 1H), 8.04 - 7.97 (m, 1H), 7.71 - 7.63 (m, 1H), 7.44 - 7.34 (m, 2H), 1.19 (s, 9H). LCMS m / z 277.8 (M+H)+(ES+).

[0850] Description 101

[0851] Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluorophenyl)propanoate (D101) D101 was prepared by the method of Description 2 but using (R,E)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (CAS 820231-35-4) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1).

[0852] 1H NMR (500 MHz, DMSO-d6) 57.42 - 7.33 (m, 2H), 7.14 (t, J = 8.9 Hz, 2H), 5.58 (d, J = 5.9 Hz, 1H), 4.63 (q, J = 6.8 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.00 (dd, J = 15.4, 6.7 Hz, 1H), 2.73 (dd, J = 15.4, 7.8 Hz, 1H), 1.09 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H). m / z 316.6 (M+H)+(ES+).

[0853] Description 102

[0854] N-(4-Bromo-3-fluoro-2-methoxy-6-methylphenyl)-2-(3,3-difluorocyclobutyl)-acetamide (D102)

[0855] D102 was prepared by the method described in Description 48 but using 2-(3,3-difluorocyclobutyl)acetyl chloride in place of 3,3-dimethylbutanoyl chloride.

[0856] 1H NMR (500 MHz, DMSO-cfe) 59.44 (s, 1 H), 7.33 (d, J = 7.1 Hz, 1 H), 3.78 (s, 3H), 2.78 -2.67 (m, 2H), 2.56 (d, J = 7.3 Hz, 2H), 2.45-2.30 (m, 2H), 2.07 (s, 3H). 1 proton obscured by residual solvent peak, m / z 365.8 / 367.8 (M+H)+ (ES+).

[0857] Description 103

[0858] N-(6-Bromo-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (D103) D103 was prepared by the route described in Description 61 but using 3,3-dimethylbutanoic acid in place of 2-(3,3-difluorocyclobutyl)acetic acid.

[0859] 1H NMR (500 MHz, DMSO-d6) 59.43 (s, 1H), 4.00 (d, J = 3.6 Hz, 3H), 2.27 (d, J = 1.2 Hz, 3H), 2.22 (s, 2H), 1.04 (s, 9H). m / z 332.8 / 334.8 (M+H)+(ES+).

[0860] Description 104

[0861] Ethyl (R)-3-(4-bromo-2-fluorophenyl)-3-((tert-butylsulfinyl)amino)-2,2-difluoropropanoate (D104)

[0862] A stirred mixture of zinc (19.2 g, 294 mmol) and copper(l) chloride (3.2 g, 32.3 mmol) in dry THF (120 mL) was refluxed for 30 minutes. The mixture was cooled to RT and ethyl 2-bromo-2,2-difluoroacetate (18.8 mL, 147 mmol) was added. The resulting mixture wasCLI-C-P3879PCT

[0863] stirred at 50 °C for a further 30 min. The reaction mixture was then cooled to 0 °C. (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) (9.00 g, 29.4 mmol) in THF (50.0 mL) was added and the mixture was stirred at RT for 18 hours. Sat. aq. NH4CI solution (50 mL) and water (30 mL) were then added. The phases were separated and the aqueous was extracted with EtOAc (2 x 50 mL). The organic layers were combined and the solvent was evaporated and loaded on to a plug of silica (5 cm long) and washed with hexane (250 mL) and then eluted with 1:1 mixture of MTBE:hexane to afford ethyl (R)-3-(4-bromo-2-fluorophenyl)-3-((tert-butylsulfinyl)amino)-2,2-difluoropropanoate (D104) (17.8 g, 99%) as a pale yellow oil. m / z 430.2 / 432.2 (M+H)+(ES+).

[0864] Descriptions 105 and 106

[0865] (R)-N-((R)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulf inamide (D105)

[0866] (R)-N-((S)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulf inamide (D106)

[0867] To a stirred solution of ethyl (R)-3-(4-bromo-2-fluorophenyl)-3-((tert-butylsulfinyl)amino)-2,2-difluoropropanoate (D104) (8.24 g, 19.14 mmol) in dry THF (100 mL) at 0 °C was added lithium aluminium hydride (2.4 M in THF) (8.772 mL, 21.05 mmol) dropwise. The mixture was stirred at RT for 1 hour. The reaction was quenched by addition of Na2SO4.10H2O until effervescence ceased and the resulting solid was filtered, washing with EtOAc (100 mL). The filtrate was dried over Na2SO4and evaporated in vacuo. The crude product was purified three times by chromatography on silica gel (40 g cartridge, 0-100% MTBE / isohexane) to afford:

[0868] D105: (R)-N-((R)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (605 mg, 4.0%) as a white solid, m / z 388.0, 390.0 (M+H)+(ES+), and:

[0869] D106: (R)-N-((S)-1 -(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (375 mg, 1.6%) as a white solid, m / z 388.0, 390.0 (M+H)+(ES+).

[0870] Description 107

[0871] (R)-2-(4-Bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidine (D107) A mixture of (R)-N-((R)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (D105) (593 mg, 49% Wt, 748 mol) and (tributylphosphoranylidene)acetonitrile (490 pL, 1.87 mmol) in toluene (8.0 mL) was stirred at 110 °C for 16 hours. The reaction mixture was evaporated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% MTBE / isohexane) to afford (R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidine (D107) (162 mg, 56%) as a tan gum.CLI-C-P3879PCT

[0872] 1H NMR (500 MHz, DMSO-cfe) 57.70 (dd, J = 9.9, 1.9 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.59 (dd, J = 8.3, 1.9 Hz, 1 H), 5.77 - 5.70 (m, 1 H), 4.58 - 4.49 (m, 1 H), 4.48 - 4.39 (m, 1 H), 0.92 (s, 9H). m / z 370.0, 372.0 (M+H)+(ES+).

[0873] Description 108

[0874] (S)-2-(4-Bromo-2-fluorophenyl)-1 -((R)-tert-butylsulfinyl)-3,3-difluoroazetidine ( D 108) A mixture of (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (D106) (370 mg, 32% Wt, 305

[0875] pmol) and (tributylphosphoranylidene)acetonitrile (0.549 mL, 2.09 mmol) in toluene (6.00 mL) was heated at 105 °C overnight. The reaction mixture was evaporated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% MTBE / isohexane) to afford (S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidine (D108) (100 mg, 71%) as an off-white solid, m / z 370.0, 372.0 (M+H)+(ES+).

[0876] Description 109

[0877] 4-((R)-1-((R)-tert-Butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D109) A stirred mixture of (R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-azetidine (D107) (155 mg, 95% Wt, 398 pmol), potassium acetate (19.5 mg, 199 pmol), potassium hexacyanoferrate(ll), 3monohydrate (84.0 mg, 199 pmol), (oxybis(2,1-phenylene))bis(diphenylphosphane) (CAS 166330-10-5) (21.4 mg, 39.8 pmol) and [Pd(cinnamyl)CI]2 (10.3 mg, 19.9 pmol) in dioxane (2.00 mL) / water (2.00 mL) was degassed and back-filled with nitrogen three times. The reaction mixture was heated at 85 °C for 16 h. Water (40 mL) was added to the to the reaction mixture and extracted with EtOAc (3 x 30 mL), dried over NazSC and evaporated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% MTBE / isohexane) to afford 4-((R)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D109) (107 mg, 81%) as a yellow solid.

[0878] 1H NMR (500 MHz, DMSO-ofe) 58.01 (dd, J = 10.1, 1.5 Hz, 1H), 7.93 (t, = 7.5 Hz, 1H), 7.88 (dd, J = 8.0, 1.5 Hz, 1 H), 5.83 (dd, = 16.7, 6.4 Hz, 1 H), 4.63 - 4.54 (m, 1 H), 4.53 -4.44 (m, 1H), 0.92 (s, 9H). m / z 317.2 (M+H)+(ES+).

[0879] Description 110

[0880] 4-((S)-1-((R)-tert-Butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D110) A stirred mixture of (S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidine (D108) (94.0 mg, 254 pmol), potassium acetate (12.5 mg, 127 pmol), potassium hexacyanoferrate(ll), trihydrate (53.6 mg, 127 pmol), (oxydi-2,1-CLI-C-P3879PCT

[0881] phenylene)bis(diphenylphosphine) (CAS 166330-1-5) (13.7 mg, 25.4 pmol) and [Pd(cinnamyl)CI]2 (6.58 mg, 12.7 pmol) in dioxane (2.00 mL) / water (2.00 mL) under a nitrogen atmosphere was stirred at 85 °C for 16 hours. Water (50 mL) was added and reaction mixture was extracted into EtOAc (3 x 50 mL), the combined organic phase dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% MTBE / isohexane) to afford 4-((S)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D110) (59.0 mg, 68%) as a yellow solid.

[0882] 1H NMR (500 MHz, DMSO-d6) 57.98 (dd, J = 10.0, 1.5 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 5.77 (dd, J = 14.3, 8.6 Hz, 1H), 4.55 (td, J = 15.1, 11.3 Hz, 1H), 4.06 - 3.97 (m, 1H), 1.18 (s, 9H). m / z 317.2 (M+H)+(ES+).

[0883] Description 111

[0884] (R)-4-(3,3-Difluoroazetidin-2-yl)-3-fluorobenzonitrile, HCI (D111)

[0885] To a solution of 4-((R)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D109) (99.0 mg, 313 pmol) in EtOAc (1 mL) was added HCI (1 M in EtOAc) (3.13 mL, 3.13 mmol) and the reaction mixture was stirred at RT for 1 h. The solvent was blown off with the aid of nitrogen gas and the mixture was taken up in MTBE (15 mL), sonicated, and the supernatant was removed. The procedure was repeated twice, and the crude material was evaporated in vacuo at room temperature to afford (R)-4-(3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile, HCI (D111) (88.0 mg, 100%) as a yellow gum.

[0886] 1H NMR (500 MHz, DMSO-cfe) 58.05 (dd, J = 10.2, 1.6 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.90 (dd, J = 8.1 , 1.6 Hz, 1 H), 6.26 (t, J = 11.2 Hz, 1 H), 4.70 - 4.60 (m, 1 H), 4.51 - 4.43 (m, 1H). Exchangeable protons not observed, m / z 213.2 (M+H)+(ES+).

[0887] Description 112

[0888] (S)-4-(3,3-Difluoroazetidin-2-yl)-3-fluorobenzonitrile, HCI (D112)

[0889] To a solution of 4-((S)-1-((R)-tert-butylsulfinyl)-3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile (D110) (56.0 mg, 177 pmol) in EtOAc (1 mL) was added HCI (1 M in EtOAc) (1.77 mL, 1.77 mmol) and the reaction mixture was stirred at RT for 1 h. The solvent was blown off with the aid of nitrogen gas and the mixture was taken up in MTBE (15 mL), sonicated, and the supernatant was removed. The procedure was repeated twice, and the material was evaporated in vacuo at room temperature to afford (S)-4-(3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile, HCI (D112) (45.0 mg, 92 %) as a yellow gum.

[0890] 1H NMR (500 MHz, DMSO-cfe) 58.04 (dd, J = 10.3, 1.5 Hz, 1H), 7.94 (t, J = 7.5 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1 H), 6.24 (t, = 11.3 Hz, 1 H), 4.64 (dt, J = 16.6, 11.3 Hz, 1 H), 4.46 (q, J = 12.1 Hz, 1H). Exchangeable protons not observed, m / z 213.0 (M+H)+(ES+).CLI-C-P3879PCT

[0891] Description 113

[0892] (R)-N-((S)-1-(2,4-Difluorophenyl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (D113)

[0893] To a 100 mL RBF containing (R,E)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide (2.64 g, 10.8 mmol) (CAS 1397715-14-8, (prepared by the method of Description 100 but using 2,4-difluorobenzaldehyde in place of 2-fluorobenzaldehyde)), 3-bromo-2-methylprop-1-ene (1.63 mL, 16.1 mmol) and THF (25 mL)was added indium (1.59 g, 13.5 mmol). The reaction mixture was stirred at 55 °C for 4 hours. The reaction mixture was filtered and the filtrate was diluted with brine (100 mL). The product was extracted into EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), passed through a phase separator, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 25-100% EtOAc / isohexane) to afford (R)-N-((S)-1-(2,4-difluorophenyl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (D113) (2.57 g, 75%) as a colourless oil.

[0894] 1H NMR (500 MHz, DMSO-cfe) 57.52 (td, J= 8.6, 6.6 Hz, 1H), 7.16 (ddd, J= 11.0, 9.4, 2.6 Hz, 1 H), 7.08 (td, J = 8.6, 2.6 Hz, 1 H), 5.21 (d, J = 4.6 Hz, 1 H), 4.74 - 4.64 (m, 2H), 4.56 (d, J = 2.3 Hz, 1 H), 2.64 (dd, J = 13.7, 6.4 Hz, 1 H), 2.48 - 2.42 (m, 1 H), 1.65 (s, 3H), 1.06 (s, 9H). m / z 302.3 (M+H)+(ES+).

[0895] Description 114

[0896] (S)-1-(2,4-Difluorophenyl)-3-methylbut-3-en-1-amine, HCI (D114)

[0897] To a 250 mL vial containing (R)-N-((S)-1-(2,4-difluorophenyl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (D113) (2.57 g, 95% Wt, 8.10 mmol) in 1,4-dioxane (10 mL) was added HCI (3.7M in dioxane) (10.9 mL, 40.5 mmol). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo, suspended in MTBE and then filtered. The filtered solids were dried by suction to give (S)-1-(2,4-difluorophenyl)-3-methylbut-3-en-1-amine, HCI (D114) (1.55 g, 74%) as a colourless solid.

[0898] 1H NMR (500 MHz, DMSO-ofe) 58.68 - 8.51 (m, 3H), 7.85 - 7.74 (m, 1 H), 7.36 - 7.28 (m, 1H), 7.25- 7.14 (m, 1H), 4.75-4.71 (m, 1H), 4.65-4.59 (m, 1H), 4.58 (s, 1H), 2.74 (dd,J = 13.5, 5.9 Hz, 1 H), 2.57 (dd, = 13.4, 10.0 Hz, 1 H), 1.65 (s, 3H). m / z 198.2 (M+H)+(ES+).

[0899] Description 115

[0900] (S)-N-(1 -(2,4-Difluorophenyl)-3-methylbut-3-en-1 -yl)-2-(trimethylsilyl)ethane-1 -sulfonamide (D115)

[0901] To a 100 mL RBF containing (S)-1-(2,4-difluorophenyl)-3-methylbut-3-en-1-amine, HCI (D114) (830 mg, 3.55 mmol) and DMF (20 mL)was added triethylamine (2.48 mL, 17.8CLI-C-P3879PCT

[0902] mmol) and then2-(trimethylsilyl)ethanesulfonylchloride (0.9 mL, 5 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and the product was extracted into EtOAc (3 x 50 mL). The combined organic extracts were washed with -10% w / w LiCI soln. (100 mL), passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 5-50% MTBE / ) to afford (S)-N-(1-(2,4-difluorophenyl)-3-methylbut-3-en-1-yl)-2-(trimethylsilyl)ethane-1 -sulfonamide (D115) (679 mg, 49 %) as a colourless oil that upon standing became a cream solid.

[0903] 1H NMR (500 MHz, DMSO-ofe) 57.81 (d, J= 9.0 Hz, 1H), 7.65-7.57 (m, 1H), 7.25-7.10 (m, 2H), 4.78-4.70 (m, 2H), 4.65 (dd, J= 2.3, 1.2 Hz, 1H), 2.63 (td, J= 14.1, 3.8 Hz, 1H), 2.50-2.43 (m, 1H), 2.41 -2.28 (m, 2H), 1.69 (t,J= 1.0 Hz, 3H), 0.71 (td,J= 13.9, 3.9 Hz, 1H), 0.60 (td, J= 14.0, 4.1 Hz, 1H), -0.14 (s, 9H). m / z 360.3 (M-H)' (ES‘).

[0904] Description 116

[0905] (S)-N-(1-(2,4-Difluorophenyl)-3-oxobutyl)-2-(trimethylsilyl)ethane-1-sulfonamide (D116)

[0906] To a 250 mL RBF containing (S)-N-(1-(2,4-difluorophenyl)-3-methylbut-3-en-1-yl)-2-(trimethylsilyl)ethane-l -sulfonamide (D115) (679 mg, 93% Wt, 1.75 mmol) in 1 ,4-dioxane (40 mL) and water (10 mL) was added potassium osmate(VI) dihydrate (35.3 mg, 87.3 pmol) and sodium periodate (1.12 g, 5.24 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched by addition of sat. aq.

[0907] Sodium sulfite solution (100 mL) and the product was extracted into EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give (S)-N-(1 -(2, 4-difluorophenyl)-3-oxobutyl)-2-(trimethylsilyl)ethane-1 -sulfonamide (D116) (689 mg, 92 %) as a colourless oil.

[0908] 1H NMR (500 MHz, DMSO-cfe) 57.76 (d, J= 8.2 Hz, 1H), 7.56 (td, J= 8.6, 6.5 Hz, 1H), 7.24 -7.17 (m, 1H), 7.16-7.09 (m, 1H), 5.01 -4.94 (m, 1H), 3.01 (dd, J= 17.1, 8.6 Hz, 1H), 2.83 (dd, J= 17.1, 5.8 Hz, 1H), 2.72 (td, J= 13.9, 4.1 Hz, 1H), 2.09 (s, 3H), 0.76-0.56 (m, 2H), -0.08 (s, 9H). 1 Proton obscured by residual solvent peak, m / z 362.3 (M-H)-(ES‘).

[0909] Description 117

[0910] N-((1 S)-1 -(2,4-Difluorophenyl)-3-hydroxybutyl)-2-(trimethylsilyl)ethane-1 -sulfonamide (D117)

[0911] To a 250 mL RBF containing (S)-N-(1-(2,4-difluorophenyl)-3-oxobutyl)-2-(trimethylsilyl)ethane-l -sulfonamide (D116) (650 mg, 90% Wt, 1.61 mmol) and MeOH (20 mL)was added NaBH4 (91.3 mg, 2.41 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (25 mL) and NH4CI (25CLI-C-P3879PCT

[0912] mL), the product was extracted with EtOAc (3 x 50 mL), the combined organic extracts were passed through a phase separator and concentrated in vacuo to afford N-((1S)-1-(2,4-difluorophenyl)-3-hydroxybutyl)-2-(trimethylsilyl)ethane-1 -sulfonamide (D117) (635 mg, 100%) as a colourless oil used directly in the next step.

[0913] Description 118

[0914] (2S)-2-(2,4-Difluorophenyl)-4-methyl-1 -((2-(trimethylsilyl)ethyl)sulfonyl)azetidine (D118)

[0915] To a 250 mL RBF containing N-((1S)-1-(2,4-difluorophenyl)-3-hydroxybutyl)-2-(trimethylsilyl)ethane-l -sulfonamide (D117) (635 mg, 95% Wt, 1.65 mmol) in toluene (25 mL)was added (tributylphosphoranylidene)acetonitrile (478 mg, 529 pL, 1.98 mmol). The reaction mixture was stirred at 110 °C for 18 hours. The reaction mixture was concentrated in vacuo and then the crude product was purified by chromatography on silica gel (40 g cartridge, 15-75% MTBE / isohexane) to afford (2S)-2-(2,4-difluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)azetidine (D118) (226 mg, 37%) as a 1:1 mixture of diastereomers.

[0916] 1H NMR (500 MHz, DMSO-cfe) 57.75 (dtd, J = 25.5, 8.7, 6.6 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.20 - 7.10 (m, 2H), 5.54 (dd, J = 8.9, 6.7 Hz, 1 H), 5.28 (t, J = 8.4 Hz, 1 H), 4.57 - 4.46 (m, 1 H), 4.39 - 4.28 (m, 1 H), 2.94 - 2.85 (m, 1 H), 2.81 - 2.71 (m, 2H), 2.68 - 2.60 (m, 1 H), 2.30 - 2.22 (m, 1H), 1.84 (dt, J = 10.8, 8.0 Hz, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.1 Hz, 3H), 0.88 - 0.69 (m, 4H),-0.03 (s, 9H) -0.08 (s, 9H). 2 protons obscured by residual solvent peak.

[0917] Description 119

[0918] (2S)-2-(2,4-Difluorophenyl)-4-methylazetidine (D119)

[0919] To a 40 mL vial containing (2S)-2-(2,4-difluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)azetidine (D118) (100 mg, 288 pmol)and DMF (2 mL)was added tris(dimethylamino)sulphonium difluoro(trimethyl)silicate (396 mg, 1.44 mmol). The reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was loaded onto a 5 g SCX-2 cartridge, the resin was washed with MeOH (3 x CV) and the eluent was set aside. The product was eluted with 2N NH3 in MeOH (3 x CV), the combined eluent was concentrated in vacuo to give (2S)-2-(2,4-difluorophenyl)-4-methylazetidine (D119) (54 mg, 97%) as a pale-yellow oil used directly in the next step (Example 36).

[0920] D119 was also prepared as an HCI salt. To a 40 mL vial containing (2S,4R)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88d) (63 mg, 95% Wt, 0.21 mmol) in EtOAc (1 mL) was added HCI (1 M in EtOAc) (1.0 mL, 1.0 mmol). The reaction mixture was stirred for 15 minutes at RT. The reaction mixture was blown down and then suspended inCLI-C-P3879PCT

[0921] MTBE, the white precipitate was filtered and then concentrated in vacuo to give (2S,4R)-2-(2,4-difluorophenyl)-4-methylazetidine, HCI (38 mg, 79 %) as a cream solid.

[0922] 1H NMR (500 MHz, D2O) 57.60 - 7.53 (m, 1 H), 7.15 - 7.07 (m, 2H), 5.81 (t, J = 9.0 Hz, 1 H), 4.62-4.51 (m, 1H), 3.25-3.16 (m, 1H), 2.65-2.57 (m, 1H), 1.71 (d, J = 6.9 Hz, 3H).

[0923] Exchangeable protons not observed.

[0924] Description 120

[0925] l-(tert-Butyl) 2-methyl 2-(5-fluoropyridin-2-yl)azetidine-1,2-dicarboxylate (D120) To a 40 mL vial containing 1 -(tert-butyl) 2-methyl azetidine-1,2-dicarboxylate (CAS 255882-72-5) (510 mg, 2.37 mmol), 2,5-difluoropyridine (225 pL, 2.49 mmol) and toluene (7.5 mL) was added KHMDS (1 M in THF) (2.84 mL, 2.84 mmol) at 0 °C. The reaction mixture was stirred for 20 minutes at the same temperature, then for 1 hour at RT. The reaction mixture was quenched by addition of sat. aq. NH4CI (50 mL) and the product was extracted into EtOAc (3x 15 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 15-75% EtOAc / isohexane) to afford 1 -(tert-butyl) 2-methyl 2-(5-fluoropyridin-2-yl)azetidine-1,2-dicarboxylate (D120) (308 mg, 40%) as an orange oil. m / z 333.3 (M+Na)+(ES+).

[0926] Description 121

[0927] tert-Butyl 2-(5-fluoropyridin-2-yl)azetidine-1 -carboxylate (D121)

[0928] To a 100 mL RBF containing 1 -(tert-butyl) 2-methyl 2-(5-fluoropyridin-2-yl)azetidine-1,2-dicarboxylate (D120) (254 mg, 818 pmol) in EtOH (4 mL) and water (1 mL) was added LiOH (98.0 mg, 4.09 mmol). The reaction mixture was stirred at room temperature for 30 mins. To the solution was added NMP (1 mL) and AcOH (3 mL), the solution was heated to 120 °C for 1 hour. The reaction mixture was cooled to RT and then quenched by addition of sat. aq. NaHCOa (100 mL). The product was extracted into EtOAc (3 x 30 mL) and the combined organic extracts were washed with ~10% w / w LiCI. (100mL), passed through a phase separator and concentrated in vacuo to give tert-butyl 2-(5-fluoropyridin-2-yl)azetidine-1-carboxylate (D121) (187 mg, 84%) as a brown oil.

[0929] 1H NMR (500 MHz, 90°C, DMSO-cfe) 68.51 (d, J = 2.9 Hz, 1H), 7.67 (td, J = 8.7, 2.9 Hz, 1H), 7.48 (dd, J = 8.7, 4.5 Hz, 1 H), 5.21 (dd, J = 8.7, 5.9 Hz, 1 H), 3.99 - 3.81 (m, 2H), 2.61 - 2.52 (m, 1H), 2.26 -2.19 (m, 1H), 1.28 (s, 9H). m / z 197.2 (M-tBu+2H)+(ES+).

[0930] Description 122

[0931] (R)-N-((R)-2,2-Difluoro-3-oxo-1 -(thiazol-2-yl)butyl)-2 -methyl propane-2-sulfinamide (D122)CLI-C-P3879PCT

[0932] To a stirred solution of (R)-N-((R)-2,2-difluoro-3-morpholino-3-oxo-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (D164) (0.837 g, 2.19 mmol)inTHF (20.0 mL)at-78 °C was added MeMgCI (3.29 mL, 3M in THF, 9.87 mmol) dropwise. The mixture was stirred at -78 °C for 1 hour then allowed to warm to room temperature and stirred for a further 1 hour. The reaction mixture was then slowly poured into a mixture of ice (50 ml) and sat. aq. NH4CI solution (50 ml). The mixture was extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (R)-N-((R)-2,2-difluoro-3-oxo-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D122) (0.594 g, 44 %) as a brown oil. UPLC-MS m / z 311.5 (M+H)+(ES+).

[0933] Description 123

[0934] (R)-N-((1R,3S)-2,2-Difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123a)

[0935] (R)-N-((1R,3R)-2,2-Difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123b)

[0936] To a stirred solution of (R)-N-((R)-2,2-difluoro-3-oxo-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D122) (0.594 g, 50 wt%, 957 pmol) in MeOH (12.0 mL)at0 °C was

[0937] added NaBI-k (73 mg, 1.91 mmol). The reaction mixture was stirred atO °C, then diluted with sat. aq. NH4CI (20 ml). The mixture was concentrated in vacuo and the remaining aqueous mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((1R,3S)-2,2-difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123a) (125 mg, 42 %)as a pale yellow solid1H NMR (500 MHz, DMSO-cfe) 57.86 - 7.76 (m, 2H), 6.29 (d, J = 9.5 Hz, 1H), 5.57 (d, J = 6.2 Hz, 1H), 5.31 -5.23 (m, 1H), 4.16-4.06 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 3.5 Hz, 9H). UPLC-MS m / z 313.1 (M+H)+(ES+); also (R)-N-((1R,3R)-2,2-difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123b) (107 mg, 36 %)as beige solid.1H NMR (500 MHz, DMSO-cfe) 67.88- 7.75 (m, 2H), 6.19 (d, J = 9.1 Hz, 1H), 5.52 (d, = 6.4 Hz, 1H), 5.27 (m, 1H), 3.93 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H), 1.13 (s, 9H). UPLC-MS m / z 313.1 (M+H)+(ES+).

[0938] The following commercial azetidines and isolated azetidine intermediates of the invention (D124 - D163), either as free base salts, were purchased or prepared by routes analogous to those described above, or as reported in the chemical literature (CAS number indicated).

[0939] (S)-2-(4-Fluorophenyl)azetidine (D124) (CAS 1213164-60-3)

[0940] (R)-2-(4-Fluorophenyl)azetidine (D125) (CAS 1213536-79-8)CLI-C-P3879PCT

[0941] (2S)-2-[4-(Trifluoromethoxy)phenyl]azetidine (D126) (CAS 1213220-55-3)

[0942] (S)-3-(Azetidin-2-yl)-5-fluoropyridine (D127) (CAS 1213673-25-6)

[0943] (S)-2-(2,4-Difluorophenyl)-2-methylazetidine (D128) (CAS 2165709-87-3)

[0944] (S)-3-(Azetidin-2-yl)benzonitrile (D129) (CAS 1213904-90-5)

[0945] (S)-4-(Azetidin-2-yl)benzonitrile (D130) (CAS 1212974-26-9)

[0946] Description 131

[0947] (S)-2-(2-Fluoro-4-(methylsulfonyl)phenyl)azetidine, HCI (D131)

[0948] D131 was prepared by the route of Description 6 but using 2-fluoro-4-(methylsulfonyl)benzaldehyde in place of 4-bromo-2-fluorobenzaldehyde in Description 1.

[0949] 1H NMR (500 MHz, DMSO-d6) 59.44 (s, 1H), 8.04 - 7.71 (m, 3H), 5.76 (s, 1H), 4.05 m, 1H), 3.76 (s, 1 H), 3.31 (s, 3H), 2.92 - 2.60 (m, 2H). peak at 3.31 ppm partially obscured by residual water. Exchangeable protons not observed, m / z 229.9 (M+H)+(ES+).

[0950] Description 132

[0951] (2S,3R)-2-(2,4-Difluorophenyl)-3-methylazetidine, HCI (D132)

[0952] D132 was prepared by the route of Description 24 but using ethyl propionate in place of ethyl isobutyrate in Description 21.

[0953] 1H NMR (500 MHz, D2O) 57.44 (td, J = 8.9, 6.1 Hz, 1 H), 7.15 - 7.09 (m, 2H), 5.89 (d, J = 8.8 Hz, 1 H), 4.40 (dd, J = 10.5, 8.3 Hz, 1 H), 3.75 (dd, = 10.5, 5.4 Hz, 1 H), 3.39 - 3.32 (m, 1H), 1.06 (d, J = 7 A Hz, 3H). Exchangeable protons not observed.

[0954] Description 133

[0955] (R)-3-(3,3-Difluoroazetidin-2-yl)benzonitrile, HCI (D133)

[0956] D133 was prepared by the route of Description 111 but using (R,E)-N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide (CAS 915089-12-2) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 104.

[0957] 1H NMR (500 MHz, DMSO-d6) 58.22 - 8.12 (m, 1H), 8.03 - 7.92 (m, 2H), 7.77 - 7.69 (m, 1 H), 6.26 - 5.95 (m, 1 H), 4.81 - 4.50 (m, 2H). Exchangeable protons not observed.

[0958] Description 134

[0959] 4-((2S,4R)-4-Methylazetidin-2-yl)benzonitrile, HCI (D134)

[0960] D134 was prepared by the route of Description 20 but using (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (CAS 336105-24-9) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 12.CLI-C-P3879PCT

[0961] 1H NMR (500 MHz, D2O) 57.93 - 7.87 (m, 2H), 7.68 - 7.62 (m, 2H), 5.74 (t, J = 8.8 Hz, 1H), 4.56-4.64 (m, 1H), 3.11 (ddd, J = 12.6, 9.1, 8.3 Hz, 1H), 2.68 (ddd, J = 12.6, 9.3, 5.5 Hz, 1H), 1.72 (d, J = 6.9 Hz, 3H). Exchangeable protons not observed.

[0962] Description 135

[0963] 4-((2S,4S)-4-Methylazetidin-2-yl)benzonitrile (D135)

[0964] D135 was prepared by the route of Description 19 but using (R,E)-N-(4-bromobenzylidene)- 2-methylpropane-2-sulfinamide (CAS 336105-24-9) in in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 12.

[0965] 1H NMR (500 MHz, DMSO-d6) 57.77 (d, J = 1.9 Hz, 2H), 7.61 - 7.51 (d, J = 1.9 Hz, 2H), 4.71 (t, J = 8.2 Hz, 1 H), 3.94 - 3.82 (m, 1 H), 2.65 (ddd, J = 10.2, 7.8, 7.0 Hz, 1 H), 1.68 -1.52 (m, 1H), 1.13 (d, J = 6.1 Hz, 3H). Exchangeable proton not observed.

[0966] Description 136

[0967] (S)-3-(3,3-Difluoroazetidin-2-yl)benzonitrile, HCI (D136)

[0968] D136 was prepared by the route of Description 111 but using (S,E)-N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide (CAS 1428527-29-0) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 104.

[0969] 1 H NMR (500 MHz, DMSO-d6) 58.11 (s, 1 H), 7.98 (d, J = 7.7 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 6.01 (s, 1H), 4.57 (s, 2H). Exchangeable protons not observed.

[0970] Description 137

[0971] 3-((2S,4S)-4-Methylazetidin-2-yl)benzonitrile (D137)

[0972] D137 was prepared by the route of Description 19 but using (R,E)-N-(3-bromobenzylidene)- 2-methylpropane-2-sulfinamide (CAS 915089-12-2) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 12.

[0973] 1H NMR (500 MHz, DMSO-d6) 57.79 (ft, J = 1.7, 0.6 Hz, 1H), 7.71 (ddd, J = 7.8, 2.1, 1.0 Hz, 1 H), 7.67 (dt, J = 8.3, 1.5 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 1 H), 4.66 (t, = 8.1 Hz, 1 H), 3.90 -3.77 (m, 1H), 2.68-2.58 (m, 1H), 1.60 (dt, = 10.2, 8.5 Hz, 1H), 1.13 (d, = 6.1 Hz, 3H). Exchangeable proton not observed.

[0974] Description 138

[0975] 3-((2S,4R)-4-Methylazetidin-2-yl)benzonitrile, HCI (D138)

[0976] D138 was prepared by the route of Description 20 but using (R,E)-N-(3-bromobenzylidene)-2-methylpropane-2-sulfinamide (CAS 915089-12-2) in in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 12.CLI-C-P3879PCT

[0977] 1 H NMR (500 MHz, D2O) 57.92 (s, 1 H), 7.90 - 7.85 (m, 1 H), 7.84 - 7.80 (m, 1 H), 7.69 (t, J = 7.8 Hz, 1H), 5.70 (t, = 8.9 Hz, 1H), 4.61 (q, J = 7.2 Hz, 1H), 3.17- 3.08 (m, 1H), 2.72 -2.61 (m, 1H), 1.72 (dd, J = 6.9, 1.2 Hz, 3H). Exchangeable protons not observed.

[0978] (S)-2-(2,4-Difluorophenyl)azetidine (CAS 1213883-59-0), HCI (D139)

[0979] (S)-2-(2-Fluorophenyl)azetidine (CAS 1213454-75-1), HCI (D140)

[0980] (S)-2-(3-Fluorophenyl)azetidine (D141) (CAS 1213976-50-1)

[0981] Description 142

[0982] (2S,4S)-2-(2,4-Difluorophenyl)-4-methylazetidine, HCI (D142)

[0983] To a 40 mL vial containing (2S,4S)-1-((R)-tert-butylsulfinyl)-2-(2,4-difluorophenyl)-4-methylazetidine (D88c) (86 mg, 95% Wt, 0.28 mmol) in EtOAc (1 mL) was added HCI (1M in EtOAc) (1.4 mL, 1.4 mmol). The reaction mixture was stirred for 15 minutes at RT. The reaction mixture was blown down and then suspended in MTBE, and the resultant white precipitate was filtered, washed with MTBE and then dried by suction to give (2S,4S)-2-(2,4-difluorophenyl)-4-methylazetidine, HCI (D142) (49 mg, 75 %) as a white solid.

[0984] 1H NMR (500 MHz, D2O) 57.64 - 7.39 (m, 1 H), 7.18 - 6.93 (m, 2H), 5.65 (t, J = 9.3 Hz, 1 H), 4.73 - 4.64 (m, 1 H), 3.06 - 2.92 (m, 1 H), 2.90 - 2.77 (m, 1 H), 1.55 (d, J = 6.7 Hz, 3H).

[0985] Exchangeable protons not observed.

[0986] Description 143

[0987] 3-Fluoro-4-((2S,4S)-4-methylazetidin-2-yl)pyridine, HCI (D143)

[0988] D143 was prepared by the acid hydrolysis used in Description 6 but in place of 4-((S)-1-((R)-tert-butylsulfinyl)-azetidin-2-yl)-3-fluorobenzonitrile (D5), using a sulfinyl azetidine prepared by the route of Description 16 in which 3-fluoroisonicotinaldehyde is utilised place of 4-bromo-2-fluorobenzaldehyde to prepare the starting Ellman imine (as in Description 1).

[0989] This isomer was used without further characterisation.

[0990] Description 144

[0991] 3-Fluoro-4-((2S,4R)-4-methylazetidin-2-yl)pyridine HCI (D144)

[0992] D144 was prepared by the route of Description 143 as an isomer separated at the penultimate step by chromatography.

[0993] 1H NMR (500 MHz, D2O) 58.83 - 8.72 (m, 1 H), 8.70 - 8.63 (m, 1 H), 7.97 - 7.82 (m, 1 H), 6.03 (q, J = 9.6 Hz, 1 H), 4.68 - 4.56 (m, 1 H), 3.30 - 3.15 (m, 1 H), 2.80 - 2.69 (m, 1 H), 1.75 (dd, J = 6.9, 1.5 Hz, 3H). Exchangeable protons not observed.

[0994] Description 145CLI-C-P3879PCT

[0995] 4-((2S,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile, HCI (D145)

[0996] To a 40 mL vial containing 4-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D202) (310 mg, 95% Wt, 891 pmol) in EtOAc (2 mL)was added HCI (1M in EtOAc) (2.67 mL, 2.67 mmol). The reaction mixture was stirred at RT for 16 hours. The material was concentrated in vacuo and slurried in TBME (5mL) over 2 hours. The white suspension was filtered under suction to afford 4-((2S,4R)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile, HCI (D145) (220 mg, 85 %)as a white solid.

[0997] 1H NMR (500 MHz, DMSO-ofe) 68.02 (d, J = 10.1 Hz, 1H), 7.88 (dd, J = 3.6, 1.3 Hz, 2H), 6.11 (s, 1 H), 4.91 (s, 1 H), 1.41 (d, J = 6.8 Hz, 3H). Exchangeable protons not observed, m / z 227.2 (M+H)+(ES+).

[0998] Description 146

[0999] 4-((2S,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile, HCI (D146) D146 was prepared by the route of Description 145 as an isomer separated at the penultimate step by chromatography as detailed in Description 203, utilising 4-((2S,4S)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D203).

[1000] 1H NMR (500 MHz, DMSO-d6) 58.06 (dd, J = 10.2, 1.6 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1 H), 6.37 (t, = 11.2 Hz, 1 H), 4.96 (dt, J = 13.9, 7.0 Hz, 1 H), 1.61 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed, m / z 227.2 (M+H)+(ES+).

[1001] Description 147

[1002] 2-((2S,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D30 alternative route)

[1003] D30 was prepared from 2-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D39) in place of 4-((S)-1-((R)-tert-butylsulfinyl)azetidin-2-yl)-3-fluorobenzonitrile (D5) by the method of Description 6.

[1004] 1H NMR (500 MHz, D2O) 58.60 (dt, J = 2.9, 0.8 Hz, 1H), 7.77 (td, J = 8.5, 2.8 Hz, 1H), 7.64 (dd, J = 8.7, 4.3 Hz, 1H), 6.13 (t, J = 9.9 Hz, 1H), 5.24-5.07 (m, 1H), 1.66 (dd, J = 7.1, 1.0 Hz, 3H). Exchangeable protons not observed, m / z 203.5 (M+H)+(ES+).

[1005] Description 148

[1006] 2-((2R,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31a alternative route)

[1007] D31a was prepared from 2-((2R,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D40) in place of 4-((S)-1-((R)-tert-butylsulfinyl)azetidin-2-yl)-3-fluorobenzonitrile (D5) by the method of Description 6.CLI-C-P3879PCT

[1008] 1H NMR (500 MHz, DMSO-d6) 68.78 (d, J = 2.9 Hz, 1H), 7.97 (td, J = 8.6, 2.9 Hz, 1H), 7.82 (dd, J = 8.7, 4.4 Hz, 1H), 6.19 (dd, J = 12.1, 7.0 Hz, 1H), 5.06 (td, J= 11.2, 6.3 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H). Exchangeable protons not observed, m / z 203.1 (M+H)+(ES+).

[1009] Description 149

[1010] 2-((2S,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-5-fluoropyridine, HCI (D31 alternative route)

[1011] D31 was prepared from 2-((2S,4S)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-5-fluoropyridine (D41) by the method of Description 6.

[1012] 1H NMR (500 MHz, DMSO-d6) 68.78 (d, J = 2.9 Hz, 1H), 7.97 (td, J = 8.7, 2.9 Hz, 1H), 7.80 (dd, J = 8.7, 4.4 Hz, 1H), 6.17 (dd, J = 12.1, 6.9 Hz, 1H), 5.04 (q, J = 10.9 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed, m / z 203.2 (M+H)+(ES+).

[1013] 4-(2S)-2-Azetidinyl-3-fluoropyridine (CAS 1213845-96-5), (D150)

[1014] 4-(2R)-2-Azetidinyl-3-fluoropyridine (CAS 1213382-31-0), (D151)

[1015] Descriptions 152 and 153

[1016] 4-((2R,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile, HCI (D152)

[1017] 4-((2R,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile, HCI (D153) These were prepared by the route of Description 145 but using (S)-2-methylpropane-2-sulfinamide in place of (R)-2-methylpropane-2-sulfinamide in Description 100. The isomers were separated by chromatography.

[1018] D152:1H NMR (500 MHz, DMSO-d6) 58.02 (d, J = 10.1 Hz, 1H), 7.88 (dd, J = 3.6, 1.3 Hz, 2H), 6.11 (s, 1H), 4.91 (s, 1H), 1.41 (d, J = 6.8 Hz, 3H). Exchangeable protons not observed, m / z 227.2 (M+H)+(ES+).

[1019] D153:1H NMR (500 MHz, DMSO-cfe) 58.06 (dd, J = 10.2, 1.6 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1 H), 7.90 (dd, J = 8.0, 1.5 Hz, 1 H), 6.37 (t, J = 11.2 Hz, 1 H), 4.96 (dt, J = 13.9, 7.0 Hz, 1 H), 1.61 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed, m / z 227.2 (M+H)+(ES+).

[1020] Description 154

[1021] 2-(4,4-Dimethylazetidin-2-yl)-5-fluoropyridine, HCI (D154)

[1022] To a 40 mL vial containing tert-butyl 4-(5-fluoropyridin-2-yl)-2,2-dimethylazetidine-1-carboxylate (D179) (180 mg, 90% Wt, 578 pmol) in EtOAc (2 mL) was added HCI (1.73 mL, 1M in EtOAc, 1.73 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue slurried in MTBE (5mL) over 2 hours. The white suspension was filtered under suction to afford 2-(4,4-dimethylazetidin-2-yl)-5-fluoropyridine HCI (D154) (0.135 g, 65 %) as a yellow solid.CLI-C-P3879PCT

[1023] UPLC-MS m / z 181.5 (M+H)+(ES+).

[1024] Descriptions 155 and 156

[1025] 6-((2S,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluoro-2-methylpyridine, HCI (D155) 6-((2S,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-3-fluoro-2-methylpyridine, HCI (D156) These were prepared by the route of Description 30 but using (R,E)-N-((5-fluoro-6-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (CAS 2413783-69-2) in place of (R,E)-N-((5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide in Description 25. The isomers were separated by chromatography.

[1026] D155:1H NMR (500 MHz, DMSO-cfeJ 67.91 - 7.78 (m, 1 H), 7.60 (dd, J = 8.4, 3.7 Hz, 1 H), 6.10 (t, J = 10.2 Hz, 1H), 5.12 -4.87 (m, 1H), 2.57 (s, 3H), 1.53 (d, J = 7.0 Hz, 3H).

[1027] Exchangeable protons not observed. UPLC-MS m / z 217.3 (M+H)+(ES+).

[1028] D156:1H NMR (500 MHz, DMSO-cfe) 57.89 - 7.81 (m, 1 H), 7.60 (td, J = 8.3, 3.7 Hz, 1 H), 6.11 (dd, J = 12.3, 6.7 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H), 2.55 (d, J = 3.0 Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 217.2 (M+H)+(ES+)

[1029] Descriptions 157 and 158

[1030] (2S,4R)-2-(4-Chloro-2-fluorophenyl)-3,3-difluoro-4-methylazetidine, HCI (D 157) (25.45)-2-(4-Chloro-2-fluorophenyl)-3,3-difluoro-4-methylazetidine, HCI (D158) These were prepared by the route of Description 145 but using (R,E)-N-(4-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (PubChem CID 67122839) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in Description 196 and omitting the Brto CN transformation step in Description 202. The isomers were separated by chromatography.

[1031] D157:1H NMR (400 MHz, DMSO-cfe) 57.73 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 10.3, 2.1 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 6.19-5.91 (m, 1H), 5.14 -4.75 (m, 1H), 1.45 (d, J = 6.9 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 236.2 (M+H)+(ES+).

[1032] D158:1H NMR (500 MHz, DMSO-cfe) 57.77 (t, J = 8.2 Hz, 1H), 7.66 (dd, J = 10.3, 2.1 Hz, 1 H), 7.50 (dd, J = 8.4, 2.1 Hz, 1 H), 6.30 - 6.12 (m, 1 H), 5.03 - 4.87 (m, 1 H), 1.59 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 236.4 (M+H)+(ES+).

[1033] Description 159 and 160

[1034] (25.45)-2-(2,4-Difluorophenyl)-3,3-difluoro-4-methylazetidine, HCI (D 159)

[1035] (2S,4R)-2-(2,4-Difluorophenyl)-3,3-difluoro-4-methylazetidine, HCI (D160)

[1036] These were prepared by the route of Description 145 but using (R,E)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide (PubChem CID: 68309449) in place of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) in DescriptionCLI-C-P3879PCT

[1037] 196 and omitting the Brto CN transformation step in Description 202. The isomers were separated by chromatography.

[1038] D159:1H NMR (400 MHz, DMSO-cfe) 610.40 (s, 2H), 7.84 (td, J = 8.7, 6.2 Hz, 1H), 7.48 (ddd, J = 11.5, 9.2, 2.6 Hz, 1 H), 7.33-7.25 (m, 1 H), 6.20 (t, J = 11.3 Hz, 1 H), 5.07 - 4.90 (m, 1 H), 1.60 (d, J = 7.1 Hz, 3H). UPLC m / z 220.5 (M+H)+(ES+).

[1039] D160:1H NMR (400 MHz, DMSO-cfe) 67.80 (td, J = 8.6, 6.2 Hz, 1 H), 7.46 (ddd, J = 11.4, 9.2, 2.6 Hz, 1 H), 7.29 (tt, J = 8.9, 1.8 Hz, 1 H), 6.17 - 5.98 (m, 1 H), 5.08 - 4.88 (m, 1 H), 1.48 (d, J = 6.9 Hz, 3H). Exchangeable protons not observed. UPLC m / z 220.3 (M+H)+(ES+).

[1040] Description 161

[1041] 2-((2R,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-3,5-difluoropyridine, HCI (D161) This was prepared by the route of Description 148 using 3,5-difluoropicolinaldehyde in place of 5-fluoropicolinaldehyde in Description 32.

[1042] 1H NMR (500 MHz, DMSO-cfe) 58.74 (d, J = 2.3 Hz, 1 H), 8.27 - 8.21 (m, 1 H), 6.31 - 6.17 (m, 1 H), 4.94 - 4.80 (m, 1 H), 1.54 (d, J = 7.0 Hz, 3H). Exchangeable protons not observed.

[1043] Description 162

[1044] 2-((2R,4S)-3,3-Difluoro-4-methylazetidin-2-yl)-3,5-difluoropyridine, HCI (D162) This was prepared by the route of Description 147 using 3,5-difluoropicolinaldehyde in place of 5-fluoropicolinaldehyde in Description 32, and using (S)-2-methylpropane-2-sulfinamide in place of (R)-2-methylpropane-2-sulfinamide in Description 33.

[1045] 1H NMR (400 MHz, DMSO-cfe) 510.19 (s, 2H), 8.72 (d, J = 2.3 Hz, 1H), 8.24 (ddd, J = 9.9, 8.8, 2.3 Hz, 1H), 6.37-6.22 (m, 1H), 5.19-5.00 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H). UPLC-MS m / z 221.1 (M+H)+(ES+).

[1046] Description 163

[1047] 2-((2S,4R)-3,3-Difluoro-4-methylazetidin-2-yl)-3,5-difluoropyridine, HCI (D163) This was prepared by the route of Description 147 using 3,5-difluoropicolinaldehyde in place of 5-fluoropicolinaldehyde in Description 32.

[1048] UPLC-MS m / z 221.1 (M+H)+(ES+) .

[1049] Further general experimental descriptions

[1050] Description 164

[1051] (R)-N-((R)-2,2-Difluoro-3-morpholino-3-oxo-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (D164)CLI-C-P3879PCT

[1052] To a stirred solution of 2,2-difluoro-1-morpholino-2-(trimethylsilyl)ethan-1-one (CAS 1630100-64-9) (2.304 g, 9.708 mmol) and (R,E)-2-methyl-N-(thiazol-2-ylmethylene)propane-2-sulfinamide (CAS 479480-50-7) (2.000 g, 9.246 mmol) in THF (50.0 mL) at room temperature was added TBAT (499.1 mg, 924.6 pmol). After 2 hours, further TBAT (499.1 mg, 924.6 pmol) was added and stirring was continued at RT for 72 hours. The reaction mixture was then diluted with sat. aq. NH4CI (50 ml). The layers were separated, and the aqueous phase was extracted into EtOAc (2 x 50 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((R)-2,2-difluoro-3-morpholino-3-oxo-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (D164) (0.837 g, 19 %) as a pale-yellow gum.

[1053] UPLC-MS m / z 382.5 (M+H)+(ES+).

[1054] Description 165

[1055] tert-Butyl (2-chloro-5-fluoropyridin-3-yl)carbamate (D165)

[1056] 2-Chloro-5-fluoronicotinic acid (CAS 38186-88-8) (4.00 g, 22.8 mmol) and triethylamine (2.54 g, 3.49 mL, 25.1 mmol) were dissolved in a solvent mixture consisting of PhMe (20.0 mL) and terf-BuOH (20.0 mL). The reaction was heated to 90 °C, diphenyl phosphorazidate (6.90 g, 5.40 mL, 25.1 mmol) was added dropwise to the solution and the mixture was stirred for 3 hours at 90 °C. The reaction was cooled to room temperature, EtOAc (75 mL) and NaHCOa (satd. aq. 75 mL) were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with EtOAc (2 x 75 mL), the organic phases were combined, and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-50% EtOAc / isohexane) to afford tert-butyl (2-chloro-5-fluoropyridin-3-yl)carbamate (D165) (2.03 g, 35 %) as a clear colourless oil.

[1057] 1H NMR (500 MHz, DMSO-cfe) 59.05 (s, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 10.1, 2.8 Hz, 1H), 1.48 (s, 9H). UPLC-MS m / z 247.02 (M+H)+(ES+).

[1058] Description 166

[1059] tert-Butyl (5-fluoro-2-methylpyridin-3-yl)carbamate (D166)

[1060] tert-Butyl (2-chloro-5-fluoropyridin-3-yl)carbamate (D165) (2.90 g, 97% Wt, 11.4 mmol), methylboronic acid (1.37 g, 22.8 mmol), potassium phosphate, tribasic (9.68 g, 45.6 mmol) and Pd(dppf)Cl2.DCM (465 mg, 570 pmol) were suspended in a solvent mixture consisting of toluene (30.0 mL) and water (3.00 mL). The mixture was purged with nitrogen for 10 minutes and then heated to 90 °C for 1.5 hours. After cooling to room temperature, water was added (50 mL) and the mixture was extracted with EtOAc (3 x 50 mL), the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. TheCLI-C-P3879PCT

[1061] crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to afford fert-butyl (5-fluoro-2-methylpyridin-3-yl)carbamate (D166) (1.88 g, 70 %) as an orange oil.

[1062] 1H NMR (500 MHz, DMSO-cfe) 58.93 (s, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.77 (dd, J = 10.8, 2.8 Hz, 1H), 2.43 -2.36 (m, 3H), 1.48 (s, 9H). UPLC m / z 227.2 (M+H)+(ES+).

[1063] Description 167

[1064] tert-Butyl (6-chloro-5-fluoro-2-methylpyridin-3-yl)carbamate (D167)

[1065] To a stirred solution of tert-butyl (5-fluoro-2-methylpyridin-3-yl)carbamate (D166) (1.88 g, 98% Wt, 8.14 mmol) in MeCN (20 mL) was added NCS (1.14 g, 8.55 mmol)at0 °Cand the reaction mixture was stirred for 5 minutes. Then, the ice bath was removed and the mixture was stirred at 65 °C for 18 hours. Upon cooling, The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to afford tert-butyl (6-chloro-5-fluoro-2-methylpyridin-3-yl)carbamate (D167) (1.30 g, 60 %) as a pale orange solid.

[1066] 1H NMR (500 MHz, DMSO-cfe) 59.08 (s, 1H), 8.00 (d, J = 10.3 Hz, 1H), 2.39- 2.37 (m, 3H), 1.48 (s, 9H). UPLC-MS m / z 260.9 (M+H)+(ES+).

[1067] Description 168

[1068] tert-Butyl (6-chloro-5-fluoro-4-iodo-2-methylpyridin-3-yl)carbamate (D168)

[1069] To a stirred solution of tert-butyl (6-chloro-5-fluoro-2-methylpyridin-3-yl)carbamate (D167) (0.40 g, 98% Wt, 1.5 mmol) in THF (6.00 mL) was added TMEDA (0.35 g, 0.45 mL, 3.0 mmol). The reaction was cooled to -78 °C and n-BuLi (0.19 g, 1.9 mL, 1.60 molar, 3.0 mmol) was added. The reaction was stirred for 30 minutes, maintaining the temperature. Then, iodine (0.76 g, mmol, dissolved in THF (3.50 mL)) was added to the mixture and the solution was stirred for 1.0 hour at -78 °C. The reaction was quenched by adding sat. aq. NH4CI (30 mL) and the mixture was extracted into EtOAc (3 x 40 mL). The combined organic layers were washed with sodium thiosulfate solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc / heptane) to afford tert-butyl (6-chloro-5-fluoro-4-iodo-2-methylpyridin-3-yl)carbamate (D168) (0.44 g, 75 %)as a white solid.

[1070] 1H NMR (500 MHz, DMSO-cfe) 59.16 (s, 1H), 2.39 (s, 3H), 1.53 - 1.25 (m, 9H). UPLC-MS m / z 387.2 (M+H)+(ES+).

[1071] Description 169

[1072] 6-Chloro-5-fluoro-4-iodo-2-methylpyridin-3-amine (D169)CLI-C-P3879PCT

[1073] tert-Butyl (6-chloro-5-fluoro-4-iodo-2-methylpyridin-3-yl)carbamate (D168) (770 mg, 1.99 mmol) was dissolved in DCM (4.00 mL), TFA (1.48 g, 1.00 mL, 13.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with sodium bicarbonate solution (20 mL). The organic phase was separated, and the aqueous phase was extracted into EtOAc (2 x 20 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford 6-chloro-5-fluoro-4-iodo-2-methylpyridin-3-amine (D169) (620 mg, 100 %)as a beige solid.

[1074] 1H NMR (500 MHz, DMSO-ofe) 55.61 (s, 2H), 2.34 - 2.30 (m, 3H). UPLC-MS m / z 287.1 (M+H)+(ES+).

[1075] Description 170

[1076] 3-Amino-6-chloro-5-fluoro-2-methylisonicotinonitrile (D170)

[1077] To a stirred degassed solution of 6-chloro-5-fluoro-4-iodo-2-methylpyridin-3-amine (D169) (610 mg, 2.13 mmol), KOAc (104 mg, 1.06 mmol), (bis(2-diphenylphosphinophenyl)ether [DPEphos, CAS 166330-10-5] (115 mg, 213 pmol) and potassium hexacyanoferrate(ll) trihydrate (153 mg, 362 pmol) in 1,4-dioxane (20.0 mL) and water (20.0 mL) was added [Pd(cinnamyl)CI]2 (55.2 mg, 0.05 eq., 106 pmol). The reaction was heated to 85 °C and stirred for 18 hours. Water (30 ml) was then added to the cooled reaction mixture and it was extracted into EtOAc (3 x 40 ml). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to afford 3-amino-6-chloro-5-fluoro-2-methylisonicotinonitrile (D170) (0.242 g, 59 %) as a yellow solid.

[1078] 1H NMR (500 MHz, DMSO-cfe) 56.77 (s, 2H), 2.31 - 2.27 (m, 3H). UPLC-MS m / z 186.4 (M+H)+(ES+).

[1079] Description 171

[1080] N-(6-Chloro-4-cyano-5-fluoro-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (D171) Trimethylsilyl trifluoromethanesulfonate (240 mg, 195 pL, 1.08 mmol) was added to a solution of 3-amino-6-chloro-5-fluoro-2-methylisonicotinonitrile (D170) (100 mg, 539 pmol) and DIPEA (188 pL, 1.08 mmol) in DCM (10.0 mL)at room temperature and stirred for 15 minutes. 3,3-Dimethylbutanoyl chloride (112 pL, 808 pmol) was added and the reaction was stirred for 18 hours. The reaction was quenched with water (10 mL) and extracted into DCM (3x 10 mL). The combined organic layers were washed with sat. NH4Claq(2 x 10 mL) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to afford N-(6-chloro-4-cyano-5-fluoro-2-CLI-C-P3879PCT

[1081] methylpyridin-3-yl)-3,3-dimethylbutanamide (D171) (104 mg, 68.0 %)as

[1082] a sticky colourless oil that solidified on standing.

[1083] 1H NMR (500 MHz, CDCI3) 67.07 (s, 1H), 2.52-2.46 (m, 3H), 2.36 (s, 2H), 1.16 (s, 9H). UPLC-MS m / z 284.5 (M+H)+(ES+).

[1084] Description 172

[1085] 2-((4-Methoxybenzyl)amino)-2-methylpropan-1-ol (D172)

[1086] To a stirred solution of4-methoxybenzaldehyde (7.64 g, 56.1 mmol) in DCM (50.0 mL) containing 4 sieves (5.00 g) under a nitrogen atmosphere at 20 °C was added 2-amino-2-methylpropan-1-ol (5.00 g, 56.1 mmol) dropwise. The reaction mixture was stirred for 18 hours. The mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was dissolved in methanol (20 mL) and NaBH4 (2.55 g, 67.3 mmol) was added. The mixture was stirred at room temperature for 1 hour, then quenched with sat aq. NH4CI (10 mL) and concentrated in vacuo. The residue was treated with 1M NaOHaq(20 mL) and extracted into EtOAc(150 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 2-((4-methoxybenzyl)amino)-2-methylpropan-1-ol (D172) (11.0 g, 89 %) as a colourless oil.

[1087] 1H NMR (500 MHz, DMSO-cfe) 57.26 - 7.16 (m, 3H), 6.87 - 6.78 (m, 2H), 3.72 (s, 3H), 3.54 (s, 2H), 3.22 (d, J= 3.7 Hz, 2H), 0.98 (s, 6H), 1 exchangeable proton unobserved.

[1088] Description 173

[1089] 2-((1-Hydroxy-2-methylpropan-2-yl)(4-methoxybenzyl)amino)acetonitrile (D173) To a stirred solution of 2-((4-methoxybenzyl)amino)-2-methylpropan-1-ol (D172) (6.00 g, 95% Wt, 27.2 mmol) in dry MeCN (50.0 mL) under a nitrogen atmosphere at 100 °C was added 2-bromoacetonitrile (4.02 mL, 59.9 mmol) followed by K2CO3 (5.65 g, 40.9 mmol). The reaction mixture was heated at 100 °C for 18 hours. The mixture was then transferred to a sealed microwave tube and heated at 100 °C overnight. The mixture was concentrated in vacuo and re-dissolved in EtOAc (200mL). The solution was washed with water (100mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / isohexane) to afford 2-((1-hydroxy-2-methylpropan-2-yl)(4-methoxybenzyl)amino)acetonitrile (D173) (5.40 g, 69 %)as a yellow oil.

[1090] 1H NMR (500 MHz, DMSO-cfe) 67.29 - 7.10 (m, 2H), 6.96 - 6.82 (m, 2H), 4.72 (t, J= 5.3 Hz, 1H), 3.73 (d, J= 6.4 Hz, 5H), 3.49 (s, 2H), 3.40 (d, J= 5.3 Hz, 2H), 1.13 (s, 6H).

[1091] Description 174

[1092] 1-(4-Methoxybenzyl)-4,4-dimethylazetidine-2-carbonitrile (D174)CLI-C-P3879PCT

[1093] To a stirred solution of2-((1-hydroxy-2-methylpropan-2-yl)(4-methoxybenzyl)amino)-acetonitrile (D173) (5.15 g, 87% Wt, 18.0 mmol) in dry THF (50.0 ml_) under a nitrogen atmosphere at -20 °C was added diethyl chlorophosphate (2.74 mL, 18.9 mmol) followed by KHMDS (7.56 g, 37.9 mL, 1 M in THF, 37.9 mmol). The reaction mixture was stirred at -20 °C for 1 hour. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSC>4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc / isohexane) to afford 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carbonitrile (D174) (3.14 g, 59 %) as a light-yellow oil.1H NMR (500 MHz, DMSO-cfe) 67.31 - 7.20 (m, 2H), 6.93-6.78 (m, 2H), 4.12 -4.05 (m, 1H), 3.73 (s, 3H), 3.61 (d, J= 13.0 Hz, 1H), 3.49 (d, J = 13.0 Hz, 1 H), 2.20 (dd, J = 10.5, 8.2 Hz, 1 H), 2.10 (dd, J = 10.4, 6.9 Hz, 1 H), 1.21 -1.16 (m, 6H). UPLC-MS m / z 231.2 (M+H)+(ES+).

[1094] Description 175

[1095] 1-(4-Methoxybenzyl)-4,4-dimethylazetidine-2-carboxylic acid (D175)

[1096] To a stirred solution of 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carbonitrile (D174) (3.14 g, 78% Wt, 10.6 mmol) in EtOH (15mL) was added NaOH (0.94 g, 23.4 mmol) in water (6 mL). The mixture was sealed in a microwave tube and heated at 80 °C overnight. The pH was then adjusted to 7 with 1M aq. HCI. The mixture was concentrated in vacuo, redissolved in DCM (100 mL) and extracted into water (100 mL). The aqueous layer was concentrated in vacuo and the resulting residue slurried in MeCN (100 mL) for 15 minutes. The mixture was filtered under suction and the filtrate concentrated in vacuo. This was repeated 3 times to give 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carboxylic acid (D175) (2.02 g, 61 %)as a brown solid.

[1097] 1H NMR (500 MHz, DMSO-cfe) 57.36 - 7.25 (m, 2H), 6.89 - 6.82 (m, 2H), 3.86 - 3.80 (m, 3H), 3.73 (s, 3H), 2.13 (dd, J= 10.6, 9.1 Hz, 1H), 1.97 - 1.90 (m, 2H), 1.34 (s, 3H), 1.14 (s, 3H). UPLC-MS m / z 250.2 (M+H)+(ES+).

[1098] Description 176

[1099] Methyl 1 -(4-methoxybenzyl)-4,4-dimethylazetidine-2-carboxylate (D176)

[1100] To a stirred solution of chlorotrimethylsilane (4.58 mL, 36.1 mmol) in MeOH (20.0 mL)was added 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carboxylic acid (D175) (2.00 g, 90% Wt, 7.22 mmol). The mixture was stirred at RT overnight, then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) to afford methyl 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carboxylate (D176) (2.01 g, 100 %)as a brown oil.

[1101] 1H NMR (500 MHz, DMSO-cfe) 57.60 - 7.49 (m, 2H), 6.98 - 6.85 (m, 2H), 5.32 (d, J= 8.6CLI-C-P3879PCT

[1102] Hz, 1H), 4.28 (d, J= 5.5 Hz, 2H), 3.76 (s, 3H), 3.61 (s, 3H), 2.48-2.36 (m, 2H), 1.66 (s, 3H), 1.42 (s, 3H). UPLC m / z 264.2 (M+H)+(ES+).

[1103] Description 177

[1104] 1-(tert-Butyl) 2-methyl 4,4-dimethylazetidine-1,2-dicarboxylate (D177)

[1105] To a 40 mL vial containing methyl 1-(4-methoxybenzyl)-4,4-dimethylazetidine-2-carboxylate (D176) (1.72 g, 95% Wt, 6.20 mmol), di-tert-butyl dicarbonate (1.35 g, 1.43 mL, 6.20 mmol) and EtOH (20.0 mL), was added 10% Pd / C (660 mg, 10% Wt, 620 pmol)at 0 °C. The reaction mixture was hydrogenated at a pressure of 2.5 bar for 16 hours. The mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% TBME / isohexane) to afford 1 -(tert-butyl) 2-methyl 4,4-dimethylazetidine-1,2-dicarboxylate (D177) (1.09 g, 58 %,) as a colourless oil.

[1106] 1H NMR (500 MHz, CDCI3) 54.51 (dd, J = 9.3, 5.9 Hz, 1 H), 3.74 (s, 3H), 2.23 (dd, J= 11.1, 9.3 Hz, 1H), 1.99 (dd, J= 11.1, 5.9 Hz, 1H), 1.56- 1.31 (m, 15H). UPLC m / z 188.5 (M+H-'Bu)+(ES+).

[1107] Description 178

[1108] l-(tert-Butyl) 2-methyl 2-(5-fluoropyridin-2-yl)-4,4-dimethylazetidine-1,2-dicarboxylate (D178)

[1109] To a 40 mL vial containing 1 -(tert-butyl) 2-methyl 4,4-dimethylazetidine-1,2-dicarboxylate (D177) (1.07 g, 80% Wt, 3.52 mmol), 2,5-difluoropyridine (334 pL, 3.69 mmol) and toluene (10.0 mL) was added KHMDS (3.87 mL, 1 M in THF, 3.87 mmol) at 0 °C. The reaction mixture was stirred for 20 minutes, then allowed to warm to room temperature and stirred for a further 1 hour. The reaction mixture was then diluted with sat. NH4CI (2 mL) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% TBME / isohexane) to afford 1 -(tert-butyl) 2-methyl 2-(5-fluoropyridin-2-yl)-4,4-dimethylazetidine-1,2-dicarboxylate (D178) (0.40 g, 27 %) as a yellow oil. UPLC-MS m / z 283.2 (M+H -'Bu)+(ES+)

[1110] Description 179

[1111] tert-Butyl 4-(5-fluoropyridin-2-yl)-2,2-dimethylazetidine-1 -carboxylate (D179)

[1112] To a 100 mL RBF containing 1 -(tert-butyl) 2-methyl 2-(5-fluoropyridin-2-yl)-4,4-dimethylazetidine-1,2-dicarboxylate (D178) (400 mg, 80% Wt, 946 pmol) in EtOH (4 mL) and water (1 mL) was added LiOH (113 mg, 4.73 mmol). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added NMP (1 mL) and AcOH (3 mL), then the solution was heated to 120 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with sat. aq. NaHCO3(50 mL) and extracted into EtOAcCLI-C-P3879PCT

[1113] (3 x 50 mL). The combined organic extracts were washed with 10% w / w LiCI solution (100mL), passed through a phase separator, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% TBME / isohexane) to afford tert-butyl 4-(5-fluoropyridin-2-yl)-2,2-dimethylazetidine-1 -carboxylate (D179) (180 mg, 61 %) as a colourless oil.

[1114] 1H NMR (500 MHz, DMSO-ofe) 58.54 (dd, J = 14.4, 2.9 Hz, 1 H), 7.71 (td, J = 8.8, 2.9 Hz, 1 H), 7.45 (dd, J = 8.5, 4.4 Hz, 1 H), 5.23 - 4.99 (m, 1 H), 2.41 - 2.26 (m, 1 H), 2.04 (ddd, J = 15.5, 10.7, 6.6 Hz, 1H), 1.39 (s, 9H), 1.15 (s, 6H). UPLC-MS m / z 225.2 (M +H-fBu)+(ES+).

[1115] Description 180

[1116] (R,E)-N-((5-Cyanothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (D180) To a stirred solution of 5-formylthiophene-2-carbonitrile (2.50 g, 18.2 mmol) and (R)-2-methylpropane-2-sulfinamide (2.65 g, 21.9 mmol) in dryTHF (15.0 mL) under a nitrogen atmosphere at RT was added titanium ethoxide (7.59 mL, 36.5 mmol). The reaction mixture was heated to 60 °C and stirred for 2 hours. Upon cooling, brine (25 mL) was added. The mixture was filtered, rinsing with EtOAc (150 mL). The filtrate was washed with brine (2x25 mL), dried overNa2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford (R,E)-N-((5-cyanothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (D180) (4.10 g, 89 %)as a pale-yellow solid.

[1117] 1H NMR (500 MHz, CDCI3) 58.67 (s, 1H), 7.63 (d, J = 3.9 Hz, 1H), 7.49 (d, J = 3.9 Hz, 1H), 1.26 (s, 9H). LCMS m / z 241.2 (M+H)+(ES+).

[1118] Description 181

[1119] Ethyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyanothiophen-2-yl)-2,2-difluoropropanoate (D181)

[1120] To a stirred suspension of zinc (3.95 g, 60.5 mmol) in dryTHF (48.00 mL) under a nitrogen atmosphere at 25 °C was added chlorotrimethylsilane (82.1 mg, 756 pmol)and the mixture stirred for 10 minutes. Ethyl 2-bromo-2,2-difluoroacetate (7.27 mL, 56.7 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes at RT, then transferred via syringe to a stirred solution of (R,E)-N-((5-cyanothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (D180) (4.78 g, 95% Wt, 18.9 mmol) in dry DMF (48.00 mL) under a nitrogen atmosphere at -20 °C. The reaction mixture was warmed to 0 °C and stirred for 10 hours, then allowed to warm to 20 °C and stirred for a further 14 hours. The reaction mixture was diluted with MTBE (50 mL), 1M aq. HCI (50 mL) added, then stirred for 10 minutes. The layers were separated, and the organic layer was washed with distilled water (2 x 10 mL) and brine (20 mL). The organic phase was dried overNa2SO4, filtered and concentrated inCLI-C-P3879PCT

[1121] vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford ethyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyanothiophen-2-yl)-2,2-difluoropropanoate (D181) (4.50 g, 54 %,) as a pale-yellow gum. mixture of diastereomers (ca. 9:1 ).

[1122] 1H NMR (500 MHz, DMSO-cfe) Major isomer 57.93 (dd, J = 7.6, 3.9 Hz, 1 H), 7.54 (d, J = 3.9 Hz, 1H), 6.57 (d, J = 10.5 Hz, 1H), 5.53 (m, 1H), 4.33 -4.25 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.10 (s, 9H). UPLC-MS m / z 365.4 (M+H)+(ES+).

[1123] Description 182

[1124] (R)-N-((R)-1-(5-Cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182a); (R)-N-((S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)- 2-methylpropane-2-sulfinamide (D182b)

[1125] To a stirred solution of ethyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyanothiophen-2-yl)-2,2-difluoropropanoate (D181) (4.50 g, 82% Wt, 10.1 mmol) in dry diethyl ether (45.0 mL) under a nitrogen atmosphere at -78 °C was added methylmagnesium bromide in diethyl ether (2.66 g, 7.43 mL, 3.00 molar, 22.3 mmol). The reaction mixture was stirred for 2 hours, then allowed to warm to 25 °C and stirred fora further 16 hours. The reaction mixture was diluted with EtOAc(100 mL)and washed with sat. NH4CI solution (25 mL), distilled water (2x25 mL) and brine (25 mL). The organic layer was dried overNa2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford:

[1126] (R)-N-((R)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182a) (2.00 g, 47 %) as a pale-yellow gum.1H NMR (500 MHz, DMSO-cfe) 67.93 (d, J = 3.9 Hz, 1H), 7.53 (dd, J = 16.4, 3.9 Hz, 1H), 6.52 (d, J = 10.6 Hz, 1H), 5.64 (m, 1H), 2.42 (d, J = 2.2 Hz, 3H), 1.08 (s, 9H).

[1127] (R)-N-((S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182b) (0.32 g, 7.6 %) as a pale-yellow gum.1H NMR (500 MHz, DMSO-cfe) 57.91 (d, J = 3.9 Hz, 1 H), 7.42 (d, J = 3.9 Hz, 1 H), 6.66 (d, J = 9.6 Hz, 1 H), 5.60 (m, 1 H), 2.43 (d, J = 2.0 Hz, 3H), 1.05 (s, 9H).

[1128] Description 183

[1129] (R)-N-((1R,3S)-1-(5-Cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D183)

[1130] To a stirred solution of (R)-N-((R)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182a) (2.00 g, 79% Wt, 4.72 mmol) in dry MeOH (25.0 mL) under a nitrogen atmosphere atO °C was added sodium borohydride (357 mg, 9.45 mmol). The reaction mixture was stirred for 30 minutes. The reaction mixture was allowed toCLI-C-P3879PCT

[1131] warm to 25 °C and stirred for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). This was washed with distilled water (2x10 mL) and brine (25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((1R,3S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D183) (0.600 g, 37.7 %) as a pale-yellow gum.

[1132] 1H NMR (500 MHz, DMSO-ofe) 67.91 (d, J = 3.9 Hz, 1 H), 7.44 (d, J = 4.0 Hz, 1 H), 6.40 (d, J = 9.9 Hz, 1H), 5.59 (d, J = 5.7 Hz, 1H), 5.22 (dd, J = 23.5, 8.6 Hz, 1H), 4.16-4.06 (m, 1H), 1.18- 1.16 (m, 3H), 1.13 (s, 9H). UPLC-MS m / z 337.4 (M+H)+(ES+).

[1133] Description 184

[1134] 5-((1R,3S)-1-Amino-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile, HCI (D184) To a stirred solution of (R)-N-((1R,3S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D183) (400 mg, 1.19 mmol) in EtOAc (1.00 mL) under a nitrogen atmosphere at 25 °C was added HCI (1.98 mL, 3.00 M in EtOAc, 5.94 mmol). The reaction mixture was stirred for 5 hours. The reaction mixture was concentrated in vacuo. The crude solid was slurried in MTBE / iso-hexane, filtered and dried to afford 5-((1R,3S)-1-amino-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile, HCI (D184) (230 mg, 69 %)as a white solid.

[1135] 1H NMR (500 MHz, DMSO-cfe) 59.13 (br s, 2H) 8.00 (d, J = 3.9 Hz, 1 H), 7.57 - 7.50 (m, 1 H), 6.25 - 5.77 (m, 1 H), 5.66 - 5.38 (m, 1 H), 4.20 - 3.88 (m, 1 H), 1.16 (d, J = 6.5 Hz, 3H). 1 exchangeable proton not observed. LCMS m / z 233.2 (M+H)+(ES+).

[1136] Description 185

[1137] 5-((1R,3S)-1-((2,4-Dimethoxybenzyl)amino)-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile (D185)

[1138] To a stirred solution of5-((1R,3S)-1-amino-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile HCI (D184) (85.0 mg, 97% Wt, 316 pmol) in dry MeOH (2.00 mL) under a nitrogen atmosphere at 25 °C was added 2,4-dimethoxybenzaldehyde (64.9 mg, 391 pmol) and acetic acid (10 pL, 178 pmol). The reaction mixture was stirred for 30 minutes. Sodium triacetoxyhydroborate (376 mg, 1.78 mmol) was added and the mixture stirred for 4 hours. The reaction mixture was concentrated in vacuo. The crude material was dissolved in EtOAc (25 mL) and washed with sat. aq. NaHCOs solution (2X 10 mL), distilled

[1139] water (2 x 10 mL) and brine (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 5-((1R,3S)-1-((2,4-CLI-C-P3879PCT

[1140] dimethoxybenzyl)amino)-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile (D185) (110 mg, 74 %) as a sticky colourless gum.

[1141] 1H NMR (500 MHz, DMSO-cfe) 67.88 (d, J = 3.9 Hz, 1 H), 7.24 (d, J = 3.9 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 8.2, 2.3 Hz, 1H), 5.63 (d, J = 6.2 Hz, 1H), 4.54 (m, 1H), 4.16 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.61 (dd, J = 13.6, 5.2 Hz, 1H), 3.49 (dd, J = 13.7, 6.6 Hz, 1H), 3.02 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H).

[1142] Description 186

[1143] 5-((2R,4R)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D186)

[1144] To a stirred solution of 5-((1R,3R)-1-((2,4-dimethoxybenzyl)amino)-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile (D185) (110 mg, 91% Wt, 262 pmol) in dry DCM (5.00 mL) under a nitrogen atmosphere at 25 °C was added triphenylphosphane (412 mg, 1.57 mmol), triethylamine (214 pL, 1.57 mmol), tetrabromomethane (521 mg, 1.57

[1145] mmol) and N,N-dimethylpyridin-4-amine (6.40 mg, 52.3 pmol). The reaction mixture was stirred for 16 hours, then diluted with DCM (50 mL) and washed with sat. aq. NaHCOs solution (25 mL), distilled water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 5-((2R,4R)-1-(2,4-dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D186) (73.0 mg, 73 %) as a pale-yellow gum.

[1146] 1H NMR (500 MHz, DMSO-cfe) 57.87 (d, J = 3.9 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.2, 2.4 Hz, 1H), 4.80 (dd, J = 13.2, 9.4 Hz, 1H), 3.75 (s, 2H), 3.74(s, 3H), 3.71 (s, 3H), 3.59 (m, 1H), 1.05 (d, J = 6.3 Hz, 3H). UPLC-MS m / z 365.1 (M+H)+(ES+).

[1147] Description 187

[1148] 5-((2R,4R)-1-(4,6-Dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D187)

[1149] 5-((2R,4R)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D186) (60.0 mg, 95% Wt, 156 pmol) was dissolved inTFA (3.00 mL) heated to 50 °C and stirred under a nitrogen atmosphere for 15 hours. The reaction mixture was concentrated in vacuo, then dissolved in THF (4.00 mL). 2-Chloro-4,6-dimethoxy-5-nitropyrimidine (52.27 mg, 238.1 pmol) and DIPEA (138 pL, 793.5 pmol) were added. The reaction mixture was heated to 70 °C, stirred for 5 hours, then allowed to cool and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 5-((2R,4R)-1-(4,6-dimethoxy-5-CLI-C-P3879PCT

[1150] nitropyrimidin-2-yl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D187) (23.0 mg, 35 %) as a pale-yellow gum.

[1151] 1H NMR (500 MHz, CDCI3) 67.59 (d, J = 3.9 Hz, 1 H), 7.15 (d, J = 3.9 Hz, 1 H), 5.72 (dd, J = 13.2, 6.1 Hz, 1H), 4.77 (dt, J = 14.8, 6.7 Hz, 1H), 3.90 (s, 6H), 1.65 (dd, J = 6.6, 1.1 Hz, 3H). UPLC m / z 398.11 (M+H)+(ES+).

[1152] Description 188

[1153] 5-((2R,4R)-1-(5-Amino-4,6-dimethoxypyrimidin-2-yl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D188)

[1154] Prepared by the method of Description 67 using 5-((2R,4R)-1-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D187) in place of (R)-3-(1-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-3,3-difluoroazetidin-2-yl)benzonitrile (D66) to form 5-((2R,4R)-1 -(5-amino-4,6-dimethoxypyrimidin-2-yl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D188).

[1155] 1H NMR (500 MHz, DMSO-cfe) 57.94 (d, J = 3.9 Hz, 1 H), 7.41 (d, J = 3.9 Hz, 1 H), 5.82 (dd, J = 13.5, 8.0 Hz, 1 H), 4.64 - 4.55 (m, 1 H), 3.76 (s, 6H), 1.53 (d, J = 6.5 Hz, 3H).

[1156] Exchangeable protons not observed.

[1157] Description 189

[1158] (R)-N-((1S,3S)-1-(5-Cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulf inamide (D189)

[1159] A stirred solution of (R)-N-((S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182b) (350 mg, 90% Wt, 942 pmol)and RuCI(p-cymene)[(S,S)-Ts-DPEN] (12.0 mg, 18.8 pmol)inTHF (3.00 mL) atO °C was purged with nitrogen for 10 minutes. Formic acid (355 pL, 9.42 mmol) was then added, followed by the drop-wise addition of triethylamine (525 pL, 3.77 mmol). The reaction mixture was stirred under nitrogen atO °C for 1 hour, then allowed to warm to RT and stirred for a further 16 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with distilled water (2 x 10 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((1S,3S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D189) (262 mg, 77 %) as a pale-yellow gum.

[1160] 1H NMR (500 MHz, DMSO-cfe) 67.89 (d, J = 3.9 Hz, 1 H), 7.36 (d, J = 3.9 Hz, 1 H), 6.35 (d, J = 6.9 Hz, 1H), 5.86 (d, J = 6.2 Hz, 1H), 5.28 (m, 1H), 3.84 (m, 1H), 1.18 (dd, J = 6.7, 2.2 Hz, 3H), 1.10 (s, 9H).

[1161] Description 190CLI-C-P3879PCT

[1162] 5-((2S,4R)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D190)

[1163] 5-((1S,3S)-1-((2,4-Dimethoxybenzyl)amino)-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile was prepared using sequentially the methods of Descriptions 184 and 185 but utilising (R)-N-((1S,3S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D189) in place of (R)-N-((1R,3S)-1-(5-cyanothiophen-2-yl)- 2.2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D183). This material was treated to the conditions of Description 187 to afford 5-((2S,4R)-1-(2,4-dimethoxybenzyl)- 3.3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D190).

[1164] 1H NMR (500 MHz, DMSO-ofe) 67.84 (d, J = 3.9 Hz, 1 H), 7.22 - 7.16 (m, 2H), 6.44 (dd, J = 6.3, 2.4 Hz, 2H), 5.32 (dd, J = 12.3, 9.7 Hz, 1H), 4.09 (t, J = 6.1 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 3.72 (s, 6H), 3.54 (d, J = 14.0 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H).

[1165] Description 191

[1166] (R)-N-((1S,3R)-1-(5-Cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D191)

[1167] A stirred solution of (R)-N-((S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D182b) (350 mg, 90% Wt, 942 pmol)and RuCI(p-cymene)[(R,R)-Ts-DPEN] (12.0 mg, 18.8 pmol)inTHF (3.00 mL) atO °C was purged with nitrogen for 10 minutes. Formic acid (355 pL, 9.42 mmol) was then added, followed by the drop-wise addition of triethylamine (525 pL, 3.77 mmol). The reaction mixture was stirred under nitrogen atO °C for 1 hour, then allowed to warm to RT and stirred for a further 16 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with distilled water (2 x 10 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford (R)-N-((1S,3R)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D191) (240 mg, 71 %) as a pale-yellow gum.

[1168] 1H NMR (500 MHz, DMSO-cfe) 57.89 (d, J = 3.9 Hz, 1 H), 7.36 (d, J = 3.9 Hz, 1 H), 6.44 (d, J = 7.1 Hz, 1H), 5.99 (d, J = 5.6 Hz, 1H), 5.35 (m, 1H), 4.21 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H), 1.11 (s, 9H).

[1169] Description 192

[1170] 5-((2S,4S)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D192)

[1171] 5-((1S,3R)-1-((2,4-dimethoxybenzyl)amino)-2,2-difluoro-3-hydroxybutyl)thiophene-2-carbonitrile was prepared using the methods of Descriptions 184 and 185 but utilising (R)-N-((1S,3R)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-CLI-C-P3879PCT

[1172] sulfinamide (D191) in place of (R)-N-((1R,3S)-1-(5-cyanothiophen-2-yl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D183). This material was treated to the conditions of Description 187 to afford 5-((2S,4S)-1-(2,4-dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiophene-2-carbonitrile (D192).

[1173] 1H NMR (500 MHz, DMSO-cfe) 67.87 (d, J = 3.8 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.2, 2.4 Hz, 1H), 4.80 (dd, J = 13.2, 9.3 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.75-3.70 (m, 2H), 3.59 (ddd, J = 14.5, 10.5, 6.2 Hz, 1H), 1.05 (d, J = 6.3 Hz, 3H).

[1174] Description 193

[1175] 2-((2R,4R)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiazole (D193) Prepared by the route of Description 194 but using (R)-N-((1R,3S)-2,2-difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123a) in place of (R)-N-((1R,3R)-2,2-difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123b)

[1176] in Description 208.

[1177] 1H NMR (500 MHz, DMSO-cfe) 57.81 (d, J = 3.2 Hz, 1H), 7.71 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.2, 2.4 Hz, 1H), 4.77 (dd, J = 13.7, 9.2 Hz, 1H), 3.80 (s, 2H), 3.74 (s, 3H), 3.71-3.61 (m, 1H), 3.69 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H). LCMS m / z 341.00 (M+H)+(ES+).

[1178] Description 194

[1179] 2-((2R,4S)-1-(2,4-Dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiazole (D194) To a stirred solution of (2R,4R)-4-((2,4-dimethoxybenzyl)amino)-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D209) (220 mg, 90% Wt, 552 pmol) in dry DCM (4.00 mL) under a nitrogen atmosphere at room temperature was added triphenylphosphine (869 mg, 3.31

[1180] mmol), tetrabromomethane (1.10 g, 3.31 mmol), N,N-dimethylpyridin-4-amine (13.5 mg, 110 pmol) and DIPEA (515 pL, 3.31 mmol). The reaction mixture was stirred for 18 hours.

[1181] The reaction mixture was then diluted with DCM (50 mL) and washed with sat. aq.

[1182] NaHCO3(25 mL), water (25 mL) and brine (25 mL). The organic layer was collected, dried overNa2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford 2-((2R,4S)-1-(2,4-dimethoxybenzyl)-3,3-difluoro-4-methylazetidin-2-yl)thiazole (D194) (171 mg, 80 %) as a pale-yellow gum.

[1183] 1H NMR (500 MHz, DMSO-cfe) 57.80 (d, J = 3.2 Hz, 1 H), 7.68 (d, J = 3.2 Hz, 1 H), 7.25 -7.19 (m, 1H), 6.48- 6.41 (m, 2H), 5.33- 5.25 (m, 1H), 4.16 (dt, J = 12.3, 6.1 Hz, 1H), 3.96 -3.89 (m, 1H), 3.71 (d, J = 1.7 Hz, 6H), 3.58 (d, J = 14.0 Hz, 1H), 1.28 (dd, J = 6.9, 1.1 Hz, 3H). LCMS m / z 341.00 (M+H)+(ES+).CLI-C-P3879PCT

[1184] Description 195

[1185] 2-(4-(5-Fluoropyridin-2-yl)-2,2-dimethylazetidin-1-yl)-4,6-dimethoxypyrimidin-5-amine (D195)

[1186] Prepared by the process of Description 67, but using 2-(4,4-dimethylazetidin-2-yl)-5-fluoropyridine, HCI (D154) in place of (R)-3-(3,3-difluoroazetidin-2-yl)benzonitrile HCI (D133) in preceding Description 66.

[1187] 1H NMR (500 MHz, DMSO-ofe) 58.50 (d, J = 2.9 Hz, 1 H), 7.66 (td, J = 8.8, 2.9 Hz, 1 H), 7.55 (dd, J = 8.7, 4.6 Hz, 1H), 5.13 (t, J = 7.9 Hz, 1H), 3.69 (d, J = 14.1 Hz, 6H), 3.38 (s, 2H), 2.37 (dd, J = 10.3, 8.4 Hz, 1H), 2.17 (dd, J = 10.4, 7.4 Hz, 1H), 1.61 (s, 3H), 1.51 (s, 3H). UPLC-MS m / z 334.3 (M+H)+(ES+).

[1188] Description 196

[1189] (R)-N-((S)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D196)

[1190] To a stirred solution of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (D1) (5.20 g, 95% Wt, 16.1 mmol) in dryTHF (50.0 mL) under a nitrogen atmosphere was added 2,2-difluoro-1-morpholino-2-(trimethylsilyl)ethan-1-one (4.68 g, 90% Wt, 17.7 mmol) and TBAT (871 mg, 1.61 mmol). The reaction mixture was stirred for 18 hours. Further TBAT (871 mg, 1.61 mmol) was added and stirring was continued for an additional 4 days. The reaction mixture was quenched with satd. aq. NH4CI (100 mL) and extracted with EtOAc (250 mL). The organic layer was dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc / DCM) to afford (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro- 3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D196) (3.76 g, 45 %) as a yellow gum.

[1191] 1H NMR (500 MHz, DMSO-cfe) 57.74 (t, J= 8.1 Hz, 1H), 7.63 (dd, J= 9.7, 2.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1 H), 6.50 (d, J = 10.6 Hz, 1 H), 5.24 (dt, J = 19.0, 9.1 Hz, 1 H), 3.75 - 3.40 (m, 8H), 1.05 (s, 9H). m / z 471.2 / 473.2 (M+H)+(ES+).

[1192] Description 197

[1193] (R)-N-((S)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D197)

[1194] Methylmagnesium chloride (3M in THF) (10.8 mL, 32.3 mmol) was added to a solution of (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-morpholino-3-oxopropyl)-2-methylpropane-2-sulfinamide (D196) (3.76 g, 90% Wt, 7.18 mmol) in THF (30.0 mL) at -78 °C and the reaction was stirred at -78 °C for 1 hour. The reaction was allowed to warm to RT and stirredCLI-C-P3879PCT

[1195] for 1 hour, then was cooled to 0 °C, quenched with sat. aq. NH4CI (20 mL) then allowed to warm to RT. The mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were dried over Na2SO4and concentrated in vacuo to afford (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D197) (2.99 g, 83 %)as a pale-yellow solid, m / z 400.5 / 402.6 (M+H)+(ES+).

[1196] Descriptions 198 and 199

[1197] (R)-N-((1S,3S)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D198)

[1198] (R)-N-((1S,3R)-1-(4-Bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D199)

[1199] Sodium borohydride (339 mg, 8.96 mmol) was added to a solution of (R)-N-((S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-oxobutyl)-2-methylpropane-2-sulfinamide (D197) (2.99 g, 80% Wt, 5.98 mmol) in MeOH (10.0 mL) and the reaction stirred at RT for 1 hour. The reaction was quenched with sat. aq. NH4CI solution (200 mL) and the volatiles removed in vacuo. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo The crude product was purified by chromatography on silica gel (40 g cartridge, 050% EtOAc / isohexane) to afford: (R)-N-((1S,3S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D198) (1.01 g, 40 %) as a colourless solid, and (R)-N-((1S,3R)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D199) (1.45 g, 57 %)as a colourless oil.

[1200] D198:1H NMR (500 MHz, DMSO-cfe) 57.69 (t, J= 8.1 Hz, 1H), 7.57 (dd, J= 9.7, 2.0 Hz, 1H), 7.51 (dd, J= 8.4, 2.0 Hz, 1H), 6.34 (d,J= 10.6 Hz, 1H), 5.55 (d, J= 6.1 Hz, 1H), 5.21 (dd, J = 25.4, 10.6 Hz, 1H), 4.11 (dt, J= 23.1, 6.3 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H), 1.10 (s, 9H). m / z 402.6 / 404.3 (M+H)+(ES+). The absolute stereochemistry of D198 was determined by single crystal X-ray crystallography.

[1201] D199:1H NMR (500 MHz, DMSO-d6) 67.63 (t, J= 8.1 Hz, 1H), 7.57 (dd, J= 9.6, 2.0 Hz, 1H), 7.49 (dd, J= 8.4, 2.0 Hz, 1H), 6.09 (d, J= 10.1 Hz, 1H), 5.41 (d, J= 6.5 Hz, 1H), 5.02 (td, J = 14.3, 10.0 Hz, 1H), 3.68 (dq, J= 15.0, 7.5 Hz, 1H), 1.14 (d, J= 6.4 Hz, 3H), 1.10 (s, 9H). m / z 402.5 / 404.5 (M+H)+(ES+).

[1202] Description 200

[1203] (2S,4R)-2-(4-Bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D200)

[1204] To a 250 mL RBF containing (R)-N-((1S,3S)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D198) (1.01 g, 95% Wt, 2.39 mmol) in tolueneCLI-C-P3879PCT

[1205] (5.00 mL) was added cyanomethylene)tributylphosphorane (1.59 mL, 5.96 mmol) and then the solution was heated to 100 °C for 24 hours. Further cyanomethylene)-tributylphosphorane (1.59 mL, 5.96 mmol) was added and the reaction stirred for an additional 48 hours. Upon cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to afford (2S,4R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D200) (0.454 g, 45 %)as a yellow oil.

[1206] 1H NMR (500 MHz, DMSO-ofe) 67.72 - 7.64 (m, 1H), 7.64 - 7.51 (m, 2H), 5.60 (dd, J = 15.8, 8.5 Hz, 1 H), 4.63 - 4.37 (m, 1 H), 1.38 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H). HPLC m / z 384.2 / 386.1 (M+H)+(ES+). The absolute stereochemistry of D200 was determined by single crystal X-ray crystallography.

[1207] Description 201

[1208] (2S,4S)-2-(4-Bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D201)

[1209] To a 250 mL RBF containing (R)-N-((1S,3R)-1-(4-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-methylpropane-2-sulfinamide (D199) (1.45 g, 95% Wt, 3.42 mmol) in toluene (5.00 mL) was added cyanomethylene)tributylphosphorane (2.29 mL, 8.56 mmol) and then the solution was heated to 100 °C for 24 hours. The mixture was then concentrated in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% MTBE / isohexane) to afford (2S,4S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D201) (1.04 g, 71 %) as a brown solid.

[1210] 1H NMR (500 MHz, DMSO-cfe) 57.74 - 7.62 (m, 2H), 7.59 (dd, J = 8.3, 1.9 Hz, 1 H), 5.81 -5.76 (m, 1 H), 5.03 - 4.89 (m, 1 H), 1.54 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H). m / z 384.2 / 386.2 (M+H)+(ES+).

[1211] Description 202

[1212] 4-((2S,4R)-1-((R)-tert-Butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D202)

[1213] To a 40 mL vial containing (2S,4R)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D200) (0.454 g, 90% Wt, 1.06 mmol), potassium hexacyanoferrate(ll), trihydrate (225 mg, 532 pmol)and Pd-117 (76.1 mg, 106 pmol) in 1,4-dioxane (4.00 mLJwas added potassium acetate (52.2 mg, 532 pmol) in water (2.00 mL). The reaction mixture was stirred for 2 hours at 90 °C. Upon cooling, the reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to give4-((2S,4R)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D202) (310 mg, 84 %)as a cream solid.CLI-C-P3879PCT

[1214] 1H NMR (500 MHz, DMSO-cfe) 58.01 (d, J = 10.1 Hz, 1H), 7.89 - 7.52 (m, 2H), 5.69 (dd, J = 15.7, 8.2 Hz, 1 H), 4.60 (dt, J = 15.3, 7.2 Hz, 1 H), 1.39 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H). m / z 331.3 (M+H)+(ES+).

[1215] Description 203

[1216] 4-((2S,4S)-1-((R)-Tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D203)

[1217] To a 40 mL vial containing (2S,4S)-2-(4-bromo-2-fluorophenyl)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidine (D201) (1.04 g, 90% Wt, 2.44 mmol), potassium hexacyanoferrate(ll), trihydrate (514 mg, 1.22 mmol) and Pd-117 (174 mg, 244 pmol)in 1,4-dioxane (4.00 mL)was added potassium acetate (120 mg, 1.22 mmol) in water (2.00 mL). The reaction mixture was stirred for 2 hours at 90 °C. Upon cooling, the reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% MTBE / isohexane) to give4-((2S,4S)-1-((R)-tert-butylsulfinyl)-3,3-difluoro-4-methylazetidin-2-yl)-3-fluorobenzonitrile (D203) (638 mg, 75 %)as a yellow oil.

[1218] 1H NMR (500 MHz, DMSO-cfe) 58.02 (dd, J = 10.1, 1.5 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.5 Hz, 1H), 5.87 (ddd, J = 18.3, 4.8, 1.6 Hz, 1H), 5.12-4.93 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H). m / z 331.4 (M+H)+(ES+).

[1219] Description 204

[1220] 2-Ethyl-5-fluoro-4-methoxy-3-nitropyridine (D204)

[1221] To a stirred, degassed solution of 2-bromo-5-fluoro-4-methoxy-3-nitropyridine (D57) (525 mg, 2.09 mmol), potassium phosphate, tribasic (888 mg, 4.18 mmol), Di(1-adamantyl)-n-butylphosphine (37.5 mg, 105 pmol)and Pd2(dba)s (23.9 mg, 26.1 pmol) in a mixture of toluene (10.0 mL) and water (1.00 mL)was added triethylborane, (837 pL, 1 M in THF, 837 pmol). The reaction mixture was heated to 95 °C and stirred for 18 hours. Upon cooling, water (25 mL) was added and the mixture was extracted into EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0- 50% MTBE / isohexane) to afford 2-ethyl-5-fluoro-4-methoxy-3-nitropyridine (D204) (304 mg, 60 %) as a yellow oil.

[1222] 1H NMR (500 MHz, CDCI3) 68.44 (d, J = 3.7 Hz, 1 H), 4.20 (d, J = 4.5 Hz, 3H), 2.72 (qd, J = 7.6, 0.9 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). UPLC-MS m / z 201.2 (M+H)+(ES+).

[1223] Description 205

[1224] 2-Ethy l-5-fl uoro-4-methoxy py ri d i n-3-am i ne ( D205)CLI-C-P3879PCT

[1225] To a solution of2-ethyl-5-fluoro-4-methoxy-3-nitropyridine (D204) (0.30 g, 95% Wt, 1.4 mmol) in THF (12.0 mL) and water (4.00 mL) was added zinc (0.56 g, 8.5 mmol) and NH4CI (0.46 g, 8.5 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was filtered and rinsed with MeOH. The filtrate was evaporated, the residue dissolved in sat. aq. NaHCOs (15 mL) and the solution extracted into EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-ethyl-5-fluoro-4-methoxypyridin-3-amine (D205) (261 mg, 99 %) as a yellow oil.

[1226] 1H NMR (500 MHz, CDCI3) 67.83 (d, J = 3.2 Hz, 1 H), 4.09 (d, J = 3.6 Hz, 3H), 3.83 (s, 2H), 2.66 (qd, J = 7.5, 0.9 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). UPLC-MS m / z171.1 (M+H)+(ES+).

[1227] Description 206

[1228] 6-Bromo-2-ethyl-5-fluoro-4-methoxypyridin-3-amine (D206)

[1229] To a stirring solution of2-ethyl-5-fluoro-4-methoxypyridin-3-amine (2) (D205) (260 mg, 1.53 mmol) in MeCN (8.00 mL) was added NBS (272 mg, 1.53 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 2 hours then at room temperature for 18 hours. The reaction mixture was diluted with brine (10 mL) and extracted into DCM (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 40% EtOAc / isohexane) to afford 6-bromo-2-ethyl-5-fluoro-4-methoxypyridin-3-amine (D206) (198 mg, 50 %) as a dark brown oil.

[1230] 1H NMR (500 MHz, CDCI3) 54.11 (d, J = 3.8 Hz, 3H), 2.65 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). Exchangeable protons not observed. UPLC-MS m / z 249.1 / 251.1 (M+H)+(ES+).

[1231] Description 207

[1232] N-(6-Bromo-2-ethyl-5-fluoro-4-methoxypyridin-3-yl)-3,3-dimethylbutanamide (D207)

[1233] Under a nitrogen atmosphere 3, 3-dimethylbutanoyl chloride (119 pL, 853 pmol) was added to a solution of 6-bromo-2-ethyl-5-fluoro-4-methoxypyridin-3-amine (D206) (195 mg, 99% Wt, 775 pmol) and triethylamine (324 pL, 2.33 mmol) in DCM (6.00 mL) atO °C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Further 3,3-dimethylbutanoyl chloride (119 pL, 853 pmol) was added and stirring was continued at room temperature for 4 hours. Sat. aq. NaHCOs (20 mL) was added, the mixture was extracted into DCM (3 x 20 mL), the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in THF (12 mL), triethylamine (324 pL, 2.33 mmol) and 3, 3-dimethylbutanoyl chloride (119 pL, 853 pmol) were added and the reaction mixture was heated to 55 °C and stirred for 20 hours. Further triethylamine (324 pL, 2.33 mmol) and 3, 3-dimethylbutanoyl chloride (119 pL, 853 pmol) were added and theCLI-C-P3879PCT

[1234] reaction mixture was stirred for 5 hours at 55 °C. The reaction mixture was cooled and sat. aq. NaHCC (20 mL) was added. The mixture was extracted with DCM (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc / isohexane). The resulting material was dissolved in in DCM (5.00 mL), then DIPEA (126 pL, 723 pmol) and trimethylsilyl trifluoromethanesulfonate (131 pL, 723 pmol) were added. The mixture was stirred at room temperature for 15 minutes. 3,3-Diimethylbutanoyl chloride (75.3 pL, 542 pmol) was added and stirring was continued for 18 hours. Water (10 mL) was then added and the mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with sat. aq. NH4CI (2 x 10 mL) then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford N-(6-bromo-2-ethyl-5-fluoro-4-methoxypyridin-3-yl)-3,3-dimethylbutanamide (D207) (77.1 mg, 29 %) as a clear yellow oil that solidified on standing.

[1235] 1H NMR (500 MHz, CDCI3) 56.54 (s, 1H), 4.11 (d, J = 4.5 Hz, 3H), 2.68 (q, J = 7.7 Hz, 2H), 2.29 (s, 2H), 1.22 (t, J = 7.5 Hz, 3H), 1.13 (s, 9H). UPLC-MS m / z 347.0 / 349.0 (M+H)+(ES+).

[1236] Description 208

[1237] (2R,4R)-4-Amino-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D208)

[1238] To a stirred solution of (R)-N-((1R,3R)-2,2-difluoro-3-hydroxy-1-(thiazol-2-yl)butyl)-2-methylpropane-2-sulfinamide (D123b) (280 mg, 95% Wt, 851 pmol) in dry DCM (3.00 mL) and MeOH (1.00 mL) at room temperature was added HCI (5.11 mL, 1 M in EtOAc, 5.11 mmol). The reaction mixture was stirred for 6 hours, then concentrated in vacuo. The residue was treated with sat. aq. NaHCOs solution (25 ml) and extracted with CHCb:IPA (9:1)(3x25 mL). The combined organic layers were dried overNa2SC>4, filtered and concentrated in vacuo to afford (2R,4R)-4-amino-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D208) (170 mg, 82 %) as sticky yellow gum. LCMS m / z 209.2 (M+H)+(ES+).

[1239] Description 209

[1240] (2R,4R)-4-((2,4-Dimethoxybenzyl)amino)-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D209)

[1241] To a stirred solution of (2R,4R)-4-amino-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D208) (170 mg, 816 pmol) in dry MeOH (3.00 mL) under a nitrogen atmosphere at room temperature was added 2,4-dimethoxybenzaldehyde (163 mg, 980 pmol) and acetic acid (5 pL, 81.6 pmol). The reaction mixture was heated to 40 °C and stirred for 2 hours, then allowed to cool to room temperature. Sodium triacetoxyborohydride (865 mg, 4.08 mmol) was added andCLI-C-P3879PCT

[1242] stirring was continued for 16 hours. The reaction mixture was then concentrated in vacuo. The reaction mixture was diluted with distilled water (25 mL) and extracted with DCM (2x25 mL). The combined organic layers were dried overNa2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford (2R,4R)-4-((2,4-dimethoxybenzyl)amino)-3,3-difluoro-4-(thiazol-2-yl)butan-2-ol (D209) (220 mg, 68 %)as a sticky yellow gum.

[1243] 1H NMR (500 MHz, DMSO-ofe) 57.81 (d, J = 3.3 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1 H), 6.53 - 6.42 (m, 2H), 5.47 (d, J = 6.0 Hz, 1 H), 4.57 - 4.48 (m, 1 H), 4.05 - 3.89 (m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.64 (d, J = 13.5 Hz, 1H), 3.53 -3.47 (m, 1H), 2.98 (s, 1 H), 1.08 (d, J = 6.4 Hz, 3H). LCMS m / z 359.2 (M+H)+(ES+).

[1244] Examples

[1245] Except where explicitly indicated, stereochemistry assignments in Examples are based on that of the component azetidines determined by methods described in the Description section. All stereochemistries form part of this claim.

[1246] Example 1

[1247] (S)-N-(3-Fluoro-4-(2-(4-fluorophenyl)azetidin-1-yl)-2-methoxyphenyl)-3,3-dimethylbutanamide (E1a), (R)-N-(3-fluoro-4-(2-(4-fluorophenyl)azetidin-1-yl)-2-methoxyphenyl)-3,3-dimethylbutanamide (E1 b)

[1248] >

[1249]

[1250] E1a and E1b were prepared by the route of Description 67 and the subsequent elaboration described for Example 89 but using (S)-2-(4-fluorophenyl)azetidine (D124) and (R)-2-(4-fluorophenyl)azetidine (D125) respectively in place of (R)-3-(3,3-difluoroazetidin-2-yl)benzonitrile, HCI (D133), 1,2-difluoro-3-methoxy-4-nitrobenzene (CAS 66684-60-4) in place of 2-chloro-4,6-dimethoxy-5-nitropyrimidine and 3,3-dimethylbutanoyl chloride in place of 2-cyclopropylacetyl chloride. Chiral HPLC analysis: Phenomenex IG, 40% MeOH: 1st eluting peak E1a, second peak E1b.

[1251] E1a1H NMR (500 MHz, DMSO-d6) 68.79 (s, 1H), 7.13 - 7.08 (m, 4H), 6.68 - 6.65 (m, 1H), 5.70 (s, 1H), 4.09 (t, J = 5.7 Hz, 1H), 3.76 (s, 3H), 3.24 - 3.15 (m, 1H), 3.04 -2.98 (m, 1H), 2.16 -2.05 (m, 2H), 2.04 - 1.95 (m, 1H), 1.91 - 1.83 (m, 1H), 0.96 (s, 9H). m / z (M+H)+(ES+) 389.5.CLI-C-P3879PCT

[1252] E1 b1H NMR (500 MHz, DMSO-d6) 68.79 (s, 1 H), 7.14 - 7.08 (m, 4H), 6.68 - 6.64 (m, 1 H), 5.70 (s, 1H), 4.09 (t, J = 5.6 Hz, 1H), 3.76 (s, 3H), 3.23- 3.16 (m, 1H), 3.05-2.98 (m, 1H), 2.15-2.05 (m, 2H), 2.04- 1.96 (m, 1H), 1.91 - 1.83 (m, 1H), 0.96 (s, 9H). m / z (M+H)+(ES+) 389.5.

[1253] Example 2

[1254] (S)-3,3-Difluoro-N-(3-fluoro-4-(2-(4-fluorophenyl)azetidin-1-yl)-2-methoxy-6-methylphenyl)cyclobutane-1 -carboxamide (E2a), (R)-3,3-difluoro-N-(3-fluoro-4-(2-(4-fluorophenyl)azetidin-1-yl)-2-methoxy-6-methylphenyl)cyclobutane-1-carboxamide (E2b)

[1255]

[1256] E2a and E2b were prepared utilising the coupling method described for Example 20 but using (S)-2-(4-fluorophenyl)azetidine (D124) and (R)-2-(4-fluorophenyl)azetidine (D125) respectively place of (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139), and in intermediate Description 102 utilising 3, 3-difluorocyclobutane-1 -carbonyl chloride in place of 2-(3,3-difluorocyclobutyl)acetyl chloride. Chiral HPLC analysis: Phenomenex Al, 20% MeOH: 1st eluting peak E2a, second peak E2b.

[1257] E2a1H NMR (500 MHz, DMSO-cfe) 59.22 (s, 1H), 7.51 (dd, J = 8.6, 5.6 Hz, 2H), 7.19 (t, J = 8.9 Hz, 2H), 6.00 (d, J = 8.9 Hz, 1 H), 5.08 (t, J = 7.9 Hz, 1 H), 4.16 - 4.05 (m, 1 H), 3.87 -3.78 (m, 1 H), 3.67 (s, 3H), 3.15 - 3.05 (m, 1 H), 2.86 - 2.68 (m, 4H), 2.68 - 2.59 (m, 1 H), 2.24 - 2.14 (m, 1 H), 1.89 (s, 3H). m / z (M+H)+(ES+) 423.0.

[1258] E2b1H NMR (500 MHz, DMSO-d6) 39.22 (s, 1H), 7.51 (dd, J = 8.6, 5.6 Hz, 2H), 7.19 (t, J = 8.9 Hz, 2H), 6.00 (d, J = 8.9 Hz, 1 H), 5.08 (t, J = 7.9 Hz, 1 H), 4.16 - 4.05 (m, 1 H), 3.87 -3.78 (m, 1 H), 3.67 (s, 3H), 3.15 - 3.05 (m, 1 H), 2.86 - 2.68 (m, 4H), 2.68 - 2.59 (m, 1 H), 2.24 - 2.14 (m, 1 H), 1.89 (s, 3H). m / z (M+H)+(ES+) 423.0.

[1259] Example 3

[1260] N-(6-((2S,4R)-2-(4-Cyano-2-fluorophenyl)-4-methylazetidin-1-yl)-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (E3)CLI-C-P3879PCT

[1261]

[1262] E3 was prepared using the route of Example 20, but using N-(6-bromo-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-3,3-dimethylbutanamide (D103) in place of N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-2-(3,3-difluorocyclobutyl)-acetamide (D102) and using 3-fluoro-4-((2S,4R)-4-methylazetidin-2-yl)benzonitrile, HCI (D20) in place of (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139), and CPhos, sodium tert-butoxide and cyclopentyl methyl ether as catalyst ligand, base and solvent, respectively, in the final coupling step.

[1263] 1H NMR (500 MHz, DMSO-d6) 58.97 (s, 1H), 7.82 (d, J = 10.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1 H), 7.54 (t, J = 7.7 Hz, 1 H), 5.72 (t, J = 8.0 Hz, 1 H), 4.63 - 4.54 (m, 1 H), 3.86 (d, J = 2.7 Hz, 3H), 2.47-2.40 (m, 2H), 2.14 (s, 2H), 2.00 (s, 3H), 1.37 (d, J = 6.2 Hz, 3H), 1.02 (s, 9H). m / z 443.4(M+H)+(ES+).

[1264] Example 4

[1265] (R)-N-(6-(2-(4-Cyano-2-fluorophenyl)-3,3-difluoroazetidin-1-yl)-5-fluoro-4-methoxy-2-methylpyridin-3-yl)-2-(3,3-difluorocyclobutyl)acetamide (E4)

[1266]

[1267] Prepared using the route of Example 26 but using 2-(3,3-difluorocyclobutyl)acetyl chloride in place of 3,3-dimethylbutanoyl chloride in Description 48 and (R)-4-(3,3-difluoroazetidin-2-yl)-3-fluorobenzonitrile, HCI (D111) in place of (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139).

[1268] 1H NMR (500 MHz, DMSO) 59.32 (s, 1H), 7.97 (dd, J = 9.9, 1.6 Hz, 1H), 7.75 (dd, J = 8.0, 1.5 Hz, 1 H), 7.64 (t, J = 7.Q Hz, 1 H), 6.03 (dd, J = 14.3, 8.3 Hz, 1 H), 4.69 (dd, J = 14.6, 11.8 Hz, 1 H), 4.56 (q, = 10.5 Hz, 1 H), 3.90 (d, J = 3.0 Hz, 3H), 2.83 - 2.59 (m, 2H), 2.54 - 2.42 (m, 3H), 2.45 - 2.26 (m, 2H), 2.04 (s, 3H). m / z 499.3 (M+H)+(ES+).

[1269] Example 5CLI-C-P3879PCT

[1270] (S)-N-(3-Fluoro-4-(2-(4-fluorophenyl)azetidin-1-yl)-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (E5a), (R)-N-(3-fluoro-4-(2-(4-fluorophenyl)azetidin-1 -yl)-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (E5b)

[1271]

[1272] E5a and E5b were prepared utilising the coupling method described for Example 20 but using (S)-2-(4-fluorophenyl)azetidine (D124) and (R)-2-(4-fluorophenyl)azetidine (D125) respectively place of (S)-2-(2,4-difluorophenyl)-azetidine, HCI (D139), and N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (D48) in place of N-(4-bromo-3-fluoro-2-methoxy-6-methylphenyl)-2-(3,3-difluorocyclobutyl)-acetamide (D102). Chiral HPLC analysis: Phenomenex C4, 20% MeOH: 1st eluting peak E5b, second peak E5a.

[1273] E5a1H NMR (500 MHz, DMSO-cfe) 58.88 (s, 1H), 7.61 - 7.44 (m, 2H), 7.24 - 7.13 (m, 2H), 5.99 (d, J = 8.9 Hz, 1H), 5.07 (t, J = 7.9 Hz, 1H), 4.15-4.07 (m, 1H), 3.81 (q, J = 7.5 Hz, 1 H), 3.69 (d, J = 0.8 Hz, 3H), 2.68 - 2.57 (m, 1 H), 2.24 - 2.16 (m, 1 H), 2.14 (s, 2H), 1.92 (s, 3H), 1.03 (s, 9H). m / z (M+H)+(ES+) 403.0.

[1274] E5b1H NMR (500 MHz, DMSO-cfe) 58.88 (s, 1H), 7.57 - 7.44 (m, 2H), 7.28 - 7.09 (m, 2H), 5.99 (d, J = 9.0 Hz, 1 H), 5.07 (t, J = 7.9 Hz, 1 H), 4.14 - 4.03 (m, 1 H), 3.87 - 3.77 (m, 1 H), 3.69 (d, J = 0.8 Hz, 3H), 2.69 - 2.57 (m, 1 H), 2.25 - 2.15 (m, 1 H), 2.14 (s, 2H), 1.92 (s, 3H), 1.03 (s, 9H). m / z (M+H)+(ES+) 403.0.

[1275] Example 6

[1276] (S)-N-(2-(4-(4-Fluorophenyl)-2,2-dimethylazetidin-1-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide (E6a), (R)-N-(2-(4-(4-Fluorophenyl)-2,2-dimethylazetidin-1-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide (E6b)

[1277]

[1278] E6 Examples were prepared by the method of Example 90 but with 4-(4-fluorophenyl)-2,2-dimethylazetidine (D43) in place of (R)-3-(3,3-difluoroazetidin-2-yl)benzonitrile, HCI (D133) in Description 67. Chiral HPLC analysis: Phenomenex Al, 10% MeOH: 1st eluting peak E6a, second peak E6b. The isomers were separated by chiral chromatography:CLI-C-P3879PCT

[1279] Phenomenex Lux A1 10 x 250 mm, 5 pm, flow rate 20 mL / min at 10% MeOH (0.1% Ammonia), 90% CO2.

[1280] E6a: 1H NMR (500 MHz, DMSO-cfe) 68.42 (s, 1H), 7.58 - 7.43 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 5.18 (t, J = 7.8 Hz, 1 H), 3.79 (s, 3H), 3.39 (s, 3H), 2.49 - 2.44 (m, 1 H), 2.06 (dd, J = 10.8, 7.3 Hz, 1 H), 2.02 (s, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 0.97 (s, 9H). m / z 431.5 (M+H)+(ES+).

[1281] E6b: 1 H NMR (500 MHz, ) 68.42 (s, 1 H), 7.52 - 7.43 (m, 2H), 7.18 - 7.08 (m, 2H), 5.18 (t, J = 7.8 Hz, 1 H), 3.79 (s, 3H), 3.39 (s, 3H), 2.49 - 2.45 (m, 1 H), 2.06 (dd, J = 10.8, 7.3 Hz, 1H), 2.02 (s, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 0.97 (s, 9H). m / z 431.5 (M+H)+(ES+).

[1282] Example 7

[1283] (S)-N-(4-(2-(2,4-Difluorophenyl)azetidin-1-yl)-3-fluoro-2-methoxy-6-methylphenyl)-3,3-dimethylbutanamide (E7)

[1284]

[1285] E7 was prepared utilising the coupling method described for Example 20 ...

Claims

CLI-C-P3879PCTCLAIMS1. A compound of formula (I):or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt, cocrystal or a solvate thereof, wherein:R1represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-8 cycloalkyl, -C1-6 alkyl-C3-8 cycloalkyl, wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R1agroups;R1arepresents C1-6 alkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or-SO2Ra;Raand Rbindependently represent hydrogen or C1-6 alkyl;R2represents aryl or heteroaryl, wherein said aryl or heteroaryl groups may be optionally substituted by one or more (e.g. 1 , 2, 3 or 4) R2agroups;R2arepresents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or -SO2Ra;X and Y are both -N=, or X and Y are both -C(R5)=, or one of X represents -N= and the other represents -C(R5)=;R5represents hydrogen or halogen;n represents an integer selected from 0 to 2;R3represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, halogen, haloCi-6 alkyl, hydroxy, C1-6 alkoxy, haloCi-6 alkoxy, cyano, nitro, oxo, -NRaRb, -CONRaRb, or -SO2Ra; p represents an integer selected from 0 to 4; andR4represents C1-6 alkyl, halogen, haloC-i-6 alkyl or oxo.

2. The compound of claim 1 , wherein R1represents C1-6 alkyl (such as -CH2-(CH3)3), C1-6 alkoxy (such as -O-CH2-CH3), C3-8 cycloalkyl (such as cyclobutyl) or -C1-6 alkyl-Cs-s cycloalkyl (such as -CH2-cyclopropyl or -CH2-cyclobutyl) wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by one or more (e.g. 1 or 2) R1agroups.CLI-C-P3879PCT3. The compound of claim 1 or claim 2, wherein R1arepresents halogen (such as fluorine) or hydroxy.

4. The compound of any of claims 1 to 3, wherein R1represents optionally substituted C1-6 alkyl (such as -CH2-(CH3)3or-CH2-(CH3)(CH3)(OH)), C1-6 alkoxy (such as -O-CH2-CH3), optionally substituted C3-8 cycloalkyl (such as difluorocyclobutyl) or optionally substituted -C1- 6 alkyl-Cs-s cycloalkyl (such as -CH2-cyclopropyl or -CH2-difluorocyclobutyl).

5. The compound of any of claims 1 to 4, wherein R2represents:phenyl or a 5 or 6 membered monocyclic heteroaryl group, wherein said phenyl or heteroaryl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups; orphenyl or a 6 membered monocyclic heteroaryl group, wherein said phenyl or heteroaryl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups; orphenyl, pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl), thiophenyl (such as thiophen-2-yl) or thiazolyl (such as thiazol-2-yl), wherein said phenyl, pyridyl, thiophenyl or thiazolyl group may be optionally substituted by one or more (e.g. 1 or 2) R2agroups; orphenyl or pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl) wherein said phenyl or pyridyl group are substituted by 1 or 2 R2agroups.

6. The compound of any of claims 1 to 5, wherein R2arepresents halogen (such as fluorine or chlorine), C1-6 alkyl (such as methyl), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SChR3(such as -SO2-Me).

7. The compound of any of claims 1 to 6, wherein R2represents:phenyl substituted by one or two halogen (such as fluorine), haloCi-6 alkoxy (such as trifluoromethoxy), cyano or -SO2Ra(such as -SO2-Me) groups; orpyridyl substituted by one halogen (such as fluorine) group; orthiophenyl substituted by a cyano group; orunsubstituted thiazolyl.

8. The compound of any of claims 1 to 7, wherein R2represents 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 2-fluoro-4-CLI-C-P3879PCT(methylsulfonyl)phenyl, 3-fluoropyridin-4-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 3,5-difluoropyridin-2-yl, 5-fluoro-6-methylpyridin-2-yl, 5-cyanothiophen-2-yl orthiazol-2-yl.

9. The compound of any of claims 1 to 8, wherein X and Y are both -N=, or X and Y are both -C(H)=, or one of X is -C(H)= and the other is -C(F)=, or one of X is -N= and the other is -C(F)=, or one of X is -N= and the other is -C(H)=.

10. The compound of any of claims 1 to 9, wherein R3represents C1-6 alkyl (such as methyl), halogen (such as chlorine or fluorine), C1-6 alkoxy (such as methoxy), haloC-i-6 alkoxy (such as trifluoromethoxy or difluoromethoxy), cyano or -NRaRb(such as -NH2).

11. The compound of any of claims 1 to 10, wherein n represents 1 and:R3represents C1-6 alkoxy (such as methoxy); orR3represents haloCi-6 alkoxy (such as trifluoromethoxy or difluoromethoxy); orR3represents cyano; orR3represents-NRaRb(such as -NH2).

12. The compound of any of claims 1 to 10, wherein n represents 2 and:both R3groups represent C1-6 alkyl (such as methyl); orboth R3groups represent C1-6 alkoxy (such as methoxy); orone of R3represents C1-6 alkyl (such as methyl or ethyl) and the other represents C1-6 alkoxy (such as methoxy); orone of R3represents C1-6 alkyl (such as methyl) and the other represents cyano; or one of R3represents C1-6 alkoxy (such as methoxy) and the other represents halogen (such as fluorine or chlorine); orone of R3represents C1-6 alkoxy (such as methoxy) and the other represents cyano; or one of R3represents C1-6 alkyl (such as methyl) and the other represents haloCi-6 alkoxy (such as difluoromethoxy).

13. The compound of any of claims 1 to 12, wherein p represents an integer selected from 0 to 3.

14. The compound of any of claims 1 to 13, wherein p represents 0.

15. The compound of any of claims 1 to 13, wherein R4represents Ci-e alkyl (such as methyl), halogen (such as fluorine) or oxo.CLI-C-P3879PCT16. The compound of any of claims 1 to 13, wherein p represents 1 and R4represents C1-6 alkyl (such as methyl) or oxo.

17. The compound of any of claims 1 to 13, wherein p represents 2 and both R4groups represent C1-6 alkyl (such as methyl) or both R4groups represent halogen (such as fluorine).

18. The compound of any of claims 1 to 13, wherein p represents 3 and one R4group represents C1-6 alkyl (such as methyl) and the other two R4groups represent halogen (such as fluorine).

19. The compound of any of claims 1 to 18, wherein R5represents hydrogen or fluorine.

20. A compound of formula (I) as defined in any one of claims 1 to 19, which is the free base of a compound of Examples 1-127 or a pharmaceutically acceptable salt or solvate thereof.

21. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 20.

22. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 20, in combination with one or more therapeutic agents.

23. A compound as defined in any of claims 1 to 20 or a pharmaceutical composition as defined in claim 21 or claim 21 for use in therapy.

24. A compound as defined in any of claims 1 to 20 or a pharmaceutical composition as defined in claim 21 or claim 21 for use in the prophylaxis or treatment of a disease or condition mediated by potassium channel inhibition, such as inhibition of Kv7, in particular diseases associated with changes in motor neuron excitability, neurodevelopmental diseases, pain, psychiatric disorders, neuropathies and hearing disorders.

25. A process for preparing a compound of formula (I) as defined in any of claims 1 to 20 which comprises:(a) reacting a compound of formula (II):CLI-C-P3879PCTwherein R1, R3, n, X and Y are as defined in claim 1 and L1represents a suitable leaving group, such as a halogen atom (e.g. bromine or iodine), with a compound of formula (III):wherein R4, p and R2are as defined in claim 1;(b) reacting a compound of formula (IV):wherein R3, n, X, Y, R4, p and R2are as defined in claim 1, with a compound of formula R1-C(=O)-L2, wherein R1is as defined in claim 1 and L2represents OH, or L2is a suitable leaving group, such as a halogen atom (e.g. chlorine);(c) deprotection of a protected derivative of a compound of formula (I);(d) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and(e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

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