Heterocyclic compounds and their use for the treatment of neurological disorders

Abstract

The present invention relates to novel synthetic compounds of Formula (I) and (II) related to naturally occurring flavonoids such as 7,8-dihydroxyflavone (7,8-DHF). The invention further relates to the method of synthesis, the use of these compounds as research tools and their use as pharmaceuticals.

Description

HETEROCYCLIC COMPOUNDS AND THEIR USE FOR THE TREATMENT OF NEUROLOGICAL DISORDERS

[0001] The present disclosure is related to and claims benefit of GB2318964.0 filed on 12 December 2023, and GB2414004.8 filed on 24 September 2024 the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to novel synthetic compounds related to naturally occurring flavonoids such as 7,8-dihydroxyflavone (7,8-DHF). The invention further relates to the method of synthesis, the use of these compounds as research tools and their use as pharmaceuticals.BACKGROUND TO THE INVENTION

[0003] Flavonoids are a large class of plant secondary metabolites, and they are also common polyphenols in the human diet. Studies have shown that flavonoids have various pharmacological activities, such as anti-tumor, anti-inflammatory, and antioxidant properties. The flavonoid, 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aesculifolio, Tridax procumbens and Primula helleri leaves. It is known to act as a potent and selective agonist of tropomyosin receptor kinase B (TrkB), which is the main signaling receptor of neurotrophin brain-derived neurotrophic factor (BDNF).

[0004] 7,8-DHF has been shown to have therapeutic efficacy in several animal models including depression, Alzheimer’s disease, cognitive deficits in schizophrenia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome and Rett syndrome.

[0005] A derivative of 7,8-DHF, 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8- yl)benzonitrile, also known as CF3CN has been shown to be useful in the treatment of various diseases and conditions including neurodegenerative diseases and movement disorders.

[0006] There is a need for the development of improved flavonoid-like compounds, as well as compositions and therapeutic uses thereof.BRIEF SUMMARY OF THE INVENTION

[0007] At its most general, the present invention relates to novel synthetic flavonoid compounds.

[0008] Compounds were tested in a primary neuronal culture functional assay to determine whether they were able to promote neuronal survival upon insult.

[0009] In a first aspect of the present invention there is provided a compound of Formula I or Formula II or a salt thereof,Formula I Formula IIWherein:3333is a single or double bond;Ri is selected from the group consisting of: Cl, F, Br, H, OH, O-alkyl (C1-C6), O-fluoroalkyl (C1- C6), alkyl (C1-C6), fluoroalkyl(C1-C6), NH2, NH-alkyl(C1-C6) N-alkyh (C1-C6), cycloalkyl (C3- C6), fluorocycloalkyl (C3-C6), CH2-cycloalkyl (C3-C6), and CHF-cycloalkyl (C3-C6).R2is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, O-alkyl (C1-C6), SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).Rs if present, when Y is selected from N or C, is selected from the group consisting of: H, alkyl(C1-C6), fluoroalkyl(C1-C6); cycloalkyl (C3-C6), alkyl (C1-C6)-OH, alkyl-(C1-C6)-OMe, alkyl-(C1-C6)-cycloalkyl (C3-C6), and deutereoalkyl (C1-C6).R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine, piperidine, or pyrrolidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyl2(C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2- heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl.Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).X is independently selected from the group consisting of: N or C.Y is independently selected from the group consisting of: O, N, C, and S.

[0010] In a second aspect of the present invention, there is provided a compound of Formula III, or a salt thereof, Formula IIIWherein:3333is a single or double bond;Ri and R2 are independently selected from the group consisting of: OH, OMe, O-alkyl(C1-C6), O-fluoro alkyl(C1-C6), OiPr, SMe, SFs, alkyl(C1-C6), fluoro alkyl(C1-C6), pyrazole, methyl pyrazole, oxazole, imidazole, thiazole, triazole oxadiazole, and thiadiazole; where the heterocycles can be substituted with alkyl(C1-C3).R3 is selected from the group consisting of: alkyl(C1-C6), fluoro alkyl(C1-C6), Cl, F, I, Br, CN, H O-alkyl (C1-C6).R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine or piperidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyh (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2-heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl.Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).

[0011] Preferably the compound of the invention with respect to either Formula I, Formula II or Formula III is defined by any one of the compounds numbered 1 to 50 in Table 1.

[0012] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III, or a salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0013] In a fourth aspect of the present invention, there is provided a compound of Formula I, Formula II, or Formula III or a pharmaceutical composition comprising the compound of Formula I, Formula II, or Formula III, for use as a medicament.

[0014] In a fifth aspect of the invention, there is a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula I, Formula II, or Formula III.

[0015] In a sixth aspect of the invention, there is provided a method of synthesizing the compound of Formula I, Formula II, or Formula III.

[0016] In a seventh aspect of the invention, there is provided an intermediate formed in the method of synthesis of the compound of Formula I, Formula II, or Formula III.

[0017] These and other aspects and embodiments of the invention are described in further detail below.DEFINITIONS

[0018] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8 alkyl) or one to six carbon atoms (C1-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0019] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0020] The term “cycloalkyl” employed alone or in combination with other terms, refers to a nonaromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g. having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring-forming carbons (C3 - C7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic or spirocyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e. having a bond in common with) to the cycloalkyl ring, e.g. benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, and cyclohexadienyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, nonane and adamantane. Spirocyclic cycloalkyl groups include, but are not limited to spiro-, heptane, octane, nonane, decane and undecane.

[0021] The term " heterocycloalkyl” employed alone or in combination with other terms, refers to both aromatic and non-aromatic rings or ring systems, which may optionally contain one or more carbon-carbon double bonds as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and which has 3 - 12 total ring members. Any heterocycloalkyl ring member may be further mono-, or di-, alkylated (C1-C6) if allowed by rules for carbon valency. Included within the term "heterocycloalkyl” are monocyclic 3-, 4-, 5-, 6-, and 7-, membered heterocycloalkyl groups. Heterocycloalkyl groups can include bicyclic (e.g. having two fused or bridged rings) or spirocyclic (e.g. having two ring systems fused by a single shared carbon atom) ring systems containing 3-12 total ring members. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1 , 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocycloalkyl group is a poly-, or spirocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g. C (O), S (O), C (S) or S (0)2, N- oxide etc.) or a nitrogen atom can be quaternized. Where a heteroatom is selected to be a nitrogen, this heteroatom may be further functionalized to the corresponding N-alkyl(C1-C6), N- fluoroalkyl (C1-C6) or N-C0-Alkyl(C1-C6). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e. having a bond in common with) to the heterocycloalkyl ring, e.g. benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of monocyclic heterocycloalkyl groups include, but are not limited to oxirane, aziridine, azetidine, pyrrolidine, piperidine, piperizine, pyridine, pyrimidine, pyridazine, pyrazole, pyrrole, imidazole, morpholine, dioxane, pyran, furan, thiophene, thoiazole, and oxazole in any variation of saturation. Examples of polycyclic heterocycloalkyl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzimidazole, chromane, chromene, and coumarine. Examples of spirocyclic heterocycloalkyls include, but are not limited to, 1-oxa-8- azaspiro[4.5]decane, 2,2-dimethyl-1-oxa-8-azaspiro[4.5]decane, 1,1-dimethyl-2-oxa-8- azaspiro[4.5]decane 3-oxa-9-azaspiro[5.5]undecane, 2,6-diazaspiro[3.4]octan-5-one

[0022] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkenyl groups containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl). Exemplary alkenyl groups include ethenyl (j.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0023] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including straightchain or branched-chain alkynyl groups containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0024] “Aryl” refers to an all carbon monocyclic or fused-ring polycyclic (i.e. , rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.

[0025] “Ester” refers to a functional group -COO and may also be referred to as an “ester link”. Esters are formed by the condensation reaction between an alcohol and a carboxylic acid.

[0026] The term “halo” or, alternatively, “halogen” means fluoro or fluorine, chloro or chlorine, bromo or bromine and iodo or iodine.

[0027] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocycle, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, a heterocycloalkyl, an aromatic and heteroaromatic moiety.

[0028] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0029] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0030] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0031] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0032] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching deuterium may afford certain therapeutic advantages, such as increased in vivo halflife and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0033] “Isomers” are different compounds that have the same molecular formula. “Regioisomers” are isomers that differ only in the attachment point of a single functional group. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system.When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0034] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0035] Isolation and purification of the chemical entities and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0036] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, / .e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization inthe presence of a resolving agent, or chromatography, using, for example, a chiral high- pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration. In addition, such certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.

[0037] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0038] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth;(5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0039] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.DETAILED DESCRIPTION OF THE INVENTION

[0040] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entirety are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0041] Modifying tropoflavin compounds can significantly change their chemical and biological properties. Such chemical functional groups can include a polar moiety, a monosaccharide, disaccharide, a carbohydrate, an amino acid, an acyl group, a diacid group, and other chemical moieties. For biological systems, the addition of such modifying functional groups can significantly alter the resulting biological activity or tissue targeting. For the end use of thesecompounds, modifications have major impacts on downstream formulations, preparations, pharmacokinetics, pharmacodynamics, and ultimate end uses.Compounds

[0042] In embodiments, the present disclosure provides a compound of Formula I, Formula II, or a salt thereof:Formula I Formula IIWherein:- is a single or double bond;Ri is selected from the group consisting of: Cl, F, Br, H, OH, O-alkyl (C1-C6), O-fluoroalkyl (CI- 06), alkyl (C1-C6), fluoroalkyl(C1-C6), NH2, NH-alkyl(C1-C6) N-alkyh (C1-C6), cycloalkyl (C3- C6), fluorocycloalkyl (C3-C6), CH2-cycloalkyl (C3-C6), and CHF-cycloalkyl (C3-C6);R2is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, O-alkyl (C1-C6), SMe, ON, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);R3if present when Y is selected from N or C, is selected from the group consisting of: H, alkyl(C1-C6), fluoroalkyl(C1-C6); cycloalkyl (C3-C6), alkyl (C1-C6)-OH, alkyl-(C1-C6)-OMe, alkyl-(C1-C6)-cycloalkyl (C3-C6) and deutereoalkyl (C1-C6).;R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine, piperidine, or pyrrolidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), acyl, fluoroalkyl (C1-C6), N-alkyl2(C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2-heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl;R5is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);X is independently selected from the group consisting of: N or C; andY is independently selected from the group consisting of: O, N, C, and S.

[0043] In embodiments, the present disclosure provides a compound of Formula III or a salt thereof:Formula IIIWherein:7333is a single or double bond;Ri and R2are independently selected from the group consisting of: OH, OMe, O-alkyl(C1-C6), O-fluoro alkyl(C1-C6), OiPr, SMe, SF5, alkyl(C1-C6), fluoro alkyl(C1-C6), pyrazole, methyl pyrazole, oxazole, imidazole, thiazole, triazole oxadiazole, and thiadiazole; where the heterocycles can be substituted with alkyl(C1-C3).R3 is selected from the group consisting of: alkyl(C1-C6), fluoro alkyl(C1-C6), Cl, F, I, Br, CN, H O-alkyl (C1-C6).R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine or piperidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl(C1-C6), N-alkyh (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2-heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl.Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).

[0044] In embodiments, provided herein is one or more compounds selected from Table 1. The compounds detailed in Table 1 , with the exception of compounds 10, 119 and 120 are within the scope of the compounds of Formulas I to III. Such compounds are further exemplified to substantiate the compounds of Formulas I to III.

[0045] In embodiments, provided herein is one or more pharmaceutically acceptable salts of a compound selected from Table 1.Table 1. CompoundsCompositions

[0046] The compounds described herein may be formulated as a pharmaceutical composition. A pharmaceutical composition may comprise: (i) a compound of Formula I, Formula II or Formula III, as detailed in Table 1, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0047] In embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone. In embodiments, suitable pharmaceuticallyacceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier. Other suitable carriers, diluents, or excipients are well- known to those in the art. (See, e.g., Gennaro (ed.), Remington's Pharmaceutical Sciences (Mack Publishing Company, 19th ed. 1995).) Formulations can further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc.

[0048] Pharmaceutical compositions comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 or a pharmaceutically acceptable salt thereof, may also contain one or more additional ingredients including, but not limited to, a mucoadhesive compound, a buffering agent, a plasticizing agent, a stabilizing agent, a taste-masking agent, a flavoring agent, a coloring agent, an antiseptic, an inert filler agent, a preservative, and combinations thereof.

[0049] In embodiments, the formulations may comprise one or more solubilizing agents that increase the solubility of active compounds in the formulation. Suitable solubilizing agents include, for example, complexing agents, surfactants, and the like. Suitable complexing agents include unsubstituted cyclodextrins (such as alpha-cyclodextrin, beta-cyclodextrin) and substituted cyclodextrins, (such as hydroxypropyl beta-cyclodextrin, sulfobutylether-beta- cyclodextrin). Suitable surfactants include polyoxyethylene sorbitan monolaurate (for example, Tween 20), polyoxyethylene sorbitans monooleate (for example, Tween 80), polyethylene glycol (15)-hydroxystearate (for example, Kolliphor® HS 15), PEG-35 castor oil (for example, Kolliphor® EL) and PEG-60 hydrogenated castor oil (for example, Cremophor® RH 60).

[0050] In embodiments, the formulations comprise one or more buffer agents that maintain the pH of the IV solution within a pharmaceutically acceptable range. In certain embodiments, the buffer maintains the pH of the IV solution between about 5 and 9. In specific embodiments, the buffer maintains the pH of the IV solution at about 7.4. Suitable buffers include, for example, citrates, lactate, acetate, maleate, phosphates, and the like. In embodiments, the formulations comprise one or more density modifiers that are used to control the density of the IV formulation. Suitable density modifiers include, for example, dextrose. In embodiments, the formulations comprise one or more isotonicity modifiers that provide a formulation that is iso- osmotic with tissue to prevent pain and irritation when the formulation is administered. Suitable isotonicity modifiers include, for example, electrolytes, monosaccharides, and disaccharides. Examples of isotonicity modifiers include glycerin, dextrose, potassium chloride, and sodium chloride.

[0051] In embodiments, the formulations comprise one or more viscosity enhancers. Suitable viscosity enhancers include, for example, povidone, hydroxyethylcellulose, polyvinyl alcohol, and carbomer (such as, acrylic acid homopolymers and acrylic acid copolymers).

[0052] In embodiments, the formulations comprise one or more preservatives that increase the stability of active compounds in the formulation and / or provide antimicrobial activity. Suitable preservatives include, for example, antimicrobial agents and antioxidants. Examples of antimicrobial agents include benzyl alcohol, methyl paraben, propyl paraben, phenol, cresol, methyl paraben, chlorbutanol, sodium metabisulphite, sodium bisulphite, benzethonium chloride, and benzalkonium chloride. Examples of antioxidants include sodium bisulphite and other sulfurous acid salts, ascorbic acid, salts of ethylenediaminetetraacetic acid (including sodium), alpha tocopherol, butylated hydroxyl hydroxytoluene, and butylated hydroxyanisole.

[0053] A pharmaceutical composition comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof; may be formulated in a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form, a liquid, a lozenge, a fast disintegrating tablet, a lyophilized preparation, a film, a spray (including a nasal spray, an oral spray, or a topical spray), or a mucoadhesive. The oral unit dosage form may be selected from the group consisting of: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays. In embodiments, the modified mesembrine alkaloid is formulated as a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, or a mucoadhesive.

[0054] The compounds of Formula (I) or Formula (II), as detailed in Table 1, or a pharmaceutically acceptable salt thereof can be administered to subjects by a variety of administration modes, including, for example, by intramuscular, subcutaneous, intravenous, intra-atrial, intra-articular, parenteral, intranasal, intrapulmonary, transdermal, intrapleural, intrathecal, and oral routes of administration. For prevention and treatment purposes, a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof can be administered to a subject in a single bolus delivery, via continuous delivery (e.g., continuous transdermal delivery) over an extended time period, or in a repeated administration protocol (e.g., on an hourly, daily, weekly, or monthly basis).

[0055] Pharmaceutical compositions comprising a compound of Formula (I) or Formula (II), as detailed in Table 1 , or a pharmaceutically acceptable salt thereof can be supplied as a kit comprising a container that comprises the pharmaceutical composition as described herein. A pharmaceutical composition can be provided, for example, in the form of an injectable solution for single or multiple doses, or as a sterile powder that will be reconstituted before injection. Alternatively, such a kit can include a dry-powder disperser, liquid aerosol generator, or nebulizer for administration of a pharmaceutical composition. Such a kit can further comprise written information on indications and usage of the pharmaceutical composition.Therapeutic Use

[0056] The compounds of Formula I, Formula II, or Formula III, as detailed in Table 1, have demonstrated efficacy in an in vitro neuronal survival assay. Therefore, the novel synthetic flavonoid compounds of the invention may be useful in the treatment or prevention of medical conditions. More specifically the activity of these compounds is likely to enable their use in the treatment or prevention of medical conditions associated with neurodegeneration.WORKED EXAMPLES

[0057] The compounds of the present invention were synthesized using the synthetic reaction schema described in Example 1.

[0058] Reaction products can be purified by known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, MeOH and the like, preparative reverse phase high pressure liquid chromatography, or preparative supercritical fluid chromatography.

[0059] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

[0060] Example 2 describes the efficacy of these compounds in an in vitro neuronal survival assay.EXAMPLE 1 :

[0061] In order to prepare the compounds of Formula I and Formula II as exemplified by the compounds 1 to 125 in Table 1, the following reaction methodologies were employed.Abbreviations:General InformationSolvents and Reagents

[0062] Organic Solvents and chemical reagents were purchased from commercial sources and used as received unless otherwise stated.Preparation of Intermediates

[0063] Known synthetic intermediates were procured from commercial vendors or were obtained using published literature procedures with reference to original published literature as annotated. Additional intermediates were prepared by the representative synthetic processes described herein.Nuclear Magnetic Resonance Spectroscopy (NMR)

[0064] NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe, or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software.Mass Spectrometry (MS)

[0065] Compounds were analysed by Ultra High Performance Liquid Chromatography Mass Spectroscopy (UPLC) or Liquid Chromatography Mass Spectrometry (LCMS) as indicated.

[0066] All UPLC / LCMS methods were 3 minute runs unless otherwise indicated.UPLC (Method 1)Apparatus: Waters HCIass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa Column: Waters ACQUITY UPLC® BEH C18, 1.7 pm, 2.1 x 30 mm at 40 °CDetection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisationSolvents: A: 0.1% Ammonia in water, B: MeCNGradient:UPLC (Method 2)Column: ACQUITY UPLC® BEH C18, 130A, 1.7 pm, 2.1 x 30 mm at 40 °CDetection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisationSolvents: A: 0.1% Ammonia in water, B: MeCNGradient:LCMS (Method 1)Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSColumn: Waters Cortecs C18, 30 x 2.1 mm, 2.7pm, at 40 °CDetection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisationSolvents: A: 0.1% formic acid in water, B: MeCNGradient:LCMS (Method 2}Column: Phenomenex Evo C18, 30 x 2.1 mm, 2.6pm, at 40 °CDetection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisationSolvents: A: 0.1% Ammonia in water, B: MeCNGradient:General ProceduresGeneral Procedure 1: Suzuki coupling with pyrazoleboronic esters

[0067] A N2-purged vial containing the 8-bromoflavone (0.37-0.91 mmol, 1 Eq), pyrazole boronic ester (1.5-2.8 Eq), and Pd(dtbpf)Cl2 (Pd-118) (5 mol%) was charged with aq. tripotassium phosphate (1.5 M, 4 Eq) and 1,4-dioxane (4 mL).

[0068] The mixture was stirred at 95 °C for 90 min, then cooled to rt. The mixture was diluted with EtOAc (25 mL), washed with 1:1 water / brine (25 mL) and brine (10 mL), dried over MgSC , filtered and concentrated. The residue was purified by chromatography or trituration as stated to give the product.General Procedure 2: Triazole displacement

[0069] A vial containing the appropriate triazole bearing chromanone (1 Eq), the amine nucleophile (1.3-2 Eq) and potassium carbonate (2-5 Eq) was charged with NMP (1-2 mL). The mixture was stirred at 80-120 °C for the indicated time.

[0070] The mixture was cooled to rt and either purified immediately if indicated or diluted with EtOAc (10 mL), washed with 1:1 brine / water (2 x 10 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography or trituration as stated to give the product.General Procedure 3: Demethylation

[0071] A N2-purged flask containing the anisole starting material and pyridine hydrochloride (0.30 g, 2.6 mmol) was stirred at 180 °C for 15 min, then cooled to rt.

[0072] The mixture was diluted with water (4 mL) and sonicated until a fine suspension was obtained. The solid was collected by filtration, rinsed with water (3 x 1 mL) and MeCN (3 x 1 mL), then dried to give the phenol. Any further purification was performed as described.General Procedure 4: Purification by Preparative High Performance Liquid Chromatography (prep HPLC)

[0073] Experiments were performed using a Waters system (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa or a Gilson system (Gilson 215 Liquid handler, Gilson 819 Injection module, Gilson 333 Pump, Gilson 334 Pump, Gilson 304 Pump, Gilson UV / Vis-155) unless otherwise specified. Specificconditions deviating from the methods mentioned below, including mobilephase compositions, gradient information and column specifications are described for individual compounds.Method 1.

[0074] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation. The solution was filtered and injected onto a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.3% Ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages, (Waters system).Method 2.

[0075] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation. The solution was filtered and injected onto a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1methanol over the entire method, which is included in the individually provided MeCN percentages, (Waters system).Method 3

[0076] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation. The solution was filtered and injected onto a Waters XSelect CSH C18, 10pm, 30 X 250 mm prep column, flow rate 42 mL min-1 eluting with a 0.1% Formic Acid in water-MeCN gradient over 18 min. Monitoring UV across all wavelengths. At-column dilution pump gives 5 mL min-1 MeCN for 1.2 min, (Gilson System).Method 4

[0077] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation. The solution was filtered and injected onto a Waters XSelect CSH C18, 10pm, 30 X 250 mm prep column, flow rate 42 mL min-1 eluting with a 0.1% Formic Acid in water-MeCN gradient over 24 min. Monitoring UV across all wavelengths. At-column dilution pump gives 5 mL min-1 MeCN for 1.2 min, (Gilson system).Method 5

[0078] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure compete solvation. The solution was filtered and injected onto a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the given MeCN percentages, (Waters system).Method 6

[0079] The product was dissolved in a suitable mixture of mobile phases and DMSO to ensure complete solvation. The solution was filtered and injected onto a on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the given MeCN percentages, (Waters system).Purification by Supercritical Fluid Chromatography (SFC)

[0080] Experiments were performed using a Waters Prep 15 with a PDA detector, 40 °C, 120 bar, a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar, a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar or a Waters UPC2 with UV detection at 220-400 nm, 124 bar. Specific conditions including mobilephase compositions, gradient information and column specifications are described for individual compounds and their purification.

[0081] The following synthetic pathways were used to prepare compound 1 to 125 of Table 1.Compound 18-Bromo-7-hvdroxy-2-phenyl-4H-chromen-4-one

[0082] To a solution of 7-hydroxy-2-phenyl-4H-chromen-4-one (5.0 g, 1 Eq, 21 mmol) in DMF (50 mL) at 3 °C (internal) was added a solution of NBS (4.0 g, 1.1 Eq, 22 mmol) in DMF (10 mL). The mixture was stirred at 3 °C for 2 h. The mixture was diluted with water (120 mL) to give a thick suspension. The solid was collected by filtration (4 x 10 mL of water was used to complete the transfer), rinsed with MeCN (4 x 10 mL) and suspended in isopropanol (150 mL).The slurry was stirred at 80 °C overnight, then left to stand at rt for 1 h. The solid was collected by filtration, rinsed with isopropanol (3 x 10 mL) and TBME (3 x 10 mL), then dried to give 8- bromo-7-hydroxy-2-phenyl-4H-chromen-4-one (5.8 g, 15 mmol, 72%) as a white solid.

[0083] 1H NMR (500 MHz, DMSO): 5 11.65 (s, 1H), 8.16 - 8.11 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.11 (d, J = 8.8 Hz, 1 H), 7.03 (s, 1 H). MS: The product was analysed by UPLC (Method 1): m / z 317 / 319 [M+H]+(ES+); 315 / 317 [M-H]’ (ES-), at0.70 min, 80% purity 210-400nm.8-Bromo-7-methoxy-2-phenyl-4H-chromen-4-one

[0084] To a suspension of 8-bromo-7-hydroxy-2-phenyl-4H-chromen-4-one (1.0 g, 83% Wt, 1 Eq, 2.6 mmol) and potassium carbonate (1.0 g, 2.8 Eq, 7.2 mmol) in DMF (10 mL) was added iodomethane (1.0 g, 0.45 mL, 2.7 Eq, 7.2 mmol). The mixture was stirred at rt for 5 h. The mixture was diluted with water (30 mL). The solid was collected by filtration, rinsed with water (3 x 5 mL) and dried (0.90 g). Purification by column chromatography using a gradient of 0-75% THF in [1 :1 DCM / isohexane] gave 8-bromo-7-methoxy-2-phenyl-4H-chromen-4-one (0.74 g, 2.2 mmol, 85%) as a white solid.

[0085] 1H NMR (500 MHz, DMSO): 5 8.17 - 8.11 (m, 2H), 8.04 (d, J = 8.9 Hz, 1 H), 7.66 - 7.57 (m, 3H), 7.34 (d, J = 8.9 Hz, 1H), 7.07 (s, 1H), 4.03 (s, 3H). MS: The product was analysed by UPLC (Method 1): m / z 331 / 333 [M+H]+(ES+); no ionisation ES-, at 1.58 min, >99% purity 210- 400 nm.7-Methoxy-8-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (1)

[0086] 8-Bromo-7-methoxy-2-phenyl-4H-chromen-4-one (300 mg, 1 Eq, 905 pmol) was coupled with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (290 mg, 1.53 Eq, 1.39 mmol) according to General Procedure 1 (with the exception that the reaction was performed at 80 °C for 1 h). Purification by column chromatography using a gradient of 0- 100% EtOAc in isohexane gave 7-methoxy-8-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-4H-chromen- 4-one (266 mg, 0.79 mmol, 88%) as a white solid.

[0087] 1H NMR (500 MHz, DMSO): 5 8.19 (d, J = 9.0 Hz, 1 H), 7.79 - 7.73 (m, 2H), 7.63 (d, J = 1.8 Hz, 1 H), 7.58 - 7.52 (m, 1 H), 7.52 - 7.45 (m, 2H), 7.42 (d, J = 9.1 Hz, 1 H), 7.03 (s, 1 H), 6.52 (d, J = 1.8 Hz, 1 H), 3.95 (s, 3H), 3.62 (s, 3H). MS: The product was analysed by UPLC (Method 1): m / z 333 [M+H]+(ES+); no ionisation ES-, at 1.22 min, >99% purity 210-400nm.Compound 28-Bromo-6-chloro-7-hvdroxy-2-phenyl-4H-chromen-4-one

[0088] A suspension of 8-bromo-7-hydroxy-2-phenyl-4H-chromen-4-one (contaminated with dibromo derivative) (0.92 g, 86% Wt, 1 Eq, 2.5 mmol) and NCS (0.50 g, 1.5 Eq, 3.7 mmol) in DMF (9 mL) was stirred at 60 °C for 90 min. The mixture was cooled to rt and diluted with TBME (20 mL). The solid was collected by filtration, rinsed with TBME (3 x 3 mL) and dried to give 8-bromo-6-chloro-7-hydroxy-2-phenyl-4H-chromen-4-one (0.58 g, 1.3 mmol, 52%) as a white solid.

[0089] 1H NMR (500 MHz, DMSO): 5 8.11 (dd, J= 7.7, 2.0 Hz, 2H), 8.08 (s, 1 H), 7.64 - 7.58 (m, 3H), 7.09 (s, 1 H). MS: The product was analysed by LCMS (Method1): m / z 351 / 353 / 355 [M+H]+(ES+); 349 / 351 / 353 [M-H]' (ES-), at 1.51 min, 78% purity 254 nm8-Bromo-6-chloro-7-methoxy-2-phenyl-4H-chromen-4-one

[0090] To a suspension of 8-bromo-6-chloro-7-hydroxy-2-phenyl-4H-chromen-4-one (0.57 g, 78% Wt, 1 Eq, 1.3 mmol) and potassium carbonate (0.60 g, 3.4 Eq, 4.3 mmol) in DMF (8 mL) was added iodomethane (0.57 g, 0.25 mL, 3.2 Eq, 4.0 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (25 mL) and stirred at rt for 10 min. The solid was collected by filtration, rinsed with water (3 x 2 mL) and dried (0.57 g). The crude product was purified by column chromatography using a gradient of 0-30% THF / [1 :1 DCM / isohexane]) to give 8-bromo-6-chloro-7-methoxy-2-phenyl-4H-chromen-4-one (0.50 g, 1.1 mmol, 90%) as a white solid.

[0091] 1H NMR (500 MHz, DMSO): 5 8.17 (s, 1 H), 8.14 - 8.10 (m, 2H), 7.67 - 7.59 (m, 3H), 7.17 (s, 1 H), 3.97 (s, 3H). MS: The product was analysed by LCMS (Method1): m / z 365 / 367 / 369 [M+H]+(ES+); no ionisiation ES-, at 1.83 min, 87% purity at 254 nm.6-Chloro-7-methoxy-2-phenyl-8-( 1 H-pyrazol-5-yl)-4H-chromen-4-one (2)

[0092] 8-Bromo-6-chloro-7-methoxy-2-phenyl-4H-chromen-4-one (140 mg, 1 Eq, 383 pmol) was coupled with 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (200 mg, 2.69 Eq, 1.03 mmol) according to General Procedure 1. Purification by column chromatography using a gradient of 0-100% [10% MeOH in THF] in isohexane followed by trituration with MeCN (2 mL) gave 6-chloro-7-methoxy-2-phenyl-8-(1 H-pyrazol-5-yl)-4H-chromen-4-one (34 mg, 94 pmol, 25%, 98% Purity) as a white solid.

[0093] 1H NMR (500 MHz, DMSO) 5 13.21 (s, 1 H), 8.52 (s, 1 H), 8.18 - 8.12 (m, 2H), 7.90 (s, 1 H), 7.68 - 7.59 (m, 3H), 7.14 (s, 1 H), 6.82 (d, J = 2.3 Hz, 1 H), 3.86 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 353 / 355 [M+H]+(ES+); 351 / 353 [M-H]’ (ES-), at 1.53 min, 98% purity at 254 nm.Compound 36-Chloro-7-methoxy-8-(1-methyl-1 H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (3)

[0094] 8-Bromo-6-chloro-7-methoxy-2-phenyl-4H-chromen-4-one (140 mg, 1 Eq, 383 pmol) was coupled with 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (200 mg, 2.51 Eq, 961 pmol) according to General Procedure 1. Purification by column chromatography using a gradient of 0-100% [10% MeOH / EtOAc] in isohexane gave the desired product with one major impurity. Trituration with 25% TBME / isohexane (2 mL) to remove the contaminant gave 6-chloro-7-methoxy-8-(1 -methyl- 1 H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (63 mg, 0.17 mmol, 44%) as a white solid.

[0095] 1H NMR (400 MHz, DMSO): 5 8.19 - 8.11 (m, 2H), 7.89 (s, 1 H), 7.69 - 7.60 (m, 3H), 7.57 (d, J = 1.9 Hz, 1 H), 7.20 (s, 1 H), 6.50 (d, J = 1.9 Hz, 1 H), 3.71 (s, 3H), 3.61 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 367 / 369 [M+H]+(ES+); No ionisation ES-, at 1.60 min, 98% purity at 254 nm.Compound 47-(Benzyloxy)-8-bromo-2-phenyl-4H-chromen-4-one

[0096] To a suspension of 8-bromo-7-hydroxy-2-phenyl-4H-chromen-4-one (1.0 g, 83% Wt, 1 Eq, 2.6 mmol) and potassium carbonate (1.0 g, 2.8 Eq, 7.2 mmol) in DMF (10 mL) was added benzyl bromide (0.72 g, 0.50 mL, 1.6 Eq, 4.2 mmol). The mixture was stirred at rt overnight.

[0097] The mixture was diluted with water (30 mL). The solid was collected by filtration, rinsed with water (3 x 5 mL) and dried. Purification by column chromatography using a gradient of 0- 25% THF in [50% DCM / isohexane] gave 7-(benzyloxy)-8-bromo-2-phenyl-4H-chromen-4-one (0.91 g, 2.2 mmol, 83%) as a white solid.

[0098] 1H NMR (500 MHz, DMSO): 5 8.17 - 8.11 (m, 2H), 8.03 (d, J = 8.9 Hz, 1 H), 7.66 - 7.56 (m, 3H), 7.56 - 7.48 (m, 2H), 7.47 - 7.40 (m, 3H), 7.40 - 7.34 (m, 1 H), 7.08 (s, 1 H), 5.41 (s, 2H). MS: The product was analysed by LCMS (Method 1): m / z 407 / 409 [M+H]+(ES+); no ionisation ES-, at 1.94 min, 97% purity at 254 nm.7-(Benzyloxy)-2-phenyl-8-( 1 H-pyrazol-5-yl)-4H-chromen-4-one

[0099] 7-(Benzyloxy)-8-bromo-2-phenyl-4H-chromen-4-one (150 mg, 1 Eq, 368 pmol) was coupled 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (200 mg, 2.80 Eq, 1.03 mmol) according to General Procedure 1. Purification by column chromatography using a gradient of 0-100% [10% MeOH / EtOAc] in isohexane gave 7-(benzyloxy)-2-phenyl-8-(1 H- pyrazol-5-yl)-4H-chromen-4-one (134 mg, 0.33 mmol, 90%) as a white solid.

[0100] 1H NMR (500 MHz, DMSO): 5 13.16 (s, 1 H), 8.07 (br-s, 1 H), 7.97 (br-s, 1 H), 7.94 - 7.84 (br-m, 1.5H), 7.68 (br-s, 0.5H), 7.58 - 7.53 (m, 1 H), 7.53 - 7.47 (m, 2H), 7.47 - 7.40 (m, 3H), 7.40 - 7.35 (m, 2H), 7.35 - 7.28 (m, 1 H), 7.02 (s, 1 H), 6.61 (s, 1 H), 5.34 (s, 2H). Fractional integrals due to pyrazole tautomers. MS: The product was analysed by LCMS (Method 1): m / z 395 [M+H]+(ES+); 393 [M-H]’ (ES-), at 1.49 min, >98% purity at 254 nm.7-hydroxy-2-phenyl-8-( 1 H-pyrazol-5-yl)-4H-chromen-4-one (4)

[0101] To a solution of 7-(benzyloxy)-2-phenyl-8-(1H-pyrazol-5-yl)-4H-chromen-4-one (50 mg, 1 Eq, 0.13 mmol) in EtOH (2 mL) and THF (2 mL) was added 5% palladium on carbon (wetted with 50% water, type 87L) (10 mg, 2.5% Wt, 0.019 Eq, 2.3 pmol). The mixture was stirred at rt under 5 bar H2 in a steel pressure reactor for 1 h. Further 5% palladium on carbon (wetted with 50% water, type 87L) (20 mg, 2.5% Wt, 0.037 Eq, 4.7 pmol) was added and the mixture was stirred at 35 °C under 5 bar H2 in a steel pressure reactor for 2 h. The mixture was filtered (Whatman GF / F glass microfibre pad) and the pad was rinsed with MeOH (50 mL). The filtrate was concentrated and the residue was triturated with MeCN (3 mL) and dried. This material was dissolved in 1.5 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At- column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 2% MeCN; 0.5-10.5 min, ramped from 2% MeCN to 25% MeCN; 10.5-10.6 min, ramped from 25% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give 7-hydroxy-2-phenyl-8-(1H-pyrazol-5-yl)-4H-chromen-4-one (6 mg, 0.02 mmol, 20%) as a white solid.

[0102] 1H NMR (400 MHz, DMSO): 5 13.51 (s, 1H), 12.57 (s, 1H), 8.07 - 7.95 (m, 3H), 7.94 (d, J = 8.8 Hz, 1H), 7.65 - 7.53 (m, 3H), 7.11 (d, J = 8.8 Hz, 1 H), 6.98 - 6.85 (m, 2H). MS: The product was analysed by LCMS (Method 1): m / z 305 [M+H]+(ES+); 303 [M-H (ES-), at 1.30 min, 98% purity at 254 nm.Compound 57-Hvdroxy-8-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (5)

[0103] A N2-purged flask containing 7-methoxy-8-(1-methyl-1 H-pyrazol-5-yl)-2-phenyl-4H- chromen-4-one (0.15 g, 1 Eq, 0.45 mmol) and pyridine hydrochloride (0.60 g, 12 Eq, 5.2mmol) was stirred at 180 °C for 1 h. The mixture was cooled to rt, then diluted with water (10 mL) and sonicated until a fine suspension was obtained. The solid was collected by filtration, rinsed with water (3 x 1 mL) and MeCN (3 x 1 mL), then dried (98 mg, 82% LCMS). Purification by column chromatography using a gradient of 0-100% [10% MeOH / THF] in isohexane) gave the product (89 mg), which was triturated with MeCN (2 mL) to give 7-hydroxy-8-(1-methyl-1H- pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (57 mg, 0.17 mmol, 37%, 94% Purity) as an off- white solid. This material was dissolved in 1.2 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramped from 5% MeCN to 30% MeCN; 10.5-10.6 min, ramped from 30% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give 7-hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-2-phenyl-4H-chromen- 4-one (14 mg, 44 pmol, 9.6%) as a white solid.

[0104] 1H NMR (500 MHz, DMSO): 5 7.99 (d, J = 8.8 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.61 (d, J = 1.9 Hz, 1 H), 7.56 - 7.51 (m, 1H), 7.51 - 7.44 (m, 2H), 7.11 (d, J = 8.8 Hz, 1 H), 6.96 (s, 1H), 6.49 (d, J = 1.9 Hz, 1H), 3.65 (s, 3H). MS: The product was analysed by UPLC (Method 1): m / z 319 [M+H]+(ES+); 317 [M-H]’ (ES-), at 0.62 min, 98% purity at 210-400 nm.Compound 66-Chloro-7-hvdroxy-2-phenyl-8-(1 H-pyrazol-5-yl)-4H-chromen-4-one (6)

[0105] 6-Chloro-7-methoxy-2-phenyl-8-(1H-pyrazol-5-yl)-4H-chromen-4-one (24 mg, 1 Eq, 68 pmol) was demethylated according to General Procedure 3 to give 6-chloro-7-hydroxy-2-phenyl- 8-(1 H-pyrazol-5-yl)-4H-chromen-4-one (20 mg, 56 pmol, 82%) as a white solid.

[0106] 1H NMR (500 MHz, DMSO): 5 13.59 (s, 1 H), 13.03 (s, 1 H), 8.36 (s, 1 H), 8.17 - 8.10 (m, 2H), 8.07 (s, 1 H), 7.67 - 7.58 (m, 3H), 7.17 (d, J = 2.5 Hz, 1 H), 7.10 (s, 1 H). MS: The product was analysed by UPLC (Method 1): m / z 339 / 341 [M+H]+(ES+); 337 / 339 [M-HJ- (ES-), at 0.75 min, 95% purity 254 nm.Compound 76-Chloro-7-hvdroxy-8-(1-methyl-1 H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (7)

[0107] 6-Chloro-7-methoxy-8-(1-methyl-1 H-pyrazol-5-yl)-2-phenyl-4H-chromen-4-one (48 mg, 1 Eq, 0.13 mmol) was demethylated according to General Procedure 3. The crude product was further purified by preparative HPLC General procedure 4, Method 1. Gradient information: 0.0- 0.5 min, 5% MeCN; 0.5-15.5 min, ramped from 5% MeCN to 35% MeCN; 15.5-15.6 min, ramped from 35% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give 6-chloro-7-hydroxy-8-(1-methyl-1 H-pyrazol-5- yl)-2-phenyl-4H-chromen-4-one (7 mg, 0.02 mmol, 20%) as a white solid.

[0108] 1H NMR (500 MHz, DMSO): 5 8.13 - 8.06 (m, 2H), 7.63 (s, 1 H), 7.62 - 7.58 (m, 3H), 7.43 (s, 1 H), 6.90 (s, 1 H), 6.26 (s, 1 H), 3.68 (s, 3H). MS: The product was analysed by UPLC (Method 1): m / z 353 / 355 [M+H]+(ES+); 351 / 353 [M-H]’ (ES-), at 0.76 min, >98% purity 210-400 nm.Compound 88-Bromo-7-hydroxy-4H-chromen-4-one

[0109] To a solution of 7-hydroxy-4H-chromen-4-one (1.50 g, 1 Eq, 9.25 mmol) in DMF (15 mL) in an isopropanol / dry ice bath at -50 °C was added a solution of NBS (1 .65 g, 1 Eq, 9.25 mmol) in DMF (3.5 mL) over ca 30 s. The mixture was allowed to warm to 0 °C over a period of 2 h. The mixture was diluted with water (50 mL) and stirred at rt for 5 min. The solid was collected by filtration, rinsed with water (3 x 10 mL) and dried in vacuo to give 8-bromo-7- hydroxy-4H-chromen-4-one (1.67 g, 5.2 mmol, 56%) as an off-white solid with minor impurities.

[0110] 1H NMR (500 MHz, DMSO): 5 11.62 (s, 1 H), 8.30 (d, J = 6.0 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 1 H), 6.31 (d, J = 6.0 Hz, 1 H). MS: The product was analysed by UPLC(Method 1): m / z 241 / 243 [M+H]+(ES+); 239 / 241 [M-H]’ (ES-), at 0.31 min, 82% purity 210- 400nm.7-(Benzyloxy)-8-bromo-4H-chromen-4-one

[0111] To a suspension of 8-bromo-7-hydroxy-4H-chromen-4-one (1.67 g, 75% Wt, 1 Eq, 5.20 mmol) and potassium carbonate (2.00 g, 2.79 Eq, 14.5 mmol) in DMF (17 mL) was added benzyl bromide (1.73 g, 1.20 mL, 1.94 Eq, 10.1 mmol). The mixture was stirred at 60 °C for 2 h. The mixture was diluted with EtOAc (60 mL), washed with 1 :1 water / brine (2 x 50 mL) and brine (30 mL), dried over MgSCU, filtered and concentrated. Purification by column chromatography using a gradient of 0-100% EtOAc in isohexane gave 7-(benzyloxy)-8-bromo- 4H-chromen-4-one (1.65 g, 4.9 mmol, 94%) as a tan solid.

[0112] 1H NMR (500 MHz, DMSO): 5 8.35 (d, J = 6.0 Hz, 1 H), 8.02 (d, J = 8.9 Hz, 1 H), 7.54 - 7.48 (m, 2H), 7.46 - 7.39 (m, 3H), 7.39 - 7.32 (m, 1 H), 6.35 (d, J = 6.0 Hz, 1 H), 5.40 (s, 2H). MS: The product was analysed by UPLC (Method 1): m / z 331 / 333 [M+H]+(ES+); no ionisation ES-, at 1.53 min, >98% purity at 254 nm.7-(Benzyloxy)-8-bromo-2-( 1 H- 1 ,2,4-triazol-1 -yl)-4H-chromen-4-one

[0113] A vial containing 7-(benzyloxy)-8-bromo-4H-chromen-4-one (1.4 g, 1 Eq, 4.2 mmol), 1 ,2,4-triazole (0.85 g, 2.9 Eq, 12 mmol), iodine (1.6 g, 1.5 Eq, 6.3 mmol) and potassium carbonate (2.9 g, 5.0 Eq, 21 mmol) was charged with DMF (20 mL). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to rt, diluted with 10% aq. Na2S20s (20 mL) and water (40 mL), then stirred at rt for 10 min. The solid was collected by filtration, rinsed with water (3 x 5 mL) and dried to give 7-(benzyloxy)-8-bromo-2-(1 H-1 ,2,4-triazol-1-yl)-4H-chromen-4-one (0.85 g, 2.1 mmol, 49%) as a pale yellow solid.

[0114] 1H NMR (500 MHz, DMSO): 5 9.24 (s, 1 H), 8.49 (s, 1 H), 8.06 (d, J = 9.0 Hz, 1 H), 7.52 (d, J = 7.4 Hz, 2H), 7.48 (d, J = 9.0 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1 H), 6.72 (s, 1 H), 5.44 (s, 2H). MS: The product was analysed by LCMS (Method 1): m / z 398 / 400 [M+H]+(ES+); no ionisation ES-, at 1 .47 min, >98% purity 254 nm.7-(benzyloxy)-8-(1-(tetrahvdro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)-2-(1 H-1 ,2,4-triazol-1-yl)-4H- chromen-4-one

[0115] A nitrogen-purged vial containing 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.8 g, 3 Eq, 6.4 mmol), 7-(benzyloxy)-8-bromo-2-(1 H-1,2,4-triazol-1-yl)-4H-chromen-4-one (0.85 g, 1 Eq, 2.1 mmol) and Pd(dtbpf)CI2(Pd-118) (70 mg, 0.05 Eq, 0.11 mmol) was charged with 1,4-dioxane (15 mL) and 1.5 M aq. tripotassium phosphate (1.59 g, 5.00 mL, 3.5 Eq, 7.50 mmol). The mixture was stirred at 95 °C for 2 h. The mixture was diluted with EtOAc (20 mL), washed with brine (10 mL), dried over MgSC , filtered and concentrated. Purification by column chromatography using a gradient of 0-100% EtOAc in isohexane gave 7-(benzyloxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)-2-(1 H- 1 ,2,4- triazol-1-yl)-4H-chromen-4-one (0.72 g, 1.5 mmol, 71%) as a white solid.

[0116] 1H NMR (500 MHz, DMSO): 58.46 (s, 0.7H), 8.43 (s, 0.7H), 8.41 (s, 0.3H), 8.36 (s, 0.3H), 8.19 (d, J= 8.9 Hz, 0.7H), 8.14 (d, J= 9.0 Hz, 0.3H), 7.74 (d, J= 1.7 Hz, 0.7H), 7.73 (d, J= 1.8 Hz, 0.3H), 7.57 (d, J= 9.0 Hz, 0.7H), 7.44 (d, J= 9.1 Hz, 0.3H), 7.40-7.25 (m, 5H), 6.67 (s, 0.3H), 6.63 (s, 0.7H), 6.60 (d, J = 1.7 Hz, 0.7H), 6.49 (d, J = 1.7 Hz, 0.3H), 5.42 - 5.35 (m, 1H), 5.35-5.29 (m, 1H), 5.15 (dd, J= 9.3, 2.7 Hz, 0.3H), 5.06 (dd, J= 9.5, 2.6 Hz, 0.7H), 3.77 - 3.71 (m, 0.3H), 3.55 - 3.48 (m, 0.7H), 3.37 - 3.32 (m, 0.3H), 3.20 (td, J = 10.9, 3.0 Hz, 0.7H), 2.28-2.14 (m, 1H), 1.90-1.78 (m, 1H), 1.75-1.68 (m, 0.3H), 1.61 - 1.54 (m, 0.7H), 1.54- 1.43 (m, 1H), 1.43- 1.30 (m, 2H). MS: The product was analysed by LCMS (Method 1): m / z 386 [M-THP+2H]+(ES+); no ionisation ES-, at 1.39 min, >99% purity at 254 nm.7-(Benzyloxy)-2-(2,2-dimethyl-1-oxa-8-azaspirof4.51decan-8-yl)-8-(1-(tetrahvdro-2H-pyran-2-yl)- 1H-pyrazol-5-yl)-4H-chromen-4-one

[0117] The title compound was prepared according to General Procedure 2 with 7-(benzyloxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(1H-1,2,4-triazol-1-yl)-4H-chromen-4-one (100 mg, 1 Eq, 213 pmol), 2,2-dimethyl-1-oxa-8-azaspiro[4.5]decane hydrochloride (88 mg, 2.0 Eq, 0.43 mmol), potassium carbonate (120 mg, 4.08 Eq, 868 pmol) and NMP (1.0 mL) for 1.5 h. The crude product was purified by column chromatography using a gradient of 0-20% MeOH in EtOAc giving the title compound, 7-(Benzyloxy)-2-(2,2-dimethyl-1-oxa-8-azaspiro[4.5]decan-8- yl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-4H-chromen-4-one (102 mg, 0.18 mmol, 82%) as a colourless glassy foam.

[0118] 1H NMR (500 MHz, DMSO): 57.98 (d, J= 8.8 Hz, 0.7H), 7.94 (d, J= 8.9 Hz, 0.3H), 7.66 (d, J= 1.7 Hz, 0.3H), 7.63 (d, J= 1.7 Hz, 0.7H), 7.38-7.24 (m, 5.7H), 7.21 (d, J= 8.9 Hz, 0.3H), 6.42 (d, J = 1.7 Hz, 0.7H), 6.39 (d, J = 1.7 Hz, 0.3H), 5.42 (s, 0.7H), 5.42 (s, 0.3H), 5.32 - 5.25 (m, 1H), 5.25-5.18 (m, 1H), 5.03-4.96 (m, 1H), 3.80-3.72 (m, 0.3H), 3.70-3.60 (m, 0.7H), 3.39-3.32 (m, 1.7H), 3.29-3.09 (m, 3.3H), 2.29-2.13 (m, 1H), 1.94-1.87 (m, 2H), 1.84-1.73 (m, 3.7H), 1.72-1.65 (m, 0.3H), 1.61 - 1.36 (m, 7H), 1.19-1.11 (m, 6H). MS: Theproduct was analysed by LCMS (Method 1): m / z 570 [M+H]+(ES+); no ionisation ES-, at 1.76 min, >99% purity at 254 nm.2-(2,2-Dimethyl-1-oxa-8-azaspiror4.51decan-8-yl)-7-hydroxy-8-(1 H-pyrazol-5-yl)-4H-chromen-4- one hydrochloride (8)

[0119] A HCI solution (2M in MeOH) was generated by dropwise addition of acetyl chloride (0.11 g, 0.10 mL, 1.4 mmol) to cold MeOH (0.60 mL). This solution was added to a vial containing 2-(2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decan-8-yl)-7-hydroxy-8-(1-(tetrahydro-2H- pyran-2-yl)-1 H-pyrazol-5-yl)-4H-chromen-4-one (35 mg, 1 Eq, 73 pmol) at rt. The reaction mixture was stirred at rt for 90 min before being diluted with TBME (2 mL) and stirred at rt for 30 min, the solid was collected by filtration, rinsed with TBME (1 mL) and dried to give 2-(2,2- dimethyl-1-oxa-8-azaspiro[4.5]decan-8-yl)-7-hydroxy-8-(1 H-pyrazol-5-yl)-4H-chromen-4-one as the hydrochloride salt (18 mg, 41 pmol, 57%) as a white solid.

[0120] 1H NMR (500 MHz, DMSO): 5 7.91 (d, J = 2.2 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 2.2 Hz, 1 H), 6.28 (s, 1 H), 3.89 - 3.78 (m, 2H), 3.57 - 3.48 (m, 2H), 1.90 - 1.84 (m, 2H), 1.84 - 1.79 (m, 2H), 1.77 - 1.63 (m, 4H), 1.20 (s, 6H). Note 3x exchangeable H not resolved. MS: The product was analysed by LCMS (Method 1): m / z 396 [M+H]+(ES+); 394 [M-H]’ (ES-), at 1.20 min, >99% purity at 254 nm.Compound 97-Hvdroxy-8-nitro-2-phenyl-4H-chromen-4-one

[0121] Method A: To a suspension of 7-hydroxy-2-phenyl-4H-chromen-4-one (2.0 g, 1 Eq, 8.4 mmol) in acetic acid (100 mL) was added aq. nitric acid (70%) (5.6 g, 4.0 mL, 70% Wt, 7.5 Eq, 63 mmol). The mixture was stirred at rt for 2 h, then at 40 °C for 1 h, then at 45 °C overnight, then at 50 °C for 90 min. The mixture was stirred at 60 °C for 90 min, UPLC showed 2% conv. to the desired product. Approximately 15-20 mins after this (no changes were made to the conditions), the mixture abruptly became homogeneous and red. The mixture was cooled to rt and poured into water (200 mL) and left to stand at rt for 30 min. The solid was collected byfiltration, rinsed with water (3 x 10 mL) and dried to give 7-hydroxy-8-nitro-2-phenyl-4H- chromen-4-one (1.93 g, 4.8 mmol, 57%)

[0122] 1H NMR (500 MHz, DMSO) 5 12.57 (s, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 7.95 - 7.90 (m, 2H), 7.65 - 7.52 (m, 3H), 7.19 (d, J = 9.0 Hz, 1 H), 7.08 (s, 1 H).

[0123] MS: The product was analysed by UPLC (Method 1): m / z 284 [M+H]+(ES+); 282 [M-H]’ (ES-), at 0.66 min, 72% purity 254 nm.

[0124] Method B: To a solution of 7-hydroxy-2-phenyl-4H-chromen-4-one (1.0 g, 1 Eq, 4.2 mmol) in DMSO (10 mL) at 40 °C was added aq. nitric acid (70%) (2.8 g, 2.0 mL, 70% Wt, 7.5 Eq, 31 mmol). The mixture was stirred at 90 °C for 1 h, then at 95 °C for 50 min. The mixture was cooled to rt, diluted with water (100 mL) and left to stand at rt for 30 min. The solid was collected by filtration, rinsed with water (3 x 5 mL) and MeCN (5 x 5 mL) and dried to give 7- hydroxy-8-nitro-2-phenyl-4H-chromen-4-one (0.82 g, 2.6 mmol, 62%) as a yellow solid.

[0125] 1H NMR (500 MHz, DMSO): 5 12.57 (s, 1 H), 8.07 (d, J = 9.0 Hz, 1 H), 7.95 - 7.90 (m, 2H), 7.65 - 7.52 (m, 3H), 7.19 (d, J = 9.0 Hz, 1 H), 7.07 (s, 1 H). MS: The product was analysed by UPLC (Method 1): m / z 284 [M+H]+(ES+); 282 [M-H]’ (ES-), at 0.69 min, 90% purity 254 nm.7-(Benzyloxy)-8-nitro-2-phenyl-4H-chromen-4-one

[0126] A suspension of 7-hydroxy-8-nitro-2-phenyl-4H-chromen-4-one (2.0 g, 72% Wt, 1 Eq,5.1 mmol), potassium carbonate (1.5 g, 2.1 Eq, 11 mmol) and benzyl bromide (1.9 g, 1.3 mL,2.1 Eq, 11 mmol) in DMF (30 mL) was stirred at rt overnight. The mixture was diluted with EtOAc (100 mL), washed with 1 :1 water / brine and brine (50 mL), dried over MgSO4, filtered and concentrated.

[0127] Purification by column chromatography using a gradient of 0-30% EtOAc in a mixture of DCM and isohexane [1 :1] gave 7-(benzyloxy)-8-nitro-2-phenyl-4H-chromen-4-one (1.5 g, 3.8 mmol, 74%) as a cream solid.

[0128] 1H NMR (500 MHz, DMSO): 5 8.21 (d, J = 9.2 Hz, 1 H), 7.95 - 7.88 (m, 2H), 7.66 - 7.55 (m, 4H), 7.49 - 7.41 (m, 4H), 7.40 - 7.35 (m, 1 H), 7.12 (s, 1 H), 5.49 (s, 2H). MS: The product was analysed by UPLC (Method 1): m / z 374 [M+H]+(ES+); No ionisation (ES-), at 1.76 min, 88% purity 210-400nm.8-Amino-7-hvdroxy-2-phenyl-4H-chromen-4-one

[0129] To a solution of 7-(benzyloxy)-8-nitro-2-phenyl-4H-chromen-4-one (1.49 g, 94% Wt, 1Eq, 3.75 mmol) in a mixture of EtOH (30 mL) and THF (30 mL) was added Pd (type 87L, 5% onC, wetted with 50% water) (0.30 g, 2.5% Wt, 0.019 Eq, 70 pmol). The suspension was stirred in a steel pressure reactor under 5 bar H2 at 25 °C overnight. The mixture was filtered (Whatman GF / F pad), rinsed through with MeOH and the filtrate was concentrated. Purification by column chromatography using a gradient of 0-100% of 10% MeOH in THF and isohexane, followed by trituration with TBME (to remove BHT stabiliser from THF) gave 8-amino-7-hydroxy-2-phenyl- 4H-chromen-4-one (0.79 g, 3.0 mmol, 79%) as a yellow solid.

[0130] 1H NMR (500 MHz, DMSO): 5 8.26 - 8.20 (m, 2H), 7.63 - 7.52 (m, 3H), 7.20 (d, J = 8.5 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 6.86 (s, 1 H). MS: The product was analysed by LCMS (Method 1): 3465-83-1-ac, m / z 254 [M+H]+(ES+); 252 [M-H]' (ES-), at 0.96 min, 93% purity at 254 nm.8-Phenyl-6H-chromeno[8,7-d1oxazole-2,6(1 H)-dione (9)

[0131] To a suspension of 8-amino-7-hydroxy-2-phenyl-4H-chromen-4-one (150 mg, 1 Eq, 592 pmol) and triethylamine (0.15 g, 0.20 mL, 2.4 Eq, 1.4 mmol) in THF (4.0 mL) was added GDI (110 mg, 1.15 Eq, 678 pmol). The mixture was stirred at rt for 2 h. The mixture was diluted with TBME (4 mL), then the solid was collected by filtration, rinsed with TBME (3 x 1 mL) and dried to give 8-phenyl-6H-chromeno[8,7-d]oxazole-2,6(1 H)-dione (104 mg, 0.37 mmol, 62%) as a white solid.

[0132] 1H NMR (500 MHz, DMSO): 5 12.92 (s, 1 H), 8.31 - 8.25 (m, 2H), 7.77 (d, J = 8.5 Hz, 1 H), 7.67 - 7.56 (m, 3H), 7.47 (d, J = 8.5 Hz, 1 H), 7.11 (s, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 280 (M+H)+ (ES+, weak ionisation); 278 (M-H)- (ES-), at 1.11 min, >99% purity at 254 nm.Compound 101-Methyl-8-phenyl-6H-chromeno[8,7-d1oxazole-2,6(1 H)-dione (10)

[0133] To a suspension of 8-phenyl-6H-chromeno[8,7-d]oxazole-2,6(1 H)-dione (40 mg, 1 Eq, 0.14 mmol) and potassium carbonate (60 mg, 3.0 Eq, 0.43 mmol) in DMF (1.0 mL) was added iodomethane (0.1 g, 0.05 mL, 6 Eq, 0.8 mmol). The mixture was stirred at rt for 30 min, then diluted with water (3 mL) and stirred for 5 min. The solid was collected by filtration, rinsed with water (2 x 2 mL) and MeCN (2 x 2 mL), then dried to give 1-methyl-8-phenyl-6H-chromeno[8,7- d]oxazole-2,6(1 H)-dione (36 mg, 0.12 mmol, 84%, 98% Purity) as a white solid.

[0134] 1H NMR (500 MHz, DMSO): 5 8.10 - 8.03 (m, 2H), 7.83 (d, J = 8.5 Hz, 1 H), 7.68 - 7.57 (m, 3H), 7.54 (d, J = 8.5 Hz, 1 H), 7.08 (s, 1 H), 3.80 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 294 (M+H)+ (ES+); no ionisation ES-, at 1.25 min, >98% purity at 254 nm.Compound 111-(4-amino-2-hvdroxy-3-nitrophenyl)-3-(4-bromophenyl)prop-2-en-1-one

[0135] A suspension of 1-(4-amino-2-hydroxy-3-nitrophenyl)ethan-1-one (2.50 g, 94% Wt, 1 Eq, 12.0 mmol) and 4-bromobenzaldehyde (3.32 g, 1.5 Eq, 18.0 mmol) in EtOH (40 mL) was heated to 50 °C. Pyrrolidine (953 mg, 1.10 mL, 1.12 Eq, 13.4 mmol) was added in one portion and the reaction mixture was stirred at 50 °C for 4 h, then allowed to cool to rt. The precipitate was collected by filtration, washed with EtOH, and dried in vacuo to afford the desired product 1-(4- amino-2-hydroxy-3-nitrophenyl)-3-(4-bromophenyl)prop-2-en-1-one (3.69 g, 10 mmol, 83 %) as a brown free-flowing solid.

[0136] 1H NMR (400 MHz, DMSO): 5 15.81 (s, 1 H), 8.20 (d, J = 9.3 Hz, 1 H), 7.97 (d, J = 15.5 Hz, 1 H), 7.91 - 7.82 (m, 2H), 7.78 (d, J = 15.5 Hz, 1 H), 7.72 - 7.64 (m, 2H), 7.56 (s, 2H), 6.42 (d, J = 9.2 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 363.0 / 365.0 (M+H)+(ES+); 361.0 / 363.0 (M-H)’ (ES-), at 1.83 min, 98% purity at 260nm + / - 80nm.7-amino-2-(4-bromophenyl)-8-nitro-4H-chromen-4-one

[0137] To a stirred suspension of 1-(4-amino-2-hydroxy-3-nitrophenyl)-3-(4-bromophenyl)prop-2-en-1-one (3.69 g, 98% Wt, 1 Eq, 9.96 mmol) in DMSO (4.40 g, 4.00 mL, 5.66 Eq, 56.4 mmol) and toluene (30 mL) was added iodine (591 mg, 0.234 Eq, 2.33 mmol). The reaction mixture was stirred at 110 °C for 4 h and then allowed to cool to rt. The reaction mixture was diluted with water (30 mL) and the precipitate was collected by filtration, washing with EtOH (very slow filtration speed). The solid was sucked dry for 15 min. and then transferred to a flask to dry in vacuo. The desired product 7-amino-2-(4-bromophenyl)-8-nitro-4H-chromen-4-one (3.356 g, 9.1mmol, 91 %) was afforded as a pale brown solid. The product was used without further purification.

[0138] 1H NMR (400 MHz, DMSO): 5 8.01 - 7.93 (m, 2H), 7.87 (d, J = 9.2 Hz, 1 H), 7.84 - 7.77 (m, 4H), 7.07 (s, 1 H), 6.99 (d, J = 9.1 Hz, 1 H).MS: The product was analysed by LCMS (Method 1): m / z 361.0 / 363.0 (M+H)+(ES+); 358.8 / 360.8 (M-H)’ (ES-), at 1.60 min, 98% purity at 260nm + / - 80nm.7,8-diamino-2-(4-bromophenyl)-4H-chromen-4-one

[0139] To a stirred suspension of 7-amino-2-(4-bromophenyl)-8-nitro-4H-chromen-4-one (3.35 g, 98% Wt, 1 Eq, 9.09 mmol) in DMSO (35 mL), EtOH (35 mL) and water (10 mL) at 80 °C was added sodium dithionite (5.00 g, 2.00 mL, 3.16 Eq, 28.7 mmol). The reaction mixture was stirred at 80 °C for 6.5 h and then allowed to cool to rt overnight. The reaction mixture was poured into ice / water (-200 mL) and the precipitate was collected by filtration. The filter cake was washed with water and then MeCN. The crude product was transferred to a flask and dried in vacuo to afford 7,8-diamino-2-(4-bromophenyl)-4H-chromen-4-one (2.95 g, 8.7 mmol, 96 %) as a pale brown solid.

[0140] 1H NMR (400 MHz, DMSO) 5 8.21 - 8.11 (m, 2H), 7.77 - 7.69 (m, 2H), 7.16 (d, J = 8.4 Hz, 1 H), 6.81 (s, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 5.60 (br s, 2H), 4.95 (br s, 2H). MS: The product was analysed by LCMS (Method 1): m / z 331.0 / 333.0 (M+H)+(ES+); 375.0 / 377.0 (M+formic acid-H)' (ES-), at 1.27 min, 98% purity at 260nm + / - 80nm.8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(1 H)-one

[0141] To a stirred suspension of 7,8-diamino-2-(4-bromophenyl)-4H-chromen-4-one (1.028 g, 98% Wt, 1 Eq, 3.042 mmol) in Pyridine (10.0 mL) at 0 °C was added trifluoroacetic anhydride (1.93 g, 1.30 mL, 3.03 Eq, 9.20 mmol) dropwise. The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with water. The resultant precipitate was collected by filtration, washing with water, and then dried in vacuo to afford 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1 H)-one (1.246 g, 2.8 mmol, 93 %) as a pale brown solid.

[0142] 1H NMR (400 MHz, MeOD): 5 8.18 - 8.14 (m, 2H), 8.12 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1 H), 7.04 (s, 1 H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD) 5 -65.66. MS: The product was analysed by LCMS (Method1): m / z 409.0 / 411.0 (M+H)+(ES+); 406.8 / 408.8 (M-H)- (ES-), at 1.56 min, 98% purity at 260nm + / - 80nm.8-(4-(pyrrolidin-1-yl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (11)

[0143] A suspension of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)- one (60.0 mg, 98% Wt, 1 Eq, 144 pmol), Pd-177 (12.0 mg, 0.110 Eq, 15.8 pmol), cesium carbonate (143 mg, 3.05 Eq, 439 pmol) and pyrrolidine (17.3 mg, 20.0 pL, 1.69 Eq, 244 pmol) in DMF (1.00 mL) was heated by microwave irradation at 100 °C for 30 min. The reaction mixture was filtered through cotton wool, washed with DCM, and then concentrated in vacuo. The residue was azeotroped with toluene (3 times) to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-5% MeOH / DCM giving 8- (4-(pyrrolidin-1-yl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (28.0 mg, 69 pmol, 48 %) as a yellow solid.

[0144] 1H NMR (400 MHz, DMSO): 5 14.76 (br s, 1 H), 8.08 - 7.95 (m, 2H), 7.98 (d, J = 8.8 Hz, 1 H), 7.75 - 7.64 (m, 1 H), 6.89 (s, 1 H), 6.75 - 6.68 (m, 2H), 3.39 - 3.33 (m, 4H), 2.04 - 1.96 (m, 4H).19F NMR (376 MHz, DMSO): 5 -62.53. MS: The product was analysed by LCMS (Method 1): m / z 400.0 (M+H)+(ES+); 398.0 (M-H)’ (ES-), at 1.72 min, 98% purity at 260nm + / - 80nm.Compound 12 8-(4-(piperidin-1-yl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (12)

[0145] A suspension of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)- one (60.0 mg, 98% Wt, 1 Eq, 144 pmol), piperidine (21.6 mg, 25.0 pL, 1.76 Eq, 253 pmol), cesium carbonate (143 mg, 3.05 Eq, 439 pmol) and Pd-177 (12.0 mg, 0.110 Eq, 15.8 pmol) inDMF (1.00 mL) was heated in the microwave at 100 °C for 3 h. The reaction mixture was filtered through cotton wool, washing with DCM, and the filtrate was concentrated in vacuo. The residue was azeotroped with toluene (3 times) to afford the crude product.

[0146] The crude product was purified by column chromatography on silica gel (dry load) (12 g cartridge, 0-5% MeOH / DCM). The product containing fractions were concentrated in vacuo and the residue was triturated with EtOH to afford 8-(4-(piperidin-1-yl)phenyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (14.0 mg, 32 pmol, 22 %) as a yellow solid.

[0147] 1H NMR (400 MHz, DMSO): 5 14.70 (s, 1 H), 8.01 - 7.97 (m, 3H), 7.76 - 7.64 (m, 1 H), 7.10 (d, J = 8.7 Hz, 2H), 6.93 (s, 1 H), 3.44 - 3.35 (m, 4H), 1.67 - 1.56 (m, 6H).19F NMR (376 MHz, DMSO): 5 -62.60. MS: The product was analysed by LCMS (Method 1): m / z 414.2 (M+H)+(ES+); 412.0 (M-H)- (ES-), at 1.71 min, 96% purity at 260nm + / - 80nm.Compound 138-(4-(azetidin-1-yl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (13)

[0148] A suspension of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)- one (60.0 mg, 98% Wt, 1 Eq, 144 pmol), Pd-177 (11.0 mg, 0.101 Eq, 14.4 pmol), cesium carbonate (140 mg, 3.0 Eq, 431 pmol) and azetidine (16.9 mg, 20.0 pL, 2.06 Eq, 297 pmol) in DMF (1.00 mL) was heated by microwave irradiation at 80 °C for 1 h. Additional azetidine (84.5 mg, 100 pL, 10.3 Eq, 1.48 mmol) was added and heated in the microwave at 100 °C for 2 h. Additional azetidine (84.5 mg, 100 pL, 10.3 Eq, 1.48 mmol) and Pd-177 (12 mg, 0.109, 15.7 pmol) was added and heated in the microwave at 100 °C for 2 h. The reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography, using a gradient of 0-5% MeOH in DCM, to afford impure fractions. The product was further purified by column chromatography using a gradient of 0-2.5% MeOH in DCM to afford 8-(4-(azetidin-1-yl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)- one (10.0 mg, 25 pmol, 17 %) as a yellow solid.

[0149] 1H NMR (400 MHz, DMSO): 5 14.72 (br s, 1 H), 8.09 - 7.92 (m, 3H), 7.70 (br s, 1 H), 6.91 (s, 1 H), 6.58 - 6.52 (m, 2H), 3.97 (t, J = 7.3 Hz, 4H), 2.43 - 2.33 (m, 2H).19F NMR (376 MHz,DMSO): 6 -62.55. MS: The product was analysed by LCMS (Method 1): m / z 386.0 (M+H) (ES+); 384.0 (M-H)' (ES-), at 1.53 min, 97% purity at 260nm + / - 80nm.Compound 147-amino-8-nitro-4H-chromen-4-one

[0150] Sodium hydride (60 wt% in mineral oil) (767 mg, 60% Wt, 4 Eq, 19.2 mmol) was added portionwise to a solution of 1-(4-amino-2-hydroxy-3-nitrophenyl)ethan-1-one (1.00 g, 94% Wt, 1 Eq, 4.79 mmol) in THF (24.0 mL). The resulting suspension was stirred for 5 min before the dropwise addition of ethyl formate (7.10 g, 7.74 mL, 20 Eq, 95.8 mmol). The reaction was heated to 40 °C for 30 min. The reaction was removed from the heating block and sodium hydride (60 wt% in mineral oil) (767 mg, 60% Wt, 4 Eq, 19.2 mmol) was added portionwise (internal temperature ~30 °C). The reaction was heated to 40 °C, then ethyl formate (3.55 g, 3.87 mL, 10 Eq, 47.9 mmol) was added in one portion. The reaction was stirred at 40 °C for 18 h. The reaction mixture was poured into ice (250 mL) and then acidified to pH 1 by addition of cone. HCI. The aqueous phase was extracted with DCM (2 x 250 mL) and the combined organic extracts were concentrated in vacuo. The residue was diluted with THF (10 mL) then vigorously stirred with 6 M aq. HCI (20 mL) for 3 h. The mixture was diluted with DCM (100 mL) and the aqueous phase was basified to pH 12 with 2 M aq. NaOH. Phases were separated and the organic layer was collected and the aqueous phase further extracted with DCM (100 mL). The combined organic extracts were washed with 1:1 water / brine (50 mL) and dried over MgSCU. The solids were filtered off and the solvent was removed in vacuo to afford 7-amino-8-nitro-4H- chromen-4-one (1.25 g, 4.9 mmol, 100 %) as an orange solid.

[0151] 1H NMR (400 MHz, DMSO): 5 8.19 (d, J = 5.9 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1 H), 7.60 (s, 2H), 6.96 (d, J = 9.1 Hz, 1 H), 6.30 (d, J = 6.0 Hz, 1H). MS: The product was analysed by LCMS (Method 1): m / z 207.0 (M+H)+(ES+); 205.0 (M-H)' (ES-), at 0.73 min, >99% purity at 260nm + / - 80nm.7,8-diamino-4H-chromen-4-one

[0152] To a stirred suspension of 7-amino-8-nitro-4H-chromen-4-one (860 mg, 80% Wt, 1 Eq, 3.34 mmol) in DMSO (7.50 mL), EtOH (7.50 mL) and water (1.9 mL) at 80 °C was added sodium dithionite (1.74 g, 697 pL, 3 Eq, 10.0 mmol). The reaction was stirred for 8 h before it was allowed to cool overnight. The reaction was diluted with water (100 mL), neutralised with sat. aq. NaHCOs and the resulting suspension was extracted with EtOAc (4 x100 mL). The combined organics were washed with 1 :1 water / brine (100 mL) and brine (50 mL) then dried over MgSC . The solids were filtered off and the solvent was removed in vacuo to afford an orange solid, contaminated with DMSO. The remaining aqueous phase was further extracted with chloroform / IPA (3 x 100 mL), DCM / MeOH (3 x 100 mL) and EtOAc / MeOH (3 x 100 mL) at various pH. The solvents were removed to yield additional product, which was acidified with AcOH and purified by SCX, eluting with 0.7M NH3 in MeOH to yield 59 mg of product. The remaining aqueous phase was concentrated in vacuo to approx. (10 mL). The resulting solids were washed with MeOH (200 mL) and the volume was reduced in vacuo. The resulting solution was acidified with AcOH and re-purified by SCX, eluting with 0.7M NH3 in MeOH to yield an orange solid. The solids were combined, affording 7,8-diamino-4H-chromen- 4-one (514 mg, 2.3 mmol, 70 %, 80% Purity) as an orange solid.

[0153] 1H NMR (400 MHz, DMSO): 5 8.07 (d, J = 5.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1 H), 6.65 (d, J = 8.5 Hz, 1 H), 6.06 (d, J = 5.9 Hz, 1H), 5.56 (s, 2H), 4.68 (s, 2H). MS: The product was analysed by LCMS (Method 1): m / z 177.0 (M+H)+(ES+) at 0.26 min, 93% purity at 254nm.2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one

[0154] Trifluoroacetic acid (5.32 g, 3.60 mL, 20 Eq, 46.7 mmol) was slowly added to 7,8- diamino-4H-chromen-4-one (514 mg, 80% Wt, 1 Eq, 2.33 mmol) while cooling over and ice bath. The mixture was stirred at reflux for 2 h, then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and the aqueous phase was neutralised with sat. aq. NaHCOs while stirring. The phases were separated and the organic phase was washed with brine (10 mL), dried over MgSCU, filtered and concentrated. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM) to afford 2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (85 mg, 0.23 mmol, 10 %) as a red solid.

[0155] 1H NMR (400 MHz, DMSO): 5 14.77 (s, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1 H), 6.47 (d, J = 5.9 Hz, 1H).

[0156] MS: The product was analysed by LCMS (Method 1): m / z 255.0 (M+H)+(ES+); 253.0 (M-H)' (ES-), at 0.85 min, >99% purity at 260nm + / - 80nm.8-(1 H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one

[0157] A stirred suspension of 2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (94 mg, 1 Eq, 0.37 mmol), 1 H-1 ,2,4-triazole (77 mg, 3 Eq, 1.1 mmol), iodine (0.14 g, 1.5 Eq, 0.55 mmol) and potassium carbonate (0.26 g, 5 Eq, 1.9 mmol) in DMF (1 mL) was heated to 60°C for 30 min. The reaction was heated to 80 °C for 2 h, iodine (94 mg, 1 Eq, 0.37 mmol) was added and the reaction was heated for a further 2 h. 1 H-1 ,2,4-triazole (77 mg, 3 Eq, 1.1 mmol) and potassium carbonate (0.26 g, 5 Eq, 1.9 mmol) were added and the reaction was heated to 80 °C for 6 h. The reaction was allowed to cool, diluted with sat. aq. Na2S20s (10 mL) and water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organics were washed with brine (20 mL) and dried over MgSC . The solids were filtered off and the solvent was removed in vacuo. The crude product was dried onto Celite and purified by column chromatography using a gradient of 0-10% MeOH in DCM to afford 8-(1 H-1 ,2,4-triazol-1 -yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (18 mg, 55 pmol, 15 %) as a light yellow solid.

[0158] 1H NMR (400 MHz, DMSO, 363K): 5 9.42 (s, 1 H), 8.43 (s, 1 H), 8.21 (s, 1 H), 8.05 (d, J = 8.6 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 1 H), 6.81 (s, 1 H).19F NMR (376 MHz, DMSO): 5 -62.73. MS: The product was analysed by LCMS (Method 1): m / z 322.0 (M+H)+(ES+); 320.0 (M-H)’ (ES-), at 0.93 min, >99% purity at 260nm + / - 80nm.8-(2,2-dimethyl-1-oxa-8-azaspiror4.51decan-8-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (14)

[0159] The title compound was prepared according to General Procedure 2 using Potassium carbonate (38 mg, 5 Eq, 280 pmol) , 8-(1 H-1 ,2,4-triazol-1-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (18 mg, 99% Wt, 1 Eq, 55 pmol), 2,2-dimethyl-1-oxa-8- azaspiro[4.5]decane hydrochloride (23 mg, 2 Eq, 110 pmol) and NMP (0.5 mL). The reaction was heated to 120 °C for 24 h.

[0160] The reaction was allowed to cool and the reaction mixture was purified directly by column chromatography using a gradient of 0-6% MeOH in DCM to afford 8-(2,2-dimethyl-1- oxa-8-azaspiro[4.5]decan-8-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (7.9 mg, 18 pmol, 32 %) as a beige solid.

[0161] 1H NMR (400 MHz, MeOD): 5 8.03 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 5.69 (s, 1 H), 4.01 - 3.93 (m, 2H), 3.78 - 3.67 (m, 2H), 2.03 - 1.97 (m, 2H), 1.97 - 1.90 (m, 2H), 1.81 (t,J = 5.7 Hz, 4H), 1.30 (s, 6H).19F NMR (376 MHz, MeOD): 5 -65.64. MS: The product was analysed by LCMS (Method 1): m / z 422.2 (M+H)+(ES+); 420.0 (M-H)’ (ES-), at 1.37 min, >99% purity at 260nm + / - 80nm.Compound 154-(6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8-yl) benzaldehyde

[0162] A solution of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (252 mg, 96% Wt, 1 Eq, 591 pmol), Pd(dppf)Ch (45.0 mg, 0.104 Eq, 61.5 pmol), triethylamine (196 mg, 270 pL, 3.28 Eq, 1.94 mmol) and triethylsilane (218 mg, 300 pL, 3.18 Eq, 1.88 mmol) in DMF (6.00 mL) was heated to 80 °C under 3 bar of CO gas for 16h. The reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-5% MeOH in DCM to afford 4-(6-oxo-2-(trifluoromethyl)- 3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzaldehyde (146 mg, 0.40 mmol, 68 %) as a pale yellow / brown solid.

[0163] 1H NMR (400 MHz, DMSO): 5 14.80 (br s, 1 H), 10.14 (s, 1 H), 8.41 - 8.36 (m, 2H), 8.18 - 8.11 (m, 2H), 8.06 - 8.01 (m, 1 H), 7.79 - 7.74 (m, 1 H), 7.34 (s, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 359.0 (M+H)+(ES+); 357.0 (M-H)- (ES-), at 1.28 min, 98% purity at 260nm + / - 80nm.8-(4-(azetidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (15)

[0164] To a solution of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzaldehyde (97.0 mg, 1 Eq, 271 pmol) and azetidine (33.9 mg, 40.0 pL, 2.19 Eq, 593 pmol) in THF (2 mL) was added acetic acid (1 drop). The reaction mixture was stirred at rt 30 min. Sodium triacetoxyborohydride (57.4 mg, 1 Eq, 271 pmol) was added in one portion and the reaction mixture was stirred at rt for 1 h. The reaction mixture was carefully quenched with MeOH (~3 mL) and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM, then 1-10% (0.7 M Ammonia in MeOH) in DCM, to afford 8-(4-(azetidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (57.0 mg, 143 pmol, 52%) as a yellow / orange solid. The product was further purified by preparative HPLC General procedure 4, Method 2. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-15.5 min, ramped from 5% MeCN to 22.5% MeCN; 15.5-15.6 min, ramped from 22.5% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 8-(4-(azetidin-1- ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one, Formic Acid (18.1 mg, 40 pmol, 15 %) as a white solid.

[0165] 1H NMR (400 MHz, MeOD): 5 8.41 - 8.33 (m, 3H), 8.03 (dd, J = 8.8, 2.5 Hz, 1 H), 7.70 (dd, J = 8.7, 2.4 Hz, 1 H), 7.65 (dd, J = 8.5, 2.3 Hz, 2H), 7.05 (dt, J = 4.0, 1.1 Hz, 1 H), 4.42 (s, 2H), 4.15 (t, J = 8.1 Hz, 4H), 2.52 (p, J = 8.1 Hz, 2H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD): 5 -65.35 (d, J = 2.8 Hz). MS: The product was analysed by LCMS (Method 1): m / z 400.0 (M+H)+(ES+); 398.0 (M-H)' (ES-), at 0.77 min, 99% purity at 260nm + / - 80nm.Compound 16 tert-butyl 4-(7-amino-8-nitro-4-oxochroman-2-yl)piperidine-1-carboxylate

[0166] A suspension of 1-(4-amino-2-hydroxy-3-nitrophenyl)ethan-1-one (393 mg, 94% Wt, 1 Eq, 1.88 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (632 mg, 1.57 Eq, 2.96 mmol) in EtOH (10 mL) was heated to 50 °C before adding pyrrolidine (147 mg, 170 pL, 1.1 Eq, 2.07 mmol) in a single portion and the reaction mixture was stirred at 50 °C for 2 h. A solution of aldehyde (300 mg) in EtOH (5 mL) was added and the reaction mixture was stirred at 50 °C for 1 h. Additional pyrrolidine (147 mg, 170 pL, 1.1 Eq, 2.07 mmol) was added and stirred at 50 °C for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (100 mL) and sat. aq NaHCOs (50 mL). The organic layer was collected and washed with 50% brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0- 5% MeOH in DCM, to afford tert-butyl 4-(7-amino-8-nitro-4-oxochroman-2-yl)piperidine-1- carboxylate (310 mg, 0.71 mmol, 38 %) as an orange foam.

[0167] 1H NMR (400 MHz, DMSO): 5 7.58 (d, J = 9.0 Hz, 1 H), 7.25 (s, 2H), 6.51 (d, J = 9.0 Hz, 1 H), 4.43 - 4.35 (m, 1 H), 4.07 - 3.88 (m, 2H), 2.81 - 2.63 (m, 2H), 1.90 - 1.79 (m, 2H), 1.71 - 1.55 (m, 2H), 1.40 (s, 9H), 1.31 - 1.12 (m, 3H). MS: The product was analysed by LCMS (Method 1): m / z 414.2 (M+Na)+(ES+); 390.2 (M-H)' (ES-), at 1.48 min, 90% purity at 260nm + / - 80nm.tert-butyl 4-(7-amino-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1-carboxylate

[0168] A solution of tert-butyl 4-(7-amino-8-nitro-4-oxochroman-2-yl)piperidine-1-carboxylate (310 mg, 90% Wt, 1 Eq, 713 pmol) and iodine (452 mg, 2.5 Eq, 1.78 mmol) in pyridine (8 mL) was stirred at 115 °C for 4 h. The reaction mixture was concentrated in vacuo and chased with toluene to remove residuel solvent. The residue was taken up in DCM (100 mL) and washed with, sat. aq sodium thiosulfate (50 mL), sat. aq. NaHCOs (50 mL), 50% brine (50 mL), dried over MgSC and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-5% MeOH in DCM to afford tert-butyl 4-(7-amino-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1-carboxylate (164 mg, 0.42 mmol, 58 %) as a yellow solid.

[0169] 1H NMR (400 MHz, DMSO): 5 7.81 (d, J = 9.1 Hz, 1 H), 7.62 (s, 2H), 6.93 (d, J = 9.1 Hz, 1 H), 6.17 (s, 1 H), 4.03 (d, J = 13.0 Hz, 2H), 2.84 - 2.74 (m, 3H), 1.93 - 1.85 (m, 2H), 1.52 (qd, J = 12.5, 4.3 Hz, 2H), 1.42 (s, 9H). MS: The product was analysed by LCMS (Method1): m / z 421.2 (M+Na)+(ES+); 388.0 (M-H)' (ES-), at 1.40 min, 100% purity at 260nm + / - 80nm.7-amino-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride

[0170] To a solution of tert-butyl 4-(7-amino-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1- carboxylate (164 mg, 99% Wt, 1 Eq, 417 pmol) in DCM (4 mL) was added HCI (3 M in CPME) (109 mg, 1.00 mL, 7.20 Eq, 3.00 mmol). The resultant suspension was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo to afford the crude product 7-amino-8-nitro-2- (piperidin-4-yl)-4H-chromen-4-one, HCI (143 mg, 0.42 mmol) as a yellow solid. The product was used in the next step without further purification assuming quantitative yield

[0171] 1H NMR (400 MHz, DMSO): 5 9.00 (d, J = 11.2 Hz, 1 H), 8.66 (d, J = 11.2 Hz, 1 H), 7.82 (d, J = 9.1 Hz, 1 H), 7.66 (br s, 2H), 6.96 (d, J = 9.1 Hz, 1 H), 6.18 (s, 1 H), 3.36 (d, J = 12.6 Hz, 2H), 3.05 - 2.91 (m, 3H), 2.09 (dd, J = 12.3, 3.6 Hz, 2H), 1.85 (qd, J = 12.8, 4.0 Hz, 2H). MS: The product was analysed by LCMS (Method 1): m / z 290.2 (M+H)+(ES+); 288.0 (M-H)' (ES-), at 0.39 min2-(1-acetylpiperidin-4-yl)-7-amino-8-nitro-4H-chromen-4-one

[0172] To a stirred suspension of 7-amino-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one, HCI (143 mg, 95% Wt, 1 Eq, 417 pmol) and triethylamine (109 mg, 150 pL, 2.58 Eq, 1.08 mmol) in DCM (5 mL) at rt was added a solution of acetyl chloride (34.2 mg, 31.0 pL, 1.05 Eq, 436 pmol) in DCM (0.5 mL) dropwise. The resultant solution was stirred at rt for 1 h.Additional acetyl chloride (11.0 mg, 10.0 pL, 0.337 Eq, 141 pmol) in DCM (0.5 mL) was added and stirred at rt for 1 h. Additional triethylamine (109 mg, 150 pL, 2.58 Eq, 1.08 mmol) and acetyl chloride (11.0 mg, 10.0 pL, 0.337 Eq, 141 pmol) in DCM (0.5 mL) was added and stirred for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM to afford the crude product. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-6% MeOH / DCM, eluted ~4%) to afford 2-(1-acetylpiperidin-4-yl)-7-amino-8-nitro- 4H-chromen-4-one (101 mg, 305 pmol, 73.1 %) as a light yellow solid.

[0173] 1H NMR (400 MHz, DMSO): 5 7.81 (d, J = 9.1 Hz, 1 H), 7.63 (s, 2H), 6.93 (d, J = 9.1 Hz, 1 H), 6.16 (s, 1 H), 4.51 - 4.43 (m, 1 H), 3.96 - 3.88 (m, 1 H), 3.12 (td, J = 13.0, 2.7 Hz, 1 H), 2.86 (tt, J = 11.7, 3.6 Hz, 1 H), 2.61 (td, J = 12.8, 2.8 Hz, 1 H), 2.02 (s, 3H), 1.99 - 1.87 (m, 2H), 1.60 (qd, J = 12.5, 4.3 Hz, 1 H), 1.45 (qd, J = 12.5, 4.3 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 332.0 (M+H)+(ES+); 330.0 (M-H)’ (ES-), at 0.88 min, >99% purity at 260nm + / - 80nm.8-(1-acetylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (16)

[0174] To a solution of 2-(1-acetylpiperidin-4-yl)-7-amino-8-nitro-4H-chromen-4-one (46.0 mg, 100% Wt, 1 Eq, 139 pmol) and triethylamine (211 mg, 290 pL, 15 Eq, 2.08 mmol) in EtOH (2 mL), THF (2 mL) and water (0.2 mL) at 60 °C was added sodium dithionite (98.0 mg, 39.2 pL, 4.05 Eq, 563 pmol). The reaction mixture was stirred at 60 °C for 30 min. and then concentrated in vacuo. The residue was diluted with DCM (20 mL) and evaporated in vacuo to afford the crude product as a mixture of 2-(1-acetylpiperidin-4-yl)-7,8-diamino-4H-chromen-4- one and (2-(1-acetylpiperidin-4-yl)-7-amino-4-oxo-4H-chromen-8-yl)sulfamic acid. The crude product was dissolved in trifluoroacetic acid (2 mL) and stirred at 60 °C for 7 h. The reaction mixture was concentrated in vacuo from DCM to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM, to afford 8- (1-acetylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (31.0 mg, 80 pmol, 58 %) as a tan solid, after trituration with diethyl ether.

[0175] 1H NMR (400 MHz, MeOD): 5 8.10 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 6.39 (s, 1 H), 4.77 - 4.69 (m, 1 H), 4.15 - 4.07 (m, 1 H), 3.35 - 3.26 (m, 1 H), 3.10 (tt, J = 12.0, 3.8 Hz,1 H), 2.80 (td, J = 12.9, 2.8 Hz, 1 H), 2.17 (s, 5H), 1.97 (qd, J = 12.5, 4.2 Hz, 1H), 1.83 (qd, J = 12.6, 4.4 Hz, 1H).19F NMR (376 MHz, MeOD): 5 -65.72. MS: The product was analysed by LCMS (Method 1): m / z 380.2 (M+H)+(ES+); 378.0 (M-H)' (ES-), at 0.98 min, >98% purity at 260nm + / - 80nm.Compound 17 tert-butyl 6-(4-(6-oxo-2-(trifluoromethyl)-1,6-dihvdrochromenof7,8-d1imidazol-8-yl)phenyl)-3,4- dihvdropyridine-1(2H)-carboxylate

[0176] A suspension of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1H)- one (200 mg, 93% Wt, 1 Eq, 455 pmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,4-dihydropyridine-1(2H)-carboxylate (169 mg, 1.2 Eq, 546 pmol) and tripotassium phosphate (289 mg, 3 Eq, 1.36 mmol) in DMF (9 mL) and water (1 mL) was sparged with N2 for 5 min. Bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(ll) (400 mg, 1.24 Eq, 565 pmol) was added and the mixture was sparged with N2 for 10 min. The reaction mixture was stirred at 90 °C for 20 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM. The product containing fractions were combined and concentrated in vacuo to afford impure product. The product was further purified by colomn chromatography using a gradient of 0-100% EtOAc in isohexane to afford tert-butyl 6-(4-(6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8-yl)phenyl)- 3,4-dihydropyridine-1(2H)-carboxylate (54.0 mg, 53 pmol, 12 %) as a yellow solid with significant impurities. The product was deemed of sufficient quality for further reaction and was not purified further.

[0177] MS: The product was analysed by LCMS (Method 1): m / z 512.2 (M+H)+(ES+); 510.0 (M-H)' (ES-), at 1.79 min, 50% purity at 260nm + / - 80nm. tert-butyl 2-(4- (6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromenof7,8-d1imidazol-8- yl)phenyl)piperidine-1-carboxylate

[0178] A suspension of tert-butyl 6-(4-(6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d]imidazol-8-yl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate (44.0 mg, 50% Wt, 1 Eq, 43.0 pmol), platinum(IV) oxide (10.0 mg, 1.02 Eq, 44.0 pmol) and palladium (5 wt% on carbon) (20.0 mg, 5% Wt, 0.218 Eq, 9.40 pmol) in EtOAc (5 mL) was stirred under H2 (5 bar.) at 30 °C for 48 h. The reaction mixture was filtered through glass fibre filter paper, washing with EtOAc, and thefiltrate was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-5% MeOH in DCM to afford tert-butyl 2-(4-(6-oxo- 2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8-d]imidazol-8-yl)phenyl)piperidine-1 -carboxylate (9.00 mg, 13 pmol, 31 %) as a pale yellow solid.

[0179] MS: The product was analysed by LCMS (Method 1): m / z 514.2 (M+H)+(ES+); 512.2 (M-H)' (ES-), at 1.84 min, 77% purity at 260nm + / - 80nm.8-(4-(piperidin-2-yl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (17)

[0180] To a solution of tert-butyl 2-(4-(6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d]imidazol-8-yl)phenyl)piperidine-1-carboxylate (9.00 mg, 77% Wt, 1 Eq, 13.5 pmol) in THF (1 mL) was added HCI (3 M in CPME) (55 mg, 0.50 mL, 1.1e+2 Eq, 1.5 mmol). The reaction mixture was stirred at rt for 28 h and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% (0.7 M Ammonia in MeOH) in DCM then 20% (0.7 M Ammonia in MeOH) in DCM, to afford 8-(4- (piperidin-2-yl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (5.00 mg, 12 pmol, 89 %) as a white solid.

[0181] 1H NMR (400 MHz, MeOD): 5 8.41 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1 H), 7.78 - 7.69 (m, 3H), 7.12 (s, 1 H), 4.40 (dd, J = 12.2, 3.0 Hz, 1 H), 3.53 (d, J = 12.6 Hz, 1 H), 3.29 - 3.20 (m, 1 H), 2.22 - 2.15 (m, 1 H), 2.12 - 1.97 (m, 3H), 1.92 - 1.78 (m, 2H).19F NMR (376 MHz, MeOD): 5 -65.62. MS: The product was analysed by LCMS (Method 1): m / z 414.2 (M+H)+(ES+); 412.0 (M-H)' (ES-), at 0.87 min, 99% purity at 260nm + / - 80nm.Compound 18

[0182] 1-(4-amino-5-chloro-2-hydroxy-3-nitrophenyl)ethan-1-one

[0183] NCS (1.04 g, 98% Wt, 1.5 Eq, 7.65 mmol) was added to a solution of 1-(4-amino-2- hydroxy-3-nitrophenyl)ethan-1-one (1.00 g, 1 Eq, 5.10 mmol) in MeCN (30 mL). The reaction was heated to 80 °C for 5 h. The reaction was allowed to cool. The reaction mixture was dried onto celite and purified by column chromatography using a gradient of 0-2% MeOH in DCM toafford 1-(4-amino-5-chloro-2-hydroxy-3-nitrophenyl)ethan-1-one (638 mg, 2.7 mmol, 54 %) as a light yellow solid.

[0184] 1H NMR (400 MHz, DMSO): 5 14.01 (s, 1 H), 8.02 (s, 1 H), 7.28 (s, 2H), 2.55 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 231.0 / 233.0 (M+H)+(ES+); 229.0 / 231.0 (M-H)’ (ES-), at 1.17 min, 99% purity at 260nm + / - 80nm.4-(3-(4-amino-5-chloro-2-hvdroxy-3-nitrophenyl)-3-oxoprop-1-en-1-yl)benzonitrile

[0185] A suspension of 1-(4-amino-5-chloro-2-hydroxy-3-nitrophenyl)ethan-1-one (638 mg, 99% Wt, 1 Eq, 2.74 mmol) and 4-formylbenzonitrile (539 mg, 1.5 Eq, 4.11 mmol) in EtOH (10 mL) was heated to 50 °C before the addition of pyrrolidine (214 mg, 247 pL, 1.1 Eq, 3.01 mmol) in one portion and the reaction mixture was stirred at 50 °C for 2 h and then allowed to cool to rt. The precipitate was collected by filtration, washing with EtOH, and dried in vacuo to afford the desired product 4-(3-(4-amino-5-chloro-2-hydroxy-3-nitrophenyl)-3-oxoprop-1-en-1- yl)benzonitrile (683 mg, 2.0 mmol, 72 %) as a yellow free-flowing solid.

[0186] 1H NMR (400 MHz, DMSO): 5 14.99 (s, 1 H), 8.59 (s, 1 H), 8.20 - 8.12 (m, 3H), 7.99 - 7.92 (m, 2H), 7.87 (d, J = 15.4 Hz, 1 H), 7.47 (s, 2H).

[0187] MS: The product was analysed by LCMS (Method 1): m / z 344.0 / 346.0 (M+H)+(ES+); 342.0 / 344.0 (M-H)- (ES-), at 1.75 min, >99% purity at 260nm + / - 80nm.4-(7-amino-6-chloro-8-nitro-4-oxo-4H-chromen-2-yl)benzonitrile

[0188] To a stirred suspension of 4-(3-(4-amino-5-chloro-2-hydroxy-3-nitrophenyl)-3-oxoprop-1- en-1-yl)benzonitrile (683 mg, 99% Wt, 1 Eq, 1.97 mmol) in DMSO (1.54 g, 1.40 mL, 10 Eq, 19.7 mmol) and Toluene (7 mL) was added iodine (99.9 mg, 0.2 Eq, 393 pmol). The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was allowed to cool to room temperature and diluted with water (20 mL). The precipitate was collected by filtration, washing with water (10 mL) and EtOH (10 mL). The solid was dried in vacuo to afford 4-(7-amino-6-chloro-8-nitro-4- oxo-4H-chromen-2-yl)benzonitrile (761 mg, 2.0 mmol, 100 %) as a pale yellow soild. The product was used without further purification.

[0189] 1H NMR (400 MHz, DMSO): 5 8.20 - 8.12 (m, 2H), 8.12 - 8.04 (m, 2H), 8.02 (s, 1 H), 7.62 (s, 2H), 7.25 (s, 1 H). MS: The product was analysed by LCMS (Method1): m / z 342.0 / 344.0 (M+H)+(ES+); 340.0 / 342.0 (M-H)’ (ES-), at 1.49 min, >99% purity at 260nm + / - 80nm.4-(7,8-diamino-6-chloro-4-oxo-4H-chromen-2-yl)benzonitrile

[0190] To a stirred suspension of 4-(7-amino-6-chloro-8-nitro-4-oxo-4H-chromen-2- yl)benzonitrile (761 mg, 90% Wt, 1 Eq, 2.00 mmol) in DMSO (5 mL), EtOH (5 mL) and Water (1 mL) at 80 °C was added sodium dithionite (1.05 g, 419 pL, 3 Eq, 6.01 mmol). After 4 h, the reaction was diluted with an additional aliquot of DMSO (5 mL), EtOH (5 mL) and Water (1 mL). The reaction was heated to 80 °C for a further 6 h. The reaction was allowed to cool then poured into a mixture of ice and water (100 mL). The resulting precipitate was filtered, washed with water (10 mL), then MeCN (5 mL) and dried in vacuo to afford 4-(7,8-diamino-6-chloro-4- oxo-4H-chromen-2-yl)benzonitrile (537 mg, 1.7 mmol, 85 %) as a light orange solid.

[0191] 1H NMR (400 MHz, DMSO): 5 8.47 - 8.39 (m, 2H), 8.05 - 7.97 (m, 2H), 7.23 (s, 1 H), 7.02 (s, 1H), 5.81 (s, 2H), 5.33 (s, 2H). MS: The product was analysed by LCMS (Method 1): m / z 312.0 / 314.0 (M+H)+(ES+); 310.0 / 312.0 (M-H)' (ES-), at 1.21 min, >99% purity at 260nm + / - 80nm.4-(4-chloro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromenof7,8-d1imidazol-8-yl)benzonitrile (18)

[0192] TFA (0.36 g, 0.24 mL, 20 Eq, 3.2 mmol) was slowly added to 4-(7,8-diamino-6-chloro-4- oxo-4H-chromen-2-yl)benzonitrile (50 mg, 99% Wt, 1 Eq, 0.16 mmol) while cooling over an ice bath. The mixture was stirred at reflux for 6 h, then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and sat. aq. NaHCOs (10 mL) was slowly added while stirring to avoid excessive gas evolution. The phases were separated and the organic phase was washed with brine (10 mL), dried over MgSC , filtered and concentrated. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM to afford 4-(4-chloro-6- oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (19 mg, 48 pmol, 30 %) as a light yellow solid.

[0193] The product was analysed by LCMS (Method 1): m / z 390.0 / 392.0 (M+H)+(ES+); 388.0 / 390.0 (M-H)' (ES-), at 1.46 min, >99% purity at 260nm + / - 80nm.

[0194] 1H NMR (500 MHz, DMSO, 298 K) 5 8.46 (b, 2H), 8.16 - 8.10 (m, 2H), 7.93 (s, 1 H), 7.40 (s, 1 H).19F NMR (471 MHz, DMSO, 298 K) 5 -62.51.1H NMR (500 MHz, DMSO, 353 K) 5 8.42 (d, J = 8.1 Hz, 2H), 8.11 - 8.06 (m, 2H), 7.95 (s, 1 H), 7.29 (s, 1 H).Compound 194-(7-amino-8-nitro-4-oxo-4H-chromen-2-yl)benzonitrileSynthesized as previously described1All experimental data was in congruence with literature values.4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile

[0195] To a stirred suspension of 4-(7-amino-8-nitro-4-oxo-4H-chromen-2-yl)benzonitrile (3.0 g, 98% Wt, 1 Eq, 9.57 mmol) in DMSO (15 mL) and EtOH (15 mL) at 80 °C was added sodium dithionite (5.00 g, 2.00 mL, 3 Eq, 28.7 mmol). The reaction mixture was stirred at 80 °C for 30 min. Water (10 mL) was added and the reaction mixture was stirred at 80 °C for 1 .5 h. The reaction mixture was diluted with DMSO (10 mL), EtOH (10 mL) and additional sodium dithionite (500 mg, 0.3 eq., 2.87 mmol) was added. The reaction mixture was stirred at 80 °C for 2.5 h. The reaction mixture was poured into a mixture of ice and water (200 mL) and allowed to stand overnight. The resultant precipitate was collected by filtration then washed with water, MeCN and EtOH. The solid was dried in vacuo (40 °C, overnight) to afford 4-(7,8-diamino-4-oxo-4H- chromen-2-yl)benzonitrile (2.778 g, 7.7 mmol, 81 %) as an orange solid.

[0196] 1H NMR (500 MHz, DMSO): 5 8.45 - 8.36 (m, 2H), 8.04 - 7.98 (m, 2H), 7.18 (d, J = 8.5 Hz, 1 H), 6.95 (s, 1 H), 6.71 (d, J = 8.4 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 278.0 (M+H)+(ES+); 276.0 (M-H)’ (ES-), at 0.99 min, 95% purity at 260nm + / - 80nm.4-(2-(1-fluorocvclopropyl)-6-oxo-3,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (19)

[0197] To a suspension of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (50.0 mg, 77%Wt, 1 Eq, 139 pmol), 1 -fluorocyclopropane- 1 -carboxylic acid (21.0 mg, 1.45 Eq, 202pmol) and DIPEA (74.2 mg, 100.0 pL, 4.13 Eq, 574 pmol) in DCM (2 mL) and DMF (2 mL) was added HATLI (79.0 mg, 1.50 Eq, 208 pmol). The reaction mixture was stirred at rt for 1 h. Additional HATLI (70.0 mg, 1.33 Eq, 184 pmol) was added and stirred for 15 min. The reaction mixture was diluted with DCM (5 mL) and washed with sat. aq. NaHCOs (10 mL). Phases were separated, the organic layer was collected and the aqueous layer was extracted with DCM (5 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The residue was azeotroped with toluene to afford the crude product. AcOH (3 mL) was added and the reaction mixture was stirred at 50 °C for 1 h 45 min. The temperature was increased to 85 °C and stirred for 5 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene to afford the crude product. The crude product was purified by colomn chromatography using a gradient of 0-5% MeOH in DCM to afford 4-(2-(1- fluorocyclopropyl)-6-oxo-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (34.0 mg, 96 pmol, 69 %) as a beige solid.

[0198] 1H NMR (400 MHz, MeOD): 5 8.49 - 8.41 (m, 2H), 8.02 (d, J = 8.6 Hz, 1 H), 7.98 - 7.93 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 1.81 - 1.70 (m, 2H), 1.68 - 1.58 (m, 2H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD): 5 -194.27. MS: The product was analysed by LCMS (Method 1): m / z 346.0 (M+H)+(ES+); 344.0 (M-H)’ (ES-), at 1.30 min, 97% purity at 260nm + / - 80nm.Compound 204-(2-methyl-6-oxo-1,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (20)

[0199] A suspension of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (50.0 mg, 77% Wt, 1 Eq, 139 pmol) and malonic acid (113 mg, 7.82 Eq, 1.09 mmol) in dioxane (2 mL) was heated to 120 °C by microwave irradiation for 5 h. The reaction mixture was diluted with sat. aq.NaHCOs (5 mL) and extracted with DCM (2 x 10 mL). The combined organic extracts were dried by phase separator and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% MeOH / DCM) to afford 4-(2- methyl-6-oxo-1 ,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (18.2 mg, 57 pmol, 41 %) as a beige solid.1H NMR (400 MHz, DMSO): 5 12.84 (s, 1 H), 8.38 - 8.31 (m, 2H), 8.09 - 8.01 (m,2H), 7.82 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.11 (s, 1 H), 2.63 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 302.0 (M+H)+(ES+); 300.0 (M-H)' (ES-), at 0.97 min, 100% purity at 260nm + / - 80nm.Compound 21

[0200] 4-(2,6-dioxo-1 ,2,3,6-tetrahydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (21)

[0201] To a stirred suspension of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (55.0 mg, 77% Wt, 1 Eq, 153 pmol) and cesium carbonate (162 mg, 3.26 Eq, 497 pmol) in THF (4 mL) was added triphosgene (136 mg, 3.00 Eq, 458 pmol) in one portion. The reaction mixture was stirred at rt for 1 h and then carefully quenched with water (4 mL). The resultant suspension was collected by filtration washing with water and MTBE. The solid was dried in vacuo to afford 4- (2,6-dioxo-1 ,2,3,6-tetrahydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (38.0 mg, 0.12 mmol, pale brown solid.

[0202] 1H NMR (400 MHz, DMSO): 5 11.96 (br s, 1 H), 11.37 (br s, J = 1.7 Hz, 1 H), 8.55 - 8.48 (m, 2H), 8.10 - 8.02 (m, 2H), 7.66 (d, J = 8.3 Hz, 1 H), 7.20 (s, 1 H), 7.12 (d, J = 8.4 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 304.0 (M+H)+(ES+); 302.0 (M-H)' (ES-), at 0.98 min, 99% purity at 260nm + / - 80nm.Compounds 22 & 234-(6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8-yl) benzonitrile Synthesized as previously described1All experimental data was in congruence with literature values.4-(3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (22) 4-(1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (23)22 23

[0203] To a stirred suspension of 4-(6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (107 mg, 98% Wt, 1 Eq, 295 pmol) and potassium carbonate (65.0 mg, 1.59 Eq, 470 pmol) in DMF (3 mL) was added Mel (45.4 mg, 20.0 pL, 1.08 Eq, 320 pmol). The reaction mixture was stirred at rt for 16 h. Additional Mel (45.4 mg, 20.0 pL, 1.08 Eq, 320 pmol) was added and stirred for 4 h. The reaction mixture was diluted with water (10 mL) and the precipitate was collected by filtration, washing with water, to afford a mixture of products (96 mg). The mixture of products (96 mg) were dissolved to 10 mg / mL in DMSO:THF (1:1) with sonication, filtered and was then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar using a ChiralpaK IH, 10 x 150mm, 5pm, flow rate 15mL / min at 30% MeOH , 70% CO2. The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5mbar overnight to afford the separated isomers.Compound 22

[0204] 4-(3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (28.4 mg, 76 pmol, 26 %) was isolated as a yellow solid.

[0205] 1H NMR (400 MHz, DMSO): 5 8.35 - 8.27 (m, 2H), 8.13 - 8.09 (m, 2H), 8.08 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1 H), 7.34 (s, 1 H), 4.11 - 4.08 (m, 3H).19F NMR (376 MHz, DMSO): 5 -61.54. MS: The product was analysed by LCMS (Method 1): m / z 370.1 (M+H)+(ES+); no ionisation (ES_), at 1.41 min, 99% purity 210-400nm.Compound 23

[0206] 4-(1-methyl-6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (30.6 mg, 82 pmol, 28 %) was isolated as a yellow solid.

[0207] 1H NMR (400 MHz, DMSO): 5 8.32 - 8.25 (m, 2H), 8.13 - 8.05 (m, 2H), 7.97 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1 H), 7.32 (s, 1 H), 4.44 (s, 3H).19F NMR (376 MHz, DMSO): 5 -61.25. MS: The product was analysed by LCMS (Method 1): m / z 370.1 (M+H)+(ES+); no ionisation (ES-), at 1.41 min, 99% purity 210-400nm.Compound 244-(7,8-diamino-6-methyl-4-oxo-4H-chromen-2-yl)benzonitrile

[0208] A suspension of 4-(7,8-diamino-6-chloro-4-oxo-4H-chromen-2-yl)benzonitrile (202 mg, 99% Wt, 1 Eq, 642 pmol), methylboronic acid (115 mg, 3 Eq, 1.92 mmol), potassium carbonate (197 mg, 2.22 Eq, 1.43 mmol) and Pd-170 (43.2 mg, 0.1 Eq, 64.2 pmol) in dioxane (4 mL) and water (0.4 mL) was stirred at 100 °C under N2 for 16 h. Additional methylboronic acid (115 mg, 3 Eq, 1.92 mmol) and Pd-170 (43.2 mg, 0.1 Eq, 64.2 pmol) were added and stirred at 100 °C for 5 h. The reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-10% MeOH in DCM to afford 4-(7,8-diamino-6-methyl-4-oxo-4H-chromen-2-yl)benzonitrile (37.0 mg, 0.11 mmol, 18 %) as a yellow solid.

[0209] 1H NMR (400 MHz, DMSO): 5 8.44 - 8.39 (m, 2H), 8.04 - 7.96 (m, 2H), 7.09 (d, J = 1.0 Hz, 1 H), 6.94 (s, 1 H), 5.42 (s, 2H), 4.92 (s, 2H), 2.18 (d, J = 0.9 Hz, 3H). MS: The product was analysed by LCMS (Method 1): m / z 292.0 (M+H)+(ES+); 290.0 (M-H)’ (ES-), at 1.05 min, 90% purity at 260nm + / - 80nm.4-(4-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromenof7,8-d1imidazol-8-yl)benzonitrile (24)

[0210] A solution of 4-(7,8-diamino-6-methyl-4-oxo-4H-chromen-2-yl)benzonitrile (37.0 mg, 90% Wt, 1 Eq, 114 pmol) in TFA (2 mL) was stirred at 70 °C for 6 h and then allowed to cool to rt. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM to afford the crude product. The crude product was purified by column chromatography using a gradient of 0-3% MeOH in DCM to afford 4-(4-methyl-6-oxo-2-(trifluoromethyl)-1 ,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (34.0 mg, 88 pmol, 77 %) as a pale yellow solid.

[0211] 1H NMR (400 MHz, MeOD): 6 8.47 (d, J = 8.5 Hz, 2H), 8.00 - 7.93 (m, 2H), 7.88 (s, 1 H), 7.15 (s, 1 H), 2.70 (d, J = 1.1 Hz, 3H). MS: The product was analysed by LCMS (Method 1): m / z 370.0 (M+H)+(ES+); 368.0 (M-H)’ (ES-), at 1.40 min, 96% purity at 260nm + / - 80nm.Compound 257-Hvdroxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde

[0212] A suspension of 7-hydroxy-2-phenyl-4H-chromen-4-one 1 (2.40 g, 1 Eq, 10.1 mmol) and hexamethylenetetramine (5.57 g, 3.94 Eq, 39.7 mmol) in AcOH (50 mL) was stirred at reflux overnight. The mixture was cooled to rt and most of the solvent was removed in vacuo. The residue was suspended in water (40 mL) and cone. aq. HCI (30 g, 25.0 mL, 36% Wt, 29 Eq, 0.30 mol) was added. The mixture was stirred at 80 °C for 90 min. The mixture was cooled to rt and the solid was collected by filtration, then rinsed with water (3 x 10 mL) and dried in vacuo to give 7-hydroxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde (1.05 g, 3.9 mmol, 39%) as a tan solid.

[0213] 1H NMR (500 MHz, DMSO) 6 12.20 (s, 1 H), 10.63 (s, 1 H), 8.24 - 8.20 (m, 2H), 8.17 (d, J = 8.9 Hz, 1 H), 7.65 - 7.56 (m, 3H), 7.11 (d, J = 8.9 Hz, 1 H), 7.09 (s, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 267 [M+H]+(ES+); 265 [M-H]- (ES-), at 1.79 min, 99% purity at 210-400 nm.7-Methoxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde

[0214] Potassium carbonate (1.90 g, 5.28 Eq, 13.7 mmol) and methyl iodide (1.4 g, 0.60 mL, 3.7 Eq, 9.6 mmol) were added sequentially to a stirred solution of 7-hydroxy-4-oxo-2-phenyl-4H- chromene-8-carbaldehyde (700 mg, 1 Eq, 2.60 mmol) in DMF (25 mL). The reaction mixture was stirred at rt for 16 h then poured onto water (100 mL). The resulting precipitate was collected and washed with water (20 mL). The solid was dried in vacuo to afford 7-methoxy-4- oxo-2-phenyl-4H-chromene-8-carbaldehyde (728 mg, 2.6 mmol, 99 %) as an off-white solid.

[0215] 1H NMR (400 MHz, DMSO) 6 10.58 (s, 1 H), 8.30 (d, J = 9.0 Hz, 1 H), 8.28 - 8.23 (m, 2H), 7.66 - 7.55 (m, 3H), 7.42 (d, J = 9.1 Hz, 1 H), 7.12 (s, 1 H), 4.07 (s, 3H). MS: The product was analysed by LCMS (Method 1): m / z 281.0 [M+H]+(ES+) at 1.38 min, >99% purity at 260nm + / - 80nm.8-(Difluoromethyl)-7-methoxy-2-phenyl-4H-chromen-4-one (25)

[0216] Deoxofluor (50% w / w in toluene) (0.43 g, 0.50 mL, 50% Wt, 2.8 Eq, 0.98 mmol) was added to a solution of 7-methoxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde (100 mg, 1 Eq, 353 pmol) in DCM (1.77 mL). The reaction was stirred at room temperature overnight. The reaction was quenched by careful addition to sat. aq. NaHCOs (20 mL) and extracted with DCM (3 x 20 mL). The combined organics were dried over MgSCU, the solids were filtered off and the solvent was removed in vacuo. The crude product was dried onto Celite and purified by chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 8-(difluoromethyl)-7-methoxy-2-phenyl-4H-chromen-4-one (94.4 mg, 0.31 mmol, 88%) as an off-white solid.

[0217] 1H NMR (400 MHz, DMSO) 5 8.21 (dd, J = 9.1 , 1.2 Hz, 1 H), 8.14 - 8.06 (m, 2H), 7.67 - 7.55 (m, 3H), 7.49 (t, J = 53.0 Hz, 1 H), 7.39 (dd, J = 9.1 , 1.4 Hz, 1 H), 7.09 (s, 1 H), 4.03 (s, 3H).19F NMR (376 MHz, DMSO) 5 -114.62. MS: The product was analysed by LCMS (Method 1): m / z 303.0 [M+H]+(ES+) at 1.59 min, >99% purity at 260nm + / - 80nm.Compounds 26 & 278-(4-bromophenyl)-3-methyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one & 8-(4- bromophenyl)-1-methyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one

[0218] A stirred suspension of 8-(4-bromophenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1 H)-one (507 mg, 98% Wt, 1 Eq, 1.21 mmol), potassium carbonate (369 mg, 2.2 Eq, 2.67 mmol) and methyl iodide (193 mg, 85.0 pL, 1.12 Eq, 1.36 mmol) in DMF (6 mL) was heated to 50 °C for 3 h. Additional methyl iodide (45.4 mg, 20.0 pL, 0.263 Eq, 320 pmol) was added and stirred at 50 °C for 30 min. The reaction mixture was diluted with water (20 mL) and the resultant precipitate was collected by filtration, washing with water. The solid was dried in vacuo (50 °C, overnight) to afford an inconsequential mixture (~2:1) of regioisomers (484 mg, 1.1 mmol, 92 %) as a tan solid. The product was taken on without separating the isomers.

[0219] MS: The product was analysed by LCMS (Method 1): m / z 423.0 / 425.0 [M+H]+(ES+); no ionisation (ES-), at 1.71 min, 98% purity at 260nm + / - 80nm.4-(3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8-yl)benzaldehyde& 4-(1-methyl-6-oxo-2-(trifluoromethyl)-1,6-dihydrochromenoR,8-d1imidazol-8-yl)benzaldehyde

[0220] A suspension of 8-(4-bromophenyl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (484 mg, 98% Wt, 1 Eq, 1.12 mmol), 8-(4-bromophenyl)-1-methyl-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (484 mg, 98% Wt, 1 Eq, 1.12 mmol), triethylamine (345 mg, 475 pL, 3.04 Eq, 3.41 mmol), triethylsilane (393 mg, 540 pL, 3.02 Eq, 3.38 mmol) and Pd(dppf)Cl2.DCM (92.0 mg, 0.101 Eq, 113 pmol) in DMF (12 mL) was stirred under CO® (3 bar) at 80 °C for 17 h. The reaction mixture was concentrated in vacuo to afford the crude product as a mixture of regioisomers (417 mg, 1.12 mmol, 100 %) as a brown solid. The crude material was taken on without further purification, assuming quantitative yield.

[0221] MS: The product was analysed by LCMS (Method 1): m / z 373.0 [M+H]+(ES+); 417.0 [M- H+formic acid]' (ES-), at 1.43 min, 96% purity at 260nm + / - 80nm.8-(4-(azetidin-1-ylmethyl)phenyl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (26) & 8-(4-(azetidin-1-ylmethyl)phenyl)-1-methyl-2-(trifluoromethyl)chromeno[7,8-dlimidazol- 6(1H)-one (27)26 27

[0222] A suspension of 4-(3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzaldehyde (417 mg, 100% Wt, 1 Eq, 1.12 mmol), 4-(1-methyl-6-oxo-2- (trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzaldehyde (417 mg, 100% Wt, 1.00 Eq, 1.12 mmol) and azetidine (131 mg, 155 pL, 2.05 Eq, 2.30 mmol) in THF (15 mL) was stirred at rt for 1 h. Additional azetidine (67.8 mg, 80.0 pL, 1.06 Eq, 1.19 mmol) was added and stirred for 1 h. Sodium triacetoxyhydroborate (522 mg, 2.20 Eq, 2.46 mmol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was carefully quenched with MeOH and then concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-10% [0.7 M Ammonia in MeOH] / DCM to afford a mixture of isomers. The mixture (402 mg) was dissolved to 50.25 mg / mL in MeOH / DCM(3:1) with sonication, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a Phenomenex A1 , 20 x 250mm, 5pm, flow rate 65mL / min at 50% MeOH (0.2% DEA), 50% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30°C 1 5 mbar over the weekend to afford:Compound 26

[0223] 8-(4-(azetidin-1-ylmethyl)phenyl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (34.4 mg, 82 pmol, 7.4 %) was afforded as a tan solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0224] 1H NMR (500 MHz, MeOD) 5 8.26 - 8.19 (m, 3H), 7.81 (d, J = 8.9 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 2H), 7.05 (s, 1 H), 4.14 (d, J = 0.9 Hz, 3H), 3.73 (s, 2H), 3.35 (t, J = 7.2 Hz, 4H), 2.16 (p, J = 7.2 Hz, 2H).19F NMR (471 MHz, MeOD) 5 -64.17. MS: The product was analysed by LCMS (Method 2): m / z 414.2 [M+H]+(ES+); no ionisation (ES-), at 1.42 min, 99% purity 210-400nm.Compound 27

[0225] 8-(4-(azetidin-1-ylmethyl)phenyl)-1-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1 H)-one (156.2 mg, 0.37 mmol, 33 %) was afforded as a tan solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0226] 1H NMR (500 MHz, MeOD) 5 8.12 - 8.05 (m, 3H), 7.81 (d, J = 8.7 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 2H), 7.02 (s, 1 H), 4.53 (d, J = 1.2 Hz, 3H), 4.02 (s, 2H), 3.68 (t, J = 7.5 Hz, 4H), 2.31 (p, J = 7.6 Hz, 2H).19F NMR (471 MHz, MeOD) 5 -63.90. MS: The product was analysed by LCMS (Method 2): m / z 414.2 [M+H]+(ES+); no ionisation (ES-), at 1.43 min, 99% purity 210-400nm.Compound 288-(4-(pyrrolidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (28)

[0227] To a solution of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzaldehyde (61.0 mg, 96% Wt, 1 Eq, 163 pmol) and pyrrolidine (26.0 mg, 30.0 pL, 2.23 Eq,365 pmol) in THF (2 mL) was added AcOH (1 drop). The reaction mixture was stirred at rt for 16 h. sodium triacetoxyborohydride (41.0 mg, 1.18 Eq, 193 pmol) was added in one portion and the reaction mixture was stirred at rt for 1 h. The reaction mixture was carefully quenched with MeOH (~3 mL) and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford 8-(4-(pyrrolidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (49.0 mg, 0.11 mmol, 70 %) as a tan solid.

[0228] 1H NMR (400 MHz, MeOD) 5 8.47 - 8.39 (m, 2H), 7.90 (d, J = 8.7 Hz, 1 H), 7.69 (d, J =8.6 Hz, 3H), 7.03 (s, 1 H), 4.33 (s, 2H), 3.27 - 3.20 (m, 4H), 2.11 - 2.03 (m, 4H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD) 5 -65.01. MS: The product was analysed by LCMS (Method 1): m / z 414.2 [M+H]+(ES+); 412.0 [M-H]' (ES-), at 0.79 min, 98% purity at 260nm + / - 80nm.Compound 298-(4-(piperidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (29)

[0229] To a solution of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzaldehyde (74.0 mg, 99% Wt, 1 Eq, 204 pmol) and piperidine (43.1 mg, 50.0 pL, 2.48 Eq, 506 pmol) in THF (2 mL) was added AcOH (1 drop). The reaction mixture was stirred at rt 16 h. Sodium triacetoxyborohydride (50.0 mg, 1.15 Eq, 236 pmol) was added in one portion and the reaction mixture was stirred at rt for 3 h. The reaction mixture was carefully quenched with MeOH (~3 mL) and then concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford 8-(4-(piperidin-1-ylmethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (38.0 mg, 87 pmol, 43 %) as a yellow solid.

[0230] 1H NMR (400 MHz, MeOD) 5 8.42 - 8.35 (m, 2H), 7.88 (d, J = 8.7 Hz, 1 H), 7.68 (d, J =8.7 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 2H), 7.01 (s, 1 H), 3.99 (s, 2H), 2.92 - 2.82 (m, 4H), 1.75 (p, J =5.7 Hz, 4H), 1.63 - 1.55 (m, 2H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD) 5 -64.93. MS: The product was analysed by LCMS (Method 1): m / z 428.2 [M+H]+(ES+); 426.0 [M-H]' (ES-), at 0.83 min, 99% purity at 260nm + / - 80nm.Compound 308-(4-(hydroxymethyl)phenyl)-2-(trifluoromethyl)chromenoR,8-d1imidazol-6(3H)-one (30)

[0231] A suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzaldehyde (60.0 mg, 98% Wt, 1 Eq, 164 pmol) and sodium triacetoxyborohydride (39.0 mg, 1.12 Eq, 184 pmol) in THF (1 mL) was stirred at rt for 16 h. Additional sodium triacetoxyborohydride (106 mg, 3.05 Eq, 500 pmol) was added and stirred at rt for 18 h. MeOH (1 mL) was added to quench the reaction mixture and then it was concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 8-(4-(hydroxy methyl) phenyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (17.0 mg, 46 pmol, 28 %) as a pale yellow solid.

[0232] 1H NMR (400 MHz, MeOD) 5 8.30 - 8.22 (m, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 4.73 (s, 2H). 2 protons not observed in CD3OD.19F NMR (376 MHz, MeOD) 5 -65.60. MS: The product was analysed by LCMS (Method 1): m / z 361.0 [M+H]+(ES+); 359.0 [M-H]’ (ES-), at 1.10 min, 98% purity at 260nm + / - 80nm.Compound 318-(4-(difluoromethyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (31)

[0233] To a suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzaldehyde (51.0 mg, 98% Wt, 1 Eq, 0.14 mmol) in DCM (4 mL) was added DMSO (dropwise) until a solution formed. To the resultant solution was added deoxofluor (50% w / w intoluene) (1.00 mL, 1.68 Eq., 0.235 mmol) and the reaction mixture was stirred at rt overnight.Silica gel was added directly to the reaction mixture and then concentrated in vacuo. The crude product was purified by chromatography on silica gel using a gradient of 0-4% (0.7 M Ammonia in MeOH) / DCM to afford impure product. The product was purified again by chromatography on silica gel using a gradient of 0-30% (1:9, MeOH / EtOAc) / hexane to afford 8-(4- (difluoromethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (11.0 mg, 27 pmol, 20 %) as an off-white solid.

[0234] 1H NMR (400 MHz, MeOD) 5 8.44 - 8.36 (m, 2H), 8.15 (d, J = 8.8 Hz, 1H), 7.81 - 7.77 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.90 (t, J = 55.9 Hz, 1 H).19F NMR (376 MHz, MeOD) 5 -65.63, -113.44. MS: The product was analysed by LCMS (Method 1): m / z 381.0 [M+H]+(ES+); 379.0 [M-H]’ (ES-), at 1.46 min, 98% purity at 260nm + / - 80nm.Compound 324-(2-cvclopropyl-6-oxo-1 ,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (32)

[0235] A suspension of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (25.0 mg, 77% Wt, 1 Eq, 69.4 pmol) in pyridine (0.5 mL) was treated with cyclopropanecarbonyl chloride (9.45 mg, 8.20 pL, 1.30 Eq, 90.4 pmol). The reaction mixture was stirred at rt for 2 h. Additional cyclopropanecarbonyl chloride (9.45 mg, 8.20 pL, 1.30 Eq, 90.4 pmol) was added and stirred for 1 h. AcOH (2.5 mL) was added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and the precipitate containing the bis addition product was removed by filtration. The filtrate was extracted with DCM (2 x 10 mL) and the combined organics were passed through a phase separator and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0- 10% MeOH / DCM to afford 4-(2-cyclopropyl-6-oxo-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (12.0 mg, 36 pmol, 52 %) as a pale yellow solid.

[0236] 1H NMR (400 MHz, DMSO) 5 12.92 (s, 1 H), 8.33 - 8.27 (m, 2H), 8.16 - 8.06 (m, 2H), 7.79 (d, J = 8.5 Hz, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.22 (s, 1 H), 2.31 - 2.21 (m, 1 H), 1.22 - 1.09 (m, 4H). Exists as a tautomeric mixture ~2:1. Tautomers do not resolve at 90 °C. Peaksreported for major tautomer. MS: The product was analysed by LCMS (Method 1): m / z 328.2 [M+H]+(ES+); 326.0 [M-H]’ (ES-), at 1.11 min, >99% purity at 260nm + / - 80nm.Compound 334-(6-oxo-1 ,6-dihydrochromenoR,8-d1imidazol-8-yl)benzonitrile (33)

[0237] A suspension of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (50.0 mg, 77% Wt, 1 Eq, 139 pmol) and cyclopropanecarboxylic acid (97.3 mg, 90.0 pL, 8.14 Eq, 1.13 mmol) in dioxane (1 mL) was heated in the microwave at 120 °C for 1 h. DMSO (1 mL) was added and the resultant solution was heated by microwave irradiation at 150°C for 1 h. Water was added and the resultant precipitate was collected by filtration to afford the crude product.

[0238] The product was further purified by General procedure 4, Method 2. Gradient information: 0.0-0.5 min, 7.5% MeCN; 0.5-15.5 min, ramped from 7.5% MeCN to 37.5% MeCN; 15.5-15.6 min, ramped from 37.5% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-(6-oxo-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (0.90 mg, 3.1 pmol, 2.3 %) as a white solid.

[0239] MS: The product was analysed by UPLC (Method 2): m / z 288.1 [M+H]+(ES+); 286.2 [M- H]’ (ES-), at 0.79 min, 99% purity 210-400nm.Compound 344-(2-(difluoromethyl)-6-oxo-3,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (34)

[0240] To a solution of 4-(7,8-diamino-4-oxo-4H-chromen-2-yl)benzonitrile (50.0 mg, 77% Wt, 1 Eq, 139 pmol), 2,2-difluoroacetic acid (14.0 pL, 1.60 Eq, 222 pmol) and DIPEA (100 pL, 4.13 Eq, 574 pmol) in DMF (0.5 mL) was added a solution of 2-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)- 1 ,1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (89.0 mg, 1.69 Eq, 234 pmol) in DMF(0.5 mL). The reaction mixture was stirred at rt for 1 h. Additional 2,2-difluoroacetic acid (7.00 pL, 0.801 Eq, 111 pmol) was added and stirred at rt for 45 min. Additional 2-(3H-[1 , 2 , 3]triazolo[4, 5-b] py ridi n-3-y I)- 1 , 1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (45.0 mg, 0.852 Eq, 118 pmol) was added and stirred for 90 min. AcOH (2.5 mL) was added and stirred at 100 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (5 times) to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-6% MeOH / DCM to afford 4-(2- (difluoromethyl)-6-oxo-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (30.0 mg, 87 pmol, 63 %) as a pale yellow solid.

[0241] 1H NMR (400 MHz, MeOD) 5 8.53 - 8.46 (m, 2H), 7.97 - 7.91 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1 H), 7.09 (s, 1 H), 6.97 (t, J = 54.3 Hz, 1H).19F NMR (376 MHz, MeOD) 5 -115.48. MS: The product was analysed by LCMS (Method 1): m / z 338.0 [M+H]+(ES+); 336.0 [M-H]' (ES-), at 1.23 min, 99% purity at 260nm + / - 80nm.Compounds 35 & 36 8-(1-acetylpiperidin-4-yl)-3-methyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (35) & 8-(1-acetylpiperidin-4-yl)-1-methyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1H)-one (36)35 36

[0242] To a stirred suspension of 8-(1-acetylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (94.0 mg, 1 Eq, 248 pmol) and potassium carbonate (55.0 mg, 1.61 Eq, 398 pmol) in DMF (3 mL) was added Mel (17.0 pL, 1.1 Eq, 273 pmol). The reaction mixture was stirred at rt for 16 h. Additional Mel (5 uL, 0.25 eq) and potassium carbonate (10 mg, 0.3 eq) was added and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine (5 x 10 mL), dried over MgSCU, filtered and concentrated in vacuo to give a mixture of regioisomers which were dissolved to 15.2 mg / mL in MeOH / DCM (3:2) with sonication. The solution was filtered and regioisomers were separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak IG, 10 x 250mm, 5pm, flow rate15mL / min at 35% MeOH (0.1% neutral), 65% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were redissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford: Compound 35

[0243] 8-(1-acetylpiperidin-4-yl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (14 mg, 34 pmol, 14 %) was afforded as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0244] 1H NMR (500 MHz, DMSO) 5 8.04 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 6.33 (s, 1 H), 4.53 (d, J = 13.1 Hz, 1 H), 4.07 (s, 3H), 3.96 (d, J = 13.5 Hz, 1 H), 3.23 - 3.14 (m, 1 H), 3.08 - 2.99 (m, 1 H), 2.71 - 2.62 (m, 1 H), 2.08 - 1.95 (m, 5H), 1.70 (qd, J = 12.5, 4.3 Hz, 1 H), 1.54 (qd, J = 12.6, 4.5 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -61.57. MS: The product was analysed by UPLC (Method 1): m / z 394.3 [M+H]+(ES+); at 1.07 min, 96.2% purity 210-400nm. Compound 36

[0245] 8-(1-acetylpiperidin-4-yl)-1-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (40.0 mg, 97 pmol, 39 %) was afforded as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0246] 1H NMR (500 MHz, DMSO) 5 7.91 (d, J = 8.7 Hz, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 6.37 (s, 1 H), 4.52 (d, J = 13.1 Hz, 1 H), 4.32 (s, 3H), 3.95 (d, J = 13.6 Hz, 1 H), 3.22 - 3.13 (m, 1 H), 3.05 (tt, J = 11.9, 3.6 Hz, 1 H), 2.66 (td, J = 12.0, 2.3 Hz, 1 H), 2.09 - 2.00 (m, 5H), 1.72 (qd, J = 12.5, 4.3 Hz, 1 H), 1.56 (qd, J = 12.5, 4.3 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -61.34. MS: The product was analysed by UPLC (Method 1): m / z 394.3 [M+H]+(ES+) at 1.09 min, >99% purity 210-400nm.Compound 378-(1-acetylpiperidin-4-yl)-3-isopropyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (37)

[0247] DIAD (120 pL, 1.44 Eq, 617 pmol) was added dropwise to a solution of IPA (35 pL, 1.1Eq, 0.46 mmol), triphenylphosphine (140 mg, 1.24 Eq, 534 pmol) and 8-(1-acetylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (166 mg, 98% Wt, 1 Eq, 429 pmol) in THF (4.5 mL) at 0 °C. After 15 min the reaction was allowed to warm to room temperature and stirred overnight. Additional IPA (18 pL, 0.55 Eq, 0.24 mmol) and triphenylphosphine (70 mg, 0.62 Eq, 0.27 mmol) were added. The reaction was cooled to 0 °C and additional DIAD (60 pL, 0.72 Eq, 0.31 mmol) was added dropwise. After 15 min, the reaction was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to afford a mixture of regio isomers. The mixture (106 mg) was dissolved to 35.3 mg / mL in THF / MeOH (2:1) with sonication, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and a QDA detector, 40 °C, 120 bar. The column was a Chiralpak IBN, 21 x 250mm, 5pm, flow rate 65mL / min at 30% MeOH (neutral), 70% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were redissolved in THF / MeOH, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford 8-(1- acetylpiperidin-4-yl)-3-isopropyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (27.9 mg, 63 pmol, 15 %) as a white solid.

[0248] 1H NMR (500 MHz, MeOD) 5 8.12 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1 H), 6.39 (s, 1H), 5.14 - 5.02 (m, 1H), 4.72 (d, J = 13.3 Hz, 1H), 4.11 (d, J = 13.9 Hz, 1H), 3.15 - 3.05 (m, 1H), 2.84 - 2.76 (m, 1H), 2.26 - 2.09 (m, 5H), 1.96 (qd, J = 12.5, 4.1 Hz, 1H), 1.87 - 1.80 (m, 1H), 1.77 (d, J = 7.0 Hz, 6H).19F NMR (471 MHz, MeOD) 5 -63.30. MS: The product was analysed by LCMS (Method 1): m / z 422.3 [M+H]+(ES+) at 1.25 min, >99% purity 210-400 nm.Compounds 38 & 39 8-(1-acetylpiperidin-4-yl)-3-ethyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (38) & 8- (1-acetylpiperidin-4-yl)-1-ethyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (39)38 39

[0249] A solution of 8-(1-acetylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)- one (500 mg, 50% Wt, 1 Eq, 659 pmol), iodoethane (60.0 pL, 1.13 Eq, 745 pmol) and DI PEA(140 pL, 1.22 Eq, 804 pmol) in DMF (3 mL) was stirred at 65 °C for 2 h. Additional DIPEA (140 pL, 1.22 Eq, 804 pmol) and iodoethane (60.0 pL, 1.13 Eq, 745 pmol) were added and stirred at 65 °C for 1 h. Additional DI PEA (140 pL, 1.22 Eq, 804 pmol) and iodoethane (60.0 pL, 1.13 Eq, 745 pmol) were added and stirred at 65 °C for 30 min. The reaction mixture was diluted with water (10 mL) and then extracted with DCM (2 x 5 mL). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was azeotroped with toluene (4 times) to afford the crude product as a mixture of regioisomers. The mixture (122 mg) was dissolved to 34.85 mg / mL in 3.5 mL MeOH with sonication then filtered and separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a Chiralpak IB-N, 20 x 250mm, 5pm, flow rate 65 mL / min at 30% MeOH (neutral), 70% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a Rocket evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 38

[0250] 8-(1-acetylpiperidin-4-yl)-3-ethyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (18.9 mg, 44 pmol, 7%) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0251] 1H NMR (400 MHz, DMSO) 5 7.95 (d, J = 8.7 Hz, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 6.40 (s, 1 H), 4.70 (q, J = 7.2 Hz, 2H), 4.53 (d, J = 13.2 Hz, 1 H), 3.97 (d, J = 13.8 Hz, 1 H), 3.19 (t, J = 12.4 Hz, 1 H), 3.11 - 3.01 (m, 1 H), 2.72 - 2.61 (m, 1 H), 2.04 (s, 5H), 1.77 - 1.65 (m, 1 H), 1.55 (q, J = 8.2 Hz, 4H).19F NMR (376 MHz, DMSO) 5 -61.16. MS: The product was analysed by LCMS (Method 1): m / z 408.2 [M+H]+(ES+) at 1.23 min, >99% purity at 260nm + / - 80nm. Compound 39

[0252] 8-(1-acetylpiperidin-4-yl)-1-ethyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (38.3 mg, 89 pmol, 14%) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0253] 1H NMR (400 MHz, DMSO) 5 8.05 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 6.33 (s, 1 H), 4.54 (q, J = 7.4 Hz, 3H), 3.96 (d, J = 13.6 Hz, 1 H), 3.24 - 3.13 (m, 1 H), 3.04 (ddd, J = 11.9, 8.3, 3.7 Hz, 1 H), 2.67 (t, J = 12.4 Hz, 1 H), 2.05 (s, 5H), 1.71 (td, J = 12.3, 4.2 Hz, 1 H), 1.61 - 1.47 (m, 1 H), 1.41 (t, J = 7.2 Hz, 3H).19F NMR (376 MHz, DMSO) 5 -61.31. MS: The product was analysed by LCMS (Method 1): m / z 408.2 [M+H]+(ES+) at 1.24 min, >99% purity at 260nm + / - 80nm.Compound 407-amino-2-(1-ethylpiperidin-4-yl)-8-nitro-4H-chromen-4-one

[0254] To a stirred suspension of 7-amino-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride (303 mg, 95% Wt, 1 Eq, 884 pmol) in DCM (9 mL) was added acetaldehyde (236 mg, 300 pL, 6.07 Eq, 5.37 mmol). The reaction mixture was stirred at rt for 2.5 h. Sodium triacetoxyborohydride (305 mg, 1.63 Eq, 1.44 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was carefully quenched with 50% sat. aq. NaHCOs (10 mL). The mixture was passed through a phase separator and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organics were washed with sat. aq. NaHCOs (20 mL), 50% brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford 7-amino-2-(1-ethylpiperidin-4-yl)-8-nitro-4H-chromen-4- one (150 mg, 0.45 mmol, 51 %) as a yellow solid.

[0255] 1H NMR (400 MHz, DMSO) 5 7.81 (d, J = 9.1 Hz, 1H), 7.60 (br s, 2H), 6.93 (d, J = 9.1 Hz, 1H), 6.15 (s, 1H), 2.99 - 2.91 (m, 2H), 2.61 - 2.51 (m, 1H), 2.33 (q, J = 7.2 Hz, 2H), 1.98 - 1.83 (m, 4H), 1.66 (qd, J = 12.2, 3.8 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H).8-(1-ethylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (40)

[0256] To a solution of 7-amino-2-(1-ethylpiperidin-4-yl)-8-nitro-4H-chromen-4-one (50.0 mg, 95% Wt, 1 Eq, 150 pmol) and triethylamine (315 pL, 15.1 Eq, 2.26 mmol) in EtOH (2 mL), THF (2 mL) and water (0.2 mL) at 60 °C was added sodium dithionite (41.7 pL, 4 Eq, 599 pmol). The reaction mixture was stirred at 60 °C for 1 h and then allowed to cool to rt overnight. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (2 times) to afford the crude product as a mixture of 7,8-diamino-2-(1-ethylpiperidin-4-yl)-4H-chromen-4- one and (7-amino-2-(1-ethylpiperidin-4-yl)-4-oxo-4H-chromen-8-yl)sulfamic acid. The crude product was dissolved in TFA (2 mL) and stirred at 60 °C for 10 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM (3 times) to afford the crude product. The crude product was purified by chromatography on silica gel using a gradient of 0-20% (0.7 M Ammonia in MeOH) / DCM to afford impure product. The product was then purified by chromatography on RP Flash C18 using a gradient of 5-30% MeCN / (0.1% AmmoniumHydroxide in Water)) to afford 8-(1-ethylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (10.0 mg, 26 pmol, 18 %) as an off-white solid.

[0257] 1H NMR (500 MHz, MeOD) 5 7.79 (d, J = 8.6 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 1 H), 6.30 (s, 1 H), 3.49 (d, J = 12.2 Hz, 2H), 2.98 (t, J = 14.6 Hz, 3H), 2.76 (s, 2H), 2.35 (d, J = 13.8 Hz, 2H), 2.11 (t, J = 13.0 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H). 1 exchangeable proton not observed.19F NMR (471 MHz, MeOD) 5 -64.88. MS: The product was analysed by LCMS (Method 1): m / z 366.0 [M+H]+(ES+); 364.0 [M-H]’ (ES-), at 0.62 min, >99% purity at 260nm + / - 80nm.Compound 417-amino-2-(1-isobutylpiperidin-4-yl)-8-nitro-4H-chromen-4-one

[0258] To a solution of 7-amino-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride (100 mg, 95% Wt, 1 Eq, 292 pmol) in DMF (2 mL) was added isobutyraldehyde (100 pL, 3.76 Eq, 1.10 mmol). The reaction mixture was stirred at rt for 3 h and then sodium triacetoxyborohydride (100 mg, 1.62 Eq, 472 pmol) was added in one portion. The reaction mixture was stirred at rt for 30 min and then diluted with DCM (10 mL). The reaction mixture was washed with sat. aq.NaHCOs (10 mL). The organic layer was collected and the aqueous layer extracted with DCM (2 x 5 mL). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was azeotroped with toluene (3 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford 7-amino-2-(1-isobutylpiperidin-4-yl)-8-nitro-4H- chromen-4-one (61.0 mg, 0.16 mmol, 56 %) as a yellow-brown solid.

[0259] MS: The product was analysed by LCMS (Method 1): m / z 346.2 [M+H]+(ES+); 344.3 [M- H]’ (ES-), at 0.65 min, 93% purity at 260nm + / - 80nm.8-(1-isobutylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (41)

[0260] To a solution of 7-amino-2-(1-isobutylpiperidin-4-yl)-8-nitro-4H-chromen-4-one (61.0 mg, 93% Wt, 1 Eq, 164 pmol) and triethylamine (350 pL, 15.3 Eq, 2.51 mmol) in EtOH (2 mL), THF (2 mL) and water (0.4 mL) at 60 °C was added sodium dithionite (49.6 pL, 4.34 Eq, 712 pmol). The reaction mixture was stirred at 60 °C for 2 h and then concentrated in vacuo. The residuewas azeotroped with DCM (2 times) to afford the crude product as a mixture of 7,8-diamino-2- (1-isobutylpiperidin-4-yl)-4H-chromen-4-one and (7-amino-2-(1-isobutylpiperidin-4-yl)-4-oxo-4H- chromen-8-yl)sulfamic acid. The crude product was dissolved in TFA (2 mL) and stirred at 70 °C for 8 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM (3 times) to afford the crude product. The product was purified by chromatography on RP Flash C18 using a gradient of 5-30% MeCN / (0.1% Ammonium Hydroxide in Water) to afford 8-(1 -isobutylpiperidin- 4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (35.0 mg, 87 pmol, 53 %) as an off- white solid.

[0261] 1H NMR (400 MHz, MeOD) 5 7.83 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 6.32 (d, J = 3.2 Hz, 1 H), 3.57 (d, J = 12.3 Hz, 2H), 3.11 - 2.98 (m, 1 H), 2.98 - 2.80 (m, 4H), 2.37 - 2.06 (m, 5H), 1.07 (dd, J = 6.6, 1.4 Hz, 6H). 1 proton not observed in MeOD.19F NMR (376 MHz, MeOD) 5 -64.98. MS: The product was analysed by LCMS (Method 1): m / z 394.0 [M+H]+(ES+); 392.0 [M-H]' (ES-), at 0.74 min, >99% purity at 260nm + / - 80nm.Compound 427-amino-2-(1-methylpiperidin-4-yl)-8-nitro-4H-chromen-4-one

[0262] To a stirred suspension of 7-amino-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride (303 mg, 95% Wt, 1 Eq, 884 pmol) in DMF (4 mL) was added formaldehyde (37 wt% in water, stab. 10-15% MeOH) (700 pL, 37% Wt, 10.6 Eq, 9.40 mmol) and 3 A mol. sieves (150 mg). The reaction mixture was stirred at 50 °C for 2.5 h. The reaction mixture was removed from the heat source and sodium triacetoxyborohydride (300 mg, 1.60 Eq, 1.42 mmol) was added. The reaction mixture was stirred on for 16 h without further heating. The reaction mixture was carefully quenched with 50% sat. aq. NaHCO3 (10 mL). The mixture was passed through a phase separator and the aqueous was extracted with DCM (2 x 10 mL) and chloroform / IPA (3:1) (2 x 25 mL). The combined organics were washed with 50% brine (25 mL), dried over MgSC and concentrated in vacuo. The residue was azeotroped with toluene (3 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford 7-amino-2-(1-methylpiperidin-4-yl)-8-nitro-4H-chromen-4-one (158 mg, 0.49 mmol, 56 %) as a yellow solid.

[0263] 1H NMR (400 MHz, DMSO) 5 7.81 (d, J = 9.1 Hz, 1 H), 7.60 (s, 2H), 6.93 (d, J = 9.1 Hz, 1 H), 6.15 (s, 1 H), 2.84 (d, J = 11.4 Hz, 2H), 2.57 - 2.51 (m, 1 H), 2.18 (s, 3H), 1.93 (td, J = 11.8, 2.4 Hz, 2H), 1.86 (d, J = 13.0 Hz, 2H), 1.67 (qd, J = 12.2, 3.7 Hz, 2H). MS: The product wasanalysed by LCMS (Method 1): m / z 304.0 [M+H]+(ES+); 302.0 [M-H]’ (ES-), at 0.43 min, 98% purity at 260nm + / - 80nm.8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (42)

[0264] To a solution of 7-amino-2-(1-methylpiperidin-4-yl)-8-nitro-4H-chromen-4-one (53.0 mg, 95% Wt, 1 Eq, 166 pmol) and triethylamine (350 pL, 15.1 Eq, 2.51 mmol) in EtOH (2 mL), THF (2 mL) and water (0.4 mL) at 60 °C was added sodium dithionite (49.6 pL, 4.29 Eq, 712 pmol). The reaction mixture was stirred at 60 °C for 1 h and then concentrated in vacuo. The residue was azeotroped with DCM (2 times) to afford a mixture of 7,8-diamino-2-(1-methylpiperidin-4- yl)-4H-chromen-4-one and (7-amino-2-(1-methylpiperidin-4-yl)-4-oxo-4H-chromen-8-yl)sulfamic acid. The crude product was dissolved in TFA (2 mL) and stirred at 70 °C for 8 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM (3 times) to afford the crude product. The product was purified by column chromatography on RP Flash C18 using a gradient of 5-30% MeCN / (0.1% Ammonium Hydroxide in Water) to afford 8-(1-methylpiperidin-4-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (31.0 mg, 84 pmol, 50 %) as an off-white solid.

[0265] 1H NMR (400 MHz, MeOD) 5 7.83 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 6.32 (s, 1 H), 3.52 (d, J = 12.1 Hz, 2H), 3.10 - 2.92 (m, 3H), 2.83 (s, 3H), 2.34 (d, J = 13.5 Hz, 2H), 2.25 - 2.10 (m, 2H). 1 exchangeable proton not observed.19F NMR (376 MHz, MeOD) 5 -65.01. MS: The product was analysed by LCMS (Method 1): m / z 352.0 [M+H]+(ES+); 350.0 [M-H]- (ES-), at 0.60 min, >99% purity at 260nm + / - 80nm.Compounds 43 & 443-(methyl-d3)-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (43) & 1-(methyl-d3)-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol- 6(1 H)-one (44)43 44

[0266] To a stirred solution of 8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (105 mg, 81% Wt, 1 Eq, 242 pmol), d3-methanol (20.0 pL, 2.03 Eq, 492 pmol) and triphenylphosphine (148 mg, 2.33 Eq, 564 pmol) was added DIAD (125 pL, 2.66 Eq, 643 pmol). The reaction mixture was stirred at rt for 1 h. Additional triphenylphosphine (148 mg, 2.33 Eq, 564 pmol) and d3-methanol (100 pL, 10.2 Eq, 2.46 mmol) were added and the reaction was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford a mixture of regioisomers. The mixture (16.4 mg) was dissolved to 5 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a ChiralpaK IB-N, 20 x 250mm, 5pm, flow rate 65 mL / min at 25% MeOH (0.2% DEA), 75% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford two isolated regioisomers which were arbitrarily assigned as compound 43 and compound 44:Compound 43:

[0267] 3-(methyl-d3)-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (7.70 mg, 20 pmol, 8.4 %) as a white solid. (Specific regioisomeric identity arbitrarily assigned)

[0268] 1H NMR (500 MHz, MeOD) 5 8.03 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1 H), 6.39 (s, 1H), 3.06 (d, J = 11.9 Hz, 2H), 2.83 (tt, J = 12.1, 3.8 Hz, 1H), 2.36 (s, 3H), 2.21 (td, J = 12.1, 2.6 Hz, 2H), 2.10 (d, J = 13.0 Hz, 2H), 1.97 (qd, J = 12.5, 3.8 Hz, 2H). MS: The product was analysed by LCMS (Method 2): m / z 369.1 [M+H]+(ES+); no ionisation (ES-), at 1.20 min, 97% purity at 260nm + / - 90nm.Compound 44:

[0269] 1-(methyl-d3)-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1H)-one (7.80 mg, 21 pmol, 8.7 %) as a white solid. (Specific regioisomeric identity arbitrarily assigned)

[0270] 1H NMR (500 MHz, MeOD) 5 8.15 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1 H), 6.36 (s, 1H), 3.05 (d, J = 11.6 Hz, 2H), 2.83 (tt, J = 11.9, 3.7 Hz, 1H), 2.34 (s, 3H), 2.26 - 2.16 (m, 4H), 1.91 (qd, J = 12.4, 3.8 Hz, 2H). MS: The product was analysed by LCMS (Method 2): m / z 369.1 [M+H]+(ES+); no ionisation (ES-), at 1.19 min, >99% purity at 260nm + / - 90nm.Compounds 45 & 464-(3-(cvclopropylmethyl)-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8- vDbenzonitrile (45) & 4-(1-(cvclopropylmethyl)-6-oxo-2-(trifluoromethyl)-1 ,6- dihvdrochromeno(7,8-d1imidazol-8-yl)benzonitrile (46)45 46

[0271] To a stirred suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (100 mg, 98% Wt, 1 Eq, 276 pmol) and potassium carbonate (61.0 mg, 1.6 Eq, 441 pmol) in DMF (3.0 mL) was added (bromomethyl)cyclopropane (29.5 pL, 1.1 Eq, 303 pmol). The reaction mixture was stirred at 60 °C for 16 h. Additional cyclopropane, (bromomethyl)- (26.8 pL, 1 Eq, 276 pmol) and potassium carbonate (38.1 mg, 1 Eq, 276 pmol) were added, and the reaction heated for a further 16 h. Additional potassium carbonate (38.1 mg, 1 Eq, 276 pmol) and (bromomethyl)cyclopropane, (26.8 pL, 1 Eq, 276 pmol) were added and the reaction heated for a further 4 h. The reaction was allowed to cool to room temperature, diluted with water (10 mL), stirred for 10 min then filtered. The solid was dried in vacuo to afford a mixture of regioisomers (86.7 mg) which was dissolved in 8 mL THF / DMSO (3:5) with heat and sonication. The solution was then filtered and separated by chiral SFC on a Waters Prep 100 with a PDA and a QDA detector, 40 °C, 120 bar. The column was a Chiralpak IH, 21 x 250mm, 5pm, flow rate 65mL / min at 50% MeOH (0.2% ammonia), 50% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotaryevaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight.Compound 45:

[0272] 4-(3-(cyclopropylmethyl)-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (34.4 mg, 81 pmol, 29 %) was afforded as a light white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0273] 1H NMR (500 MHz, MeOD) 5 8.48 - 8.42 (m, 2H), 8.22 (d, J = 8.9 Hz, 1 H), 8.01 - 7.95 (m, 2H), 7.89 (d, J = 8.9 Hz, 1 H), 7.19 (s, 1 H), 4.47 (d, J = 7.1 Hz, 2H), 1.45 - 1.37 (m, 1 H), 0.71 - 0.64 (m, 2H), 0.61 - 0.54 (m, 2H).19F NMR (471 MHz, MeOD) 5 -62.89. MS: The product was analysed by LCMS (Method 1): m / z 410.0 [M+H]+(ES+) at 1.72 min. (The sample streaked significantly on all tested systems so LCMS was not used as a measure of purity). Compound 46:

[0274] The sample was freeze dried to afford 4-(1-(cyclopropylmethyl)-6-oxo-2-(trifluoromethyl)- 1 ,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (30.6 mg, 71 pmol, 26 %) as a light white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0275] 1H NMR (500 MHz, MeOD) 5 8.30 (d, J = 8.2 Hz, 2H), 8.17 (d, J = 8.7 Hz, 1 H), 8.01 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1 H), 7.19 (s, 1 H), 4.80 (d, J = 6.8 Hz, 2H), 1.59 (app. p, J = 6.7 Hz, 1 H), 0.68 - 0.60 (m, 2H), 0.60 - 0.53 (m, 2H).

[0276] 19F NMR (471 MHz, MeOD) 5 -62.29.

[0277] MS: The product was analysed by LCMS (Method 1): m / z 410.0 [M+H]+(ES+) at 1.68 min, 99% purity at 260nm + / - 80nm.Compound 474-(3-isopropyl-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile

[0278] To a stirred suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (100 mg, 98% Wt, 1 Eq, 276 pmol) and potassium carbonate (61.0 mg, 1.6 Eq, 441 pmol) in DMF (3.0 mL) was added 2-iodopropane (30.3 pL, 1.1 Eq, 303 pmol).The reaction mixture was stirred at 60 °C for 16 h. Additional 2-iodopropane (55.1 pL, 2 Eq, 552 pmol) was added, and the reaction heated to 80 °C overnight. Additional potassium carbonate (49.6 mg, 1.3 Eq, 359 pmol) and 2-iodopropane (150 pL, 5.45 Eq, 1.50 mmol) was added and the reaction heated for a further 24 h. The reaction was allowed to cool to room temperature, diluted with water (10 mL), stirred for 10 min and the precipitate collected by filtration. The crude product was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-4% MeOH / DCM to afford a mixture of isomers (19.7 mg). The mixture was dissolved to 9.85 mg / mL in DCM / DMSO (1:1) with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a Chiralpak I H, 10 x 150mm, 5pm, flow rate 20mL / min at 20% MeOH (neutral), 80% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30°C / 5mbar overnight, and freeze dried to afford 4-(3-isopropyl-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (11.8 mg, 29 pmol, 11 %) as a light white solid.

[0279] 1H NMR (500 MHz, MeOD) 5 8.45 (d, J = 8.3 Hz, 2H), 8.20 (d, J = 8.9 Hz, 1 H), 8.05 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H), 5.12 (app. p, J = 7.0 Hz, 1H), 1.80 (d, J = 6.9 Hz, 6H).19F NMR (471 MHz, MeOD) 5 -63.28. MS: The product was analysed by LCMS (Method 1): m / z 398.2 [M+H]+(ES+) at 1.67 min, >99% purity at 260nm + / - 80nm.Compounds 48 & 494-(6-oxo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8- vDbenzonitrile (48) & 4-(6-oxo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,6- dihvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (49)

[0280] DI PEA (80 pL, 1.7 Eq, 0.46 mmol) and 2,2,2-Trifluoroiodoethane (850 pL, 31.4 Eq, 8.66 mmol) were added sequentially to a solution of 4-(6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (100 mg, 98% Wt, 1 Eq, 276 pmol) in DMF (3.0 mL). The resulting solution was sealed and heated at 100 °C 14 h. The reaction was allowed to cool, additional 2,2,2-Trifluoroiodoethane (812 pL, 30 Eq, 8.28 mmol) and DIPEA (240 pL, 5 Eq, 1.38 mmol) were added, the reaction was sealed and heated to 100 °C for 24 h. Additional 2,2,2-Trifluoroiodoethane (812 pL, 30 Eq, 8.28 mmol) and DIPEA (240 pL, 5 Eq, 1.38 mmol) were added, the reaction sealed and heated to 100 °C for 48 h. The reaction was allowed to cool, diluted with EtOAc (30 mL) and brine (30 mL) and the phases separated. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organics were washed with brine (20 mL) and dried over MgSO4. The solids were filtered off and the solvent removed in vacuo. The residue was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford a mixture of regioisomers The mixture (54 mg) was separated by chiral prep SFC. The mixture (51.1 mg) was dissolved in methanol (4 mL) with heating and sonication to give a cloudy solution. The solution was filtered through an acrodisc and the filtrate was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a Chiralpak IH, 20 x 250mm, 5pm, flow rate 65 mL / min at 25% ethanol (no modifier), 75% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were suspended in methanol, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford: Compound 48:

[0281] 4-(6-oxo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol- 8-yl)benzonitrile (13.5 mg, 31 pmol, 11 %) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0282] 1H NMR (500 MHz, DMSO) 5 8.36 - 8.31 (m, 2H), 8.18 (d, J = 8.9 Hz, 1H), 8.16 - 8.11 (m, 2H), 8.07 (d, J = 8.9 Hz, 1H), 7.38 (s, 1H), 5.69 (q, J = 8.8 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -60.24 (q, J = 5.3 Hz), -69.31 (q, J = 5.2 Hz). MS: The product was analysed by LCMS (Method 1): m / z 438.0 [M+H]+(ES+) at 1.66 min, >99% purity at 260nm + / - 80nm. Compound 49:

[0283] 4-(6-oxo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol- 8-yl)benzonitrile (10.0 mg, 22 pmol, 8.1 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0284] 1H NMR (500 MHz, DMSO) 5 8.23 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1 H), 7.33 (s, 1 H), 5.84 (d, J = 8.6 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -60.27 (d, J = 5.7 Hz), -69.36 (d, J = 5.8 Hz). MS: The product was analysed by LCMS (Method 1): m / z 438.2 [M+H]+(ES+) at 1.66 min, >99% purity at 260nm + / - 80nm.Compounds 50 & 514-(3-(bromodifluoromethyl)-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromeno(7,8-d1imidazol-8- vDbenzonitrile (50) & 4-(1-(bromodifluoromethyl)-6-oxo-2-(trifluoromethyl)-1 ,6- dihvdrochromeno(7,8-d1imidazol-8-yl)benzonitrile (51)50 51

[0285] DI PEA (80 pL, 1.7 Eq, 0.46 mmol) and dibromodifluoromethane (1.2 mL, 47 Eq, 13 mmol) were added sequentially to a solution of 4-(6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (100 mg, 98% Wt, 1 Eq, 276 pmol) in DMF (3.0 mL). The resulting solution was sealed and heated at 60 °C for 96 h.Dibromodifluoromethane (1.2 mL, 47 Eq, 13 mmol) and DIPEA (240 pL, 5 Eq, 1.38 mmol) were added, the reaction sealed and heated to 60 °C for a further 72 h. The reaction was allowed to cool, water (15 mL) was added causing some effervescence, the mixture stirred for 5 min and the precipitate was filtered off. The solid was dried in vacuo to afford a mixture of regioisomers as a pale yellow solid. The mixture (83.5 mg) was dissolved to 5.5 mg / mL in a MeOH / DCM (1 :1), with heat and sonication. It was then filtered and separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20mL / min at 38% EtOH (0.2% ammonia), 62% CO2. The clean fractions were pooled, rinsed with MeOH / DCM (1:1), and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar over the weekend to afford:Compound 50

[0286] 4-(3-(bromodifluoromethyl)-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (45.6 mg, 93 pmol, 34 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0287] 1H NMR (500 MHz, DMSO) 5 8.35 - 8.28 (m, 3H), 8.17 - 8.11 (m, 2H), 7.97 (dd, J = 8.9, 2.2 Hz, 1 H), 7.43 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -31.46 (d, J = 14.3 Hz), -61.39 (t, J = 14.4 Hz). MS: The product was analysed by LCMS (Method 1): m / z 484.0 / 486.0 [M+H]+(ES+) at 1.85 min, >99% purity at 260nm + / - 80nm.Compound 51

[0288] 4-(1-(bromodifluoromethyl)-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (4.1 mg, 8.0 pmol, 2.9 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0289] 1H NMR (500 MHz, DMSO) 5 8.36 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 8.6 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.6 Hz, 1 H), 7.42 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -60.24 (d, J = 175.2 Hz), -60.93 (t, J = 17.4 Hz). MS: The product was analysed by LCMS (Method 1): m / z 484.2 / 486.0 [M+H]+(ES+) at 1.82 min, >99% purity at 260nm + / - 80nm.Compound 528-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (52)

[0290] A suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (50.0 mg, 98% Wt, 1 Eq, 138 pmol), HCI (6M) (1mL, 43.5 Eq, 6.0 mmol) and palladium on carbon (5 wt% Pd) (33.0 mg, 0.112 Eq, 15.5 pmol) in MeOH (2 mL) and THF (1 mL) was stirred under H2 (5 bar.) at rt for 48 h. The reaction mixture was filtered through glass fibre filter paper, washing with MeOH, and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% MeOH / DCM, then 20% (0.7 M Ammonia in MeOH) / DCM to afford 8-(4- (aminomethyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (13.0 mg, 35 pmol, 26 %) as a pale yellow solid.

[0291] 1H NMR (400 MHz, DMSO) 5 8.25 - 8.18 (m, 2H), 8.15 (s, 3H), 7.72 - 7.67 (m, 2H), 7.64 (d, J = 8.6 Hz, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.05 (s, 1 H), 4.17 (s, 2H).19F NMR (376 MHz,DMSO) 5 -61.31. MS: The product was analysed by LCMS (Method 1): m / z 360.0 [M+H]+(ES+);358.0 [M-H]' (ES-), at 0.75 min, 98% purity at 260nm + / - 80nm.Compounds 53 & 544-(6-hvdroxy-2-(trifluoromethyl)-3,6,7,8-tetrahvdrochromenof7,8-d1imidazol-8-yl)benzonitrile

[0292] To a stirred suspension of 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (154 mg, 99% Wt, 1 Eq, 429 pmol) in THF (4 mL) at 0 °C was added borane tetrahydrofuran complex (1M) (450 pL, 1.05 Eq, 450 pmol). The reaction mixture was stirred at 0 °C for 15 min and then allowed to warm to rt for 1 h. Additional borane tetra hydrofuran complex (1 M) (450 pL, 1.05 Eq, 450 pmol) was added at 1 h intervals for 7 h and then stirred overnight. The reaction mixture was quenched with aq. HCI (1 M) (10 mL), then extracted with DCM (2 x 10 mL). The combined organics were passed through a phase separator and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 4-(6- hydroxy-2-(trifluoromethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (27.0 mg, 68 pmol, 16 %) as a yellow solid.

[0293] MS: The product was analysed by LCMS (Method 1): m / z 360.1 [M+H]+(ES+); 358.2 [M- H]’ (ES-), at 1.24 min, 90% purity at 260nm + / - 80nm.(R)-4-(6-oxo-2-(trifluoromethyl)-3,6,7,8-tetrahvdrochromenof7,8-d1imidazol-8-yl)benzonitrile (53) & (S)-4-(6-oxo-2-(trifluoromethyl)-3,6,7,8-tetrahvdrochromenof7,8-d1imidazol-8-yl)benzonitrile53 54

[0294] A mixture of 4-(6-hydroxy-2-(trifluoromethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazol- 8-yl)benzonitrile (24.0 mg, 90% Wt, 1 Eq, 60.1 pmol) and Dess-Martin periodinane (36.0 mg, 1.41 Eq, 84.9 pmol) in DCM (2 mL) was stirred at rt for 1 h. Sat. aq. NaHCOs (2 mL) was added and the mixture was passed through a phase separator. The aqueous layer was extracted with DCM (5 mL) and the mixture was passed through a phase separator. The combined organicswere concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% MeOH / DCM. The product containing fractions were concentrated in vacuo to afford a mixture of enantiomers. The mixture (30 mg) was dissolved in MeOH (3 ml) with sonication and heating, filtered and then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a ChiralpaK IC, 10 x 250mm, 5pm, flow rate 15mL / min at 30% MeOH (0.2% Ammonia), 70% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford compound 53 and compound 54, as white and yellow solids respectively. The stereochemistry of the enantiomers was assigned arbitrarily. Compound 53

[0295] (R)-4-(6-oxo-2-(trifluoromethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (6.90 mg, 19 pmol, 31 %), >99% ee, as a white solid.

[0296] 1H NMR (400 MHz, MeOD) 5 7.91 - 7.79 (m, 6H), 7.33 (d, J = 8.7 Hz, 1 H), 5.93 (dd, J = 12.7, 3.4 Hz, 1 H), 3.23 (dd, J = 16.9, 12.7 Hz, 1 H), 3.05 (dd, J = 16.9, 3.4 Hz, 1 H). 1 exchangeable proton not observed.19F NMR (376 MHz, MeOD) 5 -65.73. MS: The product was analysed by LCMS (Method 1): m / z 357.7 [M+H]+(ES+); 356.3 [M-H]’ (ES-), at 1.34 min, 97% purity 210-400nm.Compound 54

[0297] (S)-4-(6-oxo-2-(trifluoromethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (7.90 mg, 19 pmol, 32 %), >99% ee, as a yellow solid.

[0298] 1H NMR (400 MHz, MeOD) 5 7.92 - 7.80 (m, 5H), 7.33 (d, J = 8.7 Hz, 1 H), 5.93 (dd, J = 12.7, 3.4 Hz, 1 H), 3.23 (dd, J = 16.9, 12.7 Hz, 1 H), 3.05 (dd, J = 16.9, 3.4 Hz, 1 H). 1 exchangeable proton not observed.19F NMR (376 MHz, MeOD) 5 -65.74. MS: The product was analysed by LCMS (Method 1): m / z 358.1 [M+H]+(ES+); at 1.34 min, 88% purity 210-400nm.Compound 551-(4-amino-2-hvdroxy-3-nitrophenyl)-3-(pyrimidin-5-yl)prop-2-en-1-one

[0299] Sodium hydride (283 mg, 60% Wt, 3.5 Eq, 7.07 mmol) was added portion wise to a solution of 1-(4-amino-2-hydroxy-3-nitrophenyl)ethan-1-one (400 mg, 1 Eq, 2.02 mmol) in DMF (13.5 mL) at 3 °C. The mixture was stirred for 1 h, then pyrimidine- 5-carbaldehyde (546 mg, 2.5 Eq, 5.05 mmol) was added portion wise and the mixture was stirred at rt for 3 h. The reaction mixture was cooled on ice and quenched by dropwise addition of acetic acid (404 pL, 3.5 Eq,7.07 mmol). Aq. HCI (1M) (5 mL) was added slowly with vigorous stirring (internal temperature maintained <20 °C), the resulting suspension was poured into aq. HCI (1 M) (25 mL) and stirred for 15 min. The resulting precipitate was collected by filtration, rinsed with water (2 mL) and dried in vacuo to afford 1-(4-amino-2-hydroxy-3-nitrophenyl)-3-(pyrimidin-5-yl)prop-2-en-1-one (408 mg, 1.1 mmol, 56 %) as a brown solid.

[0300] 1H NMR (400 MHz, DMSO) 5 15.64 (s, 1 H), 9.31 (s, 2H), 9.21 (s, 1 H), 8.25 - 8.12 (m, 2H), 7.81 (d, J = 15.7 Hz, 1 H), 7.64 (s, 2H), 6.46 (d, J = 9.3 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 287.0 [M+H]+(ES+); 285.0 [M-H]’ (ES-), at 1.07 min, 80% purity at 260nm + / - 80nm.7-amino-8-nitro-2-(pyrimidin-5-yl)-4H-chromen-4-one

[0301] Iodine (57.9 mg, 0.2 Eq, 228 pmol) was added to a suspension of 1-(4-amino-2-hydroxy- 3-nitrophenyl)-3-(pyrimidin-5-yl)prop-2-en-1-one (408 mg, 1 Eq, 1.14 mmol) in toluene (3.80 mL) and DMSO (1.62 mL), and the reaction was heated to 110 °C for 18 h. The reaction was allowed to cool, then poured onto ice water (approx. 80 mL). The mixture was stirred for 10 min giving prescipitation of the crude product which was filtered and dried in vacuo to afford 7- amino-8-nitro-2-(pyrimidin-5-yl)-4H-chromen-4-one (271 mg, 0.77 mmol, 68 %) as a dark brown solid.

[0302] 1H NMR (400 MHz, DMSO) 5 9.39 (s, 2H), 9.37 (s, 1 H), 7.96 - 7.86 (m, 3H), 7.29 (s, 1 H), 7.02 (d, J = 9.2 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 285.0 [M+H]+(ES+); 283.0 [M-H]- (ES-), at 0.88 min, 81 % purity at 260nm + / - 80nm.7,8-diamino-2-(pyrimidin-5-yl)-4H-chromen-4-one

[0303] To a stirred suspension of 7-amino-8-nitro-2-(pyrimidin-5-yl)-4H-chromen-4-one (271 mg, 81% Wt, 1 Eq, 772 pmol) in DMSO (3.43 mL), EtOH (3.43 mL) and Water (858 pL) at 80 °C was added sodium dithionite (403 mg, 161 pL, 3 Eq, 2.32 mmol). The reaction was heated to 80 °C for a further 6 h. The reaction was allowed to cool then poured into ice / water (-100 mL). The resulting precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford 7,8-diamino-2-(pyrimidin-5-yl)-4H-chromen-4-one (234 mg, 0.60 mmol, 77 %) as a dark brown solid.

[0304] 1H NMR (400 MHz, DMSO) 5 9.60 (s, 2H), 9.34 (s, 1 H), 7.18 (d, J = 8.5 Hz, 1 H), 7.02 (s, 1 H), 6.70 (d, J = 8.5 Hz, 1 H). MS: The product was analysed by LCMS (Method 1): m / z 255.0 [M+H]+(ES+) at 0.64 min, >99% purity at 260nm + / - 80nm.8-(pyrimidin-5-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (55)

[0305] TFA (1.0 mL, 51 Eq, 13 mmol) was slowly added to 7,8-diamino-2-(pyrimidin-5-yl)-4H- chromen-4-one (100 mg, 1 Eq, 256 pmol) with ice cooling. The mixture was stirred at reflux for 1 h, then concentrated in vacuo. The residue was azeotroped with MeCN (3 x 10 mL), dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM then by chromatography on silica gel using a gradient of 0- 7% MeOH / DCM to afford 8-(pyrimidin-5-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)- one (8.4 mg, 24 pmol, 9.4 %) as a yellow solid.

[0306] 1H NMR (400 MHz, MeOD) 5 9.64 (s, 2H), 9.34 (s, 1H), 8.15 (d, J = 8.7 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.23 (s, 1H).19F NMR (376 MHz, MeOD) 5 -65.69. MS: The product was analysed by LCMS (Method 1): m / z 333.0 [M+H]+(ES+); 331.0 [M-H]’ (ES-), at 0.95 min, 95% purity at 260nm + / - 80nm.Compound 563,4-difluorophenyl acetate

[0307] Acetyl chloride (34.5 mL, 99% Wt, 1.25 Eq, 480 mmol) was added to a solution of 3,4- difluorophenol (50.0 g, 1 Eq, 384 mmol) in DCM (1.00 L) and triethylamine (67.0 mL, 1.25 Eq, 480 mmol) at 0 °C. The reaction was allowed to warm to rt and stirred overnight. The reaction was filtered and the precipitate washed with DCM (100 mL). The filtrate was reduced to approximately half volume, the resulting precipitate was filtered again and the filtrate was dried directly onto Celite and purified by column chromatography on silica gel using a gradient of 0- 20% MTBE / isohexane to afford 3,4-difluorophenyl acetate (64.85 g, 0.37 mol, 97 %) as a clear colourless oil.

[0308] 1H NMR (500 MHz, DMSO) 5 7.49 (dt, J = 10.8, 9.2 Hz, 1H), 7.38 (ddd, J = 11.6, 6.9, 2.8 Hz, 1H), 7.07 - 6.99 (m, 1H), 2.26 (s, 3H).19F NMR (471 MHz, DMSO) 5 -136.15 (d, J = 22.4 Hz), -142.04 (d, J = 22.3 Hz). MS: The product was analysed by LCMS (Method 1): m / z does not ionise (ES+); does not ionise (ES-), at 1.24 min, 99% purity at 210-400nm.1-(4,5-difluoro-2-hydroxyphenyl)ethan-1-one

[0309] 3,4-difluorophenyl acetate (10.0 g, 99% Wt, 1 Eq, 57.5 mmol) was dissolved in DCM (120 mL) before addition of aluminium chloride (23.0 g, 3 Eq, 173 mmol). The resulting suspension was stirred at room temperature for 1 h, the solvent was removed in vacuo and the residue was heated to 140 °C for 90 min. The reaction was allowed to cool and aq. HCI (6M) (180 mL) was added cautiously to the residue. The resulting suspension was stirred for 10 min, the solid was filtered off and dried in vacuo to afford 1-(4,5-difluoro-2-hydroxyphenyl)ethan-1- one as a light brown solid. The procedure was repeated with 3,4-difluorophenyl acetate (10.0 g, 57.5 mmol) and the products were combined to afford 1-(4,5-difluoro-2-hydroxyphenyl)ethan-1- one (18.23 g, 0.10 mol, 91 %) as a light brown solid.

[0310] 1H NMR (500 MHz, DMSO) 5 12.01 (d, J = 1.2 Hz, 1H), 7.96 (dd, J = 11.5, 9.3 Hz, 1H), 7.06 (dd, J = 12.1, 6.9 Hz, 1H), 2.61 (s, 3H).19F NMR (471 MHz, DMSO) 5 -126.32 (d, J = 23.7 Hz), -149.08 (d, J = 23.7 Hz). MS: The product was analysed by LCMS (Method 1): m / z does not ionise (ES+); 171.2 [M-H]' (ES-), at 1.20 min, >99% purity at 260nm + / - 80nm.1-(4,5-difluoro-2-hvdroxy-3-nitrophenyl)ethan-1-one

[0311] All temperatures are internal. Equipment: 500 mL 3-neck flask, equipped with thermometer, pressure equalised dropping funnel and bubbler.

[0312] Sulfuric acid (95%) (85.0 mL, 18.4 molar, 14.9 Eq, 1.56 mol) was added to 1-(4,5- difluoro-2-hydroxyphenyl)ethan-1-one (18.23 g, 99% Wt, 1 Eq, 104.8 mmol) and the solution was cooled to -5 °C (ice / brine bath). Nitric acid (69%) (11 g, 7.5 mL, 15.4 molar, 1.1 Eq, 0.12 mol) was added dropwise in portions (maintaining the temperature below 5 °C) over 40 min. The reaction mixture was stirred at 3 °C (ice / brine bath) for 30 min. An additional portion of nitric acid (69%) (0.7 mL, 15.4 molar, 0.1 Eq, 0.01 mol) was added dropwise in portions (maintaining the internal temperature below 5 °C) and the reaction stirred for a further 10 min. The reaction mixture was poured onto crushed ice (-500 g), diluted with DCM (600 mL) and the stirred until the ice had melted and the solids had dissolved. The organic layer was collected and the aqueous layer extracted with DCM (400 mL). The combined organics were washed with brine (200 mL), dried over MgSC and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (liquid load in 50% 2-Me-THF / heptane) using a gradient of 0-10% 2-Me-THF / hexane to afford 1-(4,5-difluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (14.33 g, 62 mmol, 59 %) as an orange crystalline solid.

[0313] 1H NMR (500 MHz, DMSO) 5 8.43 (dd, J = 11.0, 8.8 Hz, 1 H), 2.68 (s, 3H). 1 exchangeable proton not observed.19F NMR (471 MHz, DMSO) 5 -135.24 (d, J = 23.7 Hz), - 146.34 (d, J = 23.6 Hz).). MS: The product was analysed by LCMS (Method 1): m / z 218.2 [M+H]+(ES+); 216.0 [M-H]' (ES-), at 1.32 min, 94% purity at 260nm + / - 80nm.3-amino-4-fluoro-6-(1-iminoethyl)-2-nitrophenol

[0314] To a solution of 1-(4,5-difluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (10.94 g, 94% Wt, 1 Eq, 47.36 mmol) in DMSO (95 mL) was added aq. ammonia (30%) (23.9 mL, 30% Wt, 7 Eq, 331.5 mmol). The reaction mixture was heated to 50 °C for 1 h and then allowed to cool to rt overnight. The reaction mixture was poured onto ice / water (-500 mL) and stirred for 30 min. The resultant precipitate mixture was cooled over an (ice / water bath) and the solids were collected by filtration and washed with water, to afford the desired product 3-amino-4-fluoro-6- (1-iminoethyl)-2-nitrophenol as a yellow gum. The crude product was sucked dry for 10 min. and then taken onto the next step without further purification assuming quantitative yield.

[0315] MS: The product was analysed by LCMS (Method 1): m / z 214.2 [M+H]+(ES+); 212.1 [M- H]’ (ES-), at 0.56 min, 95% purity 210-400nm.1-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)ethan-1-one

[0316] To a suspension of 3-amino-4-fluoro-6-(1-iminoethyl)-2-nitrophenol (10.10 g, 1 Eq, 47.36 mmol) in MeCN (95 mL) was added aq. HCI (1 M) (49.73 mL, 1.00 molar, 1.05 Eq, 49.73 mmol) at rt. The reaction mixture was heated to 70 °C and stirred for 1 h. The resultant dark red solution was cooled to rt and EtOAc (800 mL) was added. The organic layer was washed with brine (2 x 200 mL), dried over MgSC and concentrated in vacuo to afford the desired product 1- (4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (9.67 g, 45 mmol, 94 %) as a brown solid.

[0317] 1H NMR (500 MHz, DMSO) 5 14.22 (s, 1 H), 7.83 (d, J = 12.3 Hz, 1 H), 7.44 (s, 2H), 2.51 (s, 3H).19F NMR (471 MHz, DMSO) 5 -140.63. MS: The product was analysed by LCMS (Method 1): m / z 215.5 [M+H]+(ES+); 212.6 [M-H]' (ES-), at 1.03 min, >99% purity 210-400nm.4-(3-(4-Amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-oxoprop-1-en-1-yl)benzonitrile

[0318] A suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (400 mg, 1 Eq, 1.83 mmol) and 4-formylbenzonitrile (360 mg, 1.5 Eq, 2.75 mmol) in EtOH (7 mL) was heated to 50 °C. Pyrrolidine (165 pL, 1.1 Eq, 2.01 mmol) was added in one portion and thereaction mixture was stirred at 50 °C for 3 h then allowed to cool to rt. The resulting precipitate was collected by filtration, washed with EtOH, and dried in vacuo to afford the desired product 4-(3-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-oxoprop-1-en-1-yl)benzonitrile (489 mg, 1.4 mmol, 78 %) as an orange solid.

[0319] 1H NMR (400 MHz, DMSO) 5 15.28 (s, 1 H), 8.39 (d, J = 12.9 Hz, 1 H), 8.16 - 8.11 (m, 2H), 8.08 (d, J = 15.5 Hz, 1 H), 8.02 - 7.92 (m, 2H), 7.86 (d, J = 15.4 Hz, 1 H), 7.66 (s, 2H).19F NMR (376 MHz, DMSO) 5 -140.42. MS: The product was analysed by LCMS (Method 1): m / z 328.0 [M+H]+(ES+); 326.0 [M-H]’ (ES-), at 1.57 min, 95% purity at 260nm + / - 80nm.4-(7-Amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)benzonitrile

[0320] To a stirred suspension of 4-(3-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-oxoprop-1- en-1-yl)benzonitrile (489 mg, 1 Eq, 1.42 mmol) in DMSO (1.0 mL,) and toluene (4.73 mL) was added iodine (72.1 mg, 0.2 Eq, 284 pmol). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was allowed to cool to rt and diluted with water (20 mL). The precipitate was collected by filtration, washed with water (10 mL) and EtOH (5 mL). The solid was dried in vacuo to afford 4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)benzonitrile (413 mg, 1.3 mmol, 89 %) as a pale yellow solid.

[0321] 1H NMR (400 MHz, DMSO) 5 8.24 - 8.16 (m, 2H), 8.12 - 8.04 (m, 2H), 7.87 (s, 2H), 7.76 (d, J = 10.9 Hz, 1 H), 7.26 (s, 1 H).19F NMR (376 MHz, DMSO) 5 -129.20. MS: The product was analysed by LCMS (Method 1): m / z 326.0 [M+H]+(ES+); 324.2 [M-H]- (ES-), at 1.34 min, >99% purity at 260nm + / - 80nm.4-(7,8-Diamino-6-fluoro-4-oxo-4H-chromen-2-yl)benzonitrile

[0322] To a stirred suspension of 4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2- yl)benzonitrile (413 mg, 1 Eq, 1.26 mmol) in DMSO (5.59 mL), EtOH (5.59 mL) and water (1 .40 mL) at 80 °C was added sodium dithionite (263 pL, 3 Eq, 3.77 mmol). The reaction was heated to 80 °C and stirred on for 6 h. The reaction was allowed to cool then poured into ice / water (-100 mL). The resulting precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford 4-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)benzonitrile (308 mg, 1.0 mmol, 82 %) as a light orange solid.

[0323] 1H NMR (400 MHz, DMSO) 5 8.47 - 8.39 (m, 2H), 8.05 - 7.97 (m, 2H), 7.01 (s, 1 H), 6.96 (d, J = 10.7 Hz, 1 H), 5.67 (s, 2H), 5.31 (s, 2H).19F NMR (376 MHz, DMSO) 5 -134.29. MS:The product was analysed by LCMS (Method 1): m / z 296.2 [M+H]+(ES+); 294.2 [M-H]’ (ES-), at 1.13 min, >99% purity at 260nm + / - 80nm.4-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8-yl)benzonitrile (56)

[0324] TFA (1.5 mL, 58 Eq, 19 mmol) was slowly added to 4-(7,8-diamino-6-fluoro-4-oxo-4H- chromen-2-yl)benzonitrile (100 mg, 1 Eq, 335 pmol) with ice cooling. The mixture was stirred at reflux for 2 h, then concentrated in vacuo. The residue was azeotroped with MeCN (3 x 10 mL), dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) in DCM. The product was dried onto Celite and repurified by chromatography on silica gel using a gradient of 0-3% MeOH in DCM to afford 4-(4-fluoro-6- oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (17 mg, 45 pmol, 13 %) as a yellow solid.

[0325] 1H NMR (400 MHz, CD3OD) 5 8.47 - 8.39 (m, 2H), 8.02 - 7.95 (m, 2H), 7.77 (d, J = 10.1 Hz, 1 H), 7.18 (s, 1 H).19F NMR (376 MHz, CD3OD) 5 -66.41 , -131.93. MS: The product was analysed by LCMS (Method 1m / z 374.0 [M+H]+(ES+); 372.0 [M-H]- (ES-), at 1.41 min, >99% purity at 260nm + / - 80nm.Compounds 57 & 584-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8- vDbenzonitrile (57) & 4-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d1imidazol-8-yl)benzonitrile (58)

[0326] To a stirred suspension of 4-(4-fluoro-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzonitrile (120 mg, 94% Wt, 1 Eq, 302 pmol) and potassium carbonate (83.5 mg, 2 Eq, 604 pmol) in DMF (3 mL) was added Mel (64.3 mg, 28.3 pL, 1.5 Eq, 453 pmol). The reaction mixture was heated to 50 °C for 24 h. Additional methyl iodide (20.0 pL, 1.06 Eq, 320 pmol) was added, and the reaction heated for a further 2 h. The reaction mixture was diluted with water (10 mL) and the precipitate was collected by filtration, washing with water, to afford a mixture of products. The mixture (96.7 mg, 90.9%) was dissolved in DMSO (9 mL) with sonication and heating to give a cloudy solution which was filtered, and then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a Chiralpak IH, 20 x 250mm, 5pm, flow rate 65mL / min at 25% MeOH (no modifier), 75% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in dichloromethane, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30°C / 5 mbar overnight to afford: Compound 57

[0327] 4-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (22.0 mg, 54 pmol, 18 %) was afforded as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0328] 1H NMR (500 MHz, MeOD) 5 8.41 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 11.2 Hz, 1H), 7.18 (s, 1H), 4.28 (s, 3H).19F NMR (471 MHz, MeOD) 5 -64.11, -135.19. MS: The product was analysed by UPLC (Method 1): m / z 388.3 [M+H]+(ES+); n / a [M-H]' (ES-), at 1.57 min, 96.1% purity 210-400nm. Compound 58

[0329] 4-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8-d]imidazol-8- yl)benzonitrile (40.0 mg, 98 pmol, 32 %) was afforded as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0330] 1H NMR (500 MHz, MeOD) 5 8.24 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 9.9 Hz, 1 H), 7.16 (s, 1H), 4.53 (s, 3H).19F NMR (471 MHz, MeOD) 5 -63.99, -130.57. MS: The product was analysed by UPLC (Method 1): m / z 388.0 [M+H]+(ES+); n / a [M-H]' (ES-), at 1.56 min, 97.7% purity 210-400nm.Compound 591-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-(4-bromophenyl)prop-2-en-1-one

[0331] A suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (2.15 g, 98% Wt, 1 Eq, 9.84 mmol) and 4-bromobenzaldehyde (2.73 g, 1.5 Eq, 14.8 mmol) in EtOH (32.8 mL) was heated to 50 °C. Pyrrolidine (889 pL, 1.1 Eq, 10.8 mmol) was added in one portion and the reaction mixture was stirred at 50 °C for 6 hours and then allowed to cool to rt. The precipitate was collected by filtration, washed with EtOH, and dried in vacuo to afford the desired product 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(4-bromophenyl)prop-2-en-1- one (2.728 g, 7.1 mmol, 72 %) as an orange solid.

[0332] 1H NMR (500 MHz, DMSO) 5 15.40 (s, 1 H), 8.38 (d, J = 12.8 Hz, 1 H), 7.98 (d, J = 15.4 Hz, 1 H), 7.91 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 15.4 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 2H), 7.61 (s, 2H).19F NMR (471 MHz, DMSO) 5 -140.58. MS: The product was analysed by UPLC (Method 1): m / z 380.0 / 382.8 [M+H]+(ES+); 379.1 / 381.4 [M-H]' (ES-), at 1.88 min, >99% purity 210- 400nm.7-amino-2-(4-bromophenyl)-6-fluoro-8-nitro-4H-chromen-4-one

[0333] To a stirred suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(4- bromophenyl)prop-2-en-1-one (2.728 g, 99% Wt, 1 Eq, 7.086 mmol) in DMSO (5.028 mL, 10 Eq, 70.86 mmol) and Toluene (23.62 mL) was added iodine (359.7 mg, 0.2 Eq, 1.417 mmol). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was allowed to cool to rt and diluted with water (20 mL). The precipitate was collected by filtration, washed with water (10 mL) and EtOH (5 mL) then dried in vacuo to afford 7-amino-2-(4-bromophenyl)-6-fluoro-8-nitro- 4H-chromen-4-one (2.69 g, 7.0 mmol, 99 %) as an off white solid.

[0334] 1H NMR (500 MHz, DMSO) 5 7.96 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.7 Hz, 4H), 7.75 (d, J = 10.9 Hz, 1 H), 7.11 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -129.52. MS: The product was analysed by UPLC (Method 1): m / z 380.5 / 382.3 [M+H]+(ES+); 377.2 / 379.1 [M-H]' (ES-), at 1.59 min, >99% purity 210-400nm.7,8-diamino-2-(4-bromophenyl)-6-fluoro-4H-chromen-4-one

[0335] To a stirred suspension of 7-amino-2-(4-bromophenyl)-6-fluoro-8-nitro-4H-chromen-4- one (2.69 g, 99% Wt, 1 Eq, 7.02 mmol) in DMSO (30 mL), EtOH (30 mL) and Water (8.6 mL) at 80 °C was added sodium dithionite (1.5 mL, 3 Eq, 21.1 mmol). The reaction was stirred at 80 °C for 4 h, allowed to cool to rt then poured onto ice water (-200 mL). The precipitate was collected by filtration and further dried in vacuo to afford 7,8-diamino-2-(4-bromophenyl)-6- fluoro-4H-chromen-4-one (2.43 g, 6.8 mmol, 96 %) as a yellow solid.

[0336] 1H NMR (500 MHz, DMSO) 5 8.21 - 8.14 (m, 2H), 7.77 - 7.70 (m, 2H), 6.95 (d, J = 10.7 Hz, 1 H), 6.87 (s, 1 H), 5.62 (s, 2H), 5.26 (s, 2H).19F NMR (471 MHz, DMSO) 5 -134.56. MS: The product was analysed by UPLC (Method 1): m / z 349.3 / 351.4 [M+H]+(ES+); 348.2 [M-H]' (ES-), at 1.30 min, >99% purity 210-400nm.8-(4-bromophenyl)-4-fluoro-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(1 H)-one

[0337] TFA (25.0 mL, 48.1 Eq, 325 mmol) was slowly added to 7,8-diamino-2-(4-bromophenyl)- 6-fluoro-4H-chromen-4-one (2.43 g, 97% Wt, 1 Eq, 6.75 mmol) while cooling over an ice bath. The mixture was stirred at reflux for 4 h, then concentrated in vacuo. The residue was azeotroped with MeCN to afford 8-(4-bromophenyl)-4-fluoro-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(1 H)-one (3.21 g, 6.6 mmol, 98 %) as a beige solid.

[0338] 1H NMR (500 MHz, DMSO) 5 8.22 (s, 2H), 7.88 - 7.82 (m, 2H), 7.67 (d, J = 10.0 Hz, 1 H), 7.26 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -62.58, -129.21. MS: The product was analysed by UPLC (Method 1): m / z 427.5 / 429.4 [M+H]+(ES+); 425.0 / 427.0 [M-H]' (ES-), at 1.71 min, >99% purity 210-400nm.4-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromeno[7,8-d1imidazol-8-yl)benzaldehvde

[0339] A suspension of 8-(4-bromophenyl)-4-fluoro-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (200 mg, 1 Eq, 468 pmol), triethylamine (196 pL, 3 Eq, 1.40 mmol), triethylsilane (224 pL, 3 Eq, 1.40 mmol) and Pd(dppf)CI2.DCM (38.2 mg, 0.1 Eq, 46.8 pmol) in DMF (4.68 mL) was stirred under CO® 3.5 bar at 80 °C for 18 hours. The reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 4-(4-fluoro-6-oxo-2- (trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzaldehyde (126 mg, 0.31 mmol, 66 %) as an orange solid.

[0340] 1H NMR (500 MHz, DMSO) 5 10.14 (s, 1 H), 8.47 (d, J = 7.9 Hz, 2H), 8.16 - 8.11 (m, 2H), 7.65 (d, J = 10.0 Hz, 1 H), 7.35 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -62.49, -129.02. MS: The product was analysed by UPLC (Method 1): m / z 377.4 [M+H]+(ES+); 375.1 [M-H]' (ES-), at 1.40 min, 92% purity 210-400nm.8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one

[0341] A suspension of 4-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzaldehyde (116 mg, 92% Wt, 1 Eq, 284 pmol) and azetidine (38.2 pL, 2 Eq, 567 pmol) in THF (2.84 mL) was stirred at rt for 1 h. Sodium triacetoxyhydroborate (132 mg, 2.2 Eq, 624 pmol) was added to the resulting solution and the reaction mixture was stirred for 16 h. The reaction was quenched with MeOH (10 mL), and the reaction mixture was dried onto Celite. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% MeOH / DCM then 0-20% [0.7 M Ammonia in MeOH] / DCM, dried in a desiccator and freeze dried from water / MeCN (5:1). The product was triturated with sat. aq. NaHCOs and dried in vacuo to afford 8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (54.3 mg, 0.13 mmol, 45 %) as a pale yellow solid.

[0342] 1H NMR (500 MHz, MeOD) 5 8.42 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 10.6 Hz, 1 H), 7.01 (s, 1H), 4.26 (s, 2H), 4.02 - 3.91 (m, 4H), 2.51 - 2.38 (m, 2H).19F NMR (471 MHz, MeOD) 5 -64.86, -130.93. MS: The product was analysed by LIPLC (Method 1): m / z 418.2 [M+H]+(ES+); 416.2 [M-H]’ (ES-), at 0.77 min, >99% purity 210-400nm.Compounds 60 & 614-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8- vDbenzaldehyde & 4-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- dlimidazol-8-yl) benzaldehyde

[0343] To a stirred suspension of 4-(4-fluoro-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzaldehyde (363 mg, 91% Wt, 1 Eq, 878 pmol) and potassium carbonate (243 mg, 2 Eq, 1.76 mmol) in DMF (8.78 mL) was added Mel (82.3 pL, 1.5 Eq, 1.32 mmol). The reaction mixture was heated to 50 °C for 6 h, allowed to cool to rt diluted with water (100 mL) and the resulting precipitate was collected by filtration. The crude product was washed with water, and dried in vacuo to afford a mixture of regioisomers. The mixture (355 mg) of products was used without further purification.

[0344] MS: The product was analysed by UPLC (Method 1): m / z 391.6 [M+H]+(ES+) at 1.49 min, 93% purity 210-400nm.8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-3-methyl-2-(trifluoromethyl)chromeno[7,8-d1imidazol- 6(3H)-one (60) & 8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-1-methyl-2- (trifluoromethyl)chromeno(7,8-d1imidazol-6(1 H)-one (61)60 61

[0345] A suspension of 4-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8- d]imidazol-8-yl)benzaldehyde (355 mg, 91% Wt, 1 Eq, 828 pmol) and azetidine (112 pL, 2 Eq, 1.66 mmol) in THF (8.28 mL) was stirred at rt for 1 hour. Sodium triacetoxyhydroborate (386 mg, 2.2 Eq, 1.82 mmol) was added to the resulting solution and the reaction mixture was stirred for 16 h. The reaction was quenched with methanol, and the reaction mixture was dried onto Celite. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% MeOH / DCM to afford a mixture of regioisomers. The mixture (310 mg) was dissolved to 23.3 mg / mL in (10:3, MeOH / DCM) with sonication, filtered and separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a Chiralpak IH, 10 x 250mm, 5pm, flow rate 20mL / min at 45% EtOH (0.1% Ammonia), 55% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in DCM, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30°C / 5mbar for 4h.Compound 60

[0346] 8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-3-methyl-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (57.4 mg, 0.13 mmol, 16 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0347] 1H NMR (500 MHz, MeOD) 5 8.16 (d, J = 7.9 Hz, 2H), 7.78 (d, J = 11.7 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 1.4 Hz, 1H), 4.26 (s, 3H), 3.72 (s, 2H), 3.34 (t, J = 7.1 Hz, 4H), 2.15 (p, J = 7.1 Hz, 2H).19F NMR (471 MHz, MeOD) 5 -64.05, -135.66. MS: The product was analysed by LIPLC (Method 1): m / z 432.2 [M+H]+(ES+) at 0.84 min, >99% purity 210-400nm.Compound 61

[0348] 8-(4-(azetidin-1-ylmethyl)phenyl)-4-fluoro-1-methyl-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(1 H)-one (88.2 mg, 0.20 mmol, 24 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0349] 1H NMR (500 MHz, MeOD) 5 8.02 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 9.9 Hz, 1 H), 7.55 (d, J = 8.2 Hz, 2H), 7.01 (s, 1 H), 4.54 (s, 3H), 3.73 (s, 2H), 3.34 (t, J = 7.2 Hz, 4H), 2.16 (p, J = 7.2 Hz, 2H).19F NMR (471 MHz, MeOD) 5 -63.98, -130.98 (d, J = 1.8 Hz). MS: The product was analysed by LIPLC (Method 1): m / z 432.2 [M+H]+(ES+) at 0.82 min, 99% purity 210-400nm.Compound 62N-(8-amino-2-(4-cvanophenyl)-6-fluoro-4-oxo-4H-chromen-7-yl)-2,2-difluoroacetamide & N-(7- amino-2-(4-cvanophenyl)-6-fluoro-4-oxo-4H-chromen-8-yl)-2,2-difluoroacetamide

[0350] To a stirred suspension of 4-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)benzonitrile (200 mg, 99% Wt, 1 Eq, 671 pmol), 2,2-difluoroacetic acid (65.0 pL, 1.54 Eq, 1.03 mmol) and DI PEA (240 pL, 2.05 Eq, 1.38 mmol) in DMF (3 mL) was added a solution of HATLI (331 mg, 1.3 Eq, 872 pmol) in DMF (2 mL) dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (10 mL) and sat. aq NaHCOs (10 mL) was added. The resultant precipitate was collected by filtration and washed with water, to afford the crude product as a mixture of N-(8-amino-2-(4-cyanophenyl)-6-fluoro-4-oxo-4H-chromen-7-yl)-2,2- difluoroacetamide (363 mg, 0.68 mmol) and N-(7-amino-2-(4-cyanophenyl)-6-fluoro-4-oxo-4H- chromen-8-yl)-2,2-difluoroacetamide (363 mg, 0.68 mmol). The mixture of products was used without further purification.4-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6-dihvdrochromeno[7,8-d1imidazol-8-yl)benzonitrile (62)

[0351] A suspension of N-(8-amino-2-(4-cyanophenyl)-6-fluoro-4-oxo-4H-chromen-7-yl)-2,2- difluoroacetamide (363 mg, 70% Wt, 1 Eq, 681 pmol) and N-(7-amino-2-(4-cyanophenyl)-6- fluoro-4-oxo-4H-chromen-8-yl)-2,2-difluoroacetamide (363 mg, 70% Wt, 1.00 Eq, 681 pmol) in AcOH (4.00 mL, 103 Eq, 69.9 mmol) was stirred at 100 °C for 1 h. The reaction mixture wasallowed to cool to rt and concentrated in vacuo. The residue was azeotroped with toluene and then carefully triturated with sat. aq NaHCOs (~10 mL). The solid was collected by filtration, washing with water (10 mL) and EtOH (10 mL). The solid was dried in vacuo to afford 4-(2- (difluoromethyl)-4-fluoro-6-oxo-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (159 mg, 0.42 mmol, 61 %) as a tan solid.[°352] n aliquot (24 mg) of product was purified by chromatography on silica gel using a gradient of 0-20% (3:1 EtOAc / EtOH) / DCM to afford 4-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile (10.0 mg, 28 pmol, 4.1 %) as a pale yellow solid.

[0353] 1H NMR (500 MHz, MeOD) 5 8.44 - 8.38 (m, 2H), 7.98 - 7.92 (m, 2H), 7.71 (d, J = 10.0 Hz, 1 H), 7.17 (t, J = 53.1 Hz, 1 H), 7.14 (s, 1 H). 1 proton not observed.19F NMR (471 MHz, MeOD) 5 -118.14, -131.41. MS: The product was analysed by LCMS (Method 4): m / z 356.0 [M+H]+(ES+); 354.0 [M-H]' (ES-), at 0.74 min, >99% purity at 260nm + / - 90nm.Compound 63(E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-2-yl)prop-2-en-1-one

[0354] A suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (500 mg, 99% Wt, 1 Eq, 2.31 mmol) and picolinaldehyde (310 pL, 1.41 Eq, 3.26 mmol) in EtOH (10 mL)was heated to 50 °C and pyrrolidine (220 pL, 1.16 Eq, 2.68 mmol) was added in one portion. The resultant solution was stirred at 50 °C for 6 h and then allowed to cool to rt. The reaction mixture was diluted with water (30 mL) and the precipitate was collected by filtration, washed with water and dried in vacuo to afford (E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-2- yl)prop-2-en-1-one (657 mg, 1.9 mmol, 84 %) as a brown solid.

[0355] 1H NMR (500 MHz, DMSO) 5 15.22 (br s, 1 H), 8.72 - 8.67 (m, 1 H), 8.21 (d, J = 12.6 Hz, 1 H), 8.13 (d, J = 15.4 Hz, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.92 (td, J = 7.7, 1.8 Hz, 1 H), 7.79 (d, J = 15.3 Hz, 1 H), 7.65 (br s, 2H), 7.45 (ddd, J = 7.5, 4.8, 1.1 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -129.58. MS: The product was analysed by LCMS (Method 4): m / z 304.0 [M+H]+(ES+); 302.0 [M-H]' (ES-), at 0.59 min, 100% purity at 260nm + / - 90nm.7-amino-6-fluoro-8-nitro-2-(pyridin-2-yl)-4H-chromen-4-one

[0356] A suspension of (E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-2-yl)prop-2- en-1-one (650 mg, 90% Wt, 1 Eq, 1.93 mmol) and iodine (490 mg, 1 Eq, 1.93 mmol) in DMSO (8.00 mL) and Toluene (4.00 mL) was stirred at 110 °C for 4 h and then allowed to cool to rt.Water (75 mL) was added and the resultant precipitate was collected by filtration. The solid was washed with water, toluene and then dried in vacuo. The crude product was triturated with TBME, filtered and dried in vacuo to afford 7-amino-6-fluoro-8-nitro-2-(pyridin-2-yl)-4H-chromen- 4-one (638 mg, 1.9 mmol, 100 %) as a tan solid.

[0357] 1H NMR (500 MHz, DMSO) 5 8.87 (br s, 2H), 8.68 (s, 2H), 8.18 (d, J = 5.4 Hz, 2H), 7.78 (d, J = 9.5 Hz, 1 H), 7.05 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -131.93. MS: The product was analysed by LCMS (Method 4): m / z 302.0 [M+H]+(ES+); 300.0 [M-H]’ (ES-), at 1.19 min, 100% purity at 260nm + / - 90nm.7,8-diamino-6-fluoro-2-(pyridin-2-yl)-4H-chromen-4-one

[0358] A stirred suspension of 7-amino-6-fluoro-8-nitro-2-(pyridin-2-yl)-4H-chromen-4-one (638 mg, 92% Wt, 1 Eq, 1.95 mmol) in DMSO (12.0 mL), EtOH (6.0 mL) and Water (1.50 mL) was heated to 80 °C and sodium dithionite (1.02 g, 407 pL, 3 Eq, 5.85 mmol) was added. The reaction was stirred at 80 °C for 2 h. The reaction was allowed to cool then poured into ice / water (-100 mL). The resulting precipitate was filtered, washed with water (10 mL), TBME (10 mL) and dried in vacuo to afford 7,8-diamino-6-fluoro-2-(pyridin-2-yl)-4H-chromen-4-one (150 mg, 0.45 mmol, 23 %) as a brown solid.

[0359] 1H NMR (500 MHz, DMSO) 5 8.78 - 8.73 (m, 1 H), 8.60 - 8.56 (m, 1 H), 8.05 (td, J = 7.8, 1.7 Hz, 1 H), 7.59 (ddd, J = 7.6, 4.7, 1.1 Hz, 1 H), 7.06 (s, 1 H), 6.97 (d, J = 10.8 Hz, 1 H). 4 protons not observed in DMSO.19F NMR (471 MHz, DMSO) 5 -134.41. MS: The product was analysed by LCMS (Method 4): m / z 272.0 [M+H]+(ES+); 270.0 [M-H]- (ES-), at 0.94 min, 82% purity at 260nm + / - 90nm.4-fluoro-8-(pyridin-2-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (63)

[0360] A solution of 7,8-diamino-6-fluoro-2-(pyridin-2-yl)-4H-chromen-4-one (150 mg, 82% Wt, 1 Eq, 453 pmol) in TFA (1 mL) was stirred at 75 °C for 5 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using agradient of 0-20% (0.7 M Ammonia in MeOH) / DCM to afford 4-fluoro-8-(pyridin-2-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one as the trifluoracetic acid salt (111 mg, 0.24 mmol, 52 %) as an orange solid.

[0361] 1H NMR (500 MHz, MeOD) 5 8.77 (d, J = 4.3 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1 H), 8.09 (td, J = 7.8, 1.8 Hz, 1H), 7.77 (d, J = 10.1 Hz, 1H), 7.61 (dd, J = 7.4, 4.8 Hz, 1H), 7.46 (s, 1 H). 1 proton not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -65.67, -77.73, -131.16. MS: The product was analysed by LCMS (Method 4): m / z 350.0 [M+H]+(ES+); 348.0 [M-H]’ (ES-), at 0.72 min, 100% purity at 260nm + / - 90nm.Compounds 64 & 654-fluoro-3-methyl-8-(pyridin-2-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one formate (64) & 4-fluoro-1-methyl-8-(pyridin-2-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one formate (65)64 65

[0362] To a solution of 4-fluoro-8-(pyridin-2-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one, Trifluoroacetic acid (60.0 mg, 97% Wt, 1 Eq, 126 pmol) and DIPEA (100 pL, 4.57 Eq, 574 pmol) in DMF (1.00 mL) was added Mel (15.0 pL, 1.91 Eq, 240 pmol). The reaction mixture was stirred at 50 °C for 1 h. Additional Mel (15.0 pL, 1.91 Eq, 240 pmol) was added and stirred at 50 °C for 1 h. The reaction mixture was diluted with MeOH (2 mL) and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1, EtOAc / EtOH) / DCM to afford a mixture of regioisomers. The mixture (44 mg) was purified by preparative HPLC General procedure 4, Method 3. Gradient information: 0.0-0.5 min, 30% MeCN; 0.5-18.0min, ramped from 30% MeCN to 61% MeCN; 18.0-18.1 min, ramped from 61% MeCN to 100% MeCN; 18.1- 21.0 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford:Compound 64

[0363] 4-fluoro-3-methyl-8-(pyridin-2-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one, formate (7.00 mg, 17 pmol, 13 %) off white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0364] 1H NMR (500 MHz, MeOD) 5 8.79 - 8.73 (m, 1 H), 8.55 (d, J = 7.9 Hz, 1 H), 8.08 (td, J = 7.8, 1.8 Hz, 1 H), 7.83 (d, J = 11.4 Hz, 1 H), 7.59 (ddd, J = 7.6, 4.7, 1.1 Hz, 1 H), 7.48 (s, 1 H), 4.28 (s, 3H). 2 protons not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -64.08, -135.33. MS: The product was analysed by LCMS (Method 4): m / z 364.0 [M+H]+(ES+); no ionisation (ES-), at 1.37 min, 100% purity at 260nm + / - 90nm.Compound 65

[0365] 4-fluoro-1-methyl-8-(pyridin-2-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one, formate (6.00 mg, 15 pmol, 12 %) off white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0366] 1H NMR (500 MHz, DMSO) 5 8.87 - 8.82 (m, 1 H), 8.50 (s, 1 H), 8.23 (d, J = 7.9 Hz, 1 H), 8.13 (td, J = 7.8, 1.8 Hz, 1 H), 7.71 (d, J = 10.1 Hz, 1 H), 7.69 - 7.66 (m, 1 H), 7.37 (s, 1 H), 6.66 (s, 1 H), 4.52 (d, J = 1.0 Hz, 3H).19F NMR (471 MHz, DMSO) 5 -61.45, -129.38. MS: The product was analysed by LCMS (Method 4): m / z 364.0 [M+H]+(ES+); no ionisation (ES-), at 1.39 min, >99% purity at 260nm + / - 90nm.Compound 66(E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-3-yl)prop-2-en-1-one

[0367] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (500 mg, 99% Wt, 1 Eq, 2.31 mmol) and nicotinaldehyde (300 pL, 1.38 Eq, 3.20 mmol) in EtOH (15 mL) at 50 °C was added pyrrolidine (220 pL, 1.16 Eq, 2.68 mmol) in one portion. The reaction mixture was stirred at 50 °C for 2 h and then allowed to cool to rt. Water (100 mL) was added and the mixture was extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (2 x 50 mL), dried over MgSCU and concentrated in vacuo to afford the crude product. The precipitate that formed in the aqueous layer was collected by filtration, washed with water, and combined with the material from the organic extract to afford the crude product (E)-1-(4- amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (574 mg, 1.7 mmol, 74 %) as an orange solid.

[0368] 1H NMR (500 MHz, DMSO) 5 15.33 (br s, 1 H), 9.02 (s, 1 H), 8.61 (d, J = 4.8 Hz, 1 H), 8.44 - 8.20 (m, 3H), 8.13 (d, J = 15.5 Hz, 1 H), 7.81 (d, J = 15.3 Hz, 1 H), 7.64 - 7.39 (m, 2H).19F NMR (471 MHz, DMSO) 6 -140.48. MS: The product was analysed by LCMS (Method 4): m / z 304.0 [M+H]+(ES+); 302.0 [M-H]’ (ES-), at 0.58 min, 93% purity at 260nm + / - 90nm.7-amino-6-fluoro-8-nitro-2-(pyridin-3-yl)-4H-chromen-4-one

[0369] A suspension of (E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-3-yl)prop-2- en-1-one (570 mg, 90% Wt, 1 Eq, 1.69 mmol) and iodine (118 mg, 0.275 Eq, 465 pmol) in DMSO (4 mL) and Toluene (8 mL) was stirred at 110 °C for 4 h and then allowed to cool to rt. DMSO (4 mL) and iodine (200 mg, 0.466 Eq, 788 pmol) were added and stirred at 110 °C for 1 h. Additional iodine (200 mg, 0.466 Eq, 788 pmol) was added and stirred at 110 °C for 30 min and then allowed to cool to rt. Water (75 mL) was added and the resultant precipitate was collected by filtration. The solid was washed with water, toluene and then dried in vacuo. The solid was triturated with TBME, filtered and dried in vacuo to afford 7-amino-6-fluoro-8-nitro-2- (pyridin-3-yl)-4H-chromen-4-one (376 mg, 1.2 mmol, 73 %) as a tan solid.

[0370] 1H NMR (500 MHz, DMSO) 5 9.23 (s, 1 H), 8.78 (d, J = 4.7 Hz, 1 H), 8.40 (dt, J = 8.1 , 1.9 Hz, 1 H), 7.85 (br s, 2H), 7.77 (d, J = 10.9 Hz, 1 H), 7.66 (dd, J = 8.1 , 4.8 Hz, 1 H), 7.22 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -129.36. MS: The product was analysed by LCMS (Method 3): m / z 301.8 [M+H]+(ES+); 299.7 [M-H]- (ES-), at 0.92 min, 95% purity 210-400nm.7-amino-6-fluoro-8-nitro-2-(pyridin-3-yl)-4H-chromen-4-one

[0371] To a stirred suspension of 7-amino-6-fluoro-8-nitro-2-(pyridin-3-yl)-4H-chromen-4-one (376 mg, 99% Wt, 1 Eq, 1.24 mmol) in DMSO (6.00 mL), EtOH (6.00 mL) and Water (1.50 mL) at 80 °C was added Sodium dithionite (645 mg, 258 pL, 3 Eq, 3.71 mmol). The reaction was heated to 80 °C for 4.5 h. The reaction was allowed to cool then poured into ice / water (-100 mL). The resulting precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford 7,8-diamino-6-fluoro-2-(pyridin-3-yl)-4H-chromen-4-one (177 mg, 653 pmol, 52.8 %) as a dark orange solid.

[0372] 1H NMR (500 MHz, DMSO) 5 9.45 (s, 1 H), 8.80 (d, J = 4.9 Hz, 1 H), 8.71 (d, J = 7.8 Hz, 1 H), 7.67 (dd, J = 8.1 , 4.9 Hz, 1 H), 7.00 (s, 1 H), 6.97 (d, J = 10.8 Hz, 1 H). 4 protons not observed in DMSO.19F NMR (471 MHz, DMSO) 5 -134.36. MS: The product was analysed by LCMS (Method 1): m / z 272.1 [M+H]+(ES+); 270.3 [M-H]’ (ES-), at 0.69 min, >99% purity 210- 400nm.4-fluoro-8-(pyridin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (66)

[0373] A solution of 7,8-diamino-6-fluoro-2-(pyridin-3-yl)-4H-chromen-4-one (177 mg, 100% Wt, 1 Eq, 653 pmol) in TFA (2 mL) was stirred at 75 °C for 5 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% (0.7 M Ammonia / MeOH) / DCM to afford 4-fluoro-8-(pyridin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (40.0 mg, 0.11 mmol, 17 %) as a white solid.

[0374] 1H NMR (500 MHz, MeOD) 5 9.42 (d, J = 2.3 Hz, 1 H), 8.77 (dd, J = 4.9, 1.6 Hz, 1 H), 8.67 (dt, J = 8.1 , 2.0 Hz, 1 H), 7.78 (d, J = 10.1 Hz, 1 H), 7.68 (dd, J = 8.2, 4.9 Hz, 1 H), 7.16 (s, 1 H). 1 proton not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -65.60, -131.18. MS: The product was analysed by LCMS (Method 4): m / z 350.0 [M+H]+(ES+); 348.0 [M-Hp (ES-), at 0.69 min, >99% purity at 260nm + / - 90nm.

[0375] The column was flushed with 20% (0.7 M Ammonia in MeOH) / DCM to afford 4-fluoro-8- (pyridin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one, as the trifluoroacetic acid salt(144 mg, 0.31 mmol, 47 %) as a tan solid. This material was used for further reactions towards compounds 67 and 68.

[0376] 1H NMR (500 MHz, MeOD) 5 9.48 (dd, J = 2.4, 0.9 Hz, 1 H), 8.81 (ddd, J = 8.1 , 2.4, 1.6 Hz, 1 H), 8.73 (dd, J = 4.9, 1.6 Hz, 1 H), 7.66 (ddd, J = 8.1 , 4.9, 0.9 Hz, 1 H), 7.46 (d, J = 10.6 Hz, 1 H), 7.09 (s, 1 H). 2 protons not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -64.94, - 76.95, -130.82. MS: The product was analysed by LCMS (Method 4): m / z 350.0 [M+H]+(ES+); 348.0 [M-Hp (ES-), at 0.68 min, >99% purity at 260nm + / - 90nm.Compounds 67 & 68 4-fluoro-3-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (67) & 4- fluoro-1-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (68)67 68

[0377] A solution of 4-fluoro-8-(pyridin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)- one, Trifluoroacetic acid (82.0 mg, 99% Wt, 1 Eq, 175 pmol), DI PEA (77.0 pL, 2.52 Eq, 442 pmol) and Mel (12.0 pL, 1.10 Eq, 192 pmol) in DMF (1.00 mL) was stirred at 50 °C for 2 h. Additional Mel (12.0 pL, 1.10 Eq, 192 pmol) was added and stirred for 1 h. Additional DIPEA (77.0 pL, 2.52 Eq, 442 pmol) and Mel (12.0 pL, 1.10 Eq, 192 pmol) were added and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% (0.7 M Ammonia in MeOH) / DCM. The product containing fractions were concentrated in vacuo. The product was purified again by column chromatography on silica gel using a gradient of 0-50% (3:1, EtOAc / EtOH) / DCM) to afford a mixture of regioisomers. The mixture (68 mg) was dissolved to 6.8 mg / mL in equal amounts MeOH / THF / DCM, filtered and was then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak IG, 10 x 250mm, 5pm, flow rate 15mL / min at 45% MeOH (0.3% ammonia), -55% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were redissolved in methanol, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford: Compound 67

[0378] 4-fluoro-3-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (13.0 mg, 35.8 pmol, 20.4 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0379] 1H NMR (500 MHz, MeOD) 5 9.36 (dd, J = 2.4, 0.9 Hz, 1H), 8.76 (dd, J = 4.9, 1.6 Hz, 1H), 8.64 (ddd, J = 8.1, 2.4, 1.6 Hz, 1 H), 7.79 (d, J = 11.3 Hz, 1 H), 7.67 (ddd, J = 8.1, 4.9, 0.8 Hz, 1H), 7.13 (s, 1H), 4.27 (s, 3H).19F NMR (471 MHz, MeOD) 5 -64.09, -135.23. MS: The product was analysed by LCMS (Method 1): m / z 363.9 [M+H]+(ES+); no ionisation (ES-), at 1.23 min, 100% purity 210-400nm.Compound 68

[0380] 4-fluoro-1-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (18.0 mg, 49.5 pmol, 28.3 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0381] 1H NMR (500 MHz, MeOD) 5 9.25 (s, 1 H), 8.79 (d, J = 5.0 Hz, 1 H), 8.52 - 8.47 (m, 1 H), 7.76 (d, J = 10.0 Hz, 1 H), 7.69 (dd, J = 8.0, 4.8 Hz, 1 H), 7.15 (s, 1 H), 4.54 (d, J = 0.9 Hz, 3H).19F NMR (471 MHz, MeOD) 5 -63.99, -130.65. MS: The product was analysed by LCMS (Method 1): m / z 363.9 [M+H]+(ES+); no ionisation (ES-), at 1.24 min, 100% purity 210-400nm.Compound 69(E)-1-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one

[0382] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (1.00 g, 99% Wt, 1 Eq, 4.62 mmol) and 4-methoxybenzaldehyde (800 pL, 1.42 Eq, 6.58 mmol) in EtOH (30.0 mL) at 50 °C was added pyrrolidine (420 pL, 1.11 Eq, 5.11 mmol) in one portion. The resultant solution was stirred at 50 °C for 8 h and then allowed to cool to rt. The reaction mixture was diluted with EtOAc (100 mL) and brine (50 mL). The mixture was filtered, washing with EtOAc, the solid was collected and dried in vacuo to afford 1-(4-amino-5-fluoro-2-hydroxy-3- nitrophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (839 mg, 2.5 mmol, 54 %) as an orange solid.

[0383] 1H NMR (500 MHz, DMSO) 5 8.42 (d, J = 15.8 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 14.5 Hz, 1 H), 7.36 (d, J = 15.8 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 2H), 6.60 (s, 2H), 3.79 (s, 3H). 1 proton not observed in DMSO. MS: The product was analysed by LCMS (Method 4): m / z 333.0 [M+H]+(ES+); 331.0 [M-H]’ (ES-), at 0.79 min, 100% purity at 260nm + / - 90nm.7-amino-6-fluoro-2-(4-methoxyphenyl)-8-nitro-4H-chromen-4-one

[0384] A suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(4-methoxyphenyl)prop- 2-en-1-one (835 mg, 99% Wt, 1 Eq, 2.49 mmol) and iodine (126 mg, 0.2 Eq, 498 pmol) in DMSO (1.8 mL) and toluene (10.0 mL) was stirred at 110 °C for 6 h. Additional iodine (126 mg, 0.2 Eq, 498 pmol) and DMSO (1.80 mL) was added and stirred at 110 °C for 16 h. Additional iodine (126 mg, 0.2 Eq, 498 pmol) and DMSO (3.6 mL) was added and stirred for 3 h. Additional iodine (253 mg, 0.4 Eq, 995 pmol) and DMSO (3.6 mL) was added and stirred for 3 h. The reaction mixture was allowed to cool to rt and diluted with EtOH (30 mL) and water (30 mL). The precipitate was collected by filtration, washed with EtOH and dried in vacuo to afford 7-amino-6- fluoro-2-(4-methoxyphenyl)-8-nitro-4H-chromen-4-one (411 mg, 1.2 mmol, 50 %) as a tan solid.

[0385] 1H NMR (500 MHz, DMSO) 5 8.02 - 7.95 (m, 2H), 7.76 - 7.70 (m, 3H), 7.17 - 7.10 (m, 2H), 6.96 (s, 1 H), 3.85 (s, 3H).19F NMR (471 MHz, DMSO) 5 -130.03. MS: The product was analysed by LCMS (Method 4): m / z 331.0 [M+H]+(ES+); 329.0 [M-H]- (ES-), at 1.42 min, 100% purity at 260nm + / - 90nm.4-fluoro-8-(4-methoxyphenyl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (69)

[0386] To a suspension of 7-amino-6-fluoro-2-(4-methoxyphenyl)-8-nitro-4H-chromen-4-one (410 mg, 99% Wt, 1 Eq, 1.23 mmol) in EtOH (10 mL), THF (10 mL) and Water (1 mL) at 60 °C was added Sodium dithionite (856 mg, 342 pL, 4 Eq, 4.92 mmol) in one portion. The reaction mixture was stirred at 60 °C for 1 h and then concentrated in vacuo, to afford the crude product as a mixture of 7,8-diamino-6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one and (7-amino-6- fluoro-2-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl) sulfamic acid. To the crude product was added TFA (5.00 mL, 52.8 Eq, 64.9 mmol). The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to afford 4-fluoro-8-(4-methoxyphenyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (58.0 mg, 153 pmol, 12.5 %) as a yellow solid.

[0387] 1H NMR (500 MHz, MeOD) 5 8.21 - 8.14 (m, 2H), 7.74 (d, J = 10.1 Hz, 1 H), 7.15 - 7.08 (m, 2H), 6.92 (s, 1 H), 3.91 (s, 3H). 1 proton not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -65.56, -131.84. MS: The product was analysed by LCMS (Method 4): m / z 379.0 [M+H]+(ES+); 377.0 [M-H]- (ES-), at 0.82 min, >99% purity at 260nm + / - 90nm.Compounds 70 & 714-fluoro-8-(4-methoxyphenyl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one (70) & 4-fluoro-8-(4-methoxyphenyl)-1-methyl-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 Hi- one (71)70 71

[0388] To a solution of 4-fluoro-8-(4-methoxyphenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (55.0 mg, 99% Wt, 1 Eq, 144 pmol) and DI PEA (65.0 pL, 2.59 Eq, 373 pmol) in DMF (1.50 mL) was added Mel (15.0 pL, 1.67 Eq, 240 pmol). The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was quenched with MeOH (1.5 mL) and then concentrated in vacuo. The residue was azeotroped with toluene to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0- 4% MeOH / DCM to afford a mixture of regioisomers. The mixture (51 mg) was dissolved to 3 mg / mL in equal amounts MeOH / THF / DCM with sonication and heat then filtered and separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak I H , 10 x 250mm, 5pm, flow rate 15mL / min at 35% MeOH, 65% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were transferred into final vials with methanol and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford:Compound 70

[0389] 4-fluoro-8-(4-methoxyphenyl)-3-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (5.00 mg, 12 pmol, 8 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0390] 1H NMR (500 MHz, DMSO) 5 8.13 - 8.05 (m, 2H), 7.73 (d, J = 11.3 Hz, 1 H), 7.22 - 7.13 (m, 2H), 7.09 (s, 1 H), 4.18 (s, 3H), 3.87 (s, 3H).19F NMR (471 MHz, DMSO) 5 -61.41, -134.07. MS: The product was analysed by LCMS (Method 1): m / z 393.2 [M+H]+(ES+); no ionisation (ES-), at 1.67 min, 97% purity 210-400nm. Compound 71

[0391] 4-fluoro-8-(4-methoxyphenyl)-1-methyl-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1H)-one (12.2 mg, 31.1 pmol, 21.6 %) as a pale yellow solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0392] 1H NMR (500 MHz, DMSO) 5 8.07 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 10.1 Hz, 1 H), 7.17 (d, J = 8.6 Hz, 2H), 7.10 (s, 1 H), 4.46 (s, 3H), 3.88 (s, 3H).19F NMR (471 MHz, DMSO) 5 -61.41 , - 129.94. MS: The product was analysed by LCMS (Method 1): m / z 393.0 [M+H]+(ES+); no ionisation (ES-), at 1.56 min, >99% purity 210-400nm.Compound 72(E)-5-(3-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-oxoprop-1-en-1-yl)picolinonitrile

[0393] To a solution of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (2.16 g, 99% Wt, 1 Eq, 9.99 mmol) and 5-formylpicolinonitrile (2.00 g, 1.52 Eq, 15.1 mmol) in EtOH (35 mL) at 50 °C was added pyrrolidine (915 pL, 1.12 Eq, 11.1 mmol) in one portion. The reaction mixture was stirred at 50 °C for 3 h and then allowed to cool to rt. The reaction mixture was poured into water (150 mL) and the resultant precipitate was collected by filtration, washed with water and EtOH then dried in vacuo to afford 5-(3-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3- oxoprop-1-en-1-yl)picolinonitrile (1.244 g, 3.8 mmol, 38 %) as an orange solid.

[0394] 1H NMR (500 MHz, DMSO) 5 9.25 - 9.21 (m, 1 H), 8.59 (d, J = 8.1 Hz, 1 H), 8.21 (d, J = 15.5 Hz, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 7.88 (s, 1 H), 7.83 (d, J = 12.4 Hz, 1 H), 7.66 (s, 2H), 7.43 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -140.67. MS: The product was analysed by LCMS (Method 4): m / z 329.0 [M+H]+(ES+); 327.0 [M-H]' (ES-), at 0.64 min, 100% purity at 260nm + / - 90nm.5-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)picolinonitrile

[0395] A suspension of 5-(3-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-oxoprop-1-en-1- yl)picolinonitrile (1.24 g, 99% Wt, 1 Eq, 3.74 mmol) and iodine (244 mg, 0.257 Eq, 961 pmol) in DMSO (2.90 mL) and Toluene (11.0 mL) was stirred at 110 °C for 2 h. The reaction mixture was allowed to cool to rt and poured into water (100 mL). The resultant precipitate was collected by filtration and washed with water and EtOH (4 x 10 mL) then dried in vacuo to afford 5-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)picolinonitrile (802 mg, 2.4 mmol, 65 %) as a tan solid.

[0396] 1H NMR (500 MHz, DMSO) 5 9.36 (dd, J = 2.3, 0.9 Hz, 1 H), 8.58 (dd, J = 8.2, 2.3 Hz, 1 H), 8.30 (dd, J = 8.2, 0.9 Hz, 1 H), 7.93 (br s, 2H), 7.78 (d, J = 10.9 Hz, 1 H), 7.39 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -128.89. MS: The product was analysed by LCMS (Method 4): m / z 327.0 [M+H]+(ES+); 325.0 [M-H]' (ES-), at 1.17 min, 100% purity at 260nm + / - 90nm.5-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)picolinonitrile

[0397] To a stirred suspension of 5-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2- yl)picolinonitrile (800 mg, 100% Wt, 1 Eq, 2.45 mmol) in DMSO (8.00 mL), EtOH (8.00 mL) and water (2.00 mL) at 80 °C was added Sodium dithionite (518.0 pL, 3.03 Eq, 7.438 mmol) in one portion. The reaction mixture was stirred at 80 °C for 6 h and then allowed to cool to rt. The reaction mixture was poured into ice / water (100 mL) and the precipitate was collected by filtration, washed with water and dried in vacuo to afford 5-(7,8-diamino-6-fluoro-4-oxo-4H- chromen-2-yl)picolinonitrile (671 mg, 2.2 mmol, 91 %) as an orange solid.

[0398] 1H NMR (500 MHz, DMSO) 5 9.56 (dd, J = 2.3, 0.8 Hz, 1 H), 8.89 (dd, J = 8.2, 2.3 Hz, 1 H), 8.24 (dd, J = 8.2, 0.8 Hz, 1 H), 7.14 (s, 1 H), 6.97 (d, J = 10.7 Hz, 1 H), 5.69 (br s, 2H), 5.37 (br s, 2H).19F NMR (471 MHz, DMSO) 5 -134.12. MS: The product was analysed by LCMS (Method 4): m / z 297.0 [M+H]+(ES+); 295.0 [M-H]’ (ES-), at 0.92 / 0.97 min, 100% purity at 260nm + / - 90nm.5-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8-yl)picolinonitrile (72)

[0399] A suspension of 5-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)picolinonitrile (332 mg, 99% Wt, 1 Eq, 1.11 mmol) in TFA (2 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DOM (3 times) to afford the crude product. The crude product was purified by column chromatography on RP Flash C18 using a gradient of 5-30% MeCN / 10 mM Ammonium Bicarbonate to afford 5-(4-fluoro-6-oxo-2- (trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)picolinonitrile (369 mg, 0.90 mmol, 81 %) as a brown solid with some impurities.

[0400] An aliquot (210 mg, 0.561 mmol) of product was purified again by column chromatography on silica gel using a gradient of 0-25% (3:1 , EtOAc / EtOH) / DCM to afford 5-(4- fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)picolinonitrile (125 mg, 0.33 mmol, 59 %) as a pale orange solid.

[0401] 1H NMR (500 MHz, MeOD) 5 9.54 (dd, J = 2.4, 0.9 Hz, 1 H), 8.81 (dd, J = 8.2, 2.3 Hz, 1 H), 8.10 (dd, J = 8.2, 0.9 Hz, 1 H), 7.76 (d, J = 10.0 Hz, 1 H), 7.25 (s, 1 H).19F NMR (471 MHz, MeOD) 5 -65.64, -130.84. MS: The product was analysed by LCMS (Method 4): m / z 375.0 [M+H]+(ES+); 373.0 [M-H]- (ES-), at 0.71 min, >99% purity at 260nm + / - 90nm.Compounds 73 & 745-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8-d1imidazol-8- vDpicolinonitrile (73) & 5-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromenof7,8- d1imidazol-8-yl)picolinonitrile (74)73 74

[0402] To a suspension of 5-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)picolinonitrile (155 mg, 91% Wt, 1 Eq, 377 pmol) and potassium carbonate (156 mg, 3 Eq, 1.13 mmol) in DMF (2 mL) was added Mel (35.0 pL, 1.49 Eq, 560 pmol). The reaction mixture was stirred at 50 °C for 2 h. Additional Mel (70.0 pL, 2.97 Eq, 1.12 mmol) was added and stirred at 50 °C for 30 min. The reaction mixture was quenched with MeOH (~3 mL) and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (3:1 , EtOAc / EtOH) / DCM to afford a mixture of regioisomers as a yellow solid. The mixture (39.2 mg) was dissolved to 10 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20mL / min at 25% MeOH (neutral), 75% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 73

[0403] 5-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)picolinonitrile (14.5 mg, 37.3 pmol, 9.91 %) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0404] 1H NMR (500 MHz, DMSO) 5 9.45 (dd, J = 2.3, 0.8 Hz, 1 H), 8.70 (dd, J = 8.2, 2.3 Hz, 1 H), 8.33 (dd, J = 8.2, 0.8 Hz, 1 H), 7.78 (d, J = 11.2 Hz, 1 H), 7.49 (s, 1 H), 4.20 (s, 3H).19F NMR (471 MHz, DMSO) 5 -61.45, -132.99. MS: The product was analysed by LCMS (Method 1): m / z 388.6 [M+H]+(ES+); no ionisation (ES-), at 1.37 min, >99% purity 210-400nm.Compound 74

[0405] 5-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8-d]imidazol-8- yl)picolinonitrile (16.8 mg, 42 pmol, 11 %, 97% Purity) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0406] 1H NMR (500 MHz, DMSO) 5 9.44 (dd, J = 2.4, 0.8 Hz, 1 H), 8.72 (dd, J = 8.2, 2.3 Hz, 1 H), 8.31 (dd, J = 8.2, 0.8 Hz, 1 H), 7.69 (d, J = 10.0 Hz, 1 H), 7.48 (s, 1 H), 4.45 (s, 3H).19F NMR (471 MHz, DMSO) 5 -61.42, -128.95. MS: The product was analysed by LCMS (Method 1): m / z 388.6 [M+H]+(ES+); no ionisation (ES-), at 1.37 min, 97% purity 210-400nm.Compound 75 N-(8-amino-2-(6-cvanopyridin-3-yl)-6-fluoro-4-oxo-4H-chromen-7-yl)-2,2-difluoroacetamide & N- (7-amino-2-(6-cvanopyridin-3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)-2,2-difluoro-N- methylacetamide

[0407] To a stirred suspension of 5-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)picolinonitrile (330 mg, 99% Wt, 1 Eq, 1.10 mmol), 2,2-difluoroacetic acid (105 pL, 1.51 Eq, 1.67 mmol) and DI PEA (390 pL, 2.03 Eq, 2.24 mmol) in DMF (3 mL) was added a solution of HATLI (545 mg, 1.3 Eq, 1.43 mmol) in DMF (2 mL) dropwise. The reaction mixture was stirred at rt for 2 h. Additional 2,2-difluoroacetic acid (105 pL, 1.51 Eq, 1.67 mmol), DIPEA (390 pL, 2.03 Eq, 2.24 mmol) and HATLI (545 mg, 1.3 Eq, 1.43 mmol) were added and stirred at rt for 30 min. The reaction mixture was diluted with DCM (10 mL) and sat. aq NaHCOs (10 mL) was added. The resultant precipitate was collected by filtration and washed with water, to afford the crude product as a mixture of N-(8-amino-2-(6-cyanopyridin-3-yl)-6-fluoro-4-oxo-4H-chromen-7-yl)-2,2- difluoroacetamide and N-(7-amino-2-(6-cyanopyridin-3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)-2,2- difluoroacetamide (549 mg, 1.1 mmol) In quantitative yields. The product was used without further purification.

[0408] MS: The product was analysed by LCMS (Method 4): m / z 375.0 [M+H]+(ES+); 373.0 [M- H]’ (ES-), at 0.54 min, 99% purity at 260nm + / - 90nm.5-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6-dihvdrochromenof7,8-d1imidazol-8-yl)picolinonitrile (75)

[0409] A suspension of N-(8-amino-2-(6-cyanopyridin-3-yl)-6-fluoro-4-oxo-4H-chromen-7-yl)- 2,2-difluoroacetamide (412 mg, 100% Wt, 1 Eq, 1.10 mmol) and N-(7-amino-2-(6-cyanopyridin- 3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)-2,2-difluoroacetamide (412 mg, 100% Wt, 1 Eq, 1.10 mmol) in AcOH (5 mL) was stirred at 100 °C for 90 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1 , EtOAc / EtOH) / DCM to afford 5-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)picolinonitrile (89.0 mg, 0.25 mmol, 22 %) as a yellow solid.

[0410] 1H NMR (500 MHz, MeOD) 5 9.54 (d, J = 2.2 Hz, 1 H), 8.81 (dd, J = 8.2, 2.3 Hz, 1 H), 7.71 (d, J = 10.0 Hz, 1 H), 7.23 (s, 1 H), 7.18 (t, J = 53.2 Hz, 2H). 1 proton not observed.19F NMR (proton decoupled) (471 MHz, MeOD) 5 -118.29, -131.15.19F NMR (471 MHz, MeOD) 5 - 118.29 (d, J = 53.3 Hz), -131.15. MS: The product was analysed by LCMS (Method 4): m / z no ionisation (ES+); 355.0 [M-H (ES-), at 0.67 min, >99% purity at 260nm + / - 90nm.Compounds 76 & 775-(2-(difluoromethyl)-4- fluoro- 3-methyl-6-oxo-3,6-dihvdrochromenof7,8-d1imidazol-8- vDpicolinonitrile (76) & 5-(2-(difluoromethyl)-4-fluoro-1-methyl-6-oxo-1 ,6-dihydrochromenof7,8- d1imidazol-8-yl)picolinonitrile (77)

[0411] To a stirred suspension of 5-(2-(difluoromethyl)-4-fluoro-6-oxo-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)picolinonitrile (75.0 mg, 99% Wt, 1 Eq, 208 pmol) and potassium carbonate (86.4mg, 3 Eq, 625 pmol) in DMF (2 mL) was added methyl iodide (20.0 pL, 1.53 Eq, 320 pmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with MeOH (~3 mL) and then concentrated in vacuo. The residue was azeotroped with toluene (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of n0-10% (3:1 EtOAc / EtOH) / DCM to afford a mixture of regioisomers. The mixture (47 mg) was dissolved in DMF / MeOH (8 mL), filtered and was then separated by chiral SFC on a Waters Prep 100 with a PDA and QDa detectors, 40 °C, 120 bar. The column was a ChiralpaK IB-N, 20 x 250mm, 5pm, flow rate 65mL / min at 50% MeOH, 50% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 76

[0412] 5-(2-(difluoromethyl)-4-fluoro-1-methyl-6-oxo-1,6-dihydrochromeno[7,8-d]imidazol-8- yl)picolinonitrile (24.3 mg, 65.6 pmol, 31.5 %, 100% Purity) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0413] 1H NMR (500 MHz, DMSO) 5 9.44 (d, J = 2.2 Hz, 1H), 8.72 (dd, J = 8.2, 2.3 Hz, 1 H), 8.31 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 10.1 Hz, 1H), 7.60 (t, J = 51.6 Hz, 1H), 7.44 (s, 1H), 4.42 (s, 3H).19F NMR (471 MHz, DMSO) 5 -117.22, -129.28. MS: The product was analysed by LCMS (Method 1): m / z 370.5 [M+H]+(ES+); no ionisation (ES-), at 1.24 min, 100% purity at 260nm + / - 90nm.Compound 77

[0414] 5-(2-(difluoromethyl)-4-fluoro-3-methyl-6-oxo-3,6-dihydrochromeno[7,8-d]imidazol-8- yl)picolinonitrile (15.5 mg, 41.9 pmol, 20.1 %, 100% Purity) as a white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0415] 1H NMR (500 MHz, DMSO) 5 9.44 (d, J = 2.3 Hz, 1H), 8.68 (dd, J = 8.2, 2.3 Hz, 1 H), 8.33 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 11.1 Hz, 1H), 7.59 (t, J = 51.7 Hz, 1H), 7.46 (s, 1H), 4.17 (s, 3H).19F NMR (471 MHz, DMSO) 5 -117.07, -133.37. MS: The product was analysed by LCMS (Method 1): m / z 370.6 [M+H]+(ES+); no ionisation (ES-), at 1.25 min, 100% purity at 260nm + / - 90nm.Compound 787-amino-6-fluoro-8-nitro-2-(tetrahvdro-2H-pyran-4-yl)chroman-4-one

[0416] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (450 mg, 99% Wt, 1 Eq, 2.08 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (300 pL, 1.39 Eq, 2.89 mmol) in EtOH (15.0 mL) at 50 °C was added pyrrolidine (190 pL, 1.11 Eq, 2.31 mmol) in one portion. The resultant solution was stirred at 50 °C for 3 h then allowed to cool to rt. The reaction mixture was diluted with EtOAc (100 mL) and washed with 50% brine (50 mL). The organic layer was collected and the aqueous layer extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 7-amino-6-fluoro-8-nitro-2-(tetrahydro-2H- pyran-4-yl)chroman-4-one (418 mg, 1.1 mmol, 55 %) as a orange solid.

[0417] 1H NMR (500 MHz, DMSO) 5 7.46 (d, J = 11.3 Hz, 1 H), 7.31 (br s, 2H), 4.40 (ddd, J = 13.2, 6.8, 2.9 Hz, 1 H), 3.93 - 3.84 (m, 2H), 3.33 - 3.26 (m, 2H), 2.77 (dd, J = 17.0, 13.0 Hz, 1 H), 2.59 (dd, J = 17.0, 2.9 Hz, 1 H), 1.96 - 1.87 (m, 1 H), 1.75 (d, J = 13.2 Hz, 1 H), 1.51 (d, J = 13.2 Hz, 1 H), 1.36 (dtd, J = 28.7, 12.2, 4.5 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -137.70. MS: The product was analysed by LCMS (Method 4): m / z 311.0 [M+H]+(ES+); 309.0 [M-H]' (ES-), at 1.17 min, 85% purity at 260nm + / - 90nm.7-amino-6-fluoro-8-nitro-2-(tetrahydro-2H-pyran-4-yl)-4H-chromen-4-one

[0418] To a solution of 7-amino-6-fluoro-8-nitro-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (418 mg, 84% Wt, 1 Eq, 1.13 mmol) in Pyridine (10 mL) was added iodine (574 mg, 2 Eq, 2.26 mmol). The reaction mixture was stirred at 110 °C for 3 h. Additional iodine (287 mg, 1 Eq, 1.13 mmol) was added and stirred at 110 °C for 30 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (3 times). EtOAc (50 mL) and sat. aq. sodium thiosulfate (50 mL) was added and the mixture was filtered through cotton wool. The organic layer was collected and washed with sat. aq. sodium thiosulfate (50 mL), brine (2 x 50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford 7-amino-6-fluoro-8-nitro-2-(tetrahydro-2H-pyran-4-yl)-4H-chromen-4-one (85.0 mg, 0.26 mmol, 23 %) as a yellow solid.

[0419] 1H NMR (500 MHz, DMSO) 5 7.69 (d, J = 11.0 Hz, 1 H), 7.63 (s, 2H), 6.20 (s, 1 H), 3.99 - 3.89 (m, 2H), 3.41 (td, J = 11.8, 2.1 Hz, 2H), 2.89 (tt, J = 11.6, 3.8 Hz, 1 H), 1.88 - 1.77 (m, 2H), 1.68 (qd, J = 12.3, 4.4 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -130.17. MS: The product wasanalysed by LCMS (Method 4): m / z 309.0 [M+H]+(ES+); no ionisation (ES-), at 1.07 min, 94% purity at 260nm + / - 90nm.4-fluoro-8-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)chromeno(7,8-d1imidazol-6(3H)-one (78)

[0420] To a suspension of 7-amino-6-fluoro-8-nitro-2-(tetrahydro-2H-pyran-4-yl)-4H-chromen-4- one (85.0 mg, 96% Wt, 1 Eq, 265 pmol) in EtOH (2 mL), THF (2 mL) and Water (0.5 mL) at 60 °C was added sodium dithionite (73.7 pL, 4 Eq, 1.06 mmol) in one portion. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated in vacuo. To the residue was added TFA (2.00 mL, 98.1 Eq, 26.0 mmol). The reaction mixture was stirred at 70 °C for 5 h and then concentrated in vacuo. The residue was azeotroped with DCM (3 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1 , EtOAc / EtOH) / DCM to afford 4-fluoro-8-(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (65.0 mg, 182 pmol, 68.9 %) as a yellow solid.

[0421] 1H NMR (500 MHz, MeOD) 5 7.72 (d, J = 10.1 Hz, 1 H), 6.36 (s, 1 H), 4.13 - 4.06 (m, 2H), 3.65 - 3.56 (m, 2H), 3.08 (tt, J = 11.7, 4.0 Hz, 1 H), 2.05 (d, J = 12.3 Hz, 2H), 1.97 (qd, J = 12.3, 4.6 Hz, 2H). 1 proton not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -65.65, - 131.93. MS: The product was analysed by LCMS (Method 1): m / z 357.5 [M+H]+(ES+); 354.9 [M-H]' (ES-), at 1.18 min, 100% purity 210-400nm.Compounds 79 & 804- fluoro- 3-methyl-8-(tetrahvdro-2H-pyran-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol- 6(3H)-one (79) & 4-fluoro-1-methyl-8-(tetrahvdro-2H-pyran-4-yl)-2- (trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (80)79 80

[0422] A solution of 4-fluoro-8-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (61.0 mg, 100% Wt, 1 Eq, 171 pmol), DI PEA (70.0 pL, 2.35 Eq, 402 pmol) and Mel (15.0 pL, 1.40 Eq, 240 pmol) in DMF (1 mL) was stirred at rt for 24 h. Additional DI PEA (70.0 pL, 2.35 Eq, 402 pmol) and Mel (10.0 pL, 0.934 Eq, 160 pmol) were added and the reaction stirred at 50 °C for 2 h. The reaction mixture was diluted with MeOH (2 mL) and then concentrated in vacuo. The residue was azeotroped with toluene (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-3% MeOH / DCM to afford a mixture of regioisomers. The mixture (56 mg) was dissolved to 6 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak IG, 10 x 250mm, 5pm, flow rate 15mL / min at 25% MeOH, 75% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10. The samples were then further dried in a vacuum oven at 30 °C / 5 mbar overnight to afford: Compound 79

[0423] 4-fluoro-3-methyl-8-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (12.5 mg, 33.8 pmol, 19.7 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0424] 1H NMR (500 MHz, DMSO) 5 7.69 (d, J = 11.3 Hz, 1H), 6.34 (s, 1H), 4.16 (s, 3H), 3.98 (ddd, J = 11.4, 4.4, 1.7 Hz, 2H), 3.48 (td, J = 11.8, 2.1 Hz, 2H), 3.05 (tt, J = 11.8, 3.7 Hz, 1H), 1.93 (ddd, J = 12.9, 4.0, 1.9 Hz, 2H), 1.76 (dtd, J = 13.2, 11.9, 4.4 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -61.49, -134.11. MS: The product was analysed by LCMS (Method 1): m / z 371.0 [M+H]+(ES+); no ionisation (ES-), at 1.31 min, >99% purity 210-400nm. Compound 80

[0425] 4-fluoro-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(1H)-one (33.9 mg, 91.5 pmol, 53.5 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0426] 1H NMR (500 MHz, DMSO) 5 7.61 (d, J = 10.1 Hz, 1 H), 6.40 (s, 1 H), 4.34 (d, J = 1.2 Hz, 3H), 4.02 - 3.95 (m, 2H), 3.47 (td, J = 11.8, 2.0 Hz, 2H), 3.07 (tt, J = 11.8, 3.7 Hz, 1 H), 1.97 - 1.89 (m, 2H), 1.85 - 1.73 (m, 2H).19F NMR (471 MHz, DMSO) 5 -61.52, -130.00. MS: The product was analysed by LCMS (Method 1): m / z 371.0 [M+H]+(ES+); no ionisation (ES-), at 1.29 min, >99% purity 210-400nm.Compounds 81 & 82(E)-1-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-(pyridin-4-yl)prop-2-en-1-one

[0427] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (500 mg, 99% Wt, 1 Eq, 2.31 mmol) and isonicotinaldehyde (310 pL, 1.42 Eq, 3.29 mmol) in EtOH (10 mL) at 50 °C was added pyrrolidine (220 pL, 1.16 Eq, 2.68 mmol) in one portion. The resultant solution was stirred at 50 °C for 6 h and then allowed to cool to rt. The reaction mixture was poured into water (-100 mL) and the resultant precipitate was collected by filtration, washed with water and EtOH then dried in vacuo to afford (E)-1-(4-amino-5-fluoro-2-hydroxy-3- nitrophenyl)-3-(pyridin-4-yl)prop-2-en-1-one (423 mg, 1.3 mmol, 54 %) as an orange solid.

[0428] 1H NMR (500 MHz, DMSO) 5 15.20 (s, 1 H), 8.69 (d, J = 5.5 Hz, 2H), 8.38 (d, J = 12.8 Hz, 1 H), 8.15 (d, J = 15.5 Hz, 1 H), 7.90 - 7.85 (m, 2H), 7.78 (d, J = 15.5 Hz, 1 H), 7.69 (s, 2H). MS: The product was analysed by LCMS (Method 4): m / z 304.0 [M+H]+(ES+); 302.0 [M-H (ES-), at 0.58 min, 100% purity at 260nm + / - 90nm.7-amino-6-fluoro-8-nitro-2-(pyridin-4-yl)-4H-chromen-4-one

[0429] A suspension of (E)-1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(pyridin-4-yl)prop-2- en-1-one (420 mg, 90% Wt, 1 Eq, 1.25 mmol) and iodine (352 mg, 1.11 Eq, 1.39 mmol) in DMSO (8.00 mL) and Toluene (4.00 mL) was stirred at 110 °C for 4 h and then allowed to cool to rt. Water (75 mL) was added and the resultant precipitate was collected by filtration, washed with water and toluene, then dried in vacuo. The solid was triturated with TBME, filtered and then dried in vacuo to afford 7-amino-6-fluoro-8-nitro-2-(pyridin-4-yl)-4H-chromen-4-one (498 mg, 1.3 mmol, 100 %) as a black solid contaminated with iodine. Product was not further purified and quantitative yield was assumed for further reaction.

[0430] 1H NMR (500 MHz, DMSO) 5 8.84 (s, 2H), 8.67 (s, 2H), 8.11 (d, J = 5.3 Hz, 2H), 7.79 (d, J = 9.5 Hz, 1 H), 7.03 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -132.05. MS: The product was analysed by LCMS (Method 4): m / z 302.0 [M+H]+(ES+); 300.0 [M-Hp (ES-), at 1.15 min, 87% purity at 260nm + / - 90nm.7,8-diamino-6-fluoro-2-(pyridin-4-yl)-4H-chromen-4-one

[0431] To a stirred suspension of 7-amino-6-fluoro-8-nitro-2-(pyridin-4-yl)-4H-chromen-4-one (498 mg, 78% Wt, 1 Eq, 1.29 mmol) in DMSO (6.00 mL), EtOH (6.00 mL) and Water (1.50 mL) at 80 °C was added sodium dithionite (350 pL, 3.90 Eq, 5.03 mmol). The reaction was heated to 80 °C for 2 h. The reaction was allowed to cool then poured into ice / water (-100 mL). The aqueous mixture was extracted with DCM (2 x 50 mL) and EtOAc (2 x 50 mL). The combined organics were dried over MgSCU and concentrated in vacuo to afford the crude product 7,8- diamino-6-fluoro-2-(pyridin-4-yl)-4H-chromen-4-one (322 mg, 1.1 mmol, 87 %) as a dark orange solid. The product was used without further purification.

[0432] MS: The product was analysed by LCMS (Method 4): m / z 272.0 [M+H]+(ES+); 270.0 [M- H]’ (ES-), at 0.88 min, 95% purity at 260nm + / - 90nm.4-fluoro-8-(pyridin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one

[0433] A solution of 7,8-diamino-6-fluoro-2-(pyridin-4-yl)-4H-chromen-4-one (350 mg, 100% Wt, 1 Eq, 1.29 mmol) in TFA (1 mL) was stirred at 75 °C for 7 h and then allowed to cool to rt. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (3 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% (0.7 M Ammonia in MeOH) / DCM to afford 4-fluoro-8-(pyridin-4-yl)- 2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (19.0 mg, 46 pmol, 3.6%) as an orange solid.

[0434] MS: The product was analysed by LCMS (Method 4): m / z 350.0 [M+H]+(ES+); 348.0 [M- H]’ (ES-), at 0.70 min, 85% purity at 260nm + / - 90nm.4-fluoro-3-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (81) & 4- fluoro-1-methyl-8-(pyridin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (82)

[0435] To a solution of 4-fluoro-8-(pyridin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (19.0 mg, 85% Wt, 1 Eq, 46.2 pmol) and DIPEA (40.0 pL, 4.97 Eq, 230 pmol) in DMF (1.00 mL) was added Mel (6.00 pL, 2.08 Eq, 96.0 pmol). The reaction mixture was stirred at 50 °C for 1 h. Additional DIPEA (40.0 pL, 4.97 Eq, 230 pmol) and Mel (6.00 pL, 2.08 Eq, 96.0 pmol) were added and stirred for 1 h. The reaction mixture was diluted with MeOH (2 mL) and then concentrated in vacuo. The residue was azeotroped with toluene (2 times) to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-30% (3:1 , EtOAc / EtOH) / DCM to afford a mixture of regioisomers. Clean fractions were collected, stripped if residual solvent and purified by preparative HPLC General procedure 4, Method 4. Gradient information: 0.0-0.5 min, 25% MeCN; 0.5-24.0min, ramped from 25% MeCN to 55% MeCN; 24.0-24.1 min, ramped from 55% MeCN to 100% MeCN; 24.1-27.0 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford: Compound 81

[0436] 4-fluoro-3-methyl-8-(pyridin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (2.60 mg, 7.1 pmol, 15 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0437] 1H NMR (500 MHz, MeOD) 5 8.84 - 8.73 (m, 2H), 8.24 - 8.15 (m, 2H), 7.80 (d, J = 11.3 Hz, 1 H), 7.23 (s, 1 H), 4.28 (s, 3H).19F NMR (471 MHz, MeOD) 5 -64.10, -135.00. MS: The product was analysed by LCMS (Method 4): m / z 364.0 [M+H]+(ES+); no ionisation (ES-), at 1.28 min, 100% purity at 260nm + / - 90nm. Compound 82

[0438] 4-fluoro-1-methyl-8-(pyridin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (2.90 mg, 7.9 pmol, 17 %, 99% Purity) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0439] 1H NMR (500 MHz, MeOD) 5 8.86 - 8.78 (m, 2H), 8.09 - 8.02 (m, 2H), 7.73 (d, J = 9.9 Hz, 1 H), 7.23 (s, 1 H), 4.55 (d, J = 1.1 Hz, 3H).19F NMR (471 MHz, MeOD) 5 -63.99, -130.39. MS: The product was analysed by LCMS (Method 4): m / z 364.0 [M+H]+(ES+); no ionisation (ES-), at 1.27 min, 100% purity at 260nm + / - 90nm.Compound 831-(4-amino-5-fluoro-2-hvdroxy-3-nitrophenyl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-one

[0440] To a stirred suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (900 mg, 99% Wt, 1 Eq, 4.16 mmol) and 4-(methylsulfonyl)benzaldehyde (1.16 g, 1.51 Eq, 6.30mmol) in EtOH (40.0 mL) at 50 °C was added pyrrolidine (380 pL, 1.11 Eq, 4.63 mmol) in one portion. The reaction mixture was stirred at 50 °C for 2 h and then allowed to cool to rt overnight. Water (-100 mL) was added and the resultant precipitate was collected by filtration and washed with water. The solid was triturated with EtOH, filtered, washed with EtOH and dried in vacuo to afford 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(4- (methylsulfonyl)phenyl)prop-2-en-1-one (1.128 g, 2.8 mmol, 68 %) as a brown solid.

[0441] 1H NMR (500 MHz, DMSO) 5 15.28 (br s, 1 H), 8.41 - 8.24 (m, 1 H), 8.22 - 8.09 (m, 3H), 8.03 - 7.97 (m, 2H), 7.84 (d, J = 15.2 Hz, 1 H), 7.67 - 7.48 (m, 2H), 3.27 (s, 3H).19F NMR (471 MHz, DMSO) 5 -140.36. MS: The product was analysed by LIPLC (Method 1): m / z 381.5 [M+H]+(ES+); 378.8 [M-H]’ (ES-), at 1.39 min, 97% purity 210-400nm.7-amino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-8-nitro-4H-chromen-4-one

[0442] A solution of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)-3-(4- (methylsulfonyl)phenyl)prop-2-en-1-one (1.128 g, 95% Wt, 1 Eq, 2.817 mmol) and iodine (715.1 mg, 1 Eq, 2.817 mmol) in Toluene (10.0 mL) and DMSO (10.0 mL) was stirred at 110 °C for 1 h and then allowed to coo to rt. Water (80 mL) was added and the resultant precipitate was collected by filtration. The solid was washed with water and then toluene and allowed to dry, to afford 7-amino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-8-nitro-4H-chromen-4-one (1.004 g, 2.5 mmol, 89 %) as a tan solid.

[0443] 1H NMR (500 MHz, DMSO) 5 8.31 - 8.24 (m, 2H), 8.15 - 8.09 (m, 2H), 7.87 (s, 2H), 7.78 (d, J = 10.9 Hz, 1 H), 7.24 (s, 1 H), 3.30 (s, 3H).19F NMR (471 MHz, DMSO) 5 -129.20. MS: The product was analysed by UPLC (Method 1): m / z 378.9 [M+H]+(ES+); 377.1 [M-H]- (ES-), at 1.11 min, 95% purity 210-400nm.7,8-diamino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-chromen-4-one and (7-amino-6-fluoro-2- (4-(methylsulfonyl)phenyl)-4-oxo-4H-chromen-8-yl)sulfamic acid

[0444] A suspension of 7-amino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-8-nitro-4H-chromen-4- one (1.004 g, 95% Wt, 1 Eq, 2.521 mmol) and sodium dithionite (1.41 g, 3.21 Eq, 8.10 mmol) in DMSO (10.0 mL), EtOH (10.0 mL) and Water (2.50 mL) was stirred at 60 °C for 5 h and then allowed to cool to rt overnight. Additional sodium dithionite (0.97 g, 2.2 Eq, 5.6 mmol) was added and stirred at 65 °C for 1 h and then allowed to cool to rt. The reaction mixture was poured into ice / water (-200 mL) and the resultant precipitate was collected by filtration. The solid was washed with water and then toluene then dried in vacuo (50 °C) to afford 7,8-diamino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-chromen-4-one (710 mg, 1.9 mmol, 77 %) as a yellow solid.

[0445] MS: The product was analysed by UPLC (Method 1): m / z 349.6 [M+H]+(ES+); 347.3 [M- H]’ (ES-), at 0.92 min, 95% purity 210-400nm.4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (83)

[0446] A solution of 7,8-diamino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4H-chromen-4-one (710 mg, 95% Wt, 1 Eq, 1.94 mmol) and (7-amino-6-fluoro-2-(4-(methylsulfonyl)phenyl)-4-oxo-4H- chromen-8-yl)sulfamic acid (710 mg, 95% Wt, 0.0428 Eq, 82.9 pmol) in TFA (15 mL) was stirred at 70 °C for 5 h and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-50% (3:1 , EtOAc / EtOH) / DCM to afford 4-fluoro-8-(4-(methylsulfonyl)phenyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (622 mg, 1.4 mmol, 69 %) as a tan solid.

[0447] 1H NMR (500 MHz, MeOD) 5 8.52 - 8.47 (m, 2H), 8.20 - 8.15 (m, 2H), 7.76 (d, J = 10.0 Hz, 1 H), 7.18 (s, 1 H), 3.22 (s, 3H). 1 proton not observed in MeOD.19F NMR (471 MHz, MeOD) 5 -65.59, -131.11. MS: The product was analysed by LCMS (Method 3): m / z 427.0 [M+H]+(ES+); 425.0 [M-H]' (ES-), at 0.73 min, >99% purity at 260nm + / - 90nm.Compounds 84 & 854- fluoro- 3-methyl-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol- 6(3H)-one (84) & 4-fluoro-1-methyl-8-(4-(methylsulfonyl)phenyl)-2- (trifluoromethyl)chromenof7,8-d1imidazol-6(1 H)-one (85)

[0448] A solution of 4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (120 mg, 96% Wt, 1 Eq, 270 pmol), DI PEA (150 pL, 3.19 Eq, 861 pmol) and methyl iodide (28.0 pL, 1.66 Eq, 448 pmol) in DMF (2.00 mL) was stirred at 50 °C for 18 h. Additional methyl iodide (28.0 pL, 1.66 Eq, 448 pmol) was added and stirred at 50 °C for 1 h. MeOH (2 mL) was added and the reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% (3:1 EtOAc / EtOH) / DCM) to afford a mixture of regioisomers. The mixture (100 mg) was dissolved to 3 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 269 nm, 40 °C, 120 bar. The column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20 mL / min at 35% MeOH, 65% CO2. The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 84

[0449] 4-fluoro-3-methyl-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (32.0 mg, 70 pmol, 26 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0450] 1H NMR (500 MHz, DMSO) 5 8.40 - 8.35 (m, 2H), 8.21 - 8.15 (m, 2H), 7.77 (d, J = 11.2 Hz, 1H), 7.35 (d, J = 1.1 Hz, 1 H), 4.19 (s, 3H), 3.36 - 3.27 (m, 3H). Sulfone CH3obscured by water peak (confirmed by HSQC).19F NMR (471 MHz, DMSO) 5 -61.39, -133.28. MS: The product was analysed by LIPLC (Method 1): m / z 440.6 [M+H]+(ES+); no ionisation (ES-), at 1.33 min, 99% purity 210-400nm. Compound 85

[0451] 4-fluoro-1-methyl-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(1H)-one (60.2 mg, 0.13 mmol, 49 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0452] 1H NMR (500 MHz, DMSO) 5 8.37 (d, J = 8.2 Hz, 2H), 8.15 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 10.0 Hz, 1 H), 7.35 (s, 1H), 4.46 (s, 3H), 3.34 (s, 3H).19F NMR (471 MHz, DMSO) 6 -61.41, - 129.25. MS: The product was analysed by LIPLC (Method 1): m / z 440.5 [M+H]+(ES+); no ionisation (ES-), at 1.33 min, 99% purity 210-400nm.Compounds 86 & 873-ethyl-4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)- one (86) & 1-ethyl-4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno|'7,8- d1imidazol-6(1H)-one (87)

[0453] A solution of 4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (120 mg, 96% Wt, 1 Eq, 270 pmol), DI PEA (150 pL, 3.19 Eq, 861 pmol) and ethyl iodide (35.0 pL, 1.60 Eq, 433 pmol) in DMF (2.00 mL) was stirred at 50 °C for 18 h. Additional ethyl iodide (35.0 pL, 1.60 Eq, 433 pmol) was added and stirred at 50 °C for 3 h. MeOH (2 mL) was added and the reaction mixture was concentrated in vacuo to afford the crude product. The crude product was purified by colomn chromatography on silica gel using a gradient of 0-20% (3:1 EtOAc / EtOH) / DCM to afford a mixture of regioisomers. The mixture (98 mg) was purified by preparative HPLC General procedure 4, Method 2. Gradient information: 0.0-0.5 min, 22.5% MeCN; 0.5-15.5 min, ramped from 22.5% MeCN to 52.5% MeCN; 15.5-15.6 min, ramped from 52.5% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford: Compound 86

[0454] 3-ethyl-4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (14.7 mg, 31 pmol, 11 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0455] 1H NMR (500 MHz, DMSO) 5 8.41 - 8.35 (m, 2H), 8.21 - 8.16 (m, 2H), 7.81 (d, J = 11.0 Hz, 1H), 7.36 (s, 1H), 4.58 (q, J = 7.2 Hz, 2H), 3.36 - 3.28 (m, 3H), 1.51 (t, J = 7.2 Hz, 3H). Sulfone CH3 obscured by water peak, confirmed by HSQC.19F NMR (471 MHz, DMSO) 5 - 61.17, -133.62. MS: The product was analysed by UPLC (Method 1): m / z 455.0 [M+H]+(ES+); 499.1 [M-H]- (ES-), at 1.43 min, 98% purity 210-400nm. Compound 87

[0456] 1-ethyl-4-fluoro-8-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1H)-one (11.4 mg, 25 pmol, 9.2 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0457] 1H NMR (500 MHz, DMSO) 5 8.33 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 9.9 Hz, 1 H), 7.39 (s, 1 H), 4.86 (q, J = 7.2 Hz, 2H), 3.34 - 3.32 (m, 3H), 1 .65 (t, J = 7.2 Hz, 3H). Sulfone CH3 obscured by water peak, confirmed by HSQC.19F NMR (471 MHz, DMSO) 5 - 61.28, -129.26. MS: The product was analysed by UPLC (Method 1): m / z 454.9 [M+H]+(ES+); 499.1 [M-H+formic acid]' (ES-), at 1.40 min, 100% purity 210-400nm.Compounds 88 & 89 tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxochroman-2-yl)pyrrolidine-1-carboxylate

[0458] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (2.23 g, 99% Wt, 1 Eq, 10.3 mmol) and tert-butyl 3-formylpyrrolidine-1 -carboxylate (3.08 g, 1.5 Eq, 15.5 mmol) in EtOH (100 mL) at 50 °C was added pyrrolidine (931 pL, 1.1 Eq, 11.3 mmol) in one portion. The resultant solution was stirred at 50 °C for 8 h and then allowed to cool to rt. The reaction mixture was evaporated to dryness, diluted with EtOAc (100 mL) and washed with 50% brine (50 mL). The organic layer was collected and the aqueous layer extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-25% (3:1 , EtOAc / EtOH) / DCM to afford tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxochroman-2- yl)pyrrolidine-1 -carboxylate (3.31 g, 6.9 mmol, 67 %) as an orange foam, as a mixture of diastereoisomers.

[0459] MS: The product was analysed by UPLC (Method 1): m / z 296.6 [M-Boc+H]+(ES+) at 1.48 / 1.50 min, 83% purity 210-400nm. tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)pyrrolidine-1-carboxylate

[0460] To a solution of tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxochroman-2-yl)pyrrolidine-1- carboxylate (3.31 g, 83% Wt, 1 Eq, 6.95 mmol) in pyridine (47 mL) was added iodine (3.53 g, 2 Eq, 13.9 mmol). The reaction mixture was stirred at 110 °C for 3 h. Additional iodine (1 .76 g, 1 Eq, 6.95 mmol) was added and stirred at 110 °C for 30 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (3 times). EtOAc (300 mL) and sat. aq. sodium thiosulfate (200 mL) was added and the mixture was filtered through cotton wool. The organic layer was collected and washed with sat. aq. sodium thiosulfate (150 mL), brine (2 x 100 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2- yl)pyrrolidine-1 -carboxylate (1.196 g, 1.7 mmol, 25 %) as a brown solid.

[0461] MS: The product was analysed by LIPLC (Method 1): m / z 338.5 [M-tBu+H]+(ES+); 392.6 [M-H]- (ES-), at 1.38 min, 56% purity 210-400nm. tert-butyl 3-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)pyrrolidine-1 -carboxylate (7-amino-2- (1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)sulfamic acid

[0462] To a solution of tert-butyl 3-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)pyrrolidine- 1-carboxylate (1.196 g, 56% Wt, 1 Eq, 1.703 mmol) and triethylamine (8.5 mL, 36 Eq, 61 mmol) in THF (30 mL), EtOH (30 mL) and water (3.0 mL) was added sodium dithionite (592.9 pL, 5 Eq, 8.513 mmol). The reaction mixture was stirred at 60 °C for 90 min and then concentrated in vacuo. The residue was azeotroped with toluene (2 times) to afford the crude intermediate as a mixture of tert-butyl 3-(7,8-diamino-6-fluoro-4-oxo-4H-chromen-2-yl)pyrrolidine-1-carboxylate and (7-amino-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)sulfamic acid. The product was used without further purification.4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one trifluoroacetate

[0463] TFA (12 mL, 91 Eq, 0.16 mol) was added to a crude mixture of tert-butyl 3-(7,8-diamino- 6-fluoro-4-oxo-4H-chromen-2-yl)pyrrolidine-1 -carboxylate and (7-amino-2-(1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-6-fluoro-4-oxo-4H-chromen-8-yl)sulfamic acid (assuming 1.703 mmol) and the reaction mixture was stirred at 70 °C for 10 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (3 times) to give the crude product as the trifluoroacetate. The crude product was used for subsequent reactions without further purification. tert-butyl 3-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihvdrochromeno[7,8-d1imidazol-8- yl)pyrrolidine-1 -carboxylate

[0464] To a stirred suspension of 4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one, trifluoroacetate (assuming 1.703 mmol) in THF (28 mL) was carefully added sodium carbonate (15.0 g, 83.1 Eq, 142 mmol) portion wise. BOC2O (587 pL, 1.5 Eq, 2.555 mmol) was added and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through filter paper, washed with EtOAc and concentrated in vacuo to afford the crude product. The crude product was dried onto Celite andpurified by column chromatography on silica gel using a gradient of 0-20% (3:1, EtOAc / EtOH) / DCM to afford tert-butyl 3-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1 -carboxylate (450 mg, 0.96 mmol, 56 %) as a pale orange solid.

[0465] 1H NMR (500 MHz, DMSO) 5 7.62 (s, 1H), 6.41 (s, 1H), 3.76 (t, J = 9.0 Hz, 1 H), 3.52 (d, J = 10.2 Hz, 4H), 2.28 (s, 2H), 1.42 (d, J = 3.6 Hz, 9H). (one exchangeable proton not observed).19F NMR (471 MHz, DMSO) 5 -62.58, -129.50. MS: The product was analysed by UPLC (Method 1): m / z 386.3 [M-tBu+H]+(ES+); 440.2 [M-H]’ (ES-), at 1.54 min, 94% purity 210- 400nm. tert-butyl 3-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d1imidazol-8- yl)pyrrolidine-1 -carboxylate & tert-butyl 3-(4-fluoro-1-methyl-6-oxo-2-(trifluoromethyl)-1,6- dihvdrochromeno[7,8-d1imidazol-8-yl)pyrrolidine-1 -carboxylate

[0466] To a stirred solution of tert-butyl 3-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1 -carboxylate (220 mg, 94% Wt, 1 Eq, 469 pmol) and DIPEA (245 pL, 3 Eq, 1.41 mmol) in THF (6.0 mL) was added Mel (43.9 pL, 1.5 Eq, 703 pmol). The reaction was heated to 50 °C, after 16 h the reaction was allowed to cool and the reaction mixture was diluted with DCM (10 mL). The reaction was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-50% (3:1, EtOAc / EtOH)isohexane to afford tert-butyl 3-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1-carboxylate and tert-butyl 3-(4-fluoro-1- methyl-6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1- carboxylate (206 mg, 0.41 mmol, 88 %) as a mixture of regioisomers as a pale orange solid.

[0467] MS: The product was analysed by UPLC (Method 1): m / z 400.6 [M-tBu+H]+(ES+); 454.1 [M-H]’ (ES-), at 1.63 / 1.64 min, 91% purity 210-400nm.4- fluoro- 3-methyl-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol-6(3H)-one hydrochloride & 4-fluoro-1-methyl-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol- 6(1H)-one hydrochloride

[0468] To a solution of a mixture of tert-butyl 3-(4-fluoro-3-methyl-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1-carboxylate and tert-butyl 3-(4-fluoro-1- methyl-6-oxo-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1- carboxylate (206 mg, 91% Wt, 1 Eq, 412 pmol) in DCM (4 mL) was added HCI (3 M in CPME)(4.0 mL, 3.00 molar, 29 Eq, 12 mmol). The reaction mixture was stirred at rt for 16 h, then concentrated in vacuo to afford 4-fluoro-3-methyl-8-(pyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride and 4-fluoro-1-methyl-8- (pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride in quantitative yields (182 mg, 0.42 mmol) as a mixture of regioisomers as a grey solid.

[0469] MS: The product was analysed by LCMS (Method 3): m / z 356.0 [M+H]+(ES+); 354.0 [M- H]’ (ES-), at 1.15 / 1.20 min, 90% purity at 260nm + / - 80nm.4- fluoro- 3-methyl-8-(1-methylpyrrolidin-3-yl)-2-(trifluoromethyl)ch romenof7,8-d1imidazol-6(3H)- one (88) & 4-fluoro-1-methyl-8-(1-methylpyrrolidin-3-yl)-2-(trifluoromethyl)chromenof7,8- d1imidazol-6(1H)-one (89)88 89

[0470] To a stirred solution of 4-fluoro-1-methyl-8-(pyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride and 4-fluoro-1-methyl-8- (pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride (100 mg, 90% Wt, 1 Eq, 230 pmol) in THF (3.0 mL) was added aq. formaldehyde (37 wt%, stab. 10-15% MeOH) (171 pL, 37% Wt, 10 Eq, 2.30 mmol) and one drop of acetic acid. After 1 h at rt, sodium triacetoxyborohydride (146 mg, 3 Eq, 689 pmol) was added and the reaction stirred for 1 h. The reaction was quenched by dropwise addition of methanol (1 mL), dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford a mixture of isomers as an orange oil. The mixture (64 mg) was dissolved to 6.4 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a ChiralpaK IH 10 x 250mm, 5pm, flow rate 15 mL / min at 15% MeOH (0.3% AMMONIA), 85% CO2. The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 88

[0471] The racemate, 4-fluoro-3-methyl-8-(1-methylpyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (9.90 mg, 26 pmol, 11 %) as an orange solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0472] 1H NMR (500 MHz, DMSO) 5 7.68 (d, J = 11.4 Hz, 1 H), 6.42 (s, 1 H), 4.16 (s, 3H), 3.50 (ddt, J = 9.9, 7.8, 6.1 Hz, 1 H), 2.86 (dd, J = 9.3, 8.0 Hz, 1 H), 2.70 (dd, J = 9.4, 6.2 Hz, 1 H), 2.65 (td, J = 8.5, 5.7 Hz, 1 H), 2.58 (td, J = 8.3, 6.1 Hz, 1 H), 2.31 (s, 3H), 2.25 (dddd, J = 13.3, 9.9, 5.9, 3.9 Hz, 1 H), 2.03 (ddt, J = 12.5, 8.1 , 6.1 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -61.46, - 134.20. MS: The product was analysed by LIPLC (Method 4): m / z 370.4 [M+H]+(ES+) at 1.22 min, 98% purity 210-400nm.Compound 89

[0473] The racemate, 4-fluoro-1-methyl-8-(1-methylpyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (29.0 mg, 75 pmol, 33 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0474] 1H NMR (500 MHz, DMSO) 5 7.58 (d, J = 10.1 Hz, 1 H), 6.43 (s, 1 H), 4.35 (d, J = 1.0 Hz, 3H), 3.52 (dq, J = 10.1 , 6.6 Hz, 1 H), 2.79 (d, J = 6.9 Hz, 2H), 2.67 (td, J = 8.6, 5.4 Hz, 1 H), 2.54 (ddd, J = 9.0, 7.8, 6.5 Hz, 1 H), 2.31 (s, 3H), 2.25 (dddd, J = 13.0, 10.1 , 7.8, 5.4 Hz, 1 H), 2.10 (ddt, J = 12.7, 8.3, 6.2 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -61.60, -130.18. MS: The product was analysed by LIPLC (Method 4): m / z 370.4 [M+H]+(ES+) at 1.26 min, 96% purity 210- 400nm.Compounds 90 & 91 tert-butyl 3-(3-ethyl-4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromenof7,8-d1imidazol-8- yl)pyrrolidine-1 -carboxylate & tert-butyl 3-(1-ethyl-4-fluoro-6-oxo-2-(trifluoromethyl)-1 ,6- dihvdrochromenof7,8-d1imidazol-8-yl)pyrrolidine-1 -carboxylate

[0475] To a stirred solution of tert-butyl 3-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1 -carboxylate (220 mg, 94% Wt, 1 Eq, 469 pmol) and DIPEA (245 pL, 3 Eq, 1.41 mmol) in THF (6.0 mL) was added ethyl iodide (56.8 pL, 1.5 Eq, 703 pmol). The reaction was heated to 50 °C for 16 h. Additional ethyl iodide (56.8 pL, 1.5 Eq, 703 pmol) and DIPEA (81.6 pL, 1 Eq, 469 pmol) were added, and the reaction was heated to 50 °C for a further 16 h. The reaction was allowed to cool and the reaction mixture was diluted with DCM (10 mL). The reaction was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-50% (3:1 EtOAc / EtOH) / isohexane to afford a mixture of tert-butyl 3-(3-ethyl-4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1 -carboxylate and tert-butyl 3-(1-ethyl-4-fluoro-6-oxo-2- (trifluoromethyl)-l ,6-dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1-carboxylate (225 mg, 0.46 mmol, 97 %) as a mixture of regioisomers as a dark orange oil.

[0476] MS: The product was analysed by UPLC (Method 1): m / z 414.7 [M-tBu+H]+(ES+); 467.8 [M-H]- (ES-), at 1.72 / 1.76 min, 95% purity 210-400nm.3-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one hydrochloride & 1-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol- 6(1H)-one hydrochloride

[0477] To a solution of a mixture of tert-butyl 3-(3-ethyl-4-fluoro-6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1 -carboxylate and tert-butyl 3-(1-ethyl-4-fluoro- 6-oxo-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8-d]imidazol-8-yl)pyrrolidine-1-carboxylate (225 mg, 95% Wt, 1 Eq, 455 pmol) in DCM (4 mL) was added HCI (3 M in CPME) (4.0 mL, 26 Eq, 12 mmol). The reaction mixture was stirred at rt for 4 h, then concentrated in vacuo to afford 3- ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride and 1-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(1H)-one hydrochloride (171 mg, 0.41 mmol, 91 %) as a mixture of regioisomers as a grey solid.

[0478] MS: The product was analysed by UPLC (Method 1): m / z 370.2 [M+H]+(ES+) at 0.70 / 0.74 min, 98% purity 210-400nm.3-ethyl-4-fluoro-8-(1-methylpyrrolidin-3-yl)-2-(trifluoromethyl)chromenoR,8-d1imidazol-6(3H)-one (90) & 1-ethyl-4-fluoro-8-(1-methylpyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d1imidazol- 6(1H)-one (91)90 91

[0479] To a stirred solution of 3-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride and 1-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride (95 mg,98% Wt, 1 Eq, 0.23 mmol) in THF (3.0 mL) was added formaldehyde (37 wt% in water, stab. 10- 15% MeOH) (175 pL, 37% Wt, 10 Eq, 2.35 mmol) and one drop of acetic acid. After 1 h at rt sodium triacetoxyborohydride (150 mg, 3.1 Eq, 708 pmol) was added and the reaction stirred for 1 h. The reaction was quenched by dropwise addition of methanol (1 mL), dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford a mixture of regioisomers as a light yellow oil. The mixture (71 mg) was dissolved to 12 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a ChiralpaK IH, 10 x 250mm, 5pm, flow rate 20 mL / min at 15% MeOH (0.1% AMMONIA), 85% CO2. The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 90

[0480] The racemate, 3-ethyl-4-fluoro-8-(1-methylpyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (9.0 mg, 23 pmol, 9.8 %) as an orange solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0481] 1H NMR (500 MHz, DMSO) 5 7.70 (d, J = 11.2 Hz, 1 H), 6.42 (s, 1 H), 4.54 (q, J = 7.2 Hz, 2H), 3.50 (dq, J = 9.9, 6.5 Hz, 1 H), 2.87 (t, J = 8.7 Hz, 1 H), 2.70 (dd, J = 9.4, 6.3 Hz, 1 H), 2.64 (dd, J = 8.4, 5.8 Hz, 1 H), 2.59 (td, J = 8.2, 6.0 Hz, 1 H), 2.31 (s, 3H), 2.30 - 2.21 (m, 1 H), 2.03 (ddt, J = 12.4, 8.0, 6.0 Hz, 1 H), 1.48 (t, J = 7.1 Hz, 3H).19F NMR (471 MHz, DMSO) 5 -61.24, - 134.55. MS: The product was analysed by LIPLC (Method 4): m / z 384.4 [M+H]+(ES+) at 1.33 min, 96% purity 210-400nm.Compound 91

[0482] The racemate, 1-ethyl-4-fluoro-8-(1-methylpyrrolidin-3-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (28.4 mg, 70 pmol, 31 %) as an orange solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0483] 1H NMR (500 MHz, DMSO) 5 7.58 (d, J = 10.1 Hz, 1 H), 6.42 (s, 1 H), 4.77 (dp, J = 32.0, 7.4 Hz, 2H), 3.51 (ddt, J = 10.3, 7.9, 5.9 Hz, 1 H), 2.82 (dd, J = 9.4, 5.6 Hz, 1 H), 2.74 (t, J = 8.8 Hz, 1 H), 2.69 (td, J = 8.5, 4.9 Hz, 1 H), 2.55 - 2.46 (m, 1 H), 2.31 (s, 3H), 2.25 (dddd, J = 12.7, 10.2, 7.6, 4.9 Hz, 1 H), 2.09 (ddt, J = 13.0, 8.2, 6.7 Hz, 1 H), 1.53 (t, J = 7.1 Hz, 3H). (one signal obscured by solvent residual peak).19F NMR (471 MHz, DMSO) 5 -61.38, -130.16. MS: The product was analysed by LIPLC (Method 4): m / z 384.4 [M+H]+(ES+) at 1.36 min, 96% purity 210-400nm.Compounds 92 & 938-(1-acetylpyrrolidin-3-yl)-3-ethyl-4-fluoro-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one(92) & 8-(1-acetylpyrrolidin-3-yl)-1-ethyl-4-fluoro-2-(trifluoromethyl)chromeno[7,8-dlimidazol- 6(1H)-one (93)92 93

[0484] To a suspension of 3-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one hydrochloride and 1-ethyl-4-fluoro-8-(pyrrolidin-3-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride (75.0 mg, 98% Wt, 1 Eq, 181 pmol) and triethylamine (75.7 pL, 3.0 Eq, 543 pmol) in DCM (5 mL) was added acetyl chloride (19.3 pL, 1.5 Eq, 272 pmol) dropwise. The reaction mixture was stirred at rt for 2 h, and the solvent was removed in vacuo. The crude product was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to afford a mixture of isomers as a pale yellow oil. The mixture (54 mg) was dissolved to 4 mg / mL in MeOH with sonication, filtered and was then separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a ReproSil Chiral-JM, 10 x 250mm, 5pm, flow rate 20 mL / min at 20% MeOH, 80% CO2. The clean fractions were pooled, rinsed with MeOH, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in MeOH, transferred into final vials and evaporated on a Biotage V10 to afford:Compound 92

[0485] The racemate, 8-(1-acetylpyrrolidin-3-yl)-3-ethyl-4-fluoro-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (2.5 mg, 5.8 pmol, 3.2 %) as an off-white solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0486] 1H NMR (500 MHz, DMSO) 5 7.74 - 7.67 (m, 1 H), 6.46 (s, 0.5), 6.40 (s, 0.5H), 4.58 - 4.49 (m, 2H), 3.97 - 3.89 (m, 0.5H), 3.81 - 3.71 (m, 1 H), 3.71 - 3.64 (m, 1 H), 3.62 - 3.51 (m, 2H), 3.40 - 3.36 (m, 0.5H), 2.39 (m, 0.5H), 2.35 - 2.20 (m, 1 H), 2.19 - 2.08 (m, 0.5H), 2.01 (s, 1.5H), 1.99 (s, 1.5H), 1.51 - 1.44 (m, 3H). (NMR is a mixture of rotamers which do not resolve at 353K, represented by half integrals).19F NMR (471 MHz, DMSO) 5 -61.27, -61.32, -134.27, -134.33. MS: The product was analysed by LIPLC (Method 4): m / z 412.4 [M+H]+(ES+) at 1.21 min, 96% purity 210-400nm.Compound 93

[0487] The racemate, 8-(1-acetylpyrrolidin-3-yl)-1-ethyl-4-fluoro-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (8.1 mg, 19 pmol, 10 %) as an orange solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0488] 1H NMR (500 MHz, DMSO) 5 7.59 (d, J = 3.8 Hz, 0.5H), 7.57 (d, J = 3.8 Hz, 0.5H), 6.49 (s, 0.5H), 6.44 (s, 0.5H), 4.73 - 4.64 (m, 2H), 3.98 - 3.90 (m, 0.5H), 3.85 (dd, J = 11.6, 7.8 Hz, 0.5H), 3.71 (ddt, J = 11.8, 8.4, 4.8 Hz, 1 ,5H), 3.65 - 3.54 (m, 1 ,5H), 3.54 - 3.48 (m, 0.5H), 3.38 (d, J = 8.3 Hz, 0.5H), 2.41 (td, J = 11.1 , 6.7 Hz, 0.5H), 2.34 (ddt, J = 9.7, 7.1 , 3.5 Hz, 0.5H), 2.26 (dq, J = 12.4, 8.6 Hz, 0.5H), 2.15 (dq, J = 10.4, 7.2 Hz, 0.5H), 2.00 (s, 1.5H), 1.99 (s, 1.5H), 1.54 (app. q, J = 7.3 Hz, 3H). (NMR is a mixture of rotamers which do not resolve at 353K, represented by half integrals).19F NMR (471 MHz, DMSO) 5 -61.38, -61.39, -129.82, -129.87. MS: The product was analysed by LIPLC (Method 4): m / z 412.2 [M+H]+(ES+) at 1.17 min, 98% purity 210-400nm.Compounds 96 & 97 tert-butyl 4-(4-fluoro-6-oxo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-3,6-dihvdrochromenof7,8- d1imidazol-8-yl)piperidine-1-carboxylate & tert-butyl 4-(4-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)-1 ,6-dihvdrochromenof7,8-d1imidazol-8-yl)piperidine-1 -carboxylate

[0489] A solution of tert-butyl 4-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8- d]imidazol-8-yl)piperidine-1-carboxylate (200 mg, 94% Wt, 1 Eq, 413 pmol), DIPEA (320 pL, 4.45 Eq, 1.84 mmol) and 2,2,2-trifluoroethyl trifluoromethylsulfonate (200 pL, 3.36 Eq, 1.39 mmol) in DMF (2.50 mL) was heated by microwave irradiation at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with brine (3 x 20 mL). The organic layer was collected, dried over MgSC and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-20% (3:1 , EtOAc / EtOH) / DCM to afford a mixture of tert-butyl 4-(4-fluoro-6-oxo-3-(2,2,2-trifluoroethyl)- 2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)piperidine-1 -carboxylate & tert-butyl 4-(4-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1 ,6-dihydrochromeno[7,8-d]imidazol- 8-yl)piperidine-1 -carboxylate (149 mg, 0.27 mmol, 66 %) as a pale orange solid.

[0490] MS: The product was analysed by LCMS (Method 4): m / z 560.0 [M+Na]+(ES+); 536.0 [M-H]' (ES-), at 1.83 min, 98% purity at 260nm + / - 90nm.4-fluoro-8-(piperidin-4-yl)-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)chromenoR,8-d1imidazol- 6(3H)-one hydrochloride & 4-fluoro-8-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)chromeno[7,8-d1imidazol-6(1 H)-one hydrochloride

[0491] To a stirred solution of tert-butyl 4-(4-fluoro-6-oxo-3-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)piperidine-1 -carboxylate and tert-butyl 4-(4-fluoro-6-oxo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1,6-dihydrochromeno[7,8-d]imidazol- 8-yl)piperidine-1 -carboxylate (149 mg, 98% Wt, 1.00 Eq, 272 pmol) in DCM (2.00 mL) was added HCI (3 M solution in CPME) (1.00 mL, 11.0 Eq, 3.00 mmol) in one portion. The reaction mixture was stirred at rt for 4 h and then concentrated in vacuo to afford a mixture of 4-fluoro-8-(piperidin-4-yl)-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride and 4-fluoro-8-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride (129 mg, 272 pmol, 100 %) in quantitative yields, as a pale pink solid.

[0492] MS: The product was analysed by LCMS (Method 4): m / z 438.0 [M+H]+(ES+); 436.0 [M- H]’ (ES-), at 1.48 / 1.55 min, >99% purity at 260nm + / - 90nm.4-fluoro-8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)chromenoR,8- d1imidazol-6(3H)-one (96) & 4-fluoro-8-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)chromenoR,8-d1imidazol-6(1 H)-one (97)96 97A suspension of 4-fluoro-8-(piperidin-4-yl)-3-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride and 4-fluoro-8-(piperidin-4- yl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one hydrochloride (129 mg, 100% Wt, 1 Eq, 272 pmol) and formaldehyde (37 wt% in water) (105 pL, 5.18 Eq, 1.41 mmol) in THF (4.00 mL) was stirred at rt for 90 min. Sodium triacetoxyborohydride (150 mg, 2.6 Eq, 707 pmol) was added in one portion and the reaction mixture was stirred at rt for 1 h and then carefully quenched with MeOH (4 mL). The reaction mixture was concentrated in vacuo toafford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford a mixture of products as a pale orange solid. The mixture (116 mg) was dissolved to 21 mg / mL in MeOH with sonication, filtered and separated by chiral SFC on a Sepiatec with UV detection at 220 nm, 40 °C, 120 bar. The column was a Lux iC5 10 x 250mm, 5pm, flow rate 20mL / min at 40% MeOH (0.4% DEA), 60% CO2. The clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residues were re-dissolved in methanol, transferred into final vials and evaporated on a Biotage V10 to afford: Compound 96

[0493] 4-fluoro-8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (28.8 mg, 63 pmol, 23 %) as a tan solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0494] 1H NMR (500 MHz, DMSO) 5 7.83 (d, J = 11.3 Hz, 1H), 6.37 (s, 1H), 5.55 (q, J = 8.5 Hz, 2H), 2.88 (d, J = 11.6 Hz, 2H), 2.71 (tt, J = 11.8, 3.7 Hz, 1H), 2.20 (s, 3H), 1.98 (dt, J = 14.7, 10.0 Hz, 4H), 1.75 (qd, J = 12.5, 3.8 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -60.27 (q, J = 5.4 Hz), -69.96 (dq, J = 10.8, 5.4 Hz), -133.08 (q, J = 10.1 Hz). MS: The product was analysed by LIPLC (Method 2) m / z 452.0 [M+H]+(ES+); no ionisation (ES-), at 1.46 min, >99% purity 210- 400nm.Compound 97

[0495] 4-fluoro-8-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(1 H)-one (43.7 mg, 95 pmol, 35 %) as a tan solid. (Specific regioisomeric identity confirmed by 2D NMR)

[0496] 1H NMR (500 MHz, DMSO) 5 7.73 (d, J = 9.9 Hz, 1H), 6.45 (s, 1 H), 5.71 (q, J = 8.4 Hz, 2H), 2.90 (d, J = 11.2 Hz, 2H), 2.71 (t, J = 12.0 Hz, 1H), 2.20 (s, 3H), 2.01 - 1.88 (m, 4H), 1.75 (qd, J = 12.2, 3.7 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -60.42 (q, J = 5.8 Hz), -69.32 - -69.42 (m), -129.45 (d, J = 2.7 Hz). MS: The product was analysed by LIPLC (Method 2) m / z 452.0 [M+H]+(ES+); no ionisation (ES-), at 1.48 min, >99% purity 210-400nm.Compound 984-fluoro-8-(piperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one hydrochloride

[0497] HCI (3M in CPME) (773 pL, 3 molar, 10 Eq, 2.32 mmol) was added to a solution of tertbutyl 4-(4-fluoro-6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)piperidine-1- carboxylate (110 mg, 96% Wt, 1 Eq, 232 pmol) in DCM (3 mL). The reaction was stirred at roomtemperature for 3 h. The solvent was removed in vacuo to yield 4-fluoro-8-(piperidin-4-yl)-2- (trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride (106 mg, 0.23 mmol, 99 %) as a white solid.

[0498] MS: The product was analysed by LCMS (Method 4): m / z 356.0 [M+H]+(ES+); 354.0 [M- H]’ (ES-), at 0.67 min, 85% purity at 260nm + / - 80nm.4-fluoro-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromenor7,,8-d1imidazol-6(3H)-one (98)

[0499] Formaldehyde (37% w / w in water) (91 pL, 5.3 Eq, 1.2 mmol) was added to a suspension of 4-fluoro-8-(piperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one hydrochloride (106 mg, 85% Wt, 1 Eq, 230 pmol) in THF (6 mL). After 30 min, sodium triacetoxyborohydride (78 mg, 1.6 Eq, 0.37 mmol) was added. After 16 h, additional sodium triacetoxyborohydride (20 mg, 0.41 Eq, 94 pmol) was added, and the reaction was stirred for a further 3 h. The reaction was quenched by dropwise addition of methanol, dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-20% MeOH / DCM to afford 4-fluoro-8-(1- methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (38.0 mg, 0.10 mmol, 44%) as an off-white solid.

[0500] 1H NMR (500 MHz, MeOD) 5 7.38 (d, J = 10.6 Hz, 1H), 6.32 (s, 1H), 3.69 - 3.58 (m, 2H), 3.22 - 3.05 (m, 3H), 2.95 (s, 3H), 2.40 - 2.34 (m, 2H), 2.32 - 2.14 (m, 2H). (one exchangeable proton not observed).19F NMR (471 MHz, MeOD) 5 -64.89, -131.20. MS: The product was analysed by LCMS (Method 1): m / z 370.1 [M+H]+(ES+); 368.5 [M-H (ES-), at 0.60 min, 99% purity 210-400nm.Compound 99(E)-4-fluoro-3-(isopropylamino)-6-(1-(isopropylimino)ethyl)-2-nitrophenol

[0501] To a solution of 1-(4,5-difluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (1.00 g, 99% Wt, 1 Eq, 4.56 mmol) in MeCN (45 mL) was added isopropylamine (1.6 mL, 4.1 Eq, 19 mmol). The reaction mixture was heated to 50 °C for 30 min and then allowed to cool to rt. The reaction mixture was used in subsequent reactions without further purification.1-(5-fluoro-2-hydroxy-4-(isopropylamino)-3-nitrophenyl)ethan-1-one

[0502] To a solution of (E)-4-fluoro-3-(isopropylamino)-6-(1-(isopropylimino)ethyl)-2-nitrophenol (1.36 g, 100% Wt 1 Eq, 4.56 mmol) in MeCN (45 mL) was added aq. HCI (1 M) (0.91 g, 25 mL, 5.5 Eq, 25 mmol) at rt. The reaction mixture was heated to 70 °C and stirred for 2 h. The reaction was allowed to cool to rt and diluted with water (100 mL). The resultant precipitate was filtered off and dried in vacuo to afford the desired product 1-(5-fluoro-2-hydroxy-4- (isopropylamino)-3-nitrophenyl)ethan-1-one (948 mg, 3.7 mmol, 80 %) as an orange solid.

[0503] 1H NMR (500 MHz, DMSO) 5 13.75 (s, 1 H), 7.85 (d, J = 14.3 Hz, 1 H), 6.65 (d, J = 8.8 Hz, 1 H), 3.83 - 3.73 (m, 1 H), 2.52 (s, 3H), 1.18 (d, J = 6.3 Hz, 6H).19F NMR (471 MHz, DMSO) 5 -137.42. MS: The product was analysed by LCMS (Method 4): m / z 257.0 [M+H]+(ES+); 255.0 [M-H]' (ES-), at 0.60 min, 99% purity at 260nm + / - 80nm. tert-butyl 4-(6-fluoro-7-(isopropylamino)-8-nitro-4-oxochroman-2-yl)piperidine-1 -carboxylate

[0504] To a suspension of 1-(5-fluoro-2-hydroxy-4-(isopropylamino)-3-nitrophenyl)ethan-1-one (919 mg, 99% Wt, 1 Eq, 3.55 mmol) and tert-butyl 4-formylpiperidine-1 -carboxylate (1.06 g, 1.4 Eq, 4.97 mmol) in EtOH (20 mL) at 50 °C was added pyrrolidine (612 pL, 2.1 Eq, 7.46 mmol) in one portion. The resultant solution was stirred at 50 °C for 4 h, allowed to cool to rt and the solvent was removed in vacuo. The residue was redissolved in DCM / MeOH, dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-40% (3:1 , EtOAc / EtOH)isohexane then re-purified by column chromatography on silica gel using a gradient of 0-50% EtOAc / DCM to afford tert-butyl 4-(6-fluoro-7-(isopropylamino)-8-nitro-4- oxochroman-2-yl)piperidine-1-carboxylate (520 mg, 1.0 mmol, 28 %) as a dark red foam.

[0505] 1H NMR (500 MHz, DMSO) 5 7.47 (d, J = 13.1 Hz, 1 H), 6.49 (dd, J = 8.8, 2.8 Hz, 1 H), 4.42 (ddd, J = 12.9, 6.4, 2.8 Hz, 1 H), 3.97 (s, 2H), 3.75 (ddd, J = 20.4, 15.5, 10.0 Hz, 2H), 2.84 - 2.56 (m, 4H), 1.88 - 1.72 (m, 3H), 1.58 (d, J = 13.0 Hz, 1 H), 1.40 (s, 9H), 1.17 (dd, J = 7.5, 4.0 Hz, 6H).19F NMR (471 MHz, DMSO) 5 -134.48. MS: The product was analysed by LCMS (Method 4): m / z 352.2 [M-Boc+H]+(ES+); 450.2 [M-H]' (ES-), at 1.90 min, 87% purity at 260nm + / - 80nm. tert-butyl 4-(6-fluoro-7-(isopropylamino)-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1 -carboxylate

[0506] To a solution of tert-butyl 4-(6-fluoro-7-(isopropylamino)-8-nitro-4-oxochroman-2- yl)piperidine-1 -carboxylate (0.52 g, 87% Wt, 1 Eq, 1.0 mmol) in pyridine (10 mL) was added iodine (0.76 g, 3 Eq, 3.0 mmol). The reaction mixture was stirred at 110 °C for 4 h. Additionaliodine (0.25 g, 1 Eq, 1.0 mmol) was added, and the reaction heated for a further 2 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (3 times). EtOAc (150 mL) and sat. aq sodium thiosulfate (50 mL) were added and the mixture was filtered through cotton wool. The organic layer was collected and washed with sat. aq sodium thiosulfate (50 mL), brine (2 x 20 mL), dried over MgSCU and concentrated in vacuo to afford the crude product. The crude product was dried onto Celite and purified by column chromatography on silica gel using a gradient of 0-20% (3:1, EtOAc / EtOH) / DCM to afford tert-butyl 4-(6-fluoro-7- (isopropylamino)-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1-carboxylate (248 mg, 0.52 mmol, 52 %) as a pale orange foam.

[0507] 1H NMR (500 MHz, DMSO) 5 7.70 (d, J = 12.9 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1 H), 6.20 (s, 1 H), 4.07 - 3.99 (m, 2H), 3.79 (app. p, J = 6.3 Hz, 1 H), 3.29 (s, 1 H), 2.83 - 2.75 (m, 2H), 1.84 (d, J = 12.9 Hz, 2H), 1.48 - 1.43 (m, 2H), 1.41 (s, 9H), 1.20 (d, J = 6.3 Hz, 6H).19F NMR (471 MHz, DMSO) 5 -127.19. MS: The product was analysed by LCMS (Method 4): m / z 394.0 [M-tBu+H]+(ES+); 448.2 [M-H]’ (ES-), at 1.82 min, >99% purity at 260nm + / - 80nm. tert-butyl 4-(8-amino-6-fluoro-7-(isopropylamino)-4-oxo-4H-chromen-2-yl)piperidine-1- carboxylate

[0508] To a solution of tert-butyl 4-(6-fluoro-7-(isopropylamino)-8-nitro-4-oxo-4H-chromen-2- yl)piperidine-1 -carboxylate (248 mg, 95% Wt, 1 Eq, 524 pmol) and triethylamine (1.46 mL, 20 Eq, 10.5 mmol) in THF (4.99 mL), EtOH (4.99 mL) and water (499 pL) was added sodium dithionite (183 pL, 5 Eq, 2.62 mmol). The reaction mixture was stirred at 60 °C for 90 mins and then concentrated in vacuo. The residue was azeotroped with toluene (2 times) to afford the crude intermediate, which was used in subsequent reactions without further purification.4- fluoro- 3-isopropyl-8-(piperidin-4-yl)-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one

[0509] TFA (3.0 g, 2.0 mL, 50 Eq, 26 mmol) was added to a crude mixture of tert-butyl 4-(8- amino-6-fluoro-7-(isopropylamino)-4-oxo-4H-chromen-2-yl)piperidine-1 -carboxylate (220 mg, 1 Eq, 524 pmol) and (2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-7-(isopropylamino)-4-oxo- 4H-chromen-8-yl)sulfamic acid (262 mg, 1 Eq, 524 pmol) and the reaction mixture was stirred at 70 °C for 8 h. The crude product was purified by column chromatography on silica gel using a gradient of 0-10% (0.7 M Ammonia in MeOH) / DCM to afford the desired product. The product was dissolved in DCM (5 mL) and washed with sat. aq. NaHCOs (6 mL). The mixture was passed through a phase separator, the organic layer was collected and the aqueous wasextracted with DCM (5 mL). The mixture was passed through a phase separator and the combined organic extracts were concentrated in vacuo to afford 4-fluoro-3-isopropyl-8- (piperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol-6(3H)-one (113 mg, 0.240 pmol, 46 %) as a yellow solid.

[0510] 1H NMR (500 MHz, DMSO) 5 7.76 (d, J = 11.9 Hz, 1 H), 6.28 (s, 1 H), 5.06 (ddd, J = 9.3, 6.9, 3.6 Hz, 1 H), 3.07 - 3.05 (m, 2H), 2.84 (tt, J = 11.8, 3.7 Hz, 1 H), 2.64 (td, J = 12.1 , 2.5 Hz, 2H), 1.92 (d, J = 12.6 Hz, 2H), 1.70 - 1.57 (m, 8H).19F NMR (471 MHz, DMSO) 5 -73.42 (d, J = 8.0 Hz), -133.69. MS: The product was analysed by LCMS (Method 4): m / z 398.0 [M+H]+(ES+) at 1.58 min, 84% purity at 260nm + / - 80nm.4- fluoro- 3-isopropyl-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno(7,8-d1imidazol-6(3H)- one (99)

[0511] A solution of 4-fluoro-3-isopropyl-8-(piperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (55.0 mg, 99% Wt, 1 Eq, 116 pmol) and formaldehyde (37 wt% in water) (50.0 pL, 5.78 Eq, 671 pmol) in toluene (2.00 mL) was stirred at rt for 1 h. Sodium triacetoxyborohydride (73.0 mg, 2.96 Eq, 344 pmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with MeOH (2 mL) and then concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica using a gradient of 0-50% [(3:1 , EtOH / EtOAc)+ 2% NH4OH] / DCM to afford 4-fluoro-3-isopropyl-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8-d]imidazol- 6(3H)-one (49.0 mg, 0.11 mmol, 79 %) as a white solid. The product was further purified by preparative HPLC General procedure 4, Method 5. Gradient information: 0.0-0.5 min,35% MeCN; 0.5-10.5 min, ramped from 35% MeCN to 65% MeCN; 10.5-10.6 min, ramped from 65% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford:

[0512] 4-fluoro-3-isopropyl-8-(1-methylpiperidin-4-yl)-2-(trifluoromethyl)chromeno[7,8- d]imidazol-6(3H)-one (27.0 mg, 65 pmol, 47 %) as a white solid.

[0513] 1H NMR (500 MHz, DMSO, 353 K) 6 7.76 (d, J = 11.9 Hz, 1 H), 6.32 (s, 1 H), 5.05 (tt, J = 7.6, 3.8 Hz, 1 H), 2.89 (dt, J = 11.7, 3.4 Hz, 2H), 2.72 (tt, J = 11.7, 4.0 Hz, 1 H), 2.23 (s, 3H), 2.05(td, J = 11.7, 2.5 Hz, 2H), 1.98 (d, J = 12.8 Hz, 2H), 1.80 (qd, J = 12.0, 3.9 Hz, 2H), 1.65 (dd, J = 6.8, 1.8 Hz, 6H).1H NMR (500 MHz, DMSO, 298 K) 5 7.77 (d, J = 11.8 Hz, 1 H), 6.35 (s, 1 H), 5.01 (s, 1 H), 2.88 (d, J = 11.0 Hz, 2H), 2.71 (td, J = 11.7, 5.9 Hz, 1 H), 2.20 (s, 3H), 1.98 (td, J = 13.3, 10.2 Hz, 4H), 1.75 (qd, J = 12.3, 4.0 Hz, 2H), 1.62 (dd, J = 6.8, 1.7 Hz, 6H).19F NMR (471 MHz, DMSO) 5 -60.72, -119.98. MS: The product was analysed by LIPLC (Method 1): m / z 412.3 [M+H]+(ES+); no ionisation (ES-), at 0.88 min, >99% purity 210-400nm.Compound 100 tert-butyl 4-(7-amino-6-fluoro-8-nitro-4-oxochroman-2-yl)piperidine-1-carboxylate

[0514] To a suspension of 1-(4-amino-5-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (1.515 g, 98% Wt, 1 Eq, 6.933 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (2.095 g, 1.417 Eq, 9.823 mmol) in EtOH (35 mL) at 50 °C was added pyrrolidine (630 pL, 1.11 Eq, 7.67 mmol) in one portion. The resultant solution was stirred at 50 °C for 6 h and then allowed to cool to rt. The reaction mixture was diluted with EtOAc (70 mL) and washed with 50% brine (50 mL). The organic layer was collected and the aqueous was extracted with EtOAc (50 mL). The combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford tert-butyl 4-(7-amino-6-fluoro-8-nitro-4- oxochroman-2-yl)piperidine-1-carboxylate (2.758 g, 4.9 mmol, 71 %) as an orange foam.

[0515] 1H NMR (500 MHz, DMSO) 5 7.46 (d, J = 11.3 Hz, 1 H), 7.31 (br s, 2H), 4.41 (ddd, J = 13.2, 6.2, 2.9 Hz, 1 H), 4.04 - 3.91 (m, 2H), 2.78 (dd, J = 17.0, 13.2 Hz, 1 H), 2.83 - 2.53 (m, 2H), 2.58 (dd, J = 16.9, 2.9 Hz, 1 H), 1.89 - 1.77 (m, 2H), 1.65 - 1.54 (m, 1 H), 1.44 - 1.34 (m, 9H), 1.29 - 1.11 (m, 2H).19F NMR (471 MHz, DMSO) 5 -137.66. MS: The product was analysed by LCMS (Method 3): m / z 432.0 [M+Na]+(ES+); 408.0 [M-H]’ (ES-), at 1.56 min, 73% purity at 260nm + / - 80nm.4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1-carboxylate

[0516] A suspension of tert-butyl 4-(7-amino-6-fluoro-8-nitro-4-oxochroman-2-yl)piperidine-1- carboxylate (2.75 g, 73% Wt, 1 Eq, 4.90 mmol) and iodine (3.11 g, 2.5 Eq, 12.3 mmol) in pyridine (50.0 mL, 126 Eq, 618 mmol) was stirred at 110 °C for 8 h. Additional iodine (1.00 g, 0.804 Eq, 3.94 mmol) was added and stirred at 110 °C for 2 h and then allowed to cool to rt. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene. The residue was taken up in DCM (200 mL) and washed with sat. aq. sodiumthiosulfate (2 x 150 mL), sat. aq. NaHCOs (150 mL), brine (150 mL), dried over MgSC and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-5% MeOH / DCM to afford the desired product tert-butyl 4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1 -carboxylate (974 mg, 1.5 mmol, 31 %) which was contaminated with pyridine. The mixture was dissolved in ethyl acetate (30 mL) before being washed with aq. CuSCU solution (10%) (2 x 25 mL) and brine (30 mL). The organic layer was dried over MgSC , filtered and concentrated in vacuo to afford tert-butyl 4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2-yl)piperidine-1 -carboxylate (790 mg, 1.2 mmol, 25 %) as a brown gum.

[0517] MS: The product was analysed by UPLC (Method 1): m / z 325.2 [M-tBu+H]+(ES+); 406.3 [M-H]' (ES-), at 1.48 min, 64% purity 210-400nm.7-amino-6-fluoro-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride

[0518] To a stirred solution of tert-butyl 4-(7-amino-6-fluoro-8-nitro-4-oxo-4H-chromen-2- yl)piperidine-1 -carboxylate (790 mg, 64% Wt, 1 Eq, 1.24 mmol) in DCM (15 mL) was added HCI (3 M in CPME) (2.50 mL, 3.00 molar, 6.04 Eq, 7.50 mmol). The reaction mixture was stirred at rt for 18 h. The precipitate was collected by filtration, washing with DCM (20 mL) and the solid was dried in vacuo to afford a brown solid. The brown solid was triturated with MeCN (10 mL) before being filtered and washed with additional MeCN (2 mL). 7-amino-6-fluoro-8-nitro-2-(piperidin-4- yl)-4H-chromen-4-one hydrochloride (478 mg, 1.1 mmol, 90 %) was afforded as a brown solid.

[0519] MS: The product was analysed by UPLC (Method 1): m / z 308.0 [M+H]+(ES+); n / a [M-H]' (ES-), at 0.44 min, 80% purity 210-400nm.2-(1-acetylpiperidin-4-yl)-7-amino-6-fluoro-8-nitro-4H-chromen-4-one

[0520] A stirred suspension of 7-amino-6-fluoro-8-nitro-2-(piperidin-4-yl)-4H-chromen-4-one hydrochloride (475 mg, 80% Wt, 1 Eq, 1.11 mmol) and triethylamine (400 pL, 2.60 Eq, 2.87 mmol) in DCM (8 mL) and THF (8 mL) was added acetyl chloride (87.0 pL, 1.11 Eq, 1.22 mmol) in one portion. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with sat. aq. NaHCOs (20 mL) and the organic layer was collected. The aqueous was extracted with DCM (2 x 10 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica gel using a gradient of 0-4% MeOH / DCM toafford 2-(1-acetylpiperidin-4-yl)-7-amino-6-fluoro-8-nitro-4H-chromen-4-one (130 mg, 0.35 mmol, 32 %) as an orange solid.

[0521] 1H NMR (500 MHz, MeOD) 5 7.76 (d, J = 11.0 Hz, 1H), 6.24 (s, 1H), 4.68 - 4.61 (m, 1H), 4.08 - 4.02 (m, 1H), 3.00 - 2.90 (m, 1 H), 2.80 - 2.68 (m, 1H), 2.15 - 2.01 (m, 6H), 1.84 - 1.69 (m, 1 H), 1.69 - 1.58 (m, 1 H).19F NMR (471 MHz, DMSO) 5 -133.95. MS: The product was analysed by UPLC (Method 1): m / z 350.2 [M+H]+(ES+); 348.5 [M-H]’ (ES-), at 0.91 min, 97% purity 210-400nm8-(1-acetylpiperidin-4-yl)-4-fluoro-2-(trifluoromethyl)chromenof7,8-d1imidazol-6(3H)-one (100)

[0522] To a solution of 2-(1-acetylpiperidin-4-yl)-7-amino-6-fluoro-8-nitro-4H-chromen-4-one (120.0 mg, 1 Eq, 343.5 pmol) and triethylamine (720 pL, 15.0 Eq, 5.17 mmol) in EtOH (5 mL), THF (5 mL) and water (0.5 mL) was added sodium dithionite (250 mg, 4.18 Eq, 1.44 mmol) in one portion. The reaction mixture was stirred at 60 °C for 2 h and then concentrated in vacuo. The residue was azeotroped with DCM (2 x 10 mL) to afford the crude product as a mixture of 2-(1-acetylpiperidin-4-yl)-7,8-diamino-6-fluoro-4H-chromen-4-one and (2-(1-acetylpiperidin-4- yl)-7-amino-6-fluoro-4-oxo-...

Claims

CLAIMS1. A compound of Formula I or Formula II or a salt thereof,Formula I Formula IIWherein:3333is a single or double bond;Ri is selected from the group consisting of: Cl, F, Br, H, OH, O-alkyl (C1-C6), O-fluoroalkyl (CI- 06), alkyl (C1-C6), fluoroalkyl(C1-C6), NH2, NH-alkyl(C1-C6) N-alkyh (C1-C6), cycloalkyl (C3- C6), fluorocycloalkyl (C3-C6), CH2-cycloalkyl (C3-C6), and CHF-cycloalkyl (C3-C6);R2is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, O-alkyl (C1-C6), SMe, ON, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);Rs if present, when Y is selected from N or C, is selected from the group consisting of: H, alkyl(C1-C6), fluoroalkyl(C1-C6); cycloalkyl (C3-C6), alkyl (C1-C6)-OH, alkyl-(C1-C6)-OMe, alkyl-(C1-C6)-cycloalkyl (C3-C6) and deutereoalkyl (C1-C6);R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine, piperidine, or pyrrolidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, acyl, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyl2(C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2- heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl;Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN, cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6);X is independently selected from the group consisting of: N or C; andY is independently selected from the group consisting of: O, N, C, and S.

2. A compound of Formula III, or a salt thereof,Formula IIIWherein:3333is a single or double bond;Ri and R2 are independently selected from the group consisting of: OH, OMe, O-alkyl(C1-C6), O-fluoro alkyl(C1-C6), OiPr, SMe, SFs, alkyl(C1-C6), fluoro alkyl(C1-C6), pyrazole, methyl pyrazole, oxazole, imidazole, thiazole, triazole oxadiazole, and thiadiazole; where the heterocycles can be substituted with alkyl(C1-C3).R3 is selected from the group consisting of: alkyl(C1-C6), fluoro alkyl(C1-C6), Cl, F, I, Br, CN, H O-alkyl (C1-C6).R4 is selected from the group consisting of: semi-saturated or saturated cycloalkyls including bridged bicyclic or spirocyclic ring systems, unsaturated, semi-saturated or saturated heterocycloalkyls including bridged bicyclic or spirocyclic ring systems, or aryls, including but not limited to benzene, pyridine, pyrimidine, pyridazine or piperidine. In the instance that R4is an aryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl then the monocyclic ring may carry a 2, 3 or 4 position substituent from the list: H, CN, F, Cl, Br, OH, alkyl(C1-C6), fluoroalkyl (C1-C6), N-alkyh (C1-C6), NH-alkyl (C1-C6), NH-cycloalkyl (C3-C6) N-cycloalkyl (C3-C6), alkyl (C1-C6)-NH2, alkyl (C1-C6)-OH , CH2-N-Cycloalkyl (C3-C6), CH2-heterocycloalkyl(C1-C6), CH2N-Alkyl2(C1-C6), CH2NH-Alkyl (C1-C6), CH2N-cycloalkyl, and CH2N-fluorocycloalkyl.Rs is selected from the group consisting of: alkyl (C1-C6), fluoroalkyl (C1-C6), Cl, F, I, Br, H, OH, OMe, SMe, CN cycloalkyl (C3-C6), and fluorocycloalkyl (C3-C6).

3. A compound of Formula I, Formula II, or Formula III or as defined by any one of the compounds numbered 1 to 50 in Table 1.

4. A pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III, or a salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

5. A compound of Formula I, Formula II, or Formula III or a pharmaceutical composition comprising the compound of Formula I, Formula II, or Formula III, for use as a medicament.

6. A method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula I, Formula II, or Formula III.

7. A method of synthesizing a compound of Formula I, Formula II, or Formula III.

8. An intermediate formed in the method of synthesis of the compound of Formula I, Formula II, or Formula III.

Images