RSV INHIBITING SPIRO BEARING DERIVATIVES

Field of the Invention

The invention concerns compounds having antiviral activity, in particular having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment or prevention of respiratory syncytial virus infection.

Background

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Pneumoviridae, genus Orthopneumovirus together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.

Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.

Today only two drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue that provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. Synagis® (palivizumab a monoclonal antibody, is used for passive immunoprophylaxis. Although the benefit of Synagis® has been demonstrated, the treatment is expensive, requires parenteral administration and is restricted to children at risk for developing severe pathology.

Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. It would be particularly preferred to provide drugs against RSV replication that could be administered perorally. Compounds that exhibit anti-RSV activity are disclosed in WO-2014/031784, WO-2015/026792, WO-2016/138158 and WO2021/066922.

Detailed description of the Invention The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom wherein each of the groups is optionally substituted with one, two or three substituents R ⁶ , R ⁷ and R ⁸ each independently selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy;

C _3-6 cycloalkyl; C _3-6 cycloalkyloxy; polyhaloC _1-4 alkyl; polyhaloC _1-4 alkyl ; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl, imidazolyl, pyridinyl or benzothiophenyl, wherein the aromatic mono- or bicyclic ring is substituted with one, two or three substituents each independently selected from hydrogen, halo, C _1-6 alkyl or polyhaloC | .g alkyl ;

W is N or CR ⁹ wherein R ⁹ is halo;

R ¹ is C _1-4 alkyl, halo, hydroxy, amino, C _1-4 alkyloxy, polyhaloC _1-4 alkyloxy, C _1-4 alkyl -carbonyl - amino, C _1-4 alkyl-oxy-C _1-4 alkyl, C _1-4 alkylamino, polyhaloC _1-4 alkylamino, isoindolinedionyl, or C _1-4 alkyl substituted with amino or mono-or di( C _1-4 alkyl)amino;

X is O, C(=O), or CR ¹⁰ R ⁿ wherein R ¹⁰ and R ¹¹ are each independently hydrogen, C _1-4 alkyl, halo, hydroxy; or alternatively R ⁹ and R ¹⁰ are taken together to form C _3-6 cycloalkyl;

Y is CH ₂ or C(=O);

Z is CH ₂ ; when n = 1 then the -Y-Z- radical may form

R ² is hydrogen, halo, hydroxy, C _1-4 alkyl, or C _1-4 alkyloxy;

R ³ is C _1-4 alkyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, hydroxy, amino, C _1-4 alkyl-SO ₂ -amino, or C _1-4 alkyl-carbonyl-amino;

R ⁴ is hydrogen, halo, hydroxy, C _1-4 alkyl, or C _1-4 alkyloxy;

R ⁵ is hydrogen or C _3-4 alkyl; or a pharmaceutically acceptable addition salt thereof.

As used in the foregoing definitions :

- halo is generic to fluoro, chloro, bromo and iodo;

- C _1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1 -methylethyl, 2-m ethylpropyl and the like; and

- polyhaloC _1-4 alkyl is defined as polyhalosubstituted C _1-4 alkyl, in particular C _1-4 alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like

■ C _3-6 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

- -(C=O) or (CO) means carbonyl. The term “compounds of the invention” as used herein, is meant to include the compounds of formula (I), and the salts and solvates thereof.

As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

Hereinbefore and hereinafter, the terms “compound of formula (I)” and “intermediates of synthesis of formula (I)” are meant to include the stereoisomers thereof and the tautomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

The term “stereoisomers” also includes any rotamers, also called conformational isomers, the compounds of formula (I) may form.

Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

Some of the compounds according to formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above formula (I) are intended to be included within the scope of the present invention.

It follows that a single compound may exist in both stereoisomeric and tautomeric form.

Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term ‘hydrate’ is used when said solvent is water.

For the avoidance of doubt, compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound. Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such as deuterium, ¹³ C, ¹⁴ C, ¹⁴ N, ¹⁵ O or the like.

In an embodiment the present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom wherein each of the groups is optionally substituted with one, two or three substituents R ⁶ , R ⁷ and R ⁸ each independently selected from halo; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl;

C _3-6 cycloalkyloxy; polyhaloC _1-4 alkyl; polyhaloC _1-4 alkyloxy; or C _3-6 cycloalkyl substituted with halo; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic mono- or bicyclic ring selected from phenyl or indolyl, wherein the aromatic mono- or bicyclic ring is substituted with one substituent selected from hydrogen or halo;

W is N or CR ⁹ wherein R ⁹ is halo; R ¹ is C _1-4 alkyl, halo, hydroxy, amino, polyhaloC _1-4 alkyloxy, C _1-4 alkyl-carbonyl-amino, C _1-4 alkyl-oxy-C _1-4 alkyl, isoindolinedionyl, or C _1-4 alkyl substituted with di(C _1-4 alkyl)amino;

X is O, C(=O), or CR ¹⁰ R ⁿ wherein R ¹⁰ and R ¹¹ are each independently hydrogen, C _1-4 alkyl, halo, hydroxy; or alternatively R ⁹ and R ¹⁰ are taken together to form C _3-6 cycloalkyl;

Y is CH ₂ or C(=O);

Z is CH ₂ ; when n = 1 then the -Y-Z- radical may form

R ² is hydrogen;

R ³ is C _{1 -4} al kyl substituted with 1 substituent selected from hydroxy;

R ⁴ is halo;

R ⁵ is hydrogen; or a pharmaceutically acceptable addition salt thereof.

In one embodiment of the present invention, the compound of formula (I) is represented by formula (I-a) : wherein ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, n and m are as previously defined and R ⁶ and R ⁷ are each independently selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl;

C _3-6 cycloalkyloxy; polyhaloC _1-4 alkyl; polyhaloC _1-4 alkyloxy; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy.

In one embodiment of the present invention, the compound of formula (I) is represented by formula (I-b) :

wherein ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, n and m are as previously defined and R ⁶ and R ⁷ are each independently selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl;

C _3-6 cycloalkyloxy; polyhaloC _-4 alkyl; polyhaloC - alkyloxy; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy.

In one embodiment of the present invention, the compound of formula (I) is represented by formula (I-c) : wherein ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, n and m are as previously defined and R ⁶ and R ⁷ are each independently selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl;

C _3-6 cycloalkyloxy; polyhaloC _1-4 alkyl; polyhaloC _1-4 alkyloxy; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy.

In one embodiment of the present invention, the compound of formula (I) is represented by formula (I-d) : wherein ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, n and m are as previously defined and R ⁶ and R ⁷ are each independently selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl;

C _3-6 cycloalkyloxy; polyhaloC _1-4 alkyl; polyhaloC _1-4 alkyloxy; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy.

In one embodiment of the present invention, the compound of formula (I) is represented by formula (I-e) : wherein ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, n and m are as previously defined and R ⁷ is selected from halo; hydroxy; C _1-4 alkyl; C _1-4 alkyloxy; C _3-6 cycloalkyl; C _3-6 cycloalkyloxy; polyhaloC C _1-4 alkyl; polyhaloC _1-4 alkyloxy; C _1-4 alkyl substituted with hydroxy; or C _3-6 cycloalkyl substituted with halo or hydroxy.

A first group of compounds are compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), wherein ring B is phenyl or indolyl and said ring B is substituted with one, two or three substituents each independently selected from hydrogen, halo, C _1-6 alkyl or polyhaloC _1-6 alkyl.

A second group of compounds are compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), wherein ring B is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C _3-6 alkyl or polyhalo C _1-6 alkyl.

A third group of compounds are compounds of formula (I) wherein ring A is selected from the groups set forth below by removal of a hydrogen atom :

Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply : a) B is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C _3-6 alkyl or polyhaloC _1-6 alkyl; or b) B is phenyl substituted with halo; or c) B is 4-fluorophenyl; or d) B is indolyl; or e) R ² is hydrogen, R ³ is C _1-4 alkyl substituted with hydroxy, and R ⁴ is halo; f) R ⁵ is hydrogen; g) X is O, Y is CH ₂ , Z is CH ₂ , n is integer 1, and m is integer 0, 1 or 2; h) X is O, Y is CH ₂ , Z is CH ₂ , n is integer 1, and m is integer 1; i) X is CR ¹⁰ R ¹¹ , Y is CH ₂ , Z is CH ₂ , n is 1, and m is integer 0, 1 or 2; j) X is CR ¹⁰ R ¹¹ , Y is CH ₂ , Z is CH ₂ , n is 1, and m is 1; k) ring A is cinnoline optionally substituted with one substituent R ⁶ selected from C _1-4 alkyl; and l) ring A is quinoline optionally substituted with one substituent R ⁶ selected from polyhaloC C _{1- 4} alkyl.

General synthetic methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

In some embodiments, compounds of the formula (I) may be synthesized according to Scheme 1. In Scheme 1, the ring A, ring B, and substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y Z, and integers n and m are as defined for compounds of formula (I), or any variation thereof as described above.

The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

Particular examples are provided in the Example section below. It is understood that the schemes above may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials.

The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention. The in vitro antiviral activity against RS V of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. in Antiviral Research, 38, p. 31 - 42 (1998).

Additionally the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of formula (I), and another antiviral agent, in particular a RSV inhibiting compound.

In order to prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection.

For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient. Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the pharmaceutical compositions of the invention in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,1,6'-trichloro-4,1,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the said concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. The bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results. In the high- dosage formulations, stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like. Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume).

Combinations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intra-muscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.

In general it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections. Other antiviral compounds (b) to be combined with a compound of formula (I) for use in the treatment of RSV are RSV fusion inhibitors or RSV polymerase inhibitors. Specific antiviral compounds for combination with any of the compounds of formula (I) that are useful in the treatment of RSV are the RSV inhibiting compounds selected from ribavirin, sisunatovir, ziresovir, lumicitabine, presatovir, ALX-0171, MDT-637, BTA-9881, BMS-433771, YM-543403, A-60444, TMC-353121, RFI-641, CL-387626, MBX-300, 3-({5-chloro-l-[3-(methyl-sulfonyl)propyl]-1H-benzimidazol-2 - yl}methyl)-l-cyclopropyl-l,3-dihydro-2H-imidazo[4,5-c]pyridi n-2-one, 3-[[7-chloro-3-(2- ethylsulfonyl-ethyl)imidazo[l,2-a]pyridin-2-yl]methyl]-l-cyc lopropyl-imidazo[4,5-c]pyridin-2- one, and 3-({5-chloro-l-[3-(methyl-sulfonyl)propyl]-1H-indol-2-yl}met hyl)-l -(2,2,2- trifluoroethyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

Experimental part

General Information

NMR analysis

^X H NMR spectra were recorded on 1) a Bruker Avance DRX 400 spectrometer or Bruker Advance III 400 spectrometer or 2) a Bruker Avance 500 MHz spectrometer and c) Bruker Advance III 400 spectrometer.

NMR spectra were recorded at ambient temperature unless otherwise stated. Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS (δ = 0 ppm) on the scale, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintuplet, sex = sextuplet, m = multiplet, b = broad, or a combination of these), coupling constant(s) J in Hertz (Hz).

HPLC and LC-MS

The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow (expressed in mL/min; column temperature (T) in °C; Run time in minutes) from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time. . .) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (RT) and ions.

All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, “HSS” High Strength silica., “Q-Tof’ Quadrupole Time-of-flight mass spectrometers, “CLND”, ChemiLuminescent Nitrogen Detector, “ELSD” Evaporative Light Scanning Detector.

Description of SFC Methods

The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SEC -MS Methods (Flow expressed in mL/min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. “IPrNH ₂ ” means isopropylamine, “iPrOH means 2-propanol, “EtOH” means ethanol, min means minutes. Optical rotation

Optical rotations were measured on a Perkin Elmer 341 polarimeter and reported as follow [a] ¹ .

X is the wavelength of light used in nm (if the wavelength of light used is 589 nm, the sodium D line, then the symbol D is used) and T is the temperature in degree Celsius. The sign (+ or -) of the rotation is given. The concentration and the solvent of the sample are provided in brackets after the rotation. The rotation is reported in degrees and no units of concentration are given (it is assumed to be g/100 mL). Stereochemical configuration

The stereochemical configuration for some compounds has been designated as R or S (or *R or *S) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereospecifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. This means that the absolute stereoconfiguration of the stereocentre indicated by * is undetermined (even if the bonds are drawn stereospecifically) although the compound is enantiomerically pure at the indicated centre.

Abbreviations

8-Methoxy-3-methylquinoline-6-carboxylic acid 1

A mixture of 4-amino-3 -methoxybenzoate (3.0 g, 18.0 mmol), methacrylaldehyde (3.0 g, 43.0 mmol) and HC1 (12 M aq., 12 mL, 12.0 mmol) was stirred at 100°C for 5 h. The reaction mixture was cooled in an ice/water bath. The suspension was filtered off. The solid was purified by trituration with EtOAc and petroleum ether (1 :30, 10 mL) (twice), to afford 1 (600 mg, 15%) as a grey solid. 'H NMR (400 MHz, DMSO-d/6) 8 13.26 (s, 1H), 8.81 (d, J=2.20 Hz, 1H), 8.25 (d, J=0.88 Hz, 1H), 8.12 (d, J=1.54 Hz, 1H), 7.50 (d, J=1.76 Hz, 1H), 4.01 (s, 3H), 2.50 (s, 3H).

2 -Fluoro-8-m ethoxy-3 -methylquinoline-6-carboxylic acid 6

SOC1 (33.6 mL, 1.6 g/mL, 460 mmol) was added to a solution of 1 (25.0 g, crude) in CH3OH (300 mL) at 0°C. The reaction mixture was stirred at 80°C for 40 min. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (100 mL) and the pH of the solution was adjusted to pH 7-8 with NaHCO ₃ (sat., aq.). The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 5: 1 to 1 :2) to afford 2 (10 g, 37 %) as a brown solid.

The reaction was performed on two batches of 5.00 g of 2. m-CPBA (14.0 g, 64.9 mmol, 80% pure) was added to a solution of 2 (5.0 g, 22.0 mmol) in CH2Q2 (50 mL) at 0°C. The reaction mixture was stirred at rt for 12 h and concentrated to dryness under reduced pressure. The two batches were combined. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 10: 1 to 1 : 1) to afford 3 (5.1 g, 85%) as a brown solid.

A mixture of 3 (3.80 g, 15.4 mmol) and POCI3 (30.0 g, 196 mmol) was stirred at 95°C for 1 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (100 mL) and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 1 :0 to 1 : 1) to afford 4 (2.5 g, 61%) as a white solid.

Tetramethylammonium fluoride (1.8 g, 19.3 mmol) was added to a solution of 4 (2.5 g, 9.4 mmol) in anhydrous DMF (20 mL). The reaction mixture was stirred at rt for 24 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 1 :0 to 1 : 1) to afford 5 (1.8 g, 68%) as a yellow solid.

LiOH.H2O (612 mg, 14.6 mmol) was added to a solution of 5 (1.8 g, 7.2 mmol) in THF (12 mL) and H2O (6 mL) at 0°C. The resulting reaction mixture was stirred at rt for 2 h. The mixture was combined with another batch (1.3 g, 5.2 mmol), acidified to pH 5 with acetic acid and was concentrated to dryness under reduced pressure. The crude mixture was purified by preparative HPLC (Phenomenex Synergi Max-RP 250 x 50 mm x 10 pm, mobile phase gradient: 5% to 45% (v/v) water (0.225% TFA)-CH3CN). The product was suspended in water (50 mL). The mixture was frozen and lyophilized to dryness to give 6 (2.2 g, 72%) as a white solid.

'H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 13.28 (br s, 1H), 8.51 (d, J=10.1 Hz, 1H), 8.17 (d, J=1.3 Hz, 1H), 7.57 (d, J=1.3 Hz, 1H), 4.00 (s, 3H), 2.41 (s, 3H).

3-(Difluoromethyl)-8-methoxyquinoline-6-carboxylic acid 12

10 11 12

2,2,3-Tribromopropanal (18.0 g, 61.1 mmol) was added to a solution of methyl 4-amino-3- methoxybenzoate (10.0 g, 55.2 mmol) in AcOH (120 mL). The reaction mixture was stirred at 100°C for 1.5 h. The reaction mixture was concentrated to dryness under reduced pressure to afford 7 (18.0 g), which was used in the next step without further purification.

SOCh (8.0 mL, 1.6 g/mL, 110 mmol) was added to a solution of 7 in CH3OH (150 mL). The reaction mixture was stirred at 80°C for 1.5 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was triturated in EtOAc and CH3OH (8: 1, 100 mL) and the suspension was isolated via filtration. The filter cake was washed with EtOAc and CH3OH (8: 1, 2 x 50 mL) and dried under vacuum to afford 8.

A mixture of 8, potassium trifluoro(prop-l-en-2-yl)borate (7.6 g, 56.7 mmol), and K3PO4 (21.6 g, 102 mmol) in 1,4-dioxane (125 mL) and H2O (25 mL) was purged with N2 for 5 min. Pd(dtbpf)C12 (3.3 mg, 5.1 mmol) was added and the mixture was purged with N2 for another 5 min. The reaction mixture was stirred at 100°C for 1 h. The mixture was cooled to rt and the reaction was quenched with water (80 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 120 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by column chromatography (petroleum ether/EtOAc, gradient from 12: 1 to 1 :2) to afford 9 (5.0 g, 33% over 3 steps) as a yellow solid.

K2OSO ₄ «2H ₂ O (310 mg, 0.8 mmol) was added to a solution of 9 (5.0 g, 21 mmol) in 1,4-dioxane (50 mL) and H2O (50 mL). NaIO ₄ (14.0 g, 65.4 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction was poured into water (50 mL), and the aqueous phase was extracted with EtOAc (3 x 80 mL). The combined organic extracts were dried (Na ₂ SO ₄ ). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by column chromatography (petroleum ether/EtOAc, gradient from 10: 1 to 1 :2) to afford 10 (4.0 g, 79%) as a light yellow solid.

DAST (10.0 mL, 1.2 g/mL, 75.7 mmol) was added dropwise to a solution of 10 (4.0 g, 16.3 mmol) in CH2Q2 (50 mL) at 0°C under N2 atmosphere. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with CH2Q2 (20 mL) and poured into NaHCO ₃ (sat., aq., 50 mL). The layers were separated, and the aqueous phase was extracted with CH2Q2 (2 x 50 mL). The combined organic extracts were dried (Na ₂ SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 10:1 to 2:3) to afford 11 (2.1 g, 46%) as a yellow solid.

NaOH (630 mg, 15.7 mmol) was added to a solution of 11 (2.1 g, 7.89 mmol) in CH3OH (20 mL) and H ₂ O (4 mL). The reaction mixture was stirred at rt for 3 h and diluted with FLO (25 mL) and CH2Q2 (30 mL). The layers were separated, and the aqueous phase was diluted with HC1 (IN) until pH 6. The suspension was isolated via filtration and washed with H ₂ O (3 x 15 mL) and dried under vacuum. The residue was suspended in H ₂ O (20 mL) and the mixture was frozen and lyophilized to dryness to afford 12 (1.7 g, 85%) as a light yellow solid.

'H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 7.66 (s, 1H), 7.52 - 7.19 (m, 1H), 4.04 (s, 3H). 8-Methoxy-3-(trifluoromethyl)quinoline-6-carboxylic acid 15

I2 (5.3 g, 21 mmol), ethyl 8-methoxyquinoline-6-carboxylate (3.0 g, 14 mmol), t-BuOOH (14.0 g, 109 mmol, 70%), and CH3CN (50 mL) was added to a 100 mL round-bottomed flask. The resultant mixture was stirred at 80°C for 16 h. The reaction mixture was poured into sat. Na ₂ SO ₃ (200 mL), extracted with ethyl acetate (100 mL x 3), the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by column chromatography (petroleum ether/ethyl acetate, gradient from 1 :0 to 3: 1) to afford compound 13 as a white solid (3.5 g, 73%).

Methyl 2-chloro-2,2-difluoroacetate (5.9 g, 41 mmol) was added to a solution consisting of 13 (3.5 g, 10 mmol), KF (1.2 g, 21 mmol), Cui (3.9 g, 21 mmol) and dimethylacetamide (60 mL). The mixture was stirred at 130°C for 16 h before cooling to room -temperature. The reaction mixture was poured into sat. NaCl (200 mL), extracted with ethyl acetate (80 mL x 3), the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by flash column chromatography (petroleum ether/ethyl acetate, gradient from 1 :0 to 3: 1) to afford compound 14 (2.5 g, 73% purity, 63%).

LiOH.H ₂ O (551 mg, 13.1 mmol) was added into to a 0°C (ice/water) mixture consisting of 14 (2.5 g, 8.8 mmol), THF (15 mL) and H2O (15 mL). The resultant mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH 5 by addition of HC1. The mixture was concentrated to dryness under reduced pressure to afford the crude product, which was purified by preparative HPLC with a Phenomenex Synergi Max - RP 250*50 mm* 10 um (eluent: 25% to 55% (v/v) water (0.1% TFA)-ACN to afford title product. The product was suspended in water (50 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford compound 15 (910 mg, 39%). 8-Methoxy-3-methylcinnoline-6-carboxylic acid 21

A solution of methyl 4-amino-3-iodo-5 -methoxybenzoate (45.0 g, 146 mmol) and HC1 (6 M in H2O, 180 mL, 1.08 mol) was cooled in an ice bath (0°C) while a solution of NaNCL (12.5 g, 181 mmol) in cold water (50 mL) was added dropwise. The resulting solution of diazonium salt was stirred at 0°C for 30 min and was added to a solution of diethylamine (39 mL, 0.71 g/mL, 377 mmol) and K2CO3 (102 g, 734 mmol) in CH3CN and H2O (1 :2, 390 mL) dropwise. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was extracted with CH2Q2 (2 x 500 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 10: 1 to 8: 1) to afford 16 (53 g, 84%) as a yellow oil.

The reaction was performed on two batches of 25 g of 16. 16 (25 g, 63.9 mmol), trimethyl(prop- l-yn-l-yl)silane (57.5 g, 512 mmol), Cui (2.5 g, 13.1 mmol) and CsF (49.0 g, 323 mmol) were dissolved in DMF (250 mL) and CH3OH (50 mL). The mixture was purged with Ar for 5 min and Pd(PPh ₃ )2Cl ₂ (2.3 g, 3.2 mmol) was added. The mixture was purged with Ar for another 5 min and the reaction mixture was stirred at rt for 2 h. The two batches were combined and poured into a brine (500 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (50 mL), and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, 15: 1) to afford 17 (36 g, 88%) as a yellow oil.

HBr (48% aq., 54 mL, 1.4 g/mL, 477 mmol) was added to a solution of 17 (18.0 g, 59.3 mmol) in acetone (200 mL) at 0°C. The reaction mixture was stirred for 1.5 h with gradual warming to rt. Acetone was evaporated under reduced pressure and the residue was dissolved in CH2Q2 (250 mL). The solution was washed with NaHCCF (sat., aq., 150 mL). The aqueous layer was extracted with CH ₂ C1 (2 x 250 mL). The combined organic extracts were dried (Na ₂ SO ₄ ). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude product 18 (18 g, 88%) was used in the next step without further purification.

10% Pd/C (5.0 g) was added to a solution of 18 (20.0 g, 64.3 mmol) in CH ₃ OH (300 mL). The reaction mixture was stirred under H2 atmosphere (15 psi) at rt for 1.5 h. The reaction mixture was filtered through a pad of Celite and washed with CH3OH (300 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude 19 (13 g) was used in the next step without further purification.

MnCL (14.5 g, 167 mmol) was added to a solution of 19 (13 g, crude) in CH2CI2 (130 mL). The reaction mixture was stirred at 40°C for 1.5 h. The reaction mixture was filtered through a pad of Celite and washed with CH2Q2 (300 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 10: 1 to 0:1) to afford 20 (4.2 g, 25% over 2 steps) as a yellow solid.

NaOH (1.1 g, 26.3 mmol) was added to a solution of 20 (3.8 g, 16.4 mmol) in CH3OH (30 mL) and H2O (6 mL). The reaction mixture was stirred at rt for 1 h. CH3OH was evaporated under reduced pressure and the aqueous phase was washed with CH2Q2 (30 mL). The pH of the solution was adjusted to pH 2 with HC1 (2 M aq.). The suspension was isolated by filtration, the solid was washed with water (20 mL) and the solvent removed under reduced pressure. The product was triturated in EtOAc (10 mL), isolated by filtration, and washed with EtOAc (10 mL) before being dried under reduced pressure to afford 21 (3.0 g, 85%) as a brown solid.

'H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.59 (br. s., 1H), 8.17 - 8.11 (m, 2H), 7.57 - 7.53 (m, 1H), 4.12 (s, 3H), 2.88 (s, 3H).

8-(Cyclopropyloxy)-3-methylcinnoline-6-carboxylic acid 33

To a mixture of 4-bromo-2-cyclopropoxy-l -nitrobenzene (350 g, 1.59 mol) and cyclopropanol (166 g, 2.9 mol) in 2-MeTHF (3.5 L) was added NaH (60% pure, 114 g, 2.9 mol) at 0°C. The reaction mixture was stirred at rt for 16 h under N2 atmosphere. The reaction was quenched with NH4CI (sat., aq., 2.5 L). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with brine (2 L), and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 22 that was used without further purification in the next step.

To a solution of 22 (410 g, 1.6 mol) in AcOH (909 mL, 1.0 g/mL, 15.9 mol) in THF (2.5 L) was added Fe (444 g, 7.9 mol). The reaction mixture was stirred at 60°C for 2 h. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 90: 10 to 85: 15) to afford 23 (320.5 g, 84% over 2 steps) as yellow oil.

A mixture of 23 (320 g, 1.4 mol) and BOC2O (368 g, 1.7 mol) in CH3OH (3 L) was stirred at 75°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether/EtOAc, 20:1) to afford 24 (420.5 g, 91%) as light yellow solid.

Three reactions were carried out in parallel. To a mixture of 24 (110 g, 335 mmol), EtsN (136 g, 1.34 mol), and dppf (18.6 g, 33.5 mmol) in CH3OH (600 mL) and DMF (300 mL) was added Pd(OAc)2 (3.8 g, 16.7 mmol). The reaction mixture was stirred at 80°C for 16 h under CO atmosphere (50 psi). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with H ₂ O (4 L) and extracted with EtOAc (3 x 1.5 L). The combined organic extracts were washed with brine (2 L) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 90: 10) to afford 25 (210.5 g, 65%) as light yellow oil.

To a solution of 25 (211 g, 685 mmol) in CH2CI2 (1.6 L) was added TFA (588.1 g, 5.2 mol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (1 L) and NaHCO ₃ (aq., 1 L) was added. The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 500 mL). The combined organic extracts were washed with brine (1 L) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 26 (140.5 g, 97%) as yellow oil.

To a solution of 26 (140 g, 676 mmol) and NaHCCf (116 g, 1.4 mol) in CH2CI2 (1 L) was added IC1 (121 g, 743 mmol) in CH2Q2 (200 mL). The reaction mixture was stirred at rt for 1.5 h. The reaction was quenched with Na ₂ SO ₃ (sat., aq., 1 L). The layers were separated, and the aqueous phase was extracted with CH2Q2 (2 x 500 mL). The combined organic extracts were washed with brine (500 mL) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 90: 10) to afford 27 (103.5 g, 46%) as yellow solid.

To a solution of 27 (103 g, 310 mmol) in HC1 (6 M, 259 mL) in CH3CN (130 mL) was added a solution of sodium nitrite (32.1 g, 466 mmol) in H2O (65 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min to afford the corresponding diazonium salt. To a suspension of N- ethylethanamine (45.5 g, 621 mmol) and K2CO3 (215 g, 1.55 mol) in CH3CN (250 mL) and H2O (500 mL) was added the freshly prepared diazonium salt at 0 ~ 5°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with FLO (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (500 mL) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 90:10) to afford 28 (114.5 g, 83%) as yellow oil.

To a suspension of 28 (114 g, 273 mmol), CsF (207 g, 1.37 mol), Cui (10.4 g, 54.6 mmol) and Pd(PPh ₃ ) ₂ C12 (9.59 g, 13.7 mmol) in DMF (1 L) and CH3OH (200 mL) was added trimethyl(prop-l-ynyl)silane (61.3 g, 546 mmol) under N2 atmosphere. The reaction mixture was stirred at rt for 16 h under N2. The reaction mixture was filtered, and the filtrate was diluted with H2O (4 L). The aqueous phase was extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 L) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 90:10 to 85: 15) to afford 29 (89.3 g, 99%) as a yellow oil.

Three reactions were carried out in parallel. To a solution of 29 (89.2 g, 271 mmol) in acetone (550 mL) was added HBr (137 g, 812 mmol, 48% pure) at 0 ~ 10°C. The reaction mixture was stirred at 0°C for 1.5 h. The solids were isolated by filtration. The filter cake was dissolved in CH2Q2 (1.5 L) and Et ₃ N (75 mL), washed with H2O (500 mL), brine (500 mL), and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 30 (83.5 g, 91%) as a yellow solid.

Two reactions were carried out in parallel. A suspension of 30 (41.5 g, 123 mmol) and wet 10% Pd/C (6.1 g) in CH3OH (600 mL) was stirred at rt for 2.5 h under EE atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (CH2C12/Et2O) to afford 31 (24.5 g, 36%,) as a yellow solid.

A suspension of 31 (24.5 g, 94.1 mmol) and MnCL (40.9 g, 471 mmol) in CH2CI2 (300 mL) was stirred at rt for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 32 (23.5 g, 97%) as a yellow solid, which was used directly in the next step without purification.

To a solution of 32 (23.5 g, 90.9 mmol) in CH3OH (200 mL) and H2O (100 mL) was added KOH (6.1 g, 109 mmol). The reaction mixture was stirred at rt for 1.5 h. To the reaction mixture was added TFA until pH ~ 2. Precipitation occurred. The solids were isolated by filtration to afford 33 (16.5 g, 74%).

'H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.16 (d, J=1.54 Hz, 1H), 8.14 (s, 1H), 7.90 (d, J=1.54 Hz, 1H), 4.17-4.26 (m, 1H), 2.88 (s, 3H), 0.92-1.01 (m, 2H), 0.84-0.92 (m, 2H); LC-MS (method D): Rt = 1.07 min; mass calcd. for C13H12N2O3 244.0, m/z found 245.0 [M+H] ⁺ . 3-(Difluoromethyl)-8-methoxycinnoline-6-carboxylic acid 41

To a cooled solution of 4-bromo-2 -fluoroaniline (7.6 g, 40 mmol) in H2O (60 mL) was added HCI (cone., 10 mL) and NaNO ₂ (3.3 g, 48.0 mmol). After 20 min at 0°C, cone. HCI (13 mL) and NaBF4 (17.6 g, 160 mmol) were added. The mixture was stirred for 40 min and the diazonium salt was isolated by filtration, washed with H2O and Et20. A solution of diazonium salt in CH3CN (60 mL) was treated with ethyl 3 -morpholinoacrylate (3.3 g, 17.6 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 80:20) to afford 34 (4.5 g, 35%) as a yellow solid.

A mixture of 34 (7.5 g, 23.7 mmol) in concentrated sulfuric acid (100 mL) was heated at 100°C for 3 h. The mixture was cooled to 0°C, and the mixture was diluted with H2O (200 mL). The brown solid was removed by filtration, and the filtrate was extracted with CH2Q2 (4 x 600 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure to afford 35 (2.5 g, 39%) as a dark solid.

To a solution of 35 (13.0 g, 48.0 mmol) in DMF (150 mL) were added N,O-dimethylhydroxyl- amine hydrochloride (6.1 g, 62.4 mmol), HATU (21.9 g, 57.6 mmol) and DIPEA (18.6 g, 144 mmol). The reaction mixture was stirred at rt for 6 h. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with H ₂ O (2 x 300 mL) and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column _c hromatography (petroleum ether/EtOAc, gradient from 100:0 to 50:50) to afford 36 (7.0 g, 46%) as a yellow solid.

To a solution of 36 (7.0 g, 22.3 mmol) in THF (6 mL) at -78°C was added LiA1H ₄ (3.4 g, 89.1 mmol). The mixture was stirred at -78°C for 1 h. The mixture was warmed to rt and the reaction was quenched with Na2SO4.10 H2O (10 g). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure to afford 37 (5.4 g, 94%) as a yellow solid.

To a solution of 37 (5.4 g, 21.0 mmol) at 0°C in CH2CI2 (30 mL) was added DMP (13.4 g, 31.5 mmol). The reaction mixture was stirred at rt for 12 h. The solvent was removed under reduced pressure and the crude mixture was purified by silica column chromatography (CH ₂ C1 ₂ EtOAc, gradient from 100:0 to 95:5) to afford 38 (2.5 g, 47%) as a yellow solid.

To a solution of 38 (408.1 mg, 1.6 mmol) at -20°C in CH2CI2 (10 mL) was added DAST (1.03 g, 6.40 mmol). The reaction mixture was stirred at rt for 12 h. The reaction was quenched with H ₂ O (10 mL). The layers were separated, and the aqueous phase was extracted with CH ₂ C1 (3 x 20 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 70:30) to afford 39 (400 mg, 90%) as a yellow solid.

To a solution of 39 (2.3 g, 8.4 mmol) in CH3OH (60 mL) was added NaOMe (1.8 g, 33.5 mmol). The reaction mixture was stirred at rt for 6 h. The reaction was quenched with H2O (15 mL) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford a yellow solid (2 g).

To a solution of the residue in CH3OH (100 mL) were added Pd(dppf)C12.CH ₂ C12 (565 mg, 0.7 mmol) and EtsN (1.4 g, 13.8 mmol). The reaction mixture was stirred under CO atmosphere (1 atm) at 50°C for 1 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude mixture was purified by silica column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 70:30) to afford 40 (1.8 g, 80%) as a yellow solid.

To a solution of 40 (1.2 g, 4.5 mmol) in CH3OH (40 mL) were added NaOH (536 mg, 13.4 mmol) and FLO (4 mL). The reaction mixture was stirred at rt for 6 h. The reaction was neutralized with 1 N HC1 (20 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with brine and dried (Na2SO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by C-18 column chromatography (CH3CN/H2O (0.05% TFA), gradient from 85: 15 to 60:40) to afford 41 (1.02 g, 89%) as a yellow solid.

'H NMR (300 MHz, DMSO-tL) δ ppm 13.77 (brs, 1H), 8.77 (s, 1H), 8.40 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.59 (t, J=54.0 Hz, 1H), 4.18 (s, 3H).

2-Cyclopropyl-4-methoxybenzoUloxazole-6-carboxylic acid 46

To a solution of 4-bromo-2,6-dimethoxy aniline (6.5 g, 28 mmol), cyclopropanecarboxylic acid (4.8 g, 56 mmol), HATU (21.3 g, 56 mmol,) and DIPEA (7.2 g, 56 mmol) in DMF (150 mL). The resulting mixture was maintained under nitrogen and stirred at 70°C for 16 h. After cooling to rt, the reaction was quenched with water (800 mL). The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether, gradient from 0: 100 to 50:50) to afford the 42 as a yellow solid (7.0 g, 83%).

To a solution of compound 42 (7 g, 23.3 mmol) in DCM (100 mL) was added tribromoborane in DCM (23 mL) at -30°C. The resulting mixture was maintained under nitrogen and stirred at rt for 3 h. The reaction was poured into ice water (150 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by column chromatography (ethyl acetate/petroleum ether, gradient from 0: 100 to 40:60) to afford 43 as a light yellow solid (5.5 g, 82%).

To a solution compound 43 (5.5 g, 19.2 mmol) and 4-methylbenzenesulfonic acid (3.3 g, 19.2 mmol) in toluene (100 mL). The resulting mixture was maintained under nitrogen and stirred at 100°C for 16 h. After cooling to rt, the reaction was quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The residue obtained was purified by column chromatography (ethyl acetate/petroleum ether, gradient from 0: 100 to 50:50) to afford the 44 as a light-yellow oil (2.5 g, 49%).

A mixture of compound 44 (2.5 g, 9.3 mmol), Pd(dppf)C12.DCM (0.8 g, 0.9 mmol) and EtsN (1.9 g, 18.5 mmol) in MeOH (100 mL) was stirred overnight at 70°C under a CO (60 psi) atmosphere. The reaction was filtered and concentrated. The residue obtained was purified by column chromatography (ethyl acetate/petroleum ether, gradient from 0: 100 to 40:60) to afford 45 as a light-yellow oil (1.9 g, 83%).

To a solution of compound 45 (1.9 g, 7.7 mmol) in MeOH (20 mL) and NaOH (1.5 g, 38.4 mmol) in H2O (10 mL) was added. The resulting mixture was maintained under nitrogen and stirred at rt for 3 h. The MeOH was removed under vacuum and the pH value of the aqueous phase was adjusted to 5 with HC1 solution (1 M). The resulting mixture was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated. The crude was dissolved in DMF. The residue obtained was purified by C18 (0-40% MeCN/Water) to afford 46 as a light pink solid (1.2 g, 99%).

2-(l-Fluorocyclopropyl)-8-methoxyimidazolL2-a1pyridine-6- carboxylic acid 49

To a solution of 5-bromo-3-methoxypyridin-2-amine (5 g, 24.6 mmol) in EtOH (50 mL) was added ethanone-2-chloro-l-(l -fluorocyclopropyl) (3.4 g, 24.6 mmol). The RM was stirred at 120°C for 2 h in the microwave. The reaction was cooled to rt, and the solvent was removed under reduced pressure. The product was purified via silica column chromatography (heptane/EtOAc, gradient form 100:0 to 0: 100), followed by a 2nd column (dichloromethane/MeOH, gradient from 100:0 to 98:2) affording the desired product 47 as a pale yellow solid (1.9 g, 26%).

A 75 mL stainless steel autoclave was charged under N2 atmosphere with the 47 (1.9 g, 6.5 mmol), dppp (54 mg, 0.1 mmol), KOAc (1.3 g, 13.0 mmol), DIPEA (4.5 mL, 26.0 mmol), methanol (30 mL), and Pd(OAc)2 (15 mg, 0.07 mmol). The autoclave was sealed and pressurized to 25 bar CO and heated at 100°C for 18 h. The reaction vessel was cooled to rt and the solids were removed by filtration over packed celite and washed with methanol. The solvents of the filtrate were concentrated under reduced pressure and the crude was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100). The best fractions were pooled and the solvents were removed under reduced pressure to afford a white solid, 48 (1.3 g, 75%).

To a solution of compound 48 (1280 mg, 4.8 mmol) in water (5 mL) and 1,4-dioxane (20 mL) was added LiOH (233 mg, 9.7 mmol) at room temperature. The mixture was allowed to stir for 2 h at 50°C and overnight at room temperature. The mixture was evaporated, diluted with 20 mL water and neutralised with 1 N HC1 solution in water. After 2 h of stirring, the white precipitate was collected by filtration and dried overnight in vacuo to afford 49 (1.0 g, 84%).

2-16-Chl oro-3 -fluoro-2-(4-fluorophenyl)pyridin-4-yl1propan-2-ol 53

52 53

A mixture of methyl 2-chl oro-3 -fluoro-4-pyidine carboxylate (23.6 g, 124 mmol), 4-fluoro- phenylboronic acid (34.8 g, 249 mmol) and K3PO4 (79.3 g, 373 mmol) in 2-MeTHF (1.4 L) and H ₂ O (292 mL) was purged with N2. XPhos Pd G2 (7.7 g, 9.8 mmol) was added and the mixture was purged again with N2. The reaction mixture was stirred at 80°C for 4 h. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the organic phase was dried (MgSO ₄ ). The solids were removed by filtration and the solvent of the filtrate was removed under reduced pressure. The crude mixture was purified by silica column chromatography (heptane/EtOAc, gradient from 9: 1 to 1 :1) to afford 50 (28.5 g, 92%) as an off-white solid.

To a solution of 50 (4.0 g, 16.1 mmol) in anhydrous CH ₂ Q ₂ (160 mL) at 0°C was added m -CPBA (14.8 g, 64.2 mmol, 75% pure). The mixture was warmed to rt and stirred for 2 days. The reaction was quenched with NaOH (1 N, aq.). The organic phase was successively washed with NH4CI (sat., aq.), Na ₂ S ₂ O ₃ (10%, aq.), water and brine, and dried (MgSO ₄ ). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was purified by silica column chromatography (CH2Q2/CH3OH, gradient from 100:0 to 90: 10) to afford 51 (3.2 g, 75%) as a pale-yellow solid.

In a sealed tube, a solution of 51 (3.2 g, 12.1 mmol) in POCI3 (51 mL) was stirred at 80°C for 20 h. The reaction mixture was concentrated under reduced pressure. The brown residue was taken up in water and EtOAc and the mixture was basified with K ₂ CO ₃ powder. The layers were separated, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried (MgSO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure to afford 52 (3.3 g, 95%) as a brown solid.

The reaction was performed on 3 batches of 38.5 g. To a solution of 52 (38.5 g, 136 mmol) in THF (550 mL) was added CH ₃ MgBr (3.4 M in 2-MeTHF, 100 mL, 340 mmol) dropwise at -50°C. The mixture was stirred at rt for 2 h, then cooled to -50°C and treated with a NH ₁ C1 solution. The mixture was diluted with water and extracted with EtOAc (twice). The combined organic layers were dried (MgSO4). The solids were removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The crude mixture was triturated in water. The solid was collected by filtration and dried at 50-60°C to afford 53 (113.3 g, 99%) as a white solid.

[17282-04-1] 54

The three batches were in parallel. To a solution of compound [17282-04-1] (2.0 kg, 15.2 mol) in 2-MeTHF (16 L) to reaction still. The mixture was cooled to -78°C. The mixture was added LDA (2.0 M, 7.6 L) dropwise at -78°C under N2. After 1 h, acetone (1.8 kg, 30.4 mol) was added to the reaction. The brown mixture was stirred at -78°C for 2 h. The reaction mixture was warmed to 0°C. The mixture was slowly quenched with sat NH4CI aq. (10.0 L) keeping the temperature at 0-5°C. Then the reaction mixture was warmed to room temperature, and the layers were separated. The aqueous phase was extracted once more with EtOAc (8.00 L). The combined organic phases were washed with H ₂ O (20.0 L). Then the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40°C. The crude product 54 (6.2 kg, 54%, 76% purity) was used into the next step without further purification. The reaction was done in two batches in parallel. A mixture of compound 54 (3.1 kg, 13.1 mol, 80.0 % purity) and 2-MeTHF (10.3 L) was cooled to 5°C. TBDMS-OTf (5.2 kg, 19.6 mol) was added keeping the temperature between 5-25°C in a N2 atm. Then 2,6-dimethylpyridine (2.8 kg, 26.2 mol) was added slowly and keeping the reaction temperature between 5-25°C. The brown mixture was heated to 50°C and stirred for 10 h. The mixture was cooled to 25°C and then slowly quenched with water (10.0 L) while keeping the temperature below 30°C. Then the reaction was acidified with HC1 to pH 2-5, and the 2 layers were separated. The organic layer was washed with 10 % NaHCO ₃ aq. solution (8 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 100/0) to yield compound 55 (5.5 kg, 67%) as a yellow oil.

To a solution of TMPMgCl.LiCl (1 M in THF, 1.8 L, 1.8 mol) was added a solution of compound 55 (140 g, 460 mmol) in THF (280 mL) at 40°C under N2. After 1 h, a solution of I2 (350 g, 1.4 mol) in THF (1.2 L) was added at 0°C and stirred for 1 h. The mixture was stirred at rt for 30 min. The reaction mixture was quenched by addition of sat. Na2SO3 aq. solution (500 mL) while keeping the temperature below 25°C, then filtered and the mother liquid was diluted with H2O (1 L) and extracted with EtOAc (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate, gradient from 100:0 to 100: 1) to yield compound 56 (173 g, 42%) as a yellow solid.

Batch 1: To a solution of compound 56 (50.0 g, 116 mmol) and compound 57 [121505-93-9] (27.9 g, 127 mmol) in 2-MeTHF (500 mL) was added z-PrMgCl (2 M in THF, 232 mL, 464 mmol) at 10°C under N2. The yellow mixture was stirred at 15°C for 1 h. Batch 2: To a solution of compound 56 (150 g, 349 mmol) and compound 57 (83.7 g, 383 mmol) in 2-MeTHF (1.5 L) was added z-PrMgCl (2 M in THF, 698 mL, 1.4 mol) at 10°C under N2. The yellow mixture was stirred at 15°C for 1 h. The two batches were combined for one work-up and purification. The reaction mixture was quenched by addition of sat. NH4CI aq. solution (1 L) dropwise at 0-10°C, and then diluted with H2O (1 L) and extracted with EtOAc (5 L). The organic layer was separated, washed with brine (5 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate, gradient from 100:0 to 100:5). The crude product was triturated with petroleum ether at -70°C for 30 min. Compound 58 (40.0 g, 18%) was obtained after filtration as a white solid. 2-(6-(l -Ethoxy vinyl)-3-fluoro-2-(4-fluorophenyl)pyridin-4-yl)propan-2-ol 59

Into a 250 mL round bottom flask sparged with nitrogen and equipped with a magnetic stir bar was placed tributyl(l -ethoxy vinyl)stannane (12.7 mL, 1.1 g/mL, 38.8 mmol) and 53 (10 g, 35.2 mmol) in 1,4-dioxane (52 mL). Then, bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.8 mmol) was added and the reaction was stirred for 2 h at 100°C. The reaction mixture was filtered through packed celite, the solvent of the filtrate was removed under reduced pressure. Heptane was added and the formed white precipitate was isolated by filtration to afford 59 (10.2 g, 91%). 2-Bromo-l-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2- yl)pyridin-2-yl)ethan-l-one 60

Into a 250 mL round bottom flask with a magnetic stir bar was placed compound 59 (10.2 g, 31.9 mmol) in THF (65 mL) and water (5 mL). At 0°C, NBS (6.3 g, 35.1 mmol) was added. The reaction mixture was allowed to reach rt and stirred for 5 h. The mixture was quenched with sat. aq. NaHCO ₃ and the product was extracted with Me-THF. The organic layer was separated, dried (MgSCL), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 50:50). The product fractions were collected and concentrated in vacuo to become compound 60 (8.3 g, 70%) as a white solid.

A-(2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl )pyridin-2-yl)-2-oxoethyl)-A- formylformamide 61

Compound 60 (8.3 g, 22.4 mmol) was dissolved in dry ACN (162 mL) and diformylimide sodium salt (6.4 g, 67.3 mmol) was added to the reaction mixture. The mixture was stirred at rt for 16 h. The mixture was diluted with Me-THF and washed with saturated NaHCO ₃ aqueous solution. The organic layer was dried over MgSCL, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 50:50). The product fractions were collected and concentrated in vacuo to become compound 61 (7.5 g, 92%) as an oil.

2-Amino-l-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan -2-yl)pyridin-2-yl)ethan-l-one hydrogen chloride 62

A flask was charged with compound 61 (7.5 g, 20.7 mmol) in EtOH (90 mL). HCI (37% in H2O) (25.5 mL, 1.2 g/mL, 310.5 mmol) was added and the mixture wat stirred at 50°C for 1 h. The mixture was cooled to rt and concentrated in vacuo. The product was triturated in diethyl ether, filtered off and dried to become compound 62 (3 g, 42%) as a white solid. A-(2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)py ridin-2-yl)-2-oxoethyl)-8- methoxy-3-methylcinnoline-6-carboxamide 63 A tube was charged with 21 (46.9 mg, 0.2 mmol) in dry DMF (2 mL). HATU [148893-10-1]

(111.5 mg, 0.3 mmol) was added and the mixture was stirred at rt for 5 min. Compound 62 (67 mg, 0.2 mmol) was added to the reaction mixture and then DIPEA (0.1 mL, 0.9 g/mL, 0.7 mmol) was added dropwise to the reaction mixture. The mixture was further stirred at rt for 30 min. The mixture was poured out in ice water and extracted with Me-THF. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/(EtOAc/EtOH (3: 1)), gradient from 100:0 to 40:60). The product fractions were collected and concentrated in vacuo to become compound 63 (60 mg, 61%).

Compounds (65), (66), (67) and (68) were prepared analogously by reacting compound (62) respectively with compound (33), 3-chloro-8-methoxy-6-quinolinecarboxylic acid, compound (49) and compound (1).

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-l,3-dioxolan-2- yl)methyl)-8-m ethoxy-3 -methylcinnoline-6-carboxamide 64 Compound 63 (100 mg, 0.2 mmol), ethylene glycol [107-21-1] (1.2 mL, 1.1 g/mL, 21.7 mmol) and -toluenesulfonic acid monohydrate [6192-52-5] (15 mg, 0.08 mmol) were mixed in a flask under N2 atmosphere and the reaction mixture was stirred at 100°C for 16 h. The mixture was diluted with EtOAc and washed with Na2COs 1 M (aq. solution). The aqueous layer was extracted once more time with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude, which was purified by silica column chromatography (DCM/MeOH, gradient from 100:0 to 98:2). The desired fractions were joined and evaporated to dryness to yield compound 64 (45 mg, 40%) as a yellowish powder.

NMR: 1H NMR (400 MHz, DMSO) d 8.77 (t, J = 6.2 Hz, 1H), 7.98 - 7.92 (m, 3H), 7.87 (d, J = 5.5 Hz, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.34 (t, J = 8.9 Hz, 2H), 5.64 (s, 1H), 4.16 - 4.11 (m, 2H), 4.09 (s, 3H), 4.01 (d, J = 6.1 Hz, 2H), 4.00 - 3.95 (m, 2H), 2.87 (s, 3H), 1.52 (s, 6H)

LCMS: Rt 3.07 min, 96%, MW: 550.2, 551 [M+H] ⁺ , Method E

MP: 169.8°C (Mettler Toledo MP50)

Following compounds were synthesized using the same method : 3-Chloro-A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxyprop an-2-yl)pyridin-2-yl)-L3- dioxolan-2-yl)methyl)-8-methoxyquinoline-6-carboxamide 70

A reaction vessel was charged with compound 66 (48 mg, 0.09 mmol), trimethyl orthoformate [149-73-5] (20 pL, 1 g/mL, 0.2 mmol), HC1 (37% in H ₂ O) [7647-01-0] (40 pL, 1.18 g/mL, 0.5 mmol) in dry ethylene glycol [107-21-1] (2 mL, 1.114 g/mL, 36 mmol). The mixture was heated at 100°C for 2 h. The mixture was cooled and diluted with Me-THF. The mixture was washed with sat. Na ₂ CO3 solution. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XB ridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again. The product was dried and triturated in DIPE, filtered off and dried under vacuum to become compound 70 (26 mg, 52%) as a white solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.52 (s, 6 H) 3.89 - 4.06 (m, 1 H) 3.94 - 4.05 (m, 6 H) 4.10 - 4.18 (m, 2 H) 5.64 (s, 1 H) 7.33 (t, J=8.4 Hz, 2 H) 7.52 (d, J=1.5 Hz, 1 H) 7.88 (d, J=5.5 Hz, 1 H) 7.93 (d, J=1.5 Hz, 1 H) 7.96 (dd, J=7.5, 5.7 Hz, 2 H) 8.53 (d, J=2.6 Hz, 1 H) 8.65 (t, J=6.1 Hz, 1 H) 8.87 (d, J=2.4 Hz, 1 H)

LCMS: Rt 1.06 min, 100%, MW: 569.2, 570 [M+H] ⁺ , Method A

Following compounds were synthesized using the same method:

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-4-methyl-L3- dioxolan-2-yl)methyl)-8-methoxy-3-methylquinoline-6-carboxam ide 73

A reaction vessel was charged with compound 68 (150 mg, 0.3 mmol), trimethyl orthoformate (37.8 pL, 1 g/mL, 0.3 mmol), HCI (37% in H2O) (118.9 pL, 1.2 g/mL, 1.4 mmol) in propylene glycol (2.4 mL, 1 g/mL, 31.3 mmol). The mixture was heated at 100°C for 2 h. The mixture was cooled and diluted with water. The mixture was basified with Na ₂ CO Ns aanNdO then extracted with

Me-THF (2x). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0:100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 73 (90 mg, 56%) as a white solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.21 - 1.31 (m, 3 H) 1.53 (s, 6 H) 2.49 (br s, 3 H) 3.40 - 3.64 (m, 1 H) 3.95 - 4.08 (m, 5 H) 4.09 - 4.34 (m, 1 H) 4.19 - 4.54 (m, 1 H) 5.60 - 5.65 (m, 1 H) 7.34 (t, J=8.9 Hz, 2 H) 7.39 - 7.49 (m, 1 H) 7.82 - 7.88 (m, 1 H) 7.88 - 7.94 (m, 1 H) 7.94 - 8.01 (m, 2 H) 8.03 - 8.10 (m, 1 H) 8.52 - 8.63 (m, 1 H) 8.73 - 8.79 (m, 1 H)

SFC: (Rt 3.18 min 18% isomer 1), (Rt 3.51 min 32% isomer 2), (Rt 3.57 min 16% isomer 3), (Rt 3.81 min 34% isomer 4), MW: 563.2, Method SFC F

LCMS: Rt 1.04 min, 100%, MW: 563.2, 564 [M+H] ⁺ , Method A

The enantiomers of 73 (76 mg, 0.1 mmol) was separated by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) followed by a second Prep SFC (Stationary phase: Chiralcel Diacel IC 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) to yield compound 74 (15.6 mg, 10%), compound 75 (14.1 mg, 9%), compound 75 (16.4 mg, 10%), and compound 76 (10.5 mg, 7%).

SFC: Rt 3.20 min, 100%, MW: 563.2, Method SFC F

LCMS: Rt 1.96 min, 100%, MW: 563.2, 564 [M+H] ⁺ , 562 [M-H]’, Method H

SFC: Rt 3.79 min, 100%, MW: 563.2, Method SFC F

LCMS: Rt 1.97 min, 100%, MW: 563.2, 564 [M+H] ⁺ , 562 [M-H]’, Method H

SFC: Rt 3.56 min, 100%, MW: 563.2, Method SFC F

LCMS: Rt 1.92 min, 100%, MW: 563.2, 564 [M+H] ⁺ , 562 [M-H]’, h SFC: Rt 3.50 min, 100%, MW: 563.2, Method SFC F

LCMS: Rt 1.93 min, 100%, MW: 563.2, 564 [M+H] ⁺ , 562 [M-H]’, Method H

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-13-dioxan-2- yl)methyl)-8-methoxy-3-methylcinnoline-6-carboxamide 78

A reaction tube was charged with compound 63 (60 mg, 0.1 mmol), trimethoxymethane [149-73- 5] (15.2 pL, 1 g/mL, 0.1 mmol), HC1 (37% in H ₂ O) (29.3 pL, 1.2 g/mL, 0.4 mmol) in 1,3- propanediol (1 mL). The mixture was heated at 100°C for 2 h. The mixture was cooled and diluted with Me-THF. The mixture was washed with sat. Na ₂ CO3 solution. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again. The product was dried and triturated in DIPE, filtered off and dried under vacuum to become compound 78 (10 mg, 15%) as a yellow solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.37 - 1.43 (m, 1 H) 1.46 (s, 6 H) 1.93 - 2.07 (m, 1 H) 2.86 (s, 3 H) 3.68 (d, J=6.4 Hz, 2 H) 3.76 - 3.85 (m, 2 H) 3.97 (br d, J=8.1 Hz, 2 H) 4.04 (s, 3 H) 5.58 (s, 1 H) 7.28 (t, J=8.9 Hz, 2 H) 7.34 (d, J=1.3 Hz, 1 H) 7.70 (d, J=1.3 Hz, 1 H) 7.78 - 7.82 (m, 2 H) 7.84 - 7.92 (m, 2 H) 8.61 (t, J=6.3 Hz, 1 H) LCMS: Rt 8.49 min, 100%, MW: 564.2, 565 [M+H] ⁺ , Method B

A-(((3aR,6aS)-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxy propan-2-yl)pyridin-2- yl)tetrahydrofuror3,4-dirU1dioxol-2-yl)methyl)-8-methoxy-3-m ethylquinoline-6-carboxamide 79

A microwave vial was charged with compound 68 (100 mg, 0.2 mmol), 1,4-anhydroerythritol (1 mL), trimethyl orthoformate (24.4 pL, 1 g/mL, 0.2 mmol) and HC1 (37% in H2O) (39 pL, 1.2 g/mL, 0.5 mmol). The vial was capped and was heated at 80°C for 48 h. H2SO4 (15.5 pL, 1.8 g/mL, 0.3 mmol) and toluene (0.7 mL) were added, and the mixture was heated at 120°C for 3 h. The mixture was cooled and diluted with Me-THF. The mixture was washed with sat. NaHCCF solution. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again. The product was triturated in DIPE, filtered and dried under vacuum to become compound 79 (31 mg, 28%) as a white solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.54 (s, 6 H) 2.45 - 2.49 (m, 3 H) 3.32 - 3.48 (m, 2 H) 3.90 - 4.11 (m, 7 H) 5.12 (s, 2 H) 5.58 - 5.66 (m, 1 H) 7.34 (td, J=8.9, 1.8 Hz, 2 H) 7.39 - 7.47 (m, 1 H) 7.83 - 7.91 (m, 1 H) 7.91 - 8.02 (m, 3 H) 8.02 - 8.07 (m, 1 H) 8.55 (t, J=6.4 Hz, 1 H) 8.76 (d, J=2.2 Hz, 1 H)

SFC: (Rt 3.78 min 62% isomer 1), (Rt 4.60 min 38% isomer 2), MW: 591.2, Method SFC G LCMS: Rt 1.00 min, 100%, MW: 591.2, 592 [M+H] ⁺ , Method A

The enantiomers of 79 (26 mg, 0.04 mmol) was separated by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) to yield compound 80 (15 mg, 13%) and compound 81 (8 mg, 7%).

SFC: Rt 3.77 min, 100%, MW: 591.2, Method SFC G

LCMS: Rt 1.93 min, 100%, MW: 591.3, 592 [M+H] ⁺ , 590 [M-H]’ , Method H SFC: Rt 4.60 min, 100%, MW: 591.2, Method SFC G

LCMS: Rt 1.92 min, 100%, MW: 591.2, 592 [M+H] ⁺ , 590 [M-H]’, Method H

A-((4-(chloromethyl)-2-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)-13- dioxolan-2-yl)methyl)-8-methoxy-3-methylquinoline-6-carboxam ide 82

A reaction vessel was charged with compound 68 (400 mg, 0.8 mmol), trimethyl orthoformate (97.7 pL, 1 g/mL, 0.9 mmol), HC1 (37% in H2O) (155.9 pL, 1.2 g/mL, 1.9 mmol) in 3-chloro- 1,2-propanediol (3 mL). The mixture was heated at 100°C for 5 h. The mixture was cooled and diluted with water. The mixture was basified with Na2COs and then extracted with Me-THF (2x). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 82 (290 mg, 64%).

7V-((4-((dimethylamino)methyl)-2-(5-fluoro-6-(4-fluorophe nyl)-4-(2-hydroxypropan-2- yl)pyridin-2-yl)-13-dioxolan-2-yl)methyl)-8-methoxy-3-methyl quinoline-6-carboxamide 83

A reaction tube was charged with compound 82 (290 mg, 0.2 mmol), dimethylamine (2 M solution in THF) (1.2 mL, 2.4 mmol) in dry DMF (5 mL) and then capped. The mixture was heated at 120°C for 16 h. The mixture was concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 83 (40 mg, 27%) as a yellow solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.50 - 1.56 (m, 6 H) 2.08 - 2.18 (m, 6 H) 2.32 - 2.47 (m, 2 H) 3.56 - 3.84 (m, 1 H) 3.94 - 4.03 (m, 5 H) 4.04 - 4.36 (m, 1 H) 4.20 - 4.54 (m, 1 H) 5.60 - 5.67 (m, 1 H) 7.30 - 7.38 (m, 2 H) 7.38 - 7.47 (m, 1 H) 7.83 - 8.00 (m, 4 H) 8.03 - 8.09 (m, 1 H) 8.53 - 8.64 (m, 1 H) 8.74 - 8.79 (m, 1 H)

LCMS: Rt 0.93 min, 96%, MW: 606.3, 607 [M+H] ⁺ , Method A A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)-4-(methoxymethyl)-

13-dioxolan-2-yl)methyl)-8-methoxy-3-methylquinoline-6-ca rboxamide 84

A microwave vial was charged with compound 68 (150 mg, 0.3 mmol), 3 -methoxy- 1,2- propanediol (274.6 pL, 1.1 g/mL, 2.8 mmol) in dry toluene (1 mL). H2SO4 (23.3 pL, 1.8 g/mL, 0.4 mmol) was added and the vial was capped. The mixture was heated at 120°C for 4 h. The mixture was cooled and diluted with Me-THF. The mixture was washed wit sat. NaHCCF solution. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XB ridge Prep C18 OBD - 10 pm, 50 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again. An extra purification was done by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 84 (26 mg, 15%) as a white solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.54 (br s, 6 H) 3.17 - 3.28 (m, 3 H) 3.36 - 3.53 (m, 2 H) 3.67 - 3.90 (m, 1 H) 3.94 - 4.07 (m, 6 H) 4.02 - 4.35 (m, 1 H) 4.31 (br t, J=6.7 Hz, 1 H) 5.62 (d, J=13.6 Hz, 1 H) 7.34 (br t, J=8.4 Hz, 2 H) 7.43 (br d, J=13.6 Hz, 1 H) 7.83 - 7.90 (m, 2 H) 7.92 - 8.02 (m, 3 H) 8.07 (br d, J=12.1 Hz, 1 H) 8.49 - 8.61 (m, 1 H) 8.76 (s, 1 H) SFC: (Rt 5.48 min 23% isomer 1), (Rt 5.74 min 23% isomer 2), (Rt 5.93 min 27% isomer 3), (Rt 6.52 min 27% isomer 4), 100%, MW: 593.2, Method SFC B LCMS: Rt 1.03 min, 97%, MW: 593.2, 594 [M+H] ⁺ , Method A

Tert-butyl N--r2-r4-ri-rterf-butyl(dimethyl)silyl]oxy-l -methyl -ethyl]-6-chloro-5-fluoro-2- pyridyl]-2-oxo-ethyl]carbamate 85 A I L flask was charged with 58 (20 g, 43.4 mmol), (4-fluorophenyl)boronic acid (12.1 g, 86.8 mmol), Na2CC>3 (13.8 g, 130.1 mmol) in toluene (335 mL) and water (90 mL). The mixture was purged with N2 for 10 min and DPPF Pd (1.6 g, 2.2 mmol) was added. The mixture was heated at 90°C for 16 h. The mixture was cooled and filtered over dicalite. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 80:20) to yield compound 85 (21.8 g, 97%) as a pale-yellow oil.

TerLbutyl (2-(4-(2-((terLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)- pyri din-2 -yl)-2-hydroxypent-4-en-l -yDcarbamate 86

Compound 85 (11.9 g, 22.9 mmol) was dissolved in dry THF (150 mL) and the solution was cooled to 0°C. Then allyl magnesium bromide (57.1 mL, 1 M in ether, 57.1 mmol) was added dropwise while keeping the temp below 5°C. After addition, the cooling was removed, and the reaction mixture was stirred at rt for 3 days. The reaction mixture was quenched with sat. NH4CI solution (100 mL) and the org layer was separated. The water layer was extracted once more with EtOAc (100 mL). The combined org layers were evaporated, and the crude oil was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 80:20) to obtain compound 86 (9.4 g, 63%) as a yellow oil.

TerLbutyl (2-(4-(2-((terLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)- pyridin-2-yl )-2.4.5-trihydroxypentyl (carbamate compound 87

A flask was charged with compound 86 (9.4 g, 14.3 mmol) in THF (70 mL) and acetone (70 mL). 4-Methylmorpholine n-oxide (50W/W% in water) (55.4 mL, 1.1 M, 31.3 mmol) and potassium osmate (VI) dihydrate (263.5 mg, 0.7 mmol) were added and the vial was capped. The mixture was stirred at rt for 16 h. The mixture was concentrated to 1/4 volume, then brine and DCM were added. The organic layer was separated, concentrated in vacuo, and purified by silica column chromatography (DCM/MeOH, gradient from 100:0 to 94:6) to obtain compound 87 (8.7 g, 99%) as a green foam.

Tertbutyl ((2-(4-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)- pyridin-2-yl)-4-hydroxytetrahydrofuran-2-yl)methyl)carbamate 88

To a solution of compound 87 (11.5 g, 19.3 mmol) in dry DCM (200 mL), was added Et ₃ N (4.2 mL, 0.7 g/mL, 29 mmol) followed by -toluenesulfonyl chloride (4.4 g, 23.2 mmol). The mixture was stirred at rt for 15 min before dibutyltin oxide dibutyltin oxide (980.7 mg, 3.9 mmol) was added. Then the mixture was stirred at 45°C for 8 days. The reaction was cooled and quenched with sat. NH4CI solution (100 mL). The organic layer was separated, concentrated in vacuo, and purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 50:50) to obtain compound 88 (8.8 g, 77%) as a green foam.

Tertbutyl ((2-(4-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)- pyridin-2-yl)-4-oxotetrahydrofuran-2-yl)methyl)carbamate 89

To a solution of compound 88 (765.2 mg, 1.3 mmol) in DCM (20 mL) was added dess-martin periodinane (841.2 mg, 2 mmol) and the suspension was stirred at rt for 16 h. The reaction mixture was quenched with saturated solution of sodium thiosulfate (15 mL) and saturated solution of sodium hydrogen carbonate (15 mL). The two phases were separated, and the water layer was once more extract with DCM. The org layers were evaporated and purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100), evaporated and dried in vacuo to obtain compound 89 (692.8 mg, 91%) as a clear glassy solid.

Tertbutyl ((2-(4-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)- pyridin-2-yl)-4,4-difluorotetrahydrofuran-2-yl)methyl)carbam ate 90

To a solution of compound 89 (390 mg, 0.7 mmol) in dry DCM (20 mL) at -60°C was added DAST (199.8 pL, 1.2 g/mL, 1.5 mmol). The solution was stirred at -60°C for 1 h and then warmed slowly to rt and stirred for 40 h. The reaction mixture was cooled to 0°C and extra DAST (199.8 pL, 1.2 g/mL, 1.5 mmol) was added and then stirred at rt for 3 days. The reaction mixture was cooled to 0°C and again extra DAST (399.7 pL, 1.2 g/mL, 3 mmol) was added and stirred at rt for 5 days. The mixture was quenched with NaHCO ₃ sat. and stirred for 10 min. The layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were dried over MgSO ₄ , filtered off and evaporated to be purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100) to obtain compound 90 (187.5 mg, 42%) as a yellow solid.

2-(6-(2-(Aminomethyl)-4,4-difluorotetrahydrofuran-2-yl)-3 -fluoro-2-(4-fluorophenyl)pyridin-4- yl)propan-2-ol hydrogen chloride 91

To compound 90 (187 mg, 0.3 mmol) was added a premixed solution of HC1 (37% in H ₂ O) (633.1 mL, 1.2 g/mL, 2.8 mmol) in 1,4-dioxane (3 mL). The mixture was heated at 60°C for 2 h. The mixture was cooled and concentrated in vacuo. The residue was coevaporated with dioxane and ether (2 times) to get crude compound 91 (137 mg, 93%) as a yellow solid. The crude was used as such. A-((4,4-difluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxy propan-2-yl)pyridin-2- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 92

To a solution of compound 21 (90.8 mg, 0.4 mmol), compound 91 (137 mg, 0.3 mmol) and DIPEA (200.8 pL, 0.8 g/mL, 1.2 mmol) in dry DMF (3 mL) was added HATU (158.3 mg, 0.4 mmol). The reaction mixture was stirred at rt for 1 h and then poured slowly into iced water. The suspension was stirred at rt for 2 h. The solid was filtered off, washed with water, and dried in vacuo. The crude was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100) to get compound 92 (14.2 mg, 9%).

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.68 (s, 3 H) 1.71 (s, 3 H) 2.27 (br s, 1 H) 2.86 (ddd, J=18.05, 15.08, 10.45 Hz, 1 H) 2.95 (s, 3 H) 3.15 - 3.32 (m, 1 H) 3.96 (d, J=5.72 Hz, 2 H) 4.07 (dt, J=17.17, 10.23 Hz, 1 H) 4.14 (s, 3 H) 4.22 - 4.37 (m, 1 H) 7.11 (br t, J=5.61 Hz, 1 H) 7.17 (t, J=8.69 Hz, 2 H) 7.35 (s, 1 H) 7.38 - 7.44 (m, 2 H) 7.93 (d, J=5.28 Hz, 1 H) 7.97 (ddd, J=8.80, 5.39, 1.43 Hz, 2 H)

SFC: (Rt 3.28 min 52% isomer 1), (Rt 3.69 min 47% isomer 2), MW: 584.2, Method SFC F LCMS: Rt 1.14 min, 100%, MW: 584, 585.2 [M+H] ⁺ , 583.2 [M-H]’, Method K

The enantiomers of 92 (90.3 mg, 0.2 mmol, 56%) were separate via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) to yield compound 93 (38.9 mg, 24%) and compound 94 (38.4 mg, 23%), both as a yellow solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.46 (s, 3 H) 1.55 (s, 3 H) 2.88 (s, 3 H) 2.89 - 3.05 (m, 1 H) 3.15 - 3.31 (m, 1 H) 3.69 - 3.80 (m, 1 H) 3.83 - 3.94 (m, 1 H) 3.95 - 4.08 (m, 1 H) 4.08 (s, 3 H) 4.35 (q, J=11.67 Hz, 1 H) 5.63 (s, 1 H) 7.33 (t, J=8.88 Hz, 2 H) 7.43 (d, J=1.25 Hz, 1 H) 7.82 (d, J=1.25 Hz, 1 H) 7.87 - 8.01 (m, 4 H) 8.93 (t, J=6.22 Hz, 1 H) SFC: Rt 3.28 min, 100 %, MW: 584.2, Method SFC F

LCMS: Rt 1.97 min, 100%, MW: 584.2, 585 [M+H] ⁺ , 583 [M-H]’, Method C

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.46 (s, 3 H) 1.55 (s, 3 H) 2.87 (s, 3 H) 2.89 - 3.05 (m, 1 H) 3.15 - 3.31 (m, 1 H) 3.69 - 3.80 (m, 1 H) 3.84 - 3.94 (m, 1 H) 3.96 - 4.08 (m, 1 H) 4.08 (s, 3 H) 4.29 - 4.44 (m, 1 H) 5.63 (s, 1 H) 7.33 (t, J=8.94 Hz, 2 H) 7.43 (d, J=1.25 Hz, 1 H) 7.82 (d, J=1.36 Hz, 1 H) 7.89 - 8.02 (m, 4 H) 8.92 (t, J=6.22 Hz, 1 H)

SFC: Rt 3.69 min, 100%, MW: 584.2, Method SFC F

LCMS: Rt 1.97 min, 98%, MW: 584.2, 585 [M+H] ⁺ , 583 [M-H]’, Method C

5-(Aminomethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydro xypropan-2-yl)pyridin-2- yl)dihydrofuran-3(2H )-one hydrogen chloride 95

Compound 89 (1000 mg, 1.6 mmol) was dissolved in a premixed solvent of 1,4-dioxane (16 mL) and HC1 (37% in H2O) (1.6 mL, 1.2 g/mL, 19.5 mmol) and the mixture was heated at 50°C for

16 h. The reaction mixture was evaporated, and the residue was coevaporated with EtOH and then diethyl ether to get crude 95 (798 mg, 65%) as a brown foam. The product was used as such in the next step. A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)-4- oxotetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 96

To a solution of compound 21 (348 mg, 1.6 mmol), compound 95 (798 mg, 1.1 mmol) and DIPEA (769.6 pL, 0.8 g/mL, 4.5 mmol) in dry DMF (15 mL) was added HATU (606.4 mg, 1.6 mmol) and the reaction mixture was stirred at rt for 2 h and then poured slowly into iced water. The formed beige solid was collected by filtration and dried in vacuo at 50°C for 3 h. The crude was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100, and then EtOAc/MeOH, gradient from 100:0 to 95:5). The fractions containing product were collected and evaporated to be purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD - 10pm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to get compound 96 (36.6 mg, 6%) as a yellow powder.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.50 (s, 3 H) 1.55 (s, 3 H) 2.88 (s, 3 H) 2.96 - 3.09 (m, 1 H) 3.12 - 3.25 (m, 1 H) 3.80 (br dd, J=13.75, 5.83 Hz, 1 H) 3.97 - 4.14 (m, 5 H) 4.36 (d, J=16.95 Hz, 1 H) 5.43 - 5.93 (m, 1 H) 7.33 (t, J=8.91 Hz, 2 H) 7.44 (d, J=1.32 Hz, 1 H) 7.83 (d, J=1.32 Hz, 1 H) 7.88 - 8.04 (m, 4 H) 8.96 (br t, J=6.16 Hz, 1 H)

SFC: (Rt 4.85 min, 49% isomer 1), (Rt 5.22 min, 49% isomer 2), MW: 562.2, Method SFC H LCMS: Rt 0.93 min, 98%, MW: 562, 563.3 [M+H] ⁺ , 561.3 [M-H]’, Method I

The enantiomers of compound 96 were separated by via Prep SFC (Stationary phase: Chiralpak Daicel IG 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrlSNH) to obtain compound 97 (2.6 mg, 1%) and compound 98 (2.6 mg, 1%).

SFC: Rt 4.85 min, 100%, MW: 562.2, Method SFC H

LCMS: Rt 1.80 min, 100%, MW: 562.2, 563 [M+H] ⁺ , 561 [M-H]’, Method C

SFC: Rt 5.23 min, 95%, MW: 562.2, Method SFC H

LCMS: Rt 1.80 min, 88%, MW: 562.00, 563 [M+H] ⁺ , 561 [M-H]’, Method C

TerLbutyl ((2-(4-(2-((terLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)- pyridin-2-yl)-4-hydroxy-4-methyltetrahydrofuran-2-yl)methyl) carbamate 99 A reaction tube was charged with 89 (500 mg, 0.9 mmol) in dry THF (4.5 mL) under N2 atm.

The mixture was cooled on an ice bath and methylmagnesium bromide (0.6 mL, 3 M in THF, 1.7 mmol) was added dropwise. After 10 min, the temperature was allowed to rise to rt and stirred for 2 days. The reaction mixture was quenched with sat. NH4CI solution and then extracted with Me-THF. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The product was used as such in the next step. 5-( Aminomethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxyprop an-2-yl)pyri din-2 -yl)-3- methyltetrahydrofuran-3-ol hydrochloride 100

To compound 99 (513.9 mg, 0.9 mmol) was added a premixed solution of HC1 (37% in H2O) (2 mL) in 1,4-di oxane (9 mL). The mixture was heated at 60°C for 1 h. The mixture was cooled and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 100 (346 mg, 96%) as a yellow solid.

A-(((2R,4R)-2-(5-fluoro-6-(4-fluorophenyl)-4-(2 -hydroxypropan-2-yl)pyri din-2 -yl)-4-hydroxy- 4-methyltetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinno line-6-carboxamide 101

To a solution of compound 100 (346 mg, 0.8 mmol) in dry DMF (9 mL) was added Hunig's base (0.4 mL, 0.8 g/mL, 2.8 mmol). After 10 min, compound 21 (181.5 mg, 0.8 mmol) was added followed by HATU (356.3 mg, 0.9 mmol). The mixture was stirred at rt for 3 h. The mixture was quenched in 70 mL of water and extracted with EtOAc (3x). The organic fractions were collected and concentrated in vacuo. A purification was performed by silica column chromatography (heptane/(EtOAc/EtOH (3: 1)), gradient from 100:0 to 0: 100) to yield compound 101 (32.7 mg, 7%).

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.43 (s, 3 H) 1.62 (s, 3 H) 1.65 (s, 3 H) 2.28 (d, J=13.7 Hz, 1 H) 2.58 (dd, J=13.7, 1.5 Hz, 1 H) 2.93 (s, 3 H) 3.66 (dd, J=13.5, 3.3 Hz, 1 H) 3.93 (d, J=9.3 Hz, 1 H) 4.07 (dd, J=9.3, 1.5 Hz, 1 H) 4.13 (s, 3 H) 4.38 (dd, J=13.6, 7.9 Hz, 1 H) 7.14 (t, J=8.7 Hz, 2 H) 7.28 (s, 1 H) 7.32 (d, J=1.5 Hz, 1 H) 7.40 (d, J=1.4 Hz, 1 H) 7.40 - 7.45 (m, 1 H) 7.88 (ddd, J=8.7, 5.4, 1.5 Hz, 2 H) 7.99 (d, J=5.4 Hz, 1 H)

SFC: (Rt 3.13 min 51% isomer 1), (Rt 3.48 min 49% isomer 2), MW: 578.2, Method SFC F LCMS: Rt 1.62 min, 100%, MW: 578.2, 579 [M+H] ⁺ , 577 [M-H]’, Method H

(TRANS)-5-(aminomethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4- (2-hydroxypropan-2-yl)pyridin-2- yl)tetrahydrofuran-3-ol 102 and (CIS)-5-(aminomethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)tetrahydrofuran-3-ol 103

A flask was charged with compound 88 (615 mg, 1.1 mmol) in chloroform (10 mL). PTS A (1.8 g, 10.6 mmol) was added, and the mixture was stirred at 60°C for 1 h. The mixture was cooled and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The water layer was concentrated, and all was combined. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again to become compound 102 (33 mg, 9%) as a white solid and compound 103 (33 mg, 9%) as a white solid.

103 104 cis cis (CIS) A-(((2R,4S)-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropa n-2-yl)pyridin-2-yl)-4- hydroxytetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnol ine-6-carboxamide 104

To a solution of compound 21 (19.7 mg, 0.09 mmol) and (compound 103 (33 mg, 0.09 mmol) in DMF (1 mL) was added DIPEA (32.2 pL, 0.8 g/mL, 0.2 mmol) and finally HATU (38.7 mg, 0.1 mmol). The mixture was stirred at rt for 16 h. The mixture was quenched in 3 mL of water and extracted with EtOAc (3x). The organic fractions were collected and concentrated in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XB ridge Prep Cl 8 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were concentrated in vacuo and the residue was dissolved in MeOH. The mixture was concentrated again in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 104 (25 mg, 49%) as a pale yellow solid.

NMR: 1H NMR (400 MHz, chloroform-d, 47°C) δ ppm 1.66 (d, J=3.3 Hz, 6 H) 2.36 (br s, 1 H) 2.44 - 2.53 (m, 1 H) 2.53 - 2.59 (m, 1 H) 2.76 (br s, 1 H) 2.94 (s, 3 H) 3.69 (dd, J=13.5, 3.9 Hz, 1 H) 4.10 - 4.15 (m, 4 H) 4.17 - 4.21 (m, 1 H) 4.25 (dd, J=13.4, 7.6 Hz, 1 H) 4.61 (br s, 1 H) 7.13 (t, J=8.1 Hz, 2 H) 7.28 (s, 1 H) 7.34 (d, J=1.4 Hz, 1 H) 7.35 - 7.39 (m, 1 H) 7.40 (d, J=1.3 Hz, 1 H) 7.91 (td, J=7.1, 1.5 Hz, 2 H) 7.99 (d, J=5.4 Hz, 1 H)

LCMS: Rt 1.63 min, 100%, MW: 564.3, 565.4 [M+H] ⁺ , 563.3 [M-H]’, Method C (TRANS) A-(((2R,4R)-2-(5-fluoro-6-(4- I-4-C2-] -2-yl)pvridin-2-yl)-4- hydroxytetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnol ine-6-carboxamide 105

To a solution of compound 21 (19.7 mg, 0.09 mmol) and 102 (33 mg, 0.09 mmol) in DMF (1 mL) was added DIPEA (32.2 pL, 0.8 g/mL, 0.2 mmol) and afterwards HATU (38.7 mg, 0.1 mmol). The mixture was stirred at rt for 16 h. The mixture was quenched in 3 mL of water and extracted with EtOAc (3x). The organic fractions were collected and concentrated in vacuo. A purification was performed by column chromatography (heptane/(EtOAc/EtOH (3: 1)), gradient from 100:0 to 0:100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 105 (25 mg, 49%) as a pale yellow solid.

NMR: 1H NMR (400 MHz, chloroform-d, 47°C) δ ppm 1.70 (s, 6 H) 2.57 - 2.65 (m, 1 H) 2.68 - 2.78 (m, 1 H) 2.84 - 2.95 (m, 4 H) 3.90 - 4.03 (m, 3 H) 4.08 (s, 3 H) 4.25 (br d, J=9.7 Hz, 1 H) 4.69 (br s, 1 H) 7.15 (t, J=8.7 Hz, 2 H) 7.31 (s, 1 H) 7.40 (s, 1 H) 7.50 (s, 1 H) 7.88 (d, J=5.5 Hz, 1 H) 7.96 (br dd, J=7.3, 5.5 Hz, 2 H) 8.19 (br s, 1 H)

LCMS: Rt 1.74 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H 5-(Aminomethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxyp ropan-2-yl)pyridin-2- yl)tetrahydrofuran-3-ol 106

To compound 88 (2 g, 3.2 mmol) was added a premixed solution of HC1 (37% in H2O) (7.3 mL, 12 M, 32.5 mmol) in 1,4-dioxane (33 mL). The mixture was heated at 60°C for 1 h. The mixture was cooled and concentrated in vacuo. The residue was treated with 7 N NH3 in MeOH and concentrated again. A purification was performed by column chromatography (DCM/(MeOH/NH3 (7 M)), gradient from 100:0 to 90: 10). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 106 (930 mg, 79%) as a pale yellow solid.

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-4-hydroxy- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 107

To a solution of compound 21 (238.9 mg, 1.1 mmol) and compound 106 (400 mg, 1.1 mmol) in DMF (7 mL) was added DIPEA (0.4 mL, 0.8 g/mL, 2.4 mmol) and finally HATU (469 mg, 1.2 mmol). The mixture was stirred at rt for 3 h. The mixture was quenched in 70 mL of water and extracted with EtOAc (3x). The organic fractions were collected and concentrated in vacuo. A purification was performed by column chromatography (heptane/(EtOAc/EtOH (3: 1)), gradient from 100:0 to 0:100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 107 (524 mg, 85%) as a pale yellow solid.

The enantiomers of 107 (524 mg, 0.9 mmol) was separated by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) followed by a purification via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNFF) to yield compound 108 (75 mg, 12%), compound 109 (75 mg, 12%), compound 110 (37 mg, 6%) and compound 111 (40 mg, 7%), all as yellow solids. 108

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.65 (d, J=1.1 Hz, 6 H) 1.68 - 1.70 (m, 2 H) 2.43 - 2.57 (m, 2 H) 2.93 (s, 4 H) 3.09 - 3.34 (m, 1 H) 3.69 (dd, J=13.4, 3.7 Hz, 1 H) 4.12 (s, 3 H) 4.12 - 4.29 (m, 3 H) 4.60 (br s, 1 H) 7.13 (t, J=8.1 Hz, 2 H) 7.26 (s, 2 H) 7.32 (d, J=1.3 Hz, 1 H) 7.40 (d, J=1.3 Hz, 1 H) 7.50 (dd, J=7.5, 3.5 Hz, 1 H) 7.87 - 7.93 (m, 2 H) 7.99 (d, J=5.7 Hz, 1 H)

SFC: Rt 3.83 min, 100%, MW: 564.2, Method SFC A

LCMS: Rt 1.63 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method C

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.64 - 1.68 (m, 6 H) 2.42 - 2.58 (m, 2 H) 2.93 (s, 3 H) 2.96 - 3.09 (m, 1 H) 3.29 (br s, 1 H) 3.70 (dd, J=13.4, 3.7 Hz, 1 H) 4.12 (s, 3 H) 4.13 - 4.30 (m, 3 H) 4.57 - 4.64 (m, 1 H) 7.10 - 7.17 (m, 2 H) 7.25 - 7.28 (m, 1 H) 7.32 (d, J=1.3 Hz, 1 H) 7.41 (s, 1 H) 7.51 (dd, J=7.4, 3.4 Hz, 1 H) 7.91 (td, J=7.0, 1.4 Hz, 2 H) 8.00 (d, J=5.5 Hz, 1 H)

SFC: Rt 4.12 min, 100%, MW: 564.2, Method SFC A

LCMS: Rt 1.63 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method C

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.72 (d, J=6.2 Hz, 8 H) 2.56 (s, 1 H)

2.66 - 2.81 (m, 2 H) 2.82 (s, 3 H) 3.85 - 4.00 (m, 3 H) 4.04 (s, 3 H) 4.33 (d, J=9.2 Hz, 1 H) 4.75 (br s, 1 H) 5.00 (br s, 1 H) 7.13 - 7.21 (m, 2 H) 7.25 (s, 1 H) 7.33 (d, J=1.3 Hz, 1 H) 7.46 (d, J=1.3 Hz, 1 H) 7.92 (d, J=5.3 Hz, 1 H) 7.96 - 8.01 (m, 2 H) 8.73 (t, J=4.3 Hz, 1 H) SFC: Rt 4.33 min, 100%, MW: 564.2, Method SFC A

LCMS: Rt 1.71 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H

NMR: 1H NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.72 (d, J=5.9 Hz, 6 H) 2.53 (s, 1 H) 2.66 - 2.82 (m, 2 H) 2.83 (s, 3 H) 3.86 - 4.01 (m, 3 H) 4.05 (s, 3 H) 4.33 (d, J=9.9 Hz, 1 H) 4.75 (br s, 1 H) 4.94 (br s, 1 H) 7.17 (t, J=8.1 Hz, 2 H) 7.26 (s, 1 H) 7.34 (d, J=1.1 Hz, 1 H) 7.46 (d, J=1.3 Hz, 1 H) 7.92 (d, J=5.5 Hz, 1 H) 7.98 (dd, J=7.5, 5.5 Hz, 2 H) 8.71 (t, J=4.2 Hz, 1 H)

SFC: Rt 4.56 min, 99%, MW: 564.2, Method SFC A

LCMS: Rt 1.71 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H

Following compounds were prepared analogously :

TerLbutyl ((2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4- fluorophenyl)pyridin-2-yl)-4-(4A4-trifluorobutoxy)tetrahydro furan-2-yl)methyl)carbamate 118

To a cooled solution of compound 88 (1397.4 mg, 2.4 mmol) in dry DMF (14 mL) was added NaH (60% dispersion in mineral oil) (236.6 mg, 5.9 mmol) at 0°C and the mixture was stirred for 30 min. Then l-bromo-4,4,4-trifluorobutane (290.6 pL, 1.6 g/mL, 2.4 mmol) was added and the ice bath was removed. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water and the product was extracted with EtOAc twice. The organic layers were combined and evaporated to dry to be purified by column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100). After evaporation of the fractions, we get crude mixture 118 (1.1 g) which was used as such in the next step.

2-(6-(2-( Aminomethyl)-4-(4A4-tri fluorobutoxy )tetrahydrofuran-2-yl)-3-fluoro-2-(4- fluorophenyl)pyridin-4-yl)propan-2-ol hydrogen chloride 119

To a solution of crude 118 (1.1 g) in 1,4-dioxane (14 mL) was added HC1 (37% in H2O) (1.4 mL, 1.2 g/mL, 16.9 mmol). The solution was heated at 50°C for 16 h. The reaction mixture was evaporated to dry, and the residue was coevaporated with EtOH to get compound 119 (1.1 g) as a brown foam. The crude product was used as such in the next step. A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)-4-(4,4,4- tri fluorobutoxy )tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6- carboxamide

(TRANS 120 and CIS 121) To a solution of compound 118 (1.1 g, 2.3 mmol), compound 21 (511.4 mg, 2.3 mmol) and DIPEA (1.6 mL, 0.8 g/mL, 9.4 mmol) in dry DMF (10 mL) was added HATU (1.2 g, 3 mmol) and then stirred at rt for 2 h. The solution was poured slowly into iced water and the suspension was stirred at rt for 16 h. The precipitate was filtered off, washed with water and dried in vacuo. The product was then purified via Prep HPLC (Stationary phase: RP XB ridge Prep C18 OBD - 10 pm, 30 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to yield compound 120 (263.9 mg, yield 16%) and compound 121 (78.5 mg, yield 5%) as yellow solid. Yield is over the 3 steps.

120

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.43 (s, 3 H) 1.47 - 1.63 (m, 2 H) 1.52 (s, 3 H) 2.08 - 2.25 (m, 2 H) 2.35 - 2.44 (m, 1 H) 2.74 (dd, J=14.09, 6.60 Hz, 1 H) 2.86 (s, 3 H) 3.34 - 3.49 (m, 2 H) 3.69 - 3.91 (m, 3 H) 4.03 - 4.14 (m, 2 H) 4.07 (s, 3 H) 5.56 (s, 1 H) 7.32 (t, J=8.91 Hz, 2 H) 7.43 (d, J=1.10 Hz, 1 H) 7.79 (d, J=1.32 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 7.94 (dd, J=7.48, 5.72 Hz, 2 H) 8.63 (t, J=6.16 Hz, 1 H)

SFC: (Rt 5.96 min 47% isomer 1) (Rt 6.49 min 46% isomer 2), MW: 674.3, Method SFC C LCMS: Rt 1.14 min, 97%, MW: 674, 675.4 [M+H] ⁺ , 673.4 [M-H]’, Method I

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.32 - 1.42 (m, 2 H) 1.46 (s, 3 H) 1.51 (s, 3 H) 1.52 - 1.67 (m, 2 H) 2.27 (dd, J=13.65, 5.06 Hz, 1 H) 2.83 (br d, J=13.42 Hz, 1 H) 2.87 (s, 3 H) 3.13 - 3.21 (m, 1 H) 3.22 - 3.30 (m, 1 H) 3.66 (dd, J=13.42, 6.16 Hz, 1 H) 3.82 (dd, J=13.53, 6.49 Hz, 1 H) 3.97 (d, J=9.02 Hz, 1 H) 4.08 (s, 3 H) 4.11 - 4.20 (m, 2 H) 5.56 (br s, 1 H) 7.33 (t, J=8.91 Hz, 2 H) 7.44 (d, J=1.10 Hz, 1 H) 7.82 (d, J=1.10 Hz, 1 H) 7.86 - 8.06 (m, 4 H) 8.74 (t, J=6.27 Hz, 1 H)

SFC: (Rt 4.28 min 50% isomer 1) (Rt 4.98 min 50% isomer 2), 100%, MW: 674.3, Method SFC E

LCMS: Rt 1.10 min, 96%, MW: 674, 675.4 [M+H] ⁺ , 673.4 [M-H]’, Method I Both fractions were submitted to SFC to purify the enantiomers.

Compound 120 (260 mg, 0.4 mmol) was purified via Prep SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) to yield compound 122 (118.7 mg, 46%) and compound 123 (112 mg, yield 44%), both as yellow solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.43 (s, 3 H) 1.48 - 1.62 (m, 2 H) 1.52 (s, 3 H) 2.08 - 2.26 (m, 2 H) 2.36 - 2.44 (m, 1 H) 2.74 (dd, J=14.09, 6.38 Hz, 1 H) 2.86 (s, 3 H) 3.34 - 3.47 (m, 2 H) 3.69 - 3.91 (m, 3 H) 4.02 - 4.14 (m, 2 H) 4.07 (s, 3 H) 5.56 (s, 1 H) 7.32 (t, J=8.91 Hz, 2 H) 7.43 (d, J=1.10 Hz, 1 H) 7.79 (d, J=1.32 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 7.94 (dd, J=7.59, 5.61 Hz, 2 H) 8.63 (t, J=6.16 Hz, 1 H) SFC: Rt 5.97 min, 98%, MW: 674.3, Method SFC D

LCMS: Rt 2.13 min, 100%, MW: 674.3, 675 [M+H] ⁺ , 673 [M-H]’, Method C

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.43 (s, 3 H) 1.52 (s, 3 H) 1.53 - 1.63 (m, 2 H) 2.09 - 2.25 (m, 2 H) 2.36 - 2.44 (m, 1 H) 2.74 (dd, J=13.97, 6.49 Hz, 1 H) 2.86 (s, 3 H) 3.34 - 3.48 (m, 2 H) 3.70 - 3.78 (m, 1 H) 3.78 - 3.92 (m, 2 H) 4.02 - 4.14 (m, 2 H) 4.07 (s, 3 H) 5.56 (s, 1 H) 7.32 (t, J=8.91 Hz, 2 H) 7.43 (d, J=1.32 Hz, 1 H) 7.79 (d, J=1.54 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 7.94 (dd, J=7.48, 5.50 Hz, 2 H) 8.63 (t, J=6.16 Hz, 1 H) SFC: Rt 6.48 min, 100%, MW: 674.3, Method SFC D

LCMS: Rt 2.13 min, 100%, MW: 674.3, 675 [M+H] ⁺ , 673 [M-H]’, Method C

Compound 121 (70 mg, 0.1 mmol) was purified via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, zPrOH + 0.4 zPrNH ₂ ) to yield compound 124 (27.8 mg, 41%) and compound 125 (28.2 mg, 42%), both as yellow solid.

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.32 - 1.43 (m, 2 H) 1.46 (s, 3 H) 1.51 (s, 3 H) 1.51 - 1.69 (m, 2 H) 2.27 (dd, J=13.53, 4.95 Hz, 1 H) 2.83 (br d, J=13.64 Hz, 1 H) 2.87 (s, 3 H) 3.12 - 3.21 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.66 (dd, J=13.42, 6.16 Hz, 1 H) 3.82 (dd, J=13.53, 6.27 Hz, 1 H) 3.97 (d, J=9.02 Hz, 1 H) 4.09 (s, 3 H) 4.11 - 4.22 (m, 2 H) 5.57 (s, 1 H) 7.33 (t, J=9.02 Hz, 2 H) 7.45 (d, J=1.32 Hz, 1 H) 7.82 (d, J=1.32 Hz, 1 H) 7.88 - 8.00 (m, 4 H) 8.74 (t,

J=6.16 Hz, 1 H)

SFC: Rt 4.30 min, 100%, MW: 674.3, Method SFC E

LCMS: Rt 2.08 min, 100%, MW: 674.3, 675 [M+H] ⁺ , 673 [M-H]’, Method C

NMR: 1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.32 - 1.42 (m, 2 H) 1.46 (s, 3 H) 1.51 (s, 3 H) 1.52 - 1.68 (m, 2 H) 2.27 (dd, J=13.64, 5.06 Hz, 1 H) 2.83 (d, J=13.64 Hz, 1 H) 2.87 (s, 3 H) 3.12 - 3.22 (m, 1 H) 3.23 - 3.30 (m, 1 H) 3.66 (dd, J=13.53, 6.27 Hz, 1 H) 3.82 (dd, J=13.42, 6.38 Hz, 1 H) 3.97 (d, J=9.02 Hz, 1 H) 4.09 (s, 3 H) 4.12 - 4.22 (m, 2 H) 5.57 (br s, 1 H) 7.33 (t,

J=8.91 Hz, 2 H) 7.45 (d, J=1.32 Hz, 1 H) 7.82 (d, J=1.54 Hz, 1 H) 7.88 - 8.00 (m, 4 H) 8.74 (t, J=6.27 Hz, 1 H)

SFC: Rt 5.02 min, 100%, MW: 674.3, Method SFC E

LCMS: Rt 2.08 min, 100%, MW: 674.3, 675 [M+H] ⁺ , 673 [M-H]’, Method C Zb/V-butyl ((2-(4-(2-((ter/-butyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)- pyridin-2-yl)-4-fluorotetrahydrofuran-2-yl)methyl)carbamate 126

In a flask under N2, to a solution of compound 88 (1.5 g, 2.6 mmol) in DCM (75 ml ) at -78°C was added diethylaminosulfur trifluoride (320.3 pL, 1.2 g/mL, 2.4 mmol), then the mixture was warmed to rt and stirred for 3 h. The mixture was quenched with NaHCO ₃ sat. and stirred for 10 min. The layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. A purification was performed by silica column chromatography (hepate/EtOAc, gradient from 100:0 to 80:20). The product fractions were collected and concentrated in vacuo to become compound 126 (640 mg, 43%) as a clear oil.

2-(6-(2-(Aminomethyl)-4-fluorotetrahydrofuran-2-yl)-3-flu oro-2-(4-fluorophenyl)pyridin-4-yl)- propan-2-ol 127

To compound 126 (640 mg, 1.1 mmol) was added a premixed solution of HC1 (37% in H2O) (2.5 mL, 12 M, 11 mmol) in 1,4-dioxane (11 mL). The mixture was heated at 60°C for 1 h. The mixture was cooled and concentrated in vacuo. Ether was added and the mixture was concentrated again. The residue was triturated in DIPE and the precipitated product was filtered off, washed with CEfiCN and diethyl ether to obtain 352 mg of crude. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CEfiCN). The product fractions were concentrated in vacuo and the residue dissolved in MeOH. The mixture was concentrated again in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 127 (215 mg, 53%). A-(((2R,4R)-4-fluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2 -hydroxypropan-2-yl)pyri din-2 -yl)- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 128

To a solution of compound 127 (215 mg, 0.6 mmol) in DMF (3.6 mL) was added DIPEA (208.6 pL, 0.8 g/mL, 1.3 mmol) and the mixture was stirred at rt for 10 min. Compound 21 (127.7 mg, 0.6 mmol) was added and finally HATU (250.7 mg, 0.6 mmol). The mixture was stirred at rt for 1 h. The mixture was quenched in 10 mL of water and extracted with EtOAc (3x). The organic fractions were collected and concentrated in vacuo. A purification was performed by silica column chromatography (heptane/(EtOAc/EtOH (3: 1)), gradient from 100:0 to 0:100). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE/CH3CN, filtered off and dried under vacuum to become compound 128 (295 mg, 89%) as a pale yellow solid.

NMR: ’H NMR (400 MHz, chloroform-7, 27°C) δ ppm 1.69 (m, 7=4.60 Hz, 6 H) 2.75 (br dd, 7=27.95, 15.41 Hz, 1 H) 2.95 (dd, 7=37.85, 15.85 Hz, 1 H) 2.96 (s, 3 H) 3.79 - 3.85 (m, 1 H) 3.89 (ddd, 7=38.29, 11.44, 2.42 Hz, 1 H) 4.08 (dd, 7=13.64, 6.16 Hz, 1 H) 4.16 (s, 3 H) 4.40 (br dd, 7=20.25, 11.22 Hz, 1 H) 5.34 (br d, 7=54.58 Hz, 1 H) 7.10 (br s, 1 H) 7.16 (br t, 7=8.58 Hz, 2 H) 7.44 (s, 1 H) 7.48 (s, 1 H) 7.56 (s, 1 H) 7.88 (d, 7=5.28 Hz, 1 H) 7.98 (br dd, 7=7.26, 5.50 Hz, 2 H)

SFC: (Rt 3.75 min 50% isomer 1), (Rt 4.21 min 49% isomer 2), only 2 isomers detected, MW: 566.2, Method SFC F

LCMS: Rt 2.29 min, 98%, MW: 566.2, 567 [M+H] ⁺ , 565 [M-H]’, Method D

The enantiomers of compound 128 (295 mg, 0.5 mmol) was separated by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNHi) to yield compound 129 (92 mg, 28%) and compound 130 (105 mg, 32%).

132

Tertbutyl ((2-(4-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)- pyridin-2-yl )-4-(1 ,3-dioxoisoindolin-2-yl )tetrahvdrofuran-2-yl (methyl (carbamate 131

To a solution of compound 88 (2 g, 3.4 mmol), phthalimide [85-41-6] (1.5 g, 10.2 mmol) and PPh ₃ [603-35-0] (4.4 g, 16.9 mmol) in dry THF (175 mL) was added slowly DIAD [2446-83-5] (3.3 mL, 1 g/mL, 16.9 mmol). The rm was stirred at rt for 1 h. The reaction mixture was quenched with sat. aq. NaHCO ₃ solution (200 mL). The organic layer was evaporated to be purified by column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100) to yield compound 131 (1.9 g, 77%) as a white foam.

2-(5-( Aminornethyl)-5-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypro pan-2-yl)pyri din-2 -yl)- tetrahydrofuran-3-yl)isoindoline-E3-dione hydrogen chloride 132

To compound 131 (942.8 mg, 1.3 mmol) was added a premixed solution of HC1 (37% in H2O) (3 mL, 12 M, 13.3 mmol) in 1,4-dioxane (19 mL). The mixture was heated at 60°C for 2 h and then stirred for 16 h at rt. The reaction mixture was evaporated to dry, and the residue was coevaporated with dioxane and diethyl ether. The crude was triturated in DIPE to get compound 132 (814.4 mg, 89%) a yellow solid.

A-((4-(L3-dioxoisoindolin-2-yl)-2-(5-fluoro-6-(4-fluoroph enyl)-4-(2-hydroxypropan-2-yl)- pyri din-2 -yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline -6-carboxamide 133

To a solution of compound 21 (109 mg, 0.5 mmol), compound 132 (230 mg, 0.3 mmol) and DIPEA (241 pL, 0.8 g/mL, 1.4 mmol) in dry DMF (5 mL) was added HATU (189.9 mg, 0.5 mmol). The reaction mixture was stirred at rt for 1 h and then poured slowly into iced water. The product was extracted with EtOAc, and the org layer was separated and evaporated. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 0: 100, followed by EtOAc/MeOH, gradient from 100:0 to 98:2) to obtain compound 133 (168.5 mg, 72%) as a yellow solid.

The enantiomers of compound 133 (168.5 mg, 0.2 mmol) was separated by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH ₂ ) followed by a second SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH - zPrOH (50-50) + 0.4% iPrNH ₂ ) to yield compound 134 (13.5 mg, 6%), compound 135 (13.3 mg, 6%), compound 136 (10.3 mg, 5%) and compound 137 (7.1 mg, 3%).

7V-((4-amino-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxyp ropan-2-yl)pyri din-2- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 138

Compound 133 (354.2 mg, 0.5 mmol) was dissolved in EtOH (4 mL) and 1,4-di oxane (4 mL), then hydrazine monohydrate (112.2 pL, 1 g/mL, 2.3 mmol) was added and the reaction mixture was heated at 90°C for 3 h. The reaction was cooled at room temperature and the solid was removed by filtration and washed with EtOH. The filtrate was concentrated and purified via silica column chromatography (DCM/(MeOH/NH3 7 M), gradient from 100:0 to 90:10) to obtain compound 138 (256.5 mg, 89%) as a yellow solid.

SFC: (Rt 4.75 min, 30% isomer 1) (Rt 5.12 min, 20% isomer 2) (Rt 5.65 min, 30% isomer 3) (Rt 6.07 min, 20% isomer 4), MW: 563.2, Method SFC J

LCMS: 2 peaks (Rt 0.75 min and 0.78 min, 55% and 45%, MW: 563, 564.4 [M+H] ⁺ , 562.4 [M- H]’, Method I

The enantiomers of compound 138 (228 mg, 0.4 mmol) were separated by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH - zPrOH (50 - 50) + 0.4% iPrNH ₂ ) to yield compound 139 (61.6 mg, 21%), compound 140 (38.6 mg, 13%), compound 141 (58.3 mg, 20%) and compound 142 (36.1 mg, 12%), all are yellow powders.

A-((4-acetamido-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydro xypropan-2-yl)pyridin-2-yl)- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 143

A reaction tube was charged with compound 138 (491 mg, 0.9 mmol), DIPEA (168.9 pL, 0.8 g/mL, 1 mmol) in dry DCM (5 mL). AC2O (88.9 pL, 1.1 g/mL, 1 mmol) was added dropwise and the mixture was stirred at rt for 1 h. The mixture was quenched with water and the organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to become compound 143 (431 mg, 82%) as a yellow solid.

Compound 143 (431 mg, 0.7 mmol) was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD - 5μm, 50 x 250 mm, Mobile phase: 0.25% NH ₄ HCO ₃ solution in water, CH3CN) to obtain compound 144 (51 mg, 10%), compound 145 (43 mg, 8%), compound 146 (35 mg, 7%) and compound 147 (50 mg, 10%), all has off-white powders.

GENERAL PROCEDURE A-F

Procedure A

Isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 2.5 eq.) was added dropwise to a stirred solution of aryl iodide 56 (1.0 eq.) in dry THF (0.24 M) at -30°C under nitrogen. A solution of Weinreb amide (2.0 eq.) in THF (3.4 M) was added to the mixture under nitrogen at -30°C. The mixture was stirred at -30°C for 1.5 h. The mixture was quenched with water, and 10% aqueous KHSO4 was added until pH = 3. The mixture was extracted with EtOAc (x 3). The organic layers were separated, combined, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was purified to yield the desired product. A mixture of ketone (1.0 eq.), potassium cyanide (1.5 eq.) in methanol (0.5 M) were stirred at 0°C for 16 h. The mixture was diluted in water and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was purified to yield the desired product.

Procedure C

Raney Nickel (1.6 eq.) was added to a solution of nitrile (1.0 eq.) in EtOH (0.12 M) under nitrogen. The nitrogen was replaced with hydrogen, and the mixture was stirred at room temperature for 16 h. The mixture was filtered over a pad of celite and the solvents evaporated in vacuo to yield the desired product.

Procedure D

TBAF (1 M in THF, 3.0 eq.) was added to a solution of silyl ether (1.0 eq.) in THF (0.25 M) at room temperature and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and DCM. The aqueous layer was separated and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was purified to yield the desired product.

Procedure E HATU (1.5 eq.) was added to carboxylic acid (1.1 eq.) and DIPEA (3.0 eq.) in dry DMF (0.13 M with respect to amine). After 10 minutes stirring, amine (1.0 eq.) in dry DMF (0.4 M) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous saturated NaHCO ₃ solution and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude residue was purified to yield the desired product.

Procedure F

HATU (1.5 eq.) was added to a solution of carboxylic acid (1.3 eq.) and DIPEA (3.0 eq.) in DMF (0.1 M with respect to amine) at room temperature. After 10 minutes stirring, amine (1.0 eq.) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude residue was purified to yield the desired product.

l-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-6-chloro-5 -fluoropyridin-2-yl)-4- chlorobutan-l-one 148

A solution of compound 56 (21.5 g, 50.0 mmol) in THF (900 mL) was stirred at -40°C under a nitrogen flow. Isopropylmagnesiumchloride-lithium chloride complex (1.3 M in THF, 77 mL, 100 mmol) was added dropwise and stirring was continued for 30 minutes. A solution of 4- chloro-A-methoxy-A-methyl-butanamide (12.4 g, 74.9 mmol) in THF (100 mL) was added dropwise at -40°C and stirring was continued for one hour at room temperature. Ice was added to the stirring solution and the mixture was extracted with 2-methyl-THF twice. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 148 as an off-white solid (20.1 g, 98%).

2,4-Dibromo-l -(6-chloro-5-fluoro-4-(2-hydroxypropan-2-yl)pyri din-2 -yl)butan-l -one 149 To a solution of compound 148 (14.2 g, 34.8 mmol) in acetic acid (100 mL), hydrogen bromide 33% in acetic acid (15 mL, 1.4 g/ mL, 87 mmol) was added dropwise. Afterwards, a solution of bromine (2.3 mL, 3.1 g/mL, 44.5 mmol) in acetic acid (10 mL) was also added dropwise at room temperature and the reaction mixture was stirred at 50°C for 3 h. The mixture was evaporated, dissolved in water and basified with sodium carbonate. The water layer was extracted with dichloromethane twice, the organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was purified by column chromatography (heptane/EtOAc, gradient from 100:0 to 80:20). The corresponding fractions were evaporated to yield compound 149 as an off-white solid (11.5 g, 79%).

4-Chl pro- l-(6-chl oro-5 -fluoro-4-(2-hydroxypropan-2-yl)pyri din-2 -yl)-l-oxobutan -2 -yl acetate 150

To a solution of compound 149 (11.5 g, 27.5 mmol) in acetonitrile (100 mL), potassium acetate (5.4 g, 55.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was evaporated, diluted with 2-methyl THF and washed with water, the organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was by column chromatography (heptane/EtOAc, gradient from 100:0 to 75:25). The corresponding fractions were evaporated to yield compound 150 as an off-white solid (10.6 g, 97%).

2-(6-Chloro-5-fluoro-4-(2-hydroxypropan-2-yl)pyri din-2 -yl)-2-(nitromethyl)tetrahydrofuran-3-yl acetate 151

A solution of compound 150 (10.6 g, 26.7 mmol) in DCM (150 mL) was stirred at room temperature. First nitromethane (24 mL, 1.14 g/mL, 542.6 mmol) and afterwards DBU (8 mL, 1.02 g/ mL, 53.6 mmol) were added dropwise and the reaction was allowed to stir at room temperature for one hour. The reaction was diluted with 150 mL DCM and two times washed with water. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude residue was purified by column chromatography (DCM/MeOH, gradient from 100:0 to 95:5). The corresponding fractions were evaporated. The residue was stirred in diisopropylether with about 10% acetonitrile. The white precipitate was filtered off and dried in vacuo to yield compound 151 as an off-white solid (3.17 g, 31%). The filtrate was evaporated to dryness to yield compound 151 as an off-white paste (4.2 g, 42%).

2-(5-Fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)py ridin-2-yl)-2-

(nitromethyl)tetrahydrofuran-3-yl acetate 152

Compound 151 (2.0 g, 5.3 mmol), 4-fluorophenylboronic acid (1.5 g, 10.6 mmol), sodium carbonate (1.69 g, 15.9 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (194.2 mg, 0.3 mmol) were added to a three-necked round bottomed flask equipped with a condenser. The flask was flushed with positive nitrogen pressure for 15 minutes. Toluene (41 mL) and water (11 mL) were added to the flask. The resulting dark red suspension was warmed to 90°C and stirred at this temperature for 16 h. The flask was allowed to cool to room temperature and filtered over dicalite, eluted with EtOAc (10 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent evaporated to dryness. The residue obtained was purified by column chromatography (MeOH/DCM, gradient from 1 :100 to 10:90) to yield compound 152 (1.7 g, 68%) as a light pink paste.

2-(5-Fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)py ridin-2-yl)-2- (nitromethyl)tetrahy drofuran-3 -ol 153

A solution of compound 152 (1.7 g, 3.6 mmol) in ammonia in methanol (7 M, 25.6 mL, 179.2 mmol) was stirred at room temperature for 3 days. The reaction mixture was evaporated to dryness. The residue was diluted with water (10 mL) and EtOAc (10 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (5 mL), dried (Na2SO4), filtered, and the solvent evaporated to dryness to yield compound 153 as a light yellow solid (1.2 g, 80%). The crude residue was used in subsequent chemistry without further purification.

2-(Aminomethyl)-2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydro xypropan-2-yl)pyridin-2- yl)tetrahydrofuran-3-ol 154

Raney Nickel (280.9 mg, 4.8 mmol) was added to a solution of compound 153 (1.2 g, 3.0 mmol) in ethanol (177 mL) under nitrogen atmosphere. The reaction vessel was evacuated then backfilled with hydrogen three times, and the resulting suspension vigorously stirred at room temperature for 20 h. The reaction mixture was filtered over dicalite, eluted with EtOH. The solvent was evaporated to dryness to yield compound 154 as a yellow viscous oil (1.1 g, 83%). The crude residue was used in subsequent chemistry without further purification.

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-3- hydroxytetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnol ine-6-carboxamide 155

HATU (615.2 mg, 1.6 mmol) and Hunig's base (512 pL, 0.8 g/mL, 3.2 mmol) were added to a suspension of compound 154 (583 mg, 1.4 mmol) and compound 21 (313.4 mg, 1.4 mmol) in DMF (15.9 mL). The suspension turned into a yellow solution. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with water (20 mL), brine (10 mL), dried (Na2SO4), filtered, and the solvent evaporated to dryness. The residue obtained was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 155 as a dark yellow viscous foam (717 mg, 85%). IH NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.63 - 1.73 (m, 6 H) 1.81 - 2.11 (m, 1 H) 1.97 - 2.00 (m, 1 H) 2.06 (td, J=6.38, 3.52 Hz, 1 H) 2.61 - 2.80 (m, 1 H) 2.83 - 2.91 (m, 3 H) 3.47 - 3.58 (m, 1 H) 4.02 - 4.13 (m, 3 H) 4.07 - 4.13 (m, 1 H) 4.31 (q, J=8.07 Hz, 1 H) 4.36 - 4.46 (m, 1 H) 4.91 - 4.99 (m, 1 H) 6.89 - 6.93 (m, 1 H) 6.97 - 7.04 (m, 2 H) 7.13 - 7.17 (m, 1 H) 7.18 - 7.25 (m, 1 H) 7.28 - 7.31 (m, 1 H) 7.84 - 7.93 (m, 2 H) 7.93 - 7.98 (m, 1 H)

LCMS Rt 1.69 min, 98%, MW: 564.2, 565.3 [M+H] ⁺ , 563.3 [M-H]’, Method H

Purification of the diastereomeric pairs of 155 (188 mg, 0.3 mmol) was performed via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to yield 2 enantiomeric pairs.

Purification of the first enantiomeric pair was performed via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNEE) to yield compound 156 (12 mg, 6%) and compound 157 (11 mg, 5%), both as yellow solid.

IH NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.66 - 1.74 (m, 6 H) 2.03 - 2.14 (m, 1 H) 2.24 - 2.33 (m, 1 H) 2.42 - 2.55 (m, 1 H) 2.93 - 2.98 (m, 3 H) 3.46 - 3.55 (m, 1 H) 3.55 - 3.65 (m, 1 H) 4.10 - 4.27 (m, 6 H) 4.64 - 4.73 (m, 1 H) 6.48 - 6.51 (m, 1 H) 7.10 - 7.17 (m, 2 H) 7.29 - 7.32 (m, 1 H) 7.32 - 7.37 (m, 2 H) 7.84 - 7.92 (m, 2 H) 7.97 - 8.02 (m, 1 H) SFC Rt 3.42 min, 95%, MW: 564.2, Method SFC F

LCMS Rt 1.62 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H

IH NMR (400 MHz, chloroform-d, 27°C) δ ppm 1.62 - 1.73 (m, 6 H) 2.03 - 2.13 (m, 1 H) 2.20 - 2.33 (m, 1 H) 2.42 - 2.54 (m, 1 H) 2.90 - 2.99 (m, 3 H) 3.47 - 3.55 (m, 1 H) 3.56 - 3.64 (m, 1 H) 4.09 - 4.27 (m, 6 H) 4.64 - 4.73 (m, 1 H) 7.09 - 7.17 (m, 2 H) 7.23 - 7.26 (m, 1 H) 7.29 - 7.32 (m, 1 H) 7.32 - 7.38 (m, 2 H) 7.82 - 7.93 (m, 2 H) 7.96 - 8.04 (m, 1 H) SFC Rt 4.01 min, 100%, MW: 564.2, Method SFC F LCMS Rt 1.62 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H

Purification of the second enantiomeric pair was performed via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH - zPrOH (50 - 50) + 0.4% zPrNEh) to yield compound 158 (28 mg, 13%) and compound 159 (30 mg, 14%), both as yellow solid.

1H NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.69 - 1.71 (m, 6 H) 1.89 - 2.12 (m, 1 H) 1.93

- 2.00 (m, 1 H) 2.43 - 2.53 (m, 1 H) 2.84 - 2.94 (m, 3 H) 3.45 - 3.57 (m, 1 H) 4.04 - 4.15 (m, 3 H) 4.14 - 4.14 (m, 1 H) 4.26 - 4.39 (m, 1 H) 4.40 - 4.43 (m, 1 H) 4.43 - 4.48 (m, 1 H) 4.86 - 4.98 (m, 1 H) 6.88 - 6.96 (m, 1 H) 6.96 - 7.05 (m, 2 H) 7.11 - 7.17 (m, 1 H) 7.17 - 7.18 (m, 1 H) 7.30

- 7.36 (m, 1 H) 7.84 - 7.93 (m, 2 H) 7.93 - 7.97 (m, 1 H) SFC Rt 3.81 min, 100%, MW: 564.2, Method SFC F

LCMS Rt 1.67 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H

1H NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.68 - 1.73 (m, 6 H) 1.88 - 2.13 (m, 2 H) 2.35 - 2.45 (m, 1 H) 2.87 - 2.93 (m, 3 H) 3.43 - 3.54 (m, 1 H) 4.07 - 4.16 (m, 4 H) 4.28 - 4.40 (m, 2 H) 4.40 - 4.50 (m, 1 H) 4.88 - 4.96 (m, 1 H) 6.91 - 6.94 (m, 1 H) 6.98 - 7.04 (m, 2 H) 7.06 - 7.15 (m, 1 H) 7.16 - 7.20 (m, 1 H) 7.33 - 7.36 (m, 1 H) 7.85 - 7.92 (m, 2 H) 7.92 - 7.96 (m, 1 H) SFC Rt 3.58 min, 100%, MW: 564.2, Method SFC F

LCMS Rt 1.67 min, 100%, MW: 564.2, 565 [M+H] ⁺ , 563 [M-H]’, Method H 7V-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl) pyridin-2-yl)-3-oxo- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 160 160

Dess-Martin periodinane (150.2 mg, 0.4 mmol) was added to a solution of compound 155 (100 mg, 0.2 mmol) in DCM (3 mL). The resulting suspension was stirred at room temperature for 20 h. Extra Dess-Martin periodinane (37.6 mg, 0.09 mmol) was added to the reaction. The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was quenched with aqueous saturated sodium thiosulfate (2 mL) and aqueous saturated sodium hydrogen carbonate (2 mL). The layers were partitioned, and the aqueous layer was extracted with DCM (2 x 2 mL). The combined organic layers were evaporated to dryness. The crude residue obtained was purified by flash chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 160 as a yellow viscous oil (85 mg, 79%).

IH NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.66 - 1.71 (m, 6 H) 2.74 - 2.83 (m, 2 H) 2.90 - 2.96 (m, 3 H) 4.02 - 4.11 (m, 4 H) 4.14 - 4.22 (m, 1 H) 4.38 - 4.55 (m, 2 H) 7.07 - 7.15 (m, 2 H) 7.22 - 7.25 (m, 1 H) 7.32 - 7.35 (m, 1 H) 7.35 - 7.38 (m, 1 H) 7.80 - 7.86 (m, 1 H) 7.86 - 7.89 (m, I H) 7.89 - 7.95 (m, 2 H)

SFC (Rt 3.63 min, 49% isomer 1), (Rt 4.08 min 51% isomer 2), MW: 562.2, Method SFC F LCMS Rt 1.76 min, 93%, MW: 562.2, 561 [M-H] ⁺ , BPM2: 563 [M+H] ⁺ , Method H

The enantiomers of 160 (85 mg, 0.1 mmol) was performed via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% zPrNFE) to yield compound 161 (27 mg, 27%) as yellow solid and compound 162 as yellow solid (27 mg, 26%). 161

IH NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.68 (s, 6 H) 2.71 - 2.86 (m, 2 H) 2.89 - 2.97 (m, 3 H) 4.01 - 4.12 (m, 4 H) 4.15 - 4.23 (m, 1 H) 4.36 - 4.57 (m, 2 H) 7.08 - 7.15 (m, 2 H) 7.20 - 7.25 (m, 1 H) 7.33 - 7.39 (m, 2 H) 7.74 - 7.83 (m, 1 H) 7.83 - 7.88 (m, 1 H) 7.88 - 7.99 (m, 1

H)

SFC Rt 3.62 min, 100%, MW: 562.2, Method SFC F

LCMS Rt 1.76 min, 99%, MW: 562.2, 563 [M+H] ⁺ , Method H 162

1H NMR (400 MHz, chloroform-d, 27 °C) δ ppm 1.66 - 1.71 (m, 6 H) 2.67 - 2.88 (m, 2 H) 2.88 - 2.99 (m, 3 H) 4.00 - 4.11 (m, 4 H) 4.11 - 4.24 (m, 1 H) 4.38 - 4.57 (m, 2 H) 7.06 - 7.15 (m, 2 H) 7.21 - 7.25 (m, 1 H) 7.32 - 7.38 (m, 2 H) 7.73 - 7.82 (m, 1 H) 7.82 - 7.88 (m, 1 H) 7.88 - 7.97 (m, 2 H) SFC Rt 4.08 min, 97%, MW: 562.2, Method SFC F

LCMS Rt 1.76 min, 95%, MW: 562.2, 563 [M+H] ⁺ , Method H (4-(2-((Tert-\ -2-yl)-6-chloro-5- i din-2 -yl)( 1 -(2-chloro- ethyl icyclopropyl (methanone 163

Compound 163 was synthesized according to procedure A. The crude residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield the desired product as a colorless oil (526 mg, 68%).

4-(4-(2-((Zer/-butyldimethylsilyl)oxy)propan-2-yl)-6-chlo ro-5-fluoropyridin-2-yl)-5- oxaspiror2.41heptane-4-carbonitrile 164

Compound 164 was synthesized according to procedure B. The crude residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield the desired product as a white solid (410 mg, 79%).

(4-(4-(2-((Zer/-butyldimethylsilyl)oxy)propan-2-yl)-6-chl oro-5-fluoropyridin-2-yl)-5- oxaspiror2.41heptan-4-yl)methanamine 165

Compound 165 (520 mg, 93%) was synthesized according to procedure C. The residue was used in subsequent chemistry without further purification. (4-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)pyridin-2-yl)-5- oxaspiror2.4]heptan-4-yl)methanamine 166

4-Fluorophenylboronic acid (151.8 mg, 1.1 mmol), Xantphos (104.7 mg, 0.2 mmol), and cesium carbonate (884 mg, 2.7 mmol) in water (2.2 mL) were added to a solution of compound 165 (388 mg, 0.9 mmol) in 1,4-dioxane (8.9 mL) (previously bubbled with nitrogen). Finally, bis(triphenylphosphine)palladium(II) dichloride (63.5 mg, 0.09 mmol) was added while nitrogen was bubbled through the solution and the reaction was stirred in a sealed tube at 100°C for 48 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10) to yield compound 166 as a beige foam (260 mg, 59%).

2-(6-(4-(Aminomethyl)-5-oxaspiror2.41heptan-4-yl)-3-fluor o-2-(4-fluorophenyl)pyridin-4- yl)propan-2-ol 167

Compound 167 was synthesized according to procedure D. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90:10) to yield the desired product as a colorless oil (173 mg, 87%). A-((4-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)-5- oxaspirol2.4]heptan-4-yl)methyl)-8-methoxy-3-methylcinnoline -6-carboxamide 168

Compound 168 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10) to yield the desired product as a yellow solid (17 mg, 47%).

1H NMR (400 MHz, DMSO-d6) d 8.34 (t, J = 6.1 Hz, 1H), 7.96 - 7.89 (m, 4H), 7.72 (d, J = 1.3 Hz, 1H), 7.39 - 7.32 (m, 3H), 5.60 (s, 1H), 4.25 (td, J = 8.0, 4.3 Hz, 1H), 4.12 (q, J = 7.9 Hz, 1H), 4.06 (s, 3H), 4.01 - 3.95 (m, 1H), 3.91 (dd, J = 13.4, 6.0 Hz, 1H), 2.85 (s, 3H), 2.36 (dt, J = 11.7, 8.1 Hz, 1H), 1.85 - 1.76 (m, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.09 - 1.02 (m, 1H), 0.77 - 0.69 (m, 1H), 0.34 - 0.26 (m, 1H), 0.14 - 0.04 (m, 1H)

SFC (Rt 7.01 min and 8.15 min), (52% and 47%), Method: 5 to 60% [EtOH + 0.1% DEA] Lux- Amylose-2-EtOH

LCMS Rt 3.62 min, 98%, MW: 574, 575.2 [M+H] ⁺ , Method E

HRMS Rt 4.73 min, MW: 574, 575.2 [M+H] ⁺ , Method F m.p. 144.7°C (Mettler Toledo MP50)

The enantiomers of Compound 168 were separated by SFC (column: Phenomenex Lux Amylose-2 250 x 30 mm 5 um; Isocratic 40% [2-Prop + 0.1% DEA]) to yield compound 169 as a yellow solid (28 mg, 25%) and compound 170 as a yellow solid (27 mg, 24%).

1H NMR (400 MHz, DMSO-d6) d 8.34 (t, J = 6.1 Hz, 1H), 7.96 - 7.89 (m, 4H), 7.72 (d, J = 1.3 Hz, 1H), 7.39 - 7.31 (m, 3H), 5.60 (s, 1H), 4.25 (td, J = 7.9, 4.3 Hz, 1H), 4.12 (dd, J = 15.4, 7.8 Hz, 1H), 4.06 (s, 3H), 3.99 (dd, J = 13.4, 6.3 Hz, 1H), 3.91 (dd, J = 13.4, 6.0 Hz, 1H), 2.85 (s, 3H), 2.36 (dt, J = 11.6, 8.0 Hz, 1H), 1.81 (ddd, J = 11.6, 6.9, 4.3 Hz, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.06 (dt, J = 10.2, 5.2 Hz, 1H), 0.74 (dt, J = 10.0, 4.9 Hz, 1H), 0.34 - 0.27 (m, 1H), 0.15 -

0.06 (m, 1H)

SFC Rt 8.47 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose-2-2-Prop

LCMS Rt 3.59 min, 99%, 575.2 [M+H] ⁺ , Method E

HRMS Rt 3.70 min, 575.3 [M+H] ⁺ , Method F

OR +79° (589 nm, c 0.1067 w/v, MeOH, 23°C) m.p. 213.2°C (Mettler Toledo MP50) 170

1H NMR (400 MHz, DMSO-d6) d 8.34 (t, J = 6.0 Hz, 1H), 7.97 - 7.89 (m, 4H), 7.72 (d, J = 1.1 Hz, 1H), 7.39 - 7.31 (m, 3H), 5.60 (s, 1H), 4.25 (td, J = 8.0, 4.3 Hz, 1H), 4.12 (dd, J = 15.3, 7.7 Hz, 1H), 4.06 (s, 3H), 3.99 (dd, J = 13.4, 6.2 Hz, 1H), 3.91 (dd, J = 13.4, 6.0 Hz, 1H), 2.85 (s, 3H), 2.36 (dt, J = 11.7, 8.1 Hz, 1H), 1.81 (ddd, J = 11.6, 6.9, 4.4 Hz, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.06 (dt, J = 10.3, 5.3 Hz, 1H), 0.74 (dt, J = 10.0, 5.1 Hz, 1H), 0.35 - 0.26 (m, 1H), 0.10 (dt, J = 9.9, 4.9 Hz, 1H)

SFC Rt 10.53 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose-2-2-Prop LCMS Rt 3.59 min, 99%, 575.2 [M+H] ⁺ , Method E

HRMS Rt 3.70 min, 575.3 [M+H] ⁺ , Method F OR -75° (589 nm, c 0.1000 w/v, MeOH, 23°C) m.p. 213.2°C (Mettler Toledo MP50) 3-(Difluoromethyl)-7V-((4-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)-

5-oxaspiror2.4]heptan-4-yl)methyl)-8-methoxyquinoline-6-c arboxamide 171

Compound 171 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90:10) to yield the desired product as a beige solid (78 mg, 48%).

1H NMR (400 MHz, DMSO-d6) d 9.03 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.23 (t, J = 6.0 Hz, 1H), 7.98 - 7.89 (m, 4H), 7.50 (d, J = 1.3 Hz, 1H), 7.47 - 7.18 (m, 3H), 5.59 (s, 1H), 4.33 - 4.22 (m, 1H), 4.17 - 4.09 (m, 1H), 4.05 - 3.96 (m, 4H), 3.91 (dd, J = 13.4, 6.0 Hz, 1H), 2.42 - 2.31 (m, 2H), 1.86 - 1.77 (m, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.11 - 1.03 (m, 1H), 0.79 - 0.70 (m, 1H), 0.36 - 0.26 (m, 1H), 0.15 - 0.06 (m, 1H)

SFC (Rt 6.65 min and 7.05 min), (51% and 49%), Method: 5 to 60% [2 -Prop + 0.1% DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 3.83 min, 99%, 610.2 [M+H] ⁺ , Method E

HRMS Rt 3.97 min, 610.2 [M+H] ⁺ , Method F m.p. 176.5°C (Mettler Toledo MP50)

The enantiomers of compound 171 (70 mg, 0.1 mmol) were separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 20% [2-Prop + 0.1% DEA]) to yield compound 172 as a white solid (27 mg, 38%) and compound 173 as a white solid (26 mg, 37%).

1H NMR (400 MHz, DMSO-d6) d 9.03 (d, J = 1.9 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.23 (t, J = 6.0 Hz, 1H), 7.96 - 7.90 (m, 4H), 7.50 (d, J = 1.2 Hz, 1H), 7.48 - 7.18 (m, 3H), 5.60 (s, 1H), 4.27 (td, J = 8.0, 4.3 Hz, 1H), 4.13 (q, J = 7.8 Hz, 1H), 4.04 - 3.97 (m, 4H), 3.91 (dd, J = 13.4, 5.9 Hz, 1H), 2.37 (dt, J = 12.0, 8.2 Hz, 1H), 1.82 (ddd, J = 11.7, 6.9, 4.4 Hz, 1H), 1.55 (s, 3H), l.45 (s, 3H), 1.10 - 1.03 (m, 1H), 0.74 (dt, J = 10.0, 5.1 Hz, 1H), 0.35 - 0.26 (m, 1H), 0.10 (dt, J = 9.7, 4.8 Hz, 1H)

SFC Rt 6.60 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1 -2-Prop

LCMS Rt 3.83 min, 99%, 610.2 [M+H] ⁺ , Method E

HRMS Rt 4.02 min, 610.3 [M+H] ⁺ , Method F

OR -65° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 143°C (Mettler Toledo MP50) 173

1H NMR (400 MHz, DMSO-d6) d 9.03 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.23 (t, J = 6.1 Hz, 1H), 7.97 - 7.89 (m, 4H), 7.50 (d, J = 1.3 Hz, 1H), 7.48 - 7.18 (m, 3H), 5.60 (s, 1H), 4.27 (td, J = 8.0, 4.3 Hz, 1H), 4.13 (q, J = 7.8 Hz, 1H), 4.04 - 3.97 (m, 4H), 3.91 (dd, J = 13.4, 6.0 Hz, 1H), 2.37 (dt, J = 12.0, 8.2 Hz, 1H), 1.81 (ddd, J = 11.5, 6.8, 4.3 Hz, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.11 - 1.03 (m, 1H), 0.74 (dt, J = 9.9, 5.1 Hz, 1H), 0.35 - 0.27 (m, 1H), 0.10 (dt, J = 9.8, 4.8 Hz, 1H)

SFC Rt 7.00 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.83 min, 99%, 610.2 [M+H] ⁺ , Method E HRMS Rt 4.05 min, 610.3 [M+H] ⁺ , Method F OR +94° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 141.4°C (Mettler Toledo MP50) l-(4-(2-((Ter/-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro- 5-fluoropyri din-2 -yl)-4-chl oro-2,2- dimethylbutan- 1-one 174

Into a round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 56 (795 mg, 1.8 mmol) and Copper(I) cyanide di(lithium chloride) complex solution

(64.6 pL, 0.99 g/mL, 0.4 mmol) in dry THF (8 mL). This was followed by the dropwise addition of isopropylmagnesiumchloride lithiumchloride complex (1.3 M in THF) (2.1 mL, 2.8 mmol) at -15°C. To this solution was added 4-chloro-2,2-dimethylbutanoyl chloride (395 mg, 2.2 mmol) in dry THF (2 mL) dropwise at -15°C. The resulting solution was agitated for 45 minutes at - 10°C. The mixture was warmed to 0°C. The reaction was quenched with aqueous saturated NH4CI solution. The resulting mixture was further agitated at room temperature for 20 minutes. The solution was extracted with EtOAc. The organic layer was dried (MgSCL), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 100:0) to yield compound 174 (567 mg, 69%).

2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-6-chlor o-5-fluoropyridin-2-yl)-3,3- dimethyltetrahydrofuran-2-carbonitrile 175 Compound 175 was synthesized according to procedure B. The crude residue was purified by flash column chromatography (EtOAc/heptane, gradient form 0: 100 to 15:85) to yield the desired product as a white solid (770 mg, 65%).

2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)pyridin-2-yl)-3,3- dimethyltetrahydrofuran-2-carbonitrile 176

A solution of CS2CO3 (1.8 g, 5.5 mmol) in water (5 mL) was added to a stirred solution of compound 175 (770 mg, 1.8 mmol) and 4-Fluorobenzeneboronic acid (330 mg, 2.4 mmol) in 1,4-dioxane (18 mL). The mixture was bubbled with nitrogen for 10 min, Pd(dppf)C12 (150 mg, 0.18 mmol) was added at room temperature. The reaction mixture was stirred at 100°C under nitrogen atmosphere for 16 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield compound 176 as a yellow oil (817 mg, 90%).

(2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluo ro-6-(4-fluorophenyl)pyridin-2-yl)-

3,3-dimethyltetrahydrofuran-2-yl)methanamine 177

Compound 177 (750 mg, 92%), was synthesized according to procedure C. The crude residue was used in subsequent chemistry without further purification. 2-(6-(2-(Aminomethyl)-3,3-dimethyltetrahydrofuran-2-yl)-3-fl uoro-2-(4-fluorophenyl)pyri din-4- yl)propan-2-ol 178

Compound 178 was synthesized according to procedure D. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 0: 100 to 80:20) to yield the desired product as a colorless oil (612 mg, 100%).

3-(Difluoromethyl)-A-((2-(5-fluoro-6-(4-fluorophenyl)-4-( 2-hydroxypropan-2-yl)pyridin-2-yl)-

3,3-dimethyltetrahydrofuran-2-yl)methyl)-8-methoxyquinoli ne-6-carboxamide 179

Compound 179 were synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10). The enantiomers were separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 20% [EtOH + 0.3% IP A]) to yield compound 180 as a white solid (22 mg, 7%) and compound 181 as a white solid (20 mg, 6%).

1H NMR (400 MHz, DMSO-d6) d 9.02 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 1.4 Hz, 1H), 8.03 - 7.96 (m, 3H), 7.87 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.48 - 7.15 (m, 4H), 5.56 (s, 1H),

4.20 - 4.09 (m, 2H), 4.05 - 4.00 (m, 1H), 3.98 (s, 3H), 3.76 (dd, J = 13.1, 5.3 Hz, 1H), 2.34 -

2.21 (m, 1H), 1.94 - 1.84 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.64 (s, 3H) SFC Rt 4.41 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH LCMS Rt 4.05 min, 99%, 612.2 [M+H] ⁺ , Method E HRMS Rt 4.17 min, 612.3 [M+H] ⁺ , Method F OR -109° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 168.1°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO-d6) d 9.02 (s, 1H), 8.56 (s, 1H), 8.04 - 7.96 (m, 3H), 7.87 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.48 - 7.18 (m, 4H), 5.56 (s, 1H), 4.19 - 4.09 (m, 2H), 4.02 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.76 (dd, J = 13.1, 5.3 Hz, 1H), 2.34 - 2.20 (m, 1H), 1.93 - l.84 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.64 (s, 3H) SFC Rt 4.75 min, 98%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH LCMS Rt 3.87 min, 98%, 612.2 [M+H] ⁺ , Method E HRMS Rt 4.17 min, 612.3 [M+H] ⁺ , Method F OR +84° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 166.4°C (Mettler Toledo MP50)

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-3,3-dimethyl- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 182 Compound 182 were synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10). The enantiomers were separated by SFC (column: Phenomenex Lux i-Amylose-A 250 x 30 mm 5 um; Isocratic 20% [EtOH + 0.3% DEA]) to yield compound 183 as a yellow solid (30 mg, 9%) and compound 184 as a yellow solid (24 mg, 8%). 183

1H NMR (400 MHz, DMSO-d6) d 8.10 (t, J = 6.0 Hz, 1H), 8.00 (dd, J = 7.6, 5.7 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), 7.26 (d, J = l.1 Hz, 1H), 5.56 (s, 1H), 4.20 - 4.09 (m, 2H), 4.07 - 3.96 (m, 4H), 3.74 (dd, J = 13.1, 5.4 Hz, 1H), 2.85 (s, 3H), 2.32 - 2.20 (m, 1H), 1.94 - 1.83 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.64 (s, 3H)

SFC Rt 4.36 min, 97%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH

LCMS Rt 3.53 min, 97%, 577.2 [M+H] ⁺ , Method E

HRMS Rt 3.85 min, 577.3 [M+H] ⁺ , Method F

OR +133° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 174.8°C (Mettler Toledo MP50) 184

1H NMR (400 MHz, DMSO-d6) d 8.10 (t, J = 6.0 Hz, 1H), 8.00 (dd, J = 7.6, 5.8 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), 7.26 (d, J = 1.1 Hz, 1H), 5.56 (s, 1H), 4.19 - 4.08 (m, 2H), 4.06 - 3.97 (m, 4H), 3.74 (dd, J = 13.1, 5.4 Hz, 1H), 2.85 (s, 3H), 2.31 - 2.20 (m, 1H), 1.93 - 1.84 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.64 (s, 3H)

SFC Rt 4.61 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH LCMS Rt 3.58 min, 99%, 577.2 [M+H] ⁺ , Method E HRMS Rt 3.84 min, 577.3 [M+H] ⁺ , Method F OR -212° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 178.1°C (Mettler Toledo MP50) l-(4-(2-((Tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro- 5-fluoropyri din-2 -yl)-4-chloro-2- methylbutan-l-one 185

Compound 185 was synthesized according to procedure A. The crude residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield the desired product as a yellowish oil (253 mg, 20%). 2-(4-(2-((Ter/-butyldimethylsilyl)oxy)propan-2 -yl)-6-chloro-5-fluoropyri din-2 -yl)-3-methyl- tetrahydrofuran-2-carbonitrile 186

Compound 186 was synthesized according to procedure B. The crude residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield the desired product as a yellowish oil which solidified upon standing under high vacuum (688 mg, 59%).

2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)pyridin-2-yl)-3- methyltetrahydrofuran-2-carbonitrile 187

A solution of CS2CO3 (1.1 g, 3.2 mmol) in water (2.7 mL) was added to a stirred solution of compound 186 (688 mg, 1.1 mmol) and 4-Fluorobenzeneboronic acid (227 mg, 1.6 mmol) in 1,4-dioxane (11 mL). The mixture was bubbled with nitrogen for 10 min, Pd(dppf)C12 (88.4 mg, 0.11 mmol) was added at room temperature. The reaction mixture was stirred at 100°C under nitrogen atmosphere for 16 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield compound 187 as a yellowish sticky oil (647 mg, 82%). (2-(4-(2-((Zer/-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)pyridin-2-yl)-3- methyltetrahydrofuran-2-yl)methanamine 188

Compound 188 was synthesized according to procedure C for 48 h to yield the desired product as a yellowish oil (653 mg, 100%).

2-(6-(2-(Aminomethyl)-3-methyltetrahydrofuran-2-yl)-3-flu oro-2-(4-fluorophenyl)pyridin-4- yl)propan-2-ol 189

Compound 189 (255 mg, 73%) was synthesized according to procedure D. The crude residue was used in subsequent chemistry without further purification.

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)-3-methyl- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 190

Compound 190 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95). The resulting residue was repurified by FCC reverse phase (Gemini C18 100 x 30 mm 5 um) (from 75% [65 mM NH ₄ OAC + ACN (90: 10)] - 25% [ACN] to 38% [65 mM NH ₄ OAc + ACN (90: 10)] - 62% [ACN]). The products obtained were extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 190 as a yellowish solid (99 mg, 42%). 1H NMR (400 MHz, DMSO-d6) d 8.29 (t, J = 6.0 Hz, 1H), 7.98 (dd, J = 7.5, 5.6 Hz, 2H), 7.90 - 7.85 (m, 2H), 7.67 (d, J = 1.4 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.31 (d, J = 1.3 Hz, 1H), 5.53 (s, 1H), 4.18 - 4.11 (m, 1H), 4.05 (s, 3H), 4.04 - 3.99 (m, 1H), 3.90 (q, J = 7.8 Hz, 1H), 3.64 (dd, J = 13.3, 5.2 Hz, 1H), 2.85 (s, 3H), 2.63 - 2.56 (m, 1H), 2.13 - 2.02 (m, 1H), 1.86 - 1.75 (m, 1H), l.52 (s, 3H), 1.35 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H)

SFC (Rt 8.14 min and 9.08 min), (50% and 50%), Method: 5 to 60% [2Prop + 0.1% DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 3.66 min, 99%, 563.2 [M+H] ⁺ , Method E

HRMS Rt 3.69 min, 563.3 [M+H] ⁺ , Method F m.p. 186.5°C (Mettler Toledo MP50)

The enantiomers of compound 190 (80.8 mg, 0.1 mmol) were separated by SFC (column: Lux i- Cellulose-C, 250 x 30 mm, 5 um; Isocratic 35% [MeOH + 0.1% DEA]) to yield compound 191 as a yellowish solid (24 mg, 30%) and compound 192 as a yellowish solid (26 mg, 32%). 191

1H NMR (400 MHz, DMSO-d6) d 8.29 (t, J = 6.1 Hz, 1H), 7.98 (dd, J = 7.6, 5.6 Hz, 2H), 7.90 - 7.85 (m, 2H), 7.67 (d, J = 1.3 Hz, 1H), 7.35 (t, J = 8.9 Hz, 2H), 7.31 (d, J = 1.2 Hz, 1H), 5.54 (s, 1H), 4.17 - 4.11 (m, 1H), 4.05 (s, 3H), 4.04 - 3.99 (m, 1H), 3.90 (q, J = 7.9 Hz, 1H), 3.64 (dd, J = 13.3, 5.2 Hz, 1H), 2.85 (s, 3H), 2.63 - 2.56 (m, 1H), 2.13 - 2.02 (m, 1H), 1.86 - 1.75 (m, 1H), l.52 (s, 3H), 1.35 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H)

SFC Rt 1.18 min, 99%, Method: 5 to 60% [2Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.44 min, 99%, 563.2 [M+H] ⁺ , Method E

HRMS Rt 3.62 min, 563.3 [M+H] ⁺ , Method F

OR +99° (589 nm, c 0.066 w/v, MeOH, 23°C) m.p. 173.1 °C (Mettler Toledo MP50) 1H NMR (400 MHz, DMSO-d6) d 8.29 (t, J = 6.0 Hz, 1H), 7.98 (dd, J = 7.6, 5.7 Hz, 2H), 7.90 - 7.85 (m, 2H), 7.67 (d, J = 1.3 Hz, 1H), 7.35 (t, J = 8.9 Hz, 2H), 7.31 (d, J = 1.3 Hz, 1H), 5.54 (s, 1H), 4.18 - 4.10 (m, 1H), 4.05 (s, 3H), 4.04 - 3.99 (m, 1H), 3.90 (q, J = 7.8 Hz, 1H), 3.64 (dd, J = 13.3, 5.2 Hz, 1H), 2.85 (s, 3H), 2.63 - 2.55 (m, 1H), 2.13 - 2.03 (m, 1H), 1.87 - 1.74 (m, 1H), l.52 (s, 3H), 1.35 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H).

SFC Rt 1.12 min, 99%, Method: 5 to 60% [2Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.35 min, 99%, 563.2 [M+H] ⁺ , Method E

HRMS Rt 3.67 min, 563.3 [M+H] ⁺ , Method F OR -147° (589 nm, c 0.066 w/v, MeOH, 23°C) m.p. 168.0°C (Mettler Toledo MP50)

3-(Difluoromethvl)-A-((2-(5-fluoro-6-(4-: I-4-C2-] -2-vl)Dvridin-2-vD-

3-methvltetrahvdrofuran-2-vl)methvl)-8-i :-6-carboxamide 193

Compound 193 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 05:95). The desired fractions were collected and concentrated in vacuo. The resulting product was repurified by FCC reverse phase (Gemini C18 100 x 30 mm 5 um) (from 47% [25 mM NH4HCO3] - 53% [MeCN:MeOH 1 : 1] to 18% [25 mM NH ₄ HCO ₃ ] - 82% [MeCN:MeOH 1 : 1]). The products obtained were extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 193 as a white solid (79 mg, 46%). 1H NMR (400 MHz, DMSO-d6) d 9.03 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 1.5 Hz, 1H), 8.18 (t, J = 6.0 Hz, 1H), 7.98 (dd, J = 7.5, 5.6 Hz, 2H), 7.89 (dd, J = 7.1, 3.5 Hz, 2H), 7.48 - 7.18 (m, 4H), 5.53 (s, 1H), 4.15 (dt, J = 8.2, 4.1 Hz, 1H), 4.03 (dd, J = 13.3, 6.8 Hz, 1H), 3.98 (s, 3H), 3.91 (q, J = 7.8 Hz, 1H), 3.67 (dd, J = 13.3, 5.3 Hz, 1H), 2.59 (dd, J = 15.3, 7.5 Hz, 1H), 2.14 - 2.03 (m, 1H), 1.87 - 1.76 (m, 1H), 1.52 (s, 3H), 1.37 - 1.30 (m, 6H)

SFC (Rt 5.07 min and 6.73 min), (54% and 46%), Method: 5 to 60% [2Prop + 0.1% DEA] Lux- Amylose- 1 -2 -Prop

LCMS Rt 3.80 min, 98%, 598.2 [M+H] ⁺ , Method E

HRMS Rt 3.98 min, 598.3 [M+H] ⁺ , Method F m.p. 210.0°C (Mettler Toledo MP50)

The enantiomers of compound 193 (67 mg, 0.1 mmol) were separated by SFC (Column: Lux i- Cellulose-C, 250 x 30 mm, 5 um; Isocratic 30% [EtOH + 0.1% DEA]) to yield compound 194 (25 mg, 34%) as a white solid and compound 195 (25 mg, 38%) as a white solid.

1H NMR (400 MHz, DMSO-d6) d 9.03 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.18 (t, J = 6.0 Hz, 1H), 7.98 (dd, J = 7.5, 5.7 Hz, 2H), 7.89 (dd, J = 7.3, 3.5 Hz, 2H), 7.47 - 7.17 (m, 4H), 5.53 (s, 1H), 4.15 (td, J = 8.1, 4.4 Hz, 1H), 4.03 (dd, J = 13.3, 6.8 Hz, 1H), 3.98 (s, 3H), 3.91 (q, J = 7.9 Hz, 1H), 3.67 (dd, J = 13.2, 5.2 Hz, 1H), 2.62 - 2.58 (m, 1H), 2.13 - 2.04 (m, 1H), 1.86 - l.75 (m, 1H), 1.52 (s, 3H), 1.36 - 1.31 (m, 6H)

SFC Rt 4.74 min, Method: 5 to 60% [2Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.69 min, 98%, 598.2 [M+H] ⁺ , Method E

HRMS Rt 3.97 min, 598.3 [M+H] ⁺ , Method F OR -94° (589 nm, c 0.066 w/v, MeOH, 23°C) m.p. 141.3°C (Mettler Toledo MP50) 1H NMR (400 MHz, DMSO-d6) d 8.90 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.05 (t, J = 5.9 Hz, 1H), 7.85 (dd, J = 7.5, 5.7 Hz, 2H), 7.76 (dd, J = 7.2, 3.5 Hz, 2H), 7.35 - 7.04 (m, 4H), 5.40 (s, 1H), 4.02 (td, J = 8.3, 4.4 Hz, 1H), 3.94 - 3.87 (m, 1H), 3.85 (s, 3H), 3.78 (q, J = 7.7 Hz, 1H), 3.54 (dd, J = 13.3, 5.2 Hz, 1H), 2.50 - 2.44 (m, 1H), 2.00 - 1.90 (m, 1H), 1.74 - 1.62 (m, 1H), 1.39 (s, 3H), 1.25 - 1.17 (m, 6H).

SFC Rt 6.13 min, Method: 5 to 60% [2Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.86 min, 99%, 598.2 [M+H] ⁺ , Method E

HRMS Rt 3.95 min, 598.3 [M+H] ⁺ , Method F

OR +159° (589 nm, c 0.066 w/v, MeOH, 23°C) m.p. 129.6°C (Mettler Toledo MP50)

l-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-6-chloro-5 -fluoropyridin-2-yl)-5- chloropentan-l-one 196

Isopropylmagnesium chloride lithium chloride complex solution (1.3 M, 8.9 mL, 11.6 mmol) was added dropwise to a stirred solution of compound 56 (2.0 g, 4.7 mmol) in dry THF (20 mL) at

-30°C under nitrogen. A solution of 5-chloro-A-methoxy-A-methylpentanamide [138344-21-5] (1.7 g, 9.3 mmol) in dry THF (4 mL) was added to the mixture under nitrogen at -30°C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water. 10% aqueous H2SO4 solution was added until pH = 3. The mixture was extracted with EtOAc (3 x 150 mL). The organic layers were separated, combined, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by reverse phase (Phenomenex Gemini C18 30 x 100 mm 5 pm Column; from 25% [25 mM NH4HCO3] - 75% MeCN to 0% [25 mM NH4HCO3] - 100% MeCN) to yield compound 196 as a colorless oil (1.07 g, 54%).

3-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chlo ro-5-fluoropyridin-2-yl)-7-chlorohept- l-en-3-ol 197

Vinylmagnesium bromide solution (1 M, 3.0 mL, 3.0 mmol) was added to a stirred solution of compound 196 (1.1 g, 2.5 mmol) in dry THF (17 mL) at -30°C under nitrogen. The reaction was stirred for 3 h with an increase of the temperature from -30°C to 0°C. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 30:70) to yield compound 197 as a colorless oil (983 mg, 86%).

4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloro- 3-fluoro-6-(2-vinyltetrahydro-2H- pyran-2-yl)pyridine 198

Potassium bis(trimethylsilyl)amide solution (1 M in THF, 2.2 mL, 2.2 mmol) was added to a stirred solution of compound 197 (980 mg, 2.2 mmol) in dry THF (32 mL) at 0°C under nitrogen. The reaction was stirred for 30 minutes. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 20:80) to yield compound 198 as a colorless oil (866 mg, 95%).

4-(2-((TerLbutyldirnethylsilyl)oxy)propan-2-yl)-3-fluoro- 2-(4-fluorophenyl)-6-(2-vinyl- tetrahydro-2//-pyran-2-yl (pyridine 199

A solution of cesium carbonate (2.0 g, 6.2 mmol) in degassed water (3 mL) was added to a stirred solution of compound 198 (861 mg, 2.1 mmol) and (4-Fluorophenyl)boronic acid (349 mg, 2.5 mmol) in degassed 1,4-dioxane (10 mL) at room temperature while nitrogen was bubbling. The mixture was stirred at room temperature for 5 minutes while nitrogen was bubbling. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (170.2 mg, 0.2 mmol) was added and the mixture was stirred in a sealed tube at 100°C for 18 h. The mixture was allowed to cool to room temperature. The mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 199 as a yellowish oil (780 mg, 78%). l-(2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-2H-pyran-2-yl)ethane-E2-diol 200

Osmium tetroxide (4% in water, 589 pL, 0.1 mmol) was added to a stirred solution of compound 199 (776 mg, 1.6 mmol), 2,6-lutidine (558 pL, 0.92 g/mL, 4.8 mmol) and 4-methylmorpholine A -ox ide (451 mg, 3.9 mmol) in acetone/water (10: 1, v/v, 24 mL) at room temperature. The mixture was stirred for 3 days at room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 12:88) to yield compound 200 as a viscous yellowish oil (764 mg, 94%).

2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-2H-pyran-2-carbaldehyde 201

Sodium periodate (384.2 mg, 1.8 mmol) was added to a stirred mixture of compound 200 (760 mg, 1.5 mmol) in THF (6 mL) and water (3 mL) at room temperature, and the mixture was stirred for 3 h. The organic solvent was evaporated in vacuo and the aqueous phase was extracted with EtOAc (x 3). The organic layers were separated, combined, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield compound 201 as a yellow oil (408 mg, 69%). The crude product was used in the next step without further purification. (2-(4-(2-((Zer/-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro -6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-2H-pyran-2-yl)methanol 202

Sodium borohydride (58.5 mg, 1.5 mmol) was added to a solution compound 201 (736 mg, 1.5 mmol) in methanol (8 mL) at 0°C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 202 as a white solid (624 mg, 84%).

2-((2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-f luoro-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-27/-pyran-2-yl (methyl )isoindoline- 1.3-di one 203

DIAD (383 pL, 1.03 g/mL, 1.9 mmol) was added dropwise to a stirred solution of compound 202 (619 mg, 1.3 mmol), phthalimide (210 mg, 1.4 mmol) and triphenylphosphine (510 mg, 1.9 mmol) in dry THF (2 mL) under nitrogen at 50°C. The mixture was stirred at 50°C for 4 h. The solvents were evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 203 as an off-white solid (736 mg, 84%). (2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-2H-pyran-2-yl)methanamine 204

Hydrazine hydrate (134 pL, 1.03 g/mL, 2.4 mmol) was added to stirred solution of compound 203 (360 mg, 0.6 mmol) in ethanol (9 mL) at room temperature. The mixture was stirred at 40°C for 16 h. The mixture was diluted with 0.2 M aqueous solution NaOH (10 mL) and extracted with DCM (x 3). The organic layer was separated, combined, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 204 as a sticky transparent oil (270 mg, 96%). The crude product was used in the next step without further purification.

A-((2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5- fluoro-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydro-2H-pyran-2-yl)methyl)-8-methoxy-3-methylcinnoline -6-carboxamide 205

HATU (113.2 mg, 0.3 mmol) was added to a solution of compound 21 (47.7 mg, 0.2 mmol) and DIPEA (81.7 pL, 0.8 g/mL, 1.0 mmol) in DMF (1 mL) at room temperature. After 10 minutes stirring, compound 204 (104 mg, 0.2 mmol, 91% purity) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and DCM. The aqueous layer was separated and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 205 as a sticky yellow solid (119 mg, 74%). A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)tetrahydro-2H-pyran- 2-yl)methyl)-8-m ethoxy-3 -methylcinnoline-6-carboxamide 206

TBAF (1 M in THF, 0.4 mL, 0.4 mmol) was added to a stirred solution of compound 205 (115 mg, 0.1 mmol) in THF (2 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layers were separated, combined, washed with brine (x 3), dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0). The desired fractions were collected and concentrated in vacuo. The crude residue was triturated with DIPE to yield compound 206 as a pale yellow solid (60 mg, 74%).

1H NMR (400 MHz, CDCh) d 7.96 - 7.89 (m, 2H), 7.80 (d, J = 5.5 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.13 (s, 1H), 7.12 - 7.04 (m, 3H), 4.05 (s, 3H), 3.99 (dd, J = 13.3, 6.7 Hz, 1H), 3.91 (dt, J = 9.4, 4.3 Hz, 1H), 3.68 (ddd, J = 11.9, 8.8, 3.2 Hz, 1H), 3.61 - 3.54 (m, 1H), 2.88 (s, 3H), 2.51 - 2.43 (m, 1H), 1.99 (d, J = 1.3 Hz, 1H), 1.84 (ddd, J = 13.6, 9.7, 4.0 Hz, 1H), 1.79 - 1.70 (m, 1H), 1.70 - 1.60 (m, 4H), 1.58 (s, 3H), 1.55 - 1.40 (m, 2H) LCMS Rt 3.57 min, 99%, 563.2 [M+H] ⁺ , Method E HRMS Rt 3.55, 563.3 [M+H] ⁺ , Method F m.p. 164.7°C (Mettler Toledo MP50)

The enantiomers of compound 206 (50 mg, 0.09 mmol) were separated by SCF (AMYLOSE-1; (isocratic) [30% methanol - 0.1% DEA] - 70% CO2). The desired fractions were collected and concentrated in vacuo. DIPE was added and the solvents were evaporated in vacuo to yield compound 207 as a pale yellow solid (20 mg, 40%) and 208 as a pale yellow solid (22 mg, 44%). 1H NMR (400 MHz, CDCh) d 8.02 - 7.97 (m, 2H), 7.87 (d, J = 5.5 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 7.20 (s, 1H), 7.19 - 7.11 (m, 3H), 4.12 (s, 3H), 4.06 (dd, J = 13.4, 6.8 Hz, 1H), 3.98 (dt, J = 9.5, 4.2 Hz, 1H), 3.75 (ddd, J = 11.9, 8.9, 3.3 Hz, 1H), 3.64 (dd, J = 13.4, 4.3 Hz, 1H), 2.95 (s, 3H), 2.54 (ddd, J = 12.9, 6.2, 3.8 Hz, 1H), 2.09 (d, J = 1.1 Hz, 1H), 1.91 (ddd, J = 13.5, 9.7, 3.9 Hz, 1H), 1.86 - 1.77 (m, 1H), 1.77 - 1.67 (m, 4H), 1.64 (s, 3H), 1.62 - 1.47 (m, 2H)

SFC Rt 5.69 min, 99%, Method: [30% MeOH - 0.1% DEA] - 70% CO ₂

LCMS Rt 3.55 min, 99%, 563.2 [M+H] ⁺ , Method E

HRMS Rt 4.45 min, 563.3 [M+H] ⁺ , Method F

1H NMR (400 MHz, CDCh) d 8.02 - 7.96 (m, 2H), 7.87 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H), 7.20 (s, 1H), 7.19 - 7.12 (m, 3H), 4.12 (s, 3H), 4.07 (dd, J = 13.4, 6.8 Hz, 1H), 4.01 - 3.94 (m, 1H), 3.80 - 3.72 (m, 1H), 3.64 (dd, J = 13.4, 4.3 Hz, 1H), 2.95 (s, 3H), 2.59 - 2.49 (m, 1H), 2.05 (d, J = 1.3 Hz, 1H), 1.91 (ddd, J = 13.5, 9.8, 4.0 Hz, 1H), 1.86 - 1.78 (m, 1H), 1.77 - 1.67 (m, 4H), 1.64 (s, 3H), 1.55 (s, 2H)

SFC Rt 5.16 min, 99%, Method: [30% MeOH - 0.1% DEA] - 70% CO ₂

LCMS Rt 3.55 min, 99%, 563.2 [M+H] ⁺ , Method E

HRMS Rt 4.44 min, 563.3 [M+H] ⁺ , Method F A-((2-(4-(2-((ter/-butyldimethylsilyl)oxy)propan-2-yl)-5-flu oro-6-(4-fluorophenyl)pyridin-2- yl)tetrahydro-2J/-pyran-2-yl)methyl)-5-methoxy-1H-pyrrolo[2, 3-c1pyridine-2-carboxamide 209

HATU (83.8 mg, 0.2 mmol) was added to a solution of 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2- carboxylic acid [17288-36-7] (38.6 mg, 0.2 mmol) and DIPEA (60.4 pL, 0.8 g/mL, 0.4 mmol) in DMF (1 mL) at room temperature. After 10 minutes stirring, compound 202 (70 mg, 0.1 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and DCM. The aqueous layer was separated and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 209 as a yellowish solid (53 mg, 56%).

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)tetrahydro-2J/-pyran-

2-yl)methyl)-5-methoxy-17/-pyrrolo[2,3-c1pyridine-2-carbo xamide

Compound 209 (49 mg, 0.08 mmol) was dissolved in THF (1 mL). TBAF (1 M solution in THF, 264 pL, 0.3 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc and washed with water, the organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 97:3). The desired fractions were joined and evaporated to dryness in order to be repurified by reverse phase using the following method: (Phenomenex, Gemini C18, 100 x 30 mm, 5 pm;) started (70% [25 mM NH4HCO3] - 30% [ACN]) finished (27% [25 mM NH ₄ HCO ₃ ] - 73% [ACN]). The desired fractions were concentrated in vacuo and was then co-evaporated three times with 8 mL of ACN (bath temperature was set to 60°C) to yield Compound 210 as a white powder (8 mg, 20%). 1H NMR (400 MHz, DMSO-d6) d 11.63 (s, 1H), 8.47 (t, J = 6.2 Hz, 1H), 8.34 (s, 1H), 7.90 (dd, J = 7.7, 5.7 Hz, 2H), 7.77 (d, J = 5.5 Hz, 1H), 7.29 (t, J = 8.9 Hz, 2H), 7.01 (s, 1H), 6.87 (d, J = 0.8 Hz, 1H), 5.42 (s, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.82 (s, 3H), 3.67 - 3.43 (m, 3H), 2.70 - 2.56 (m, 1H), 1.81 - 1.63 (m, 3H), 1.50 (s, 3H), 1.48 - 1.38 (m, 1H), 1.33 (s, 4H)

SFC (Rt 6.76 min and 8.43 min), (50% and 50%), Method: 5 to 60% [MeOH + 0.1% DEA] Lux- Amylose-l-MeOH

LCMS Rt 3.17 min, 99%, 537.2 [M+H] ⁺ , Method E

HRMS Rt 4.11 min, 537.2 [M+H] ⁺ , Method F m.p 240.1°C (Mettler Toledo MP50)

2-(6-(2-(aminomethyl)tetrahydro-2H-pyran-2-yl)-3-fluoro-2 -(4-fluorophenyl)pyridin-4- yl)propan-2-ol 211

Compound 202 (270 mg, 0.6 mmol) was dissolved in THF (7 mL). TBAF (1 M solution in THF, 850 pL, 0.8 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc and washed with a saturated aqueous NaHCO ₃ solution and brine. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 211 as a yellowish oil (203 mg, 99%). A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)tetrahydro-2//-pyran-

2-yl)methyl)-2-(l-fluorocyclopropyl)-8-methoxyimidazorE2- a]pyridine-6-carboxamide 212

Compound 212 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 96:4) to yield the desired product 212 as an off-white powder (25 mg, 75%).

1H NMR (400 MHz, DMSO) d 8.53 (d, J = 1.2 Hz, 1H), 8.42 (t, J = 6.2 Hz, 1H), 7.97 - 7.88 (m, 3H), 7.81 (d, J = 5.5 Hz, 1H), 7.31 (t, J = 8.9 Hz, 2H), 6.92 (d, J = 1.0 Hz, 1H), 5.56 (s, 1H), 3.89 (s, 3H), 3.84 (s, 1H), 3.60 (dd, J = 13.4, 6.8 Hz, 1H), 3.55 - 3.43 (m, 2H), 2.76 - 2.62 (m, 1H), l.74 - 1.63 (m, 2H), 1.61 - 1.55 (m, 1H), 1.53 (s, 3H), 1.47 (ddd, J = 19.0, 8.0, 5.5 Hz, 3H), 1.38

(s, 3H), 1.27 - 1.18 (m, 3H)

SFC (Rt 4.80 min and 5.18 min), (50% and 50%), Method: 5 to 60% [EtOH + 0.1% DEA] Lux- Amylose-1 -EtOH LCMS Rt 3.72 min, 99%, 595.2 [M+H] ⁺ , Method E

HRMS Rt 5.07 min, 595.3 [M+H] ⁺ , Method F m.p. 137.9°C (Mettler Toledo MP50) 2-Cyclopropyl-A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydrox ypropan-2-yl)pyridin-2- yl)tetrahydro-2//-pyran-2-yl)methyl)-4- 6-carboxamide 213

Compound 213 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 96:4) to yield the desired product as a yellowish powder (18 mg, 75%).

1H NMR (400 MHz, DMSO-d6) d 8.29 (t, J = 6.3 Hz, 1H), 7.92 (dd, J = 7.7, 5.7 Hz, 2H), 7.80 (d, J = 5.5 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.31 (t, J = 8.9 Hz, 2H), 7.22 (d, J = 0.9 Hz, 1H), 5.49 (s, 1H), 3.90 (s, 3H), 3.89 - 3.82 (m, 1H), 3.63 - 3.44 (m, 3H), 2.69 - 2.58 (m, 1H), 2.30 -

2.19 (m, 1H), 1.77 - 1.27 (m, 11H), 1.22 - 1.16 (m, 2H), 1.14 - 1.10 (m, 2H).

SFC (Rt 5.65 min and 6.21 min), (51% and 49%), Method: 5 to 60% [2Prop + 0.1% DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 4.01 min, 99%, 578.3 [M+H] ⁺ , Method E HRMS Rt 5.32 min, 578.2 [M+H] ⁺ , Method F m.p. 129.6°C (Mettler Toledo MP50) A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)tetrahydro-2//-pyran-

2-yl)methyl)-8-methoxy-3-(trifluoromethyl)quinoline-6-car boxamide 214

Compound 214 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 4:96) to yield the desired product as a white powder (21 mg, 81%).

1H NMR (400 MHz, DMSO) d 9.17 (d, J = 2.1 Hz, 1H), 8.79 (s, 1H), 8.55 (t, J = 6.3 Hz, 1H), 8.03 (s, 1H), 7.93 (dd, J = 7.8, 5.8 Hz, 2H), 7.86 (d, J = 5.5 Hz, 1H), 7.57 (s, 1H), 7.29 (t, J = 8.9 Hz, 2H), 5.58 (s, 1H), 4.00 (s, 3H), 3.93 - 3.82 (m, 1H), 3.72 - 3.45 (m, 3H), 2.75 - 2.61 (m, 1H), 1.79 - 1.65 (m, 3H), 1.53 (s, 3H), 1.49 - 1.40 (m, 1H), 1.38 (s, 3H), 1.37 - 1.30 (m, 1H) SFC (Rt 4.49 min and 6.20 min), (59% and 41%), Method: 5 to 60% [MeOH + 0.1% DEA] Lux- Amylose-l-MeOH

LCMS Rt 4.07 min, 98%, 616.2 [M+H] ⁺ , Method E HRMS Rt 4.75 min, 616.2 [M+H] ⁺ , Method F m.p. 151.4°C (Mettler Toledo MP50) 3-(Difluoromethyl)-A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-h ydroxypropan-2-yl)pyridin-2- yl)tetrahydro-2//-pyran-2-yl)methyl)-8-methoxyquinoline-6-ca rboxamide 215

Compound 215 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 6:94) to yield the desired product as a white-off powder (20 mg, 80%).

NMR 1H NMR (400 MHz, DMSO) d 9.04 (d, J = 1.7 Hz, 1H), 8.56 - 8.48 (m, 2H), 7.98 (d, J = 1.1 Hz, 1H), 7.93 (dd, J = 7.8, 5.8 Hz, 2H), 7.86 (d, J = 5.5 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.33 (t, J = 55.2 Hz, 1H), 7.30 (t, J = 8.9 Hz, 2H), 5.55 (s, 1H), 3.98 (s, 3H), 3.92 - 3.83 (m, 1H),

3.69 - 3.46 (m, 3H), 2.77 - 2.60 (m, 1H), 1.80 - 1.66 (m, 2H), 1.64 - 1.55 (m, 1H), 1.53 (s, 3H), l.50 - 1.41 (m, 1H), 1.38 (s, 3H), 1.37 - 1.27 (m, 1H)

SFC (Rt 5.28 min and 7.32 min), (56% and 44%), Method: 5 to 60% [MeOH + 0.1% DEA] Lux- Amylose-l-MeOH LCMS Rt 3.83 min, 99%, 598.2 [M+H] ⁺ , Method E

HRMS Rt 5.42 min, 598.2 [M+H] ⁺ , Method F m.p. 154.7°C (Mettler Toledo MP50) 2-Fluoro-A-((2-(5-fluoro-6-(4- i-4-(2- -2-yl)pyridin-2-yl)tetrahydro-

2//-pyran-2-yl)methyl)-8-methoxy-3-i :-6-carboxamide 216

Compound 216 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95) to yield the desired product as a white powder (28 mg, 69%).

1H NMR (400 MHz, DMSO, 27 °C) d 8.45 (t, J = 6.1 Hz, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.93 (dd, J = 7.3, 6.2 Hz, 2H), 7.85 (d, J = 5.4 Hz, 1H), 7.82 (s, 1H), 7.40 (s, 1H), 7.31 (t, J = 8.8 Hz, 2H), 5.54 (s, 1H), 3.92 (s, 3H), 3.87 (d, J = 11.2 Hz, 1H), 3.64 (dd, J = 13.2, 6.5 Hz, 1H), 3.58 - 3.44 (m, 2H), 2.75 - 2.59 (m, 1H), 2.39 (s, 3H), 1.80 - 1.64 (m, 2H), 1.62 - 1.48 (m, 4H), 1.48 - l.29 (m, 5H)

SFC (Rt 5.17 min and 6.23 min), (48% and 52%), Method: 5 to 60% [EtOH + 0.1% DEA] Lux- Amylose-1 -EtOH

LSMC Rt 4.01 min, 99%, 580.2 [M+H] ⁺ , Method E

HRMS Rt 5.38 min, 580.3 [M+H] ⁺ , Method F m.p. 220°C (Mettler Toledo MP50) 3-(4-(2-((Ter/-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro- 5-fluoropyridin-2-yl)-6-chlorohex- l-en-3-ol 217

Vinylmagnesium bromide solution (1 M, 4.7 mL, 4.7 mmol) was added to a stirred solution of compound 148 (1.7 g, 3.9 mmol) in dry THF (17 mL) at -30°C under nitrogen. The reaction was stirred for 3 h with an increase of the temperature from -30°C to 0°C. The mixture was diluted with saturated aqueous NH4CI solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 217 as a colorless oil (1.8 g, 94%). 4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-2-chloro-3-fl uoro-6-(2-vinyltetrahydrofuran-2- vDpyridine 218

Potassium bis(trimethylsilyl)amide solution (1 M in THF, 4.3 mL, 4.3 mmol) was added to a solution of compound 217 (1.8 g, 4.1 mmol) in dry THF (50 mL) at 0°C under nitrogen. The reaction was stirred for 30 minutes at 0°C and 30 minutes at room temperature. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 218 as a white solid (1.4 g, 82%).

4-(2-((TerLbutyldirnethylsilyl)oxy)propan-2-yl)-3-fluoro- 2-(4-fluorophenyl)-6-(2 -vinyl- tetrahydrofuran-2-yl)pyridine 219

Cesium carbonate (1.3 g, 9.6 mmol), (4-fhiorophenyl)boronic acid (0.6 g, 4.5 mmol) and Xantphos (370 mg, 0.6 mmol) were added to a solution of compound 218 (1.3 g, 3.2 mmol) in 1,4-di oxane (42 mL) and water (10 mL) (previously bubbled with nitrogen). Finally, Pd(PPh ₃ ) ₂ Cl ₂ (224 mg, 0.3 mmol) was added while nitrogen was bubbled and the reaction was stirred in a sealed tube at 105°C for 16 h. The mixture was diluted with EtOAc and the organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography

(EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 219 as a colorless oil (1.0 g, 64%). l-(2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluor o-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydrofuran-2-yl)ethane-L2-diol 220

Osmium tetroxide (4% in water, 0.9 mL, 0.1 mmol) was added to a stirred solution of compound

219 (1.1 g, 2.3 mmol), 2,6-lutidine (0.8 mL, 0.92 g/mL, 7.0 mmol) and 4-methylmorpholine N- oxide (653 mg, 5.6 mmol) in acetone/water (10: 1, v/v, 8.0 mL) at room temperature. The mixture was stirred for 16 h at room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield compound 220 as a colorless oil (1.2 g, 99%).

2-(4-(2-((TerLbutyldirnethylsilyl)oxy)propan-2-yl)-5-fluo ro-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydrofuran-2-carbaldehyde 221

Sodium periodate (0.7 g, 3.3 mmol) was added to a stirred mixture of compound 220 (1.2 g, 2.3 mmol) in THF (19 mL) and water (8 mL) at room temperature, and the mixture was stirred for 16 h. The organic solvent was evaporated in vacuo and the aqueous phase was extracted with EtOAc (x 3). The organic layers were separated, combined, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield compound 221 as a yellow oil

(1.1 g, 69%). (2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)pyridin-2-yl)- tetrahydrofuran-2-yl)methanol 222

Sodium borohydride (0.1 g, 3.7 mmol) was added to a solution of compound 221 (0.7 g, 1.6 mmol) in methanol (8 mL) at 0°C. The mixture was stirred at room temperature for 3 h. The mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 222 as a white solid (0.5 g, 68%).

2-((2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-f luoro-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydrofuran-2-yl)methyl)isoindoline-L3-dione 223

DIAD (326 pL, 0.8 g/mL, 1.7 mmol) was added dropwise to a stirred solution of compound 222 (512 mg, 1.1 mmol), phthalimide (179 mg, 1.2 mmol) and triphenylphosphine (435 mg, 1.7 mmol) in dry THF (2 mL) under nitrogen at 50°C. The mixture was stirred at 50°C for 16 h. The solvents were evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 20:80) to yield compound 223 as a white solid (524 mg, 76%).

(2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluo ro-6-(4-fluorophenyl)pyridin-2-yl)- tetrahydrofuran-2-yl)methanamine 224 Hydrazine hydrate (89 pL, 1.03 g/mL, 1.6 mmol) was added to stirred solution of compound 223 (234 mg, 0.4 mmol) in ethanol (6 mL) at room temperature. The mixture was stirred at 40°C for 16 h. The mixture was diluted with 0.2 M aqueous solution NaOH (10 mL) and extracted with DCM (x 3). The organic layer was separated, combined, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 224 as a transparent oil (172 mg, 94%). The crude product was used in the next step without further purification.

2-(6-(2-(Aminomethyl)tetrahydrofuran-2-yl)-3-fluoro-2-(4- fluorophenyl)pyridin-4-yl)propan-2- ol 225

Compound 224 (425 mg, 0.9 mmol) was dissolved in THF (9 mL). TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added at room temperature and the mixture was stirred at room temperature for 20 h. Extra TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added. The mixture was stirred for 4 h. The reaction was diluted with EtOAc and washed with a saturated aqueous NaHCO ₃ solution and brine. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 225 as a colorless oil (230 mg, 68%).

2-Fluoro-A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxyp ropan-2-yl)pyridin-2-yl)tetrahydro- furan-2-yl)methyl)-8-methoxy-3-methylquinoline-6-carboxamide 226

Compound 226 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95) to yield the desired product as an off-white powder (27 mg, 54%).

1H NMR (400 MHz, DMSO-d6) d 8.56 (t, J = 6.2 Hz, 1H), 8.28 (d, J = 10.0 Hz, 1H), 7.94 (dd, J = 7.6, 5.7 Hz, 2H), 7.88 (d, J = 5.3 Hz, 2H), 7.48 (d, J = 1.2 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 5.57 (s, 1H), 4.04 (q, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.94 - 3.82 (m, 2H), 3.69 (dd, J = 13.4, 6.2 Hz, 1H), 2.45 - 2.35 (m, 4H), 2.29 - 2.17 (m, 1H), 2.01 - 1.87 (m, 1H), 1.82 - 1.68 (m, 1H), l.53 (s, 3H), 1.46 (s, 3H)

SFC (Rt 5.39 min and 5.83 min), (50% and 50%), Method: 5 to 60% [EtOH + 0.1% DEA] Lux- Amylose-1 -EtOH

LCMS Rt 3.83 min, 98%, 566.2 [M+H] ⁺ , Method E

HRMS Rt 4.79 min, 566.3 [M+H] ⁺ , Method F m.p. 231.6°C (Mettler Toledo MP50)

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)tetrahydrofuran-2- yl)methyl)-8-methoxy-3-(trifluoromethyl)quinoline-6-carboxam ide 227

Compound 227 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 4:96) to yield the desired product as a white powder (26 mg, 59%).

1H NMR (400 MHz, DMSO-d6) d 9.18 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.09 (s, 1H), 7.98 - 7.81 (m, 3H), 7.63 (s, 1H), 7.30 (t, J = 8.5 Hz, 2H), 5.59 (s, 1H), 4.13 - 3.98 (m, 4H), 3.98 - 3.84 (m, 2H), 3.71 (dd, J = 13.2, 5.3 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.35 - 2.17 (m, 1H), 2.03 - 1.89 (m, 1H), 1.86 - 1.71 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H)

SFC (Rt 4.77 min and 5.90 min), (51% and 46%), Method: 5 to 60% [EtOH + 0.1% DEA] Lux- Amylose-1 -EtOH

LCMS Rt 3.91 min, 98%, 602.2 [M+H] ⁺ , Method E HRMS Rt 5.55 min, 602.2 [M+H] ⁺ , Method F m.p. 253.3°C (Mettler Toledo MP50)

A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-y l)pyridin-2-yl)tetrahydrofuran-2- yl)methyl)-2-(l-fluorocyclopropyl)-8-methoxyimidazorL2-a1pyr idine-6-carboxamide 228

Compound 228 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 4:96) to yield the desired product as a white-off powder (37 mg, 78%).

1H NMR (400 MHz, DMSO-d6) d 8.60 (d, J = 1.1 Hz, 1H), 8.48 (t, J = 6.2 Hz, 1H), 8.00 (s, 1H), 7.93 (dd, J = 7.5, 5.7 Hz, 2H), 7.86 (d, J = 5.5 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 6.99 (s, 1H), 5.57 (s, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.91 (s, 3H), 3.90 - 3.81 (m, 2H), 3.65 (dd, J = 13.5, 6.1 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.26 - 2.14 (m, 1H), 2.01 - 1.87 (m, 1H), 1.83 - 1.68 (m, 1H), l.53 (s, 3H), 1.52 - 1.42 (m, 5H), 1.25 - 1.19 (m, 2H)

SFC (Rt 6.12 min and 6.38 min), (48% and 51%), Method: 5 to 60% [2PrOH + 0.1% DEA] Lux- Amylose- 1 -2PrOH

LCMS Rt 3.52 min, 96%, 581.2 [M+H] ⁺ , Method E

HRMS Rt 4.34 min, 581.3 [M+H] ⁺ , Method F m.p. 156.3°C (Mettler Toledo MP50)

230

A-((2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5- fluoro-6-(4-fluorophenyl)pyridin-2- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 229

HATU (197.2 mg, 0.5 mmol) was added to a solution of compound 21 (83 mg, 0.4 mmol) and DIPEA (142 pL, 0.8 g/mL, 1.0 mmol) in DMF (1.0 mL) at room temperature. After 10 minutes stirring, compound 223 (160 mg, 0.3 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and DCM. The aqueous layer was separated and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 229 as a yellow powder (211 mg, 83%). A-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)p yridin-2-yl)tetrahydrofuran-2- yl)methyl)-8-m ethoxy-3 -methylcinnoline-6-carboxamide 230

Compound 229 (154 mg, 0.2 mmol) was dissolved in THF (3 mL). TBAF (1 M in THF, 0.6 mL, 0.6 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc and washed with brine (x 2) and water (x 1). The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 230 as a light yellow solid (60 mg, 45%).

1H NMR (400 MHz, chloroform-d, 25°C): d 7.9 - 8.00 (m, 2H), 7.80 - 7.90 (m, 1H), 7.75 (br d, J = 4.6 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J = 1.3 Hz, 1H), 7.16 (m, 2H), 4.09 - 4.24 (m, 6H), 3.62 - 3.71 (m, 1H), 3.00 (s, 3H), 2.29 - 2.46 (m, 2H), 2.09 (br s, 1H), 1.94 - 2.04 (m, 1H), 1.61 - 1.75 (m, 6H)

LCMS Rt 3.42 min, 95%, 549.2 [M+H] ⁺ , Method E

HRMS Rt 4.44 min, 549.2 [M+H] ⁺ , Method F m.p. 144.6°C (Mettler Toledo MP50)

The enantiomers of compound 230 (80 mg, 0.14 mmol) were separated by QUIRAL SFC by method (i-Amylose-1 SFC isocratic Mode 25% Propanol + 0.1% DEA). The fractions obtained were crystallized in diisopropyl ether to yield compound 231 as a light yellow solid (20 mg, 33%) and compound 232 as a light yellow solid (20 mg, 33%). 231

1H NMR (400 MHz, chloroform-d, 25 °C): d 7.85 - 7.92 (m, 2H), 7.81 (d, J = 5.5 Hz, 1H), 7.56

- 7.72 (m, 1H), 7.20 (d, J = 5.9 Hz, 2H), 7.00 - 7.14 (m, 3H), 3.99 - 4.14 (m, 6H), 3.52 - 3.65 (m, 1H), 2.88 (s, 3H), 2.17 - 2.38 (m, 2H), 1.99 - 2.15 (m, 2H), 1.81 - 1.96 (m, 1H), 1.62 (br d, J = 8.5 Hz, 6H)

SFC Rt 5.50 min, 99%, Method: i-amilose-1

LCMS Rt 3.40 min, 98%, 549 [M+H] ⁺ , Method E HRMS Rt 3.97 min, 549.2 [M+H] ⁺ , Method F m.p. 181.4°C (Mettler Toledo MP50) 232

1H NMR (400 MHz, chloroform-d, 25 °C): d 7.85 - 7.91 (m, 2H), 7.81 (d, J = 5.6 Hz, 1H), 7.57 - 7.70 (m, 1H), 7.18 - 7.22 (m, 2H), 7.03 - 7.10 (m, 3H), 4.06 - 4.13 (m, 3H), 4.05 (s, 3H), 3.53 - 3.62 (m, 1H), 2.88 (s, 3H), 2.19 - 2.37 (m, 2H), 2.03 (br dd, J = 13.7, 6.2 Hz, 1H), 1.81 - 1.96

(m, 1H), 1.62 (d, J = 8.6 Hz, 6H)

SFC Rt 5.72 min, 98%, Method: i-amilose-1

LCMS Rt 3.40 min, 99%, 549 [M+H] ⁺ , Method E

HRMS Rt 3.97 min, 549.2 [M+H] ⁺ , Method F m.p. 161.4°C (Mettler Toledo MP50)

2-(4-(2-((Zer/-butyldimethylsilyl)oxy)propan-2-yl)-6-chlo ro-5-fluoropyridin-2- yl)tetrahydrofuran-2-carbonitrile 233

Compound 148 (2.5 g, 6.1 mmol), KCN (600.3 mg, 9.2 mmol) and MeOH (13 mL) were cooled to 0°C for 40 h. The mixture was diluted in water and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield compound 233 as a colourless oil which solidified upon standing under high vacuum (1.1 g, 44%).

(2-(4-(2-((ZerAbutyldimethylsilyl)oxy)propan-2-yl)-6-chlo ro-5-fluoropyridin-2- yl)tetrahydrofuran-2-yl)methanamine 234

Compound 234 was synthesized according to procedure C. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95) to yield the desired product as a colorless oil (1.5 g, 68%). (2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro- 6-(4-fluorophenyl)pyridin-2- yl)tetrahydrofuran-2-yl)methanamine 224

Compound 234 (600 mg, 1.5 mmol) was dissolved in 1,4-dioxane (15 mL) and water (4 mL) in a sealed tube. 4-Fluorophenylboronic acid (250 mg, 1.8 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were added and the mixture was degassed with nitrogen stream for 5 minutes. Pd(PPh ₃ ) ₂ Cl ₂ (104.5 mg, 0.1 mmol) and Xantphos (172.3 mg, 0.3 mmol) were added under nitrogen atmosphere and the mixture was heated at 100°C for 16 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95) to yield compound 224 a white foam (429 mg, 62%).

2-(6-(2-(Aminomethyl)tetrahydrofuran-2-yl)-3-fluoro-2-(4- fluorophenyl)pyridin-4-yl)propan-2- ol 225

Compound 224 (425 mg, 0.9 mmol) was dissolved in THF (9 mL). TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added at room temperature and the mixture was stirred at room temperature for 20 h. Extra TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added. The mixture was stirred for 4 h. The reaction was diluted with EtOAc and washed with a saturated aqueous NaHCO ₃ solution and brine. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield compound 225 as a colorless oil (230 mg, 68%). 3-(Difluoromethyl)-7V-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2- yl)tetrahydrofuran-2-yl)methyl)-8-methoxyquinoline-6-carboxa mide 235

Compound 235 was synthesized according to procedure F. The purification was performed by flash column chromatography (EtOAc/DCM, gradient from 0: 100 to 100:0) to yield the desired product as a white solid (77 mg, 69%).

1H NMR (400 MHz, DMSO-d6) d 9.05 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.58 (s, 1H), 8.04 (s, 1H), 7.99 - 7.91 (m, 2H), 7.89 (d, J = 5.6 Hz, 1H), 7.57 (s, 1H), 7.50 - 7.17 (m, 3H), 5.58 (s, 1H), 4.08 - 4.00 (m, 4H), 3.96 - 3.83 (m, 2H), 3.71 (dd, J = 13.4, 6.1 Hz, 1H), 2.46 - 2.37 (m, 1H), 2.30 - 2.20 (m, 1H), 2.03 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.54 (s, 3H), 1.45 (s, 3H) SFC (Rt 5.53 min and 7.37 min), (48% and 52%), Method: 5 to 60% [EtOH + 0.1% DEA] UV- 1 -Amylose- 1 -EtOH

LCMS Rt 3.66 min, 98%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 5.20 min, 584.2 [M+H] ⁺ , Method F m.p. 236.6°C (Mettler Toledo MP50)

The enantiomers of compound 235 (69 mg, 0.1 mmol) were separated by chiral SFC (Phenomenex; Lux Amylose-1 250 x 30 mm 5 um; Isocratic 30% [EtOH + 0.1% DEA]) to yield compound 236 as a white solid (31 mg, 44%) and compound 237 as a white solid (31 mg, 45%). 236

1H NMR (400 MHz, DMSO-d6) d 9.05 (d, J = 2.0 Hz, 1H), 8.62 (t, J = 6.3 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.94 (dd, J = 7.5, 5.6 Hz, 2H), 7.89 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.50 - 7.16 (m, 3H), 5.58 (s, 1H), 4.09 - 3.97 (m, 4H), 3.96 - 3.84 (m, 2H), 3.71 (dd, J = 13.5, 6.1 Hz, 1H), 2.44 - 2.37 (m, 1H), 2.30 - 2.19 (m, 1H), 2.02 - 1.90 (m, 1H), 1.82 - 1.70 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H) SFC Rt 4.90 min, 97%, Method: 5 to 60% [EtOH + 0.1% DEA] UV-1 -Amylose- 1-EtOH

LCMS Rt 3.64 min, 97%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 4.55 min, 584.2 [M+H] ⁺ , Method F

OR -15.35° (589 nm, c 0.0667 w/v, MeOH, 23.0°C) m.p. 127.9°C (Mettler Toledo MP50) 237

1H NMR (400 MHz, DMSO-d6) d 9.05 (d, J = 2.0 Hz, 1H), 8.62 (t, J = 6.3 Hz, 1H), 8.57 (d, J = l.6 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.94 (dd, J = 7.5, 5.6 Hz, 2H), 7.89 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.51 - 7.17 (m, 3H), 5.58 (s, 1H), 4.09 - 3.98 (m, 4H), 3.96 - 3.84 (m, 2H), 3.71 (dd, J = 13.4, 6.1 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.30 - 2.18 (m, 1H), 2.02 - 1.88 (m, 1H), 1.83 - 1.70 (m, 1H), 1.53 (s, 3H), 1.45 (s, 3H)

SFC Rt 6.19 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] UV-1 -Amylose- 1-EtOH LCMS Rt 3.64 min, 99%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 4.54 min, 584.2 [M+H] ⁺ , Method F

OR +74.031° (589 nm, c 0.1067 w/v, MeOH, 23.0°C) m.p. 138.0°C (Mettler Toledo MP50)

7V-((2-(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2- yl)pyridin-2-yl)tetrahydrofuran-2- yl)methyl)-5-methoxy-lH-pyrrolo[2,3-c]pyridine-2-carboxamide 238 Compound 238 was synthesized according to procedure F. The purification was performed by flash column chromatography (EtOAc/DCM, gradient from 0: 100 to 100:0). The desired fractions were combined and the solvent was evaporated to dryness. The crude was further purified by reverse phase (Phenomenex Gemini C18 30 x 100 mm 5 pm Column; from 72% [65 mM NH ₄ OAC + ACN (90: 10)] - 28% MeCN to 36% [65 mM NH ₄ OAc + ACN (90: 10)] - 64% MeCN) to yield compound 238 as a white solid (122 mg, 59%).

1H NMR (400 MHz, DMSO-d6) d 11.70 (s, 1H), 8.56 (t, J = 6.2 Hz, 1H), 8.37 (s, 1H), 7.93 (dd, J = 7.5, 5.7 Hz, 2H), 7.84 (d, J = 5.6 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.02 (s, 1H), 6.89 (d, J = 0.7 Hz, 1H), 5.53 (s, 1H), 4.02 (dd, J = 14.9, 7.0 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.83 (s, 3H), 3.66 (dd, J = 13.5, 6.1 Hz, 1H), 2.41 - 2.30 (m, 1H), 2.27 - 2.17 (m, 1H), 2.00 - 1.85 (m, 1H), 1.82 - l.67 (m, 1H), 1.52 (s, 3H), 1.44 (s, 3H)

SFC (Rt 8.33 min and 9.33 min), (52% and 50%), Method: 5 to 60% [EtOH + 0.1% DEA] UV- 1 -Amylose-2-Prop

LCMS Rt 3.00 min, 99%, 523.2 [M+H] ⁺ , Method E

HRMS Rt 3.60 min, 523.2 [M+H] ⁺ , Method F m.p. 218.2°C (Mettler Toledo MP50)

The enantiomers of compound 238 (110 mg, 0.2 mmol) was separated by chiral SFC (Phenomenex; Lux i-Amylose-1 250 x 30 mm 5 um; Isocratic 30% [2-Prop + 0.1% DEA]) to yield compound 239 as a white solid (38 mg, 34%) and compound 240 as a white solid (37 mg, 33%).

1H NMR (400 MHz, DMSO-d6) d 11.70 (s, 1H), 8.56 (t, J = 6.2 Hz, 1H), 8.37 (s, 1H), 7.93 (dd, J = 7.5, 5.7 Hz, 2H), 7.84 (d, J = 5.6 Hz, 1H), 7.31 (t, J = 8.9 Hz, 2H), 7.03 (s, 1H), 6.89 (s, 1H), 5.53 (s, 1H), 4.08 - 3.96 (m, 1H), 3.95 - 3.84 (m, 2H), 3.83 (s, 3H), 3.66 (dd, J = 13.5, 6.0 Hz, 1H), 2.39 - 2.29 (m, 1H), 2.27 - 2.16 (m, 1H), 1.99 - 1.84 (m, 1H), 1.83 - 1.68 (m, 1H), 1.52 (s, 3H), 1.44 (s, 3H)

SFC Rt 8.20 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] UV-i-Amylose-1 -2-Prop LCMS Rt 3.0 min, 99%, 523.2 [M+H] ⁺ , Method E

HRMS Rt 3.06 min, 523.2 [M+H] ⁺ , Method F OR -62° (589 nm, c 0.0733 w/v, MeOH, 23°C) m.p. 225.0°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO-d6) d 11.69 (s, 1H), 8.56 (t, J = 6.3 Hz, 1H), 8.37 (s, 1H), 7.93 (dd, J = 7.5, 5.6 Hz, 2H), 7.84 (d, J = 5.6 Hz, 1H), 7.31 (t, J = 8.9 Hz, 2H), 7.03 (s, 1H), 6.89 (s, 1H), 5.53 (s, 1H), 4.10 - 3.97 (m, 1H), 3.95 - 3.85 (m, 2H), 3.83 (s, 3H), 3.66 (dd, J = 13.6, 6.1 Hz, 1H), 2.39 - 2.29 (m, 1H), 2.27 - 2.17 (m, 1H), 1.98 - 1.84 (m, 1H), 1.81 - 1.68 (m, 1H), 1.52 (s, 3H), 1.44 (s, 3H)

SFC Rt 9.86 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] UV-i-Amylose-l-2-Prop LCMS Rt 3.0 min, 99%, 523.2 [M+H] ⁺ , Method E

HRMS Rt 3.06 min, 523.2 [M+H] ⁺ , Method F

OR +34° (589 nm, c 0.0933 w/v, MeOH, 23°C) m.p. 225.0°C (Mettler Toledo MP50)

TerLbutyl((2-(3-chloro-2,4-difluorophenyl)propan-2-yl)oxy )dimethylsilane 241

Chlorotrimethylsilane (39.1 mL, 0.86 g/mL, 307.8 mmol) was added to a solution of 2-(3-chloro- 2,4-difluorophenyl)propan-2-ol [1891438-87-1] (21.2 g, 102.6 mmol) and triethylamine (42.9 mL, 0.73 g/mL, 307.8 mmol) in DCM (250 mL). The resulting mixture was stirred at 45°C for 16 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 241 as a colorless oil (17.4 g, 60%).

TerLbutyl((2-(3-chloro-2,4-difluoro-5-iodophenyl)propan-2 -yl)oxy)dimethylsilane 242 nBuLi in hexanes (2.5 M, 41.6 mL, 104 mmol) was added dropwise at 0°C to a solution of diisopropylamine (14.6 mL, 0.72 g/mL, 104 mmol) in anhydrous THF (50 mL). The reaction was stirred for 60 minutes at 0°C. Then, the solution was added dropwise to a solution of compound 241 (11.6 g, 41.6 mmol) in anhydrous THF (100 mL) at -78°C (the solution turned yellow/orange). The reaction was stirred at -78°C for another 30 minutes. Then, the mixture was allowed to slowly warm at -40°C for 3 h (the solution turned red). After that, iodine (15.8 g, 62.4 mmol) in anhydrous THF (20 mL) was added to the mixture at -78°C. The reaction medium was allowed to slowly warm to room temperature and stirred for 16 h (the solution turned yellow). TLC and LCMS showed total consumption of starting material. The mixture was diluted with a saturated aqueous Na2S20s solution and extracted with DCM. The organic layer was separated, dried (MgSCL), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 20:80) to yield compound 242 as a colorless oil (15.3 g, 86%). l-(5-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-3-chloro-2 ,4-difluorophenyl)-4-chlorobutan- 1-one 243

Into a round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 242 (8.0 g, 19.8 mmol) and copper (I) bromide (567.1 mg, 4.0 mmol) in dry THF (55 mL). This was followed by the dropwise addition of isopropylmagnesium chloride lithium chloride complex solution in THF (1.3 M, 22.8 mL, 29.7 mmol) at -15°C. To this solution was added 4-chlorobutyryl chloride (2.7 mL, 1.26 g/mL, 23.7 mmol) in dry THF (32 mL) dropwise at -15°C. The resulting solution was agitated for 45 minutes at -10°C. The mixture was allowed to reach 0°C and then was quenched with saturated aqueous NH4CI solution. The resulting mixture was further agitated at room temperature for 20 minutes. Afterwards, the solution was extracted with EtOAc. The combined organic phase was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 40:60) to yield compound 243 as a colorless oil (4.3 g, 56%).

2-(5-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-3-chlor o-2,4-difluorophenyl)tetrahydrofuran- 2-carbonitrile 244

Potassium cyanide (343.2 mg, 5.3 mmol) was added portion wise to a solution of compound 243 (1.3 g, 3.5 mmol) in MeOH (8 mL) at 0°C. After the addition, the reaction medium was allowed to slowly warm to room temperature and stirred at this temperature for 16 h. TLC (stained with phosphomolybdic acid) confirmed reaction's completion. The mixture was diluted in water and extracted with DCM (x 3). The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 30:70) to yield compound 244 as a colorless oil (465 mg, 35%).

(2-(5-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-3-chlo ro-2,4-difluorophenyl)- tetrahydrofuran-2-yl)methanamine 245

Raney Nickel (39.3 mg, 0.7 mmol) was added to solution of compound 244 (159 mg, 0.4 mmol) in EtOH (3 mL) at room temperature under nitrogen atmosphere. The nitrogen was replaced by hydrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of celite and the mother liquors were concentrated in vacuo to yield compound 245 as a colorless oil (159 mg, 99%) which was used as such in the next step.

(2-(5-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-2,4\6- trifluoro-rLl'-biphenyl1-3- yl)tetrahydrofuran-2-yl)methanamine 246

A solution of K3PO4 (267.9 mg, 1.3 mmol) in water (0.7 mL) was added to a stirred solution of compound 245 (159 mg, 0.4 mmol) and 4-fluorobenzeneboronic acid (88.3 mg, 0.6 mmol) in 1,4-dioxane (3 mL). The mixture was bubbled with nitrogen for 10 min, x-Phos (40.1 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (48.6 mg, 0.04 mmol) were sequentially added at room temperature. The reaction mixture was heated at 100°C under nitrogen atmosphere for 16 h. The crude was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 246 as a brownish oil (182.3 mg, 99%) which were used as such in the next step. 2-(5-(2-(Aminomethyl)tetrahydrofuran-2-yl)-2,4\6-trifluoro-r Ll'-biphenyl]-3-yl)propan-2-ol

247

Compound 247 was synthesized according to procedure D. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90:10) to yield the desired product as a brownish foam (138 mg, 91%).

8-Methoxy-3-methyl-A-((2-(2,4\6-trifluoro-5-(2-hydroxypro pan-2-yl)-rLl'-biphenyl]-3- yl)tetrahydrofuran-2-yl)methyl)cinnoline-6-carboxamide 248

Compound 248 was synthesized according to procedure F. The purification was performed by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 4:96) to yield the desired product as a yellowish powder (241 mg, 85%).

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.2 Hz, 1H), 7.99 (s, 1H), 7.92 (t, J = 9.3 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.40 (d, J = 1.3 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.08 (s, 3H), 4.05 - 4.00 (m, 1H), 3.89 - 3.82 (m, 1H), 3.78 (dd, J = 13.6, 6.7 Hz, 1H), 3.69 (dd, J = 13.5, 5.8 Hz, 1H), 2.87 (s, 3H), 2.43 - 2.34 (m, 1H), 2.20 - 2.09 (m, 1H), 2.03 - 1.91 (m, 1H), 1.88 - 1.78 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H)

SFC (Rt 7.46 min and 7.85 min), (50% and 50%), Method: 5 to 60% [2PrOH + 0.1% DEA]

Lux- Amylose- 1 -2PrOH

LCMS Rt 3.47 min, 98%, 566.2 [M+H] ⁺ , Method E

HRMS Rt 5.42 min, 566.2 [M+H] ⁺ , Method F m.p. 149.7°C (Mettler Toledo MP50)

The enantiomers of compound 248 (340.4 mg, 0.6 mmol) were separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 20% [MeOH + 0.1% DEA]) to yield compound 249 as a yellowish powder (121 mg, 36%) and compound 250 as a yellowish powder (133 mg, 39%). 249

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.2 Hz, 1H), 7.99 (s, 1H), 7.92 (t, J = 9.3 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.40 (d, J = 1.2 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.13 - 3.98 (m, 4H), 3.85 (dd, J = 15.1, 7.1 Hz, 1H), 3.78 (dd, J = 13.6, 6.7 Hz, 1H), 3.69 (dd, J = 13.5, 5.8 Hz, 1H), 2.87 (s, 3H), 2.43 - 2.34 (m, 1H), 2.22 - 2.07 (m, 1H), 2.03 - l.91 (m, 1H), 1.89 - 1.77 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H)

SFC Rt 6.02 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amylose-l-MeOH LCMS Rt 3.47 min, 99%, 566.2 [M+H] ⁺ , Method E

HRMS Rt 3.56 min, 566.2 [M+H] ⁺ , Method F OR +68° (589 nm, c 0.1000 w/v, DMSO, 23°C) m.p. 161.4°C (Mettler Toledo MP50) 250

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.2 Hz, 1H), 7.99 (s, 1H), 7.92 (t, J = 9.3 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.40 (d, J = 1.2 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.17 - 3.99 (m, 4H), 3.85 (dd, J = 15.1, 7.1 Hz, 1H), 3.78 (dd, J = 13.6, 6.7 Hz, 1H), 3.69 (dd, J = 13.5, 5.9 Hz, 1H), 2.87 (s, 3H), 2.42 - 2.34 (m, 1H), 2.20 - 2.09 (m, 1H), 2.02 - l.91 (m, 1H), 1.88 - 1.77 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H)

SFC Rt 6.95 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amylose-l-MeOH LCMS Rt 3.47 min, 99%, 566.2 [M+H] ⁺ , Method E

HRMS Rt 3.57 min, 566.2 [M+H] ⁺ , Method F OR -46° (589 nm, c 0.1200 w/v, DMSO, 23°C) m.p. 168.1°C (Mettler Toledo MP50)

Tert-butyl 7 -fluoro-3-(4A5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-lH-indo le-l -carboxylate 251

Bis(pinacolate)diboron (13.6 g, 53.6 mmol) and 1,5-cyclooctadiene-methoxy Iridium (I) dimer (118.3 mg, 0.2 mmol) were added to a stirred solution of 4,4 '-ditertbutylbipyridine (95.8 mg, 0.4 mmol) in anhydrous hexane (55 mL) under nitrogen. The mixture was stirred for 20 minutes at room temperature. A dark red solution appeared. Then tert-butyl 7-fluoro- IT/-indole- l - carboxylate [138344-05-5] (14.0 g, 59.5 mmol) in anhydrous hexane (20 mL) was added and the mixture was stirred at 55°C under nitrogen for 16 h. The reaction was diluted with EtOAc and the resulting mixture was washed with water and brine. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 20:80) to yield compound 251 as a white solid (17.0 g, 74%).

7-Fluoro-3-(4A5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-l.H -indole 252

The following reaction was split into 14 vessels and carried out simultaneously due to higher impurity formation if done at larger scale:

Compound 251 was heated at 180°C for 1 h. Then, the combined residues were dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 40:60) to yield compound 252 as a white solid (11.3 g, 75%). 2-(3-Chloro-2,4-difluoro-5-(2-hydroxypropan-2-yl)phenyl)tetr ahydrofuran-2-carbonitrile 253

Potassium cyanide (1.1 g, 16.7 mmol) was added portion wise to a solution of compound 243 (4.3 g, 11.1 mmol) in MeOH at 0°C. After addition, the reaction medium was allowed to slowly warm to room temperature and stirred at this temperature for 16 h. TLC (stained with phosphomolybdic acid) confirmed reaction's completion. The mixture was diluted in water and extracted with EtOAc. The combined organic layers were dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The resulting crude was dissolved in THF (65 mL), TBAF (1 M in THF, 22.2 mL, 22.2 mmol) was added at room temperature and the mixture was stirred at room temperature for 2 h. TLC (stained with phosphomolybdic acid) confirmed reaction's completion. The mixture was diluted with EtOAc and sequentially washed with saturated aqueous NaHCO ₃ solution and water. The organic layer dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (heptane/EtOAc, gradient from 100:0 to 50:50) to yield compound 253 as a colorless oil (1.4 g, 4.7 mmol). 2-(5-(2-(Aminomethyl)tetrahydrofuran-2-yl)-3-chloro-2,4-difl uorophenyl)propan-2-ol 254

Raney Nickel (170.7 mg, 2.9 mmol) was added to solution of compound 253 (1.4 g, 4.7 mmol) in EtOAc (50 mL) at room temperature under nitrogen atmosphere. The nitrogen was replaced by hydrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of celite and the mother liquors were concentrated in vacuo to yield compound 254 as a colorless oil (1.3 g, 88%) which was used as such in the next step.

2-(5 -(2-( AminomethyDtetrahy drofuran-2-yl)-2,4-difluoro-3 -(7 -fluoro- 17/-i ndol -3 - yl)phenyl)propan-2-ol 255

A solution of K3PO4 (624.8 mg, 2.9 mmol) in water (2 mL) was added to a stirred solution of compound 254 (300 mg, 1.0 mmol) and compound 252 (384.3 mg, 1.5 mmol) in 1,4-dioxane (7 mL). The mixture was bubbled with nitrogen for 10 minutes. x-Phos (93.6 mg, 0.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (113.4 mg, 0.1 mmol) were sequentially added at room temperature. The reaction mixture was heated at 100°C under nitrogen atmosphere for 16 h. The crude was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (DCM/(MeOH/NH3 7 M), gradient from 100:0 to 90: 10) to yield compound 255 as a yellowish foam (300 mg, 76%). A-((2-(2,4-difluoro-3-(7-fluoro-1H-indol-3-yl)-5-(2-hydroxyp ropan-2-yl)phenyl)tetrahydrofuran- 2-yl)methyl)-8-m ethoxy-3 -methylcinnoline-6-carboxamide 256

HATU (282.1 mg, 0.7 mmol) was added to a solution of compound 21 (147.7 mg, 0.6 mmol) and compound 255 (200 mg, 0.49 mmol) and Hunig’s base (204 pL, 0.8 g/mL, 1.5 mmol) in DMF (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and the solvent evaporated to dryness. The residue obtained was charged onto silica column and purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 4:96) to yield compound 256 as a yellowish solid (163 mg, 54%).

1H NMR (400 MHz, DMSO-d6) d 12.03 (d, J = 1.7 Hz, 1H), 8.75 (t, J = 6.3 Hz, 1H), 7.97 (s, 1H), 7.90 (t, J = 9.2 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 0.7 Hz, 1H), 7.43 (d, J = 1.0 Hz, 1H), 7.27 (d, J = 4.9 Hz, 1H), 7.07 - 6.93 (m, 2H), 5.35 (s, 1H), 4.11 - 4.00 (m, 4H), 3.86 (dd, J = 15.0, 7.2 Hz, 1H), 3.76 (d, J = 6.1 Hz, 2H), 2.86 (s, 3H), 2.42 (dd, J = 12.7, 6.4 Hz, 1H), 2.22 - 2.10 (m, 1H), 2.06 - 1.92 (m, 1H), 1.91 - 1.78 (m, 1H), 1.51 (s, 3H), 1.38 (s, 3H) SFC (Rt 7.75 min and 8.48 min), (50% and 50%), Method: 5 to 60% [EtOH + 0.1% DEA]Lux- Amylose-1 -EtOH

LCMS Rt 3.26 min, 99%, 605.2 [M+H] ⁺ , Method E

HRMS Rt 3.39 min, 606.2 [M+H] ⁺ , Method F m.p. 216.6°C (Mettler Toledo MP50)

The enantiomers of compound 256 (151 mg, 0.2 mmol) was separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 25% [EtOH + 0.1% DEA]) to yield compound 257 as a yellowish powder (38.5 mg, 25%) and compound 258 as a yellowish powder (41 mg, 27%). 257

1H NMR (400 MHz, DMSO-d6) d 12.02 (s, 1H), 8.75 (t, J = 6.2 Hz, 1H), 7.97 (s, 1H), 7.90 (t, J = 9.2 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.06 - 6.94 (m, 2H), 5.35 (s, 1H), 4.13 - 3.99 (m, 4H), 3.86 (dd, J = 15.1, 7.1 Hz, 1H), 3.76 (d, J = 6.2 Hz, 2H), 2.86 (s, 3H), 2.45 - 2.37 (m, 1H), 2.21 - 2.11 (m, 1H), 2.03 - 1.91 (m, 1H), 1.89 - 1.80 (m, 1H), 1.51 (s, 3H), 1.38 (s, 3H)

SFC Rt 7.98 min, 98%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH

LCMS Rt 3.25 min, 98%, 605.2 [M+H] ⁺ , Method E

HRMS Rt 3.36 min, 605.2 [M+H] ⁺ , Method F

OR -65° (589 nm, c 0.1000 w/v, DMSO) m.p. 263.5 °C (Mettler Toledo MP50) 258

1H NMR (400 MHz, DMSO-d6) d 12.03 (d, J = 2.1 Hz, 1H), 8.75 (t, J = 6.3 Hz, 1H), 7.97 (s, 1H), 7.90 (t, J = 9.2 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 7.05 - 6.92 (m, 2H), 5.35 (s, 1H), 4.10 - 4.01 (m, 4H), 3.86 (dd, J = 15.0, 7.1 Hz, 1H), 3.76 (d, J = 6.2 Hz, 2H), 2.86 (s, 3H), 2.45 - 2.37 (m, 1H), 2.20 - 2.11 (m, 1H), 2.02 - l.92 (m, 1H), 1.90 - 1.81 (m, 1H), 1.51 (s, 3H), 1.38 (s, 3H)

SFC Rt 8.65 min, 98%, Method: 5 to 60% [EtOH + 0.1% DEA] Lux-Amylose-l-EtOH

LCMS Rt 3.25 min, 98%, 605.2 [M+H] ⁺ , Method E

HRMS Rt 3.35 min, 605.2 [M+H] ⁺ , Method F OR +51° (589 nm, c 0.1067 w/v, DMSO, 23°C) m.p. 260.8°C (Mettler Toledo MP50)

TerAbutyl(2-(5-(2-((terAbutyldimethylsilyl)oxy)propan-2-y l)-3-chloro-2,4-difluorophenyl)-2- oxoethyDcarbamate 259

Isopropylmagnesium chloride lithium chloride complex solution (1.3 M, 44.7 mL, 58.11 mmol) was added over 10 minutes to a stirred solution of compound 242 (6.5 g, 14.55 mmol) in dry THF (30 mL) at -30°C under nitrogen. Then, A-(/c/7-butoxycarbonyl)glycine A'-m ethoxy -N'- methylamide (7.9 g, 36.4 mmol) in dry THF (60 mL) was added over 10 minutes at -30°C. The reaction was stirred for 1 h at -30°C and allowed to reach room temperature. The mixture was stirred for 16 additional hours at room temperature. The reaction was then quenched by the addition of aqueous saturated NH4CI solution and EtOAc, and was extracted with EtOAc (x 3), dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 30:70) to yield compound 259 as yellowish sticky oil (3.3 g, 47%).

TerAbutyl(2-(5-(2-((terAbutyldimethylsilyl)oxy)propan-2-y l)-2,4\6-trifluoro-rLl'-biphenyl]-3- yl)-2-oxoethyl)carbamate 260 A solution of K3PO4 (4.4 g, 20.8 mmol) in water (12 mL) was added to a stirred solution of compound 259 (3.3 g, 6.9 mmol) and 4-fluorobenzeneboronic acid (1.5 g, 10.5 mmol) in 1,4- dioxane (50 mL). The mixture was bubbled with nitrogen for 10 minutes. X-Phos (0.7 g, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.7 mmol) were sequentially added to the reaction at room temperature. The reaction mixture was heated to 100°C and stirred at this temperature under a nitrogen atmosphere for 40 h. The crude was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield compound 260 as an orange oil (3.7 g, 99%).

TerLbutyl(2-(5-(2-((terLbutyldimethylsilyl)oxy)propan-2-y l)-2,4\6-trifluoro-rLT-biphenyl]-3- yl)-2-hydroxypent-4-en-l-yl)carbamate 261

A round bottom flask was charged with compound 260 (3.7 g, 6.9 mmol) in dry THF (46 mL). The mixture was cooled in an ice bath and allylmagnesium bromide solution in diethyl ether (1 M, 15.3 mL, 15.3 mmol) was added dropwise at 0 to 5°C. After 30 minutes the mixture was allowed to warm to room temperature and the mixture was further stirred at room temperature for 2 h. The mixture was cooled again in an ice bath and allylmagnesium bromide solution in diethyl ether (1 M, 3.5 mL, 15.3 mmol) was added dropwise at 0 to 5°C. After 30 minutes the mixture was allowed to warm to room temperature and the mixture was further stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NH4CI solution and the mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield compound 261 as an orange foam (2.8 g, 65%). TerLbutyl(2-(5-(2-((terLbutyldimethylsilyl)oxy)propan-2-yl)- 2,4\6-trifluoro-rLT-biphenyl]-3- yl)-2A5-trihvdroxypentyl)carbamate 262 and 263

A round bottom flask was charged with compound 261 (2.6 g, 4.1 mmol, 91% purity), THF (25 mL), acetone (25 mL) and water (25 mL). 4-methylmorpholine A -ox ide (950 mg, 8.1 mmol) and potassium osmate(VI) dihydrate (76 mg, 0.2 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was concentrated partially and partitioned between brine and DCM. The organic layer was separated, dried (MgSCL), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 70:30) to yield diastereomeric pairs 262 (1.2 g, 46%) and 263 (1.1 g, 42%), both as a yellowish oil.

ANTI-ter/-butyl((2-(5-(2-((ter/-butyldimethylsilyl)oxy)pr opan-2-yl)-2,4\6-trifluoro-rLT- biphenyl]-3-yl)-4-hydroxytetrahydrofuran-2-yl)methyl)carbama te 264

A pirex screw cap tube was charged with compound 263 (1.1 g, 1.7 mmol) in dry DCM (14 mL). EtsN (524 pL, 0.73 g/mL, 3.8 mmol), p-toluenesulfonyl chloride (359 mg, 1.9 mmol) and dibutyltin oxide (90 mg, 0.4 mmol) were added at room temperature. Then, the mixture was heated and stirred at 50°C for 16 h. The mixture was cooled and quenched with saturated aqueous NH4CI solution and extracted with DCM. The organic layer was separated, dried (MgSCL), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 30:70) to yield compound 264 as a white sticky solid (780 mg, 77%).

TerLbutyl((2-(5-(2-((terLbutyldimethylsilyl)oxy)propan-2- yl)-2,4\6-trifluoro-rLl'-biphenyl1-3- yl)-4-oxotetrahydrofuran-2-yl)methyl)carbamate 265

To a solution of compound 264 (780 mg, 1.3 mmol) in dry DCM (20 mL) was added Dess- Martin periodinane (835 mg, 2.0 mmol) and the suspension was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of NaHCOy The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield compound 265 as a colourless oil (625 mg, 80%).

TerLbutyl((2-(5-(2-((terLbutyldimethylsilyl)oxy)propan-2- yl)-2,4\6-trifluoro-rLl'-biphenyl1-3- yl )-4.4-difluorotetrahvdrofuran-2-yl (methyl (carbamate 266

To a solution of compound 265 (625 mg, 1.1 mmol) in dry DCM (25 mL) at -60°C was added di ethylaminosulfur trifluoride (417 pL, 1.2 g/mL, 3.2 mmol). The solution was stirred at -60°C for 1 h and then warmed slowly to room temperature and stirred for 40 h. The reaction mixture was cooled to 0°C and extra di ethylaminosulfur trifluoride (417 pL, 1.2 g/mL, 3.2 mmol) was added and then stirred at room temperature for 1 day. The reaction mixture was cooled to 0°C and extra diethylaminosulfur trifluoride (695 pL, 1.2 g/mL, 5.3 mmol) was added and then stirred at room temperature for 3 days until conversion was complete. The mixture was quenched with saturated aqueous NaHCO ₃ solution and then stirred for 15 minutes. The layers were separated, and the aqueous layer was extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield compound 266 as a yellowish oil (430 mg, 66%).

2-(5-(2-(Aminomethyl)-4A-difluorotetrahydrofuran-2-yl)-2, 4\6-trifluoro-rEr-biphenyl]-3- yl)propan-2-ol 267

HC1 4 M in water (10.5 mL, 42.0 mmol) was added to a solution of compound 266 (430 mg, 0.7 mmol) in 1,4-di oxane (11 mL). The mixture was stirred and heated at 30°C for 48 h. Partial conversion was observed. The mixture was stirred at 30°C for 48 additional hours until half conversion. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 267 as a yellow oil (310 mg, 55%, 50% purity). The crude residue was used in subsequent chemistry without further purification.

A-((4,4-difluoro-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2- yl)-rLT-biphenyl]-3-yl)- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 268

Compound 268 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield the desired product as a yellowish oil (132 mg, 40%). 1H NMR (400 MHz, DMSO-d6) d 8.92 (t, J = 6.3 Hz, 1H), 7.99 (s, 1H), 7.89 (t, J = 9.2 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.39 (d, J = 1.4 Hz, 1H), 7.36 - 7.30 (m, 2H), 5.43 (s, 1H), 4.40 - 4.29 (m, 1H), 4.15 - 4.04 (m, 4H), 3.81 (d, J = 6.2 Hz, 2H), 3.14 - 3.01 (m, 1H), 2.92 - 2.81 (m, 4H), 1.48 (s, 3H), 1.32 (s, 3H) LCMS Rt 3.66 min, 99%, 602.1 [M+H] ⁺ , Method E

The enantiomers of compound 268 (130 mg, 0.22 mmol) was separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 40% [2-propanol + 0.1% DEA]). The desired fractions were combined and evaporated. Resultant fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. Obtained solids were dried in vacuo at 60°C to yield Compound 269 (39 mg, 30%) and compound 270 (34 mg, 26%), both as yellowish solids. 269

1H NMR (400 MHz, DMSO-d6) d 8.91 (t, J = 6.4 Hz, 1H), 7.99 (s, 1H), 7.89 (t, J = 9.1 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.39 (d, J = 1.2 Hz, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.43 (s, 1H), 4.34 (q, J = 11.6 Hz, 1H), 4.15 - 4.04 (m, 4H), 3.81 (d, J = 6.2 Hz, 2H), 3.13 - 3.02 (m, 1H), 2.92 - 2.80 (m, 4H), 1.48 (s, 3H), 1.32 (s, 3H)

SFC Rt 5.65 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.65 min, 99%, 602.2 [M+H] ⁺ , Method E

HRMS Rt 3.67 min, 602.2 [M+H] ⁺ , Method F

OR +72.6° (589 nm, c 0.1000 w/v, MeOH, 23°C) m.p. 199.9°C (Mettler Toledo MP50) 270 1H NMR (400 MHz, DMSO-d6) d 8.92 (t, J = 6.3 Hz, 1H), 7.99 (s, 1H), 7.89 (t, J = 9.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.39 (d, J = 1.1 Hz, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.43 (s, 1H), 4.34 (q, J = 11.4 Hz, 1H), 4.14 - 4.04 (m, 4H), 3.81 (d, J = 6.1 Hz, 2H), 3.14 - 3.01 (m, 1H), 2.92 - 2.79 (m, 4H), 1.48 (s, 3H), 1.32 (s, 3H) SFC Rt 6.20 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.65 min, 99%, 602.2 [M+H] ⁺ , Method E

HRMS Rt 3.66 min, 602.2 [M+H] ⁺ , Method F

OR -89.5° (589 nm, c 0.1200 w/v, MeOH, 23°C) m.p. 208.3°C (Mettler Toledo MP50)

ANTI-terZ-butyl ((2-(5-(2-((terf-butyldimethylsilyl)oxy)propan-2-yl)-2,4\6-t rifluoro-rL 1'- biphenyl]-3-yl)-4-hydroxytetrahydrofuran-2-yl)methyl)carbama te 271

HCI 4 M in water (6.3 mL, 25 mmol) was added to a solution of compound 265 (250 mg, 0.4 mmol) in 1,4-dioxane (6 mL) at 0°C. The mixture was stirred and heated at 30°C for 48 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 271 as a white solid (158 mg, 99%). The crude residue was used in subsequent chemistry without further purification.

ANTI-A-((4-hydroxy-2-(2,4\6-trifluoro-5-(2-hydroxypropan- 2-yl)-[El'-biphenyl]-3-yl)- tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline-6-c arboxamide 272

Compound 272 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 0: 100 to 90: 10). The residue obtained was re-purified by reverse phase chromatography (Phenom enex, Gemini Cl 8, 100 x 30 mm, 5 pm; from 50% [25 mM NH ₄ HCO ₃ ] - 50% [MeCN:MeOH 1 : 1] to 25% [25 mM NH4HCO3] - 75% [MeCN:MeOH 1 : 1]) to yield compound 272 as a yellow solid (60 mg, 25%).

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.90 (t, J = 9.3 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.43 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.47 (s, 1H), 5.36 (s, 1H), 4.38 (s, 1H), 4.08 (s, 3H), 3.95 (d, J = 9.2 Hz, 1H), 3.84 - 3.74 (m, 3H), 2.87 (s, 3H), 2.40 (s, 2H), 1.46 (s, 3H), 1.31 (s, 3H)

LCMS Rt 3.07 min, 99%, 582.2 [M+H] ⁺ , Method E

The enantiomers of compound 272 (105 mg, 0.18 mmol) were separated by SFC (column: Whelk-01 100 x 4.6 mm, 3.5 um; Isocratic 50% [EtOH + 0.1% DEA]). The desired fractions were combined and evaporated. Resultant fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. Obtained solids were dried in vacuo at 60°C to yield compound 273 (31 mg, 30%) and compound 274 (31 mg, 30%), both as yellow solids. 1H NMR (400 MHz, DMSO-d6) d 8.71 (t, J = 5.4 Hz, 1H), 7.99 (s, 1H), 7.90 (t, J = 9.3 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.42 (d, J = 1.1 Hz, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.47 (d, J = 3.0 Hz, 1H), 5.36 (s, 1H), 4.39 (brs, 1H), 4.08 (s, 3H), 3.95 (d, J = 9.2 Hz, 1H), 3.83 - 3.71 (m, 3H), 2.86 (s, 3H), 2.40 (brs, 2H), 1.46 (s, 3H), 1.31 (s, 3H)

SFC Rt 6.27 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] Welk-Ol-EtOH

LCMS Rt 2.93 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.22 min, 582.2 [M+H] ⁺ , Method F

OR +42° (589 nm, c 0.0800 w/v, MeOH, 23°C) m.p. 173.2°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO) d 8.71 (t, J = 5.5 Hz, 1H), 7.99 (s, 1H), 7.90 (t, J = 9.3 Hz, 1H), 7.79 (d, J = 1.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.42 (d, J = 1.3 Hz, 1H), 7.37 - 7.29 (m, 2H), 5.47 (d, J = 3.1 Hz, 1H), 5.36 (s, 1H), 4.39 (brs, 1H), 4.08 (s, 3H), 3.95 (d, J = 8.8 Hz, 1H), 3.84 - 3.69 (m, 3H), 2.86 (s, 3H), 2.40 (brs, 2H), 1.46 (s, 3H), 1.31 (s, 3H)

SFC Rt 6.65 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] Welk-01-EtOH

LCMS Rt 2.81 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.22 min, 582.2 [M+H] ⁺ , Method F

OR -104° (589 nm, c 0.1000 w/v, MeOH, 23°C) m.p. 176.5°C (Mettler Toledo MP50)

SYN-terAbutyl ((2-(5-(2-((terAbutyldimethylsilyl)oxy)propan-2-yl)-2,4\6-tr ifluoro-rL 1'- biphenyl]-3-yl)-4-hydroxytetrahydrofuran-2-yl)methyl)carbama te 275

A pirex screw cap tube was charged with compound 262 (1.2 g, 1.9 mmol) in anhydrous DCM (15 mL). EtsN (580 pL, 0.73 g/mL, 4.2 mmol), p-toluenesulfonyl chloride (394 mg, 2.1 mmol) and dibutyltin oxide (100 mg, 0.4 mmol) were added at room temperature. Then, the mixture was heated and stirred at 50°C for 16 h. The mixture was cooled and quenched with saturated aqueous NH4CI solution and extracted with DCM. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 40:60) to yield compound 275 as a yellowish oil (434 mg, 39%).

SYN-54aminomethyl)-5-(2,4\6-trifluoro-5-(2-hydroxypropan- 2-yl)-rLl'-biphenyl]-3-yl)- tetrahydrofuran-3-ol 276

HC1 4 M in water (7.5 mL, 30 mmol) was added to a solution of compound 275 (300 mg, 0.5 mmol) in 1,4-di oxane (8 mL) at 0°C. The mixture was stirred and heated at 30°C for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 276 as a brown oil (190 mg, 99%).

SYN-A-((4-hydroxy-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2 -yl)-[Ll'-biphenyl]-3- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 277

Compound 277 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10). The obtained product was re-purified by reverse phase chromatography (Phenom enex, Gemini Cl 8, 100 x 30 mm, 5 pm; from 70% [25 mM NH ₄ HCO ₃ ] - 27% [MeCN:MeOH 1 : 1] to 73% [25 mM NH4HCO3] - 83% [MeCN:MeOH 1 : 1]) to yield compound 277 as a yellow solid (77 mg, 26%).

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.2 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.78 (s, 1H), 7.54 - 7.47 (m, 2H), 7.39 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.83 (d, J = 3.9 Hz, 1H),

4.46 - 4.34 (m, 1H), 4.13 - 4.05 (m, 4H), 3.73 - 3.60 (m, 3H), 2.87 (s, 3H), 2.70 - 2.57 (m, 2H),

1.47 (s, 3H), 1.31 (s, 3H)

LCMS Rt 0.80 min, 99%, 582.2 [M+H] ⁺ , Method G

The enantiomers of compound 277 (77 mg, 0.13 mmol) was separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 30% [MeOH + 0.1% DEA]). The desired fractions were combined and evaporated. Resultant fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. Obtained solids were dried in vacuo at 60°C to yield compound 278 (16 mg, 21%) and compound 279 (16 mg, 21%), both as off-white solids. 1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.1 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.78 (s, 1H), 7.54 - 7.47 (m, 2H), 7.39 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.84 (d, J = 3.9 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.11 - 4.06 (m, 4H), 3.73 - 3.61 (m, 3H), 2.87 (s, 3H), 2.67 - 2.59 (m, 1H), 2.09 (d, J = 14.9 Hz, 1H), 1.47 (s, 3H), 1.31 (s, 3H)

SFC Rt 4.69 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amylose-l-MeOH

LCMS Rt 2.79 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.06 min, 582.2 [M+H] ⁺ , Method F

OR +96° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 225°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 6.1 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.78 (s, 1H), 7.53 - 7.48 (m, 2H), 7.39 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.36 (s, 1H), 4.83 (d, J = 3.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.11 - 4.06 (m, 4H), 3.72 - 3.60 (m, 3H), 2.87 (s, 3H), 2.63 (dd, J = 13.8, 6.3 Hz, 1H), 2.09 (d, J = 14.7 Hz, 1H), 1.47 (s, 3H), 1.31 (s, 3H)

SFC Rt 5.08 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amylose-l-MeOH LCMS Rt 2.65 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.04 min, 582.3 [M+H] ⁺ , Method F

OR -80° (589 nm, c 0.0667 w/v, MeOH, 23°C) m.p. 225°C (Mettler Toledo MP50) SYN-terLbutyl ((2-(5-(2-((terLbutyldimethylsilyl)oxy)propan-2-yl)-2,4\6-tr ifluoro-rL 1'- biphenyl]-3-yl)-4-fluorotetrahydrofuran-2-yl)methyl)carbamat e 280

This reaction was carried out as three separate experiments, whose crude residues were combined in one single purification to yield the desired product:

Experiment 1 :

DAST (14 pL, 1.2 g/mL, 0.7 mmol) was added dropwise to a solution of compound 264 (50 mg, 0.08 mmol) in dry DCM (2.4 mL) at -78°C under nitrogen. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution and stirred for 10 minutes. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo.

Experiment 2:

DAST (94 pL, 1.2 g/mL, 0.7 mmol) was added dropwise to a solution of compound 264 (250 mg, 0.4 mmol) in dry DCM (12 mL) at -78°C under nitrogen. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution and stirred for 10 minutes. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo.

Experiment 3 :

DAST (94 pL, 1.2 g/mL, 0.7 mmol) was added dropwise to a solution of compound 264 (250 mg, 0.4 mmol) in dry DCM (12 mL) at -78°C under nitrogen. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution and stirred for 10 minutes. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo.

The crude residues of experiments 1, 2, and 3 were combined and purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 30:70) to yield compound 280 as a colourless oil (398 mg, 71% combined yield). SYN-2-(5-(2-(aminomethyl)-4-fluorotetrahydrofuran-2-yl)-2,4\ 6-trifluoro-rLl'-biphenyl1-3- yl)propan-2-ol 281

HC1 4 M in water (10 mL, 40 mmol) was added to a solution of compound 280 (398 mg, 0.7 mmol) in 1,4-dioxane (10 mL) at 0°C. The mixture was stirred and heated at 30°C for 48 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (x 3). The combined organic layers washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 281 as a yellowish oil (252 mg, 99%).

SYN-A-((4-fluoro-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2- yl)-rLl'-biphenyl1-3- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 282

Compound 282 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90: 10) to yield compound 282 as a yellowish solid (207 mg, 54%).

1H NMR (400 MHz, DMSO-d6) d 8.77 (t, J = 6.2 Hz, 1H), 8.02 - 7.91 (m, 2H), 7.76 (d, J = 1.2 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.37 (d, J = 1.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 5.55 - 5.33 (m, 2H), 4.24 - 4.10 (m, 2H), 4.08 (s, 3H), 3.79 (dd, J = 13.8, 6.8 Hz, 1H), 3.70 (dd, J = 13.7, 5.7 Hz, 1H), 2.87 (s, 3H), 2.71 - 2.55 (m, 2H), 1.47 (s, 3H), 1.29 (s, 3H)

SFC (Rt 6.28 min and 6.74 min), (51% and 49%), Method: 5 to 60% [2 -Prop + 0.1% DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 3.16 min, 99%, 584.1 [M+H] ⁺ , Method E

HRMS Rt 3.46 min, 584.3 [M+H] ⁺ , Method F m.p. 165.2°C (Mettler Toledo MP50) The enantiomers of compound 282 (192.4 mg, 0.3 mmol) was separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 40% [2-Prop + 0.3% IP A]) to yield compound 283 (56 mg, 29%) and compound 284 (55 mg, 28%), both as a yellow solid.

1H NMR (400 MHz, DMSO-d6) d 8.77 (t, J = 6.2 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.76 (s, 1H), 7.56 - 7.49 (m, 2H), 7.37 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.54 - 5.33 (m, 2H), 4.24 - 4.10 (m, 2H), 4.08 (s, 3H), 3.79 (dd, J = 13.7, 6.8 Hz, 1H), 3.72 - 3.65 (m, 1H), 2.87 (s, 3H), 2.72 - 2.53 (m, 2H), 1.47 (s, 3H), 1.29 (s, 3H)

SFC Rt 6.09 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose-1 -2-Prop

LCMS Rt 3.12 min, 99%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 3.43 min, 584.2 [M+H] ⁺ , Method F

OR +147° (589 nm, c 0.0733 w/v, MeOH, 23°C) m.p. 213.3°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO-d6) d 8.77 (t, J = 6.2 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.76 (s, 1H), 7.57 - 7.49 (m, 2H), 7.37 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.56 - 5.33 (m, 2H), 4.26 - 4.11 (m, 2H), 4.08 (s, 3H), 3.79 (dd, J = 13.8, 6.8 Hz, 1H), 3.70 (dd, J = 13.7, 5.7 Hz, 1H), 2.87 (s, 3H), 2.72 - 2.53 (m, 2H), 1.47 (s, 3H), 1.29 (s, 3H)

SFC Rt 6.43 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose-1 -2-Prop LCMS Rt 3.22 min, 99%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 3.42 min, 584.2 [M+H] ⁺ , Method F

OR -81° (589 nm, c 0.1267 w/v, MeOH, 23°C) m.p. 156.4°C (Mettler Toledo MP50)

ANTI-terf-butyl ((2-(5-(2-((ter/-butyldimethylsilyl)oxy)propan-2-yl)-2,4\6-t rifluoro-rE T- biphenyl]-3-yl)-4-fluorotetrahydrofuran-2-yl)methyl)carbamat e 285 DAST (113 pL, 1.2 g/mL, 0.9 mmol) was added dropwise to a solution of compound 275 (300 mg, 0.5 mmol) in dry DCM (14 mL) at -78°C under nitrogen. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution and was then stirred for 10 minutes. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 30:70) to yield compound 285 as a white foam (127 mg, 42%).

ANTI-2-(5-(2-(aminomethyl)-4-fluorotetrahydrofuran-2-yl)- 2,4\6-trifluoro-ri,r-biphenyl1-3- yl)propan-2-ol 286 HC1 4 M in water (3 mL, 12 mmol) was added to a solution of compound 285 (127 mg, 0.2 mmol) in 1,4-dioxane (3 mL) at 0°C. The mixture was stirred and heated at 30°C for 72 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 286 as a yellowish oil (80 mg, 98%).

ANTI-A-((4-fluoro-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2 -yl)-rLl'-biphenyl]-3- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 287

Compound 287 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (DCM/MeOH, gradient from 100:0 to 90:10) to yield the desired product 287 as a yellowish solid (62 mg, 50%).

1H NMR (400 MHz, DMSO-d6) d 8.78 (t, J = 6.5 Hz, 1H), 7.97 (s, 1H), 7.89 (t, J = 9.1 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.39 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 5.46 - 5.26 (m, 2H), 4.27 (dd, J = 20.9, 11.3 Hz, 1H), 4.12 - 4.02 (m, 4H), 3.87 (dd, J = 13.6, 6.0 Hz, 2H), 3.79 - 3.68 (m, 2H), 2.86 (s, 3H), 1.45 (s, 3H), 1.29 (s, 3H)

LCMS Rt 3.30 min, 99%, 584.2 [M+H] ⁺ , Method E

The enantiomers of compound 287 (62 mg, 0.11 mmol) was separated by SFC (column: Phenomenex Lux Amylose-1 250 x 30 mm 5 um; Isocratic 40% [2-propanol + 0.1% DEA]). The desired fractions were combined and evaporated. The resultant fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The obtained solids were dried in vacuo at 60°C to yield compound 288 (15 mg, 24%) and compound 289 (15 mg, 24%), both as yellowish powders. 1H NMR (400 MHz, DMSO-d6) d 8.78 (t, J = 6.3 Hz, 1H), 7.97 (s, 1H), 7.89 (t, J = 9.2 Hz, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.39 (d, J = 1.2 Hz, 1H), 7.32 (t, J = 8.9 Hz, 2H), 5.44 - 5.28 (m, 2H), 4.33 - 4.22 (m, 1H), 4.07 (s, 3H), 3.90 - 3.69 (m, 3H), 2.86 (s, 3H), 2.83 - 2.70 (m, 1H), 2.63 - 2.55 (m, 1H), 1.45 (s, 3H), 1.29 (s, 3H)

SFC Rt 6.25 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1-2 -Prop

LCMS Rt 3.31 min, 99%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 3.25 min, 584.2 [M+H] ⁺ , Method F

OR +60.5° (589 nm, c 0.0667 w/v, DMSO, 23°C) m.p. 223.3°C (Mettler Toledo MP50)

1H NMR (400 MHz, DMSO-d6) d 8.78 (t, J = 6.3 Hz, 1H), 7.97 (s, 1H), 7.89 (t, J = 9.2 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.39 (d, J = 1.3 Hz, 1H), 7.35 - 7.29 (m, 2H), 5.45 - 5.27 (m, 2H), 4.33 - 4.22 (m, 1H), 4.07 (s, 3H), 3.90 - 3.69 (m, 3H), 2.86 (s, 3H), 2.82 - 2.69 (m, 1H), 2.62 - 2.56 (m, 1H), 1.45 (s, 3H), 1.29 (s, 3H)

SFC Rt 6.66 min, 99%, Method: 5 to 60% [2-Prop + 0.1% DEA] Lux-Amylose- 1 -2-Prop

LCMS Rt 3.19 min, 99%, 584.2 [M+H] ⁺ , Method E

HRMS Rt 3.52 min, 584.2 [M+H] ⁺ , Method F

OR -116.1° (589 nm, c 0.0667 w/v, DMSO, 23°C) m.p. 223.3°C (Mettler Toledo MP50)

Pyridinium tribromide (3.1 g, 9.7 mmol) was added to a solution of compound 243 (3.3 g, 8.6 mmol) in dry THF (53 mL) in a round bottom flask. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO ₃ solution was added until pH = 5-6. Saturated aqueous Na2S20s solution was added. The aqueous layer was extracted with EtOAc (x 3). The organic layers were combined, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 290 as a yellowish oil (2.7 g, 79%). 4-Chloro-l -(3-chloro-2,4-difluoro-5-(2-hydroxypropan-2-yl)phenyl)-l -oxobutan-2-yl acetate

291

To a solution of compound 290 (2.7 g, 6.8 mmol) in acetonitrile (24 mL), potassium acetate (3.4 g, 34.6 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 291 as a white solid (1.8 g, 71%).

2-(3-Chloro-2,4-difluoro-5-(2-hydroxypropan-2-yl)phenyl)- 2-(nitromethyl)tetrahydrofuran-3-yl acetate 292

A solution of compound 291 (1.8 g, 4.9 mmol) and nitromethane (5.3 mL, 1.14 g/mL, 96.2 mmol) in DCM (48 mL) was stirred at room temperature. DBU (1.6 mL, 1.02 g/mL, 10.5 mmol) was added dropwise, and the reaction was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield compound 292 as a white solid (1.5 g, 77%).

2-(3-Chloro-2,4-difluoro-5-(2-hydroxypropan-2-yl)phenyl)- 2-(nitromethyl)tetrahydrofuran-3-ol 293

Compound 292 (1.0 g, 2.5 mmol) was dissolved in NH3 in MeOH (7 N, 10 mL, 70 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted with CHCL/isopropanol (3: 1, v/v). The organic layer was dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 293 as a yellowish oil (884 mg, 99%). 2-(Aminomethyl)-2-(3-chloro-2,4-difluoro-5-(2-hydroxypropan- 2-yl)phenyl)tetrahydrofuran-3- ol 294

Raney Nickel (233 mg, 4.0 mmol) was added to solution of compound 293 (884 mg, 2.5 mmol) in EtOAc (20 mL) under nitrogen. The nitrogen was replaced by hydrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered over a pad of celite and washed with MeOH/DCM (1 : 1, v/v) and then with THF at 60°C. The solvent was concentrated in vacuo to yield compound 294 as a yellowish solid (1.3 g,). The crude residue was used in subsequent chemistry without further purification.

2-(Aminomethyl)-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2-y l)- biphenyl]-3-

A solution of K3PO4 (2.6 g, 12.2 mmol) in water (7 mL) was added to a stirred solution of compound 294 (1.3 g, 4.0 mmol) and 4-fhiorobenzeneboronic acid (850 mg, 6.1 mmol) in 1,4- di oxane (28 mL). The mixture was bubbled through with nitrogen for 10 minutes. x-Phos (390 mg, 0.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (475 mg, 0.4 mmol) were sequentially added at room temperature. The reaction mixture was heated at 110°C under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 20:80) to compound 295 (267 mg, 28%) and compound 296 (132 mg, 14%), both as an orange oil. ANTI-A-((3-hydroxy-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2-y l)-[Ll'-biphenyl]-3- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 297

Compound 297 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95). The desired fractions were collected and concentrated in vacuo. The obtained residue was re-purified by FCC reverse phase (Gemini C18 100 x 30 mm 5 um) (from 70% [25 mM NH4HCO3] - 30% [MeCN:MeOH 1 : 1] to 27% [25 mM NH4HCO3] - 73% [MeCN:MeOH 1 : 1]). The product obtained was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 297 as a yellowish solid (48 mg, 12%).

1H NMR (400 MHz, DMSO-d6) d 8.40 (dd, J = 8.5, 4.0 Hz, 1H), 7.93 (s, 1H), 7.81 (t, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, J = 8.0, 5.9 Hz, 2H), 7.30 (t, J = 8.9 Hz, 2H), 7.25 (d, J = 1.0 Hz, 1H), 5.53 (d, J = 4.4 Hz, 1H), 5.31 (s, 1H), 4.60 (s, 1H), 4.41 (dd, J = 13.9, 8.5 Hz, 1H), 4.15 - 4.07 (m, 1H), 4.03 (s, 3H), 3.97 (td, J = 8.1, 3.9 Hz, 1H), 3.52 - 3.43 (m, 1H), 2.85 (s, 3H), 1.96 - 1.80 (m, 2H), 1.43 (s, 3H), 1.14 (s, 3H)

SFC (Rt 5.98 min and 6.46 min), (52% and 48%), Method: 5 to 60% [2Prop + 0.1% DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 2.71 min, 99%, 582.2 [M+H] ⁺ , Method E

The enantiomers of compound 297 (86 mg, 0.2 mmol) were purified by SFC (column: Phenomenex Lux i-Amylose-1 250 x 30 mm 5 um; Isocratic 30% [MeOH + 0.1% DEA], The desired fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 298 (19 mg, 22%) and compound 299 (20 mg, 23%), both as yellowish solids. 298 1H NMR (400 MHz, DMSO-d6) d 8.40 (dd, J = 7.3, 3.3 Hz, 1H), 7.93 (s, 1H), 7.82 (t, J = 9.1 Hz, 1H), 7.58 (s, 1H), 7.55 - 7.46 (m, 2H), 7.30 (t, J = 8.7 Hz, 2H), 7.25 (s, 1H), 5.53 (d, J = 4.3 Hz, 1H), 5.31 (s, 1H), 4.60 (s, 1H), 4.42 (dd, J = 13.5, 8.8 Hz, 1H), 4.11 (dd, J = 15.9, 7.9 Hz, 1H), 4.03 (s, 3H), 3.97 (dd, J = 7.5, 3.8 Hz, 1H), 3.47 (dd, J = 13.5, 3.3 Hz, 1H), 2.85 (s, 3H), l.95 - 1.80 (m, 2H), 1.43 (s, 3H), 1.15 (s, 3H)

SFC Rt 4.73 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amyllose-l-MeOH LCMS Rt 2.75 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.02 min, 582.3 [M+H] ⁺ , Method F

OR +134° (589 nm, c 0.0733 w/v, MeOH, 23°C) m.p. 158.1°C (Mettler Toledo MP50) 299

1H NMR (400 MHz, DMSO-d6) d 8.40 (dd, J = 8.0, 3.7 Hz, 1H), 7.93 (s, 1H), 7.82 (t, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.53 - 7.46 (m, 2H), 7.30 (t, J = 8.8 Hz, 2H), 7.25 (s, 1H), 5.53 (d, J = 4.5 Hz, 1H), 5.31 (s, 1H), 4.60 (s, 1H), 4.41 (dd, J = 13.8, 8.7 Hz, 1H), 4.11 (dd, J = 16.0, 7.9 Hz, 1H), 4.03 (s, 3H), 3.97 (td, J = 7.9, 3.6 Hz, 1H), 3.47 (dd, J = 13.7, 3.8 Hz, 1H), 2.85 (s, 3H), l.95 - 1.81 (m, 2H), 1.43 (s, 3H), 1.14 (s, 3H)

SFC Rt 5.41 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Amyllose-l-MeOH LCMS Rt 2.88 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 3.03 min, 582.3 [M+H] ⁺ , Method F OR -99° (589 nm, c 0.0733 w/v, MeOH, 23°C) m.p. 154.8°C (Mettler Toledo MP50) SYN-A-((3-hydroxy-2-(2,4\6-trifluoro-5-(2-hydroxypropan-2-yl )-[Ll'-biphenyl]-3- yl)tetrahydrofuran-2-yl)methyl)-8-methoxy-3-methylcinnoline- 6-carboxamide 300

Compound 300 was synthesized according to procedure E. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95). The desired fractions were collected and concentrated in vacuo. The resulting residue was re-purified by FCC reverse phase (Gemini C18 100 x 30 mm 5 um) (from 75% [65 mM NFLOAc + ACN (90: 10)] - 25% [MeCN:MeOH 1 : 1] to 0% [65 mM NBOAc + ACN (90: 10)] - 100% [MeCN:MeOH 1 : 1]). The residue obtained was extracted with DCM (x 3). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 300 (44 mg, 22%) as a yellowish solid.

1H NMR (400 MHz, DMSO-d6) d 8.58 (t, J = 6.3 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J = 9.1 Hz, 1H), 7.74 (s, 1H), 7.52 - 7.44 (m, 2H), 7.36 (s, 1H), 7.30 (t, J = 8.9 Hz, 2H), 5.33 (s, 1H), 4.93 (d, J = 4.8 Hz, 1H), 4.58 (d, J = 4.0 Hz, 1H), 4.10 (t, J = 8.4 Hz, 1H), 4.06 (s, 3H), 4.04 - 3.97 (m, 1H), 3.77 (dd, J = 13.7, 7.4 Hz, 1H), 3.48 (dd, J = 13.6, 5.5 Hz, 1H), 2.87 (s, 3H), 2.40 - 2.32 (m, 1H), 1.95 - 1.87 (m, 1H), 1.48 (s, 3H), 1.31 (s, 3H)

SFC (Rt 4.86 min and 5.10 min), (50% and 50%), Method: 5 to 60% [2Prop + 0.1 %DEA] Lux- Amylose-1 -2 -Prop

LCMS Rt 2.76 min, 99%, 582.2 [M+H] ⁺ , Method E

The enantiomers of compound 300 (47 mg, 0.08 mmol) were purified by SFC (column: Phenomenex Lux i-Cellulose-1 250 x 30 mm 5 um; Isocratic 30% [MeOH + 0.1% DEA]). The desired fractions were diluted with DCM and washed with water. The organic layer was separated, dried (MgSO ₄ ), filtered and the solvents evaporated in vacuo to yield compound 301 (10 mg, 21%) and compound 302 (11 mg, 23%), both as yellowish solids. 1H NMR (400 MHz, DMSO-d6) d 8.58 (t, J = 5.9 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J = 9.0 Hz, 1H), 7.74 (s, 1H), 7.54 - 7.43 (m, 2H), 7.36 (s, 1H), 7.30 (t, J = 8.7 Hz, 2H), 5.33 (s, 1H), 4.93 (d, J = 5.0 Hz, 1H), 4.58 (d, J = 4.2 Hz, 1H), 4.14 - 4.08 (m, 1H), 4.06 (s, 3H), 4.03 - 3.97 (m, 1H), 3.78 (dd, J = 13.5, 7.1 Hz, 1H), 3.48 (dd, J = 13.5, 5.4 Hz, 1H), 2.87 (s, 3H), 2.38 - 2.30 (m, 1H), l.91 (dd, J = 12.2, 5.4 Hz, 1H), 1.48 (s, 3H), 1.31 (s, 3H)

SFC Rt 4.55 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Cellulose-l-MeOH LCMS Rt 2.71 min, 99%, 582.2 [M+H] ⁺ , Method E

HRMS Rt 2.89 min, 582.2 [M+H] ⁺ , Method F

OR +44.1° (589 nm, c 0.1133 w/v, DMSO, 23°C) m.p. 159.7°C (Mettler Toledo MP50) 302

1H NMR (400 MHz, DMSO-d6) d 8.58 (t, J = 5.8 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J = 9.1 Hz, 1H), 7.74 (s, 1H), 7.53 - 7.43 (m, 2H), 7.36 (s, 1H), 7.30 (t, J = 8.7 Hz, 2H), 5.33 (s, 1H), 4.93 (d, J = 4.8 Hz, 1H), 4.58 (d, J = 3.7 Hz, 1H), 4.14 - 4.09 (m, 1H), 4.06 (s, 3H), 4.03 - 3.97 (m, 1H), 3.77 (dd, J = 13.2, 7.1 Hz, 1H), 3.48 (dd, J = 13.5, 5.0 Hz, 1H), 2.87 (s, 3H), 2.40 - 2.30 (m, 1H), l.96 - 1.87 (m, 1H), 1.48 (s, 3H), 1.31 (s, 3H)

SFC Rt 4.85 min, 99%, Method: 5 to 60% [MeOH + 0.1% DEA] Lux-Cellulose-l-MeOH LCMS Rt 2.63 min, 99%, 582.2 [M+H] ⁺ , Method E HRMS Rt 2.92 min, 582.3 [M+H] ⁺ , Method F OR -34.8° (589 nm, c 0.1333 w/v, DMSO, 23°C) m.p. 159.7°C (Mettler Toledo MP50)

Biological Assays

Antiviral Activity

Black 384-well clear-bottom microtiter plates (Coming, Amsterdam, The Netherlands) were filled via acoustic drop ejection using the echo liquid handler (Labcyte, Sunnyvale, California). 200 nL of compound stock solutions (100% DMSO) were transferred to the assay plates. 9 serial 4-fold dilutions of compound were made, creating per quadrant the same compound concentration. The assay was initiated by adding 10 pL of culture medium to each well (RPMI medium without phenol red, 10% FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition steps are done by using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium). Next, rgRSV224 virus (MOI = 1) diluted in culture medium was added to the plates. rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection; Journal of virology (2000), 74(22), 10508-13) and was in-licensed from the NIH (Bethesda, MD, USA). Finally, 20 pL of a HeLa cell suspension (3,000 cells/well) were plated. Medium, virus- and mock-infected controls were included in each test. The wells contain 0.05% DMSO per volume. Cells were incubated at 37°C in a 5% CO2 atmosphere. Three days post-virus exposure, viral replication was quantified by measuring GFP expression in the cells by an in house developed MSM laser microscope (Tibotec, Beerse, Belgium). The EC ₅₀ was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 384-well microtiter plates (Coming) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instructions. The CC ₅₀ was defined as the 50% concentration for cytotoxicity. Table of Biological Activity

Table : antiviral data (averaged data of several repeat experiments)

F. Prophetic composition examples

“Active ingredient” as used throughout these examples relates to a final compound of Formula (I), the pharmaceutically acceptable salts thereof, the solvates and the stereochemically isomeric forms and the tautomers thereof.

Typical examples of recipes for the formulation of the invention are as follows:

F.l . Tablets

Active ingredient 5 to 50 mg

Di calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

F,2, Suspension

An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

F,3, Injectable

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol in water.

F.4. Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g Lanoline 5 g

White petroleum 15 g

Water ad 100 g In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.