OA16821A

OA16821A - 5- Amino-4-hydroxypentoyl amides

Info

Publication number: OA16821A
Application number: OA1201200253
Authority: OA
Inventors: Genadiy Kalayanov; Bart Rudolf Romanie Kesteleyn; Kevin Parkes; Bengt Bertil Samuelsson; Wim Bert Griet Schepens; Johannes Wilhelmus J. Thuring; Hans Kristian Wallberg; Jörg Kurt WEGNER
Original assignee: Janssen R&D Ireland; Medivir Ab
Priority date: 2009-12-11
Filing date: 2010-12-10
Publication date: 2016-01-07

Abstract

HIV inhibitors of formula (I) wherein R1 is halo, C1-4alkoxy, trifluoromethoxy; R2 is a group of formula (A); R3 is a group of formula (B); R4 is a group of formula (C); n is 0 or 1; A is CH or N; R5 and R6 are hydrogen; C1-4alkyl, halo; R7 and R8 are C1-4alkyl or C1-4alkoxy-C1-4alkyl; R9 is C1-4alkyl, cyclopropyl, trifluoromethyl, C1-4alkoxy, or dimethylamino; R10 is hydrogen, C1-4alkyl, cyclopropyl, trifluoromethyl, C1-4alkoxy, or dimethylamino; pharmaceutically acceptable addition salts and solvates thereof; pharmaceutical compositions containing these compounds as active ingredient and processes for preparing said compounds.

Description

5-AMINO-4-HYDROXYPENTOYL AMIDES

This invention concerns 5-amino-4-hydroxy-pcntoyl amides having HIV (Human 5 Jmmunodeficicncy Virus) réplication inhibiting properties, the préparation thereof and pharmaceutical compositions comprising these compounds.

Initially, treatment of HIV infection consistcd of monotherapy with nuclcoside dérivatives and althougli successful in suppressing viral réplication, these drugs quickly io lost their effectiveness due to the émergence of drug-rcsistant strains. It became clear that a high mutation rate combined with rapid réplication made HIV a partîcularly challenging target for antiviral therapy. The introduction of combination therapy of several antt-HIV agents improved therapeutic outcome. The current standard of care is the so-called HAART (Highly Active Anti-Retroviral Therapy), which offers a 15 powcrful and sustaincd viral suppression. HAART typically involvcs combinations of nuclcoside or nucléotide reverse transcriptase inhibitors (NRTIs or NtRTIs respectively) with a non-nuclcoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Current guidelines for antirétroviral therapy recommend such triple combination therapy regimen even for initial treatment. Although HAART is 20 capable of suppressing HIV up to undetectablc levels, résistance can emerge due to compliance problems. It also has been shown that résistant virus is carried over to ncwly infcctcd individuals, resulting in scvcrcly Iimited therapy options for these drugnaivc patients.

Thcreforc there is a continued need for new and effective compounds that can be used as anti-HIV drugs. In particular, there is need for further HIV protease inhibitors that are more effective in ternis of activity against wild type virus, but also against mutated strains, in particular toward mutated strains selected by the currently approved protease inhibitors. There is a need for protease inhibitors that are bénéficiai in terms of their pharmacokinctical profile, in particular that exhibit reduced plasma protein binding.

The présent invention is aimed at providing particular novel sériés of5-amino-4hydroxy-pentoyl amides having HIV réplication inhibiting properties.

The compounds of the invention differ Irom prior art compounds in structure, pharmacological activity and/or pharmacological potcncy. It has been found that they not only arc very active against wild type virus, but also against mutant strains, in

-2particular against strains that havc bccome résistant to one or more known protease inhibitors, which strains are referred to as drug- or multidrug-resistant HIV strains.

Thus, in one aspect, the présent invention concerns compounds of formulai I, including the stéréochemically isomeric forms thereof, which can be represented by formula I:

, wherein

R* is halo, Cj^alkoxy, trifluoromethoxy;

R² is a group of formula:

£

OH

O

R³ is a group of formula:

R⁴ is a group of formula:

n is 0 or 1 ;

each A independently is CH or N;

-3R^s and R⁶ independently are hydrogen, Cnalkyl, or halo;

R⁷ is Cualkyl or CMalkoxyC’i^alkyl;

R is CMalkyl or CMalkoxyCMalkyl;

each R⁹ independently is CMalkyl, cyclopropyl, trifluoromethyl, CMalkoxy, or dimethylamino;

R*° is hydrogen, CMalkyl, cyclopropyl, trifluoromethyl, CMalkoxy, or dimethylamino; R¹¹ is hydrogen or CMalkyl;

the pharmaceutically acceptable addition salts and the pharmaceutically acceptable solvatés thereof.

Whenever used in a molecular fragment or group, a bond with an asterisk ( — ·) represents the bond ltnking that fragment or group with the remainder ofthe molécule.

As used herein, CMalkyl as a group or part ofa group defincs straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-mcthyl-propyl, t.butyl. Of interest among CMalkyl is Cj.3alkyl or CMalkyl; C).jalkyl defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms; CMalkyl defines methyl or ethyl.

The term “halo” is gcncric to fluoro, chlore, bromo or iodo, in particular to fluoro or chlore.

Whenever a radical occurs in the définition of the compounds of formula I or in any of the subgroups of compounds of formula I spccificd herein, said radical independently is as spccificd above in the définition ofthe compounds of formula I or in the more rcstrictcd définitions as specified hercinaftcr.

It should also be noted that the radical positions on any molecular moiety used in the définitions may be anywhcrc on such moiety as long as it is chcmically stable. For instance radical R¹ may be on any position of the phenyl to which it is attached.

When any variable (e.g. halogen, CMalkyl) occurs more than once in any moiety, each définition is independent, Any limited définitions of the radicals spccificd herein arc mcant to be applicable to the group of compounds of formula I as well as to any subgroup defincd or mentioned herein. Unes drawn from substituents into ring Systems indicate that the bond may be attached to any of the suitable ring atoms.

-4The pharmaceutically acceptable addition sait forms, which the compounds ofthe présent invention arc ablc to form, can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromîc acid, sulfuric, hcmisulphuric, nitric, phosphorîc, and the like acids; or 5 organic acids such as, for example, acctic, aspartic, dodecyl-sulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacctic, lactic, pyruvic, oxalic, malonic, succinic, malcic, fumaric, malic, tartane, citric, mcthancsulfonic, cthancsulfonic, benzcncsulfonic.p-toluencsulfonic, cyclamic, salicylic,p-amino-salicylic, pamoic, and the like acids. Conversely said acid addition sait forms can be converted into the free base form 10 by treatment with an appropriate base.

The compounds of formula I containing acidic protons may bc converted into their pharmaceutically acceptable métal or amine addition sait forms by treatment with appropriate organic and inorganic bases. Appropriate base sait forms comprise, for 15 example, the ammonium salts, the alkali and earth aikaline métal salts, e.g. the lithium, sodium, potassium, magnésium, calcium salts and the like, salts with organic bases, e.g. prîmary, secondary, and tertiary alipliatic and aromatic amines such as methylamine, ethylaminc, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, dicthylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butyi20 amine, pyrrolidinc, piperidine, morpholinc, trimcthylamine, triethylamine, tripropylaminc, quinuclidînc, pyridine, quinoline and isoquinolinc, the bcnzathinc, jV-mcthylD-glucamine, 2-amîno-2-(hydroxymethyl)-l,3-propancdiol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the sait form can bc converted by treatment with acid into the free acid form.

The term “pharmaceutically acceptable solvaté” is mcant to comprise hydrates and solvent addition forms that the compounds of formula I, including stereoisomeric forms thereof, can form. Examples of such solvatés are e.g. hydrates, alcoholates, such as ethanolates, i.propanolates, n.propanolates, and the like.

The compounds of formula I thereof may contain one or more centers of chirality and may exist as stereochemically isomeric forms. Of spécial interest arc those compounds of formula I that are stereochemically pure. The term stereochemically isomeric forms” as used herein defines ail the possible stereoisomeric forms of the compounds 35 of formula I, the pharmaceutically acceptable addition salts thereof, and the pharmaceutically acceptable solvatés thereof. Unless otherwise mentioncd or indicated, the chemical désignation of compounds dénotés the mixture of ail possible stereochemically isomeric forms, said mixtures containing ail diastercomers and

-5cnantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula I, the pharmaceutically acceptable addition salts thereof, and the pharmaceutically acceptable solvatcs thereofsubstantially frcc, Le. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than l % of the other isomers. Stercogcnic ccnters may hâve the R- or S-configuration; substituents on bivalent cyciic (partially) saturated radicals may hâve either the cis- or tran.v-configuration; double bonds can hâve an E (entgegen) or Z (zusammen) -stereochcmistry.

io Some of the compounds of formula I may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be includcd within the scopc of the présent invention.

The présent invention is also intended to include any isotopes ofatoms présent in the 15 compounds of the invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹³C and ^HC.

Whenever used hereinabove or hcreinafter, the terms “compounds of formula 1, “the présent compounds”, “the compounds of the présent invention” or any équivalent 20 terms, and similarly, the terms “subgroups of compounds of formula I”, “subgroups of the présent compounds”, “subgroups of the compounds of the présent invention” or any équivalent terms, are meant to include the compounds of general formula 1, or subgroups of the compounds of general formula I, as well as their salts, solvatés, and stereoisomers.

Whenever mention is made hercinbefore or hcreinafter that substituents can be selected each independently out of a list of définitions, such as for example for R¹ or R², any possible combinations are intended to be included that are chemîcally possible or that lead to molécules of such chemical stability that they can be processed in standard pharmaceutical procedures.

Particular subgroups of the compounds of formula I or any subgroup of compounds of formula 1 specified herein wherein (a) R’ is halo; or R¹ is fluoro or chloro; which halo (or fluoro or chloro) in particular is 35 substituted in ortho position; or (b) R¹ is methoxy; which methoxy in particular is substituted in meta position.

Particular subgroups of the compounds of formula l or any subgroup of compounds of formula I spccified herein wherein (a) R² is a group of formula

OH (b) or wherein R² is a group of formula:

or

ÔH

Further embodiments of the présent invention arc those compounds of formula I or any of the subgroups of compounds of formula I wherein

R^s is hydrogen, and R⁶ is halo or Ci^alkyl; R^s is halo and R⁶ is hydrogen; R⁵ is halo or Cj^alkyl, and R⁶ is hydrogen; or R^s and R⁶ are both hydrogen, or are both halo.

Further embodiments of the présent invention arc those compounds of formula I or any of the subgroups of compounds of formula I wherein in the définitions of R⁵ and R⁶halo is fluoro or chloro, and Cualkyl is metliyl.

Particular embodiments ofthe présent invention are those compounds of formula I or any of the subgroups of compounds of formula l, including the compounds wherein R²is as defined above under (a) or (b), wherein R⁵ is hydrogen and R⁶ is fluoro or chloro; R⁵ is fluoro or chloro and R⁶ is hydrogen; R^s is hydrogen and R⁶ is methyl; R⁵ and R⁶are both hydrogen, or R^s is chloro and R⁶ is fluoro; more in particular wherein R^s is hydrogen and R⁶ is fluoro; R^s is chloro and R⁶ is hydrogen; R⁵ is hydrogen and R⁶ is methyl; R⁵ and R⁶ are both hydrogen, R^s is chloro and R⁶ is fluoro, R⁵ is methyl and R⁶ is fluoro, or R^s is fluoro and R⁶ is metliyl.

Embodiments of the présent invention arc those compounds of formula I or any of the subgroups of compounds of formula I wherein R³ is a group of formula

A further embodiment concems those compounds of the invention wherein R^J is a group of formula

Embodiments of the présent invention are those compounds of formula 1 or any of the subgroups of compounds of formula I wherein

R⁸ is methyl or 2-methoxy ethyl; or wherein R⁸ is methyl.

R⁹ is C|.zalkoxy or dimethylamino; or R⁹ is methoxy or dimethylamino; or R⁹ is methoxy.

Embodiments of the présent invention arc those compounds of formula 1 or any of the subgroups of compounds of formula I wherein

R⁴ is a group having the chcmical structure specified above, but wherein in the first group R⁹ is R⁹ in the second group R⁹ is R^9b in the thîrd group R⁹ is R^9c in the fourth group R⁹ is R^9d in the fiftli and in the sixth group R⁹ is R^9c ; which groups 20 therefore can be represented as follows:

wherein each A independently is CH or N; or wherein cach A is CH;

R⁹¹* is Cj^alkoxy or dimethylamino;

R⁹¹' is CMalkoxy or dimethylamino;

R^9c îs Cmalkoxy or dimethylamino;

R^9d is CMalkyl, cyclopropyl, trifluoromethyl;

R^,ois hydrogen, CMalkyl, cyclopropyl, or trifluoromethyl; or R^l0is hydrogen, methyl, cyclopropyl, or trifluoromethyl;

-8cach R^,c independently is Ci .₄alkyl, cyclopropyl, CMalkoxy, or dimcthylamino.

Of particular interest arc those compounds wherein in R⁹*, R^9b, R⁹', R^9d, or R⁹' Ci-jalkoxy is methoxy and Cj^alkyl is methyl.

In further embodiment R⁴ is a group having the chcmical structure:

_R9a

« wherein A is CH and R⁹“ is methoxy or dimcthylamino.

Embodiments ofthe présent invention are those compounds of formula I or any of the subgroups of compounds of formula I wherein Rⁿ is Ci^alkyl; or wherein R¹¹ is methyl

One embodiment concerna the compounds 1 - 102 listcd in Table 1 at the end ofthe experimental part, including the pharmaceutically acceptable salts and solvatés thereof. A particular embodiment concems the free form (non pharmaceutically acceptable salts and solvatés) ofthe compounds 1 - 102 listcd in Table L

Of particular interest arc the compounds with numbers 7, 8, 52, 67, 91, 93,96,101 and 20 102 listed in the table at the end of the examples including the pharmaceutically acceptable salts and solvatés thereof

The compounds of formula I wherein R^J is a group of formula:

said compounds being represented by formula I-a can be prepared by coupling an intermediate of formula II with a carboxylic acid dérivative of formula III in an amidc forming reaction. The reaction conditions for this amide forming réaction are those 30 used to couple amino acids in peptide synthesis. Coupling agents that may be uscd can be selected from /V-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), jV-isobutoxycarbonyl-2-isobutoxy-l,2-dihydroquinoline (IIDQ), ?/,?/,/V_lA^/’-tctramcthy l-O(7-azabcnzotriazol-l-yl)uronium hcxafluorophosphatc (HATU), bcnzotriazolc-l-yl-

·9· oxy-tris-(dimethylamino)-phosphonium hexafluorophosphatc (BOP), benzotriazol-l-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphatc (PyBOP*), dicyclohexylcarbodiimidc (DCC), 3-cthy)-J(N,N-dimcthyl)aminopropylcarbodiimidc (EDCI), or l,3-diisopropylcarbodiimide. A catalyst may be added, for example l-hydroxybenzotriazolc (HOBt) or 4-dimcthylartiinopyridinc (DMAP). The reaction is usually conducted in the présence of a base, in parlicular an amine base such as a tertiary amine, e.g. tricthylaminc, N-mcthylmorpholinc, N./V-diisopropylcthylaminc, (the lattcr also being referred to as or Hünig’s base, DIPEA, or DIEA). Solvents that can be used include bipolar aprotic solvents such as DMA, DMF or acetonitrile, halogenated hydrocarbons such as CH2CI2 or CHClj, ether solvents such as THF. In one embodiment, the coupling réaction is conducted with HATU using triethylamine as base in DMF.

formula I-b, can be preparcd by an urethanc fonning reaction ofan intermediate of formula II with an appropriate electrophilîc carbonyl compound of formula IV such as a chloroformate, or an activatcd 2,5-dioxopyrroltdin-l-olate,para-nitrophcnolate or 2-pyridyl carbonate.

Lg in the above scheme is a leaving group such as chloro, bromo, 2,5-dioxopyrrolidinl -date, para-nitrophcnolate.

-10Thc intermcdiates of formula II in tum can be prepared as outlincd in the following reaction scheme:

protection

ln the above scheme M represents a -B(0R^a)2 group or a -Sn(R^b)j group, wherein R’ represents a hydrogen or an alkyl or alkanediyl group, e.g. 2,3-dimethyl-2,3-butanediyl and R^b represents an alkyl group such as methyl or butyl. PG represents a hydroxyprotccting group that canbc selectively clcaved in the prcsence of the Boc group. Y represents bromo, iodo or a trifluoromcthancsulfonyl (iriflate orTfO-) group. X lo represents chloro, bromo, or iodo.

The triflate group can be introduced by reacting an intermediate of formula X bearing a hydroxy group at the position of the bromo with a trifluoromethanesulfonimide, in the prcsence of a base in a solvent such as dichloromethane. The intermediate of formula X 15 bearing a hydroxy group in tum can bc prepared from an intermediate XI bearing a protected hydroxy group at the position of the the group Y, following the procedures

-IIdescribcd hcreinafter for the conversion of XI to X, followed by a dcprotection step. A protecting group that can be used in this procedure îs a bcnzyl group, which can be removed with hydrogen in the presence of a catalyst.

In a first step, the lactonc XI is alkylated with a bcnzyl halide to the benzylated lactonc X. This reaction is conductcd in an aprotic solvent such as THF, with a base, e.g. lithium bis(trimcthylsilyl) amide, sodium bis(trimcthylsilyl) amide, or lithium diisopropylamidc at low température, e.g. at -78°C, followed by the addition of the bcnzyl halide. The lactonc in the intermédiares X is ring-opened by hydrolysis using a I0 base such as LiOH, NaOH, or KOH in an aqueous solvent such as a mixture of DMF, DMA, dioxanc, THF and water. This hydrolysis results in intermediates IX wherein subsequcntly the alcohol fonction is protected with a suitablc protecting group PG, for example with a silyl group such as triisopropylsilyl, t-butyldimethylsilyl or the like, under art-known conditions, to gcncratc intermediates of formula VIII. The carboxyl fonction is convcrtcd to the corresponding amide in VII, by coupling reaction of intermédiare VIII with a primary amine of formula R²-NH2. The conditions for this réaction are as described above, Optionally R²-NH2 can be used in racémie form and the rcsulting diastcrcoisomcric mixture of intermediates Vil can be separated, e.g. by chroniatography.

In a next step the O-protccting group in Vil is removed yiclding intermediates VI. For example in case of a t-butyldimethylsilyl group use can be made of tctrabutylammonium fluoride (TBAF) or HF in acetonitrile. The intermediates VI, which can be bromo, iodo or triflatc (-OTf) dérivatives, are then subjected to a carbon-carbon cross25 coupling reaction such as a Suzuki, Stilie, Heck, or Negishi réaction that is metalcatalyscd (usualiy with Pd, Ni or Cu catalysts). One cxample of such cross-coupling réaction is the Suzuki reaction, in which case VI is reacted with a substituted heteroaryl boronic acid or ester (e.g. pinacolatoboronatc) in the presence of a palladium catalyst at elevated température The reaction is carried out in the presence of a base such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, césium carbonate, potassium phosphate, etc. When an inorganic base is difficult to dissolve in an organic solvent, it is used as an aqueous solution. Another such crosscoupling réaction is the Stille réaction in which case VI is reacted with a substituted heteroaryl stannane at elevated température in the presence ofa palladium catalyst. A nictal sait like lithium chloride, lithium bromide or lithium iodidc can be used as an additive. Palladium catalysts suitable for the Suzuki or Stille réactions comprise Pd(PPhj)₄ (Ph = phcnyl), Pd₂(dba)₂ (dba = dïbenzylideneacetone), Pd(OAc)₂, Pd(dppf)Cl₂(dppf = l,r-bis(diphenylphosphino)fenOcene). In some cases additional

-12ligands (e.g. tri-t-butylphospîne, l,l ’-bis(diphenylphospino)fenocene, tri-o-tolylphospine or the like) may be added to facilitate the coupling reaction. Still another such a réaction is the Heck réaction which is the réaction of an unsaturated halide (or triflatc) with an alkene and a base and palladium catalyst to form a substituted alkene. In the présent case it involves a palladium catalysed cross-coupling between an aryl halide or triflatc and a thiazole. A suitable catalyst for this reaction is Pd(PPhj)^. Suitable organic solvents for this type ofréactions include tetrahydroftiran, J,4-dioxanc and 1,2-dimethoxyethane, aromatic solvents such as benzene or toluene, alcohol solvents such as methanol or éthanol, acetonitrile, dimethylforniamidc, or a mixture of these solvents. A l o base that can be used is an alkali métal acetate such as potassium acetate.

Removal ofthe Boc N-protecting group in V, for examplc by acidic treatment using trifluoroacetic acid in a halogenated solvent such as CH2CI2, or hydrochloric acid in isopropanol finally Icads to intermediate II. The Boc-dcprotcction can also bc accomplished by treatment of intermediate V with trimethylsilyl iodide or a mixture of trimethylsilyl chloride andNal in an appropriate solvent e.g. acetonitrile, CHClj or CH2CI2. The Boc-deprotection reactions preferably arc conducted at room température.

The intermediates of formula XI can bc prepared as in the following reaction scheme wherein Y is as specifïed above and PG is a N-protecting group such as a BOC-group.

-BIn a first step, the alcohol function in the 2-phenethyl alcohol XVII is oxidized to the correspond ing acetaldehyde XVI using a weak oxidant such as sodium hypochlorite in the présence of 2,2,6,6-tctramcthylpipcridinc-l-oxyl (or TEMPO), which is a sélective oxidant generating aldéhydes from primary alcohols. In a next step the acetaldehyde 5 XVI is rcactcd with a protected amine and with a benzene sulfinate. Reaction of the thus obtained sulfone XV with lactone XIV yields the lactone derivative XIII, which is separated with chiral chromatography to cnantiomcrïc pure XII, whcrin the double bond is reduced, for examplc with hydrogen in the presence of Raney Ni.

Where appropriate, the synthetic steps in the préparation of compounds according to formula II, can be performed in another order. For example, the cross-coupling réaction can be carried out at various stages in the synthetic sequence in the above scheme, such as on intermediates VI, VH, VIII, IX and XI. The cross coupling can be even performed at a latcr stage of the synthesis, for example at the end ofthe synthesis as illustrated in the following reaction scheme. In this scheme, M is as specificd above and the crosscoupling réaction conditions also arc as described above. Intermediates XVIII can bc prepared following the procedures for the préparation of intermediates II, but without cross-coupling reaction, followed by a coupling reaction to introduce the R³-CO-group.

The compounds of formula I wherein R³ is a group of formula:

said compounds being represented by formula 1-c can be prepared by an amide formîng reaction between an intermediate of formula XIX and cyanocyclopropyl carboxylic acid XX as illustrated in the following réaction scheme. The conditions for this reaction are as described above, e.g. in the transformation of II into I-a.

The intermédiares of formula XIX can be prepared as outlined in the following scheme:

In a first step, an intermediatc II is coupled with jV-protccted t.butyiglycine XXI, such as Boc-t.butylglycine, in an amidc-forming réaction, following réaction conditions as described above in the transformation of II to I-a, yiclding an intermediate XXII. The Boc protecting group in XXII can be removed under art-known conditions, as described hcreinbeforc to obtain the free amino intermediatc XIX.

The compounds of formula I wherein R? is a group of formula:

-15Y Ύ ^R·

A °

I * said compounds being represented by formula l-d, can be prepared by an urcthane forming reaction at the end ofthe synthesis as illustratcd in the following reaction scheme, by condensation of an intermediate of formula XIX with an appropriate eicctrophilic carbonyl compound such as a chloroformate, or an activated succinimidyl, para-nitrophcnyl, or pyridyl carbonate. This réaction is particularly suited for preparing

The compounds of formula l wherein R^J is a group of formula:

said compounds being represented by formula l-c, can be prepared either by a coupling réaction with pyrrolidinyl acctic acid in an amidc-forming réaction, following réaction conditions as described above. As illustrated in the réaction scheme below, the compounds l-e can also be prepared by a two-step procedure involving first the reaction of an intermediate XIX with chloroacetyl chloridc in the presence of a base, e.g. a tertiary amine such as tricthylaminc, in a solvent such as dichloromctlianc, resulting in intermediates XXIII. This réaction can e.g. be conducted iniatially at lowcr température such as at 0 C, followed by strirring at room température. The intermediates XXIII are then reacted with pyrrolidine in the presence of a nucleophilic catalyst such as tetrabutylammonium iodidc or the like, preferentially in a bipolar aprotic solvent (e.g. DMA, DMF, W-methylpyrrolidinonc). This réaction preferably is conducted at room température.

Thc compounds of formula l wherein R² is 3-hydroxychromanyl can also be prepared by first coupling a 3-hydroxy-4-chromanamÎnc XXIV with a 3-arylpropionic acid XXV 5 resulting in an intermediate XXVI, using conditions as described hcrcinbcfore for the formation of an amide bond. Subscquently the NH and OH fonctions are protccted with

2-methoxypropene resulting in intermediates XXVII. This transformation can be cffcctcd using a halogcnatcd solvent, such as dichloromcthanc, in the présence ofan acid catalyst, such as pyridinium/7-toluenesulfonate, between 0 C and room temperature.The resulting amides XXVII and oxiranc XXVIII arc treated with a strong base, such as «-butyl lithium, at a température range between -78 C and -25 C to afford intermediate XXIX. The lattcr is subjectcd to a cross-coupling réaction with a boronatc or tin derivative XXX, as described hcreinbefore, yielding XXXI, which in tum is dcprotccted to XXXII under acid conditions. The lattcr corresponds to an intermediate of formula II, and can be forther processed as described above to compounds of formula 1.

The compounds of formula I can also be converted into each other by functional group

R^s

transformation reactions. Compounds of formula I whcrèin R² is ^0H wherein onc or both of R⁵ and R⁶ is chloro, bromo, or iodo can bc converted to the corresponding compounds wherein one or both of R⁵ and R⁶ is hydrogen using hydrogen in the presence of a catalyst, such as palladium on carbon. Vice versa, where onc or both of R⁵ and R^e is hydrogen, these compounds can be halogcnatcd at the 6- or 8-position using an halogcnating agent such as Λ'-bromosuccinimide (NBS) or

V-chlorosuccininiidc (NCS). These conversion can also bc performed ou intermediates having the above R² group.

-18Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.

The intermediates of formula R²-NHî wherein R² is a chromanol group can bc prepared 5 from a phénol XXXIII in 5 synthetic steps. In a first step phénol XXXIII is treated with 3-bromopropionic acid, in water in the presence of a base such as NaOH, at elevated température, such as reflux température. In a second step, the rcsulting

3-phcnoxypropionic acid XXXIV undergoes a Fricdel Crafts acylation, using oxalyl chloride and AlCb in a solvent such as dichloromethane to afford the chromanonc ίο XXXV, which in turn is brominated (with bromine or CuBr2) in a halogenatcd solvent, such as dichloro méthane to afford the bromo chromanonc XXXVI.. Réduction with a métal hydridc reagent, such as NaBHj in a protic solvent, such as mcthanol between 0°C and room température affords the bromo alcohol XXXVII. The bromo alcohol XXXVII undergoes a Ritter reaction, using acetonitrile and an aqueous solution of a strong acid, such as sulfuric acid, to afford the intermediate oxazotinc XXXV11I, that is hydrolyzcd in diluted acid at a température between 80°C and I2O°C to afford the racemic 4-amino chromanol of the formula XXXlX.Said 4-amino chromanol can bc separated in the corresponding enantiomers using art known conditions, such as chromatography using a chiral stationary phase, or by diastercomeric sait formation using an optically pure organic acid as the rcsolving agent, such as mandclic acid, or the like.

^xxxl11 XXXIV _xxxv XXXVI

XXXiX

XXXVII XXXVIII

4-Amino-chromanol XXXIX can be halogenated at the 6- or 8-position, e.g. with

V-chlorosuccinîmidc, to afford the corresponding 6- or 8-halo substituted 4-amino 25 chroma no ls.

-19Tlic intcrmediates of formula R²-NH₂ which are

can be prepared from

6,7-dihydro-5H-bcnzo[b]thiophcn-4-onc by introducing a hydroxyl-group with (+)-(8,8-dichloro-camphorylsulfonyl)oxaziridinc in the presence of a base such as sodium bis(trimcthylsîlyIJamidc in a polar solvent, such as THF, at low température, such as -78°C. The keto group is then convcrtcd to the corresponding bcnzyloxîmc XL1I using O-bcnzylhydroxylaminc in pyridine, and the oxime is rcduccd to the corresponding amine XLIII using e.g. borane in a polar solvent, such as THF, in a température range between 0°C and 70°C.

nh₂

XLIII

Cyclohcxanol amine ofthe formula XLIVIII can bc prepared in 4 steps from 3-(R)-mcthyl cyclohexanonc. In a first stop, the acetate XLVa is obtaincd by treatment in isopropenyl acetate at 100°C in the presence of an acid catalyst, such asp-toluenc sulfonic acid. The corresponding nitro ketone XLVl is obtained by reaction in a mixture of acetic anhydride and concentrated nitric acid at a température between room température and 50°C.Thc keto fiinction is rcduccd by a métal hydridc rcagcnt, such as sodium borohydride, in an alcoholic solvent, such as methanol at room température, to afford the nitro alcohol XLVII. Réduction to the amino alcohol XLVIII is achieved by hydrogenolysis in the presence of Raney nickel in ethyl acetate.

O (XLIV) acétylation

(XLVIII)

The compounds of formula I and most of the intermediates in the présent invention contain an asymmetric carbon atoms. Pure stereochemically isomeric forms of said

-20compounds and said intermcdiates can bc obtained by the application of art-known procedures. For example, diastercoisomers can be separated by physical methods such as sélective crystallization or chromatographie techniques, e.g. countcr current distribution, liquid chromatography and the like methods. Enantiomcrs can be obtained from racornie mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastcrcomcric salts or compounds; then physically separating said mixtures of diastcrcomcric salts or compounds by, for example, sélective crystallization or chromatographie techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomcrs. Pure stereochcmically isomeric forms may also be obtained from the pure stereochemically isomcric forms of the appropriate intermcdiates and starting materials, provided that the intervening réactions occur with rétention of stercochenu’cal integrity. An alternative manner of separating the cnantiomeric forms of the compounds of formula I and intermcdiates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase, such as high performance liquid chromatography or chromatography using supercritîcal carbon dioxide.

The compounds of formula I show anti-HIV properties, in particular they behave as

HIV protease inhibitors. HIV is the aetiological agent of Acquired Immune Dcfîciency Syndrome (AIDS) in humans and prefcrentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune System. As a rcsult, an infcctcd patient has an cvcr-dccrcasing number of T-4 cells, which morcover behave abnormally. Hencc, the immunological dcfence System is unable to combat infections and ncoplasms and the HIV infected subject usually dies by opportuniste infections such as pneumonia, or by cancers.

The compounds of the invention also show activity against drug- and multidrug— résistant HIV strains, in particular against HIV strains that hâve acquired résistance to 30 one or more of the approved protease inhibitors, in particular to atazanavir, lopinavir, and ritonavir.

Duc to their anti-HIV properties, the compounds of formula I, the pharmaceutically acceptable addition salts and solvatés thereof, including any stereoisomeric forms thereof, are useful in the treatment of indivîduals infected by HIV and for the prophylaxis of these infections. Conditions that may be prevented or treated with the compounds of the présent invention, espccially conditions associated with HIV, include AIDS, AlDS-relaled complex (ARC), progressive generalized lymphadenopathy

-21(PGL), as well as chronic Central Nervous System diseases causcd by retroviruses, such as, for examplc HIV mediated dementia and multiple sclerosis.

The compounds of the présent invention may thcreforc be used as a mcdicinc against any of the above-mentioned conditions. In particular, the compounds of formula I may be used in the manufacture ofa médicament for the treatment or the prévention of HIV infection.

In a further aspect this invention provides a method of treating a human, suffering from, or a method of preventing humans to suffer fi'om viral infections, especially HIV infections. Said method comprises the administration, of an effective amount of a compound of formula I, a pharmaceutically acceptable addition sait, a pharmaceutically acceptable solvaté thereof, or a possible stcrcoisomeric form thereof, to humans. Said usé as a medicinc or method of treatment comprises the administration to IlIV-infcctcd subjccts ofan amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially Hl V-l.

The présent invention also provides compositions for treating HIV infection comprising a thcrapcutically effective amount of a compound of formula 1 and a pharmaceutically acceptable carrier or diluent.

The compounds of the présent invention or any subgroup thereof may bc formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may bc cited ail compositions usually employed for systcmically admînistering drugs. To préparé the pharmaceutical compositions of this invention, an effective amount ofthe particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may takc a widc variety o f forms depending on the form of préparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for cxample, for oral, rectal, or percutancous administration. For examplc, in preparing the compositions in oral dosage form, any of the usual pharmaceutical ntedia may bc employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid préparations such as suspensions, syrups, élixirs, émulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Bccausc of their case in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers arc obviousiy employed. Also iticludcd are solid form préparations that can be converted, shortly before use, to liquid forms. In the

-22compositions suitable for percutancous administration, the carrier optionally comprises a pénétration enhancing agent and/or a suitable wctting agent, optionally combined with suitable additivcs of any nature in minor proportions, which additivcs do not introduce a significant delcterious effect on the skin. Said addittves may facilîtate the administration to the skin and/or may bc hclpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an oîntment. The compounds of the présent invention may also bc administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way, Thus, in general the compounds of lü the présent invention may be administered to the lungs in the form of a solution, a suspension or a dry powder,

It is espccialty advantageous to formulate the aforcmcntioncd pharmaceutical compositions in unit dosage form for case of administration and uniformity of dosage.

Unit dosage form as used herein refers to physically discrète units suitable as unitary dosages, each unit containing a predetermined quantîty of active ingrédient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Exemples of such unit dosage forrns arc tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and scgrcgaled multiples thereof.

Those of skill in the treatment of HIV-infcction will bc able to déterminé the effective amount from the test résulte presented hercinaftcr. In general it is contcmplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from O.l mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doscs at appropriate intcrvals throughout the day. Said sub-doses may bc formulatcd as unit dosage forrns, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ’—- ingrédient per unit dosage form.

The exact dosage and ffequency of administration dépends on the particular compound of formula 1 used, the particular condition being treated, the severity ofthe condition being treated, the âge, weight and general physical condition ofthe particular patient as well as other médication the individual may bc taking, as is well known to those skilled 35 in the art. Furthemiore, it is évident that the effective amount may bc lowered or increased depending on the response of the treated subject and/or depending on the évaluation ofthe physician prcscribing the compounds ofthe instant invention. The

-23effective amount ranges mentioned above are thcreforc only guidelincs and are not intended to limit the scope or use of the invention to any extent.

Also, the combination of one or more additional antirétroviral compounds and a compound of formula (I) can be used as a mcdicinc. Thus, the présent invention also relates to a product containing (a) a compound of formula (I), and (b) one or more additional antirétroviral compounds, as a combined préparation for simultaneous, separate orsequential use in anti-HIV treatment, The different drugs may be combined in separate préparations or in a single préparation, together with pharmaceutically lû acceptable carriers. Said other antirétroviral compounds may bc any known antirétroviral compounds such as nucleoside reverse transcriptase inhibitors (NRTls), e.g. zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), amdoxovir (DAPD), elvucitabinc (ACH126,443), apricitabinc (AVX 754, (-)-dOTC), fozalvudinc tidoxil (FZT, HDP-990003), 15 phosphazide, KP-1461, racivir (PSI-5004), MIV-210, and GS-9131; non-nuclcoside reverse transcriptase inhibitors (NNRTls) such as dclavirdine (DLV), efavirenz (EFV), nevirapine (NVP), dapivirine (TMC120), etravirine (ETR, TMC125), rilpîvirine (TMC278), IDX899, RDEA-806, UK-453601, RDEA-427, and UC-781; nucléotide reverse transcriptase inhibitors (NtRTIs), e.g. tenofovirand its pro-drug tenofovir disoproxil fumarate (TDF); protease inhibitors, e.g. ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378, LPV), indinavir (IDV), amprenavir (VX-478), nelfinavir (AG-1343), atazanavir (BMS 232,632), darunavir (TMC114), fosamprenavir (GW433908 or VX-175), brccanavir (GW-640385, VX-385), tipranavir (PNU-140690), DG-17, SPI256, PPL-100 (MK 8122), and TMC310911 ; entry inhibitors, which comprise fusion inhibitors (e.g. enfuvirtidc (T-20) sifuvirtidc, HRG-214, albuvirtide, SUC-H AS, and maC46/M87o), attachment inhibitors, modulators of intraccllular cholestérol and corticostcroid biosynthesis (e.g. SP-01A), and co-receptor inhibitors, the latter comprise the CCR5 antagoniste (e.g. CCR5mAb004, maraviroc (UK-427,857), PRO-140, TAK-220, TAK-652, PF232798, vicriviroc (SCH-D, SCH-417,690), GSK-706769, nifeviroc, and SCH-532706) and CXR4 antagonists (e.g. AMD-070), further examplcs of entry inhibitors arc TNX-355, INCB 9471, BMS-488043, nonakinc, and VGV-1; maturation inhibitors, e.g. bevirimat (PA-457) and vivccon; and inhibitors of the viral integrasc, e.g. raltegravir (MK-0518), elvitegravir (JTK-303, GS-9137), BMS-538158, S-349572, JTK-656 S-247303, and 35 GS-265744.

The following cxamples arc intended to illustrate the présent invention and not to limit its scope thereto.

-24Examplcs

Analytical thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates (Mcrck) with visualization by ultraviolet, potassium permanganate or phosphomolybdic acid. Silicagel column chromatography was performed on SuperFlash® (50 gm) or

GraceResolv® (35 -45 gm) silicagel cartridges. 'H Nuclear magnetic résonance (NMR) spectra were recordcd at 400 or 500 MHz. Chemical shifts ô arc given in ppm rcfcrcnccd to tctramcthylsilanc (TMS) and /values in Hz. MuItiplicy is indicated using the following abbreviations: s for singlet, br. s forbroad singlet, d for doublet, t for triplet, q for quartet, spt for septet and m for multiplet. Optical rotations [a]²°D are reported in deg/dm and the concentration c is given in g/100 mL in the specificd solvent. Infrarcd (IR) and vibrational circular dichroism (VCD) spectra were rccorded in a 0.09 mm ccll with CaF2 Windows, on a Brukcr Equinox-55® instrument with a PMA-37 module at 4-cm'¹ resolution (samples were dissolvcd in DMSO-dù). VCD’s were collected three times with one hour collection time each. Unless otherwise indicated, cnantiomeric excess (ce) was determined by supercritîcal fluid chromatography (SFC) on a Chiralpak Daiccl®AD-H column. Compound names were gcncratcd using ChemDraw Ultra®, version 9.0 (CambridgcSoft*).

Examnle 1: Synthesis of /er/-butvl 6y)-2-(4-bromoplienyl)-1-(ÏS)-5-oxotclrahydrofiiran20

2-yl')cthyÎ-carbamate ((-Î-Precursor 1)

Method A:

NaOCI, NaBr TEMPO

DCM, O’C

Step 1

1-1

-25Stcp l: 2,2,6,6-Tetramcthylpipcridine-l-oxyl (TEMPO; 1.6 g, l.O mmol,

0.002 cq.) and NaBr (6 g, 500 mmol, l .0 cq.) were succcssivcly added under vigorous stirring to a solution of alcohol 1-1 ([CAS No.: 4654-39-1 ]; 100 g, 500 mmol, 1.0 cq.) in dichloromethanc (2300 mL) at 0°C. A solution of aqueous saturated NaHCOj and 10% NaOCl (400 mL) were added. The mixture was stirred for approximately ten minutes until thin-layer chromatography (TLC) indicatcd that the starting material had disappeared. The dichloromethane layer was separated. The aqueous layer was rapidly extracted with diethyl cther. The combined organic phases were washed with an aqueous solution of NaHSOj (10%) and Kl (4%), brine, and dried with anhydrous sodium sulfate. After removing most of the volatiles under vacuum (keep température below 25°C), the resulting solution of aldéhyde 1-2 in dichloromethane (50 mL) was used as such directly in the next step.

Step 2: A mixture of the dichloromethane solution of aldéhyde 1-2 (460 mmol,

1.0 eq.), ie/7-butyl carbamate ( 107.8 g, 920 mmol, 2.0 eq.), sodium benzene sulfinatc (151.0 g, 920 mmol, 2.0 cq.) and formic acid (42.3 g, 920 mmol, 2.0 eq.) in a mixture of methanol (250 mL) and water (500 mL) was stirred at 40°C for 24 hours (réaction was rnonitored by TLC). The reaction mixture was cooled to room température. The resulting precipitate was filtered off, washed with water and diethyl ether, and dried 20 under reduced pressure to afford 150 g (72% starting from Intermediate 1-1) of Intennediate (rac)-l-3.

Step 3: To a mixture of diisopropylaminc (26 g, 250 mmol, 1.1 cq.) in dry tetrahydrofuran (THF; 100 mL) was added dropwise n-butyllithium (100 mL of2.5 M solution, 250 mmol, 1.1 cq.) at -78°C under nitrogen. The mixture was allowed to 25 warm to room température and stirred at room température for 30 minutes. The mixture was re-cooled to -78°C and a solution of 2(5H)-furanone (21 g, 250 mmol, 1.1 cq.) in dry TI-IF (100 mL) was added dropwise. After stirring for another 20 minutes at -78°C, the réaction mixture was transferred to a solution of Intermediate (rac)-l-3 (100 g, 227 mmol, 1.0 eq.) in dry THF (800 mL) at -78°C. The resulting mixture was stirred 30 for another 20 minutes at -78°C. A saturated aqueous NaHCOj solution was added dropwise to the reaction mixture at -40^c'C, extraction was done with ethyl acetate. The combined organic phases were washed with a saturated aqueous NaîCOj solution and brine, dried with MgSCL and concentrated under vacuum. The resulting residue was washed with a diethyl ether / methanol (10:1) mixture and dried to afford 40 g of 35 (rnc)-l-4. The mother liquid was evaporated to dryness, the resulting residue was purified by préparative high-performance liquid chromatography (HPLC) to afford 10 g of (rac)-l-4. In total, 50 g (58%) of the racemic product was obtained.

-26Stcp 4: The racemic mixture (rac)-l-4 was separatcd via préparative supercritical fluid chromatography (SFC) on a Chiralpak Daîcel* AD-20 pm column (50 x 300 mm, mobile phase: isocratic 30% propan-2-ol, flow rate: 130 mL/min). The desired (lS,2S)-enantiomer 1-4 was isolated as the second fraction with a yield of42%.

Step5: A solution of Intermediate 1-4 (10 g, 26.2 mmol, 1.0 eq.) in THF (200 mL) was hydrogenated (1.0 atm of hydrogen) at 25°C for three hours with Raney Ni (2 g, 20% mass ratio) as catalyst. After uptake of hydrogen (1.0 eq.), the catalyst was filtered off and the fïltrate was evaporated. The residue was purified by silica gel column chromatography to give 7.0 g (70%, cc >95%) of (-)-Precursor 1 as white crystals. Tl NMR (400 MHz, CDCh) δ ppm 1.39 (s, 9 H) 2.05 - 2.23 (m, 2 H) 2.45 2.61 (m, 2 H) 2.85 (dd, .7=13,5, 8.6 Hz, I H) 2.91 (dd, >13.7, 7.4 Hz, 1 H) 3.98 (q, >8.5 Hz, 1 H) 4.46 (t, J=7.6 Hz, 1 H) 4.62 (d, >9.8 Hz, 1 H) 7.12 (d, >7.8 Hz, 2 H) 7.43 (d, >8.0 Hz, 2 H); [a]²°_D = -23.4° (c 0.99, CHjCN).

Method B:

Step 1 : lodine (2.2 g, 8.0 mmol, 0.03 eq.) was added to a reaction flask charged with magnésium (79.8 g, 3282 mmol, 12.3 cq.) and THF (2.7 L) under nitrogen. The reaction mixture was heated to 30-35°C and maintained at this température. 4-Bromobutene (361.4 g, 2677 mmol, 10.0 eq.) was slowly added over a period of two hours, the température of the réaction was kept below 65°C. After the addition was complète, the reaction mixture was stirred for a minimum of two hours at 60-65°C and then cooled in an icc bath. A solution of amide 1-5 ([CAS No,: 949885-93-2]; 103.7 g,

267 mmol, 1.0 eq.) in THF (560 mL) was dropwise added to the reaction mixture over a period of at least one hour, the température was kept below 3°C. The reaction mixture

-27was allowcd to warm to room température and stirred for a minimum of four hours at this température. After cooiing to -5°C, the reaction was qucnched by the slow addition of an aqueous ammonium chloridc solution. The organic layer was separated, washed with brine and partially conccntrated under redueed pressure. Heptane was added, the mixture was again partially concentratcd under redueed pressure and cooled to 15°C. The precipitate was fîltcred off and washed with heptane. After drying at 45°C for 16 hours, 112.2 g (wt% 72%, 80% yield) of crudc Intermediate 1-6 was obtained.

Step 2: A solution of RuCIjJHîO (2.04 g, 7 mmol, 0.03 eq.) in water (77 mL) was added to a solution of N11IO4 (236 g, 1105 mmol, 5.5 eq.) in water (1.9 L). This lü reaction mixture was added over 30 minutes to a solution of Intermediate 1-6 (107.7 g (wt% 71%), 201 mmol, 1.0 eq.) in acétone (1.9 L) at room température. The réaction mixture was stirred at room température until conversion was complété (approximatcly one hour). An aqueous Na₂S20j solution was added to the reaction mixture over 30 minutes. The réaction mixture was concentratcd under redueed pressure until no more 15 acetone came out. Water (1.9 L) was added to the residuc, the suspension was stincd for 30 minutes at room température. The precipitate was fîltcred off and the wet cake was re-slurried in water. The wet cake obtained after filtration and washing with water was dried at 45°C to give 80.6 g (wt% 90%, 90% yield) of cnide Intermediate 1-7.

Step 3: A mixture of Intermediate 1-7 (67.0 g (wt% 90%), 150 mmol, i.O eq.) and KHCOî (75.1 g, 750 mmol, 5.0 eq.) in dimcthylformamidc (DMF; 1200 mL) was stirred at room température for 20 minutes. Iodomethanc (42.6 g, 300 mmol, 2.0 eq.) was added over a period of 20 minutes to the reaction mixture, the reaction mixture was stirred at room température for seven hours. After the reaction mixture was filtercd over Celitc, an aqueous solution of ammonium chloride was added at such a rate that 25 the température stayed below 25°C. Ncxt teri-butyl methyl ether was added and the mixture was fîltcred over Celite. The organic layer was separated, washed with brine and concentratcd under redueed pressure. Heptane was added to the residuc, after the suspension was stirred for six hours at room température, the precipitate was filtercd off, washed with heptane and dried in a vacuum oven at40°C for 16 hours. 50.0 g (wt% 91 %, 73% yield) of Intermediate 1-8 was obtained.

Step 4; /V-Selcctride ( 135 mL of a 1M solution in THF, 135 mmol, 1.24 eq.) was dropwise added over a minimum of 1.5 hours to a solution of ester 1-8 (45 g, 109 mmol, 1.0 eq.) in dry THF (900 mL) at -65°C under nitrogen. After the réaction mixture was stirred for an extra hour at -65°C, the température was raised to -35°C and 35 stirring was continued for 30 minutes at this température. Subsequcntly an aqueous 10% citric acid solution was dropwise added at 0 to 10°C, followcd by the addition of toï-butyI methyl ether. After the mixture was stirred for 30 minutes, the organic layer

28· was separated, washed with a saturated aqueous NaHCCh solution and brine, and concentrated under reduced pressure, The residue was re-dissolved in zerr-butyl methyl ether and concentrated agaîn under rcduccd pressure. The crude product was purified by flash silica gel column chromatography (eluent; heptane / ieri-butyl methyl ether 5 2:1 ) to give 37.0 g (94%, ee > 95%) of (-)-Precursor 1 as an off-white solid. [α]²% =

- 20.9° (c 1.0, MeOH)

The pi imary amines mentioned below were used as Precursors representing examples of formula R²-NH2 as defined hereinbefore. Thosc for which no commercial 10 supply is available can be synthesized according to literature procedures (Precursors 2, 14a, 15 and 17) or through procedures described in Examples 2-13 (Precursors 3 14b).

nh₂

(+)-Precursor 3

NH₂ - NHj

(-)-Precursor 5 (+)-Precursor 2 (rac)-Precursor 4

(+)-Precursor 7 (+)-Precursor 8 (+)-Precursor 9 (+)-Precursor 6

nh₂	nh₂	nh₂
'oct	w	ΧζΓ
I	I F
R-CI (+)-Precursor 10a	R=CI (-)-Precursor 11a	(-)-Precursor 12
R=Mb (+)-Precursor 10b	R=Me (+)-Precursor 11b

NH₂

(+)-Precursor 13

R=H (-)-Precursor 14a (-)-Precursor 15

R=Me (-)-Precursor 14b

H

O (-)-Precursor 16

H ?

XT γ NH₂CI O

Precursor 17

-29Example 2: (3S.4S>4-amino-8-chloiOchiOman-3-ol i(+)-Precursor 3)

2-1

2-2

1. (CO)₂CI₂. O’C

2. AICI₃ rt

DCM

Step 2

OH

Y J	NaBHj
	' MeOH.rt
Cl .	Step 4
2-6

Step 3

Br_z

DCM, reflux

Step I : An ice-coolcd solution ofS-broniopropionic acid (298 g, 1.95 mol,

1.25 eq.) and NaOH (156 g of an aqueous 50% solution, 1.95 mol, i .25 eq.) in water (500 mL) was added over a period of 90 minutes to a mixture of 2-chlorophenol ([CAS No.: 95-57-8]; 200 g, 1.56 mol, 1.0 cq.) and NaOH (124 gofan aqueous 50% solution, 1.56 mol, 1.0 cq.) in water (1 L) at reflux température. The réaction mixture was stirred at reflux température for three hours. Aller cooling down to room température, the reaction mixture was acidifïcd with a concentrated aqueous hydrochloric acid solution. The precipitate was filtered off and washed with water to give a first crop of acid 2-2. The filtratc was extracted with dichloromcthane, the combined organic phases were subsequently extracted with saturated NaHCOj. The aqueous layer was acidified with a concentrated aqueous hydrochloric acid solution; the precipitate was filtered off and washed with water to give a second crop of acid 2-2. After drying in a vacuum oven over weekend, 112 g (36%) of Intermediatc 2-2 was obtained as a whitc solid.

-30Step 2: A solution of acid 2-2 (l 12 g, 558 mmol, l.O eq.) and some dropsof

DMF in dichloromethane (1.5 L) was coolcd in an ice bath. Oxalylchloride (142 g, l. 12 mol, 2.0 cq.) was added dropwisc, the réaction mixture was allowcd to warm to room température and stirred overnight. The solvent was concentrated under reduced pressure. The residue was reconstituted in dichloromcthanc (1.5 L). Aluminium trichloridc (89 g, 670 mmol, 1.2 cq.) was added portion wise and the réaction mixture was stirred overnight at room température. The reaction mixture was slowly poured into a coolcd l M hydrochloric acid solution. The layers were separated and the water phase was extracted with dichloromethane. The combined organic layers were washed K) with a saturated aqueous Na₂COj solution and brine, dried with anhydrous MgSO₄ and concentrated under reduced pressure, to obtain 104 g (102%) of crudc Intcrmcdiate 2-3.

Step 3: Brominc (30.7 mL, 598 mmol, 1.05 cq.) was slowly added to a solution of crudc Intcrmcdiate 2-3 (104 g) in dichloromcthanc at reflux température. Aflcr the addition was complété, the resulting mixture was stirred at reflux température for 30 15 minutes. The réaction mixture was coolcd to room température, washed with a saturated aqueous sodium mctabisulfitc solution and brine, dried with anhydrous MgSO.i, and concentrated under vacuum to give a mixture of dibramine 2-4 and monobromine 2-5. The residue was dissolved in acetic acid (750 mL), and sodium sulfite (93 g, 740 mmol) was added. The réaction mixture was stirred at 70°C for three 20 hours. The reaction mixture was coolcd to room température and partially evaporated, water and dichloromethane were added. The organic layer was separated and concentrated under reduced pressure. Crude Intcrmcdiate 2-5 was used as such in the next step (no yicld was determined).

Step 4: NaBH₄ (21.7 g, 574 mmol) was added in portions to a solution of crudc

Intcrmcdiate 2-5 in methanol ( 1.5 L) at 0°C and the mixture was stirred at room température for 30 minutes. The reaction mixture was partially concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnésium sulphate and concentrated under reduced pressure. The crudc product was purified by silica gel column chromatography 30 (eluent: dichloromethane -> dichloromethane ! methanol 96:4) to provide 105.5 g (67% starting from Intcrmcdiate 2-3) of Intcrmcdiate 2-6.

Step 5: Concentrated sulfuric acid (16 mL, 300 mmol, 2.0 cq.) was dropwise added to a solution of Intcrmcdiate 2-6 (39.5 g, 150 mmol, 1.0 cq.) in acctonitrilc (800 mL). The réaction was stirred at 45-50°C until no more starting material was 35 présent (about five hours) and then concentrated under reduced pressure. Water (800 mL) and acetonitrile (200 mL) were added, the reaction mixture was stirred at reflux température for two days. The reaction mixture was then coolcd to room

température, washed with dichloromcthane and basified with an aqueous 50% NaOH solution to pH - 12-13. The precipitate was filtered off, washed with water and dried in a vacuum oven to give 25.2 g (84 %) of raccmic Precursor 3.

The racemic mixture was separated via préparative HPLC on a Chiralpak Daicel*

AD column (mobile phase: acetonilrilc), the desired (3S,45)-enantiomer ((+)-Precursor 3) was isolated as the fïrst fraction (ec > 95%). 'H NMR (400 MHz, DMSO-Zî) δ ppm 1.92 (br. s., 2 H) 3.84 - 3.92 (m, 2 H) 4.14 (dd, >10.9,2.5 Hz, 1 H) 4.17 (dd, >11.1, 5.5 Hz, 1 H) 5.17 (br. s., 1 H) 6.85 (t,>7.8 Hz, 1 H) 7.23 (d,>7.6 Hz, 1 H) 7.41 (d, >7.8 Hz, 1 II); [a]²% = +59.2° (c 0.37, MeOH). The absolute ü configuration of (+)-Precursor 3 was establishcd by cotnparison of the optical rotation ([α]^2ί1ο ~ +45.8° (c 0.27, MeOH)) aller reductive rcmoval ofthe chlorine (hydrogen gas ( 1 atm), palladium on carbon as catalyst) with that of (+)-Pi‘ecursor 2.

Example 3: Synthesis of (rac)-cM-4-amino-7-chlorochroman-3-ol ((>Îic)-Precursor 4) (rac)-Precursor 4 was prepared starting from 3-chlorophenol using the procedures as cxcmplificd for the préparation of (rac)-Precursor 3. ‘H NMR (400 MHz, DMSO-rfc) δ ppm 1.83 (br. s„ 2 H) 3.79 - 3.89 (m, 2 H)4.03 - 4.12 (m, 2 H) 5.12 (br. S„ 1 H) 6.76 (d, >2.0 Hz, 1 H) 6.90 (dd, >8.2,2.0 Hz, 1 H) 7.44 (d, >8.4 Hz, 1 H)

Example 4: Synthesis of (35,45)-4-amino-6-chlorochroman-3-ol ((-l-Precursor 5)

nh₂ cçr	Boc₂O, NaHCOa	NHBoc
THF / H₂O. O’C Step 1
(+)-Precursor 2		4-1
		Step 2 NCS I DMF, 80°C
nh₂ W	TFA	NHBoc — ^Cl OQ
DCM, rt Step 3
(-)-Precursor 5	4-2

Stop 1 : Di-ierr-butyl dicarbonatc (14.5 g, 66.6 mmol, 1.1 cq.) was dissolved in

THF (100 mL), the solution was cooled to 0°C and stirred. (35,45)-4-Amino-chroman25 3-ol ((+)-Precursor 2) (10 g, 60.5 mmol, 1.0 cq.) and NaHCOj (5.1 g, 60.5 mmol,

1.0 eq.) were added simultaneously while maintaining good stirring. The reaction mixture was stirred at room température for four hours. The solvent was partially

-32cvaporated, water was added and the resulting mixture was extracted with diethylether. The combined organic cxtracts were washed with a 10% citric acid solution and brine, dried with MgSO-i, filtcred and evaporated to dryness to givc 21 g of crude carbamatc 4-1.

Step 2: The crude carbamate 4-1 was dissolved in DMF (100 mL) and

A/-chlorosuccinimidc (NCS; 8.9 g, 66.6 mmol, 1.1 eq.) was added. The reaction mixture was stirred at 80°C for one hour. The réaction mixture was coolcd to room température, diluted with diethylether, washed with a saturated aqueous Na2COj solution and brine, dried with anhydrous MgSO-j and concentrated under redueed pressure to givc 16.3 g ü (82% over two steps) of crude Intermediate 4-2.

Step 3: A solution of4-2 (16.3 g, 54.2 mmol, 1.0 cq.) and trifluoroacctic acid (TFA; 124 g, 1084 mmol, 20.0 cq.) in dichloromethane (100 mL) was stirred at room température for onc hour. The reaction mixture was basified with a saturated b^COj solution and extracted with dichloromethane. The combined organic phases were washed with water and brine, and dried with MgSO₄. The crude product was rccrystallizcd form clhyl acetate to givc 6.8 g (61%) of (-)-Precursor 5 (ce >95%). *H NMR (400 MHz, DMSO-î/₆) 5 ppm 1.88 (br. s„ 2 H) 3.79 - 3.90 (ni, 2 H) 4.05 (dd, J=l 1.5, 2.5 Hz, 1 H) 4.08 (dd, 7=11.0,4.8 Hz, 1 H) 5.12 (br. s., 1 H) 6.71 (d, >8.5 Hz, 1 H) 7.10 (dd, 7=8.7,2.6 Hz, 1 H) 7.47 (d, 7=2.3 Hz, 1 H); [α]²% = -20.7° (c 0.36,

MeOH).

Examplc 5: Synthesis of (3S,45h-4-amino-8-fluorochroman-3-ol (f-H-Precursor 6) (/•ac)-c/s-4-amino-8-fluorochroman-3-ol was prepared starting from commercially available 8-fluorochroman-4-onc [CAS No.: 11141-00-5] using the procedures as cxcmplified for the préparation of (rac)-Precursor 3. The raccniic mixture was separated via préparative SFC on a Chîralpak Daiccl⁴ AD-H column (30 x 250 mm, mobile phase: isocralîc 32% methanol (containing 0.2% isopropylaminc) / 68% CO2, flowrate: 50 mL/min), the desired (3S,4S)-cnantiomer ((-t-)-Precursor 6) was isolated as the first fraction (ce > 95%). ^lH NMR (400 MHz, DMSO-dô) δ ppm 1.90 (br. s.,

2 H) 3.84 - 3.92 (m, 2 H)4.09 (dd,7=1 l.l, 2.7 Hz, 1 H)4.14 (dd,>10.9, 5.5 Hz, 1 H)

5.15 (br. s., 1 H) 6.82 (td,-7=7.9, 5.1 Hz, 1 H) 7.01 (ddd, <7=11.3,8.2, 1.4 Hz, 1 H) 7.24 (d, J=l.% Hz, 1 H); [α]^2<ο = +24.6° (c 0.43, MeOH). The absolute stcrcochemical configuration was determined using VCD.

Example 6: Synthesis of (35.45)-4-amino-7-fluorochroman-3-ol ((-t-)-Precursor 7) (rac)-cis-4-Amino-7-fluorochroman-3-ol was prepared using the procedures as exemplified for the préparation of(rac)-Prccursor 3. A mixture of (rac)-cù-4-amino-

-337-fluorochroman-3-ol (31.8 g, 174 mmol, ).Oeq.)and (+)-(5)-mandclîc acid (26.4 g, 174 mmol, 1.0 eq.) was refluxed in mcthanol (600 mL) until a clcar solution was obtained. The mandelic acid sait, obtained after crystallization overnight, was collcctcd by filtration and dîssolvcd in a 3 M aqueous NaOH solution. The water layer was extracted with ethyl acetate, the combined organic phases were dried with anhydrous MgSO^ and concentrated under reduced pressure to givc 6.5 g (21%) of cnantiomcrically enrichcd (+)-Precursor 7 (ce >95%). 'H NMR (400 MHz, DMSO-c/ù) δ ppm 2.03 (br. s., 2 H) 3.81 - 3.86 (m, 2 H) 4.01 - 4.10 (m, 2 H) 5.09 (br. s., 1 H) 6.53 (dd, 7=10.6, 2.6 Hz, 1 H) 6.68 (td, 7=8.5, 2.6 Hz, 1 H) 7.43 (dd, 7=8.4,7.2 Hz, 1 H);

lü [a]²⁰n = +36.0° (c 0.42, MeOHJ.Thc absolute stcrcochcmical configuration was determined using VCD.

Example 7: Svnthesis of(3£4S)-4-amino-6-fluorochroman-3-ol (ï+)-Precursor 8) (rac)-as=4-Amino-6-fluorochroman-3-ol was prepared starting from the commercially available 6-fluorochroman-4-onc [CAS No.: 66892-34-0] using the procedures as exemplified for the préparation of(r«c)-Precursor 3. (rac)-ci$-4-amino6-fluorochroman-3-ol (7.63 g, 41.7 mmol, 1.0 eq.) was dîssolvcd in éthanol (30 mL) while heating, (-)-(Æ)-mandclic acid (6.68 g, 45.8 mmol, 1.1 eq.) was added portion wise and the solution was heated to reflux température. Then, heptane (6 mL) was added dropwisc. The formed suspension was allowed to cool to room température and was loft to stand for 1 hour. Filtration gave the mandelic acid sait as a whitc solid which was rccrystallizcd from éthanol. The obtained sait was dîssolvcd in an aqueous 2 M NaOH solution. The water phase was extracted with ethyl acetate, the combined organic phases were dried with anhydrous MgSOj and concentrated under rcduccd pressure to givc 2.0 g (26%) of cnantiomcrically enrichcd (+)-Precursor 8 (ce 82%).‘H NMR (400 MHz, DMSO-7₆) 8 ppm 1.88 (br. s., 2 H) 3.79 - 3.89 (m, 2 H) 4.01 (ddd, 7=11.1,2.6, 1.0 Hz, 1 H) 4.06 (dd, 7=11.1,5.1 Hz, 1 H) 5.08 (d, 7=3.5 Hz, 1 H) 6.69 (dd, 7=9.0,4.9 Hz, 1 H) 6.90 (td, 7=8.6, 3.3 Hz, 1 H) 7.24 (dd, 7=9.7,3.2 Hz, 1 H); [ct]^Mo ^{= +}25.8° (c 0.50, McOH). The absolute stéréochemical configuration was determined using VCD.

Example 8: Svnthesis of (3S,45)-4-amino-6.8-difluorochroman-3-ol f(+)-Precursor 9) (rüc)-c/.i'-4-Amino-6,8-difluorochroman-3-ol was prepared starting from 2,4-difluorophenol [CAS No.: 367-27-1 ] using the procedures as exemplified for the préparation of (rac)-Precursor 3. The raccmic mixture was separated via préparative SFC on a Chiralpak Daicel* AD-H column (30 x 250 mm, mobile phase: isocratic 50% mcthanol (containing 0.2% isopropylamine) / 50% CO2, flow rate: 50 mL/min), the desired (3S,4S)-enantiomer ((+)-Prccursor 9) was isolatcd as the first fraction (ee > 95%). *H

-34NMR (400 MHz, DMSO-t/₆) δ ppm 1.92 (br. s., 2 H) 3.84 - 3.90 (m, 2 H) 4.11 (ddd, J=ll.2, 2.2, 0.8 Hz, l H) 4.16 (dd, J=l l.l, 4.6 Hz, l H) 5.19 (br. s., I H) 7.06 (ddd, ./=11.3, 8.5,3.1 Hz, 1 H) 7.14 (dm, ,7=9.7 Hz, 1 H); [α]²% =+9.7° (c 0.41, McOH). The absolute stereochemical configuration was detcrmincd using VCD,

Example 9a: Synthesis of (3S,4y)-4-amtno-8-chloro-6-fluorochroman-3-ol ((+)Prccursor 10a) (/•<7c)-cÎ5-4-Amino-8-chloro-6-fluorochroman-3-ol was prepared starting from 2-chloro-4-fluorophcnol [CAS No.: 1996-41-4] using the procedures as exemplified for 10 the préparation of(rac)-Precursor 3. The desired (3S,45)-enantiomcr ((+)-Precursor 10a) was isolated via préparative SFC on Chiralpak Daiccl® AD-H column (30 x 250 mm, mobile phase: isocratic 40% mcthanol (containing 0.6% isopropylaminc) / 60% CO2, flow rate: 50 mL/min), the desired (3S,4S)-enantiomcr ((+)-Precursor 10a) was isolated as the first fraction (ce > 95%). 'H NMR (400 MHz, DMSO-ί/β) δ ppm 15 2.03 (br. s., 2 H) 3.84 - 3.91 (m, 2 H) 4.15 (ddd, J=11.3,2.5, 0.8 Hz, 1 H) 4.20 (dd,

J=11.3,4.4 Hz, 1 H) 5.21 (br.s., 1 H) 7.20 (dd, .7=8.2, 3.1 Hz, 1 H) 7.30 (ddd, .7=9.5, 3.1,0.9 Hz, 1 H); [α]²% = +39.7° (c 1.0, MeOH). The absolute stereochemical configuration was determined using VCD.

Example 9b: Synthesis of (3S.4S)-4-amino-6-fiuoro-8-methylchroman-3-ol ((+)Precursor 10b)

(rae)-c/5-4-amino-6-fluoro-8-mcthylchroman-3-ol was prepared starting from commcrcially available 2-mcthyl-4-fluorophcno! [CAS No.: 452-72-2] (9b-l) using a slightly modified synthesis procedure as exemplified for lhe préparation of(rac)Precursor 3.

Step 1 : To a solution of NaH (9.1 g of a 60% dispersion in oil, 238 mmol,

1.2 eq.) in DMF (300 mL) at 0°C was drop wise added a solution of 2-methyl-4fluorophcnol [CAS No.: 452-72-2]; 25.0 g, 198 mmol, 1.0 cq.) in DMF (40 mL). The suspension was stirred at room température for 30 minutes and cooled again to 0°C, a solution of 1-chLoro-3-hydroxypropane (22.5 g, 238 mmol, 1.2 cq.) in DMF (40 mL) was added drop wise. The réaction was heated for two hours at 60°C (an additîonal

-35amount of NaH and l-chloro-3-hydroxypropanc may be needcd to complété the réaction). The reaction mixture was coolcd to room température and water was added, the water layer was extracted with dicthyl ether. the combined organic phases were washed with an aqueous NaOH solution and brinc, dried with anhydrous MgSO^ and 5 concentrated under rcduccd pressure. The crude product was used as such in the next step.

Step 2: lntcrmcdiatc 9b-2 (12.9 g, 70 mmol) was dissolved in a l:l mixture of

CH3CN / HîO (425 mL). TEMPO ( 1094 mg, 7 mmol., O.l eq.) and bis(acetoxy)iodobenzene (BAIB; 56.4 g, 175 mmol, 2.5 eq.) were added portion wise and the lü reaction mixture was stirred at room température ovemight (additional TEMPO and

BAIB may be required to complète the oxidation). The reaction was qucnchcd by the addition of an aqueous Na2S₂0j solution, the aqueous phase was extracted with DCM and the combined organic layers were subscquently extracted with an aqueous Na₂COî solution. After acidification with a l M aqueous hydrochloric acid, the water phase was 15 extracted with DCM. The combined organic layers were dried with anhydrous MgSO-i and concentrated under rcduccd pressure to afford 13.2 g (96%) of lntcrmcdiatc 9b-3. The lattcr was further convcrtcd to (rac)-c/s-4-amino-6-fluoro-8-methylchroman-3-ol using the procedures as exemplified in Example 2. The desired (3S,45)-cnantiomcr ((T)-Prccursor 10b) was tsolatcd as the first fraction via préparative HPLC on a 20 Chiralpak Daicel* AD column (mobile phase: acetonitrile). *H NMR (400 MHz,

DMSO-ί/ή) 5 ppm 1.89 (br. s„ 2 H) 2.08 (s, 3 H) 3.83 (br. s., 2 H) 4.04 (d, >10.9 Hz, 1 H) 4.09 (dd, >11.5, 4.9 Hz, 1 H) 5.07 (br. s„ l H) 6.82 (d, ./=9.6 Hz, 1 H) 7.07 (d, >9.6 Hz, 1 H); [a]²⁰o = +50.3° (e 0.38, McOH). The absolute stercochemical configuration was determined using VCD.

Example 10a: Synthesis of(3S.45)-4-amino-6-chloro-8-fluorochroman-3-ol ((-)Precursor lia) (rac)-cA-4-Amino-6-chloro-8-fluorochroman-3-ol was prepared starting from 4-chloro-2-fluorophenol [CAS No.: 348-62-9] using the procedures as exemplified for the préparation of (rac)-Precursor 3. The racémie mixture was separated via préparative SFC on Chiralpak Daicel® AD-H column (20 ^x 250 mm, mobile phase: isocratic 40% mcthanol (containing 0.2% isopropylamine) / 60% CO2, flow rate: 50 mL/min), the desired (3S,4S)-cnantiomer ((-)-Precursor lia) was isolated as the first fraction (ee > 95%). ’H NMR (400 MHz, DMSO-r/₆) 8 ppm 1.93 (br. s„ 2 H) 3.88 (br. s., 2 H) 4.11 -4.16 (m, 1 H) 4.18 (dd, >11.3,4.3 Hz, 1 H) 5.22 (d, >3.1 Hz, 1 H)

7.22 (dd, ./=10.7,2.5 Hz, 1 H) 7.35 (s, 1 H); [α]²% = -32.0° (c 0.42, McOH). Tlie absolute stereochcmical configuration was determined using VCD.

-36Examplc 10b: Synthesis of (3S.4S)-4-nmÎno-8-fluoro-6-methylchroman-3-ol ((+)Prccursor Ub) (rac)-ctf-4-arnino-8-fluoro-6-mcthylcliroman-3-ol was prepared starting from mcthyl-2-fluorophcnol [CAS No.: 452-81-3] using the procedures as exemplifîcd for the préparation of(rac)-Precursor 10b. The racemic mixture was separated via préparative SFC on Chiralpak Daicel® AD-H column (30 ^x 250 mm, mobile phase: isocratic 20% mcthanol (with 0.6% isopropylaminc) / 20% CO₂, flow rate: 50 mL/min), the desired (35,45)-enantiomcr ((+)-Precursor 1 Ib) was isolated as the first fraction (ee > 95%). ’H NMR (400 MHz, DMSO-r/s) Ô ppm 1.82 (br. s., 2 H) 2.20 (s, 3 H) 3.84 (br. s, 2 H) 4.04-4.12 (m, 2 II) 5.10 (br.s., 1 H) 6.84 (dd, 7=12.1, 2.0 Hz, 1 11)7.05 (br. s., 1 H); [a]²°D - +88.8° (c 0.18, MeOH). The absolute stercocbemical configuration was determined using VCD,

Example 11 : Synthesis of (3S',4S)-4-amino-6-mcthvlchroman-3-ol ((-)-Precursor 12) (/i7i')-c/i-4-Amino-6-methylchroman-3-ol was prepared starting from 6-mcthyl4-cliromanone [CAS No.: 39513-75-2] using the procedures as exemplified for the préparation of (rac)-Precursor 3. The racemic mixture was separated via préparative SFC on Chiralpak Daicel® AD-H column (30 x 250 mm, mobile phase: isocratic 17% methanol (with 0.5% isopropylamine) / 83% CO₂, flow rate: 50 mL/min), the desired (3S,45)-enantiomer ((-)-Precursor 12) was isolated as the second fraction (ce > 95%). ’H NMR (400 MHz, DMSO-i/c) δ ppm 1.78 (br. s„ 2 H) 2.20 (s, 3 H) 3.77 - 3.84 (m, 2 H) 3.94 (ddd, 7=10.7, 2.4, 1.3 Hz, 1 H) 3.96 - 4.03 (m, 1 H) 5.00 (br. s., 1 H) 6.58 (d, 7=8.2 Hz, 1 H) 6.88 (dd, .7=8.2, 2.0 Hz, 1 H) 7.19 (d, 7=2.0 Hz, 1 H); [a]²°o = -18.7° (c 0.43, MeOH). The absolute stcrcochcmical configuration was determined using VCD.

Examnlc 12: Synthesis of (4S.5/?)-4-amino-4,5,6.7-tctrahydrobcnzo[blthiophcn-5-ol ((+)-Precursor 13)

O

12-1

Step 1

(+>Precursor13

-37Stcp l : A solution of 6,7-dihydro-5H-benzo[b]thiophcn-4-one (starting material

12-1, [CAS No.: 13414-95-4]; 39 g, 256 mmol, 1.0 eq.) in THF (150 mL) was added dropwisc to a mixture of sodium bis(trimcthylsilyl)amidc (NHMDS; 307 mL of a 1 M solution in THF, 307 mmol, 1.2 eq.) and THF (200 mL) at -78°C under argon atmosphère, the réaction mixture was stirred for an additional 30 minutes at -78°C. A solution of (+)-(8,8-dichloro-camphorylsulfonyl)oxaziridinc (94 g, 307 mmol, 1.2 eq.) in THF (300 mL) was added dropwisc. After being stirred for two hours at -78°C, the reaction mixture was quenched by the addition of an excess of acetic acid and allowed to warm to room température. Water and ethyl acetate were added, and the water phase was separated and extracted with ethyl acetate. The combincd organic phases were dried with anhydrous MgSCU and concentrated under reduced pressure. The residue was rc-dissolvcd in dichloromcthanc (300 mL) and triturated with hcptanc (500 mL), the precîpitate was removed by filtration and washed with diisopropyl ether. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: heptane heptane / ethyl acetate 4:6) to provide 50 g (116%) of impure lntcrmcdiatc 12-2. The crudc product was uscd as such in the next step.

Step 2: O-benzylhydroxylamine hydrochloride (41 g, 256 mmol, 1.0 eq.) was added to a solution of crude Intermcdiate 12-2 (50 g) in pyridine (500 mL). The reaction mixture was stirred at room température over weekend. The mixture was evaporated and co-cvaporated two tintes with toluène. The residue was rc-dissolvcd in ethyl acetate, the organic phase was washed with an aqueous 5% citric acid solution and brine, dried with anhydrous MgSOj and concentrated under reduced pressure to givc 72 g of crudc Intermcdiate 12-3.

Step 3; Boranc dimethyl sulfide complcx (198 mL of a 1 M solution in THF 395 mmol, 1.54 eq.) was added dropwisc to a solution of crude Intermcdiate 12-3 (72 g) in THF (1 L) at 0°C. The reaction mixture was stirred at reflux température ovemight. After the solvent was partially removed by distillation (the rçaetion flask was equipped with a distillation condenser), the réaction was further stirred at reflux température until complète conversion. The reaction mixture was cooled in an ice bath and quenched by the cautious addition of water. The water phase was saturated with NaCl and several times extracted with methyltetrahydrofuran. The combined organic phases were dried with anhydrous MgSO« and concentrated under reduced pressure to givc an 8:2 cû/rrans-isomcric mixture. The desired cw-isomer was isolated via silica gel column chromatography (clucnt: dichloromcthane -> dichloromethane / 7 M ammonia in méthanol 96:4), 17.8 g was obtained (40% over 3 steps, 60% ee (the ee was determined by liquid chromatography (LC) after amide formation with

-38(+)-(5)-mandelic acid)), (+)-Precursor 13 (17.7 g, 105 mmol, 1.0 eq.) was recrystallizcd with (+)-(5)-mandelic acid (16 g, 105 mmol, 1.0 eq.) in metbanol overnight. The whitc solid was filtered off. The filtratc was concentrated and the obtained residue was recrystallizcd again. Both batchcs were combined and dissolved S in a 3 M aqueous NaOH solution. The water phase was cxtracted with dichloromethanc, the combined organic layers were dried with anhydrous MgSO₄ and concentrated under rcduccd pressure to gîvc 11.5 g (65%) of enantiomerically pure (4-)-Precursor 13 (ce > 95%). *H NMR (400 MHz, CHLOROFORM-J) δ ppm 1.78 2,03 (m, 2 H) 2.20 (br. s„ 3 H) 2.76 (ddd, > 16.6,9.4, 6.2 Hz, 1 H) 2.93 (dd, > 16.6,

5.3 Hz, 1 H) 3.80 - 4.00 (m, 2 H) 6.94 (d, >5.0 Hz, 1 H) 7.13 (d, >5.3 Hz, 1 H);

[a]²⁰» = +59.6° (c 0.49, MeOH). The absolute stereochemical configuration was determined using VCD.

Example 13: Synthesis of (lS,2R.6R)-2-hydroxy-6-methylcvclohexanamine hydrochloride ((-)-Precursor 14b)

13-1 13-2A 13-2B 13-3

Step 3 NaBH₄

MeOH. rt

(-)-Precursor 14b

1. Raney Ni, H₂ ethyl acetate, 5°C

OH

13-4

2. HCl / dioxane

Step 4

Step 1: Kctonc 13-1 ([CAS No.; 13368-65-5]; 430 g, 3.83 mol, 1.0 eq.) and pura-toluenesulfonic acid monohydrate (pTSA.H₂O; 72.9 g, 0.38 mol, 0.1 eq.) in isopropcnyl acetate (2.5 L) were refluxed for 6 hours at ÎOO^C. After the reaction mixture was cooled to room température, water was added. The organic layer was separated and washed with a saturated aqueous NaHCOj solution and brinc, dried with anhydrous NaSO₄ and concentrated under vacuum to afford 530 g (90%) of a 7:10 mixture of the desired isomer 13-2A and the undesired isomer 13-2B (isomeric ratio was determined by *H NMR). This mixture was used as such in the next step.

-39Stcp 2: The isomeric mixture 13-2A and 13-2B (106.2 g, 0,95 mol, l.O eq.) was dissolved in acctic acid anhydride (400 mL). Concentrated nitric acid (61 mL, 0.95 mol, l .0 eq.) was added dropwisc at such a rate that the réaction température was maintained between 3O°C and 40°C. After the addition was complète, the reaction was stirred at room température for two hours, TLC showed completion of the reaction (eluent: pctroleum ether / ethyl acetate 5:l, R/= 0.4, two spots, closcly). The reaction mixture was added dropwisc to an aqueous saturated NaHCOj solution (79.8 g NaHCO₃ in water, 0.95 mol, l .0 eq.). The mixture was cxtracted with ethyl acetate, the combined organic layers were washed with brine, dried with anhydrous Na2SO.| and lü concentrated under vacuum. The crudc product was purified by silica gel column chromatography (eluent: petroleum ether ! ethyl acetate 97:3 -> 91:9) to afford 12.5 g (l l%) of Intermediate 13-3 (the second spot).

Step 3: NaBIL (40 g, 1.03 mol, 1.3 eq.) was added in portions to a solution of

Intermediate 13-3 (125 g, 795 mmol, 1.0 eq.) in dry methano! (3.0 L) at room température. The reaction mixture was stirred for 30 minutes at room température. The mixture was neutralized with an aqueous 10% KHSO₄ solution to pH ~ 7 and concentrated under redueed pressure. Water was added and the mixture was cxtracted with ethyl acetate. The combined organic phases were washed with brine, dried with anhydrous MgSO₄ and concentrated under redueed pressure to give a 1:1 mixture of

Intermediate 13-4 and its epimeric alcohol. Both epimers were separated via préparative SFC on a Chiralpak Daiccl® AD-5 pm column (30 * 250 mm, mobile phase: isocratic 20% isopropanol / 80% CO₂, flow rate 60 mL/min), 29 g (22%) of the desired isomer 13-4 was obtained as the first fraction. 'H NMR (400 MHz, CDCU) S ppm 0.99 (d, 7=6.8 Hz, 3 II), 1.10 (m, 1 II), 1.50 (m, 2 H), 1.75-1.91 (m, 2 H), 2.01 (m, 1 H), 2.50 (m, 1 H), 2.85 (br. s, 1 H), 4.20 (dd, 7=11.6, 2.0 Hz, 1 H), 4.51 (s, I H).

Step4; A solution of 13-4 (29 g, 169.6 mmol, 1.0 eq.) in ethyl acetate (1.25 L) was hydrogenated at atmospheric pressure for five hours at 5°C with Raney Ni (32 g) as catalyst. After uptake of hydrogen gas (3.0 eq.), the catalyst was filtered off. A hydrochloric acid solution in dioxanc was added to the filtrate at 0°C, the resulting 30 mixture was stirred for 30 minutes. The solvent was partially removed under redueed pressure, the precipitate was collectcd by filtration and washed with petroleum ether and diethyl ether to give 20.9 g (74%) of (-)-Prccursor 14b (ce > 95%, the ec was determined by LC after amide formation with (S)-(+)-a-mcthoxy-a-trifluoromethylphcnylacctylchloridc). 'H NMR (400 MHz, McOD) δ ppm 1.01 (d, 7=6.5 Hz, 3 H) 1.04 35 - 1.19(m, I H) 1.42- 1.60 (m,2 H) 1.70- 1.81 (m, 1 H) 1.81 -2.01 (m, 1 H) 1.81 2.01 (m, 1 H) 2.79 (dd, 7=10.8, 3.0 Hz, 1 H) 4.02 - 4.06 (m, 1 H); [a]²⁰ _D =-0.53° (c 1.01, MeOH).

-40Mentioncd below are the carboxylic acid and carbonate Precursors rcquired as building blocks lcading to the introduction of R³ as defined hcrcinbcforc. Those for which no commercial supply is available, can be synthesized according to literaturc 5 procedures (Precursor 23 and 24) or through the procedure described in Example 14 (Precursor 22).

Precursor18

Precursor 22

Precursor19

Precursor 20

Precursor 21

Example 14: Synthesis of (S)-2-(l-cvanocvclonropanecarboxamido)-3.3-dimethylbutanoic acid (Precursor 22)

HATU, DIPEA

HCk V.

DMF, rt

Step 1

H₂,Pd

MeOH, rt

Step 2

Amine 14-1 was synthesized according to literature procedures starting from

Precursor 19.

Step 1: HATU (3.56 g, 9.35 mmol, 1.15 eq.) was added to a solutionofamine

14-1 (1.8 g, 8.13 mmol, 1.0 eq.), 1-cyanocyclopropanecarboxylic acid (0.90 g,

8.13 mmol, 1.0 eq.) and A^r-cthyl-A-isopropylpropan-2-amine (DIPEA; 3.15 g, 8.13 mmol, 1.0 cq.) in DMF (80 mL) at -20°C. The réaction mixture was stirred at room température for one hour. Ethyl acetate was added, the organic phase was washed with a saturated NaHCOj solution, dried with anhydrous MgSOj and concentratcd under

-4)reduced pressure to give l .83 g (72%) oferude Intcrmcdiate 14-2. This was used as such in the ncxt step.

Step 2; A solution of Intcrmcdiate 14-2 (1.83 g, 5.81 mmol, l.Ocq.) hi mcthanol was hydrogenated at atmospheric pressure at 25°C for 3 hours with Pd (Pd/C !0%) as catalyst. The réaction mixture was filtcrcd over Celite and the fiItrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (clucnt: dïchloro méthane / mcthanol / acctic acid 97:2:1) to givc 0.75 g (58%) of Precursor 22. (It was observed that during the execution of the above mentioned synthesis sequence, extensive racemization had taken place!) 'H NMR (400 MHz,

CHLOROFORMA) Ô ppm 1.07 (s, 9 H) 1.56 (d, J=3.7 Hz, 2 H) 1.63 - 1.79 (m, 2 H)

4.41 (d, ./=9.0 Hz, 1 H) 6.87 (d, J=8.8 Hz, 1 H) 11.12 (br. s., 1 H)

Mentioned below arc Precursors representing examples of formula R⁴-M as defined hcrcinbcforc which were used for Suzuki or Stillc cross-coupling réactions. Those for which no commercial supply is availablc, can be synthesized according to litcraturc procedures (Precursor 25 and 26) or by procedures described in Examplcs 15 and 16 (Precursors 27, 28,36 and 37).

Y

Sn{nBu)3

Sn(nBu)î

Precursor 28

Sn(nBu)₃

Precursor 25

Precursor 26

Precursor 27

Precursor 29

Precursor 31

Precursor 30

Precursor 32

HO OH

Precursor 33

-__HO OH

Precursor 34

Precursor 36

Precursor 35

Precursor 37

Precursor 38

Precursor 39

X n H	M	A H	N- n	X φ H
Precursor 40	Precursor 41	Precursor 42	Precursor 43	Precursor 44

Examnle 15: Synthesis of 2-isonropyl-5-(tributylstannvDthiazole (Precursor 27)

LDA; nBu₃SnCI ------------------------------------!

THF

-78’C -> rl Sn(nBu)₃

Precursor 27

Lithium diisopropylamide (LDA; 245 mL of a 2.5 M solution, 613.2 mmol, 1.2 eq.) was added over a period of two hours to a solution of 2-isopropylthiazolc ([CAS No.: 15679-10-4]; 65 g, 511 mmol, l.O eq.) in dry THF (1.3 L) at -78°C. After stirring for one hour at this température, tributyltin chloride (l 11 mL, 408.8 mmol, 0.8 eq.) was added dtopwisc. The réaction mixture was allowcd to gradually wami to room JO température over about three hours, whcrcupon the mixture was qucnchcd with a saturated aqueous NH<iC) solution and diluted with diethyl ether. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried with MgSO₄ and concentrated under reduced pressure to afford 51 g (24%) of Precursor 27. 'H NMR (300 MHz, CHLOROFORM-rT) 8 ppm

0.90 (t, .7=7.3 Hz, 9 H) 1.06 -1.16 (m, 6 H) 1.25- 1.39 (m, 6 H) 1.42 (d, >7.0 Hz, 6 H)

1.48 - 1.6Hm, 6 H) 3.38 (spt, >6.9 Hz, l H) 7.60 (s, 1 H).

Precursor 28 was synthesized analogously to Precursor 27 starting from 2cyclopropylthiazolc [CAS No.: 1159821-56-3], but using n-butyllithium as a base.

·43·

Example 16: Synthesisof 2-cyclopronyl-6-methyl-4-(4,4.5.5,-tetramethyl-].3,2-dioxaborolan-2-vl)-pvriditie (Precursor 36)

Pin₂B₂ dtbpy, [lrCI(COD)]₂ octane, 80°C

Precursor 36

A mixture of2-cyclopropyl-6-methylpyridine ([CAS No.: 41765-00-8];!.99 g,

14.9 mmol, LO eq.), bis(pinacolato)diboron(Pin2B2;3.79g, I4.9mmol, l.0cq.)and

4,4’-di-ie/7butyl-2,2’-bipyridinc (dtbpy; 0.08 g, 0.30 mmol, 0.02 cq.) in octane (25 mL) was flushed with nitrogen. Chloro-l,5-cyclooctadiene iridium(I) dimer ([IrCl(COD)]₂; 0.10 g, 0.149 mmol, 0.01 cq.) was added and the reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was coolcd to room température and diluted with dichlorométhane. Water was added and the mixture was stirred for 15 minutes. The water phase was extractcd with dichloromethane (6 times), the combined organic phases were dried with anhydrous MgSO^ and concentratcd under redueed pressure to give 3.7 g (95%) of crude Precursor 36. The lattcr was used without further purification.

Precursor 37 was synthesized anaiogously to Precursor 36 starting from 2,6-dimcthylpyridinc [CAS No.: 108-48-5],

The following examples illustrate typical synthèses of the compounds of formula 1. The corresponding NMR data and/or mclting points arc listcd in table 2.

Example 17: Synthesis of Compound 7

(-)-Precursor

1. LHMDS

THF, - 78°C

Step 1

NaOH

---------------------------------<

CH₃OH/ H₂O, rt

Step 2

1. TBDMSCI, Imidazole

2. MeOH

DMF, rt

Step3

1. HATU, Et₃N, rt

NH₂ (+)-Precursor 2

2. TB AF, 50°C

DMF

Step 4

Step 1 : A solution of (-)-Precursor i (12.5 g, 32.5 mmol, 1.0 cq.) in dry THF (100 mL) was cooled to -78°C under nitrogen. Lithium bis(trimethylsilyl)amide (LHMDS; 68.3 mL of a 1 M solution in THF, 68.3 mmol, 2.1 cq.) was added slowly. Aller 30 minutes at -78°C, 2-fluorobcnzyl bromide (4.19 mL, 34.2 mmol, 1.05 cq.) was added in onc portion to the réaction mixture. Stirring was continued for 90 minutes at -78°C. Acetic acid (I mL) and water were added, the mixture was allowed to warm to room température. Ethyl acétate was added, the organic phase was separated and successively washed with a 10% citrie acid solution, a saturated aqueous NaHCOj solution and brine, dried with anhydrous MgSCL and concentrated under reduced pressure. The crudc product was purified by silica gel column chromatography (eluent: heptane -> heptane / ethyl acétate 7:3) to provide 10.7 g (67%) of Intermediate 17-1.

Step 2: NaOH (33.5 mL of a 1 M aqueous solution, 33.5 mmol, 5.0 cq.) was added to a solution of Intermediate 17-1 (3.3 g, 6.7 mmol, 1.0 eq.) in methanol (20 mL). The reaction mixture was stirred at room température for three hours. The reaction mixture was partially concentrated under reduced pressure and then acidified to pH - 2-3 with a 10% citric acid solution. The whîte prccipitatc was filtered off, washed with water and dried under high vacuum. Crudc Intermediate 17-2 (3.33 g,

96%) was used as such in the next step.

Step 3: Imidazole (3.08 g, 45.2 mmol, 7.0 cq.) and rerr-butyldimcthylsilylchlorîde (4.87 g, 32.4 mmol, 5.0 cq.) were added to a solution of Intermediatc 17-2 (3.33 g, 6.47 mmol, l .0 cq) in DMF (650 mL). The réaction was stirred at room température overnight. Methanol (30 nrL) was added and stirring was continued until 5 liquid chromatography-mass spectromctry (LCMS) showed complété TBDMSdcprotection of the carboxylic acid. Ethyl acetate and a 10% citric acid solution were added to the réaction mixture. The organic phase was separated, washed with brine, dried with anhydrous MgSO.i and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elucnt; heptanc -> heptanc / io ethyl acetate 7:4) to provide 3.7 g(91%) ofpure Intermediatc 17-3.

Step 4: Trîethylamine (0.89 g, 8.83 mmol, 1.2 cq.), HATU (2.94 g, 7.73 mmol,

1.05 cq.) and (+)-Prccursor 2 (1.54 g, 7.73 mmol, 1.05 cq.) wcrc succcssivcly added to a solution of Intermediate 17-3 (4.60 g, 7.36 mmol, 1.0 eq.) in DMF (70 mL). The réaction mixture was stirred for one hour at room température. Tctrabutylammonium J 5 fluoride (TBAF, 73.64 mL of a 1 M solution in THF, 73.64 mmol, 10.0 cq.) was added and the réaction mixture was stirred at 50°C until complète TBDMS-dcprotcction. Intermediate 17-4 was prccipitated by the addition of a saturated aqueous Na₂COj solution to the réaction mixture. The prccipitate was fiitered off, washed with water and dried under high vacuum. The crude product was used as such in the next step.

\

M_

17-6

Compound 7

46·

Step 5: A mixture of lntermediate 17-4 (400 mg, 0.61 mmol, 1,0 cq.),

Precursor 34 (303 mg, 1.83 mmol, 3.0 eq.), tetrakis(triphcnylphospine)pailadium (Pd(PPIb)₄,; 141 mg, 0.12 mmol, 0.2 cq.) and Na₂CCh (2.74 mL of a 2 M aqueous solution, 5.47 mmol, 9.0 cq.) in dioxane (3 mL) was stirred at 110°C for 30 minutes (to prevent the formation of side-products short réaction times were applied) under argon. The réaction mixture was then rapidly cooled in an ice bath and a saturated aqueous Na₂COi solution was added. The water layer was extracted with ethyl acetate, the combined organic phases were dried with anhydrous MgSO₄ and concentrated under reduced pressure. Crude Intermediatc 17-5 was used as such in the next step.

Step 6; Crude lntermediate 17-5 was dissolved in a 5 to 6 M HCl solution in isopropanol and stirred at room température until complète deprotection (~ 30 minutes, to prevent the formation ofside-products the réaction time has to be kept as short as possible). The reaction mixture was basified with a saturated aqueous Na₂CO3 solution and extracted with ethyl acetate. The combined organic phases were washed with water, dried with anhydrous MgSO₄ and concentrated under reduced pressure to give crude Intermediatc 17-6 which was used as such in the next step without purification.

Step 7: Triethylamine (246 mg, 2.43 mmol, 4.0 eq.) and HATU (266 mg, 0.69 mmol, 1.15 eq.) were succcssively added to a mixture of crude lntermediate 17-6 and Precursor 18 (132 mg, 0.69 mmol, 1.15 cq.) in DMF (8 mL). The reaction mixture was stirred for two hours at room température. Ethyl acetate was added, the organic phase was washed with a saturated Na₂COj solution and water, dried with anhydrous MgSO.i and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichlorométhane -> dîchloromethanc / methanol 97:3) to give 144 mg (31% starting from Intermediatc 17-4) of Compound 7.

Compounds 99 and 100 were prepared analogously to Compound 7. Compounds 8, 10, 13, 16, 26, and 27 wcrc prepared analogously to Compound 7 but with Step 6 involving a T-EA mediated Boc-deprotcction step using the procedure as described for Step 2 in Example 27. Compound 11 was prepared analogously to Compound 7, but using a Stille cross-coupling réaction as described in Exemple 23 and a TFA mediated Boc-deprotcction step as described for Step 2 in Examplc 27.

-47Example 18: Synthesis of Compound 33

HO' ΌΗ Precursor 34

Pd(PPh₃)₄, Na₂CO₃dioxane / H₂O 110’C Slep2

18-2	_J HCl, rt Γ	- 18-3 R = Boc
	^Step4PrOnL	► 18-4	R = H

*- Compound 33 ίο

Step 1 : HATU (2.36 g, 6.22 mmol, 1.1 eq.) was added to a solution of

Intermediatc 17-3 (3.53 g, 5.65 mmol, 1.0 cq.), (+)-Precursor 8 (1.04 g, 5.65 mmol, 1.0 eq.) and tricthylaminc (1.72 g, 16.95 mmol, 3.0 cq.) in DMF (25 mL). The reaction mixture was stirred for one hour at room température. The réaction mixture was diluted with ethyl acetate and washed a 10% citric acid solution, a saturated Na₂CO₃ solution and brine, dried with MgSO₄ and concentrated under reduced pressure to give 4.48 g (96%) of crudc Intermediate 18-1. The crude product was used as such in the.next step.

Step 2: A mixture of Intcrmcdiate 18-1 (4,33 g, 5,48 mmol, 1.0 cq.), Precursor (1.82 g, 10.96 mmol, 2.0 cq.), Pd(PPh₃)₄ (0.63 g, 0.55 mmol, 0.1 cq.) and Na₂CO₃(30 mL of a 2 M aqueous solution, 60.3 mmol, 11.0 eq.) in dioxane (100 mL) was stirred at 100°C for 50 minutes (to prevent the formation of side-products the réaction time has to be kept as short as possible) under nitrogen. The reaction mixture was then rapidly coolcd in an ice bath and a saturated aqueous Na₂CO₃ solution was added. The water layer was extracted with ethyl acetate, the combined organic phases were washed with brine, dried with anhydrous MgSO₄ and concentrated under reduced pressure. The

residue was purified by silica gel column chromatography (elucnt: dichloromethane -> dichloromethanc / methanol 95:5) to give 4.95 g (92%) of Intermediate 18-2.

Step 3: TBAF (10.9 mL ofa 1 M solution in THF, 10.97 mmol, 2.0 cq.) was added to a solution of Intermediate 18-2 (4.56 g, 5.49 mmol, 1.0 eq.) in THF (30 mL). The reaction mixture was stirred at 50°C until complété dcprotection. Water was added, the precipitate was filtered off, thoroughly washed with water and dried under high vacuum to give 3.77 g (86%) of Intermediate 18-3.

Intermediate 18-3 was forther converted to Compound 33 according to the procedures as described for Step 6 and Step 7 in Example 17.

Compound 35 was prepared analogously to Compound 33.

Example 19: Synthesis of Compound 66

Compound 66

Intermediate 19-1 was prepared using the procedures as exemplified for the préparation of Intermediate 17-5.

Nal (984 mg, 6.56 mmol, 5.5 cq.) and chlorotrimethylsilane (TMSC1; 584 mg, 5.37 mmol, 4.5 eq.) were added to a solution of Intermediate 19-1 in acetonitrilc (10 mL). The réaction mixture was stirred at room température for two hours. Methanol and an aqueous NaOH solution (12 mL of 1 M NaOH solution, 11.9 mmol, 10.0 cq.) were added, stirritig was continued for an addittonal 30 minutes. The reaction mixture was partially concentrated under reduced pressure, ethyl acetate and water were added. The water layer was separated and extractcd with ethyl acetate, the combined organic phases were dried with MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elucnt: dichloromcthane dichloromethanc ! methanol 93:7) to give 360 mg (50%) of Intermediate 19-2.

Intermediate 19-2 was converted to Compound 66 according to the procedure as described for Step 7 in Examplc 17.

-49Compounds 36, 40, 85 and 92 were prepared analogously to Compound 66.

Example 20: Synthesis of Compound 96

20-4

20-5

Stcp l : A solution of(-)-Precursor 1 (54.0 g, 131 mmol, 1.0 cq.) in dry THF (1000 mL) was cooled to -70°C under nitrogen. Lithium bis(trimethylsilyl)amide (306.8 mL of a 1 M solution in THF, 307 mmol, 2.35 eq.) was dropwise added over a.

period of one hour, after which the reaction mixture was stirred for an extra four hours. A solution of2-fluorobenzyl iodidc (34.0 g, 144 mmol, 1.1 cq.) in THF (100 mL) was added to the reaction mixture over one hour. Stirring was continued for 60 minutes at -70°C. Propionic acid and water were added, the mixture was allowed to warm to room 10 température. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried with anhydrous NajSCL and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petrolcum ether / ethyl acetate 40:1) to provide 46.3 g (72%) of Intermediate 20-1.

Step 2: LiOH (1.4 L of a 1 M aqueous solution, 1.4 mol, 5.0 eq.) was dropwise added to a solution of Intermediate 20-1 (140 g, 284 mmol, 1.0 eq.) in methanol (3.5 L) at room température. The réaction mixture was stirred at room température until no more starting material was left. The reaction mixture was concentrated under reduced pressure and filtered. The precipitate was filtered off, washed with water and dried under vacuum at 50°C to give 120 g (82%) of Intermediate 20-2.

Stcp 3: À~3 L réaction flask was chargcd with water and stirred at reflux température for 30 minutes under N₂. After the water was cooled to 40°C, methanol (300 mL), Intermediate 20-2 (100 g, 194 mmol, 1.0 eq.), Na₂CO3 (83 g, 783 mmol, 4,0 eq.), Pd(OÀc)₂ (661 mg, 2.9 mmol, 0.015 eq.) and Precursor 30 (60 g, 392 mmol, 2.0 eq.) were successively added. The réaction mixture was degassed with N₂ and heated to 25 75°C over 10 minutes. The reaction mixture was stirred at 75°C for 30 minutes and then cooled to room température. The precipitate was filtered off, washed with a water / methanol mixture (3:1, 100 mL) and dried under vacuum at 50°C to give 108 g (99 %) of Intermediate 20-3.

-51Stcp 4: intermediate 20-3 was converted to Intermediate 20-4 with 70% yield using the procedure as described for Step 3 in Examplc I7.

Step 5; Tricthylamine (2.67 g, 38.7 mmol, 3.0 cq.) was dropwise added to mixture of Intermediate 20-4 (8.45 g, 12.9 mmol, l.O eq.), HATU (5.15 g, 13.6 mmol, 5 1.05 cq.) and (-)-Precttrsor 14 (2.25 g, 13.6 mmol, 1.05 eq.) in acetonitrile (20 mL).

After the reaction mixture was stirred at room température for onc hour the pH of the réaction solution was adjusted to 8-9 by the addition of an aqueous Na₂CO3 / NaHCCh solution. Extraction was carried out with ethyl acctate, the combined organic phases were washed with water, dried with Na₂SO₄ and concentrated under reduced pressure to afford 12.4 g (86%) of Intermediate 20-5.

Stop 6: A mixture of Intermediate 20-5 (12.44 g, 16.3 mmol, 1.0 cq.) and Nal (15,86 g, 105.8 mmol, 6.5 eq.) in acetonitrile (130 mL) was stirred at 0~5°C. A solution of TMSC1 (9.76 g, 89.5 mmol, 5.5 cq.) in acetonitrile (20 mL) was dropwise added over a period of onc hour, Stirring was continued until complété Boc-deprotection (~ 90 minutes). TBAF (163 mL ofa 2 M solution in THF, 326 mmol, 20.0 eq.) was dropwise added over five hours to the réaction mixture at 0-5°C. The réaction mixture was stirred overnight at 30°C. The pH was adjusted to 8-9 by the addition of an aqueous Nu₂COj / NaHCCh solution. Extraction was carried out wilh dichloromethane, the combined organic phases were washed with water, dried with Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane / methanol 50:1) to give 8.0 g (90%) of Intermediate 20-6.

Step 7: Intermediate 20-6 was converted to Compound 96 according to the procedure as described for Step Ί in Examplc 17.

Compounds 45, 52, 93 and 67 were prepared analogously to Compound 96.

For Compound 52 the structure is:

-52\

For Compound 93 its synthesis is the same as above mentioned up to Step 4, but as of Step 5, starting with Intcrmcdiate 20-4, the synthesis is as follows:

20-8

HATU, Et₃N CH₃CN, rt

Step 7

Compound 93

-53Step 5: Triethylaminc (31 g, 306 mmol, 2,0 eq.) was dropwise added to mixture of Intermediate 20-4 (27.2 g, 153 mmol, l.O eq.), HATU (61.2 g, 161 mmol, 1.05 cq.) and (-t-)-Precnrsor 13 (2.25 g, 13.6 mmol, 1,05 cq.) in acctonitrilc (700 mL). After the reaction mixture was stirred at room température for one hour the pH ofthe reaction solution was adjusted to 8-9 by the addition of an aqueous Na₂COi / NaHCOj solution. Extraction was carried out with ethyl methyl tcrt-butyl ether, the combined organic phases were washed with water, dried with Na₂SO,j and concentrated under reduced pressure to afford 122 g (99%) of Intermediate 20-7.

Step 6; A mixture of Intermediate 20-7 (122 g, 152 mmol, 1.0 cq.) and Nal (149 g, 996 mmol, 6.5 eq.) in acctonitrile (1200 mL) was stirred at 0-5°C. A solution ofTMSCl (91.5 g, 842 mmol, 5.5 eq.) in acetonitrile (200 mL) was dropwise added over a period of one hour. Stining was contînucd until complète Boc-dcprotcction (~ 30 minutes). TBAF (1600 mL of a 2 M solution în THF, 3.04 mol, 20.0 cq.) was dropwise added over five hours to the reaction mixture at 0-5°C. The réaction mixture was stirred ovemight at 25-30°C. The pH was adjusted to 8-9 by the addition of an aqueous Na₂COj / NaHCOj solution. Extraction was carried out with dichloromcthanc, the combined organic phases were washed with water, dried with Na2SO.| and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / mcthanol 50:1) to givc 77 g (86%) of Intermediate 20-8.

Step 7: Triethylaminc (26.4 g, 264 mmol, 2.0 eq.) was added to a mixture of

HATU (52.2 g, 137 mmol, 1.05 cq.), Intermediatc 20-8 (77 g, 131 mmol, 1.0 eq.) and Prccursor 18 (25.9 g, 137 mmol, 1.05 eq.) in DMF (770 mL). The reaction mixture was stirred for one hour at room température. An aqueous Na2COj solution and water were added, the mixture was stirred for 30 minutes. The prccipitatc was fiitered off, washed with water and dried under vacuum at 50°C to give 83 g crude of Compound 93. After rccrystallization in a watcr/ethanol mixture, 78 g (79%) of Compound 93 was obtained.

-54Example 21 Synthesisof Compound 64

Intermediate 21-1 was prepared using the procedures as exemplified for the préparation of Intermediate 17-3.

Step 1: Tricthylamine (119 mg, 1.18 mmol, 1.2 eq.), HATU (412 mg,

1.09 mmol, 1.1 eq.) and i+j-Precursor 8 (199 mg, 1.18 mmol, 1.1 cq.)wcrc successively added to a solution of Intermediate 21-1 (681 mg, 0.99 mmol, 1.0 eq.) in 10 acctonitrile (10 mL). The reaction mixture was stirred for one hour at room

température. Nal (961 mg, 6.41 mmol, 6.5 eq.) and TMSCI (589 mg, 5.42 mmol, 5.5 eq.) were succcssively added to the reaction mixture, stirring was continued until complète Boc-dcprotcction (- 2 hours). TBAF (l 1.8 mntol, 11.8 mL of a l M solution in THF, 12.0 cq.) was then added and the reaction mixture was stirred overnight at

60°C. A saturated aqueous Na₂CO₃ solution was added, the precipitate was filtered off and thoroughly washed with water. The crude product was purified by silica gel column chromatography (clucnt: dichloromethane dichloromethane / mcthanol 90:10) to givc 288 mg (46%) of Intcrmcdiatc 21-2.

Step 2: Triethylamine (91 mg, 0.90 mmol, 2.0 cq.) and HATU (179 mg,

It) 0.47 mmol, 1.05 cq.) were succcssively added to a mixture of Intermcdiate 21-2 (288 mg, 0.45 mmol, LO eq.) and Prccursor 18 (89 mg, 0.47 mntol, 1.05 cq.) in DMF (4 mL). The réaction mixture was stirred for two hours at room température. Intermcdiate 21-3 was prccipitated by the addition of a saturated aqueous Na₂CO₃solution. The precipitate was filtered off, washed with water and dried under high 15 vacuum to give 330 mg (90%) of crude Intermediate 21-3.

Step 3; A mixture of Intcrmcdiatc 21-3 (165 mg, 0.203 mmol, 1.0 cq.), Precursor 30 (62 mg, 0.406 mmol, 2.0 cq.), Ρά(ΡΡ1ι₃)<ι (23 mg, 0.020 mmol, 0.1 cq.) and Na₂CO₃ (0.91 mL ofa 2 M aqueous solution, 1.83 mmol, 9.0 eq.) in dioxane (2 mL) was stirred at 110°C for 15 minutes under argon. The réaction mixture was then 20 rapidly cooled in an icc bath and a saturated aqueous Na₂CO₃ solution was added. The precipitate was filtered off, washed with water and dried under reduccd pressure. The crude product was purified by silica gel column cluomatography (eluent: dichloromethane dichloromethane / methanol 95:5) to give 115 mg (67%) of Compound 64.

Compounds 41, 54, 62, 63, 65 and 94 were prepared analogousiy to Compound 64.

Example 22 Synthesis of Compound 44

22-1

*- Compound 44

Intermediatc 22-1 was prepared using the procedures as exemplified for the préparation of Intermediatc 17-4. Intermediatc 22-1 was converted to Intermediatc 22-2 using the Boc-dcprotection procedure as described in Example 19. The latter was converted to 5 Compound 44 via intermediatc 22-3 using respectively the procedures from Stcp 2 and

Step 3 as described in Example 21.

Compounds 12,18, 2», 21,22,23,24, 25, 29, 30,31, 39,42, 43, 46,48,49 and 91 were prepared analogously to Compound 44.

Example 23: Synthesis of Compound 32

Λ mixture of Intermediate 22-3 (230 mg, 0.301 mmol, 4.0 eq.), Precursor 27 (501 mg, 1.21 mmoi, 4.0 eq.), Pd(PPh₃)<i (35 mg, 0.030 mmol, 0.1 cq.) and LiCI (26 mg, 0.603 mmol, 2.0 eq.) in dioxane (3 mL) was stirred at 85°C for 40 minutes under argon. The réaction mixture was cooled in an icc bath and an cxccss of water was added. The prccipitate was filtered off, washed with water and dried under reduced pressure. The crude product was purified by silica gel column chromatography (eluent:

-57dichloromethanc -½ dichloromcthanc / mcthanol 96:4) to give 137 mg (56%) of Compound 32.

Compounds 14, 28, and 29 were prepared analogously to Compound 32.

Example 24: Synthesis of Compound 38

Compound 32

Compound 38

A solution of Compound 32 (50 mg, 0.06 mmol, 1.0 cq.) in mcthanol (6 mL) was hydrogenated (1.0 atm of hydrogen) at 25°C for 90 minutes with Pd (Pd/C 10%, 50 mg) as catalyst. The reaction mixture was filtercd over Celite, the filtratc was concentrated under reduced pressure to give 31 mg (61%) of Compound 38.

Example 25: Synthesis of Compound 17

•58Intcrmcdiate 25-1 was prepared using the procedures as exemplified for the préparation of Intermediate 17-3.

Step 1 : HATU (1.25 g, 3.30 mmol, 1.05 cq.) was added to a mixture of triethylamine (954 mg, 9.42 mmol, 3.0 eq.), (+)-Precursor 2 (519 mg, 3.14 mmol,

1.0 cq.) and Intermediate 25-1 (2.0 g, 3.14 mmol, 1.0 eq.) in DMF (10 mL). The réaction mixture was stirred for 30 minutes at room température. Ethyl acetate was added, the organic phase was washed with a saturated aqueous Na₂CO₃ solution and brine, dried with MgSO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane ->

dichloromcthanc / methanol 99:3) to give 1.67 g (68%) of Intermediate 25-2.

Step 2: A mixture of Intermediate 25-2 (1.67 g, 2.13 mmol, 1.0 cq.) and TBAF (32.0 mL of a 1 M solution in THF, 32.0 mmol, 15.0 eq.) in THF (40 mL) was stirred at room température overnight. Ethyl acétate and brine were added to the réaction mixture, The organic layer was separated, thoroughly washed with water and dried to give 1.47 g (100%) of crude Intermediate 25-3, The crude product was used as such in the next step.

Step 3: Intermediate 25-3 was converted to Intermediate 25-4 involving a TFA mediated Boc-deprotection step using the procedure as described for Step 2 in Example 27. The lattcr was converted to Compound 17 using respectively the procedures from 20 Step 2 and Step 3 as described in Example 21.

Compounds 15 and 87 and were prepared analogously to Compound 17. Compound 37 was prepared analogously to Compound 17, but involving a HCl mediated Boc-deprotection step as described for Step 6 in Example 17.

Example 26: Synthesis of Compound 51

toluene, reflux

-59Step l : A mixture of (-)-Precursor 1 (10.0 g, 26.0 mmol, 1.0 eq.), Prccursor (6.5 g, 39.0 mmol, 1.5 eq.) and an aqucous NaHCOj solution (21.9 g in 50 mL of water, 260.2 mmol, 10 cq.) in dioxane (200 mL) was stirred at room température under argon. Pd(PPhj)^ ( 1.5 g, 1.3 mmol, 0.05 cq.) was added and the réaction mixture was 5 stirred at 80°C for one hour and then coolcd to room température. Ethyl acetate was added, followcd by the addition of a saturated aqucous NazCOî solution. The organic and the water layer were separated, the organic layer was washed with brinc and dried with anhydrous MgSCL to givc a first batch of crude Intcrmedîatc 26-2. The water layer was acidificd with a 2 M HCl solution to pH ~ 2 and washed with ethyl acetate.

Subscquently, the pH was adjusted to pH - 6 with NaïCOj powder and an extraction was carried out with ethyl acetate. The combincd organic phases were dried with anhydrous MgSO^ and concentrated under reduced pressure to givc a crudc lactonc hydrolyzed side-product (Intermcdiate 26-1). This was refluxed in toluene under DeanStark conditions until re-lactonization was complète. After rcmoval ofthe solvent under reduced pressure, a second bath of crude Intermcdiate 26-2 was obtained. Both batches were combincd and purified by silica gel column chromatography (clucnt: heptane / ethyl acetate 90; 10 -> 30:70) to givc 7.9 g (71%) of pure Intcrmediatc 26-2.

-60\

Step 2: Lactone 26-2 was convcrtcd to Intcrmediate 26-3 according to the procedure as described for Step l in Example 17. Purification by silica gel column chromatography (elucnt: hcptanc hcptanc / ethyl acétate 5:5) gave lntcrmcdiatc 26-3 with 73% yield.

Step 3: NaOH (124,5 mL ofa 1 M aqueous solution, 124,5 mmol, 9.3 eq.) was added to a solution of Intcrmediate 26-3 (7.18 g, 13.5 mmol, 1.0 cq.) in THF (120 mL). The réaction mixture was stiricd at room température for onc hour. The réaction to mixture was partially concentrated under rcduccd pressure and then acidifïed with an aqueous 10% citric acid solution until pH - 6. The water phase was extracted with dichlorometliane, the combined organic phases were dried with anhydrous MgSO4 and concentrated under rcduccd pressure to givc 7.40 g (99%) of Intermédiare 26-4.

Step 4: Intermcdiatc 26-4 was converted to Intcrmediate 26-5 according to the procedure as described for Step 3 in Example 17. Purification by silica gel column chromatography (elucnt: dichloromcthanc -> dichloromcthanc / methanol 96:4) gave Intermcdiate 26-5 with 84% yield.

Step 5: Intermcdiate 26-5 was convcrtcd to Intermediate 26-6 using the procedure as described for Step 1 in Example 21. The latter was converted to Compound 51 using 20 the procedure as described for Step 7 in Example 17.

Compounds 50, 58, 59, 80, 89 and 95 wcrc prepared analogously to Compound 51. Chlorination of Compound 51 according to the procedure as described in Example 33 gave Compound 60.

-61Examplc 27: Syndicats of Compound 86

TFA p ^27-1A ^DCM-^rtL₂7-2A

R=Boc

Step 2

R=H

TFA DCM, rt

27-1B R=Boc

27-2B R=H f

Compound 86

Step 1 : Intermediate 26-5 was reacted with racémie (rac)-Prccursoi' 4 using the procedure as described for Step 4 in Example 17. The crude reaction product was suspended in a mixture of acctonitrilc and mcthanol (1:1) at reflux température. After cooling down to 0°C, the precipitate was filtered off to give a 1 : i mixture of Intermediate 27-1A and Intermediate 27-1B as a whitc powder (71%). This mixture was used as such in the next step.

Step 2: TFA (10 mL, 135 mmol, 129 eq.) was added to a 1:1 mixture of

Intermediate 27-1A and Intermediate 27-1B (765 mg, 1.04 mmol, 1.0 eq.) in dichloromcthanc (200 mL). The reaction mixture was stirred at room température until LCMS

-62showed complété conversion (—30 minutes, to prevent the formation of sidc-products the reaction time has to be kept as short as possible). A saturated aqueous Na₂CO3 solution was added, the layers were separated, the water layer was extracted with dichloromethanc. The combined organic phases were washed with brine, dried with anhydrous MgSO₄ and concentrated under reduced pressure. Both isomers were separated by silica gel column chromatography (eluent: dichloromcthane dichloromethanc / mcthanol 93:7) to providc 320 mg (48%) of Intermediatc 27-2A (first fraction) and 298 mg (45%) of lntermediate 27-2B (second fraction).

lntermediate 27-2A was converted to Compound 86 using the procedure as described for Step 7 in Example 17.

Example 28: Synthcsis of Compound 61

26-1

TMSCI, NalP

CH₃CN, rt I _r

28-2 R=Boc

28-3 R=H *- Compound 61

Intermediatc 28-1, prepared analogously to Intermediatc 26-5, was rcactcd with (-)-Precursor lia according to the procedure as described for Step 4 in Example 17, to give lntermediate 28-2. Subséquent Boc-deprotection was accomplishcd applying the procedure as described in Example 19. lntermediate 28-3 was further converted to Compound 61 using the procedure as described for Step 7 in Example 17.

Compound 56, 98, 101 and 102 were prepared analogously to Compound 61.

-63Example 29: Synthesis of Compound 90

OBn

1.LHMDS

THF,-78°C

Step 1

OBn

H₂₁ Pd/C

MeOH. rt

Step 2

Step I: Lactone 29-1 [CAS No.: 165453-05-4] was convcrtcd to Intermediate 29-2 with 5 62% yicld using the procedure as described for Step 1 in Example 17. -Step 2: Intcrmcdiate 29-2 (290 mg, 558 mmol, 1.0 eq.) was dissolved in MeOH (15 mL) and hydrogenated in a H-Cube with 10% Pd/C as a catalyst cartridge. Hydrogénation was performed by pumping the réaction solution through the H-cube with a flow of 1 mL/min at atmosphcric pressure. After évaporation of solvents,

230 mg (96%) of Intcrmcdiate 29-3 was obtained.

Step 3: Intermediate 29-3 (1.38 g, 3.36 mmol, 1.0 eq.) was dissolved in dry dichloromethane. /V-Pheiiyl-bis-(trifluoromethanesulfonimide) (1.44 g, 4,03 mmol, 1.2 cq.) and CsîCOj (1.31 g, 4.03 mmol, 1.2 eq.) were added and the resulting

-64suspcnsion was stirred at room température for ]6 hours until complété conversion according LCMS analysis. The mixture was diluted with dichloromcthanc and washed with an aqueous NaHCCh solution and brine. The organic phase was dried with Na₂SO₄and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elucnt: isohexane / ethyl acetate) to give 1.74 g (92%) of Intermediate 29-4.

Step 4: Intermediate 29-4 ( l .55 g, 2.78 mmol, l .0 cq.) was dissolvcd in THF (25 mL) followed by the addition of LiOH (5 mL ofa l M aqueous solution, 5.0 mmol, l .8 eq.) and McOH (10 mL). The réaction was left stirring at room température for l hour. Solvents were co-cvaporatcd with toluène and dried in vacuo. The residue and imidazole (3.79 g, 55.6 mmol, 20.0 eq.) were dissolvcd in dry DMF (10 mL). TBDMSCI (4.19 g, 27.8 mmol, 10.0 cq.) was added and the réaction mixture was stirred at room température for 16 hours. McOH was added and tlie stirring was . continued for two hours until LCMS showed complète TBMS-dcprotcction ofthe carboxylic acid. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was concentrated under reduced pressure and tlie product was purified by silica gel column chromatography (eluent: dichloromcthane ! methanol) to give l .68 g (87%) of Intermediate 29-5.

HO' Oh

Precursor 34 ---------------------------------------------------------------------------------------------------------------1 Pd(PPh₃)₂CI₂, DIPEA DMEI H₂O / EtOH 70°C

Step 6

65.

Step 5: DIPEA (l .5 mL, 8.65 mmol, 4.0 eq.) was added to a stirred solution of

Intermediate 29-5 (1.5 g, 2.16 mmol, l.O eq.), (-)-Prccursor 16 (437 mg, 3.03 mmol,

1.4 eq.) and (benzotriazol-l-yloxy)tripynOlidinophosphonium hexafluorophosphate (PyBOP, 1.35 g, 2.59 mmol) in dry DMF (15 mL). After two hours the mixture was diluted with dichloromethane (50 mL) and washed with aqueous NaHCOj, dried and concentrated to dryness to give crude Intermediate 29-6 which was used as such in the next step.

Step 6: A suspension of crude Intermediate 29-6, the HCl sait of Prccursor 34 (109 mg, 0.55 mmol), PdfPPhjJjCh (35 mg, 0.055 mmol) and DIPEA (288 mg,

2.23 mmol, ) in a dimcthoxycthanc / water/cthanol 7:3:1 mixture was stirred at 70°C for 16 hours. The réaction mixture was concentrated under redueed pressure, the residue was purified by silica gel column chromatography (eluent: hcxanc /ethyl acetate 93:7 -> 40:60) to give 360 mg (21% over two steps) of Intermediate 29-7.

Step 7: HCI (1.25 mL ofa 4 M solution in dioxane) was added to a solution of

Intermediate 29-7 (180 mg, 0.23 mmol, 1.0 cq.) in dioxane (5 mL) and methanol (1 mL). After 40 minutes stirring at room température, the mixture was concentrated to dryness and the residue dried under vacuum. The residue was rcdissolvcd in DMF (10 mL), Precursor 18 (51 mg, 0.27 mmol, 1.2 eq.), PyBOP (142 mg, 0.27 mmol,

1.2 eq.) and DIPEA (121 mg, 0.94 mmol, 4.0 cq.) were added. The reaction mixture was stirred for four hours at room température. Dichloromethane was added, the organic layer was washed with aqueous NaHCOj, dried with MgSO₄ and concentrated under redueed pressure. Purification by préparative reversed phase HPLC gave 79 mg (46%) of Compound 90.

-66Example 30: Synthesis of Compound 84

OTf

29-4

1. HCI, dioxane, rt

2. HATU, DIPEA

Η0-^γ-^Νγ⁰'' xfvs ⁰

Precursor18

DCM.rl

Step 2

1. LiOH, rt MeOH l H_ZO

2. TBDMSCI, Imldazole DMF. ri

HATU, DIPEA DCM, rt Slep4

3, MeOH

Step 3 _Ηψ ^ΧΝΥ^Λ'ΝΗ₂Ο (-)-Precursor 16

OTBDMS

Compound 84

30-4 ch₃cn, rt

Step 5

N'

OTBDMS

Step 1: Intermediate 29-4 (430 mg, 0.765 mmol) dissolved in TV./V-dimethyl5 acctamidc (DMA; 11 mL) was loadcd in a microwavc vial together with 2-cthylthiazolc ([CAS No.: 1-5679-09-1 ]; 433 mg, 3.83 mmol, 5.0 cq.), KOAc(113mg, 1.17 mmol,

1.5 cq.) and Pd(PPIi3)₄ (44 mg, 38.3 pmol, 0.05 eq.). The reaction mixture was degassed with N2 and then heated in a microwave at 150°C for one hour. The réaction mixture was diluted with dichloromethane and washed with aqueous 1 M HCl, a saturated NaHCOj solution and brine. The organic phase was dried with Na₂SOi and concentrated under rcduccd pressure. The rcsidue was purified by silica gel column chromatography (eluent: heptane / ethyl acetate) to give 169 mg (42%) of Intermediate 30-1.

Step 2: HCl (10 mL of a 4 M solution in dioxane) was added to Intermediate

30-1 (169 mg, 0.323 mmol, 1.0 eq.), the mixture was stirred at room température for

-67onc liour. The reaction mixture was freeze dried over night. The residue was rcdissolvcd in dichloromethanc ( 10 mL), followed by the addition of Precursor 18 (67 mg, 0.355 mmol, l.l cq.) and DIPEA (281 μι, l.62 mmol, 5.0 cq.).Theréaction mixture was cooled to 0”C, HATU (I29 mg, 0.339 mmol, l .05 eq.) was added and stirring was continucd at room température .for three hours. The réaction mixture was washed with i M HCl, a saturated aqueous NaHCOj solution and brine. The organic phase was dried with Na₂SO4 and concentrated under reduced pressure to give 185 mg (96%) of Intermediate 30-2.

Step 3: Intermediate 30-2 was converted to Intermediate 30-3 according to the procedure as described for Step 4 in Example 29 (49% yield).

Step 4: HATU (74 mg, 194 pmol, l.l cq.) was added to a solution of

Intermediate 30-3 (128 mg, 176 gmol, i .0 cq.), (-)-Preciirsor 16 (38 mg, 264 pmol,

1.5 cq.) and DIPEA (153 pL,-880 pmol, 5.0 cq.) in DCM (5 mL) at 0°C. The réaction mixture was stirred to room température for two hours. The réaction mixture was diluted with DCM and washed with an aqueous 1 M HCl solution, saturated aqueous NaHCOj and brine. The organic phase was dried with NaîSCL and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (clucnt: heptane ! ethyl acctatc) to give 35 mg (23%) of Intermediate 30-4.

Step 5: A solution of Intermediate 30-4 (35 mg, 41 pmol, 1.0 eq.) in CHjCN (3 mL) was cooled to 0°C. HF (170 pL) was dropwisc added and stirring was continucd at room température for two hours. The reaction was quenchcd by careful addition of a saturated aqueous NalICOa solution, followed by ethyl acetate. Both phases were separated, the organic phase was washed with saturated aqueous NaHCOj, dried with anhydrous Na₂SO4 and evaporated under reduced pressure, The residue was purified by reversed phase préparative HPLC affording 10 mg (3 l%)of Compound 84.

Example 31 : Synthesis of Compound 87

HO' OH

Precursor 34

Pd(PPti₃)₂CI₂, DIPEA

DME / H₂O / EtOH 80°C Step 1

\

N—

1. LÎOH, ri

CH₃OH/H₂O

2. TBDMSCI, Imidazole DMF. rt

31-1

Compound 87

Stcp 1: Intermediate 29-4 was reacted with Prccursor 34 accordîng to the procedure as described for Stcp 6 in Example 29.

Step 2: Intermediate 31-1 was converted to Intermediatc 31-2 using the procedure as exemplified for Step 4 in Example 29.

Step 3: Intermediate 31-2 was reacted with (-)-Precursor 15 to give

Intermediate 31-3 using the procedure as described for Stcp 5 in Example 29. The latter was converted to Compound 87 accordîng to the procedure from Step 7 in Example 29.

i() Compound 83 was prepared analogously to Compound 87, but using a Heck crosscoupling réaction as described in Example 30, Stcp 1.

nBuLI

THF, -78°C Step 3

Pd(PPti₃)₄, Na₂CO₃dioxane / H₂O,110’C Step 4

32-4

Step 1 : (+)-Precursor 2(10.0 g, 60.5 mmol, 1.0 eq.) was added (o a mixture of

3-(3-chlorophcnyl)propanoic acid (11.2 g, 60.5 mmol, 1.0 cq.), triethylaminc (12.3 g,

121 mmol, 2.0 eq.) and HATU (10.0 g, 60.5 mmol, 1.0 cq.) in DMF (120 mL) at -10°C.

The réaction mixture was stirred at 0°C for two hours. Ethyl acetate and water were added. The organic layer was separated and washed with water, a 1 M HCl solution and a saturated aqueous NaîCCh solution, dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane -^dichloromethane / methanol 96:4) to give 15.8 g (79%) of Intermediate 32-1.

Step 2: 2-Methoxypropene (34.3 g, 476 mmol, 10.0 eq.) was dropwise added over a period of 30 minutes to a solution of intermediate 32-1 (15.8 g, 47.6 mmol, 1.0 cq.) and pyridiniump-tolucncsulfonatc (PPTS, 1.2 g, 4.8 mmol, 0.1 cq.) in dichloromethane at 0°C. The reaction mixture was stirred at room température for hours. Ethyl acetate and water were added. The organic layer was separated, washed with water, a 1 M HCl solution and a saturated aqueous Na2COj solution, dried with MgSCh and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: heptane ! ethyl acetate 80:20 -> 40:60) to give 10.1 g (57%) of Intermediate 32-2.

-70Step 3: n-Butyllithium (17.4 mL of a 2.5 M solution in hcxane, 43.6 mmol,

2.05 cq.) was dropwise added to a solution of Intermediate 32-2 (7.9 g, 21.2 mmol, l.O cq.) and cpoxidc 32-3 ([CAS No.: 1003871 -37-1 ]; 7.2 g, 21.2 mmol, 1.0 cq.) in THF (200 mL) at -78°C. The réaction mixture was stirred at -25°C for two hours.

Water was dropwise added, foilowed by the addition ofethyl acctate. The organic layer was separatcd, dried with MgSO.i and concentrated under reduced pressure. The crudc product was purificd by silica gel column chromatography (eluent: heptane ! ethyl acétate 12:88 40:60) to give 5.0 g (33%) of Intermediate 32-4.

The latter was converted to Compound 4 using the procedures of Step 5, Step 6 and 10 Step 7 as described in Example 17.

----►- Compound 5

A solution of Intermediate 32-4 (3.6 g, 5.0 mmol, 1.0 eq.) and jV-chlorosuccinimide (NCS; 806 mg, 6.0 mmol, 1,2 eq.) in DMF was stirred at 80°C until no more starting material was le fl. After the réaction mixture was allowcd to cool to room température, water was added. The water phase was extracted with ethyl acctate, the combined organic phases were washed with a 1 M NaOH solution, dried with MgSO₄ and concentrated under reduced pressure. The residue was purificd by silica gel column chromatography (eluent: dichloromethane -> dichloromethane / methanol 97.5:2.5) to give 3.1 g (82%) of Intermediate 33-1. The latter was converted to Compound 5 using respectively the procedures as described for Step 4, Step 5 and Step 6 in Examplc 32.

Compound 6 was prepared similarly to Compound 5, but using a Stille crosscoupling réaction as described in Example 23 and a TFA mediated deprotection stop as 25 described in Examplc 27, Step 2.

-71Example 34: Synthesis of Compound 1

Compound1

Intermediate 32-4 was treated with HCl using the procedure as described for Stcp 6 in Example 17. The crude reaction product was purified by silica gel column chromatography (eluent: dichloromethanc dichloromcthane / methanol 93:7) to give Intermediate 34-1 (42%). The lattcr was converted to Compound 1 using the procedures from Stcp 2 and Step 3 as described in Example 21.

Compounds 2 and 3 were prepared analogously to Compound 1.

Example 35: Synthesis of Compound 79

Amine 35-1 was prepared using the procedures as exemplified for the préparation of Intermediate 28-3. A solution of intermediate 35-1 (250 mg, 0.39 mmol, 1.0 eq.) and Precursor 24 (150 mg, 0.55 mmol, 1.4 eq.) in DMF (4 mL) was stirred for one hour at room température. Water and a saturated aqueous Na₂COj solution were added to the reaction mixture, the precipitate was filtered off and washed with water. The cnidc product was suspended in boiling acetonitrile and subsequently allowed to cool to room température, 236 mg (73%) of Compound 79 was obtained as a white powder.

-72Compound 81 was prepared analogously to Compound 79. Compound 68 was prepared analogously to Compound 79, but starting from amine 18-4. In case of Compounds 70, 71, 72, 73 and 76 the appropriate amine was prepared according to the synthesis of Intermediate 19-2 as described in Examplc 19. In case of Compounds 74, 5 74, 76, 77 and 81 the appropriate amine was prepared according to the synthesis of

Intermediate 26-6 as described in Example 26. ln case of Compound 69 the appropriate amine (hydrochloride sait) was prepared as described in Examplc 29.

O—

Amine 36-1 was prepared using the procedures as exemplified for the préparation of Intermediate 26-6.

Step 1 : Amine 36-1 (164 mg, 0.26 mmol, 1.0 eq.) and Precursor 19 (67 mg,

0.29 mmol, 1.1 cq.) were dissolved in acetonitrïle (15 mL). Triethylamînc (55 pL,

0.40 mmol, 1.5 eq.) and HATU (111 mg, 0.29 mmol, 1.1 cq.) were succcssively added.

The réaction mixture was stirred for 30 minutes at room température. Nal (436 mg,

2.91 mmol, 11.0 eq.) and TMSC1 (287 mg, 2.65 mmol, 10.0 cq.) were added and

-73stirring was continuée! for one hour. Mcthanol (10 mL) and an aqueous NaOH solution ( 10 mL of l M NaOH solution, 10.0 mmol, 38.0 eq.) were added, the reaction mixture was stirred for an additional 30 minutes. An cxccss of water was added, the prccipitatc was filtered off, washed with water and dried under high vacuum to give 149 mg (69%) 5 o f crudc I ntermed iate 36-2.

Step 2: A solution of intermediate 36-2 (149 mg, 0.20 mmol, l.O eq.),

Precursor 23 (66 mg, 0.31 mmol, 1.5 eq.) and triethylamine (41 mg, 0.41 mmol, 2.0 eq.) in DMF (15 mL) was stirred at room température for one hour. Water and a saturated aqueous Na₂COj solution were added to the réaction mixture, the precipitatc 10 was filtered off and washed with water. After purification by silica gel column chromatography (cluent: dichloromethane -> dichloromethane / mcthanol 96:4) 62 mg (36%) of Compound 57 was obtained.

Compound 55 was prepared analogously to Compound 57. Compound 34 was prepared analogously to Compound 57 but starting from amine 18-4.

Example 37: Svnthesis of Compound 97

O- O-

-74Intermcdiatc 37-1 was prepared analogously to lntermcdiate 26-5 as excmplified in Example 26.

Stop 1 : Intcrmediate 37-1 was convcrtcd to lntermcdiate 37-2 using the procedure as described for Step 1 in Example 36.

Step 2: A solution of lntermcdiate 37-2 (287 mg, 0.43 mmol, 1.0 eq.) in dichloromcthanc (4 mL) was slowly added to a mixture of chloroacctyl chloridc (73 mg, 0.65 mmol, 1.5 cq.) and triethylamîne (0.18 mL, 1.30 mmol, 3.0 eq.) in dichloromcthanc (4 mL) at 0°C. The réaction mixture was stirred at room température untii complété conversion and then washed with a saturated aqueous NH4CI solution, dried with anhydrous MgSO^ and concentrated under rcduccd pressure to givc 240 mg (77%) of crudc lntermcdiate 37-3.

Step 3: A mixture of lntermcdiate 37-3 (240 mg, 0.33 mmol, 1.0 cq.), pyrrolidinc (0.286 mL, 3.25 mmol, 10 eq.) and tctrabutylammoniüm iodidc (TBA1;

mg, 0.03 mmol, 0.1 eq.) in Y-mcthylpyrrolidinone (NMP; 3 mL) was stirred at room température untii complète conversion. Water was added to the réaction mixture, the precipitatc was filtered off, washed with water and dried under high vacuum. The crude product was purified by silica gel column chromatography (eluent: dichloromcthanc dichloromcthanc / mcthanol 95:5) to givc 216 mg (85%) of Compound 97.

Example 38: Synthesis of Compound 9

ci·

38-1

HATU, Et₃N DMP, ri Step 1

CI

Intcrmcdiate 38-1 was prepared analogously to Intermediate 17-6 with Step 6 involving a TFA mediated Boc-deprotection step as described for Step 2 in Example 27.

Step I : Intermediate 38-1 (610 mg, 0.96 mmol, 1.0 cq.) and Precursor 19 (223 mg, 0.96 mmol, 1.0 eq.) were dissolved in DMF (4 mL). DIPEA (374 mg, 2.89 mmol, 3.0 eq.) and HATU (385 mg, 1.01 mmol, 1.05 eq.) were successivcly added. The reaction mixture was stirred for 30 minutes at room température. A saturated aqueous Na₂CO₃ solution was added, the water phase was extracted with ethyl acétate. The combined organic phases were washed with brine, dried with MgSO.₍and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromcthanc ·$ dichloromethane / methanol 93:7) to give 207 mg (25%) of Intermediate 38-2.

Step 2: Intermediate 38-2 was converted to Intermediate 38-3 according to the

TFA mediated Boc-deprotection procedure as described for Step 2 in Example 27.

Step 3: DIPEA (74 mg, 0.57 mmol, 3.0 cq.) and HATU (76 mg, 0.20 mmol, 1.05 cq.) were successivcly added to a solution of Intermediate 38-3 (142 mg, 0.19 mmol, 1.0 cq.) and Precursor 20 (25 mg, 0.19 mmol, 1.0 cq.) in DMF (3 mL). The réaction mixture was stirred for 30 minutes at room température. A saturated aqueous Na₂CO₃ solution was added, the water phase was extracted with ethyl acetate. The combined organic phases were washed with brine and concentrated under reduced pressure. The crudc product was purified by préparative HPLC to give 45 mg (26% over two steps) of Compound 9.

Compound 19 was synthesized starting from Intermediate 35-1 using the reaction sequence as exemplified for Example 38, but Step 2 involving a HCl mediated Bocdeprotection step as described in Example 17, Step 6.

-76Example 39: Synthesis of Compountl 53

Amine 39-1 was prepared starting from Intermcdiate 18-4 using the procedure as described for Step 1 in Example 36. Intermcdiate 39-1 (210 mg, 0.29 mmol, 1.0 eq.) and Prccursor 21 (32 mg, 0.29 mmol, 1.0 cq.) were dissolved in DMF (10 mL).

Tricthylaminc (58 mg, 0.58 mmol, 2.0 cq.) and HATU (115 mg, 0.30 mmol, 1.05 cq.) were successively added. The réaction mixture was stirred for one hour at room température. A saturated aqueous NaiCOj solution was added, the precipitate was filtered off, washed with water and dried under high vacuum. The crudc product was purified by silica gel column chromatography (clucnt: dichloromcthane -> dichloromethane / méthanol 97:3) to givc 143 mg (59%) of Compound 53.

In case of Compound 47 the amine uscd for amidc coupling was prepared via a synthesis sequence analogously to the one as described for the préparation of Intermcdiate 38-3, but in which Boc-dcprotection was carricd out according to the procedure as described in Examplc 19.

Table 1

Comp. N°	R^l	R*	R⁵	R¹	R⁴
l	/h-CI	H	H	OCHj	.AA
2	/H-CI	II	H	OCHj	..cr
3	///-CI	H	H	OCHj	I rv° ..-V
‘4	///-Cl	H	H	OCHj	il ^N
5	HÎ-CI	Cl	H	OCFIj	I ..A^ⁿ
6	Hl-Cl	Cl	H	OCHj	,,d
7	o-F	H	H	OCHj	.,cr
8	o-F	Cl	H	OCHj	..xr
9	z/i-Cl	F	H	•--O	♦A^n
10	o-F	F	F	OCHj	..-X^N

Comp. N°	R¹	R⁶	R⁵	R^J	R⁴
11	o-F	Cl	H	OCHj	..-M
12	o-F	Cl	H	OCHj
13	ZH-Cl	F	H	och₃	...a¹'
14	o-F	Cl	H	och₃
15	»<-o-ch₃	H	H	och₃	..cr
16	o-F	H	H	och₃	i
17	m-O-CHj	H	II	OCHj	..n¹
18	o-F	Cl	H	OCHj	...a¹
19	o-F	Cl	H	•-Ό
20	o-F	Cl	H	och₃	\ N— ...-O

Comp. N°	R¹	R⁶	R*	R⁵	R⁴
2I	o-F	Cl	II	OCHj	I .XZk
22	O-F	Cl	H	OCH₃	.--Ά^Ν
23	o-F	Cl	H	OCHj	-O t)
24	o-F	Cl	H	och₃	(Z Λ
25	o-F	Cl	U	och₃	Aj
26	m-O-CHj	F	H	och₃	jX
27	nrO-CHj	Cl	H	och₃	o—
28	o-F	Cl	H	och₃	.-M
29	o-F	Cl	H	och₃	o— u .A/

Comp. N°	R¹	R⁶	R^s	R’	R^J
30	o-F	Cl	H	OCHj	.0
31	o-F	Cl	H	OCHj	,,Ογ; F
32	o-F	Cl	H	och₃	y
33	o-F	F	H	OCHj	γύ^κ
34	o-F	F	H	O-(CH₂)jOCH₃
35	o-F	F	H	V	,ΌΤ
36	ni-F	H	H	och₃
37	o-CI	H	H	OCHj	--O
38	o-F	H	H	OCHj	y-
39	îh-F	Cl	H	OCHj	rv°

Conip. N°	R¹	R⁶	R⁵	R·’	R⁴
40	m-F	H	F	OCHj	—o
41	m-O-CFj	H	II	OCHj	.,cf
42	ni-O-CFj	Cl	11	OCIIj	-O
43	o-F	Cl	II	och₃	1
44	o-F	Cl	H	OCHj	Y O--'
45	o-F	H	Cl	OCHj	...d
46	ni-F	Cl	H	OCHj	Y ...O
47	o-F	Cl	H	V	rv° .X*^N
48	o-F	Cl	H	OCHj	fV
49	m-O-CFî	Cl	H	OCHj	..Y

Coinp. N°	R’	R	R^s	R¹	R¹
50	o-F	H	F	OCHj	—o *
51	o-F	H	F	OCHj	AC
52	o-F	F	Cl	OCHj	AC
53	o-F	F	H	V	.AC
54	o-F	H	Cl	OCHj	.A
55	o-F	Cl	H	-O(CH₂)₂OCHj	l γυ° ..-Aaⁿ
56	o-F	F	Cl	OCHj	.,a°
57	o-Cl	F	H	-O(CH₂)₂OCHj	-O •
58	o-Cl	Cl	H	OCHj	-O «
59	o-F	F	H	OCHj	.,a^A

Comp. N°	R'	R⁶	R⁴	R¹	R^J
60	o-F	Cl	F	OCHj	.xr
61	o-F	Cl	F	OCHj	...a¹
62	»î-F	F	H	och₃	1
63	o-Cl	F	H	OCHj	xr
64	m-O-CFj	F	H	OCHj	-O
65	ni-F	F	H	OCHj	-O
66	o-F	CHj	H	OCHj	-O
67	o-Cl	F	H	OCHj	--O

Comp. N°	R'	R¹	R⁴
68	o-F	★ XÇT	.XC
69	o-F	* 1 >V^h 0	ΓΎ^
70	oi-O- CH₃	xjr	1 rv°
71	in-O- CH,		\ N— N =4 ,,-O
72	o-F	°XÔ'	...σ
73	oi-O-CFî	OÔ'	rv°

Comp. N°	R*	R¹
74	o-F	ÇjQ	γυ°
75	o-F	çô' C!	ΓΎ° .,'V^N
76	o-F		A
77	o-CI	*	1 fY° ./V
78	o-Cl	^Cl	1 fr°
79	o-F	oA”	py^Nx
80	o-F	* ^F\<X'XA\>^OH ΌΟ	ΓΎ° ..-V
81	o-F	* γΜ F	I ΓΎ° ./V

Coinp. N°	R'	R²	R⁴
82	o-F	•	l ΓΥ°

R⁴

Comp. N°	R'	R²	R^J	R⁴
83	o-F		OCHj	,,d-
84	o-F	* I >V^H ^x 0	OCHj	A
85	m-F	.rçr	OCI-I₃	I fv°
⁸⁶	o-F	M	OCHj	..a¹'

-87_R4a

Comp. N°	R¹	R¹	R^J	R⁴’
87	o-F		OCHj	-N(CHj)₂
88	o-F	^λ 0	OCHj	OCHj
89	o-F	Λ	OCHj	-N(CH₃)j
90	o-F	xV	OCHj	-N(CHj)₂
9)	o-C)	Λ	OCHj	OCHj
92	w-F	\ L Π XY^h 0	OCHj	OCHj

Contp. N°	R*	R²	R³	R·”
93	o-F	00'	OCHj	och₃
94	w-O-CFj		OCHî	OCHj
95	o-Cl	ocr	OCHj	och₃
96	o-F	Λ	OCHj	och₃
97	o-F		-XJ	och₃
98	o-CI	\ L O AV^NH	0CH₃	och₃
99	o-F	*^2^·’'^ύ0Η	OCHj	och₃
WO	O-F	★	OCHj	och₃
Wl	0-F	* γΑ F	0CH3	och₃

Comp. N°	R*	R²	R^J	R⁴*
102	o-F	ch₃	0CJ-I3	OCII3

Table 2

Rétention tîme (R_t) arc given in minutes and were determined via Reversed phase UPLC (Ultra Performance Liquid Chromatography) on a BEH Cl8 column (1.7 pm,

2.1 x 50 mm, Waters Acquity) with a flow rate of 0.7 ml/min and column température of70°C. Two mobile phases (mobile phase A: McOH; mobile phase B: 10 mM NH4OAC in 90% H2O and 10% CH₃CN) were used to run a gradient condition starting from 5% A and 95% B to 95% A and 5% B in l .3 minutes, hold for 0.2 minutes, then back to 5% A and 95% B in 0.2 minutes and finally hold these conditions for

0.3 minutes. An injection volume of 0.75 pl was used.

Melting points (m.p.) were determined with a DSCl STAR⁶ (Mcttler-Tolcdo). Melting points were mcasurcd with a température gradient of l0°C/min. The starting température was 30°C, the maximum température 300°C. Values are peak values.

Comp. N°	R, (min)	MW	m.p. (°C)
l	1.33	756.33
2	l.4l	786.36
3	I.38	772.32
4	1.36	770.35	229.07
5	1.44	819.32	239.39
6	1.40	796.25
7	1.36	769.39	228.12
8	l,40	803.35	271.61
9	1.46	856.41
ÎO	L37	805.37
11	1.36	780.28	255.90
12	1.38	788.34	253.22
13	1.38	803.35	252.99
14	1.39	794.29
15	1.35	781.41	214.14

Comp. N°	R₍(tnin)	MW	m.p. (°C)
16	1.35	756.35
I7	1.35	768.37	221.37
18	1.39	790.32
I9	1.43	856.41
20	l.4l	809.30
21	1.43	814.35	237.24
22	1.36	804.34
23	1.39	791.31
24	1.38	791.31	240.69
25	1.37	804.34
26	1.35	799.40
27	1.38	802.34
28	l.4l	806.29	239.55
29	1.40	796.27
30	1.42	790.32
3)	1.39	828.29
32	1.43	808.31	236.06
33	1.36	787.38	258.20
34	1.33	831.40	244.49
35	1.39	822.39	238.80
36	1.39	769.39	226.05
37	l.4l	772.32
38	1.43	774.35
39	1.43	790.32	243.66
40	1.36	774.34	222.56
41	1.43	822.35	228.45
42	W7	856.31	237.32
43	l.4l	804.34	271.32
44	1.46	804.33	265.19
45	1.38	790.32	235.74
46	1.47	819.34	244.40
47	1.39	825.33	226.41
48	1.33	791.31	246.19
49	1.46	870.33	256.86
50	1.32	774.34	219.44
5]	1.35	787.38	207.05

Comp. N°	IMmïii)	MW	m.p, (°C)
52	1.40	821.34	255.44
53	1.33	822.39	239.87
54	1.34	788.34
55	1.37	834.34	228.27
56	1.38	808.31
57	I.36	834.34
58	I.40	806.29
59	1.33	774.34	254.86
60	1.42	821.34
61	1.37	808.31	265.41
62	1.35	788.37	244.51
63	1.37	804.34
64	l.4l	840.34
65	1.28	775.34
66	1.42	770.37
67	l.4l	790.32
68	1.33	772.33
69	1.28	733.39
70	1.35	787.29
71	1.37	806.28	262.44
72	1.35	775.27	234.86
73	l.4l	841.26
74	1.29	745.28
75	1.29	775.27	228.26
76	1.29	773.29	290.48
77	1.30	775.27	205.21
78	1.34	791.24
79	1.32	788.30
80	1.27	759.30	239.42
81	1.33	793.26	254.01
82	1.30	705.34
83	1.31	696.34
84	1.35	739.38
85	1.39	774.34	215.00
86	1.38	803.35	237.42
87	n.d.	n.d.

Comp. N°	R, (min)	MW	m.p. (°C)
88	1.35	735.40
89	1.37	733.42
90	1.35	748.43
91	1.39	736.36	215.60
92	1.39	779.43
93	1.40	760.33	219.41
94	1.42	786.38
95	1.39	776.30	234.17
96	1.35	720.39
97	1.42	773.45	127.74
98	1.39	795.40
99	1.38	706.37
100	1.35	706.37
ΙΟΙ	1.38	788.36	254.88
102	1.39	788.36	236.58

(n.d. means not determined)

Table 3

Comp. N°	'11 NMR (δ ppm)
1	(400 MHz, DMSO-rf_t) 0.80 (s, 9 H) 1.34- 1.43 (m, 1 11) 1.64- 1.73 (m, 1 H) 2.50 (s, 3 H) 2.56 - 2.63 (m, 1 H) 2.69 - 2.74 (m, 1 H) 2.80 - 2.97 (m, 3 I I) 3.49 (s, 3 H) 3.55 - 3.62 (m, 1 H) 3.72 - 3.77 (m, 1 H) 3.89 (d,7=10.4 Hz, 1 H) 3.95 (br. s., 1 H) 4.06 (dd,7=I1.5,4.3 Hz, I H) 4.13 (d, 7=11.5 Hz, 1 H) 4.83 (d, 7=3.9 Hz, 1 H) 5.07 (dd, 7=8.4, 3.7 Hz, 1 H) 5.12 (d, 7=2.7 Hz. I H) 6.71 (d, >8.0 Hz, 2 H) 6.80 (t, 7=7.6 Hz, l H) 7.00 (d, 7=7.2 Hz, 1 H) 7.04 7.15(111,2 H) 7.22- 7.28 (m, 3 H) 7.34 (d, 7=8.0 Hz, 2 H) 7.41 (d,7=5.3 Hz, 1 H)7.48(s, 1 H) 7.59 (d, 7=7.6 Hz, 2 H) 7.66 (d, 7=8.6 Hz, 1 H) 7.89 (d,7=9.0 Hz, l H) 8.45 (d,7=5.3 Hz, 1 H)
6	(400 MHz, DMSO-7_fl) 0.76 (s, 9 H) 1.33 - 1.42 (ni, 1 H) 1.59 - 1.70 (m, 1 H) 2.54 - 2.61 (m, 1 H) 2.64 (s, 3 H) 2.69 - 2.80 (m, 2 H) 2.85 - 3.05 (m, 2 H) 3.50 (s, 3 H) 3.58 (br. s„ 1 H) 3.76(br. s., 1 H) 3.87 (d,7=10.2 Hz, 1 H) 3.89-3.95 (m, 1 H) 4.10 (d,7=11.9 Hz, 1 H) 4.15 - 4.22 (m, 7=11.3 Hz, l H) 4.84 (d,7=3.1 Hz, 1 H) 5.09 (d,7=6.8 Hz, 1 H) 5.32 (br. s„ ! H) 6.64 (d,7=9.6 Hz, 1 H) 6.76 (d, 7=8.6 Hz, 1 I I) 7.07 (br. s., 1 H) 7.12 (d, 7=6.8 Hz, I H) 7,15 (d,7=8.6Hz, 1 H) 7.19 · 7.30 (m, 5 H)7.37 (d,7=7.2 Hz, 2H) 7.61 (d,7=10.0 Hz, 1 H)7.89 (s. 1 H) 8.02 (d, 7=9.0 Hz, 1 H)

Comp. N°	'H NMR (δ ppm)
7	¢400 MHz, DMSO-J₆) 0.80 (s, 9 H) l .37 - 1.49 (m, l H) 1.65 - l .76 (m, l H) 2.60 - 2.88 (m, 4 H) 2.90 - 2.99 (in, l H) 3.Û5 (s, 6 H) 3.50 (s, 3 H) 3.61 (br. s., I H) 3.64 - 3.69 (in, l H) 3.91 (d, J=9.5 Hz, l H) 3.94 (br. s„ l H) 4.00-4.07 (ni, J-l I.8, 4,0 Hz, l H) 4.i l (d, J-J 1.3 Hz, l H) 4.88 (d, J=5,0 Hz, l H) 5.06 (dd,./=9.0, 3.8 Hz, I H) 5.12 (d, J=3.3 Hz, l H) 6.70 (d, ./=8.5 Hz, 2 H) 6.79 (t, ./=7.5 Hz, l H) 6.76 (d, J=8.3 Hz, I H) 6.99 (d, J=7.5 Hz, l H) 7.03 - 7.I4 (m, 3 H) 7.20 - 7.29 (ni, 2 H) 7.25 (d, J-8.0 Hz, 2 H) 7.4! (d, J=8.0 Hz, 2 H) 7.65 (d, ./=8.0 Hz, l H) 7.74 (dd, ./=8.8, 2.5 Hz, l H) 7.79 (d, >9.3 Hz, l H) 8.35 (d,./=2.5 Hz, l H)
8	(400 MHz,DMSO-<4) 0,77 (s,9H) 1.36- l.5l (m, l H) 1.61 -1.75 (m, I H) 2.68 - 2.89 (ni, 4 H) 2.90 - 3.01 (m, 1 H) 3.05 (s, 6 H) 3.49 (s, 3 H) 3.62 (br. s., 1 H) 3.69 (br. s„ 1 H) 3.88 (d, J=9.4Hz, 1 II) 3.91 -4.01 (m, i H) 4.08 (dd, J-l 1.1,3.5 Hz, 1 H) 4.17 (d, J-ll.l Hz, 1 H) 4.89 (d, ,/=3.7 Hz, 1 11) 5.08 (dd, ./=7.4, 2.2 Hz, 1 II) 5.29 (br. s., 1 H) 6.69 (d, J=8.8 Hz, l H) 6.68 (d, J=9.2 Hz. 1 H) 6.76 (d,./=8.6 Hz, 1 H) 7.03 - 7.13 (m,4 H) 7.15 (d, J=8.4 Hz, 1 H) 7.19 - 7,28 (m, 4 H) 7.37 (d, ./=7.6 Hz, 2 H) 7.58 (d, J=8.4 Hz, 0 H) 7.72 (d, J=8.8 Hz, 1 H) 7.91 (d, ./=7.8 Hz, 1 H) 8.33 (s, 1 H)
K)	(400 MHz, DMSO-Jj,) 0.78 (s, 9 H) 1.40 1.49 (m, 1 H) 1.64- 1.75 (m, 1 H) 2.62 - 2.88 (ni, 4 H) 2.92 - 3.01 (m, 1 H) 3.04 (s, 6 H) 3.50 (s, 3 H) 3.59 (br. s., 1 H) 3.70 (br. s., 1 H) 3.89 (d, J=9.4 Hz, 1 H) 3.92 (br. s., 1 H) 4.15 (dd,J=l 1.7,2.9 Hz, 1 H) 4,22 (d,J=l 1.5 Hz, 1 H) 4.88 (d,,/=4.7 Hz, 1 H) 5.1Û (dd, J=8.0, 2.0 Hz, 1 H) 5.33 (br. s., 1 H) 6.69 (d, ./=8.4 Hz, 3 H) 7.05 - 7.18 (m, 3 H) 7.18 - 7.28 (m, 4 H) 7.37 (d, J=7.6 Hz, 2 H) 7.64 (d, J=8.8 Hz, 1 H) 7.72 (dd, J=8.9, 1.9 Hz, 1 H) 7.92 (d, >8.8 Hz, 1 H) 8.32 (s. 1 H)
16	(400 MHz, DMSO-Js) 0.80 (s, 9 H) 1.35 - 1.49 (m, l H) 1.63 - 1.78 (m, 1 H) 2.67 - 2.77 (m, 2 H) 2.76 - 2.88 (m, 2 H) 2.88 - 3.02 (m, 1 H) 3.49 (s, 3 H) 3.61 (br. s., 1 H) 3.67 (br. s., 1 H) 3.88 (s, 3 H) 3.91 (br. s„ 1 H) 3.96 (br. s., 1 H) 4.04 (dd, J-ll.9, 4.1 Hz, 1 H) 4.12 (d, >11.5 Hz, 1 H) 4.89 (d, J=4.5 Hz, 1 H) 5.06 (dd, J-7.7,3.2 Hz, 1 H) 5.13 (br. s., 1 H) 6.69 (d, J=8.2 Hz, 1 H) 6.75 (d, ./=9.4 Hz, 1 H) 6.78 (t, ./=7.4 Hz, 1 H) 6.89 (d, ./=8.6 Hz, 1 II) 6.99 (d, ./=7.2 Hz, 1 H) 7.02 - 7.15 (m, 3 H) 7.19 - 7.34 (ni, 4 H) 7.46 (d, >7.6 Hz, 2 H) 7.66 (d, J-8.8 Hz, 1 H) 7.80 (d, J=8.4 Hz, 1 H) 7.92 (dd, J=8.4, 2.5 Hz, 1 H) 8.40 (d, J=1.8 Hz, 1 H)
' 18	(400 MHz, DMSO-J₆) 0.76 (s, 9 H) 1.39 - 1.50 (ni, 1 H) 1.63 · 1.75 (in, 1 H) 2.63 - 2.90 (ni, 4 H) 2.92 - 3.03 (m, 1 H) 3.47 (s, 3 H) 3,62 (br. s., 1 H) 3.70 (br. s., 1 H) 3.88 (s, 3 H) 3.88 (d,J=10.0Hz, 1 H) 3.92-4.02 (m, 111)4.08 (dd, ./=11.9, 3.5 Hz, 1 H) 4,13-4.22 (m, J-l 1.3 Hz, 2 H) 4.90 (d, J=5.1 Hz, 1 H) 5.09 (dd, J=8.6,3.3 Hz, 1 H) 5.29 (br. s., 1 H) 6.69 (d, ./=9.6 Hz, 1 H) 6.76 (d, J=8.6 Hz, 1 H) 6.88 (d, J=8.6 Hz, 1 H) 7.05 - 7.13 (m, 3 H) 7.16 (dd, J=8.6, 2.3 Hz, 1 H) 7.21 - 7.30 (ni. 4 H) 7.43 (d,>7.8 Hz, 2 H) 7.60 (d, J=9.2Hz, 1 H) 7.91 (dd, ,/=8.5, 1.9 Hz, 1 H) 8.38 (d, >2.2 Hz, 1 H)

Comp. N°	‘Π NMR (δ ppm)
19	(400 MHz, DMSO-tk)0.78 (s.9 H) I.38- \|.47(m, l H) 1.55 - 1.63 (ni,4 H) 1.67 - 1.77 (m, 1 H) 2.23 - 2.39 (m, 4 H) 2,65 - 2,77 (m, 3 H) 2.78 - 2.89 (ni, 2 H) 2.92 - 3.00 (m, 2 H) 3.04 (s, 6 H) 3.62 (br. s., I H) 3.7! (br. s.. 1 H) 3.90 - 3.99 (ni, 1 H) 4.09 (dd, >1 1.9, 3.5 Hz, 1 H) 4.18 (d, ./= 11.9 Hz, 1 I I) 4.22 (d,.7= 10.0 Hz, 1 H) 4.86 (d, ./=4.7 Hz, 1 H) 5.09 (dd,./=9.0, 2.7 Hz, 1 H) 5.30 (d, >3.1 Hz, 1 H) 6.69 (d, ./=9.0 Hz, I H) 6.76 (d, .7=8.8 Hz, 1 H) 7.05 7.28 (m, 9 H) 7.37 (d,>8.0 Hz, 2 H) 7.73 (dd,>9.0, 2.0 Hz, 1 H) 7,81 (d, ./=9.0 Hz, 1 H) 7.91 (d, >8.4 Hz. 1 H) 8.34 (d,>2.3 Hz, 1 H)
20	(400 MHz, DMSO-</₆) 0.77 (s, 9 H) 1.33 - 1.46 (m, 1 H) 1.57 - 1.70 (m, 1 H) 2.59 (dd, ./=12.9, 7.2 Hz, 1 H) 2.68 - 2'.83 (ni, 2 H) 2.84 - 3.02 (m, 2 H) 3.06 (s, 6 H) 3,53 (s, 3 H) 3.55 - 3.64 (m, 1 H) 3.73 (br. s., 1 H) 3.89 (d,>9.8 Hz, 1 H) 3.91 (br. s„ 1 H) 4.06 - 4.13 (m, ./=11.7, 3.1 Hz, 1 H) 4.18 (d,>l1.5 Hz. 1 H) 4.80 (d, >5.3 Hz, 1 H) 5.09 (dd,.7=8.3, 3.6 Hz, 1 H) 5.29 (br. s„ 1 H) 6.64 (d, >9.8 Hz, 1 H) 6.76 (d, >8.6 Hz, 1 H) 6.96 - 7.04 (m, 4 H) 7.08 (s, 1 H) 7.18 (d, >8.0 Hz, 2 H) 7.16 (dd, >8.6, 2.0 Hz, I H) 7.23 - 7.32 (m, 1 H) 7.65 (d,>8.0 Hz. 2 H) 7.62 (d,> 10.6 Hz, 1 H) 7.96 (d_t>8.6 Hz, 1 H)
22	(400 MHz, DMSO-dJ 0.75 (s, 9 H) 1.35 - 1.44 (m, 0 H) 1.60 - 1.70 (m, 1 H) 2.55 - 2.64 (m, 1 H) 2.68 - 2.83 (m, 2 H) 2.87 - 3.01 (ni, 2 H) 3.09 (s, 6 H) 3.49 (s, 3 H) 3.60 (br. s., 1 H) 3.73 (br. s, 1 11) 3.88 (d,>9.4 Hz, 1 H) 3.92 (br. s, 1 H) 4.08 (d,>l 1.3 Hz, 1 H) 4.17 (d, >11.2 Hz, 1 H) 4.83 (d,>3.7 Hz, 1 H) 5.08 (d,.>8.4Hz, 1 H) 5.30 (br. s, 1 H) 6.64 (d. .7=9.0 Hz, 1 H) 6.75 (d,./=8.6 Hz, 1 H) 6.96 - 7.02 (m, 4 H) 7.07 (s, 1 H) 7.15 (d, >8.6 Hz, 1 H) 7.20 - 7.31 (m, 1 H) 7.23 (d,>7.2 Hz, 2 H) 7.61 (d,>8.4 Hz, 1 H) 7.74 (d, >7.2 Hz, 2 H) 7.97 (d, >8.4 Hz, 1 H) 8.17 (s, 1 H) 8.55 (s, I H)
23	(400 MHz, DMSO-î4) 0.76 (s, 9 H) 1.34 - 1.45 (ni, 1 H) 1.60-1.71 (m, 1 H) 2.55 -2.64 (m, 1 H) 2.70 - 2.85 (m, 2 H) 2,87 - 3.01 (m, 2 H) 3.48 (s, 3 H) 3.60 (br. s, 1 H) 3.74 (br. s„ 1 H) 3.93 (br.s, 1 H) 3.89 (d, >10.0 Hz, 1 H) 3.94 (s, 3 H) 4.09 (d,>l 1.5 Hz, 1 H) 4.18 (d, >11.2 Hz, 1 H) 4,85 (d,>4.3 Hz, 1 H) 5.09 (d,>8.4Hz, 1 H) 5.31 (s. 1 H) 6.64 (d,>9.6 Hz, 1 H) 6.76 (d, >8.6 Hz, 1 H) 6.96 - 7.03 (m, 3 H) 7.07 (s, 1 H) 7.15 (d, >8.8 Hz, 1 H) 7.24 - 7.33 (m, 3 H) 7.63 (d,>9.0 Hz, 1 H) 7.82 (d, >7.4 Hz, 2 H) 7.98 (d,./=8.4 Hz, i H) 8.35 (s, 1 H) 8.70 (sTT H)
25	(400 MHz, DMSO-c4) 0.77 (s, 9 H) 1.35 -1.45 (m, 1 H) 1.60 -1.69 (ni, 1 H) 2.56 - 2.64 (ni, 1 H) 2.71 -2.87 (m,2 H) 2.88-3.03 (ni, 2 H) 3.12 (s, 6 H) 3.48 (s, 3 H) 3.56-3.64 (m, 1 H) 3.70 - 3.77 (ni, 1 H) 3.88 (d,>9.8 Hz, 1 H) 3.92 - 3,99 (m, 1 H) 4.09 (dd,>11.4, 2.9 Hz, 1 H) 4.18 (d,>11.5 Hz, 1 H)4.83 (d,>5.3 Hz, I II) 5.08(dd,>8.0, 2.7 Hz, l H) 5.29 (d, ./=2.5 Hz, 1 H) 6.67 (d, >9.6 Hz, 1 H) 6.76 (d, >8,8 Hz, 1 H) 6.96 · 7.03 (ni, 3 H) 7.08 (s, I H) 7.15 (d,>8.6 Hz, 1 H) 7.24 - 7.32 (m, 3 H) 7.64(d,>9.0 Hz, 1 H) 7.87 (d,>7.6 Hz, \| 2 H) 7.98 (d, >8.6 Hz, 1 H) 8.06 (s. 1 H) 8.28 (s, 1 H)

Comp. N°	'H NMR (δ ppm)
27	(400 MHz, DMSCMO 0.76 (s, 9 H) 1.39 l .48 (m, l H) l .60 - l .71 (m, l H) 2.64 - 3.04 (m, 5 H) 3.47 (s, 3 H) 3.61 (br. s., I H) 3.72 (s, 3 H) 3.75 (br. s., I H) 3.87 (d,7=10.0 Hz, 1 H) 3.88 (s, 3 H) 3.95 (br. s„ 1 H) 4.10 (dd,7=l 1.9, 3.5 Hz, l H) 4.19 (d,>11.5 Hz, l H) 4.82 (d,./=5.3 Hz, 1 H) 5.10(dd,./=9.0, 3.5 Hz, l H) 5.26(d,./=3.3 Hz, l H) 6.66 (d,./= 10.0 Hz, 1 H) 6.70 - 6.79 (m, 4 H) 6.88 (d, >8,6 Hz, 1 H) 7.08 (br. s„ 1 I I) 7.11 - 7.19 (m, 2 H) 7,27 (d,7=8.2 Hz, 2 H) 7.43 (d,>8.2 Hz, 2 H) 7.59 (d,>9.2 Hz, 1 H) 7.91 (dd,>8.6, 2.5 Hz, I H) 7.92 (d, 7=8.2 Hz, 1 H) 8.38 (d,7=2.1 Hz, 1 H)
29	(400 MHz, DMSO-7₆) 0.77 (s, 9 H) 1.35 -1.44 (m, 1 H) 1.60 -1.70 (m, 1 H) 2.56 - 2.63 (ni, 1 H) 2.70 - 2.82 (m, 2 H) 2.87 - 3,01 (m, 2 H) 3.52 (s, 3 H) 3.59 (br. s., 1 H) 3.74 (br. s., 1 H) 3.86-3.95 ( m, 2 H) 4.07 (s, 3H)4.10(d, 7=12.5 Hz, 1 H) 4.18 (d, 7=12.5 Hz, I H)4.82(br. s., 1 H) 5.09 (d,7=7.4 Hz. 1 H) 5.30 (s, 1 H) 6.63 (d, 7=10.0 Hz, 1 H) 6.76 (d, 7=8.2 Hz, 1 H) 6.96 - 7.03 (m, 3 H) 7.07 (s, 1 H) 7.16 (d, 7=9.6 Hz, 1 H) 7.22 (d,7=7.2 Hz, 2 H) 7.26 7.30 (in, 1 H) 7.32 (s, 1 H) 7.62 - 7.68 (m, 3 H) 7.97 (d, 7=9.6 Hz, 1 H)
30	(400 MHz, DMSO-7₆) 0.77 (s, 9 H) 1.36- 1.45 (ni, I H) 1.60 - 1.70 (m, 1 H) 2.55 - 2.64 (m. 1 H) 2.69 - 2.87 (m, 2 H) 2.87 - 3.03 (m, 2 H) 3.47 (s, 3 H) 3.56 (s, 1 H) 3.61 (d,7=9,8 Hz, t H) 3.74 (br. s., 1 H) 3.88 (d,7=10.2 Hz, 1 H) 3.95 (br. s., 1 H) 3.92 (s, 3 H) 4.09 (dd,7=11.7, 3.3 Hz, 1 H) 4.18 (d, 7=11.5 Hz, 1 H) 4.88 (br. s., 1 H) 5.08 (d, 7=6.1 Hz, 1 H) 6.67 (d, 7=10.2 Hz, 1 H) 6.76 (d,7=8.8 Hz, 1 H) 6.73 (d, 7=8.2 Hz, 1 11)6.96-7.03 (m, 3 H) 7.08 (s, 1 H) 7.11 - 7.19 (m, 1 11) 7.25 - 7.32 (m, 3 11) 7.45 (d, 7=7.4 Hz, 1 H) 7.65 (d, ./»9.4 Hz, l H) 7.74 (t, 7=7.7 Hz, 1 H) 7.89 (d. 7=8.0 Hz, 2 H) 8.04 (d. 7=8.8 Hz. 1 H)
31	(400 MHz, DMSO-7_fl) 0.76 (s, 9 H) 1.35 - 1.45 (m, 1 H) 1.61 -1.71 (m, 1 H) 2.60 (dd, 7=13.1, 7.4 Hz, 1 H) 2.74 - 2.88 (m, 2 H) 2.88 - 3.02 (ni, 2 H) 3.44 (s, 3 H) 3.60 (br. s„ 1 H) 3.75 (br. s., 1 H) 3.87 (d,7=9.8 Hz, 1 H) 3.92 - 4,01 (m, 1 H) 4.09 (dd,7-11.7,3.5 Hz, 1 H) 4.18 (d, 7=11.5 Hz, 1 H) 4.85 (d, 7=5.5 Hz, 1 H) 5.08 (dd,7=8.6, 3.5 Hz, 1 H) 5.31 (d, 7=2.5 Hz, 1 H) 6.63 (d, 7=9.6 Hz, 1 H) 6.74 (d, 7=8.8 Hz. 1 H) 6.75 (none, 1 H) 6.95 - 7.03 (m, 3 H) 7.05 (d, 7=2.0 Hz, 1 H) 7.14 (dd, 7=8.7, 2.4 Hz, 1 H) 7.24 - 7.31 (m, 1 H) 7.36 (d, 7=8.2 Hz, 2 H) 7.63 (d, 7=9.2 Hz, 1 H) 7.70 (d, 7=8.2 Hz, 2 H) 7.95 (dd, 7=5.3,1.4 Hz, 1 H) 7.98 (d,7=9.0 Hz, 1 H) 8.06 (s, 1 H) 8.77 (d, 7=5.1 Hz, 1 H)
34	(400 MHz, DMSO-7₆) 0.78 (s, 9 H) 1.37-1.51 (m, 1 H) 1.61 - l.75(m, 1 H) 2.62 - 2.90 (m, 4 H) 2.92-3.01 (m, I H) 3.04 (s, 6 H) 3.18 (s, 3 H) 3.37 - 3.44 (m, 2 H) 3.61 (br. s., 1 H) 3.68 (br. s., 1 H) 3.89 (d, 7=9.6 Hz, 1 H) 3.92 - 3.98 (ni, 1 H) 3.99 - 4.09 (ni, 3 H) 4.13 (d, 7=11.3 Hz, 1 H) 4.91 (d, 7=5.1 Hz, 1 H) 5.07 (dd, 7=8.4,2.7 Hz, 1 H) 5.21 (d, 7=2.9 Hz, 1 H) 6.69 (d, 7=9.0 Hz, 1 H) 6.71 - 6.80 (m, 2 H) 6.83 (dd,7=9,3, 2.4 Hz, 1 H) 6.97 (id,7=8.6, 2.3 Hz, l H) 7.03 - 7.15 (m, 2 H) 7.17 - 7.30 (m, 4 H) 7.38 (d,7=8.0 Hz, 2 H) 7.62 (d, 7=9.0 Hz, l H) 7.73 (dd,7=8.9, 2.1 Hz, 1 H) 7.88 (d,7=9.0 Hz, 1 H) 8.33 (d, 7=1.8 Hz, 1 H)

Coinp. N°	Ή NMR (δ ppm)
54	(400 MHz, DMSO-/,) 0.80 (s, 9 H) 1.38 - 1.48 (m, l H) 1.66 - l .75 (m, I H) 2.45 (s, 6 H) 2.68 - 2.77 (m, 2 H) 2.78 - 2.88 (m, 2 H) 2,91 - 3.01 (ni, l H) 3.50 (s, 3 H) 3.58 (br. s., I H) 3.68 (br. s., I H) 3.90 (d,/=l0.0 Hz, I H) 3.93 - 3.99 (m, I H) 4.I7 (dd,./=11.9, 3.5 Hz, 1 H) 4.25 (d,./=l 1.1 Hz, 1 H) 4.89 (d, ./=4.9 Hz., 1 H) 5.09 (dd,./=8.3, 3.6 Hz, 1 H) 5.27 (br. s., I H) 6.74 (d, ./=9.6 Hz, 1 H) 6.79 (t, >7.8 Hz, 1 H) 6.94 (d,>7.6 Hz, 1 H) 7.06 - 7.14 (m, 2 H) 7.20 - 7.28 (ni, 3 H) 7.26 (s, 2 H) 7.32 (d, /=8.4 Hz, 2 H) 7.56 (d, /=8.0 Hz, 2 H) 7.66 (d, /=8.8 Hz, 1 H) 7.84 (d,/=9.0 Hz, 1 H)
56	(400 MHz, DMSO-</₆) 0.78 (s, 9 H) 1.40 - 1.49 (ni, 1 H) 1.66 - 1.75 (τη, 1 H) 2.66 - 2.90 (ni, 4 H) 2.94 - 3.03 (ni, 1 H) 3.48 (s, 3 H) 3.60 (br. s„ 1 H) 3.70 (br. s., 1 H) 3.88 (s, 3 H) 3,89 (d,>10.0 Hz, 1 H) 3.92 - 4.00 (ni, 1 H) 4.19 (dd,/=l 1.7, 3.3 Hz, 1 H) 4.27 (d,/=l 1.3 Hz, l HJ4.90 (d,>4.5 Hz, 1 H) 5,12 (dd,/=8.7, 3,2 Hz, 1 H) 5.35 (br. s., 1 H) 6.69 (d, >9.6 Hz, 1 H) 6.81 (dd,/=9.1,2.2 Hz, 1 H) 6.88 (d, /=8.6 Hz, 1 H) 7.06 - 7.14 (ni, 2 H) 7.21 - 7.29 (ni, 3 H) 7.27 (d,/=8.2 Hz, 2 H) 7.43 (d,>8.2 Hz, 2 H) 7.64 (d,/=9.2 Hz, 1 H) 7.90 (dd, ./=8.6, 2.5 Hz, 1 H) 7.94 (d,.7=8.8 Hz, 1 H) 8.38 (d,/=2.! Hz, 1 H)
57	(400 MHz, DMSO-/») 0.77 (s, 9 H) 1.42 - ! .54 (m, ! H) 1.65 - 1.79 (m, 1 H) 2.66 - 2.89 (m, 3 H) 2.89 - 3.06 (ni, 2 H) 3.17 (s, 3 H) 3.39 (d,/=5.7 Hz, 2 H) 3.67 (br. s„ 1 H) 3.65 (br. s, 1 H) 3.90 (d,/=10.0 Hz, 1 H) 3.88 (s, 3 H) 3.94-4.09 (ni, 4 H) 4.13 (d,/=l l.l Hz, 1 H) 4.97 (d,>4.9 Hz, 1 H) 5.08 (dd,/=8.8, 3.5 Hz, 1 H) 5.22 (br. s., 1 H) 6.76 (d,/=9.2 Hz, 1 H) 6.73 (dd, /=9.0,4.9 Hz, 1 H) 6.83 (dd, /=9.4, 2.5 Hz, 111) 6.87 (d,/=8.6 Hz, 1 H) 6.95 (td, /=8.6, 3.0 Hz, 1 H) 7.17 - 7.26 (m, 2 H) 7.26 - 7.32 (m. 3 H) 7.35 - 7.41 (m, 1 H) 7.44 (d, /=8.2 Hz, 2 H) 7.63 (d, /=9.2 Hz, 1 H) 7.86 (d,/“8.8 Hz, 1 H) 7.91 (dd,>8.8,2.5 Hz, 1 H) 8,39 (d,/=2.1 Hz, 1 H)
58	(400 MHz, DMSO-/) 0.76 (s, 9 H) 1.40 - ! .54 (m, 1 H) 1.66 -1.80 (m, 1 H) 2.72 - 2.88 (m, 3 H) 2.87 - 2.98 (tn, 1 H) 2.98 - 3.09 (m, 1 H) 3.48 (s, 3 H) 3.66 (br. s, 1 H) 3.69 (br. s, i H) 3.88 (s, 3 II) 3.89 (d,> 10.0 Hz, 1 H) 3.95 - 4,04 (m, 1 H) 4.08 (dd,/=11.7,3.5 Hz, 1 H) 4.12-4.25 (m,>!1.5 Hz, 1 H) 4.96 (d, ./=4.9 Hz, 1 H) 5.09 (dd,/=8.6,3.5 Hz, 1 H) 5.31 (br. S„ 1 H) 6.68 (d, ./=9.6 Hz, 1 H) 6.75 (d,>8.8 Hz, 1 H) 6.88 (d,/=8.6 Hz, l H) 7.08 (d, /=1.8 Hz, 1 H) 7.15 (00,/=8.8,2.3^, 1 H) 7.19 - 7.32 (ni, 5 H) 7.34-7.41 (m, 1 H) 7.43 (d,/=8.0 Hz, 2 H) 7.60 (d,/=9.2 Hz, 1 H) 7.91 (dd.>8.6, 2.5 Hz, 1 H) 7.90 (d, >8.2 Hz, 1 H) 8.39 (d,/=2.3 Hz, 1 H)

Comp. N°	'H NMR (8 ppm)
60	(400 MHz, DMSO-î/₆) 0.80 (s, 9 H) l .38 -1.50 (m, l H) l .65 - l .77 (m, l H) 2.62 - 2.88 (m, 4 H) 2.90 - 3.00 (m, l H) 2.95 (s, 6 H) 3.50 (s, 3 H) 3.59 (br. s„ l H) 3.68 (br. s., I H) 3.89 (d,/=9.6 Hz, l H) 3.96 (br. s., I H) 4.I4 (dd, J=\ 1.5, 3.5 Hz, l H) 4.21 (d, /=l l.l Hz, l H) 4.89 (d,./=4.5 Hz, l II) 5.09 (dd,./=8.8, 3.7Hz, l I I) 5.27 (br. s., I H) 6.7! -6.83 (ni, 3 H) 6.96 - 7.05 (m, I H) 7.05 - 7.I4 (m, 2 H) 7.28 (d,/=8.2 Hz, 2 H) 7.20 - 7.27 (m, 2 H) 7.49 (d, ,/=8.2 Hz, 2 H) 7.65 (d, /=8.8 Hz, I H) 7.84 (d,/=9.0 Hz, f H) 7.93 (d,/=2.0 Hz, l H) 8.42 (d,/=2.2 Hz, l H)
61	(400 MHz, DMSO-/₀) 0.77 (s, 9 H) 1.39 -1.51 (m, l H) l .62 -1.77 (m, I H) 2.65 - 2.90 (m, 4 H) 2.98 (d,/=7.0 Hz, l H) 3.48 (s, 3 H) 3.60 (br. s., I H) 3.72 (br, s., I H) 3.88 (s, 3 H) 3.84 - 3.92 (in, l H) 3.97 (br. s., I H) 4,18 (dd,/=l I.7,2.9 Hz, l H) 4.27 (d, J=!l,5 Hz, ! H) 4.87 (d,/=4.9 Hz, l H) 5.11 (dd./=8.0, 2.I Hz, l H) 5.38 (d,/=2.9 Hz. I H) 6,68 (d,/=9.6 Hz, I H) 6.88 (d,/=8.6 Hz, l H) 6.90 (br. s., I H) 7.04-7.14 (ni, 2 H) 7.27 (d,/=8.0 Hz, 5 H) 7.43 (d,/=7.8 Hz, 2 H) 7.60 (d,/=8.8 Hz, l H) 7.92 (d, l H) 7.90 (dd,/=8.2,2.3 Hz, l H) 8.38 (d,/=1.8 Hz. I H)
63	(400 MHz, DMSO-(4) 0.78 (s, 9 H) 1.47 (1,/=10.0 Hz, 1 H) 1.74 (t,/=l 1.7 Hz, I H) 2.692.87 (ni, 3 H) 2.87 - 3.06 (ni, 2 H) 3.15 (s, 6 H) 3.49 (s, 3 H) 3.65 (br. s., 1 H) 3.68 (br. s., 1 H) 3.89 (d,/=9.6 Hz, 1 H) 3.92 - 4.00 (m, 1 H) 4.05 (dd,/= 11.7, 3.7 Hz, 1 H) 4.09 - 4.17 (m,/=l 1.5 Hz, 1 H) 4.91 (br. s., 1 H) 5.08 (dd,/=9.0, 3.7 Hz, 1 H) 5.17 (br. s., 1 H) 6.70 (d, /=9.8 Hz, 1 H) 6.73 (dd,/=9.0,4.9 Hz, 1 H) 6.83 (dd,./=9.7, 3.0 Hz, 1 H) 6.95 (td,/=8.5, 3.0 Hz, 1 H) 7,17 - 7.32 (m, 5 H) 7.36-7.40 (m, 1 H) 7.41 (d,./=8.0 Hz, 2 H) 7.64 (d,/=9.0 Hz, 1 H) 7.81 (d, /=9.0 Hz, 1 H) 8.59 (s, 2 H)
64	(400 MHz, DMSO-i4) 0.77 (s, 9 H) 1.35 - 1.44 (ni, 1 H) 1.62 - 1.72 (m, I H) 2.61 - 2.66 (m, 1 H) 2.69 - 2.83 (m, 2 H) 2.92 - 3.03 (m, 2 H) 3.48 (s, 3 H) 3.57 - 3.65 (m, 1 H) 3.70 - 3.74 (m, 1 H) 3.88 (s, 3 H) 3.88 (d,/=!0.0 Hz, 1 H) 3,91 - 3.96 (m, 1 H) 4.07 (dd,/=l 1.7, 3.7 Hz, 1 H) 4.14 (d,/=11.3 Hz, 1 H) 4,85 (d,/=5.3 Hz, 1 H) 5.08 (dd,/=8.6, 3.5 Hz, 1 1-1)5.23 (d, /=2.9 Hz, 1 H) 6.67 (d,./=9.4 Hz. 1 H) 6.74 (dd,/=9.0,4.9 Hz, 1 H) 6.83 (dd,/=9.4,2.7 Hz, 1 H) 6.88 (d,/=8.6 Hz, 1 H) 6.96 (td,/=8.4, 3.0 Hz, I H) 7.14 - 7.22 (ni, 3 H) 7.27 (d,/=8.2 Hz, 2 H) 7.35 - 7.41 (m, 1 H) 7.43 (d, /=8.2 Hz, 2 H) 7.64 (d,/=8.8 Hz, 1 H) 7.90 (dd, /=8.6, 2.5 Hz, 1 H) 7.99 (d,/=8.8 Hz, l H) 8.38 (d,/=2.3 Hz, 1 H)
65	(400 MHz, DMSO-/₆) 0.77 (s, 9 H) 1.35 - 1.44 (m, 1 H) 1.62 - 1.72 (m, 1 H) 2.57 - 2.65 (m, 1 H) 2.65 - 2.84 (m, 2 H) 2.87 - 3.02 (ni, 2 H) 3.47 (s, 3 H) 3.55 - 3.63 (m, 1 H) 3.74 (br. s., 1 H) 3.88 (d, /=9.6 Hz, 1 H) 3.93 (br. s., 1 H) 3.95 (s, 3 H) 4.07 (dd,/=l 1.5,3.7 Hz, 1 H) 4.15 (d,/=l 1.3 Hz, 1 H) 4.85 (d,./=5.5 Hz, 1 H) 5.09 (dd,./=8.9, 3.6 Hz, 1 H) 5.22 (d,/=3.1 Hz, 1 H) 6.67 (d,/=9.6 Hz, 1 H) 6.73 (dd,/=8.9,4.8 Hz, 1 H) 6.8! (dd,/=9.4,2.7 Hz, l H) 6,95 (td,/=8.6, 2.9 Hz, l H) 6.97 - 7.04 (m, 3 H) 7.24 - 7.35 (m, 1 H) 7.31 (d,/=8.2 Hz, 2 H) 7.51 (d, /=8.2 Hz, 2 H) 7.64 (d, /=8.8 Hz, 1 H) 7.95 (d. /=8.8 Hz, 1 H) 8.83 (s, 2 H)

.98-

Coinp. N°	‘11 NMR (5 ppm)
66	(400 MHz, DMSOAQ 0.77 (s, 9 H) 1.39- 1.48 (m, 1 H) 1.70 - 1.78 (m. 1 H) 2.19 (s. 3 H) 2.69 - 2.80 (m, 3 H) 2.80 - 2.90 (tn, 1 H) 2.92 - 3.01 (ni, 1 H) 3.48 (s, 3 H) 3.68 (br. s., 2 H) 3.88 (d, >10.0 Hz, 1 H) 3.88 (s, 3 H) 4.01 (br. s., 1 H) 4.0! (dd, J= i 1.5,4.i Hz, 1 H) 4.08 (dd,>8.8,3.5 Hz, 1 H) 4.88 (d, >4.9 Hz, 1 H) 5.05 (d,>3.9 Hz, 1 H) 5.07 (d.>3.1 Hz, 1 H) 6.61 (d,>8.0 Hz, 1 H) 6.65 (d,.7=9.6 Hz, 1 H) 6.86 - 6.92 (m, 3 H) 7.06 - 7.13 (m, 2 H) 7.20 - 7.29 (m, 2 H) 7.27 (d,>8.2 Hz, 2 H) 7.43 (d, >8.2 Hz, 2 H) 7.61 (d,>9.2 Hz, 1 H) 7.77 (cl,.7=9.0 Hz, 1 H) 7.91 (dd. >8.6, 2.5 Hz, I H) 8.39 (d, >2.1 Hz, 1 H)
67	(400 MHz, DMSOA₆) 0.78 (s, 9 H) 1.41-1.53 (m, 1 H) 1.68 - 1.80 (ni, 1 H) 2.65 - 2.87 (m, 3 H) 2.87 - 3.08 (m, 2 H) 3.48 (s, 3 H) 3.60 - 3,72 (m, 2 H) 3.88 (s, 3 H) 3.90 (d,>11.5 Hz, 1 H) 3.93 -4.02 (ni, 1 H) 4.05 (dd,>l 1.7, 3.5 Hz, 1 H) 4.13 (d,>! 1.3 Hz, 1 H) 4.96 (d, >4.9 Hz, 1 H) 5.08 (dd. >8.8, 3.5 Hz, 1 H) 5.23 (br. s., 1 H) 6.69 (d,>9.8 Hz, 1 H) 6.73 (dd,>9.0,4.9 Hz, 1 H) 6.83 (dd,.7=9.4,3.1 Hz, 1 H) 6.88 (d, .7=8.8 Hz, 1 H) 6.95 (td, .7=8.5, 3.1 Hz, 1 H) 7.18 - 7.25 (ni, 2 H) 7.25 - 7.32 (m, 3 H) 7.35 - 7.41 (ni, 1 H) 7.44 (d,>8.2 Hz, 2 H) 7.64 (d, .7=9.4 Hz, 1 H) 7.87 (d,>9.0 Hz, 1 H) 7.91 (dd,>8.7, 2.6 Hz, 1 H) 8.38 (d, >2.1 Hz, i H)
68	(400 MHz,DMSOA₆) 1.17 -1.38 (m. 2 H) 1.39- 1.53 (ni, 1 H) 1.77 - 1.89 (ni, l H) 2.64 2.94 (m, 5 H) 2.95 - 3.05 (ni, 1 H) 3,06 (s, 6 H) 3.48 (ckl,.7=9.6, 5.5 Hz, 1 H) 3.52 - 3.79 (m, 6 H) 4.07 (dd,>l 1.9,3.7 Hz, 1 H) 4.15 (d,>11.5 Hz, 1 H) 4.80 (du >8.1, 5.7 Ηζ,ΟΗ) 4.89 (d,>4.9 Hz, 1 H) 5.10 (dd,.7=8.5, 3.6 Hz, 1 H) 5.27 (br. s„ 1 H) 5.46 (d,>5.3 Hz, 1 H) 6.71 (d, >8,8 Hz, 1 H) 6.74 (dd,.7=9.0,4.9 Hz, 1 H) 6.80 (dd,>9.4, 2.7 Hz, 1 H) 6.96 (td,>8.5, 2.8 Hz, 1 H) 7.08 - 7.18 (ni, 3 H) 7.25 (d,>8.4 Hz, 2 H) 7.24-7,33 (m, 2 H) 7.46 (d,>8.2 Hz, 2 H) 7.77 (dd, .7=9.0,2.5 Hz, 2 H) 7.82 (d, >9.0 Hz, 1 H) 8.38 (d,>2.3 Hz, 1 H)
69	(500 MHz, DMSOAî) 0.78 (s, 9 H), 1.30 - 1.47 (in, 3 H), 1.74 (t,> 11.4 Hz, 1 H), 2.48 (d, >4.5 Hz, 3 H), 2.59 (dd,>13.7, 10.8 Hz, 1 H), 2.64 - 2.84 (m, 4 H), 2.90 - 2.99 (m, l H), 3.05 (s, 6 H), 3,49 - 3.57 (ni, 2 H), 3.59 - 3.72 (m, 3 H), 3.83 (dd,.7=9.5, 6.0 Hz, 1 H), 4.12 (d, >9.5 Hz, 1 H), 4.85 - 4.93 (m, 2 H), 5.50 (d,>5.2 Hz, 1 H), 6.70 (d,>8.9 Hz, 1 H), 7.01 (t,>7.4 Hz, 1 H), 7.05 - 7.10 (iiî?! H), 7.12 - 7.17 (ni, 2 H), 7.21 (ni, 3 H), 7.41 - 7.48 (in, 3 H), 7.56 -7.78 (ni, 2 H), 8.38 (d, >2.5 Hz, 1 H)

•99-

Comp. N°	¹H NMR (δ ppm)
70	¢400 MHz, DMSO-<4) 1.17- 1.24 (ni, 1 H) 1.28- 1.38 (ni, 1 H) 1.41 - 1.50 (m, 1 H) 1.73 1.82 (m, 1 H) 2.55 - 2.68 (m, 1 H) 2.68-2.83 (in, 3 H) 2.89 - 2.98 (in, 2 H) 3.48 (dd, >9.6, 5.5 Hz, 1 H) 3.53 - 3.66 (m. 3 H) 3.69 - 3.77 (ni. 3 H) 3.73 (s, 3 H) 3.88 (s. 3 H) 4.11 (dd, >11.7, 3.3 Hz, 1 H) 4,20 (d,>l 1.4 Hz, 1 H) 4.77 - 4.84 (m, 2 H) 5.12 (dd,>8.6, 2.9 Hz, 1 H) 5.32 (d,>2.2 Hz, 1 H) 5.46 (d, >5.1 Hz, 1 H) 6.73 - 6.80 (m, 4 H) 6.88 (d,>8.6 Hz, 1 H) 7.06 (d,>l.8 Hz, l H) 7.09 (d,>9.6 Hz, 1 H) 7,12 - 7.22 (ni, 2 H) 7.29 (d,>8.0 Hz, 2 H) 7,52 (d,>8.2 Hz, 2 H) 7.87 (d, >8.8 Hz, 1 H) 7.95 (dd,>8.6, 2.3 Hz, 1 H) 8.43 (d, >2.3 Hz, 1 H)
73	(400 MHz, DMSO-c4) 1.17 -1.37 (m, 2 H) 1.41 - 1.50 (ni, 1 H) 1.76 - 1.86 (ni, 1 H) 2.65- 2.86 (m, 4 H) 2.94 - 3.04 (m, 2 H) 3.49 (dd,>9.6, 5.5 Hz, l H) 3.53 - 3.67 (m, 3 H) 3,68 - 3.77 (ni, 3 H) 3.88 (s, 3 H) 4.10 (dd,>11.7, 3.3 Hz, 1 H) 4.19 (d,>l 1.5 Hz, 1 H) 4.76 - 4.85 (ni, 2 H) 5.10 (dd,>8.5,3.2 Hz, 1 H) 5.29 (d,>3.3 Hz, 1 H) 5.46 (d,>5.3 Hz, 1 H) 6.76 (d, >8.6 Hz, I H) 6.88 (d, >8.6 Hz, 1 H) 7,07 (s, 1 H) 7.07 (d, >9.3 Hz, 1 H) 7.12 - 7.22 (ni, 3 H) 7,25 (d,>7.8 Hz, 1 H) 7.30 (d,>8.0 Hz, 2 H) 7.41 (t, >7.8 Hz, l H) 7,52 (d, >8.2 Hz. 2 H) 7.90 (d, >8.8 Hz, 1 H) 7.95 (dd,>8.6.2.5 Hz, 1 H) 8.43 (d.>2.3 Hz, 1 H)
74	(400 MHz, DMSCM) 1-21 - 1.46(m,3 H) 1.74 - 1,88 (ni, 2 H) 1.89-2.04 (m, 1 H) 2.562.95 (ni, 8 H) 3.49 (dd,>9.6, 5.3 Hz. 1 H) 3.53 - 3.81 (m. 6 H) 3.88 (s, 3 H) 4.72 (d, >3.7 Hz, 1 H) 4.82 - 4.90 (m, 3 H) 5.48 (d,>5.3 Hz, 1 H) 6.66 (d,>5.1 Hz, 1 H) 6.89 (d,>8.6 Hz, 1 H) 7.07-7.21 (in, 4 H) 7.29 (d,>8.0 Hz, 2 H) 7.22 - 7.29 (m. 2 H) 7,53 (d, .>8.2 Hz, 2 H) 7.66 (d, >9.0 Hz, 1 H) 7.97 (dd, >8.7. 2.6 Hz. 1 H) 8.44 (d.>2.0 Hz, 1 H)
78	(400 MHz,DMS0-î4) 1.10 - 1.20 (m, 1 H) 1.21 - 1.36(tn, 1 H) 1.46-1.59 (m, 1 H) 1.75- 1.88 (m, 1 H) 2.63 - 2.75 (ni, 1 H) 2.75 - 2.84 (m, 2 H) 2.84 - 2.95 (m, 1 H) 2.95 - 3.07 (m, 2 H) 3.43 (dd, >9.5, 5.0 Hz, 1 H) 3.49 - 3.75 (ni. 5 H) 3.75 - 3.86 (in, 1 H) 3.88 (s, 3 H) 4.08 (dd, >11.7, 2.9 Hz, 0 H) 4.19 (d,>l 1.3 Hz, 0 H) 4.67-4.78 (m, 1 H) 4.96 (d, >4.3 Hz, 1 H) 5.03 - 5,19 (m, 1 H) 5.35 - 5.52 (m, 2 H) 6.75 (d,>8.8 Hz, 3 H) 6.89 (d,>8.6 Hz, 1 H) 7.01 (s, 1 H) 7.14 (dd,>8.6, 2.1 Hz, 1 H) 7.18 (d,>9.6 Hz, 1 H) 7.21 - 7.37 (m, 5 H) 7.37 7.46 (ni, 1 H) 7.52 (d, ./=8.0 Hz, 2 H) 7.82 (d, >9.2 Hz, 1 H) 7.95 (dd,>8.5, 2.2 Hz, l H) 8.43 (d,> 2.0 Hz, 1 H)
79	(400 MHz, DMSO-fifc) 1.17 -1.37 (ni, 2 H) 1.44- 1.53 (m, 1 H) 1.76- 1.86 (m, 1 H) 2.67 2.84 (m, 3 H) 2.85 - 2.93 (ni, 1 H) 2.94 - 3.09 (m, 2 H) 3.05 (s, 6 H) 3.46 - 3.52 (m, l H) 3.52 - 3.80 (m, 6 H) 4.05 - 4.13 (ni, 1 H) 4.19 (d,>l 1.3 Hz, 1 H) 4.75 - 4.82 (m, 1 H) 4.86 (d_t>4.5 Hz, l H) 5.10 (br. s„ 1 H) 5.32 (s, 1 H) 5.45 (d, J=4.7 Hz, l H) 6.75 (d.>8.4 Hz, 1 H) 6.70 (d, ./=8.6 Hz, 1 H) 7.02 - 7.19 (m, 5 H) 7,21 - 7.31 (m, 4 H) 7.45 (d,>7.2 Hz, 2 H) 7.77 (d, ./=8.2 Hz, 1 H) 7.82 (d, >8.8 Hz, 1 H) 8.37 (br. s., 1 H)

-ÎOO-

Comp. N°	'il NMR (δ ppm)
81	(400 MHz, DMSO-î/₆) 1.14- I.26(ni, l H) 1.26- !.39(m, l H) 1.42- l.55 (m, I H) I.74 l .87 (m, l H) 2.64 - 2.84 (ni, 4 H) 2.84 - 2.94 (ni, l H) 2.94 - 3.09 (ni, l H) 3.45 - 3.53 (ni, l H) 3.53 -3,67 (m, 3 H) 3,68-3.79 (m, 3 H) 3,88 (s, 3 H) 4.18 (dd, >11.7,2.9 Hz, l H) 4.28 (d,./=l 1.3 Hz, 0 H)4.79(dt,>8.0,5.8 Hz, 0 H) 4.87 (d,./=5.3 Hz, l H) 5.13 (dd,./=8.4, 2.9 Hz, I H) 5.43 (d,./=3.5 Hz, 0 H) 5.46 (d,./=5.3 Hz, l H) 6.85 - 6.92 (m, 2 H) 7.07 - 7.I8 (m, 3 H) 7.29 (d,>8.2 Hz, 2 H) 7.22 - 7.29 (m, 3 H) 7.52 (d,J=8.0 Hz, 2 H) 7.86 (d,>9.0 Hz, 0 H) 7.95 (dd, >8.6,2.5 Hz, l H) 8.42 (d, >2.3 Hz, l H)
82	(400 MHz, DMSO-î/s) 0.67 (d.>6,4 Hz, 3 H) 0.79 - 0.98 (ni, l H) l.2l - I.66(ni, 9 H) l .67 - 1.78 (m, I H) 2.56 - 2.84 (ni, 6 H) 3.25 (1,./=10.5 Hz, J H) 3.34 (br. s., 1 H) 3.47 3.72 (in, 5 H) 3.83 (dd,>9.6,6.0 Hz, 1 H) 3.88 (s, 3 H) 4.25 (d,./=3.3 Hz, 1 H) 4.81 (d, >5.1 Hz, 1 H) 4.88 (dt,./=8,2,5,7 Hz, 1 H) 5.50 (d,>5.3 Hz, 1 H) 6.89 (d, >8.8 Hz, 1 II) 7.04 - 7.31 (ni,./=8.2 Hz, 2 II) 7.04 - 7.26 (m, 6 11) 7.52 (d, >8.2 Hz, 2 H) 7.96 (dd, >8.6, 2.5 Hz, 1 H) 8.44 (d,>2.5 Hz, ) H)
83	(500 MHz, DMSO-r/o) 0.73 (d,./=6.0 Hz, 3 H), 0.84 (s, 9 H), 0.96 - 0.99 (m, l H), 1.35 (t, >10.2 Hz, 1 H), 1.42-1.45(111, 1 H), 1.49 (1,,/=12.2 Hz, I H), 1.81-1.71 (ni, 3 H), 2.56- 2.71 (ni, 5 H), 2.73 - 2.96 (ni, 3 H), 3.36 - 3.40 (ni, 1 H), 3.44 - 3.46 (ni, 1 H), 3.52 (s, 3 H), 3.71 (q,>3.9 Hz, l H), 3.84 (q,>7.8 Hz, 1 H), 3,88 (d,>9.8 Hz, 1 H), 4.41 (d,>3.8 Hz, 1 H), 4,86 (d,>5.0 Hz, 1 H), 6.75 (d,>9.6 Hz, 1 H). 7.05 - 7.08 (ni, 2 H), 7.14 (d,>8.8 Hz, i H), 7.18-7.24 (m, 4 H), 7.41 (d,>8.1 Hz, 2 11),7.62 (d,.>8.7 Hz, 1 H). 7.92 (s, 1 H)
84	(500 MHz, DMSO-î/î) 0.71 (s, 9 H), 0,82 (s, 9 H), 1.31 (t,>7.3 Hz, 3 H), 1.38 (t,>10.8 Hz, 1 H), 1.52 (1,./=12.2 Hz, 1 H), 2.47 (d,.>4.4 Hz,3 H), 2.57 - 2.70 (m,3 H), 2.78(dd, >13.0, 6.4 Hz, IH), 2.92 (q,./=7.2 Hz, 1 H), 2.99 (m, 1 H), 3.43 (d,>10.3 Hz, 1 H), 3.52 (s, 3 H), 3.85 (q,>7.8 Hz, 1 H), 3.90 (d,>9.3 Hz, 1 H), 4.05 (d,>9.3 Hz, 1 H), 5.02 (s, l H), 6.82 (d,>9.6 Hz, H), 6.98 (t,>7.5 Hz, 1 H), 7.05 (i,>9.3 Hz, 1 H), 7,12 (t,>7.3 Hz, 1 H), 7.18 (1, ./=7.2 Hz, 1 H), 7.19 (d, >8.3 Hz, 2 H), 7.41 (d, >7.9 Hz, 2 H), 7.57 (d, J=9.3 Hz, 1 H), 7,65 (d,./=8.9 Hz, 1 H), 7.81 (q,>4.3 Hz, 111), 7,94 (s, 1 H)
87	(500 MHz, DMSO-î/î) 0.75 (d,>6.1 Hz, 3 H), 0.87 (s, 9 H), 1.07 (dd,>8.5, 14.7 Hz, 1 H), 1.30 - 1.48 (ni, 2 H), 1.48 - 1.59 (m, 1 H), 1.69 - 1.87 (m, 3 H), 2.55 - 2.70 (m, 2 H), 2.70 2.86 (m, 3 H), 3.05 (s, 6 H), 3.35 - 3.42 (ni, 1 H), 3.55 (s, 3 H), 3.43 - 3.59 (m, 1 H), 3.69 (d, >4.1 Hz, 1 H), 3.78 - 3.97 (ni, 2 H), 4.40 (d,>3.6 Hz, 1 H), 4.85 (d,>4.9 Hz, 1 H), 6.70 (d, >8.9 Hz, 1 H), 6.77 (d, >9.6 Hz, 1 H), 6.99 - 7.30 (m, 7 H), 7.50 (d, >8.0 Hz, 2 H), 7.69 (d,>8.9 Hz, 1 H). 7.74 (dd,./=2.6,8.9 Hz, 1 H), 8.35 (d,>2.6 Hz, 1 H)

•ΙΟΙ-

Comp. Ν°	'il NMR (δ ppm)
88	(400 MHz, CHLOROFORM-d) 0.91 (s, 18 H) l .64 - l .86 (m, 2 H) 2.73 (d,>4.3 Hz, 3 H) 2.75 - 2.82 (m, l H) 2.85 - 2.99 (m, 4 H) 3.59 (s, 3 H) 3.80 - 3.91 (m, 2 H) 3.96 (s, 3 H) 4.04 - 4.13 (m, 1 H) 4.15 (d,>8.8 Hz, 1 H) 4.25 (br. s.. 1 H) 5.45 (br. s.. 1 H) 5.88 (br, s., 1 H) 6,44 (d, ./=7.0 Hz, 1 I I) 6.61 (d,>8.6 Hz, 1 H) 6.78 (d,./=8.8 Hz. 1 II) 6.85 - 6.98 (m, 3 H) 7.08 - 7.16 (ni, 1 H) 7.23 (d,>7.8 Hz, 2 H) 7.36 (d, >7.2 Hz, 2 H) 7.70 (d,>8.4 Hz, 1 H) 8.31 (s, 1 H)
89	(400 MHz, DMSO-d_fl) 0.58 (d,./=6.4 Hz, 3 H) 0.81 (s,9 H) 0.81 - 0.92 (m, 1 H) 1.17 -1.43 (ni, 3 H) 1.43 - ! .66 (m, 5 H) 2.57 - 2.83 (m, 5 H) 3.05 (s, 6 H) 3.14 - 3.24 (m, 1 H) 3.30 (br. s., 1 H) 3.48 (br. s., 1 H) 3.51 (s, 3 H) 3.81 - 3.89 (m, 1 H) 3.89 (d,>9.4 Hz, 1 H) 4.22 (d, >3.3 Hz, 1 H) 4.81 (d,>4.7 Hz, 1 H) 6.71 (d,>8.8 Hz, 1 H) 6.79 (d,>9.6 Hz, 1 H) 7.09 (d, >9.6 Hz, 1 H) 7.05 (dd,>7.6,1.2 Hz, 1 II) 7.15 - 7.26 (m, 5 II) 7.39 (d, >8.2 ilz, 2 H) 7.61 (d, >9.0 Hz, l H) 7.74 (dd,./=9.0, 2.5 Hz. 1 H) 8.35 (d,>2.1 Hz, 1 H)
90	(500 MHz, DMSO-f/i) 0.71 (s, 9 H), 0.82 (s, 9 H), 1.40 (t,>l 1.5, i H), 1.53 (1,./=12.3 Hz, 1 H), 2.47 (d,./=4.4 Hz, 3 H). 2.56-2.71 (m, 3 H), 2.79 (dd,./=13.2,6.8 Hz, IH), 2.86 - 2.96 (ni, IH), 3.05 (s, 6 H), 3.41 -3.49()11, I H), 3.52(s, 3 H), 3.86 (q,>7.3 Hz, I H), 3.90(d, J=9.3 Hz, 1 H), 4.05 (d.>9.3 Hz, 1 H), 4.86 (d, >4.8 Hz, H), 6.71 (d,>8.9 Hz. 1 H), 6.83 (d,>9.6 Hz, 1 H), 6.98 (t,>7.5 Hz, 1 H), 7.04 (dd,>10.5,8.5 Hz, 1 H), 7.11 (t, >7.3 Hz, 1 H), 7.17-7.21 (m. 3 H), 7.40 (d, >8.0 Hz, 2 H), 7.45 (d.>9.5 Hz, i H), 7.61 (d,>8.8 Hz, 1 H), 7.72 - 7.80 (m, 2 H), 8.35 (d../=2.4 Hz, 1 H)
9Ι	(400 MHz, DMSO-d₆) 0.58 (d, >6.4 Hz, 3 H) 0.76 - 0.93 (m. 1 H) 0.81 (s, 9 H) 1.20 - 1.34 (ni, 2 H) 1.35 - 1.46 (m, 1 H) 1.47 - 1.66 (m, 5 H) 2.57- 2.89 (m, 5 H) 3.21 (1,,/=10.0 Hz, 1 H) 3.34 (br. s., i H) 3.51 (br. s., 1 H) 3.50 (s, 3 H) 3.88 (s, 3 H) 3.89 - 3.94 (m, 2 H) 4.23 (d, >2.7 Hz, 1 H) 4.87 (d,>4.5 Hz, 1 H) 6.80 (d,>9.8 Hz, l H) 6.89 (d,>8.8 Hz, 1 H) 7.15 (d,>9.2 Hz, 1 H) 7.18-7.23 (m, 3 H) 7.25 (d, >8.2 Hz, 2 H) 7.36 (dd, 1 H) 7.46 (d, >8.0 Hz. 2 H) 7.63 (d.>8,8 Hz, 1 H) 7.93 (dd,>8.6, 2.5 Hz. 1 H) 8.41 (d,>2.3 Hz, l H)
92	(400 MHz, CHLOROFORM-d) 0.91 (s, 9 H) 0.94 (s, 9 H) 1.65 - 1.76 (m, 1 H) 1.76-1.88 (m, 1 H) 2.65 (dd,>12.2, 5.6 Hz, 1 H) 2.84-2.97 (m, 4 H) 3.22 - 3.32 (m, 1 H) 3.34 (s, 3 H) 3.38 - 3.44 (m, 2 H) 3.44 - 3.55 (m, 1 H) 3.59 (s, 3 H) 3.63 - 3.69 (m, l H) 3.8373, ./=10.4 Hz, 1 H) 3.90 (d,./=9.2 Hz, 1 II) 3.97(s, 3 H) 4.10-4.l6(m, 1 H) 4.20 (d.>8.8 Hz, I H) 4.34 (br. s., 1 H) 5.50 (d, >8.6 Hz, 1 H) 6.18 (br. s„ 1 H) 6.51 (d,>8.8 Hz, 1 H) 6.63 (d,>8.4 Hz, l H) 6.71 (d, >9.8 Hz, 1 H) 6.75 -6.85 (in, 2 H) 6.78 (d,>8.4 Hz, 1 H) 7.10 (td,>7.8, 6.3 Hz, 1 H) 7.23 (d,./=7.8 Hz, 2 H) 7.36 (d,>7.8 Hz, 1 H) 7.70 (dd, >8.4, 1.6 Hz, IH) 8.31 (d,>1.8 Hz, 1 H)

-102-

Comp. N°	’H NMR (δ ppm)
93	(600 MHz, DMSO-4.) δ ppm 0.81 (s, 9 H), l .43 (ddd, J=l 3.2, 10.9,3.2 Hz, l H), 1.68 (t, J=l 1.9 Hz, l H), î.74 1.83 (m, l H), t.90 - 2.00 (ni, I H), 2.63 (dt, 7=16.4,4.7 Hz, I H), 2.66 - 2.74 (m, 2 H), 2.78 - 2.86 (ni, 3 H), 2.86 - 2.92 (ni, l H), 3.50 (s, 3 H), 3.55 (br. d, ./=10.0 Hz, 1 H), 3.77 (br. s., 1 H), 3.85 - 3.89 (m, 1 H). 3.89 (s, 3 H), 3.96 (hr. q, 7=7.8,7.8, 7.8 Hz, 1 H), 4.50 (d, >3.7 Hz, 1 H), 4.74 (br, s, 1 H), 4.84 (br. d,>8.9 Hz, l H), 6.58 (s, 1 H), 6.64 (d, 7=5.2 Hz, 1 H), 6.87 (d, >8.6 Hz, 1 H), 7.04 - 7.10 (m, 2 H), 7.12 (d,>5.2 Hz, 1 H), 7.20 - 7.23 (m, 1 H), 7.24 - 7.27 (m, 1 H), 7.28 (d, >7.8 Hz, 2 H), 7.47 (d,>7.8 Hz, 2 H), 7.50 (d,>9.1 Hz, 1 H), 7.58 (d, >8.8 Hz, 1 H), 7.92 (dd,>8.6, 2.6 Hz, 1 H), 8.40 (d, ./=2.6 Hz, 1 H)
94	(400 MHz, DMSO-</_fl) 0.59 (d, >6.4 Hz, 3 H) 0.80 (s, 9 H) 0.82 - 0.93 (m, 1 H) 1.21 - 1.41 (m, 3 H) 1.46 - 1.67 (m, 5 H) 2.54 - 2.66 (m, 2 H) 2.74 - 2.90 (m, 3 H) 3.20 (t, >10.3 Hz, 1 H) 3.34 (br. s., 1 H) 3.47 (br. s„ 1 H) 3.49 (s, 3 H) 3.83 - 3.91 (ni, 2 H) 3.88 (s, 3 H) 4.25 (d, >3.5 Hz, 1 H) 4.81 (d,>5.1 Hz, 1 H) 6.75 (d,./=9.6 Hz. 1 H) 6.89 (d,>8.6Hz, 1 H) 7.10 (s, 1 H) 7.15 (d,>7.2 Hz, 2 H) 7.25 (d, >8.2 Hz, 3 H) 7.36 (t, >8,0 Hz, 1 H) 7.46 (d, >8.2 Hz, 2 H) 7.63 (d, 7=8.8 Hz. 1 H) 7.94 (dd,./=8.7,2.6 Hz, 1 H) 8.41 (d,>2.1 Hz, 1 H)
96	(400 MHz, DMSO-î4) 0.58 (d, >6.4 Hz, 3 H) 0.81 (s, 9 H) 0.80 - 0,88 (m, 1 H) 1.21 - 1.65 (m, 8 H) 2.59 - 2.84 (m, 5 H) 3.15 - 3.24 (in, 1 H) 3.29 - 3.36 (m, 1 H) 3.48 (br. s., 1 H) 3.49 (s, 3 H) 3.83 - 3.89 (ni, 2 H) 3.88 (s, 3 H) 4.22 (d,>3.3 Hz, 1 H) 4.82 (d,>4.9 Hz, 1 H) 6.78 (d, ./=9.4 Hz, 1 H) 6.89 (d,./=8,6 Hz, 1 H) 7.05 (dd,>7.4, 1.2 Hz, l H) 7.09 (d, >9.4 Hz, 1 H) 7.15 - 7.27 (ni, 3 H) 7.24 (d,>8.2 Hz, 2 H) 7.45 (d,>8.2 Hz, 2 H) 7.62 (d,7=9.0 Hz, 1 H) 7.93 (dd, 7=8.6,2.5 Hz, 1 H) 8.40 (d, 7=2.1 Hz, 1 H)
98	(400 MHz, DMSO-4;) 0.72 (s, 9 H) 0.82 (s, 9 H) 1.38 - 1.48 (ni, 1 H) 1.53 - 1.62 (m, 1 H) 2.62 - 2.74 (m, 2 H) 2.75 - 2.86 (m, 2 1 1) 2.89 - 2.98 (m, 1 H) 3.02 - 3.18 (ni, 2 H) 3.21 (s, 3 H) 3.25 (t,7=5.9 Hz, 2 H) 3.51 (s, 3 H) 3.48 (br. s., 1 H) 3.88 (s, 3 H) 3.91 (d,7=9.6 Hz, 2 H) 4.12 (d,7=9.6 Hz, 1 H) 4.93 (br. s., 1 H) 6.84 (d, 7=9.6 Hz, 1 H) 6.90 (d,7=8.6 Hz, 1 H) 7.09 - 7.21 (m, 3 H) 7.25 (d,7=8.0 Hz, 2 H) 7.35 (d, 7=7.8 Hz, 1 II) 7.43 (d, 7=10.0 Hz, 1 H) 7.46 (d, 7=8.0 Hz, 2 H) 7.64 (d,7=8.8 Hz, 1 H) 7.94 (dd, 7=8.5, 2.6 Hz, 1 H) 7.94 (br. s„ 1 H) 8.4 Hd, 7=2.1 Hz, I H)
99	(400 MHz,DMSO-î/₆)δppm 0.72(d,7=6,0Hz, 3 H)0.80 (s,9 H)0.90- 1.03(m, 1 H) 1.31 - 1.47 (m, 2 H) 1.47- 1.59 (m, 1 H) 1.66- 1.85 (m, 3 H) 2.58 - 2.69 (m, 2 H) 2.71-2.85 (m, 3 H) 3.35 - 3.43 (m, 1 H) 3.44 - 3.52 (nt, 1 H) 3.49 (s, 3 H) 3.65 - 3.72 (m, 1 H) 3.83 - 3.93 (m, 2 H) 3.88 (s, 3 II) 4.40 (d,,7=3.7 Hz, 1 H) 4.86 (d,7=5.1 Hz, 1 H) 6.76 (d,7=9.4 Hz, 1 H) 6.89 (d, 7=8.8 Hz, 1 H) 7.08 (d, 7=6.6 Hz, 2 H) 7.12 - 7.23 (m, 3 H) 7.25 (d,7=8.2 Hz, 2 H) 7.45 (d, 7=8.2 Hz, 2 H) 7.62 (d, 7=8.6 Hz, 1 H) 7.93 (dd, 7=8.7, 2.6 Hz, 1 H) 8.41 (d, 7=2.3 Hz, 1 H)

-J03-

Comp. N°	'11 NMR (δ ppm)
100	(400 MHz, DMSO-/4) δ ppm 0.81 (s, 9 H) 0.99 - 1.67 (m, 10 H) 2.55 - 2.87 (m, 5 H) 3.36 3.46 (m, 2 H) 3.46 - 3.50 (m, i H) 3.50 (s, 3 H) 3.80 - 3.93 (m, 2 H) 3.88 (s, 3 H) 4.42 (d, >2.7 Hz, 1 H) 4.86 (d,>4.3 Hz, 1 H) 6.79 (d, 7=9.6 Hz, 1 H) 6.89 (d, 7=8.6 Hz, 1 H) 7.01 7.13 (m, 2 H) 7.13 - 7.24 (m, 3 H) 7.25 (d, 7=7.8 Hz, 2 H) 7.47 (d, 7=7.6 Hz, 2 H) 7.61 (d, 7=8.4 Hz, 1 H) 7.95 (d,7=8.6 Hz, 1 H) 8.35 - 8.50 (m, l H)
102	(400 MHz, DMSO-7₆) 0.78 (s, 9 H) 1.38- 1.51 (m, 1 H) 1.63 - 1.75 (in, 1 H) 2.10 (s, 3 H) 2.63 - 2.88 (m, 4 H) 2.96 (m, 7=6.8 Hz, 1 H) 3.48 (s, 3 H) 3.61 (br. s., 1 H) 3.69 (br. s., 1 H) 3.88 (s, 3 H) 3.89 - 3.91 (ni, 1 H) 3.93 (br. s., 1 H) 4.06 - 4.17 (m, 2 H) 4.87 (d,7=4.5 Hz, 1 H) 5.03 - 5.10 (ni, l H) 5.15 (br. s., 1 H) 6.61 - 6.72 (m, 2 H) 6.88 (d,7=8.4 Hz, 1 H) 6.84 6.90 (m, 1 H) 7.03 - 7.14 (ni, 2 H) 7.20 - 7.31 (m, 4 H) 7.42 (s, 2 H) 7.62 (d, 7=9.0 Hz, 1 H) 7.84 (d, 7=8.8 Hz, 1 H) 7.90 (dd,7=8.6,2.5 Hz, 1 H) 8.38 (d.7=2.3 Hz, i H)

Biological Exemptes

General Antiviral Assay

MT4-LTR-EGFP cells were obtained by transfecting MT4 cells with a selcctable construct cncompassing the séquences coding for the HIV long terminal repeat (LTR) as a promoter for the expression of enhanced green fluorescent protein (EGFP) and subséquent sélection ofpermanently transfccted cells.

The antiviral activity on different HIV-l strains, was determined in a cell-bascd virus réplication assay. Here MT4-LTR-EGFP cells (150,000 cells/ml) arc infectcd o (multiplîcity of infection [MOI] of 0.0025) in the présence or absence of different inhibitor concentrations. Two méthodologies for rcad-out were used, either quantification of GFP-fluorcscnce on day 3 post-infection, or quantification of cellviability using rezazurin (as described by Ficlds, R. D„ and Μ. V. Lancaster (1993) Am. Biotcchnol. Lab. 11:48-50) on day 4 post infection. Both methods showed similar dosc-rcspons curves from which EC50s could be determined.

General Toxicity Assay

The toxicity of inhibitors is determined in parallel on mock-infccted MT4 cells (150,000 cclls/ml) stably transformed with a CMV-EGFP reporter gene and eultured in 20 the presence or absence of test compound concentrations. Two méthodologies for rcadout were used, either quantification of GFP-fluorescnce on day 3, or quantification of cell-viability using rezazurin on day 4. Both methods showed similar dosc-respons curves from which CC50s could be determined.

-10450% HS- Rezazurin

For the Antiviral assay in the presence of 50% human sérum MT-4 cells were infectcd with HIV-l IIIB at a MOI of 0,001 to 0.01 CCID50/ccll in RPMH640 medium. Following l h of incubation, cells were washed and platcd into a 96-well plate containing serial dilutions of compound in the presence of 10% fêtai calf sérum (FCS), or 50% human sérum. After 4 days incubation, the EC50 in the presence of 50% human sérum was determined by a cell viability assay using rcsazurin.

Table 4

Kl In the following Table, Strains A, B, and C arc clinical isolâtes that include the following protease inhibitor résistance mutations in the protease domain (background mutations arc not mentioned).

B M0461 I050V

A M0461 J084V

C G048G/V V082A

The last column lists the results for the wild-type strain ΠΒ in the presence of 50% human sérum MT-4 cells.

Comp. N°	HIV- IIIB	TOX- MT4CMV	TOX- MT4LTR	A	B	C	HIV-IllB + 50%HS
	nM	μΜ	μΜ	ECso, iiM	ECjo, nM	EC50, nM	EC50, nM
I	7.7	>32		5.7	4.8	3.7	39.3
2	3.0	>32		3.3	2.2	l.l	19.7
3	2.6	>32		2.3	3.5	2.4	13.6
4	5.6	>32		3.9	3.9	2.7	31.2
	4.7	>32		5.4	4.4	5.1	28.6
6	3.2	>32		3.9	2.7	1.5	15.2
7	1.6	>32	>49.	1.5	0.9	0.8	10.4
8	1.8	>32	>49	2.0	1.2	l.O	12.4
9	8.8	>27		8.8	6.6	3.7	31.7
10	3.2	>32		4.0	2.5	1.7	20.)
11	4.2	>32		3.9	3.5	2.1	22.4
12	4.0	>32		3.7	3.0	2.2	35.7
I3	4.7	>32		4.6	3.0	2.4	22.6
I4	3.0	>32		3.5	2.1	1.3	24.6

-105-

Comp. N°	HIV- ΙΓΙΒ	TOX- MT4CMV	TOX- MT4LTR	A	B	C	HIV-I1IB + 50%HS
15	2.0	>32		2.1	1.2	1.3	8.7
16	2.5	>32		2.0	1.3	1.1	6.6
17	1.9	>32		2.0	1.2	1.1	6.4
18	2.7	>32	>32	3.0	2.0	1.6	14.0
19	5.3	>27		3.7	2.4	1.8	22.1
20	3.1	6		7.4	3.1	2.7	11.2
21	6.1	>32		3.8	3.2	3.6	34.9
22	3.8	>32		3.5	2.6	2.1	26.4
23	3.0	19		3.7	2.4	2.0	12.3
24	3.3	>32		3.3	1.9	1.7	16.1
25	4.9	>32		4.6	2.7	2.5	26.4
26	5.0	>32		4.2	3.4	3.2	15.4
27	3.1	>32	>32	2.8	2.2	1.6	10.7
28	3.2	>32		3.1	2.1	1.4	22.5
29	5.5	10		6.6	3.4	3.1	13.7
30	4.0	>32		5.9	2.8	2.5	17.4
31	7.0	>32		5.0	3.2	3.4	26.4
32	5.9	2.2		5.0	3.7	3.1	28.6
33	2.5	>32		1.5	1.0	0.9	9.8
34	2.7	>32	>32	2.0	1.5	1.3	10.0
35	2.1	>32	>32	4.0	2.2	2.0	8.4
36	2.9	>32	>32	2.4	1.4	1.3	14.3
37	1.7	>32	>32	2.5	0.9	0.8	4.6
38	7.1	10		4.4	3.6	2.6	37.9
39	3.0	>32	>32	3.9	2.1	1.3	16.4
40	2.4	>32	>32	1.6	1.0	0.8	11.2
41	3.0	>32	>32	2.4	1.2	1.1	10.5
42	4.2	>32	>32	7.2	4.1	3.9	23.7
43^	2.0		>32	1.7	1.0	1.1	10.6
44	3.2		>32	3.2	2.2	2.0	13.7
45	3.5		>32	1.2	0.8	0.7	5.2
46	5.3		10	9.4	5.6	3.7	34.6
47	3.2		>32	11.1	6.8	5.5	10.4
48	3.8		>32	2.6	2.2	1.3	7.5
49	4.1		>32	5.2	3.5	2.9	19.0

-106-

Comp. N°	HIV- IIIB	TOX- MT4CMV	ΊΌΧ- MT4LTR	A	B	C	HIV-ΙΠΒ + 50%HS
50	2.8		>32	2.0	1.4	1.1	6.9
51	3.0		>32	2.3	1.5	1.3	7.0
52	1.8		>32	1.2	0.9	0.7	6.2
53	2.3		>32	4.1	2.0	2.0	9.5
54	4.8		>32	2.7	2.1	1.6	19.8
55	2.7		>32	2.1	1.5	1.2	12.5
56	2.6		>32	1.4	1.2	0.7	8.4
57	I.9		>32	1.9	0.9	0.8	8.7
58	3.9		>32	6.0	2.5	1.8	13.3
59	I.2		>32	0.9	0.6		5.8
60	4.1		10	2.6	1.9	1.2	25.2
61	4.1		>32	3.0	2.1	1.6	16.1
62	3.2		>32	2.2	1.5	0.9	16.3
63	I.5		>32	1.2	0.7	0.6	9.4
64	2.6		>32	3.0	1.6	1.3	15.1
65	9.1		>32	4.5	3.6	2.3	24.7
66	0.9		>32	0.8	0.8	0.5	7.7
67	2.9	>32	>32	2.1	1.2	1.0	5.3
68	3.0	>32		2.2	1.5	1.3	9.4
69	ll.6	>32		11.6	7.0	5.7	26.6
70	2.6	>32	>32	1.6	1.6	1.2	11.4
71	2.1	>32	>32	2.2	2.3	1.0	10.9
72	1.5		>32	0.8	0.8	0.5	5.8
73	3.3		>32	3.7	4.1	1.9	9.2
74	0.9		>32	0.8	0.6	0.4	3.5
75	2.4 -		>32	1.4	0.9	0.8	9.3
76	2.9		>32	1.7	1.5	1.1	20.5
77	I.9		>32	1.6	1.0	0.7	6.5
78	2.1		>32	1.9	1.4	0.9	10.6
79	1.7		>32	1.1	1.0	0.7	12.8
80	2.4		>32	1.5	1.1	0.8	10.9
81	4.1		>32	2.8	2.4	1.3	13.4
82	1.8		>27	l.l	0.8	0.7	5.1
83	4.0	>32		8.3	2.5	2.7	14.3
84	6.4	>32		4.7	3.3	2.4	28.0

-107-

Comp, N°	HIV- ΠΙΒ	TOX- MT4CMV	TOX- MT4LTR	A	B	C	HIV-IIIB + 50%HS
85	2.9	>32	>32	3.0	1.3	l.l	97.5
86	2.6		>32	7.5	1.4	1.3	I7.l
87	4.7	>32		8.0	9.9	5.4	14.4
88	3.4	>32		4.8	2.8	3.0	9.9
89	l.l	>32	>32	l.l		0.8	4.9
90	4.7	>32		4.8	2.6	2.8	93.6
91	l.l	17	96	2.6	0.7	l.O	3.2
92	2.6	>32	>32	4.2	1.8	2.9	8.4
93	1.3	>32	>32	0.8	0.6	0.4	3.5
94	0.9		>32	1.9	0.8	9.4	7.1
95	1.5		23	2.2	1.3	l.O	5.9
96	0.9		>32	0.7	0.4	0.5	2.0
97	5.6		>32	4.7	2.8	2.0	12.7
98	2.1		>32	3.7	l.O	2.2	ll.2
99	l.l		>32	1.7	0.6	0.9	3.3
IOO	1.8		>32	I.8	0.7	0.8	5.9
iOl	2.8		>32	2.5	2.4	1.7	9.8
102	2.3		>32	5.4	3.3	1.5	6.8
LPV	13	20	>32	HO	320	31	69
ATV	7.6	26	>32	59	3.3	62	16

Claims

Claims

l. A compound formula I:

, wherein

R¹ is halo, Oalkoxy, trifluoiomcthoxy;

5 R¹ is a group of formula:

ÔH

R? is a group of formula:

10 R⁴ is a group of formula:

A

R⁹ n is 0 or 1 ;

each A independently is CH or N;

R^s and R⁶ independently arc hydrogen, Cualkyl, or halo;

15 R⁷ is C|.₄alkyl or Ci^alkoxyCualkyl;

R⁸ is CMdlkyl or CMalkoxyCMalkyl;

-109each R⁹ independently is Ci^alkyl, cyclopropyl, trifluoromethyl, C'Malkoxy, or dimethylamino;

R^lü is hydrogen, C;^alkyl, cyclopropyl, trifluoromethyl, Ci^alkoxy, or dimcthylamino; R¹¹ is hydrogen or Ci-^alkyl;

5 the pharmaceutically acceptable addition salts and the pharmaceutically acceptable solvatés thereof.
2. The compound of claim 1 wherein R¹ is halo or methoxy.

10
3, The compound of claim 1 wherein R¹ is fluoro or chloro; which fluoro or chloro is substituted în ortho position; or R¹ is methoxy; which methoxy is substituted in meta position.
4. The compound of any ofclaims 1 to 3, wherein R² is a group of formula

R⁵ Λ (^{z or} Y J., Az^r6î Ί ^or sό '-··' * 15 ÔH ÔH ÔH
5. The compound of any of claims 1 to 3, wherein R² is a group of formula

ÔH
6. The compound of any of claims 1 to 5, wherein

20 R⁵ is hydrogen, and R⁶ is halo or C_Malkyl; R^s is halo and R⁶ is hydrogen; R⁵ is halo or Cwalkyl, and R⁶ is hydrogen; or R^s and R⁶ arc both hydrogen, or arc both halo; R¹¹ is Cj-ialkyl.
7. The compound of any of claims 1 to 5, wherein

25 R^s is hydrogen and R⁶ is fluoro or chloro; R⁵ is fluoro or chloro and R⁶ is hydrogen; R^sis hydrogen and R⁶ is methyl; R^s and R⁶ arc both hydrogen, or R⁵ is chloro and R⁶ is fluoro; more in particular wherein R^s is hydrogen and R⁶ is fluoro; R⁵ is chloro and R⁶

-HOis hydrogen; R⁵ is hydrogen and R⁶ is methyl; R⁵ and R⁶ are both hydrogen, or R^s is chloro and R⁶ is fluoro; and

Rⁿ is methyl.

5
8. The compound of any of claims 1 to 7, wherein R³ is a group of formula
9. The compound of any of claims 1 to 7, wherein R³ is a group of formula
10 10. The compound of claim 9 wherein R⁸ is methyl or 2-methoxyethyl.
11. The compound of claims 1-10 wherein R⁹ is CMalkoxy or dimethylamino.
12. The compound of any of claims I to H, wherein R⁴ is a group having the chemical

15 structure spccificd in claim 1, but wherein in the first group R⁹ is R⁹“ in the second group R⁹ is R^9b in the third group R⁹ is U^9c in the fourth group R⁹ is R^9d in the fifth and in the sixth group R⁹ is R^9c ; which groups can be represented as follows:

wherein each A independently is CH or N; or wherein each A is CH;

20 R^,fl is Ci^alkoxy or dimethylamino;

R⁹¹’ is CMalkoxy or dimethylamino;

R^9c is CMalkoxy or dimethylamino;

R^9d is CMalkyl, cyclopropyl, trifluoromethyl;

R¹⁰ is hydrogen, CMalkyl, cyclopropyl, or trifluoromethyl; or R^1C is hydrogen, methyl,

25 cyclopropyl, or trifluoromethyl;

each R^9f independently is CMalkyl, cyclopropyl, CMalkoxy, or dimethylamino.

-lll-
13. The compound of claim 12 wherein in R’“, R^9h, R⁹', R^9d, or R⁹' C|₄alkoxy is methoxy and C|_4alkyl is methyl
14. The compound of any of claims i to 7 wherein R*¹ is:

R^9a

A wherein A is CH and R^9u is methoxy or dimethylamino.
15, The compound ofclaim 1 having the formula
16. The compound of claim I having the formula

-112-
17. The compound of claim l having the formula
18. A compound as claimed in any one ofclaims l-17 for use as a mcdicinc.
19. A pharmaceutical composition comprising an effective amount of a compound of formula I as defined in any of daims l - 17 and a carrier.