OA17199A

OA17199A - Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B.

Info

Publication number: OA17199A
Application number: OA1201500046
Authority: OA
Inventors: Koen Vandyck; Stefaan Julien Last; Geert Rombouts; Wim Gaston Verschueren; Pierre Jean-Marie Bernard Raboisson
Original assignee: Janssen Sciences Ireland Uc
Priority date: 2012-08-28
Filing date: 2013-08-28
Publication date: 2016-04-05

Abstract

Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B. Inhibitors of HBV replication of formula (I)

Description

SULFAM0YL-ARYLAM1DES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B.

Background Art

The Hepatitis B virus (HBV) is an cnveloped, partiaily double-stranded DNA (dsDNA) virus of the Hepadnaviras family (Hepadnaviridaé). Its gcnome contains 4 overlapping reading frames: the precorc/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 envelope proteins; and the X gene.

Upon infection, the partiaily double-stranded DNA genomc (the relaxed circular DNA; 10 rcDNA) is converted to a covalcntly closed circular DNA (cccDNA) in the nucléus of the host cell and the viral mRNAs are transcribcd. Once encapsidated, the pregenomie RNA (pgRNA), which also codes for core protein and Pol, serves as the tcmplate for reverse transcription, which regenerates the partiaily dsDNA gcnome (rcDNA) in the nuclcocapsid.

HBV has caused épidémies in parts of Asia and Africa, and it is endemic in China.

HBV has infected approximately 2 billion people worldwide of which approximately 350 million people hâve developed chronic infections. The virus causes the disease hepatitis B and chronic infection is correlated with a strongly increased risk for the development cirrhosis and hepatocellular carcinome,

Transmission of hepatitis B virus results from exposure to infectious blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titer DNA in sérum.

An effective and well-tolcrated vaccine exists, but direct treatment options arc currently 25 limited to interferon and the following antivirals; tenofovir, lamivudine, adefovir, cntccavir and telbivudine.

In addition, heteroaryldihydropyrimidines (HAPs) were identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78).

WO2013/006394, published on January 10,2013, and WO2013/096744, published on June 27,2013 relate to subclasses of Sulphamoyl-arylamides active against HBV.

Amongst the problème which HBV direct antivirals may encounter are toxicity, mutagenicity, lack of selectivity, poor efïïcacy, poor bioavailability and diffïculty of synthesis.

-2There is a need for additional HBV inhibitors that may overcome at least one of these disadvantages or that hâve additional advantages such as increased potency or an increased safety window.

Description of the Invention

The présent invention relates to compounds of Formula (I) (D or a stereoisomer or tautomeric form thereof, wherein:

B represents a monocyclic 5 to 6 membered aromatic ring, optionally containïng one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, CN, CFH₂, CF₂H and CF₃;

Ri represents hydrogen or Ci-C₃alkyl;

R₂ represents Ci-Cealkyl, Ci-Cealkenyl, Ci-Cialkyl-Rj, C(=O)-R5, CFH₂, CF₂H, CFj.a dihydro-indenyl or tetrahydronaphtalenyl moiet y optionally substituted with OH, or a 3-7 membered saturated ring optionally containïng one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring, Ci-Cialkyl-Rjor Ci-Cialkyl optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C4alkyloxy, Ci-C4alkyloxycarbonyl, oxo, C(=O)-Ci-CjaIkyI, Ci^alkyl, OH, CN, CFH₂, CF₂H and CF₃;

Or Ri and R₂ together with the Nitrogen to which they are attached form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, such bicyclic, bridged or saturated ring moiety optionally containïng one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C4alkytoxy, Ci-C4alkyloxycarbonyl, oxo, C(=O)-Ci-C₃ alkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CF₃;

-3Each R4 is independently selected from hydrogen, halogen, Ci-C₄alkyloxy, Ci-C₄alkyl, C|-C₄alkenyl, OH, CN, CFH2, CF2H, CF3, HOC or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N, such Ci-C₄alkyl optionally substituted with OH;

Rs represents Ci-Cealkyl, CFH2, CF2H, CFj, phenyl, pyridyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C|-C₄alkyloxy, C|-C₄alkyloxycarbonyl, oxo, C(=O)-C|-C3alkyl, C|-C₄alkyl, OH, CN, CFH2, CF₂H and CF3;

or a pharmaceutically acceptable sait or a solvaté thereof.

The invention further relates to a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable carrier.

The invention also relates to the compounds of Formula (I) for use as a médicament, preferably for use in the prévention or treatment of an HBV infection in a mammal.

In a further aspect, the invention relates to a combination of a compound of Formula (I), and another HBV inhibitor.

Définitions

The term C 1.3alkyl or Ci-Cjalkyl as a group or part of a group refers to a hydrocarbyl radical of Formula CJLn+i wherein n is a number ranging from 1 to 3. In case Ci^alkyl is coupled to a further radical, it refers to a Formula Cn^n., Ctjalkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Ci. salkyl includes ail linear, or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, and i-propyl. Ci^alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from I to 4 carbon atoms such as the group defined for Cualkyl and butyl and the like.

Ci^alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defïned for Cualkyl and pentyl, hexyl, 2-methylbutyl and the like.

Ci^alkenyl as a group or part of a group dcfincs straight or branched chain hydrocarbon radicals having front 1 to 4 carbon atoms with at least one double bond at any possible position. Examples of such alkenyls are ethenyl, propenyl, 1-butenyl,

2-butcnyl. Ci ^alkenyl as a group or part of a group defînes straight or branched chain 5 hydrocarbon radicals having from 1 to 6 carbon atoms with at least one double bond.

The term “Ci-îalkyloxy as a group or part of a group refera to a radical having the Formula —OR* wherein R* is Cualkyl. Non-limiting examples ofsuitable Cijalkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.

The term oxo, C(=O), or carbonyl refera to a group composed of a carbon atom double bonded to an oxygen atom.

As used herein, the term “3-7 membered saturated ring” means saturated cyc lie hydrocarbon with 3,4,5,6 or 7 carbon atoms and is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Such saturated ring optionally contains one or more heteroatoms, such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N 20 and O. Examples include oxetane, azetîdine, tetrahydro-2H-pyranyl, pîperidinyl, tetrahydrofûranyl, morpholinyl and pyrrolidinyl. Preferred are saturated cyclic hydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxetane and tetrahydrofûranyl.

As used herein, the term monocyclic 5 to 6 membered aromatic ring (“aryl”), means an aromatic cyclic hydrocarbon with 5 or 6 carbon atoms. A preferred example of an aryl group is phenyl.

Such saturated ring optionally contains one or more heteroatoms each independently , selected from the group consisting of O, S and N(hctcroaryl) For the purposes of the 30 invention, a heteroaryl group need only hâve some degree of aromatic character.

Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thîazolyl, isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted or substituted with 35 one or more suitable substituents.

As used herein, the term 6-10 membered bicyclic ring indicates a saturated bi-cyclîc ring with 6-7-8-9 or 10 atoms. Such saturated bi-cyclic ring optionally contains one or

-5more heteroatoms, such that at least one carbon atom is rcplaced by a heteroatom selected from N, O and S, in particular from N and O.

Examples of such 6-10 membered bicyclic ring as used herein areanl,4-dioxa-8 aza$piro[4.5] dccyl moiety indïcating a group with structural formula

structural formula a 6-Oxa-2-azaspiro[3.4]octane moiety indicating a group with

a 2-oxa-6-azaspiro[3.3]heptyl moiety indïcating a group with structural formula oCK or a 6-oxa-l-azaspiro[3.3]heptyl moiety with structural formula

As used herein, the term 6-10 membered bridged ring indicates a saturated bridged ring with 6-7-8-9 or 10 atoms. Such saturated bi-cyclic ring optionally contains one or more heteroatoms, such that at least onc carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N and O. An example of such 6-10 membered bridged ring as used herein is -oxabicyclo[2.2.l]heptan represented by structure

As used herein, a dihydroindenyl moiety represents a group with structural formula

. Such dihydroindenyl moiety can be optionally substituted with OH. One example as used herein, a 2-hydroxy-2,3-dihydro-lH-indenyl moiety, indicates a group with structural formula

As used herein, a tetrahydronaphtalenyl moiety represents a group with structural formula

If not indicated, for any of the moieties above, the attachaient to the main structure may be anywhere on such moiety as long as it is chemically stable.

It should be noted that different isomers of the various heterocycles may exîst within the définitions as used throughout the spécification. For example, pyrrolyl may be

1 H-pyrrolyl or 2H-pyrrolyl.

The term halo and halogen are generic to fluoro, chlore, bromo or iodo. Preferred halogens are fluoro and Chlore.

It should also be noted that the radical positions on any molecular moiety used in the définitions may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl indudes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl indudes 1-pentyl,

2-pcntyl and 3-pentyl.

Positions indicated on phenyl (e.g. ortho, meta and/orpara) are indicated relative to the bond connecting the phenyl to the main structure. An example with regard to the

position of R4, any location is indicated relative to the nitrogen (*) connected to the main structure:

When any variable (e.g. halogen or CMalkyl) occurs more than one time in any constituent, each définition is indepcndent.

For therapeutic use, the salts of the compounds of formula (I) are those wherein the counter ion is pharmaceuticaily or physiologically acceptable. However, salts having a 10 pharmaceuticaily unacceptable counter ion may also find use, for example, in the préparation or purification of a pharmaceuticaily acceptable compound of formula (I). ΑΠ salts, whether pharmaceuticaily acceptable or not are included within the ambit of the présent invention.

The pharmaceuticaily acceptable or physiologically tolerable addition sait forms which the compounds of the présent invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fuma rie, malïc, tartaric, citric, methanesuifonic, ethanesulfonîc, benzenesulfonic.p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

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

The term “salts also comprises the hydrates and the solvent addition forms that the compounds of the présent invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The présent compounds may also exist in their tautomeric forms for example, tautomeric forms of amide (-C(=O)-NH-) groups are iminoalcohols (-C(OH)=N-). Tautomeric forms, although not explicit ly indicated in the structural formulae

represented herein, are intended to be included within the scopc of the présent invention.

The term stereochemically isomeric forms of compounds of the présent invention, as used hereinbefore, de fi nés ail possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensiona! structures which are not interchangeable, which the compounds ofthe présent invention may possess. Unless otherwise mentioned or indicated, the chemical désignation of a compound encompasses the mixture of ail possible stereochemically isomeric forms which said

I0 compound may possess. Said mixture may contain ail diastereomers and/or enantiomers ofthe basic molecular structure ofsaid compound. Al! stereochemically isomeric forms of the compounds of the présent invention both in pure form or in admixture with each other are intended to be embraced within the scope of the présent invention.

I5

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free ofother enantiomeric or diastereomerie forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoiso mcrically pure' conccms compounds or intermediates having a stereoisorncric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomerie excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the sélective crystallization of their diastereomerie salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Altematively, enantiomers may be separated by chromatographie techniques using chiral stationary phases. Saîd pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a spécifie

stereoisomer is desircd, said compound will be synthesized by stercospccifîc methods ofpréparation. These methods will advantageously employ enantiomerically pure starting materiais.

The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical séparation methods that may advantageously be employed are, for example, sélective crystallization and chromatography, e.g. column chromatography.

The présent invention is also intendcd to include ail isotopes of atoms occurring on the présent compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Detailed description of the invention

Whcncver used hcreïnafler, the term “compounds of formula (I)”,

or “the présent compounds” or similar term is mcant to include the compounds of general formula (I),(I*), (la) ,(lb),(Ic) and (Id), salts, stercoïsomeric forms and racemic 20 m ixtures or any subgroups thereof.

Compounds for use in the prévention or treatment of an HBV infection in a mammal are disclosed as compounds per se and not limited to this use unlcss rcstrictcd by the daims.

The présent invention relates to compounds of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

B représente a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substîtuted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C₃alkyl, CN, CFH₂, CF₂H and CF₃;

Ri represents hydrogen or Ci-Cjalkyl;

R₂ represents Ci-C₆alkyl, Ci-C_ealkenyl, Ci-C_ealkyl-R₃, C(=O)-Rj, CFH₂, CF₂H, CF₃,a 10 dihydro-indenyl or tetrahydronaphtalenyl moïety optionally substîtuted with OH, or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring, Ci-Cealkyl-Rj or Ci-Cealkyl optionally being substîtuted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C^alkyloxy, Ci-C4alky!oxycarbonyl, oxo, C(=O)-Ci-C₃alkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CF₃;

Or R| and R₂ together with the Nitrogen to which they are attached form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, such bicyclic, bridged or saturated ring moiety optionally containing one or more additional 20 heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substîtuted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C^alkyloxy, Ci-C^alkyloxycarbonyl, oxo, C(=O)-Ci-C₃alkyl, Q-Qalkyl, OH, CN, CFH₂, CF₂H and CF₃;

Each R4 is independently selected from hydrogen, halogen, Ci-C₄alkyloxy, C)-C₄alkyl, Ci-C4alkenyl, OH, CN, CFH₂, CF₂H, CF₃, HC=C or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N, such Ci-C₄alkyl optionally substîtuted with OH;

Rj represents Ci-Cô alkyl, CFH₂, CF₂H, CF₃₎phenyl, pyridyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substîtuted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Cj-C^alkyloxy,

Ci-C₄alkyloxycarbonyl, oxo, C(=O)-Ci-C₃alkyl, Ci-C4alkyl, OH, CN, CFH₂, CF₂H and CF₃;

or a pharmaceutically acceptable sait or a solvaté thereof.

-11In a first aspect, the invention further provides compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

B represents a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C₃alkyl, CN, CFH₂, CF₂H and CF₃;

Ri represents hydrogen or C|-C₃alkyl;

R₂ represents Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkyl-Rs, C(=O)-Rj, CFH₂, CF₂H, CF₃,a

2-hydroxy-2,3-dihydro-1 H-indenyl moiety or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring, Ci-CealkylRs or Ci-Cealkyl optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-Cxalkyl20 oxy, Ci-C^alkyloxycarbonyl, oxo, C(=O)-C|-C₃ alkyl, Ci-C<alkyl, OH, CN, CFH₂, CF₂H and CF₃;

Or Ri and R₂ together with the Nitrogen to which they are attached form a l,4-dioxa-8-azaspiro[4.5]decyl moiety, a 2-oxa-6-azaspiro[3.3]hcptyl moiety or a 5-7 membered saturated ring optionally containing one or more additions!

heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C^alkyloxy, Ci-C^alkyloxycarbonyl, oxo, C(=O)-Ci-C₃alkyl, Cj-C^alkyl, OH, CN, CFH₂, CF₂H and CF₃;

Each Ri is independently selected from hydrogen, halogen, Ci-C^alkyloxy, Cj-C^alkyl, Cj-C^alkenyl, OH, CN, CFH₂, CF₂H, CF₃, HC=C or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N, such Cj-C^alkyl optionally substituted with OH;

-12Rs représente Cj-Cealkyl, CFH2, CF2H, CFj.phenyl, pyndyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C)-C4alkyloxy, C)-C4alkyloxycarbonyl, oxo, C(=O)-C)-Cjalkyl, Ci-Cialkyl, OH, CN, CFH2, CF2H and CF3;

or a pharmaceutically acceptable sait or a solvaté thereof.

In one embodiment, at least one R« représente Fluor, and one other R* is selected from the group consisting of Ci-Cjalkyl, Cj-Cjalkenyl, CHF2 or cyclopropyl.

In a sub-embodiment, one R« représente Fluor and one other R4 is selected from the group consisting of methyl or CHF₂, preferably methyl, and wherein the location of said Fluor is on the para position and the location of said methyl or CHF2 is on the meta position related to the Nitrogen(*) as indicated In Formula (I*) below.

least one R4 représente Fluor, and one other R* is selected from the group consisting of Ci-Cgalkyl, Ci-Cîalkenyl, CHF2 or cyclopropyl; more preferably, one R4 représente Fluor and one other R4 is selected from the group consisting of methyl or CHF2 and wherein the location of said Fluor is on the para position and the location of said methyl or CHF2 is on the meta position related to the Nitrogen (*) and R2 représente a

4-7 membered saturated ring containing carbon and one or more oxygen atoms, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C^alkyloxy, Ci-Qalkyloxycarbonyl, C(=O)-C|-Cjalkyl, Ci-C<ialkyl, OH, CN, CFH2, CF₂H and CFj.

In yet another embodiment, compounds are disclosed wherein one R« on the para position représente Fluor and the other one R4 on the meta position représente methyl and such compound is not

In another embodiment of the présent invention, compounds according to Formula (I) are provided wherein R₂ represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently seiected from the group consisting of hydrogen, halogen, Cj-C₄alkyloxy, Ci-C₄alkyloxycarbonyl, C(=O)-Ci-C₃alkyl, C|-C₄alkyl, OH, CN, CFH₂, CF₂H and CF₃. A preferred substituent for such a 4-7 membered saturated ring containing carbon and one or more oxygen atoms is Cj-C₄alkyl. In a sub-embodiment, the saturated ring is a 4,5 or 6 membered ring.

In another embodiment of the présent invention, compounds according to Formula (I) are provided wherein R2 represents a 4-7 membered saturated ring containing carbon and one or more nitrogen atoms, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently seiected from the group consisting of hydrogen, halogen, Cj-C₄alkyloxy, Ci-C₄alkyloxycaibonyl, C(=O)-Ci-C₃aIkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CFj.In a further embodiment,

R₂ represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such 4-7 membered saturated ring optionally being substituted with one or more halogen, C_rC₄alkyloxy, Ci-C₄alkyloxycarbonyl, C(=O)-C_rC₃alkyl, C_rC₄alkyl, OH, CN, CFH₂, CF₂H and CF₃ wherein such compound is not

Prcferably, any optional substituent on such 3-7,4-7 and 5-7 membered saturated ring,

6-10 membered bicyclic or bridged ring, Ci-Cealkyl-Rj or Cj-Cealkyl is independently selected from the group consisting of hydrogen, Fluoro, OH, Ci-C₃alkyl and CF₃, most preferably from the group consisting of hydrigen Ci-C₃alkyl, Fluoro and CF₃.

In another embodiment of the présent invention, compounds according to Formula (I) are provided wherein B represents phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C₃alkyl, CN, CFH₂, CF₂H and CF₃.

In one sub-embodiment, compounds according to the présent invention are represented by Formula (la)

(la), wherein Ri, R₂ and Ri are defined as in any one of the embodiments as described.

In a sub-embodiment, such compounds are represented by Formula (Ib)

wherein Ri, R₂, Ri are defined as in any one of the embodiments as described and R₃ is selected from the group comprising hydrogen, halogen, Ci-C₃alkyl, CN, CFH₂, CF₂H,

-15CFj. In a preferred embodiment, R3 represents Fluor or hydrogen, more preferably hydrogen.

In yet another sub-embodiment, compounds are represented by Formula (le):

(le) wherein Rt, R2 and R4 are defined as in any one of the embodiments as described.

In one sub-embodiment, compounds according to the présent invention are represented by Formula (Id)

^R3 (Id) wherein Rt, R2 and R4 are defined as in any one of the embodiments described and Rj is selected from the group comprising hydrogen, halogen, Ci-Cjalkyl, CN, CFH₂, CF₂H, CF3.

In a preferred embodiment, the compounds according to the invention are envisioned for use in the prévention or treatment of an HBV infection ïn a mammal.

In one further aspect, the présent invention provides compounds which can be represented by Formula (I):

or a stereoisomer or tautomeric form thereof, wherein:

B represents a monocyclic 5 to 6 membered aromatic ring, optionaily containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionaily being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C|-C₃alkyl, CN, CFH₂, CF₂H and CF₃;

Ri represents hydrogen or Ci-C₃alkyl;

R₂ represents Ci-Cealkyl, Ci-C₃alkyl-Rj, benzyl, C(=O)-Rj, CFH2, CF2H, CF₃or a 10 3-7 membered saturated ring optionaily containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such

3-7 membered saturated ring or Ci-Cealkyl optionaily being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Cialkyloxy, oxo, C(=O)-Ci-C₃aIkyl, CrQalkyl, OH, CN, 15 CFH₂, CF2H and CF₃;

Or Ri and R2 together with the Nitrogen to which they are attached form a l,4-dioxa-8-azaspiro[4.5] moiety or a 5-7 membered saturated ring, optionaily containing one or more additional heteroatoms each independently selected from 20 the group consisting of O, S and N, such 5-7 membered saturated ring optionaily being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C^alkyloxy, oxo, C(=O)-Ci-C₃aIky1, Ci-C4alkyL OH, CN, CFH₂, CF₂H and CF₃;

Each R4 is independently selected from hydrogen, halo, Ci-C4alkytoxy, Ci-C4alkyl, OH, CN, CFH₂, CF₂H, CF₃ , HOC or a 3-5 membered saturated ring optionaily containing one or more heteroatoms each independently selected from the group consisting of O and N;

Rj represents Ci-Qalkyl, CFH₂, CF₂H, CF₃ or a 3-7 membered saturated ring optionaily containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionaily being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C4alkyloxy, oxo, C(=O)-Ci-C₃aIkyl, 35 Ci-C4alkyl, OH, CN, CFH₂, CF₂H and CF₃;

or a pharmaceutically acceptable sait or a solvaté thereof. These compounds are especially suited for use in the prévention or treatment of an HBV infection in a mammal.

In yet a further aspect, the invention relates to compounds according to Formula (1)

B represents a monocyclic 5 to 6 membered aromatîc ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S 10 and N, such 5 to 6 membered aromatîc ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Cjalkyl, CN, CFH2, CF2H and CFj;

Ri represents hydrogen or CpCjalkyl;

R2 represents a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, 20 halo, Ci-C4alkyloxy, oxo, C(=O)-Ci-C3alkyl, Ci-C4alkyl, OH, CN, CFH2, CF₂H and CFj;

Each R< is independently selected from hydrogen, halo, Ci-C4alkyloxy, CrGall^l, OH, CN, CFH2, CF₂H, CFj , HChC or a 3-5 membered saturated ring optionally 25 containing one or more heteroatoms each independently selected from the group consisting of O and N;

or a pharmaceutically acceptable sait or a solvaté thereof.

The présent invention addïtionally relates to compound of Formula (1)

solvaté thereof wherein:

B represents a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting ofO, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Cjalkyl, CN, CFH₂, CF₂H and CFj;

Ri represents hydrogen or C1-C3alkyl;

R₂ represents Cj-Cealkyl, Ci-Cjalkyl-Rj, benzyl, C(=O)-Rj, CFH₂, CF₂H, CFj or a

3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such

3-7 membered saturated ring or Ci-Cialkyl optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Qalkyloxy, oxo, C(=O)-C|-C3alkyl, Ci-Qalkyl, OH, CN, CFH₂, CF₂H and CFj;

Or Ri and R₂ together with the Nitrogen to which they are attached form a l,4-dioxa-8-azaspiro[4.5] moiety or a 5-7 membered saturated ring, optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally 25 being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C4alkyloxy, oxo, C(=O)-C|-Cjalkyl, Ci-Cialkyl, OH, CN, CFH₂, CF₂H and CFj;

Each R4 is independently selected from hydrogen, halo, Ci-Cialkyloxy, C|-C4alkyl, 30 OH, CN, CFH₂, CF₂H, CF3, HC^C or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N;

-19Rî represents C) -Cealkyl, CFH₂, CF₂H, CFj or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C^alkyloxy, oxo, C(=O)-Ci-C₃alkyl, Ci-Qalkyl, OH, CN, CFH₂, CF₂H and CF₃;

One sub-embodiment of the invention provides compounds which can be represented by formula (la)

wherein Ri, R₂, B are defined as above and each R4 is independently selected from hydrogen, halo, Ci-C4alkyloxy, C)-C4a!kyl, OH, CN, CFH₂, CF₂H, CFjor a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N.

In one embodiment, R₂ represents a 3-7 membered saturated ring, containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, CrC^alkyloxy, oxo, C^OKi-Cjalkyl, Ci-C^alkyl, OH, CN, CFH₂, CF₂H and CFj.

In yet another embodiment, R₂ represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Cialkyloxy, C(=O)- C)-C3alkyl, Ci-C4alkyl, OH, CN, CFH₂, CFjH and CFj.

In another embodiment, Ri and R₂ together with the Nitrogen to which they are attached form a 5-7 membered saturated ring, optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C4alkyloxy, oxo, C(=O)-C_l-C_îalkyl, Ci-C4alkyl, OH, CN, CFH₂, CF₂H and CFj.

-20In a preferred embodiment of the invention, B represents phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, CpCjalkyl, CN, CFH2, CF_ZH and CF3.

In a sélection of compounds according to the invention, or compounds for use in the prévention or treatment of an HBV infection in a mammal at least one R4 represents Fluor, Ci-Cjalkyl, CHF₂ or cyclopropyl.

Preferably, at least one R4 represents methyl, z-propyl or cyclopropyl. In another embodiment, one R4 represents methyl, ί-propyl or cyclopropyl and the other R4 represents Fluor, or hydrogen. The position of R4 preferably is meta and/orpara (position indicated from -N~).

One spécifie embodiment is a compound of Formula (I) wherein one R4 on the para position represents Fluor and the other one R4 on the meta position represents Fluor or methyl (position indicated from -N~).

One sub-embodiment of the invention provides compounds which can be represented by formula (Ib)

r₃ (Ib) wherein Rt, R2, R4 are defined as above and Rj is selected from the group comprising hydrogen, halo, Ct-Cjalkyl, CN, CFH2, CF2H, CFj. In a preferred embodiment, Rj represents Fluor or hydrogen.

The invention further relates to compounds according to Formula (I)

(D

-21or a stereoisomer or tautomeric form thereof, wherein:

B représenta a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or 5 more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Cjalkyl, CN, CFH₂, CF₂H and CFj;

Ri représente hydrogen or C)-C₃alkyl;

R₂ représenta Ci -C₃alkyl-R$ or a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-Qalkyloxy, oxo, C(=O)-Ci-Cjalkyl, Ci-C₄alkyl,

OH, CN, CFH₂, CF₂H and CFj,

Each R4 is independently selected from hydrogen, halo, Ci-C₄alkyloxy, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H, CFj , HC^C or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group 20 consisting of O and N;

R« représenta a 4-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O or S, such

4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, Ci-C₄alkyloxy, oxo, C(=O)-Ci-Cjalkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CFj;

or a pharmaceutically acceptable sait or a solvaté thereof.

-22whereîn R₍, R₂, B are defined as above and each R4 is independently selected from hydrogen, halo, Cj-Qalkyloxy, C|-C₄alkyl, OH, CN, CFH₂, CF₂H, CFjor a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N.

In one embodiment, R₂ represents Ci-Cjalkyl-Reor a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, CpC^alkyloxy, oxo, C(=O)-Ci-Cjalkyl, Ci-Cialkyl, OH, CN, CFH₂, CF₂H and CF₃.

In a preferred embodiment for the compounds of the invention, B represents phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-Cîalkyl, CN, CFH₂, CF₂H and CF₃.

In a sélection of compounds according to the invention at least one R4 represents Fluor, Ci-Cîalkyl ,CHF₂or cyclopropyl. Preferably, at least one R4 represents methyl, i-propyl or cyclopropyl. In another embodiment, one R4 represents methyl, /-propyl or cyclopropyl and the other R4 represents Fluor, or hydrogen. The position of R4 preferably is meta and/or para.

One spécifie embodiment is a compound of Formula (I) wherein one R4 on the para position represents Fluor and the other onc R4 on the meta position represents Fluor or methyl.

One sub-embodiment of the compounds of the invention relates to compounds according Formula (Ib) .R·

Ra (Ib) wherein Ri represents hydrogen or Ci-Cjalkyl;

R₂ represents Ci-CjalkyLRsor a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted 5 with one or more substituents each independently selected from the group consisting of hydrogen, halo, Cj-Galkyloxy, oxo, C(=O)-Ci-C₃alkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CF_3;

Each R< is independently selected from hydrogen, halo, Ci-C^alkyloxy, Ci-C^alkyl, 10 OH, CN, CFH₂, CF₂H, CF₃ or a 3-5 membered saturated ring optionally containîng one or more heteroatoms each independently selected from the group consisting of O and N;

Rc represents a 4-7 membered saturated ring optionally containîng one or more heteroatoms each independently selected from the group consisting of O or S, such

4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C]-C4alkyloxy, oxo, C(=O)-C₁-C₃alkyl, CÎ-C^alkyl, OH, CN, CFH₂, CF₂H and CF₃;

R₃ is selected from the group comprising hydrogen, halo, Cj-C₃alkyl, CN, CFH₂, CF₂H, CF₃. In a preferred embodiment, R₃ represents Fluor or hydrogen.

In one embodiment, Re represents a 4-7 membered saturated ring consisting of carbon 25 atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C|-C₄alkyloxy, oxo, C(=O)-Ci-C₃alkyl, Cj-C4alkyl, OH, CN, CFH₂, CF₂H and CF₃.

Further combinations of any ofthe sub- or preferred embodiments are also envisioned to be in the scope of the présent invention.

Preferred compounds according to the invention are compounds or a stereoisomer or 35 tautomeric form thereof with a formula or reference to a formula selected from the following tables 1 and 2:

Table 2.

Co. no.
1
2
3
4
5
6
7
8
9
10
11
12
14
16
17
18
19
38
39
42
43
45
46
48
56
63

Co. no.
64
65
66
67
68
69
70
71
72
73
74
76
77
79
81
82
83
84
85
86
87
89
90
91
92
93

Co. no.
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119

Co. no.
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145

Co. no.
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171

Co. no.
172
173
174
175
176
177
178
179
180
181
182
183
184
184a
184b
185
186
187
188
189
190
191
192
193
194
195

Co. no.
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221

Co. no.
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243

or a pharmaceutically acceptable sait or a solvaté thereof

In a further aspect, the présent invention concems a phannaceutical composition comprising a therapcutically or prophylactically effective amount of a compound of Formula (I) as specified herein, and a pharmaceutically acceptable carrier. A prophylactically effective amount in this context is an amount sufficient to prevent I0 HBV infection in subjects being at risk of being infccted. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV infection, or to eradicate HBV infection, in infected subjects. In still a further aspect, this invention relates to a process of preparing a pharmaccutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable

-25carrier with a therapeutically or prophylactically effective amount of a compound of Formula (I), as specificd herein.

Therefore, the compounds of the présent invention or any subgroup thereof may be formulatcd into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited ail compositions usually employed for systemically administering drugs. To préparé the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimatc admixture with a pharma10 ceutically acceptable carrier, which carrier may takc a widc varicty of forms depcnding on the form of préparation desired for administration. These pharmaceutical compositions are désirable in unitary dosage form suitable, particularly, for administration orally, rectally, pereutaneously, or by parentéral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral Iiquid préparations such as suspensions, syrups, élixirs, émulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, bînders, disintcgrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. For parentéral compositions, the carrier will usually comprise stérile water, at least in large part, though other ingrédients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.

Injectable suspensions may also be prepared in which case appropriate Iiquid carriers, suspending agents and the like may be employed. Also included are solid form préparations intended to be converted, shortly before use, to Iiquid form préparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a pénétration cnhancing agent and/or a suitable wettîng agent, optionally 30 combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. The compounds of the présent invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any art-known delivery system.

It is especïally advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease 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 quant îty of active ingrédient calculated

to produce the desired therapeutic effect in association with the rcquircd p h arm ac eut ica! carrier. Examples of such unit dosage fonns are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

The compounds of Formula (I) are active as inhibitors of the HBV réplication cycle and can be used in the treatment and prophylaxie of HBV infection or discases associated with HBV. The lattcr include progressive liver fibrosis, inflammation and necrosis leading to cîrrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, particularly their anti-HBV properties, the compounds of Formula (I) or any subgroup thereof, are usefiil in the inhibition of the HBV réplication cycle, in particular in the treatment of warm-blooded animais, in particular humans, infected with HBV, and for the prophylaxie of HBV infections, The présent invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HBV, or being at risk of infection by HBV, said method comprising the administration of a therapeuticany effective amount of a compound of Formula (I).

The compounds of Formula (I), as specificd herein, may therefore be used as a me die inc, in particular as medicine to treat or prevent HBV infection. Said use as a mcdicinc or method of treatment comprises the systemic administration to HBV infected subjects or to subjccts susceptible to HBV infection of an amount effective to combat the conditions associated with HBV infection or an amount effective to prevent 25 HBV infection.

The présent invention also relates to the use of the présent compounds in the manufacture of a médicament for the treatment or the prévention of HBV infection. In general it is contemplatcd that an antiviral effective daily amount would be from 30 about 0.01 to about 50 mg/kg, or about 0.01 to about 30 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doscs at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing about 1 to about 500 mg, or about 1 to about

300 mg, or about l to about 100 mg, or about 2 to about 50 mg of active ingrédient per 35 unit dosage form.

The présent invention also concems combinations of a compound of Formula (I) or any subgroup thereof as specified herein with other anti-HBV agents. The term

“combination” may relate to a product or kit containing (a) a compound of Formula (1), as spccified above, and (b) at least one other compound capable of treating HBV infection (herein designated as anti-HBV agent), as a combined préparation for simultaneous, separate or sequential use in treatment of HBV infections. In an embodiment, the invention concems combination of a compound of Formula (1) or any subgroup thereof with at least one anti-HBV agent. In a particular embodiment, the invention concems combination of a compound of formula (I) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the invention concems combination of a compound of formula (1) or any subgroup thereof with at least three 10 anti-HBV agents. In a particular embodiment, the invention concems combination of a compound of formula (1) or any subgroup thereof with at least four anti-HBV agents.

The combination of previously known anti-HBV agents, such as interferon-α (IFN-a), pegylated interferon-a, 3TC, adefovir or a combination thereof, and, a compound of 15 formula (1) or any subgroup thereof can be used as a mcdicine in a combination therapy.

Generic synthesis:

Compound according to Formula (I) can bc synthesized as described in general schemes 1 to 7.

A carboxylic acid chloride of general Formula 11 can be selectively reacted with an aniline of general formula III, for example in an organic solvent Iike CH2CI2 in the presence of an organic base Iike triethylamine or DIPEA (Ν,Ν-diisopropylethylamine), or, as another example, by addition of the aniline III to a refluxing toluene solution of compound II, resulting in compound IV. The remaining sulfonic acid chloride functionality in compound IV is further reacted with an amine of general formula V, resulting in a compound of general Formula (I). Altematively a compound of general

Formula (I) might be obtained as described in scheme 2. This time the sulfonic acid chloride VI is reacted with an amine of general formula V, for example in an organic solvent Iike CH2CI2 in the presence of an organic base Iike triethylamine or DIPEA or or, as another example, in the presence of Na2COj in a mixture of H2O/THF. The formed compound VII is coupled with aniline of general formula III in the presence of 35 an activating reagent Iike for example HATU and an organic base Iike triethylamine or DIPEA.

II

Scheme 1

Scheme 2

A general synthesis of compounds of formula IX and X is described in scheme 3. Intermediate IV is rcacted with ammonia, resulting in a compound of formula VIII.

This intermediate can be further transformed to a compound of formula IX by reacting with a carbonyl chloride, for example cyclohexane carbonyl chloride in the presence of S1O2 and H2SO4 at reflux in CHCb. The compound of general formula IX can be further transformed to a compound of formula X. In case Ri equals Me, this can be done by reacting IX with TMSCHN2 in MeOH/CHîCh

IV

IX

VIII

X

Scheme 3

In another example, compound IV can be reacted with an amino acid XI, in the presence of a base like NaOH, resulting in compound XII as described in scheme 4. This intermediate XII can then optionally be cyclised to compound XIII for example by heating with acetic anhydride and KOAc in toluene, or converting the carboxylic acid to an acid chloride followed by cyclisation in the presence of a base like triethylamine. Suitable examples of amino acids of structure XI are dérivatives of 5-aminopentanoic 10 acid or 4-aminobutanoic acid

Scheme 4

Scheme 5

A synthetic route to compounds of general formula XVI is described in Scheme 5. A aminoethano! dérivative XIV, prepared as described in scheme I for the compounds of general Formula (I), is transformed in a aziridine dérivative XV by treatement with Diethy! diazene- ! ,2-dicarboxylate and PPh₃ in THF. The aziridine of general formula XV is reacted with a nucleophile Nu, resulting in a compound of general formula XVI.

! 0 Examples of such nucleophiles (Nu) are, but are not limited to, morpholine and I-methylpiperazine. Examples of a compound synthesized according to the route described in scheme 5, are compounds 116 and 117.

Scheme 6

An alternative method for the synthesis of compounds of general formula VII, is via ester XVII as described in scheme 6. Reaction of XVII with amine V, for example in an 20 organic solvent like CH2CI2 or THF in the presence of an organic base like for example

tricthylamîne or D1PEA, followed by hydroiysis of the ester, for example with LiOH in THF/H2O, followed by acidification, results in a compound of general formula Vil. A compound of general formula VII, obtained via the route in scheme 2 or scheme 6, can be transformed to and acid chloride of formula XIX, for example by treatement with 5 oxalyl chloride or thionyl chloride. A compound of general formula XIX can then be transformed to a compound of general Formula (I) by reaction with an aniline of general formula III.

A compound of general formula VI can be converted to a compound of general formula II, for example by treatement with oxalyl chloride in CH2CI2.

o

A s (CrCjalkylJ-O^B-^ R;

XXII

I (C^alk/J-O

XX

A

XXI ⁰ Cl, n

A *-(C,-C₃afkyi)—ο'Έ — *₀

XVII (C_rCîalkyf)—O^zA'B'^NHî

XXV

NHî

XXIV o

XXIII

Scheme 7

Possible synthetic routes, for compounds of general formula XVII or VI are described in scheme 7, and further exemplifïed in the experimental section. Chlorosulfonation of carboxylic acids XXI or carboxylic esters XX, can results in compounds ofgeneral formula VI or XVII respectively, for example by treatement with chlorosulfonte acid (for example as reviewed in Phosphores, Sulfur, and Silicon and the Related Eléments 20 Vol. 56, Iss. 1-4,1991). Altematively, compounds of general formula XXV or XXIV, may be converted to compound of general formula XVII and VI respectively, by conversion to the corresponding diazonium salts (for example by NaNO2/HCl), followed by conversion of the diazonium sait to a sulfonyl chloride (for example by

-32SO₂/CuCI)(for example as described in Organic Process Research & Development, 13(5), 875-879; 2009). Altematively, compounds of general formula XXII and XXIII (with R7 equaling H, benzyl or methyi) may be converted to compound of general formula XVII and VI respectively, for example by treatement with Cl₂ or N5 Chlorosuccinimide in AcOH/H₂O.

The subsitutents represented by R4 in this general synthesis section are meant to include any substituent or reactive species that is suitable for transformation into any R4 subsitutent according to the présent invention without undue burden for the person 10 skilled in the art.

Compounds not speci fically described in the synthesis of compounds section below can be sysnthesized according to the Schemes 1-7 above and were commerciaily acquîred.

Synthesis of compounds:

LC-MS methods:

Method A: mobile phase A : H₂O (0.1%TFA; B:CH₃CN (0.05% TFA) Stop Time : 10 min; gradient time(min) [%A/%B] 0.0 [100/0] to 1 [100/0] to 5 [40/60] to 7.5 [40/60] to 8.0 [100/0]; flow: 0.8 mL/min; column temp.: 50°C, YMC-PACK ODS-AQ, 50x2.0mm 5pm

Method B: mobile phase A : H₂O (0.1%TFA; B:CH₃CN (0.05% TFA) Stop Time : 10 min; gradient time(min) [%A/%B] 0.0 [90/10] to 0.8 [90/10] to 4.5 [20/80] to 7.5 [20/80] to 8.0 [90/10]; flow; 0.8 mL/min; column temp.: 50°C, YMC-PACK ODS-AQ, 50x2.0mm 5μτη

Method C: mobile phase A : H₂O (0.1 % TFA); B:CHjCN (0.05 % TFA) Stop Time : 10 min; gradient time(min) [%A/%B] 0.0 [90/10] to 0.8 [90/10] to 4.5 [20/80] to 7.5 [20/80]; 9.5 [90/10] flow: 0.8 mL/min; column temp.: 50°C; Agilent TC-C18, 50x2.1mm, 5pm

Method D: mobile phase A : H₂O (0.05 % NHa.H₂O ); B: CH3CN Stop Time : 10 min; gradient time(min) [%A/%B] 0.0 [100/0] to I [100/0] to 5 [40/60] to 7.5 [40/60]; 8 [100/0] flow: 0.8 mL/min; column temp.: 40 °C, XBridge Shield-RP18,50*2.1mm 5pm

Method E: mobile phase A : H₂O (0.1%TFA; B:CHjCN (0.05% TFA) Stop Time : 10 min; Post Time: 0.5 min; gradient time(min) [%A/%B]0 [100/0] to I [100/0] to 5

-33[40/60] to 7.5 [15/85] to 9.5 [100/0]; flow: 0.8 mL/min; column temp.: 50°C, Agitent TC-C18,50x2.1mm, 5pm

Method F: The LC measurement was performed using an Acquity UPLC (Waters) system with column heater (set at 55 °C). Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 pm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 mL/min. Two mobile phases (10 mM ammonium acetate in ILO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.3 minutes. An injection volume of 0.5 μΐ was used. Cône voltage was 10 V for positive ionization mode and 20 V for négative ionization mode.

Method G: The LC measurement was performed using an Acquity UPLC (Waters) with column heater (set at 55 °C). Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a Acquity UPLC HSS T3 column (1.8 pm, 2.1 x 100 mm; Waters Acquity) with a flow rate of 0.8 mL/min. Two mobile phases (A: 10 mM ammonium acetate in H₂O/acetonitrilc 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 100 % A and 0 % B to 5 % A and 95 % B in 2.1 minutes and subsequently to 0 % A and 100 % B in 0.9 minutes to 5% A and 95% B in 0.5 min. An injection volume of 1 μΐ was used. Cône voltage was 30 V for positive ionization mode and 30 V for négative ionization mode.

Method H: Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 pm,

4.6 x 100 mm) with a flow rate of 1.6 mL/min. Column heater was set at 45 °C. Two mobile phases (mobile phase A: 70 % methanol + 30 % H₂O; mobile phase B: 0.1 % formic acid in H₂O/methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 9 minutes and hold these conditions for 3 minutes. An injection volume of 10 pl was used. Cône voltage was 10 V for positive ionization mode and 20 V for négative ionization mode.

Compounds 21,49-55,57-62 were purchased from Aurora Fine Chemicals.

O.

Compound 1

3-(chlorosulfony!)benzoyl chloride (207 mg, 1 mmol) was dissolved in dichloromethane (3 mL) and 4-fluoroaniline (111 mg, 1.0 mmol) and triethylamine (112 mg, 1 .Ommol) in dichloromethane (2 mL) were added to the mixture at 0°C. The mixture 5 was next stirred at 20°C for I hour. To this reaction mixture containing 3-(4-fluorophenylcarbamoyl)benzene-l-sulfonyl chloride at 0°C, a solution of triethylamine (121 mg, 1.2 mmol) and 4-aminotetrahydropyran (88 mg, 0.861 mmol) in dichloromethane (3 mL) was added. The mixture was stirred at 20°C for 1 hour. The solvent was removed in vacuo. The residue was purified by high performance liquid chromatography (Column: Phenomenex Synergi C18 150*20mm*5um. A: Η₂Ο+0.1%ΤΡΑ; B: MeCN)· The product fractions were collected and the organic solvent was evaporated. The fraction was neutralized by saturated NaHCOj. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SOi and concentrated resulting in compound 1 (85.4 mg) Method A; Rt: 4.88 min. m/z :

379.2 (M+H)* Exact mass: 378.1

Following compounds were prepared similarly as compound 1 using the corresponding

Compound 2 amines instead of 4-aminotetrahydropyran:

Method B; Rt: 4.27 min. m/z : 363.1 (M+H)* Exact mass: 362.1

Compound 3

Method A; Rt: 4.64 min. m/z : 351.1 (M+H)* Exact mass: 350.1

Compound 4

Method A; Rt: 4.87 min. m/z : 365.1 (M+H)* Exact mass: 364.1

-35Compound 5

Method A; Rt: 5.32 min, m/z : 349.1 (M+H)* Exact mass: 348.1

Compound 79

Method A; Rt: 5.39 min. m/z : 365.2 (M+H)* Exact mass: 364.1 'H NMR (400 MHz, CHLOROFORM-7) δ ppm 8.37 (1 H, t,7=1.5 Hz), 8.16 (1 H, br. s.), 8.11 (1 H, dm, ./=8.0 Hz), 8.05 (1 H, dm, .7=8.0 Hz), 7.57 - 7.70 (3 H, m), 7.08 (2 H, t, 7=8.7 Hz), 4.78 ( 1 H, s), 1.55 (2 H, q, J=7.5 Hz), 1.18 (6 H, s), 0.84 (3 H, t, 7=7.5 Hz).

Compound 83

Method A; Rt: 4.20 min. m/z : 415.0 (M+Na)* Exact mass: 392.1;

Purified by silica gel chromatography (gradient eluent: petroleum ether/ethyl acetate from 100/1 to 1/1). 'H NMR (400 MHz, DMSO-</₆) δ ppm 10.57 (1 H, br. s), 8.33 -

8.47 (1 H, m), 8.19 (1 H, dm, 7=7.5 Hz), 8.06 (1 H, dm,7=7.5 Hz), 7.72 - 7.85 (3 H, m), 7.66 - 7.73 (1 H, br. s), 7.12 - 7.31 (2 H, m), 3.42 - 3.58 (4 H, m), 1.71-1.92 (2 H, m), 1.27 - 1.50 (2 H, m), 1.06 (3 H, s).

Compound 87

Method B; Rt: 3.94 min. m/z : 363.1 (M+H)* Exact mass: 362.1

Purified by high performance liquid chromatography over RP-18 (eluent: CHjCN in water (0.1%TFA) from 25 to 55, v/v). ^lH NMR (400 MHz, DMSO-dô), Ô ppm 0.340.42 (m, 2 H), 0.46-0.54 (m, 2H), 0.75(t, J=7.3 Hz, 3 H), 1.28 (q, J=7.3 Hz, 2 H), 7.157.25 (m,2 H) 7.67-7.83 (m, 3 H), 7.97 (d, >8.3 Hz; 1 H), 8.14-8.25 (m, 2 H), 8.33 (s, 1 H), 10.55 (s, 1 H).

Compound 89

Method E; Rt: 4.83 min. m/z : 379.1 (M+H)⁺ Exact mass: 378.1; ’H NMR (400 MHz, DMSO-d6), δ ppm 10.60 (s, 1H), 8.48 (br. s., 1H), 8.39 (s, 1H), 8.23 (d, >7.8 Hz, 1 H), 8.04 (d, >7.8 Hz, 1 H), 7.74-7.87 (m, 3 H), 7.23 (t, >9.0 Hz, 2 H), 4.5 l(d, >

6.5 Hz, 2 H), 4.20(d, >6.5 Hz, 2 H), 1.84 (q, >7.3 Hz, 2 H), 0.64(t, >7.3 Hz, 3 H). Prepared similarly as described for compound 1, using 3-ethyloxetan-3-amine instead of4-aminotetrahydropyran. Synthesis of 3-ethyloxetan-3-amine: 3-ethyloxetane-3carboxylic acid (3.0g, 23.1 mmol), DPPA (Diphenylphosphoryl azidc, 7.61 g, 27.7 mmol), triethylamine (3.0 g, 23.1 mmol) and BnOH (2.99 g, 27.7 mmol) were dissolved in toluene (50 mL). The mixture was stirred at 110°C ovemight. The solvent was removed in vacuo. Dichloromethane (50 mL) was added. The mixture was washed with IN HCl (20 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether t ethyl acetate from 100/1 to 60/40) resulting in benzyl 3-ethyloxetan-3-ylcarbamate (4.0 g). To a solution of benzyl 3-ethyloxetan-3-ylcarbamate (2.0g, 8.5mmol) and cyclohexa-1,4-diene (1.02 g, 12.75 mmol) in MeOH (20 mL) was added Pd-C (10%, 0.2 g) under N₂. The mixture was stirred under H₂balloon at 25°C for 4 hours. After filtration, the filtrate was concentrated resulting in

3-ethyloxetan-3-amine (860 mg), which was used as such ίη the next reaction.

To a solution of 3-(chlorosulfonyl)benzoic acid (1 g, 4.53 mmol) in CH₂C1₂(2O mL) at 5°C, cyclohexanamîne (0.899 g, 9.06 mmol) and triethylamine ( 1.38 g, 13.60 mmol) were successively added drop wise.The solution was stirred at room température ovemight. The mixture was washed with IN HCl (50 mL). The organic phase was dried over MgSO₄ and concentrated resulting in 3-(N-cyclohexylsulfamoyl)benzoic acid as a white solid (1.2 g), which was used in the next step without purification. To a solution of 3-(N-cyclohcxyIsulfamoyl)benzoic acid (1.2 g, 4.24 mmol) in DMF

-37(15 mL) at 5°C, 4-fluoroaniiine (0.52 g, 4.66 mmol) and DIPEA (1.64 g, 12.71 mmol) were successively added.. The mixture was stirred for 20 minutes and then HATU (1.93 g, 5.08 mmol) was added. The solution was stirred at room température ovemight. To the reaction mixture aqueous NaHCOj (50 mL) was added followed by EtOAc (50 mL). The organic layer washed with HCl (5%; 50 mL) and brine. The organic layer was dried with MgSO₄ and concentrated, resulting in a residue. The obtained residue was purified by a silica gel chromatography column (Petroleum ether:EtOAc=2:l) resulting in compound 6 as a white solid (850 mg). Method B; Rt:

4.50 min. m/z : 377.2 (M+H)⁺ Exact mass: 376.1

Synthesis of compound 7

Compound 7

To 5-(chlorosulfonyl)-2-fluorobenzoic acid (10 g, 41.91 mmol) in EtOAc (150 mL) cyclohexanamine (12.47 g, 125.72 mmol) was added at room température. The reaction mixture was stirred at room température for 10 minutes and washed with IN HCl (100 mL). The organic phase was dried over MgSO₄ and concentrated resulting in 5-(N-cyclohexylsulfamoyl)-2-Îluorobenzoic acid as a white solid (10.9 g), which was used in the next steps without further purification. To a solution of 5-(N-cyclohexylsulfamoyl)-2-fluorobenzoic acid (1 g, 3.32 mmol) in DMF (15 mL) 3-(triiluoromethyl)aniline (0.54 g, 3.32 mmol) and DIPEA (1.29 g, 9.96 mmol) were successively added at 5°C. The mixture was stirred for 20 minutes and then HATU ( 1.51 g, 3.98 mmol) was added. The solution was stirred at room température ovemight. To the reaction mixture aqueous NaHCOj (50 mL), was added followed by EtOAc (50 mL). The organic layer was washed with HCl (5%) and brine. The organic layer was dried with MgSO₄, concentrated in vacuo, and the obtained residue was purified by préparative HPLC resulting in compound 7 (902 mg) as a white solid. Method B; Rt: 4.85 min. m/z :

445.2 (M+H)⁺ Exact mass: 444.1; ‘H NMR (400 MHz, DMSO-J₆) δ ppm 10.94 (1 H, br. s), 8.15 - 8.22 (1 H, m), 8.12 (1 H, dd, J=6.5,2.5 Hz), 8.03 (l H, ddd, J=9.0,4.5,

2.5 Hz), 7.88 - 7,97 (1 H, m), 7.83 (1 H, d, J=7.5 Hz), 7,58 - 7.67 (2 H, m), 7.46 - 7.54 (1 H, m), 2.90 - 3.07 (1 H, m), 1.51 - 1.67 (4 H, m), 1.38-1.51 (1 H, m), 0.96 -1.27 (5H,m)

Examples of compounds prepared similar as compound 7, using the corresponding anilines instead of 3-(triiluoromethyl)aniline:

‘h NMR (400 MHz, DMSO-J₆) 5 ppm 10.68 (1 H, br. s), 8.08 (1 H, dd, J=6.0,2.5 Hz), 8.01 (1 H, ddd, 8.5,4.5,2.5 Hz), 7.83 (1 H, br. s), 7.70 - 7.77 (2 H, m), 7.60 (1 H, app. t,J= 9.0 Hz), 7.18 - 7.27 (2H, m), 2.90 - 3.07 (1 H, m), 1.53 - 1.67 (4 H, m), 1.40 5 1.53 (1 H, m), 0.96 - 1.25 (5 H, m). Method C; Rt: 4.21 min. m/z : 395.1 (M+H)⁺

Exact mass: 394.1

Compound 19

To a solution of (Æ)-tetrahydrofuran-3-aminc (0.87 g, 9.97 mmol) in THF (20 mL) aqueous sodium hydroxide was added (4 mL, 5 N) in ice bath followed by 3-(chlorosulfonyl)benzoic acid (2.2 g, 9.97 mmol). After stirring at 25°C for 3 hours, the reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL). The aqueous layer was adjusted to pH=3 by aq. HCl (2 N) and then the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed by brine, dried over anhydrous MgSO₄ and concentrated in vacuo resulting in

-39compound (Æ)-3-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid (900 mg). To a solution of compound (R)-3-(N-(tetrahydrofiiran-3-yl)sulfamoyl)benzoic acid (0.80 g,

2.95 mmol), 4-fluoroaniline (0.39g, 3.54 mmol), and HATU (3.36 g, 8.85 mmol) in CH2CI2 ( 10 mL) cooled in an ice bath under Ni atmosphère,DIPEA (0.57g, 0.44 mmol) was added. The resulting mixture was diluted with CH2CI2 (15 mL) and washed with saturated aqueous NaHCOj (15 mL) and brine ( 10 mL). After diying over anhydrous MgSO₄ the solvent was removed in vacuo. The obtained residue was purified by préparative high performance liquid chromatography over RP-18 (eluent: CHjCN in H2O: from 40% to 80%, v/v; 0.05% TFA as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to PH=7 with Amberlite IRA-900 ion exchange resin (OH form), filtrated and lyophilized. The obtained residue was further purified by prep. SFC (Column:Chiralpak AD-3 150><4.6mm I.D., 3um Mobile phase: 40% of methanol (0.05% diethylamine) in CO₂. Flow rate: 2.5 mL/min) resulting in compound 8 (370 mg) Method A; Rt: 4.6 min. m/z : 365.2 (M+H)* Exact mass: 364.1; [«]”= - 13.60 (c=0.11, MeOH) 'H NMR (400 MHz, DMSO-4,) δ ppm 10.57 (l H, br. s), 8.34- 8.40 (1 H,m), 8.18 - 8.27 (1 H, m), 8.09 (1 H, br. s), 7.99 - 8.06 (1 H, m), 7.74 - 7.84 (3 H, m), 7.13 - 7.33 (2 H, m),

3.64 - 3.83 (2 H, m), 3.50 - 3.64 (2 H, m), 3.35 - 3.39 (1 H, m), 1.80 - 1.99 (1 H, m), 1.51-1.68(1 H,m).

Compound 9

To an iced-cooled mixture of (S)-tetrahydrofuran-3 -amine hydrochloride (0.500 g,

4.41 mmol) and NaOH (0.485 g, 12.138 mmol) in H2O (5 mL) and THF (5 mL)

3-(chlorosulfonyl)benzoic acid (0.893 g, 4.406 mmol) was added in several portions. Then, the reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL). The pH value of aqueous layer was adj’usted to 3 by adding IN HCl and then the mixture was extracted with ethyl acetate (3x10 mL). The combined organic layer was washed by brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure resulting in (S)-3-(N-(tetrahydrofiiran-3-yl)suIfamoyl)benzoic acid (0.60 g). To an ice cooled mixture of (S)-3-(N-(tetrahydrofùran-3-yl)sulfamoyl)benzoic acid (600 mg, 2.212 mmol), 4-fluoroaniline (270 mg, 2.433mmol) and HATU (1.01 g, 2.654 mmol) in DMF (5 mL) DIPEA (1.15 mL, 6.636 mmol) was added under N₂ atmosphère. The resulting mixture was stirred at 20°C for 2 hour. The solvent was removed in vacuo.

The mixture was washed with saturated aqueous cntic actd (10 mL), brine and dned over Na₂SO₄. The solvent was removed in vacuo. The residue was purified by column chromatography over silica gel (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 10/90). The pure fractions were collected and the solvent was removed in vacuo. The residue was further purified by préparative high performance liquid chromatography over RP-18 (eluent: CHjCN in H₂O from 40% to 80%, v/v; 0.06% NH4HCO3 as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 9 (0,48 g) Method A; Rt: 4.6 min. m/z : 365.2 (M+H)⁺ Exact mass: 364.1;[a]n = +15.56 (c 0.10, MeOH); *H NMR (400 MHz, 80°C, DMSO-J₆) δ ppm 10.35 (1 H, br. s), 8.32 -

8.48 (1 H, m), 8.15 - 8.32 (1 H, m), 8.03 (1 H, br. s), 7.83 - 7.94 (1 H, m), 7.68 - 7.83 (3 H, m), 7.06 - 7.31 (2 H, m), 3.70 - 3.87 (2 H, m), 3.51 - 3.70 (2 H, m), 3.32 - 3.48 (l H, m), 1.85 - 2.04 (1 H, m), 1.59 - 1.78 (1 H, m)

Compounds prepared similarly as described for compound 8 and 9 from the corresponding amines instead of tetrahydrofuran-3-amine :

Compound 10

Method B; Rt: 4.24 min. m/z : 365.2 (M+H)⁺ Exact mass: 364.1;

Compound 76

Using 1-methylcyclopentanamine instead of tetrahydrofuran-3-amine, purified using Gemini 250*20mm*5um (eluent: CHjCN in H₂O (0.1% TFA) from 40% to 70%, v/v).Method B; Rt: 4.24 min. m/z : 377.2 (M+H)⁺ Exact mass: 376.1;

Synthesis of 3-(N-cyclopentylsulfamoyT)benzoic acid:

To an iced-cooled mixture of cyclopentanamine (1.93 g, 22.66 mmol) and a solution of NaOH (1.81 g, 45.32 mmol) in H₂O (25 mL) and THF (25 mL) was added 3-(chlorosulfonyl)benzoic acid (5.0 g, 22.66 mmol) in portions. The reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was diluted with H₂O (20 mL) and extracted with ethyl acetate (30 mL). The aqueous layer was separated and adjusted pH =2 by 4 N HCl and extracted with dichloromethane (3 x 30 mL). The combined organic layer

-41was washed by brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 3-(N-cyclopentylsulfamoyl)benzoic acid (4.5 g).

Compound 11

To an ice cooled mixture of 3-(N-cyclopentylsulfamoyl)benzoîc acid (250 mg, 0.928 mmol), 4-fluoro-3-mcthylaniline (116,2 mg, 0.928 mmol), HATU (388.2 mg, 1.021 mmol) in CH₂C1₂ (15 mL) DIPEA (359.8 mg, 2.784 mmol) was added under a N₂atmosphère. The resulting mixture was stirred at 20°C for ! 6 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous critic acid (10 mL), brine and dried over Na₂SO₄. The solvent was removed in vacuo. The residue was purified by column chromatography over silica gel (gradient eluent: petroleum cther/ethyl acetate from 100/0 to 10/90). The pure fractions were collected and the solvent was removed in vacuo. The residue was further purified by préparative high performance liquid chromatography over RP-18 (eluent: CH3CN in H₂O from 45% to 75%, v/v; 0.01% HCl as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to Ph-7 with Amberlite 1RA900 ion exchange resîn (OH form), filtrated and lyophilized to dryness to afford compound 11 (170.0 mg). Method B; Rt: 4.31 min. m/z : 377.2 (M+H)⁺ Exact mass:

376.1; 'H NMR (400 MHz, DMSO-J₆) δ ppm 10.47(1 H, br.s), 8.33-8.35(1 H,m), 8.17(1 H, dm, /=8.0),7.98(1 H, dm,/=8.0), 7.78 (1 H, d,/=7.0 Hz), 7.74(1 H, t, /=8.0 Hz), 7.62 - 7.68 (1 H, m), 7.53 - 7.61 (1 H, m), 7.13 (1 H, t, /=9.0 Hz), 3.37 3.48(1 H, m), 2.23 (3 H, d,/=1.8 Hz), 1.44 -1.69 (4 H, m), 1.12 -1.45 (4 H, m)

Prepared similarly as compound 11 starting from the corresponding anilines instead of 4-fluoro-3-mcthylaniline :

Compound 12 ’H NMR (400 MHz, DMSCMs) δ ppm 10,60 (I H, bs), 8.36 (I H, t,/=1.5 Hz), 8.19 (1 H, dm,/=7.5 Hz), 8.02 (1 H, dm,/=7.5 Hz), 7.8! (1 H, d, /=7.5 Hz), 7.78 (1 H, t, /=7.5 Hz), 7.55 (1 H, dm, /=11.0 Hz), 7.38 - 7.46 (1 H, m), 6.82 (1 H, dm,/=9.5 Hz),

3.41 - 3.54 (1 H, m), 2.34 (3 H, s), 1.45 - 1.70 (4 H, m), 1.19-1.45 (4 H, m); Method

B; Rt: 4.41 min. m/z : 377.2 (M+H)⁴ Exact mass: 376.1

Compound 13

The residue was purified by column chromatography over silica gel (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 40/60). Method B; Rt: 4.41 min. m/z :

377.2 (M+H)⁴ Exact mass: 376.1

Compound 14

Method B; Rt: 4.34 min. m/z : 381.2 (M+H)⁺ Exact mass: 380.1 *H NMR (400 MHz, DMSO-Æ) δ ppm 1.20 - 1.44 (m, 4 H), 1.44 - 1.68 (m, 4 H), 3.44 (sxt, J=6.8 Hz, 1 H), 7.45 (dt,J=10.6,9.0 Hz, 1 H), 7.51 - 7.60 (m, 1 H), 7.77 (1,.7=7.8 Hz, 1 H), 7.80 (d, *7=7.2 Hz, 1 H), 7.93 (ddd, .7=13.2,7.5,2.5 Hz, 1 H), 8.02 (d, J=7.8 Hz, 1 H), 8.19 (d, .7=7.7 Hz, 1 H), 8.35 (t, .7=1.7 Hz, 1 H), 10.70 (s, 1 H)

Compound 15

Method B; Rt: 4.43 min. m/z : 381.2 (M+H)⁴ Exact mass: 380.1

Compound 77

Method B; Rt: 5.45 min. m/z : 363.2 (M+H)⁴ Exact mass: 362.1

Compound 81 purified by préparative high performance liquid chromatography (column: Phenomenex Synergi 200mm*77mm, lOum; mobile phase: CH₃CN in water (0.1% TFA) from 45% to 75%,). Method A; Rt: 5.87 min. m/z : 413.2 (M+H)⁺ Exact mass: 412.1

Compound 16

A solution of 3-(N-cyclopentylsulfamoyl)benzoic acid (500 mg, 1.73 mmol) in oxalyl dichlorîde (10 mL) was stirred at 45°C for 5 hours. The solvent was removed in vacuo. The crude 3-(N-cyclopentylsulfamoyl)benzoyl chloride (600 mg) was used as such in the next step.To an ice cooled mixture of 3-(N-cyclopentylsulfamoyl)benzoyl chloride (600 mg, 1.74 mmol) and 4-amino-2-methylbenzonitrile (230 mg, 1.74 mmol) in CH2CI2 (5 mL) was added pyridine (10 mL) under N2 atmosphère. The resulting mixture was stirred at 20°C for 16 hours. The solvent was removed in vacuo. The residue was purified by préparative high performance liquid chromatography over RP-18 (eluent: CH3CN in H2O from 50% to 80%, v/v; 0.05% TFA as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to PH=7 with Amberlite 1RA-900 ion exchange resin (OH form), filtrated and lyophilized resulting in compound 16 (250mg). Method B; Rt: 4.23 min. m/z : 384.2 (M+H)⁺ Exact mass: 383.1.

Compound 75

Prepared similarly as described for compound 16 using 3-aminobenzonitrile instead of 25 4-amino-2-methylbenzonitrile. Method A; Rt: 5.24 min. m/z : 370.2 (M+H)⁺ Exact mass: 369.1.

Compound 80

Prepared similarly as described for compound 16 using 4-aminobenzonitrile instead of

4-amino-2-methylbenzonitrile. Method A; Rt: 5.32 min. m/z : 370.2 (M+H)⁺ Exact mass: 369.1.

Prepared similarly as described for compound 16 using 3-amino-5-methylbenzonitrile instead of4-amino-2-methylbenzonitrile, Method A; Rt: 5.52 min. m/z : 384.2 (M+H)⁺Exact mass: 383.1.

To a solution of compound 2,4-dichloro-5-(piperidin-l-ylsulfonyl)benzoic acid (1.0 g,

2.96 mmol), m-toluidine (0.38 g, 3.55 mmol), and HATU (1.69 g, 4,44 mmol) in CH2CI2 (10 mL) cooled in an icc bath, DIPEA (1.15g, 8.88 mmol) was added under N₂atmosphère. The resulting mixture was diluted with CH2CI2 (15 mL) and washed with saturated aqueous NaHCOj (15 mL) and brine (10 mL), dried over anhydrous MgSO₄and the solvent was removed in vacuo, The residue was purified by coiumn chromatography over silica gel (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 40/60). The pure fractions were collected and the solvent was removed in vacuo, resulting in compound 17 (0.65 g). Method B; Rt: 4.70 min. m/z : 427.1 (M+H)⁺Exact mass:426.1

Compound 46

To a solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 4.97 mmol) in THF (60mL) sodium hydroxide was added (aq., 2 mL, 5N) in ice bath followed by adding N-methyl

-4510 cyclopentanaminc (0.50 g, 4.97 mmol). After stirring at 25°C for 3 hours, the reaction mixture was diluted with H₂O (50mL) and extracted with EtOAc (50mL). The aqueous layer was adjusted to pH=3 by HCl (2N) and extracted with EtOAc (3 x 50mL). The combined organic layer was washed by brine, dried over anhydrous MgSO₄ and concentrated in vacuo resulting in 3-(N-cyclopentyl-N-methylsulfamoyl)benzoic acid (0.8 g). To a solution of 3-(N-cyclopentyl-N-methylsulfamoyl)benzoic acid (0.80 g,

2.82 mmol), 4-fluoroanîlîne (0.31 g, 2,82 mmol), and HATU (1.61 g, 4.24 mmol) in CH₂C1₂ (10 mL), cooled in an icebath, DIPEA (1.09 g, 8.47mmol) was added under N₂atmosphère. The resulting mixture was diluted with CH₂C1₂ (15 mL) and washed with saturated aqueousNaHCO₃(I5 mL) and brine (10 mL), dried over anhydrous MgSO₄and the solvent was removed in vacuo. The obtained residue was purified by préparative high performance liquid chromatography over RP-18 (eluent: CH3CN in H₂O from 30% to 80%, v/v, 0.05% TFA as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to Ph=7 with Ambcrlite 1RA-900 ion exchange resin (OH form), filtrated and lyophilized to dryness resulting in compound 46 (0.73g). Method B; Rt: 4.43 min. m/z : 377.2 (M+H)* Exact mass:376.1

Compound 56

4-fluoroaniline (0.93 g, 8.366 mmol) and DIPEA (2.91 mL, 16.732 mmol) were dîssolved în CH₂C1₂ (20 mL). 3-(chlorosulfonyl)benzoyl chloride (2 g, 8.366 mmol) in CH₂CI₂ (20 mL) was added in one portion at 0°C. The mixture was stirred for 1 hour at 0°C. The reaction mixture (40 mL) containing 3-(4-fluorophcnylcarbamoyl)benzene-lsulfonyl chloride was used to the next step without further purification. Ammonia (2.52 g, 18 mmol, 25-28% wt) was added to a solution of 3-(4-fluorophenylcarbamoyl)benzene-l-sulfonyl chloride (obtained as above, 6 mmol) in CH₂C1₂ (30 mL) at 0°C. The mixture was stirred for 1 hour at 20°C. 1 N HCl (30 mL) was added to the réaction mixture and the volatiles were partely removed in vacuo. The formed precipitate was filtered and co-evaporated with toluene (10 mL), resulting în N-(4-fluorophcnyl)-330 sulfamoylbenzamide (1.6 g). A solution of N-(4-fluorophenyl)-3-sulfamoylbenzamide (1.8 g, 6.12 mmol) and cyclohexanecarbonyl chloride (1.79 g, 12.23 mmol) în chloroform (40 mL) with SiO₂ (180 mg) and H₂SO4 (0.5 mL) was refluxed for 1 hour. Dichloromethane (20 mL) was added and the solid was filtered ofT. The filtrate was washed with water (10 mL) and dried over Na₂SO4. The solvent was removed in vacuo.

The obtained residue was purified by silica gel column chromatography (gradient

-46eluent: petroleum ether/ethy! acetate from 100/0 to 70/30). The obtained product (1.2 g, purity 95%) was further washed with methyl t-butyl ether (10 mL) resulting in compound 56 (500 mg, 99.7 % purity). Method A; Rt: 5.51 min. m/z : 405.2 (M+H)⁺Exact mass: 404. !; *H NMR (400 MHz, DMSO-î/₆) δ ppm 12.16 (1 H, br. s), 10.62 (1 H, br. s), 8.41 (I H, t, J=2.0 Hz), 8.27 (1 H, dm, J=7.5 Hz), 8.09 (I H, dm, J=7.5 Hz),

7.73 - 7.82 (3 H, m), 7.07 - 7.33 (2 H, m), 2.11 - 2.31 (1 H, m), 1.43 - 1.80 (5 H, m), 0.94- 1.32 (5 H, m)

Compound 48

Compound 56 (600 mg) was dissolved in CH₂C1₂ (6 mL) and MeOH (2 mL) and TMSCHN2 (3.7 mL, 7.415 mmol, 2M in hexane) were added drop wise at 20°C. The mixture was stirred for 2 hours at 20°C. The solvent was removed in vacuo. The residue was purified by flash column (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 70/30) resulting in a residue (0.41 g). The obtained product was further purified by préparative high performance liquid chromatography over RP-18 (eluent: CHîCN in H₂O (0.1% TFA) from 20% to 50%, v/v). The pure fractions were collected and the volatiles were removed in vacuo. The prccipitate was fïltered and the rcsidual water was removed by lyophilization resulting in compound 48 (300 mg). Method B; Rt: 4.60 min. m/z : 419.2 (M+H)⁺ Exact mass:418.1; *H NMR (400 MHz, DMSO-rf₆) δ ppm 10.62 (1 H, br. s), 8.40 - 8.45 (1 H, m), 8.28 (1 H, dm,.7=7.5 Hz), 8.13 (1 H, dm, .7=7.5 Hz), 7.66 - 7.95 (3 H, m), 7.07 - 7.33 (2 H, m), 3.40 (3 H, s), 2.73 - 2.92 (1 H, m), 1.42 - 1.77 (5 H, m), 0.90 - 1.35 (5 H, m).

Compound 63

A mixture of ethyl 2-(chlorosulfonyl)-lH-imidazole-4-carboxylate (1 g, 4.19 mmol), EtjN (1.27 g, 12.55 mmol) and cyclohexanamine (0.623 g, 6.28 mmol) in THF (25 mL) was stirred at room température for 15 hours. The mixture was concentrated and purified by préparative HPLC (Column: Cl8; Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient:

-4725-55%, 30 min) resulting in ethyl 2-(N-cyclohcxylsulfamoyl)-lH-imidazolc-4carboxylate (0.6 g) as a light yellow solid. To a solution of ethyl 2-(N-cyclohexylsulfamoyl)-lH-imidazole-4-carboxylate (0.6 g, 1.99 mmol) in EtOlI-ILO (3/1; 20 mL), LÎOH (0.145 g, 6.055 mmol) was added. The mixture was stirred at room température for 15 hours. The réaction mixture was neutralized with HCl (2M), diluted with water and then extracted into EtOAc, dried over MgSO₄, filtered and concentrated resulting in 2-(N-cyclohexylsuIfamoyl)-lH-imidazole-4-carboxylic acid (400 mg) as a white solid. A mixture of 2-(N-cyclohexylsulfamoyl)-lH-imidazole-4-carboxylic acid (0.3 g, 1.098 mmol), aniline (0.102 g, 1.098 mmol), DIPEA (0.284 g, 2.196 mmol) and HATU (0.501 g, 1.317 mmol) in DMF (25 mL) was stirred at room température for 15 hours. The mixture was purified by préparative HPLC (Coiumn: YMC 150x30mm.

Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrile; Flow rate: 30mL/min; Gradient: 40-70%, 8 min) resulting in compound 63 (218 mg). Method

B; Rt: 3.98 min. m/z : 349.2 (M+H)* Exact mass:348.1. *H NMR (400 MHz, METHANOL-J₄) δ ppm 1.26 (s, 5 H) 1.51 -1.62 (m, 1 H) 1.65 - 1.80 (m, 4 H) 3.23 3.29 (m, 1 H) 7.10 - 7.18 (m, 1 H) 7.32 - 7.39 (m, 2 H) 7.67-7.74 (m, 2 H) 7.86 (s,

IH);

Compound 64 —

A mixture of ethyl 2-(chlorosulfonyl)thiazolc-4-carboxylate (3 g, 11.73 mmol), EtjN (3.56 g, 35.2 mmol) and cyclohexanamine (1.75 g, 17.65 mmol) in THF (100 mL) was stirred at room température for 15 hours. The mixture was concentrated and purified by préparative HPLC resulting in ethyl 2-(N-cycIohexylsulfamoyl)thiazoIe-4-carboxylate (2 g) as a white solid. To a solution of ethyl 2-(N-cyclohexylsulfamoyl)thiazolc-4carboxylate (2 g) in EtOH-THF (1/1,60 mL) was added LiOH (0.451 g, 18.83 mmol). The mixture was stirred at room température for 15 hours. The réaction mixture was neutralized with HCl (2M), diluted with water and then extracted into EtOAc, dried over MgSO₄, filtered and concentrated in vacuo, resulting in 2-(N-cyclohexylsulfamoyl)thiazolc-4-carboxylic acid (1.7 g) as a white solid. A mixture of 2-(N-cycIohexylsulfamoyI)thiazole-4-carboxylic acid (1 g), aniline (0.321 g, 3.44 mmol), DIPEA (1.33 g, 10.29 mmol) and HATU (1.57 g, 4.13 mmol) in DMF (40 mL) was stirred at room température for 15 hours. The mixture was concentrated and purified by préparative HPLC (Coiumn: SYNERG1 250*50 lOum; Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrileFlow rate: 80 mL/min Gradient: 3517199

-4865%, 30min) resulting in compound 64 (895 mg) as a white solid. Method B; Rt: 4.45 min. m/z : 366.1 (M+H)* Exact mass: 365.1

Compound 65

The mixture of 6-chloro-N-phenylpicolinamide (4 g, 17.19 mmol), phenylmethanethio! (3.23g, 25.79 mmol) and K2CO3 (4.75g, 34.38 mmol) in DMF was stirred at 80°C for 18 hour. The reaction mixture was diluted with EtOAc (150 mL), and washed with brine (2 x 200 mL). The organic layer was dried over MgSOj, filtered and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc in petroleum ether) to obtain 6-(benzylthio)-N-phenylpicolinamide (2.8 g). N-Chlorosuccinimide (3.42 g, 25.6 mmol) was added to the mixture of 6-(bcnzylthïo)N-phenylpicolinamide (2 g, 6.24 mmol) in acetic acid (60 mL) and water (40 mL). The reaction mixture was stirred at room température for 3 hours. The reaction was diluted with CH2CI2 (100 mL). After washing with water, the organic layer was added to the mixture of cyclohexanamine (12.4 g, 125 mmol) and EtjN (50 mL) in CH2CI2 (200 mL). The resulting mixture was stirred at room température for 4 hours. The reaction mixture was washed with NH4CI (saturated), brine, dried over MgSO<, filtered and concentrated. The obtained residue was purified by preparative HPLC (Column: Synergi 150*30mm*5um; Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrile; Flow rate: 30mL/min; Gradient: 46-76% (solvent B), 8min) resulting in compound 65 (330 mg). Method B; Rt: 4.46 min. m/z : 360.2 (M+H)* Exact mass: 359.1. *HNMR (400 MHz, DMSO-J_é) δ ppm 1.00 -1.31 (m, 5 H) 1.34 1.47 (m, 1 H) 1.51 - 1.71 (m, 4 H) 3.02 - 3.13 (m, 1 H) 7.15 - 7.21 (m, 1 H) 7.40 - 7.46 (m, 2 H) 7.82 - 7.88 (m, 2 H) 8.15 (dd, 7=6.3, 2.5 Hz, 1 H) 8.23 - 8.28 (m, 1 H) 8.298.36 (m, 2 H) 10.47 (s, 1 H)

Compound 66

A mixture of 2-chloro-N-phenylisonicotinamide (2 g, 8.6 mmol), phenylmethanethio 1 (2.11 g, 17 mmol) and KîCOj (2.35 g, 17 mmol) in DMF was stirred at 80°C for 18 hours. The reaction was diluted with water (200 mL) and extracted with EtOAc (2 x

100 mL). The combined organic layers were washed with brine, dried over MgSO«,

-49filtered and concentrated. The obtained residue was punficd by silica gel chromatography (0-20 % EtOAc in petrolcum ether) resulting in 2-(benzylthio)-N-phcnylisonicotinamide (1.7 g). N-Chlorosuccinimide (2.56 g, 19.2 mmol) was added to a mixture of 2-(bcnzylthio)-N-phenylisonicotinamide (1.5 g, 4.68 mmol) in acetic acid (20 mL) and water ( 10 mL). The reaction mixture was stirred at room température for 4 hours. The réaction was diluted with CH2CI2 (20 mL). After washing with water, the organic layer was added to the mixture of cyclohexanamine (4.64lg, 46.8 mmol) and EtjN ( 10 mL, 71.74 mmol) in CH₂C12 (50mL). The resulting mixture was stirred at room température for 4 hours. The reaction mixture was washed with NlLCl (saturated), brine, dried over MgSOj, filtered and concentrated. The obtained residue was purified by préparative HPLC (Column: Cl 8-1 Oum; Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 40-70% (solvent B), 25min) resulting in compound 66 (250 mg). Method B;

Rt: 4.22 min. m/z: 360.2 (M+H)⁺ Exact mass: 359.1. *H NMR (400 MHz, DMSO-7₆) δ ppm0.96 - 1.08 (m, 1 H) 1.08 - 1.24 (m, 4 H) 1.40 - 1.52 (m, 1 H) 1.53 - 1.67 (m, 4 H)

3.11 - 3.22 (m, 1 H) 7.14 - 7.21 (m, 1 H) 7.37 - 7.44 (m, 2 H) 7.78 (d, 7=7.8 Hz, 2 H)

7.97 (br. s, 1 H) 8.12 (dd, 7=5.0,1.5 Hz, 1 H) 8.40 (s, 1 H) 8.94 (d, 7=5.0 Hz, 1 H) 10.75 (s, 1 H)

Compound 67

2-chloro-N-cyclohexylpyridine-4-sulfonamide (540 mg, 1.965 mmol), PdCfcdppf (100 mg, 0.137 mmol) and EtjN (5.89 mmol) in methanol (50 mL) was stirred at 50°C for 18 hours under CO (50Psî) atmosphère. The solvent was removed under reduced pressure. The obtained residue (700 mg) containing methyl 4-(N-cyck>hexylsulfamoyl)picolinate was used in the next step without further purification. K2COJ (421 mg, 3.05mmol) was added to the mixture of methyl 4-(N-cyclohexylsulfamoyl)pico1inate in methanol and water. The mixture was stirred at 20°C for 18 hour. The solvent was removed, the residue was diluted with water (50 mL) and washed with EtOAc (2 x 50 mL). The aqueous layer was then acidified to pH = 3 with 1 M HCl and extracted with EtOAc (2 x 50mL). The combined organic layers were dried over MgSO₄, filtered and concentrated resulting in 4-(N-cyclohexylsulfamoyl)picolinic acid (380 mg). HATU (0.76 g, 2.0 mmol) was then added to a mixture of 4-(N-cyclohexylsulfamoyl)pîcolinic acid (380 mg, 1.34 mmol), aniline (251 mg, 2.7 mmol) and DIPEA (0.517 g, 4.0 mmol) in DMF (50 mL) at room température The resulting mixture was stirred at room température for 18 hour. The mixture was diluted with water (200 mL), and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (10-20% EtOAc in petroleum ether) resulting in compound 67 as a white solid (330 mg). Method B; Rt: 4.58 min. m/z : 360.2 (M+H)⁺ Exact mass: 359.1. *H NMR (300 MHz, DMSO-Æ) 5 ppm 0.93 - 1.26 (m, 5 H) 1.37 - 1.50 (m, 1 H) 1.50 -

1.69 (m, 4 H) 2.98-3.12 (m, 1 H) 7.15 (t,/=7.2 Hz, 1 H) 7.32-7.45 (m, 2 H) 7.86-7.97 (m, 2 H) 8.03 (dd,/=5.0,1.5 Hz, 1 H) 8.25 (d,/=7.3 Hz, 1 H) 8.47 (d, /=1.5 Hz, 1 H) 9.00 (d, /=5.0 Hz, 1 H) 10.78 (s, 1 H)

Compound 68 ^N

Thionyl chloride (10 mL, 137 mmol) was added drop wise to water (60 mL) at 0-5°C. The mixture was stirred at room température for 16 hour. CuCl(40 mg, 0.4 mmol) was added, and the mixture (mixture A) was cooled to -5°C. To a mixture of 5-aminonicotinic acid in con. HCl (35 mL), a solution of NaNO? (2.76g, 40 mmol) in of water (40 mL) at -5°C to 0°C, was added (mixture B), The mixture B was added portionwise to the mixture A over 30 minutes, maintaining température at -5°C to 0°C.Aftcr stirring at 0°C for 1 hour, the solid was collected by filtration, washed with water, and dried in vacuo resulting in 5-(chlorosulfonyl)nicotinic acid (1.05 g). The mixture of 5-(chlorosulfonyl)nicotinic acid (1 g, 4.5 mmol), cyclohexanamine (0.893g, 9 mmol) and EtjN (1.37 mmol, 13.5 mmol) in CH₂C1₂(3O mL) was stirred at room température for 18 hours. The solvent was removed under reduced pressure. The residue was purified by HPLC (Column: Cl8 lOum; Mobile phase A: purified water (0.075%TFA, V/V); Mobile phase B: acetonitrile; Flow rate: 80mL/min; Gradient: 30-60% (solvent B), 30 min) resulting in 5-(N-cyclohexylsulfamoyl)nicotinic acid as a white solid (1 g). HATU (2,6g, 7mmol) was added to the mixture of 5-(N-cyclohexylsulfamoyl)nicotinic acid (1 g, 3.5 mmol), aniline (391 mg, 4.2 mmol) and DIPEA (1.36 g, 10.5 mmol) in DMF (50 mL) at room température The resulting mixture was stirred at room température for 18 hour. The mixture was diluted with of water (200 mL) and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, The residue was purified by silica gel chromatography (10-100% EtOAc in petroleum ether) resulting in compound 68 (708 mg) as white solid. Method B; Rt: 4.58 min. m/z : 360.2 (M+H)⁺ Exact mass: 359.1

Toan ice-cooled solutionof5-amînopentanoic acid(1.2 g, 3.44 mmol) and INNaOH (8 mL) in THF (16 mL) was added 3-(4-fluorophenylcarbamoyl)benzene4-sulfonyl chloride (0.444 g, 3.78mmol). Then the reaction mixture was stirred at 25°C ovemight. The resultîng mixture was diluted with IN HCl (l 0 mL) and extracted with ethyl acetate (2x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SÛ4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether: ethyl acetate:

from 100:0 to 65:35) resultîng in 5-(3-(4-fluorophenylcarbamoyl)phenylsulfonamido) pentanoic add (0.9 g), A mixture of 5-(3-(4-fluorophenylcarbamoyl)phenylsulfonamido) pentanoic acid (400 mg, 0.913 mmol), acetic anhydride (0.466 g, 4.57 mmol) and AcOK.(1.79 g, 18.3 mmol) in toluene (25 mL) was heated by microwave irradiation at 15O°C for 30 minutes. The formed precipitate was filtered offand the filtrate was concentrated in vacuo. The residue was purified by préparative high performance liquid chromatography (eluent: CHjCN in H₂O (0.05% HCI) from 0% to 35%, v/v). The pure fractions were collected and adjusted to pH=7 with Amberlite IRA-900(OH)anionic exchange resin. The resin was filtered off and the filtrate was lyophilized to dryness resultîng in compound 69 (200 mg). Method A; Rt: 4.97 min.

m/z : 377.2 (M+H)⁺ Exact mass: 376.1 ; 'H NMR (400 MHz, CHLOROFORM-J) δ ppm 1.78 - 1.87 (m, 2 H), 1.90 - 1.99 (m, 2 H), 2.44 (t, 7=6.8 Hz, 2 H), 3.95 (t, 7=6.0 Hz, 2 H), 7.08 (t, 7=8.7 Hz, 2 H), 7.55 - 7.70 (m, 3 H), 8.15 (d, 7=8.0 Hz, l H), 8.20 (d, 7=7.8 Hz, l H), 8.26 (br. s., I H), 8.49 (s, l H)

Compound 70

To an iced-cooled mixture of (Æ)-butan-2-amine (0.500 g, 6.837 mmol) and NaOH (0.547 g, 13.67 mmol) in H₂O (15 mL) and THF (15 mL), 3-(chlorosulfonyl)benzoic acid was added (1.508 g, 6.84 mmol) in portions. The reaction mixture was stirred at

20°C for 2 hours. The resultîng mixture was diluted with H₂O (l5 mL) and extracted with ethyl acetate (15 mL). The aqueous layer was separated and pH was adjusted to 3 by l N HCl and extracted with ethyl acetate (3 x I0 mL). The combined organic layer

-52was washed by brine (10 mL), dried over anhydrous Na₂SÛ4 and concentrated under reduced pressure resulting in (R)-3-(N-sec-butylsulfamoyl)benzoic acid (0.73 g). To an ice cooled mixture of (R)-3-(N-sec-butylsulfamoyl)benzoic acid (730 mg),

4-fluoroaniline (347 mg, 3.12 Immol), HATU (1.294 g, 3.404 mmol) in DMF (10 mL) DIPEA (1.48 mL, 8.51 mmol) was added under N₂ atmosphère. The resulting mixture was stirred at 20°C for 2 hour. The solvent was removed in vacuo. The mixture was washed with saturated aqueous critic acid (10 mL), brine and dried over Na₂SO4. The solvent was removed in vacuo. The residue was purified by column chromatography over silica gel (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 55/45). The pure fractions were collected and the solvent was removed in vacuo. The residue was purified by SFC séparation (Chiralcel OJ, 20 pm; Supercritical CO₂ : MeOH (0.2% dicthylamine)). The pure fractions were collected and the solvent was removed in vacuo, resulting in compound 70 (300 mg). Method A; Rt: 5.25 min. m/z : 351.2 (M+H)⁺ Exact mass: 350.1. [«]□= - ( c= 0.2, MeOH). [a]i>°= -9.9 (c 0.435 w/v %, DMF); Column: Chiralpak AD-3 150*4.6mm I.D., 3um; Mobile phase: methanol (0.05% diethylamine) in CO₂ from 5% to 40%; Flow rate: 2.5 mL/min; Rt: 7.58 min; ‘H NMR (400 MHz, DMSO-7₆) δ ppm 0.70 (t, 7=7.4 Hz, 3 H), 0.88 (d, 7=6.5 Hz, 3 H), 1.30 (quin,7=7.2 Hz, 2 H), 3.01 - 3.18 (m, 1 H), 7.21 (t, 7=8.8 Hz, 2 H), 7.67 (br. d, 7=5.5 Hz, 1 H), 7.75 (t, 7=7.8 Hz, 1 H), 7.78 (dd, 7=8.8,5.1 Hz, 2 H), 8.00 (d, 7=7.8 Hz, 1 H), 8.19 (d, 7=7.8 Hz, 1 H), 8.36 (s, 1 H), 10.55 (s, 1 H).

Compound 71

Prepared similar as described for compound 70 starting from (S)-butan-2-amine instead of (R)-butan-2-amine.Method B; Rt: 4.03 min. m/z : 351.2 (M+H)⁺ Exact mass: 350.1 ([«]”= + ( c= 0.2, MeOH). [a]n = + 9.49 (c 0.611 w/v %, DMF), Column: Chiralpak AD-3 150^x4.6mm I.D., 3um; Mobile phase: methanol (0.05% dicthylamine) in CO₂from 5% to 40%; Flow rate: 2.5 mL/min; Rt: 7.73 min. [α]Π, +9.49 ⁰ (c 0.61 w/v %, MeOH)

Compound 72

3-(chlorosulfonyl)benzoyl chloride (1200 mg, 5.0 mmol) was dissolved m dichloromethane (15 mL). A solution of 4-fluono-3-methylani!ine (625 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) in dichloromethane (15 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour. The réaction mixture was used to the next step without further purification. To the above reaction mixture a solution of triethylamine (606 mg, 6.0 mmol) and (S)-tetrahydrofùran-3-amine (460.0 mg, 5.3 mmol) in dichloromethane (15 mL) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The solvent was removed in vacuo. The residue was purified by reversed phase high performance liquid chromatography (eluent: CHjCN in water (0.1% TFA) from 25 to 55, v/v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCOi to pH-7-8. The mixture was extracted with dichloromethane (3x15 mL). The combined organic layers were dried over Na₂SO₃ and concentrated in vacuo resulting in compound 72 (620 mg). Method A; Rt: 4.88 min. m/z : 379.2 (M+H)⁺

Exact mass: 378.1. *H NMR (400 MHz, DMSO-</₆) δ ppm 1.56 - 1.65 (m, 1 H), 1.85 -

1.94 (m, 1 H), 2.22 - 2.28 (m, 3 H), 3.33 - 3.39 (m, 1 H), 3.52 - 3.65 (m, 2 H), 3.65 -

3.73 (m, 1 H), 3.73 - 3.79 (m, 1 H), 7.14 (t, J=9.2 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.67 (dd, >7.0,2.3 Hz, 1 H), 7.78 (t, >7.8 Hz, 1 H), 8.02 (d,>7.8 Hz, 1 H), 8.10 (d, J=4.5 Hz, 1 H), 8.21 (d, >7.8 Hz, 1 H), 8.37 (s, I H), 10.49 (s, I H)

Compound 85 ^F

Prepared similarly as described for compound 72 using 1-ethylcyclopnopanamine hydrochloride înstead of (S)-tctrahydrofuran-3-amine. Compound 85 was purified by préparative high performance liquid chromatography over RP-18 (eluent: CHjCN in H₂O (0.5% NH4HCO3) from 43% to 73%, v/v). Method B; Rt: 4.17 min. m/z : 377.1 (M+H)⁺ Exact mass: 376.1. 'H NMR (400 MHz, DMSO-J₀) δ ppm 0.35-0.45 (m, 2 H), 0.49-0.58 (m, 2 H), 0.77 (t, >7.2 Hz, 3 H), 1.31 (q, >7.1 Hz, 2 H). 2.26 (s, 3 H). 7.15 (t, >9.3 Hz, 1 H), 7.55 - 7.64 (m, 1 H) 7.69 (d,>7.0 Hz, 1 H), 7.76 (t, >7.8 Hz, 1 H),

7.98 (d, >7.8 Hz, 1 H), 8.16 - 8.25 (m, 2 H), 8.35 (s, 1 H), 10.50 (s, 1 H).

Compound 86

-54Prcparcd similarly as described for compound 72 using 2-mcthylbutan-2-aminchydrochloride instead of (S)-tetrahydrofûran-3-aminc. Purified by high performance liquid chromatography over RP-18 (eluent: CHjCN in water from 47% to 77%, v/v). Method D; Rt: 5.97 min. m/z : 379.1 (M+H)* Exact mass: 378.1. 'H NMR (400 MHz, DMSOd₆), δ = 0.73 (t,>7.5 Hz, 3 H), 1.02 (s, 6 H), 1.44 (q, >7.5 Hz, 2 H), 2.23 (d,>1.0 Hz, 3 H), 7.12 (ζ >9.3 Hz, 1 H), 7.52 - 7.61 (m, 2 H), 7.64 - 7.77 (m, 2 H), 8.01 (d, >7.8 Hz, 1 H), 8.14 (d, >7.8 Hz, 1 H), 8.36 (s, 1 H). 10.45 (s, 1 H).

Alternative synthesis of compound 72:

A mixture of 3-(chlorosulfony])benzoyl chloride (4.61 g ,19.28mmol) in toluene (45 mL) was refluxed under a gentle flow of nitrogen. 4-fluoro-3-methylaniline (2.19 g, 17.53 mmol) in toluene (15 mL) was added drop wise to the refluxing solution. After addition, the mixture was refluxed for another 30 minutes. The mixture was next cooled to room température, and a mixture of (S)-3-ammotetrahydrofüran tosylate (5 g, 19.28 mmol) and diisopropylethylaminc (15 mL) in toluene (15 mL) and CH2CI2 (10 mL) was added drop wise. After addition, the mixture was stirred for 4 hours at room tempera ture.The resulting mixture was washed with HCl (2 x 100 mL, 1M aq), water (2 x 100 mL) and NalICOj (2 x 100 mL, sat. aq). The organic layer was dried on MgSO₄, filtered and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (CHîCh-MeOH 100:0 to 95:5) yiclding

3-(4-fluoro-3-methy!phenylcarbamoyl)bcnzcne-l-sulfonyl chloride (1.07 g) during CH2CI2 elution. followed by compound 72 (2.85 g) as a white solid after removal of the solvent (dried in a vacuum oven at 55°C for 20 hours). ([a]“ = - 5.21 (c 0.67 w/v %, MeOH), Method F; Rt: 0.88 min. m/z : 379.1 (M+H)* Exact mass: 378.1. The compound was crystallized from CH2CI2: DSC (From 30 to 300 °C at 10°C/min): 149°C. [«]□ = + 3.21 (c 0.65 w/v %, DMF).

Compound 73 —

To an iced-coolcd solution of 3-(chlorosulfonyl)benzoic acid (50.0 g, 226.6 mmol) in ethylacetate (1000 mL) was added isopropyl amine (67.0 g, 1.13 mol) in one portion. The reaction mixture was stirred at 25°C for 3 hours. The resulting mixture was diluted with IN HCl (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure resulting 3-(N-îsopropylsulfamoyl)benzoic acid

-55(46 g). To an icc-coolcd mixture of 3-(N-îsopropylsulfamoyl)benzoic acid (7.0 g, 28.77 mmol), 4-fluoro-3-methy (aniline (3.6 g, 28.77 mmol) and D1PEA (18.6 g,

143.91 mmol) in CH2CI2 (70 mL) HATU (12.0 g, 31.56 mmol) was added under N2 atmosphère. The resulting mixture was stirred at 20° for 16 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous cri tic acid (30 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by préparative high performance liquid chromatography on SYNERGI 250*50 lOum (eluent: CHjCN in H₂O (0.05% TFA) from 35% to 65%, v/v). The pure fractions were collected and adjusted to pH~7 with Amberlite IRA-900(OH) anionic exchange resin. The resin was fïltered off. The filtrate was lyophilized to dryness resulting in compound 73 (7.5 g). Method B; Rt: 3.44 min. m/z : 351.1 (M+H)⁺ Exact mass: 350.1 *H NMR (400 MHz, DMStW₆) δ ppm 10.49 (1 H, br. s), 8.36 (1 H, t, J-1.5 Hz), 8.19(1 H, ddd, J=7.8, 1.5, 1.0 Hz), 8.01 (1 H,ddd,J^7.8, 1.5,1.0 Hz), 7.76 (1 H, t, J=7.8 Hz), 7.68 (1 H, dd, J=7.0,3.0 Hz), 7.75 (1 H, bs), 7.59 (1 H, ddd, J=9.0,

4.5,3.0 Hz), 7.15 (1 H, t, J=9.0 Hz), 3.14 - 3.33 (1 H, m), 2.25 (3 H, d, J=1.5 Hz), 0.96 (6 H, d, .7=6,5 Hz).

Prepared similarly as described for compound 73, using 4-fluoro-3-(trifluoromethyl)aniline insteadof 4-fluoro-3-methylaniline. Purified on HPLC Synergi 150x30mmx5u (eluent: CHjCN in H₂O (0.05% HCl) from 45% to 75%, v/v). Method A; Rt: 5.62 min. m/z : 405.2 (M+H)⁺ Exact mass: 404.1. *H NMR (400 MHz, DMSCWe) δ ppm 10.82 (1 H, s), 8.39 (1 H, t, J=d.5 Hz), 8.17 - 8.30 (2 H, m), 8.07 - 8.17 (1 H, m), 8.03 (1 H, d. .7=7.8), 7.73-7.83 (2 H, m), 7.55 (1 H, t, J-10.0 Hz), 3.20 - 3.33 (1 H, m), 0.95 (6 H, d, .7=6.5 Hz).

Compound 84

A mixture of N-(3-bromo-4-fluorophenyl)-3-(N-isopropylsulfamoyl)benzamide (prepared similarly as described for compound 73, using 3-bromo-4-fluoroaniline instead of 4-fluoro-3-mcthylaniline and purified via préparative high performance liquid chromatography over RP-18 (eluent: CHjCN in H2O (0.05% NHtHCOj) from 40% to 70%, v/v); 700 mg, 1.69 mmol), cyclopropylboronic acid (0.22 g, 2.529 mmol),

Pd(PPhj)j (0.20 g, 0.169 mmot) and NaÆOj (1.43 g, 13.49 mmol) in water (7 mL), EtOH (7 mL) and toluene (7 mL) was heated by microwave irradiation for 40 minutes at 100°C under N₂. The réaction mixture was filtered through cclitc. Water (10 mL) was added to the filtrate and the mixture was extracted with ethyl acetate (2x10 mL).

The combined organic layers were washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo. The residue was purified by préparative high performance liquid chromatography over RP-18 (eluent: CH₃CN in H₂O (0.1% TFA) from 20% to 50%, v/v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH=7 with saturated aqueous 10 NaHCO₃ and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na₂SO₄. The solvent was removed in vacuo and the obtained residue was further purified by supercritical fluid chromatography (Column: Chiralpak AD-3 l50^x4.6mm I.D., 3um Mobile phase: methanol (0.05% diethylamine) in CO₂ from 5% to 40%. Flow rate: 2,5mL/min). The pure fractions were collected and the volatiles were removed in vacuo. The residue was suspended in water (5 mL) and lyophilized to dryness resulting in compound 84 (35 mg) Method B; Rt: 4.18 min. m/z : 377.1 (M+H)⁺ Exact mass: 376.1 ; *H NMR (400 MHz, chloroform-d) δ ppm 8,34 (s, 1 H),

8.12 (d, J=8.0 Hz, 1 H), 7.97 - 8.07 (m, 2 H), 7.65 (t, J=8.0 Hz, 1 H), 7.36 - 7.46 (m, 1 H), 7.15-7.22 (m, 1 H), 7.01 (t, J=9.3 Hz, 1 H), 4.65 (d, J=7.5 Hz, 1 H), 3.44-3.58 (m, 1 20 H), 2.04 - 2.16 (m, 1 H), 1.10 (d, >6.5 Hz, 6 H), 0.96 -1.06 (m, 2 H), 0.71 - 0.82 (m, 2

H).

Compound 88

Prepared similarly as described for compound 73, using 3,4-difluoroaniline instead of

4-fluoro-3-methylaniline, Method E; Rt: 5.31 min. m/z : 355.1 (M+H)⁺ Exact mass: 354.1;^lH NMR (400 MHz, DMSO-J₆) δ ppm 10.71 (s, I H), 8.36 (t,>1.5 Hz, I H), 8.19 (d, >7.8 Hz, 1 H), 7.98 - 8.08 (m, 1 H), 7.94 (ddd,>13.2,7.5,2.4 Hz, 1 H), 7.71 - 7.83 (m, 2 H), 7.53 - 7.59 (m, I H), 7.42 - 7.51 (m, 1 H), 3.21 - 3.29 (m, 1 H), 0.96 (d, 30 >6.5 Hz, 6 H).

F

Compound 90

3-(chlorosulfonyl)bcnzoyl chlondc (1200 mg, 5.0 mmol) was dissolved in dichloromethane (15 mL). A solution of 3,4-difluoroaniline (650 mg, 5.0 mmol) and triethylamine (606 mg, 6.0mmol) in dichloromethane (15 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour. To the obtained reaction mixture a solution of triethylamine (606 mg, 6.0 mmol) and (S)-tetrahydrofûran-

3-amine (460.0 mg, 5.3mmol) in dichloromethane (15 mL) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The solvent was removed in vacuo. The obtained residue was purified by high performance liquid chromatography over RP-18 (eluent: CHjCN in water (0.1%TFA) from 30 to 60, v/v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCOj to pH=7-8. The mixture was extracted with dichloromethane (3x15 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo resulting in compound 90 (710 mg) Method A; Rt: 4.16 min. m/z : 383.0 (M+H)⁺ Exact mass: 382.1; 'H NMR(400 MHz, DMSO-Jî) δ ppm 1.54 -1.63 (m, 1 H), 1.83 - 1.93 (m, 1 H), 3.32 - 3.38 (m, 1 H), 3.52 - 3.63 (m, 2 H), 3.63 - 3.77 (m, 2 H), 7.45 (dt, >10.5,9.0 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.78 (t, >7.8 Hz, I H),

7.92 (ddd, >13.3,7.5,2.5 Hz, 1 H), 8.02 (d,>7.8Hz, 1 H), 8.09 (d,>6.5 Hz, 1 H),

8.20 (d, >7.8 Hz, I H), 8.35 (s, I H), 10.70 (s, 1 H). SFC: Column: Chiralcel OJ-H 250x4.6mm I.D., 5um; Flow: 2.35 mL/min; Mobile phase: methanol (0.05% diethylamine) in CO₂ from 5% to 40%; Rt: 5.61 Min.[a]o = + 3.21 (c 0.624 w/v %, DMF)

Compound 91

N-(3-bromo-4-fluorophenyl)-3-(N-isopropylsulfamoyl)benzamide (1.5 g, 3.61 mmol), ethynyltrimethylsilane (1.77 g, 18.06 mmol), Pd(PPh₃)₂Cl₂ (0.127g, 0.18 Immol) and copper iodide (34.4 mg, 0.181mmol) were dissolved in diisopropylamine (10 mL). The mixture was stirred at 80°C in autoclave for 24 hours. The solvent was removed in vacuo and dichloromethane (30 mL) was added. The mixture was washed with water (20 mL) and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether ! ethyl acetate from 100/1 to 60/40) resulting in N-(4-fluoro-3-((trimethy!silyl)ethyny!)phenyl)-3-(N-isopropylsu!famoyl)benzamide

-58(0.8 g). N-(4-fluoro-3-((tnmethylsiIyI)cthynyl)phenyl)-3-(N-isopropylsulfamoyl)benzamide (0.8 g, 1.66 mmol) and TFA (4 mL) were dissolved in anhydrous CH2CI2 (16 mL). The mixture was stirred at 25°C ovemight and next concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (gradient eluent: petrolcum ether/ethyl acetate from 100/0 to 75/25) resulting in compound 91 (220 mg). Method A; Rt: 5.12 min. m/z : 361.3 (M+H)⁺ Exact mass: 360.1. ’HNMR (400 MHz, DMSO-Je) δ ppm 10.60 (1 H, s), 8.35 (1 H, t, >1.5 Hz), 8.18 (1 H, d, >8.0 Hz), 8.00 (1 H, d,>8.0 Hz), 7.97 (1 H, dd,>6.5,3.0 Hz), 7.77 - 7.84 (1 H, m),

7.70 - 7.79 (2 H, m), 7.32 (1 H, t,>9.0 Hz), 4.52 (1H, s) 3.22 - 3.31 (1 H, m), 0.94 (6 H, d,>6.5 Hz).

Compound 92

N-(4-fluoro-3-((trimethylsÎlyI)ethynyI)phenyI)-3-(N-isopropylsuIfamoyl)benzamide (0.8g, 1.66mmol) and TFA (4 mL) were dissolved in anhydrous CH2CI2 (16 mL). The mixture was stirred at 25° ovemight The mixture was concentrated resulting in crude N-(3-ethynyl-4-nuorophenyl)-3-(N-isopropylsulfamoyl)benzamidc which was used as such in the next step (650 mg). To a solution ofN-(3-ethynyl-4-fluoropheny[)-3(N-isopropylsuIfamoyl)benzamide (0.6 g) in MeOH (20 mL) was added Pd-C (10%, 0.2 g) under N2 atmosphère. The mixture was stirred under hydrogen atmosphère (50 psi) at 25°C for 4 hours. After filtration on celite, the solvent was removed in vacuo and the obtained residue was purified by préparative high performance liquid chromatography on reversed phase C-l 8 (eluent: CHjCN in H₂O (0.05% HCI) from 42% to 72%, v/v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to PH=7 with Amberlite 1RA-900 anionic exchange resin (OH form), filtered and lyophilized to dryness resulting in compound 92 (160 mg). Method B; Rt: 4.13 min. m/z : 365.3 (M+H)⁺ Exact mass: 364.1; ’H NMR (400 MHz, DMSO-Je) δ ppm 10.48 (1 H, s), 8.35 (1 H, t,>1.5 Hz), 8.18 (1 H, d, >8.0 Hz), 7.99 (1 H, d, >8.0 Hz), 7.70 - 7.78 (2 H, m), 7.65 - 7.70 (1 H, m), 7.57 -

7.65 (1 H, m), 7.13 (1 H.t, >9.0 Hz), 3.21-3.32 (1 H, m), 2,62 (2 H, q,>7.5 Hz),

1.18 (3 H, t, >7.5 Hz), 0.94 (6 H, d, >6.5 Hz).

To a solution of 3-(chlorosulfonyl)benzoyl chloride (0.50 g, 2.09 mmol) in CH₂Cl₂(ÎO mL), DIPEA was added (1.35 g, 10.45 mmol) followed by slow addition of

4-fluoro-3-mcthylaniline (0.25 g, 1.99 mmol). After stirring at 25°C for 0.5 hour,

3-ethyloxetan-3-amine (0.21 g, 2.09 mmol) was added. After 1 hour, the resulting mixture was diluted with CH₂C1₂ (15 mL), washed with saturated aqueous NaHCOj ( 15 mL) and brine ( 10 mL) and dried over anhydrous MgSO₄. The solvent was removed in vacuo and the obtained residue was purified by silica gel coiumn chromatography (gradient eluent: petroleum ethcr/ethyl acetate from 100/0 to 80/20) resulting in compound 93 (70 mg). Method B; Rt: 3.79 min. m/z : 393.3 (M+H)⁺ Exact mass: 392.1; ‘H NMR (400 MHz, DMSO-J₆) δ ppm 10.50 (1 H, s), 8.47 (1 H, br. s),

8.38 (1 H, t,>1.5 Hz), 8.22 (1 H, d, >8.0 Hz), 8.03 (1 H, d,>8.0 Hz), 7.78 (1 H, t, >8.0 Hz), 7.68 (1 H, dd, J=7.5_t 2.5 Hz), 7.56 - 7.64 (1 H, m), 7.15 (1 H, t, >9.0 Hz),

4.51 (2 H, d, >6.5 Hz), 4.19 (2 H, d, >6.5 Hz), 2.25 (3 H, d, >1.5 Hz), 1.84 (2 H, q, >7.0 Hz), 0.64 (3 H, t, >7.0 Hz).

3-(chlorosulfonyl)benzoyl chloride (1200 mg, 5.0 mmol) was dissolved in dichloromethane (15 mL). A solution of 4-fluoro-3-methylaniline (625 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) in dichloromethane (15 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was used to the next step without further purification (crude, 30 mL). To the above reaction mixture was added a solution of triethylamine (606 mg, 6.0 mmol) and 1-methylcyclopropanamine (425.0 mg, 5.9 mmol) in dichloromethane (15 mL) at 0°C. The mixture was stirred at 25°C for 1 hour. The solvent was removed in vacuo. The residue was purified by high performance liquid chromatography on reversed phase (eluent: CH3CN in water from 40% to 70%, v/v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCOj to pH=7-8. The mixture was extracted with dichloromethane (3 x

mL). The combined organic layers were dried over NajSCL and concentrated in vacuo resulting in compound 94 (365 mg). Method B; Rt: 3.40 min. m/z : 363.0 (M+H)⁺ Exact mass: 362.1; 'H NMR (400 MHz, DMSO-J₆) δ ppm 10.49 (1 H, s), 8.35 (1 H, t,>1.5 Hz), 8.17 - 8.23 (2 H, m), 7.99 (1 H, d,>8.0 Hz), 7.76 (I H, t, >8.0

Hz), 7.68 (I H, dd,>7.0,2.5 Hz), 7.56 - 7.62 (1 H, m), 7.14 (1 H, t,>9.0 Hz), 2.25 (3 H, d, >1.5 Hz), 1.06 (3 H, s), 0.58 - 0.63 (2 H, m), 0.37 - 0.42 (2 H, m)

Compound 95

A mixture of N-(3-bromo-4-fluorophenyl)-3-(N-isopropyIsulfamoyl)bcnzamîde (800 mg, 1.93 mmol), 4,4,5,5-tetramethyl-2-(prop-I-en-2-yI)-l,3,2-dioxaborolane (0.65 g,3.85mmol), Pd(PPhj)₄ (lll mg,0.096mmol))andKiCOj (0.53 g,3.85 mmol) in dioxane (8 mL) and water (2 mL) was heated by microwave irradiation for 110 minutes at I20°C under N2 atmosphère. The reaction mixture was diluted with ethyl acetate (20 mL) and the catalyst was fîltered off. The filtrate was concentrated in vacuo. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine and dried over Na2SO₄. The solvent was removed in vacuo and the obtained residue was purified by préparative high performance liquid chromatography over reversed phase C-18 (eluent: CHjCN in H2O (0.1 % TFA) from 40% to 70%, v/v). The pure fractions were collected and the organic solvent was removed in vacuo. The aqueous layer was lyophilized to dryness resulting in N-(4-f!uoro-3-(prop’l-en-2-yl)phenyl)-3-(N-isopropylsulfamoyl)bcnzamide (300 mg). N-(4-fluoro-3-(prop-l-en-2-yl)phenyl)-3(N-isopropylsuIfamoyl)benzamide (180 mg) and Pd/C(wet) (20 mg) were stirred in méthanol (4 mL) under a hydrogen atmosphère at 25°C for 3 hours. The mixture was fîltered over celite and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 70/30). The volatiles were removed in vacuo, resulting in compound 95 (175 mg). Method B; Rt: 4.33 min. m/z : 379.3 (M+H)⁺ Exact mass:

378.1;

3-(difluoromethyl)-4-fluoroaniline (1.20 g, 7.448 mmol), 3-(N-isopropylsulfamoyl)benzoic acid (0.90 g, 3.699 mmol) and DIPEA (1.93 mL, 11.10 mmol) were dissolved in CH2CI2 ( 10 mL) and HATU ( 1.41 g, 3.699 mmo 1) was added at 0°C. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with CH2CI2 (10 mL) and H2O ( 10 mL). The organic layer was separated, washed with saturated aqueous NaHCOj (10 mL) and brine (10 mL) and dried over Na₂SO4. The solvent was removed în vacuo and the obtained residue was purified by preparative high performance liquid chromatography over reversed phase C-l 8 (eluent: CH3CN in H2O (0. l%o NH4HCO3) from 45% to 75%, v/v). The pure fractions were collected and the organic solvent was removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 96 (0.885 g). Method A; Rt: 5.16 min. m/z : 387.3 (M+H)⁺ Exact mass: 386.1; 'H NMR (400 MHz, DMSO-f/₆) δ ppm 10.72 (1 H, s), 8.38 (1 H, t,> 1.5 Hz),

8.21 (1 H, d, 8.0 Hz), 8.06 - 8.13 (1 H, m), 8.02 (1 H, d, 8.0 Hz), 7.92 - 8.00 (1

H, m), 7.72 - 7.82 (2 H, m), 7.40 (1 H, t, J= 9.5 Hz), 7.25 (l H, t,J= 55 Hz), 3.23 - 3.32 (1 H, m), 0.95 (6 H, d, J= 6.5 Hz).

To 3-(4-fluoro-3-methylphcnylcarbamoyl)benzene-l-sulfonyl chloride (500 mg,

1.53 mmol) in toluene (10 mL) at room température, a solution of diisopropylethylamine (0.657 mL, 141.6 mmol) and 3-mcthyl-3-oxetanamine hydrochloride (207 mg, 1.68 mmol) in toluene (5 mL) and dichioromethane (10 mL) was added drop 25 wise. After 2 hours, the reaction mixture was washed with 1M hydrochloric acid (2 x mL, saturated NaHCOj (2 x 10 mL) and brine (2x10 mL). The organic layer was dried on MgSÛ4, filtered and concentrated under reduced pressure until only toluène remained. The formed white preclpitate was filtered and recrystallised out of diisopropylether and acetonitrile. The crystals were dried in a vacuum oven at 55°C for 30 20 hours yielding compound 97 (361 mg) as a white solid. Method F; Rt: 0.89 min. m/z : 379.0 (M+H)⁺ Exact mass: 378.1; *H NMR (400 MHz, DMSO-</₆) δ ppm 1.41 (s, 3

-62H), 2.25 (d, J=1.5 Hz, 3 H), 4.14 (d, >6.3 Hz, 2 H), 4.56 (d,>6.3 Hz, 2 H), 7.14 (t, >9.0 Hz, 1 H), 7.52 - 7.64 (m, 1 H), 7.68 (dd,>7.0,22 Hz, 1 H), 7.77 (t,>8.0 Hz, 1

H), 7.99 - 8.06 (m, 1 H), 8.20 (d, >8.0 Hz, 1 H), 8.37 (t, >1.5 Hz, 1 H), 8.50 (br. s„ 1 H), 10.48 (s, 1 H).

To 3-(4-fluoro-3-methylphenylcarbamoyl)benzene-l-sulfonyl chloride (500 mg,

1.53 mmol) in toluene (10 mL) at room température, a solution of diisopropylethylamine (0.657 mL, 141.6 mmol) and (Æ)-(-)-2-aminobutanc (130 mg, 1.83 mmol) in toluene (5 mL) and dichloromethane (10 mL) was added drop wise. After 2 hours, the reaction mixture was washed with IM aqueous HCl (2 xlO mL), NaHCOj (2x10 mL) and brine (2x10 mL). The organic layer was dried on MgSOi, fîltered and concentrated under reduced pressure until only toluene remained. The formed white precipitate was fîltered, recrystallised (diisopropylether and acetonitrile) and dried in vacuo at 55°C for 20 hours resulting in compound 98 (257 mg) as a white solid. Method F; Rt: 1.04 min. m/z : 382.1 (M+NH₄)⁺ Exact mass: 364.1; *H NMR (400 MHz, DMSO-</î) δ ppm 0.71 (t, >7.5 Hz, 3 H), 0.88 (d, >6.6 Hz, 3 H), 1.31 (quin, >7.5 Hz, 2 H), 2.25 (d, >1.8 Hz, 3 H), 3.05-3.18 (m, 1 H), 7.14 (t, >9.0 Hz, 1 H), 7.55 - 7.62 (m, 1 H), 7.63 - 7.72 (m, 2 H), 7.75 (t,>8.0 Hz, 1 H), 8.00 (d,>8.0 Hz, 1 H), 8.18 (d,>8.0 Hz, 1 H), 8.36 (t, >1.5 Hz, 1 H), 10.46 (s, 1 H).

Compound 99

A mixture of 3-(N-isopropylsulfamoyl)benzoic acid (2.3 g, 9.615 mmol), 3-bromo-4,5difluoroanilinc (2 g, 9.615 mmol) and DIPEA (5 mL) in CH₂C1₂ (30 mL) was cooled to 0°C and HATU (4.39 g, 11.538 mmol) was added. The mixture was stirred for 2 hours at 20°C. The mixture was washed with IN HCl (30 mL) and brine (30 mL) and dried over Na₂SO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether/ethyl acetate from 100/0 to

70/30) resulting in crude N-(3-bromo-4,5-difluorophenyl)-3-(N-isopropylsulfamoyl)benzamide (4 g). A mixture of N-(3-bromo-4,5-difluorophenyl)-3-(N-isopropylsulfamoyl)benzamide (l g, 2.308 mmol), mcthylboronic acid (1 g, 4.616 mmol), Cs₂COj (2.26 g, 6.924 mmol), 2-Dicycfohexylphosphino-2',6'-dimethoxybiphenyl (95 mg, 0.231 mmol) andTris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.231 mmol) in dioxane (15 mL) was heated by microwave irradiation for 40 minutes at 120°C under N₂ atmosphère, After cooling, the mixture was fïltered through celite and the filtrate was evaporated to dryness. The obtained residue was purified by silca gel column chromatography (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 70/30) and further purified by préparative high performance liquid chromatography over reversed phase C-18 (eluent: CHjCN in H₂O (0.1% TFA) from 38% to 68%, v/v). The pure fractions were collected and half of the volatiles were removed in vacuo. The mixture was adjusted to pH=7 with Amberlite IRA-900 (OH) anionic exchange resin and the resin was fïltered ofî. The organic solvent was concentrated in vacuo and the aqueous layer was lyophîlîzed to dryness. The obtained product was further purified by silica gel chromatography (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 70/30) resulting in compound 99 (190 mg). Method A; Rt: 6.09 min. m/z : 369.2 (M+H)⁺ Exact mass: 368.1, 'H NMR (400 MHz, CHLOROFORM-J) δ ppm 8.35 (1 H, t, J-1.5 Hz), 8.09 - 8.17 (2 H, m), 8.04 (1 H, dt, J=8.0,1.5 Hz), 7.66 (1 H, t, J=8.0 Hz),

7.54 (1 H, ddd, J=11.5,6.5,3.0 Hz), 7.14 - 7.22 (1 H, m), 4.72 (1 H, d, J=8.0 Hz), 3.43-3.60 (l H, m), 2.32 (3 H, d, J=2.0 Hz), 1.10 (6 H, d, J=6.5 Hz).

5-(chlorosulfonyl)-2-fluorobenzoic add (7g, 29.3 mmol) was dissolved in dichloromethane (70 mL). DMF (0.7 mL) was added, followed by drop wise addition of oxalyl chloride (4.46 g, 35.16 mmol) at 0°C. The mixture was stirred for 1 hour at 20°C. The mixture was concentrated in vacuo and the crude 5-(chlorosulfonyl)-2-fluorobenzoyl chloride was dissolved in dichloromethane (15 mL). A solution of 3,4-difluoroaniline (3.6g, 27.87 mmol ) and DIPEA (4.6g, 35.20 mmol) in dichloromethane (60 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour and used to the next step directly. To the above reaction mixture, a solution of (/?)-(-)-2-aminobutanc (2.2 g, 29.34 mmol) and DIPEA (4.6g, 35.20 mmol) in dichloromethane (60 mL) was

-64added at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo and the obtained residue was purified by high performance liquid chromatography on reversed phase (eluent: CHjCN in water (0.1% TFA) from 25% to 55%, v/v). The pure fractions were collected and the organic solvent was evaporated. The aqueous solution was adjusted to pH =7 with saturated aqueous NaHCOj. The mixture was extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over Na₂SO.i and concentrated in vacuo. The obtained residue was suspended in water (10 mL) and the aqueous layer was lyophilized to diyness resulting in compound 100 (4.7 g). Method B; Rt: 4.70 min. m/z : 387.2 (M+H)⁺ Exact mass:

386.1.

Compound 101 (S)-tetrahydrofuran-3-amine hydrochloride (5.17 g, 42 mmol) and NaOH (5 g, 126 mmol) were dissolved in THF (50 mL) and H₂O (50 mL). 5-(chlorosulfonyl)-2fluorobcnzoic acid (10 g, 42 mmol) was added at 0°C. The mixture was stirred at 20°C for 4 hours. The mixture was washed with ethyl acetate (3 x 20 mL). The aqueous layer was separated and adjusted to pH=3 with IN HCL The aqueous layer was extracted with ethyl acetate (3 x 50 mL), The combined organic layers were washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo resulting in (S)-2-fluoro-5(N-(tetrahydrofiiran-3-yl)sulfamoyl)benzoic acid (2.1 g). (S)-2-fluoro-5-(N-(tctrahydrofuran-3-yl)sulfamoyl)benzoic acid (1 g, 3.457 mmol), 3,4-difluoroaniline (0.53 g,

4.15 mmol) and triethylamine (0.7 g, 6.9 mmol) were dissolved in DMF (400 mL) and HATU (1.57 g, 4.15 mmol) was added at 0°C. The mixture was next stirred at 20°C for 6 hours. The solvent was removed in vacuo and the obtained residue was purified by silica gel chromatography (eluent: pctrolcum ether: ethyl acetate=5:l) resulting in compound 101 (0.8 g). Method B; Rt: 4.15 min. m/z : 401.3 (M+H)⁺ Exact mass: 400.1 Synthesis of 3-[[(3S)-tetrahydrofuran-3-y[]sulfamoylJbenzoic acid: (35)-tetrahydrofiiran-3-amine hydrochloride (5,6 g, 45.3 mmol) and NaOH (5.2 g, 130 mmol) were dissolved in THF (50 mL) and H₂O (50 mL). 3-(chlorosulfonyl)benzoie acid (10 g, 45.325 mmol) was added at 0°C. The mixture was stirred at 20°C for 4 hours. The aqueous layer was separated and the pH was adjusted to 2 with IN HCL The mixture was washed with ethyl acetate (3 x 100 mLJ.The combined organic layers were concentrated in vacuo resulting in 3-[[(35)-tetrahydrofuran-3yljsulfamoyljbenzoic acid (11.2 g).

A mixture of (S)-tetrahydrofùran-3-amine hydrochloride (l 1.2 g, 90.7 mmol) and NEtj 5 (50.5 mL, 362.6 mmol) in dry CH2CI2 (400 mL) was stirred for 5 minutes at 20° C.

3-(chlorosulfonyl)benzoic acid (20 g, 90.7 mmol) was added and the mixture was stirred ovemight at 20°C. The reaction mixture was washed with IN HCl (100 mL), the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over NajSCL and the solvent was removed in vacuo, resulting 10 in 3-[[(3S)-tctrahydrofüran-3-yl]sulfamoyl]benzoic acid ( 16.3 g). 3-[[(3S)-tetrahydrofiiran-3-yl]sulfamoyl]benzoic acid (3 g, 11.058 mmol), 3-(difluoromethyl)-4-fluoroaniline (2.1 g, I3.3 mmol) and triethylamine (3.3 g, 33 mmol) were dissolved in DMF (400 mL). PyBrOP (l32705-51-2,6.2 g, I3.3 mmol) was added at 0°C. The mixture was stirred at 50°C for 12 hours. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (mobile phase: CHjCN in water (0.1% TFA) from 30% to 60%). The pure fractions were collected and neutralized with solid NaHCOj. The organic solvent was removed in vacuo and the formed precîpitate was filtered, washed with H2O (5 mL) and dried under high vacuum. The obtained residue was suspended in water (5 mL) and lyophilized to dryness resulting in compound 102 (2.3 g). Method A; Rt: 5.32 min. m/z : 415.2 (M+H)* Exact mass: 414.1. *H NMR (400 MHz, DMSO-</₆) δ ppm 1.53-1.68 (m, 1 H) 1.82 - 1.99 (m, 1 H) 3.27 - 3.42 (m, 1 H) 3.51 - 3.90 (m, 4 H) 7.26 (t, 7=55 Hz, 1 H) 7.36-7.51 (m, 1 H) 7.80 (t, 7=7.8 Hz, 1 H) 7.92 - 8.00 (m, 1 H) 8.01 - 8.08 (m, 1 H) 8.08 - 8.15 (m, 2 H) 8.25 (d, 7=7.8 Hz, 1 H) 8.40 (s, 1 H) 10.75 (s, 1 H).

3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]benzoÎc acid (400 mg, 1.47 mmol) was dissolved in DMF (0.5 mL) and CH2CI2 (10 mL). (COC1)₂ (223 mg, 1.76 mmol) was added at 0°C. The mixture was stirred at 20°C for 2 hours. The solvent was removed in vacuo and the obtained residue was co-evaporated with toluene (2 x 10 mL) resulting in crude 3-[[(3S)-tetrahydrofùran-3-yl]sulfamoyl]benzoyl chloride (400 mg).The crude product was used in the next step without purification. 3-[[(3S)-tetrahydrofùran-3-yl]17199

-66sulfamoyljbenzoyl chloride (200 mg) was dissolved in dichloromethane (5 mL).

4-fluoro-3-methoxy-aniline (78 mg, 0.552 mmol) and triethylamine (167 mg, 165 mmol) were added at 0°C. The mixture was stirred at 20°C for 2 hours, washed with H₂O (5 mL) and the waterlayer extracted with dichloromethane (3x10 mL). The combined organic layers were concentrated in vacuo. The obtained residue was purified by reversed phase high performance liquid chromatography (mobile phase: CHjCN in water (0.1% TFA) from 30% to 60%). The pure fractions were collected and neutralized with solid NaHCOj. The organic solvent was removed in vacuo. The obtained precipitate was filtered, washed with H₂O (5 mL) and dried under high vacuum. The residue was suspended in water (5 mL) lyophilized to dryness resulting in compound 103 (140 mg). Method A; Rt: 4.98 min. m/z : 395.2 (M+H)⁺ Exact mass:

394.1

Prepared similarly as described for compound 103:

Method A; Rt: 5.17 min. m/z: 397.3 (M+H)* Exact mass: 396.1

Method A; Rt: 5.10 min. m/z: 389.1 (M+H)⁺ Exact mass: 390.2

Compound 106

Method A; Rt: 5.18 min. m/z : 397.2 (M+H)⁺ Exact mass: 396.1 ^lHNMR (400 MHz, DMSO-J₆) δ ppm 1.54 - 1.69 (m, 1 H) 1.82 - 1.98 (m, 1 H) 2.24 (s, 3 H) 3.35 - 3.40 (m, 1 H) 3.52 - 3.66 (m, 2 H) 3.66 - 3.83 (m, 2 H) 7.32 (t, /=10.0 Hz, 1 H) 7.49 (t, /=8.5 Hz, 1 H) 7.79 (t, /=7.8 Hz, 1 H) 8.04 (d, /=8.0 Hz, 1H)8.O7-

8.18 (m, 1 H) 8.23 (d,/=7.8 Hz, 1 H) 8.39 (s, 1 H) 10.40 (br. s, 1 H)

Compound 107

3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]benzoic acid (270 mg, 1.0 mmol) was dissolved in dichlorométhane (5 mL). 3-methyl-4-methoxyanilîne (165 mg, 1.2 mmol) and triethylamine (145 mg, 1.4 mmol) were added to the mixture at 20°C. The mixture was stirred at 20°C for 5 minutes. HATU (456 mg, 1.2 mol) was added and the mixture was further stirred at 20°C for 8 hours. The solvent was removed in vacuo and the obtained residue was purified by high performance liquid chromatography (Column: Phenomcnex Syncrgi Cl 8 150*20mm*5um.. A: H2O+0.1%TFA B: MeCN from 30% to 60 % B in A). The product fractions were collected and the organic solvent was evaporated in vacuo. The aqueous layer was neutralized with saturated aqueous NaHCOj and extracted with dichlorométhane (2 x 10 mL). The combine organic layers was dried over Na2SO< and concentrated in vacuo resultîng in compound 107 (135 mg). Method A; Rt: 5.24 min. m/z : 391.3 (M+H)⁺ Exact mass: 390.1

Compound 108

5-amino-2-fluoro-phenol (234 mg, 1.84 mmol) and 3-[(3-mcthyloxetan-3-yl)sulfamoyljbenzoic acid (500 mg, 1.84 mmol) were dissolved in dichlorométhane (8 mL). PyBrOP (132705-51-2, 1030 mg, 2.21 mmol) was added followed by drop wîse addition of D1PEA (714 mg, 5.53 mmol) at 0°C. The mixture was stirred for 1 hour at 25°C. The mixture was washed with saturated aqueous citric acid (15 mL), saturated aqueous NaHCOj ( 15 mL) and brine and dried over Na2SO<. The solvent was removed in vacuo. The obtained residue was purified by reversed phase préparative high-performancc liquid chromatography (mobile phase: CH3CN in water (0.05% NH4HCO3) from 29% to 39%). The pure fractions were collected and the volatiles were removed in vacuo. The residual aqueous layer was lyophi lized to dryness re sulting in compound 108 (60 mg). Method A; Rt: 4.47 min. m/z: 381.2 (M+H)⁺ Exact mass:

380.1

Compound 109

Prepared similarly as described for compound 108, using 4-fluoro-3-methoxy-aniline instead of 5-amino-2-fIuoro-phenol. Method A; Rt: 5.03 min. m/z: 395.2 (M+H)⁺ Exact mass: 394.1

Compound 110

DIPEA (2.85 g, 22.08 mmol) was added to a solution of 3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (3.0 g, 11.06 mmol) and HATU (4.20 g, 11.05 mmol) in DMF (100 mL) at 25°C. After 30 minutes, 3-bromo-4-fluoro-ani!ine (2.1 g, 11.05 mmol) was added to the solution. The reaction mixture was stirred at 25°C ovemight. The solvent was removed in vacuo and the obtained residue was purified by silica gel column chromatography (gradient eluent: petroleum ether/ethyl acetate from 10/1 to 5/1). The pure fractions were collected and the solvent was removed in vacuo resulting în N-(315 bromo-4-fIuoro-phenyl)-3-[(3-methyloxetan-3-yl)sulfamoyl]benzamide (compound

160,2.5 g). A mixture of N-(3-bromo-4-fluoro-phenyl)-3-[(3-methyloxetan-3yl)sulfamoyl]benzamide (0.3 g, 0.68 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2dioxaborotane (54.2 mg, 0.35 mmol), Pd (dppf) Ct₂ (50 mg, 0.068 mmol), KOAc (108 mg, 1.1 mmol) andNa₂CO₃ (100 mg, 0.94 mmol) inCH₃CN(10mL) and H₂O (2 mL) 20 was heated by microwave irradiation for 30 minutes at 130°C under a N₂ atmosphère.

The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate (2x10 mL). The organic layer was separated from the fîltrate, washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo. The obtained residue was purified by reversed phase préparative high performance liquid chromatography (eluent: CH₃CN in H₂O (0.05% NH₃.H₂O) from 30% to 80%, v/v).

The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 110 (70 mg). Method B; Rt: 4.19 min. m/z : 391.3 (M+H)⁺ Exact mass: 390.1.

Compound 111

3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (3 g, 11.06 mmol), methyl 5-amino-2fluoro-benzoate (2.33 g, 13.2 mmol) and DIPEA (2.84 g, 22 mmol) were dîssolved in

DMF (40 mL). HATU (5.02 g, 13.2 mmol) was added at 0°C. The mixture was stirred at 20°C for 2 hours. The solvent was removed in vacuo and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:l) resulting in methyl 2-fluoro-5-[[3-[(3-methyloxetan-3-yl)sulfamoyl]benzoyl]amino]benzoate (2.3 g). Methyl 2-fluoro-5-[[3-[(3-methyloxetan-3-yl)sulfamoyl]benzoyl]amino]benzoate (0.3 g, 0.71 mmol) was dissolved in THF (5 mL) and éthanol (5 mL). NaBHj (53 mg, 1.4 mmol) was added at 0°C. The mixture was stirred for 2 hours at 20°C. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance Iiquid chromatography (mobile phase: CH₃CN in water (0.1% TFA) from 34% to 64%). The pure fractions were collected and neutralized with solid NaHCOj. The organic solvent was removed in vacuo. The precipitate was filtered, washed with HjO (5 mL) and dried under high vacuum. The residue was suspended in water (5 mL) and the aqueous layer was lyophilized to dryness resulting in compound 111 (220 mg). Method A; Rt: 4.34 min. m/z : 395.3 (M+H)⁺ Exact mass: 394.1.

Compound 127 — (2-fluoro-5-nitro-phenyl)methanol(4.3 g, 25.1 mmol) was dissolved in dichloromethane (50 mL). Diethylaminosulfur trifluoride (4.5 g, 27.9 mmol) was added drop wise to the mixture at -30°C. The mixture was stirred at 10° C for 4 hours. Methanol (10 mL) was added to the mixture and the mixture was further stirred at 10°C for 30 minutes. The mixture was washed with brine (30mL) and the aqueous layer was extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo, resulting in l-fluoro-2-(fluoromethyl)-4-nitrobenzene (3.9 g). A mixture of l-fluoro-2-(fluoromethyl)-4-nitro-benzene (3.1 g,

17.9 mmol), iron (4.0 g, 71.6 mmol) and methanol (30 mL) was stirred at 65° for 8 hours. The mixture was filtrated and the filtrate was concentrated in vacuo, resulting in

4-fluoro-3-(fluoromethyl)aniline (1.5 g). 3-(chlorosulfonyl)benzoyl chloride (300 mg,

1.2 mmol) and triethylamine (150 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-fluoro-3-(fluoromethyl)aniline (175 mg, 1.22 mmol) was added to the mixture at 0° C. The mixture was stirred at 10°C for 30 minutes. The mixture was used to the next step without further purification.Triethylamine (152 mg, 1.5 mmol) and

3-methyl-3-oxetanamine (131 mg. 1.5 mmol) were added to the above obtained reaction mixture at 0° C. The mixture was stirred at 20° C for l hour. The solvent was removed m vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (Column: Gemini 250*20mm* 5 um.. A: H₂O+0.1%TFA B: MeCN. 27% to 57% B in A). The product fractions were collected and the organic solvent was removed in vacuo. The fraction was neutralized by saturated NaHCOj. The mixture was extracted with dichloromethane (3 x 20 mL) and the combined organic layer was dried over Na₂SO4 and concentrated in vacuo, resulting in compound 127 (91.1 mg). Method A; Rt: 4,95 min. m/z : 397.3 (M+H)⁺ Exact mass:

396.1. 'H NMR (400 MHz, DMSO-J«) δ ppm 1.41 (s, 3 H) 4.14 (d,7=6.3 Hz, 2 H)

4.56 (d,7=6.3 Hz, 2 H) 5.52 (d,7=48 Hz, 2 H) 7.31 (t,7=9.4 Hz, 1 H) 7.72 - 7.89 (m, 2 H) 7.92-7.97 (m, 1 H) 8.03 (d, 7=8.0 Hz, 1 H) 8.23 (d, 7=7.8 Hz, 1 H) 8.39 (s, 1 H)

8.55 (s, 1 H) 10.67 (s, 1 H).

Compound 112

Compound 123 (255 mg, 0.592 mmol) and Pd/C (50 mg) were stirred in methanol (25 mL) under a hydrogen atmosphère for 3 hours. The reaction mixture was fîltered, concentrated and the obtained residue dried in vacuo at 50°C resulting in compound 112 as a colorless resin.(174 mg). Method G; Rt: 1.57 min. m/z : 397.1 (M+H)⁺ Exact mass: 396.1. 'HNMR (400MHz, DMSO-de)δppm 1.65 - 1.80 (m, I H), 1.91 -2.04 (m, 1 H), 2.24 (d, >1.5 Hz, 3 H), 3.43 (dd, J=9.0,4.6 Hz, 1 H), 3.55 - 3.79 (m, 3 H),

3.80 - 3.91 (m, 1 H), 7.14 (t, J=9.2 Hz, 1 H), 7.45 - 7.57 (m, 2 H), 7.64 (dd, >7.0,2.4 Hz, 1 H), 7.85 - 8.02 (m, 2 H), 8.40 (d, >6.8 Hz, 1 H), 10.62 (s, 1 H)

Compound 113

3-methyloxctan-3-amine hydrochloride (210 mg, 1.7 mmol) andNaOH (204 mg,

5.1 mmol) were dissolved ίη 2-methyltetrahydrofiiran (5 mL) and H₂O (5 mL).

5-ch!orosulfonyl-2-methy!-bcnzoic acid (400 mg, 1.7 mmol) was added at 0°C. The mixture was sti rred at 20°C for 4 hours. The aqueous layer was separated and adjusted to pH=3 by aq.HC! (lN).The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated in vacuo resulting in 2-methyl-5[(3-methyloxetan-3-y!)sulfamoyl]bcnzoic acid (250 mg). 2-methyl-5-[(3-methyloxetan·

3-yl)sulfamoyl]bcnzoic acid (250 mg, 0.876 mmol), 3-(difluoromethyl)-4-fluoroaniline (178 mg, 1.1 mmol) and DIPEA (232 mg, 1.8 mmol) were dissolved in DMF (5 mL). HATU (399 mg, 1.05 mmol) was added at 0°C. The mixture was stirred at 20°C for 2 hours. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 34% to 64%). The pure fractions were collected and neutralized with solid NaHCOj. The organic solvent was removed in vacuo and the formed precipitate was Filtered, washed with H2O (5 mL) and dried under high vacuum. The residue was suspended in water (5 mL) and the aqueous layer was lyophilized to dryness resulting in compound 113 (220 mg). Method A; Rt: 5.28 min. m/z : 429.3 (M+H)⁺ Exact mass: 428.1. *HNMR (400 MHz, DMSO-</₆) δ ppm 1.44 (s, 3 H) 2.47 (s, 3 H) 4.15 (d, >6.3 Hz, 2 H) 4.57 (d, >6.0 Hz, 2 H) 7.24 (t, >54.5 Hz, 1 H) 7.40 (t, >9.5 Hz, 1 H) 7.56 (d,>8.0 Hz, 1 H) 7.71 - 7.98 (m, 3 H) 8.09 (d,>4.3 Hz, 1 H)

8.37 (br. s., I H) 10.74 (br. s., 1 H) .O

Compound 114

3-(isopropylsulfamoyl)benzoic acid (190 mg, 0.78 mmol) was dissolved in dichloromethane (5 mL). 3-fluoro-4-methoxyaniline (139 mg, 0.94 mmol) and triethylamine (112 mg, 1 mmol) were added to the mixture at 20° C. The mixture was stirred at 20°C for 5 minutes. HATU (358 mg, 0.94 mmol) was added to the mixture at 20°C, The mixture was stirred at 20°C for 8 hours. The solvent was removed in vacuo and the obtained residue was purified by high performance liquid chromatography (Coiumn: Phenomenex Synergi C18 l50*20mm*5um.. A: H2Û+0.1%TFA B: MeCN 30% to 60% B in A). The product fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCOj. The mixture was extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried overNa2SO₄ and concentrated in vacuo resulting in compound 114 (135 mg). Method A; Rt: 5.60 min. m/z: 367.2 (M+H)⁺ Exact mass: 366.1

Compound 115

Prepared similarly as desribed for compound 127 using 4-fluoro-2,3-dimethyl-aniline

-72instcad of 4-fluoro-3-(fluoromcthyl)aniIine. Method A; Rt: 4.98 min. m/z : 393.3 (M+H)⁺ Exact mass: 392.1.

Compound 116

4-fluoro-3-methyl-aniline (9.04 g, 72.2 mmol) was added drop wîse to a solution of

3-(chlorosuIfonyI) benzoyl chloride (19.0g, 79.47 mmol) in toluene (300 mL) at 1 !0°C. The résultant mixture was stirred at 110°C for 1 hour and allowed to cool to 20°C ovemight. The precipitate was filtered and reCTystallized from dry toluene resulting in

3-[(4-fluoro-3-methy!-phenyl)carbamoyI]benzenesulfonyl chloride (20 g). 3-[(4-fluoro-

3-methyl-phenyl)cafbamoyl]benzenesulfonyl chloride (15 g, 45.77 mmol) was added drop wise at 0°C to a solution of 2-aminopropan-l-ol (3.437 g, 45.77 mmol) and triethylamine (6.946 g) in THF (200 mL). The résultant mixture was stirred for 10 minutes and then allowed to warm to 20° C during 2 hours. The reaction mixture was quenched with IN HCl (50 mL). The mixture was extracted with dichloromethane (3 x 30 mLJ.The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient eluent: petroleum ether ! ethyl acetate from 100/1 to 50/50), resulting in N-(4-fluoro-3-methyl-phenyI)-3-[(2-hydroxy-1 -methyl-ethyOsuIfamoyl]benzamide (15.6 g). Diethyl diazene-l,2-dicarboxylate (4.91 g, 28.19 mmol) was added drop wise to a solution of N-(4-fluoro-3-methyI-phenyI)-3-[(2-hydroxy-l-methylethyl)sulfamoyl]benzamide (7.8 g, 21.29 mmol) and PPhj (6.14 g, 23.41 mmol) in THF (500 mL) at -70°C under Argon. The résultant mixture was stirred for 1 hour and then allowed to warm to 20°C ovemight The réaction mixture was quenched with 1N HCl (300 mL). The mixture was extracted with dichloromethane (4 x 400 mL) and the combined organic layers were washed with brine, dried over MgSQi, filtered and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate from 100/1 to 60/40) resulting in N-(4-fluoro-3-methyl-phenyI)-3-(2-methy!aziridÎn- l-yl)sulfonyl-benzamîde (6.5 g). A mixture of N-(4-fluorO’3-methyl-phenyl)’3-(2-methyIaziridin-l-yl)sulfonylbenzamide (300 mg, 0.861 mmol) and 1-methylpiperazine (862 mg, 8.61 mmol) in

1.4-dioxane (3 mL) was heated by microwave irradiation at 150°C for 30 minutes. The volatiles were removed in vacuo. The obtained residue was purified by silica gel column chromatography (gradient eluent: petroleum ether/ethy! acetate from 100/1 to 1/100). The pure fractions were collected and the solvent was removed in vacuo. The

obtained residue was purified by préparative high-performance liquid chromatography (column: Luna l50*30mm*5u, mobile phase: CH₃CN in water (0.1% NH₄HCO₃) from 44% to 74%). The pure fractions were collected, concentrated in vacuo and the residual aqueous solution was lyophilized to dryness resulting in compound 116 (250 mg).

Method A; Rt: 4.26 min. m/z : 449.4 (M+H)⁺ Exact mass: 448.2

Compound 117

Prepared similarly as desribed for compound 116 using morpholine instead of

1-methylpiperazine. Method A; Rt: 4.45 min. m/z : 436.3 (M+H)⁺ Exact mass: 435.2

To a stirred solution of 3,4-difluoro-2-methyl-aniline (369 mg, 2.6 mmol), 3-[[(35)tetrahydrofùran-3-yl]sulfamoylJbenzoic acid (700 mg, 2,58 mmol) and N,N15 diisopropylcthylamine(1.35 ml, 7.74 mmol) in DMF (10 mL), Pybrop (132705-51-2,

1.82 g, 3.9 mmol) was added at 0° C. The resulting mixture was stirred ovemight at 18 °C. The mixture was concentrated in vacuo, ethyl acetate (15 mL) was added and the organic layer was washed with IN HCl (15 ml) and saturated aqueous NaHCCh (15 mL). After drying over Na₂SO₄ and concentration in vacuo, the crude residue was purified by reversed phase préparative high-performance liquid chromatography (eluent: CHjCN in H2O (0.05% NHj.H₂O) from 37% to 37%, v/v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness, resulting in compound 118 (238 mg). Method D; Rt: 5.01 min. m/z : 396.9 (M+H)⁺ Exact mass: 396.1

Compound 119

-74Preparcd similarly as described for compound 127 using 4-fluoro-2,5-dimcthyl-anihnc instead of 4-fluoro-3-(fluoromethyl)aniline, and DIPEA instead of N Et 3. Method A; Rt:

5.27 min. m/z: 393.3 (M+H)⁺ Exact mass: 392.1

Compound 120

A mixture of l-(2-pyridyl)propan-2-amïne (207.8 mg, 1.53 mmol) and DIPEA (0.532 mL, 3.05 mmol) were dissolved in CH2CI2 (10 mL). 3-[(4-fluoro-3-methylphenyl)carbamoyl]benzenesulfonyl chloride (500 mg, 1.53 mmol) was added portion wise at 0°C and the mixture was stirred at 0°C for 1 hour. The mixture was washed with saturated citric acid (10 mL), saturated aqueous NaHCOj (10 mL), brine and dried over Na2SO₄. The solvent was removed in vacuo and the obtained residue was purified by silica gel column chromatography (gradient eluent: pctroleum cthcr/cthyl acetate from 100/1 to l/100).The pure fractions were collected and the solvent was removed in vacuo. The obtained solid was suspended in water (10 mL) and acetonitrile (10 mL) and the solution was lyophilizcd to dryness resulting in compound 120 (550 mg).

Method B; Rt: 3.36 min. m/z: 428.3 (M+H)⁺ Exact mass: 427.1. *H NMR (400 MHz, DMSOfe) 8 ppm 0.95 (d, 7=6.5 Hz, 3 H) 2.26 (d, 7=1.5 Hz, 3 H) 2.69 (dd, 7=13.6, 7.3 Hz, I H) 2.80 (dd, 7=13.6,7.0 Hz, 1 H) 3.64 - 3.74 (m, 1 H) 7.08 - 7.19 (m, 3 H) 7.55-

7.64 (m, 2 H) 7.64 - 7.71 (m, 2 H) 7.84 - 7.89 (m, 1 H) 7.89 - 7.95 (m, 1 H) 8.12 - 8,17 (m, 1 H) 8.25 (t, 7=1.5 Hz, 1 H) 8.32 - 8.36 (m, I H) 10.45 (s, I H).

Compound 224

Compound 224 was prepared similarly as described for compound 223, using 1 -(4pyridyl)propan-2-amine instead of l-(2-pyridyl)propan-2-amine. Compound 224 was purified by préparative high-performance liquid chromatography (column: Luna 150*30mm*4u, mobile phase: CHjCN in water (0.05% NH₄HCOj) from 40% to 70%). Method A; Rt: 4.6 min. m/z: 428.3 (M+H)⁺ Exact mass: 427.1.

Synthesis of 5-chlorosulfonvl-2-methvl-bcnzovl chloride and 3-[(4-fluoro-3-methyl· Dhenvr)carbamovll-4-methvl-benzenesulfonv! chloride

5-(chlorosulfonyl)-2-mcthyIbenzoic acid (10 g, 42.61 mmol) was dissolved in dichioromethane (200 mL). N,N-dimethylfonnamide (166 pL, 2.13 mmol) was added and the mixture was stirred at room température under a nitrogen atmosphère.

Oxaly! chloride (18.3 mL, 213 mmol) was added in four portions over one hour.

The resulting mixture was stirred for one hour at room température. The mixture was concentrated in vacuo and co-evaporated twice using toluene (2 x 100 mL) yielding 5chlorosulfonyl-2-methyl-benzoyl chloride as a yellow oil which was used as such. 5chlorosulfonyl-2-methyl-benzoyl chloride_(10.7 g, 42.3 mmol) was dissolved in toluene (220 mL) and this was heated to reflux and stirred under a gentle flow of nitrogen.

4-fluoro-3-methy (aniline (4.76 g, 38.1 mmol) in toluene (80 mL) was added drop wise using a syringe pump (0,8 mL / min). The resulting mixture was stirred for 30 minutes while heating was continued. Then the mixture was cooled to room température. A précipitation was formed and collected on a glass filter. The obtained solid was dried in vacuo at 55°C, yielding 3-[(4-fluoro-3-mcthyl-phenyl)carbamoyl]-4-methyl15 benzenesulfonyl chloride (10.4 g) as a solid which was used as such in the next step.

A solution of (S)-3-aminotetrahydrofùran tosylate (0.76 g, 2.93 mmol) and diisopropylethylamine (1.26 mL, 7.31 mmol) in dichioromethane (10 mL) was added drop wise to a solution of 3-[(4-fluoro-3-mcthyI-phenyl)carbamoylJ-4-mcthylbenzenesulfonyl chloride (1 g, 2.93 mmol) in dichioromethane (10 mL). The resulting mixture was stirred for 1 hour at room température. The mixture was quenched using HCl (aq /14.6 mL, 14.6 mmol). The layers were separated and the water layer was extracted with dichioromethane (2 x 20 mL). The combined organics were concentrated in vacuo and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and dried în vacuo at 55^QC yielding compound 121 as a bright white solid. Method F; Rt: 0.90 min. m/z: 393.2 (M+H)⁺ Exact mass: 392.1. *H NMR (400 MHz, DMSO-cb) δ ppm 1.58 - 1.69 (m, 1 H), 1.85 - 1.98 (m, 1 H), 2.24 (d, J=1.3 Hz, 3 H), 2.45 (s, 3 H),

3.38 (dd, J=8.8,4.4 Hz, 1 H), 3.53 - 3.65 (m, 2 H), 3.66 - 3.76 (m, 2 H), 7.13 (t, >9.2

Hz, 1 H), 7.46 - 7.59 (m, 2 H), 7.66 (dd, J=7.0,2.2 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 7.96 (br. s., 1 H), 10.46 (s, 1 H).

-76Compound 122

A solution of 3-methyl-3-oxetanamine hydrochloride (0.4 g, 3.22 mmol) and diîsopropylethylamine (1.26 mL, 7.31 mmol) in of dichloromethane (10 mL) was added drop wise to a solution of 3-[(4-fluoro-3-methyl-phenyl)cafbamoyl]-4-methylbenzenesulfonyl chloride (1 g, 2.93 mmol) in dichloromethane(10 mL). The resulting mixture was stirred for 1 hour at room température. The mixture was quenched using HCl (aq / 14.63 mL, 14.63 mmol). The layers were separated and the water layer was extracted using dichloromethane (2 x 20 mL). The combined organic layers were concentrated in vacuo and purified using column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55°C yielding compound 122 as a bright white solid. Method F; Rt: 0.90 min. m/z: 410.2 (M+NH₄)⁺ Exact mass: 392.1.'H NMR (400 MHz, DMSOtk) δ ppm 1.43 (s, 3 H), 2.19 - 2.29 (m, 3 H), 2.44 (s, 3 H), 4,14 (d, J=6.4 Hz, 2 H),

4.56 (d, >6.2 Hz, 2 H), 7.13 (t, J=9.1 Hz, 1 H), 7.42 - 7.57 (m, 2 H), 7.59 - 7.71 (m, 1 H), 7.74 - 7.90 (m, 2 H), 8.36 (s, 1 H), 10.46 (s, 1 H).

Compound 123 Cl

Compound 123 was prepared similarly as described for compound 121 starting from

5-chloro-3-chlorosulfonyl-2-fluoro-bcnzoic acid (commercial from Enamine EN30035191) via 5-chloro-3-chlorosulfonyl-2-fluoro-benzoyl chloride (^lH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (dd, >5.4,2.8 Hz, 1 H), 8.37 (dd, >5.5,2.6 Hz, 1 H)). After silica gel column chromatography (gradient elution: EtOAc-heptane 10:90 to 100:0) compound 123 was crystallised by addition of H₂O to a hot iPrOH solution of compound 123, resulting in compound 123 as white solid (3153 mg). Method G; Rt:

1.81 min. m/z: 431.0 (M+H)⁺ Exact mass: 430,1. 'H NMR (400 MHz, DMSO-d«) δ ppm 1.65 - 1.79 (m, 1 H), 1.93 - 2.06 (m, 1 H), 2.25 (d, >1.8 Hz, 3 H), 3.44 (dd, J=9.0,

4.4 Hz, 1 H), 3.62 (td, >8.0,5.9 Hz, 1 H), 3.69 (dd, >8.9,6.3 Hz, 1 H), 3.71 - 3.79 (m, I H), 3.84 - 3.98 (m, 1 H), 7.15 (t, >9.1 Hz, 1 H), 7.45 - 7.55 (m, 1 H), 7.61 (dd, >6.9,2.3 Hz, 1 H), 7.91 (dd, J=5.7,2.6 Hz, 1 H), 8.07 (dd, J=5.2,2.8 Hz, 1 H), 8.57 (d, >6.8 Hz, 1 H), 10.68 (s, 1 H)

Compound 124

Compound 125 (167 mg,0.371 mmol) and Pd/C (25 mg) were stirred in methanol (19 mL) under hydrogen atmosphère during 80 minutes. The reaction mixture was fîltered and concentrated. The obtained residue was purified by préparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO₂, MeOH with 0.2% iPrNH₂), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again resulting in compound 124 (67 mg). Method G; Rt: 1.61 min. m/z: 430.0 (M+NHî)* Exact mass: 412.1. ^lH NMR (400 MHz, DMSO-cfc ) δ ppm 1.68 -

1.83 (m, 1 H), 1.89 - 2.03 (m, 1 H), 2.24 (d, >1.5 Hz, 3 H), 3.45 (dd, >8.9,4.7 Hz, 1 H), 3.56 - 3.69 (m, 2 H), 6 3.70-3.86 (m, 2 H), 7.14 (t, >9.1 Hz, 1 H), 7.45 - 7.55 (m, 1 H), 7.60-7.69 (m, 2 H), 7.82 (dd, >7.6,1.7 Hz, 1 H), 8.09 (dd, >7.8,1.7 Hz, 1 H), 8.34 (s, 1 H), 10.62 (s, 1 H)

Compound 125

Compound 125 was prepared similarly as described for compound 126 starting from

2,6-dichloro-3-chlorosulfonyl-benzoic acid instead of 3-chlorosulfonyl-2-methylbenzoic acid. Method G; Rt: 1.77 min. m/z: 464.0 (M+NH4/ Exact mass: 446.0. ‘HNMR (400 MHz, CHLOROFORMA) δ ppm 1.75-1.86 (m, 1 H), 2.04 - 2.16 (m, 1 H), 2.30 (d, >1.8 Hz, 3 H), 3.57 - 3.65 (m, 1 H), 3.66 - 3.76 (m, 2 H), 3.82 - 3.95 (m, 2 H), 5.45 (d, >7.5 Hz, 1 H), 7.01 (t, >8.9 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 7.47 - 7.56 (m, 2 H), 7.83 (s, 1 H), 8.05 (d, >8.6 Hz, 1 H).

3-chlorosulfonyl-2-methyl-benzoic acid (commercial fromEnamine EN300-I095I6;

508.4 mg, 2.17 mmol) was dissolved in dichloromethane (50 mL). DMF (I drop) and oxalylchloride (1375mg, 10,83 mmol) were added and the mixture was stirred for 4 hours under an inert atmosphère. The reaction mixture was concentrated resulting in 35 chlorosulfonyl-2-methyl-benzoyl chloride as a yellow oil (554 mg) which was used as such în the next step. *H NMR (400 MHz, CHLOROFORM-î/) δ ppm 2.92 - 3.01 (m, 3 H), 7.60 (t, >7.9 Hz, 1 H), 8.27 - 8.41 (m, 2 H). 4-Fluoro-3-methylaniline (227 mg,

1.98 mmol) dissolved in dichloromethane (10 mL) was added drop wise, over 5 minutes, to a solution of 3-chlorosulfonyl-2-methyl-benzoyl chloride (550 mg, 10 2.17 mmol) in toluene (50 mL) at reflux. The reaction mixture was refluxed for 30 minutes and next cooled in an icebath. A solution of (S)-3-aminotetrahydrofuran tosylate (564 mg, 2.17 mmol) and DIPEA (0.85 ml, 4.94 mmol) dissolved in dichloromethane (10 mL) was added and the obtained mixture was stirred for 30 minutes. The resulting mixture was washed with HCl (2 x 100 mL / IM aq), water (2 x 15 100 mL) and NaHCOj (2x100 mL ! sat. aq). The organic layer was dried over MgSO₄, fîltered and concentrated in vacuo. The obtained residue was purified using silica gel column chromatography (CHîCb-MeOH 100:0 to 90:10) and repurified by applying a gradient from 10 ttll 100% EtOAc in heptane. The product fractions were concentrated and dried ovemight in vacuo at 50°C yiclding compound 126 as colourless oil (16.6 mg). Method G; Rt: 1.65 min. m/z: 393.1 (M+H)⁺ Exact mass: 392.1. *H NMR (400 MHz, CHLOROFORMEZ) δ ppm 1.73 - 1.87 (m, 1 H), 2.06 - 2.20 (m, 1 H), 2.30 (d, >1.8 Hz, 3 H), 2.69 (s, 3 H), 3.54 - 3.63 (m, I H), 3.65 - 3.78 (m, 2 H), 3.83 - 3.97 (m, 2 H), 4.99 (d, >8.1 Hz, I H), 7.01 (t, >8.9 Hz, 1 H), 7.31 - 7.44 (m, 2 H), 7.51 (dd, >6.7,2.5 Hz, 1 H), 7.58 - 7.69 (m, 2 H), 8.06 (dd, >8.0,1.2 Hz, 1 H)

Procedure SI: A solution of 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (0.50 g, 1.52 mmol, 1 eq) in toluene (10 mL) was added to a flask containîng an amine (1.1 eq). DIPEA (657 pL, 3.81 mmol, 2.5 eq) was added and the reaction mixture was stirred for I hour. Next, IM HCl (5 mL) was added to thereaction mixture.

Procedure S2: A tube was charged with 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (250 mg, 0.76 mmol) and an amine (1.1 eq) and CH2CI2 (5 mL) was added. The solution was stirred, DIPEA (329 pL, 1.9 mmol, 2.5 eq) was added and the mixture was further stirred for 30 minutes.Then, HCl (IM aq / 5 mL) 35 was added and the mixture was stirred for 5 minutes more.

Procedure S3: To a solution of 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (0.50 g, 1.52 mmol, I eq) and DIPEA (657 pL, 3.81 mmol, 2.5 eq) in

-79CH2CI2 ( 10 mL), an amine ( 1.1 eq) was added. The reaction mixture was stirred for 1 hour. Next, IM HCl (5 mL) was added to the reaction mixture.

Procedure S4:3-[(4-fluoro-3-mcthyl-phcnyl)carbamoyl]benzenesulfonyl chloride (250 mg, 0.76 mmol) and DIPEA (329 pL, 1.9 mmol, 2.5 eq) dissolved in CH₂C1₂(5 mL) were added to a tube containing an amine (1.1 eq). The reaction mixture was stirred for 3 hours. IM HCl (5 mL) was added.

Workup Wl: A precipitate was formed. The precipitate was fïltered off, rinced with diisopropylether and dried in a vacuum oven at 55 °C.

Workup W2: The organic layer was separated and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using a heptane to EtOAc gradient as eluent.

Workup W3: The layers were separated and the organic layer was loaded on a silica gel column for purification (with gradient elution: ClFCL-medianol 100:0 to 97:3). Workup W4: The organic layer was separated and loaded on a silica gel column. The mixture was purified using gradient elution from heptane to EtOAc.

Compound 128

Synthesis following procedure S4 with 7-oxabicyclo[2.2.1]heptan-2-amine. as amine, workup W4. Method F; Rt: 0.94 min. m/z: 422.1 (M+NH»)* Exact mass:

4O4.I.‘H NMR(400 MHz, DMSO-J₆) δ ppm 1.22- 1.48 (m, 5 H), 1.68 (dd, >12.5,

7.9 Hz, 1 H), 2.25 (d, >1.8 Hz, 3 H), 3.25 - 3.29 (m, 1 H), 4.14 (d, J=4.8 Hz, 1 H),

4.44 (t, J=4.8 Hz, 1 H), 7.14 (t, J=9.2 Hz, 1 H), 7.54 - 7.63 (m, I H), 7.68 (dd, >7.2,

2.3 Hz, 1 H), 7.74 - 7.80 (m, 1 H), 7.86 (d, >6.8 Hz, 1 H), 7.98 - 8.03 (m, 1 H), 8.20 (dt, >7.8, 1.4 Hz, 1 H), 8.35 (t, >1.5 Hz, I H), 10.46 (s, 1 H).

Compound 129

Synthesis following procedure S3 with R-(+)-3-aminotetrahydrofuran toluene-4sulfonate as amine, workup W2.

Method F; Rt: 0.89 min. m/z: 396.1 (M+NH₄)⁺ Exact mass: 378.1.¹ H NMR (400

MHz, DMSO-de ) ppm 1.56 - 1.65 (m, 1 H), 1.85 - 1.94 (m, 1 H), 2.25 (d, >1.8 Hz, 3 H), 3.36 (dd, >9.0,4.4 Hz, 1 H), 3.52 - 3.65 (m, 2 H), 3.65 - 3.73 (m, l H), 3.73 - 3.79

-80(m, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.67 (dd, >7.0,2.3 Hz, 1 H),

7.78 (t, >7.8 Hz, 1 H), 7.99 - 8.05 (m, 1 H), 8.08 (bs, 1 H), 8.20-8.23(m, 1 H), 8.37 (t, >1.7 Hz, 1 H), 10.47 (s, 1 H), [«]□ = + 5.8 (c 0.61 w/v %, MeOH)

Method F; Rt: 0.95 min. m/z: 424,2 (M+NH₄)⁺ Exact mass: 406.1.

Synthesis following procedure S3 with racemic trans-2-aminocyclohexanol hydrochloride as amine, workup W2.

Compound 131

Synthesis following procedure S3 with(lS,2S)-trans-2-aminocyclohexanol hydrochloride as amine, workup W2.

Method F; Rt: 0.95 min. m/z: 424.2 (M+NH»)* Exact mass: 406.1.

'H NMR (400 MHz, DMSO-de) δ ppm 1.01 - 1.23 (m, 4 H), 1.41 - 1.58 (m, 2 H), 1.59

- 1.70 (m, 1 H), 1,71 - 1.83 (m, 1 H), 2.25 (d, >1.3 Hz, 3 H), 2.77 - 2.90 (m, 1 H), 3.15

- 3.27 (m, 1 H), 4.50 (d, J=4.6 Hz, 1 H), 7.14 (t, J=9.2 Hz, 1 H), 7.54 - 7.64 (m, 2 H),

7.64 - 7.69 (m, 1 H), 7.72 (t, J=7.9 Hz, 1 H), 8.04 (d, >7.7 Hz, 1 H), 8.16 (d, >7.9 Hz, 1 H), 8.39 (s, 1 H), 10.43 (s, 1 H)

Compound 132

Synthesis following procedure S3 with racemic cis-2-aminocyclohexanol hydrochloride as amine, workup W2. Method F; Rt: 0.96 min. m/z: 424.1 (M+NHi)⁺ Exact mass:

406.1. 'H NMR (400 MHz, DMSO-de ) δ ppm 1.01 - 1.26 (m, 4 H), 1.26 - 1.36 (m, 1 H), 1.38 - 1.62 (m, 3 H), 2.25 (d, >1.8 Hz, 3 H), 3.03 - 3.14 (m, 1 H), 3.57 (br. s., 1 H), 4.52 (d, >4.2 Hz, 1 H), 7.14 (t, >9.1 Hz, 1 H), 7.46 (d, >7.9 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.68 (dd, >7.0,2.6 Hz, 1 H), 7.73 (t, >7.8 Hz, 1 H), 8.05 (dt, >8.1,1.2 Hz, 1 H), 8.14 - 8.19 (m, 1 H), 8.39 (t, >1.7 Hz, 1 H), 10.43 (s, 1 H)

Synthesis following procedure S3 with trans-4-aminocyclohexanol hydrochloride as amine, workup W2.

Method F; Rt: 0.84 min. m/z: 424,2 (M+NH<)* Exact mass: 406.1.

¹ H NMR (400 MHz, DMSO-de) 8 ppm 1.01 - 1.31 (m, 4 H), 1.57 (d, J=I0.3 Hz, 2 H),

1.69 (d, >12.5 Hz, 2 H), 2.25 (d, >1.8 Hz, 3 H), 2.84 - 3.01 (m, 1 H), 3.22 - 3.29 (m,

H), 4.46 (d, >4.4 Hz, 1 H), 7.14 (t, >9.1 Hz, 1 H), 7.53 - 7.64 (m, 1 H), 7.68 (dd, >7.0,2.2 Hz, 1 H), 7.72 - 7.79 (m, 2 H), 7.95 - 8.04 (m, 1 H), 8.18 (dt, >7.7,1.3 Hz, 1 H), 8.36 (t, >1.7 Hz, 1 H), 10.46 (s, I H)

Method F; Rt: 0.89 min. m/z: 424.2 (M+NHj)⁺ Exact mass: 406.1.

Synthesis following procedure S3 with 3-amino-cyclohexanol as amine, workup W2. Compound 134 was separated in it’s isomers by préparative SFC (Stationary phase: 15 Chiralpak Daicel IC 20 x 250 mm), Mobile phase: CO2, iPrOH with 0.4% iPrNHî), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, yielding 134a, 134b, 134c, 134d. SFC Columns: ID-H 250 mm x 4.6 mm Flow: 3 ml/min Mobile phase: 25 % iPrOH (containing 0.2% iPrNH2) hold 18.0 min. Température: 30°C; Rt: 134 a (10.0 min), 134b (11.1 min), 134c (13.6 min), 134d (14.7 min). Cîs: Enantiomers 134a and 134b N-(4-fluoro-3-methyl-phenyl)-3[[(lR,3S)-3-hydroxycyclohexyl]sulfamoyl]bcnzamide orN-(4-fluoro-3-methylphenyl)-3-[[(lS,3R)-3-hydroxycyclohexyl]suIfamoyI]bcnzamide. *H NMR (400 MHz, DMSO-</₆ ) δ ppm 0.84 - 1.14 (m, 4 H), 1.48 - 1.60 (m, 2 H), 1.60-1.72 (m, 1 H), 1.72

- 1.82 (m, 1 H), 2.26 (d, >1.8 Hz, 3 H), 2.93 - 3.07 (m, I H), 3.20 - 3.30 (m, 1 H), 4.58 25 (d, >4.6 Hz, 1 H), 7.14 (t, >9.1 Hz, 1 H), 7.55 - 7.64 (m, I H), 7.69 (dd, >7.0,2.2

Hz, I H), 7.76 (t, >7.8 Hz, I H), 7.83 (br. s., ! H), 7.96 - 8.06 (m, 1 H), 8.13 - 8.24 (m, 1 H), 8.38 (t, >1.7 Hz, 1 H), 10.47 (s, I H)

Trans: enantiomers 134c and 134d N-(4-fluoro-3-methyl-phenyl)-3-[[(lR,3R)-3 hydroxycyclohexyl]sulfamoyl]benzamide or N-(4-fluoro-3-methyl-phenyl)-330 [[(lS,3S)-3-hydroxycyclohexyl]sulfamoyl]benzamide ’H NMR (400 MHz, DMSO-Je ) δ ppm 1.08 - 1.20 (m, 1 H), 1.25 - 1.42 (m, 4 H), 1.42 - 1.58 (m, 3 H), 2.25 (d, >1.8

-82Hz, 3 H), 3.36 - 3.45 (m, 1 H), 3.71 - 3.89 (m, 1 H), 4.38 (d, /=3.5 Hz, 1 H), 7.14 (t, /=9.1 Hz, 1 H), 7.51 (br. s., 1 H), 7.56 - 7.63 (m, 1 H), 7.69 (dd, /=7.2,2.3 Hz, 1 H),

7.73 - 7.78 (m, 1 H), 7.97 - 8,05 (m, 1 H), 8.19 (dt,/=7,9,1.2 Hz, 1 H), 8.37 (t, /=1.7 Hz, IH), 10.47 (br. s., 1 H)

Compound 135

Synthesis following procedure S3 with 2-oxa-6-azaspiro[3.3] heptane as amine, workup W2. Method F; Rt: 0.91 min. m/z: 389.1 (M-H)' Exact mass: 390.1. *H NMR (400 MHz, DMSO-de ) δ ppm 2,26 (d, >1.8 Hz, 3 H), 3.95 (s, 4 H), 4.44 (s, 4 H), 7.15 (t, >9.2 Hz, 1 H), 7.57 - 7.65 (m, 1 H), 7.68 (dd, J=7.0,2.4 Hz, 1 H), 7.85 (t, J=7.8 Hz, 1 H), 8.01 (dt, J=8.0,1.3 Hz, 1 H), 8.28 - 8.38 (m, 2 H), 10.51 (s, 1 H).

Synthesis following procedure SI with (lR,2S)-(+)-cis-l-aminoindan-2-ol as amine, workup Wl. Method G; Rt: 1.79 min. m/z: 439.0 (M-H)' Exact mass: 440.1. ’ H NMR (400 MHz, DMSO-dtf) δ ppm 2.25 (d, >1.8 Hz, 3 H), 2.72 (d, >15.0 Hz, 1 H), 2.93 (dd, >16.1,4.6 Hz, 1 H), 4.15 (qd, JM.7,1.8 Hz, 1 H), 4.69 (dd, >8.7,4.7 Hz, 1 H),

4.96 (d, >4.4 Hz, 1 H), 6.87 (d,>7.3 Hz, 1 H), 7.04 -7.10(m, 1 H), 7.10-7.21 (m, 3 H), 7.55 - 7.64 (m, 1 H), 7.68 (dd, >7.0,2.4 Hz, 1 H), 7.77 (t, >7.8 Hz, 1 H), 7.93 (d, >9.0 Hz, 1 H), 8.15 (dt, >8.1,1.2 Hz, 1 H), 8.21 (dd, >7.7,1.5 Hz, 1 H), 8.48 (t, >1.7 Hz, 1 H), 10.44 (s, 1 H)

Synthesis following procedure S4 with (lS,2R)-2-aminotetralin-l-ol hydrochloride as amine, workup W4. Method F; Rt: 1.03 min. m/z: 472.2 (M+NH₄)* Exact mass:

454.1. ’H NMR (400 MHz, DMSO-J_e ) δ ppm 1.35- 1.46 (m, 1 H), 1.96 (qd, >11.8,

6.2 Hz, 1 H), 2.25 (d, >1.5 Hz, 3 H), 2.62 (ddd, >17.2,10.9,6.3 Hz, 1 H), 2.70 - 2.82 (m, 1 H), 3.34 - 3.45 (m, 1 H), 4.39 (br. s., 1 H), 5.29 (d, >5.7 Hz, 1 H), 7.04 (d, >6.8

Hz, 1 H), 7.09 - 7.24 (m, 4 H), 7.55 - 7.63 (m, 1 H), 7.62-7.70 (m, 2 H), 7.75 (t, >7.8 Hz, 1 H), 8.06 - 8.13 (m, 1 H), 8.19 (d, >8.1 Hz, 1 H), 8.43 (t, >1.5 Hz, 1 H), 10.44 (s, 1 H), [et]”: +66 ° (c 0.55 w/v %, DMF). DSC (From 30 to 300 °C at 10^oC/min): 170°C.

Compound 138 ^OH

Synthesis following procedure SI with trans-(lS,2S)-2-aminocyc!opentanol hydrochloride as amine, workup Wl. Method F; Rt: 0.88 min. m/z: 410.4 (M+NH<)⁺Exact mass: 392.1.¹H NMR (400 MHz, DMSO-&) Ô ppm 1.16 -1.29 (m, 1 H), 1.29 1.40 (m, 1 H), 1.50 (quin, >7.4 Hz, 2 H), 1.61 - 1.78 (m, 2 H), 2.25 (d, >1.8 Hz, 3 H),

3.16 - 3.26 (m, 1 H), 3.74 - 3.82 (m, 1 H), 4.67 (d, >4.4 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.65 - 7.72 (m, 2 H), 7.75 (t, >7,8 Hz, 1 H), 7.98 - 8.04 (m, 1 H), 8.18 (dt, >7.9,1.3 Hz, 1 H), 8.36 (t, >1.7 Hz, 1 H), 10.45 (s, 1 H)

Compound 139 ^OH

Synthesis following procedure SI with cis-(l/î,2S)-2-aminocyclopentanol hydrochloride as amine, workup Wl. Method F; Rt: 0.92 min. m/z: 410.1 (M+NHi)⁺Exact mass: 392.1. ’ H NMR (400 MHz, DMSO-d<) δ ppm 1.25 - 1.51 (m, 4 H), 1.51 -

1.67 (m, 2 H), 2.25 (d, >1.5 Hz, 3 H), 3.21 - 3.28 (m, 1 H), 3.72 - 3.79 (m, 1 H), 4.63 (d, >4.0 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.42 (d, >8.1 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.68 (dd, >7.3,2.4 Hz, 1 H), 7.73 (t, >7.8 Hz, 1 H), 8.06 (dt, >8.1,1.2 Hz, 1 H),

8.17 (d, >8.1 Hz, 1 H), 8.40 (t, >1.5 Hz, 1 H), 10.43 (s, 1 H)

Compound 172 ^OH

Synthesis following procedure S2 with cis-(15',2/?)-2-aminocyclopcntanol hydrochloride as amine.The formed prccipitate was collected on a glassfilter and rinsed with CH2CI2 (2x5 mL). The precipitate was further purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). Drying in vacuo at 55°C resulted in compound 172 as a bright white powdcr. Method G; Rt: 1.65 min. m/z: 392.9 (M+H)⁺ Exact mass: 392.1. DSC (From 30 to 300 °C at 10°Cmin):145 °C.

Compound 173

Synthesis following procedure S4 (reaction timc= 20 hours instead of 3 hours) with trans-(l/ï,2/î)-2-aminocyclopentanol as amine, workup W4. Method F; Rt: 0,87 min. m/z: 410.1 (M+NH₄)⁺ Exact mass: 392.1.

Synthesis following procedure SI with l,l-dioxothiolan-3-amine hydrochloride as amine, workup Wl. Method F; Rt: 0.85 min. m/z: 444.2 (M+NH»)⁺ Exact mass: 426.1. ¹H NMR (400 MHz, DMSO-d<s) δ ppm 1.90 - 2.04 (m, 1 H), 2.16 - 2.24 (m, 1 H), 2.25 10 (d, J=1.8 Hz, 3 H), 2.81 (dd, J=13.4,7.0 Hz, 1 H), 3.08 (ddd, J=13.1,9.1,7.5 Hz, 1 H),

3.15 - 326 (m, 2 H), 3.94 - 4.06 (m, 1 H), 7.15 (t, J=9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H),

7.68 (dd, J=7.2, 2.3 Hz, 1 H), 7.79 (t, >7.8 Hz, 1 H), 8.01 - 8.07 (m, 1 H), 8,23 (dt, >7.7, 1.3 Hz, 1 H), 8.38 (t, J=1.7 Hz, 1 H), 8.40 (br. s., 1 H), 10.48 (s, 1 H)

Synthesis following procedure S4 with 2-amino indan-l-ol hydrochloride as amine, workup W4. Method F; Rt: 0.98 and 1.01 min. m/z: 458.1 (M+NH»)⁺ Exact mass: 440.1. Compound 141 was separated in it’s isomers by préparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm), Mobile phase: CO₂, MeOH with 0.2% iPrNH₂), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. SFC, Column: OD-H (Diacel) 250 mm x 4.6 mm

Flow: 5 mL/min, Mobile phase: 30% MeOH (containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1 min and hold 2.00 min @ 50% Température: 40°C.Rt: 141a (1.8 min), 25 141b (2.1 min), 141c (2.5 min), 141d (2.7 min).

141a, 141c: N-(4-fluoro-3-mcthyl-phenyl)-3-[((lS,2S)-l-hydroxyindan-2-yl]sulfamoyljbenzamide or N-(4-fluoro-3-mcthyl-phcnyl)-3-[[( 1 R,2 R)-1 -hydroxyindan-2yl]sulfamoyl]benzamîde. ‘H NMR (400 MHz, DMSO-î/₆ ) δ ppm 2.25 (d, J=1.5 Hz, 3 H), 2.43-2.55 (m, 1 H), 2.83 (dd, J=15.7,7.8 Hz, 1 H), 3.59 - 3.70 (m, 1 H), 4.83 (d,

-85>6.8 Hz, 1 H), 5.58 (br. s„ 1 H), 7.03 - 7.27 (m, 5 H), 7.56 - 7.65 (m, 1 H). 7.68 (dd, >7.0,2.4 Hz, 1 H), 7.78 (t, >7.8 Hz, ! H), 8.05 - 8.11 (m, 1 H), 8.16 (br. s., 1 H), 8.22 (d, >8.1 Hz, 1 H), 8.43 (ζ >1.7 Hz, 1 H), 10.47 (br. s., 1 H) Method F; Rt: 0.98 m/z:

458.3 (M+NH₄)⁺ Exact mass: 440. !.

141b, 141d: N-(4-fluoro-3-methyl-phenyl)-3-[[(!/î,25)-l-hydroxyindan-2yljsulfamoyljbcnzamidc or N-(4-fluoro-3-mcthy!-phcnyl)-3-[[(lS,2R)-l-hydroxyindan-

2-yl]sulfamoyl]benzamidc. 'H NMR (600MHz, ACETONE-d<$, -14 °C) δ ppm 2.25 (d, >1.9 Hz, 3 H), 2.80 - 2.90 (m, 2 H), 3.94 - 3.99 (m, 1 H), 4.72 (d, >5.3 Hz, 1 H), 4.87 (d, >3.8 Hz, 1 H), 6.96 (d, >5.0 Hz, 1 H), 7.08 (t, >9.2 Hz, 1 H), 7.14 - 7.19 (m, 2 H), 7.21 (td, >7.3,1.2 Hz, 1 H), 7.29 (d, >7.3 Hz, 1 H), 7.65 - 7.70 (m, 1 H), 7,74 (dt, >6.8,3.1 Hz, 1 H), 7,79 (t, >7.8 Hz, 1 H), 8.19 (ddd, >7.8,1.8,1.1 Hz, 1 H), 8.27 (ddt, >7.8,1.8,0.9,0.9 Hz, 1 H), 8.54 (q, >1.6 Hz, 1 H), 10.09 (s, 1 H) Method F; Rt: 1.00 m/z: 458.2 (M+NH₄)⁺ Exact mass: 440.1.

Synthesis following procedure S4 with (l/î,2/?)-2-amino-l-phenyl-propan-l-ol as amine, workup W4. Method F; Rt: 1.00 min. m/z: 460.1 (M+NHf)* Exact mass: 442.1.¹H NMR (400 MHz, DMSO-</₆) δ ppm 0.76 (d, >6.8 Hz, 3 H), 2.25 (d, >1.3 Hz, 3 H), 3.37-3.46 (m, 1 H), 4.56 (d, >4.6 Hz, 1 H), 5.41 (br. s., 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.18 - 7.23 (m, 1 H), 7.23 - 7.32 (m, 4 H), 7.49 (br. s., 1 H), 7.56 - 7.64 (m, 1 H), 7.64 - 7.72 (m, 2 H), 7.88 - 7.96 (m, 1 H), 8.15 (d, >7.9 Hz, 1 H), 8.31 (t, >1.5 Hz, 1 H), 10.42 (s, 1 H).

Compound 143

Synthesis following procedure SI with(!/ï,2S)-(-)-norephedrine as amine, workup Wl. Method F; Rt: 1.01 min. m/z: 460.1 (M+NH₄)⁺ Exact mass: 442.1.¹ H NMR (400 MHz, DMSO-ds ) δ ppm 0.79 (d, >6.8 Hz, 3 H), 2.25 (d, >1.8 Hz, 3 H), 3.33 -

3.37 (m, 1 H), 4.48 (t, J=4.6 Hz, 1 H), 5.42 (d, >4.6 Hz, 1 H), 7.10 - 7.27 (m, 6 H),

7.55 - 7.63 (m, 1 H), 7.64 - 7.71 (m, 2 H), 7.78 (d, >8.4 Hz, 1 H), 7.91 (dt, >8.2,122 Hz, 1 H), 8.12 - 8.18 (m, 1 H), 8.30 (t, >1.7 Hz, 1 H), 10.42 (s, I H)

Synthesis following procedure SI with (IS, 2Æ)-(+)-norephedrine as amine, workup Wl. Method F; Rt: l.Ol min. m/z: 460.2 (M+NH₄)⁺ Exact mass: 442.1.

'H NMR (400 MHz, DMSO-dô) 5 ppm0.79 (d, >6.8 Hz, 3 H), 2.25 (d, >1.8 Hz, 3 H),

3.32 - 3.38 (m, 1 H), 4.48 (t, >4.6 Hz, 1 H), 5.42 (d, >4.8 Hz, 1 H), 7.10 - 7.27 (m,

H), 7.56 - 7.63 (m, 1 H), 7.65 - 7.71 (m, 2 H), 7.78 (d, >8.4 Hz, 1 H), 7.89 - 7.94 (m,

H), 8.15 (dt, >7.8,1.3 Hz, 1 H), 8.30 (t, >1.7 Hz, 1 H), 10.42 (s, 1 H)

Compound 145

Synthesis following procedure S4 with 3-aminocyclopentanol as amine, after completion, the reaction mixture was directly loaded on a silica gel column for purification, using a heptane to EtOAc gradient yielding compound 145 as a 83 (145a, 145b): 17 (145c, 145d) mixture of diastereomers. Method F; Rt: 0.82 and 0.86 min. m/z: 410.2 (M+NH₄)⁺ Exact mass: 392.1. Compound 145 was separated in it’s isomers by preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, MeOH with 0.4% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again yielding compound 145a (238 mg) and 145b (236 mg) and a mixture of compound 145c and 145d. The mixture of 145c and 145d was further purified by Preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, EtOH with 0.4% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again yielding 145c (29 mg) and 145d (27 mg). 145a and 145b: N-(4-fluoro-3-methyl-phenyl)-3[[(l/?,35)-3-hydroxycyclopcntyl]sulfamoyl]bcnzamide or N-(4-fluoro-3-methylphenyl)-3-[[(lS,3/î)-3-hydroxycyclopentyl]sulfamoyl]benzamide.

Method F; Rt: 0.85 min. m/z: 410.2 (M+NH₄)⁴ Exact mass: 392.1.

‘H NMR (400 MHz, DMSO-rfc) δ ppm 1.21 (ddd, >13.3,7.8,6.1 Hz, 1 H), 1.36 -

1.64 (m, 4 H), 1.84 - 1,95 (m, 1 H), 2.25 (d, >1.1 Hz, 3 H), 3.37 - 3.47 (m, 1 H), 3.85 -

3.96 (m, 1 H), 4.25-5.00 (IH, br. s), 7.14 (t, >9.2 Hz, 1 H), 7.35-7.75 (IH, br. s), 7.54 7.63 (m, 1 H), 7.68 (dd, >7.0,2.2 Hz, 1 H), 7.75 (t, >7.8 Hz, 1 H), 8.01 (d, >7.9 Hz,

H), 8.19 (d, >7.7 Hz, 1 H), 8.36 (s, 1 H), 10.46 (br. s., 1 H)

145c and 145d: N-(4-fluoro-3-methyl-phenyl)-3-[[(lS,35)-3-hydroxycyclopentyl]sulfamoyljbenzamide or N-(4-fluoro-3-methyl-phenyl)-3-[[( !/?,3/?)-3-hydroxycyclo

-87pentyljsulfamoyljbenzamide. Method F; Rt: 0.82 min. m/z: 410.2 (M+NH|) Exact mass: 392.1.

*HNMR (400 MHz,DMSO-i/e ) δ ppm 1.17-1.35 (m.2H), 1.41 (ddd, >13.4,8.0,

5.7 Hz, 1 H), 1.56 (ddd, >13.2,7.3,2.6 Hz, 1 H), 1.69 - 1.83 (m, 2 H), 2.25 (d, >1.8 Hz, 3 H), 3.59 - 3.72 (m, 1 H), 3.99 - 4.09 (m, 1 H), 4.43 (d, >3.5 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.68 (dd, >7.0,2.2 Hz, 1 H), 7.73 - 7.84 (m, 2 H),

7.96 - 8.02 (m, 1 H), 8.20 (dt, >7.9,1.2 Hz, 1 H), 8.36 (t, >1.7 Hz, 1 H), 10.48 (br. s„ 1 H) 145a: [a]?: +5.2 ⁰ (c 0.56 w/v %, DMF); I45b: [a]?: -5.4 ° (c 0.60 w/v %, DMF); 145c: [a]“ : -3.5 ⁰ (c 0.46 w/v %, DMF); I45d: [a]“ : +2.5 °(c 0.44 w/v %, DMF)

Compound 146

Synthesis following procedure S2 with 6-oxa-2-azaspiro[3.4]octane oxalate as amine, after completion, the réaction mixture was directly loaded on a silica gel coiumn for purification, using a heptane to EtOAc gradient yielding compound 146. Method F; Rt:

0.93 min. m/z: 422.3 (M+NH^)* Exact mass: 404.1.¹ H NMR (400 MHz, DMSO-de) ppm 1.81 (t, >6.9 Hz, 2 H), 2.26 (d, >1.8 Hz, 3 H), 3.46 (s, 2 H), 3.57 (t, >6.9 Hz, 2 H), 3.72 - 3.80 (m, 4 H), 7.15 (t, >9.1 Hz, 1 H), 7,58 - 7.64 (m, 1 H), 7.69 (dd, >7.0,

2.2 Hz, 1 H), 7.87 (t, >7.8 Hz, 1 H), 8.04 (dt, >8.0,1.3 Hz, 1 H), 8.32 - 8.41 (m, 2 H),

10.53 (s, 1 H).

Compound 147

Synthesis following procedure S2 with 6-oxa-l-azaspiro[3.3]heptane as amine, after completion, the reaction mixture was directly loaded on a silica gel coiumn for purification, using a heptane to EtOAc gradient yielding compound 147. Method F; Rt: 0.92 min. m/z: 408.2 (M+NH₄)⁺ Exact mass: 390.1. ¹H NMR (400 MHz, DMSO-Je ) δ ppm 2.25 (d, >1.8 Hz, 3 H), 2.53 (t, >7.3 Hz, 2 H), 3.73 (t, >7.4 Hz, 2 H), 4.53 (d, >7.9 Hz, 2 H), 5.01 (d, >7.9 Hz, 2 H), 7.15 (t, >9.1 Hz, 1 H), 7.56 - 7.64 (m, 1 H),

7.68 (dd, >7.0,2.2 Hz, 1 H), 7.82 (t, >7.8 Hz, 1 H), 8.05 - 8.11 (m, 1 H), 8.29 (dt, >7.8,1.3 Hz, 1 H), 8.40 (t, >1.7 Hz, 1 H), 10.51 (s, 1 H)

Compound 148

Synthesis following procedure S4 with ($)-(+)-1-cyclohexylethylamine as amine, workup W4. Method F; Rt: 1.23 min. m/z: 436.2 (M+NHj)⁺ Exact mass: 418.2

Compound 149

Synthesis following procedure S4 with 4,4-dîfluorocyclohexylamine as amine, workup W4. Method F; Rt: 1.06 min. m/z: 444.5 (M+NH<)⁺ Exact mass: 426.1.

Compound 150

Synthesis following procedure S4 with 3-buten-2-amine, hydrochloride as amine, workup W4. Method F; Rt: 1.01 min. m/z: 380.3 (M+NH₄)⁺ Exact mass:

362.1. 'H NMR (400 MHz, DMSO-de) δ ppm 1.03 (d, J=6.8 Hz, 3 H), 2.25 (d, J=1.8 Hz, 3 H), 3.74 - 3.87 (m, 1 H), 4.87 (dt, >10.5,1.4 Hz, 1 H), 5.00 (dt, >17.3,1.4 Hz, 1 H), 5.61 (ddd, >17.3,10.5,6.1 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.68 (dd, >7.2,2.3 Hz, 1 H), 7.74 (t, >7.8 Hz, 1 H), 7.93 (d, >7.9 Hz, 1 H), 7.96 8.01 (m, 1 H), 8.18 (dt, >7.7,1.3 Hz, 1 H), 8.35 (t, >1.7 Hz, 1 H), 10.45 (s, 1 H).

Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with ($)-(+)-

2-amino-3-mcthylbutane as amine, workup W4. Method F; Rt: 1.11 min. m/z: 396.2 (M+NH<)⁴ Exact mass: 378.1. ’H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (d, >6.8 Hz, 6 H), 0.95 (d, >6.8 Hz, 3 H), 1.57 - 1.67 (m, 1 H), 2.28 (d, >1.8,3 H), 3.13 - 3.28 (m, 1 H), 4.85 (d, >8.6 Hz, 1 H), 6.98 (t, >9.0 Hz, 1 H), 7.36 - 7.46 (m, 1 H),

7.49 - 7.57 (m, 1 H), 7.61 (t, >7.8 Hz, 1 H), 8.00 (dt, >7.9,1.5 Hz, 1 H), 8.12 (dt, >7.9,1.5 Hz, 1 H), 8.25 (s, 1 H), 8.39 (ζ >1.9 Hz, 1 H).

Synthesîs following procedure S4 (stirred for 20 hours înstead of 3 hours) with (1R)-1 cyclopropylethylaminc as amine, workup W4.¹ H NMR (400 MHz, CHLOROFORMd) δ ppm -0.05 - 0.05 (m, 1 H), 0.09-0.16 (m, 1 H), 0.20 - 0.36 (m, 1 H), 0.38 - 0.51 (m, 1 H), 0.69-0.81 (m, 1 H), 1.13 (d, >6.6 Hz, 3 H), 2.27 (d, >1.8 Hz, 3 H), 2.63 - 2.85 (m, 1 H), 5.10 (d, >6.8 Hz, 1 H), 6.98 (t, >8.9 Hz, 1 H), 7.37-7.45 (m, 1 H), 7.52 (dd, >6.6,2.4 Hz, 1 H), 7.60 (t, >7.8 Hz, 1 H), 7.98-8.02 (m, 1 H), 8.08-8.13 (m, 1 H), 8.25 (s, 1 H), 8.38 (t, >1.7 Hz, 1 H). Method F; Rt: 1.07 min. m/z: 394.2 (M+NH|)⁺Exact mass: 376.1.

Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with ( 1 R)-1 cyclopropylethylamine as amine, workup W4. The obtained residue was recrystallised from disopropylether/acetonitrile. The precipitate was collected and dried in vacuo at 55°C, resulting in compound 174. 'H NMR (400 MHz, DMSO-de) δ ppm-0.11 --0.01 (m, I H), 0.07 - 023 (m, 2 H), 029 - 0.38 (m, 1 H), 0.70 - 0.82 (m, 1 H), 0.99 (d, >6.6 Hz, 3 H), 221 - 2.30 (m, 3 H), 2.66 (quîn, >6.8 Hz, 1 H), 7.14 (t, >9.1 Hz, 1 H), 7.56 - 7.64 (m, ! H), 7.68 (dd, >7.0,2.4 Hz, 1 H), 7.75 (t, >7.8 Hz, I H), 7.85 (br. s., 1 H),

7.93 - 8.07 (m, 1 H), 8.18 (d, >7.9 Hz, 1 H), 8.37 (t, >1.7 Hz, 1 H), 10.46 (br. s., 1 H)

Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with

3-amino-l-phcnylbutane as amine, workup W4. Method F; Rt: 1.19 min. m/z: 4582 (M+NH₄)⁺ Exact mass: 4402. ’HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.06 (d, >6.6 Hz, 3 H), 1.62 - 1.76 (m, 2 H), 225 (d, > 1.8 Hz, 3 H), 2.44 - 2.64 (m, 2 H), 3.30 - 3.43 (m, 1 H), 5.05 (d, >8.4 Hz, 1 H), 6.96 (t, >8.9 Hz, 1 H), 7.00-7.04 (m, 2 H), 7.09 - 7.17 (m, 1 H), 7.17 - 725 (m, 2 H), 7.36-7.42 (m, 1 H), 7.50 (dd, >6.8,2.4

Hz, 1 H), 7.57 (t, >7.8 Hz, 1 H), 7.95 (m, J=7.8,1 H), 8.10 (m, >7.8 Hz, 1 H), 8.25 (s, 1 H), 8.37 (t, >1.5 Hz, 1 H)

Compound 154

3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (500 mg,

1.53 mmol) and DIPEA (657 gL, 3.8 mmol, 2.5 eq) dissolved in CH2CI2 (15 mL) were added to a tube containing 3-amino-l-Boc-3-methyl-azetidine (1.1 eq). The reaction mixture was stirTcd for 20 hours. IM HCl (5 mL) was addedand the mixture was stirred for 5 minutes. The organic layer was separated and loaded on a silica gel column. The mixture was purified using gradient elution from heptane to EtOAc, resultingincompound 154 (721 mg). Method F;Rt: l.l 1 min.m/z:478.2 (M+H)⁺Exact mass: 477.2.

Compound 155

Prepared as described for compound 154 using l-Boc-3-aminopiperidine instead of

3-amino-l-Boc-3-methyl-azetidine. Method F; Rt: 1.13 min. m/z: 492.1 (M+H)⁺ Exact mass: 491.2.

Compound 156 '

Prepared as described for compound 154 using (+/-)-3-amino-l-N-Boc-pyiTolidine instead of 3-amino-l-Boc-3-methyl-azetidine. Method F; Rt: 1.08 min. m/z: 478.2 (M+H)⁺ Exact mass: 477.2 *H NMR (400 MHz, CHLOROFORMA) 5 ppm 1.36 (s, 9 H), 1.71 -1.92 (m, l H), 1.92-2.15 (m, 1 H), 2.28 (d,>1.8 Hz, 3 H), 3.10-3.24 (m, 1 H), 3.24-3.44 (m, 3 H), 3.81 - 3.94 (m, l H), 5.50 - 6.00 (m, 1 H), 6.98 (t, >9.0 Hz, 1 H), 7.40 - 7.48 (m, l H), 7.52 - 7.71 (m, 2 H), 7.93-8.03 (m, 1 H), 8.04 - 8.17 (m, 1 H), 8.31 (br. s., 1 H), 8.45 - 8.88 (m, 1 H).

Compound 154 (721 mg, 1.51 mmol) was dissolved in CH2CI2 (10 mL) and HCl (6M in iPrOH, 2.5 mL) was added. The mixture was stirred ovcmight and the volatiles were removed in vacuo, resulting in N-(4-fluoro-3-methyl-phenyl)-3-[(3-methylazetidin5 3-yl)sulfamoyl]benzamide hydrochloride as a white solid (0.57 g). To N-(4-fluoro-3methyl-phenyl)-3-[(3-methylazetidin-3-yl)sulfamoyl]benzamide hydrochloride (150 mg) in CH2CI2 (10 mL), DIPEA (263 pL, 1.5 mmol) and methyl chloroformate (44 pL, 0.57 mmol) were added. The mixture was concentrated under a gentle flow of nitrogen at 55°C until only 2 mL remained. This residue was purified using silica gel 10 coiumn chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated under reduced pressure and the obtained product was dried in a vacuum oven at 55°C yielding compound 157 (74.2 mg) as a bright white powder. Method F; Rt: 0.93 min. m/z: 436.1 (M+H)⁺ Exact mass: 435.1. ’H NMR (400 MHz, DMSO-de) δ ppm 1.36 (s, 3 H), 2.25 (d, J=1.5 Hz, 3 H), 3.52 (s, 3 H), 3.56-3.68 (m, 2 15 H), 3.83-3.93 (m, 2 H), 7.14 (t, J - 9.2 Hz, 1 H), 7.57 - 7.62 (m, I H), 7.68 (dd, >6.8,

2.4 Hz, 1 H), 7.77 (t, >7.9 Hz, 1 H), 8.01 (m, >7.9 Hz, I H), 8.21 (m, >7.9 Hz, 1 H),

8.37 (t, >1.5 Hz, I H), 8.48 (bs, I H), 10.49 (s, 1 H)

Prepared similarly as described for compound 157, starting from compound 156 instead of compound 154, via intermediate N-(4-fluoro-3-methyl-phenyl)-3-(pyrrolidin-3-ylsulfamoyl)benzamide hydrochloride. Method F; Rt: 0.91 min. m/z: 436.2 (M+H)⁺Exact mass: 435.1.¹H NMR (400 MHz, DMSO-de) δ ppm 1.61-1.77 (m, I H), 1.80-

1.98 (m 1 H), 2.25 (d, >1.5 Hz, 3 H), 3.00-3.12 (m, I H), 3.14 - 3.27 (m, 1 H), 3.26 -

3.39 (m, 2 H), 3.50-3.58 (m, 3 H), 3.67 - 3.76 (m, 1 H), 7.14 (t, >9.2 Hz, I H), 7.57 7.63 (m, I H), 7.68 (dd, >7.2,2.3 Hz, 1 H), 7.78 (t, >7.8 Hz, 1 H), 7.97 - 8.04 (m, I

H), 8.04 - 8.18 (m, 1 H), 8.18 -8.25 (m, 1 H), 8.37 (t, >1.5 Hz, 1 H), 10.48 (s, I H)

-92Compound 159

Prepared similarly as described for compound 157, starting from compound 155 instead of compound 154, via intermediate N-(4-fluoro-3-methyl-phenyl)-3-(3-piperidylsulfamoyl)benzamide hydrochloride. Method F; Rt: 0.96 min. m/z: 467.1 (M+NH₄)* Exact mass: 449.1. The racemic compound 159 was separated by Préparative SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm), Mobile phase: CO₂, MeOH with 0.2% iPrNH₂), the desired fractions were collected, evaporated, dissolved in methanol and evaporated again, resulting in enantiomer 159a and 159b.

Columns: ID-H (Daicel) 250 mm x 4.6 mm; Flow: 3 mL/min; Mobile phase: 20% EtOH (containing 0.2% iPrNH₂) hold 15.00 min; Température: 30°C ; Rt: 9.6 min (159a), Rt: 11.0 min (159b)

Method B; Rt: 4 min. m/z: 443.1 (M+H)⁺ Exact mass: 442.0 *H NMR (400 MHz, DMSO-de) δ ppm 1.41 (s, 3 H) 4.14 (d, > 6.3 Hz, 2 H) 4.56 (d, J=6.0 Hz, 2 H) 7.42 (t, J=8.8 Hz, I H) 7.74 - 7.82 (m, 2 H) 8.04 (s, I H) 8.15 - 8.24 (m, 2 H) 8.37 (t, J=I .5 Hz, 1 H) 8.54 (br. s, 1 H) 10.67 (br. s, 1 H).

Compound 161

l-pyridin-4-yl-ethyl amine (220 mg, 1.8 mmol) and 3-[(4-fluoro-3-methy!-phcnyl)carbamoyl]benzcnesulfonyl chloride (500 mg, 1.53 mmol) were dissolved in CH₂C1₂(10 mL). DIPEA (6.2 mmol) was added at 0°C and the mixture was stirred at 25°C for 4 hours. The mixture was washed with water (20 mL) and the aqueous layer was extracted with CH₂C1₂ (3 x 20 mL). The combined organic layers were washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (mobile phase: CHjCN in water (0.1% TFA) from 30% to 60%).

-93The pure fractions were collected and neutralized with solid NaHCOj. The organic solvent was removed in vacuo and the formed precipitate was filtered, washed with H₂O (5 mL) and dried under high vacuum. The obtained residue was suspended in water (5 mL) and the aqueous layer was lyophiltzed to dryness, resulting in compound

161 (410 mg). Method A; Rt: 4.34 min. m/z: 414.3 (M+H)⁺ Exact mass: 413.1. *H NMR (400 MHz, DMSO-Je) δ ppm 1.23 (d, >7.0 Hz, 3 H) 2.26 (d, >1.5 Hz, 3 H)

4.34 - 4.50 (m, 1 H) 7.15 (t, >9.3 Hz, 1 H) 7.20 - 7.24 (m, 2 H) 7.56 - 7.66 (m, 2 H)

7.68 (dd, >7.0,2.3 Hz, 1 H) 7.86 (m, >7.8 Hz, 1 H) 8.13 (m, >7.8 Hz, 1 H) 8.26 (t, >1.3 Hz, 1 H) 8.32 - 8.39 (m, 2 H) 8.55 (d,>8.3 Hz, 1 H) 10.41 (s, 1 H).

Compound 162

Prepared similarly as described for compound 161, using l-(3-pyridyI)cthanamine instead of l-pyridin-4-yl-ethyIamine. Method D; Rt: 5.16 min. m/z: 414.3 (M+H)⁺Exact mass: 413.1.

Compound 163

Prepared similarly as described for compound 161, using l-(2-pyridyl)cthanamine instead of l-pyridin-4-yl-cthylamine. Method A; Rt: 4.60 min. m/z: 414.3 (M+H)⁺Exact mass: 413.1.

Compound 164

Prepared similarly as described for compound 161, using l-(l-methyl-4pipcridyl)ethanamine instead of l-pyridin-4-yl-ethylamine. Method B; Rt: 3.35 min. m/z: 434.4 (M+H)⁺ Exact mass: 433.2.

Compound 165

Prepared similarly as described for compound 161, using 4-morpholinobutan-2-aminc instead of !-pyridin-4-y!-ethy lamine. Method B; Rt: 3.33 min. m/z: 450.3 (M+H)⁺Exact mass: 449.2.

Compound 166

Prepared similarly as described for compound 161, using (Æ)-l-phenylethanamine instead of l-pyridin-4-yl-ethylaniine. The impure compound was purified by préparative high-performance Iiquid chromatography (column: Luna !50*30mm*5u, mobile phase: CH₃CN in water (0.1% NH₄HCO₃) from 40% to 70%, flow rate: 35 ml/min). Method B; Rt: 4.45 min. m/z: 413.3 (M+H)* Exact mass: 412.1. [a]”: + 55° (c 10 0.12 w/v, methanol).

Prepared similarly as described for compound 166, using (S)-1 -phenyl ethanamine instead of (/?)-!-phcnylethanamïne. Method B; Rt: 4.45 min. m/z: 413.3 (M+H)* Exact mass: 412.1. [a]“ : - 57° (c 0.12 w/v, methanol).

Synthesis following procedure S4 (20 hours reaction time instead of 3 hours) with

2-aminoindane as amine, workup W4. The obtained residue was recrystallised from Diisopropylethcr/acetonitrile, resulting in compound 168. Method F; Rt: 1.14 min. m/z: 20 442.2 (M+NH₄)⁺ Exact mass: 424.1. ‘H NMR (400 MHz, DMSO-Je) δ ppm 2.25 (d,

3= 1.8 Hz, 3 H), 2.72 (dd, >15.6,7.0 Hz, 2 H), 2.96 (dd, 3=15.8,7.5 Hz, 2 H), 3.95 (quin, 3=7.3 Hz, 1 H), 7.08 - 7.17 (m, 5 H), 7.57 - 7.63 (m, 1 H), 7.68 (dd, J=6.9,2.3 Hz, ! H), 7.79 (t, 3=7.8 Hz, 1 H), 8.03 - 8.12 (m, 1 H), 8.13 - 8.28 (m, 2 H), 8.4! (t, 3=1.7 Hz, 1 H), 10.49 (br. s., 1 H)

Prepared similarly as described for compound 166, using 1 -phenyl propan-2-amine instead of (Æ)-l-phenylethanamine. Method B; Rt: 4.60 min. m/z: 427.3 (M+H)⁺ Exact mass: 426.1.

H	Av	Amine used	Synthctlc/ work up Procedure	LC-MS method	Rt (min.)	[M+NH< for \|M+Hf	Exact mass
170		2-cyclopropylethanaminc	S4/W4	H	8.63	377.1	376.1
171		4-amïnolctrahydrofuran-3-ol	S4/W4	F	0.79	412.1	394.1
175	OH	(1R,2R)-1amino-2,3dihydro-lHînden-2-ol	S4*/W4	F	0.97	458.1	440.1
176	OH	(1S,2S)-1Amino-2,3dihydro-lH- inden-2-ol	S4*/W4	F	1.01	458.1	440.1
177	Qÿ' OH	(lS^R)-(-)-Cisl-amîno-2indanol	S4*/W4	F	0.97	458.4	440,1
178	OH y	(lR^R)-2aminoletralin-Ιοί hydrochloride	S4*/W4	F	1.01	472.2	454.1

#		Amine used	Synthetic/ work up Procedure	LC-MS method	Rt (min.)	for [M+H]*	Exact mass
179	1	4-Amino-lmethylpyrrolidm-2-one	S4*/W4	F	0.81	406.1	405.1
180		5-Amino-1mcthylpiperidin-2-onc	S4*/W4	F	0.81	420.2	419.1
181	1	3-Amino-lmclhylpyrrolidi n-2-onc	S4/W4	F	0.84	423.1	405.1
182	H r/V BoZ	3-Amîno-l-Nboc-azetidine	S4*/W4	F	1.06	481,2	463,2
183		l-(trifluoromethyljcyclopropanamine	S4*/W4	F	1.03	434.1	416.1

S4*: reaction time 20 hours instead of 3 hours

Compound 175. ’H NMR (400 MHz, DMSO-de) δ ppm 2.25 (d, J-1.5 Hz, 3 H), 2.62 (dd, >15.7,6.5 Hz, 1 H), 3.07 (dd, >15.7,6.7 Hz, 1 H), 4.11 (quin, >6.2 Hz, 1 H),

4.50 (dd, >7.9,6.2 Hz, 1 H), 5.14 (d, >5.7 Hz, 1 H), 6.92 (d, >7.5 Hz, 1 H), 7.06 -

7.24 (m, 4 H), 7.55 - 7.65 (m, 1 H), 7.69 (dd, >7.0, 2.4 Hz, 1 H), 7.77 (t, >7.8 Hz, 1 H), 8.05 - 8.15 (m, 1 H), 8.19 - 8.26 (m, 1 H), 8.31 (d, >8.4 Hz, 1 H), 8.47 (t, >1.7 Hz, 1 H), 10.45 (s, 1 H)

Compound 178. ’H NMR (400 MHz, DMSO-de) δ ppm 1.51 - 1.72 (m, 1 H), 1.86 10 1.99 (τη, 1 H), 2.22 - 2.31 (m, 3 H), 2.60-2.74 (m, 1 H), 2.74 - 2.85 (m, 1 H), 3.26 -

3.41 (τη, 1 H), 4.38 (t, >6.2 Hz, 1 H), 5.32 - 5.39 (m, 1 H), 6.96 - 7.09 (m, 1 H), 7.11 -

7.21 (m, 3 H), 7.28 - 7.37 (m, 1 H), 7.51 - 7.65 (m, 1 H), 7.69 (dd, >7.0,2.4 Hz, 1 H), 7.72 - 7.82 (m, 2 H), 8.05 - 8.12 (τη, 1 H), 8.17 - 8.24 (m, 1 H), 8.43 (t, >1.7 Hz, 1 H),

10.48 (s, 1 H)

Compound 179. 'HNMR(400 MHz, DMSO-de) δ ppm 1.99(dd, >5.1, 16.7 Hz, 1 H),

2.25 (d, >1.8 Hz, 3 H), 2.35 (dd, >8.4,16.7 Hz, 1 H), 2.66 (s, 3 H), 3.10 (dd, >10.1, 4.6 Hz, 1 H), 3.47 (dd, >10.3,7.3 Hz, 1 H), 3.80 - 3.92 (m, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.53 - 7.63 (m, 1 H), 7.68 (dd, >7.0, 2.2 Hz, I H), 7.74 - 7.86 (m, I H), 7.97 - 8.08 (m, 1 H), 8.15 - 8.32 (m, 2 H), 8.37 (s, 1 H), 10,48 (s, 1 H). Racemic compound 179 was separated in enantiomers 179a and 179b by Préparative SFC (Stattonary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO₂, iPrOH with 0.4% iPrNH₂) The collected fractions were concentrated in vacuo resulting in compound 179a and 179b. Columns: AD-H (diacel) 250 mm x 4.6 mm; Flow: 5 mL/min; Mobile phase: 30% iPrOH (containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1 min and hold 2.00 min @ 50%; Température: 40°C Rt: 2.2 min (179a); 2.9 min (179b). 179a: +6.1 ⁰ (589 nm, c 0.6225 w/v %, MeOH, 20 °C). 179b: -6.1 ⁰ (589 nm, c 0.506 w/v %, MeOH, 20°C).

Compound 180. *H NMR (400 MHz, DMSO-de) δ ppm 1.55 - 1.79 (m, 2 H), 2.01 2.36 (m, 5 H), 2.68 (s, 3 H), 3.06 (dd, >12.3,6.8 Hz, 1 H), 3.25 - 3.30 (m, 1 H), 3.46 -

3.58 (m, 1 H), 7.14 (t, >9.1 Hz, 1 H), 7.52 - 7.63 (m, 1 H), 7.64 - 7.71 (m, 1 H), 7.78 (t, >7.8 Hz, 1 H), 8.01 - 8.09 (m, 1 H), 8.11 - 8.27 (m, 2 H), 8.39 (t, >1.7 Hz, 1 H),

10.47 (s, 1 H)

Compound 181. ^lH NMR (400 MHz, DMSO-de) δ ppm 1.59 (dq, >12.4,9.3 Hz, 1 H),

1.93 - 2.16 (m, 1 H), 2.25 (d, >1.5 Hz, 3 H), 2.69 (s, 3 H), 3.06 - 3.24 (m, 2 H), 4.00 (t, >9.1 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.54 - 7.64 (m, 1 H), 7.65 - 7.71 (m, 1 H), 7.74 (t, >7.8 Hz, 1 H), 7.99 - 8.09 (m, 1 H), 8.25 (br. s, 1 H), 8.11 - 8.20 (m, 1 H), 8.44 (t, >1.7 Hz, 1 H), 10.42 (s, 1 H).

Compound 182. *H NMR (400 MHz, DMSO-de) δ ppm 1.12 -1.52 (m, 9 H), 2.26 (d, >1.3 Hz, 3 H), 3.40-3.60 (m 2 H), 3.80-4.00 (m, 2 H), 4.02 - 4.19 (m, 1 H), 7.15 (t, >9.2 Hz, 1 H), 7.57 - 7.66 (m, 1 H), 7.70 (dd, >7.0,2.2 Hz, 1 H), 7.80 (t, >7.8 Hz, 1 H), 8.01 (m, >8.1 Hz, 1 H), 8.26 (m, >7.9 Hz, 1 H), 8.38 (t, >1.0 Hz, 1 H), 8.51 (d, >8.4 Hz, 1 H), 10.50 (s, 1 H).

Compound 183. 'H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 -1.43 (m, 4 H),

2.28 (d, >1.8 Hz, 3 H), 5.74 (br. s., 1 H), 6.99 (t, >8.8 Hz, 1 H), 7.37 (m, >8.4,3.7 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 7.64 (t, >7.8 Hz, 1 H), 7.88 (br. s., 1 H), 8.03 (m, >8.1 Hz, 1 H), 8.10 (m, >7.9 Hz, 1 H), 8.29 - 8.38 (m, 1 H)

HO'

Compound 184

Synthesis following procedure S4 with 3-aminocyclobutanol as amine, 1 hour reaction time instead of 3 hour, workup W4. Method F; Rt: 0.81 min. m/z: 396.2 (M+NH₄)⁺ Exact mass: 378.1. SFC: Columns: Diacel AD-H (250 mm x 4.6 mm); Flow: 5 mL/min Mobile phase: 30% MeOH (containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1 min and hold 2.00 min at 50%; Température: 40°C; Rt: 184a (2.5

-98min), 184b (3.4 mm). The diastereomeric mixture of compound 184 was separated in diastereoisomers (Prep SFC (Stationarçr phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, MeOH with 0.4% ÎPrNHj). The obtained fractions were concentrated under reduced pressure and dried in vacuo at 55°C, resulting in compound

184a and 184 b.

Compound 184 a

'H NMR (600 MHz, DMSO-de) δ ppm 1.84 -1.91 (m, 2 H), 1.92 -1.98 (m, 2 H), 2.25 (d, > 1.8 Hz, 3 H), 3.77 (quin, J=6.9 Hz, 1 H), 4.10 - 4.14 (m, 1 H), 4.93 (d, J=4.9 Hz, 1 H), 7.14 (t, >9.2 Hz, 1 H), 7.59 (ddd, J=8.8,4.6,2.7 Hz, 1 H), 7.68 (dd, >7.1,2.7 Hz, 1 H), 7.76 (t, >7.8 Hz, 1 H), 7,96 (ddd, 1=7.8,1.9,1.1 Hz, 1 H), 8.06 (br. s., 1 H), 8.20 (dt, >7.8,1.5 Hz, 1 H), 8.33 (t, >1.8 Hz, 1 H), 10.49 (br. s., 1 H).

‘H NMR (600 MHz, DMSO-de) δ ppm 1.54 - 1.60 (m, 2 H), 2.19 - 2.24 (m, 2 H), 2.25 (d, >1.8 Hz, 3 H), 3.09 - 3.19 (m, 1 H), 3.62 - 3.68 (m, 1 H), 5.00 (d, >5.6 Hz, 1 H),

7.14 (t, >9.2 Hz, 1 H), 7.59 (ddd, >8.5,4.5,2.8 Hz, 1 H), 7.68 (dd, >7.0,2.2 Hz, 1 H), 7.75 (t, >7.8 Hz, 1 H), 7.97 (ddd, >7.8,1.9,1.0 Hz, 1 H), 8.02 (br. s., 1 H), 8.19 (ddd, >7.8, 1.8, 1.1 Hz, 1 H), 8.34 (t, >1.6 Hz, 1 H), 10.48 (s, 1 H)

Compound 185

Prepared similarly as described for compound 157, starting from compound 182 instead of compound 154, via intermediate 3-(azetidin-3-ylsulfamoyl)-N-{4-fluoro-3-methylphenyl)benzamide hydrochloride. Method F; Rt: 0.89 min. m/z: 439.2 (M+NH₄)⁺Exact mass: 421.1 .‘H NMR(400 MHz, DMSO-de) δ ppm 2.25 (d, >1.8 Hz, 3 H), 3.45-3.60 (m, 5 H), 3.85-4.05 (m, 2 H), 4.07 - 4.17 (m, 1 H), 7.15 (t, >9.1 Hz, 1 H),

7.53 - 7.64 (m, 1 H), 7.65 - 7.71 (m, 1 H), 7.78 (t, >7.8 Hz, 1 H), 7.94 - 8.03 (m, 1 H),

8,23 (m, >7.9 Hz, 1 H), 8.33 (t, >1.7 Hz, 1 H), 8.44 - 8.63 (br. s, 1 H), 10.49 (s, 1 H).

3-(isopropylsulfamoyl)benzoic acid (250 mg, 1.03 mmol), 4-fluoro-3,5-dimethylaniline (157 mg, 1.13 mmol) and DIPEA (398 mg, 3.08 mmol) were mixed in acetonitrile (10 mL) at room température under a nitrogen atmosphère. HATU (430 mg, 1.13 mmol) was added and the mixture was stirred ovemight. EtOAc (100 mL) was added and themixture was washed with IM HCl, satNaHCOj andbrine. After drying over MgSO₄ and évaporation to dryness in vacuo, the obtained residue was crystallizcd from MeOH (10 mL) to providc a white solid (216 mg). Method F; Rt: 1.04 min. m/z: 382.2 (M+NH₄)* Exact mass: 364.1.¹H NMR (400 MHz, DMSO-de) δ ppm 0.96 (d, >6.6 Hz, 6 H), 2.23 (d, >2.0 Hz, 6 H), 3.23 - 3.29 (m, 1 H), 7.48 (d, >6.6 Hz, 2 H), 7.66 - 7.80 (m, 2 H), 7.95 - 8.04 (m, 1 H), 8.18 (d, >7.9 Hz, 1 H), 8.35 (t, >1.7 Hz, 1 H), 10.37 (s, I H).

Compound 187

A solution of 2-fluoro-6-methylbenzoic acid (10 g, 0.0649 mol) in HOAc (300 mL) was stirred on a water-bath containing a bit of ice. At ~ 15°C, HNOj (65%, 32.7 mL) was added dropwise. After addition, H₂O (30 mL) was added slowly. After addition, Br₂ (3.7 mL) was added dropwise. A solution of silver nitrate (14.33 g, 0.0844 mol) in H₂0 (100 mL) was added dropwise over a period of 30 minutes. After addition, the réaction mixture was stirred at room température for 3 hours 30 minutes. The reaction mixture was poured into H₂O (850 mL), and EtOAc (300 mL) was added. The mixture was stirred vigorously for 5 minutes. Both upper liquid layers were dccanted from a residue. The separated water layer was combined with the residue, and extracted with EtOAc. Both upper liquid layers were decanted from the residue. The separated water layer was combined with the residue, and extracted again with EtOAc. The organic layers were combined, washed with satured NaCl and dried with Na₂SO₄, filtered off, evaporated, and co-evaporatcd with toluene. The obtained solid residue was stirred in a small amount of diisopropylether, filtered off, washed with diîsopropylether, resulting

in 3-bromo-6-fluoro-2-mcthyl-bcnzoic acid (4 g).Thc filtrate was evaporated. The residue was stirred in heptane, filtered off, washed with heptancs (3x), and dried at 50°C in vacuo, resulting in a mixture of bromo-6-fluoro-2-methyl-benzoic acid and 2fluoro-6-methylbenzoic acid (12 g, 1/0.4 ratio). 3-bromo-6-fluoro-2-methyl-benzoic acid (4 g, 0.0172 mol) was added portionwise to stirring chlorosulfonic acid (25 mL). The resulting solution was stirred at 115°C for 2 hours, left standing at room température ovemight and next stirred at 115°C for 3 hours more. The reaction mixture was allowed to reach room température, and added dropwise to a stirring mixture of crushed ice (150 g) and H₂O (50 mL). The product was extracted with EtOAc (2 x).

The combined organic layers were washed with brine, dried with Na₂SÛ4, filtered off, and evaporated, resulting in a crude mixture containing 5-bromo-3-chlorosulfonyl-2fluoro-6-methyl-benzoic acid (4.4 g) (Na₂CO₃,1.407 g, 0.0133 mol) was dissolved in water (25 mL). A solution of (S)-3-aminotetrahydrofùran (2.312 g, 0.0265 mol) in THF (20 mL) was added, and the reaction mixture was cooled to 0°C on an ice-bath. A solution of crude 5-bromo-3-chlorosulfonyl-2-fluoro-6-mcthyl-benzoic acid (4.4 g) in THF (30 mL) was added dropwise at 0°C. After addition, the reaction mixture was stirred at 0°C for 1 hour, and at room température for 2 hours. The mixture was concentrated tîll ~ 35 mL remained, then left standing for 70 hours. The solid was filtered offand washed with H₂O (2x). The filtrate was washed with Et₂O. The separated waterlayer was acidified with IN HCl (30 mL), and the product was extracted with 2-MeTHF. The separated waterlayer was acidified further till pH ~ 2 and extracted with 2-MeTHF. The organic layer was washed with brine, dried with Na₂SÛ4 and filtered, resulting in crude 5-bromo-2-fluoro-6-methyl-3-[[(3S)-tetrahydrofiiran-3yljsulfamoyljbenzoic acid (6.5 g). To a stirring solution of crude 5-bromo-2-fluoro-625 methyl-3-[[(3S)-tctrahydrofiiran-3-yl]sulfamoyl]bcnzoic acid ( 1.3 g) in CH₃CN (30 mL ) under N₂-atm triethylamine (1.42 mL, 0.0102 mol ), 3,4-difluoroaniIine (0.446 mL,

4.42 mmol ) and HATU (1.55 g, 4.08 mmol ) were suecessively added. The reaction mixture was stirred at room température for 16 hours. The volatiles were evaporated and the obtained residue was purified by silica gel chromatography (heptane-EtOAc

100/0 to 0/100 ], resulting in compound 187 (0.45 g) An impure fraction was further purified by Préparative HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD10pm,30x 150mm), Mobile phase: 0.25%NH4HCO₃ solution in water, CH₃CN). resulting in more compound 187 (0.048 g) Method F; Rt: 1.06 min. m/z: 491.0 (M-H)' Exact mass:492.0. ’H NMR (400 MHz,

DMSO-J₆) S ppm 1.66 - 1.76 (m, I H), 1.94 - 2.05 (m, 1 H), 2.41 (s, 3 H), 3.43 (dd, >8.9,4.5 Hz, 1 H), 3.58 - 3.65 (m, 1 H), 3.68 (dd, >8.9,6.3 Hz, 1 H), 3.71 - 3.78 (m, 1 H), 3.83 - 3.92 (m, 1 H), 7.36 - 7.42 (m, 1 H), 7.43 - 7.52 (m, 1 H), 7.85 (ddd, >12.8,

7.5,2.4 Hz, 1 H), 8.02 (d, >6.8 Hz, 1 H), 8.55 (s, 1 H), 11.09 (s, 1 H)

-101-

Compound 188

Compound 187 (0.45 g, 0.912 mmol ) was dissolved in MeOH (20 mL) and THF (30 mL). To the resulting solution, triethylamine (0.254 mL, 1.82 mmol) was added and the mixture was stirred with 10% Pd/C (0.2 g) under hydrogen atmosphère at room température. After 3 hours, the catalyst was filtered off over dicalite, and washed with MeOH (3x) and THF ( 1 x). The volatiles were removed in vacuo and the obtained residue was dissolved in hot MeOH (10 mL) and hot HjO (10 mL) was added. The volume was concentrated till ~ 15 mL, and left standing for 1 hour. The precipitated product was filtered off, washed with H₂O (3x), and dried at 50°C in vacuo, resulting in compound 188 (245 mg). Method F; Rt: 0.93 min. m/z: 413.2 (M-H)‘ Exact mass: 414.1.¹⁹ F NMR (377 MHz, DMSO-de) δ ppm-143.7--143.2 (m, 1 F),-137.1 --136.5 (m, 1 F), -114.8 (d, J=7.9 Hz, 1 F).¹H NMR (400 MHz, DMSO-de) 6 ppm 1.66 1.77 (m, 1 H), 1.91 - 2.03 (m, 1 H), 2.39 (s, 3 H), 3.43 (dd, J=9.0,4.6 Hz, 1 H), 3.57 -

3.70 (m, 2 H), 3.70 - 3.77, (m, 1 H), 3.78 - 3.86 (m, 1 H), 7.35 (d, J=8.1 Hz, 1 H), 7.39 - 7.52 (m, 2 H), 7.79 (t, J=7.8 Hz, 1 H), 7.87 (ddd, >12.9,7.5,2.1 Hz, 1 H), 8.32 (br. s., 1 H), 11.00 (s, 1 H).

Compound 189

Compound 189 was prepared similarly as described for compound 188, using 4-fluoro-

3-mcthylanilinc instead of 3,4-difluoroaniline. Method F; Rt: 0.94 min. m/z: 409.2 (ΜΗ)’ Exact mass:410.1. ^,9F NMR (377 MHz, DMSO-de) δ ppm-122.40 (dtd, >9.3,4.6, 4.6,2.1 Hz, 1 F), -114.96 (d, >7.2 Hz, 1 F). ‘H NMR (400 MHz, DMSO-ί/β) δ ppm 1.67 - 1.77 (m, 1 H), 1.92 - 2.03 (m, 1 H), 2.24 (d, >1.5 Hz, 3 H), 2.38 (s, 3 H), 3.43 (dd, >8.8,4.6 Hz, 1 H), 3.58 - 3.64 (m, 1 H), 3.65 - 3.70 (m, 1 H), 3.70 - 3.77 (m, 1 H), 3.78 - 3.86 (m, 1 H), 7.14 (dd, >9.1 Hz, 1 H), 7.34 (d, >8.1 Hz, 1 H), 7.45 - 7.53 (m, 1 H), 7.63 (dd, >7.0,2.4 Hz, I H), 7.77 (dd, >7.9 Hz, 1 H), 8.30 (br. s., 1 H), 10.72 (s, 1 H). Differential scanning calorimetry From 30 to 300 °C at 10°C/min:

-102-

Peakat 157.0 °C

Compound 190

Na₂CO₃ (1.60 g, 0.0151 mol) was dissolved in water (25 mL). A solution of 3methyloxetan-3-amine (2.63 g, 0.0302 mol) in THF (20 mL) was added, and the reaction mixture was cooled to 0°C on an ice-bath. A solution of crude 5-bromo-3chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (5 g) in THF (30 mL) was added dropwise at 0°C. After addition, the reaction mixture was stirred vigorously at 0°C for 30 minutes, and at room température for 2 hours. The organic volatiles were evaporated, and the remaining ~ 30 mL was washed with Et₂O (50 mL). The separated waterlayer was acidified with IN HCl (40 mL), and the product was extracted with 2MeTHF (2x). The combined organic layers were washed with brine, dried with Na₂SO₄, filtered off, evaporated, and co-evaporatcd with CH₃CN, resulting in crude 5-bromo-2-fluon)-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (3.6 g) To a solution of crude 5-bromo-2-fluoro-6-mcthyl-3-[(3-mcthyloxetan-3yl)sulfamoyl]benzoic acid (0.72 g, 0.00188 mol ) in CH₃CN (15 mL ) under N₂-atm was successively added NEt₃ (0.786 mL, 0.00565 mol ), 4-fluoro-3-methy!anilinc (0.313 g, 0.00245 mol), and HATU (0.86 g, 0.00226 mol ). The reaction mixture was stirred at room température for 20 hours. More 4-fluoro-3-methylaniline (0.1 g) and HATU (0.3 g) were added, and the reaction was continued for 20 hours. The volatiles were evaporated. The residue was purified by silica gel Chromatography (heptancEtOAc 100/0 to 0/100). The desired fractions were combined and evaporated. The residue was stirred in diisopropylether, filtered off, washed with diisopropylether (3x), and dried at 50°C, resulting in compound 190 (0.38 g), m/z: 486.9 (M-H)' Exact mass:488.0.¹⁹F NMR (377 MHz, DMSO-de) δ ppm-122.15 --121.89 (m, 1 F),-116.05 (d, >6.4 Hz, 1 F). *H NMR (400 MHz, DMSO-</₆) δ ppm 1.47 (s, 3 H), 2.25 (d, > 1.5 Hz, 3 H), 2.40 (s, 3 H), 4.22 (d, >6.6 Hz, 2 H), 4.62 (d, >6.4 Hz, 2 H), 7.16 (dd, >9.2 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 7.61 (dd, >6.9,2.3 Hz, 1 H), 8.01 (d, >6.8 Hz, 1 H),

8.86 (br. s., 1 H), 10.81 (s, 1 H)

Synthesis of2-fluoro-6-methyl-3-rf3-methy1oxetan-3-yl)sulfamoy11benzoic acid

-103A solution of 5-bromo-2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (0.9 g) and triethy lamine (0.98 mL, 7.1 mmol) in MeOH (30 mL) was stirred with Pd/C 10% (0.1 g) at room température under a hydrogen atmosphère. After the calculated amount of hydrogen was taken up, the catalyst was filtered off. The filtrate was concentrated in vacuo, and co-evaporated with CH3CN. The obtained residue containing 2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid was used as such. Method F; Rt: 0.38 min. m/z: 302.0 (M-H)' Exact mass:303.1

Compound 191 o,

Tricthylaminc (0.206 mL, 0,00149 mol ) was added to a stirring mixture of 2-fluoro-6methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]bcnzoie acid (0.15 g, 0.000495 mol ) and CHjCN ( 10 mL ) under Nî-atm. To the resultîng solution was added HATU (0,207 g, 0.545 mmol). After stirring for 5 minutes, 5-amino-2-fluorobenzonitrile, (79.9 mg, 0.569 mmol ) was added, and the reaction mixture was stirred at room température for 20 hours. The reaction was next continued at 50°C for 4 hours. The volatiles were evaporated and the obtained residue was dissolved in CH2CI2 (2.5 mL) and purified by silica gel Chromatography (heptane-EtOAc 100/0 to 0/100) followed by repurification with CH2C12-MeOH 100/0 to 98/2 as eluent. The desired fractions were combined and evaporated, and co-evaporated with EtOAc. The residue was dried further at 50°C in vacuo, resultîng in compound 191 (63 mg). Method F; Rt: 0.88 min. m/z: 420.1 (M-H)' Exact mass:421.1. 'H NMR (400 MHz, DMSO-ds) d ppm 1.46 (s, 3 H), 2.40 (s, 3 H),

4.19 (d, >6.6 Hz, 2 H), 4.62 (d, >6.2 Hz, 2 H), 7.36 (d, >8.1 Hz, 1 H), 7.58 (t, >9.1 Hz, 1 H), 7.80 (t, >7.9 Hz, 1 H), 7.96 (ddd, >9.1,4.8,2.8 Hz, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 8.64 (s, 1 H), 11.16 (s, 1 H). ^I9FNMR (377 MHz, DMSO-&) δ ppm 115.10 (d, >7.9 Hz, 1 F), -113.61 (dt, >8.9, 5.2 Hz, 1 F).

Synthesis o f 3-chloro-4.5-d i fluoro-an il i ne

3-chloro-4,5-difluorobenzoie acid (commercial from astatech, 25.5 g, 0.132 mol ) was dissolved in tert-butyl alcohol (200 mL) at 50°C. EtjN (20.2 mL, 0.146 mol ) was added. Diphenylphosphoryl azide, 30.0 mL, 0.139 mol ) was added slowly, and the reaction mixture was stirred and refluxed for 18 hours. The volatiles were evaporated, and co-evaporated with EtOAc. The residue was stirred in Et₂O (300 mL)/Sat. NaHCOj (300 mL) /H₂O (50 mL) for 15 minutes. The separated organic layer was dried with

-I04MgSOj, fîltered off, and evaporated. The solid residue was stirred in diisopropylether (20 mL), fîltered off, washed with diisopropylether (3x) and dried at 50°C, resulting in tert-butyl N-(3-chloro-4,5-difluoro-phenyl)carbamate (8.5 g). The filtrate was concentrated in vacuo. The residue was stirred in CH₂CI₂ (20 mL) + heptanes (20 mL), 5 fîltered off, washed with CH₂Cl₂-heptane l/l (2x) and heptanes (2x), and dried at 50°C in vacuo, resulting in more tert-butyl N-(3-chloro-4,5-difluoro-phenyl)carbamate, 11.8 g), tert-butyl N-(3-ch!oro-4,5-difluoro-phenyl)carbamate (8.5 g, 0.0322 mol) was added portion wise to stirring HCl (40 mL, 0.16 mol, 4 M in dioxane). The mixture was stirred at room tempertaure for 2 hours, then left standing for 65 hours. Stirring was 10 continued for another 2 hours. The formed precipitate was fîltered off, washed with dioxane (4x) and dried at 50°C in vacuo, resulting in 3-chlonM,5-difluoro-aniline hydrochloride (5.95 g). A mixture of 3-ch!oro-4,5-difluoro-aniline hydrochloride ( ! g, 0.005 mol), NaOH (IM in H₂0,10 mL, 0.01 mol) and toluene (15 mL) was stirred at room température for l hour. The separated organic layer was dried with MgSOi, fîltered off, and evaporated. The obtained 3-chloro-4,5-difluoro-aniline (0.81 g) was used as such.

Compound 192

Compound 192 was prepared similarly as described for compound 191, using 3-chloro-

4,5-difluoro-aniline hydrochloride instead of 5-amino-2-fluorobenzonitrile.”F NMR (377 MHz, DMSO-de) d ppm -144.93 (br. s., 1 F), -134.02 - -133.17 (m, 1 F), -115.09 (d, J=7.9 Hz, 1 F). 'H NMR (400 MHz, DMSO-de) δ ppm 1.45 (s, 3 H), 2.38 (s, 3 H),

4.18 (d, J=6.4 Hz, 2 H), 4.61 (d, J=6.2 Hz, 2 H), 7.35 (d, J=8.1 Hz, 1 H), 7.71 - 7.83 (m, 3 H), 8.64 (br. s., 1 H), 11.14 (br. s„ 1 H). Method F; Rt: 1.05 min. m/z: 447.1 (ΜΗ)* Exact mass:448.0.

Compound 193

Oxalyl chloride (12.3 mL, 0.143 mol) was added dropwîse to a stirring solution of 5bromo-3-ch!orosulfonyl-2-fluoro-6-methyl-benzoic acid (9.5 g) and DMF (0.111 mL)

-105in CH2CI2 (IOO mL). After addition, the reaction mixture was stirred at room température for 2 hours and 30 minutes. The volatiles were removed in vacuo, and coevaporated with toluene. The obtained residue containing 5-bromo-3-chlorosulfonyl-2fluoro-6-methyl-benzoyl chloride was used as such. A solution of 5-bromo-35 chlorosulfonyl-2-fluoro-6-methyl-benzoyl chloride ( 1.75 g) in toluene (20 mL) was stirred at reflux under N2-flow. A solution of 3-chloro-4,5-difluoroanilinc (0.818 g, 0.005 mol) in toluene (10 mL) was added dropwise. After addition, the reaction mixture was refluxed for 45 minutes, then allowed to reach room température, and left standing for 18 hours. A precipitate (0.51 g) was filtered off, washed with toluene (2 x), 10 and dried at 50°C invacuo. (R)-l,l,l-trifluoro-2-propylaminc (0.181 g, 0.0016 mol ) was dissolved in CHjCN (5 mL ) under N2-atm. 5-bromo-3-[(3-chloro-4,5-difluorophenyl)carbamoyl]-2-fluoro-4-methyl-benzenesulfonyl chloride (0.51 g) was added, then DIPEA (0.461 mL, 0.00267 mol). The mixture was stirred in a sealed tube at 80°C for 20 hours. The reaction mixture was allowed to reach room température, and left standing for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in CH2CI2 (2 mL), and purified by silica gel chromatography [heptane-EtOAc 100/0 to 0/100 ]. The fractions containing the desired compound were combined and evaporated, and co-evaporated with EtOH, resulting in crude 5-bromoN-(3-chloro-4,5-difluoro-phcnyl)-2-fluoro-6-methyl-3-[[( l R)-2,2,2-trifluoro-1 -methyl20 ethyl]sulfamoyl]benzamide (0.12 g).To a solution of 5-bromo-N-(3-chloro-4,5difluoro-phenyl)-2-fluoro-6-methyl-3-[[( l R)-2,2,2-trifluoro-1 -methylethyl]sulfamoyl]bcnzamidc (O.l g) in EtOH (l l mL ) was added H2O (3.5 mL ), then K2CO3 aq. sat. sol., (1.25 mL) and next Palladium(0)tctrakis(tripheny!phosphine (26.1 mg, 0.023 mmol). The mixture was stirred 15O°C by microwave irradiation for 45 minutes. The reaction mixture was combined with a similar réaction mixture starting from 20 mg 5-bromo-N-(3-chloro-4,5-difkioro-phenyl)-2-fluoro-6-methyl-3-[[(lR)-

2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]benzamide) allowed to reach room température and left standing for 15 minutes. The upper layer was isolated by means of a séparation funnel, and evaporated. The obtained residue was purified by silica gel chromatography (heptane-EtOAc 100/0 to 0/100, also ClhCk-MeOH 100/0 to 98/2), fo llowed by séparation by préparative HPLC (Stationary phase: RP Vydac Denali C18 - lOpm, 200g, 5cm), Mobile phase: 0.25% NH4HCO3 solution in water, CHjCN), resulting in compound 193 (11.4 mg). Method F; Rt: 1.17 min. m/z: 473.0 (M-H)' Exact mass:474.0. ‘H NMR (400 MHz, DMSO-Je) δ ppm 1.17 (d, >6.8 Hz, 3 H), 2.38 (s, 3 H), 4.00-4.15 (m, 1 H), 7.35 (d, >8.4 Hz, 1 H), 7.71 - 7.78 (m, 2 H), 7.82 (t, >7.8

Hz, 110,9.00 (br. s., 1 H), 11.13 (s, 1 H). ^,9FNMR(377 MHz, DMSO-de) d ppm -

145.3 to -144,5 (m, 1 F), -134.4 to -132.8 (m, 1 F), -114.9 (br. s., 1 F), -76.0 (d, >7.2 Hz, 3 F).

-106-

Compound 194

2-fluoro-6-methyl-3-[(3-methyIoxetan-3-yl)sulfamoy!]benzoic acid (0.15 g, 0.473 mmol) was dissolved in DMF (5 mL) and tricthylamine (0.2 mL) and HATU (233 mg, 0.61 mmol) were added to the reaction mixture. The réaction mixture was stirred for 10 minutes and 3,4-difluoroaniline (123 mg, 0.945 mmol) was added. The reaction mixture was stirred at room température for 42 hours. The reaction mixture was poured into ice water (50 mL). The mixture was extracted with Me-THF (3 x 20 mL). The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100% and methanol in dichloromethane from 0 to 2%) to afford compound 194 (79 mg) as a white powder which was dried in vacuum oven ovemight. Method F; Rt: 0.94 min. m/z: 413.2 (M-H)' Exact mass: 414.1. *HNMR (400 MHz, DMSO-de) 5 ppm 1.45 (s, 3 H), 2.39 (s, 3 H), 4.18 (d, >6.6 Hz, 2 H), 4.62 (d, >6.2 Hz, 2 H), 7.35 (d, >8.1 Hz, 1 H), 7.39 - 7.51 (m, 2 H), 7.79 (t, >7.8 Hz, 1 H), 7.87 (ddd, >12.9,7.4,2.0 Hz, 1 H), 8.64 (br. s., 1 H), 11.00 (s, 1 H)

Compound 195

Compound 195 (98 mg) was prepared similarly as described for compound 194, using

3-chIoro-4-fluoroaniline instead of 3,4-difluoroaniline. Method F; Rt: 0.99 min. m/z: 429.1 (M-H*)' Exact mass:430.1. ^!H NMR (400 MHz, DMSO-de) δ ppm 1.45 (s, 3 H),

2.39 (s, 3 H), 4.18 (d, J=6.4 Hz, 2 H), 4.62 (d, >6.2 Hz, 2 H), 7.35 (d, >8.1 Hz, 1 H),

7.45 (t, >9.0 Hz, 1 H), 7.60 (ddd, >9.0,4.3,2.5 Hz, 1 H), 7.79 (t, >7.9 Hz, 1 H), 8.02 (dd, >6.8,2.6 Hz, 1 H), 8.63 (br. s., 1 H), 10.99 (s, 1 H)

Compound 196

-107-

F

Sodium carbonate (2.07 g, 19.48 mmol) was dissolved in distilled water (30 mL). To this was added (S)-3-aminotetrahydrofûran (3.4 g, 38.97 mmol) at once followed by THF (30 mL). The obtained solution was stirred and cooled in an ice bath. 35 (chlorosulfonyl)-2,6-dîfluorobenzoic acid (5 g, 19.48 mmol) was dissolved in THF (40 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then the mixture was stirred for 3 hours at room température. The mixture was concentrated in vacuo until only water remained. Water (20 mL) was added and the mixture was acidified with HCl (1M / aq;

40 mL). This was extracted using Me-THF (3 x 50 mL). The combined organics were washed with of brine (50 mL), dried on Na₂SO₄₍ filtered and concentrated in vacuo yielding 2,6-difluoro-3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]benzoic acid as a yellow powder (5.9 g). Method F, Rt: 0.33 min. m/z : 306.0 (M-H)‘Exact mass: 307.0.2,6difluoro-3-[[(3S)-tetrahydrofûran-3-yl]sulfamnyl]bcnzoic acid (1 g, 2.99 mmol) was dissolved in N,N-dimethylformamidc (5 mL). HATU (1.42 g, 3.74 mmol) was added followed by diisopropylethylamine (1.55 mL, 8.98 mmol). The resulting mixture was stirred for 30 minutes at room température. Then, 3,4-difluoroaniline (0.77 g, 5.99 mmol) was added. The resulting mixture was stirred for 24 hours and next poured in water (50 mL) and extracted using Mc-THF (3 x 50 mL). The combined organics were 20 washed with brine, dried on Na₂SO₄₍ filtered and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55°C for 24 hours yielding compound 196. Method F, Rt: 0.92 min. m/z : 417.1 (M-H)' Exact mass: 418.1. ^lH NMR (400 MHz, DMSO-dfe) δ ppm 1.64 - 1.79 (m, 1 H), 1.92 - 2,07 (m, 1 H), 3.43 (dd, J=9.0,4.6 Hz, 1 H), 3.56 -

3.79 (m, 3 H), 3.80 - 3.92 (m, 1 H), 7.32 - 7.43 (m, 1 H), 7.44 - 7.54 (m, 2 H), 7.84 (ddd, >12.7,7.4,2.5 Hz, l H), 8.01 (td, >8.6,6.2 Hz, 1 H), 8.49 (br. s., 1 H), 11.21 (br. s., 1 H)

Compound 197 to 201 were prepared as described for compound 196, using the corresponding aniline instead of 3,4-difluoroaniline:

Compound 197

-108-

4-fIuoro-3-methyIaniIine was used as aniline. ’H NMR (400 MHz, DMSO-d$) δ ppm

1.64 - 1.76 (m, 1 H), 1.91 - 2.05 (m, 1 H), 2.25 (d, >1.8 Hz, 3 H), 3.42 (dd, >8.9,4.7 Hz, 1 H), 3.56 - 3.78 (m, 3 H), 3.79 - 3.88 (m, 1 H), 7.16 (t, >9.1 Hz, 1 H), 7.41 - 7.51 (m, 2 H), 7.60 (dd, >7.0,2.2 Hz, 1 H), 7.97 (td, >8.6,6.2 Hz, 1 H), 8.49 (br. s, 1 H),

10.93 (s, 1 H). Method F, Rt: 0.93 min. m/z : 413.2 (M-H)- Exact mass: 414.1

Compound 198

3-bromo-4-fluoroaniline was used as aniline. Method G, Rt: 1.74 min. m/z : 478.8 (ΜΗ)' Exact mass: 480.0.¹H NMR (400 MHz, DMSO-&) δ ppm 1.67 - 1.77 (m, 1 H),

I. 93 - 2.05 (m, 1 H), 3.43 (dd, >9.0,4.6 Hz, 1 H), 3.57 - 3.78 (m, 3 H), 3.80 - 3.89 (m, 1 H), 7.43 (t, >8.7 Hz, 1 H), 7.49 (m, >8.7, 8.7 Hz, 1 H), 7.61 (ddd, >9.0, 4.4, 2.6 Hz, 1 H), 8.00 (td, >8.6,6.2 Hz, 1 H), 8.11 (dd, >6.3,2.5 Hz, 1 H), 8.49 (br. s., 1 H),

II. 19 (br. s., I H)

Compound 199

5-amino-2-fluorobenzonitrile was used as aniline

Method G, Rt: 1.56 min. m/z : 423.9 (M-H)' Exact mass: 425.1.¹H NMR (400 MHz, DMSO-de) δ ppm 1.65-1.80 (m, 1 H), 1.94 - 2.06 (m, 1 H), 3.43 (dd, >9.0,4.6 Hz, 1 H), 3.57 - 3.78 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.49 (t, >8.5 Hz, 1 H), 7.59 (t, >9.1 Hz, 1 H), 7.94 (ddd, >9.2,4.8,2.6 Hz, 1 H), 8.02 (td, >8.6,6.2 Hz, 1 H), 8,19 (dd, >5.7,

2.9 Hz, 1 H), 8.50 (br. s., 1 H), 11.37 (br. s., 1 H).

Compound 200

-109-

4-fluoro-3-(trifluoromethyl)aniline was used as aniline

Method F, Rt: 1.02 min. m/z : 467.1 (M-H)- Exact mass: 468.1. *H NMR (400 MHz, DMSO-J₆) δ ppm 1.72 (ddt, J=12.6,7.2,5.6, 5.6 Hz, l H), 1.93 - 2.08 (m, 1 H), 3.43 (dd, >9.0,4.6 Hz, 1 H), 3.58 - 3.79 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.49 (t, J=8.4 Hz, 1 H), 7.58 (t, J=9.7 Hz, 1 H), 7.93 (s, 1 H), 8.02 (td, >8.6, 6.2 Hz, 1 H), 8.16 (dd, >6.4, 2.6 Hz, 1 H), 8.50 (br. s., 1 H), 11.35 (br. s., 1 H)

3-chloro-4-fluoroanïline was used as aniline.

Method F, Rt: 0.97 min. m/z: 433.1 (M-H)- Exact mass: 434.0. 'H NMR (400 MHz, DMSO-ifc) δ ppm 1.72 (ddt, >12.5,7.2,5.6, 5.6 Hz, 1 H), 1.92 - 2.12 (m, 1 H), 3.43 (dd, >8.8,4.6 Hz, 1 H), 3.55 - 3.79 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.35 - 7.52 (m, 2 H), 7.53 - 7.67 (m, 1 H), 7.90 - 8.12 (m, 2 H), 8.49 (br. s., 1 H), 11.20 (br. s., 1 H)

Compound 202 and 203 were prepared similarly as described for compound 196, using isopropyl amine instead of (S)-3-aminotetrahydrofuran and for compound 203, using 3(trifluoromethyl)aniline instead of 3,4-difluoroaniline.

Compound 202

Method G, Rt: 1.80 min. m/z : 388.9 (M-H)- Exact mass: 390.1.

¹H NMR (400 MHz, DMSO-dé) δ ppm 1.03 (d, >6.6 Hz, 8 H), 3.34 - 3.46 (m, 1 H),

7.36 - 7.53 (m, 3 H), 7.84 (ddd, >12.7,7.4,2.5 Hz, 1 H), 8.00 (td, >8.6, 6.2 Hz, 1 H), 8.09 (br. s., 1 H), 11.20 (br. s., 1 H)

-110Compound 203

F

Method G, Rt: 1.82 min. m/z : 421.1 (M-H> Exact mass: 422.1. ‘ H NMR (400 MHz, DMSO-dô) 5 ppm 1.04 (d, >6.6 Hz, 6 H), 3.34 - 3.46 (m, 1 H), 7.47 (t, >8.6 Hz, 1 H), 7.54 (d, J=7.9 Hz, 1 H), 7.65 (t, J=7.9 Hz, 1 H), 7.87 (d, >8.4 Hz, 1 H), 8.01 (td, >8.6,6.2 Hz, 1 H), 8.11 (d, >7.5 Hz, 1 H), 8.15 (s, 1 H), 11.32 (s, 1 H).

Compound 204

Compound 204 (0.19 g) was prepared starting from compound 190 (0.34 g), similar as described for the conversion of compound 187 to compound 188. Compound 204 was crystallised from Et₂O, filtered off, washed with 3x Et₂O, and dried at 50°C in vacuo. Method F; Rt: 0.94 min. m/z: 409.1 (M-H)‘ Exact mass:410.1. 'H NMR (400 MHz, DMSO-di) δ ppm 1.46 (s, 3 H), 2.24 (d, J=1.8 Hz, 3 H), 2.38 (s, 3 H), 4.18 (d, J=6.6 Hz, 2 H), 4.62 (d, J=6.2 Hz, 2 H), 7.14 (dd, >9.1 Hz, 1 H), 7.33 (d, >8.1 Hz, 1 H),

7.45 - 7.53 (m, 1 H), 7.63 (dd, J=7.0,2.2 Hz, 1 H), 7.77 (t, J=7.9 Hz, 1 H), 8.61 (br. s., 1 H), 10.72 (s, I H).

Compound 205

3-(tert-butylsulfamoyl)-2-fluoro-6-methyl-benzoic acid was prepared similarly as described for 2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid, using tert-butylamine instead of 3-methyloxetan-3-amine. Compound 205 was prepared similar as described for compound 194, using 4-fluoro-3-methylanilïne instead of 3,4 difluoroaniline and starting from 3-(tert-butylsulfamoyl)-2-fluoro-6-mcthyl-benzoic acid instead of 2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid. Method F; Rt: 1.08 min. m/z: 395.2 (M-H) Exact mass: 396.1.*H NMR (400 MHz, DMSO-di) 6 ppm 1.16 (s, 9 H), 2.24 (d, >1.8 Hz, 3 H), 2.37 (s, 3 H), 7.14 (t, >9.2

-111Hz, 1 H), 7.30 (d, >8.1 Hz, 1 H), 7.50 (ddd, >9.0,4.7,2.3 Hz, 1 H), 7.64 (dd, >6.9,

2.3 Hz, 1 H), 7.73 - 7.84 (m, 2 H), 10.70 (br. s, 1 H).

Compound 206

Compound 206 was prepared simiiar as described for for compound 194, starting from 3-(tert-butyIsuIfamoyI)-2-fluoro-6-methyl-benzoic acid instead of 2-fluoro-6-methyl-3[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid. Method F; Rt: 1.08 min. m/z: 399.1 (ΜΗ)' Exact mass:400.1. 'H NMR (400 MHz, DMSO-d«) δ ppm 1.16 (s, 9 H), 2.31 (s, 3 10 H), 7.32 (d, >8.1 Hz, 1 H), 7.40 - 7.51 (m, 2 H), 7.76 - 7.82 (m, 2 H), 7.88 (ddd, >13.0,7.5,2.4 Hz, 1 H), 10.97 (br. s., 1 H)

Synthesis of6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyllbenzoic acid and2chloro-6-fluoro-3-[f3-methyloxetan-3-yï)sulfamoynbenzoic acid

2-chloro-6-fluorobenzoîc acid (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100°C and stirred for 5 hours. The resulting mixture was cooled to room température and added dropwise to ice-water (I liter), This was then extracted using dichloromethane (2 x 500 mL). The combined 20 organics were dried on NaîSCh, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fIuoro-benzoic acid and 6-chloro-3chlorosulfonyI-2-fluoro-bcnzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass:

271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL).

To this was added 3-methyl-3-oxctanamine(1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fIuoro-bcnzoic acid and 6-chIoro-3chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirrîng solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidifïed with HCI (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na₂SO4, filtered and concentrated in vacuo. The residue was purified, and isomers

-112wcre separated using préparative HPLC (Stationary phase: Uptisphere Cl8 ODB lOpm, 200g, 5cm), Mobile phase: 0.25% NH4HCO3 solution in water, MeOH), yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoÎc acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)' Exact mass: 323.0. IH NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, >6.6 Hz, 2 H), 4.61 (d, >5.9 Hz, 13 H),

7,29 (dd, >8.5, 0.8 Hz, 1 H), 7.36-7,73 (m, 5 H).

and 2-ch!oro-6-fluoro-3-[(3-methyloxetan-3-y!)sulfamoy!]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)* Exact mass: 323.0

Compound 207 to 210 were prepared similarly as described for compound 196 using 6ch!oro-2-fluoro-3-[(3-methyloxetan-3-y!)su!famoyl]benzoic acid instead of 2,6difluoro-3-[[(3S)-tetrahydrofiiran-3-yl]sulfamoyl]benzoic acid and the corresponding aniline instead of 3,4-difluoroaniline.

Compound 207

Using 5-amino-2-fluorobenzonitrilc as aniline. Method F, Rt: 0.92 min. m/z : 440.0 (M· H)‘ Exact mass: 441.0. 'H NMR (400 MHz, DMSO-Je) δ ppm 1.46 (s, 2 H), 4.21 (d, >6.4 Hz, 2 H), 4.61 (d, >6.2 Hz, 2 H), 7.59 (t, >9.1 Hz, 1 H), 7.66 (d, >8.8 Hz, 1 H), 7.89 - 7.99 (m, 2 H), 8.18 (dd, >5.6,2.8 Hz, 1 H), 8.93 (br. s, 1 H), 11.37 (br. s., 1 H)

Compound 208

F

Using 4-fluoro-3-(trifluoromethyl)ani!ine as aniline. Method F, Rt: 1.06 min. m/z : 483 (M-H)* Exact mass: 484.0. *H NMR (400 MHz, DMSO-î/₆) δ ppm 1.46 (s, 2 H), 4.20 (d, >6.2 Hz, 2 H), 4.61 (d, >6.2 Hz, 2 H), 7.58 (t, >9.9 Hz, 1 H), 7.66 (d, >8.6 Hz, 1 H), 7.94 (m, >8.1,8.1 Hz, 2 H), 8.07 - 8.25 (m, 1 H), 8.91 (br. s, 1 H), 11.34 (br. s., 1 H)

-113Compound 209

Using 3,4-difluoro-5-methyl-aniline as aniline. Method F, Rt: 1.03 min. m/z : 447.1 (M-H)' Exact mass: 448.1. *H NMR (400 MHz, DMSO-</₆) 5 ppm 1.45 (s, 3 H), 2.30 (d, J=2.0 Hz, 3 H), 4.20 (d, >6.4 Hz, 2 H), 4.61 (d, J=6.2 Hz, 2 H), 7.32 (m, >5.9 Hz, 1 H), 7.54 - 7.69 (m, 2 H), 7.91 (t, >8.3 Hz, 1 H), 8.92 (br. s, 1 H), 11.09 (br. s, 1 H)

Compound 210

Using 3-chloro-4,5-difluoro-aniline hydrochloride as aniline. Method F, Rt: 1.07 min. m/z : 467.0 (M-H)' Exact mass: 468.0. *H NMR (400 MHz, DMSO-Je) 5 ppm 1.45 (s, 3 H), 4.20 (d, >6.6 Hz, 2 H), 4.60 (d, >6.2 Hz, 2 H), 7.64 (d, >8.6 Hz, 1 H), 7.67 -

7.79 (m, 2 H), 7.93 (t, >8.1 Hz, 1 H), 9.08 (br. s, 1 H), 11.34 (br. s., 1 H)

Compound 211

Compound 211 was prepared similarly as described for compound 196 using 2-chloro-

6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid instead of 2,6-difluoro-3[[(3S)-tetrahydrofuran-3-yI]sulfamoyl]benzoÎc acid. Method F, Rt: 0.94 min. m/z : 433.1 (M-H)' Exact mass: 434.0. *H NMR (400 MHz, DMSO-t/e) 5 ppm 1.46 (s, 3 H),

4.20 (d, >6.6 Hz, 2 H), 4,62 (d, >6.4 Hz, 2 H), 7.30 - 7.43 (m, 1 H), 7.43 - 7.54 (m, 1 H), 7.61 (t, >8.6 Hz, 1 H), 7,84 (ddd, >12.7,7.4,2.3 Hz, 1 H), 8.17 (dd, >9.0,5.9 Hz, 1 H), 8.75 (br. s, 1 H), 11.18 (br. s, 1 H).

114.

2-bromo-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 6-bromo-2fluoro-3-[(3-methyloxctan-3-yl)sulfamoyl]benzoic acid were prepared similarly as described for 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 6chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid, starting from 2bromo-6-fluorobenzoic acid instead of 2-chloro-6-fluorobenzoic acid.

Compound 212

Compound 212 was prepared similarly as described for compound 196 using 2-bromo-

6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid instead of 2,6-difluoro-3[[(35)-tetrahydrofùran-3-yl]sulfamoyl]bcnzoic acid and 4-fluoro-3(trifluoromethyl)aniline instead of 3,4-difluoroaniline.¹ H NMR (400 MHz, DMSO-de) 5 ppm 1.48 (s, 3 H), 4.20 (d, J=6.6 Hz, 2 H), 4.64 (d, >6.2 Hz, 2 H), 7.57 (t, >9.7 Hz, 1 H), 7.65 (t, >8.6 Hz, I H), 7.93 (dt, >8.4,3.7 Hz, l H), 8.08 - 8.31 (m, 2 H), 8.70 (br. s., 1 H), 11.29 (br. s., 1 H).

Compound 213 to 216 were prepared similarly as described for compound 196 using 6bromo-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid instead of 2,6difluoro-3-[[(3S)-tetrahydrofùran-3-yl]sulfamoyl]benzoic acid the corresponding aniline instead of 3,4-difluoroaniline.

Compound 213

Br

Using 4-fluoro-3-mcthylaniline as aniline. Method F, Rt: 0.99 min. m/z: 473.0 (M-H)' Exact mass: 474.0. ‘HNMR (400 MHz, DMSO-de) δ ppm 1.46 (s, 3 H), 2.25 (d, >1.5 Hz, 3 H), 4.20 (d, >6.4 Hz, 2 H), 4.62 (d, >6.2 Hz, 2 H), 7.16 (t, >9.1 Hz, 1 H), 7.42 - 7.52 (m, 1 H), 7.60 (dd, >7.0,2.4 Hz, 1 H), 7.68 - 7.93 (m, 2 H), 8.65 (br. s, 1 H),

10.82 (br. s, 1 H).

Compound 214

-115-

Using 5-amino-2-fluorobenzonitrile as aniline. Method F, Rt: 0.92 min. m/z : 484.0 (ΜΗ)' Exact mass: 485.0. ^lH NMR (400 MHz, DMSO-de) δ ppm 1.39 - 1.55 (m, 3 H),

4.20 (d, J=6.6 Hz, 2 H), 4.61 (d, >6.4 Hz, 2 H), 7.59 (t, >9.1 Hz, 1 H), 7.77 - 7.89 (m, 2 H), 7.95 (ddd, >9.2,4.8,2.8 Hz, 1 H). 8.18 (dd, >5.7,2.6 Hz, 1 H), 8.90 (br. s, 1 H).

11.34 (br. s., 1 H).

Compound 215

Using 4-fluoro-3-(trifluoromethyl)aniline as aniline. Method F,Rt: 1.07 min. m/z : 527.0 (M-H)' Exact mass: 528.0. ^lH NMR (400 MHz, DMSO-de) δ ppm 1.46 (s, 3 H),

4.20 (d, >6.6 Hz, 2 H), 4.61 (d, >6.2 Hz, 2 H), 7.58 (t, >9.8 Hz, 1 H), 7.74 - 7.89 (m, 2 H), 7.90 - 7.98 (m, 1 H), 8.16 (dd, >6.3,2.5 Hz, 1 H), 8.84 (br. s, 1 H), 11.31 (br. s., 1 H).

Compound 216

F

Using 3,4-difluoro-5-methyl-aniline as aniline. Method F, Rt: 1.03 min. m/z : 491.0 (M-H)' Exact mass: 492.0. *H NMR (400 MHz, DMSO-de) δ ppm 1.46 (s, 3 H), 2.30 (d, >1.8 Hz, 3 H), 4.20 (d, >6.6 Hz, 2 H), 4.61 (d, >6.4 Hz, 2 H), 7.32 (m, >5.7 Hz, 1 H), 7.61 (ddd, >12.3,6.9,2.6 Hz, 1 H), 7.72 - 7.89 (m, 2 H), 8.86 (br. s.. 1 H), 11.07 (br. s, 1 H).

Compound 217

-116-

A solution of 3-(difluoromethyl)-4-fluoro-aniline (1.02 mL, 8.58 mmol) in dry toluene (10 mL) was added dropwise (over 15 min) to a refluxing solution of 5chloro-3-chlorosulfonyl-2-fluoro-benzoy! chloride (2500 mg, 8.576 mmol) in dry toluene (100 mL). After the addition, the reaction mixture was left to stir at reflux for 1 h. The reaction mixture was left to cool to room température under nitrogen atmosphère while stirring.The brown solution containing 5-chloro-3-[[3-(difluorotnethyl)-4-fluorophenyl]carbamoyl]-2-fluoro-benzenesutfonyl chloride was used without further purification. 3-methyl-3-oxetanamine (580 mg, 6.66 mmol) was added dropwise to the above solution at room température. EtjN (2.10 mL 15.14 mmol) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room température for 45 minutes. The solvent was evaporated and the residue was taken up in EtOAc. HCl (0.5 N, 30 mL) was added to the réaction mixture and the layers were separated. The organic layer was washed again with NaOH (0.5 N, 30 mL).

The organic layer was dried on MgSO₄ and was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: CH₂Ct₂:MeOH 100:0 -> 95:5), resulting in compound 217 (1.8 g). 'H NMR (360 MHz, DMSO-<U) 5 ppm 1.45 (s, 3 H) 4.23 (d, >6.2 Hz, 2 H) 4.63 (d, >6.2 Hz, 2 H) 7.27 (t, >54.3 Hz, 1 H) 7.43 (t, >9.7 Hz, I H) 7.83 (dt, >8.1,4.0 Hz, 1 H) 7.95 (dd, >5.9,2.6 Hz, 1 H) 8.04 (dd, >6.0,2.4 Hz, 1 H) 8.13 (dd, >5.3,2.7 Hz, 1 H) 8.98 (s, 1 H) 10.98 (s, 1 H) Method F, Rt: 1.03 min. m/z : 465.1 (M-H)* Exact mass: 466.0.

Compound 218

Pd/C (10%) (716 mg) was suspended in a solution of compound 217 (345 mg, 0.673 mmol) and EtjN (0.467 mL) in MeOH (100 mL) at room température under nitrogen atmosphere.The reaction mixture was next stirred at room température under an

-117atmosphere of hydrogen until one équivalent of hydrogen was absorbed.The réaction mixture was filtered on decalite and the solvent was evaporated.The obtained residue was purified by silica gel column chromatography (CHiChiMeOH 100:0 -> 95:5) resulting in compound 218 (206 mg) as a white solid, dried in vacuo at 50 °C.

'H NMR (360 MHz, DMSO-de ) δ ppm 1.44 (s, 3 H) 4.19 (d, >6.6 Hz, 2 H) 4.63 (d, >6.2 Hz, 2 H) 7.26 (t, >54.3 Hz, 1 H) 7.42 (t, >9.5 Hz, 1 H) 7.52 (t, >7.7 Hz, 1 H)

7.86 (dd, >8.1,3.7 Hz, 1 H) 7.93 - 8.01 (m, 2 H) 8.06 (dd, >6.4,2.4 Hz, 1 H) 8.77 (s, t H) 10.92 (s, 1 H). Method F, Rt: 0.92 min. m/z : 431.1 (M-H)' Exact mass: 432.1.

Compound 219

F

Compound 219 (828 mg), was prepared similar as described for compound 217 and 218. Using 4-fluoro-3-(trifluoromethyl)aniline insteadof 3-(difluoromethyl)-4-fluoroaniline. Method F, Rt: 1.00 min. m/z : 449.1 (M-H)‘ Exact mass: 450.1.

'H NMR (360 MHz, DMSO-de) δ ppm 1.44 (s, 3 H) 4.19 (d, >5.9 Hz, 2 H) 4.62 (d, >6.2 Hz, 2 H) 7.53 (t, >7.9 Hz, 1 H) 7.57 (t, J=9,9 Hz, 1 H) 7,94 - 8.02 (m, 3 H) 820 (dd, >6.4,2.7 Hz, 1 H) 8.78 (s, 1 H) 11.02 (s, 1 H).

Compound 220

Compound 220 was prepared similar as described for compound 217 and 218, using (S)-3-aminotetrahydrofuran instead of 3-methyl-3-oxetanamine. Method F, Rt: 0.90 min. m/z : 431.1 (M-H)* Exact mass: 432.1. ’HNMR (360 MHz, DMSO-de ) δ ppm

1.66 - 1.77 (m, 1 H) 1.91 - 2.03 (m, I H) 3.43 (dd, >8.8, 4.8 Hz, 1 H) 3.57 - 3.70 (m, 2 H) 3.70 - 3.78 (m, 1 H) 3,79 - 3.90 (m, 1 H) 7.26 (t, >54.2 Hz, 1 H) 7.42 (t, >9.5 Hz, 1 H) 7.53 (t, >7.7 Hz, 1 H) 7.81 - 7.88 (m, 1 H) 7.94 - 8.00 (m, 2 H) 8.07 (dd, >6.4,

2.4 Hz, 1 H) 8.45 (d, >6.6 Hz, 1 H) 10.92 (s, 1 H).

Compound 221

-118-

Compound 221 was prepared similar as described for compound 217 and 218, using 2methylpropan-2-amine instead of 3-methyl-3-oxetanamine, and 4-fluoro-3-methylanilîne instead of 3-(difluoromethyl)-4-fluoro-aniline Method F, Rt: 1.06 min. m/z :

381.2 (Μ-H)' Exact mass: 382.1.1 H NMR (360 MHz, DMSO-de) 5 ppm 1.15 (s, 9 H) 2.24 (d, >1.5 Hz, 3 H) 7.15 (t, J=9.1 Hz, 1 H) 7.47 (t, >7.7 Hz, 1 H) 7.43 - 7.55 (m, 1 H) 7.65 (dd, >7.0,2.6 Hz, 1 H) 7.87 (ddd, >7.8,6.1, 1.8 Hz, 1 H) 7.93 (s, 1 H) 7.90 - 7.99 (m, 1 H) 10.63 (s, 1 H).

Compound 243

Compound 243 was prepared similar as described for compound 217 and 218, using tert-butylamine instead of 3-methyl-3-oxctanamine. Method G, Rt: 1.76 min. m/z :

417.1 (Μ-H)'Exact mass: 418.1.'H NMR (360 MHz, DMSO-de) δ ppm 1.15 (s, 9 H)

7.41 (t, >9.7 Hz, 1 H) 7.26 (t, >54.5 Hz, 1 H) 7.49 (t, >7.7 Hz, 1 H) 7.85 (ddd, >8.6,

4.4.3.1 Hz, 1 H) 7.88 - 8.01 (m, 3 H) 8.08 (dd, >6.2,2.6 Hz, 1 H) 10.90 (s, 1 H).

Compound 222

Compound 222 was prepared similar as described for compound 221, using 3-methyl-

3-oxetanamine instead of 2-methylpropan-2-amine. Method F, Rt: 0.91 min. m/z :

395.1 (M-H)‘ Exact mass: 396.1.¹ H NMR (360 MHz, DMSO-de) δ ppm 1.44 (s, 3 H)

2.24 (d, >1.5 Hz, 3 H) 4.19 (d, >6.6 Hz, 2 H) 4.62 (d, >6.2 Hz, 2 H) 7.15 (t, >9.3 Hz, 1 H) 7.46 - 7.55 (m, 2 H) 7.63 (dd, >7.0,2.6 Hz, 1 H) 7.88 - 7.99 (m, 2 H) 8.75 (s, 1 H) 10.65 (s, 1 H).

-119-

Compound 223

3-methyloxolan-3-amine hydrochloride (165.9 mg, 1.21 mmol) was added to a solution of 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzencsulfonyl chloride (499 mg, 1.096 mmol) in dry CH2CI2 (20 mL) at room température. EtjN (381 pL) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room température for 1 hour.The reaction mixture was diluted with EtOAc (250 mL). HCl 0.5 N (50 mL) was added and the layers were separated. The organic layer was washed again with NaOH 0.5 N (30 mL). The organic layer was dried on MgSO₄ and was evaporated. The obtained residue was purified t by silica gel column chromatography (CfyChWeOH 100:0 -> 95:5) andby préparative HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-10pm,30x 150mm), Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) resulting in compound 223 (257 mg) as a white solid after drying in vacuo at 50°C. Method F, Rt: 0.93 min. m/z : 391.2 (M-H)' Exact mass: 392.1.' H NMR (360 MHz, DMSO-de) ppm 1.17 (s, 3 H) 1.72 (dt, >12,8,7.7 Hz, 1 H) 2.14 (ddd, >12.8,7.1,6.0 Hz, 1 H) 2.25 (d, >1.8 Hz, 3 H) 3.30-3.40 (τη, 1 H) 3.61 - 3.77 (m, 3 H) 7.15 (t, J=9.3 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.69 (dd, >7.0,2.2 Hz, 1 H) 7.75 (t, >7.9 Hz, 1 H) 8.04 (d, >8.0 Hz, 1 H) 8.10 (br. s„ 1 H) 8.18 (dt, >7.7,1.3 Hz, 1 H) 8.39 (t, >1.6 Hz, 1 H) 10.49 (br. s., 1 H).

Compound 225

3-[(4-fluoro-3-methyl-phenyl)cafbamoyl]benzenesulfonyl chloride (0.5 g, 1.53 mmol) and (Æ)-1,1,1-tri fluoro-2-propylamine (0.38 g, 3.36 mmol) were dîssolved in of dichloromethane (10 mL). Then diisopropylethylamînc (0.66 mL, 3.81 mmol) was added and the resulting mixture was stirred for two hours. Then IM HCl (5 mL) was added and the organic layer was separated, loaded on silica and subjected to silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100). The desired fractions were concentrated in vacuo and dried în a vacuum oven at 55°C for 24 hours compound 225 (233 mg) as a white powder. Method F, Rt: 1.05 min.

120 m/z : 403.1 (M-H)' Exact mass: 404.1. 'H NMR (400 MHz, DMSO-dé) 6 ppm 1.01 (d, >6.8 Hz, 3 H), 2.25 (d, >1.8 Hz, 3 H), 4.06-4.22 (m, 1 H), 7.15 (t, >9.2 Hz, 1 H),

7.51 - 7.63 (m, 1 H), 7.67 (dd, >7.2,2.3 Hz, 1 H), 7.78 (t, >7.8 Hz, 1 H), 8.00 - 8.10 (m, 1 H), 8.16 - 8.28 (m, 1 H), 8.40 (t, >1.7 Hz, 1 H), 8.66 (br. s., 1 H), 10.46 (s, 1 H).

Compound 226

Compound 226 (416 mg) was prepared as described for compound 225, using ($)-

1,1,1 -tri fluoro-2-propy!amine instead of (/?)-1,1,1-tri fl uoro-2-propy lamine. Method F, Rt: 1.05 min. vrJz : 403.1 (M-H)' Exact mass: 404.1.

Compound 227

Compound 227 (444 mg) was prepared similarly as described in synthetic procedure S3 (using 2,2-difluoroethy!amine as amine), workup W4. Method F, Rt: 0.93 min. m/z :

371.1 (M-H)' Exact mass: 372.1.¹H NMR (400 MHz, DMSO-dé ) δ ppm 225 (d, >1.8 Hz, 3 H), 3.26 (td, >15.8,3.7 Hz, 2 H), 6.00 (tt, >55.2,3.5 Hz, 1 H), 7.14 (t, >9.0 Hz, 1 H), 7.52 - 7.62 (m, 1 H), 7,63 - 7.70 (m, 1 H), 7.77 (t, >7.9 Hz, 1 H), 7.96

- 8.06 (m, 1 H), 8.14 - 8.25 (m, 1 H), 8.30-8.45 (m, 2 H), 10.46 (s, 1 H)

Compound 228

Compound 228 (238 mg) was prepared similarly as described in synthetic procedure S3

121 (using 2,2-difluoroethylamine as amine), workup W4, followed by préparative HPLC (SunFire Prep C18 OBD-10gm,30x 150mm). Mobile phase (0.25% NH4HCO3 solution in water, MeOH). Method F, Rt: 0.97 min. m/z : 389.1 (M-H)‘ Exact mass: 390.1. ¹H NMR (400 MHz, DMSO-d«) δ ppm 2.25 (d, >1.8 Hz, 3 H), 3.74 (q, >9.5 Hz, 2 H), 7.15 (t, >9.2 Hz, 1 H), 7.48 - 7.62 (m, 1 H), 7.64 - 7.71 (m, 1 H), 7.77 (t, >7.8 Hz. 1 H), 7.94-8.10 (m, 1 H), 8.20 (m,>8.1 Hz, 1 H), 8.37 (t,>1.7 Hz, 1 H), 8.49- 9.15 (bs, 1 H), 10.45 (s, 1 H)

Compound 229

Compound 243 (239 mg) was prepared similar to synthctic procedure S2 (using 3,3difluoro-cyclopentanamine as amine), workup W4. Method F, Rt: 1.03 min. m/z : 411.2 (M-H)· Exact mass: 412.1. 'H NMR (400 MHz, DMSO-di) δ ppm 1.50-1.165 (m, 1 H), 1.81 - 2.04 (m, 3 H), 2.04 - 2.23 (m, 2 H), 225 (s, 3 H), 3.63 - 3.76 (m, 1 H), 7.14 (t, J=9.1 Hz, 1 H), 7.59 (dt, >8.1,3.9 Hz, 1 H), 7.65 - 7.72 (m, 1 H), 7.78 (t, >7.8 Hz, 1 H), 8.02 (d, >7.9 Hz, 1 H), 8.14 (d, >6.8 Hz, 1 H), 8.22 (d, >7.7 Hz, 1 H), 8.37 (s, 1 H), 10.47 (s, 1 H).

Compound 230

F

2-methyl-3-fùroic acid (4.2 g, 32.6 mmol) was dissolved in CH2CI2 (100 mL) and cooled with an ice-bath to -5°C. Then chlorosulfonic acid (10.85 mL, 163.2 mmol) was added dropwise at a rate of 0.250 mL/min. The reaction mixture was allowed to warm to room température and stirred ovemight. The réaction mixture was quenched on ice and extracted with 2-MeTHF. The organic layer was washed with brine, dried over MgSO₄ and evaporated to dryness yielding crude 5-chlorosulfonyl-2-methylfuran-3-carboxylic acid (420 mg) as a brown oil. 5-chlorosulfonyl-2-methyl-furan-3carboxylic acid (420 mg) was dissolved in CH2CI2 (10 mL). Hunig's base (0.64 mL,

3.74 mmol) and isopropylamine (0,478 mL, 5.61 mmol) were added and the reaction mixture was stirred ovemight at room température. The volatiles were removed under reduced pressure and the residue was used as such in the next step. The above residue

-122was dissolved in CH₂Cl₂ (20 mL), 4-fluoro-3-mcthylaniline(228 mg, 1.82 mmol), HATU (830 mg, 2.18 mmol) and N,N-diisopropylethylamine (0.94 mL, 5.46 mmol) were added and the reaction mixture was stirred for 30 minutes. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane 5 to EtOAc gradient resulting in compound 230 (174 mg) as a white powder. Method F,

Rt: l.OO min. m/z : 353.1 (M-H)' Exact mass: 354.1. * H NMR (400 MHz, DMSO-de) Ô ppm l .03 (d, J=6.4 Hz, 6 H), 2.23 (s, 3 H), 2.64 (s, 3 H), 3.35 - 3.43 (m, l H), 7.11 (t, J=9.2 Hz, l H), 7.53 (dd, J=7.9,4.0 Hz, l H), 7.59 - 7.69 (m, l H), 7.72 (s, l H), 8.06 (d, J=5.5 Hz, l H), 9.87 (s, l H).

Compound 231

3-methyl-3-oxetanamine hydrochloride (302.6 mg, 2.45 mmol) and Hunig’s base (1.15 15 mL, 6.68 mmol) dissolved in CH₂C1₂ (2 mL) were added to a solution of methyl 5- (chlorosulfonyl)-2-furoatc (thcrmo scicntific, 500 mg, 2.23 mmol) in CH₂C1₂ (10 mL), The reaction mixture was stirred ovemight at room température. The volatiles were removed under reduced pressure and the obtained residue was used as such.

The residue was dissolved in THF (10 mL). LiOH (60.2 mg, 2.514 mmol), dissolved in 20 H2O (1 mL), was added to the reaction mixture, MeOH (1 mL) was added and this was stirred ovemight at room température. The volatiles were removed under reduced pressure and the residue was dissolved water (25 mL). 1M HCl (2.5 mL) was added and then 2-MeTHF (50 mL) was added. The aqueous layer was removed and the organic layer was washed with brine (50 mL), The organic layer was dried over 25 MgSO₄, filtered and evaporated to dryness yielding an oil which was used as such in the next step. The oil and HATU (573 mg, 1.51 mmol) were stirred in CH2CI2 (5 mL) and 4-fluoro-3-methylaniline (157.3 mg,l .26 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.77 mmol) were added. The reaction mixture was stirred ovemight at room température. The volatiles were removed under reduced pressure and the residue was 30 purified on silica using a heptane to EtOAc gradient followed by by préparative HPLC (Stationary phase: RP Vydac Denali Cl8 - ΙΟμτη, 200g, 5cm), Mobile phase: 0.25% NHiHCO₃ solution in water, CHjCN), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. This fraction was triturated in MeOH (4 mL), filtered and dried in the oven yielding compound 231 (305 mg) as a white solid.

Method F, Rt: 0.89 min. m/z: 367.1 (M-H)' Exact mass: 368.1.¹H NMR (400 MHz,

DMSO-cU) δ ppm 1.53 (s, 3 H), 2.24 (d, >1.8 Hz, 3 H), 4.21 (d, >6.6 Hz, 2 H), 4.61 (d, >6.2 Hz, 2 H), 7.14 (t, >9.2 Hz, 1 H), 7.26 (d, >3.7 Hz, 1 H), 7.50 (d, >3.7 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.60 (dd, >7.0,2.4 Hz, 1 H), 8.92 (s, 1 H), 10.34 (s, 1 H).

Compound 232 to 239 were prepared by slow addition of an aniline to a refluxing toluène solution of a 3-chlorosulfonylbcnzoyl chloride dérivative, followed by réaction with an amine in the presence of a base like NEtî or D1PEA, as described above.

	Structure	Aniline	Amine	3-chlorosulfbnyl benzoyl chloride derivatlve
232	xy --Or a	4-(luon>3mcthylanilinc	3-mcthyl-3oxctanamïnc	2-chlcro-5(chlorosulfonyl)bcn zoyl chloride
233		4-iluoro-3(trifluoroTnclh y1)anilinc	3-methyl-3oxetanaminc	2-chloro-5(chlorœulfonyl)bcn zoyl chloride
234		3,4- diriuoroaniline	3-methyl-3oxetanaminc	2-chloro-5(chlorosulfonyl) benzoyl chloride
235		3- (difluorometh yl)-4-fluoroanïlinc	3-mcthyl-3oxetanamine	2-chloro-5(chlorosulfonyl) benzoyl chloride
236		4-fluon>3methylaniline	(S)-3aminotetrahydro furan tosylale	5-chlorosulfonyl -2fluorobcnzoyl chloride
237		4-f!uoro-3methylaniline	(5)-3aminotetrahydro furan tosylale	2-bromo-5chlorosulfonylbenzoyl chloride
238	xz --cr	4-fluOTo3(trifluorometh yl)ani1ine	3-mcthyl-3oxetanamine	5-chlorosulfonyl-2methylbenzoyl chloride

-124-

	Structure	Aniline	Amine	3-chlorosulfonyl benzoyl chloride derivattve
239		4-fluoro-3mcthylaniline	(S te 3- h]	)’ trabydrofuranaminc zdrochloride	3-chlorosulfonyl-4fluorobenzoyl cbloridc
Compound	LC method	Rt (min)	m/z (M-H)'	Exact mass
232	G	1.67	410.8	412.1
233	G	1.83	464.9	466.0
234	G	1.68	414.9	416.0
235	G	1.69	446.9	448.1
236	F	0.90	395.1	396.1
237	F	0.93	457.1	458.0
238	F	1.03	445.1	446.1
239	G	l,64	394.9	396.1

Compound	’H-NMR
232	¹H NMR (360MHz, DMSO-de ) δ ppm 10.67 (s, 1 H), 8.57 (s, 1 H), 7.96 - 7.88 (m, 2 H), 7.84 - 7.79 (m, 1 H), 7.62 (dd, J = 2.6,7.0 Hz, 1 H), 7.54 - 7.46 (m, 1 H), 7.15 (t, J = 9.1 Hz, 1 H), 4.56 (d, J = 6.2 Hz, 2 H), 4.17 (d, J = 6.2 Hz, 2 H), 224 (d, J = 1.8 Hz, 3 H), 1,43 (s, 3 H)
233	¹H NMR (360MHz, DMSO-de ) δ ppm 1.44 (s, 3 H) 4,18 (d, >6.6 Hz, 2 H) 4.57 (d, J=6.0Hz, 2 H) 7.57 (t, J=9.9 Hz, 1 H) 7.85 (d, >8.4 Hz, 1 H) 7.91 - 7.98 (m, 2 H) 8.02 (d, >2.2 Hz, 1 H) 8.20 (dd, >6.2,2.6 Hz, 1 H) 8.58 (s, 1 H) 11.06 (s, IH)
234	‘H NMR (360 MHz, CHLOROFORM-d) δ ppm 1.64 (s, 3 H) 4.37 (d, >6.5Hz, 2 H) 4.66 (d, J=6.5 Hz, 2 H) 5.74 (s, 1 H) 7.09 7.24 (m, 2 H) 7.59 (d, >8.2 Hz, 1 H) 7.70 (ddd, >11.8,7.0,2.4 Hz, 1 H) 7.88 (dd, >8.4,2.2 Hz, 1 H) 8.19 (d, >2.2 Hz, 1 H) 8.30 (s, 1 H)
235	¹H NMR (360MHz, DMSO-de ) δ ppm 1.44 (s, 3 H) 4.18 (d, >6.2 Hz, 2 H) 4.57 (d, >6.2 Hz, 2 H) 7.26 (t, >54.2 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.84 (d, >8.4 Hz, 2 H) 7.91 (d, >2.2 Hz, 1 H) 8.00 (d, >2.2 Hz, 1 H) 8.03 - 8.10 (m, 1 H) 8.58 (s, 1 H) 10.95 (s, 1 H)

-125-

Compound	’H-NMR
236	¹H NMR (400 MHz, DMSO-de) δ ppm 1.57 - 1.70 (m, 1 H), 1.87 - 2.04 (m, 1 H), 2.25 (d, >1.0 Hz, 3 H), 3.38 (m, 1 H), 3.54 - 3.81 (m, 4 H), 7.15 (t, >9.1 Hz, 1 H), 7.47 - 7.56 (m, 1 H), 7.57-7.72 (m, 2 H), 7.95-8.20 (ddd, >8.6,4.6,2.4 Hz, 1 H), 8.06 - 8.19 (m, 2 H), 10.60 (s, 1 H)
237	¹H NMR (400 MHz, DMSO-de) δ ppm 1.60 - 1.70 (m, 1 H), 1.89 - 2.00 (m, 1 H), 2.24 (d, >1.6 Hz, 3 H), 3.38 (dd, >8.9,4.4 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.63 - 3.67 (m, 1 H), 3.68-3.72 (m, 1 H), 3.73 - 3.80 (m, 1 H), 7.14 (t, J=9.3 Hz, 1 H), 7.49 (ddd, >8.9,4.4, 2.8 Hz, 1 H), 7.63 (dd, J=6.9,2.4 Hz, 1 H), 7.80 (dd, >8.3, 2.2 Hz, 1 H), 7.89 (d, >2.4 Hz, 1 H), 7.97 (d, >8.5 Hz, 1 H), 8.12 (br. s., 1 H), 10.63 (s, 1 H)
238	’ H NMR (360MHz, DMSO-de ) δ ppm 1.42 (s, 3 H) 2.46 (s, 3 H) 4.14 (d, >6.2 Hz, 2 H) 4.56 (d, >6.2 Hz, 2 H) 7.51 - 7.59 (m, 2 H) 7.84 (dd, >8.1,1.8 Hz, 1 H) 7.89 (d, >1.8 Hz, 1 H) 7.95 8.02 (m, 1 H) 8.24 (dd, >6.6,2.6 Hz, 1 H) 8.42 (s, 1 H) 10.87 (s, IH)
239	¹H NMR (400 MHz, DMSO-de) δ ppm 1.65 - 1.74 (m, 1 H), 1.90 - 2.00 (m, 1 H), 2.25 (d, >1.5 Hz, 3 H), 3.41 (dd, >8.9,4.7 Hz, 1 H), 3.57 - 3.77 (m, 3 H), 3.83 - 3.91 (m, 1 H), 7.14 (dd, >9.2 Hz, 1 H), 7.54 - 7.61 (m, 1 H), 7.61 - 7.69 (m, 2 H), 8.29 (ddd, >8.5, 4.6,2.3 Hz, 1 H), 8.40 (dd, >7.0,2.2 Hz, 1 H), 8.44 (br. s., 1 H), 10.47 (s, 1 H)

Differential scanning calorimetry From 30 to 300 °C at lO°C/mîn: Compound 232: Peak at 169.6 °C

Optical rotation;

Compound 236: [a]?= - 5.83 (c 0.67 w/v %, MeOH).

Compound 240

F

-126SOCI₂ (20.1 mL, 277.2 mmol) was added slowly to water (125 mL) cooled to 5 °C, maïntaining the température between 4 and 7 °C (addition took about 1.5 hour). The solution was then kept stirring ovemight while the température was allowed to slowly reach room température. Copper(l) chloride (76.6 mg, 0.774 mmol) was then added to the solution and it was cooled to -10 °C (dry ice/acetone bath), (resulting in solution A). In another flask cooled to 0 °C, HCl (37% tn H₂O, 65 mL) was added dropwise to 3-amino-5-fIuorobenzoic acid (10 g, 64.46 mmol), keeping the température below 20 °C. This slurry was cooled to -10 °C (dry ice/acetone bath) and a solution of sodium nitrite (4.803 g, 69.62 mmol) in H₂O (20 mL) was added very slowly (1 drop/5 sec) to the slurry, keeping the température below -5°C.

After addition, the orange mixture was allowed to warm to -2 °C for 5 min before cooling back to -15 °C (solution B). Solution B was then added portionwise (plastic pipette) to solution A, cooled to -10 °C. After addition (~30 min), the reaction mixture was stirred at 0 °C for 2 h. The resulting orange solid was filtered and rinsed with water (2 x 25 mL) resulting in 3-chlorosulfonyl-5-fIuoro-bcnzoic acid as an orange solid (dried at 35 °C tn vacuo). EtjN (1.22 mL, 8.8 mmol) was slowly added to a solution of 3-chlorosulfonyl-5-fluoro-benzoic acid (525 mg, 2.2 mmol) in dry CH₂CI₂ (10 mL). tsopropylamine (198 pL, 2.42 mmol) was then added dropwise at room température to the reaction mixture.The reaction mixture was stirred at room température for 30 min.The brown reaction mixture was diluted with CH₂C1₂ and water. HCl IN was added to pH 2. The layers were separated and the aqueous layer was extracted twice with CH₂CI₂.The organic layer was dried on MgSO, filtered, and evaporated resulting in 3-fIuoro-5-(isopropylsulfamoyl)benzoîc acid as an orange solid, which was used without further purification. HATU (356.7 mg, 0.94 mmol) was added to a solution of crude 3-fluoro-5-(isopropyIsulfamoyl)benzoic acid (190 mg), 4-fluoro-3-methylaniline (78.3 mg, 0.625 mmol) and N,N-diisopropylethylamine (326.8 pL, 1.88 mmol) in CH₂CI₂ (30 mL)at room température. The mixture was stirred at room température for I h. The reaction mixture was diluted with CH₂C1₂, washed with HCl 0.5 N, filtered on Extrclut NT3 and evaporated. The obtained residue was purified by column chromatography on silica gel (Grâce Resolv 12g, eluent: CH₂Cl₂:MeOH 100:0 -> 95:5) resulting in compound 240 (136 mg) as a white solid, dried at 50 °C in vacuo. Method G, Rt: 1.87 min. m/z: 366.9 (M-H)‘ Exact mass: 368.1.*H NMR (360 MHz, DMSO-di) δ ppm 0.97 (d, >6.2 Hz, 6 H) 2.25 (d, J=1.5 Hz, 3 H) 3.30-3.39 (m, 1H),

7.16 (t, J=9.3 Hz, 1 H) 7.55 - 7.62 (m, 1 H) 7.67 (dd, >7.1, 2.4 Hz, 1H) 7.83 (dt, J=8.0,

1.9 Hz, t H) 7.88 (d, >7.0 Hz, 1 H) 8.08 (dt, >9.3,1.7 Hz, 1 H) 8.22 (s, t H) 10.52 (s,

1H).

Compound 241

-127F

Compound 241 was prepared similarly as described for compound 240 using (S)-3aminotetrahydrofùran tosylate instead of isopropylamine. Method G, Rt: 1.70 min. m/z:

394.9 (M-H)’ Exact mass: 396.1. 'H NMR (360 MHz, DMSO-d^) d ppm 1.55 -1.67 (m, 1 H) 1.93 (dq, >12.8, 7.4 Hz, 1 H) 2.25 (d, >1.8 Hz, 3 H) 3.37 (dd, >9.0,4.2 Hz, 1 H) 3.55 - 3.75 (m, 3 H) 3.75 - 3.85 (m, 1 H) 7.16 (t, >9.1 Hz, 1 H) 7.56-7.62 (m, 1 H) 7.67 (dd, >7.3,2.6 Hz, 1 H) 7.82 - 7.88 (m, 1 H) 8.08 - 8.13 (m, 1 H) 8.20 - 8.25 (m, 2 H) 10.53 (s, 1 H).

Compound 242

Compound 237 (400 mg, 0.87 mmol) was dissolved in a mixture of DMF (2.5 mL) and N-methylpyrrolidine (0.12 mL) containing Copper(I)iodide (45.43 mg, 0.24 mmol) and

2.2- difIuoro-2-fIuorosulfonyl acetic acid methylester (0.21 g, 1.09 mmol).

The resulting mixture was stirred at room température for 2 hours. An extra amount of

2.2- difluoro-2-fluorosulfonyl acetic acid methylester (0.21 g, 1.09 mmol) was added and the mixture was stirred at 60°C for 1 hour. The mixture was stirred at 60°C for 18 hours. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture. Then this was extracted using EtOAc (3 x l5mL). The combined extracts were dried on Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified using coiumn chromatography on silica (gradient elutîon: cthylacetate: heptane from 0 to 100%). Ail desired fractions were combined and concentrated under reduced pressure and then dried at 50°C in a vacuum oven overnight yielding compound 242 (314 mg) as a white powder. Method G, Rt: 1.73 min. m/z: 445.0 (M-H) Exact mass:

446.1.

Biological examples - anti-HBV activity of compounds of Formula (1)

The anti-HBV activity was measured using a stable transfected cell line,

HepG2.2.15. This cell line was described to secretc rclatively consistent high levels of

HBV virion particles, which hâve been shown to cause both acute and chronic infection and disease in chimpanzccs.

For the antiviral, assay cclls were treated twice for three days with serially diluted compound in 96-well plates in duplicate. After 6 days of tretament the antiviral activity was determined by quantification of purified HBV DNA from secreted virions using realtime PCR and an HBV spécifie primer set and probe.

Cytotoxicity of the compounds was tested in HepG2 cells using CellTiter-Blue, with the same incubation period and dose range as in the HepG2.2.l5 assay.

The anti HBV activity was also measured using the HepG2.117 cell line, a stable, inducibly HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off system). For the antiviral assay, HBV réplication was induced, followed by a treatment with serially diluted compound in 96-wcll plates in duplicate. After 3 days of treatment, the antiviral activity was determined by quantification of intracellular HBV

DNA using realtime PCR and an HBV spécifie primer set and probe. Cytotoxicity of the compounds was tested using HepG2 cells, incubated for 4 days in the presence of compounds. The viability of the cells was assessed using a Resazurin assay. Results are displayed in Table l.

Table l.

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50(gM)	HcpG2 117 EC50 (μΜ)	IfcpG2 4 days CC50 (μΜ)
ct/qW'	1	0.93		1.67	>100
	2	0.47		0.56	32.7

-129-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IIcpG2 6 dayi CC50 (μΜ)	IIepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
	3	2.10		3.05	>100
	4	0.96		0.93	>100
	5	0.83		0.90	57.7
°-'s'^N_O ^F-W^_Ny_^ °	6			0.58	>25
	7	0.66	-	0.56	11.4

-130-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (UM)	HepG2 6 days CC50(pM)	IIepG2 117 ECSO (μΜ)	HepG2 4 days CC50 (UM)
Ύ11*5?	8	1.18		2.03	>100
	9	0.54		1.36	>100
/vv° s zy^ffeT «rQA^	10	0.75		3.63	40.3
zfe-fe S XX^F<y _/ΊφΑ^	11	0.10		0.42	19.6
/vJt/ 5 jOs <j	12	0.11		1.51	13.3

-131-

STRUCTURE	Co. No.	IIcpG2 2.15 EC50 (μΜ)	HcpG2 6 dayi CC50 (μΜ)	HcpG2 117 EC50(gM)	HepG2 4 days CC50 (μΜ)
	13	1.99		15.31	13.8
σΥοΑ'	14	0.09		0.36	11.7
F	15	0.28		0.78	10.1
	16	1.21		2.8	10.3
_C\|XiAx_C\|	17	0.56		2.65	>100

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IkpG2 6days CC50(pM)	lkpG2 117 EC50 (μΜ)	lkpG2 4 days CC50 (μΜ)
_F ç> Vr^cr»	18	0.78	51.6	1.30	>50
	19	0.66	42.5	0.60	>25
q» -,Ό W	20	0.50	>25	1.00	79.6
	21	0.60	27.2	0.76	41.1
0./. ï XX Aeê	22	0.52	>25

-133-

STRUCTURE	Co. Νο.	HcpG2 2.15 EC50 (μΜ)	HepG2 6 days <Χ50(μΜ)	IIcpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
XX °ΧΛ	23	0.66	17.0	1.30	19.6
F ο ο hn-CX /γγ^° _αζ<Α_α	24	0.79	>25
θΊ . -fi¹'Αχό	25	0.80	>25	1.02	>6.25
α’γθϊ'γ?	26	1.04	>25
Ο/θχ,Χλ	27	1.13	>25

-134-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50(pM)	IkpG2 117 EC50 (μΜ)	IIepG2 4 days CC50 (μΜ)
	28	1.24		2.28	52.5
Cl	29	1.39	>25
0--iT XX.	30	1.67	>25
q^Pvy> ^{H 0} 0 AA	31	2.23	16.4
0. Vnh O-m 0 a o—	32	2.59	9.9	4.58	>25

-135-

STRUCTURE	Co. No.	HcpG2 2.15 EC50 (UM)	HcpG2 6days CC50(pM)	IIcpG2 117 EC50 (μΜ)	IIcpG2 4 days CC50 OiM)
<vv« τη Ο ^{0 0 M}	33	3.56	>25
’Α,ίΤ ά	34	4.18	>25
	35	4.50		2.70	70.4
	36	4.53		3.03	97.0
I o fl 0Y^F ό’Υγκ	37	5.02		2.99	>100

-136-

STRUCTURE	Co. No.	llcpG2 2.15 EC50 (μΜ)	l!cpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
	38	<6.25	18.4	15.54	22.10
_γσνν^,χτ' 0	39	6.77		4.68	>100
0	40	7,10		6.29	>100
ΟΛθϊΤΧ	41	8.49	-	10.95	>100
OÛL/xj>° οσ··>	42	11.64	37.2	>25

-137-

STRUCTURE	Co. No.	IIepG2 2.15 EC50 (\|A1)	HcpG2 6 days CC50(pM)	IIcpG2 117 EC50 (μΜ)	IIepG2 4 days CC50 (UM)
	43	15.13	36.3	>25	>25
	44	26.49		11.08	>100
	45	59.33		16.03	>100
Îcj-Xr'	46	2.61		11.09	23.8
	47	0.74		0.96	57.5

STRUCTURE	Co. No.	HepG2 2.15 EC50 (pM)	IIepG2 6days CC50(pM)	HepG2 117 EC50 (pM)	HepG2 4 days CC50 (PM)
.jCr'rP-êP	48	2.92		1.88	97.2
a.	49	13.4		9.15	>100
^zTl. ..	50	45.9		15.80	11.3
Xk ÂQ-W	51	3.98		9.44	20.8
%jOÇ° cP n.	52	1.94		2.44	>50

STRUCTURE	Co. No.	HcpG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50(pM)	IIepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
Ό ... F	53	0.36		0.44	>50
	54	1.63		1.55	>50
«=A> fx)	55	3.06		3.26	>100
yyXxP	56	1.64		5.45	>100
C ^m~O_F	57	15.53		12.74	52.1

-140-

STRUCTURE	Co. No.	IkpG2 2.15 EC50 (μΜ)	HcpG2 6days CC50(pM)	IkpG2 117 EC50 (μΜ)	HcpG2 4 days CC50 (UM)
Ο ° -Q	58	14.62		19.94	62.5
HN _Λ Ό	59	12.79		19.27	46.7
α·νίχ<· A M	60	0.85		0.67	29.1
\=/ _oAq	61	7.07		15.44	35.7
Cm / co-p \—NH O	62	7.06		10.07	>50

-14I-

STRUCTURE	Co. No.	IIepG2 2.15 EC50 (μΜ)	HepG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	IIcpG2 4 days CC50 (UM)
Ww O	63	9.94		21.12	>100
Cl JA3a	64			7.83	>25
r^xx<^'/⁵ n. JL Ij) U o'Xjnr^	65	10.76		>25	35.3
Cl °u A	66	4.27		14.49	>100
xxA/ î Ij]	67	11.10		18.55	>100
^1/ î JÛ CT ΊΤ	68	18.60		>25	68.0

STRUCTURE	Co. No.	HepG2 2.15 EC50 (UM)	HcpG2 6 days CC50(pM)	lkpG2 117 EC50 (μΜ)	HcpG2 4 days CC50 (μΜ)
	69	3.90		10.38	>25
	70	0.34		0.89	>25
-O	71	0.75		8.63	>25
σνΑ	72	0.12		0.37	>25
_vh./> ? rr	73	0.073		0.15	>25
H,O O ^Y^F	74	0.64		0.53	>25

STRUCTURE	Co. No.	HepG2 2.15 EC50 (\|1M)	HepG2 6 days CC50 (μΜ)	liepG2 117 EC50 (μΜ)	lïepG2 4 days CC50 (UM)
	75	0.39		0.82	>25
	76	0.72		2.5	>25
(j ό- ΥΥΥ^^	77	0.27		0.43	>25
<Χ θΎτ^	78	0.90		0.65	>25
.^Α? χ xx^{F ό}' Ίφτ Μ	79	0.96		1.69	>25
Η ο Q iXV^CN /Ύ^ν'^ X ί Π <J AQT^	80	8.4		17.9	>25

-144-

STRUCTURE	Co. No.	lkpG2 2.15 EC50 (UM)	lkpG2 6 days CC50 (μΜ)	IkpG2 117 EC50 (μΜ)	IïcpG2 4 days CC50 (UM)
H p o	81	0.24		0.81	15.3
	82	1.20		3.13	>25
O-n./___£ jQf^F	83	1.04		1.23	>25
H 0 0 ^Y^F ν/χ/Α	84	0.32		0.91	>25
v. vr? jOC^f -n' Or	85	0.05		0.38	>25

STRUCTURE	Co. No.	IIcpG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50(pM)	HepG2 117 EC50 (μΜ)	IIcpG2 4 days CC50 (μΜ)
	86	0.14		0.11	>25
	87	0.41		0.89	>25
	88	0.21		0.40	>25
	89	0.54		0.72	>25
F μ-λ^α ώ^ρ0 d^piR^	90	0.38		0.51	>25

-146-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (UM)	IIcpG2 6 days CC50 (μΜ)	IIcpG2 117 EC50 (μΜ)	HcpG2 4 days CC50 (μΜ)
Ά- M	91	0.53		0.77	>25
Âj-Vv	92	0.31		2.59	>25
I £I^Fp /χ/τ¹^	93	0.07		0.22	>25
	94	0.15		0.23	>25
Vr o^QAT	95	1.4		2.79	>25
7¾ W ^oAq%	96	0.10		0.29	>25

-147-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	HepG2 6 days CC50(pM)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
F-0-NH_^⁰⁰	97	0.12		0.37	>25
F—/=( °	98	0.10		0.31	>25
A	99	0.09		0.46	>25
xi^FUy ί/χχ^	100	0.13		0.43	>25
	101	0.43		1.51	>25
	102	0.18		0.33	>25

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IIepG2 6 days CC50 (μΜ)	IIcpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
°Cr ôWA®	103	2.33		2.66	>25
✓«Λ/ î XT^F°CT H	104	0.29		0.78	>25
	105	0.81		0.98	>25
σ^ΒΧζ/Α	106	2.22		3.30	>25
σ’/'ζ/Α	107	7.82		13.82	>25
<χ^Ο^ΧΧ	108	7.20		9.27	>25

-149-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (UM)	HepG2 6 days CC50(pM)	IkpG2 117 EC50 (μΜ)	IkpG2 4 days CC50 (μΜ)
	109	1.23		2.53	>25
oOx^ZqAjjXX^	110	0.66		0.85	>25 .
	111	4.48		1.48	>25
Â Xj^	112	0.03		0.14	>25
H ο ο <Χ.^_Β-Ογ’	113	0.15		0.18	>25
jjj XX° T °Vj rr^^F	114	1.35		3.15	>25

-ISO-

STRUCTURE	Co. No.	IkpG2 2.15 EC50 (μΜ)	IkpG2 6 days CC50(pM)	HepG2 117 Εϋ50(μΜ)	HepG2 4 days CC50 (μΜ)
_Λ H o O r^y^F	115	2,74		1.65	>25
¹ ° η	116	1.94		0.90	>25
oAyA	117	0.88		0.50	>25
F Ηθ O 'Vi<^F	118	3.63		1.91	>25
	119	3.06		1.91	>25
QA /'QW'	120	0.53		0.51	>25

STRUCTURE	Co. No.	IkpG2 2.15 EC50 (μΜ)	IIepG2 6 days CC50(pM)	lkpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
σ^Α	121	0.16		0.13	>25
	122	0.13		0.18	>25
Δ V °'TJ Cl	123	0.15		0.3	>25
H 0 Cl o Λ/	124	0.33		0.68	>25
σ^Α	125	1.44		1.15	>25
σ’/^Α	126	1.38		0.89	>25

-152-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (pM)	HepG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	IIepG2 4 days CC50 (PM)
	127	0.23		0.58	>25
	128	0.23		0.54	>25
xx^F °Cj o'Vyp'^''	129	0.35		0.78	>25
^hj⁵ î fY^F	130	0.88		1.03	>25
î XX □Μ χτ h	131	2.63		1.74	>25
iXX WXj	132	0.59		0.73	>25

-153-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50(pM)	HepG2 117 EC50(pM)	IIepG2 4 days CC50 (μΜ)
jOC x> z-QrW·	133	0.60		1.69	>25
	134	0.18		0.57	>25
	134a	0.66		0.72
	134b	0.57		0.20
	134c	0.49		0.38
	134d	0.25		1.22
	135	0.56		0.36	>25
OH	136	0.47		0.81	>25
	137	0.66		0.92	23.7

-154-

STRUCTURE	Co. No.	lkpG2 2.15 EC50 (μΜ)	IkpG2 6 days CC50 (μΜ)	IkpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
N o o	138	1.28		2.27	>25
Ho o (î^j:îV^f	139	1.00		1.75	>25
	140	1.10		1.12	>25
	141	0.36		0.60	>25
	141a	0.70		1.65	>25
	141b	0.27		0.23	>25
	141c	0.17		0.29	>25
	141d	0.56		1.14	>25
7+7+	142	0.14		0.56	>25

-155-

STRUCTURE	Co. No.	HcpG2 2.15 EC50 (UM)	HepG2 6 days CC50(gM)	IkpG2 117 EC50 (μΜ)	HepG2 4 days CC50 <μΜ)
	143	0.91		2.66	>25
c+r'/c/A	144	0.13		0.24	>25
	145	0.22		0.27	>25
	145a	0.14		0.21	>25
	145b	0.44		0.58	>25
	145c	0.34		0.34	>25
	145d	0.40		0.64	>25
	146	0.45		0.42	>25
	147	0.26		0.15	>25

-156-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (pM)	HepG2 6 days CC50(pM)	!IcpG2 117 EC50 (pM)	HepG2 4 days CC50 (pM)
	148	0.90		3.11	18.2
	149	0.22		0.73	20.8
	150	0.10		0.73	>25
	151	0.66		2.74	>25
	152	<0.1		0.57	>25
	153	0.22		0.25	>25

-157-

STRUCTURE	Co. Νο.	HepG2 2.15 EC50 (μ*«)	IkpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HcpG2 4 days CC50 (μΜ)
	155	0.36		0.81	>25
	156	0.19		0.21	>25
JHxyçyÇC^	157	0.13		0.23	>25
	158	0.15		0.50	>25
	159	0.15		0.30	>25
	159a	0.17		0.86
	159b	0.16		0.23

-158-

STRUCTURE	Co. No.	HepG2 2.15 ECSO (μΜ)	HepG2 6 days CC50 (μΜ)	HcpG2 117 ECSO (μΜ)	HepG2 4 days CC50 (UM)
	160	0.20		0.69	>25
x*OC	161	0.20		0.35	>25
	162	0.17		1.26	>25
fe/feA'	163	0.53		8.53	>25
θτΖζ//Χ	164	3.71		0.97	>25
	165	0.71		0.36	>25

STRUCTURE	O O U Z.	HepG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
	166	0.19		2.39	14.6
	167	0.62		9.84	>25
xx^F	168	0.27		0.37	11.8
σ^'/γρΑ	169	0.24		1.41	14.9
	170	0.26		0.45	>25
^H9 H „ crSC-JLXX °^J °u »	171	0.79		4.39	>25

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50 (μΜ)	HcpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
/ ί ,, ,ί ,Q^r	172	0.26		0.61	>25
ZX^F	173	0.37		0.36	>25
ν/ζ/Α	174	0.47		2.84	>25
	175	0.23		0.15	>25
	176	0.62		0.56	>25
	177	0.77		0.72	>25

-161-

STRUCTURE	Co. No.	IlcpG2 2.15 EC50 (μΜ)	IlcpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
^0H H _Λ	178	0.75		2.54	>25
k <p i rr^Fr -Χο	179	0.21		0.44	>25
	179a	0.38		0.25	>25
	179b	1.11		1.84	>25
M ^H	180	0.76		1.30	>25
jk, î jTT^fcy. i'CÔM 1	181	2.59		2.04	>25
rry»·⁰'	182	0.31		0.88	>25

-162-

STRUCTURE	Co. No.	IïepG2 2.15 EC50 (μΜ)	IkpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (UM)
	183	0.08		0.84	>25
	184	0.15		0.40	>25
	184a	0.31		0.77	>25
	184b	0.30		0.33	>25
χ-°	185	0.22		0.62	>25
	186	0.20		1.34	>25

-163-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IIepG2 6days CC50(pM)	HepG2 117 EC50(pM)	HepG2 4 days CC50 (μΜ)
Br	187			0.95	>25
	188			0.24	>25
	189			0.35	>25
Br	190			0.27	>25
/ o o Ç θ \|<V ‘Φγ	191	0.33		0.36	>25
a	192			0.19	>25

-164-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IkpG2 6 days CC50 (μΜ)	lkpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
	193			0.10	13.5
·..· ! A 'OÇ⁵'^»	194	0.38		0.31	>25
χχ , ο ο f ΗΝ· Ο ^^χδχ5ό°	195	0.27		0.18	>25
ΗΚ.ΐΖ'ΐ F-/V \ X 5—ΝΗ \ ✓ ^0 F	196	0.13		0.07	>25
₀ ΗΝϋιί^***? W \ X χΖ V / ~^ΝΗ /—Ζ^^η F	197			0.09	>25
—₀ HNlr/.^!X^9 _/Υ \ X V / *^ΝΗ V_/^> F	198			0.15	>25

-165-

STRUCTURE	Co. No.	HcpG2 2.15 EC50 (μΜ)	HcpG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (UM)
'-/V \ X a 9—NH V / % F	199			0.43	>25
_o rfX'·? Αν \ x k-j \ >—NH y ✓ 03 F	200			0.45	>25
\°χΌ y 5—nh V / 0D F	201	0.06		0.06	>25
	202			0.11	>25
H Ο Γ Ç I^Tl v XÀA AJA, T ο* γΧΑ’Γ¹'	203			0.24	16.7

-166-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	lkpG2 6 days CC50(gM)	IkpG2 117 EC50 (μΜ)	HcpG2 4 days CC50 (μΜ)
	204			0.09	>25
.A	205			0.35	>25
V i A	206			0.64	>25
-p _{F o} JL ^bÇ° I i AJ	207			>1	>25
F S-'. , o ζ^γ’	208			>1	>25
P ^f ° Ar^F	209			0.15	>25

-167-

STRUCTURE	Co. No.	IIcpG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50 (μΜ)	IIepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
f⁷. ! « A	210			0.46	>25
XX H 0 CI W	211			0.65	>25
\XX	212			7.3	>25
...xc A·	213			0.28	>25
XX H 0 f •A:	214			>1	>25
.· i -Ab, '	215			>1	>25

-168-

STRUCTURE	Co. No.	HcpG2 2.15 EC50 (μΜ)	HepG2 6 days CC50 (μΜ)	HepG2 117 EC50 (μΜ)	IkpG2 4 days CC50 (μΜ)
<>C °>ς __/ X) b	216			0.29	>25
a aXv'ÿ,	217	0.20		0.60	>25
	218	0.12		0.10	>25
ολ’τΫφ, d>	219			0.46	>25
^xVïyi,	220	0.11		0.09	>25
AXSyi,	221			0.13	>25

-169-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50 (μΜ)	IIepG2 117 EC50 (μΜ)	IIepG2 4 days CC50 (μΜ)
	222	0.05		0.10	>25
	223			0.21	>25
O^zvyQfAr^L	224	0.16		0,76	>25
o	225	0.09		1.34	>25
^Fy^ _F	226	0.27		1.9	>25

-170-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50 (μΜ)	lïcpG2 117 EC50(pM)	HcpG2 4 days CC50 (μΜ)
F	227	0.16		0.71	>25
	228	0.17		1.19	>25
	229	0.20		0.49	>25
	230	0.73		1.52	>25
ÿ_sXXH0_,	231	0.21		0.32	>25
a	232			0.31	>25

-171-

STRUCTURE	Co. No.	HepG2 2.15 EC50 (μΜ)	IlepG2 6 days CC50(pM)	IIcpG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
Cl	233	>1		>1	>25
YyY' Cl	234	0.72		0.34	>25
	235	0.83		0.33	>25
	236	0.48		1.58	>25
	237	0.43		0.13	>25
^;e^;C'	238	0.61		0.50	>25

-172-

STRUCTURE	Co. No.	IïcpG2 2.15 EC50 (μΜ)	IIcpG2 6 days CC50(pM)	IIepG2 117 EC50 (μΜ)	IIcpG2 4 days CC50 (μΜ)
	239	0.48		0.53	>25
,ΧτΑ·Υ	240	0.40		2.86	>25
	241	0.38		1.79	>25
%oêA^F	242	1.91		1.80	>25

Claims

Claims

I. A compound of Formula (I) or a stereoisomer or tautomcric form thereof, wherein:

B represents a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or 10 more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-Cjalkyl, CN, CFH2, CFjH and CF₃;

Ri represents hydrogen or Ci-Cjalkyl;

15 R₂ represents CpCealkyl, Ci-Cealkenyl, Ci-Cealkyl-Rj, C(=O)-Rj, CFH₂, CF₂H, CF₃, a dihydro-indenyl or tetrahydronaphtalenyl moiety optionally substituted with OH, or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring, Ci-Ctalkyl-Rsor Ci-Cfialkyl optionally being substituted

20 with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C₄alkyloxy, Ci-C₄alkyloxycarbonyl, oxo, C(=O)-Ci-C₃alkyl, C_rC₄aIkyl, OH, CN, CFH₂, CF₂H and CFy,

Or R| and R₂ together with the Nitrogen to which they are attached form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, such bîcyclic, 25 bridged or saturated ring moiety optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C₄alkyloxy, Ci-C₄alkyloxycatbonyl, oxo, C(=O)-Ci-C₃aIkyl,

30 C,-C₄alkyl, OH, CN, CFH₂, CF₂H and CF₃;

Each R4 is independently selected from hydrogen, halo, Ci-C₄alkyloxy, C|-C₄alkyl, C|-C₄alkcnyl, OH, CN, CFH₂, CF₂H, CF₃, IIC^C or a 3-5 membered saturated ring

-174optionally containing one or more heteroatoms each independently selected from the group consisting of O and N, such Ci-C₄alkyl optionally substituted with OH;

Rj represents Cj-Cealkyl, CFH₂, CF₂H, CFj, phenyl, pyridyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C|-C₄alkyloxy, Ci-C^alkyloxycarbonyl, oxo, C(=O)-Ci-Cjalkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CF₃;

or a pharmaceutically acceptable sait or a solvaté thereof.
2. A compound according to claim 1, wherein at least one R4 represents Fluor, and one other R4 is selected from the group consisting of Cj-Cjalkyl, Cj-Cjalkenyl, CHF₂ or cyclopropyl.
3. A compound according to claim l or 2 wherein one R4represents Fluor and one other R4 is selected from the group consisting of methyl or CHF₂and wherein the location of said Fluor is on the para position and the location of said methyl or CHF₂ is on the meta position related to the Nitrogen(*),
4. The compound according to any one of claims 1 to 3, wherein R₂ represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such

4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C)-C₄alkyloxy, C]-C₄alkyloxycarbonyl, C(=O)-Ci-Cjalkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CFj.
5. The compound according to any one of claimsl to 3, wherein R₂ represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such

4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-C₄alkyloxy, C]-C₄alkyloxycarbonyl, C(=O)-Cj-Cjalkyl, Ci-C₄alkyl, OH, CN, CFH₂, CF₂H and CFj wherein such compound is not
6. The compound according to any one of the preceding claims, wherein B represents 5 phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, Ci-Cjalkyl, CN, CFH₂, CF₂H and CF₃.
7. A compound for according to any one of the preceding claims, which is of Formula wherein Ri, R₂, Rj are defined as in any one of the previous claims and Rj is selected from the group comprising hydrogen, halogen, Ci-C₃alkyl, CN, CFH₂, 15 CF₂H,CF₃.
8. A compound for according to any one of the preceding claims l to 6, which is of Formula (Id) v

-176wherein Ri, R₂, Ri are defined as in any one of the previous claims and Rj is selected from the group comprising hydrogen, halogen, Ci-Cîalkyl, CN, CFHi, CF₂H, CF₃.

5
9. A compound according to claim 7 or 8, wherein Rj représenta hydrogen.
10. A compound for according to any one ofthe preceding claims, which is of Formula (le)

10 wherein R_b R₂, R-j are defined as in any one of the previous claims
11. A compound according to any one of the previous claims for use in the prévention or treatment of an HBV infection in a mammal.

15
12. A pharmaceutical composition comprising a compound according to any ofclaims

1 to 10, and a pharmaceutically acceptable carrier.
13. A product containing (a) a compound of formula I as defined in any one ofclaims 1 to 10, and (b) another HBV inhibitor, as a combined préparation for

20 simultaneous, separate or sequential use in the treatment of HBV infections.