NZ713201B2 - Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b - Google Patents

Abstract

Inhibitors of HBV replication of Formula (ID) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, Ra to Rd and R4 to R6 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy. ns containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.

Description

TIP 296 PCT SULPHAMOYLPYRROLAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B Background Art The tis B virus (HBV) is an enveloped, partially -stranded DNA (dsDNA) virus of the Hepadnavirus family naviridae). Its genome contains 4 overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 pe proteins; and the X gene.

Upon infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cccDNA) in the nucleus of the host cell and the viral mRNAs are transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also codes for core protein and Pol, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.

HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected imately 2 billion people worldwide of which approximately 350 million people have developed chronic ions. The virus causes the disease hepatitis B and chronic infection is correlated with a strongly increased risk for the development cirrhosis and hepatocellular carcinoma.

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 c carriers with high titer DNA in serum.

An effective and well-tolerated vaccine exists, but direct treatment options are currently limited to interferon and the following antivirals; tenofovir, lamivudine, ir, entecavir 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, relates to a subclass of Sulphamoylarylamides active against HBV. WO2013/096744, published on June 26, 2013 s to compounds active against HBV.

In addition, WO2014/033170 and WO2014/033176, published on March 6, 2014 relate further compounds active against HBV.

Amongst the ms which HBV direct antivirals may encounter are toxicity, nicity, lack of selectivity, poor efficacy, poor ilability, and difficulty of synthesis.

TIP 296 PCT There is a need for additional HBV inhibitors that may overcome at least one of these disadvantages or that have additional advantages such as increased potency or an increased safety window.

Description of the Invention The present invention relates to a compound of Formula (ID) or a stereoisomer or tautomeric form thereof, n: Each X independently represents CR7; Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, , -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; Rd is en or Fluoro; R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic 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 C2-C6alkyl optionally being tuted with one or more substituents each independently selected from the group consisting of en, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, -CN, Fluoro, , Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl optionally substituted with methoxy, C2-C3alkenyl or C3-C4cycloalkyl; R8 represents 3-7 membered ted ring optionally containing one or more heteroatoms each ndently selected from the group consisting of O, S and N, such 3-7 membered TIP 296 PCT saturated ring optionally being substituted with one or more lkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 ents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof n such compound is not or .

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

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

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

The pharmaceutical composition, use and combination of compounds of a (ID) as provided according to the present invention includes the pharmaceutical ition, use and combination of and .

Definitions The terms "C1-xalkyl" and C1-Cxalkyl can be used interchangeably.

The term "C1-3alkyl" as a group or part of a group refers to a arbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 3. In case kyl is coupled to a further radical, it refers to a Formula CnH2n. C1-3alkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C1-3alkyl includes all linear, or branched alkyl groups with TIP 296 PCT between 1 and 3 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, and i-propyl.

C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for kyl and butyl and the like.

C1-6alkyl and C2-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, or from 2 to 6 carbon atoms such as the groups defined for C1-4alkyl and pentyl, hexyl, 2-methylbutyl and the like.

The term "C2-3alkenyl" as a group or part of a group refers to a hydrocarbon l comprising 2 or 3 carbon atoms having at least one double bond therein, and thus includes such as for example, ethenyl (vinyl), 1-propenyl, and 2-propenyl.

The term "C1-3alkyloxy" as a group or part of a group refers to a radical having the Formula -- ORc wherein Rc is C1-3alkyl. Non-limiting examples of suitable C1-3alkyloxy include oxy (also methoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.

As used herein, the term "3-7 membered mono or polycyclic saturated ring" means saturated cyclic hydrocarbon with 3, 4, 5, 6 or 7 carbon atoms and is c to cyclopropyl, cyclobutyl, cyclopentyl, exyl and cycloheptyl (monocyclic) and fused or spiro ring systems with 2 or more saturated rings with at most 7 carbon atoms (polycyclic).

Such saturated ring ally 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 and O.

Examples include oxetane, tetrahydro-2H-pyranyl, dinyl, tetrahydrofuranyl, morpholinyl, thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclic hydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples e oxetane, and tetrahydrofuranyl.

It should be noted that different isomers of the various heterocycles may exist within the definitions as used throughout the specification. For example, if not structurally specified according to the chemical name or structure, pyrrolyl may be rolyl or 2H-pyrrolyl.

The term halo and halogen are c to Fluoro, Chloro, Bromo or Iodo. Preferred halogens are Bromo, Fluoro and Chloro.

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

TIP 296 PCT Positions indicated on phenyl (e.g. ortho, meta and/or para) are indicated relative to the bond connecting the phenyl to the main structure. An example with regard to the on of para R2, location is indicated relative to the nitrogen (*) connected to the main structure: R6 O X * N N S H R3 (I) R5 X N When any variable (e.g. halogen or C1-4alkyl) occurs more than one time in any constituent, each definition is ndent.

For therapeutic use, the salts of the compounds of Formula (ID) are those wherein the counter ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter ion may also find use, for example, in the preparation or cation of a pharmaceutically acceptable compound of Formula (ID). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present ion.

The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be ed using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or romic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecylsulphuric, oic, ic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, c, succinic, maleic, c, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said acid addition salt 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 present invention are able to form. es of such forms are e.g. hydrates, alcoholates and the like.

The present compounds may also exist in their tautomeric forms For example, tautomeric forms of amide )-NH-) groups are iminoalcohols (-C(OH)=N-). eric forms, although not explicitly indicated in the structural formulae represented herein, are intended to be included within the scope of the present invention.

The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same ce of bonds but having different three-dimensional structures which are not TIP 296 PCT hangeable, which the nds of the present invention may possess. Unless otherwise mentioned or indicated, the al designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may s. Said mixture may contain all diastereomers and/or enantiomers of the basic lar structure of said compound.

All stereochemically isomeric forms of the compounds of the present ion both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates as ned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular ure of said compounds or ediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric 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 of 97% 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 diastereomeric 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 selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically ic forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, ed that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is d, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric forms of Formula (ID) can be obtained separately by conventional methods. riate physical separation s that may advantageously be employed are, for example, ive crystallization and chromatography, e.g. column chromatography.

The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass TIP 296 PCT numbers. By way of general example and without tion, isotopes of en include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Detailed description of the invention Whenever used hereinafter, the term "compounds of formula (ID)", or "the present compounds" " compounds of the present invention" or similar term is meant to include the compounds of l formula (ID), (IA), (IB), (IC), (I), (Ia), (II), (III) salts, stereoisomeric forms and racemic mixtures or any ups thereof.

In a first aspect, the present invention relates to a compound of Formula (ID) or a isomer or tautomeric form thereof, wherein: Each X independently represents CR7; Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, ethyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; Rd is Hydrogen or Fluoro; R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally tuted with one or more Fluoro, and a 3-7 membered mono or polycyclic saturated ring optionally containing one or more TIP 296 PCT heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 ed saturated ring or lkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, -CN, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl optionally substituted with methoxy, lkenyl or C3-C4cycloalkyl; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof wherein such compound is not or .

In a further aspect, , the present invention relates to a compound of Formula (IA) or a stereoisomer or eric form thereof, wherein: Each X independently represents CR7; Ra, Rb and Rc are independently selected from the group ting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; TIP 296 PCT R4 is en, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group ting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic 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 C2-C6alkyl ally being tuted with one or more substituents each independently ed from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, -CN, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl or C3-C4cycloalkyl; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -N(R11)2; R10 represents -CN, -OH, , -CHF2, -CH2F or -CF3; R11 represents en or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof, wherein such compound is not or .

In one embodiment, the present invention relates to a compound Formula (IC) TIP 296 PCT or a stereoisomer or tautomeric form thereof, wherein: X represents CR7; Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, , Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is ed from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic 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 C2-C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 ents en, -CN, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl or C3-C4cycloalkyl; R8 represents 3-7 membered saturated ring optionally containing one or more heteroatoms each independently ed from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more C1-C4alkyl ally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a ceutically acceptable salt or a solvate thereof, wherein such compound is TIP 296 PCT not or .

Of interest are compounds of the present ion wherein: Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, and C1-C3alkyl; R4 is Hydrogen, or methyl; R5 is Hydrogen; R6 is selected from the group consisting of lkyl and a 3-7 membered saturated ring ally ning one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C2-C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, -CN, , Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3 or methyl; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2 R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl.

Another embodiment of the present invention relates to those compounds of Formula (ID), (IA) or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply: (a) R4 is C1-C3alkyl, preferably ; R6 is selected from the group consisting of C2- C6alkyl optionally being substituted with one or more Fluoro; and R7 ents hydrogen Fluoro, Chloro or C1-C3alkyl, preferably hydrogen Fluoro, Chloro or . (b) Rb is Hydrogen or Fluoro. (c) Ra and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Chloro -CN and methyl.

TIP 296 PCT (d) Rb is Hydrogen or Fluoro and Ra and Rc are independently selected from the group consisting of en, Fluoro, Chloro and –CN. (e) R6 contains a 3-7 membered saturated ring optionally containing one oxygen, more specifically R6 is a 4 or 5 membered saturated ring ning one oxygen, such 4 or 5 membered saturated ring optionally substituted with lkyl optionally substituted with R10. (f) R6 comprises a ed C3-C6alkyl optionally tuted with one or more Fluoro, or wherein R6 ses a C3-C6cycloalkyl wherein such C3-C6cycloalkyl is substituted with one or more Fluoro or substituted with lkyl substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl optionally substituted with one or more Fluoro and/or tuted with C1-C4alkyl optionally substituted with one or more Fluoro. (g) R6 comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or R6 ses a C3-C6cycloalkyl wherein such C3-C6cycloalkyl is substituted with one or more Fluoro or substituted with C1-C4 substituted with one or more Fluoro. More specifically, R6 is a branched C3-C6alkyl substituted with one or more Fluoro. (h) R4 is C1-C3alkyl, preferably methyl; R6 is selected from the group consisting of C2- C6alkyl optionally being substituted with one or more Fluoro; and R7 represents hydrogen, , Chloro or C1-C3alkyl, preferably hydrogen Fluoro, Chloro or methyl.

In one aspect, the present invention relates to a compound of Formula (IA) or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents CR7; Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN and methyl; R4 is Hydrogen or C1-C3alkyl; R5 is Hydrogen; TIP 296 PCT R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, lkyl-R9 optionally tuted with one or more Fluoro, and a 3-7 ed mono or polycyclic saturated ring optionally containing one or more heteroatoms each independently selected from the group ting of O, S and N, such 3-7 membered saturated ring or lkyl optionally being substituted with one or more substituents each independently ed from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, CN, Fluoro or Chloro; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate f, wherein such compound is not H O N Cl S H or .

In a further aspect, the present invention s to a compound of Formula (IA) or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents CR7; TIP 296 PCT Ra, Rb and Rc are independently selected from the group consisting of en, , Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN and methyl; R4 is Hydrogen or C1-C3alkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, lkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 ed ted ring or lkyl optionally being tuted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; R8 represents 3-7 membered saturated ring ally 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 C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof, wherein such compound is not H O N Cl S H or .

In a further aspect, the invention relates to compound of Formula TIP 296 PCT or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents CR7; Ra, Rb and Rc are independently ed from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, ethyl, -CH2F, -CF3, -OCF3, -CN and methyl; R4 is Hydrogen or C1-C3alkyl; R5 is en; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally tuted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic 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 C2-C6alkyl ally being substituted with one or more substituents each ndently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents, lkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2 R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; TIP 296 PCT R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof, wherein such compound is not or .

In one embodiment of compounds of the present invention, R4 is methyl.

In a further embodiment of compounds of the present invention, Rb is en or Fluoro.

Furthermore, compounds according to the invention are described wherein Ra and Rc are independently selected from the group consisting of en, Fluoro, Chloro -CN and methyl.

Preferably, Rb is Hydrogen or Fluoro and Ra and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Chloro and -CN.

In one embodiment of compounds of the present invention, R6 is ed from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 ally substituted with one or more Fluoro, C1- l-R9 optionally substituted with one or more Fluoro, and a 3-7 membered saturated ring ally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C2-C6alkyl ally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10. In a further embodiment, R6 contains a 3-7 membered ted ring optionally containing one oxygen, more specifically R6 is a 5 ed saturated ring containing one oxygen, such 5 membered saturated ring optionally tuted with C1-C4alkyl optionally substituted with R10.

In one ment of compounds of the present invention,R6 comprises a branched C3-C6alkyl ally substituted with one or more Fluoro, or R6 comprises a C3-C6cycloalkyl wherein such C3-C6cycloalkyl is substituted with one or more Fluoro or substituted with C1-C4 substituted with one or more Fluoro. More specifically, R6 is a branched C3-C6alkyl substituted with one or more Fluoro.

TIP 296 PCT In a further aspect, the invention provides nd of Formula (I) R6 O X N N S H R3 R5 X N O (I) or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents CR7; R2 is Hydrogen, CN, Chloro or Fluoro; R1 and R3 are ndently selected from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CH2F, -CF3, -OCF3, -CN and methyl, wherein at maximum one of R1 R2 and R3 is Hydrogen if one of R1 and R3 is Chloro or -OCF3; R4 is Hydrogen or C1-C3alkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 ed 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 -C2-C6alkyl optionally being substituted with one or more substituents each ndently ed from the group consisting of Hydrogen, -OH, Fluoro, oxo and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, ethyl, -C(=O)-OR11 or -N(R11)2 R10 ents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; TIP 296 PCT R11 represents hydrogen or lkyl; or a pharmaceutically acceptable salt or a solvate thereof.

In one embodiment, compounds of Formula (I) are disclosed wherein: Each X independently represents CR7; R2 is Hydrogen, CN, or Fluoro; R1 and R3 are independently selected from the group consisting of en, Fluoro, Bromo, Chloro, -CHF2, -CH2F, -CF3, -CN and , n at maximum one of R1 R2 and R3 is Hydrogen if one of R1 and R3 is Chloro; R4 is Hydrogen or lkyl; R5 is Hydrogen; R6 is ed from the group consisting of lkyl, C1-C4alkyl-R8, C1-C4alkyl-R9 and 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 -C2- C6alkyl ally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; R8 represents 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 C1-C4alkyl optionally substituted with R10; R9 represents -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, , -CHF2, -CH2F or -CF3; and R11 represents hydrogen or C1-C3alkyl.

In one further embodiment, compounds of Formula (I) are disclosed wherein: TIP 296 PCT Each X independently represents CR7; R2 is Hydrogen or ; R1 and R3 are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, , CHF2, CH2F, CF3 and methyl, wherein at maximum one of R1 , R2 and R3 is Hydrogen; R4 is Hydrogen or methyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C3alkyl-R8 and a 3-7 ed saturated ring optionally containing one or more heteroatoms each independently selected from the group ting of O, S and N, such 3-7 membered saturated ring or C2-C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of en, OH, Fluoro, and C1-C4alkyl; R7 represents Hydrogen, methyl, Fluoro or Chloro; R8 ents 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N.

In one embodiment, for compounds according to Formula (I), at least one X represents CH.

In a further aspect, the invention provides compounds of Formula (Ia) R6 O N N S H R3 N (Ia) R5 O or a stereoisomer or eric form thereof, wherein: R2 is Hydrogen, CN or Fluoro; R1 and R3 are independently ed from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CH2F, -CF3, -CN and methyl, wherein at maximum one of R1, R2 and R3 is Hydrogen if one of R1 and R3 is Chloro; TIP 296 PCT R4 is Hydrogen or lkyl; R5 is Hydrogen; R6 is selected from the group ting of C2-C6alkyl, C1-C4alkyl-R8, C1-C4alkyl-R9 and a 3- 7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group ting of O, S and N, such 3-7 membered saturated ring or -C2- C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo and C1-C4alkyl ally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; R8 represents 3-7 membered ted 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 C1-C4alkyl optionally tuted with R10; R9 represents -C(=O)-OR11 or -C(=O)-N(R11)2 R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salts or a solvate thereof.

In a sub-embodiment, compounds of a (I) are disclosed wherein: R2 is Hydrogen or Fluoro; R1 and R3 are independently selected from the group consisting of Hydrogen, Fluoro, CHF2, CH2F, CF3 and methyl, wherein at maximum one of R1, R2 and R3 is Hydrogen; R4 is Hydrogen or methyl; R5 is Hydrogen; TIP 296 PCT R6 is selected from the group consisting of C2-C6alkyl and 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 ed saturated ring or C1-C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, OH and C1-C4alkyl.

In another embodiment, compounds of the ion are represented by Formula (II) R6 O N R3 N S H R5 N O (II) R4 .

In yet another ment, compounds of the invention are represented by Formula (III) R6 O N N S H N (III) R5 O For both compounds of Formula (II) and (III): R2 is Hydrogen, CN or Fluoro; R1 is independently selected from the group consisting of Fluoro, Bromo, Chloro, -CHF2, - CH2F, -CF3, -CN and methyl, wherein if R1 is Chloro, R2 is not Hydrogen; R4 is Hydrogen or lkyl; R5 is Hydrogen; R6 is selected from the group consisting of lkyl, lkyl-R8, C1-C4alkyl-R9 and a 3- 7 membered saturated ring ally containing one or more atoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or -C2- C6alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of Hydrogen, -OH, Fluoro, oxo and C1-C4alkyl optionally substituted with R10; R7 represents hydrogen, methyl, Fluoro or Chloro; TIP 296 PCT R8 represents 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 ed saturated ring optionally being substituted with one or more C1-C4alkyl optionally tuted with R10; R9 represents -C(=O)-OR11 or -C(=O)-N(R11)2 R10 ents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl.

In one embodiment, nds of the present invention are disclosed wherein R1 is selected from either Bromo, Chloro, Fluoro or methyl, or Fluoro or methyl. In another embodiment, R1 is selected from either Fluoro or methyl and at least one of R1 and R3 is Fluoro. In yet a further embodiment, R1 is selected from either Fluoro or methyl and at least one of R1 and R3 is Fluoro, and the other R1 or R3 is selected from methyl, Fluoro, CHF2, CH2F, CF3 and methyl.

In another embodiment, at least two of R1, R2 and R3 are halogens, preferably Bromo, Fluoro or Chloro, even more preferably Fluoro or Chloro. In a r embodiment, each of R1, R2 and R3 are halogen, preferably Bromo, Fluoro or Chloro, even more preferably Fluoro or Chloro.

In yet another ment, compounds of the present invention are disclosed wherein R4 is methyl or ethyl, preferably methyl.

In a further embodiment, compounds of the present invention are disclosed wherein R6 contains a 3-7 membered saturated ring optionally containing one oxygen, preferably R6 is a 5 membered saturated ring containing one oxygen.

In another embodiment, compounds of the present invention are disclosed wherein R6 comprises a C1-C4alkyl substituted with one or more Fluoro. In addition, compounds of the present ion are disclosed wherein R6 ses a branched C3-C6alkyl substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl wherein such C3-C6cycloalkyl is tuted with one or more Fluoro or substituted with C1-C4 substituted with one or more Fluoro.

In yet another embodiment, compounds of the invention are disclosed wherein R6 comprises a carbon atom without hydrogen substituent. Preferably, carbon without en substituent is directly attached to the Nitrogen of the –N-SO2 moiety.

TIP 296 PCT Further combinations of any of the embodiments are also envisioned to be in the scope of the present invention.

Preferred compounds according to the invention are compound or a stereoisomer or eric form thereof with a formula as represented in the synthesis of compounds section and of which the activity is displayed in Table 1.

In a further aspect, the present invention concerns a pharmaceutical ition sing a therapeutically or prophylactically effective amount of a compound of Formula (ID) as specified herein, and a pharmaceutically acceptable carrier. A lactically effective amount in this context is an amount sufficient to prevent HBV infection in ts being at risk of being infected. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV infection, or to ate HBV ion, in infected subjects. In still a r , this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically able carrier with a therapeutically or prophylactically effective amount of a compound of Formula (ID), as specified herein. ore, the compounds of the present ion or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for ically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in on salt form, as the active ingredient is combined in te admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of ation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral 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 liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be ed. Injectable solutions, for example, may be prepared in which the r comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also ed are solid form preparations intended to be converted, shortly before use, to liquid form TIP 296 PCT ations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable g agent, optionally 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 present invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any own ry system.

It is especially advantageous to formulate the entioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit ning a ermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or sions and the like, and ated les thereof.

The compounds of Formula (ID) are active as inhibitors of the HBV replication cycle and can be used in the treatment and prophylaxis of HBV infection or diseases associated with HBV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, age liver disease, and hepatocellular carcinoma.

Due to their ral properties, particularly their anti-HBV properties, the compounds of Formula (ID) or any subgroup thereof, are useful in the inhibition of the HBV replication cycle, in particular in the treatment of warm-blooded animals, in particular humans, infected with HBV, and for the prophylaxis of HBV infections. The present invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HBV, or being at risk of ion by HBV, said method sing the administration of a therapeutically effective amount of a compound of Formula (ID).

The compounds of Formula (ID), as specified herein, may therefore be used as a medicine, in particular as medicine to treat or prevent HBV infection. Said use as a ne or method of treatment comprises the systemic administration to HBV ed subjects or to subjects susceptible to HBV infection of an amount effective to combat the conditions associated with HBV infection or an amount effective to prevent HBV infection.

The present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or the prevention of HBV infection.

In general it is contemplated that an antiviral effective daily amount would be from 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-doses at riate intervals TIP 296 PCT 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 1 to about 100 mg, or about 2 to about 50 mg of active ingredient per unit dosage form.

The present invention also concerns combinations of a nd of Formula (ID) or any subgroup thereof, as specified herein with other anti-HBV . The term "combination" may relate to a product or kit containing (a) a compound of Formula (ID), as specified above, and (b) at least one other compound capable of treating HBV infection (herein designated as anti-HBV agent), as a combined ation for simultaneous, te or sequential use in treatment of HBV infections. In an embodiment, the invention concerns combination of a compound of Formula (ID) or any subgroup thereof with at least one BV agent. In a particular embodiment, the ion concerns combination of a compound of Formula (ID) or any subgroup thereof with at least two anti-HBV agents. In a particular ment, the invention ns combination of a nd of Formula (ID) or any subgroup thereof with at least three anti-HBV agents. In a particular embodiment, the invention concerns combination of a compound of Formula (ID) or any subgroup thereof with at least four anti-HBV agents.

The term anti-HBV agent also includes compounds capable of treating HBV infection via immunomodulation. Examples of immunomodulators are interferon-α (IFN-α), ted interferon-α or stimulants of the innate immune system such as Toll-like receptor 7 and/or 8 agonists. One embodiment of the present invention relates to combinations of a compound of Formula (ID) or any subgroup thereof, as specified herein with an immunomodulating nd, more specifically a Toll-like or 7 and/or 8 agonist.

The combination of previously known BV agents, such as interferon-α ), pegylated interferon-α, 3TC, adefovir or a combination thereof, and, a compound of Formula (ID) or any subgroup thereof can be used as a medicine in a combination therapy.

Generic synthesis: The substituents represented in this general synthesis section are meant to include any tuent or reactive species that is suitable for ormation into any substituent according to the present invention without undue burden for the person skilled in the art.

A possible synthesis of compound of general formula (I) is described in schemes 1 and 2.

Similarly, the synthesis of compounds of general formula (IA) are described in schemes 1a, 2a.

Also similarly, the synthesis of nds of general formula ID is described in scheme 1b and scheme 2b. A carboxylic acid chloride of general formula (IV) (for example prepared according to the synthesis described for compound 2) can be selectively reacted with an aniline of general formula (V), for example by slow addition of aniline (V) to a refluxing solution of compound TIP 296 PCT (IV) in toluene, resulting in compound (VI). The remaining sulfonic acid chloride functionality in compound (VI) is further reacted with an amine of general formula (VII), resulting in a compound of general formula (I), for example in a solvent like acetonitrile in the presence of an inorganic base like sodium bicarbonate or as r exemplified in the experimental synthetic description of compounds.

Scheme 1 Scheme 1a TIP 296 PCT Scheme 1b Alternatively a compound of general formula (I) might be obtained as described in scheme 2.

This time the sulfonic acid de (VIII) (for example prepared according to the sis described for nd 2) is reacted with an amine of general formula (VII), for example in an organic solvent like CH2Cl2 in the presence of an organic base like triethylamine or DIPEA. The formed compound (IX) is coupled with aniline of general formula (V) in the presence of an activating reagent like for example HATU and an organic base like triethylamine or DIPEA.

Scheme 2 TIP 296 PCT Scheme 2a Scheme 2b Scheme 3 TIP 296 PCT An alternative method for the synthesis of compounds of general a IX, is via ester X as described in scheme 3. Reaction of X with amine VII, for example in an organic solvent like acetonitrile in the presence of an organic base like for e triethylamine or DIPEA, or an nic base like for example sodium bicarbonate, resulting in a nd of l formula XI, followed by hydrolysis of the ester, for example with LiOH in THF/H2O, followed by acidification, results in a compound of general formula IX.

A compound of general formula VIII can be converted to a compound of general a IV, for example by treatment with oxalyl chloride in CH2Cl2.

Scheme 4 Possible synthetic routes, for compounds of general formula X and VIII are described in scheme 4, and further exemplified in the experimental section. Chlorosulfonation of carboxylic ester XII or carboxylic acid XIII, can results in compounds of general formula X or VIII respectively, for e by treatment with chlorosulfonic acid at for example 0°C, if necessary, followed by quenching with water. Alternatively, compound XII can be treated with chlorosulfonic acid, resulting in a sulfonic acid derivative, for example by ment of compound XII with 1-1.2 equiv chlorosulfonic acid in CH2Cl2, the resulting ic acid derivative can be converted the sulfonyl chloride compound X, for example by treatement with SOCl2 at 80°C.

Scheme 5 TIP 296 PCT Ra Rb Rc Ra Rb H2N O R6 O X (C1-C3alkyl) Rd O R6 O Rc N S Vd X N S R5 O X N H Rd R4 R5 X N XI (ID) Scheme 5a Alternatively a compound of general formula (IA) might be obtained as described in scheme 5.

A compound of general formula XI can be coupled with a compound of general formula Va in the presence of a base like for example m bis(trimethylsilyl)amide, in a solvent like for example THF, resulting in the formation of a compound of general formula (IA). Similarly, a compound of general formula ID can be prepared as described in scheme 5a.

General procedure LCMS methods The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion . It is within the dge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate re. nds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion ponds to the [M+H]+ (protonated molecule) and/or [M-H]- tonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. ]+, O]-, etc.). All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass ive Detector, "RT" room temperature, "BEH" bridged ethylsiloxane/silica hybrid, "DAD" Diode Array Detector, "HSS" High Strength silica., "Q-Tof" Quadrupole Time-of-flight mass spectrometers, "CLND", ChemiLuminescent Nitrogen Detector, "ELSD" Evaporative Light Scanning Detector, TIP 296 PCT LCMS Methods (Flow expressed in ; column temperature (T) in °C; Run time in minutes).

Flow Method Run Instrument Column Mobile phase Gradient ------- code time Col T Waters From 100% A : A: 10mM : HSS to 5% A in Acquity® CH3COONH4 0.8 T3 2.10min, to 0% A UPLC® - in 95% H2O + - 3.5 (1.8µm, A in 0.90min, DAD and 5% CH3CN 55 2.1*10 to 5% A in SQD B: CH3CN 0mm) 0.5min Waters Waters: A: 10mM : BEH From 95% A Acquity® CH3COONH4 0.8 C18 to 5% A in 1.3 B UPLC® - in 95% H2O + ------- 2 (1.7µm, min, held for DAD and 5% CH3CN 55 2.1*50 0.7 min.

SQD B: CH3CN Waters Waters: A: 10mM : HSS From 95% A Acquity® CH3COONH4 0.8 T3 to 0% A in C UPLC® - in 95% H2O + ------- 3 (1.8µm, 2.5min, to 5% DAD and 5% CH3CN 55 2.1*10 A in 0.5min SQD B: CH3CN 0mm) Waters From 100% A Waters: A: 10mM : HSS to 5% A in Acquity® CH3COONH4 0.7 T3 2.10min, to 0% D UPLC® - in 95% H2O + ------- 3.5 (1.8µm, A in 0.90min, DAD and 5% CH3CN 55 2.1*10 to 5% A in SQD B: CH3CN 0mm) 0.5min Synthesis of compounds: Compound 1: N-(4-fluoromethyl-phenyl)(isopropylsulfamoyl)-1H-pyrrolecarboxamide HN HN O O TIP 296 PCT 4-(isopropylsulfamoyl)-1H-Pyrrolecarboxylic acid (857 mg, 3.69 mmol), 4-Fluoro Methylaniline (461.8 mg, 369 mmol), COMU ((1-Cyanoethoxyoxoethylidenaminooxy )dimethylamino-morpholino-carbenium hexafluorophosphate; CAS Number 1075198- -9; 1738 mg, 4.06 mmol) and triethylamine (2.0 mL, 4.06 mmol) in dichloromethane (43 mL) was d for 3 hours. The reaction mixture was treated with 1M HCl (50 mL). The itate was ed off and was recrystallized from hot acetonitrile (50 mL). The solid was filtered and dried overnight in vacuo yielding a beige powder (58 mg). 1H NMR (400 MHz, DMSO-d6)  ppm 1.00 (d, J=6.4 Hz, 6 H), 2.23 (d, J=1.5 Hz, 3 H), 3.20 - 3.31 (m, 1 H), 7.05 - 7.20 (m, 2 H), 7.31-7.34 (m, 1 H), 7.34 - 7.38 (m, 1 H), 7.54 - 7.60 (m, 1 H), 7.62 (dd, J=7.2, 2.3 Hz, 1 H), 10.01 (s, 1 H), 12.33 (br. s., 1 H). Method A; Rt: 1.51 min. m/z : 338.0 (M-H)- Exact mass: 339.1.

Compound 2: N-(4-fluoromethyl-phenyl)(isopropylsulfamoyl)methyl-pyrrole carboxamide HN F S HN N O A mixture of propylsulfamoyl)methyl-pyrrolecarboxylic acid (Commercial from enamine, EN300-30498, 954 mg, 3.87 mmol) 4-FluoroMethylaniline (485 mg, 3.87 mmol), COMU (1825mg, 4.261 mmol) and ylamine (2.15 mL, 4.26 mmol) in dichloromethane (50 mL) was stirred for 3 hours. The reaction mixture was washed with 1M HCl (50 mL), water and NaHCO3 solution, dried over sodium te, filtered and concentrated. The ed residue was purified by Preparative HPLC (Stationary phase: RP Vydac Denali C18 - 10µm, 200g, 5cm), Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were concentrated yielding a white powder which was dried overnight in vacuo at 50°C (30 mg).

Method A; Rt: 1.73 min. m/z : 354.0 (M+H)+ Exact mass: 353.1. 1H NMR (400 MHz, DMSO- d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 2.23 (d, J=1.8 Hz, 3 H), 3.21 - 3.30 (m, 1 H), 3.91 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.17 (d, J=6.8 Hz, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.45 - 7.57 (m, 2 H), 7.64 (dd, J=7.0, 2.4 Hz, 1 H), 10.01 (s, 1 H).

Synthesis of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride and 5-[(4-fluoromethyl- phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride 1-Methyl-1H-pyrrolecarboxylic acid (5520 mg, 44.1 mmol) was dissolved portion wise in chlorosulfonic acid (25 mL) in an ice bath. The mixture was stirred for 70 minutes. The mixture was added drop wise to ice/water (200 mL) and stirred for 5 minutes. The precipitate was filtered, rinsed with water and dried overnight in vacuo at 50° C resulting in 4-chlorosulfonyl TIP 296 PCT methyl-pyrrolecarboxylic acid as a powder (5632 mg). Oxalyl chloride (22.4 g, 176.8 mmol) was added portion wise to 4-chlorosulfonylmethyl-pyrrolecarboxylic acid (obtained as described above, 7.9 g, 35.37 mmol) and DMF (0.14 mL) in CH2Cl2 (200 mL) and the mixture was stirred over weekend at room temperature. The reaction mixture was concentrated ng 4-chlorosulfonylmethyl-pyrrolecarbonyl de as a brown solid (8.6 g) which was used as such. 4-fluoromethyl-aniline (2049 mg, 16.37 mmol) was dissolved in toluene (20 mL) and added drop wise to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl de (3963 mg, 16.37 mmol) in e (200 mL) at reflux. The reaction mixture was refluxed 1 hour and allowed to cool to room temperature overnight. The formed precipitate was filtered and dried in vacuo at 50°C resulting in 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (3.14 g) as a powder. Method A; Rt: 1.96 min. m/z : 328.9 (M-H)- Exact mass: 330.0. 1H NMR (400 MHz, CHLOROFORM-d)  ppm 2.29 (d, J=1.8 Hz, 3 H), 4.05 (s, 3 H), 7.00 (t, J=9.0 Hz, 1 H), 7.15 (d, J=1.8 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 7.42 (dd, J=6.6, 2.6 Hz, 1 H), 7.50 (d, J=1.8 Hz, 1 H), 7.63 (br. s., 1 H).

Compound 3: N-(4-fluoromethyl-phenyl)[[(1R)hydroxymethyl-ethyl]sulfamoyl] methyl-pyrrolecarboxamide H O F HO (R) O N H A mixture of D-alaninol (696 mg, 9.08 mmol) and DIPEA (1.3 mL, 7.57 mmol) dissolved in dichloromethane (25 mL) was added to a solution of 5-[(4-fluoromethyl-phenyl)carbamoyl]- 1-methyl-pyrrolesulfonyl chloride (2250 mg). The reaction mixture was stirred 15 minutes.

More D-alaninol (1.5 eq) and DIPEA (2 eq) were added and the on mixture was d 15 minutes more. The reaction mixture was washed with 1M HCl (3 x), water and NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The ed residue was purified by column chromatography on silica using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the obtained residue was crystallized from warm EtOAc (50 mL) by slowly adding heptane. Compound 3 was filtered off as white crystals and dried in vacuo at 50°C (342 mg). Method A; Rt: 1.47 min. m/z : 370.2 (M+H)+ Exact mass: 369.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.98 (d, J=6.2 Hz, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.07 - 3.18 (m, 2 H), 3.32 - 3.39 (m, 1 H), 3.91 (s, 3 H), 4.65 (t, J=5.5 Hz, 1 H), 7.03 - 7.15 (m, 2 H), 7.30 (d, J=1.8 Hz, 1 H), 7.47 - 7.57 (m, 2 H), 7.64 (dd, J=7.0, 2.4 Hz, 1 H), 10.02 (s, 1 H).

TIP 296 PCT Compound 4: luoromethyl-phenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide O F H O (S) S N O N A mixture of (S)-Tetrahydrofurylamine p-toluenesulfonate salt (822 mg, 3.17 mmol) and DIPEA (1.09 mL, 6.34 mmol) in dichloromethane (25 mL), was added to a solution of 5-[(4- fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (785 mg) in dichloromethane (50 mL) and d overnight. The reaction mixture was washed with 1M HCl (3 x), water and NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 10 to 100% EtOAc in heptane. The product fractions were trated yielding compound 4 as a beige solid which was dried overnight in vacuo at 50°C (696 mg). Method A; Rt: 1.57 min. m/z : 382.0 (M+H)+ Exact mass: 381.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.66 - 1.77 (m, 1 H), 1.91 - 2.04 (m, 1 H), 2.23 (d, J=1.5 Hz, 3 H), 3.39 - 3.47 (m, 1 H), 3.61 (td, J=8.0, 5.9 Hz, 1 H), 3.66 - 3.76 (m, 3 H), 3.92 (s, 3 H), 7.09 (t, J=9.1 Hz, 1 H), 7.31 (d, J=2.0 Hz, 1 H), 7.47 - 7.59 (m, 3 H), 7.64 (dd, J=7.2, 2.3 Hz, 1 H), 10.03 (s, 1 H).

Compound 5: N-(4-fluoromethyl-phenyl)methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide HN S N O N A mixture of 3-methyloxetanamine hloride (1:1) (391.5 mg, 3.17 mmol) and DIPEA (1.09 mL, 6.34 mmol) in dichloromethane (25 mL) was added to a solution of 5-[(4-fluoro methyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (785 mg) in romethane (50 mL) and stirred overnight. The reaction mixture was washed with 1M HCl (3x), water and NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The obtained residue was purified by silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated yielding compound 5 as a beige solid which was dried overnight in vacuo at 50°C (584 mg). Method A; Rt: 1.57 min. m/z : 399.2 (M+NH4)+ Exact mass: 381.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.55 (s, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.91 (s, 3 H), 4.13 (d, J=6.0 Hz, 2 H), 4.60 (d, J=6.0 Hz, 2 H), 7.09 (t, J=9.1 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.48 - 7.54 (m, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 7.63 (dd, J=7.0, 2.4 Hz, 1 H), 7.94 (s, 1 H), 10.02 (s, 1 H).

TIP 296 PCT Compound 6: N-(4-fluoromethyl-phenyl)methyl[[(1R)methylpropyl]- oyl]pyrrolecarboxamide A mixture of (R)-(-)aminobutane (231.7 mg, 3.17 mmol) and DIPEA (1.09 mL, 6.34 mmol) in dichloromethane (25 mL) was added to a solution of 5-[(4-fluoromethyl-phenyl)carbamoyl]- 1-methyl-pyrrolesulfonyl chloride (785 mg) in dichloromethane (50 mL) and stirred overnight. The reaction mixture was washed with 1M HCl (3x), water and NaHCO3 solution.

The organic layer was dried over MgSO4, ed and concentrated. The obtained residue was purified by column chromatography on silica using a nt from 10 to 100% EtOAc in heptane. The product fractions were concentrated yielding compound 6 as a beige solid which was dried overnight in vacuo at 50°C (540 mg). Method A; Rt: 1.78 min. m/z : 368.1 (M+H)+ Exact mass: 367.1. 1H NMR (400 MHz, DMSO-d 6)  ppm 0.77 (t, J=7.4 Hz, 3 H), 0.96 (d, J=6.4 Hz, 3 H), 1.29-1.41 (m, 2 H), 2.23 (d, J=1.5 Hz, 3 H), 3.01-3.12 (m, 1 H), 3.91 (s, 3 H), 7.04 - 7.16 (m, 2 H), 7.30 (d, J=2.0 Hz, 1 H), 7.46 - 7.57 (m, 2 H), 7.64 (dd, J=7.0, 2.4 Hz, 1 H), .00 (s, 1 H).

Alternative synthesis of compound 2: A solution of isopropylamine (499 mg, 8.45 mmol) in dichloromethane (25 mL) was added to a solution of 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (785 mg). The reaction mixture was stirred overnight. The on e was washed with 1M HCl (3 x), water and NaHCO3 solution. The c layer was dried over MgSO4, ed and concentrated. The obtained residue was recrystallized by slowly adding heptanes to warm EtOAc (50 mL) solution of compound 2. Compound 2 was filtered off as white solid and dried in vacuo at 50°C (357 mg).

Compound 7: N-(4-fluoromethyl-phenyl)methyl[(3-methyloxetanyl)methylsulfamoyl ]pyrrolecarboxamide A solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (5.05 g, 0.021 mol) in toluene (225 mL) was stirred at reflux under N2-flow. A solution of 4-fluoromethyl-aniline (2.56 g, 0.020 mol) in toluene (25 mL) was added dropwise over 35 minutes. After addition, the TIP 296 PCT reaction mixture was stirred and refluxed for 1 hour. The reaction e was cooled to ~50°C and the solvent was removed in vacuo resulting in crude 5-[(4-fluoromethylphenyl )carbamoyl]methyl-pyrrolesulfonyl chloride . Part of this crude 5-[(4-fluoro -phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride ( 0.63 g, 1.9 mmol) and 3- methyloxetanyl)methanamine (212 mg, 2.1 mmol) were dissolved in dichloromethane (10 mL). Then diisopropylethylamine (820 µL, 4.8 mmol) was added and the resulting mixture was stirred for two hours. HCl (5 mL, aq / 1M) was added to the mixture and the organic layer was separated and loaded directly on a silica plug purified by silica gel column chromatography using gradient elution from heptane to EtOAc (100:0 to 0:100). The d fractions were concentrated in vacuo and dried in vacuo resulting in compound 7 (586 mg) as a white powder.

Method A; Rt: 1.60 min. m/z : 394.0 (M-H)- Exact mass: 395.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 - 1.24 (s, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 2.96 (s, 2 H), 3.92 (s, 3 H), 4.17 (d, J=5.8 Hz, 2 H), 4.34 (d, J=5.8 Hz, 2 H), 7.10 (t, J=9.2 Hz, 1 H), 7.32 (d, J=1.8 Hz, 1 H), 7.41 - 7.54 (m, 2 H), 7.57 (d, J=1.8 Hz, 1 H), 7.64 (dd, J=6.6, 2.2 Hz, 1 H), 10.04 (s, 1 H).

Compound 8: N-(4-fluoromethyl-phenyl)methyl[[(1S)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxamide Crude fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (obtained as described in the synthesis of compound 7, 0.5 g, 1.51 mmol) and (S)-1,1,1-trifluoro propylamine (0.38 g, 3.33 mmol) were dissolved in of acetonitrile (9 mL). Then diisopropylethylamine (0.78 mL, 4.53 mmol) was added and the resulting mixture was stirred for two hours. HCl (5 mL, aq / 1M) was added and the mixture was extracted using dichloromethane (3 x 25 mL) The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column tography using gradient elution from heptane to EtOAc (100:0 to 0:100). The desired ons were concentrated in vacuo and dried in vacuo resulting in compound 8 (557 mg) as a white powder. Method B; Rt: 1.03 min. m/z : 406.1 (M-H)- Exact mass: 407.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.83 - 4.01 (m, 4 H), 7.10 (t, J=9.1 Hz, 1 H), 7.33 (d, J=2.0 Hz, 1 H), 7.47 - 7.55 (m, 1 H), 7.57 - 7.69 (m, 2 H), 8.15 (br. s., 1 H), 9.90 - 10.13 (br. s., 1 H).

Columns: AD-H (250 mm x 4.6 mm), Flow: 5 ml/min, Mobile phase: 25% MeOH (containing 0.2% ) hold 4.00 min, up to 50% in 1 min and hold 2.00 min at 50%, Temperature: 40°C Rt (compound 8): 1.2 min.

TIP 296 PCT Compound 9: N-(4-fluoromethyl-phenyl)methyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxamide Crude 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (obtained as described in the synthesis of compound 7, 0.69 g, 2.09 mmol), (R)-1,1,1-trifluoro propylamine (472 mg, 4.2 mmol) and DIPEA (0.72 mL, 4.2 mmol) where stirred in a sealed tube at 55°C for 16 hours. The reaction mixture was allowed to reach room temperature, and left for 4 hours. The solid was filtered off and washed with CH3CN (2x). The solvent of the filtrate was evaporated and the obtained residue was dissolved in CH2Cl2-heptane and then purified by silica gel column chromatography (heptane-EtOAc 100/0 to 0/100]. The desired fractions were ed and the solvent removed in vacuo. The obtained residue was stirred in CH2Cl2 (5 mL), filtered and washed with CH2Cl2 (2x) resulting in compound 9 (0.244 g). Method A; Rt: 1.78 min. m/z : 408.1 (M+H)+ Exact mass: 407.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.87- 3.96 (m, 4 H), 7.10 (dd, J=9.2 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.47 -7.55 (m, 1H), 7.59 - 7.66 (m, 2 H), 8.15 (br. s., 1 H), 10.03 (s, 1 H). s: AD-H (250 mm x 4.6 mm), Flow: 5 ml/min, Mobile phase: 25% MeOH (containing 0.2% iPrNH2) hold 4.00 min, up to 50% in 1 min and hold 2.00 min at50%, Temperature: 40°C Rt und 9):1.6 min.

Compound 10: N-(4-fluoromethyl-phenyl)[[3-(hydroxymethyl)oxetanyl]sulfamoyl] methyl-pyrrolecarboxamide DIPEA (1.44 mL, 0.008 mol ) was added to a stirring mixture of crude 5-[(4-fluoromethylphenyl )carbamoyl]methyl-pyrrolesulfonyl chloride (obtained as described in the synthesis of compound 7, 1.38 g, 0.0042mol ) and CH2Cl2 (45 mL ). (3-aminooxetanyl)methanol, 0.47 g, 0.0046 mol ) was added, and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were ated. The residue was stirred in EtOAc (50 mL) and washed with HCl 1M (25 mL). The separated c layer was dried with Na2SO4, filtered off and evaporated. The obtained residue was ved in EtOAc (3 mL), and heptane (2 mL) was added. The resulting solution was left ng overnight. The formed precipitate was filtered TIP 296 PCT off, washed with a minimum amount EtOAc (3x) and dried in vacuo.The obtained solid was recrystalyzed from CH3CN (20 mL) filtered off, washed with CH3CN (3x), and dried in vacuo, resulting in compound 10 (767 mg). Method A; Rt: 1.41 min. m/z : 395.9 (M-H)- Exact mass: 397.1. 1H NMR (400 MHz, DMSO-d6)  ppm 2.23 (d, J=1.8 Hz, 3 H), 3.61 (d, J=5.7 Hz, 2 H), 3.91 (s, 3 H), 4.39 (d, J=6.4 Hz, 2 H), 4.56 (d, J=6.4 Hz, 2 H), 5.08 (t, J=5.6 Hz, 1 H), 7.10 (t, J=9.2 Hz, 1 H), 7.33 (d, J=2.0 Hz, 1 H), 7.49 - 7.54 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.64 (dd =7.2, 2.3 Hz, 1 H), 7.88 (s, 1 H), 10.02 (s, 1 H).

Compound 11: N-(4-fluoromethyl-phenyl)methyl[(3-methyltetrahydrofuran- 3-yl)sulfamoyl]pyrrolecarboxamide Crude fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl de (obtained as described in the synthesis of compound 7, 690 mg) was stirred in CH2Cl2 (25 mL), 3- methyloxolanamine hydrochloride (316 mg, 2.3 mmol) and DIPEA (0.9 mL, 5.2 mmol) were added and the e was stirred at room temperature for 17 hours. Ethylacetate (300 mL) was added and the mixture was washed with 0.5 M HCl (1x100mL). The organic layer was dried with Na2SO4 and the solvent was evaporated. The obtained residu was purified by silica gel column chromatography Methanol/Dichloromethane 2/98 to 4/96]. The desired fractions were ed and the solvent was evaporated. The mixture was repurified by silica gel column chromatography using EtOAc/Heptane 50/50 to 100/0]. The desired ons were combined and the solvent was evaporated. The obtained residue was recrystallized from 2-Propanol (7 mL). The obtained white solid was filtered off, washed with anol (2x2mL) and dried in vacuo, resulting in compound 11 (211 mg). Method A; Rt: 1.62 min. m/z : 394.1 (M-H)- Exact mass: 395.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.29 (s, 3 H), 1.73 (dt, J=12.7, 7.3 Hz, 1 H), 2.11 - 2.28 (m, 4 H), 3.39 (d, J=8.6 Hz, 1 H), 3.66 - 3.79 (m, 3 H), 3.91 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.31 (d, J=1.8 Hz, 1 H), 7.46 - 7.56 (m, 3 H), 7.64 (dd, J=7.0, 2.2 Hz, 1 H), 10.02 (s, 1 Compound 12: N-(4-fluoromethyl-phenyl)[[1-(hydroxymethyl)cyclopropyl]sulfamoyl] methyl-pyrrolecarboxamide TIP 296 PCT Compound 12 was prepared similarly as described for compound 11, using 1-aminocyclopropanemethanol instead of 3-methyloxolanamine hydrochloride. After work up, the obtained solid was stirred in boiling CH2Cl2and ed off. The obtained white solid was recrystallized from Acetonitrile, resulting in compound 12 (1.021 g). Method B; Rt: 0.84 min. m/z : 380.1 (M-H)- Exact mass: 381.1. 1H NMR (360 MHz, DMSO-d6)  ppm 0.54 - 0.65 (m, 4 H), 2.23 (d, J=1.8 Hz, 3 H), 3.37 (d, J=5.9 Hz, 2 H), 3.90 (s, 3 H), 4.59 (t, J=5.9 Hz, 1 H), 7.10 (t, J=9.1 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.49 - 7.55 (m, 2 H), 7.65 (dd, J=7.1, 2.4 Hz, 1 H), 7.75 (s, 1 H), 10.03 (s, 1 H).

Compound 13: N-(4-fluoromethyl-phenyl)methyl[(1-methyloxo-pyrrolidin yl)sulfamoyl]pyrrolecarboxamide Compound 13 was prepared similarly as described for compound 7, using 4-aminomethylpyrrolidinone hydrochloride instead of 3-methyloxetanyl)methanamine. Method B; Rt: 0.81 min. m/z : 409.1 (M+H)+ Exact mass: 408.1. 1H NMR (400 MHz, DMSO-d6)  ppm 2.07 - 2.15 (m, 1 H), 2.23 (d, J=1.8 Hz, 3 H), 2.35-2.50 (m, 1 H), 2.67 (s, 3 H), 3.18 (dd, J=10.1, 4.6 Hz, 1 H), 3.52 (dd, , 7.3 Hz, 1 H), 3.76 - 3.85 (m, 1 H), 3.92 (s, 3 H), 7.10 (t, J=9.2 Hz, 1 H), 7.31 (d, J=2.0 Hz, 1 H), 7.46 - 7.55 (m, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.64 (dd, J=7.0, 2.6 Hz, 1 H), 7.72 (br. s, 1 H), 10.03 (s, 1 H). Compound 13, was separated in it’s enantiomers compound 13a and compound 13b by preperative SFC (Stationary phase: Chiralpak Daicel IC x 250 mm), Mobile phase: CO2, MeOH with 0.4% iPrNH2) The desired fractions were concentrated in vacuo and dried in vacuo ng compound 13a (192 mg) and nd 13b (200 mg) as white powders. s: ID-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 at 50%. Temperature: 40ºC Rt: 13a : 2.2 min; 13b 2.5 min.

Compound 14: N-(4-fluoromethyl-phenyl)[[3-(2-hydroxyethyl)oxetanyl]sulfamoyl] methyl-pyrrolecarboxamide TIP 296 PCT Compound 14 was prepared similarly as described for compound 7, using 2-(3-aminooxetan yl)ethanol instead of 3-methyloxetanyl)methanamine, resulting in compound 14 (1.09 g) as a white powder. Method B; Rt: 0.80 min. m/z : 410.1 (M-H)- Exact mass: 411.1. 1H NMR (400 MHz, DMSO-d6)  ppm 2.14 (t, J=6.6 Hz, 2 H), 2.23 (d, J=1.5 Hz, 3 H), 3.42 - 3.50 (m, 2 H), 3.91 (s, 3 H), 4.32 (d, J=6.4 Hz, 2 H), 4.45 (br. s, 1 H), 4.56 (d, J=6.4 Hz, 2 H), 7.10 (t, J=9.1 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.46 - 7.54 (m, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 7.63 (dd, J=7.0, 2.4 Hz, 1 H), 7.84 (br. s., 1 H), 10.02 (s, 1 H).

Compound 15: N-(4-fluoromethyl-phenyl)[(3-hydroxycyclobutyl)sulfamoyl]methyl- pyrrolecarboxamide -[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (0.56 g, 1.7 mmol) was stirred in CH2Cl2 (15 mL). cisaminocyclobutanol hydrochloride (0.23 g, 1.9 mmol) and DIPEA(1.5 mL, 8.5 mmol) were added at room temperature and the mixture was d for 60 hour. The solvent was evaporated and the obtained residue was purified by silica gel column tography nol/Dichloromethane 2/98 to 4/96). The pure fractions were combined and the solvent was evaporated and the ed residue was crystallized from dichloromethane, resulting in compound 15 (273 mg) as a white solid after filtration and drying in vacuo.Method B; Rt: 0.81 min. m/z : 380.1 (M-H)- Exact mass: 381.1 1H NMR (360 MHz, DMSO-d6)  ppm 1.59 - 1.71 (m, 2 H), 2.22 (d, J=1.5 Hz, 3 H), 2.28 - 2.38 (m, 2 H), 3.02 - 3.16 (m, 1 H), 3.63 - 3.75 (m, 1 H), 3.90 (s, 3 H), 5.02 (d, J=5.9 Hz, 1 H), 7.10 (dd, J=9.1 Hz, 1 H), 7.28 (d, J=1.8 Hz, 1 H), 7.47 - 7.55 (m, 3 H), 7.65 (dd, J=7.1, 2.4 Hz, 1 H), 10.03 (s, 1 H).

Compound 16: t-butylsulfamoyl)-N-(4-fluoromethyl-phenyl)methyl-pyrrole carboxamide -[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (0.60 g, 1.8 mmol) was stirred in CH2Cl2 (15 mL). tert-butylamine (0.23 g, 1.9 mmol) and DIPEA (0.8 mL, 4.5 mmol) were added at room temperature and the mixture was stirred for 18 hours. The solvent was evaporated and EtOAc (50 mL) was added. After g with 1M HCl (20 mL), the organic layer was dried with Na2SO4 and the solvent was evaporated. The obtained solid was dissolved in dichloromethane (10 mL) and the solvent was slowly evaporated at 50°C. The TIP 296 PCT evaporation was stopped when precipitation commenced, and stirring was continued at room temperature for 15 minutes. The itate was filtered off, washed with dichloromethane (1 mL) and dried in vacuo at 50°C, resulting in compound 16 (136 mg). Method A; Rt: 1.79 min. m/z : 366.1 (M-H)- Exact mass: 367.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 2.23 (d, J=1.5 Hz, 3 H), 3.90 (s, 3 H), 7.05 - 7.13 (m, 2 H), 7.29 (d, J=1.8 Hz, 1 H), 7.45-7.55 (m, 2 H), 7.64 (dd, J=7.0, 2.2 Hz, 1 H), 10.00 (s, 1 H).

Compound 17: 4-[[3-(cyanomethyl)oxetanyl]sulfamoyl]-N-(4-fluoromethyl-phenyl) methyl-pyrrolecarboxamide Compound 10 (0.46 g, 1.2 mmol) was dissolved in dry dichloromethane (30 mL) and dry DIPEA (0.31 mL, 1.8 mmol) was added. This mixture was cooled in an ice bath and d for minutes. Then Methanesulfonyl de (0.10 mL, 1.3 mmol) in dry dichloromethane (10 mL) was added dropwise over 10 minutes, after stirring 30 minutes more at 0°C, the mixture was washed with 0.5 M HCl (50 mL) and saturated aqueous NaHCO3 (5 mL). The water layer was extracted with EtOAc (200 mL) and the combined organic layers were dried with Na2SO4.

The solvent was removed in vacuo and the obtained residue was dissolved in dry DMSO. This solution was added dropwise to a solution of sodium cyanide (0.12 g, 2.4 mmol) in dry DMSO (25 mL) at 40°C. The mixture was stirred 2.5 hour at 40°C. After cooling to room ature water (50 mL) was added. This mixture was extracted with diethylether (3x100 mL) and EtOAc (3 x 150 mL). The combined organic layer were dried on Na2SO4 and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography by gradient elution with Heptane 0/100 to 100/0]. The desired fractions were combined and the t was removed, resulting compound 17 (264 mg) as a beige solid after drying in vacuo.

Method B; Rt: 0.86 min. m/z : 405.2 (M-H)- Exact mass: 406.1 1H NMR (360 MHz, DMSO-d6)  ppm 2.23 (d, J=1.8 Hz, 3 H), 3.28 (s, 2 H), 3.91 (s, 3 H), 4.28 (d, J=7.0 Hz, 2 H), 4.55 (d, J=7.0 Hz, 2 H), 7.11 (t, J=9.3 Hz, 1 H), 7.35 (d, J=2.2 Hz, 1 H), 7.47 - 7.55 (m, 1 H), 7.61 - 7.67 (m, 2 H), 8.46 - 8.53 (m, 1 H), 10.05 (s, 1 H).

Compound 18: 4-[[1-(cyanomethyl)cyclopropyl]sulfamoyl]-N-(4-fluoromethyl-phenyl) methyl-pyrrolecarboxamide TIP 296 PCT Prepared similarly as described for compound 17, starting from compound 12 instead of compound 10. Method C; Rt: 1.69 min. m/z : 389.1 (M-H)- Exact mass: 390.1. 1H NMR (360 MHz, FORM-d)  ppm 0.63 - 0.74 (m, 4 H), 2.23 (d, J=1.8 Hz, 3 H), 2.81 (s, 2 H), 3.92 (s, 3 H), 7.07 - 7.15 (m, 1 H), 7.26 - 7.31 (m, 1 H), 7.49 - 7.59 (m, 2 H), 7.62 - 7.68 (m, 1 H), 8.13 - 8.20 (m, 1 H), 10.02 - 10.09 (m, 1 H).

Compound 19: 4-(tert-butylsulfamoyl)-N-(3,4-difluorophenyl)methyl-pyrrolecarboxamide A solution of fluoroaniline (1.9 mL, 19.2 mmol) in toluene (20 mL) was added dropwise (over 15 minutes) to a refluxing solution of 4-chlorosulfonylmethyl-pyrrole carbonylchloride in toluene (250 mL). After the on, the reaction mixture was left to stir at reflux for 1 hour. The reaction mixture was left to cool to room temperature under nitrogen here while stirring. The grey suspension was concentrated and the obtained residue containing 5-[(3,4-difluorophenyl)carbamoyl]methyl-pyrrolesulfonyl chloride was dried in vacuo and further used without further purification. Tert-butylamine (0.3 mL, 2.8 mmol) was added to a suspension of crude 5-[(3,4-difluorophenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.2 g, 2.55 mmol) in dry dichloromethane (20 mL) at room temperature. Next, NEt3 (0.9 mL, 6.4 mmol) was added dropwise and the reaction mixture was d at room temperature for 1 hour and at 50°C for 1.5 hour. The reaction mixture was diluted with EtOAc (250 mL). 0.5 N HCl (30 mL) was added to the reaction mixture and the layers were ted.

The organic layer was washed again with 0.5 N NaOH (30 mL), followed by water. The organic layer was dried on MgSO4, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (eluent: CH2Cl2:MeOH 100:0 -> 95:5). The obtained white solid was triturated in a small amount of CH2Cl2. After tion, washing with CH2Cl2 and drying in vacuo, compound 19 (310 mg) was obtained as a white solid. Method B; Rt: 1.02 min. m/z : 370.1 (M-H)- Exact mass: 371.1. 1H NMR (360 MHz, DMSO-d6)  ppm 1.16 (s, 9 H) 3.90 (s, 3 H) 7.16 (s, 1 H) 7.31 (d, J=1.8 Hz, 1 H) 7.35 - 7.46 (m, 1 H) 7.45-7.53 (m, 1 H) 7.54 (d, J=1.5 Hz, 1 H) 7.88 (ddd, J=13.5, 7.8, 2.2 Hz, 1 H) 10.24 (s, 1 H).

TIP 296 PCT Compound 20: N-(3,4-difluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]pyrrole amide Compound 20 was prepared similarly as bed for compound 19, using 3-methyl oxetanamine hydrochloride instead of tert-butylamine. After p the obtained residue was triturated in a small amount of CH2Cl2 and filtered resulting in a white powder. The powder was triturated in EtOAc (1 mL), filtered and rinsed with a small amount of CH2Cl2 resulting in compound 20 (421 mg) as a white powder after drying in vacuo. Method B; Rt: 0.86 min. m/z : 384.1 (M-H)- Exact mass: 385.1. 1H NMR (360 MHz, DMSO-d6)  ppm 1.54 (s, 3 H) 3.91 (s, 3 H) 4.13 (d, J=6.2 Hz, 2 H) 4.59 (d, J=6.2 Hz, 2 H) 7.33 (d, J=1.8 Hz, 1 H) 7.37 - 7.46 (m, 1 H) 7.46 - 7.52 (m, 1 H) 7.61 (d, J=1.8 Hz, 1 H) 7.87 (ddd, J=13.5, 7.4, 2.6 Hz, 1 H) 8.00 (s, 1 H) .25 (s, 1 H).

Compound 21: N-(3,4-difluorophenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide A solution of 3,4-difluoroaniline in toluene (50 mL) was slowly added (over 1 hour) to a refluxing solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride in e (200 mL).

After addition, the reaction mixture was left to stir at reflux for 45 minutes.

The reaction mixture was left to cool to room temperature under nitrogen atmosphere while stirring and was then cooled with an ice bath. The precipitate was filtered and the filtrate was concentrated and dried in vacuo, resulting in a residue containing -[(3,4-difluorophenyl)carbamoyl]methyl-pyrrolesulfonyl chloride.

(S)aminotetrahydrofuran tosylate (0.59 g, 2.3 mmol) was added to a suspension of 5-[(3,4- difluorophenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.0 g of the above obtained crude) in dry dichloromethane (50 mL) at room temperature. NEt3 (0.72 mL, 5.2 mmol) was added dropwise and the mixture was further stirred at room temperature for 1 hour. 0.5 N HCl (30 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed again with 0.5 N NaOH (30 mL) followed by water. The c layer was dried on MgSO4 and was evaporated.

The ed residue was triturated in a small amount of CH2Cl2, filtered, and washed with a small amount of CH2Cl2, ing in compound 21 (408 mg) as a white solid, after drying in TIP 296 PCT vacuo. Method B; Rt: 0.84 min m/z : 384.0 (M-H)- Exact mass: 385.1. 1H NMR (360 MHz, DMSO-d6)  ppm 1.66 - 1.76 (m, 1 H) 1.91 - 2.03 (m, 1 H) 3.40 - 3.47 (m, 1 H) 3.61 (td, J=8.1, .9 Hz, 1 H) 3.65 - 3.75 (m, 3 H) 3.92 (s, 3 H) 7.33 (d, J=1.83 Hz, 1 H) 7.37 - 7.46 (m, 1 H) 7.46 - 7.52 (m, 1 H) 7.57 - 7.62 (m, 2 H) 7.88 (ddd, J=13.5, 7.6, 2.4 Hz, 1 H) 10.26 (s, 1 H).

Compound 22: N-(3,4-difluorophenyl)(isopropylsulfamoyl)methyl-pyrrolecarboxamide Compound 22 was ed similarly as described for compound 21, using isopropylamine instead of (S)aminotetrahydrofuran tosylate. After work-up (only 0.5 N HCl was used for washing) the obtained residue was purified by silica gel column chromatography (CH2Cl2:MeOH 100:0 -> 95:5) resulting in compound 22 (534 mg) as a white solid after drying in vacuo. Method B; Rt: 0.94 min. m/z : 356.1 (M-H)- Exact mass: 357.1. 1H NMR (360 MHz, DMSO-d6)  ppm 1.01 (d, J=6.2 Hz, 6 H) 3.18-3.28 (m, 1 H) 3.91 (s, 3 H) 7.23 (d, J=7.0 Hz, 1 H) 7.32 (d, J=1.8 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.46 - 7.53 (m, 1 H) 7.56 (d, J=1.8 Hz, 1 H) 7.88 (ddd, J=13.4, 7.5, 2.6 Hz, 1 H) 10.25 (s, 1 H).

Compound 23: N-(3,4-difluorophenyl)methyl[[(1R)methylpropyl]sulfamoyl]pyrrole amide Compound 23 was prepared similarly as described for compound 22, using )aminobutane instead of isopropylamine. After work up, the obtained residue was triturated in a small amount of CH2Cl2, filtered and washed with a small amount of CH2Cl2. The obtained solid was triturated with 0.5 N NaOH and filtered. The white solid was washed with water resulting in compound 23 (499 mg) as a white solid, after drying in vacuo. Method B; Rt: 1.00 min. m/z : 370.1 (M-H)- Exact mass: 371.1. 1H NMR (360 MHz, DMSO-d6)  ppm 0.76 (t, J=7.5 Hz, 3 H) 0.95 (d, J=6.6 Hz, 3 H) 1.28 - 1.41 (m, 2 H) .13 (m, 1 H) 3.91 (s, 3 H) 7.18 (d, J=7.7 Hz, 1 H) 7.32 (d, J=1.8 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.46 - 7.53 (m, 1 H) 7.56 (d, J=1.8 Hz, 1 H) 7.88 (ddd, J=13.4, 7.7, 2.4 Hz, 1 H) 10.25 (s, 1 H).

TIP 296 PCT Compound 24: N-(3,4-difluorophenyl)[[(1R)hydroxymethyl-ethyl]sulfamoyl]methylpyrrolecarboxamide Compound 24 was prepared similarly as described for compound 19, using D-alaninol instead of tert-butylamine, using 5 equiv of NEt3 and 1.5 hour stirring at room temperature. The reaction e was diluted with EtOAc (250 mL), 0.5 N HCl (30 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed again with 0.5 N NaOH (30 mL) followed by water. The organic layer was dried on MgSO4, filtered and ated.The obtained residue was triturated in a small amount of CH2Cl2, filtered and washed with a small amount of CH2Cl2 resulting in compound 24 (717 mg) as a white powder, after drying in vacuo.

Method B; Rt: 0.81 min. m/z : 372.0 (M-H)- Exact mass: 373.1 1H NMR (360 MHz, DMSO-d6)  ppm 0.97 (d, J=5.9 Hz, 3 H) 3.06 - 3.17 (m, 2 H) 3.32 - 3.39 (m, 1 H),3.91 (s, 3 H) 4.69 (t, J=5.3 Hz, 1 H) 7.14 (d, J=6.6 Hz, 1 H) 7.32 (d, J=1.5 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.46 - 7.53 (m, 1 H) 7.57 (d, J=1.5 Hz, 1 H) 7.88 (ddd, J=13.5, 7.6, 2.4 Hz, 1 H) 10.25 (s, 1 H).

Compound 25: N-(3,4-difluorophenyl)[(3-hydroxycyclobutyl)sulfamoyl]methyl-pyrrole carboxamide Compound 25 was prepared similarly as described for compound 19, using cisamino- cyclobutanol hydrochloride instead of tert-butylamine and adding 2.5 equiv more NEt3 before heating to 50°C.

The e obtained after work up was triturated in a small amount of CH2Cl2, ed and washed with a small amount of CH2Cl2 resulting in a white powder, which was further triturated in MeOH/ CH2Cl2 5/95. After filtration, washing and drying in vacuo, nd 25 (150 mg) was obtained as a white powder. Method A; Rt: 0.80 min. m/z : 384.0 (M-H)- Exact mass: 385.1. 1H NMR (360 MHz, DMSO-d 6)  ppm 1.59 - 1.71 (m, 2 H) 2.27 - 2.39 (m, 2 H) 3.03 - 3.15 (m, 1 H) 3.64 - 3.76 (m, 1 H) 3.91 (s, 3 H) 5.02 (d, J=5.5 Hz, 1 H) 7.28 - 7.33 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.46 - 7.57 (m, 2 H) 7.88 (ddd, J=13.5, 7.6, 2.0 Hz, 1 H) 10.24 (s, 1 H).

Compound 91: N-(3,4-Difluorophenyl)methyl[(3-methyltetrahydrofuranyl)sulfamoyl]- 1H-pyrrolecarboxamide TIP 296 PCT O N F O H Compound 91 was prepared similarly as described for compound 19 using 3-methyloxolan amine hydrochloride instead of tert-butylamine. nd 91 (206 mg) was obtained as a white solid. Method B; Rt: 0.91 min. m/z : 398.1 (M-H)- Exact mass: 399.1. 1 H NMR (360 MHz, 6) ppm 1.28 (s, 3 H) 1.72 (dt, J=12.5, 7.5 Hz, 1 H) 2.12 - 2.21 (m, 1 H) 3.38 (d, J=8.8 Hz, 1 H) 3.69 - 3.75 (m, 3 H) 3.91 (s, 3 H) 7.33 (d, J=2.2 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.46 - 7.52 (m, 1 H) 7.55 - 7.59 (m, 2 H) 7.88 (ddd, J=13.4, 7.6, 2.4 Hz, 1 H) 10.25 (s, 1 H).

Compound 92: N-(3,4-Difluorophenyl)methyl{[(1R)-2,2,2-trifluoromethylethyl]- sulfamoyl}-1H-pyrrolecarboxamide nd 92 was prepared similarly as described for compound 19 using (R)-1,1,1-trifluoro propylamine instead of tert-butylamine. Compound 92 precipitated from the basic 0.5 N NaOH water layer upon neutralization. Compound 92 was further purified by Preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10µm, 200g, 5cm), Mobile phase: 0.5% NH4OAc solution in water + 10% CH3CN, CH3CN). The collected ons were concentrated (to the aqueous phase). The aqueous phase was acidified with HCl 1N and was extracted with EtOAc.

The organic layer was dried on MgSO4, filtered, and evaporated resulting in compound 92 (49 mg) as a white solid after drying in vacuo at 50 °C. Method B; Rt: 1.03 min. m/z : 410.1 (M-H)- Exact mass: 411.1. 1H NMR (360 MHz, DMSO-d 6)  ppm 1.06 (d, J=7.0 Hz, 3 H) 3.92 (s, 3 H) 3.87 - 4.00 (m, 1 H) 7.35 (d, J=1.8 Hz, 1 H) 7.37 - 7.52 (m, 2 H) 7.66 (d, J=1.8 Hz, 1 H) 7.88 (ddd, J=13.4, 7.6, 2.4 Hz, 1 H) 8.18 (d, J=8.8 Hz, 1 H) 10.27 (s, 1 H).

Compound 93: N-(3,4-Difluorophenyl)methyl{[(1S)-2,2,2-trifluoromethylethyl ]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Compound 93 was prepared rly as described for compound 92 using (S)-1,1,1-trifluoro propylamine instead of (R)-1,1,1-trifluoropropylamine. Method B; Rt: 1.03 min. m/z : 410.1 (M-H)- Exact mass: 411.1.

Alternative synthesis of compound 92: Methyl 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (6.61 g, 21.0 mmol) and 3,4-difluoroaniline (3.26 g, 25.24 mmol) were dissolved in tetrahydrofuran (150 mL) and this was stirred and cooled in an ice-water bath. Lithium bis(trimethylsilyl)amide in toluene (63.1 mL, 1 M, 63.1 mmol) was added dropwise over a period of 5 minutes. The resulting mixture was stirred for 1 h while cooling was continued. Another two equivalents of lithium bis(trimethylsilyl)amide in toluene (42.06 mL, 1 M, 42.06 mmol) were added and the resulting mixture was d for 2 hours at room temperature. The resulting mixture was quenched using ammonium chloride (sat. / 200 mL). The resulting mixture was extracted using EtOAc (3 x 250 mL). The combined extracts were washed with brine (250 mL), dried on Na2SO4, filtered and concentrated in vacuo yielding a brown powder. This was llised twice out of methanol/water. The precipitation was collected on a glass . The ed powder was purified by silica gel column chromatography using nt elution from heptane to EtOAc. (100:0 to 0:100) and next by silica gel column chromatography using gradient elution from dichloromethane to MeOH (100:0 to 99:1). The desired fractions were concentrated in vacuo yielding a powder. The ed residue was crystallized out of methanol/water. The white crystals were collected on a glass filter and dried in a vacuum oven at 55°C for 24 hours yielding nd 92 (4.32 g) as white s. [α]20365= -11.6 ° (c 0.85 w/v %, MeOH). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 219.6°C.

Compound 95: N-(3,4-Difluorophenyl)methyl[(2,2,2-trifluoro-1,1-dimethylethyl)- sulfamoyl]-1H-pyrrolecarboxamide -[(3,4-difluorophenyl)carbamoyl]methyl-pyrrolesulfonyl de (648 mg, 1.374 mmol), 2,2,2-trifluoro-1,1-dimethyl-ethylamine (262 mg), DIPEA (0.296 mL, 1.72 mmol) in acetonitrile (65 mL) was refluxed overnight. 2,2,2-trifluoro-1,1-dimethyl-ethylamine (349 mg) were added and the reaction mixture was refluxed over weekend. The reaction mixture was concentrated.

The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated. The obtained residue was ted to silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The pure fractions were collected, concentrated and dried in vacuo at 50°C yielding compound 95 as a white powder TIP 296 PCT (162 mg). Method A; Rt: 1.78 min. m/z: 424.1 (M-H)- Exact mass: 425.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.36 (s, 6 H), 3.92 (s, 3 H), 7.32 (d, J=1.8 Hz, 1 H), 7.36 - 7.45 (m, 1 H), 7.46 - 7.52 (m, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.87 (ddd, J=13.4, 7.6, 2.5 Hz, 1 H), 8.04 (s, 1 H), 10.25 (s, 1 H). nd 26: yl[[(3S)-tetrahydrofuranyl]sulfamoyl]-N-(3,4,5-trifluorophenyl )pyrrolecarboxamide A solution of 3,4,5-trifluoroaniline (0.99 g, 6.7 mmol) in toluene (20 mL) was added dropwise to a refluxing solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride in toluene (80 mL).

After the on, the reaction mixture was left to stir at reflux for 1 hour. The mixture was cooled and concentrated in vacuo. The obtained crude containing yl[(3,4,5- trifluorophenyl)carbamoyl]pyrrolesulfonyl chloride was used a such.A solution of (S)-(-) aminotetrahydrofuran p-toluenesulfonate (647 mg, 2.5 mmol) and DIPEA (0.98 mL, 5.7 mmol) in CH2Cl2 (10 mL) was added to crude 1-methyl[(3,4,5-trifluorophenyl)carbamoyl]pyrrole sulfonyl de (800 mg) in CH2Cl2 (150 mL) and stirred for 1 hour. The mixture was diluted with dichloromethane (400 mL) and washed with 1M HCl (2x), water and saturated NaHCO3 solution. The organic layer was dried over magnesium sulphate, filtered and concentrated. The obtained e was dissolved in hot MeOH (100 mL) and water was added. The formed white precipitate was filtered off, dried in vacuo and purified by silica gel column chromatography using a gradient from 20 to 100% EtOAc in heptane. The product fractions were concentrated and dried in vacuo resulting in compound 26 (286 mg) as a white powder. Method A; Rt: 1.67 min. m/z : 401.9 (M-H)- Exact mass: 403.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.66 - 1.76 (m, 1 H), 1.91 - 2.03 (m, 1 H), 3.39 - 3.47 (m, 1 H), 3.55-3.65 (m, 1 H), 3.65 - 3.75 (m, 3 H), 3.92 (s, 3 H), 7.33 (d, J=2.0 Hz, 1 H), 7.58 (d, J=5.5 Hz, 1 H), 7.61 (d, J=1.5 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 10.33 (s, 1 H).

Compound 27: 1-methyl[(3-methyloxetanyl)sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole- 2-carboxamide TIP 296 PCT 3-methyloxetanamine hydrochloride (526 mg, 4.3 mmol) and DIPEA (1.8 mL) were dissolved in CH2Cl2 (5 mL). Crude 1-methyl[(3,4,5-trifluorophenyl)carbamoyl]pyrrolesulfonyl chloride (1.2 g, obtained as described for compound 26) was added and the on mixture was stirred for 30 minutes. The reaction e was directly loaded on silica gel column and purified by gradient elution from heptane to EtOAc, yieding compound 27 (758 mg) as a white powder after trituration in CH2Cl2 and drying in vacuo. Method A; Rt: 1.68 min. m/z : 401.9 (MH )- Exact mass: 403.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.5 Hz, 2 H), 4.60 (d, J=6.1 Hz, 2 H), 7.34 (d, J=1.6 Hz, 1 H), 7.62 (d, J=2.0 Hz, 1 H), 7.66 (dd, J=10.3, 6.7 Hz, 2 H), 7.98 (s, 1 H), 10.32 (s, 1 H).

DSC: From 30 to 300 °C at 10°C/min, Peak: 218 °C.

Compound ethyl[(3-methyloxetanyl)sulfamoyl]-N-[3-(trifluoromethyl)- phenyl]pyrrolecarboxamide 3-(trifluoromethyl)aniline (0.41 mL, 3.3 mmol) was added dropwise to a refluxing solution of 4- chlorosulfonylmethyl-pyrrolecarbonylchloride in toluene (25 mL). After the addition, the reaction mixture was left to stir at reflux for 4 hours. The mixture was cooled to room temperature and a solution of 3-methyloxetanamine hydrochloride (408 mg, 3.3 mmol) and DIPEA (0.57 mL) in CH2Cl2 (2 mL) was added. The mixture was stirred overnight at room ature. More 3-methyloxetanamine hydrochloride (0.5 equiv) and DIPEA (0.5 equiv) in CH2Cl2 (2 mL) were added and the e was stirred for 2 hours at room temperature and 2 hours more at 50°C. The reaction mixture was allowed to reach room temperature and the formed precipitate was filtered off, triturated in MeOH (12 mL), filtered and dried in vacuo, resulting in compound 28 as a white powder. Method B; Rt: 0.99 min. m/z : 416.1 (M-H)- Exact mass: 417.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.39 (d, J=2.0 Hz, 1 H), 7.43 (d, J=7.7 Hz, 1 H), 7.58 (t, J=8.0 Hz, 1 H), 7.61 (d, J=1.8 Hz, 1 H), 7.95 - 8.02 (m, 2 H), 8.19 (s, 1 H), 10.32 (s, 1 H). nd 29: 1-ethyl-N-(4-fluoromethyl-phenyl)(isopropylsulfamoyl)pyrrole carboxamide TIP 296 PCT To 4-chlorosulfonylethyl-pyrrolecarboxylic acid (1 g, cial from enamine, EN300- 43738, 4.2 mmol ) in CH2Cl2, (10 mL ) at room temperature under N2-atmosphere, DMF (1 drop) was added followed by dropwise on of a on of oxalyl chloride (1.44 mL, 0.0168 mol ) in CH2Cl2 (5 mL) over 10 minutes. After addition, the reaction mixture as stirred at room temperature for 24 hours. The volatiles were evaporated, and co-evaporated with dry toluene (2 x). The obtained residue containing 4-chlorosulfonylethyl-pyrrolecarbonyl chloride was used as such in the next step.

A solution of 4-fluoromethylaniline (527 mg, 4.2 mmol) in toluene was added se to a solution of the above obtained crude 4-chlorosulfonylethyl-pyrrolecarbonyl chloride in e at reflux over 5 minutes. The reaction e was refluxed 30 minutes and next allowed to reach room temperature. After ng at room temperature for 2 hours the volatiles were removed in vacuo resulting in a residue containing 1-ethyl[(4-fluoromethylphenyl )carbamoyl]pyrrolesulfonyl chloride that was used as such in the next step. Part of the as such obtained crude 1-ethyl[(4-fluoromethyl-phenyl)carbamoyl]pyrrolesulfonyl chloride (708 mg) was dissolved in CH2Cl2 (5 mL) and isopropylamine(0.13 mL, 1.6 mmol) and DIPEA (0.72 mL, 4.2 mmol) were added and the reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc (100 mL) and washed with 1 M HCl (2 x mL). The organic layer was dried on Na2SO4, filtered and concentrated resulting in a residue that was purified using silica gel columnchromatography (ethyl acetate in heptane from 10 to 100%) ing in compound 29 (270 mg). Method B; Rt: 1.02 min. m/z : 366.2 (M-H)- Exact mass: 367.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.01 (d, J=6.6 Hz, 6 H), 1.31 (t, J=7.0 Hz, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.20 - 3.33 (m, 1 H), 4.38 (q, J=7.0 Hz, 2 H), 7.09 (t, J=9.1 Hz, 1 H), 7.16 (d, J=7.0 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.48 - 7.54 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.64 (dd, J=7.0, 2.4 Hz, 1 H), 10.03 (br. s, 1 H).

Compound 30: 1-ethyl-N-(4-fluoromethyl-phenyl)[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide Crude 1-ethyl[(4-fluoromethyl-phenyl)carbamoyl]pyrrolesulfonyl de (obtained as described for compound 29) was dissolved in CH2Cl2 (5 mL) and (S)-(-)aminotetrahydrofuran p-toluenesulfonate (410 mg, 1.6 mmol)) and DIPEA (0.7 mL, 4.2 mmol) were added and the reaction mixture stirred at room temperature for 30 minutes. The e was diluted with EtOAc (100 mL) and washed with 1M HCl (2 x 10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford a residue that was purified using silica gel column chromatography (ethyl acetate in heptane from 10 to 100%) resulting in compound 30 (282 mg) TIP 296 PCT as white powder after drying in vacuo. Method B; Rt: 0.92 min. m/z : 394.1 (M-H)- Exact mass: 395.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.32 (t, J=7.0 Hz, 3 H), 1.64 - 1.75 (m, 1 H), 1.90 - 2.02 (m, 1 H), 2.23 (d, J=1.5 Hz, 3 H), 3.36 - 3.45 (m, 1 H), 3.61 (td, J=8.0, 5.9 Hz, 1 H), 3.66 - 3.78 (m, 3 H), 4.39 (q, J=7.1 Hz, 2 H), 7.09 (t, J=9.1 Hz, 1 H), 7.30 (d, J=1.8 Hz, 1 H), 7.46 - 7.56 (m, 2 H), 7.61 (d, J=1.8 Hz, 1 H), 7.64 (dd, J=7.0, 2.4 Hz, 1 H), 10.04 (br. s, 1 H). nd 31: N-(4-fluoro-3,5-dimethyl-phenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide 4-fluoro-3,5-dimethyl-benzenamine (995 mg, 7.1 mmol) dissolved in toluene (20 mL) was added dropwise to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (1.7 g) in e (100 mL) at reflux. The reaction e was refluxed 1 hour and next allowed to cool to room temperature. (S)-(-)aminotetrahydrofuran p-toluenesulfonate (2.0 g, 7.9 mmol) and DIPEA (3.1 mL, 17.9 mmol) dissolved in CH2Cl2 (50 mL) was added, the reaction mixture was stirred for 1 hour and then concentrated in vacuo. The obtained e was dissolved in EtOAc (300 mL), washed with 1 M HCl (2x), water and saturated NaHCO3. The solution was dried over magnesium sulphate, filtered and concentrated. The obtained e was purified by silica gel column chromatography (gradient from 20 till 100% EtOAc in heptanes). The product ons were concentrated and the obtained residue was recrystallized from hot EtOAc (100 mL) upon addition of heptane. The white crystals were filtered off and dried in vacuo resulting in compound 31 (1.7 g) as a white powder. Method A; Rt: 1.68 min. m/z : 393.9 (M-H)- Exact mass: 395.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.66 - 1.77 (m, 1 H), 1.92 - 2.03 (m, 1 H), 2.21 (d, J=2.0 Hz, 6 H), 3.40 - 3.47 (m, 1 H), 3.61 (td, J=8.1, 5.9 Hz, 1 H), 3.66 - 3.76 (m, 3 H), 3.91 (s, 3 H), 7.31 (d, J=2.0 Hz, 1 H), 7.43 (d, J=6.8 Hz, 2 H), 7.50 - 7.58 (m, 2 H), 9.94 (s, 1 H).

Compound 32: N-(3-fluoromethyl-phenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide Compound 32 was prepared similarly as decribed for compound 31, using 3-fluoro methylaniline instead of ro-3,5-dimethyl-benzenamine. After silica gel column chromatography (EtOAc in heptanes 20 % to 100%), compound 32 (2.2 g) was obtained as a TIP 296 PCT white powder. Method A; Rt: 1.62 min. m/z : 379.9 (M-H)- Exact mass: 381.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.66 - 1.77 (m, 1 H), 1.92 - 2.03 (m, 1 H), 2.30 (s, 3 H), 3.40 - 3.47 (m, 1 H), 3.61 (td, J=8.0, 5.9 Hz, 1 H), 3.66 - 3.76 (m, 3 H), 3.92 (s, 3 H), 6.75 (d, J=9.7 Hz, 1 H), 7.34 (d, J=1.8 Hz, 1 H), 7.35 - 7.38 (m, 1 H), 7.47 (d, J=11.7 Hz, 1 H), 7.55 (d, J=5.5 Hz, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 10.12 (s, 1 H).

Compound 33: N-(3,4-difluoromethyl-phenyl)(isopropylsulfamoyl)methyl-pyrrole carboxamide 3,4-difluoromethylbenzoic acid (Alfa Aesar, H32313-03, 4.8 g, 26.9 mmol) was ved in t-BuOH (100 mL). NEt3 (4.1 mL, 29.6 mmol) was added followed by diphenylphosphoryl azide (7.5 g, 27.4 mmol) and the reaction mixture was refluxed overnight. The e was concentrated and the obtained e was purified by silica gel column chromatography using a gradient from 30 till 100% EtOAc in heptane. The product fractions were concentrated in vacuo yielding tert-butyl N-(3,4-difluoromethyl-phenyl)carbamate (4.15 g) as a white powder. 1H NMR (400 MHz, DMSO-d6)  ppm 1.47 (s, 9 H), 2.22 (d, J=1.8 Hz, 3 H), 7.11 (d, J=5.1 Hz, 1 H), 7.26 - 7.38 (m, 1 H), 9.47 (br. s., 1 H). To a tert-butyl N-(3,4-difluoromethylphenyl )carbamate (4.15 g) in CH2Cl2 (100 mL), HCl (6M in iPrOH, 13.7 mL) was added and the mixture was stirred for 3 hours. The reaction e was concentrated in vacuo. The white solid residue was dissolved in water (100 mL), alkalinized with 1M NaOH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated yielding 3,4-difluoro- yl-aniline as a colorless oil which was stored under nitrogen in the dark and used a such. 1H NMR (400 MHz, DMSO-d 6)  ppm 2.13 (d, J=2.2 Hz, 3 H), 5.11 (s, 2 H), 6.16 - 6.23 (m, 1 H), 6.31 (ddd, J=12.9, 6.5, 2.8 Hz, 1 H). 3,4-difluoromethyl-aniline (209 mg, 1.5 mmol) dissolved in toluene (20 mL) was added dropwise to a solution of 4-chlorosulfonylmethylpyrrolecarbonylchloride (353 mg) in toluene (30 mL) at reflux. The reaction mixture was ed 2 hours, allowed to cool to room temperature and concentrated in vacuo.

Isopropylamine (216 mg, 3.7 mmol) dissolved in CH2Cl2 (50 mL) was added and the reaction mixture was stirred overnight and next trated in vacuo. The obtained e was dissolved in hot methanol (100 mL) and H2O was added. The formed precipitate was filtered off and dried in vacuo, resulting in compound 33 (385 mg). Method A; Rt: 1.83 min. m/z : 370.0 (M-H)- Exact mass: 371.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.4 Hz, 6 H), 2.28 (d, J=2.0 Hz, 3 H), 3.21 - 3.30 (m, 1 H), 3.91 (s, 3 H), 7.19 (d, J=7.0 Hz, 1 H), 7.31 (d, J=1.8 Hz, TIP 296 PCT 1 H), 7.41 (d, J=5.9 Hz, 1 H), 7.54 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=12.9, 7.1, 2.4 Hz, 1 H), 10.13 (s, 1 H).

Compound 34: N-(3,4-difluoromethyl-phenyl)methyl[[(1R)methylpropyl]- sulfamoyl]pyrrolecarboxamide Compound 34 (1.18 g) was prepared similarly as bed for compound 33, using (R)-(-) aminobutane instead of iPrNH2. Method A; Rt: 1.87 min. m/z : 384.1 (M-H)- Exact mass: 385.1. 1H NMR (400 MHz, DMSO-d 6)  ppm 0.76 (t, J=7.4 Hz, 3 H), 0.96 (d, J=6.6 Hz, 3 H), 1.29 - 1.42 (m, 2 H), 2.28 (d, J=1.8 Hz, 3 H), .12 (m, 1 H), 3.91 (s, 3 H), 7.15 (d, J=7.7 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.42 (d, J=5.7 Hz, 1 H), 7.54 (d, J=1.8 Hz, 1 H), 7.67 (ddd, J=13.0, 7.0, 2.4 Hz, 1 H), 10.11 (s, 1 H). nd 35: N-(3,4-difluoromethyl-phenyl)methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide 3,4-difluoromethyl-aniline (600 mg, 4.2 mmol) dissolved in toluene (20 mL) was added dropwise to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (1.0 g) in toluene (50 mL) at reflux. The reaction mixture was refluxed 2 hour, allowed to cool to room temperature and concentrated in vacuo. A e of 3-methyloxetanamine hydrochloride (570 mg, 4.6 mmol) and DIPEA (1.8 mL, 10.5 mmol) dissolved in CH2Cl2 (100 mL) was added and the reaction mixture was stirred ght and next concentrated in vacuo. The obtained residue was dissolved in hot methanol (200 mL) and H2O was added. The formed precipitate was filtered off and dried in vacuo, resulting in compound 35 (1.1 g) as a white powder. Method A; Rt: 1.66 min. m/z : 398.1 (M-H)- Exact mass: 399.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 2.28 (d, J=2.0 Hz, 3 H), 3.91 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.33 (d, J=1.8 Hz, 1 H), 7.41 (d, J=5.9 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1 H), 7.96 (s, 1 H), 10.13 (s, 1 H).

Compound 36: N-(3,4-difluoromethyl-phenyl)[[(1R)hydroxymethyl-ethyl]- sulfamoyl]methyl-pyrrolecarboxamide TIP 296 PCT 3,4-difluoromethyl-aniline (600 mg, 4.2 mmol) dissolved in e (20 mL) was added dropwise to a on of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (353 mg) in e (100 mL) at reflux. The reaction mixture was refluxed 2 hours, allowed to cool to room temperature and concentrated in vacuo. D-alaninol (787 mg, 10.5 mmol) in CH2Cl2 (100 mL) was added, followed by CH3CN (50 mL) and the reaction mixture was stirred overnight and next concentrated in vacuo. The obtained residue was dissolved in warm methanol (50 mL) and H2O was added. The formed precipitate was filtered off and dried in vacuo, ing in compound 36 (1.16 g).

Method A; Rt: 1.57 min. m/z : 386.0 (M-H)- Exact mass: 387.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.98 (d, J=6.2 Hz, 3 H), 2.28 (d, J=2.0 Hz, 3 H), 3.07 - 3.20 (m, 2 H), 3.32 - 3.39 (m, 1 H), 3.91 (s, 3 H), 4.65 (t, J=5.5 Hz, 1 H), 7.10 (d, J=6.8 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.42 (d, J=5.9 Hz, 1 H), 7.55 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1 H), 10.13 (s, 1 H).

Compound 37: N-(3,4-difluoromethyl-phenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide Compound 37 was prepared rly as described for compound 35, using (S)-(-) aminotetrahydrofuran p-toluenesulfonate instead of 3-methyloxetanamine hydrochloride.

After on, the obtained residue was dissolved in EtOAc (300 mL), washed with 1M HCl (2x), water and saturated NaHCO3. The solution was dried over magnesium sulphate, filtered and concentrated. The obtained residue was recrystallized from hot methanol (50 mL) upon addition of water. nd 37 (464 mg) was obtained as white fluffy crystals after drying in vacuo. Method A; Rt: 1.65 min. m/z : 398.1 (M-H)- Exact mass: 399.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.66 - 1.77 (m, 1 H), 1.90-2.03 (m, 1 H), 2.28 (d, J=1.8 Hz, 3 H), 3.40 - 3.47 (m, 1 H), 3.61 (td, J=8.0, 5.9 Hz, 1 H), 3.66 - 3.76 (m, 3 H), 3.92 (s, 3 H), 7.33 (d, J=2.0 Hz, 1 H), 7.41 (d, J=5.9 Hz, 1 H), 7.56 (d, J=5.5 Hz, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1 H), 10.14 (s, 1 H).

Compound 38: 4-(tert-butylsulfamoyl)-N-(3,4-difluoromethyl-phenyl)methyl-pyrrole carboxamide TIP 296 PCT Compound 38 (399 mg) was prepared similarly as described for compound 33, using tertbutylamine instead of iPrNH2. Method A; Rt: 1.86 min. m/z : 384.1 (M-H)- Exact mass: 385.1. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.17 (s, 9 H), 2.28 (d, J=2.0 Hz, 3 H), 3.90 (s, 3 H), 7.11 (s, 1 H), 7.31 (d, J=1.8 Hz, 1 H), 7.38 - 7.44 (m, 1 H), 7.52 (d, J=1.5 Hz, 1 H), 7.66 (ddd, J=1.0 Hz, 1 H), 10.11 (s, 1 H).

Compound 39: N-[3-(difluoromethyl)fluoro-phenyl]methyl[(3-methyloxetan yl)sulfamoyl]pyrrolecarboxamide To 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (1.6 g) in toluene (100 mL) at reflux, 3-(difluoromethyl)fluoro-aniline (1 equiv) was added dropwise (0.1 mL/min). After addition, the mixture was further refluxed for 15 minutes. The reaction mixture, containing 5-[[3- (difluoromethyl)fluoro-phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride was allowed to reach room temperature and was used as such in the next step. To half of the above ed solution ning (difluoromethyl)fluoro-phenyl]carbamoyl]methyl-pyrrole sulfonyl chloride, 3-methyloxetanamine hydrochloride (449 mg, 3.6 mmol) and DIPEA (1.14 mL, 6.6 mmol) dissolved in CH2Cl2 (5 mL) were added and the reaction mixture was d overnight. More DIPEA (1.14 mL, 6.6 mmol) was added and the mixture was d over weekend. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient yielding compound 39 (681 mg) as a white powder.

Method C; Rt: 1.60 min. m/z : 416.1 (M-H)- Exact mass: 417.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.22 (t, J=54.4 Hz, 1 H), 7.32 - 7.40 (m, 2 H), 7.59 (d, J=1.8 Hz, 1 H), 7.84 - 7.93 (m, 1 H), 7.96 (s, 1 H), 8.05 (dd, J=6.3, 2.5 Hz, 1 H), 10.25 (s, 1 H).

TIP 296 PCT Compound 40: N-[3-(difluoromethyl)fluoro-phenyl][[(1R)hydroxymethylethyl ]sulfamoyl]methyl-pyrrolecarboxamide Compound 40 (670 mg) was prepared similarly as described for compound 39 using inol instead of 3-methyloxetanamine hydrochloride. Method C; Rt: 1.50 min. m/z : 404.0 (M-H)- Exact mass: 405.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.98 (d, J=6.2 Hz, 3 H), 3.05 - 3.21 (m, 2 H), 3.33 - 3.38 (m, 1 H), 3.92 (s, 3 H), 4.66 (t, J=5.5 Hz, 1 H), 7.10 (d, J=6.8 Hz, 1 H), 7.22 (t, J=54.4 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.36 (t, J=9.5 Hz, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.89 (dd, J=8.8, 3.3 Hz, 1 H), 8.06 (dd, J=6.3, 2.5 Hz, 1 H), 10.26 (s, 1 H).

Compound 41: N-[4-fluoro(trifluoromethyl)phenyl][[(1R)hydroxymethylethyl ]sulfamoyl]methyl-pyrrolecarboxamide Compound 41 (376 mg) was prepared similarly as described for compound 40 using 4-fluoro (trifluoromethyl)aniline instead of 3-(difluoromethyl)fluoro-aniline.

Method B; Rt: 0.93 min. m/z : (M-H)- Exact mass: 423.1. 1H NMR (400 MHz, 6)  ppm 0.98 (d, J=6.2 Hz, 3 H), 3.07 - 3.20 (m, 2 H), 3.34 - 3.39 (m, 1 H), 3.92 (s, 3 H), 4.66 (t, J=5.5 Hz, 1 H), 7.11 (d, J=6.8 Hz, 1 H), 7.35 (d, J=1.8 Hz, 1 H), 7.50 (t, J=9.9 Hz, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.99 - 8.08 (m, 1 H), 8.20 (dd, J=6.6, 2.6 Hz, 1 H), 10.34 (s, 1 H).

Compound 42: N-[4-fluoro(trifluoromethyl)phenyl]methyl[[(3S)-tetrahydrofuran yl]sulfamoyl]pyrrolecarboxamide Compound 42 (569 mg) was prepared similarly as described for nd 41, using (S)-(-) aminotetrahydrofurantoluene-sulfonate instead of D-alaninol. Method C; Rt: 1.77 min. m/z : 434.1 (M-H)- Exact mass: 435.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.67 - 1.77 (m, 1 H), 1.91 - 2.04 (m, 1 H), 3.40 - 3.48 (m, 1 H), 3.61 (td, J=8.0, 5.9 Hz, 1 H), 3.66 - 3.77 (m, 3 H), TIP 296 PCT 3.93 (s, 3 H), 7.36 (d, J=2.0 Hz, 1 H), 7.50 (t, J=9.8 Hz, 1 H), 7.57 (d, J=5.7 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.99 - 8.07 (m, 1 H), 8.20 (dd, J=6.4, 2.6 Hz, 1 H), 10.35 (s, 1 H).

Compound 43: N-[4-fluoro(trifluoromethyl)phenyl]methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide Compound 43 (164 mg) was prepared similarly as described for compound 41, using yl- 3-oxetanamine hydrochloride instead of D-alaninol. After silica gel column chromatography, the compound was recrystallized from MeOH. Method A; Rt: 1.73 min. m/z : 434.0 (M-H)- Exact mass: 435.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.2 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.36 (d, J=2.0 Hz, 1 H), 7.50 (t, J=9.8 Hz, 1 H), 7.61 (d, J=1.8 Hz, 1 H), 7.97 (s, 1 H), 7.99 - 8.07 (m, 1 H), 8.20 (dd, J=6.5, 2.5 Hz, 1 H), 10.34 (s, 1 H). nd 44: luoro(trifluoromethyl)phenyl](isopropylsulfamoyl)methyl- pyrrolecarboxamide Compound 44 (146 mg) was prepared similarly as described for compound 41, using isopropylamine instead of D-alaninol. After silica gel column chromatography, the compound triturated with MeOH and diisopropylether, resulting in compound 44 as a white solid. Method B; Rt: 1.06 min. m/z : 406.1 (M-H)- Exact mass: 407.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 3.22 - 3.29 (m, 1 H), 3.92 (s, 3 H), 7.20 (d, J=7.0 Hz, 1 H), 7.35 (d, J=2.0 Hz, 1 H), 7.50 (t, J=9.8 Hz, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.98 - 8.07 (m, 1 H), 8.20 (dd, J=6.4, 2.6 Hz, 1 H), 10.33 (s, 1 H).

Compound 45: N-[3-fluoro(trifluoromethyl)phenyl]methyl[(3-methyloxetan- 3-yl)sulfamoyl]pyrrolecarboxamide TIP 296 PCT 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (800 mg) was dissolved in toluene (25 mL) and brought to reflux. 3-aminofluorobenzotrifluoride (592 mg, 3.3 mmol) was added dropwise. After on the reaction was ed for 4 hours. The on mixture was allowed to reach room temperature and 3-methyloxetanamine hydrochloride (408 mg, 3.3 mmol) and DIPEA (1.4 mL , 8.3 mmol) dissolved in CH2Cl2 (2 mL) were added and the reaction mixture was stirred overnight. More 3-methyloxetanamine hloride (0.5 equiv) and DIPEA (0.5 equiv) in CH2Cl2 (2 mL) was added and the reaction mixture was stirred 2 hours more. The on mixture was brought to 50ºC and d for 2 hours. The les were removed under reduced pressure and the residue was redissolved in EtOAc (30 mL). The formed precipitates were filtered off and the filtrate was evaporated to dryness. The obtained residue was triturated in MeOH (15 mL), filtered and dried in vacuo, yielding compound 45 (704 mg) as a white powder. Method B; Rt: 1.05 min. m/z : 434.2 (M-H)- Exact mass: 435.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=6.2 Hz, 2 H), 7.37 (d, J=8.6 Hz, 1 H), 7.40 (d, J=2.0 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.91 - 8.02 (m, 3 H), 10.46 (s, 1 H).

Compound 46: N-(3-bromo-4,5-difluoro-phenyl)(isopropylsulfamoyl)methyl-pyrrole carboxamide 3-bromo-4,5-difluoroaniline (2.6 g, 12.8 mmol) in toluene (20 mL) was added dropwise to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (3100 mg, 12.8 mmol) in toluene (160 mL) at reflux. The reaction mixture was refluxed 2 hours and next allowed to cool to room temperature. To one third of the above mixture containing 5-[(3-bromo-4,5-difluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride, Isopropylamine (7.3 mL, 85.4 mmol) and DIPEA (2.2 mL, 12.8 mmol) in CH2Cl2 (70 mL) was added. The reaction mixture was stirred at room temperature. After a few seconds the homogeneous e became a suspension.

The solids were filtered, washed with CH2Cl2 (4 mL) and dried overnight in vacuo resulting in compound 46 (1.02 g) as an off white powder. Method B; Rt: 1.10 min. m/z : 436.1 (M-H)- Exact mass: 437.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 3.14 - 3.30 (m, 1 H), 3.92 (s, 3 H), 7.22 (d, J=7.0 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.74 - 7.95 (m, 2 H), 10.27 (s, 1 H).

Compound 47: N-(3-bromo-4,5-difluoro-phenyl)methyl[[(1R)methylpropyl]- sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 47 was ed similarly as described for compound 46 using (R)-(-)aminobutane (4 equiv) instead of isopropylamine. After addition of (R)-(-)aminobutane, the mixture was stirred overnight. The solid was filtered, washed with CH2Cl2 and dried in vacuo, resulting in nd 47 (1.17 g) as an off-white solid. Method B; Rt: 1.15 min. m/z : 448.0 (M-H)- Exact mass: 449.0. 1H NMR (400 MHz, DMSO-d6)  ppm 0.76 (t, J=7.5 Hz, 3 H), 0.96 (d, J=6.6 Hz, 3 H), 1.24 - 1.46 (m, 2 H), 3.07 (spt, J=6.7 Hz, 1 H), 3.91 (s, 3 H), 7.17 (d, J=7.5 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.78 - 7.95 (m, 2 H), 10.26 (s, 1 H).

Compound 48: N-(3-bromo-4,5-difluoro-phenyl)methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide Compound 48 was prepared similarly as described for nd 46 using 3-methyl oxetanamine (4 equiv) instead of isopropylamine. After addition of 3-methyloxetanamine, the mixture was stirred for 5 days. The formed precipitate was filtered, washed with CH2Cl2 and dried in vacuo, resulting in compound 48 (707 mg) as an off white powder. Method B; Rt: 1.00 min. m/z : 464.0 (M-H)- Exact mass: 465.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.59 (d, J=6.2 Hz, 2 H), 7.35 (d, J=2.0 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.84 (td, J=6.3, 2.5 Hz, 1 H), 7.89 (ddd, J=7.7, 5.1, 2.4 Hz, 1 H), 7.98 (br. s., 1 H), 10.28 (br. s., 1 H). nd 49: methyl 2-[[5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrol yl]sulfonylamino]methyl-propanoate -[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.96 g) was stirred in CH2Cl2 (90 mL). DIPEA (1.0 mL, 5.9 mmol) and alpha-aminoisobutyric acid methyl ester hydrochloride (1 g, 6.5 mmol) were added under osphere at room temperature. The TIP 296 PCT reaction mixture was d for 3 hour. More DIPEA (2 mL) was added and the reaction mixture was stirred for 80 hours. Next, the reaction mixture was washed with 1M HCl (100 mL). The organic layer was dried on Na2SO4. After evaporation of the solvent, the e was purified by silica gel column chromatography (EtOAc/Heptane 0/100 to 100/0). The desired fractions were combined, the solvent was evaporated and the obtained solid dried in vacuo. Compound 49 (1.6 g) was ed as a white solid. Method A; Rt: 1.70 min. m/z : 410.1 (M-H)- Exact mass: 411.1. 1H NMR (360 MHz, DMSO-d 6)  ppm 1.35 (s, 6 H), 2.23 (d, J=1.1 Hz, 3 H), 3.54 (s, 3 H), 3.90 (s, 3 H), 7.10 (t, J=9.1 Hz, 1 H), 7.29 (d, J=1.5 Hz, 1 H), 7.48- 7.56 (m, 2 H), 7.65 (dd, J=7.0, 2.6 Hz, 1 H), 7.85 (s, 1 H), 10.04 (s, 1 H).

Synthesis of yl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid Chlorosulfonic acid (80 mL) was cooled to 0°C and methyl 1-methylpyrrolecarboxylate (20 g, 143.73 mmol) was added dropwise. After addition, the mixture was allowed to reach room temperature and stirred for r hour. The resulting mixture was added drop wise to a mechanically stirred, temperature controlled, ice-water mixture (1500 mL) keeping the temperature under 5°C. A white precipitation was formed. The obtained aqueous mixture was extracted using dichloromethane (3 x 500 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl 4-(chlorosulfonyl)methyl-1H- pyrrolecarboxylate (29.4 g) as a white powder which was used as such. Methyl 4- (chlorosulfonyl)methyl-1H-pyrrolecarboxylate (5 g, 1.04 mmol) was dissolved in acetonitrile (50 mL). diisopropylethylamine (9.06 mL, 52.6 mmol) was added, followed by 3- oxetanamine (1.92 g, 22.1 mmol) and the resulting mixture was refluxed for 2 hours.

Then, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and this was washed with HCl (2 x 150 mL).

The organics were dried on sodium sulphate, filtered and trated in vacuo yielding methyl 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylate (6.07 g) as a beige powder which was used as such. Method B; Rt: 0.63 min. m/z : 287.1 (M-H)- Exact mass: 288.1.

Methyl 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylate (6.07 g, 21.05 mmol) was dissolved in tetrahydrofuran (60 mL). Lithium hydroxide (0.76 g, 31.58 mmol) in distilled water (8 mL) was added, followed by ol (3 mL). The resulting mixture was stirred for 72 hours. Next, it was concentrated until only water remained and extra distilled water (15 mL) was added. After neutralization with hloric acid (1M / aq / 31.6 mL, 31.58 mmol). The resulting mixture was ted using 2-methyltetrahydrofuran (3 x 20 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding 1- TIP 296 PCT methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid (5.77 g) as a bright white powder which was used as such. Method B; Rt: 0.26 min. m/z : 273.1 (M-H)- Exact mass: 274.1 Compound 50: N-(3-cyanofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide A tube was charged with 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid (0.25 g, 0.91mmol) and HATU (0.36 g, 0.96 mmol). methylformamide (1 mL) and diisopropylethylamine (0.47 mL, 2.73 mmol) were added and the e was stirred for 30 minutes. Next, 5-aminofluorobenzonitrile (0.26 g, 1.82 mmol) was added at once and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was added to distilled water (10 mL) under stirring and the mixture was allowed to stir for 1 hour. A precipitation was formed which was collected on a filter and dried in vacuo, yielding nd 50 (0.25 g) as a white powder. Method B; Rt: 0.83 min. m/z : 391.1 (M-H)- Exact mass: 392.1. 1H NMR (400 MHz, DMSO-d 6) ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.2 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.35 (d, J=1.5 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.61 (d, J=1.5 Hz, 1 H), 7.93 - 8.07 (m, 2 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 10.36 (s, 1 H).

Compound 51: N-[4-cyano(trifluoromethyl)phenyl]methyl[(3-methyloxetanyl)- sulfamoyl]-1H-pyrrolecarboxamide A tube was charged with 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid (0.2 g, 0.73 mmol) and HATU (0.29 g, 0.77 mmol). N,N-dimethylformamide (1 mL) and diisopropylethylamine 0.38 mL, 2.19 mmol) were added and the mixture was d for 30 minutes. To this was added 4-amino(trifluoromethyl)benzonitrile (0.27 g, 1.46 mmol) at once and the resulting mixture was stirred at room temperature for 2 hours. The ing mixture was added to distilled water (10 mL) under stirring. The resulting mixture was allowed to stirr for 1 hour and then it was extracted using 2-methyl tetrahydrofuran (3 x 20 mL). The ed extracts were dried on sodium sulphate, filtered and concentrated in vacuo. The obtained crude was dissolved in dichloromethane (3 mL) and loaded directly on a silica plug. This was purified TIP 296 PCT using column chromatography (gradient elution EtOAc/heptane 0:100 to 100:0) The d fractions were tratcd in vacuo and dried in vacuo, ing in compound 51 (18.1 mg) as a bright white powder. Method A; Rt: 1.67 min. m/z : 440.9 (M-H)- Exact mass: 442.1 1H NMR (400 MHz, DMSO-d 6) ppm 1.54 (s, 3 H), 3.94 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.41-7.46 (m, 1 H), 7.62 - 7.68 (m, 1 H), 8.00 (br. s., 1 H), 8.07 - 8.14 (m, 1 H), 8.16 - 8.23 (m, 1 H), 8.34 - 8.45 (m, 1 H), 10.69 (br. s., 1 H).

Compound 52: N-(3-cyano-4,5-difluoro-phenyl)(isopropylsulfamoyl)methyl-pyrrole carboxamide A degassed suspension of compound 46 (400 mg, 0.917 mmol), Zn(CN)2 (93.0 mg, 0.79 mmol) and tetrakis(triphenylphosphine)palladium (57.3 mg, 0.050 mmol) in DMF (3 mL) was stirred at 75°C overnight. The e was cooled to room temperature and the solids were filtered off and washed with DMF (2 mL). The filtrate was then poured into water (50 mL). The precipitates were filtered and washed with water to afford an off white powder. This solid was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 50%) to afford a white powder (310 mg). This white powder is purified using Prep. LCMS. (Hypersyl C18 BDS- 3µm,100 x 4.6 mm) Mobile phase (NH4HCO3 0.2% in water, methanol) the desired fractions were combined and evaporated to dryness, dissolved in methanol again and ated to dryness and dried in vacuo to afford nd 52 (27.8 mg) as a white powder. Method B; Rt: 1.01 min. m/z : 381.1(M-H)- Exact mass: 382.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.02 (d, J=6.6 Hz, 6 H), 3.20 - 3.30 (m, 1 H), 3.92 (s, 3 H), 7.23 (br. s., 1 H), 7.34 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.98 (dt, J=4.6, 2.2 Hz, 1 H), 8.14 (ddd, J=12.9, 7.5, 2.5 Hz, 1 H), 10.47 (br. s., 1 H).

Compound 53: 4-(tert-butylsulfamoyl)-N-(3-cyanofluoro-phenyl)methyl-pyrrole carboxamide -aminofluorobenzonitrile (1034 mg, 7.6 mmol) dissolved in toluene (10 mL) was added dropwise during 5 minutes to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl TIP 296 PCT chloride (1839 mg, 7.6 mmol) in toluene (190 mL) at reflux. The reaction mixture was refluxed 3 hours and concentrated in vacuo yielding crude 5-[(3-cyanofluoro-phenyl)carbamoyl] methyl-pyrrolesulfonyl chloride as a brown powder which was used as such. (2.74g). 1H NMR (400 MHz, acetonitrile-d3)  ppm 3.97 (s, 3 H), 7.24 - 7.29 (m, 1 H), 7.42 (d, J=2.0 Hz, 1 H), 7.75 (d, J=1.8 Hz, 1 H), 7.79 - 7.86 (m, 2 H), 8.93 (br. s, 1 H).A on of 5-[(3-cyano fluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (892 mg, 2.48 mmol) and tylamine (544 mg, 7.44 mmol) in acetonitrile (100 mL) wer stirred overnight. Water was added untill crystallisation started. The crystals were ed of and dried overnight in vacuo at 50°C, resulting in compound 53 (631 mg) Method A, Rt: 1.74 min m/z: 377.1 (M-H)- Exact mass: 378.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.17 (s, 9 H), 3.92 (s, 3 H), 7.15 (s, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.52 - 7.56 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.96 (d, J=11.2 Hz, 1 H), 7.99 - 8.01 (m, 1 H), 10.44 (s, 1 H).

Compound 54: N-(3-cyanofluoro-phenyl)methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide A solution of 5-[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (924 mg, 2.57 mmol) and 3-methyloxetanamine (559 mg, 6.4 mmol) in acetonitrile (100 mL) was stirred ght. Water was added untill crystallisation d. The crystals were filtered of and dried overnight in vacuo at 50°C, resulting in compound 54 (630 mg) Method A, Rt: 1.52 min m/z: 391.1 (M-H)- Exact mass: 392.1 1H NMR (400 MHz, DMSO-d 6) ppm 1.54 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.38 (d, J=2.0 Hz, 1 H), 7.52 - 7.58 (m, 1 H), 7.64 (d, J=1.5 Hz, 1 H), 7.93 - 7.98 (m, 1 H), 7.98 - 8.01 (m, 2 H), 10.46 (s, 1 H).

Compound 55: N-(3-cyanophenyl)methyl[(3-methyloxetanyl)sulfamoyl]pyrrole carboxamide 3-aminobenzonitrile (360 mg, 3.0 mmol) dissolved in toluene (10 mL) was added dropwise to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (752 mg, 3.1 mmol) in toluene (90 mL) at reflux. The reaction mixture was refluxed 2.5 hours, decanted hot and TIP 296 PCT concentrated in vacuo yielding crude 5-[(3-cyanophenyl)carbamoyl]methyl-pyrrolesulfonyl chloride. A solution of 3-methyloxetanamine (0.271 g, 3.11 mmol ) in CH3CN (10 mL, p.a. dried on molecular sieves ) was added to a stirring solution of 5-[(3-cyanophenyl)carbamoyl] methyl-pyrrolesulfonyl chloride (1.00 g, 3.11 mmol ) in CH3CN (40 mL, p.a. dried on molecular sieves ). DIPEA (1.07 mL, 6.21 mol ) was added, and the on mixture was stirred at room temperature for 18 hours. The volatiles were evaporated. The residue was purified by silica gel column chromatography using EtOAc-heptane 0/100 to 100/0 as eluent. The desired ons were combined and evaporated. The residue was stirred in CH2Cl2 (4 mL), filtered off, washed with CH2Cl2 (3x), and dried in vacuo at 50°C, resulting in nd 55 (0.43 g).

Method A; Rt: 1.42 min. m/z: 373.0 (M-H)- Exact mass: 374.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.55 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.38 (d, J=2.0 Hz, 1 H), 7.50 - 7.59 (m, 2 H), 7.61 (d, J=1.5 Hz, 1 H), .10 (m, 2 H), 8.16 - 8.24 (m, 1 H), .00 - 10.67 (m, 1 H).

Compound 56: N-(2,6-dideuteriofluoromethyl-phenyl)methyl[(3-methyloxetan yl)sulfamoyl]pyrrolecarboxamide 4-fluoromethyl-aniline (1386 mg, 11.075 mmol), 1M DCl (2075 mg, 11.075 mmol) in 11 mL D2O was heated in the microwave at 180°C during 30 s. The reaction mixture was diluted with distilled water (50 mL), alkalanised with 1M NaOH, diluted with brine untill t separates as oil and extracted with Et2O. The organic layer was dried over magnesium sulphate, filtered and concentrated yielding 2,6-dideuteriofluoromethyl-aniline (1068 mg) as a light brown colored oil which used as such. 1H NMR (400 MHz, DMSO-d 6) ppm 2.09 (d, J=2.0 Hz, 3 H), 4.79 (br. s., 2 H), 6.75 (d, J=9.9 Hz, 1 H). 2,6-dideuteriofluoromethyl-aniline (1068mg, 8.40 mmol) dissolved in toluene (10 mL) was added dropwise during 5 minutes to a solution of 4-chlorosulfonylmethylpyrrolecarbonyl chloride (2033 mg, 8.40 mmol) in toluene (210 mL) at . The reaction mixture was refluxed 90 minutes and concentrated in vacuo yielding crude 6-dideuterio fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride as a grey powder which was used as such. (2810 mg). Method A,; Rt: 1.91 min m/z: 331.0 (M-H)- Exact mass: 332.0. 1H NMR (400 MHz, CHLOROFORM-d)  ppm 2.30 (d, J=2.0 Hz, 3 H), 4.05 (s, 3 H), 7.01 (d, J=9.2 Hz, 1 H), 7.14 (d, J=1.8 Hz, 1 H), 7.50 (d, J=1.5 Hz, 1 H), 7.57 (br. s., 1 H). 3- methyloxetanamine (491 mg, 5.63 mmol) and DIPEA (0.97 mL, 5.63 mmol) were added to a solution of 5-[(2,6-dideuteriofluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (750 mg, 2.25 mmol) in dichloromethane (100 mL) and stirred overnight and TIP 296 PCT concentrated in vacuo at 50°C. The residue was dissolved in EtOAc (150 mL), washed twice with 1M HCl, water and ted NaHCO3 solution. The solution was dried over sodium sulphate, filtered and concentrated. The residue was dissolved in warm EtOAc (75 mL) and the product crystallized upon addition of heptane (350 mL) The white crystals were ed off and dried overnight in vacuo at 50°C, resulting in compound 56 (532 mg). Method A, Rt: 1.56 min m/z: 382.1 (M-H)- Exact mass: 383.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.55 (s, 3 H), 2.23 (d, J=2.0 Hz, 3 H), 3.91 (s, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.09 (d, J=9.5 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 7.94 (s, 1 H), 10.02 (s, 1 H).

Compound 57: N-(3-chloro-4,5-difluoro-phenyl)(isopropylsulfamoyl)methyl-pyrrole carboxamide 3-chloro-4,5-difluorobenzoic acid (1011 mg, 52.5 mmol) was dissolved in tert-butyl alcohol (200 mL). Triethylamine (8 mL, 57.8 mmol) was added followed by ylphosphoryl azide (14.74 g, 53.6 mmol) and the reaction mixture was refluxed overnight. The reaction e was concentrated and purified by column chromatography on silica using a gradient from 10 till 100% EtOAc in heptane and again with 10% CH2Cl2 in heptane till 100% CH2Cl2. The product fractions were trated in vacuo yielding tert-butyl N-(3-chloro-4,5-difluorophenyl )carbamate as a white powder (10.68 g). Method A. Rt: 2.09 min m/z: 262.0 (M-H)- Exact mass: 263.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.48 (s, 9 H), 7.37 - 7.57 (m, 2 H), 9.74 (s, 1 H). HCl (6 M in iPrOH) (20 mL, 120 mmol) was added to tert-butyl N-(3-chloro-4,5- ro-phenyl)carbamate (10.68 g, 40.5 mmol) dissolved in dichloromethane (200 mL) and stirred overnight. The reaction mixture was concentrated. The white solid e was dissolved in water (100 mL), nised with NaOH 1M and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated yielding 3-chloro-4,5-difluoro-aniline (6.53 g) as a colorless oil which was stored under nitrogen in the dark. 1H NMR (400 MHz, DMSO-d6) ppm .53 (s, 2 H), 6.34 - 6.61 (m, 2 H). 3-chloro-4,5-difluoro-aniline (3.43g, 20.95 mmol) dissolved in toluene (10 mL) was added dropwise during 5 s to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (5.07 g, 20.95 mmol) in toluene (525 mL) at reflux. The on mixture was refluxed 90 minutes and then concentrated in vacuo yielding crude 5-[(3-chloro-4,5-difluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride (7.83 g) as a brown powder which was used as such. A mixture of 5-[(3-chloro-4,5-difluorophenyl)carbamoyl]methyl-pyrrole sulfonyl chloride (1002 mg, 2.58 mmol) and isopropylamine (457 mg, 7.73 mmol) in acetonitrile (100 mL) was stirred 60 minutes. Water was added untill crystallisation began. The beige TIP 296 PCT crystals were filtered off and dried in vacuo overnight at 50°C, resulting in compound 57 (706 mg). Method A, Rt: 1.88 min m/z: 390.0 (M-H)- Exact mass: 391.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.02 (d, J=6.6 Hz, 6 H), 3.20 - 3.30 (m, 1 H), 3.92 (s, 3 H), 7.22 (d, J=6.8 Hz, 1 H), 7.33 (d, J=2.0 Hz, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 10.29 (s, 1 H).

Compound 58: 4-(tert-butylsulfamoyl)-N-(3-chloro-4,5-difluoro-phenyl)methyl-pyrrole carboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl de (1008 mg, 2.59 mmol), tert-butylamine (569 mg, 7.78 mmol) in acetonitrile (100 mL) was stirred 60 minutes. Water was added untill crystallisation began. The beige crystals were filtered off and dried in vacuo overnight at 50°C, resulting in compound 58 (773 mg) Method A: Rt: 1.95 min m/z: 404.0 (M-H)- Exact mass: 405.1 1H NMR (400 MHz, DMSO-d6) ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.14 (s, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.55 (d, J=1.8 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 10.28 (s, 1 H).

Compound 59: N-(3-chloro-4,5-difluoro-phenyl)methyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.0 g, 2.57 mmol) yloxetanamine (560 mg, 6.43 mmol) and acetonitrile (100 mL) was refluxed 30 minutes. The reaction mixture was cooled to 20°C and d with water (350 mL).

The product crystallized, was filtered off and dried in vacuo overnight yielding compound 59 as a beige powder (677 mg). Method A, Rt: 1.77 min m/z: 418.0 (M-H)- Exact mass: 419.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=6.2 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.74 - 7.87 (m, 2 H), 7.98 (s, 1 H), 10.30 (s, 1 H).

Compound 60: N-(3-chloro-4,5-difluoro-phenyl)methyl[[(1R)-2,2,2-trifluoromethyl- ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1008 mg, 2.59 mmol), (R)-1,1,1-trifluoropropylamine (1026 mg, 9.07 mmol) in acetonitrile (100 mL) was refluxed overnight. Water was added untill crystallisation started. The beige crystals were ed of and dried overnight in vacuo at 50°C, resulting in compound 60 (673 mg). Method A Rt: 1.92 min m/z: 444.0 (M-H)- Exact mass: 445.0. 1H NMR (400 MHz, DMSO- d6) ppm 1.08 (d, J=7.0 Hz, 3 H), 3.83 - 4.01 (m, 4 H), 7.36 (d, J=1.8 Hz, 1 H), 7.67 (d, J=1.8 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 8.19 (d, J=8.8 Hz, 1 H), 10.32 (s, 1 H).

Alternative synthesis of compound 60: 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (8.0 g, 26.7 mmol), HATU (12.7 g, 33.3 mmol), Et3N (9.3 mL, 66.6 mmol) and 3-chloro-4,5-difluoroaniline (5.44 g, 33.3 mmol) in DMF (30 mL) was stirred overnight at room temperature. The solution was subjected directly to column chromatography on a 330 g Reveleris cartridge in a Biotage system using a nt from 10 till 100% EtOAc in heptane. The product fractions were concentrated and purified again in the same way. The product fractions were concentrated, dissolved in warm EtOAc en the product crystallized upon addition of heptane. The white crystals were filtered off and dried over weekend in vacuo at 50°C. The crystals (7.97 g) were ved in warm methanol (150 mL) and the product crystallized upon addition of water. The product was ed off and dried in vacuo at 50°C ght, resulting in compound 60 (7.44 g). [α]20365= -9.5 ° (c 1.30 w/v %, MeOH). Differential scanning metry: From 30 to 300 °C at °C/min: peak at 204.6°C.

Compound 65: N-(3-chloro-4,5-difluoro-phenyl)[(3,3-difluoromethyl-cyclo- butyl)sulfamoyl]methyl-pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (622 mg, 1.69 mmol) 3,3-difluoromethyl-cyclobutanamine hydrochloride (306 mg, 2.527 mmol), DIPEA (0.87 mL, 5.06 mmol) and acetonitrile (100 mL) was refluxed 60 minutes. The reaction mixture was concentrated and the obtained residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium te, filtered and concentrated. The obtained TIP 296 PCT residue was dissolved in acetonitrile (50 mL). Water was added untill itation was observed. The mixture was allowed to triturate r overnight. The beige crystals were ed off and dried in vacuo at 50°C, resulting in compound 65 (473 mg). Method A; Rt: 1.89 min. m/z : 452.0 (M-H)- Exact mass: 453.0. 1H NMR (400 MHz, acetonitrile-d3)  ppm 1.46 (s, 3 H), 2.44 - 2.59 (m, 2 H), 2.78 - 2.94 (m, 2 H), 3.92 (s, 3 H), 5.89 (s, 1 H), 7.14 (d, J=2.0 Hz, 1 H), 7.36 (d, J=2.0 Hz, 1 H), 7.59 (dt, J=5.8, 2.4 Hz, 1 H), 7.65 (ddd, J=12.4, 6.8, 2.6 Hz, 1 H), 8.64 (br. s., 1 H).

Compound 66: N-(3-chloro-4,5-difluoro-phenyl)(1,1-dimethylpropylsulfamoyl)methyl- pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (572 mg, 1.472 mmol), tert-amylamine (327 mg, 3.68 mmol) in acetonitrile (75 mL) was stirred 48 hours. Water was added untill crystallisation began. The crystals were filtered off and dried in vacuo at 50°C, resulting in compound 66 (356 mg) . Method A; Rt: 2.09 min. m/z : 418.1 (MH )- Exact mass: 419.1. 1H NMR (400 MHz, 6)  ppm 0.78 (t, J=7.4 Hz, 3 H), 1.12 (s, 6 H), 1.49 (q, J=1.0 Hz, 2 H), 3.91 (s, 3 H), 7.01 (s, 1 H), 7.33 (d, J=2.0 Hz, 1 H), 7.54 (d, J=1.8 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 10.28 (s, 1 H).

Compound 72: N-(3-chloro-4,5-difluoro-phenyl)methyl[[1-(trifluoromethyl)- cyclopropyl]sulfamoyl]pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1274 mg, 3.28 mmol), 1-(trifluoromethyl)cyclopropanamine (1000 mg, 7.99 mmol) and triethylamine (0.57 mL, 4.1mmol) in acetonitrile (100 mL) was refluxed overnight. An equal amount of 1-(trifluoromethyl)cyclopropanamine was added and the raction mixture was further refluxed overnight. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated. The e was purified by column chromatography on silica using a gradient from 10 to 100% EtOAc in heptane. The pure fractions were concentrated yielding compound 72 (42.4 mg) as a TIP 296 PCT powder. Method A; Rt: 1.95 min. m/z : 456.0 (M-H)- Exact mass: 457.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.10 - 1.22 (m, 4 H), 3.91 (s, 3 H), 7.31 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.74 - 7.86 (m, 2 H), 8.74 (s, 1 H), 10.30 (s, 1 H).

Compound 73: N-(3-chloro-4,5-difluoro-phenyl)methyl[[2,2,2-trifluoro (methoxymethyl)methyl-ethyl]sulfamoyl]pyrrolecarboxamide A mixture of chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (318 mg, 0.817 mmol), 1,1,1-trifluoromethoxymethyl-propanamine hloride (237 mg, 1.23 mmol) and triethylamine (0.34mL, 1.45mmol) in acetonitrile (7 mL) was heated in a microwave oven at 150°C during 30 minutes. The reaction mixture was concentrated. The residue was dissolved in water (50 mL) and washed with 1M HCl. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was subjected to column chromatography on silica using a gradient from 10 to100% EtOAc in heptane. The product fractions were concentrated and the residue was crystallized by dissolving in methanol (5 mL) upon addition of water. The crystals were filtered off and dried ght in vacuo at 50°C, resulting in compound 73 (17.8 mg). Method A; Rt: 1.97 min. m/z : 488.0 (M-H)- Exact mass: 489.0. 1H NMR (360 MHz, DMSO-d6)  ppm 1.41 (s, 3 H), 3.23 (s, 3 H), 3.46 (s, 2 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.74 - 7.89 (m, 2 H), 8.04 (s, 1 H), 10.34 (s, 1 H).

Compound 96: N-(3-Chloro-4,5-difluorophenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide 2,2,2-trifluoro-1,1-dimethyl-ethylamine (0.344 g, 2.71 mmol) was dissolved in pyridine (10 mL, dried on molecular sieves) under N2-atm. chloro-4,5-difluoro-phenyl)carbamoyl] -pyrrolesulfonyl chloride (0.5 g, 1.35 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was treated with HCl 1M (100 mL) and extracted with EtOAc. The combined organic layer was washed with water followed by saturated NaHCO3, dried with Na2SO4 and the solvent was ated. The residue TIP 296 PCT was dissolved in CH2Cl2 (5 mL) and the formed precipitate was filtered off and washed with CH2Cl2 (2x5mL). The filtrate was concentrated and the obtained residue was purified by silica gel chromatography -heptane 0/100 to 100/0) and further purified by reverse phase column chromatography, resulting in compound 96 (45 mg) as a white solid. Method A; Rt: 2.03 min. m/z : 457.9 (M-H)- Exact mass: 459.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.35 (s, 6 H), 3.92 (s, 3 H), 7.34 (d, J=2.0 Hz, 1 H), 7.59 (s, 1 H), 7.75 - 7.89 (m, 2 H), 8.08 (br. s., 1 H), 10.33 (br. s., 1 H).

Compound 61: 2-[[5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolyl]- sulfonylamino]methyl-propanoic acid LiOH (0.567 g, 13.5 mmol) was dissolved in water (20 mL) and added dropwise to a mixture of compound 49 (1.39 g, 3.38 mmol) in MeOH (40 mL). The reaction mixture was stirred at 50°C for 7 hour. Then HCl 1N (15 mL, 15.2 mmol) was added dropwise After 16 hour without stirring the white precipitate was filtered off, washed with Methanol/Water (2:1 ; 2 x 60 mL). The white solid was dried in vacuo at 50°C resulting in compound 61 (1.09 g). Method A; Rt: 1.19 min. m/z : 396.0 (M-H)- Exact mass: 397.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.32 (s, 6 H), 2.22 (d, J=1.5 Hz, 3 H), 3.89 (s, 3 H), 7.05 - 7.13 (m, 1 H), 7.30 (d, J=1.8 Hz, 1 H), 7.45-7.55 (m, 2 H), 7.57 - 7.68 (m, 2 H), 10.01 (s, 1 H), 12.42 - 12.58 (m, 1 H).

Compound 62: 4-[[1,1-dimethyl(methylamino)oxo-ethyl]sulfamoyl]-N-(4-fluoro methyl-phenyl)methyl-pyrrolecarboxamide 1,1'-carbonyldiimidazole (CDI, 0.326 g, 2.013 mmol) was added to a ng solution of nd 61 (0.32 g, 0.805 mmol) in acetonitrile dried on molecular sieves (10 mL). The reaction mixure was stirred in a sealed tube at room temperature for 2 hour. Next, amine (2M in Methanol, 4.0 mL, 8.1 mmol) was added. The on mixture was stirred for 2.5 hour at room temperature. The solvent and the excess of methylamine were removed and the mixture was ed by silica gel column chromatography (EtOAc/Heptane 0/100 to 100/0). The desired fractions were combined and the solvent was evaporated and dried in vacuo resulting in compound 62 (221 mg) as a white solid. Method A; Rt: 1.49 min. m/z : 409.0 (M-H)- Exact mass: 410.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.30 (s, 6 H), 2.23 (d, J=1.5 Hz, 3 H), 2.53 TIP 296 PCT (d, J=4.6 Hz, 3 H), 3.89 (s, 3 H), 7.06 - 7.13 (m, 1 H), 7.27 - 7.30 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.43 - 7.48 (m, 1 H), 7.50 - 7.54 (m, 2 H), 7.61 - 7.66 (m, 1 H), 9.97 - 10.04 (m, 1 H).

Compound 63: 4-[[2-(dimethylamino)-1,1-dimethyloxo-ethyl]sulfamoyl]-N-(4-fluoro -phenyl)methyl-pyrrolecarboxamide arbonyldiimidazole (CDI, 0.149 g, 0.921 mmol) was added to a stirring mixture of compound 61 (0.366 g, 0.921 mmol) in itrile in a sealed tube under N2 atmosphere. The resultant solution was stirred at room temperature for 18 hours. Then , more (CDI, 0.224 g, 1.381 mmol) was added and the mixture was further stirred for 2 hours. An excess of dimethylamine was added (10 drops out of a pressure bottle) .The reaction mixture was stirred at rrom temperature for 5h. The precipitate was filtered off, washed with AcCN (1x2 mL) and the solid was dried at 50°C in vacuo yielding compound 63 ) as a a white powder. Method A; Rt: 1.51 min. m/z : 423.2 (M-H)- Exact mass: 424.2. 1H NMR (400 MHz, DMSO-d6, 100°C) ppm 1.39 (s, 6 H), 2.22 (d, J=1.8 Hz, 3 H), 2.97 (s, 6 H), 3.91 (s, 3 H), 7.02 (t, J=9.2 Hz, 1 H), 7.25 (d, J=1.8 Hz, 2 H), 7.37 (d, J=1.8 Hz, 1 H), 7.45 - 7.52 (m, 1 H), 7.58 (dd, J=7.0, 2.4 Hz, 1 H), 9.74 (br. s., 1 H). nd 64: 4-[(2-amino-1,1-dimethyloxo-ethyl)sulfamoyl]-N-(4-fluoromethyl- phenyl)methyl-pyrrolecarboxamide 1,1'-carbonyldiimidazole (CDI, 0.295 g, 1.820mmol) was added to a stirring mixture of compound 61 (0.289 g, 0.727 mmol) in acetonitrile in a sealed tube under N2 atmosphere and stirred 3 hours.The reaction mixture was added dropwise to 7M NH3 in methanol (25mL) . The solvent was evaporated leaving a yellow oil which was purified by silica gel column chromatography (EtOAc/Heptane 0/100 to 100/0). The desired fractions were combined and the t was evaporated and dried in vacuo resulting in compound 64 (123 mg) as a solid.

Method A; Rt: 1.44 min. m/z : 395.0 (M-H)- Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6, 60°C)  ppm 1.35 (s, 6 H), 2.22 (d, J=1.8 Hz, 3 H), 3.90 (s, 3 H), 6.91 (br. s., 2 H), 7.02 - 7.08 (m, 1 H), 7.11 (br. s., 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.47 - 7.54 (m, 2 H), 7.61 (dd, J=7.4, 2.3 Hz, 1 H), 9.86 (br. s., 1 H).

TIP 296 PCT Compound 67: 4-(tert-butylsulfamoyl)-N-(2,6-dideuteriofluoromethyl-phenyl)methylpyrrolecarboxamide t-Butylamine (245 mg, 3.35 mmol) was added to a solution of 5-[(2,6-dideuteriofluoro methyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (372 mg, 1.116 mmol) in itrile (25 mL) and stirred ght.Water was added until crystallization began. The precipitate was filtered off and dried in vacuo at 50°C, resulting in nd 67 (260 mg) Method A; Rt: 1.76 min. m/z : 368.1 (M-H)- Exact mass: 369.2. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 2.22 (d, J=2.0 Hz, 3 H), 3.90 (s, 3 H), 7.06 - 7.11 (m, 2 H), 7.29 (d, J=2.0 Hz, 1 H), 7.49 (d, J=1.5 Hz, 1 H), 10.00 (s, 1 H).

Compound 68: 4-(tert-butylsulfamoyl)methyl-N-(3,4,5-trifluorophenyl)pyrrole carboxamide t-Butylamine (498 mg, 6.806 mmol) was added to a solution of 1-methyl[(3,4,5- trifluorophenyl)carbamoyl]pyrrolesulfonyl chloride (800 mg, 2.269 mmol) in acetonitrile (50 mL) and stirred 3 hours. Water was added until crystallization began. The precipitate was filtered off and dried in vacuo at 50°C. Method A; Rt: 1.91 min. m/z : 388.1 (M- H)- Exact mass: 389.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.14 (s, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.55 (d, J=1.5 Hz, 1 H), 7.67 (dd, J=10.6, 6.6 Hz, 2 H), 10.30 (s, 1 H).

Compound 69: N-(4-fluoromethyl-phenyl)methyl[[2,2,2-trideuterio-1,1- bis(trideuteriomethyl)ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT 1,1,1,3,3,3-hexadeuterio(trideuteriomethyl)propanamine (473 mg, 5.76 mmol) was added to a solution of 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride , 1.92 mmol) in acetonitrile (43 mL) and stirred overnight. Water was added until crystallization began. The precipitate was filtered off and dried in vacuo at 50°C. Method A; Rt: 1.74 min. m/z : 375.1 (M-H)- Exact mass: 376.2. 1H NMR (400 MHz, DMSO-d6)  ppm 2.23 (d, J=1.5 Hz, 3 H), 3.90 (s, 3 H), 7.04 - 7.13 (m, 2 H), 7.29 (d, J=1.8 Hz, 1 H), 7.47 - 7.56 (m, 2 H), 7.64 (dd, J=7.2, 2.5 Hz, 1 H), 10.00 (s, 1 H).

Compound 70: N-(2,6-dideuteriofluoromethyl-phenyl)methyl[[2,2,2-trideuterio-1,1- bis(trideuteriomethyl)ethyl]sulfamoyl]pyrrolecarboxamide 1,1,1,3,3,3-hexadeuterio(trideuteriomethyl)propanamine (377 mg, 4.59 mmol) was added to a solution of 5-[(2,6-dideuteriofluoromethyl-phenyl)carbamoyl]methyl-pyrrole sulfonyl chloride (611 mg, 1.84 mmol) in acetonitrile (41 mL) and stirred overnight. Water was added until crystallization began. The precipitate was filtered off and dried in vacuo at 50°C.

Method A; Rt: 1.82 min. m/z : 377.1 (M-H)- Exact mass: 378.2. 1H NMR (400 MHz, DMSO-d6)  ppm 2.23 (d, J=2.0 Hz, 3 H), 3.90 (s, 3 H), 7.05 - 7.12 (m, 2 H), 7.29 (d, J=2.0 Hz, 1 H), 7.49 (d, J=1.8 Hz, 1 H), 10.00 (s, 1 H).

Compound 71: t-butylsulfamoyl)-N-(2,6-dideuterio-3,4,5-trifluoro-phenyl)methylpyrrolecarboxamide t-Butylamine (331 mg, 4.53 mmol) was added to a solution of 5-[(2,6-dideuterio-3,4,5-trifluorophenyl moyl]methyl-pyrrolesulfonyl de (666 mg, 1.51 mmol) (obtained similarly as described in the synthesis for compound 56, starting from 3,4,5-trifluoroaniline instead of 4-fluoromethyl-aniline, via deuterio-3,4,5-trifluoro-aniline) in acetonitrile (30 mL) and stirred 1 hour. Water was added until crystallization began. The precipitate was filtered off and dried overnight in vacuo at 50°C. Method A; Rt: 1.89 min. m/z : 389.9 (M-H)- Exact TIP 296 PCT mass: 391.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.14 (s, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.55 (d, J=1.5 Hz, 1 H), 10.30 (s, 1 H).

Synthesis of 3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid Sodium hydride (914 mg, 23.87 mmol) was added to a on of ethyl 3-fluoro-1H-pyrrole carboxylate (2885 mg, 18.36 mmol) and iodomethane (3888 mg, 23.9 mmol) in dry DMF (43 mL) and the mixture was stirred for 17 hours. The reaction mixture was acidified with 1M HCl and concentrated. The residue was dissolved in water/ EtOAc. The organic layer was dried over sodium sulphate, filtered and concentrated. The obtained residue was dissolved in acetonitrile (50 mL), washed with heptane and concentrated yielding a brown liquid of crude ethyl 3-fluoro- 1-methyl-pyrrolecarboxylate, which was used as such. Chlorosulfonic acid (1344 mg, 11.53 mmol) was dissolved in romethane (50 mL) and cooled in an icebath. Crude ethyl 3- fluoromethyl-pyrrolecarboxylate (1880 mg) was added and the reaction mixture was stirred 90 minutes.The reaction mixture was concentrated and the brown residual powder was dried for 17 hours in vacuo at 50°C. (5-ethoxycarbonylfluoromethyl-pyrrolesulfonic acid, 2477 mg) Method A; Rt: 0.76 min. m/z : 250.0 (M-H)- Exact mass: 251.0. A mixture of crude 5-ethoxycarbonylfluoromethyl-pyrrolesulfonic acid (2318 mg) in thionylchloride (20 mL) was heated at 80°C during 30 minutes. The solution was concentrated and the residue (containing ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate) dissolved in itrile (25 mL). 3-methyloxetanamine (3035 mg, 34.84 mmol) dissolved in acetonitrile (20 mL) was added and the raction mixture was stirred 1 hour at room temperature. The reaction mixture was concentrated. The obtained residue was ved in dichloromethane (200 mL), washed with water, dried over sodium sulphate, ed and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 to 100% EtOAc in heptane.

The product fractions were concentrated in vacuo yielding ethyl 3-fluoromethyl[(3- methyloxetanyl)sulfamoyl]pyrrolecarboxylate (1900 mg) as a white powder. 1H NMR (400 MHz, DMSO-d6)  ppm 1.28 (t, J=7.2 Hz, 3 H), 1.52 (s, 3 H), 3.83 (s, 3 H), 4.15 (d, J=6.4 Hz, 2 H), 4.27 (q, J=7.0 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.57 (d, J=4.6 Hz, 1 H), 8.28 (s, 1 H). A mixture of ethyl 3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (1900 mg, 5.93 mmol), lithium hydroxide (426 mg,17.8 mmol), THF (20 mL) and distilled water (5 mL) was stirred 210 minutes at room ature. THF was distilled off and the mixture neutralized with 1M HCl (5.9 mL, 5.9 mmol). The mixture was extracted with 2- methyltetrahydrofuran (3 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and trated. The ing white powder was dried overnight in vacuo at 50°C (3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid,1710 mg) Method A; Rt: 0.68 min. m/z : 290.9 (M-H)- Exact mass: 292.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.52 (s, 3 H), 3.82 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.52 (d, J=4.6 Hz, 1 H), 8.26 (s, 1 H), 13.11 (br. s, 1 H).

TIP 296 PCT Compound 74: N-(3,4-difluorophenyl)fluoromethyl[(3-methyloxetanyl)- sulfamoyl]pyrrolecarboxamide Triethylamine (0.19 mL,1.36 mmol) was added to a solution of 3-fluoromethyl[(3- methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (133 mg,0.57 mmol) in DMF (1 mL) ed by HATU (216 mg, 0.57 mmol) and stirred 20 s. Then 3,4-difluoroaniline (117 mg, 0.91 mmol) was added and the reaction mixture stirred overnight. The mixture was concentrated in vacuo. The residue was mixed with water (10 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was dried over sodium sulphate, ed and concentrated. The obtained residue was purified by column chromatography on silica using a gradient from 10 to 100% EtOAc in heptane. The product fractions were trated and the remaining white powder was dissolved in warm EtOAc (10 mL) and upon addition of heptane the compound crystallized. The white crystals were filtered off and dried in vacuo, resulting in compound 74 (102 mg) Method A; Rt: 1.62 min. m/z : 401.9 (M-H)- Exact mass: 403.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.64 (d, J=6.2 Hz, 2 H), 7.35 - 7.47 (m, 2 H), 7.51 (d, J=4.6 Hz, 1 H), 7.75 - 7.87 (m, 1 H), 8.30 (s, 1 H), 10.24 (s, 1 H).

Compound 75: N-(3,5-Dichlorofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide 3,5-dichlorofluoroaniline (1534 mg, 8.5 mmol) ved in toluene (10 mL) was added to 4- chlorosulfonylmethyl-pyrrolecarbonyl de (2063 mg, 8.52 mmol) in toluene (115 mL) at reflux and refluxed 2 hours. The reaction e was filtered while still hot and the filtrate was concentrated , yielding crude 5-[(3,5-dichlorofluorophenyl)carbamoyl]methyl- pyrrolesulfonyl chloride as a crude beige powder which was used as such.1H NMR (400 MHz, acetonitrile-d3)  ppm 3.96 (s, 3 H), 7.39 (d, J=2.0 Hz, 1 H), 7.71 - 7.77 (m, 3 H), 8.78 (br. s., 1 H). 3-methyloxetanamine (407.3 mg, 4.68 mmol) was added to crude 5-dichloro fluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (601 mg) in acetonitrile (57 mL) and stirred overnight. Water was added untill crystallisation began. The formed white crystals were filtered off and dried in vacuo at 50°C during 4 hours. Compound 75 was recrystallized from EtOAc upon addition of heptane. The white crystals (346 mg) were filtered off and dried in TIP 296 PCT vacuo at 50°C over weekend. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.35 (d, J=2.0 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.95 (d, J=6.2 Hz, 2 H), 7.99 (s, 1 H), 10.27 (s, 1 H). Method A; Rt: 1.77 min. m/z : 434.0 (MH )- Exact mass: 435.0.

Compound 76: 4-(tert-Butylsulfamoyl)-N-(3,5-dichlorofluorophenyl)methyl-1H-pyrrole carboxamide tert-butylamine (450.6 mg, 6.16 mmol) was added to crude 5-[(3,5-dichlorofluoro- phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (792 mg) in acetonitrile (75 mL) and stirred 2 hours. Water was added untill crystallisation began. The white crystals were filtered off and dried ght in vacuo at 50°C, resulting in compound 76 (517 mg). 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.14 (s, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.55 (d, J=1.5 Hz, 1 H), 7.95 (d, J=6.2 Hz, 2 H), 10.26 (s, 1 H). Method A; Rt: 1.99 min. m/z : 420.0 (M- H)- Exact mass: 421.0.

Compound 77: N-(4-Chloromethylphenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide DIPEA (0.471 mL, 2.73 mol ) was added to a stirring mixture of 1-methyl[(3-methyloxetan yl)sulfamoyl]pyrrolecarboxylic acid (0.25 g, 0.000911 mol) and CH3CN (5 mL ) under N2- atmosphere. To the resulting solution was added 4-chloromethylaniline (0.142 g, 1 mmol), then HATU (364 mg, 0.957 mmol). The reaction mixture was stirred at room temperature for 3 hours and left standing for 2 hours. The product was filtered off, washed with CH3CN (5x), and dried at 50°C in vacuo, resulting in nd 77 (190 mg). 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 2.32 (s, 3 H), 3.92 (s, 3 H), 4.13 (d, J=6.2 Hz, 2 H), 4.60 (d, J=6.2 Hz, 2 H), 7.31 - 7.40 (m, 2 H), 7.54 - 6 7.62 (m, 2 H), 7.73 (d, J=2.2 Hz, 1 H), 7.95 (s, 1 H), 10.08 (s, 1 H).

Method A; Rt: 1.70 min. m/z : 396.0 (M-H)- Exact mass: 397.1.

Compound 78: N-(3-Chlorofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT 1-methyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (250 mg, 0.911 mmol) and HATU (433 mg, 1.14 mmol) were dissolved in DMF (5 mL) and stirred for 10 minutes. 3- chlorofluoroaniline (265 mg, 1.8 mmol) and DIPEA (0.471 mL, 2.73 mmol) were added and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOac gradient yielding compound 78 as a white powder after ation in MeOH. Method B; Rt: 0.93 min. m/z : 400.0 (M-H)- Exact mass: 401.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 7.40 (t, J=9.1 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=9.1, 4.3, 2.6 Hz, 1 H), 7.96 (br. s., 1 H), 8.01 (dd, J=6.9, 2.5 Hz, 1 H), 10.21 (s, 1 H).

Compound 79: N-[4-Fluoromethyl(trifluoromethyl)phenyl]methyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide nd 79 (1.9 g) was prepared similarly as described for compound 75, using 4-fluoro (trifluoromethyl)aniline instead of 3,5-dichlorofluoroaniline 1H NMR (400 MHz, DMSO-d 6)  ppm 1.55 (s, 3 H), 2.31 (d, J=2.0 Hz, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.36 (d, J=2.0 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.92 - 8.03 (m, 3 H), 10.25 (br. s, 1 H). Method B; Rt: 1.04 min. m/z : 448.1 (M-H)- Exact mass: 449.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 192.0 °C.

Compound 80: luoro-3,5-dimethylphenyl)methyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide 1-methyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (200 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (2 mL). HATU (0.35 g, 0.91 mmol) was added TIP 296 PCT followed by diisopropylethylamine (0.38 mL, 2.19 mmol). The resulting mixture was stirred for minutes at room temperature. Then, 4-fluoro-3,5-dimethylaniline (0.2 g, 1.46 mmol) was added. The ing e was stirred for 24 hours and next poured onto 10 mL of ice. The mixture was extracted using 2-Me-THF (3 x 10 mL). The ed organics were 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 80 (130 mg): Method B; Rt: 0.93 min. m/z : 394.2 (M-H)- Exact mass: 395.1.1 H NMR (400 MHz, 6 )  ppm 1.55 (s, 3 H), 2.21 (d, J=1.8 Hz, 6 H), 3.91 (s, 3 H), 4.13 (d, J=5.7 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.31 (d, J=1.8 Hz, 1 H), 7.43 (d, J=6.6 Hz, 2 H), 7.56 (d, J=1.8 Hz, 1 H), 7.94 (br. s., 1 H), 9.94 (br. s, 1 H).

Compound 81: N-(3-Bromofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide nd 81 (129 mg) was prepared as described for compound 80 using 3-bromo fluoroaniline instead of 4-fluoro-3,5-dimethylaniline. Method B; Rt: 0.93 min. m/z : 444.1 (MH )- Exact mass: 445.0. 1 H NMR (400 MHz, DMSO-d6)  ppm 1.47 - 1.60 (m, 3 H), 3.83 - 3.99 (m, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.28 - 7.44 (m, 2 H), 7.59 (d, J=1.8 Hz, 1 H), 7.71 (ddd, J=9.0, 4.4, 2.4 Hz, 1 H), 7.97 (br. s., 1 H), 8.13 (dd, J=6.5, 2.5 Hz, 1 H), .20 (br. s., 1 H).

Compound 82: 1-Methyl[(3-methyloxetanyl)sulfamoyl]-N-[3-methyl(trifluoro- methyl)phenyl]-1H-pyrrolecarboxamide Compound 82 (167 mg) was prepared as described for compound 80 using 3-methyl trifluoromethylaniline instead of 4-fluoro-3,5-dimethylaniline. Method B; Rt: 1.01 min. m/z : 430.2 (M-H)- Exact mass: 431.1. 1 H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 2.39 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.26 (s, 1 H), 7.39 (d, J=2.0 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.84 (s, 1 H), 7.90 - 8.08 (m, 2 H), 10.24 (br. s., 1 H).

TIP 296 PCT Compound 83: N-(4-Cyanomethylphenyl)methyl[(3-methyloxetanylsulfamoyl]-1H- pyrrolecarboxamide Compound 83 (76 mg) was prepared as described for compound 80 using 4-aminomethyl- benzonitrile d of 4-fluoro-3,5-dimethylaniline. Method B; Rt: 0.81 min. m/z : 387.1 (M-H)- Exact mass: 388.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.48 - 1.59 (m, 3 H), 2.46 (s, 3 H), 3.87 - 3.98 (m, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.40 (d, J=2.0 6 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.69 - 7.77 (m, 2 H), 7.86 (s, 1 H), 7.98 (br. s., 1 H), 10.32 (br. s., 1 H).

Compound 84: N-(4-Chlorofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide 1-methyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (200 mg, 0.729 mmol) was dissolved in DMF (5 mL) and triethylamine (0.405 mL, 2.92 mmol) and HATU (360 mg, 0.95 mmol) were added. After 10 minutes, 4-chlorofluoroaniline (212 mg, 1.46 mmol) was added. The reaction mixture was d at room temperature for 1 hour and heated at 50°C for 1 hour. More 4-chlorofluoroaniline (424 mg, 2.92 mmol) was added to the reaction mixture.

The reaction mixture was stirred at 60°C for 1 hour. The mixture was poured into water (50 mL) and filtered. The formed precipitate was filtered and the solid was washed with water. The filtrate was stored for 42 hours and the formed precipitate was ed and washed with water.

The solids were combined, and further purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) resulting in compound 84 as a white solid. The white solid was triturated in methanol (5 mL), filtered and dried in vacuum oven overnight ing in compound 84 (119 mg) as a white powder. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.36 (d, J=1.8 Hz, 1 H), 7.45 - 7.67 (m, 3 H), 7.68 - 8.56 (m, 2 H), 10.30 (br. s., 1 H). Method B; Rt: 0.96 min. m/z : 400.1 (MH )- Exact mass: 401.1.

Compound 85: N-(2,4-Difluoromethylphenyl)methyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide TIP 296 PCT 2,4-difluoromethyl-aniline (0.306 g, 2.14 mol) was dissolved in acetonitrile (50 mL, 0.957 mol), 1-methyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (0.645 g, 2.35 mmol) and Et3N (0.891 mL, 6.41 mmol) were added. HATU (0.975 g, 2.57 mmol) was added at once. The reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture was stirred at 40°C for 80 hours. The t was removed, water (1 x 50 mL) was added and the mixture was washed with brine (1 x 5mL) and extracted with EtOAc (2x50 mL). The combined organic layers were dried with Na2SO4 and the solvent was removed by evaporation. The crude mixture was purified by silica gel chromatography (EtOAc-heptane 0/100 to 100/0). The desired fractions were ed and evaporated. The ed solid was llized by evaporation of a acetonitrile/H2O solution, the precipitate was filtered off, washed with water (2 mL) and dried at 50°C in vacuo, resulting in compound 85. Method A; Rt: 1.55 min. m/z : 398.1 (M-H)- Exact mass: 399.1.1H NMR (360 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 2.18 (s, 3 H), 3.89 (s, 3 H), 4.13 (s, 2 H), 4.59 (s, 2 H), 7.07 (td, J=9.0, 1.8 Hz, 1 H), 7.28 - 7.39 (m, 2 H), 7.59 (d, J=1.8 Hz, 1 H), 8.00 (br. s., 1 H), 9.95 (br. s., 1 H).

Compound 86: N-[4-Fluoro(trifluoromethoxy)phenyl]methyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 86 (127 mg) was prepared similar as described for compound 80 using 4-fluoro uoromethoxy)aniline instead of 4-fluoro-3,5-dimethylaniline. Method B, Rt: 1.01 min. m/z: 450.2 (M-H)- Exact mass: 451.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.2 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.35 (d, J=2.0 Hz, 1 H), 7.45 - 7.53 (m, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.68 - 7.77 (m, 1 H), 7.97 (s, 1 H), 7.99 - 8.07 (m, 1 H), 10.29 (br. s, 1 H).

Compound 87: N-(3-Chlorocyanophenyl)methyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT Compound 87 was prepared similar as described for compound 75 using 3-amino chlorobenzonitrile instead of 3,5-dichlorofluoroaniline. The on e was filtered and the solids were washed with water. The grey powder was dissolved in ethyl acetate (300 mL) and washed with aqueous HCl (1 N, 50 mL), saturated aqueous sodium bicarbonate (30 mL) and brine, dried (Na2SO4), and evaporated to dryness and dried overnight in vacuum oven at 50°C, resulting in compound 87 (867 mg) as a white powder. Method B; Rt: 0.91 min. m/z : 407.1 (MH )- Exact mass: 408.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.38 (d, J=1.8 Hz, 1 H), 7.64 (d, J=1.5 Hz, 1 H), 7.74 (dd, J=2.0, 1.3 Hz, 1 H), 8.00 (s, 1 H), 8.10 - 8.13 (m, 1 H), 8.15 (t, J=2.0 Hz, 1 H), 10.42 (s, 1 H). Differential ng calorimetry: From 30 to 300 °C at in: peak at 209.4 °C.

Compound 88: N-(4-Fluoromethylphenyl)-1,3,5-trimethyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide Ethyl 1,3,5-trimethylpyrrolecarboxylate (1000 mg, 5.52 mmol) was added in 5 portions to chlorosulfonic acid (5 mL) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction mixture was slowly added to ice cold water (50 mL), followed by extraction with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated resulting in crude ethyl 4-chlorosulfonyl-1,3,5- hyl-pyrrolecarboxylate (510 mg) as brown oil which solidified on standing.

Crude ethyl 4-chlorosulfonyl-1,3,5-trimethyl-pyrrolecarboxylate (500 mg) was dissolved in acetonitrile (50 mL) and 3-methyloxetanamine (622.9 mg, 7.15 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3 x 50 mL) and the combined c layers were washed with brine, dried and evaporated to afford a brown sticky oil. The oil was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) resulting in ethyl 1,3,5- trimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (100 mg) as a white solid.

Method B; Rt: 0.83 min. m/z : 329.1 (M-H)- Exact mass: 330.1. Ethyl trimethyl[(3- methyloxetanyl)sulfamoyl]pyrrolecarboxylate was ved in ethanol (10 mL) and NaOH (1M in H2O, 0.61 mL) was added. The resulting solution was stirred at room temperature for 42 TIP 296 PCT hours. The on mixture was d at 70°C for 20 hours. NaOH (1 M in H2O, 0.61 mL) was added to the reaction mixture which was stirred at 80°C for 64 hours. The reaction mixture was allowed to reach room temperature. Triethylamine hydrochloride (222 mg, 1.61 mmol) was added, the reaction mixture was evaporated to dryness and co evaporated with toluene (2 x 20 mL) to afford a residue which was used as such. The obtained residue was dissolved in DMF (5 mL). Triethylamine (0.23 mL, 1.654 mmol) and HATU (150.9 mg, 0.397 mmol) were added and the reaction mixture was stirred at room temperature for 10 minutes. 4-fluoromethylaniline (124 mg, 0.99 mmol) was added to the reaction mixture which was stirred at room temperature for 42 hours. The reaction e was poured into water. The dark brown precipitate was filtered and washed with water. The filtrate was extracted with Me-THF (2 x 20 mL) and EtOAc (2 x 30 mL). The combined organic layers were washed with brine, ed with the dark brown precipitate, dried (Na2SO4) and evaporated. The ed residue was ed using silica gel column cromatography (ethyl acetate in heptane from 0 to 100% and methanol in CH2Cl2 from 0 to 2%) to afford compound 88 (17.2 mg) as a powder. 1H NMR (400 MHz, DMSO-d6)  ppm 1.49 (s, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 2.28 (s, 3 H), 2.43 (s, 3 H), 3.56 (s, 3 H), 4.12 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.10 (t, J=9.2 Hz, 1 H), 7.46 - 7.54 (m, 1 H), 7.61 (dd, J=7.0, 2.2 Hz, 1 H), 7.78 (br. s, 1 H), 10.09 (s, 1 H). Method B; Rt: 0.90 min. m/z: 408.2 (M-H)- Exact mass: 409.1.

Compound 89: N-(4-Fluoromethylphenyl)-1,5-dimethyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide Ethyl methyl-1H-pyrrolecarboxylate (2.5 g, 14.95 mmol) was added drop wise to sulfonic acid (10 mL) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction mixture was slowly added to ice cold water, followed by extraction with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated resulting in crude ethyl 4-chlorosulfonyl-1,5-dimethylpyrrolecarboxylate (2.9 g) as light purple powder. 1H NMR (400 MHz, itrile-d3)  ppm 1.32 (t, J=7.0 Hz, 3 H), 2.54 (s, 3 H), 3.86 (s, 3 H), 4.28 (q, J=7.2 Hz, 2 H), 7.30 (s, 1 H). Crude ethyl 4-chlorosulfonyl-1,5-dimethyl-pyrrolecarboxylate (1500 mg, 5.65 mmol was dissolved in acetonitrile (15 mL). Hunig's base (2.4 mL, 14.1 mmol) and 3-methyloxetanamine (639 mg, 7.33 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 42 hours. Water was added and the mixture was extracted with CH2Cl2 (2 x 50 mL) and EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and evaporated to dryness. The obtained crude ethyl methyl[(3-methyloxetanyl)sulfamoyl]pyrrole carboxylate (1.8 g) was used as such. Method B; Rt: 0.77 min. m/z: 315.1 (M-H)- Exact mass: TIP 296 PCT 316.1. Crude ethyl 1,5-dimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (1800 mg, 5.689 mmol) was dissolved in ol (8 mL), LiOH (720 mg, 30.1 mmol) in water (2 mL) was added and the reaction mixture was heated at 50°C for 2 hours. The reaction mixture was evaporated to dryness and coevaporated with toluene (2 x 50 mL) to afford a beige powder.

Half of the above obtained powder was dissolved in DMF (10 mL). Triethylamine hydrochloride (2349 mg, 17.1 mmol), triethylamine (1.19 mL) and HATU (1298 mg, 3.41 mmol), were added and the reaction mixture was stirred at room temperature for 10 minutes. ro methylaniline (712 mg, 5.688 mmol), was added to the reaction mixture which was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the solids were filtered and washed with water to afford a beige solid which was purified using silica gel column chromatography (ethylacetate in heptane from 0 to 100%) to afford compound 89 as a white powder. Method B; Rt: 0.92 min. m/z : 394.1 (M-H)- Exact mass: 395.1. 1 H NMR (400 MHz, DMSO-d 6 )  ppm 1.50 (s, 3 H), 2.22 (d, J=1.6 Hz, 3 H), 2.43 (s, 3 H), 3.83 (s, 3 H), 4.11 (d, J=6.5 Hz, 2 H), 4.59 (d, J=6.1 Hz, 2 H), 6 7.08 (t, J=9.3 Hz, 1 H), 7.29 (s, 1 H), 7.49 - 7.54 (m, 1 H), 7.63 (dd, J=7.3, 2.4 Hz, 1 H), 7.92 (s, 1 H), 9.94 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 186.6 °C.

Compound 90: N-(4-Fluoromethylphenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]- rolecarboxamide Ethyl 1,3-dimethylpyrrolecarboxylate (1.3 g, 7.78 mmol) was added drop wise to chlorosulfonic acid (5.2 mL) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir 1.5 hours. The reaction mixture was slowly added to ice cold water, followed by extraction with CH2Cl2. The combined organic extracts were dried 4) and concentrated in crude ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole carboxylate (1300 mg) as a brown oil. Crude ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole carboxylate (1.3 g, 4.89 mmol) was dissolved in acetonitrile (5 mL) and 3-methyloxetanamine (852 mg, 9.79 mmol) was adedd followed by Hunig's base (2.11 mL, 12.23 mmol). The reaction e was stirred at room temperature for 1 hour. The reaction mixture was filtered. The solids were washed with CH2Cl2 and discarded. The filtrate was evaporated and the e was purified using silica gel column tography ethyl acetate in heptane from 0 to 100% resulting in ethyl 1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (302 mg) as sticky oil. Method B; Rt: 0.79 min. m/z : 315.1 (M-H)- Exact mass: 316.1. Ethyl 1,3- dimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (302 mg, 0.955 mmol) was ved in THF (40 mL) and LiOH (114.3 mg, 4.77 mmol) in water (10 mL) was added. The reaction mixture was stirred at room temperature. ol (20 mL) was added to the raction TIP 296 PCT mixture. The on mixture was stirred at room temperature ght. More LiOH (5 equiv.) in water was added and the reaction mixture was heated at 60°C for 42 hours. The reaction mixture was evaporated to dryness and coevaporated with toluene (2 x 50 mL). The residue was used as such in next step. The obtained residue was dissolved in DMF (10 mL). triethylamine hydrochloride (1575 mg, 11.4 mmol), triethylamine (0.663 mL, 4.7 mmol) and HATU (435 mg, 1.15 mmol) were added and the reaction mixture was stirred at room temperature for 10 minutes. 4-fluoromethylaniline (239 mg, 1.91 mmol) was added to the reaction mixture which was stirred at room temperature for 2 hours. The reaction mixture was stirred at 50°C for 2 hours.

Water was added to the reaction mixture and the mixture was extracted with 2-Methyl THF. The combined organic layers were washed with brine, dried (Na2SO4) and ated to afford a brown oil. The oil was purified using silica gel column chromatography (ethylacetate in heptane from 0 to 100%) to afford a sticky light brown oil. nd 90 was purified using Preparative LC (Hypersyl C18 BDS-3µm,100 x 4.6 mm) Mobile phase (NH4HCO3 0.2% in water, methanol) the d fractions were combined and evaporated to dryness, ved in methanol and evaporated to dryness. After drying in vacuo compound 90 was obtained as a white powder. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.53 (s, 3 H), 2.23 (d, J=1.6 Hz, 3 H), 2.31 (s, 3 H), 3.70 (s, 3 H), 4.11 (d, J=6.5 Hz, 2 H), 4.61 (d, J=5.7 Hz, 2 H), 6 7.11 (t, J=9.3 Hz, 1 H), 7.44 (s, 1 H), 7.47 - 7.53 (m, 1 H), 7.62 (dd, J=6.9, 2.4 Hz, 1 H), 7.88 (br. s., 1 H), 10.09 (s, 1 H). Method B; Rt: 0.88 min. m/z : 394.2 (M-H)- Exact mass: 395.1. Differential scanning metry: From 30 to 300 °C at 10°C/min: peak at 160.5 °C.

Compound 97: N-(4-Fluoromethylphenyl)methyl{[(1R)methyl(methylsulfonyl ]sulfamoyl}-1H-pyrrolecarboxamide 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (0.269 g, 0.813 mmol) was stirred in acetonitrile (50 mL). Et3N (0.339 mL, 2.44 mmol) and (2R) methylsulfonylpropanamine (0.123 g, 0.895 mmol) were added under N2-atmosphere at room temperature. The reaction mixture was stirred for 22 hours and next concentrated. The compound was precipitated from CH2Cl2/MeOH (4 mL, 3:1). The precipitate was filtered off, washed with CH2Cl2 (2 x 3 mL) and dried in vacuo at 50°C, resulting in compound 97 (123 mg). Method A; Rt: 1.47 min. m/z : 430.1 (M-H)- Exact mass: 431.1. 1 H NMR (400 MHz, DMSO-d6, 80°C)  ppm 1.20 (d, J=6.6 Hz, 3 H), 2.22 (d, J=1.8 Hz, 3 H), 2.94 (s, 3 H), 3.10 - 3.17 (m, 1 H), 3.27 - 3.34 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.92 (s, 3 H), 7.04 (t, J=9.2 Hz, 1 H), 7.30 (d, J=1.8 Hz, 2 H), 7.46 - 7.52 (m, 2 H), 7.59 (dd, J=7.3, 2.6 Hz, 1 H), 9.80 (br. s., 1 H).

TIP 296 PCT Compound 98: 4-(tert-Butylsulfamoyl)-N-[4-fluoro(trifluoromethoxy)phenyl]methyl-1H- pyrrolecarboxamide 4-fluoro(trifluoromethoxy)aniline (991 mg, 5.08 mmol) dissolved in e (10 mL) was added to 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (1.23 g, 5.079 mmo) in toluene (65 mL) at reflux and refluxed 2 hours. The reaction mixture was filtered while still hot and concentrated yielding crude 5-[[4-fluoro(trifluoromethoxy)phenyl]carbamoyl]methylpyrrolesulfonyl chloride as a beige powder which was used as such.1H NMR (400 MHz, acetonitrile-d3)  ppm 3.97 (s, 3 H), 7.27 - 7.35 (m, 1 H), 7.38 (d, J=2.0 Hz, 1 H), 7.57 (ddd, J=9.0, 4.0, 2.6 Hz, 1 H), 7.73 (d, J=1.5 Hz, 1 H), 7.87 - 7.94 (m, 1 H), 8.79 (br. s., 1 H). Tertbutylamine (342.7 mg, 4.69 mmol) was added to crude 5-[[4-fluoro (trifluoromethoxy)phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride (626 mg) in acetonitrile (52 mL) and stirred 2 hours. Water was added untill crystallisation began. The white crystals were filtered off and dried in vacuo at 50°C during 4 hours. Method A; Rt: 1.90 min. m/z : 436.1 (M-H)- Exact mass: 437.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.12 (s, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.48 (s, 1 H), 7.54 (d, J=1.5 Hz, 1 H), 7.69 - 7.77 (m, 1 H), 7.98 - 8.07 (m, 1 H), 10.28 (s, 1 H).

Compound 99: N-(2,4-Difluoromethylphenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide 4-(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (0.426 g, 1.73 mol) was ved in itrile (40 mL). Et3N (0.962 mL, 6.92 mmol) and 2,4-difluoromethyl-aniline (0.342 g, 1.9 mmol) were added. HATU (0.789 g, 2.08 mmol) was next added at once. The reaction mixture was stirred at room temperature for 1 hour. Then the solution was stirred at 50°C for 80 hours. The on was allowed to cool and water (2 x 50 mL) and brine (5mL) were added. The solution was extracted with EtOAc (2 x 100 mL) and dried with Na2SO4. The solvent was evaporated leaving yellow oil which purified by silica gel chromatography (EtOAc-heptane 0/100 to 100/0). The obtained solid was dissolved in boiling 2-propanol (1.5 mL) and water was added dropwise (1.5 mL) when still boiling. The solution was allowed to cool down After 90 min the white precipitate was filtered off, washed with 2-Propanol/water (2 x 1mL) and dried at 50°C in vacuo yielding compound 99 as white cristals. Method A; Rt: 1.72 min. m/z: 370.0 (MH )- Exact mass: 371.1. 1H NMR (400 MHz, DMSO-d6, 80°C)  ppm 1.06 (d, J=6.4 Hz, 6 H), TIP 296 PCT 2.18 (t, J=1.9 Hz, 3 H), 3.33 (dt, J=13.0, 6.6 Hz, 1 H), 3.89 (s, 3 H), 6.85 (br. s., 1 H), 7.00 (td, J=8.9, 1.8 Hz, 1 H), 7.25 (s, 1 H), 7.37 (m, J=8.8, 8.8, 6.2 Hz, 1 H), 7.43 (d, J=1.8 Hz, 1 H), 9.62 (br. s., 1 H) Synthesis of 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid Methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate (5 g, 21.04 mmol) was dissolved in acetonitrile (50 mL). To this was added diisopropylethylamine (9.06 mL, 52.6 mmol) ed by (S)-1,1,1-trifluoropropylamine (3.57 g, 31.6 mmol) and the resulting e was refluxed overnight. Then the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and this was washed with HCl (2 X 150 mL). The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding crude methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (6.6 g) which was used as such. Methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl- sulfamoyl]pyrrolecarboxylate (6.6 g, 19.7 mmol) was dissolved in tetrahydrofuran (56 mL). To this was added lithium hydroxide (1.655 g, 69.1 mmol) in distilled water (7.5 mL) ed by methanol (3 mL). The resulting e was stirred overnight. The mixture was concentrated until only water remained and extra distilled water (15 mL) was added. The mixture was neutralised with hydrochloric acid (1M, aq). The resulting mixture was extracted using 2- methyltetrahydrofuran (3 X 20 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding 1-methyl[[(1S)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid (5.34 g).

Compound 100 to 105 were prepared similarly as described for compound 80, using 1-methyl [[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid instead of 1-methyl thyloxetanyl)sulfamoyl]pyrrolecarboxylic acid and the corresponding aniline instead of 4-fluoro-3,5-dimethylaniline. After on of the aniline, the mixture was stirred at 50°C for 6 hours instead of 24 hours at room temperature.

Compound 100: N-(3-Bromo-4,5-difluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 100 was ed by silica gel chromatography heptane-EtOAc 100/0 to 0/100.

The product was crystallized from ropylether (15 mL)/iPrOH (3.5 mL). The product was filtered off, washed with diisopropylether (3x), and dried at 50°C in vacuo, resulting in TIP 296 PCT compound 100 (251 mg). Method A; Rt: 1.98 min. m/z: 489.8 (M-H)- Exact mass: 491.0. 1H NMR (400 MHz, 6)  ppm 1.08 (d, J=6.8 Hz, 3 H), 3.84 - 4.00 (m, 4 H), 7.36 (d, J=2.0 Hz, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.80 - 7.93 (m, 2 H), 8.20 (br. s., 1 H), 10.31 (br. s., 1 H).19F NMR (377 MHz, DMSO-d6)  ppm -138.51 - -138.34 (m, 1 F), -133.99 - -133.81 (m, 1 F), - 76.07 (d, J=7.9 Hz, 3 F). Differential scanning metry: From 30 to 300 °C at 10°C/min: peak at 199.0 °C.

Compound 101: N-(3-Bromofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 101 was stirred in CH2Cl2 (5 mL), filtered off, and washed with CH2Cl2 (1x).

The product (0.289 g ) was crystallized from iPrOH-H2O 3/1 (6 mL), filtered off, washed with iPrOH-H2O 3/1 (3x), and dried at 50°C in vacuo, resulting in compound 101 (70 mg). Method B; Rt: 1.07 min. m/z: 470.0 (M-H)- Exact mass: 471.0. 1H NMR (400 MHz, 6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 3.88 - 3.96 (m, 4 H), 7.33 - 7.41 (m, 2 H), 7.63 (d, J=1.5 Hz, 1 H), 7.71 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 8.11 - 8.28 (m, 2 H), 10.21 (s, 1 H).

Compound 102: N-(3-Cyanofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 102 was stirred in CH2Cl2 (5 mL), ed off, and washed with CH2Cl2 (2x).

The product was crystallized from iPrOH (12.5 mL) + H2O (2.5 mL), filtered off, washed with iPrOH-H2O 4/1 (2 x) and iPrOH, and dried at 50°C in vacuo, resulting in compound 102 (93 mg). Method B; Rt: 0.97 min. m/z: 417.1 (M-H)- Exact mass: 418.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=7.0 Hz, 3 H), 3.84 - 3.99 (m, 4 H), 7.36 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.64 (br. s., 1 H), 7.97 - 8.04 (m, 1 H), 8.22 (dd+br. s., J=5.7, 2.6 Hz, 2 H), 10.38 (br. s., 1 H).

Alternative synthesis of compound 102: TIP 296 PCT Methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (5 g, .9 mmol) was dissolved in of dry tetrahydrofuran (50 mL) under a blanket of nitrogen. 5- 2-fluorobenzonitrile (2.82 g, 20.68 mmol) was added and the e was cooled in an ice-water bath while ng under nitrogen. Lithium bis(trimethylsilyl)amide (1M in toluene, 47.73 mL, 47.73 mmol) was added drop wise over a period of 10 s. The resulting mixture was stirred for 1 hour while cooling was continued.

An extra 2 equivalents of lithium bis(trimethylsilyl)amide (1M in toluene, 31.82 mL, 31.82 mmol) were added drop wise over a period of 10 minutes. The resulting mixture was stirred for 1 hour while cooling was continued. An extra equivalent of lithium bis(trimethylsilyl)amide (1M in toluene, 15.9 mL, 15.9 mmol) was added drop wise over a period of 5 minutes. Next, the mixture was quenched with saturated ammonium chloride (150 mL / aq) and the resulting mixture was extracted using EtOAc (3 x 150 mL). The combined extracts were washed with brine (200 mL), dried on Na2SO4, filtered and concentrated in vacuo. The obtained residue was dissolved in dichloromethane (10 mL) and this was loaded on a dry silica plug (330 g). This was purified by column chromatography using gradient elution from heptane to EtOAc. (100:0 to . The desired fractions were collected and concentrated in vacuo yielding a slightly red powder. This powder was recrystallized out of MeOH/water. The obtained crystals were ted on a filter, rinsed with water and diisopropylether and dried in a vacuum oven at 55°C for 24 hours ng compound 102 (3.92 g) as a bright white powder. [α]20589= +2.7 ° (c 0.96 w/v %, MeOH). [α]20589= +21.8 ° (c 0.37 w/v %, DMF). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 213.4 °C. SFC analysis: AD-H 250 mm x 4.6 mm, Flow: 5 mL/min Mobile phase: 10-55 % MeOH (containing 0.2% ) @ 14.5% rate, down to 50% and hold for 2.55 min @ 50%, Temperature: 40°C: Compound 102 (first g), containing no detectable compound 157 (second eluding). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.08 (d, J=7.0 Hz, 3 H), 3.88 - 3.97 (m, 1 H), 3.93 (s, 3 H), 7.37 (d, J=1.9 Hz, 1 H), 7.53 (t, J=9.2 Hz, 1 H), 7.67 (d, J=1.9 Hz, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.7 Hz, 1 H), 8.19 (br. s., 1 H), 8.22 (dd, J=5.8, 2.7 Hz, 1 H), 10.39 (br. s., 1 H).

Compound 103: N-(3-Chloro-4,5-difluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 103 was triturated from refluxing CH2Cl2 (10 mL). The suspension was cooled to room temperature, the solids were filtered and washed with CH2Cl2 (2 mL) resulting in compound 103 (308 mg) as white solid after drying in vacuo at 50°C. Method B; Rt: 1.13 min. m/z: 444.0 (M-H)- Exact mass: 445.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=6.8 Hz, TIP 296 PCT 3 H), 3.85 - 3.98 (m, 4 H), 7.36 (d, J=1.5 Hz, 1 H), 7.65 (d, J=1.3 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 8.19 (br. s, 1 H), 10.33 (br. s., 1 H).

Compound 104: N-(3,4-Difluoromethylphenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 104 was triturated from refluxing CH2Cl2 (10 mL). The sion was cooled to room temperature, the solids were filtered and washed with CH2Cl2 (2 mL) resulting in compound 104 (481 mg) as white solid after drying in vacuo at 50°C. Method B; Rt: 1.08 min. m/z: 424.0 (M-H)- Exact mass: 425.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=7.0 Hz, 3 H), 2.28 (d, J=2.0 Hz, 3 H), 3.86 - 3.98 (m, 4 H), 7.34 (d, J=2.0 Hz, 1 H), 7.38 - 7.44 (m, 1 H), 7.62 (d, J=1.3 Hz, 1 H), 7.66 (ddd, J=12.9, 7.1, 2.4 Hz, 1 H), 8.16 (br. s., 1 H), 10.15 (s, 1 H).

Compound 105: N-(3-Chlorofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Crude compound 105 was triturated from refluxing CH2Cl2 (10 mL). The suspension was cooled to room temperature, the solids were filtered and washed with CH2Cl2 (2 mL). The obtained solid was triturated with warm itrile, the e was cooled to room temperature. The solids were filtered and to the obtained filtrate, water (3 mL) was added to form a white solid which was filtered and washed with water, resulting in compound 105 as white powder. Method B; Rt: 1.08 min. m/z: 426.0 (M-H)- Exact mass: 427.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 3.87 - 3.98 (m, 4 H), 7.35 (d, J=2.0 Hz, 1 H), 7.40 (t, J=9.1 Hz, 1 H), 7.60 - 7.70 (m, 2 H), 8.01 (dd, J=6.9, 2.5 Hz, 1 H), 8.16 (br. s., 1 H), 10.23 (s, 1 H).

TIP 296 PCT Compound 94: 3-Fluoro-N-(4-fluoromethylphenyl)methyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide A solution of Et3N (0.179 mL , 1.29 mmol) in DMF (1.9 mL) was added to 3-fluoromethyl thyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (125 mg, 0.428 mmol), HATU (204 mg, 0.535 mmol), 4-fluoromethylaniline (107 mg, 0.857 mmol) and stirred overnight. The solution was subjected to column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were ed and concentrated. Compound 94 (78 mg) was obtained as a white powder after drying in vacuo at 50°C. Method A; Rt: 1.66 min. m/z: 397.9 (M-H)- Exact mass: 399.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 2.23 (d, J=1.5 Hz, 3 H), 3.79 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 7.10 (t, J=9.2 Hz, 1 H), 7.43 - 7.51 (m, 2 H), 7.59 (dd, J=7.0, 2.4 Hz, 1 H), 8.28 (s, 1 H), 10.01 (s, 1 H).

Compound 106: N-(3-Bromofluorophenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 106 (131 mg) was ed similarly as described for compound 94, using 3-bromo- 4-fluoroaniline instead of 4-fluoromethylaniline. Method A; Rt: 1.73 min. m/z: 463.8 (M-H)- Exact mass: 465.0. 1H NMR (400 MHz, 6) ppm 1.56 (s, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.64 (d, J=5.9 Hz, 2 H), 7.37 (t, J=8.8 Hz, 1 H), 7.51 (d, J=4.4 Hz, 1 H), 7.64 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 8.08 (dd, J=6.4, 2.6 Hz, 1 H), 8.30 (s, 1 H), 10.20 (s, 1 H).

Compound 107: N-[3-(Difluoromethyl)fluorophenyl]fluoromethyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 107 (149 mg) was prepared similarly as described for compound 94, using 3- (difluoromethyl)fluoro-aniline instead of 4-fluoromethylaniline. Method A; Rt: 1.63 min. m/z: 334.0 (M-H)- Exact mass: 435.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 3.80 TIP 296 PCT (s, 3 H), 4.18 (d, J=6.6 Hz, 2 H), 4.65 (d, J=5.9 Hz, 2 H), 7.04 - 7.43 (m, 2 H), 7.51 (d, J=4.6 Hz, 1 H), 7.76 - 7.86 (m, 1 H), 8.01 (dd, J=6.3, 2.5 Hz, 1 H), 8.30 (s, 1 H), 10.26 (s, 1 H).

Compound 108: N-(3-Chlorofluorophenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 108 (149 mg) was prepared rly as described for nd 94, using 3-chloro- 4-fluoroaniline instead of 4-fluoromethylaniline. Method A; Rt: 1.70 min. m/z: 417.9 (M-H)- Exact mass: 419.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.64 (d, J=6.2 Hz, 2 H), 7.41 (t, J=9.1 Hz, 1 H), 7.51 (d, J=4.4 Hz, 1 H), 7.60 (ddd, J=9.1, 4.3, 2.6 Hz, 1 H), 7.96 (dd, J=6.8, 2.4 Hz, 1 H), 8.30 (s, 1 H), 10.22 (s, 1 H).

Compound 109: 3-Fluoromethyl[(3-methyloxetanyl)sulfamoyl]-N-(2,4,5- trifluorophenyl)-1H-pyrrolecarboxamide F O HN S N O N F O Compound 109 (35 mg) was prepared similarly as described for compound 94, using 2,4,5- trifluoroaniline instead of 4-fluoromethylaniline. After overnight stirring at room temperature, the mixture was stirred at 60°C for 3 hours. Method A; Rt: 1.56 min. m/z: 420.1 (M-H)- Exact mass: 421.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.81 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.64 (d, J=5.9 Hz, 2 H), 7.53 (d, J=4.6 Hz, 1 H), 7.67 (td, J=10.6, 7.3 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.32 (s, 1 H), 9.79 (s, 1 H).

Compound 110: N-(2,4-Difluoromethylphenyl)fluoromethyl[(3-methyloxetan famoyl]-1H-pyrrolecarboxamide Compound 110 (90mg) was prepared similarly as described for compound 94, using 2,4- difluoromethyl-aniline instead of 4-fluoromethylaniline. Method A; Rt: 1.68 min. m/z: TIP 296 PCT 415.9 (M-H)- Exact mass: 417.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 2.15 - 2.22 (m, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 7.06 (td, J=9.0, 1.5 Hz, 1 H), 7.46 - 7.56 (m, 2 H), 8.30 (s, 1 H), 9.63 (s, 1 H).

Compound 111: N-(3-Chloro-4,5-difluorophenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 111 (46 mg) was ed similarly as described for compound 94, using 3-chloro- 4,5-difluoro-aniline instead of 4-fluoromethylaniline. The mixture was stirred at 65°C overnight instead of room temperature. Method A; Rt: 1.80 min. m/z: 435.9 (M-H)- Exact mass: 437.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.64 (d, J=6.2 Hz, 2 H), 7.54 (d, J=4.4 Hz, 1 H), 7.70 - 7.80 (m, 2 H), 8.32 (s, 1 H), 10.30 (s, 1 H).

Compound 112: 4-(tert-butylsulfamoyl)-N-(2,4-difluoromethyl-phenyl)methyl-pyrrole carboxamide -[(2,4-difluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (prepared similarly as described for 5-[(3,4-difluorophenyl)carbamoyl]methyl-pyrrole sulfonyl chloride, using 2,4-difluoromethyl-aniline instead of fluoroaniline; 0.25 g, 0.72 mmol) was stirred in acetonitrile (20 mL). DIPEA (0.494 mL, 2.87 mmol) and tert-butylamine (0.152 mL, 1.43 mmol) were added under N2-atmosphere at room ature. The reaction mixture was stirred in a sealed tube at 80°C for 5 hours and further at room temperature for more than 80 hours. The solvent was evaporated and the residue was dissolved in (CH2Cl2/MeOH (5mL, 90:10) and purified by silica gel chromatography -heptane 0/100 to 100/0 ] and further ed by reverse phase column chromatography. The resulting solid was triturated from Heptane/diisopropyl ether (4:1, 2.5 mL). The formed suspension was filtered. The filtercake was washed with heptane/diisopropylether (4:1, 5 mL) and dried at 50°C in vacuo yielding compound 112 (120 mg) as a white solid. Method A; Rt: 1.71 min. m/z: 384.1 (M-H)- Exact mass: 385.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H), 2.18 (s, 3 H), 3.88 (s, 3 H), 7.05 (td, J=8.9, 1.5 Hz, 1 H), 7.12 (s, 1 H), 7.29 (s, 1 H), 7.34 (td, J=8.7, 6.3 Hz, 1 H), 7.50 (d, J=1.8 Hz, 1 H), 9.89 (s, 1 H).

TIP 296 PCT Compound 113: N-(3-cyanofluoro-phenyl)fluoromethyl[(3-methyloxetan- 3-yl)sulfamoyl]pyrrolecarboxamide Compound 113 (43 mg) was prepared similarly as described for compound 94, using 5-amino fluoro-benzonitrile instead of 4-fluoromethylaniline but stirred 24 hours at 65°C and 48 hours at 100°C. The residue after column was llized from acetonitrile (10 mL) upon on of water. The crystals were dried overnight at 50°C in vacuo. Method A; Rt: 1.44 min. m/z: 409.0 (M-H)- Exact mass: 410.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 3.80 (s, 3 H), 4.18 (d, J=6.4 Hz, 2 H), 4.64 (d, J=5.9 Hz, 2 H), 7.48 - 7.58 (m, 2 H), 7.96 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.16 (dd, J=5.7, 2.6 Hz, 1 H), 8.32 (s, 1 H), 10.34 (s, 1 H).

Compound 114: 4-[(1-Carbamoylcyclopropyl)sulfamoyl]-N-(3-chloro-4,5-difluorophenyl) methyl-1H-pyrrolecarboxamide Methyl 1-aminocyclopropanecarboxylate (1.016g, 6.7mmol) was dissolved in dry dichloromethane (50ml) and dry DIPEA l) under N2-atm. 5-[(3-chloro-4,5-difluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride (prepared similarly as described for compound 57, 1.65g , 4.47 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Dry DMF (1 mL) was added and the reaction mixture was stirred for 22 h.

Then the mixture was washed with HCl 1M (50 mL). The layers were separated, precipitate 1 was filtered off and washed with CH2Cl2 (10 mL). The organic layer was dried with Na2SO4 and the filtrate was evaporated ing in residue 1. The water layer was ted with EtOAc (100 mL). The layers were separated and the organic layer was dried with Na2SO4 and the filtrate was evaporated ing in residue 2. Residue 1, 2 and precipitate 1 were combined giving methyl 1- [[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolyl]sulfonylamino]- cyclopropanecarboxylate (2.0 g) This material was dissolved in ol (20 mL) and NaOH 1M (13.4 mL,13.4 mmol) was added. The reaction mixture was stirred for 20 h. After 8 h, THF (6 mL) was added and the mixture was stirred further for 18 h. Then the mixture was successively stirred at 50°C for 9 h, room temperature for 80 h, 50°C for 8 h and 18 h at room temperature.The methanol/THF was distilled off and the mixture was extracted with Et2O. The TIP 296 PCT layers were separated and HCl 1M (14 mL) was added to the water layer. The water layer was extracted with MeTHF. The organic layer was evaporated resulting in 1-[[5-[(3-chloro-4,5- ro-phenyl)carbamoyl]methyl-pyrrolyl]sulfonylamino]cyclopropanecarboxylic acid as a yellow residue (1164 mg) which was used as such.This al (700 mg,16.1 mmol) was stirred in CH3CN (50 mL), CDI (654 mg, 40.3 mmol) was added and the resulting solution was stirred at room temperature in a sealed tube for 2.5 h [white precipitation was ed]. Then, NH3 (0.4 M in THF, 80.7 mL, 32.3 mmol) was added at once. The mixture was stirred at room temperature for more than 80 h. The solvent was evaporated and the yellow residue was dissolved in EtOAc (80 mL). The solution was washed with HCl 1M (50 mL) and saturated NaCl solution (5mL). The layers were separated and the organic was dried with Na2SO4. The solvent was evaporated and the beige residue was stirred in warm CH3CN. The suspension was filtered off leaving a white filtercake. The filtercake was washed with CH3CN and dried in vacuo at 50°C, resulting in nd 114 (319 mg) Method A; Rt: 1.56 min. m/z: 431.0 (M-H)- Exact mass: 432.05. 1H NMR (400 MHz, DMSO-d6)  ppm 0.94 - 0.99 (m, 2 H), 1.10 - 1.18 (m, 2 H), 3.91 (s, 3 H), 6.87 (br. s., 1 H), 7.21 (br. s., 1 H), 7.32 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.76 - 7.87 (m, 2 H), 8.20 (br. s., 1 H), 10.29 (br. s., 1 H).

Compound 115: hloro-4,5-difluorophenyl)methyl{[1-(methylcarbamoyl)cyclopropyl ]sulfamoyl}-1H-pyrrolecarboxamide 1-[[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolyl]sulfonylamino]- cyclopropanecarboxylic acid (364 mg, 0.839 mmol) was stirred in dry CH3CN (30 mL). After addition of CDI (340 mg, 2.1 mmol) the mixture became a solution. The reaction mixture was d at room temperature in a sealed tube for 2.5 h. Then Methylamine (2 M in THF, 12 mL, 24 mmol) was added at once. The mixture was stirred at room temperature for 2 h. The reaction was stirred during 80 h. The solvent was distilled off and the e dissolved in 5 mL CH2Cl2/MeOH (90:10) and purified by flash chromatography on silica using a gradient EtOAcheptane 0/100 to 100/0 . The desired fractions were combined and the solvent was ated, resulting in compound 115 (199 mg) Method A; Rt: 1.60 min. m/z: 445.0 (M-H)- 447.0 (M+H)+ Exact mass: 446.10. 1H NMR (400 MHz, DMSO-d6)  ppm 0.91 - 0.98 (m, 2 H), 1.08 - 1.15 (m, 2 H), 2.55 (d, J=4.6 Hz, 3 H), 3.91 (s, 3 H), 7.31 (d, J=2.0 Hz, 1 H), 7.41 (d, J=4.6 Hz, 1 H), 7.58 (d, J=1.5 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 8.14 (br. s., 1 H), 10.31 (br. s., 1 H).

TIP 296 PCT Compound 116: N-(2,4-Difluoromethylphenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide -[(2,4-difluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (310 mg, 0.89 mmol) prepared similarly as described in the synthesis for compound 57 using 2,4-difluoro- 3-methyl-aniline (251mg, 2.22 mmol) was stirred in dry CH3CN (25 mL). (2R)-1,1,1- trifluoropropanamine (251 mg, 2.22 mmol) was added under N2-atm at room temperature.

The mixture was stirred in a sealed tube at 75° C for 42 hours. Then the on mixture was concentrated, water was added (8 mL) and the formed precipitate was filtered off and washed with water/CH3CN (10 mL 5:1).The ed red solid was suspended in boiling diisopropyl ether (3 mL) and 2-propanol (2 mL) was added dropwise. The mixture was left standing for 90 min and then filtered. The precipitate was washed with ropyl ether/2-propanol (4:1, 6 mL) and dried in vacuo at 50°C yielding compound 116 as a slightly red-purple solid (240 mg) Method A; Rt: 1.71 min. m/z: 424.0 (M-H)- 426.0 (M+H)+ Exact mass: . 1H NMR (360 MHz, 6) ppm 1.08 (d, J=7.0 Hz, 3 H), 2.18 (s, 3 H), 3.87 - 3.97 (m, 4 H), 7.07 (td, J=9.0, 1.5 Hz, 1 H), 7.31 - 7.39 (m, 2 H), 7.64 (d, J=1.8 Hz, 1 H), 8.18 (br. s., 1 H), 9.95 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 206.64 °C. nd 117: N-(2,4-Difluoromethylphenyl)methyl{[1-(trifluoromethyl)- cyclopropyl]sulfamoyl}-1H-pyrrolecarboxamide -[(2,4-difluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (310mg, 0.89 mmol) was stirred in dry acetonitrile (25mL) and dry DIPEA (0.61mL, 3.56mmol). 1- (trifluoromethyl)cyclopropanamine (222mg,1.78mmol) was added under N2-atm at room temperature. The reaction mixture was d in a sealed tube at 75°C for 24 h and 110 h at 95°C. Then 1 eq of fluoromethyl)cyclopropanamine was added and the mixture was stirred at 95° for 24 h. The solvent was evaporated leaving yellow oil which was dissolved in CH2Cl2/Methanol (80/20; 5mL) and purified by Flash Chromatography [Biotage Isolera 1 // GraceResolve Silica 12 g // EtOAc-heptane 0/100 to 100/0]. The desired fractions were combined and the solvent was evaporated leaving a red d solid, which was dissolved in a boiling mixture of 2 mL of diisopropyl ether and 3 mL of CH3CN. The solution was allowed to TIP 296 PCT cool while ng. After 45 min the formed precipitate was filtered off and was washed once with its own filtrate and at the end with 2 mL of diisopropyl ether. The white solid was dried in vacuo at 50°C. Method B; Rt: 1.01 min. m/z: 436.0 (M-H)- Exact mass: 437.08. 1H NMR (360 MHz, 6) ppm 1.08 - 1.22 (m, 4 H), 2.18 (s, 3 H), 3.88 (s, 3 H), 7.07 (td, J=9.0, 1.5 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.34 (td, J=8.8, 6 6.2 Hz, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 8.76 (br. s., 1 H), 9.95 (s, 1 H).

Compound 118: N-(2,4-Difluoromethylphenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide The compound was ed similarly as compound 117 using 2.5 eq of 1,1,1-trifluoro methyl-propanamine instead of 1-(trifluoromethyl)cyclopropanamine. The reaction mixture was stirred in a sealed tube at 75°C for 18 h and for 80 h at 95°C. Method B; Rt: 1.01 min. m/z: 438.0 (M-H)- Exact mass: . 1H NMR (400 MHz, DMSO-d6)  ppm 1.37 (s, 6 H), 2.19 (s, 3 H), 3.90 (s, 3 H), 7.06 (td, J=9.0, 1.4 Hz, 1 H), 7.28 - 7.39 (m, 2 H), 7.56 (d, J=1.8 Hz, 1 H), 6 8.05 (br. s., 1 H), 9.94 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at °C/min: peak at 164.23 °C. nd 119: N-(2,4-Difluoromethylphenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide The compound was prepared similarly as compound 117 using (2S)-1,1,1-trifluoropropan amine instead of 1-(trifluoromethyl)cyclopropanamine, the reaction mixture was stirred in a sealed tube for 42 h at 95°C. Then the reaction mixture was concentrated and water was added (8 mL) and the formed precipitate was filtered off and dried in vacuo at 50°C yielding compound 119 as a powder. Method A; Rt: 1.71 min. m/z: 424.0 (M-H)- Exact mass: 425.08. 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=7.0 Hz, 3 H), 2.18 (s, 3 H), 3.87 - 3.98 (m, 4 H), 7.06 (td, J=8.9, 1.5 Hz, 1 H), 7.30 - 7.40 (m, 2 H), 7.63 (d, J=1.8 Hz, 1 H), 8.16 (d, J=8.6 Hz, 1 H), 9.92 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 207.52.

TIP 296 PCT nd 120: N-(3-Chloro-2,4-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide -[(3-chloro-2,4-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (900 mg, 2.44 mmol) prepared similarly as in the synthesis for compound 57 using 3-chloro-2,4- difluoro-aniline (3.5g, 14.46 mmol) was stirred in dry CH3CN (10 mL). (2R)-1,1,1- trifluoropropanamine (689 mg, 6.1mmol) was added under N2-atm at room temperature. The reaction mixture was stirred in a sealed tube at 85°C for 6h and left standing for 18h. The solvent was evaporated and the red residue was ded in DCM. The formed precipitate was filtered off and dried under vacuum at 50 °C. The filtrate was concentrated till precipitation took place.

The formed precipitate was filtered off. The combined precipitates were recrystallized in DIPE/ACN (1:1; 6 mL), left stirring for 2 h then left standing for 18 h, ed off and dried under vacuum at 50°C. The filtrate was left standing for 18h. The formed precipitate was ed off and dried under vacuum at 50°C. The obtained white solid was recrystallized in DIPE/ACN (1:1; 4 mL), left stirring for 2h then left standing for 18h, filtered off and dried under vacuum at 50°C. The 2 solids were combined (394 mg). Method A; Rt: 1.85 min. m/z: 444.0 (M-H)- Exact mass: 445.03. 1H NMR (400 MHz, DMSO-d6)  ppm 1.10 (d, J=7.0 Hz, 3 H), 3.85 - 4.00 (m, 4 H), 7.30 - 7.41 (m, 2 H), 7.53 (td, J=8.7, 5.8 Hz, 1 H), 7.65 (d, J=1.5 Hz, 1 H), 7.97 (br. s., 1 H), .14 (br. s., 1 H).

Alternative synthesis of compound 120: Methyl 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (6.61 g, 21.03 mmol) and 3-chloro-2,4-difluoroaniline (4.13 g, 25.2 mmol) were dissolved in ydrofuran (150 mL) and this was stirred and cooled in an ice-water bath. Over a period of 5 minutes lithium bis(trimethylsilyl)amide in toluene (63.1 mL, 1 M, 63.1 mmol) was added dropwise. The resulting mixture was stirred for 1 h while cooling was continued. Another 2 eq of lithium bis(trimethylsilyl)amide in toluene (42.1 mL, 1 M, 42.1 mmol) were added and the resulting mixture was stirred for 1 hour at room temperature. The ing mixture was quenched using ammonium de (sat. / 200 mL). The resulting mixture was extracted using EtOAc (3 x 250 mL). The combined ts were washed with brine (250 mL), dried on Na2SO4, filtered and concentrated in vacuo ng a brown . This powder was crystallized twice out of methanol/water. The precipitation was collected on a glass filter. The obtained powder was purified by silica gel column chromatography using gradient elution from heptane to EtOAc (100:0 to 0:100). The obtained e was crystallized again out of methanol/water. The white crystals were collected on a glass filter and dried in a vacuum oven at TIP 296 PCT 55°C for 24 hours yielding compound 120 (3.03 g) as a white powder. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 217.6°C.

Compound 121: N-(3-Chloro-2,4-difluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide chloro-2,4-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (900mg, 2.44 mmol) prepared similarly as in the synthesis for compound 57 3-chloro-2,4- difluoro-aniline (3.5g, 14.46 mmol) was stirred in dry CH3CN (10 mL). 3-methyloxetanamine (255 mg, 2.93mmol) was added under N2-atm. The reaction mixture was stirred in a sealed tube at room temperature for 18 h. The solvent was evaporated. The residue was stirred in .

The formed precipitate was filtered off [fraction 1]. The te was evaporated and the residue was dissolved in CH2Cl2/MeOH (9/1, 5 mL) and purified by Flash Chromatography [Biotage Isolera 1 // GraceResolve Silica 12 g // EtOAc-heptane 0/100 to 100/0 ]. The desired fractions were combined and the solvent was ated leaving a white solid which was tallized in diisopropyl ether/CH3CN (1:1; 6 mL), left stirring for 2 h then left standing for 18 h, filtered off and dried in vacuo at 50°C yielding white powder which was ed with fraction 1. Method B; Rt: 0.88 min. m/z: 418.0 (M-H)- Exact mass: .1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 3.89 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.31 - 7.38 (m, 2 H), 7.53 (td, J=8.7, 5.8 6 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.98 (br. s., 1 H), 10.14 (br. s., 1 H).

Synthesis of methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate sulfonic acid (200 mL, 3.01 mol) was cooled to 0°C and to this stirring liquid was added methyl 1-methylpyrrolecarboxylate (75 g, 538.97 mmol) drop wise. After addition the mixture was d to reach room temperature. Then it was stirred for r hour. The resulting mixture was added drop wise to a mechanically stirred, temperature controlled icewater mixture (2500 mL) keeping the temperature under 5°C. A white precipitation was formed.This precipitate was collected on a glass filter and this was washed with cold water (1000 mL). The obtained white powder was dried in a vacuum oven at 55°C for 24 hours yielding methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate (99 g) as a bright white powder.

Synthesis of methyl 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate Methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate (15 g, 63.11 mmol) was loaded in a pressure tube and this was dissolved in acetonitrile (150 mL). To this solution was added TIP 296 PCT diisopropylethylamine (27.2 mL, 157.8 mmol) followed by (R)-1,1,1-trifluoropropylamine (10.7 g, 94.7 mmol). The pressure tube was flushed with nitrogen and closed. Then it was stirred in a pre-heated oil bath at 80°C for 6 hours.The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL) and this was washed with HCl (1M / aq / 2x 250 mL). The organics were dried on , ed and concentrated in vacuo. The ed residue was dried in a vacuum oven at 55°C for 24 hours yielding methyl 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate as a yellowish powder (18 g).

Compound 122: 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]-N- [3-(trifluoromethyl)phenyl]pyrrolecarboxamide Into a 100 mL round bottom flask equipped with a magnetic stir bar was placed methyl 1- methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (1 g, 3.18 mmol), anhydrous THF (40 mL), and 3-aminobenzotrifluoride (666 mg, 4.14 mmol). The vial was sealed and placed into an ice-water bath and to it was added LHMDS (9.6 mL of a 1 M solution in THF) slowly via syringe (approx rate of 2mL/min). Conversion to product seen after min at 0°C. Sat. aq. ammonium chloride was added to quench the reaction. This was diluted with ethyl e (100 mL) and the mixture partitioned with ethyl acetate (3 x 100 mL). The c layers were ed, dried (magnesium sulfate), the solids were removed by filtration and the solvents of the te were removed under reduced pressure. The crude was partially purified via silica column chromatography using a dichloromethane to ethylacetate gradient.

The solvent of the best fractions were removed under reduced pressure and the crude was recrystallized in ethanol/water. (1228 mg) Method B; Rt: 1.92 min. m/z: 442.0 (M-H)- Exact mass: 443.10. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 3.86 - 3.92 (m, 1 H), 3.94 (s, 3 H), 7.33 - 7.47 (m, 2 H), 7.58 (t, J=8.0 Hz, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.99 (d, J=8.8 Hz, 1 H), 8.11 - 8.24 (m, 2 H), 10.34 (s, 1 H).

Compound 123:N-(3-Chlorofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Into a 100 mL round bottom flask, equipped with a magnetic stir bars was placed methyl 1- methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (1 g, 3.18 mmol), anhydrous THF (40 mL), and 3-chlorofluoro-aniline (602.1 mg, 4.136 mmol).The flask was sealed and placed into an ice-water bath and to it was added LHMDS (9.6 mL of a 1M solution in THF/ethylbenzene) slowly via e (approx rate of 2 ). Conversion to t seen after 30 min at 0°C. Sat. aq. ammonium chloride was added to quench the reaction. This was diluted with ethyl acetate (100 mL) and the mixture partitioned with ethyl acetate (3 x 100 mL). The organic layers were ed, dried (magnesium sulfate), the solids were removed by tion and the solvents of the filtrate were removed under reduced re. The crudes were partially purified via silica column chromatography using a dichloromethane to ethylacetate gradient. The solvent of the best fractions were removed under d pressure.The residue was recrystalized from iPrOH (772 mg) Method A; Rt: 1.79 min. m/z: 426.0 (M-H)- Exact mass: 427.04. 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=7.0 Hz, 3 H), 3.85 - 4.01 (m, 1 H), 3.94 (s, 3 H), 7.38 (d, J=2.0 Hz, 1 H), 7.51 (t, J=9.8 Hz, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.99 - 8.09 (m, 1 H), 8.14 - 8.24 (m, 2 H), .36 (s, 1 H).

Compound 124: N-(3-Bromofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 124 (598 mg) was prepared similarly as described for compound 123, using 3- bromofluoro-aniline instead of 3-chlorofluoro-aniline. Method B; Rt: 1.07 min. m/z: 472.0 (M-H)- 960(2M+18) Exact mass: 471.0.1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 3.84 - 3.99 (m, 1 H), 3.92 (s, 3 H), 7.32 - 7.41 (m, 2 H), 7.64 (d, J=1.8 Hz, 1 H), 7.70 (ddd, 6 J=9.0, 4.4, 2.6 Hz, 1 H), 8.11 - 8.20 (m, 2 H), 10.21 (s, 1 H).

Compound 125: N-[4-Fluoro(trifluoromethyl)phenyl]methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 125 (664 mg) was prepared similarly as compound 123 using 4-fluoro (trifluoromethyl)aniline (740.9 mg, 4.136 mmol) 3-chlorofluoro-aniline . Method B; Rt: 1.96 TIP 296 PCT min. m/z: 460.0 (M-H)- 479.2(M+18) Exact mass: 461.06. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=7.04 Hz, 3 H) 3.87 - 3.98 (m, 1 H) 3.93 (s, 3 H) 7.40 (t, J=9.13 Hz, 1 H) 7.38 (d, J=1.76 Hz, 1 H) 7.65 (d, J=1.76 Hz, 1 H) 7.68 (ddd, J=9.02, 4.40, 2.64 Hz, 1 H) 8.03 (dd, J=6.82, 2.64 Hz, 1 H) 8.17 (d, J=8.80 Hz, 1 H) 10.28 (s, 1 H). nd 126: yanofluorophenyl)[(2,2-difluoroethyl)sulfamoyl]methyl-1H- pyrrolecarboxamide 4-(chlorosulfonyl)methyl-1H-pyrrolecarboxylate (made by the procedure described in the synthesis of 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid) (5.0 g, 21.0 mmol) was dissolved in acetonitrile (50 mL). To this was added diisopropylethylamine (9.06 mL, 52.6 mmol) followed by 2,2-difluoroethylamine (1.93 g, 23.1 mmol) and the resulting mixture was refluxed for 2 hours. Then the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and this was washed with aqueous hydrochloric acid (2 x 150 mL, 1N). The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl 4-(2,2-difluoroethylsulfamoyl )methyl-pyrrolecarboxylate (5.4 g) as light brown oil which solidified while standing and was used as such. Methyl 4-(2,2-difluoroethylsulfamoyl)methyl-pyrrole ylate (5.4 g, 19.1 mmol) was dissolved in tetrahydrofuran (50 mL). To this was added an s solution of lithium hydroxide (0.69 g, 28.7 mmol) in distilled water (7 mL) and a turbid mixture was obtained. Then methanol (3 mL) was added. The resulting mixture was stirred for 24 hours at room temperature and at 60°C for 1 hour. To this was added lithium hydroxide (0.458 g, 19.1 mmol). The on mixture was further heated at 60°C for 3 hours.

Then it was concentrated to keep ~ 5 mL aqueous solution and extra 15 mL of distilled water was added. Then this was neutralized using an exact amount of hydrochloric acid (47.8 mL, 47.83 mmol/ 1M / aq /). The ing mixture was extracted using methyltetrahydrofuran (3 x 20 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo ng of 4-(2,2-difluoroethylsulfamoyl)methyl-pyrrolecarboxylic acid (4.88 g) as white powder which was used as such. 1H NMR (400 MHz, DMSO-d6)  ppm 3.15 (tdd, J=15.4, 15.4, 6.4, 4.0 Hz, 2 H), 3.88 (s, 3 H), 5.99 (tt, J=55.7, 4.2 Hz, 1 H), 6.98 (d, J=2.0 Hz, 1 H), 7.61 (d, J=2.0 Hz, 1 H), 7.84 (t, J=6.4 Hz, 1 H). 4-(2,2-difluoroethylsulfamoyl)methyl-pyrrole carboxylic acid (500 mg, 1.77 mmol) and 5-aminofluorobenzonitrile (0.5 g, 3.54 mmol) and HATU (0.81 g, 2.12 mmol) were dissolved in DMF (2.5 mL) containing diisopropylethylamine (1. 22 mL, 7.08 mmol). The reaction mixture was stirred at room ature for 66 hours. The reaction mixture was directly loaded on column and purified using silica gel column TIP 296 PCT chromatography (ethyl acetate in heptane from 20 to 80%). The desired fractions were combined and ated to keep ~50 mL of the solvent and 20 mL of diethyl ether was added. The formed precipitate was filtered and washed with diethyl ether to afford compound 126 (412 mg) as white solid. Method B; Rt: 0.88 min. m/z: 385 (M-H)- Exact mass: 386.07.1H NMR (400 MHz, DMSO-d6)  ppm 3.20 (td, J=15.3, 4.0 Hz, 2 H), 3.92 (s, 3 H), 6.02 (tt, J=55.7, 4.0 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.65 (d, J=1.5 Hz, 1 H), 7.93 (br. s, 1 H), 8.01 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 10.36 (br. s., 1 H).

Compound 127: N-(3-Bromofluorophenyl)[(2,2-difluoroethyl)sulfamoyl]methyl-1H- pyrrolecarboxamide Compound 127 (452 mg) as white powder was synthesized rly as described for compound 126 using 3-bromofluoroaniline instead of ofluorobenzonitrile in the last step.

Method B; Rt: 1.00 min. m/z: 438 (M-H)- Exact mass: . 1H NMR (400 MHz, DMSO-d6)  ppm 3.20 (td, J=15.3, 4.0 Hz, 2 H), 3.92 (s, 3 H), 6.02 (tt, , 4.0 Hz, 1 H), 7.34 - 7.39 (m, 2 H), 7.63 (d, J=1.5 Hz, 1 H), 7.70 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 7.88 (br. s., 1 H), 8.14 (dd, J=6.5, 2.5 Hz, 1 H), 10.21 (br. s., 1 H).

Compound 128: N-(3-Chlorofluorophenyl)[(2,2-difluoroethyl)sulfamoyl]methyl-1H- pyrrolecarboxamide F N O S H N F N O Cl Compound 128 (372 mg) as white powder was synthesized similarly as described for compound 126 using 3-chlorofluoroaniline instead of 5-aminofluorobenzonitrile in the last step.

Method B; Rt: 0.99 min. m/z: 394 (M-H)- Exact mass: 395.03. 1H NMR (400 MHz, DMSO-d6)  ppm 3.20 (td, J=15.3, 4.0 Hz, 2 H), 3.92 (s, 3 H), 6.02 (tt, J=55.7, 4.0 Hz, 1 H), 7.35 (d, J=1.8 Hz, 1 H), 7.40 (t, J=9.1 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.89 (br. s., 1 H), 8.02 (dd, J=6.9, 2.5 Hz, 1 H), 10.22 (br. s., 1 H).

Compound 129: 4-[(2,2-Difluoroethyl)sulfamoyl]-N-(3,4-difluorophenyl)methyl-1H-pyrrole- 2-carboxamide TIP 296 PCT Compound 129 (371 mg) as white powder was synthesized similarly as described for compound 126 using fluoroaniline instead of 5-aminofluorobenzonitrile in the last step. Method B; Rt: 0.94 min. m/z: 378 (M-H)- Exact mass: . 1H NMR (400 MHz, DMSO-d 6)  ppm 3.20 (td, J=15.2, 4.1 Hz, 2 H), 3.92 (s, 3 H), 6.02 (tt, J=55.5, 4.0 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.41 (dt, J=10.3, 9.0 Hz, 1 H), 7.46 - 7.53 (m, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.79 - 7.94 (m, 2 H), .24 (br. s., 1 H).

Compound 130: N-(3-Chloro-4,5-difluorophenyl)[(2,2-difluoroethyl)sulfamoyl]methyl- 1H-pyrrolecarboxamide Compound 130 was synthesized similarly as described for compound 126. In the last step, 3- chloro-4,5-difluoroaniline hydrochloride (synthesis bed in sis for compound 57) instead of 5-aminofluorobenzonitrile was used and the reaction time was 18 hours instead of 66 hours. The reaction mixture was ed using silica gel column chromatography ent elution: ethyl acetate in heptane from 0 to 100 % and from 30 to 50 %). The purest fractions were combined and stored as such for 66 hours. White precipitates were filtered and washed with heptane to afford a white solid. The solids were dissolved in methanol and concentrated to dryness to afford a white powder which was warm triturated in methanol (3 mL) and cooled to room temperature. The white solids were filtered and washed with methanol to afford compound 130 (131 mg) as white powder. Method B; Rt: 0.94 min. m/z: 412 (M-H)- Exact mass: 413.02. 1H NMR (400 MHz, DMSO-d 6)  ppm 3.20 (td, J=15.3, 4.0 Hz, 2 H), 3.91 (s, 3 H), 6.02 (tt, J=55.7, 4.0 Hz, 1 H), 7.35 (d, J=2.0 Hz, 1 H), 7.49 - 8.27 (m, 4 H), 10.31 (br. s., 1 H).

Compound 131: N-(3-Chlorofluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT 4-(chlorosulfonyl)methyl-1H-pyrrolecarboxylate (made by the procedure described in the synthesis of 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid) (5.0 g, 21.0 mmol) was dissolved in acetonitrile (50 mL). To this was added DIPEA (9.06 mL, 52.6 mmol) followed by 2,2,2-trifluoroethylamine (2.29g, 23.1 mmol) and the resulting mixture was refluxed for 2 hours. Then the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and this was washed with aqueous hydrochloric acid (2 x 150 mL, 1N). The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl 1-methyl(2,2,2-trifluoroethyl- oyl)pyrrolecarboxylate (5.3 g) as light brown oil which fied while standing and was used as such. Methyl 1-methyl(2,2,2-trifluoroethylsulfamoyl)pyrrolecarboxylate (5.3 g, 17.65 mmol) was dissolved in tetrahydrofuran (50 mL) and a solution of lithium hydroxide (0.634 g, 26.5 mmol) in distilled water (7 mL) was added and a turbid mixture was ed.

Then methanol (3 mL) was added and the e became clear. The resulting mixture was stirred at room temperature for 24 hours and at 60°C for 1 hour. To this was added lithium hydroxide (0.423 g, 17.7 mmol). The reaction mixture was further heated at 60°C for 3 hours.

Then the reaction mixture was concentrated to keep ~ 5 mL and led water (15 mL) was added. The mixture was neutralized using an exact amount of hydrochloric acid (1M / aq / 31.6 mL, 31.58 mmol). The resulting mixture was ted using methyltetrahydrofuran (3 x 20 mL).

The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding 1-methyl(2,2,2-trifluoroethylsulfamoyl)pyrrolecarboxylic acid (4.62 g) as beige powder which was used as such. 1-methyl(2,2,2-trifluoroethylsulfamoyl)pyrrolecarboxylic acid (500 mg, 1.66 mmol) and 3-chlorofluoroaniline (0.48 g, 3.32 mmol) and HATU (0.76 g, 1.99 mmol) were dissolved in DMF (2 mL) containing diisopropylethylamine (1.14 mL, 6.64 mmol). The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was directly loaded on column and purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 80%). The desired fractions were combined and ated to keep ~50 mL of the t and 20 mL of diethyl ether was added. The formed precipitate was filtered and washed with diethyl ether to afford an off white solid which was recrystalized from acetonitrile (5 mL) to afford compound 131 (117 mg) as white solid. Method B; Rt: 1.03 min. m/z: 412 (M-H)- 431(M+18) Exact mass: 413.02 1H NMR (400 MHz, DMSO-d6)  ppm 3.62 (q, J=9.5 Hz, 2 H), 3.91 (s, 3 H), 7.31 - 7.45 (m, 2 H), 7.61 - 7.70 (m, 2 H), 8.02 (dd, J=6.8, 2.6 Hz, 1 H), 8.27 (br. s., 1 H), 10.23 (br. s, 1 H).

TIP 296 PCT Compound 132: N-(3,4-Difluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]-1H- ecarboxamide nd 132 was synthesized similarly as described for compound 131 using 3,4-difluoroaniline(433 mg, 3.32 mmol) instead of 3-chlorofluoroaniline in the last step. The off white solid was recrystalized from methanol to afford compound 132 (208 mg) as white powder. Method B; Rt: 0.98 min. m/z: 396 (M-H)- Exact mass: 397.05 . 1H NMR (400 MHz, DMSO-d6)  ppm 3.62 (q, J=9.6 Hz, 2 H), 3.91 (s, 3 H), 7.35 (d, J=1.8 Hz, 1 H), 7.41 (dt, J=10.5, 9.1 Hz, 1 H), 7.45 - 7.52 (m, 1 H), 7.65 (d, J=1.8 Hz, 1 H), 7.87 (ddd, J=13.4, 7.5, 2.4 Hz, 1 H), 8.26 (br. s., 1 H), 10.24 (s, 1 H).

Compound 133: N-(3-Chloro-4,5-difluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]- 1H-pyrrolecarboxamide nd 133 was synthesized similarly as described for compound 131. 3-chloro-4,5- difluoroaniline hydrochloride (664 mg, 332 mmol) (synthesis described in synthesis for compound 57) was used instead of 3-chlorofluoroaniline in the last step. The reaction mixture was directly loaded on column and purified using silica gel column tography (ethyl e in heptane from 0 to 100 %) The purest fractions were combined and stored as such for 66 hours. Off white crystals were formed and filtered and washed with heptane to afford a beige solid. The solid was triturated in diethyl ether (15 mL) and filtered and washed with diethyl ether to afford a white powder. The white powder was purified using silica gel column chromatography (methanol in CH2Cl2 from 0 to 2%) The purest fractions were ed and concentrated to dryness to afford compound 133 (41 mg) as white powder. Method B; Rt: 1.09 min. m/z: 430 (M-H)- 863(2M+H) Exact mass: 431.01 . 1H NMR (400 MHz, DMSO-d6)  ppm 3.62 (q, J=9.6 Hz, 2 H), 3.91 (s, 3 H), 7.36 (d, J=1.8 Hz, 1 H), 7.67 (d, J=1.8 Hz, 1 H), 7.77 - 7.85 (m, 2 H), 8.29 (br. s., 1 H), 10.32 (br. s., 1 H).

Compound 134: N-(3-Cyanofluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT Compound 134 was synthesized similarly as described for compound 131 using 5-amino fluorobenzonitrile (466 mg,3.32 mmol) instead of 3-chlorofluoroaniline in the last step. The reaction mixture was directly loaded on column and purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 80%). The desired fractions were combined and evaporated to keep ~50 mL of the solvent and 20 mL of diethyl ether was added. The formed precipitate was filtered and washed with diethyl ether to afford an off white solid which was purified using Prep. LCMS. (Hypersyl C18 BDS-3µm,100 x 4.6 mm) Mobile phase (NH4HCO3 0.2% in water, acetonitrile) the desired fractions were combined and evaporated to dryness, dissolved in ol again and evaporated to dryness and dried in vacuum oven overnight to afford compound 134 (147 mg) as white . Method B; Rt: 0.93 min. m/z: 403 (M-H)- Exact mass: . 1H NMR (400 MHz, DMSO-d6)  ppm 3.61 (q, J=9.5 Hz, 2 H), 3.92 (s, 3 H), 7.37 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.66 (d, J=1.5 Hz, 1 H), 8.00 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.33 (br. s, 1 H), 8.22 (dd, J=5.9, 2.6 Hz, 1 H), 10.38 (br. s., 1 H).

Compound 135: romofluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]-1H- pyrrolecarboxamide Compound 135 was synthesized similarly as bed for compound 134 using 3-bromo fluoroaniline (631 mg, 3.32 mmol) d of 5-aminofluorobenzonitrile in the last step.

Method B; Rt: 1.04 min. m/z: 456 (M-H)- Exact mass: 456.97 . 1H NMR (400 MHz, DMSO-d 6)  ppm 3.62 (q, J=9.5 Hz, 2 H), 3.91 (s, 3 H), 7.34 - 7.40 (m, 2 H), 7.65 (d, J=1.8 Hz, 1 H), 7.70 (ddd, J=9.1, 4.3, 2.4 Hz, 1 H), 8.14 (dd, J=6.4, 2.6 Hz, 1 H), 8.26 (br. s., 1 H), 10.21 (br. s, 1 H).

Compound 136: N-(3-Chloro-4,5-difluorophenyl)-1,5-dimethyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Crude ethyl 1,5-dimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylate (described in synthesis of compound 89)(1800 mg, 5.689 mmol) was dissolved in methanol (8 mL), lithium hydroxide (720 mg, 30.1 mmol) in water (2 mL) was added and the reaction mixture was heated at 50°C for 2 hours. The reaction mixture was evaporated to dryness and co evaporated with toluene (2 x 50 mL) to afford a beige powder. Half of the above obtained powder was dissolved in water (5 mL), and HCl (1M in water, 15.02 mL) was added. The water layer was extracted with Me-THF (3 x 20 mL). The combined organic layers were washed with Brine, dried 4) and concentrated to dryness to afford 1,5-dimethyl(N-(3-methyloxetan yl)sulfamoyl)-1H-pyrrolecarboxylic acid (600 mg). 1,5-dimethyl(N-(3-methyloxetanyl)- sulfamoyl)-1H-pyrrolecarboxylic acid (600 mg, 2.08 mmol) was ved in DMF (3 mL). diisopropylethylamine (1.08 mL, 6.24 mmol), HATU (950 mg, 2.50 mmol), and 3-chloro-4,5- difluoroaniline hydrochloride (described in the synthesis of compound 57) were added and the on mixture was stirred at room temperature for 68 hours and at 60°C for 2 hours. The reaction mixture was ly loaded on column. The reaction mixture was purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 80%). The desired fraction were ed and concentrated to keep ~ 100 mL of t. The white precipitate was filtered and washed with petroleum ether and dried in vacuum oven overnight to afford compound 136 (604 mg) as white powder. Method B; Rt: 1.03 min. m/z: 432 (M-H)- Exact mass: 433.07 . 1H NMR (400 MHz, 6)  ppm 1.49 (s, 3 H), 2.44 (s, 3 H), 3.83 (s, 3 H), 4.11 (d, J=6.4 Hz, 2 H), 4.59 (d, J=5.9 Hz, 2 H), 7.35 (s, 1 H), 7.77 - 7.86 (m, 2 H), 7.97 (s, 1 H), 10.20 (s, 1 H).

Compound 137: N-(3-Chloro-4,5-difluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide In a pressure tube, crude ethyl 4-chlorosulfonyl-1,5-dimethyl-pyrrolecarboxylate (3.03 g, 11.4 mmol) (synthesis described in sis for compound 89) was dissolved in acetonitrile (30 mL).

To this was added diisopropylethylamine (4.91 mL, 28.5 mmol) followed by (R)-1,1,1-trifluoro- 2-propylamine (3.22 g, 28.5 mmol) and the tube was closed and resulting mixture was heated at 80°C for 2 hours. The reaction mixture was concentrated and the resulting orange sticky oil was TIP 296 PCT dissolved in dichloromethane (50 mL) and this was washed with aqueous hloric acid (1N, 2 x 20 mL). The cs were dried on sodium sulphate, filtered and concentrated in vacuo ng orange oil (3.41 g) which was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 80%). The desired fractions were combined and evaporated to dryness to afford (R)-ethyl 1,5-dimethyl(N-(1,1,1-trifluoropropanyl)sulfamoyl)-1H- pyrrolecarboxylate (2.3 g) as white powder which was used as such.(R)-ethyl 1,5-dimethyl (N-(1,1,1-trifluoropropanyl)sulfamoyl)-1H-pyrrolecarboxylate (2.3 g, 6.72 mmol) was dissolved in ethanol (30 mL) and sodium hydroxide in water (13.4 mL, 13.4 mmol, 1 M) was added and the reaction mixture was stirred at 40°C for 2 hours and at room temperature for 66 hours. The reaction mixture was heated at 70°C for 2 hours. Sodium hydroxide in water (6.72 mL, 6.72-mmol, 1 M) was added to the reaction mixture which was heated at 70°C for 2 hours more. The reaction mixture was allowed to reach room temperature and was concentrated to keep ~20 mL. HCl (20.15 mL, 20.15 mmol, 1M) was added. The water layer was extracted with Me-THF (3 x 20 mL). The combined organic layers were washed with Brine, dried (Na2SO4) and concentrated to dryness to afford (R)-1,5-dimethyl(N-(1,1,1-trifluoropropanyl)sulfamoyl)- 1H-pyrrolecarboxylic acid (2.05 g). (R)-1,5-dimethyl(N-(1,1,1-trifluoropropan yl)sulfamoyl)-1H-pyrrolecarboxylic acid (450 mg, 1.43 mmol) and 3-chloro-4,5- difluoroaniline hydrochloride (0.57 g, 2.86 mmol) (synthesis described in synthesis for compound 57) and HATU (0.73 g, 1.91 mmol) were ved in DMF (2 mL) containing ropylethylamine (0.82 mL, 4.77 mmol). The reaction mixture was d at 40°C for 66 hours. The on mixture was ly loaded on column. The reaction mixture was purified using silica gel column chromatography (ethyl e in heptane from 20 to 80%). The desired fractions were combined and evaporated to keep ~50 mL of solvent. The precipitates were filtered and washed with petroleum ether and dried in vacuum oven at 50°C overnight to afford compound 137 (490 mg) as white powder. Method B; Rt: 1.16 min. m/z: 458 (M-H)- 460 (M+H)+ Exact mass: 459.04 . 1H NMR (400 MHz, DMSO-d 6)  ppm 1.07 (d, J=6.8 Hz, 3 H), 2.44 (s, 3 H), 3.69 - 3.95 (m, 4 H), 7.37 (s, 1 H), 7.76 - 7.86 (m, 2 H), 8.21 (br. s., 1 H), 10.24 (br. s., 1 H).

Compound 138: N-(3-Chlorofluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 138 (510 mg) as white powder was synthesized similarly as described for compound 137 using 3-chlorofluoroaniline instead of 3-chloro-4,5-difluoroaniline hydrochloride in the TIP 296 PCT last step. Method B; Rt: 1.10 min. m/z: 440 (M-H)- Exact mass: 441.05 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=7.0 Hz, 3 H), 2.44 (s, 3 H), 3.75 - 3.87 (m, 4 H), 7.36 (s, 1 H), 7.39 (t, J=9.1 Hz, 1 H), 7.66 (ddd, J=9.1, 4.3, 2.6 Hz, 1 H), 8.02 (dd, J=6.9, 2.5 Hz, 1 H), 8.19 (br. s, 1 H), 10.15 (s, 1 H).

Compound 139: N-(3,4-Difluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 139 (462 mg) as white powder was synthesized similarly as described for compound 137 using 3,4-difluoroaniline instead of 3-chloro-4,5-difluoroaniline hydrochloride in the last step. Method B; Rt: 1.06 min. m/z: 424 (M-H)- H)+ Exact mass: 425.08 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=6.8 Hz, 3 H), 2.44 (s, 3 H), 3.75 - 3.88 (m, 4 H), 7.35 (s, 1 H), 7.40 (dt, J=10.5, 9.2 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 7.87 (ddd, J=13.4, 7.6, 2.5 Hz, 1 H), 8.19 (br. s., 1 H), 10.17 (s, 1 H).

Compound 140: N-(3-Cyanofluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide (R)-1,5-dimethyl(N-(1,1,1-trifluoropropanyl)sulfamoyl)-1H-pyrrolecarboxylic acid (168 mg, 0.53 mmol) (synthesis described in sis for compound 137) 5-amino fluorobenzonitrile (0.15 g, 1.07 mmol) and HATU (0.24 g, 0.64 mmol) were dissolved in DMF (1 mL) containing diisopropylethylamine (0.23 mL, 1.34 mmol). The reaction mixture was stirred at 50°C for 1 hour. The on mixture was purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 80%). The desired ons were combined and evaporated to keep ~50 mL of the solvent. The white solids were filtered and dried in vacuum oven to afford compound 140 (180 mg) as white powder. Method B; Rt: 1.00 min. m/z: 431 (M-H)- Exact mass: 432.09 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=6.8 Hz, 3 H), 2.44 (s, 3 H), 3.76 - 3.87 (m, 1 H), 3.84 (s, 3 H), 7.38 (s, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.10 - 8.35 (m, 1 H), 8.22 (dd, J=5.9, 2.6 Hz, 1 H), 10.30 (br. s, 1 H).

TIP 296 PCT Compound 141: N-(3-Bromofluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 141 (210 mg) as white powder was synthesized similarly as described for nd 140 using 3-bromofluoroaniline (0.20 g, 1.07 mmol) instead of 5-aminofluorobenzonitrile.

Method B; Rt: 1.11 min. m/z: 484 (M-H)- Exact mass: 485.00 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=7.0 Hz, 3 H), 2.43 (s, 3 H), 3.74 - 3.89 (m, 1 H), 3.83 (s, 3 H), 7.29 - 7.40 (m, 2 H), 7.70 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 8.13 (dd, J=6.4, 2.6 Hz, 1 H), 8.18 (br. s., 1 H), 10.13 (s, 1 H).

Compound 142: N-[4-Fluoro(trifluoromethyl)phenyl]-1,5-dimethyl{[(1R)-2,2,2-trifluoro- 1-methylethyl]sulfamoyl}-1H-pyrrolecarboxamide nd 142 (187 mg) as white powder was synthesized similarly as described for compound 140 using 4-fluoro(trifluoromethyl)aniline (0.19 g, 1.07 mmol) instead of 5-amino fluorobenzonitrile. Method B; Rt: 1.14 min. m/z: 474 (M-H)- Exact mass: 475.08 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=7.0 Hz, 3 H), 2.44 (s, 3 H), 3.76 - 3.85 (m, 1 H), 3.84 (s, 3 H), 7.39 (s, 1 H), 7.49 (br. t, J=9.8, 9.8 Hz, 1 H), 8.00 - 8.08 (m, 1 H), 8.10 - 8.30 (m, 1 H), 8.19 (dd, J=6.6, 2.6 Hz, 1 H), 10.28 (s, 1 H).

Compound 143: N-(3-Chloro-2,4-difluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Compound 143 (147 mg) as white powder was synthesized similarly as described for compound 140 using 3-chloro-2,4-difluoroaniline (0.17 g, 1.07 mmol) instead of 5-amino fluorobenzonitrile. The reaction mixture was stirred at 60°C for 2 hours more. Method B; Rt: 1.07 min. m/z: 458 (M-H)- Exact mass: 459.04 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=7.0 Hz, 3 H), 2.44 (s, 3 H), 3.82 (s, 3 H), 3.76 - 3.91 (m, 1 H), 7.34 (td, J=9.0, 2.0 Hz, 1 H), 7.35 (s, 1 H), 7.52 (td, J=8.7, 5.8 Hz, 1 H), 8.20 (br. s., 1 H), 10.05 (s, 1 H).

Synthesis of ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrolecarboxylate (step1) Ethyl 1, 3-dimethylpyrrolecarboxylate (10.7 g, 61.0 mmol) was added drop wise to sulfonic acid (33.3 mL, 500 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir 2 hours. The resulting mixture was added drop wise to a stirred, ature controlled ice-water mixture (200 mL) keeping the temperature under 5°C. A white precipitation was formed. The obtained aqueous suspension was extracted using dichloromethane (3 x 100 mL). The combined extracts were washed with Brine and dried on sodium sulphate, filtered and trated in vacuo yielding ethyl 4-chlorosulfonyl- 1,3-dimethyl-pyrrolecarboxylate (13.96 g) as a brown powder which was used as such.

Method B; Rt: 1.11 min. m/z: 264 (M-H)- Exact mass: 265.02.

Synthesis of Ethyl 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (step 2).

In a pressure tube, ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrolecarboxylate (4.65 g, 17.5 mmol) was dissolved in itrile (30 mL). To this was added diisopropylethylamine (7.54 mL, 43.8 mmol) ed by (R)-1,1,1-trifluoropropylamine (2.97 g, 26.3 mmol) and the tube was closed and resulting mixture was heated at 80°C overnight. Then the mixture was cooled to room ature and trated. The resulting brown sticky oil was dissolved in dichloromethane (100 mL) and this was washed with hydrochloric acid (1N, 2 x 30 mL). The organics were dried on sodium te, filtered and concentrated in vacuo yielding brown oil (5.12 g). The brown oil was purified using silica gel column chromatography (gradient elution: ethyl acetate: heptane from 0 to 80%). The desired fractions were combined and evaporated to dryness to afford ethyl 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole- 2-carboxylate (3.05 g) as light yellow . Method B; Rt: 0.96 min. m/z: 341 (M-H)- Exact mass: 342.09.

Synthesis of 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylic acid ).

Ethyl 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (3.05 g, 8.46 mmol) was dissolved in ethanol (50 mL) and sodium hydroxide in water (1 M, 42.3 mL, 42.3 mmol) was added. The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was allowed to reach room temperature and was concentrated to keep ~20 mL solvent.

TIP 296 PCT The solution was diluted with aqueous hydrochloride (1 M, 42.3 mL, 42.3 mmol) and extracted with Me-THF (3 x 30 mL). The combined organic layers were washed with Brine, dried (Na2SO4) and concentrated to dryness to afford 1,3-dimethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid (2.71g). Method B; Rt: 0.45 min. m/z: 313 (M-H)- Exact mass: 314.05.

Compound 144: N-(3,4-Difluorophenyl)-1,3-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide (step 4) 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (450 mg, 1.43 mmol) and 3,4-difluoroaniline (0.37 g, 2.86 mmol) and HATU (0.73 g, 1.91 mmol) were dissolved in DMF (1.92 mL, 24.7 mmol) containing diisopropylethylamine (0.82 mL, 4.77mmol). The reaction mixture was stirred at 40°C for 42 hours and allowed to reach room temperature. The reaction mixtures were purified using silica gel column chromatography (gradient n: ethyl acetate in heptane from 10 to 70%). The d fractions were combined and evaporated to keep ~50 mL of the solvent. The white solids were ed and dried overnight in vacuum oven at 50°C to afford compound 144 (470 mg) as white powder. Method B; Rt: 1.01 min. m/z: 424 (M-H)- Exact mass: 425.08 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.29 (s, 3 H), 3.72 (s, 3 H), 3.82 (quin, J=7.5 Hz, 1 H), 7.37 - 7.46 (m, 2 H), 7.50 (s, 1 H), 7.73 - 7.92 (m, 1 H), 8.16 (br. s., 1 H), 10.31 (s, 1 H).

Compound 145: N-(3-Chlorofluorophenyl)-1,3-dimethyl{[(1R)-2,2,2-trifluoro ethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 145 (452 mg) as white powder was synthesized similarly as described for nd 144 using 3-chlorofluoroaniline instead of 3,4-difluoroaniline . Method B; Rt: 1.06 min. m/z: 440 (M-H)- Exact mass: 441.05 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.30 (s, 3 H), 3.72 (s, 3 H), 3.83 (quin, J=6.6 Hz, 1 H), 7.41 (t, J=9.1 Hz, 1 H), 7.50 (s, 1 H), 7.55 - 7.71 (m, 1 H), 7.98 (dd, J=6.7, 2.1 Hz, 1 H), 8.16 (br. s., 1 H), 10.29 (s, 1 H).

TIP 296 PCT Compound 146: N-(3,4-Difluorophenyl)-1,3-dimethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 146 (353 mg) as white powder was synthesized similarly as described for compound 144 using (S)-1,1,1-trifluoropropylamine (1.50 g, 13.3 mmol) instead of (R)-1,1,1-trifluoro propylamine in Step2 (resulting in 1,3-dimethyl[[(1S)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid as intermediate). Method B; Rt: 1.01 min. m/z: 424 (M-H)- Exact mass: 425.08 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.29 (s, 3 H), 3.72 (s, 3 H), 3.76 - 3.87 (m, 1 H), 7.34 - 7.46 (m, 2 H), 7.49 (s, 1 H), 7.74 - 7.91 (m, 1 H), 8.16 (br. s., 1 H), 10.31 (s, 1 H).

Compound 147: N-(3-Chlorofluorophenyl)-1,3-dimethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 147 (443 mg) as white powder was synthesized similarly as described for compound 144 using 1,1-trifluoropropylamine (1.50 g, 13.3 mmol) instead of (R)-1,1,1-trifluoro amine in Step2 (resulting in 1,3-dimethyl[[(1S)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid as intermediate) and 3-chlorofluoroaniline instead of fluoroaniline in Step 4. Method B; Rt: 1.06 min. m/z: 440 (M-H)- Exact mass: 441.05 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=7.0 Hz, 3 H), 2.30 (s, 3 H), 3.72 (s, 3 H), 3.83 (quin, J=7.2 Hz, 1 H), 7.41 (t, J=9.1 Hz, 1 H), 7.50 (s, 1 H), 7.62 (ddd, J=9.0, 4.2, 2.6 Hz, 1 H), 7.98 (dd, J=6.8, 2.4 Hz, 1 H), 8.17 (br. s., 1 H), 10.29 (s, 1 H).

Compound 148: N-(3,4-Difluorophenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT Compound 148 was synthesized similarly as described for compound 144 using 3-methyl oxetanamine instead of (R)-1,1,1-trifluoropropylamine in Step2 . In Step4, the desired fractions were evaporated to afford oil which was purified again using silica gel column chromatography (gradient elution: ethyl acetate in heptane from 40 to 70%). The desired ons were combined and evaporated to afford compound 148 (475 mg) as white powder.

Method B; Rt: 0.86 min. m/z: 398 (M-H)- Exact mass: 399.11 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.53 (s, 3 H), 2.32 (s, 3 H), 3.72 (s, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.62 (d, J=5.9 Hz, 2 H), 7.36 - 7.51 (m, 3 H), 7.62 - 8.16 (m, 2 H), 10.32 (br. s., 1 H).

Compound 149: N-(3-Chlorofluorophenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 149 was sized as compound 144 using 3-methyloxetanamine d of (R)- 1,1,1-trifluoropropylamine in Step2 and 3-chlorofluoroaniline instead of 3,4- difluoroaniline in Step4. In Step4, the d fractions were evaporated to afford oil which solidified while standing. The powder was triturated in warm CH2Cl2 (10 mL) and allowed to reach room temperature. The white solids were filtered and washed with CH2Cl2 (5 mL) and eum ether (5 mL) and dried in vacuum oven at 50°C to afford compound 149 (435 mg) as white powder. Method B; Rt: 0.92 min. m/z: 414 (M-H)- Exact mass: 415.08 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.53 (s, 3 H), 2.32 (s, 3 H), 3.72 (s, 3 H), 4.12 (d, J=6.4 Hz, 2 H), 4.62 (d, J=5.9 Hz, 2 H), 7.41 (t, J=9.1 Hz, 1 H), 7.47 (s, 1 H), 7.62 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 7.91 (br. s., 1 H), 7.99 (dd, J=6.8, 2.6 Hz, 1 H), 10.29 (br. s., 1 H).

Compound 150: N-(3-Cyanofluorophenyl)-1,3-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Compound 150 (416 mg) as white powder was synthesized as compound 144 using 5-amino fluorobenzonitrile instead of 3,4-difluoroaniline and the on time was 20 hours instead of 42 hours in Step4. Method C; Rt: 1.68 min. m/z: 431 (M-H)- Exact mass: 432.09 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=7.0 Hz, 3 H), 2.31 (s, 3 H), 3.73 (s, 3 H), 3.83 (quin, J=7.2 Hz, 1 H), 7.52 (br. s, 1 H), 7.54 (t, J=9.1 Hz, 1 H), 7.97 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.09 - 8.27 (m, 1 H), 8.18 (dd, J=5.7, 2.6 Hz, 1 H), 10.42 (br. s., 1 H).

Compound 151: N-(3-Cyanofluorophenyl)-1,3-dimethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 151 (420 mg) as white powder was synthesized rly as described for compound 144 using (S)-1,1,1-trifluoropropylamine (1.50 g, 13.3 mmol) instead of (R)-1,1,1-trifluoro propylamine in Step2 and 5-aminofluorobenzonitrile instead of 3,4-difluoroaniline and the reaction time was 20 hours instead of 42 hours in Step4. Method B; Rt: 0.96 min. m/z: 431 (MH )- Exact mass: 432.09 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.31 (s, 3 H), 3.73 (s, 3 H), 3.83 (quin, J=7.2 Hz, 1 H), 7.51 (s, 1 H), 7.54 (t, J=9.2 Hz, 1 H), 7.97 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.09 - 8.27 (m, 1 H), 8.18 (dd, J=5.9, 2.6 Hz, 1 H), 10.42 (br. s., 1 H). nd 152: N-(3-Cyanofluorophenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 152 was synthesized rly as described for compound 144 using 3-methyl oxetanamine instead of (R)-1,1,1-trifluoropropylamine in Step2 and 5-amino TIP 296 PCT benzonitrile instead of 3,4-difluoroaniline in Step4. In Step4, the desired fractions were evaporated to afford light yellow oil which was purified again using silica gel column chromatography (gradient elution: ethyl acetate in heptane from 40 to 70%). The desired fractions were combined and evaporated to afford compound 152 (332 mg) as white powder.

Method B; Rt: 0.80 min. m/z: 405 (M-H)- Exact mass: 406.11 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.53 (s, 3 H), 2.34 (s, 3 H), 3.73 (s, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.62 (d, J=5.9 Hz, 2 H), 7.48 (s, 1 H), 7.54 (t, J=9.1 Hz, 1 H), 7.92 (br. s., 1 H), 7.98 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 10.43 (br. s., 1 H).

Compound 153: N-[4-Fluoro(trifluoromethyl)phenyl]-1,3-dimethyl{[(1R)-2,2,2-trifluoro- 1-methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 153 (270 mg) as beige solid was synthesized similarly as described for compound 144 using 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (260 mg, 0.83 mmol) and 4-fluoro(trifluoromethyl)aniline (0.31 g, 1.65 mmol) instead of 3,4-difluoroaniline in Step4. Method B; Rt: 1.10 min. m/z: 474 (M-H)- Exact mass: 475.08 . 1H NMR (400 MHz, 6)  ppm 1.12 (d, J=6.8 Hz, 3 H), 2.32 (s, 3 H), 3.73 (s, 3 H), 3.84 (quin, J=7.3 Hz, 1 H), 7.48 - 7.56 (m, 2 H), 7.91 - 8.00 (m, 1 H), 8.12 - 8.24 (m, 2 H), 10.41 (s, 1 Synthesis of methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate: In a pressure tube methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate (15 g, 63.11 mmol) was dissolved in 100 mL of dry acetonitrile. To this was added (S)-1,1,1-trifluoropropylamine (8.56 g, 75.74 mmol) followed by diisopropylethylamine (27.19 mL, 157.79 mmol). The pressure tube was d with nitrogen and closed. The mixture was stirred in a pre-heated oil bath at 80°C for 15 hours. Then it was cooled to room temperature and concentrated in vacuo.

The obtained residue was ved in dichloromethane (400 mL) and this was washed with HCl (1M / aq / 2 x 100 mL). The obtained organics were dried on , filtered and concentrated in vacuo resulting in Methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole- 2-carboxylate as a beige powder (17.5 g) which was used as such. Method B; Rt: 0.83 min. m/z : 313.1 (M-H)- Exact mass: 314.05.

TIP 296 PCT Synthesis of 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid: Methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (6.6 g, 19.7 mmol) was dissolved in tetrahydrofuran (56 mL). To this was added lithium hydroxide (1.655 g, 69.1 mmol) in distilled water (7.5 mL) followed by ol (3 mL). The resulting e was stirred ght. The e was concentrated until only water remained and extra distilled water (15 mL) was added. The mixture was neutralised with hydrochloric acid (1M, aq).

The resulting mixture was extracted using 2-methyltetrahydrofuran (3 x 20 mL). The ed extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding 1-methyl [[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (5.34 g). Method B; Rt: 0.45 min. m/z : 299.0 (M-H)- Exact mass: 300.04.

Compound 154: 1-Methyl{[(1S)-2,2,2-trifluoromethylethyl]sulfamoyl}-N-(2,3,4- trifluorophenyl)-1H-pyrrolecarboxamide 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (500 mg, 1.67 mmol) was dissolved in of N,N-dimethylformamide (1 mL).Then HATU (0.76 g, 2 mmol) was added and this mixture was stirred for 20 minutes. Then diisopropylethylamine (0.86 mL, 5 mmol) was added folowed by 2,3,4-trifluoroaniline ( 0.49 g, 3.33 mmol).The reaction mixture was stirred at 50°C for 5 hours.Then this mixture was cooled to room temperature and injected directly onto a silica plug. The mixture was purified by silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100) yielding compound 154 as a white powder (253 mg) Method B; Rt: 0.99 min. m/z : 428.1 (M-H)- Exact mass: 429.06.1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=7.0 Hz, 3 H), 3.90 (s, 3 H), 3.91 - 4.02 (m, 1 H), 7.24 - 7.48 (m, 3 H), 7.65 (d, J=1.8 Hz, 1 H), 7.76 - 8.97 6 (br.s, 1 H), 9.58 - 11.00 (br.s, 1 H).

TIP 296 PCT Compound 155: N-(3-Bromo-2,4-difluorophenyl)methyl{[(1S)-2,2,2-trifluoro- 1-methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 155 (314 mg) was prepared rly as described for compound 154 using 3-bromo- 2,4-difluoro-aniline (0.69 g, 3.33 mmol) instead of 2,3,4-trifluoroaniline resulting in white powder. Method B; Rt: 1.04 min. m/z : 490.03 (M-H)- Exact mass: 491.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=7.0 Hz, 3 H), 3.90 (s, 3 H), 3.91 - 4.02 (m, 1 H), 7.23 - 7.39 (m, 2 H), 7.57 (td, J=8.7, 5.9 Hz, 1 H), 7.64 (d, J=1.5 Hz, 1 H), 8.18 (br. s., 1 H), 10.12 (br. s., 1 H).

Compound 156: N-(3-Chloro-2,4-difluorophenyl)methyl{[(1S)-2,2,2-trifluoro- 1-methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 156 (289 mg) was prepared similarly as compound 154 using 3-chloro-2,4-difluoroaniline (0.54 g, 3.33 mmol) instead of 2,3,4-trifluoroaniline resulting in white powder. Method B; Rt: 1.03 min. m/z : 444.11 (M-H)- Exact mass: 445.03.1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=6.8 Hz, 3 H), 3.90 (s, 3 H), 3.91 - 4.00 (m, 1 H), 7.29 - 7.43 (m, 2 H), 7.53 (td, J=8.7, 5.9 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 8.17 (br. s., 1 H), 10.14 (br. s., 1 H).

Compound 157: N-(3-cyanofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro ethyl]sulfamoyl]pyrrolecarboxamide ed similarly as bed for compound 123 using 5-aminofluoro-benzonitrile (580.5 mg, 4.14 mmol) instead of 3-chlorofluoro-aniline, resulting in compound 157 as a white TIP 296 PCT powder (136 mg). Method B; Rt: 0.96 min. m/z : 417.13 (M-H)- Exact mass: 418.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=6.8 Hz, 3 H), 3.82 - 4.00 (m, 4 H), 7.36 (d, J=2.0 Hz, 1 H), 7.43 - 7.59 (m, 1 H), 7.65 (d, J=1.5 Hz, 1 H), 7.96 - 8.04 (m, 1 H), 8.05 - 8.33 (m, 2 H), .38 (br. s., 1 H).

Compound 158: N-(3-Cyanophenyl)methyl{[(1R)-2,2,2-trifluoromethylethyl]- sulfamoyl}-1H-pyrrolecarboxamide To methyl 1-methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (5.0g, mol, prepared as in the synthesis for compound 122 ) dissolved in e (59 mL) and water (10 mL) was added LiOH (2.34 g, 55.68 mmol) and the reaction mixture stirred 16 h.

The mixture was concentrated in vacuo. The residue was dissolved in water and acidified with 1N HCl solution till pH~3. The mixture was stirred at room ature for 30'. The product was filtered off and dried in vacuo to become a pale yellow solid of 1-methyl[[(1R)-2,2,2- oromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (3.95g). This acid (700 mg, 2.33mmol), 3-aminobenzonitrile (347.8mg, 2.91 mmol), HATU (1108mg, 2.914mmol) and DIPEA (1.2mL, 6.99 mmol) was dissolved in DMF (7 mL) and the mixture was stirred at room temperature for 16 h. The mixture was poured in 100 mL ice water and was extracted with EtOAc. The organic layer was ted, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a silica using a nt eluent Heptane- EtOAc 100-0 -> 50-50. The product fractions were collected and concentrated in vacuo. The product was crystallized from 2-propanol, filtered off and dried in vacuo, yielding compound 158 (518 mg) as a white solid. Method B; Rt: 0.93 min. m/z : 399.1 (M-H)- Exact mass: 400.08. 1H NMR (600 MHz, DMSO-d 6)  ppm 1.08 (d, J=7.04 Hz, 3 H) 3.86 - 4.00 (m, 4 H) 7.39 (d, J=1.91 Hz, 1 H) 7.50 - 7.61 (m, 2 H) 7.66 (d, J=1.61 Hz, 1 H) 7.99 (dt, J=7.56, 2.02 Hz, 1 H) 8.12 - 8.21 (m, 2 H) 10.35 (s, 1 H).

TIP 296 PCT Compound 159: N-[2-Fluoro(trifluoromethyl)phenyl]methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 159 (582 mg) was prepared similarly as described for compound 158 using 3-amino- 2-fluorobenzotrifluoride (0.387 mL, 2.91 mmol) instead of obenzonitrile resulting in a white solid. Method B; Rt: 1.06 min. m/z : 460.1 (M-H)- Exact mass: 461.06.1H NMR (400 MHz, DMSO-d6)  ppm 1.10 (d, J=6.8 Hz, 3 H), 3.87 - 3.98 (m, 4 H), 7.37 - 7.47 (m, 2 H), 7.61 - 7.67 (m, 2 H), 7.88 (t, J=7.2 Hz, 1 H), 8.19 6 (d, J=8.4 Hz, 1 H), 10.21 (s, 1 H).

Compound 160: N-(3-Cyanofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 160 (202 mg) was was prepared similarly as described for compound 158 using 3- aminofluorobenzonitrile (396.7 mg, 2.91 mmol) instead of 3-aminobenzonitrile resulting in a white solid. Method B; Rt: 0.92 min. m/z : 417.1 (M-H)- Exact mass: 418.07.1H NMR (400 MHz, 6)  ppm 1.10 (d, J=7.0 Hz, 3 H), 3.89 - 3.99 (m, 4 H), 7.38 (d, J=2.0 Hz, 1 H), 7.43 (t, J=7.9 Hz, 1 H), 7.67 (d, J=1.8 Hz, 1 H), 6 7.78 (ddd, J=7.8, 5.9, 1.5 Hz, 1 H), 7.88 - 7.93 (m, 1 H), 8.19 (d, J=8.6 Hz, 1 H), 10.26 (s, 1 H).

Compound 161: N-[3-(1,1-Difluoroethyl)fluorophenyl]methyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide sis of 2-(1,1-difluoroethyl)fluoronitro-benzene: 1-(2-fluoronitrophenyl)ethanone (19 g, 103.7mmol) was dissolved in dichloromethane (300 mL) The e was stirred at -78°C under N2-atmosphere. Diethylamino)sulfur trifluoride (33.4 g, 207 mmol) was added to the TIP 296 PCT e via cannula over a period of 30 min.The reaction mixture was stirred at 35° C for 16 h.The cold on e was poured into ice water (200mL).The aqueous layer was extracted with dichloromethane (80 mL) twice . The combined organic layers were washed with water, dried over sodium sulfate and evaporated to dryness to provide a yellow oil. The crude product was purified by column chromatography to provide a yellow oil (13 g).

Synthesis of 3-(1,1-difluoroethyl)fluoro-aniline: 2-(1,1-difluoroethyl)fluoro nitrobenzene:(13 g ,63.37 mmol) was dissolved in ol (65 mL) and water (65 mL). Iron powder (10.6 g) and HCl (25 mL) were added.The mixture was stirred at room temperature for 45 min.The reaction mixture was then filtered through celite, the filtrate was washed with saturated solution of sodium carbonate and dried over sodium sulfate and evaporated to dryness to provide a yellow oil. The crude product was ed by column chromatography to provide a yellow oil (5845 mg).

Synthesis of 5-[[3-(1,1-difluoroethyl)fluoro-phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride: 3-(1,1-difluoroethyl)fluoro-aniline (1099.8 mg, 6.28 mmol) dissolved in toluene (10 mL) was added dropwise during 5' to a solution of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (1520 mg, 6.28 mmol) in toluene (100 mL) at reflux. The reaction e was refluxed 90 minutes and then concentrated in vacuo, yielding a brown powder which was used as such.(2566 mg) Method A; Rt: 2.01 min. m/z : 378.9 (M-H)- Exact mass: . 3-methyloxetanamine (390 mg, 4.47 mmol) was added to a on of -[[3-(1,1-difluoroethyl)fluoro-phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride (605 mg, 1.49 mmol) in CH3CN (50mL) and stirred 17 hr. Water was added untill crystallisation began. The white powder was filtered off and dried overnight in vacuo at 50°C, resulting in nd 161 (514 mg); Method A; Rt: 1.70 min. m/z : 430.1 (M-H)- Exact mass: 431.11. 1H NMR (400 MHz, DMSO-d6)  ppm 1.55 (s, 3 H), 1.95 - 2.06 (m, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.35 (d, J=2.0 Hz, 2 H), 7.59 (d, J=1.8 Hz, 1 H), 7.85 - 7.92 (m, 1 H), 7.93 - 8.02 (m, 2 H), 10.23 (s, 1 H).

Compound 162: 4-(tert-Butylsulfamoyl)-N-[3-(1,1-difluoroethyl)fluorophenyl]methyl-1H- pyrrolecarboxamide tert-butylamine (400.6 mg, 5.48mmol) was added to a solution of 5-[[3-(1,1-difluoroethyl) fluoro-phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride (622mg, 1.53 mmol) in CH3CN (50mL) and stirred 17 hr. Water was added untill crystallisation began. The white powder was TIP 296 PCT filtered off and dried overnight in vacuo at 50°C, resulting in nd 162 (355 mg). Method A; Rt: 1.91 min. m/z : 416.1 (M-H)- Exact mass: 417.13. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 1.93 - 2.08 (m, 3 H), 3.91 (s, 3 H), 7.11 (s, 1 H), 7.27 - 7.37 (m, 2 H), 7.52 (d, J=1.5 Hz, 1 H), 7.85 - 7.93 6 (m, 1 H), 7.96 - 8.02 (m, 1 H), 10.21 (s, 1 H).

Compound 163: -Dichlorofluorophenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide 3,5-dichlorofluoroaniline (1534 mg,18.52 mmol) dissolved in toluene (10 mL) was added to 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (2063 mg,8.52 mmol) in toluene (125 mL) at reflux and refluxed 2 hours. The on mixture was filtered while still hot and concentrated yielding a crude beige powder (2833 mg, 5-[(3,5-dichlorofluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride) which was used as such. 1H NMR (400 MHz, ACETONITRILE-d3)  ppm 3.96 (s, 3 H), 7.39 (d, J=2.0 Hz, 1 H), 7.71 - 7.77 (m, 3 H), 8.78 (br. s., 1 H) 2,2,2-trifluoro-1,1-dimethyl-ethylamine (692 mg,5.45 mmol) was added to 5-[(3,5-dichloro fluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (700.2 mg, 1.82 mmol) and DIPEA (0.47 mL,2.72 mmol) dissolved in CH3CN (66 mL) and refluxed overnight. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with 1M HCl, dried over sodium sulphate, ed and concentrated. The residue was purified by column chromatography on silica using a gradient from 10 till 100% EtOAc in heptane. The obtained powder was recrystallized from methanol (25 mL), upon addition of water and further purified by by Prep HPLC onary phase: RP XBridge Prep C18 OBD-10µm,30x150mm), Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) , yielding a white powder which was dried in vacuo at 50°C during 6 hours.Method A; Rt: 2.13 min. m/z : 473.9 (M-H)- Exact mass: 475.01.1H NMR (400 MHz, 6)  ppm 1.36 (s, 6 H), 3.92 (s, 3 H), 7.34 (d, J=2.0 Hz, 1 H), 7.61 (d, J=1.5 Hz, 1 H), 7.95 (d, J=6.2 Hz, 2 H), 8.07 (s, 1 H), 6 10.30 (s, 1 H).

Compound 164: N-(3-Chloro-4,5-difluorophenyl)[(3,3-difluorocyclobutyl)sulfamoyl] methyl-1H-pyrrolecarboxamide TIP 296 PCT A mixture of chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (561.7 mg,1.15 mmol) (prepared as in the sis for compound 57) 3,3- difluorocyclobutanamine hydrochloride (248.5 mg, 1.73 mmol) DIPEA (0.6 mL,3.46mmol) in CH3CN( 22 mL) was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was subjected to column tography on silica using a gradient from 10 till 100% EtOAc in heptane. The product fractions were partially concentrated untill product crystallized. The white crystals were filtered off and dried overnight in vacuo at 50°C, resulting in compound 164 (175 mg) Method A: Rt: 1.86 min m/z: 438.0 (M-H)- Exact mass: 439.04. 1H NMR (400 MHz, DMSO-d6)  ppm 2.36 - 2.58 (m, 2 H), 2.72 - 2.90 (m, 2 H), 3.48 - 3.63 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.63 (d, J=1.8 6 Hz, 1 H), 7.75 - 7.88 (m, 3 H), 10.29 (s, 1 H) 1H NMR (400 MHz, ACETONITRILE-d3)  ppm 2.40 - 2.58 (m, 2 H), 2.74 - 2.89 (m, 2 H), 3.59 - 3.72 (m, 1 H), 3.93 (s, 3 H), 5.84 (d, J=1.0 Hz, 1 H), 7.13 3 (d, J=1.8 Hz, 1 H), 7.36 (d, J=1.8 Hz, 1 H), 7.56 - 7.61 (m, 1 H), 7.61 - 7.69 (m, 1 H), 8.63 (s, 1 H).

Compound 165: N-(3-chloro-4,5-difluoro-phenyl)methyl[[1-methyl(trifluoromethyl )propyl]sulfamoyl]pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1034 mol) (prepared as in the synthesis for compound 57) 1,1,1-trifluoromethylbutanamine hydrochloride (754 mg, 4.25 mmol) DIPEA (1.14 mL, 36.58 mmol) in CH3CN (31 mL)was refluxed 2 days. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated. The residue was subjected to column chromatography on silica using a nt from 10 till 100% EtOAc in heptane. The product fractions were concentrated yielding compound 165 (300.1 mg) as a white solid. The racemic mixture 165 was separated in enantiomers 165a and 165b by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm), Mobile phase: CO2, iPrOH with 0.2% ), the desired fractions were collected, evaporated, ved in MeOH and evaporated again, yielding 165a (first g, white solid, 45 mg).

Method A: Rt: 2.10 min m/z: 472.0 (M-H)- Exact mass: 473.06. 1H NMR (400 MHz, DMSO-d6) TIP 296 PCT  ppm 0.79 (t, J=7.3 Hz, 3 H), 1.37 (s, 3 H), 1.45 - 1.59 (m, 1 H), 1.73 - 1.87 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 7.90 (s, 1 H), 10.31 (s, 1 H) and 165b (second eluding, 40 mg, white solid). Method A: Rt: 2.10 min m/z: 472.0 (M-H)- Exact mass: 473.06. 1H NMR (400 MHz, DMSO-d6)  ppm 0.79 (t, J=7.3 Hz, 3 H), 1.37 (s, 3 H), 1.46 - 1.59 (m, 1 H), 1.74 - 1.87 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 7.90 (s, 1 H), 10.31 (s, 1 H).

Compound 166: hloro-4,5-difluorophenyl)[(3,3-difluorocyclopentyl)sulfamoyl] methyl-1H-pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1496 mg.3.07 mmol) (prepared as in the synthesis for compound 57) 3,3- rocyclopentanamine (819 mg,6.76 mmol) DIPEA (0.79 mL,4.61 mmol) in CH3CN(23 mL) was refluxed 1 hour. The on mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated.

The residue was subjected to column chromatography on silica using a gradient from 10 till 100% EtOAc in heptane. The product fractions were partially concentrated untill the t started to crystallize. The white crystals were filtered off and dried overnight in vacuo at 50°C, ing in compound 166 (856.3 mg) Method A: Rt: 1.87 min m/z: 452.0 (M-H)- Exact mass: 453.05. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 - 1.75 (m, 1 H), 1.87 - 2.07 (m, 3 H), 2.07 - 2.23 (m, 1 H), 2.24 - 2.40 (m, 1 H), 3.55 - 3.70 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=2.0 Hz, 1 H), 7.62 (d, J=1.5 Hz, 1 H), 7.65 (d, J=6.8 Hz, 1 H), 7.77 - 7.86 (m, 2 H), 10.31 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 198.05 °C.

The racemic mixture 166 was was separated in enantiomers 166a and 166b by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm), Mobile phase: CO2, MeOH-iPrOH (50- 50) with 0.2% iPrNH2), the d fractions were collected, evaporated, dissolved in MeOH and evaporated again, The residues were ved in methanol (20 mL) and crystallized upon addition of water. The white s were filtered off and dried overnight in vacuo at 50°C , resulting in compound 166a (285.5 mg, first eluding enantiomer), 166b (296 mg, second eluding enantiomer) Method A: Rt: 1.96 min m/z: 452.0 (M-H)- Exact mass: 453.05.1H NMR (400 MHz, DMSO-d6)  ppm 1.58 - 1.73 (m, 1 H), 1.88 - 2.07 (m, 3 H), 2.07 - 2.23 (m, 1 H), 2.24 - 2.41 (m, 1 H), 3.57 - 3.69 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.62 (d, J=1.5 Hz, 1 H), 7.65 (d, J=6.6 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 10.31 (s, 1 H).

TIP 296 PCT Compound 167: 4-(Bicyclo[1.1.1]pentylsulfamoyl)-N-(3-chloro-4,5-difluorophenyl) methyl-1H-pyrrolecarboxamide Compound 167 was prepared similarly as bed for compound 164 using bicyclo[1.1.1]pentanamine hydrochloride instead of 3,3-difluorocyclobutanamine hydrochloride. The product fractions after column chromatography were concentrated and the residue dissolved in hot methanol (25 mL). The product crystallized upon addition of a small amount of water. The white powder was filtered off and dried overnight in vacuo at 50°C, resulting in nd 167 (226 mg) Method A: Rt: 1.89 min m/z: 414.0 (M-H)- 416.0 (M+H)+ Exact mass: 415.06. 1H NMR (400 MHz, DMSO-d6)  ppm 1.81 (s, 6 H), 2.31 (s, 1 H), 3.93 (s, 3 H), 7.34 (d, J=2.0 Hz, 1 H), 7.58 (d, J=1.5 Hz, 1 H), 7.77 - 7.86 (m, 2 H), 8.22 (s, 1 H), 10.29 (s, 1 H).

Compound 168: N-(3-Chloro-4,5-difluorophenyl)methyl[(3,3,3-trifluoropropyl)sulfamoyl]- 1H-pyrrolecarboxamide nd 168 was prepared similarly as described for compound 164 using 3,3,3-trifluoropropylamine instead of 3,3-difluorocyclobutanamine hydrochloride but was d 3 hours at room temperature. Water was added untill the product start to crystallize. The white powder was filtered off and dried overnight in vacuo at 50°C. Method A: Rt: 1.95 min m/z: 444.0 (M-H)- Exact mass: 445.03 .1H NMR (400 MHz, DMSO-d6)  ppm 2.40 - 2.55 (m, 2 H), 2.95 - 3.05 (m, 2 H), 3.92 (s, 3 H), 7.35 (d, J=2.0 Hz, 1 H), 7.52 (t, J=5.9 Hz, 1 H), 7.65 (d, J=1.8 6 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 10.31 (s, 1 H). nd 169: N-(3-Chloro-4,5-difluorophenyl)methyl[(3,3,3-trifluoro methylpropyl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Compound 169 was prepared similarly as compound 164 using trifluorobutanamine hydrochloride instead of 3,3-difluorocyclobutanamine hydrochloride. Water was added untill the product starts to crystallize. The white powder was filtered off and dried overnight in vacuo at 50°C, resulting in compound 169 (542 mg). Method A: Rt: 1.91 min m/z: 458.0 (M-H)- Exact mass: 459.04. 1H NMR (400 MHz, 6)  ppm 1.06 (d, J=6.8 Hz, 3 H), 2.32 - 2.47 (m, 2 H), 3.43 - 3.55 (m, 1 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.55 (d, J=7.9 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 10.30 (s, 1 H).The racemic compound 169 (492 mg) was separated in enantiomers 169a and 169b by Prep SFC (Stationary phase: pak Diacel AD 20 x 250 mm), Mobile phase: CO2, MeOH with 0.2% iPrNH2), the desired fractions were collected, evaporated, solved in MeOH and evaporated again. The residue was crystallized from mL methanol upon addition of water, filtered off and dried overnight in vacuo at 50°C yielding white ls, resulting in compound 169a (first eluding enantiomer, 144 mg) and 169b (second eluding omer, 135 mg).

Compound 170: N-(3-Cyanofluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (prepared similarly as described in the synthesis of 3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid for compound 74, from 5-ethoxycarbonylfluoromethyl-pyrrolesulfonic acid ng 60 minutes at 80°C in thionylchloride instead of 30 minutes at 80°C ; 4880 mg, 19.4 mmol ) was dissolved in CH3CN (50 mL), DIPEA (10.04 mL, 58.27 mmol) was added followed by (2R)-1,1,1-trifluoropropanamine (3295 mg, 29.14 mmol) and the mixture was refluxed for 3 hours. The reaction mixture was trated. The residue was dissolved in EtOAc (200 mL), washed with water, dried over sodium sulphate, filtered and concentrated.The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were concentrated in vacuo yielding ethyl 3-fluoromethyl [[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate as a light brown semisolid TIP 296 PCT which was used as such (1705 mg). Method A: Rt 1.68 min, m/z: 345 (M-H)- 347.0 (M+H)+ Exact mass: 346.06. A mixture of ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate (1705 mg, 4.92 mmol), LiOH (354 mg, 14.77 mmol) THF (17 mL) and water (4 mL) was stirred overnight. The reaction mixture was trated, the residue dissolved in water (50 mL) and the solution was neutralised with HCl 1M (14.77 mL, 14.77 mmol). The mixture was extracted with Me-THF (2 x 100 mL). The organic layer was dried over sodium sulphate, ed and trated resulting in 3-fluoromethyl[[(1R)- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (1533 mg) as a powder, which was used as such. Method A: Rt: 0.88 m/z: 317 (M-H)- Exact mass: 318.03. 1H NMR (400 MHz, 6)  ppm 1.15 (d, J=7.0 Hz, 3 H), 3.82 (s, 3 H), 3.88 - 4.04 (m, 1 H), 7.56 (d, J=4.8 Hz, 1 H), 8.56 (d, J=8.8 Hz, 1 H), 13.13 (br. s., 1 H). Compound 170 (531 mg) was synthesized similarly as described for compound 94 using 3-fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (601.7 mg 1.89 mmol) instead of romethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid and 5-amino fluorobenzonitrile (531 mg, 3.78 mmol) d of 4-fluoromethylaniline and the reaction mixture was stirred overnight at 65°C. The column fractions were concentrated and the residue was crystallized by dissolving in 100 mL warm methanol upon addition of water. The crystals were filtered off and dried overnight in vacuo at 50°C. Method A: Rt: 1.66 min m/z: 435 (M-H)- Exact mass: 436.06.1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=6.8 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.05 (m, 1 H), 7.50 - 7.59 (m, 2 H), 7.96 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.17 (dd, J=5.8, 2.8 Hz, 1 H), 8.62 (d, J=8.8 Hz, 1 H), 10.36 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 190.99 °C.

Alternative synthesis of compound 170: Sodium hydride (6.99 g, 183 mmol) was added portionwise to ethyl 3-fluoropyrrole carboxylate (23.9 g, 152 mmol), iodomethane (25.9 g, 183 mmol) in DMF (238 mL) under nitrogen in an icebath and stirred overnight at room temperature. The reaction mixture was acidified with 1M HCl and concentrated. The residue was ved in water/ EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The ed residue was dissolved in CH3CN (150 mL), washed with heptane and concentrated at 60°C and 40 mbar yielding a brown liquid which was submitted to silica gel column chromatography using a gradient from 10 to 25% EtOAc in heptane. The product fractions were trated resulting in ethyl 3-fluoromethyl-pyrrolecarboxylate as a clear oil (14.0 g). Chlorosulfonic acid (9.97 g, 85.6 mmol) dissolved in dichloromethane (50 mL) was added to ethyl 3-fluoromethyl- ecarboxylate (14.0 g, 81.5 mmol) dissolved in dichloromethane (250 mL) in an icebath and stirred 30 minutes. The formed light beige crystals were filtered off and dried overnight in vacuo at 50°C, resulting in 5-ethoxycarbonylfluoromethyl-pyrrolesulfonic acid (14.3 g). 1H NMR (400 MHz, DMSO-d 6)  ppm 1.26 (t, J=7.2 Hz, 3 H), 3.72 (s, 3 H), 4.23 (q, J=7.0 Hz, 2 H), 7.02 (d, J=5.1 Hz, 1 H). Method D: Rt: 0.88 min. m/z: 250.0 (M-H)- Exact mass: 251.0. 5- TIP 296 PCT ethoxycarbonylfluoromethyl-pyrrolesulfonic acid (20.3 g, 80.7 mmol) in SOCl2 (80 mL, 1.1 mol) was d 2 hours at 80°C. The reaction mixture was concentrated. The obtained dark green solid was subjected to silica gel column chromatography using a gradient from 10 to 50 % EtOAc in heptane. The product fractions were trated yielding ethyl 4-chlorosulfonyl fluoromethyl-pyrrolecarboxylate (18.9 g) as light yellow crystals which was used as such.

Ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (18.9 g, 70.1 mmol) (2R)-1,1,1- trifluoropropanamine (11.89 g, 105.2 mmol) NaHCO3 (17.7 g, 210 mmol) in acetonitrile (150 mL) with molecular sieves 4A (15 g) and was refluxed overnight. The reaction e was filtered and concentrated. The e was dissolved in EtOAc and washed with 1 M HCl. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified via silica gel column chromatography (2x) using a gradient from 10 to 100 % EtOAc in heptane, resulting in ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate as a white powder which was dried overnight at 50°C in vacuo (19.1 g in . Method D: Rt: 1.77 min. m/z: 345.0 (M-H)- Exact mass: 346.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.15 (d, J=7.0 Hz, 3 H), 1.28 (t, J=7.2 Hz, 3 H), 3.83 (s, 3 H), 3.90 - 4.03 (m, 1 H), 4.28 (q, J=7.2 Hz, 2 H), 7.60 (d, J=4.8 Hz, 1 H), 8.60 (d, J=8.8 Hz, 1 H). To ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (10.0 g, 28.9 mmol) and 5-aminofluoro-benzonitrile (5.11 g, 37.6 mmol)) dissolved in dry THF (200 mL) at 5°C under nitrogen atmosphere, lithium bis(trimethylsilyl)amide in toluene (115.6 mL, 1 M, 115.6 mmol) was added. The mixture was stirred 4 hours allowing to reach room temperature. The reaction mixture was quenched with NH4Cl (250 mL) solution and extracted with EtOAc (500 mL), diluted with brine (200 mL) and extracted again with EtOAc (300 mL). The combined organic layers were dried over sodium te, filtered and concentrated. The residue was purified by silica gel column chromatography with a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the solid residue was crystallised from warm methanol (300 mL) upon addition of water. The pink crystals were filtered off and dried in vacuo at 50°C overnight. The compound was edly purified by silica gel tography (using 10 to 100% EtOAc in heptane and using dichloromethane). The ing product was crystallised once more from hot methanol (500 mL) and the product crystallised upon addition of water. The white powder was filtered off and dried overnigth in vacuo at 50°C, resulting in compound 170 (9.28 g). Method D: Rt: 1.86 min m/z: 435.3 (M-H)- Exact mass: 436.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 192.2 °C. [α]20589= -23.2 ° (c 0.504 w/v %, DMF).

TIP 296 PCT Compound 171: N-(3-Cyanofluorophenyl)fluoromethyl[(1-methylethyl)sulfamoyl]- 1H-pyrrolecarboxamide Intermediate ethyl 3-fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylate was made rly as described for ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate starting from 5-ethoxycarbonylfluoromethylpyrrolesulfonic acid (1220 mg, 4.86 mmol), converting it to the sulphonyl chloride with l chloride (heating at 80°C during 1 hour) and reaction with isopropylamine (1160 mg,19.42 mmol) resulting in ethyl 3-fluoro(isopropylsulfamoyl)methyl-pyrrole ylate (1169 mg) as a white powder. 1H NMR (400 MHz, DMSO-d6)  ppm 1.03 (d, J=6.6 Hz, 6 H), 1.28 (t, J=7.2 Hz, 3 H), 3.26 - 3.37 (m, 1 H), 3.82 (s, 3 H), 4.27 (q, J=7.2 Hz, 2 H), 7.52 (d, J=4.6 Hz, 1 H), 7.56 (d, J=7.3 Hz, 1 H) Method A: Rt: 1.48 min m/z: 291 (M-H)- Exact mass: 292.09. Intermediate 3-fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid was made similarly as for compound 170 using ethyl 3-fluoro(isopropylsulfamoyl)methyl- pyrrolecarboxylate (1169 mg, 4.0 mmol) The reaction mixture was concentrated. The residue was dissolved in water (75 mL) and neutralised with HCl 1M (12.0 mL, 12.0 mmol). The product crystallized and was filtered off. The white powder was dried overnight in vacuo at 50°C, resulting in 3-fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (856 mg) Method A: Rt: 0.75 min m/z: 263.0 (M-H)- Exact mass: 264.06. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 3.22 - 3.38 (m, 1 H), 3.81 (s, 3 H), 7.47 (d, J=4.8 Hz, 1 H), 7.54 (d, J=7.5 Hz, 1 H), 13.06 (s, 1 H). Compound 171 was made similarly as nd 170 using 3- fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (594 mg, 2.25 mmol) resulting in nd 171 (670 mg) as a white powder. Method A: Rt: 1.59 min m/z: 381 (MH )- Exact mass: 382.09. 1H NMR (400 MHz, DMSO-d6)  ppm 1.05 (d, J=6.6 Hz, 6 H), 3.26 - 3.42 (m, 1 H), 3.80 (s, 3 H), 7.48 (d, J=4.6 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.59 (d, J=7.3 Hz, 1 H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.17 (dd, J=5.8, 2.8 Hz, 1 H), 10.32 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 204.47 °C.

TIP 296 PCT Compound 172: N-(3-Chloro-2,4-difluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide 4-(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (250 mg, 1.02 mmol was dissolved in CH3CN (15 mL). Triethylamine (0.56 mL), 3-chloro-2,4-difluoroaniline (183 mg, 1.12 mmol) and HATU (463 mg, 1.22 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, next at 50°C for 80 h and then for 24 h at 75°C. The solution was allowed to cool down. The solvent was evaporated leaving a yellow oil which was dissolved in CH2Cl2/MeOH (2 mL, 95:5) and purified by Flash Chromatography on silica using a gradient of EtOAc-heptane 0/100 to 100/0]. The desired ons were combined and the solvent was evaporated leaving a brown stable foam which was dissolved in a boiling e of of diisopropyl ether (3 mL) and CH3CN (0.5 mL). The solution was allowed to cool while stirring.

The precipitate was filtered off, washed once with its own filtrate and with of diisopropyl ether (2 mL). The product was collected as a white solid and dried in vacuo at 50°C, resulting in nd 172 (60 mg). Method B: Rt: 0.98 min m/z: 390.1 (M-H)- Exact mass: 391.06. 1H NMR (360 MHz, DMSO-d6) ppm 1.02 (d, J=6.6 Hz, 6 H), 3.26 (dd, J=13.4, 6.8 Hz, 1 H), 3.89 (s, 3 H), 7.25 (d, J=6.6 Hz, 1 H), 7.28 - 7.39 (m, 2 H), 7.48 - 7.59 (m, 2 H), 10.16 (s, 1 H). nd 173: N-(3-Chlorofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide 4-(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (0.75 g, 3.05 mmol) was dissolved in N,N-dimethylformamide (2 mL). HATU (1.27 g, 3.35 mmol) was added and the mixture was stirred for 20 minutes. DIPEA (1.31 mL, 7.61 mmol) was added followed by 3-chloro fluoroaniline (0.44 g, 3.05 mmol).The reaction mixture was d at 50°C for 16 hours. Then this mixture 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 the ed residue was llized out of MeOH/water. The precipitate was collected on a glass filter and dried in a vacuum oven at 55°C for 24 hours yielding compound 173 (477 mg) as a white powder. Method B: Rt: 0.97 min m/z: 372.1 (M-H)- Exact mass: 373.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.03 (d, J=6.6 Hz, 6 H), 3.21 - 3.30 (m, 1 H), 3.90 (s, 3 H), 7.18 - 7.27 TIP 296 PCT (m, 2 H), 7.32 (d, J=1.8 Hz, 1 H), 7.44 (ddd, J=8.2, 6.8, 1.5 Hz, 1 H), 7.50 (ddd, J=8.1, 6.8, 1.8 Hz, 1 H), 7.55 (d, J=1.8 Hz, 1 H), 10.12 (s, 1 H).

Compound 174: hlorofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide Compound 174 (681mg) was prepared similarly as described for compound 173 using 3-chloro- 4-fluoroaniline (0.44 g, 3.05 mmol) instead of rofluoroaniline resulting in a white powder. Method B: Rt: 1.02 min m/z: 372.1 (M-H)- Exact mass: 373.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 3.19 - 3.29 (m, 1 H), 3.92 (s, 3 H), 7.20 (br. s., 1 H), 7.32 (d, J=1.8 Hz, 1 H), 7.39 (t, J=9.1 Hz, 1 H), 7.55 (d, J=1.8 Hz, 1 H), 7.66 (ddd, J=9.0, 4.2, 2.6 Hz, 1 H), 8.02 (dd, J=6.8, 2.6 Hz, 1 H 10.22 (br. s., 1 H).

Compound 175: N-(3-Cyanofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide N O S H N F N O Compound 175 (576 mg) was prepared similarly as described for compound 173 using 5-amino- 2-fluorobenzonitrile (0.41 g, 3.05 mmol) instead of 3-chlorofluoroaniline resulting in a white powder. Method B: Rt: 0.91 min m/z: 363.2 (M-H)- Exact mass: 364.10. 1H NMR (400 MHz, DMSO-d6) ppm 1.02 (d, J=6.6 Hz, 6 H), 3.18 - 3.29 (m, 1 H), 3.92 (s, 3 H), 7.22 (d, J=5.5 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.49 - 7.56 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.89 - 8.10 (m, 1 H), 8.15 - 8.27 (m, 1 H), 10.37 (br. s., 1 H).

Compound 176: yanofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide TIP 296 PCT Compound 176 (294 mg) was prepared similarly as described for compound 173 using 3-cyano- 2-fluoroaniline (0.41 g, 3.05 mmol) instead of 3-chlorofluoroaniline resulting in a white powder. Method B: Rt: 0.85 min m/z: 363.1 (M-H)- Exact mass: 364.10. 1H NMR (400 MHz, DMSO-d6)  ppm 1.03 (d, J=6.4 Hz, 6 H), 3.18 - 3.30 (m, 1 H), 3.79 - 3.97 (m, 3 H), 7.22 (d, J=6.8 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.37 - 7.48 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.71 - 7.81 (m, 1 H), 7.83 - 7.98 (m, 1 H), 10.25 (br. s., 1 H).

Compound 177: N-(3-Cyanophenyl)methyl[(1-methylethyl)sulfamoyl]-1H-pyrrole carboxamide nd 177 (629 mg) was prepared similarly as described for compound 173 using 3- aminobenzonitrile (0.36 g, 3.05 mmol) instead of 3-chlorofluoroaniline resulting in a white powder. Method A: Rt: 1.49 min m/z: 345.1 (M-H)- Exact mass: 346.11. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 3.20 - 3.30 (m, 1 H), 3.93 (s, 3 H), 7.21 (br. s., 1 H), 7.36 (d, J=1.8 Hz, 1 H), 7.48 - 7.61 (m, 3 H), 7.94 - 8.04 (m, 1 H), 8.11 - 8.26 (m, 1 H), 10.34 (br. s., 1 H). nd 178: N-(3-Cyano-2,4-difluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- ecarboxamide Compound 178 (244 mg) was was prepared similarly as described for nd 173 using 3-amino-2,6-difluorobenzonitrile (0.47 g, 3.05 mmol) instead of 3-chlorofluoroaniline resulting in a white powder. Method B: Rt: 0.89 min m/z: 381.1 (M-H)- Exact mass: 382.09. 1H NMR (400 MHz, DMSO-d6)  ppm 1.03 (d, J=6.6 Hz, 6 H), 3.20 - 3.29 (m, 1 H), 3.90 (s, 3 H), 7.22 (d, J=6.8 Hz, 1 H), 7.32 (d, J=1.8 Hz, 1 H), 7.45 (td, J=8.9, 1.5 Hz, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 7.94 (td, J=8.9, 6.2 Hz, 1 H), 10.25 (br. s., 1 H).

TIP 296 PCT Compound 179: N-[4-Fluoro(trifluoromethyl)phenyl]-1,3-dimethyl[(3-methyloxetan famoyl]-1H-pyrrolecarboxamide Compound 179 was was prepared similarly as bed for compound 144 using 3-methyl oxetanamine (2.29 g, 26.3 mmol) instead of (R)-1,1,1-trifluoropropylamine in Step2 and, in step 4, 1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (155 mg, 0.54 mmol), 4-fluoro(trifluoromethyl)aniline (0.2 g, 1.08 mmol) and HATU (0.25 g, 0.65 mmol) were dissolved in DMF (0.72 mL) containing DIPEA (0.23 mL, 1.34 mmol). The reaction mixture was stirred at 40°C for 42 hours and allowed to reach room ature. The reaction mixture was purified using silica gel column chromatography (ethyl acetate in heptane from 10 to 70%). The d fractions were combined and evaporated to afford light yellow oil. The yellow oil was purified using silica gel column chromatography (ethyl acetate in heptane from 40 to 70%) yielding compound 179 (93 mg) as white powder which was dried in vacuum oven at 50°C. Method B: Rt: 0.97 min m/z: 448.1 (M-H)- Exact mass: 449.10. 1H NMR (400 MHz, DMSO-d6)  ppm 1.54 (s, 3 H), 2.34 (s, 3 H), 3.73 (s, 3 H), 4.13 (d, J=6.4 Hz, 2 H), 4.63 (d, J=5.9 Hz, 2 H), 7.48 (s, 1 H), 7.52 (t, J=9.8 Hz, 1 H), 7.89 - 8.00 (m, 2 H), 8.20 (dd, J=6.6, 2.6 Hz, 1 H), 10.42 (br. s., 1 H).

Compound 180: N-(3-Cyanophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 180 was ed similarly as described for compound 170 using 3-aminobenzonitrile (138 mg, 1.16 mmol) instead of 5-aminofluorobenzonitrile. The column fractions were concentrated and the residue was crystallized by dissolving in 10 mL warm ol upon addition of water. The crystals were filtered off and dried overnight in vacuo at 50°C resulting in a white powder (121 mg). Method A: Rt: 1.72 min m/z: 417.0 (M-H)- Exact mass: 418.07.1H NMR (360 MHz, DMSO-d6) ppm 1.18 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.05 (m, 1 H), 7.54 - 7.61 (m, 3 H), 7.89 - 7.96 (m, 1 H), 8.14 (d, J=1.1 Hz, 1 H), 8.64 (d, J=8.4 Hz, 1 H), 10.40 (s, 1 H).

TIP 296 PCT Compound 181:N-(3-Cyano-2,4-difluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 181 was prepared similarly as described for compound 180 using 3-amino-2,6- robenzonitrile (143 mg, 0.928 mmol) instead of 3-aminobenzonitrile resulting in a white powder (79 mg). Method A: Rt: 1.77 min m/z: 453.0 (M-H)- Exact mass: . 1H NMR (360 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.04 (m, 1 H), 7.43 - 7.51 (m, 1 H), 7.59 (d, J=4.4 Hz, 1 H), 7.98 - 8.08 (m, 1 H), 8.66 (d, J=8.8 Hz, 1 H), 10.06 (s, 1 H).

Compound 182: yanofluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 182 was prepared similarly as described for compound 180 using 3-amino fluorobenzonitrile (127.5mg, 0.936mmol) instead of 3-aminobenzonitrile resulting in a white powder (66 mg). Method A: Rt: 1.78 min m/z: 435.1 (M-H)- Exact mass: 436.06. 1H NMR (360 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.82 (s, 3 H), 3.91 - 4.06 (m, 1 H), 7.43 (t, J=7.7 Hz, 1 H), 7.59 (d, J=4.4 Hz, 1 H), 7.78 (ddd, J=7.8, 5.9, 1.6 Hz, 1 H), 8.03 (td, J=8.0, 1.6 Hz, 1 H), 8.66 (d, J=8.8 Hz, 1 H), 10.06 (s, 1 H).

Compound 183: 3-Fluoromethyl{[(1R)-2,2,2-trifluoromethylethyl]sulfamoyl}-N-(2,3,4- trifluorophenyl)-1H-pyrrolecarboxamide Compound 183 was prepared similarly as described for compound 180 using 2,3,4-tri- fluoroaniline (136.8 mg, 0.911 mmol) d of 3-aminobenzonitrile resulting in a white powder (79 mg). Method A: Rt: 1.89 min m/z: 446.0 (M-H)- Exact mass: 447.05. 1H NMR (400 MHz, TIP 296 PCT DMSO-d6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.04 (m, 1 H), 7.29 - 7.39 (m, 1 H), 7.42 - 7.50 (m, 1 H), 7.56 (d, J=4.6 Hz, 1 H), 8.61 (d, J=8.8 Hz, 1 H), 9.93 (s, 1 H).

Compound 184: N-(3-Bromo-2,4-difluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 184 was prepared similarly as described for compound 180 using 3-bromo-2,4- difluoroaniline (194.9 mg, 0.937 mmol) instead of 3-aminobenzene resulting in a white powder (115 mg). Method A: Rt: 1.98 min m/z: 508.0 (M-H)- Exact mass: 506.97. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.90 - 4.04 (m, 1 H), 7.27 - 7.35 (m, 1 H), 7.56 (d, J=4.4 Hz, 1 H), 7.64 - 7.73 (m, 1 H), 8.61 (d, J=8.8 Hz, 1 H), 9.86 (s, 1 H).

Compound 185: N-(3-Chloro-2,4-difluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 185 was ed rly as described for 180 using 3-chloro-2,4-difluoroaniline (150.9 mg, 0.923 mmol) instead of 3-aminobenzene resulting in a white powder (115 mg).

Method A: Rt: 1.97 min m/z: 462.0 (M-H)- Exact mass: 463.02. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.04 (m, 1 H), 7.35 (td, J=8.9, 2.0 Hz, 1 H), 7.56 (d, J=4.6 Hz, 1 H), 7.65 (td, J=8.7, 5.8 Hz, 1 H), 8.61 (d, J=8.6 Hz, 1 H), 9.88 (s, 1 H).

TIP 296 PCT Compound 186: N-(3-Cyanofluorophenyl)fluoromethyl{[(1R)methylpropyl ]sulfamoyl}-1H-pyrrolecarboxamide Intermediate ethyl romethyl[[(1R)methylpropyl]sulfamoyl]pyrrolecarboxylate was made similarly as described for compound 170 using 5-ethoxycarbonylfluoromethylpyrrolesulfonic acid (541.4 mg, 2.155 mmol), converting it to the corresponding sulphonylchloride with lchloride (heating at 80°C during 90’) and reacting this with (R)-(- )aminobutane (238.8 mg, 3.233 mmol) resulting in ethyl 3-fluoromethyl[[(1R) propyl]sulfamoyl]pyrrolecarboxylate(354 mg) as a white . 1H NMR (400 MHz, DMSO-d6)  ppm 0.76 (t, J=7.4 Hz, 3 H), 0.98 (d, J=6.6 Hz, 3 H), 1.28 (t, J=7.0 Hz, 3 H), 1.31 - 1.40 (m, 2 H), 3.01 - 3.18 (m, 1 H), 3.81 (s, 3 H), 4.27 (q, J=7.2 Hz, 2 H), 7.47 - 7.57 (m, 2 H).To ethyl 3-fluoromethyl[[(1R)methylpropyl]sulfamoyl]pyrrolecarboxylate (354 mg, 1.156 mmol) and 5-aminofluoro-benzonitrile (201.7mg, 1.483 mmol) in dry THF (20 mL) at 0°C, lithium bis(trimethylsilyl)amide in THF (4.62 mL, 4.62 mmol) was added. The mixture was stirred 1 hour at 0°C. The reaction mixture was quenched with NH4Cl solution (30 mL) and extracted with EtOAc (50mL), diluted with brine (50 mL) and extracted again with EtOAc (50 mL). The combine organic layers were dried over sodium sulphate, filtered and concentrated. The residue lved in 1 mL DMF) was purified by column chromatography on silica using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the solid residue was crystallized from 50 mL warm methanol upon on of water. The white crystals were filtered off and dried in vacuo at 50°C overnight, resulting in compound 186 (306 mg) Method A: Rt: 1.83 min m/z: 395.1 (M-H)- Exact mass: 396.11. 1H NMR (400 MHz, DMSO-d6)  ppm 0.78 (t, J=7.4 Hz, 3 H), 1.01 (d, J=6.6 Hz, 3 H), 1.31 - 1.44 (m, 2 H), 3.06 - 3.20 (m, 1 H), 3.80 (s, 3 H), 7.47 (d, J=4.6 Hz, 1 H), 7.50 - 7.58 (m, 2 H), 7.96 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 10.31 (s, 1 H). nd 187: N-(3-Cyanofluorophenyl)[(3,3-difluoromethylcyclobutyl)sulfamoyl] fluoromethyl-1H-pyrrolecarboxamide Compound 187 (290 mg) was prepared similarly as described for compound 186 using 3,3- difluoromethyl-cyclobutanamine hydrochloride (509.4 mg, 3.232 mmol) instead of (R)-(-) TIP 296 PCT utane resulting in a white powder. Method A: Rt: 1.84 min m/z: 443.1 (M-H)- Exact mass: 444.09. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.42 (s, 3 H), 2.47 - 2.62 (m, 2 H), 2.80 - 2.97 (m, 2 H), 3.81 (s, 3 H), 7.49 - 7.58 (m, 2 H), 7.96 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.16 (dd, J=5.7, 2.6 Hz, 1 H), 8.22 (s, 1 H), 10.33 (s, 1 H).

Compound 188: N-(3-Cyanofluorophenyl)fluoromethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 188 (409 mg) was prepared similarly as described for compound 186 using (2S)- 1,1,1-trifluoropropanamine instead of (R)-(-)aminobutane resulting in a white .

Method A: Rt: 1.89 min m/z: 435.0 (M-H)- Exact mass: 436.06. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.05 (m, 1 H), 7.50 - 7.59 (m, 2 H), 7.96 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.62 (d, J=8.8 Hz, 1 H), 10.36 (s, 1 H). Differential scanning calorimetry: peak at 190.92°C.

Compound 189: hloro-4,5-difluorophenyl)methyl{[1-(trifluoromethyl)- cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide -[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (470.2 mg, 0.966 mmol) 1-trifluoromethyl)cyclobutanamine (268.7 mg, 1.932 mmol DIPEA (0.518 mL, 2.99 mmol) was dissolved in CH3CN and refluxed over weekend. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and trated. The residue was ed by column chromatography on a silica using a gradient from 10 till 100 % EtOAc in heptane. The product fractions were concentrated yielding a beige powder. This powder was fied by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm), Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) , yielding a white powder which was dried in vacuo at 50°C, resulting in compound 189 (32.9 mg). Method B: Rt: 1.18 min m/z: 470.0 (M-H)- Exact mass: 471.04. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.71 - 1.87 (m, 2 H), 2.24 - 2.36 (m, 2 H), TIP 296 PCT 2.39 - 2.48 (m, 2 H), 3.93 (s, 3 H), 7.37 (d, J=2.0 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.76 - 7.87 (m, 2 H), 8.37 (s, 1 H), 10.33 (s, 1 H).

Compound 190: 4-(tert-Butylsulfamoyl)-N-(3-cyanofluorophenyl)methyl-1H-pyrrole carboxamide methyl 4-chlorosulfonylmethyl-pyrrolecarboxylate (5 g, 1.04 mmol) was dissolved in acetonitrile (100 mL). To this was added diisopropylethylamine (9.06 mL, 52.6 mmol) followed by Tert-Butylamine (3.23 g, 44.2 mmol) and the resulting mixture was refluxed for 2 hours.

Then the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and was washed with HCl (2 x 150 mL).

The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding a powder of methyl 4-(tert-butylsulfamoyl)methyl-pyrrolecarboxylate which was used as such.(6.07 g) Method B: Rt: 1.52 min m/z: 273.0 (M-H)- Exact mass: 274.10. 1H NMR (360 MHz, DMSO-d6) ppm 1.13 (s, 9 H), 3.77 (s, 3 H), 3.88 (s, 3 H)7.00 (d, J=1.8 Hz, 1H), 7.18 (s, 1 H), 7.60 (d, J=2.2 Hz, 1 H). methyl 4-(tert-butylsulfamoyl)methyl-pyrrolecarboxylate (11.269 g, 41.077 mmol) was ved in THF (120 mL). To this was added lithium hydroxide (1.476 g, 1.5 eq) in distilled water (16 mL) and a turbid mixture was obtained. Then MeOH (6 mL) was added and the mixture became clear. The resulting e was stirred for 18 hours.

Then it was concentrated until water remained and led water (30 mL) was added. The mixture was neutralized using an exact amount of hydrochloric acid (1M / aq / 61.6 mL, 61.62 mmol). The resulting mixture was extracted using 2-methyltetrahydrofuran. The combined extracts were dried on MgSO4, filtered and concentrated under reduced pressure resulting in 4- (tert-butylsulfamoyl)methyl-pyrrolecarboxylic acid as a white powder which was used t further purifications for the next step (10.62g). Method B: Rt: 0.83 min m/z: 258.9 (MH )- Exact mass: 260.08 .Compound 190 (2140 mg) was prepared similarly as described for compound 158 using 5-aminofluorobenzonitrile (1348 mg, 9.604 mmol) and 4-(tertbutylsulfamoyl )methyl-pyrrolecarboxylic acid and stirring at 50°C instead of room ature, resulting in a white solid. Method B: Rt: 0.96 min m/z: 377.1 (M-H)- Exact mass: 378.12. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H) 3.91 (s, 3 H) 7.14 (s, 1 H) 7.34 (d, J=1.76 Hz, 1 H) 7.48 - 7.56 (m, 2 H) 7.98 - 8.05 (m, 1 H) 8.22 (dd, J=5.83, 2.75 Hz, 1 H) 10.34 (s, 1 H).

Compound 191: 4-(tert-Butylsulfamoyl)-N-(3-cyanophenyl)methyl-1H-pyrrole carboxamide TIP 296 PCT nd 191 (758 mg) was prepared similarly as described for compound 190 using 3- aminobenzonitrile (458.4 mg, 3.84 mmol) instead of 5-aminofluorobenzonitrile resulting in a white solid. Method B: Rt: 0.92 min m/z: 359.1 (M-H)- Exact mass: 360.13. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H) 3.92 (s, 3 H) 7.13 (s, 1 H) 7.36 (s, 1 H) 7.51 - 7.59 (m, 3 H) 7.99 (d, J=7.04 Hz, 1 H) 8.19 (s, 1 H) 10.31 (s, 1 H).

Compound 192: 4-(tert-Butylsulfamoyl)-N-(3-cyanofluorophenyl)methyl-1H-pyrrole carboxamide Compound 192 (733 mg) was prepared similarly as described for compound 190 using 3-amino- robenzonitrile (522.9 mg, 3.842 mmol) d of 5-aminofluorobenzonitrile resulting in a white solid. Method B: Rt: 0.90 min m/z: 377.1 (M-H)- Exact mass: 378.12. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H) 3.89 (s, 3 H) 7.15 (s, 1 H) 7.34 (d, J=2.0 Hz, 1 H) 7.42 (t, J=7.9 Hz, 1 H) 7.55 (d, J=1.76 Hz, 1 H) 7.77 (ddd, J=7.7, 5.9, 1.8 Hz, 1 H) 7.90 (td, J=7.90, 1.5 Hz, 1 H) 10.23 (s, 1 H).

Compound 193: 4-(tert-Butylsulfamoyl)-N-(3-chlorofluorophenyl)methyl-1H-pyrrole carboxamide Compound 193 (787 mg) was prepared similarly as described compound 190 using 3-chloro fluoroaniline (0.435 mL, 3.84 mmol) resulting in a white solid. Method B: Rt: 1.02 min m/z: 386.1 (M-H)- Exact mass: 387.08. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.18 (s, 9 H) 3.89 (s, 3 H) 7.14 (s, 1 H) 7.20 - 7.26 (m, 1 H) 7.32 (d, J=1.76 Hz, 1 H) 7.41 - 7.46 (m, 1 H) 7.48 - 7.54 (m, 2 H) 10.10 (s, 1 H).

TIP 296 PCT Compound 194: 4-(tert-Butylsulfamoyl)-N-(3-chloro-2,4-difluorophenyl)methyl-1H-pyrrole- 2-carboxamide Compound 194 (708 mg) was prepared rly as described for compound 190 using 3-chloro- fluoroaniline (628.3, 3.84 mmol) ing in a white solid. Method B: Rt: 1.03 min m/z: 404.1 (M-H)- Exact mass: 405.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H) 3.89 (s, 3 H) 7.15 (s, 1 H) 7.30 - 7.37 (m, 2 H) 7.48 - 7.58 (m, 2 H) 10.11 (s, 1 H).

Compound 195: 4-(tert-Butylsulfamoyl)-N-(3-chlorofluorophenyl)methyl-1H-pyrrole carboxamide Compound 195 (705mg) was prepared similarly as described for compound 190 using 3-chlorofluoroaniline (559.2mg, 3.842 mmol) resulting in a white solid. Method A: Rt: 1.95 min m/z: 386.0 (M-H)- Exact mass: 387.08. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 3.91 (s, 3 H), 7.12 (s, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.39 (t, J=9.1 Hz, 1 H), 7.53 (d, J=1.8 Hz, 1 H), 7.63 - 7.70 (m, 1 H), 8.02 (dd, J=6.8, 2.6 Hz, 1 H), 10.19 (s, 1 H).

Compound 196: N-(3-Cyano-2,4-difluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Methyl 1-methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (0.7 g, 2.23 mmol) was dissolved in THF (10 mL) under nitrogen. To this was added 3-amino-2,6- difluorobenzonitrile (0.45 g, 2.9 mmol) and the mixture was cooled in an ice-water bath while stirred under nitrogen. To this was added drop wise lithium bis(trimethylsilyl)amide 1M in e (6.68 mL, 6.68 mmol) over a period of 10 minutes. The resulting mixture was stirred for 1 hour while cooling was ued. The mixture was quenched with saturated ammonium TIP 296 PCT chloride (25 mL) and the resulting mixture was extracted using EtOAc (3 x 25 mL). The combined ts were washed with brine (20 mL), dried on Na2SO4, ed and concentrated in vacuo. The obtained residue was dissolved in 2 mL dichloromethane and this was loaded on a dry silica plug. This was purified by column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100). The desired fractions were collected and trated in vacuo yielding a powder. This powder was recrystallized out of MeOH/water. The ed crystals were collected on a filter, rinsed with water followed by diisopropylether and dried in a vacuo at 55°C for 24 hours ing in N-(3-Cyano-2,4-difluorophenyl)methyl{[(1S)- 2,2,2-trifluoromethylethyl]sulfamoyl}-1H-pyrrolecarboxamide (563 mg) as a powder.

Method A: Rt: 1.75 min m/z: 435.0 (M-H)- Exact mass: 436.06. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.09 (d, J=6.8 Hz, 3 H), 3.80 - 4.06 (m, 4 H), 7.36 (d, J=2.0 Hz, 1 H), 7.40 - 7.51 (m, 1 H), 7.66 (d, J=1.5 Hz, 1 H), 7.85 - 8.02 (m, 1 H), 8.54 (br. s, 1 H), 10.14 (br. s, 1 H).

Compound 197: N-(3-Cyanophenyl)methyl{[(1S)-2,2,2-trifluoromethylethyl]- sulfamoyl}-1H-pyrrolecarboxamide Compound 197 (697.6 mg) was prepared similarly as described for compound 196 using 3- aminobenzonitrile (342 mg, 2.895 mmol) instead of 3-amino-2,6-difluorobenzonitrile resulting in N-(3-cyanophenyl)methyl[[(1S)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxamide as a solid. Method B: Rt: 0.93 min m/z: 399.1 (M-H)- Exact mass: 400.08. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=6.8 Hz, 3 H) 3.93 (s, 4 H) 7.39 (d, J=1.9 Hz, 1 H) 7.52 - 7.60 (m, 2 H) 7.65 (d, J=1.9 Hz, 1 H) 7.99 (dt, J=6.9, 2.3 Hz, 1 H) 8.20 (br. s, 1 H) 8.17 - 8.20 (m, 1 H) 10.35 (br. s., 1 H).

Compound 198: N-(3-Cyanofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 198 (691 mg) was prepared similarly as described for compound 196 using 3-amino- 2-fluoro-benzonitrile , 2.895mmol) instead of 3-amino-2,6-difluorobenzonitrile resulting TIP 296 PCT in as a solid. Method B: Rt: 0.91 min m/z: 417.1 (M-H)- Exact mass: 418.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.03 - 1.18 (m, 3 H), 3.84 - 4.03 (m, 4 H), 7.38 (d, J=2.0 Hz, 1 H), 7.42 (t, J=7.9 Hz, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.77 (ddd, J=7.6, 6.0, 1.5 Hz, 1 H), 7.91 (td, J=7.8, 1.5 Hz, 1 H), 7.99 - 9.14 (m, 1 H), 10.26 (br. s., 1 H).

Compound 199: 3-Chloro-N-(3-cyanofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Sodium hydride (3.46 g, 90.2 mmol, 60 % dispersion in oil) was added portion wise, over a period of 10 s, to a on of methyl 3-chloro-1H-pyrrolecarboxylate (12 g, 75.2 mmol), iodomethane (12.8 g, 90.2 mmol) and DMF (120 mL) at 0°C under nitrogen in an ice bath. The ice bath was removed and the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was acidified with aqueous hydrochloric acid (15.04 mL, 1 M) and concentrated. The residue was dissolved in water (100 mL)/ethyl acetate (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in acetonitrile (150 mL), washed with heptane (100 mL) and concentrated at 70°C yielding methyl 3-chloromethyl-pyrrolecarboxylate (12.0 g) as yellow liquid which was used as such. 1H NMR (400 MHz, CHLOROFORM-d)  ppm 3.87 (s, 3 H), 3.88 (s, 3 H), 6.13 (d, J=2.9 Hz, 1 H), 6.69 (d, J=2.9 Hz, 1 H) Methyl 3-chloromethyl-pyrrolecarboxylate (5.0 g, 25.1 mmol) was added drop wise to chlorosulfonic acid (11 mL) at 0°C under nitrogen atmosphere. The on mixture was warmed to room temperature and allowed to stir 2 hours. The resulting mixture was added drop wise to a stirred, temperature controlled ice-water mixture (200 mL) keeping the temperature under 5°C. A white precipitation was formed. The obtained aqueous suspension was extracted using romethane (3 x 100 mL). The combined organic extracts were washed with Brine and dried on sodium sulphate, filtered and trated in vacuo yielding methyl 3-chloro- 4-chlorosulfonylmethyl-pyrrolecarboxylate (5.56 g) as light green powder which was used as such. 1H NMR (400 MHz, CHLOROFORM-d)  ppm 3.94 (s, 3 H), 3.98 (s, 3 H), 7.46 (s, 1 H). In a microwave tube methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1.5 g, 5.51 mmol) was dissolved in acetonitrile (10 mL). To this was added DIPEA (1.42 mL, 0.75 g/mL, 8.27 mmol) followed by (R)-1,1,1-trifluoropropylamine (0.94 g, 8.27 mmol) and molecular sieves and the tube was closed and resulting mixture was heated at 80°C 30 minutes under ave irradiation. The on e was concentrated and the resulting brown sticky oil was dissolved in dichloromethane (50 mL) and this was washed with HCl (1N, 2 x 10 mL) and Brine (5 mL) and dried on sodium sulphate. The solids were filtered off and the te was concentrated in vacuo yielding brown oil. The brown oil was purified using silica gel TIP 296 PCT column chromatography (ethyl e in heptane from 0 to 100 %) to afford methyl 3-chloro methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (660 mg) as white powder which was used as such. Method B: Rt: 0.88 min m/z: 347 (M-H)- Exact mass: 348.02. 1H NMR (400 MHz, DMSO-d6)  ppm 1.15 (d, J=7.0 Hz, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 3.89 - 4.02 (m, 1 H), 7.76 (s, 1 H), 8.51 (d, J=8.8 Hz, 1 H). Methyl 3-chloromethyl [[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (660 mg, 1.89 mmol) and -aminofluorobenzonitrile (332 mg, 2.37 mmol) were dissolved in dry tetrahydrofuran (30 mL) under nitrogen. The on mixture was cooled to 0°C and lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.46 mL, 5.46 mmol, 1M) was added over a period of 2 minutes. The resulting mixture was stirred for 2 minutes while cooling was continued. The mixture was quenched with saturated s ammonium chloride (15 mL) and the resulting mixture was ted using ethyl acetate (3 x 30 mL). The combined extracts were washed with Brine (10 mL), dried on Na2SO4, filtered and concentrated in vacuo to afford a red powder. The ed residue was triturated in a refluxing mixture of CH2Cl2/EtOAc/methanol (10/5/5 mL).

The solids were filtered to afford a dark pink powder which was recrystallized from ol/water (7/0.5 mL) to afford compound 199 as a powder (325 mg) Method B: Rt: 0.99 min m/z: 451.0 (M-H)- Exact mass: 452.03. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.78 (s, 3 H), 3.91 - 4.05 (m, 1 H), 7.56 (t, J=9.1 Hz, 1 H), 7.69 (s, 1 H), 7.98 (ddd, J=9.2, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 8.51 (d, J=8.8 Hz, 1 H), 10.68 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at in: peak at 190.1 °C.

Alternative procedure for the synthesis of methyl 3-chloromethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxylate Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1 g, 3.68 mmol) was ved in hot acetonitrile (5 mL), molecular sieves (about 100 mg) were added and the reaction mixture was stirred. In a separate vessel (R)-1,1,1-trifluoropropylamine (623 mg, .51 mmol) was dissolved in acetonitrile (5 mL), molecular sieves (about 100 mg) was added.

This suspension was added to the reaction mixture and then NaHCO3 (926 mg, 11.0 mmol) was added. The vessel was closed and it was stirred overnight at 80°C. The volatiles were removed under reduced pressure and the obtained residue was purified by silica gel chromatography, using a gradient from heptane to EtOAc, yielding methyl 3-chloromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (1.04 g) as a white powder.

Compound 200: N-(3-Cyanofluorophenyl){[2,2-difluoromethylethyl]sulfamoyl} methyl-1H-pyrrolecarboxamide TIP 296 PCT -aminofluoro-benzonitrile (5.62 g, 41.3 mmol) was added to a solution of 4-chlorosulfonyl- 1-methyl-pyrrolecarbonyl chloride (described in the synthesis of compound 3) (10 g, 41.3 mmol), toluene (300 mL) at reflux. The reaction mixture was ed 4 hours and filtered warm.

The filtrate was concentrated to dryness to afford a yellow powder which was dried over weekend in vacuo. The yellow powder was triturated in warm ethyl acetate (50 mL) and filtered and washed with dichloromethane. The filtrate was concentrated to dryness and the residue was purified using silica gel column tography (ethyl e in heptane from 0 to 100%) to afford cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (5.05 g) as off white powder. 5-[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.00 g, 2.93 mmol) was dissolved in a solution of 1,1-difluoropropanamine (417 mg, 4.39 mmol, synthesized according ot PCT Int. Appl., 2012049277) in THF (17 mL) dried on molecular sieves and stirred at 60 °C for 20 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified using silica gel column chromatography (ethyl acetate in heptane from 10 to 70%) to afford crude compound 200 as white powder. Compound 200 was purified by Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm), Mobile phase: CO2, methanol with 0.2% iPrNH2), the desired ons were collected, evaporated, solved in methanol and evaporated again, ng compound 200 a (192 mg) as white powder. Method A: Rt: 1.67 min m/z: 399.1 (M-H)- Exact mass: 400.08 1H NMR (400 MHz, DMSO-d6)  ppm 0.99 (d, J=7.0 Hz, 3 H), 3.42 - 3.56 (m, 1 H), 3.93 (s, 3 H), .90 (td, J=56.1, 2.6 Hz, 1 H), 7.36 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.2 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.83 (br. s., 1 H), 8.01 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 10.37 (s, 1 H). And compound 200b (190 mg) as white powder. Method A: Rt: 1.67 min m/z: 399.0 (M-H)- Exact mass: 400.08. 1H NMR (400 MHz, DMSO-d6)  ppm 0.99 (d, J=7.0 Hz, 3 H), 3.42 - 3.57 (m, 1 H), 3.93 (s, 3 H), 5.90 (td, , 2.6 Hz, 1 H), 7.36 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.77 (br. s., 1 H), 8.01 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.21 (dd, J=5.9, 2.6 Hz, 1 H), 10.37 (br. s., 1 H).

Compound 201: N-(3-Chloro-4,5-difluorophenyl)-1,3-dimethyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Compound 201 (69 mg) as white powder was prepared similarly as described for compound 179 using 3-chloro-4,5-difluoro-aniline (0.18 g, 1.08 mmol) instead of 4-fluoro (trifluoromethyl)aniline. The reaction was stirred at 50 °C for 92 hours. Method B: Rt: 0.98 min m/z: 432.1 (M-H)- Exact mass: 433.07 . 1H NMR (400 MHz, DMSO-d6)  ppm 1.53 (s, 3 H), 2.32 (s, 3 H), 3.72 (s, 3 H), 4.12 (d, J=6.4 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.49 (s, 1 H), 7.71 - 7.81 (m, 2 H), 7.93 (br. s., 1 H), 10.40 (br. s., 1 H).

Compound 243: N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl[(3-methyloxetan- 3-yl)sulfamoyl]-1H-pyrrolecarboxamide 1,3-dimethyl(N-(3-methyloxetanyl)sulfamoyl)-1H-pyrrolecarboxylic acid (500 mg, 1.73 mmol), 3-chloro-2,4-difluoroaniline (0.57 g, 3.47 mmol) and HATU (0.88 g, 2.31 mmol) were dissolved in DMF (2 mL) containing DIPEA (0.69 mL, 3.98 mmol). The reaction mixture was stirred at 65°C for 28 hours and at room temperature for 60 hours. The reaction mixture was purified using silica gel column chromatography (ethyl acetate in heptane from 10 to 70%). The desired ons were combined and evaporated to afford a light brown oil which fied while standing. The solid was recrystallized from l (5 mL) to afford a white solid which was filtered and washed with ethanol (1 mL). The white solid was dried overnight in vacuo, resulting in compound 243 (318 mg) as off white solid. Method D: Rt: 1.73 min m/z: 432.0 (MH )- Exact mass: 433.1 .1H NMR (400 MHz, DMSO-d6)  ppm 1.52 (s, 3 H), 2.37 (s, 3 H), 3.73 (s, 3 H), 4.11 (d, J=6.4 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.35 (td, J=9.0, 2.0 Hz, 1 H), 7.47 (s, 1 H), 7.67 (td, J=8.7, 5.8 Hz, 1 H), 7.91 (br. s., 1 H), 10.03 (br. s., 1 H).

Compound 202: N-(3-Chloro-4,5-difluorophenyl)-1,3-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Compound 202 was prepared similarly as described for compound 144. In Step 4, 1,3-dimethyl- 4-[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (260 mg, 0.83 mmol) was used and 3-chloro-4,5-difluoro-aniline (0.27 g, 1.65 mmol) d of 3,4- difluoroaniline was used . This reaction was performed at 50°C for 92 hours. The desired fractions were combined and evaporated to afford a powder which was recrystalized from CH2Cl2. The white crystals were filtered and washed with CH2Cl2 and dried overnight in vacuum oven at 50°C to afford a white solid (170 mg). Method B: Rt: 1.12 min m/z: 458.0 (M-H)- Exact mass: 459.04. 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.30 (s, 3 H), 3.72 (s, 3 H), 3.78 - 3.90 (m, 1 H), 7.53 (s, 1 H), 7.66 - 7.84 (m, 2 H), 8.18 (br. s., 1 H), 10.39 (s, 1 H).

Compound 203: N-(2,3-Difluorophenyl)methyl{[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl}-1H-pyrrolecarboxamide Into a 100 mL round bottom flask equipped with a magnetic stir bar was placed methyl 1- methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (0.9 g, 2.86 mmol), anhydrous THF (40 mL), and 2,3-difluoroaniline (490 mg, 3.72 mmol). The vial was sealed and placed into an ice-water bath and to it was added LHMDS (8.6 mL of a 1M solution in THF/ethylbenzene) slowly via syringe (approx rate of 2mL/min). Conversion to product seen after 30 min at 0°C. Sat. aq. ammonium chloride was added to quench the reaction. This was d with ethyl acetate (100 mL) and the mixture ioned with ethyl acetate (3 x 100 mL).

The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration and the solvents of the te were removed under reduced pressure. The crude was partially purified via silica column tography using a heptane to ethylacetate gradient.

The t of the best fractions were removed under reduced pressure and the compound was recrystallized from ether/heptane to afford compound 203 as a white solid (395 mg). Method A: Rt: 1.75 min m/z: 410.1 (M-H)- Exact mass: 411.07. 1H NMR (400 MHz, DMSO-d6)  ppm 1.10 (d, J=7.0 Hz, 3 H), 3.85 - 4.00 (m, 1 H), 3.91 (s, 3 H), 7.16 - 7.40 (m, 4 H), 7.65 (d, J=1.8 Hz, 1 H), 8.17 (d, J=7.7 Hz, 1 H), 10.15 (s, 1 H). Differential ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 157.94 °C.

TIP 296 PCT Compound 204: N-(3-Chloro-2,6-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 204 was prepared similarly as described for compound 203 using 3-chloro-2,6- difluoro-aniline (627.7mg, 3.72mmol) and the crude was recrystallized in diisopropyl ether/heptane to afford a white solid (423 mg) Method A: Rt: 1.79 min m/z: 444.0 (M-H)- Exact mass: 445.03. 1H NMR (400 MHz, DMSO-d6)  ppm 1.12 (d, J=6.8 Hz, 3 H), 3.84 - 4.01 (m, 1 H), 3.91 (s, 3 H), 7.31 (t, J=8.8 Hz, 1 H), 7.41 (s, 1 H), 7.57 - 7.66 (m, 1 H), 7.69 (s, 1 H), 8.21 (d, J=8.1 Hz, 1 H), 10.17 (s, 1 H). nd 205: N-(3-Bromo-4,5-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 205 (893 mg) was prepared similarly as described for compound 158 using 3-bromo- fluoroaniline (970 mg, 4.663 mmol) instead of 3-aminobenzonitrile and stirring at 60°C during 18 h. The ed residue was warmed with CH2Cl2/heptanes and the white solid collected by tion. Method A: Rt: 1.79 min m/z: 489.9 (M-H)- Exact mass: 488.98. 1H NMR (400 MHz, DMSO-d6)  ppm 1.08 (d, J=7.0 Hz, 3 H), 3.84 - 3.99 (m, 1 H), 3.92 (s, 3 H), 7.36 (d, J=1.8 Hz, 1 H), 7.67 (d, J=1.5 Hz, 1 H), 7.80 - 7.93 (m, 2 H), 8.19 (br. s., 1 H), 10.30 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 196.72 °C.

Compound 206: N-(3-Bromofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Compound 206 (637 mg) was prepared similarly as described for compound 158 using 3-bromo- roaniline (886 mg,4.663 mmol) instead of 3-aminobenzonitrile and stirring at 60°C during 18 h. The residue was warmed with heptane,1 drop EtOAc added precipitation occures. A white solid was filtered off and dried in vacuo. Method A: Rt: 1.88 min m/z: 470.0 (M-H)- Exact mass: . 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 (d, J=6.8 Hz, 3 H), 3.85 - 4.00 (m, 1 H), 3.90 (s, 3 H), 7.18 (td, J=8.0, 1.3 Hz, 1 H), 7.36 (d, J=2.0 Hz, 1 H), 7.50 - 7.60 (m, 2 H), 7.65 (d, J=1.8 Hz, 1 H), 8.17 (br. s., 1 H), 10.11 (br. s., 1 H) Differential scanning calorimetry: From 30 to 300°C at in: peak at 216.73 °C.

Compound 207: N-(3-chloro-4,5-difluoro-phenyl)[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl] methyl-pyrrolecarboxamide -[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl de (212.7 mg, 0.437 mmol) [1124330], 1-fluoromethyl-propanamine hydrochloride(69.7 mg, 0.546 mmol) and Et3N (0.152 mL, 1.09 mmol) was ved in CH3CN (35.4 mL, 678.73 mmol) stirred overnight and concentrated. The residue was dissolved in DMF (2 mL) and purified by column chromatography on silica using a gradient from 10 till 100% EtOAc in heptane. The t fractions were concentrated. The residue was crystallized from methanol (10 mL) upon addition of water. The white crystals of were filtered off and dried overnight in vacuo at 50°C, resulting in compound 207 (93 mg). Method A: Rt: 2.02 min m/z: 422.0 (M-H)- Exact mass: 423.06. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (d, J=1.8 Hz, 6 H), 3.91 (s, 3 H), 4.23 (d, J=1.0 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 7.42 (s, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 10.29 (s, 1 H).

Compound 208: N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl[(1-methylethyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 208 was prepared from ethyl 4-[tert-butoxycarbonyl(isopropyl)sulfamoyl]-1,3- dimethyl-pyrrolecarboxylate and 3-chloro-2,4-difluoroaniline using LiHMDS in THF, followed by removal of the Boc-protection by treatement with HCl in iPrOH/CH2Cl2, resulting TIP 296 PCT in compound 208 (266 mg). Method B: Rt: 1.02 min m/z: 404.1 (M-H)- Exact mass: 405.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.02 (d, J=6.6 Hz, 6 H), 2.34 (s, 3 H), 3.14 - 3.25 (m, 1 H), 3.73 (s, 3 H), 7.20 (d, J=7.5 Hz, 1 H), 7.35 (td, J=9.0, 2.1 Hz, 1 H), 7.44 (s, 1 H), 7.66 (td, J=8.7, .8 Hz, 1 H), 9.99 (s, 1 H).

Compound 209: N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide nd 209 was prepared rly as described for compound 146, using 3-chloro-2,4- difluoroaniline instead of 3,4-difluoroaniline.Compound 209 was recrystallized from EtOH, resulting in a white powder (211 mg). Method D: Rt : 1.97 min m/z: 458.0 (M-H)- Exact mass: 459.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.35 (s, 3 H), 3.73 (s, 3 H), 3.76 - 3.90 (m, 1 H), 7.36 (td, J=9.0, 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.66 (td, J=8.7, 5.8 Hz, 1 H), 8.16 (br. d, J=7.3 Hz, 1 H), 10.02 (s, 1 H).

Compound 210: N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 210 was prepared similarly as described for compound 144 using 3-chloro-2,4- difluoroaniline instead of 3,4-difluoroaniline. The obtained solid was recrystallized from l (5 mL) to afford compound 210 (206 mg) as a white solid. Method D: Rt: 1.97 min m/z: 458.0 (M-H)- Exact mass: 459.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.11 (d, J=6.8 Hz, 3 H), 2.35 (s, 3 H), 3.73 (s, 3 H), 3.76 - 3.89 (m, 1 H), 7.36 (td, J=9.0, 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.66 (td, J=8.7, 5.7 Hz, 1 H), 8.16 (d, J=8.6 Hz, 1 H), 10.02 (s, 1 H).

Compound 211: 4-(tert-Butylsulfamoyl)-N-(3,4-difluorophenyl)fluoromethyl-1H-pyrrole- 2-carboxamide TIP 296 PCT Compound 211 (516 mg, white crystals) was prepared similarly as described for compound 214, using 3,4-difluoroaniline instead of 5-aminofluoro-benzonitrile.

Method D: Rt: 1.96 min m/z: 388.1 (M-H)- Exact mass: 389.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.20 (s, 9 H), 3.79 (s, 3 H), 7.35 - 7.48 (m, 4 H), 7.77 - 7.86 (m, 1 H), 10.19 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at: 184.9 °C.

Compound 212: 4-(tert-Butylsulfamoyl)-N-(3-chloro-2,4-difluorophenyl)fluoromethyl-1H- ecarboxamide Compound 212 (396 mg, white crystals) was prepared similarly as described for compound 214, using 3-chloro-2,4-difluoro-aniline instead of 5-aminofluoro-benzonitrile. Method D: Rt: 2.05min m/z: 422.1 (M-H)- Exact mass:423.1 1H NMR (400 MHz, DMSO-d 6)  ppm 1.20 (s, 9 H), 3.80 (s, 3 H), 7.34 (d, J=2.0 Hz, 1 H), 7.45 - 7.50 (m, 2 H), 7.60 - 7.70 (m, 1 H), 9.80 (br. s., 1 H). Differential scanning calorimetry: From to 300 °C at 10°C/min: peak at: 230.3 °C.

Compound 213: 4-(tert-Butylsulfamoyl)fluoromethyl-N-(2,3,4-trifluorophenyl)-1H- pyrrolecarboxamide Compound 213 (25 mg, white crystals) was prepared similarly as bed for compound 214, using 2,3,4-trifluoroaniline instead of ofluoro-benzonitrile.

Method D: Rt: 1.97 min m/z: 406.1 (M-H)- Exact mass: 407.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.20 (s, 9 H), 3.80 (s, 3 H), 7.27 - 7.39 (m, 1 H), 7.41 - 7.51 (m, 3 H), 9.85 (br. s, 1 H).

Differential ng calorimetry: From 30 to 300 °C at 10°C/min: peak at: 223.3 °C.

TIP 296 PCT Compound 214: 4-(tert-Butylsulfamoyl)-N-(3-cyanofluorophenyl)fluoromethyl-1H- ecarboxamide A mixture of ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (purified by column chromatography with 10 to 50 % EtOAc in heptane, 1.50 g, 5.6 mmol), tert-butylamine (934 mg, 12.8 mmol) and acetonitrile (75 mL) was stirred 2 hours and then concentrated. The residue was dissolved in EtOAc (150 mL) washed with water, dried over sodium sulphate, filtered and concentrated yielding ethyl 4-(tert-butylsulfamoyl)fluoromethyl-pyrrole carboxylate (1.65 g) as light yellow crystals. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (s, 9 H), 1.28 (t, J=7.0 Hz, 3 H), 3.82 (s, 3 H), 4.27 (q, J=7.1 Hz, 2 H), 7.45 (s, 1 H), 7.51 (d, J=4.8 Hz, 1 H). Method D: Rt: 1.79 min m/z: 305.1 (M-H)- Exact mass: 306.1. A mixture of ethyl 4- (tert-butylsulfamoyl)fluoromethyl-pyrrolecarboxylate (1.65 g, 5.4 mmol), lithium hydroxide (386 mg, 16.1 mmol), THF (20 mL) and water (5 mL) was stirred overnight. The reaction mixture was concentrated and the obtained residue was dissolved in water (50 mL) and neutralised with HCl (1M in H2O). The formed white crystals were filtered off and dried in vacuo at 50°C during 4 hours, resulting in 4-(tert-butylsulfamoyl)fluoromethyl-pyrrole carboxylic acid (1.1 g). 1H NMR (400 MHz, 6)  ppm 1.16 (s, 9 H), 3.81 (s, 3 H), 7.42 (s, 1 H), 7.46 (d, J=4.8 Hz, 1 H), 13.02 (br. s, 1 H) Method B: Rt: 0.43 min m/z: 277.1 (M-H)- Exact mass: 278.1. t-butylsulfamoyl)fluoromethyl-pyrrolecarboxylic acid (100 mg, 0.359 mmol), HATU (170.781 mg, 0.449 mmol), Et3N (0.15 mL, 0.728 g/mL, 1.078 mmol), 5-aminofluorobenzonitrile (97.8 mg, 0.72 mmol) in DMF (1 mL) was d overnight at 65°C. The solution was cooled to room temperature and, as such, subjected to silica gel (120 g) column chromatography using a gradient from 10 to 100% EtOAc in heptane. The t fractions were concentrated and the obtained residue was dissolved in warm methanol (10 mL). Water was added untill crystallisation began. The crystals were filtered off and dried overnight in vacuo at 50°C, resulting in compound 214 (94 mg). Method D: Rt: 1.87 min m/z: 395.1 (M-H)- Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.20 (s, 9 H), 3.80 (s, 3 H), 7.44 - 7.49 (m, 2 H), 7.53 (t, J=9.1 Hz, 1 H), 7.92 - 8.00 (m, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 10.29 (s, 1 H). ential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at: 198.3 °C. nd 215: N-(3-Chloro-2,4-difluorophenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Compound 215 (94 mg, white solid) was prepared from 3-chloro-2,4-difluoro-aniline and 3- fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid similarly as described for the synthesis of compound 214 from 5-aminofluoro-benzonitrile and 4-(tert- butylsulfamoyl)fluoromethyl-pyrrolecarboxylic acid. Method D: Rt: 1.80 min m/z: 436.1 (M-H)- Exact mass: 437.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.56 (s, 3 H), 3.81 (s, 3 H), 4.18 (d, J=6.4 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 7.35 (td, J=9.0, 2.0 Hz, 1 H), 7.53 (d, J=4.4 Hz, 1 H), 7.64 (td, J=8.7, 5.8 Hz, 1 H), 8.32 (s, 1 H), 9.87 (s, 1 H).

Compound 216: 3-Cyano-N-(3-cyanofluorophenyl)methyl[(1-methylethyl)sulfamoyl]- 1H-pyrrolecarboxamide nd 171 (60 mg, 0.16 mmol) and potassium cyanide (102 mg, 1. 6 mmol) were dissolved in itrile (2 mL, 38.3 mmol) and heated at 130°C for 8.5 hours by microwave irradiation.

The reaction mixture was filtered, decalite was added to the filtrate and the suspension was evaporated to dryness. The solid was purified using silica gel column chromatography (ethyl acetate in heptane from 10 to 100 %) to afford nd 216 as a yellow powder.Method B: Rt: 0.90 min m/z: 388.1 (M-H)- Exact mass: 389.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.07 (d, J=6.4 Hz, 6 H), 3.35 - 3.46 (m, 1 H), 3.85 (s, 3 H), 7.58 (t, J=9.1 Hz, 1 H), 7.72 (s, 1 H), 7.74 (br. s., 1 H), 7.94 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.18 (dd, J=5.7, 2.6 Hz, 1 H), 11.15 (br. s., 1 H).

Compound 217: 3-Chloro-N-(3,4-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (4 g, 14.7 mmol) was dispensed in itrile (20 mL), (R)-1,1,1-trifluoropropylamine (2493 mg, 22.1 mmol), Hunig's base (3.8 mL, 22.1 mmol) and molecular sieves (100 mg) were added and the reaction TIP 296 PCT mixture was heated overnight at 80ºC. The reaction mixture was cooled down, filtered and evaporated to s. The obtained e was purified by silica gel column chromatography using a heptane to EtOAc gradient yielding methyl 3-chloromethyl[[(1R)-2,2,2-trifluoro -ethyl]sulfamoyl]pyrrolecarboxylate(1.76 g) as a white powder. Methyl 3-chloro methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (590 mg, 1.69 mmol) and 3,4-difluoroaniline (286 mg, 2.2 mmol) were dissolved in THF (10 mL) and cooled to 0ºC. Lithium bis(trimethylsilyl)amide (1M in THF), 5.08 mL, 1 M, 5.08 mmol) was added and the reaction mixture was allowed to reach room temperature. The volatiles were removed under reduced pressure to keep +/- 5 mL. The residue was partitioned between CH2Cl2 and water. The water layer was neutralised using aqueous hydrochloric acid (1M) to form a white precipitate. The white solids were filtered and washed with water. The organic layer was loaded on a silica gel cartridge and a gradient from heptane to EtOAc was applied. The desired fractions were evaporated to - 50 mL. A white precipitate was . The white solid was filtered and washed with heptane to afford a second solid fraction. The two solids were combined and recrystallized from methanol (5 mL) to afford compound 217 (255 mg) as a white powder. The filtrate was concentrated to s and recrystallized from ethyl acetate (6 mL) heptane (20 mL) to afford more compound 217 (185 mg) as a white powder which was dried in vacuo. Method B: Rt: 1.06 min m/z: 444.1 (M-H)- Exact mass: 445.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.77 (s, 3 H), 3.89 - 4.06 (m, 1 H), 7.38 - 7.50 (m, 2 H), 7.66 (s, 1 H), 7.78 - 7.91 (m, 1 H), 8.49 (br. s., 1 H), 10.56 (br. s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at: 203.9 °C (EtOAc/heptane).

Compound 218: 3-Chloro-N-(3-chloro-2,4-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 218 was prepared similarly as described for the synthesis of compound 217 using 3- chloro-2,4-difluoro-aniline instead of 3,4-difluoroaniline. After partitioning between CH2Cl2 and water, the water layer was neutralised using aqueous hydrochloric acid (1M) to form a white precipitate. The water layer was extracted with CH2Cl2 (2 x 50 mL) and EtOAc (2 x 150 mL).

The combined organic layers were washed with brine and dried (Na2SO4) and concentrated to dryness. The obtained brown powder was recrystallized from ethyl e (20 mL) ing in compound 218 (576 mg) as a powder which was dried in vacuo. Method B: Rt: 1.13 min m/z: 478.0 (M-H)- Exact mass: 479.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.79 (s, 3 H), 3.90 - 4.05 (m, 1 H), 7.37 (td, J=9.0, 2.0 Hz, 1 H), 7.69 (s, 1 H), 7.66 - 7.76 (m, TIP 296 PCT 1 H), 8.50 (br. s., 1 H), 10.24 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at °C/min: peak at 213.0 °C.

Compound 219: 3-Chloro-N-(3-chloro-2,4-difluorophenyl)methyl{[1-(trifluoro- )cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 219 (136 mg) was prepared similarly as described for the synthesis of compound 221 using 3-chloro-2,4-difluoro-aniline instead of 5-aminofluorobenzonitrile. 1H NMR (400 MHz, DMSO-d6)  ppm 1.75 - 1.87 (m, 2 H), 2.24 - 2.35 (m, 2 H), 2.41 - 2.47 (m, 2 H), 3.80 (s, 3 H), 7.37 (td, J=9.0, 2.1 Hz, 1 H), 7.68 (s, 1 H), 7.69 - 7.75 (m, 1 H), 8.60 (br. s., 1 H), 10.22 (s, 1 H).

Method D: Rt: 2.14 min m/z: 504.0 (M-H)- Exact mass: 505.0. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 237.3 °C.

Compound 220: 4-(tert-Butylsulfamoyl)chloro-N-(3-chlorofluorophenyl)methyl-1H- pyrrolecarboxamide Compound 220 (614 mg) was prepared similarly as described for the synthesis of compound 226 using 3-chlorofluoro-aniline instead of ofluorobenzonitrile. Method D: Rt: 2.07min m/z: 420.1 (M-H)- Exact mass: 421.0. 1H NMR (400 MHz, 6)  ppm 1.18 (s, 9 H), 3.76 (s, 3 H), 7.34 (s, 1 H), 7.42 (t, J=9.1 Hz, 1 H), 7.59 (s, 1 H), 7.60 - 7.67 (m, 1 H), 7.98 (dd, J=6.7, 2.5 Hz, 1 H), 10.48 (s, 1 H). Differential scanning metry: From 30 to 300 °C at 10°C/min: peak at 195.9 °C.

Compound 221: 3-Chloro-N-(3-cyanofluorophenyl)methyl{[1-(trifluoro- methyl)cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (2000 mg, 7.35 mmol) was dispensed in acetonitrile (15 mL) in a microwave tube, 1-(trifluoromethyl)cyclobutanamine (1.53 mg, 11.0 mmol) and Hunig's base (1.9 mL, 11.03 mmol) were added and the tube was sealed and heated at 85ºC for 8 hours. The solids were filtered off and the filtrate was evaporated to dryness. The residue was purified on silica gel using a heptane to EtOAc gradient yielding methyl 3-chloromethyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole carboxylate as an off-white powder (382 mg). Methyl 3-chloromethyl[[1- (trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylate (150 mg, 0.4 mmol) and 5-amino- 2-fluorobenzonitrile (0.52 mmol) were dissolved in dry THF and cooled to 0ºC. Lithium bis(trimethylsilyl)amide (1.24 mL, 1 M in THF, 1.24 mmol) was added dropwise and the on mixture was allowed to reach room temperature. After 1 hour lithium bis(trimethylsilyl )amide (0.5 mL, 1 M in THF, 0.5 mmol) was added and the reaction mixture was stirred for another hour. The volatiles were removed under reduced pressure and the residue was purified on silica gel using a heptane to EtOAc gradient. The collected fractions were evaporated to dryness and the residue was crystallized from a heptane/EtOAc mixture yielding nd 221 (91 mg) as off-white powder. Method D: Rt: 1.95min m/z: 477.1 (M-H)- Exact mass: 478.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.75 - 1.88 (m, 2 H), 2.25 - 2.37 (m, 2 H), 2.41 - 2.48 (m, 2 H), 3.79 (s, 3 H), 7.56 (t, J=9.1 Hz, 1 H), 7.68 (s, 1 H), 7.99 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.61 (s, 1 H), 10.67 (s, 1 H).

Compound 222: 3-Chloro-N-(3-chlorofluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 222 was prepared similarly as described for the synthesis of nd 217 using 3- chlorofluoro-aniline instead of 3,4-difluoroaniline. After ioning between CH2Cl2 and water, the water layer was neutralised using aqueous hydrochloric acid (1M) to form a white precipitate. The water layer was extracted with CH2Cl2 (4 x 50 mL). The ed organic layers were washed with brine and dried (Na2SO4) and trated to keep (15 mL). The white solid was filtered and washed with heptane to afford compound 222 (632 mg) as off white powder. Method B: Rt: 1.12 min m/z: 460.1 (M-H)- Exact mass: 461.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.77 (s, 3 H), 3.92-4.04 (m, 1 H), 7.43 (t, J=9.0 Hz, 1 H), 7.63 (ddd, J=9.0, 4.2, 2.6 Hz, 1 H), 7.67 (s, 1 H), 7.99 (dd, J=6.8, 2.6 Hz, 1 H), 8.14 (br. s., 1 H), 10.56 (br. s., 1 H). ential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 218.8 °C.

TIP 296 PCT Compound 223: 4-(tert-Butylsulfamoyl)chloro-N-(3,4-difluorophenyl)methyl-1H-pyrrole- oxamide Compound 223 (579 mg) was prepared similarly as described for the synthesis of nd 226 using 3,4-difluoroaniline instead of 5-aminofluorobenzonitrile. 1H NMR (400 MHz, DMSO- d6)  ppm 1.18 (s, 9 H), 3.76 (s, 3 H), 7.34 (s, 1 H), 7.39 - 7.50 (m, 2 H), 7.59 (s, 1 H), 7.78 - 7.91 (m, 1 H), 10.50 (Br. s., 1 H). Method D: Rt: 1.99 min m/z: 404.1 (M-H)- Exact mass: 405.1.

Compound 224: 4-(tert-Butylsulfamoyl)chloro-N-(3-chloro-2,4-difluorophenyl)methyl-1H- pyrrolecarboxamide Compound 224 (405 mg) was prepared similarly as described for the synthesis of compound 226 using 3-chloro-2,4-difluoroaniline instead of 5-aminofluorobenzonitrile. Method B: Rt :1.16 min m/z: 438.1 (M-H)- Exact mass: 439.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H), 3.78 (s, 3 H), 7.31 - 7.40 (m, 2 H), 7.61 (s, 1 H), 7.65 - 7.75 (m, 1 H), 10.16 (br. s., 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 241.6 °C.

Compound 225: ro-N-(3-cyanofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 225 was ed similarly as described for compound 199, using (S)-1,1,1-trifluoro- 2-propylamine instead of (R)-1,1,1-trifluoropropylamine. Method D: Rt :1.86 min m/z: 451.0 (M-H)- Exact mass: 452.0.1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.78 (s, 3 H), 3.92 - 4.05 (m, 1 H), 7.56 (t, J=9.1 Hz, 1 H), 7.68 (s, 1 H), 7.98 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J=5.7, 2.6 Hz, 1 H), 8.51 (br. s., 1 H), 10.67 (s, 1 H).

TIP 296 PCT Compound 226: 4-(tert-Butylsulfamoyl)chloro-N-(3-cyanofluorophenyl)methyl-1H- pyrrolecarboxamide Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (4 g, 14.7 mmol) was dispensed in acetonitrile (25 mL) and tert-butylamine (4388 mg, 58.8 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature. The solids were filtered off and the filtrate was evaporated to dryness. The residue was ed on silica using a heptane to EtOAc gradient yielding methyl 4-(tert-butylsulfamoyl)chloromethyl-pyrrole ylate (3.57 g) as a white powder after ation in CH2Cl2 and diisopropylether. 1H NMR (400 MHz, DMSO-d6)  ppm 1.14 (s, 9 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 7.35 (s, 1 H), 7.69 (s, 1 H). Methyl 4-(tert-butylsulfamoyl)chloromethyl-pyrrolecarboxylate (500 mg, 1.619 mmol) and 5-aminofluorobenzonitrile (295.4 mg, 2.11 mmol) were dissolved in THF (10 mL) and cooled to 0ºC. Lithium bis(trimethylsilyl)amide (5 mL, 1 M in toluene, 5 mmol) was added and the on mixture was allowed to reach room temperature. More lithium bis(trimethylsilyl)amide (1 mL, 1M in THF, 1 mmol) was added and the on mixture was stirred for 30 minutes more. The volatiles were removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The organic layer was loaded on a silica cartridge and a gradient form heptane to EtOAc was applied. The desired fractions were evaporated to dryness and the residue was crystallized from a EtOAc/heptane mixture. The precipitate was filtered off, triturated with diisopropylether and dried, ng compound 226 (513 mg) as a white powder. Method B: Rt: 1.01 min m/z: 411.2 (M-H)- Exact mass: 412.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (s, 9 H), 3.77 (s, 3 H), 7.36 (s, 1 H), 7.55 (t, J=9.1 Hz, 1 H), 7.61 (s, 1 H), 7.99 (ddd, J=9.2, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 10.61 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at in: peak at 207.0 °C.

Compound 227: yanofluorophenyl)methyl{[1-(trifluoromethyl)cyclopropyl ]sulfamoyl}-1H-pyrrolecarboxamide -[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (600 mg, 1.76 mmol) was mixed with 1-trifluoromethylcyclopropylamine (329 mg, 2.63 mmol), acetonitrile TIP 296 PCT (10 mL), molecular sieves and Hunig's base (0.91 mL, 0.75 g/mL, 5.27 mmol) in a microwave vial (20 mL) and d at 100 °C for 1 hour and next at 110 °C for 1 hour under MW- irradiation. The reaction mixture was filtered and the filtrate trated to dryness. The obtained residue was purified using silica gel column chromatography (ethyl e in heptane from 10 to 70%) and further by preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10µm, 200g, 5cm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN), resulting in compound 227 (63 mg) after concentration and drying in vacuo at 50°C.

Method B: Rt: 0.98 min m/z: 429.1 (M-H)- Exact mass: 430.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.09 - 1.21 (m, 4 H), 3.91 (s, 3 H), 7.31 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.56 - 7.58 (m, 1 H), 8.01 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.21 (dd, J=5.8, 2.8 Hz, 1 H), 8.74 (br. s., 1 H), 10.36 (br. s., 1 H).

Compound 228: N-(3-Cyanofluorophenyl)methyl{[3-(trifluoromethyl)tetrahydrofuran- 3-yl]sulfamoyl}-1H-pyrrolecarboxamide Compound 228 (153 mg) was prepared rly as described for compound 227, using 3- (trifluoromethyl)tetrahydrofuranamine hydrochloride instead of 1-trifluoromethyl cyclopropylamine. Racemic compound 228 was separated in enantiomers by Prep SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm, Mobile phase: CO2, 12-50% MeOH with 0.4% iPrNH2), resulting in compound 228a (first eluding) and 228b (second eluding, 41 mg). 228a was further purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) ing in compound 228a (28 mg) as white solid. 228a: Method D: Rt: 1.79 min m/z: 459.0 (M-H)- Exact mass: 460.1. 1H NMR (400 MHz, DMSO-d 6)  ppm 2.18 (dt, J=13.8, 8.1 Hz, 1 H), 2.42 - 2.49 (m, 1 H), 3.60 (q, J=7.8 Hz, 1 H), 3.83 (td, J=8.3, 4.4 Hz, 1 H), 3.92 (s, 3 H), 3.91 - 3.96 (m, 1 H), 4.04 - 4.10 (m, 1 H), 7.35 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.21 (dd, J=5.8, 2.8 Hz, 1 H), 8.49 (br. s., 1 H), 10.39 (s, 1 H). 228b: Method D: Rt: 1.79 min m/z: 459.0 (M-H)- Exact mass: 460.1. 1H NMR (400 MHz, DMSO-d6) ppm 2.20 (dt, , 8.1 Hz, 1 H), 2.43 - 2.49 (m, 1 H), 3.60 (q, J=7.7 Hz, 1 H), 3.79 - 3.88 (m, 1 H), 3.92 (s, 3 H), 3.91 - 3.96 (m, 1 H), 4.04 - 4.10 (m, 1 H), 7.35 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 8.01 (ddd, J=9.3, 4.9, 2.8 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 8.46 (br. s., 1 H), 10.38 (s, 1 H).

Synthesis of 3-(trifluoromethyl)tetrahydrofuranamine hydrochloride: TIP 296 PCT A e of 3-oxotetrahydrofuran (30 g, 348.5 mmol), benzylamine (39.2 g, 365.8 mmol), MgSO4 (21 g, 174.5 mmol) and CH2Cl2 (200 mL) was stirred at 28°C for 24 hours. The mixture was ted. The filtrate was concentrated in vacuo and the obtained residue (63.1 g) was used directly in the next step. The obtained residue (63 g) was dissolved in acetonitrile (600 mL).

Trifluoroacetic acid (45 g, 394 mmol), potassium enfluoride (22.5 g, 288 mmol) and DMF (60 mL) were added to the mixture at 0°C. The mixture was stirred at 0° for 10 s. (trifluoromethyl)trimethylsilane (77 g, 541 mmol) was added to the reaction mixture and the mixture was stirred at ambient temperature for 12 h. Saturated aqueous Na2CO3 (200 mL) was added and the mixture was stirred for 5 min. The mixture was diluted with water (500 mL), and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. The obtained residue was dissolved in 2M OH and the solvent was evaporated.

The resulting hydrochloride salt was crystallized from CH3CN to provide N-benzyl (trifluoromethyl)tetrahydrofuranamine (30.5 g). A mixture of N-benzyl uoromethyl)tetrahydrofuranamine (30.5 g), ium on alumina (1.5 g) and MeOH was stirred under H2 (20 psi) atmosphere at 28 ℃ for 12 hours.

The mixture was ed and the te was concentrated in vacuo resulting in 3-(trifluoromethyl)tetrahydrofuranamine hydrochloride (20.5 g). 1H NMR (400 MHz, DMSO- d6)  ppm 2.21 - 2.43 (m, 2 H) 3.83 - 4.16 (m, 4 H) 9.68 (br. s., 3 H).

Compound 229: N-(3,4-Difluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide To ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (1H NMR (400 MHz, DMSO-d6)  ppm 1.15 (d, J=7.0 Hz, 3 H), 1.28 (t, J=7.0 Hz, 3 H), 3.83 (s, 3 H), 3.90 - 4.02 (m, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 7.60 (d, J=4.6 Hz, 1 H), 8.59 (d, J=8.8 Hz, 1 H); 1.10 g, 3.18 mmol) and 3,4-difluoroaniline (534 mg, 4.14 mmol) dissolved in THF (47 mL) under nitrogen atmosphere, at 0°C, m bis(trimethylsilyl)amide (12.7 mL, 1 M in toluene, 12.72 mmol) was added. The mixture was stirred 1 hour at 0°C and further overnight at room ature. The reaction mixture was quenched with NH4Cl (30 mL) solution and extracted with EtOAc (50 mL), diluted with brine (50 mL) and extracted again with EtOAc (50 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue (dissolved in 1 mL DMF) was purified by column chromatography on silica (120g ) with a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the solid residue was crystallized from warm methanol (20 mL) upon addition TIP 296 PCT of water. The white ls were filtered off and dried in vacuo at 50°C overnight, resulting in compound 229 (945 mg). Method D: Rt: 1.93 min m/z: 428.1 (M-H)- Exact mass: 429.1.1H NMR (400 MHz, DMSO-d6 )  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.80 (s, 3 H), 3.91 - 4.04 (m, 1 H), 7.37 - 7.48 (m, 2 H), 7.54 (d, J=4.4 Hz, 1 H), 7.76 - 7.86 (m, 1 H), 8.59 (d, J=8.6 Hz, 1 H), 10.26 (s, 1 H).

Compound 230: N-(3-Bromofluorophenyl)fluoromethyl[(1-methylethyl)sulfamoyl]- 1H-pyrrolecarboxamide 3-fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (153 mg, 0.579 mmol), HATU (275 mg, 0.724 mmol), Et3N (0.242 mL, 1.74 mmol), 3-bromofluoro-aniline (220 mg, 1.16 mmol) and DMF (1.1 mL) were stirred overnight at 65°C. The solution was subjected to column chromatography on a 120g Reveleris silica gel cartridge using a gradient from 10 till 100% EtOAc in heptane. The t fractions were concentrated. The residue was ved in warm methanol (50 mL). Water was added untill crystallisation began. The white crystals were filtered off and dried overnight in vacuo at 50°C. Method D: Rt: 2.04 min m/z: 436.2 (M-H)- Exact mass: 437.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.05 (d, J=6.6 Hz, 6 H), 3.31 - 3.40 (m, 1 H), 3.79 (s, 3 H), 7.37 (t, J=8.8 Hz, 1 H), 7.45 (d, J=4.4 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.64 (ddd, J=9.0, 4.4, 2.6 Hz, 1 H), 8.08 (dd, J=6.4, 2.4 Hz, 1 H), 10.18 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 200.9 °C.

Compound 231: yano-2,4-difluorophenyl)fluoromethyl[(1-methylethyl )sulfamoyl]-1H-pyrrolecarboxamide Compound 231 (88 mg) was ed similarly as described for compound 230, using 3-amino- 2,6-difluoro-benzonitrile instead of 3-bromofluoro-aniline. Method D: Rt: 1.86 min m/z:399.3 (M-H)- Exact mass:400.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.06 (d, J=6.4 Hz, 6 H), 3.31 - 3.40 (m, 1 H), 3.81 (s, 3 H), 7.41 - 7.52 (m, 2 H), 7.61 (d, J=7.3 Hz, 1 H), 8.03 (td, J=8.9, 6.2 Hz, 1 H), 9.96 (s, 1 H).

TIP 296 PCT Compound 232: N-(3,4-Difluorophenyl)fluoromethyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide Compound 232 (144 mg) was prepared similarly as described for compound 230, using 3,4- difluoroaniline instead of 3-bromofluoro-aniline. Method D: Rt: 1.95 min m/z: 374.3 (M-H)- Exact mass: 375.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.05 (d, J=6.6 Hz, 6 H), 3.31 - 3.41 (m, 1 H), 3.79 (s, 3 H), 7.35 - 7.49 (m, 3 H), 7.57 (d, J=7.3 Hz, 1 H), 7.76 - 7.87 (m, 1 H), 10.22 (s, 1 H). Differential scanning metry: From 30 to 300 °C at in: peak at 195.8 °C.

Compound 233: 3-Fluoromethyl[(1-methylethyl)sulfamoyl]-N-(2,3,4-trifluorophenyl)-1H- pyrrolecarboxamide Compound 233 (89 mg) was prepared similarly as described for nd 230, using 2,3,4- trifluoroaniline instead of 3-bromofluoro-aniline. Method D: Rt: 1.95 min m/z: 392.3 (M-H)- Exact mass: 393.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.06 (d, J=6.6 Hz, 6 H), 3.31 - 3.40 (m, 1 H), 3.80 (s, 3 H), 7.28 - 7.39 (m, 1 H), 7.41 - 7.51 (m, 2 H), 7.59 (d, J=7.3 Hz, 1 H), 9.87 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 214.3 °C.

Compound 234: N-(3-Chloro-2,4-difluorophenyl)fluoromethyl[(1-methyl- ethyl)sulfamoyl]-1H-pyrrolecarboxamide Compound 234 (95 mg) was ed similarly as described for compound 230, using 3-chloro- 2,4-difluoro-aniline instead of 3-bromofluoro-aniline. Method D: Rt: 2.03 min m/z: 408.3 (MH )- Exact mass: 409.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.06 (d, J=6.4 Hz, 6 H), 3.31 - 3.40 (m, 1 H), 3.81 (s, 3 H), 7.35 (td, J=9.0, 2.1 Hz, 1 H), 7.48 (d, J=4.6 Hz, 1 H), 7.59 (d, J=7.3 Hz, 1 H), 7.65 (td, J=8.7, 5.8 Hz, 1 H), 9.83 (s, 1 H).

TIP 296 PCT Compound 235: N-(3-Chlorofluorophenyl)fluoromethyl[(1-methylethyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 235 (156 mg) was prepared similarly as described for compound 230, using 3-chloro- 4-fluoro-aniline instead of 3-bromofluoro-aniline. Method D: Rt: 2.03 min m/z: 390.3 (M-H)- Exact mass: 391.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.05 (d, J=6.6 Hz, 6 H), 3.31 - 3.40 (m, 1 H), 3.80 (s, 3 H), 7.40 (t, J=9.1 Hz, 1 H), 7.45 (d, J=4.6 Hz, 1 H), 7.54 - 7.64 (m, 2 H), 7.96 (dd, J=6.8, 2.4 Hz, 1 H), 10.19 (s, 1 H). ential scanning calorimetry: From 30 to 300 °C at in: peak at 201.9 °C. nd 236: N-(3-Chloro-2,4-difluorophenyl){[2,2-difluorocyclopentyl]sulfamoyl} methyl-1H-pyrrolecarboxamide -[(3-chloro-2,4-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (532.5 mg, 1.442 mmol), 2,2-difluorocyclopentanamine hydrochloride (261mg, 1.66 mmol) and Et3N (0.501 mL, 3.61 mmol) in acetonitrile (50 mL) was stirred and refluxed 2 hours. The reaction mixture was trated and the obtained residue was dissolved in EtOAc (50 mL) washed with HCl 1M, dried over sodium sulphate, filtered and concentrated. The obtained e was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated resulting in compound 236 (518 mg) as a white solid.

Racemic compound 236 was separated in its enantiomers 236a (first eluding) and 236b (second eluding) via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, 30% EtOH-iPrOH (50-50) with 0.2% ) 236a: Method D: Rt: 1.98 min m/z: 452.3 (M-H)- Exact mass: 453.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.41 - 1.72 (m, 3 H), 1.76 - 1.87 (m, 1 H), 1.90 - 2.18 (m, 2 H), 3.61 - 3.78 (m, 1 H), 3.89 (s, 3 H), 7.31 - 7.38 (m, 2 H), 7.53 (td, J=8.7, 5.9 Hz, 1 H), 7.58 (d, J=1.5 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 10.12 (s, 1 H). 236b: Method D: Rt: 1.98 min m/z: 452.3 (M-H)- Exact mass: 453.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.40 - 1.74 (m, 3 H), 1.75 - 1.89 (m, 1 H), 1.90 - 2.18 (m, 2 H), 3.62 - 3.78 TIP 296 PCT (m, 1 H), 3.89 (s, 3 H), 7.29 - 7.39 (m, 2 H), 7.48 - 7.61 (m, 2 H), 7.81 (d, J=8.1 Hz, 1 H), 10.12 (s, 1 H).

Compound 237: N-(3-Cyanofluorophenyl)methyl[(2,2,2-trifluoro-1,1-di- methylethyl)sulfamoyl]-1H-pyrrolecarboxamide -[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (0.25 g, 0.73 mmol) was dissolved in acetonitrile (6 mL) and dried with molecular sieves 4A powder over a period of 30 minutes in a re tube. 2,2,2-trifluoro-1,1-dimethyl-ethylamine (139 mg, 1.1 mmol) and sodium onate (307.3 mg, 3.66 mmol) were dispersed in acetonitrile (2 mL), dried with molecular sieves 4A powder over a period of 30 minutes and the resulting mixture was added to the pressure tube, which was flushed with nitrogen, capped and stirred in a heating block at 80°C for 24 hours. Then the reaction mixture was filtered and rinsed using dichloromethane (50 mL). The filtrate was concentrated in vacuo and the obtained e was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The d fractions were concentrated under reduced pressure and the obtained powder was dried in a vacuum oven at 55°C for 24 hours yielding compound 237 (213 mg). Method D: Rt:1.89 min m/z: 431.1 (M-H)- Exact mass: 432.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.36 (s, 6 H), 3.93 (s, 3 H), 7.35 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 7.84 - 8.15 (m, 2 H), 8.21 (dd, J=5.9, 2.6 Hz, 1 H), 10.38 (br. s., 1 H).

Compound 238: yanofluorophenyl)methyl[(3,3,3-trifluoromethylpropyl )sulfamoyl]-1H-pyrrolecarboxamide Compound 238 (206 mg) was prepared similarly as described for compound 237, using 4,4,4- orobutanamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction time instead of 24 hours. Method D: Rt: 1.86 min m/z: 431.1 (M-H)- Exact mass: 432.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.06 (d, J=6.6 Hz, 3 H), 2.29 - 2.47 (m, 2 H), 3.50 (sxt, TIP 296 PCT J=6.6 Hz, 1 H), 3.93 (s, 3 H), 7.36 (d, J=2.0 Hz, 1 H), 7.40 - 7.88 (m, 3 H), 8.01 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.38 (br. s., 1 H).

Compound 239: N-(3-Cyanofluorophenyl)methyl{[(1S)(trifluoromethyl)- ]sulfamoyl}-1H-pyrrolecarboxamide Compound 239 (236 mg) was prepared similarly as described for compound 237, using (S) trifluoromethyl-propylamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method D: Rt: 1.89 min m/z: 431.1 (M-H)- Exact mass: 432.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.70 (t, J=7.4 Hz, 3 H), 1.32 - 1.51 (m, 1 H), 1.56 - 1.74 (m, 1 H), 3.68 - 3.85 (m, 1 H), 3.95 (s, 3 H), 7.37 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.06 - 8.33 (m, 2 H), 10.37 (br. s., 1 H).

Compound 240: N-(3-Cyanofluorophenyl)methyl{[(1R)(trifluoromethyl)- propyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 240 (244 mg) was prepared similarly as bed for compound 237, using (R) trifluoromethyl-propylamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine Method D: Rt: 1.89 min m/z: 431.1 (M-H)- Exact mass: 432.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.70 (t, J=7.4 Hz, 3 H), 1.35 - 1.53 (m, 1 H), 1.55 - 1.73 (m, 1 H), 3.62 - 3.83 (m, 1 H), 3.92 (s, 3 H), 7.37 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.06 - 8.51 (m, 2 H), 10.37 (br. s., 1 H).

TIP 296 PCT Compound 241: yanofluorophenyl)methyl{[1-(trifluoromethyl)cyclobutyl ]sulfamoyl}-1H-pyrrolecarboxamide Compound 241 (119 mg) was prepared similarly as described for compound 237, using 1- trifluoromethyl-cyclobutylamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction time instead of 24 hours. Method D: Rt: 1.91 min m/z: 443.1 (M-H)- Exact mass: 444.1. 1 H NMR (400 MHz, DMSO-d 6 )  ppm 1.67 - 1.90 (m, 2 H), 2.23 - 2.36 (m, 2 H), 2.39 - 2.48 (m, 2 H), 3.94 (s, 3 H), 7.39 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.63 (d, J=1.8 Hz, 1 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 8.37 (br. s., 1 H), 10.39 (br. s., 1 H).

Compound 242: N-(3-Cyanofluorophenyl){[2-fluoro(fluoromethyl)ethyl]sulfamoyl} methyl-1H-pyrrolecarboxamide Compound 242 (162 mg) was ed similarly as described for compound 237, using 1,3- difluoropropanamine hydrochloride instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine.

Method D: Rt: 1.70 min m/z: 399.0 (M-H)- Exact mass: 400.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 3.50 - 3.76 (m, 1 H), 3.92 (s, 3 H), 4.26-4.54 (m, 4 H), 7.37 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 7.73 - 8.17 (m, 2 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.38 (br. s., 1 H).

Compound 244: N-(3-cyanofluoro-phenyl)methyl[(1-methylcyclopropyl)- sulfamoyl]pyrrolecarboxamide Compound 244 (144 mg) was prepared similarly as described for nd 237, using (1- methylcyclopropyl)amine hydrochloride instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine.

TIP 296 PCT Method B: Rt: 0.93 min m/z: 375.1 (M-H)- Exact mass: 376.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.30 - 0.47 (m, 2 H), 0.63 - 0.73 (m, 2 H), 1.18 (s, 3 H), 3.93 (s, 3 H), 7.33 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.68 (s, 1 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.9, 2.6 Hz, 1 H), 10.36 (s, 1 H).

Compound 245: N-(3-cyanofluoro-phenyl)[(3,3-difluoromethyl-cyclobutyl)sulfamoyl]- yl-1H-pyrrolecarboxamide Compound 245 (243 mg) was prepared similarly as described for compound 237, using 3,3- difluoromethylcyclobutanamine hydrochloride instead of 2,2,2-trifluoro-1,1-dimethylethylamine.

Method B: Rt: 0.99 min m/z: 425.2 (M-H)- Exact mass: 426.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.39 (s, 3 H), 2.40 - 2.57 (m, 2 H), 2.74 - 2.95 (m, 2 H), 3.93 (s, 3 H), 7.35 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.61 (d, J=1.8 Hz, 1 H), 7.87 (br. s., 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 10.37 (br. s., 1 H).

Compound 246: yanofluoro-phenyl)methyl{[1-methyl(trifluoromethyl )propyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 246 (130 mg) was prepared similarly as described for compound 237, using 1,1,1- trifluoromethylbutanamine hydrochloride instead of 2,2,2-trifluoro-1,1-dimethylethylamine and 48 hours reaction time d of 24 hours.

Method B: Rt: 1.05 min m/z: 445.2 (M-H)- Exact mass: 446.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.79 (t, J=7.4 Hz, 3 H), 1.37 (s, 3 H), 1.46-1.58 (m, 1 H), 1.73 - 1.89 (m, 1 H), 3.92 (s, 3 H), 7.35 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.89 (br. s., 1 H), 8.02 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.21 (dd, J=5.8, 2.8 Hz, 1 H), 10.37 (s, 1 H).

TIP 296 PCT Compound 247: N-(3-cyanofluoro-phenyl)methyl{[4-(trifluoromethyl)tetrahydropyran- 4-yl]sulfamoyl}-1H-pyrrolecarboxamide Compound 247 (23 mg) was prepared similarly as described for compound 237, using 4- (trifluoromethyl)oxanamine hydrochloride instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction time instead of 24 hours. An extra purification was performed via Prep HPLC onary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 0.96 min m/z: 473.1 (M-H)- Exact mass:474.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.64 - 1.79 (m, 2 H), 2.11 (d, J=13.4 Hz, 2 H), 3.50 (t, J=11.4 Hz, 2 H), 3.70-3.81 (m, 2 H), 3.93 (s, 3 H), 7.36 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.57 - 7.65 (m, 1 H), 7.92 (br. s., 1 H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.41 (br. s., 1 H).

Compound 248: yanofluoro-phenyl){[1-ethyl(trifluoromethyl)propyl]sulfamoyl}- 1-methyl-1H-pyrrolecarboxamide Compound 248 (40 mg) was prepared similarly as described for compound 237, using 3- (trifluoromethyl)pentanamine hydrochloride d of 2,2,2-trifluoro-1,1-dimethylethylamine.

Method B: Rt: 1.11 min m/z: 459.2 (M-H)- Exact mass: 460.1 1 H NMR (400 MHz, DMSO-d 6 )  ppm 0.82 (t, J=7.4 Hz, 6 H), 1.70-1.83 (m, 2 H), 1.84 - 1.97 (m, 2 H), 3.92 (s, 3 H), 7.34 (d, J=1.8 Hz, 1 H), 7.47 - 7.61 (m, 2 H), 7.73 (br. s., 1 H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 10.38 (br. s., 1 H).

TIP 296 PCT Compound 249: N-(3-cyanofluoro-phenyl)[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl] methyl-1H-pyrrolecarboxamide Compound 249 (178 mg) was prepared similarly as described for compound 237, using ro- 2-methylpropanamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine Method B: Rt: 0.94 min m/z: 395.1 (M-H)- Exact mass: 396.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.13 - 1.20 (m, 6 H), 3.92 (s, 3 H), 4.24 (d, J=47.5 Hz, 2 H), 7.35 (d, J=2.0 Hz, 1 H), 7.41 (br. s., 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 8.01 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, J=5.9, 2.6 Hz, 1 H), 10.36 (br. s., 1 H).

Compound 250: N-(3-Bromophenyl)chloromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide 3-bromoaniline (92 mg, 0.53 mmol) and methyl 3-chloromethyl[[(1R)-2,2,2-trifluoro -ethyl]sulfamoyl]pyrrolecarboxylate (143 mg, 0.41 mmol) were dissolved in THF (10 mL). m bis(trimethylsilyl)amide (1M in THF) (1.23 mL, 1 M, 1.23 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was quenched with sat. NH4Cl (aq) (5 mL). The aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The combined c layers were evaporated to s and the residue was purified on silica using a heptane to EtOAc gradient. The obtained products was crystallized from CH2Cl2, triturated with diisopropylether and dried yielding, compound 250 (156 mg) as a white powder. Method D: Rt: 2.05 min m/z: 487.9 (M-H)- Exact mass: 489.0.1 H NMR (400 MHz, DMSO-d6 )  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.77 (s, 3 H), 3.91 - 4.01 (m, 1 H), 7.29 - 7.37 (m, 2 H), 7.61 - 7.69 (m, 2 H), 7.97 - 8.04 (m, 1 H), 8.48 (s, 1 H), 10.51 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 197.9°C.

TIP 296 PCT Compound 251: N-(3-Bromophenyl)fluoromethyl[(3-methyloxetanyl)sulfamoyl]-1H- pyrrolecarboxamide 3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid (250 mg, 0.855 mmol), HATU (407 mg, 1.07 mmol), Et3N (0.36 mL, 2.57 mmol) and 3-bromoaniline (294mg, 1.71 mmol) in DMF (4 mL) were stirred 4 hours at 65°C. The solution was subjected to column chromatography on a 120g silica gel Reveleris cartridge using a nt from 10 till 100% EtOAc in heptane. The product fractions were concentrated and compound 251 was crystallized by dissolving the ed liquid residue in ol (30 mL) upon addition of water. The white crystals were filtered off and dried overnight in vacuo at 50°C. Method D: Rt: 1.81 min m/z: 446.0 (M-H)- Exact mass: 447.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.56 (s, 3 H), 3.80 (s, 3 H), 4.17 (d, J=6.4 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 7.26 - 7.35 (m, 2 H), 7.50 (d, J=4.6 Hz, 1 H), 7.62 (dt, J=6.5, 2.4 Hz, 1 H), 7.96 - 8.01 (m, 1 H), 8.30 (s, 1 H), 10.19 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 193.4°C.

Compound 252: N-(3-chloro-2,4-difluoro-phenyl)[(2,2-difluoromethyl-ethyl)sulfamoyl] methyl-1H-pyrrolecarboxamide -[(3-chloro-2,4-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (0.25 g, 0.68 mmol) was dissolved in acetonitrile (6 mL) in a pressure tube and this was dried with powdered molecular sieves (4Å) over a period of 30 minutes. Another tube was loaded with 1,1- difluoropropanamine (1.0 mmol) and sodium bicarbonate (284 mg, 3.39 mmol) and this was dispersed in itrile (2 mL) and dried with powdered molecular sieves (4Å) over a period of minutes. This was added to the pressure tube which was flushed with nitrogen, capped and stirred in a heating block at 80°C for 24 hours. Then the reaction mixture was filtered and rinsed using dichloromethane (50 mL). The filtrate was concentrated in vacuo and the obtained e was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The obtained powder was dried in a vacuum oven at 55°C for 24 hours yielding nd 252 (204 mg) as a white powder. Method B: Rt: 1.00 min m/z: 426.1 (M-H)- Exact mass: 427.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.01 (d, J=7.0 Hz, 3 H), 3.39 - 3.59 (m, 1 TIP 296 PCT H), 3.92 (s, 3 H), 5.91 (td, J=55.9, 2.4 Hz, 1 H), 7.29 - 7.39 (m, 2 H), 7.46 - 7.58 (m, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 7.85 (br. s., 1 H), 10.14 (br. s., 1 H).

Compound 253: N-(3-chloro-2,4-difluoro-phenyl)methyl{[1-(trifluoromethyl)- ropyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 253 (104 mg) was ed similarly as described for compound 252, using 1- trifluoromethylcyclopropylamine instead of 1,1-difluoropropanamine and 48 hours reaction time d of 24 hours. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 1.05 min m/z: 456.1 (M-H)- Exact mass: 457.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.07 - 1.24 (m, 4 H), 3.89 (s, 3 H), 7.29 (d, J=1.8 Hz, 1 H), 7.35 (td, J=9.0, 1.9 Hz, 1 H), 7.46 - 7.56 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 8.65 (br. s, 1 H), 10.13 (br. s., 1 H).

Compound 254: N-(3-chloro-2,4-difluoro-phenyl)methyl[(2,2,2-trifluoro-1,1-dimethylethyl )sulfamoyl]-1H-pyrrolecarboxamide Compound 254 (75 mg) was prepared similarly as described for compound 252, using 2,2,2- trifluoro-1,1-dimethyl-ethylamine instead of fluoropropanamine. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 1.09 min m/z: 458.1 (M-H)- Exact mass: 459.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.37 (s, 6 H), 3.90 (s, 3 H), 7.28 - 7.42 (m, 2 H), 7.47 - 7.57 (m, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 8.08 (br. s., 1 H), 10.16 (br. s., 1 H).

TIP 296 PCT Compound 255: N-(3-chloro-2,4-difluoro-phenyl)methyl[(1-methylcyclopropyl)- sulfamoyl]-1H-pyrrolecarboxamide Compound 255 (211 mg) was prepared similarly as described for compound 252, using (1- methylcyclopropyl)amine hydrochloride instead of 1,1-difluoropropanamine. Method B: Rt: 1.00 min m/z: 402.1 (M-H)- Exact mass: 403.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.36 - 0.44 (m, 2 H), 0.66 - 0.75 (m, 2 H), 1.20 (s, 3 H), 3.90 (s, 3 H), 7.30 (d, J=2.0 Hz, 1 H), 7.34 (td, J=8.9, 2.0 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.67 (br. s., 1 H), 10.13 (br. s., 1 H). nd 256: N-(3-chloro-2,4-difluoro-phenyl)[(3,3-difluoromethyl-cyclobutyl )sulfamoyl]methyl-1H-pyrrolecarboxamide Compound 256 (258 mg) was prepared similarly as described for compound 252, using 3,3- romethylcyclobutanamine instead of 1,1-difluoropropanamine. Method B: Rt: 1.05 min m/z: 452.1 (M-H)- Exact mass: 453.1. 1 H NMR (400 MHz, DMSO-d6)  ppm 1.41 (s, 3 H), 2.43 - 2.57 (m, 2 H), 2.73 - 2.94 (m, 2 H), 3.90 (s, 3 H), 7.30 - 7.40 (m, 2 H), 7.48 - 7.57 (m, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.87 (br. s., 1 H), 10.14 (br. s., 1 H).

Compound 257: N-(3-chloro-2,4-difluoro-phenyl)methyl{[1-methyl(trifluoromethyl l]sulfamoyl}-1H-pyrrolecarboxamide Compound 257 (71mg) was ed similarly as described for compound 252, using 1,1,1- trifluoromethylbutanamine hydrochloride instead of 1,1-difluoropropanamine and 48 h reaction time instead of 24 h. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 TIP 296 PCT solution in water, MeOH). Method B: Rt: 1.13 min m/z: 472.1 (M-H)- Exact mass: 473.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.81 (t, J=7.3 Hz, 3 H), 1.38 (s, 3 H), 1.53 (dq, J=14.0, 7.2 Hz, 1 H), 1.73 - 1.89 (m, 1 H), 3.89 (s, 3 H), 7.29 - 7.39 (m, 2 H), 7.47 - 7.56 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.89 (br. s., 1 H), 10.14 (br. s., 1 H).

Compound 258: N-(3-chloro-2,4-difluoro-phenyl)methyl[[4-(trifluoromethyl)- tetrahydropyranyl]sulfamoyl]-1H-pyrrolecarboxamide nd 258 (29 mg) was prepared similarly as described for compound 252, using 4- (trifluoromethyl)oxanamine hydrochloride instead of 1,1-difluoropropanamine and 48 h on time instead of 24 h. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 1.03 min m/z: 500.1 (M-H)- Exact mass: 501.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.64 - 1.78 (m, 2 H), 2.06 - 2.18 (m, 2 H), 3.51 (t, J=11.4 Hz, 2 H), 3.71 - 3.82 (m, 2 H), 3.90 (s, 3 H), 7.27 - 7.41 (m, 2 H), 7.49 - 7.57 (m, 1 H), 7.57 - 7.61 (m, 1 H), 7.91 (br. s., 1 H), 10.17 (br. s., 1 H).

Compound 259: N-(3-chloro-2,4-difluoro-phenyl)[[1-ethyl(trifluoromethyl)- propyl]sulfamoyl]methyl-1H-pyrrolecarboxamide Compound 259 (114 mg) was prepared similarly as described for compound 252, using 3- (trifluoromethyl)pentanamine hydrochloride instead of 1,1-difluoropropanamine. Method B: Rt: 1.16 min m/z: 486.1 (M-H)- Exact mass: 487.1. 1 H NMR (400 MHz, 6 )  ppm 0.84 (t, J=7.4 Hz, 6 H), 1.68 - 2.02 (m, 4 H), 3.90 (s, 3 H), 7.29 - 7.41 (m, 2 H), 7.47 - 7.54 (m, 1 H), 7.55 (d, J=1.5 Hz, 1 H), 7.62 - 7.94 (m, 1 H), 10.14 (br. s., 1 H).

Compound 260: N-(3-chloro-2,4-difluoro-phenyl)methyl[(3,3,3-trifluoro methylpropyl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Compound 260 (252 mg) was prepared similarly as described for compound 252, using 4,4,4- trifluorobutanamine instead of fluoropropanamine. Method B: Rt: 1.06 min m/z: 458.1 (M-H)- Exact mass: 459.0. 1 H NMR (400 MHz, 6)  ppm 1.08 (d, J=6.6 Hz, 3 H), 2.24 - 2.49 (m, 2 H), 3.50 (sxt, J=6.5 Hz, 1 H), 3.92 (s, 3 H), 7.20 - 7.41 (m, 2 H), 7.42 - 7.81 (m, 3 H), 10.13 (br. s., 1 H).

Compound 261: N-(3-chloro-2,4-difluoro-phenyl)[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl] methyl-1H-pyrrolecarboxamide Compound 261 (143 mg) was prepared similarly as described for compound 252, using 1-fluoro- 2-methylpropanamine instead of 1,1-difluoropropanamine. The desired fractions were trated under reduced pressure yielding a powder. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 1.03 min m/z: 422.1 (M-H)- Exact mass: 423.1. 1 H NMR (400 MHz, DMSO-d6 )  ppm 1.13-1.22 (m, 6 H), 3.90 (s, 3 H), 4.24 (d, J=47.3 Hz, 2 H), 7.29 - 7.37 (m, 2 H), 7.41 (br. s., 1 H), 7.49 - 7.55 (m, 1 H), 7.56 (d, J=1.8Hz 1 H), 10.13 (br. s., 1 H). nd 262: N-(3-chloro-2,4-difluoro-phenyl)methyl{[(1S)(trifluoromethyl )propyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 262 (227 mg) was prepared similarly as described for compound 252, using (S) oromethyl-propylamine instead of 1,1-difluoropropanamine.

Method B: Rt: 1.08 min m/z: 458.1 (M-H)- Exact mass: 459.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.73 (t, J=7.5 Hz, 3 H), 1.38-1.52 (m, 1 H), 1.58 - 1.73 (m, 1 H), 3.62 - 3.84 (m, 1 H), TIP 296 PCT 3.89 (s, 3 H), 7.28 - 7.40 (m, 2 H), 7.45 - 7.58 (m, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 8.15 (br. s., 1 H), 10.12 (br. s, 1 H).

Compound 263: N-(3-chloro-2,4-difluoro-phenyl)methyl{[1-(trifluoromethyl)- cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 263 (154 mg) was prepared similarly as described for compound 252, using 1- trifluoromethyl-cyclobutylamine instead of 1,1-difluoropropanamine and 48 h reaction time instead of 24 h. An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH). Method B: Rt: 1.10 min m/z: 470.1 (M-H)- Exact mass: 471.0. 1 H NMR (400 MHz, 6 )  ppm 1.71 - 1.92 (m, 2 H), 2.21 - 2.37 (m, 2 H), 2.39 - 2.49 (m, 2 H), 3.91 (s, 3 H), 7.25 - 7.43 (m, 2 H), 7.46 - 7.58 (m, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 8.38 (br. s., 1 H), 10.16 (br. s., 1 H).

Compound 264: N-(3-chloro-2,4-difluoro-phenyl){[2-fluoro(fluoromethyl)- ethyl]sulfamoyl}methyl-1H-pyrrolecarboxamide nd 264 (231 mg) was prepared similarly as described for compound 252, using 1,3- difluoropropanamine hydrochloride instead of fluoropropanamine. Method B: Rt: 0.96 min m/z: 426.1 (M-H)- Exact mass: 427.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 3.53 - 3.75 (m, 1 H), 3.89 (s, 3 H), 4.28 - 4.53 (m, 4 H), 7.24 - 7.41 (m, 2 H), 7.45 - 7.58 (m, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 8.04 (br. s., 1 H), 10.02 (br. s, 1 H).

TIP 296 PCT Compound 265: N-(3-chloro-2,4-difluoro-phenyl)methyl{[(1R)(trifluoromethyl )propyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 265 (241 mg) was prepared rly as described for compound 252, using (R)- 1,1,1-trifluorobutylamine instead of 1,1-difluoropropanamine and 48 hours reaction time d of 24 h. Method B: Rt: 1.09 min m/z: 458.1 (M-H)- Exact mass: 459.0. 1 H NMR (400 MHz, DMSO-d6 )  ppm 0.73 (t, J=7.5 Hz, 3 H), 1.38-1.52 (m, 1 H), 1.58 - 1.73 (m, 1 H), 3.67 - 3.83 (m, 1 H), 3.89 (s, 3 H), 7.29 - 7.39 (m, 2 H), 7.45 - 7.58 (m, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 8.16 (br. s., 1 H), 10.13 (br. s., 1 H).

Compound 266: N-(3-chloro-2,4-difluoro-phenyl)methyl{[3-(trifluoromethyl)- ydrofuranyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 266 (140 mg) was prepared similarly as described for compound 252, using 3- (trifluoromethyl)tetrahydrofuranamine hydrochloride instead of 1,1-difluoropropanamine.

An extra purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH).

Method B: Rt: 1.03 min m/z: 486.1 (M-H)- Exact mass: 487.0. 1 H NMR (400 MHz, 6 )  ppm 2.19 (dt, J=13.8, 8.1 Hz, 1 H), 2.40 - 2.48 (m, 1 H), 3.62 (q, J=7.8 Hz, 1 H), 3.79-3.87 (m, 1 H), 3.89 (s, 3 H), 3.95 (d, J=10.1 Hz, 1 H), 4.01 - 4.11 (m, 1 H), 7.27 - 7.41 (m, 2 H), 7.49-7.57 (m, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 8.52 (br. s., 1 H), 10.15 (br. s., 1 H).

Compound 267: 3-chloro-N-(3,4-difluorophenyl)methyl{[1-(trifluoromethyl)- cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Methyl 3-chloromethyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylate (83 mg, 0.22 mmol) and 3,4-difluoroaniline (37 mg, 0.29 mmol) were dissolved in dry THF (10 mL) and cooled to 0º C. Lithium bis(trimethylsilyl)amide (1M in THF) (0.66 mL, 1 M, 0.66 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature.

The volatiles were removed under reduced re and the residue was purified on silica using a heptane to EtOAc gradient and further by preparative HPLC onary phase: RP XBridge Prep C18 µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN); - resulting in compound 267 (60 mg). Method B: Rt:1.11 min m/z: 470.1 (M-H)- Exact mass: 471.0. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.74 - 1.91 (m, 2 H), 2.24 - 2.36 (m, 2 H), 2.41 - 2.50 (m, 2 H), 3.78 (s, 3 H), 7.38 - 7.51 (m, 2 H), 7.65 (s, 1 H), 7.80 - 7.90 (m, 1 H), 8.59 (br. s., 1 H), .55 (s, 1 H).

Compound 268: 3-chloro-N-(3-chlorofluoro-phenyl)methyl{[1-(trifluoro- methyl)cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide Methyl 3-chloromethyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylate (155 mg, 0.2 mmol) and rofluoro-aniline (38 mg, 0.26 mmol) were dissolved in dry THF (10 mL) and cooled to 0ºC. Lithium bis(trimethylsilyl)amide (1M in THF) (0.6 mL, 1 M, 0.6 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature.

After 1 hour more lithium bis(trimethylsilyl)amide (1M in THF) (0.6 mL, 1 M, 0.6 mmol) was added and the reaction mixture was d for r hour. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient and further Preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) – resulting in compound 268 (23 mg). Method B: Rt: 1.17 min m/z:486.0 (M-H)- Exact mass: 487.0. 1H NMR (400 MHz, DMSO- d6)  ppm 1.72 - 1.88 (m, 2 H), 2.20 - 2.36 (m, 2 H), 2.41 - 2.53 (m, 2 H), 3.78 (s, 3 H), 7.43 (t, J=9.1 Hz, 1 H), 7.58 - 7.69 (m, 2 H), 7.99 (dd, J=6.8, 2.4 Hz, 1 H), 8.61 (br. s., 1 H), 10.53 (s, 1 TIP 296 PCT Compound 269: 3-Chloro-N-(3-cyanofluorophenyl)methyl[(1-methylethyl)sulfamoyl]- rolecarboxamide Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1.5 g, 5.51 mmol) was dissolved in acetonitrile (8 mL) and dried on molecular sieves. NaHCO3 (1389 mg, 16.54 mmol) was added. Isopropylamine (493.71 mg, 8.27 mmol) was dissolved in acetonitrile (2 mL) and dried on molecular sieves. The two suspensions were combined and heated at 70°C for 2 hours.

The reaction mixture was ed and washed with acetonitrile and evaporated to dryness to afford a crude residue (1.68 g). The crude was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to afford methyl 3-chloro(isopropylsulfamoyl) methyl-pyrrolecarboxylate (1.62 g). Method D: Rt:1.62 min m/z: 293.0 (M-H)- Exact mass: 294.0. Methyl 3-chloro(isopropylsulfamoyl)methyl-pyrrolecarboxylate (500 mg, 1.7 mmol) and ofluorobenzonitrile (0.26 g, 1.86 mmol) were dissolved in dry THF under a blanket of nitrogen. The reaction mixture was cooled to 0°C and lithium bis(trimethylsilyl)amide (1M in toluene) (5.09 mL, 1 M, 5.09 mmol) was added over a period of 2 minutes. The resulting e was d for 2 minutes while cooling was continued. The mixture was quenched with saturated ammonium chloride (50 mL) and extracted using EtOAc (2 X 100 mL). The combined extracts were washed with brine (50 mL), dried on Na2SO4, filtered and concentrated in vacuo to afford a dark brown powder which was purified using silica gel column chromatography (ethyl acetate in e from 0 to 100%) and further via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) yielding nd 269 (449 mg). Method B: Rt:0.94 min m/z: 397.1 (M-H)- Exact mass: 398.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.05 (d, J=6.6 Hz, 6 H), 3.24 - 3.38 (m, 1 H), 3.77 (s, 3 H), 7.49 (br. d, J=6.8 Hz, 1 H), 7.55 (t, J=9.1 Hz, 1 H), 7.62 (s, 1 H), 7.99 (ddd, J=9.2, 4.8, 2.8 Hz, 1 H), 8.20 (dd, J=5.8, 2.8 Hz, 1 H), 10.67 (br. s., 1 H).

TIP 296 PCT Compound 270: 3-Chloro-N-(3-cyanofluorophenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide Compound 270 was prepared similarly as bed for compound 269, using 3 equiv 2,2,2- trifluoro-1,1-dimethyl-ethylamine, d of 1.5 equiv isopropylamine (heating was continued for more then 44 hours at 80°C instead of 2 hours at 70°C). Method B: Rt:1.04 min m/z: 465.1 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.38 (s, 6 H), 3.78 (s, 3 H), 7.56 (t, J=9.1 Hz, 1 H), 7.66 (s, 1 H), 7.99 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.34 (br. s., 1 H), 10.64 (br. s., 1 H). nd 271: 3-Chloro-N-(3-cyanofluorophenyl)methyl{[1-(trifluoromethyl )cyclopropyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 271 was prepared similarly as described for compound 270, using 1- (trifluoromethyl)cyclopropanamine instead of 2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method B: Rt:1.01 min m/z: 463.1 (M-H)- Exact mass: 464.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 209.5°C. 1H NMR (400 MHz, DMSO-d6)  ppm 1.10-1.25 (m, 4 H), 3.78 (s, 3 H), 7.56 (t, J=9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 9.01 (br. s., 1 H), 10.67 (br. s., 1 H).

Compound 272: ro-N-(2-cyanofluoromethyl-phenyl)methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide: Compound 272 was prepared similarly as described for compound 250, using 6-aminofluoro- 2-methyl-benzonitrile instead of 3-bromoaniline. Differential ng calorimetry: From 30 to TIP 296 PCT 300 °C at 10°C/min: peak at C. Method B: Rt: 1.05 min m/z: 465.1 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, 6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 2.43 (d, J=2.2 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.05 (m, 1 H), 7.50 (dd, J=8.8, 4.8 Hz, 1 H), 7.59 (t, J=9.0 Hz, 1 H), 7.70 (s, 1 H), 8.49 (d, J=6.6 Hz, 1 H), 10.44 (br. s., 1 H).

Compound 273: 3-chloro-N-(2-cyanofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide nd 273 was prepared similarly as described for compound 250, using 2-amino fluorobenzonitrile instead of 3-bromoaniline. Method D: Rt:1.82 min m/z: 451.0 (M-H)- Exact mass: 452.0. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 200.7°C. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.06 (m, 1 H), 7.61 - 7.69 (m, 2 H), 7.70 (s, 1 H), 7.87 - 7.95 (m, 1 H), 8.50 (d, J=8.6 Hz, 1 H), 10.49 (s, 1 Compound 274: 3-chloro-N-[4-fluoro(trifluoromethyl)phenyl]methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 274 was prepared similarly as bed for compound 250, using 4-fluoro (trifluoromethyl)aniline instead of 3-bromoaniline. Method B: Rt:1.15 min m/z: 494.1 (M-H)- Exact mass: 495.0. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 189.8°C.1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.78 (s, 3 H), 3.91 - 4.04 (m, 1 H), 7.54 (t, J=9.8 Hz, 1 H), 7.68 (s, 1 H), 7.91 - 8.02 (m, 1 H), 8.19 (dd, J=6.4, 2.4 Hz, 1 H), 8.49 (br. s., 1 H), 10.67 (s, 1 H).

Compound 275: 3-chloro-N-(2-fluoromethyl-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 275 was prepared similarly as bed for compound 250, using 2-fluoro methylaniline instead of 3-bromoaniline. Method B: Rt:0.99 min m/z: 440.1 (M-H)- Exact mass: 441.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.14 - 1.29 (m, 3 H), 2.28 (s, 3 H), 3.76 (s, 3 H), 3.91 - 4.03 (m, 1 H), 7.08 - 7.18 (m, 2 H), 7.22 - 7.32 (m, 1 H), 7.65 (s, 1 H), 8.45 (br. s., 1 H), 9.85 (s, 1 H).

Compound 276: 3-chloro-N-(3-cyano-2,4-difluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide nd 276 was prepared similarly as described for compound 250, using 3-amino-2,6- difluorobenzonitrile instead of 3-bromoaniline. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 217.6°C. Method B: Rt:1.03 min m/z: 469.1 (M-H)- Exact mass: 470.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.79 (s, 3 H), 3.91 - 4.04 (m, 1 H), 7.47 (dt, J=8.9, 1.5 Hz, 1 H), 7.70 (s, 1 H), 8.09 (td, J=9.0, 6.2 Hz, 1 H), 8.50 (br. s., 1 H), 10.36 (br. s., 1 H).

Compound 277: 3-chloro-N-(2,3-dichlorofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide nd 277 was prepared rly as described for compound 250, using 2,3-dichloro fluoroaniline instead of 3-bromoaniline. Differential scanning calorimetry: From 30 to 300 °C at °C/min: peak at 206.0°C. Method B: Rt:1.20 min m/z: 496.0 (M-H)- Exact mass: 495.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.03 (m, 1 H), TIP 296 PCT 7.52 (t, J=8.9 Hz, 1 H), 7.70 (s, 1 H), 7.76 (dd, J=9.1, 5.4 Hz, 1 H), 8.49 (br. s., 1 H), 10.08 (br. s., 1 H).

Compound 278: 3-chloro-N-[3-(difluoromethyl)-2,4-difluoro-phenyl]methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Diethylaminosulfur trifluoride (23.4 mL) was added to the solution of 2,6-difluoronitrobenzaldehyde (18 g, 96.21 mmol) in dichloromethane (180 mL) at -78°C under N2 atmosphere.

The mixture was stirred for 1 hour and then warmed to 25°C for 4 hours. The mixture was poured into aqueous NaHCO3/ice and the aqueous phase was extracted twice with ethyl acetate.

The ed organic layers were dried and concentrated in vacuo, resulting in crude 2- (difluoromethyl)-1,3-difluoronitro-benzene (15 g). 2-(difluoromethyl)-1,3-difluoronitrobenzene (10 g, 47.8 mmol) was stirred in water (100 mL) and l (100 mL). Fe (16.0 g, 286.8 mmol) and ammonium chloride (15.34 g, 286.8 mmol) were added at 0°C. The mixture was stirred at 70° C for 2 hours, ed off and the filtrate was concentrated in vacuo.

The residue was dissolved in water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined c layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the obtained residue was dissolved in ethyl acetate (5 mL), and then HCl/ethylacetate (2 mL) was added. The mixture was stirred at 20° C for 20 minutes. The volatiles were removed in vacuo, resulting in 3-(difluoromethyl)-2,4-difluoro-aniline hydrochloride (5.1 g). Compound 278 was prepared similarly as described for compound 250, using 3-(difluoromethyl)-2,4-difluoro-aniline hydrochloride instead of 3-bromoaniline. ential scanning calorimetry: From 30 to 300°C at 10°C/min: peak at C. Method B: Rt:1.07 min m/z: 494.1 (M-H)- Exact mass: 495.0. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.79 (s, 3 H), 3.97 (br. s., 1 H), 7.32 (t, J=9.8 Hz, 1 H), 7.35 (t, J=52.0 Hz, 1 H), 7.68 (s, 1 H), 7.87 - 7.98 (m, 1 H), 8.48 (br. s., 1 H), 10.19 (br. s., 1 H).

TIP 296 PCT nd 279: 3-chloro-N-[3-(difluoromethyl)fluoro-phenyl]methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 279 was prepared rly as described for compound 250, using 3-(difluoromethyl)fluoro-aniline instead of 3-bromoaniline. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 190.4°C. Method B: Rt: 1.06 min m/z: 476.1 (M-H)- Exact mass: 477.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=6.8 Hz, 3 H), 3.77 (s, 3 H), 3.90 - 4.06 (m, 1 H), 7.24 (t, J=54.4 Hz, 1 H), 7.39 (t, J=9.7 Hz, 1 H), 7.67 (s, 1 H), 7.80 - 7.88 (m, 1 H), 8.01 - 8.08 (m, 1 H), 8.49 (d, J=7.0 Hz, 1 H), 10.58 (s, 1 H).

Compound 280: N-(3-bromophenyl)fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxamide Compound 280 (344 mg) was prepared similarly as bed for compound 229, using 3- bromoaniline instead of 3,4-difluoroaniline. Method D: Rt:2.02 min m/z: 472.0 (M-H)- Exact mass: 473.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.80 (s, 3 H), 3.91 - 4.04 (m, 1 H), 7.27 - 7.35 (m, 2 H), 7.54 (d, J=4.4 Hz, 1 H), 7.59 - 7.65 (m, 1 H), 7.96 - 8.01 (m, 1 H), 8.59 (d, J=8.6 Hz, 1 H), 10.21 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 216.8°C.

Compound 281: yanofluoro-phenyl)fluoromethyl[[1-(trifluoromethyl )cyclopentyl]sulfamoyl]pyrrolecarboxamide A mixture of ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (302 mg, 1.04 mmol), 1-(trifluoromethyl)cyclopentanamine (216 mg, 1.4 mmol) NaHCO3 (261 mg, 3.1 mmol) TIP 296 PCT acetonitrile (20 mL) and molecular sieves 4A (1000 mg) was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated yielding ethyl 3-fluoromethyl[[1- (trifluoromethyl)cyclopentyl]sulfamoyl]pyrrolecarboxylate (60.5 mg) as a light yellow powder. Lithium bis(trimethylsilyl)amide in toluene (0.59 mL, 1 M, 0.59 mmol) was added to ethyl 3-fluoromethyl[[1-(trifluoromethyl)cyclopentyl]sulfamoyl] pyrrolecarboxylate (57 mg, 0.148 mmol) and 5-aminofluoro-benzonitrile (26.1 mg, 0.19 mmol) in THF (10 mL) at room temperature under nitrogen. The reaction mixture was stirred 1 hour, quenched with NH4Cl (25 mL) solution, diluted with brine (25 mL) and extracted with EtOAc (50 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue was purified by silica gel column tography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were trated. The residue was dissolved in hot methanol (10 mL). The product crystallised upon addition of water. Compound 281 (30.5 mg) was filtered off and dried overnight in vacuo at 50°C. Method D: Rt: 2.02 min m/z: 475.3 (M-H)- Exact mass: 476.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.42 - 1.54 (m, 2 H), 1.58 - 1.71 (m, 2 H), 1.72 - 1.85 (m, 2 H), 2.21 - 2.32 (m, 2 H), 3.81 (s, 3 H), 7.50 - 7.57 (m, 2 H), 7.97 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.17 (dd, J=5.8, 2.8 Hz, 1 H), 8.32 (s, 1 H), 10.33 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at in: peak at 187.0 °C.

Compound 282: 3-chloro-N-(3-cyanofluoro-phenyl)-1,5-dimethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Ethyl rosulfonyl-1,5-dimethyl-pyrrolecarboxylate (600 mg, 2.26 mmol) was dissolved in acetonitrile (4 mL), dried on molecular sieves and NaHCO3 (569 mg, 6.77 mmol) was added.

(R)-1,1,1-trifluoropropylamine (766 mg, 6.77 mmol) was dissolved in acetonitrile (1 mL) and dried on molecular . The two suspensions were combined and heated at 80°C for 4 hours.

The reaction mixture was filtered, washed with acetonitrile and evaporated to dryness to afford a yellow sticky powder (730 mg) which was purified using silica gel column tography resulting in ethyl 1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (600 mg) as colorless sticky powder. Ethyl methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxylate (402 mg, 1.17 mmol) was ved in HOAc (10 mL) and N-Chlorosuccinimide (156.8 mg, 1.17 mmol) was added. The on mixture was heated at 40°C over weekend. The reaction mixture was evaporated to dryness and the residue TIP 296 PCT was purified using silica gel column chromatography (first ethylacetate in heptane from 0 to 100%, then again using methanol in CH2Cl2 from 0.1 to 0.5 %) to afford ethyl 3-chloro-1,5- dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (177 mg).

Method D: Rt: 1.89 min m/z: 375.3 (M-H)- Exact mass: 376.0. Lithium bis(trimethylsilyl)amide in toluene (0.934 mL, 1 M, 0.934 mmol) was added to ethyl 3-chloro-1,5-dimethyl[[(1R)- 2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (88 mg, 0.234 mmol) and 5- aminofluoro-benzonitrile (41.3 mg, 0.30 mmol) dissolved in THF (5 mL) and stirred overnight. The reaction mixture was ed with NH4Cl solution (5 mL) and diluted with brine (5 mL) then extracted with EtOAc (20 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated. The obtained residue was dissolved in DMF (1 mL) and purified by silica gel column tography using a gradient from 10 to 100% EtOAc in heptane. The product ons were trated and the residue ved in hot methanol (10 mL). Water was added untill crystallisation began. Compound 282 (44 mg) was filtered off and dried overnight in vacuo at 50°C. Method D: Rt: 1.89 min m/z: 465.0 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, DMSO-d 6)  ppm 1.17 (d, J=6.8 Hz, 3 H), 2.49 (s, 3 H), 3.64 (s, 3 H), 3.87 - 4.00 (m, 1 H), 7.56 (t, J=9.1 Hz, 1 H), 7.98 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.40 (d, J=9.0 Hz, 1 H), 10.71 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 240.0°C.

Compound 283: yanofluoromethyl-phenyl)fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide 2-fluoromethylbenzonitrile (18 g, 133 mmol) was added to a on of potassium nitrate (13.5 g, 133 mmol) in sulfuric acid (250 mL) cooled at 0º C, the mixture was allowed to stir at room temperature for 40 minutes. The reaction mixture was poured into ice water and the pale yellow itate was filtered off and dried in the vacuum oven yielding crude 2-fluoro methylnitro-benzonitrile (18 g). Crude 2-fluoromethylnitro-benzonitrile (18 g) was stirred in MeOH (210 mL) and water (70 mL). Fe powder (16.7 g) and HCl (36 mL, 5 equiv) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered through celite and after removal of organic t, the mixture was adjusted to pH 9 with saturated solution of sodium carbonate and extracted with CH2Cl2 twice. The combined organic layers were dried over sodium sulfate and evaporated to dryness to provide an yellow oil. The crude product was purified by column chromatography to provide 5-amino fluoromethyl-benzonitrile (5.1 g) as a pale yellow solid. Compound 283 (123 mg) was prepared rly as described for compound 229, using 5-aminofluoromethyl- TIP 296 PCT itrile instead of 3,4-difluoroaniline. Method D: Rt:1.95 min m/z: 449.3 (M-H)- Exact mass: 450.1. 1H NMR (600 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 2.30 (d, J=1.8 Hz, 3 H), 3.80 (s, 3 H), 3.98 (dq, J=15.2, 7.6 Hz, 1 H), 7.57 (d, J=4.3 Hz, 1 H), 7.87 (dd, J=6.5, 2.3 Hz, 1 H), 7.97 (dd, J=5.2, 2.6 Hz, 1 H), 8.64 (d, J=8.7 Hz, 1 H), 10.31 (s, 1 H). Differential ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 214.8°C.

Compound 284: N-(3-cyanofluoro-phenyl)fluoromethyl[[(1S)(trifluoromethyl l]sulfamoyl]pyrrolecarboxamide Compound 284 was prepared similarly as described for compound 281 using (S)trifluoromethyl-propylamine instead of 1-(trifluoromethyl)cyclopentanamine. Method D: Rt:1.92 min m/z: 449.3 (M-H)- Exact mass: 450.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.80 (t, J=7.4 Hz, 3 H), 1.43 - 1.56 (m, 1 H), 1.62 - 1.74 (m, 1 H), 3.70 - 3.79 (m, 1 H), 3.80 (s, 3 H), 7.50 - 7.57 (m, 2 H), 7.94 - 7.99 (m, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.58 (d, J=8.6 Hz, 1 H), 10.33 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 177.3°C.

Compound 285: 3-fluoro-N-(4-fluorophenyl)methyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxamide Compound 285 (105 mg) was prepared similarly as described for compound 229, using 4- fluoroaniline instead of 3,4-difluoroaniline. Method D: Rt:1.87 min m/z: 410.3 (M-H)- Exact mass: 411.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=7.0 Hz, 3 H), 3.80 (s, 3 H), 3.91 - 4.03 (m, 1 H), 7.14 - 7.22 (m, 2 H), 7.51 (d, J=4.4 Hz, 1 H), 7.65 - 7.72 (m, 2 H), 8.57 (d, J=8.8 Hz, 1 H), 10.12 (s, 1 H). Differential ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 212.9°C.

Compound 286: difluoromethyl)fluoro-phenyl]fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 286 (130 mg) was prepared similarly as described for compound 229, using 3- oromethyl)fluoro-aniline instead of 3,4-difluoroaniline.Method D: Rt:1.93 min m/z: 460.0 (M-H)- Exact mass: 461.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=6.8 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.03 (m, 1 H), 7.07 - 7.41 (m, 2 H), 7.54 (d, J=4.4 Hz, 1 H), 7.78 - 7.84 (m, 1 H), 8.01 (dd, J=6.3, 2.5 Hz, 1 H), 8.60 (d, J=8.8 Hz, 1 H), 10.28 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 198.8°C.

Compound 287: N-[3-(difluoromethyl)-2,4-difluoro-phenyl]fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 287 (80 mg) was prepared similarly as described for compound 229, using 3- (difluoromethyl)-2,4-difluoro-aniline instead of 3,4-difluoroaniline. Method D: 5 min m/z: 478.3 (M-H)- Exact mass: 479.1. 1H NMR (400 MHz, 6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.04 (m, 1 H), 7.19 - 7.48 (m, 2 H), 7.56 (d, J=4.6 Hz, 1 H), 7.82 - 7.91 (m, 1 H), 8.62 (d, J=8.8 Hz, 1 H), 9.84 (s, 1 H). nd 288: N-(3-cyanofluoro-phenyl)fluoromethyl[[(1R)(trifluoromethyl )propyl]sulfamoyl]pyrrolecarboxamide Compound 288 was prepared similarly as described for compound 281 using (R) trifluoromethyl-propylamine instead of 1-(trifluoromethyl)cyclopentanamine. Method D: Rt:1.92 min m/z: 449.0 (M-H)- Exact mass: 450.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.80 (t, J=7.3 Hz, 3 H), 1.43 - 1.56 (m, 1 H), 1.62 - 1.74 (m, 1 H), 3.70 - 3.79 (m, 1 H), 3.80 (s, 3 H), 7.50 - TIP 296 PCT 7.57 (m, 2 H), 7.97 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.58 (d, J=8.6 Hz, 1 H), 10.34 (s, 1 H). Differential ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 175.7°C.

Compound 289: 3-chloro-N-(3-cyanofluoro-phenyl)methyl[[(1S)(trifluoromethyl )propyl]sulfamoyl]pyrrolecarboxamide Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1000 mg, 3.68 mmol) was dissolved in CH3CN (18 mL) in a pressure tube and this was dried with powdered molecular sieves (4Å) over a period of 30 minutes. Another tube was loaded with (S)trifluoromethylpropylamine (700.7 mg, 5.51 mmol) and NaHCO3 (926 mg, 11.03 mmol) and this was sed in itrile (2 mL) and dried with powdered molecular sieves (4Å) over a period of 30 minutes. This was added to the pressure tube which was flushed with nitrogen, capped and stirred in a heating block at 80°C for 48 hours and next 1 hour at 125°C by microwave irradiation. The reaction mixture was filtered and trated. The e was dissolved in CH2Cl2 (5mL) filtered and subjected to silica gel column chromatography using a gradient from to 100% EtOAc in heptane. The product fractions were concentrated yielding methyl 3- methyl[[(1S)(trifluoromethyl)propyl]sulfamoyl]pyrrolecarboxylate (829 mg) as a white solidified resin. Lithium bis(trimethylsilyl)amide in toluene (1.844 mL, 1 M, 1.84 mmol) was added to methyl 3-chloromethyl[[(1S) (trifluoromethyl)propyl]sulfamoyl]pyrrolecarboxylate (167.2 mg, 0.461 mmol) and 5-amino- 2-fluoro-benzonitrile (81.6 mg, 0.599 mmol) dissolved in THF (2 mL) and stirred overnight. The reaction mixture was quenched with NH4Cl on (5mL) and diluted with brine (5mL) then extracted with EtOAc (20 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the residue dissolved in ol (10mL). Water was added untill crystallisation began. Compound 289 (160 mg) was filtered off and dried overnight in vacuo at 50°C. Method D: Rt:1.92 min m/z: 465.0 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, DMSO-d6)  ppm 0.81 (t, J=7.4 Hz, 3 H), 1.46 - 1.59 (m, 1 H), 1.61 - 1.73 (m, 1 H), 3.72 - 3.82 (m, 4 H), 7.56 (t, J=9.1 Hz, 1 H), 7.66 (s, 1 H), 7.99 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.49 (d, J=8.6 Hz, 1 H), 10.65 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 184.8°C.

TIP 296 PCT Compound 290: 3-chloro-N-(3-cyanofluoro-phenyl)methyl[[(1R)(trifluoromethyl )propyl]sulfamoyl]pyrrolecarboxamide nd 290 (133 mg) was prepared similarly as described for compound 289 using (R)-1,1,1- trifluorobutylamine instead of (S)trifluoromethyl-propylamine. Method D: Rt:1.95 min m/z: 465.3 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, DMSO-d6)  ppm 0.81 (t, J=7.4 Hz, 3 H), 1.45 - 1.59 (m, 1 H), 1.61 - 1.73 (m, 1 H), 3.71 - 3.82 (m, 4 H), 7.56 (t, J=9.1 Hz, 1 H), 7.66 (s, 1 H), 7.99 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.49 (d, J=8.8 Hz, 1 H), 10.65 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 183.8°C.

Compound 291: 3-chloro-N-(3-cyanofluoro-phenyl)isopropyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Methyl 3-chloro-1H-pyrrolecarboxylate (2 g, 12.5 mmol) was dissolved in DMF (20 mL) under N2 atmosphere. NaH (60% dispersion in l oil) [(601.6 mg, 15.0 mmol) was added portion wise and the mixture was stirred for 10 minutes at room temperature. 2-iodopropane (1.5 mL, 15.0 mmol) was added dropwise and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and the mixture was ted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using gradient eluent Heptane-EtOAc; 100-0 - > 50-50. The product fractions were collected and concentrated in vacuo resulting in methyl 3-chloroisopropyl-pyrrolecarboxylate (1.2 g) as an oil. Methyl 3-chloroisopropylpyrrolecarboxylate (1.2 g, 5.95 mmol) was added drop wise to sulfonic acid (1.99 mL, 29.9 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir for 1 hour.The resulting e was added dropwise to a stirred, temperature controlled ter mixture (100 mL) keeping the temperature under 5°C. A white suspension was formed. The obtained s suspension was extracted using Me-THF (2 x 50 TIP 296 PCT mL). The combined extracts were washed with Brine and dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl 3-chlorochlorosulfonylisopropyl-pyrrole carboxylate (1.7 g) which was used as such in the next step. Methyl 3-chlorochlorosulfonyl isopropyl-pyrrolecarboxylate (1.7 g, 5.66 mmol) was dissolved in hot itrile (3 mL), molecular sieves (~ 0.7 g) were added and the reaction mixture was stirred. In a separate vessel (R)-1,1,1-trifluoropropylamine (960.7 mg, 8.5 mmol) was dissolved in acetonitrile (2 mL), molecular sieves (~0.7 g) were added. This suspension was added to the reaction mixture and then NaHCO3 (1.43 g, 17.0 mmol) was added. The vessel was closed and it was stirred overnight at 80ºC. The reaction mixture was filtered and the solids were washed with acetonitrile (2 x 50 mL). The organic fractions were ed and concentrated in vacuo. The mixture was concentrated and purified by silica gel chromatography using gradient eluent heptane-EtOAc; 100-0 -> 50-50. The t fractions were combined and concentrated in vacuo resulting in methyl 3-chloroisopropyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate (907 mg) as a fluffy solid. Methyl 3-chloroisopropyl [[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (450 mg, 1.194 mmol) and ofluorobenzonitrile 201mg, 1.43 mmol) was dissolved in THF (dried on molecular sieves) (10.1 mL, 124.7 mmol). m bis(trimethylsilyl)amide (1M in THF) (3.58 mL, 1 M, 3.583 mmol) was added drop wise and the reaction mixture was d for 1 hour at room temperature. The mixture was quenched with sat. NH4Cl-sol. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was ed by silica gel chromatography using gradient eluent Heptane-EtOAc; 100-0 -> 50-50. The product fractions were collected and concentrated in vacuo. The product was crystallized from 2-propanol, ed and dried under vacuum to resulting in compound 291 (58 mg) as a pale yellow solid. The filtrate was concentrated in vacuo and further purified by preperative HPLC, resulting in more compound 291 (247 mg). Method B: Rt:1.10 min m/z: 479.1 (M-H)- Exact mass: 480.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.18 (d, J=6.8 Hz, 3 H) 1.42 (d, J=6.6 Hz, 6 H) 4.00 - 4.09 (m, 1 H) 4.71 (quin, J=6.7 Hz, 1 H) 7.56 (t, J=9.1 Hz, 1 H) 7.78 (s, 1 H) 7.95 - 8.00 (m, 1 H) 8.20 (dd, J=5.6, 2.5 Hz, 1 H) 8.47 (d, J=8.6 Hz, 1 H) 10.91 (s, 1 H).

Compound 292: o-N-(3-cyanofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Methyl 3-bromomethyl-pyrrolecarboxylate (5 g, 22.93 mmol) was added drop wise to chlorosulfonic acid (13.4 g, 114.7 mmol) at 0°C. The reaction mixture was warmed to room TIP 296 PCT temperature and allowed to stir for 1 hour. The resulting mixture was added dropwise to a stirred ice-water mixture (300 mL) keeping the temperature below 5°C. An off white precipitation was formed. The solids were filtered and washed with water (20 mL), triturated with diisopropylether and dried in vacuum oven overnight, resulting in methyl o chlorosulfonylmethyl-pyrrolecarboxylate (3.9 g).

Methyl 3-bromochlorosulfonylmethyl-pyrrolecarboxylate (3.9 g, 12.32 mmol) was dissolved in hot acetonitrile (20 mL) in a pressure vessel (100 mL), molecular sieves (10 g) were added and the reaction mixture was stirred. In a seperate vessel (R)-1,1,1-trifluoro propylamine (2.09 g, 18.5 mmol) was dissolved in acetonitrile (20 mL), molecular sieves (5 g) were added. This suspension was added to the reaction mixture and then NaHCO3 (3.1 g, 36.96 mmol) was added. The vessel was closed and it was stirred overnight at 80ºC. The reaction mixture was filtered and the volatiles were removed under reduced pressure. The residue was purified on silica using a heptane to EtOAc gradient. The fractions containing the product were evaporated to dryness ing in methyl 3-bromomethyl[[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl]pyrrolecarboxylate (4.24 g) as a white powder. Methyl 3-bromo methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (150 mg, 0.38 mmol) and 5-aminofluorobenzonitrile (69.6 mg, 0.5 mmol) were dissolved in dry THF (5 mL). Lithium bis(trimethylsilyl)amide (1M in THF) (1.14 mL, 1 M, 1.14 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. NH4Cl (5 mL). The c layer was removed and the aqueous layer ted with CH2Cl2 (2 x 5 mL). The combined organic layers were evaporated to dryness and the residue was ed on silica using a heptane to EtOAc gradient resulting in compound 292 (146 mg) as a light pink powder after trituration in /diisopropylether. Method B: Rt:1.00 min m/z: 496.9 (M-H)- Exact mass: 498.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.20 (d, J=7.0 Hz, 3 H), 3.77 (s, 3 H), 4.01 (br. s., 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.71 (s, 1 H), 7.98 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.19 (dd, J=5.7, 2.6 Hz, 1 H), 8.44 (br. s., 1 H), 10.74 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 189.2°C.

Compound 293: 3-cyano-N-(3-cyanofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide A microwave vial was d with compound 292 (94 mg, 0.189 mmol) and zinc cyanide (13.6 mg, 0.113 mmol) in DMF (0.8 mL). The e was purged with N2 for 5 minutes. tetrakis(triphenylphosphine)palladium(0) (10.9 mg, 0.00945 mmol) was added and the vial TIP 296 PCT capped. The e was heated at 160°C for 30 minutes by microwave irradiation. The mixture was concentrated in vacuo. A purification was performed via Preperative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again resulting in compound 293 (8.3 mg) as a white solid. Method B: Rt:0.97 min m/z: 442.1 (M-H)- Exact mass: 443.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.22 (d, J=6.8 Hz, 3 H) 3.85 (s, 3 H) 4.01 - 4.12 (m, 1 H) 7.60 (t, J=9.0 Hz, 1 H) 7.82 (s, 1 H) 7.95 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H) 8.19 (dd, J=5.7, 2.6 Hz, 1 H) 8.80 (br. s., 1 H) 11.18 (br. s., 1 H).

Compound 294: N-(3-cyanofluoro-phenyl)methyl[[(1R)methylpropyl]- sulfamoyl]pyrrolecarboxamide -[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (200 mg, 0.59 mmol) was dissolved in acetonitrile (6 mL) in a pressure tube and this was dried with powdered molecular sieves (4Å) over a period of 30 minutes. Another tube was loaded with (R)-(-) aminobutane (64.2 mg, 0.88 mmol) and NaHCO3 (245.81 mg, 2.93 mmol) and this was dispersed in acetonitrile (4 mL) and dried with powdered molecular sieves (4Å) over a period of minutes. This was added to the pressure tube which was flushed with nitrogen, capped and d in a heating block at 80°C for 2 hours. Then the reaction mixture was ed over a small path of te and rinsed using romethane (50 mL). The filtrate was concentrated in vacuo and the obtained residue was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0), resulting in compound 294 (136 mg).

Method B: Rt:1.00 min m/z: 377.1 (M-H)- Exact mass: 378.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.76 (t, J=7.4 Hz, 3 H), 0.91 - 0.99 (m, 3 H), 1.29 - 1.41 (m, 2 H), 3.01 - 3.15 (m, 1 H), 3.92 (s, 3 H), 7.17 (d, J=7.5 Hz, 1 H), 7.35 (d, J=1.8 Hz, 1 H), 7.49 - 7.59 (m, 2 H), 8.02 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.19 - 8.25 (m, 1 H), 10.36 (s, 1 H).

Compound 295: ro-N-(3-cyanofluoro-phenyl)methyl[[(1R)methyl- propyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 295 (515 mg) was prepared similarly as described for compound 289 using ) aminobutane instead of (S)trifluoromethyl-propylamine, stirring at70°C for 2 hours for the formation of methyl 3-chloromethyl[[(1R)methylpropyl]sulfamoyl]pyrrole carboxylate instead of 80°C for 48 hours as described for methyl 3-chloromethyl[[(1S) (trifluoromethyl)propyl]sulfamoyl] pyrrolecarboxylate. Method B: Rt:1.01 min m/z: 411.1 (M-H)- Exact mass: 412.1.1H NMR (400 MHz, DMSO-d6)  ppm 0.79 (t, J=7.4 Hz, 3 H), 1.00 (d, J=6.6 Hz, 3 H), 1.31 - 1.45 (m, 2 H), 3.03-3.18 (m, 1 H), 3.77 (s, 3 H), 7.42 (d, J=7.9 Hz, 1 H), 7.55 (t, J=9.1 Hz, 1 H), 7.60 (s, 1 H), 7.98 (ddd, J=9.1, 4.9, 2.8 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 10.64 (br. s., 1 H).

Compound 296: N-(3-cyanofluoro-phenyl)[(3-hydroxy-1,1-dimethyl-propyl)sulfamoyl] methyl-pyrrolecarboxamide Compound 296 was prepared similarly as described for compound 294 using 3-amino butanol instead of (R)-(-)aminobutane. Method B: Rt:0.85 min m/z: 407.1 (M-H)- Exact mass: 408.1.1H NMR (400 MHz, DMSO-d6)  ppm 1.13 - 1.20 (m, 6 H), 1.67 (t, J=7.0 Hz, 2 H), 3.48 (t, J=6.9 Hz, 2 H), 3.91 (s, 3 H), 4.45 (br. s., 1 H), 7.07 (br. s., 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.49 - 7.57 (m, 2 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.25 - 10.51 (m, 1 H).

Synthesis of (2S)-3,3-difluorobutanamine hydrochloride (S)((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), N,O-dimethylhydroxylamine hloride (24 g, 246 mmol), HATU (117 g, 308 mmol) and N,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room temperature for 16 hours. The reaction e was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(1S)[methoxy(methyl)amino]methyloxo-ethyl]carbamate (36 g) as a white powder. tert-butyl N-[(1S)[methoxy(methyl)amino]methyloxo-ethyl]carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0ºC. magnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the reaction mixture was stirred 16 hours at room temperature. The on mixture was poored into water (100 mL) and TIP 296 PCT ated to dryness. The residue was dissolved in EtOAc, washed with water, dried over Na2SO4, filtered and evaporated to dryness yielding tert-butyl N-[(1S)methyloxopropyl ]carbamate (22 g) as a white powder. To a cooled ) solution of tert-butyl N-[(1S) methyloxo-propyl]carbamate (12 g, 64.1 mmol) in CH2Cl2 (200 mL) bis(2-methoxyethyl)- aminosulfur trifluoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poored into water and extracted with CH2Cl2. The organic layer was washed with water, dried over , filtered and evaporated to dryness. The obtained residue was purified by silica gel chromatography yielding tert-butyl N-[(1S)-2,2-difluoromethyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(1S)-2,2-difluoromethyl-propyl]carbamate (5.8 g, 27.7 mmol) was dissolved in EtOAc (100 mL). HCl (g) was bubbled through for 30 s and then the les were removed under reduced pressure yielding (2S)-3,3-difluorobutanamine hydrochloride (3.8 g) 1H NMR (400MHz, DMSO-d 6)  ppm 8.69 (br. s., 3H), 3.76 - 3.63 (m, 1H), 1.72 (t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H). nd 297: N-(3-cyanofluoro-phenyl)[[(1S)-2,2-difluoromethyl-propyl]sulfamoyl]- yl-pyrrolecarboxamide O H N (S ) F NH S F O N Compound 297 was prepared similarly as described for compound 294 using ,3- difluorobutanamine hydrochloride instead of (R)-(-)aminobutane. Method D: Rt: 1.79 min m/z: 413.0 (M-H)- Exact mass: 414.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.97 (d, J=6.8 Hz, 3 H), 1.57 (t, J=19.1 Hz, 3 H), 3.42 - 3.56 (m, 1 H), 3.93 (s, 3 H), 7.36 (d, J=1.8 Hz, 1 H), 7.53 (t, J=9.2 Hz, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 7.78 (d, J=9.0 Hz, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.36 (s, 1 H).

Synthesis of (2R)-3,3-difluorobutanamine (R)((tert-butoxycarbonyl)amino)propanoic acid (30 g, 159 mmol), N,O-dimethylhydroxylamine hydrochloride (17.5 g, 178 mmol), HATU (74 g, 195 mmol) and N,N-diisopropylethylamine (30 g, 232 mmol) were dissolved in DMF (300 mL) and stirred at room temperature for 15 hours. The reaction mixture was concentrated under vacuum and the e was dissolved in CH2Cl2 (500 mL) and washed with brine (3 x 200 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified via silica gel chromatography using petroleum ether: EtOAc 2:1 as eluent yielding tert-butyl N-[(1R) [methoxy(methyl)amino]methyloxo-ethyl]carbamate (28.9 g). Tert-butyl N-[(1R) TIP 296 PCT [methoxy(methyl)amino]methyloxo-ethyl]carbamate was dissolved in THF (300 mL) and cooled to 0ºC. Methylmagnesium e 3.0 m in diethyl ether (85 mL, 255 mmol) was added drop wise and the reaction e was stirred 15 hours at room temperature. The reaction mixture was quenched with sat. NH4Cl and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The obtained residue was purified via silica gel chromatography yielding tert-butyl N-[(1R)methyloxopropyl ]carbamate (18.9 g). To a cooled ) solution of tert-butyl N-[(1R)methyloxopropyl ]carbamate (10 g, 53.4 mmol) in CH2Cl2 (200 mL) bis(2-methoxyethyl)aminosulfur trifluoride (18.9 g, 117.5 mmol) was added drop wise and stirring was ued for 2 hours at - 78ºC. The on mixture was allowed to warm to room temperature and stirred overnight.

The reaction e was quenched with sat. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness.

The residue was purified by silica gel tography using a gradient from petroleum ether to petroleum ether:EtOAc 1:1 yielding tert-butyl N-[(1R)-2,2-difluoromethyl-propyl]carbamate (6.77 g). Tert-butyl N-[(1R)-2,2-difluoromethyl-propyl]carbamate (6.77 g) was dissolved in EtOAc (50 mL). HCl in EtOAc was added at 0ºC and the reaction mixture was stirred for 4 hours at room temperature. The formed itate was filtered off and dried under high vacuum yielding (2R)-3,3-difluorobutanamine hydrochloride (3.5 g). nd 298: N-(3-cyanofluoro-phenyl)[[(1R)-2,2-difluoromethyl-propyl]- sulfamoyl]methyl-pyrrolecarboxamide Compound 298 was prepared similarly as described for compound 294 using (2R)-3,3- difluorobutanamine hydrochloride instead of (R)-(-)aminobutane. Method D: Rt: 1.79 min m/z: 413.0 (M-H)- Exact mass: 414.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.97 (d, J=7.0 Hz, 3 H), 1.57 (t, J=19.1 Hz, 3 H), 3.43 - 3.57 (m, 1 H), 3.93 (s, 3 H), 7.36 (d, J=2.0 Hz, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.63 (d, J=1.5 Hz, 1 H), 7.78 (d, J=9.0 Hz, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 10.36 (s, 1 H).

Compound 299: N-(3-cyanofluoro-phenyl)fluoro-1,5-dimethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Br2 (510 mg, 3.191 mmol) dissolved in HOAc (20 mL) was added to ethyl 3-fluoromethyl [[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (1050 mg, 3.03 mmol) and the solution was refluxed for 1 hour. More Br2 (0.25 equiv) was added and the solution was refluxed for 1 hour moer. More Br2 (0.3 equiv) was added and the reaction mixture was d to reach room temperature overnight. The reaction mixture was concentrated and the obtained residue was dissolved in EtOAc (50mL) washed with NaHCO3 solution, dried over magnesium sulphate, filtered and concentrated, resulting in ethyl ofluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (1.19 g) as a white powder. Method D: Rt: 1.92 min m/z: 423.2 (M-H)- Exact mass: 424.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.19 (d, J=7.0 Hz, 3 H), 1.28 (t, J=7.2 Hz, 3 H), 3.87 (s, 3 H), 3.94 - 4.07 (m, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 8.88 (d, J=8.8 Hz, 1 H). A solution ethyl 5-bromofluoromethyl[[(1R)-2,2,2- oromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (963 mg, 2.265 mmol), tetramethyltin (852.8 mg, 4.53 mmol) in DMF (7 mL), was flushed with nitrogen during 5 minutes.

Tetrakis(triphenylphosphine)palladium(0) (261.7 mg, 0.226 mmol) was added and the reaction mixture was heated at 140°C during 30 minutes by microwave irradiation. The reaction e was concentrated and the obtained residue was purified by silica gel column chromatography using a gradient from 10 to 100% EtOAc in e. The product fractions were concentrated yielding ethyl 3-fluoro-1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole- 2-carboxylate (769 mg) as a white fluffy powder. Method D: Rt: 1.89 min m/z: 359.3 (M-H)- Exact mass: 360.1. 1H NMR (400 MHz, 6)  ppm 1.14 (d, J=6.8 Hz, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 2.42 (s, 3 H), 3.76 (s, 3 H), 3.86 - 3.98 (m, 1 H), 4.26 (q, J=7.0 Hz, 2 H), 8.54 (d, J=8.8 Hz, 1 H). Lithium imethylsilyl)amide in toluene (1.66 mL, 1 M, 1.66 mmol) was added to ethyl 3-fluoro-1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (149.6 mg, 0.415 mmol) and 5-aminofluoro-benzonitrile (73.5 mg, 0.54 mmol) dissolved in THF (2 mL) and stirred overnight. The reaction mixture was quenched with NH4Cl solution (5mL) and diluted with brine (5mL) then extracted with EtOAc (20 mL). The organic layer was dried over magnesium te, filtered and concentrated. The residue was dissolved in DMF (1 mL) and purified by silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were trated and the residue dissolved in methanol (2 mL). Water was added untill crystallisation began. The powder was filtered off and dried overnight in vacuo at 50°C, resulting in compound 299 (76 mg). Method D: Rt:1.88 min m/z: 449.1 (M-H)- Exact mass: 450.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.17 (d, J=6.8 Hz, 3 H), 2.44 (s, 3 H), 3.70 (s, 3 H), 3.85 - 3.99 (m, 1 H), 7.53 (t, J=9.1 Hz, 1 H), 7.95 (ddd, J=9.2, TIP 296 PCT 4.8, 2.9 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.55 (d, J=8.8 Hz, 1 H), 10.35 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 177.5°C.

Compound 300: 5-bromochloro-N-(3-cyanofluoro-phenyl)methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 199 (1100 mg, 2.43 mmol), DMF (15 mL), N-bromosuccinimide (449.8 mg, 2.5 mmol) were stirred at room temperature for 64 hours. The reaction mixture was poured into water (150 mL). The pink solids were filtered, washed with water and purified using silica gel column tography (ethyl acetate in heptane from 0 to 40%) resulting in compound 300 (348 mg). Method B: Rt:1.07 min m/z: 530.9 (M-H)- Exact mass: 531.9. 1H NMR (400 MHz, DMSO-d6)  ppm 1.20 (d, J=6.8 Hz, 3 H), 3.73 (s, 3 H), 3.89 - 4.09 (m, 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.97 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.77 (br. s., 1 H), 10.88 (br. s., 1 H).

Compound 301: 5-bromo-N-(3-cyanofluoro-phenyl)fluoromethyl[[(1R)-2,2,2- oromethyl-ethyl]sulfamoyl]pyrrolecarboxamide A e of ethyl 5-bromofluoromethyl[[(1R)-2,2,2-trifluoromethyl- ethyl]sulfamoyl]pyrrolecarboxylate (174 mg, 0.409 mmol), Lithium hydroxide (29.4 mg, 1.23 mmol), THF (20 mL) and water (distilled, 20 mL) was stirred overnight. More LiOH was added (3 equiv) and the on mixture was stirred for 4 hours. The reaction mixture was concentrated, the obtained residue dissolved in water (50 mL) and the solution was neutralised with HCl (1 M in H2O). The formed white powder was ed off and dried in vacuo at 50°C, resulting in 5-bromofluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid (111 mg). Method D: Rt: 1.05 min m/z: 397.0 (M-H)- Exact mass: 397.9. 5-bromofluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid (106.9 mg, 0.269 mmol), HATU (127.9 mg, 0.336 mmol) and 5-aminofluoro-benzonitrile (73.3 mg, 0.538 mmol) were dissolved in DMF (1 mL), Et3N (0.112 mL, 0.808 mmol) was added and the reaction mixture was stirred over TIP 296 PCT weekend at 55°C. The solution was subjected to silica gel column tography using a gradient from 10 to 100% EtOAc in e. The t fractions were concentrated. The residue was dissolved in methanol (2 mL). Water was added untill crystallisation began. The white powder was filtered off and dried overnigth in vacuo at 50°C, resulting in compound 301 (54 mg). Method D: Rt:1.99 min m/z: 515.2 (M-H)- Exact mass: 516.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.22 (d, J=7.0 Hz, 3 H), 3.80 (s, 3 H), 3.95 - 4.07 (m, 1 H), 7.55 (t, J=9.1 Hz, 1 H), 7.95 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.91 (d, J=8.8 Hz, 1 H), .55 (s, 1 H).

Compound 302: 3-chloro-N-(3-cyanofluoro-phenyl)cyclopropylmethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 300 (130 mg, 0.24 mmol) and potassium cyclopropyltrifluoroborate (54.3 mg, 0.37 mmol) were dissolved in dimethoxyethane (1.5 mL,) and distilled water (0.4 mL). The mixture was degassed with N2 for 5 minutes. Cs2CO3 (239 mg, 0.73 mmol) was added and the mixture was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (28.3 mg, 0.024 mmol) was added and the re was degassed with N2. The vial was capped and the mixture was heated at 90°C for 30 s under microwave irradiation, next at 120 °C for 30 minutes under microwave irradiation and at 140°C in MW for 30 minutes under microwave irradiation. The mixture was cooled and EtOAc was added. The organic layer was separated. The water layer was made acidic with HCl (1M) and extracted with ethyl acetate (5 mL), The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The product was purified using silica gel column chromatography using gradient eluent Heptane-EtOAc; 100-0 -> 0-50 and further via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN), ing in compound 302 (10 mg).

Method B: 0 min m/z: 491.0 (M-H)- Exact mass: 492.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.73 - 0.91 (m, 2 H), 1.03-1.15 (m, 2 H), 1.22 (d, J=6.8 Hz, 3 H), 1.72-1.83 (m, 1 H), 3.74 (s, 3 H), 3.93 - 4.09 (m, 1 H), 7.56 (t, J=9.1 Hz, 1 H), 7.97 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 8.29 (br. s., 1 H), 10.73 (br. s., 1 H).

Compound 303: N-(3-cyanofluoro-phenyl)isopropylmethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT A microwave vial was charged with methyl 3-bromomethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate (500 mg, 1.27 mmol) and potassium isopropenyltrifluoroborate (291 mg, 1.9 mmol). Toluene (6.5 mL) and distilled water, (0.65 mL) were added and the mixture was purged with N2 for 5 minutes. Pd(OAc)2 (57.1 mg, 0.254 mmol) and butyldiadamantylphosphine (137 mg, 0.382 mmol) were added under N2 and then Cs2CO3 (1243 mg, 3.82 mmol) was added. The vial was capped and the mixture was heated at 110°C for 16 hour. The mixture was cooled and Me-THF was added. The c layer was separated, dried (MgSO4), filtered and trated in vacuo. The residue was purified by silica gel column chromatography using gradient eluent Heptane-EtOAc; 100-0 to 70-30. The product fractions were collected and concentrated in vacuo resulting in methyl ropenylmethyl[[(1R)- 2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (350 mg) as a semi solid. Methyl 3-isopropenylmethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (350 mg, 0.988 mmol) was dissolved in THF (50 mL), Pd/C (10%) (158 mg) was added under N2-atmosphere and the reaction mixture was stirred under H2-atmosphere until 1 eq. H2 was absorbed. The st was removed by filtration over te under nitrogen atmosphere, and the solvent was removed in vacuo, resulting in crude methyl 3-isopropylmethyl[[(1R)- 2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (352 mg). Methyl 3-isopropyl methyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (175 mg, 0.491 mmol) and 5-aminofluorobenzonitrile (89.61 mg, 0.638 mmol) were dissolved in THF (3.9 mL) dried on moleculair . Lithium imethylsilyl)amide (1M in THF, 1.5 mL, 1.5 mmol) was added drop wise and the reaction mixture was stirred 1 hour at room temperature.

The mixture was quenched with sat. NH4Cl-sol. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica gel column chromatography using gradient eluent Heptane-EtOAc; 100-0 to 50-50 and further by prep HPLC onary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 on in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated in vacuo again resulting in compound 303 (77 mg) as a light yellow solid. Method B: Rt: 1.06 min m/z: 459.1 (M-H)- Exact mass: 460.1. 1H NMR (400 MHz, DMSO-d6)  ppm 1.16 (d, J=6.8 Hz, 3 H) 1.18-1.30 (m, 6 H) 3.32 - 3.41 (m, 1 H) 3.64 (s, 3 H) 3.75 - 3.90 (m, 1 H) 7.39 (s, 1 H) 7.56 (t, J=9.1 Hz, 1 H) 7.90 - 8.02 (m, 1 H) 8.12 - 8.25 (m, 2 H) 10.81 (s, 1 H).

Compound 304: N-(3-cyanofluoro-phenyl)cyclopropylfluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT en was flushed through a mixture of compound 301 (44.4 mg, 0.086 mmol) potassium cyclopropyltrifluoroborate (38.3 mg, 0.26 mmol) Cs2CO3 (84 mg, 0.26 mmol) in dimethoxyethane (2 mL) and distilled water (0.2 mL) during 5 minutes. tetrakis(triphenylphosphine)palladium(0) (19.9 mg, 0.0172 mmol) was added and the reaction mixture was heated at 140°C during 30 s. The reaction mixture was concentrated. The residue was dissolved in EtOAc (10 mL) and water (5 mL) The organic layer was dried over ium sulphate, filtered and concentrated. The residue was ted to silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the residue was dissolved in methanol (2 mL). Water was added untill crystallisation began. The white powder was filtered off and dried in vacuo at 50°C, resulting in compound 304 (21 mg). Method D: Rt: 1.98 min m/z: 475.1 (M-H)- Exact mass: 476.1. 1H NMR (400 MHz, DMSO-d6)  ppm 0.82 - 0.91 (m, 2 H), 1.04 - 1.10 (m, 2 H), 1.23 (d, J=7.0 Hz, 3 H), 1.71 - 1.81 (m, 1 H), 3.81 (s, 3 H), 3.90 - 4.03 (m, 1 H), 7.54 (t, J=9.1 Hz, 1 H), 7.95 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 8.47 (d, J=8.4 Hz, 1 H), 10.37 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 161.4°C.

Compound 305: 3-chloro-N-(3-cyanofluoro-phenyl)cyclopropyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide A flask (250 mL) was d with methyl 3-chloro-1H-pyrrolecarboxylate (2 g, 12.53 mmol), cyclopropylboronic acid (2.153 g, 25.07 mmol), Na2CO3 (2.66 g, 25.07 mmol) in dichloroethane (50 mL). 2,2'-bipyridine (1.98 g, 12.53 mmol) and copper(II) acetate (2.3 g, 12.53 mmol) were added and the mixture was vigourously stirred on air and heated at 70°C for 2 hours.

The e was cooled and washed with water/NH4OH. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The e was purified by silica gel chromatography using gradient eluent Heptane-EtOAc; 100-0 -> 70-30. The product fractions were collected and trated in vacuo resulting in methyl 3-chlorocyclopropyl-pyrrole carboxylate (1.15 g) as a yellow oil. Chlorosulfonic acid (0.46 mL, 6.91 mmol) dissolved in dichloromethane (1 mL) was added to methyl 3-chlorocyclopropyl-pyrrolecarboxylate TIP 296 PCT (1.15 g, 5.76 mmol) in CH2Cl2 (17.7 mL, 275.9 mmol) in an ice bath and stirred 30 minutes. The reaction was further stirred at room temperature for 1 hour, the precipitate was filtered off washed with diisopropylether and used as such in the next step (0.7 g after drying in vacuo). The atate (0.7 g) was added to SOCl2 (0.7 g, 2.503 mmol) and the mixture was stirred at 80°C for 30 minutes. The mixture was cooled and stirred at room temperature for 16 hours and concentrated in vacuo. To the residue ice was added and the mixture was extracted with Me- THF. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using gradient eluent Heptane-EtOAc; 100-0 - > 70-30. The product fractions were ted and concentrated in vacuo resulting in methyl 3- chlorochlorosulfonylcyclopropyl-pyrrolecarboxylate (359 mg) as an oil which solidified on standing. Methyl 3-chlorochlorosulfonylcyclopropyl-pyrrolecarboxylate (359 mg, 1.20 mmol) was dissolved in hot acetonitrile (3 mL), molecular sieves (about 0.7 g) were added and the reaction mixture was stirred. In a seperate vessel (R)-1,1,1-trifluoropropylamine (204.2 mg, 1.81 mmol) was dissolved in acetonitrile (2 mL), lar sieves ( about 0.7 g) was added. This suspension was added to the reaction mixture and then NaHCO3 (303.5 mg, 3.61 mmol) was added. The vessel was closed and it was stirred ght at 80ºC. The reaction mixture was filtered and the solids were washed with acetonitrile (2 x 50 mL). The organic fractions were combined and concentrated in vacuo. The mixture was concentrated and purified by silica gel chromatography (solid phase, 40g) using gradient eluent heptane-EtOAc; 100-0 -> 50-50. The product ons were combined and concentrated in vacuo to resulting in methyl 3- cyclopropyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (281 mg) as an oil which solidified on standing.

Methyl 3-chlorocyclopropyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (100 mg, 0.267 mmol) and 5-aminofluorobenzonitrile 1 mg, 0.347 mmol) were dissolved in THF (2.1 mL, 25.8 mmol). Lithium bis(trimethylsilyl)amide (1M in THF) (0.8 mL, 1 M, 0.8 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. The e was quenched with sat. NH4Cl-sol. The organic layer was separated, dried ), filtered and concentrated in vacuo. A purification was performed via ative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, . The product fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated in vacuo again to obtain compound 305 (80 mg) as a white solid. Method B: Rt: 1.06 min m/z: 477.0 (M-H)- Exact mass: 1H NMR (400 MHz, DMSO-d6) ppm 0.85 - 1.05 (m, 4 H), 1.17 (d, J=7.0 Hz, 3 H), 3.61 - 3.76 (m, 1 H), 3.93 - 4.12 (m, 1 H), 7.53 - 7.60 (m, 2 H), 7.95 - 6 8.01 (m, 1 H), 8.17 - 8.23 (m, 1 H), 8.49 (d, J=8.6 Hz, 1 H), 10.86 (s, 1 H).

Compound 306:3-chloro-N-(3-cyanofluoro-phenyl)methyl[(3-methyloxetan yl)sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 306 (179 mg) was prepared in two steps from methyl 3-chlorochlorosulfonyl methyl-pyrrolecarboxylate similarly as described for compound 269, using 3 equiv yl- 3-oxetanamine, instead of 1.5 equiv isopropylamine in the first step. Method B: Rt: 0.86 min m/z: 425.1 (M-H)- Exact mass: 426.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.53 (s, 3 H), 3.77 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.66 (d, J=5.9 Hz, 2 H), 7.55 (t, J=9.1 Hz, 1 H), 7.66 (s, 1 H), 7.78 - 8.76 (m, 1 H), 7.98 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.19 (dd, J=5.8, 2.8 Hz, 1 H), 10.65 (br. s., 1 H).

Compound 307: 3-chloro-N-(3-cyanofluoro-phenyl)(cyclopentylsulfamoyl)methylpyrrolecarboxamide Compound 307 (241mg) was prepared in two steps from methyl 3-chlorochlorosulfonyl methyl-pyrrolecarboxylate similarly as described for nd 269, using 3 equiv cyclopentylamine, instead of 1.5 equiv isopropylamine in the first step. Method B: Rt: 1.05 min m/z: 423.1 (M-H)- Exact mass: 424.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.34 - 1.51 (m, 4 H), 1.51 - 1.77 (m, 4 H), 3.41 - 3.52 (m, 1 H), 3.77 (s, 3 H), 7.52 - 7.59 (m, 2 H), 7.61 (br. s, 1 H), 7.91 - 8.07 (m, 1 H), 8.14 - 8.27 (m, 1 H), 10.65 (br. s., 1 H).

Compound 308: 3-bromo-N-(4-fluoromethyl-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 308 can be prepared rly as described for compound 292, using 4-fluoro methyl-aniline instead of 5-aminofluorobenzonitrile. Method B: Rt: 1.07 min m/z: 486.0 (MH )- Exact mass: 487.0. 1H NMR (400 MHz, DMSO-d6) ppm 1.20 (d, J=6.8 Hz, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 3.75 (s, 3 H), 3.93 - 4.07 (m, 1 H), 7.13 (t, J=9.1 Hz, 1 H), 7.47 - 7.55 (m, 1 H), 7.59 - 7.65 (m, 1 H), 7.67 (s, 1 H), 8.39 (br. s., 1 H), 10.36 (s, 1 H).

TIP 296 PCT Compound 309: N-(3-cyanofluoro-phenyl)fluoro(methoxymethyl)methyl[[(1R)- 2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Nitrogen was bubbled through a mixture of compound 301 (prepared similarly as described in the synthesis of 301, but on a larger scale, 100.1 mg, 0.194 mmol) potassium trifluoro(methoxymethyl)borate (88.6 mg, 0.58 mmol), Cs2CO3 (189.9 mg, 0.58 mmol), DME (3 mL, ol), water (distilled, 0.25 mL) during 5 minutes. Then tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added and the on mixture was heated at 140°C during 30 minutes by microwave irradiation. The on mixture was further heated by microwave irradiation for 60 min at 160°C and next the on mixture was concentrated. The residue was dissolved in EtOAc (50 mL) and water (50 mL) The organic layer was dried over magnesium sulphate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in e. The product fractions were concentrated and further purified by prep HPLC (Stationary phase: RP XBridge Prep C18 ODB- 5µm,30x250mm, Mobile phase: 0.25% 3 solution in water, CH3CN) yielding compound 309 (20 mg) as a white powder after drying overnight in vacuo at 50°C. Method D: Rt: 1.91 min m/z: 479.1 (M-H)- Exact mass: 480.1.

Differential scanning calorimetry: From 30 to 300 °C at in: peak at 180.7°C. 1H NMR (400 MHz, DMSO-d6) ppm 1.16 (d, J=7.0 Hz, 3 H), 3.31 (s, 3 H), 3.77 (s, 3 H), 3.90 - 4.02 (m, 1 H), 4.64 - 4.73 (m, 2 H), 7.55 (t, J=9.1 Hz, 1 H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.18 (dd, J=5.7, 2.6 Hz, 1 H), 8.69 (d, J=8.4 Hz, 1 H), 10.54 (s, 1 H).

Compound 310: 5-cyano-N-(3-cyanofluoro-phenyl)fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 301 (prepared similarly as described in the synthesis of 301, but on a larger scale, TIP 296 PCT 185.6 mg, 0.346 mmol), copper (I) cyanide (93.04 mg, 1.04 mmol), DMF (2 mL, 25.8 mmol) was heated 110 minutes at 160°C under microwave irradiation. This was diluted with EtOAc (50 mL) washed with ammonia, dried over magnesium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography with EtOAc/heptane gradient from 10 to 50%. The product fractions were concentrated. The e was dissolved in ol (5 mL) and the product crystallised upon addition of water. The white powder was filtered off and dried ght in vacuo at 50°C, resulting in compound 310 (45 mg). Method D: Rt: 1.91 min m/z: 460.3 (M-H)- Exact mass: 461.1. ential scanning calorimetry: From 30 to 300 °C at °C/min: peak at C.1H NMR (400 MHz, DMSO-d6) ppm 1.24 (d, J=7.0 Hz, 3 H), 3.94 (s, 3 H), 4.04 - 4.15 (m, 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 8.17 (dd, J=5.7, 2.6 Hz, 1 H), 9.32 (d, J=8.6 Hz, 1 H), 10.87 (s, 1 H).

Compound 311: N-(3-cyanofluoro-phenyl)fluoromethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]vinyl-pyrrolecarboxamide Nitrogen was flushed through a mixture of compound 301 (prepared similarly as described in the synthesis of 301, but on a larger scale, 446 mg, 0.87 mmol) ium vinyltrifluoroborate (348.0 mg, 2.60 mmol), Cs2CO3 (846.5 mg, 2.60 mmol), DME (7 mL), water (1 mL) during 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (200.1 mg, 0.17 mmol) was added and the reaction mixture was heated at 140°C during 30 minutes by microwave irradiation. The reaction mixture was concentrated. The obtained e was dissolved in EtOAc (50 mL) and water (25 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the obtained residue was ved in ol (10 mL). Water was added untill crystallisation began. The white powder was filtered off and dried in vacuo at 50°C, resulting in compound 311 (297 mg). Method D: Rt: 1.94 min m/z: 461.1 (M-H)- Exact mass: 462.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 195.8°C. 1H NMR (400 MHz, DMSO-d6) ppm 1.17 (d, J=6.8 Hz, 3 H), 3.77 (s, 3 H), 3.87 - 3.98 (m, 1 H), 5.78 - 5.82 (m, 1 H), 5.84 (s, 1 H), 6.80 - 6.91 (m, 1 H), 7.55 (t, J=9.1 Hz, 1 H), 7.96 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.19 (dd, J=5.7, 2.6 Hz, 1 H), 8.66 (d, J=8.8 Hz, 1 H), 10.51 (s, 1 H).

Compound 312: N-(2,4-difluorophenyl)fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Et3N (0.19 mL, 1.35 mmol) was added to romethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylic acid (146 mg, 0.46 mmol), HATU (218 mg, 0.57 mmol) 2,4-difluoroaniline (119.8 mg, 0.92 mmol) in DMF (1 mL, 12.92 mmol) and stirred at 65°C overnight. The solution was directly charged on a silica gel column and purified by column chromatography using a gradient from 10 till 100% EtOAc in heptane. The t ons were trated and the residue was crystallised from methanol (10 mL) upon addition of water. The white crystals were filtered off and dried at 50°C overnight, resulting in compound 312 (105 mg). Method D: Rt: 1.88 min m/z: 428.0 (M-H)- Exact mass: 429.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at C.1H NMR (400 MHz, DMSO-d6) ppm 1.18 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.91 - 4.03 (m, 1 H), 7.07 - 7.14 (m, 1 H), 7.31 - 7.39 (m, 1 H), 7.54 (d, J=4.6 Hz, 1 H), 7.63 - 7.72 (m, 1 H), 8.59 (d, J=8.8 Hz, 1 H), 9.69 (s, 1 H).

Compound 313: N-(3-chlorocyanofluoro-phenyl)fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide To a solution of 3-chlorofluoronitro-benzoic acid (9 g, 40.99 mmol) in DMF (150 mL), HATU (31.17 g, 82.0 mmol) and DIPEA (15.89 g, 123.0 mmol) were added The reaction was stirred at room ature for 10 minutes. NH4Cl (3.29 g, 61.5 mmol) was added and the mixture was stirred overnight. Water was added and the mixture was ted with ethyl acetate. The organic layer was collected, washed with brine, dried and evaporated.

The crude was purified by column chromatography over silica gel (petrol ether/ethyl acetate=1/1) resulting in 3-chlorofluoronitro-benzamide (3 g). To a solution of 3-chloro fluoronitro-benzamide (3 g) in CH3CN (50 mL), POCl3 was added (6.86 g, 44.74 mmol) dropwise. The mixture was stirred at 80°C overnight. The mixture was evaporated and NaHCO3 solution was added to adjust the pH to 7-8. CH2Cl2 was added and the organic layer was collected, dried and evaporated resulting in 3-chlorofluoronitro-benzonitrile (1.6 g). A mixture of 3-chlorofluoronitro-benzonitrile (1.5 g, 7.48 mmol) in ethyl acetate (40 mL) was hydrogenated at room temperature with Pd/C (0.3 g) as a catalyst. After uptake of H2, the TIP 296 PCT catalyst was filtered off and the te was evaporated. The crude compound was purified by high-performance liquid chromatography (Column: ADIKMA Diamonsil(2) C18, *5um, Flow rate: 35 mL/min, Mobile Phase A: Purified water ining 0.5% HCl), Mobile Phase B: CH3CN, Gradient: 53-83% (%B). NaHCO3 solution was added to adjust the pH to 8.The desired fraction was collected and the solvent was concentrated in vacuo resulting in 5-aminochloro- 2-fluoro-benzonitrile (253 mg).

Compound 313 (118 mg) was prepared similarly as described for compound 312 using 5-amino- 3-chlorofluoro-benzonitrile instead of 2,4-difluoroaniline. Method D: Rt: 2.01 min m/z: 469.0 (M-H)- Exact mass: 470.0. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 205.4°C. 1H NMR (400 MHz, DMSO-d6) ppm 1.18 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.92 - 4.04 (m, 1 H), 7.58 (d, J=4.4 Hz, 1 H), 8.08 (dd, J=5.1, 2.6 Hz, 1 H), 8.21 (dd, J=6.7, 2.5 Hz, 1 H), 8.64 (d, J=8.4 Hz, 1 H), 10.40 (s, 1 H). nd 314: 5-chloro-N-(3-cyano-2,4-difluoro-phenyl)fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide NCS (20.0 mg, 0.15 mmol) was added to compound 181 (synthesized similarly as described for compound 181, but on a larger scale, 68 mg, 0.15 mmol) acetonitrile (1 mL, 19.15 mmol) DMF (1 mL) and stirred over weekend. More NCS (0.75 eq) was added and the reaction mixture was stirred overnight. The on mixture was charged directly on a silica gel column and purified using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated.

The obtained e was dissolved in methanol (5mL) and the product crystallised upon on of water. The white powder was filtered off and dried overnight in vacuo at 50°C, resulting in compound 314 (9.6 mg). Method B: Rt: 1.05 min m/z: 486.9 (M-H)- Exact mass: 488.0. 1H NMR (400 MHz, DMSO-d 6) ppm 1.22 (d, J=7.0 Hz, 3 H), 3.80 (s, 3 H), 3.95-4.15 (m, 1 H), 7.47 (td, J=9.0, 1.4 Hz, 1 H), 8.03 (td, J=8.9, 6.2 Hz, 1 H), 8.96 (d, J=8.8 Hz, 1 H), 10.22 (s, 1 Compound 315: 5-bromo-N-(3-cyano-2,4-difluoro-phenyl)fluoromethyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 181 (synthesized similarly as described for compound 181, but on a larger scale, 221 mg, 0.486 mmol) and NBS (129.9 mg, 0.73 mmol) were dissolved in DMF (1.5 mL) and acetonitrile (1.5 mL) and stirred overnight. Extra NBS (50 mg) was added and the e was stirred for 30 minutes. The reaction mixture was ted directly to column chromatography on a silica gel column chromatography system using a gradient from 10 till 100 % EtOAc in heptane. The product fractions were concentrated. The residue was crystallised from ol (10 mL) upon addition of water. The white crystals were filtered off and dried overnight in vacuo at 50°C, resulting in compound 315 (125 mg). Method D: Rt: 1.93 min m/z: 533.0 (M-H)- Exact mass: 534.0. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 197.6°C. 1H NMR (360 MHz, DMSO-d 6) ppm 1.22 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 3.95 - 4.08 (m, 1 H), 7.48 (s, 1 H), 7.98 - 8.07 (m, 1 H), 8.95 (d, J=8.8 Hz, 1 H), 10.28 (s, 1 H).

Compound 316: 3-cyano-N-(3-cyanofluoro-phenyl)-1,5-dimethyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Ethyl 3-fluoro-1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (211 mg, 0.59 mmol), potassium cyanide (190.9 mg, 2.93 mmol), DMA (5 mL, 54.0 mmol), 18-crown-6 (156.6 mg, 0.59 mmol) were heated at 165°C during 6 hours and further overnight at 150°C. The reaction mixture was concentrated. The obtained residue was dissolved in EtOAc (10/20 mL) The organic layer was dried over magnesium sulphate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The t fractions were concentrated yielding ethyl 3-cyano-1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole ylate (27 mg) as a clear oil which was used as such. Method D: Rt: 1.74 min m/z: 366.0 (M-H)- Exact mass: 367.1. Lithium bis(trimethylsilyl)amide in e (0.296 mL, 1 M, 0.296 mmol) was added to a mixture of ethyl 3-cyano-1,5-dimethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate (27mg, 0.07 mmol) and 5-aminofluoro-benzonitrile (13.1 mg, 0.10 mmol) in THF (2 mL) and d overnight. The reaction mixture was quenched TIP 296 PCT with NH4Cl solution (5 mL) and diluted with brine (5 mL), then extracted with EtOAc (20 mL).

The c layer was dried over magnesium sulphate, filtered and concentrated. The residue was dissolved in DMF (1 mL) and purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the e dissolved in ol (2 mL). Water was added untill crystallisation began. The crystals were filtered off and dried in vacuo at 50°C, resulting in compound 316 (8 mg). Method D: Rt: 1.78 min m/z: 456.1 (M-H)- Exact mass: 457.1. 1H NMR (360 MHz, DMSO-d6) ppm 1.20 (d, J=6.8 Hz, 3 H), CH3 overlapping DMSO , 3.72 (s, 3 H), 3.93 - 4.05 (m, 1 H), 7.59 (t, J=9.1 Hz, 1 H), 7.94 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 8.75 (d, J=9.0 Hz, 1 H), 11.16 (s, 1 H).

Compound 317: N-(3-cyanofluoro-phenyl)[[(1R)-2,2-difluoromethyl-propyl]sulfamoyl]- 3-fluoromethyl-pyrrolecarboxamide Ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (725 mg, 2.54 mmol), (2R)-3,3- difluorobutanamine hydrochloride (415.7 mg), NaHCO3 (853 mg, 10.2 mmol), itrile (10 mL) and molecular sieves 4A (3000 mg) were heated at 80°C for 18 hours in a pressure tube.

The reaction mixture was filtered and the solids on filter were washed with acetonitrile (2 x 10 mL). The filtrate was trated. The residue (1 g) was subjected to silica gel column chromatography using a gradient from 0 till 100 % EtOAc in e. The product ons were concentrated in vacuo at 50°C yielding ethyl 4-[[(1R)-2,2-difluoromethylpropyl ]sulfamoyl]fluoromethyl-pyrrolecarboxylate (882 mg) as a white powder. Ethyl 4-[[(1R)-2,2-difluoromethyl-propyl]sulfamoyl]fluoromethyl-pyrrolecarboxylate (150 mg, 0.42 mmol) and 5-aminofluorobenzonitrile (75.9 mg, 0.54 mmol) were dissolved in THF (5 mL). m bis(trimethylsilyl)amide (1.67 mL, 1 M, 1.67 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with sat. NH4Cl (aq;, 5 mL). The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were evaporated to s and the residue was purified by silica gel chromatography (ethyl acetate in heptane 0 to 100% and again with ethyl acetate in heptane 0 to 60%). The desired fractions were evaporated to dryness, the resulting residue was dissolved in refluxing isopropanol (7 mL) and sonicated to afford a suspension. The white solids were filtered and washed with isopropanol (1 mL) to afford compound 317 (115 mg) as off white powder. 1H NMR (400 MHz, DMSO-d6) ppm 1.07 (d, J=6.8 Hz, 3 H), 1.58 (t, J=19.1 Hz, 3 H), 3.45 - 3.61 (m, 1 H), 3.81 (s, 3 H), 7.48 - 7.54 (m, 1 H), 7.54 (t, J=9.2 Hz, 1 H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.04 - 8.37 (m, 1 H), 8.17 (dd, J=5.7, TIP 296 PCT 2.6 Hz, 1 H), 10.32 (br. s., 1 H). Method B: Rt: 0.98 min m/z: 431.1 (M-H)- Exact mass: 432.1.

Compound 318: N-(3-cyanofluoro-phenyl)[[(1S)-2,2-difluoromethyl-propyl]sulfamoyl]- 3-fluoromethyl-pyrrolecarboxamide nd 318 (111 mg) was prepared similarly as described for compound 317, using (2S)-3,3- difluorobutanamine hydrochloride instead of (2R)-3,3-difluorobutanamine hydrochloride.

Method B: Rt: 0.98 min m/z: 431.1 (M-H)- Exact mass: 432.1. 1H NMR (400 MHz, DMSO-d 6) ppm 1.07 (d, J=6.8 Hz, 3 H), 1.58 (t, J=19.1 Hz, 3 H), 3.48 - 3.61 (m, 1 H), 3.82 (s, 3 H), 7.52 (d, J=4.6 Hz, 1 H), 7.54 (t, J=9.2 Hz, 1 H), 7.96 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.10 - 8.28 (m, 1 H), 8.17 (dd, J=5.8, 2.8 Hz, 1 H), 10.34 (br. s., 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 167.9°C.

Compound 319: N-(3-cyanofluoro-phenyl)fluoromethyl[[1- (trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxamide A mixture ethyl rosulfonylfluoromethyl-pyrrolecarboxylate (640 mg, 2.20 mmol) 1-(trifluoromethyl)cyclobutanamine (1710mg, 12.29 mmol), NaHCO3 (553mg, 6.58 mmol), acetonitrile (12.8 mL, 245.1 mmol) and molecular sieves 4A (250 mg) was stirred and refluxed in total for 5 days (After 2 days another 4 equiv of 1-(trifluoromethyl)cyclobutanamine were added). The reaction mixture was filtered while still hot. The filtrate was concentrated.and the obtained residue was purified by column chromatography by silica gel chromatography using a nt from 10 to100% EtOAc in heptane. The product ons were concentrated in vacuo at 50°C yielding ethyl romethyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole carboxylate (631 mg) as white crystals. Method D: Rt: 1.90 min m/z: 371.3 (M-H)- Exact mass: 372.1. A solution of ethyl 3-fluoromethyl[[1- (trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylate (624 mg, 1.68 mmol), LiOH (120.4 mg, 5.03 mmol) in THF (10 mL) and water (distilled, 10 mL) was stirred ght. HCl (1M in H2O) (5.03 mL, 1 M, 5.03 mmol) was added and THF distilled off. The white precipitate was filtered off and dried overnight in vacuo at 50°C, resulting in 3-fluoromethyl[[1- TIP 296 PCT (trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylic acid (412 mg) Method D: Rt: 1.04 min m/z: 343.0 (M-H)- Exact mass: 344.0. 1H NMR (400 MHz, DMSO-d6)  ppm 1.82 (quin, J=8.1 Hz, 2 H), 2.26 - 2.35 (m, 2 H), 2.39 - 2.48 (m, 2 H), 3.82 (s, 3 H), 7.53 (d, J=4.8 Hz, 1 H), 8.67 (s, 1 H), 13.12 (br. s., 1 H). Et3N (0.23 mL, 1.62 mmol) was added to a e of 3-fluoro- 1-methyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylic acid (186 mg, 0.54 mmol), HATU (257. mg, 0.676 mmol) and 5-aminofluoro-benzonitrile (147.323 mg, 1.082 mmol) in DMF (2 mL) and the mixture was stirred 4 hours at 65°C. The reaction e was purified directly by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane.The product fractions were concentrated in vacuo yielding a white powder which was dried overnight in vacuo at 50°C. This powder was dissolved in warm ol (25 mL) and water was added untill crystallisation began. The white crystals were filtered off and dried in vacuo at 50°C overnight, resulting in compound 319 (157 mg). Method D: Rt: 1.96 min m/z: 461.3 (M-H)- Exact mass: 462.1. 1H NMR (400 MHz, 6)  ppm 1.78 - 1.91 (m, 2 H), 2.28 - 2.37 (m, 2 H), 2.41 - 2.48 (m, 2 H), 3.82 (s, 3 H), 7.50 - 7.58 (m, 2 H), 7.97 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.17 (dd, J=5.8, 2.8 Hz, 1 H), 8.71 (s, 1 H), 10.36 (s, 1 H).

Biological examples – anti-HBV activity of compounds of Formula (ID) The anti-HBV activity was measured using a stable transfected cell line, HepG2.2.15. This cell line was described to secrete relatively consistent high levels of HBV virion particles, which have been shown to cause both acute and chronic infection and disease in chimpanzees.

For the ral, assay cells were treated twice for three days with serially diluted nd in 96-well plates in duplicate. After 6 days of treatment the ral activity was determined by quantification of purified HBV DNA from secreted s using realtime PCR and an HBV specific primer set and probe.

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 cline (Tet-off system).

For the antiviral assay, HBV replication was induced, followed by a treatment with serially diluted compound in 96-well 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 specific primer set and probe.

Cytotoxicity of the compounds was tested using HepG2 cells, incubated for 4 days in the presence of compounds. The ity of the cells was assessed using a Resazurin assay. Results are displayed in Table 1.

TIP 296 PCT Table 1 HepG2 HepG2 HepG2 HepG2 HepG2 HepG2 Co. 2.15 117 4 days Co. 2.15 117 4 days No. EC50 (M) EC50 ( M) CC50 (M) No. EC50 (M) EC50 ( M) CC50 (M) 1 0.42 3.10 >25 33 0.03 0.04 >25 2 0.03 0.06 >25 34 0.03 <0.02 >25 3 0.07 0.10 >25 35 0.03 0.02 >25 4 0.10 0.06 >25 36 0.08 0.04 >25 0.03 0.02 >25 37 0.73 0.38 >25 6 0.02 0.02 >25 38 0.05 0.02 >25 7 0.12 0.10 >25 39 0.05 0.04 >25 8 0.02 0.02 >25 40 0.20 0.12 >25 9 0.01 0.03 >25 41 0.52 0.33 >25 0.11 0.08 >25 42 0.54 0.72 >25 11 0.03 0.02 >25 43 0.11 0.13 >25 12 0.12 0.06 >25 44 0.37 0.26 >25 13 0.46 0.14 >25 45 0.32 0.34 >25 13a 0.35 0.20 >25 46 0.12 0.17 >25 13b 1.01 0.46 >25 47 0.10 0.10 >25 14 0.04 0.02 >25 48 0.05 0.06 >25 0.16 0.13 >25 49 0.07 0.02 >25 16 0.06 0.03 >25 50 0.07 0.05 >25 17 0.03 0.02 >25 51 >1 >1 >25 18 <0.02 0.03 >25 52 0.26 0.33 >25 19 0.06 0.08 >25 53 0.26 0.18 >25 0.07 0.06 >25 54 0.20 0.25 >25 21 0.22 0.84 >25 55 0.21 0.11 >25 22 0.08 0.07 >25 56 0.02 <0.02 >25 23 0.02 0.13 >25 57 0.06 0.05 >25 24 0.20 0.30 >25 58 0.09 0.06 >25 0.34 0.23 >25 59 0.03 0.03 >25 26 0.14 0.26 >25 60 0.02 0.03 24.1 27 0.04 0.06 >25 61 >1 >25 28 0.10 0.14 >25 62 0.27 0.14 >25 29 0.15 0.21 >25 63 0.06 0.04 >25 0.45 0.33 >25 64 0.13 0.05 >25 31 0.13 0.39 >25 65 0.01 0.01 >25 32 0.18 0.34 >25 66 0.03 0.03 >25 TIP 296 PCT HepG2 HepG2 HepG2 HepG2 HepG2 HepG2 Co. 2.15 117 4 days Co. 2.15 117 4 days No. EC50 (M) EC50 ( M) CC50 (M) No. EC50 (M) EC50 ( M) CC50 (M) 67 0.02 0.03 >25 101 0.03 0.03 >25 68 0.07 0.07 >25 102 0.06 0.06 >25 69 0.03 0.07 >25 103 0.05 0.02 >25 70 0.02 0.04 >25 104 0.02 0.02 >25 71 0.10 0.13 >25 105 0.03 0.02 >25 72 0.01 0.01 >25 106 0.01 0.01 >25 73 0.10 14.1 107 0.01 0.01 >25 74 0.02 0.02 >25 108 0.01 >25 75 0.18 0.18 >25 109 0.24 0.10 >25 76 0.18 0.13 >25 110 0.02 0.03 >25 77 0.07 0.18 >25 111 0.007 0.007 >25 78 0.02 0.03 >25 112 0.06 0.09 >25 79 0.53 0.46 >25 113 0.03 0.02 >25 80 0.04 0.09 >25 114 0.10 0.05 >25 81 0.01 0.05 >25 115 0.30 0.11 >25 82 0.17 0.49 >25 116 0.03 0.02 >25 83 >1 1.35 >25 117 0.007 0.01 >25 84 0.46 0.61 >25 118 0.05 0.02 >25 85 0.03 0.05 >25 119 0.03 0.01 >25 86 0.37 0.35 >25 120 0.03 0.03 >25 87 0.96 >1 >25 121 0.05 0.04 >25 88 0.02 0.03 >25 122 0.07 >1 13.1 89 0.02 0.02 >25 123 0.04 0.04 >25 90 0.05 0.03 >25 124 0.04 0.04 >25 91 0.06 0.04 >25 125 0.19 0.08 16.7 92 0.04 0.03 >25 126 0.59 0.23 >25 93 0.03 0.03 >25 127 0.05 0.19 >25 94 0.009 0.01 >25 128 0.15 0.09 >25 95 0.13 0.06 >25 129 0.17 0.08 >25 96 0.01 0.03 23.7 130 0.09 0.15 >25 97 0.03 0.03 >25 131 0.01 0.01 >25 98 0.81 0.54 >25 132 0.08 0.07 >25 99 0.13 0.10 >25 133 0.04 0.08 >25 100 0.06 0.05 12.2 134 0.18 0.13 >25 TIP 296 PCT HepG2 HepG2 HepG2 HepG2 HepG2 HepG2 Co. 2.15 117 4 days Co. 2.15 117 4 days No. EC50 (M) EC50 ( M) CC50 (M) No. EC50 (M) EC50 ( M) CC50 (M) 135 0.02 0.26 >25 166b 0.31 0.17 21.3 136 0.06 0.06 >25 167 0.12 0.31 >25 137 0.03 0.04 16.5 168 0.12 0.32 >25 138 0.10 0.03 >25 169 0.12 0.07 11.2 139 0.05 0.03 >25 169a 0.14 0.05 16.1 140 0.10 0.06 >25 169b 0.04 0.03 17.1 141 0.04 0.15 >25 170 <0.005 0.005 >100 142 0.15 0.42 >25 171 0.02 0.02 >25 143 0.05 0.15 >25 172 0.10 0.08 >25 144 0.05 0.07 >25 173 0.21 0.32 >25 145 0.04 0.03 >25 174 0.08 0.04 >25 146 0.07 0.04 >25 175 0.07 0.13 >25 147 0.08 0.04 >25 176 0.50 0.37 >25 148 0.11 0.07 >25 177 0.33 0.26 >25 149 0.04 0.03 >25 178 0.04 0.09 >25 150 0.09 0.06 >25 179 0.30 0.27 >25 151 0.08 0.07 >25 180 0.01 0.02 >25 152 0.24 0.08 >25 181 0.008 0.006 >25 153 0.27 0.15 >25 182 0.01 0.03 >25 154 0.13 0.08 >25 183 0.02 0.01 >25 155 0.03 0.05 >25 184 0.008 0.006 >25 156 0.04 0.03 >25 185 0.006 0.005 >25 157 0.08 0.05 >25 186 0.008 0.005 >25 158 0.12 0.36 >25 187 0.008 0.006 >25 159 0.09 0.81 >25 188 0.04 0.03 >25 160 0.16 0.13 >25 189 0.007 0.007 11.3 161 >1 0.91 >25 190 0.09 0.10 >25 162 >1 0.89 >25 191 0.18 0.16 >25 163 0.18 0.11 14.3 192 0.57 0.19 >25 164 0.13 0.13 >25 193 0.14 0.11 >25 165a 0.15 0.04 9.3 194 0.09 0.05 >25 165b 0.12 0.02 4.8 195 0.04 0.04 >25 166 0.14 0.12 >25 196 0.10 0.08 >25 166a 0.14 0.10 17.9 197 0.12 0.09 >25 TIP 296 PCT HepG2 HepG2 HepG2 HepG2 HepG2 HepG2 Co. 2.15 117 4 days Co. 2.15 117 4 days No. EC50 (M) EC50 ( M) CC50 (M) No. EC50 (M) EC50 ( M) CC50 (M) 198 0.15 0.08 >25 230 0.008 0.03 >25 199 0.006 0.008 >25 231 0.04 0.03 >25 200a 0.10 0.05 >25 232 0.02 0.02 >25 200b 0.09 0.10 >25 233 0.09 0.16 >25 201 0.07 0.02 >25 234 0.02 0.03 >25 202 0.03 0.02 >25 235 0.01 0.01 >25 203 0.38 0.47 >25 236a 0.02 0.05 >25 204 0.65 0.62 >25 236b 0.06 0.05 >25 205 0.08 0.03 13.0 237 0.08 0.10 >25 206 0.03 0.09 >25 238 0.10 0.11 >25 207 0.05 0.14 >25 239 0.02 0.01 >25 208 0.20 0.66 >25 240 0.02 0.05 >25 209 0.09 0.09 >25 241 0.01 0.01 >25 210 0.05 0.05 >25 242 0.20 0.30 >25 211 0.04 0.04 >25 243 0.11 0.10 >25 212 0.09 0.04 >25 244 0.14 0.53 >25 213 0.21 0.31 >25 245 0.04 0.04 >25 214 0.06 0.02 >25 246 0.05 0.06 >25 215 0.02 0.010 >25 247 0.03 0.03 >25 216 0.18 0.46 >25 248 0.03 0.07 >25 217 0.005 0.005 >25 249 0.07 0.18 1.7 218 0.009 0.007 >25 250 0.007 0.40 20.0 219 0.01 0.009 >25 251 0.01 0.06 >25 220 0.10 0.04 >25 252 0.05 0.08 >25 221 0.007 0.006 >25 253 0.01 0.01 >25 222 0.004 0.009 >25 254 0.05 0.05 >25 223 0.12 0.09 >25 255 0.09 0.10 >25 224 0.22 0.26 >25 256 0.02 0.03 >25 225 0.07 0.07 >25 257 0.08 0.09 >25 226 0.19 0.21 >25 258 0.03 0.02 >25 227 0.02 0.04 >25 259 0.05 0.05 >25 228a 0.03 0.03 >25 260 0.07 0.09 >25 228b 0.03 0.03 >25 261 0.04 0.13 >25 229 0.004 0.004 >25 262 0.02 0.02 >25 TIP 296 PCT HepG2 HepG2 HepG2 HepG2 HepG2 HepG2 Co. 2.15 117 4 days Co. 2.15 117 4 days No. EC50 (M) EC50 ( M) CC50 (M) No. EC50 (M) EC50 ( M) CC50 (M) 263 0.005 0.008 >25 292 0.03 15.5 264 0.09 0.13 >25 293 0.02 0.05 >25 265 0.01 0.03 >25 294 0.04 0.10 >25 266 0.02 0.03 >25 295 0.02 0.03 >25 267 0.006 0.009 >25 296 0.10 0.23 >25 268 0.005 0.006 >25 297 0.04 0.09 22.6 269 0.05 0.07 >25 298 0.02 0.05 23.7 270 0.06 0.11 >25 299 0.009 >25 271 0.009 0.02 >25 300 0.008 14.2 272 0.30 0.76 >25 301 0.007 >25 273 0.42 0.70 >25 302 0.03 >25 274 0.02 0.04 19.4 303 >12.5 >25 275 0.60 0.70 >25 304 0.01 >25 276 0.01 0.01 >25 305 0.17 0.35 >25 277 0.03 0.04 >25 306 0.03 0.06 >25 278 0.006 0.01 >25 307 0.03 >25 279 <0.004 0.005 >25 308 0.01 >25 280 0.005 0.06 >25 309 0.53 0.32 >25 281 <0.004 0.007 >25 310 0.07 0.16 >25 282 <0.005 0.005 >25 311 0.06 >25 283 0.02 0.03 >25 312 0.06 >25 284 0.009 >25 313 0.02 0.05 >25 285 0.007 >25 314 0.007 >25 286 0.005 21.9 315 0.007 >25 287 0.004 0.005 >25 316 0.05 0.05 >25 288 0.007 0.01 >25 317 0.006 >25 289 0.04 0.05 >25 318 0.019 >25 290 0.02 >25 319 <0.004 >25 291 0.42 0.39 >25 TIP 296 PCT

Claims (51)

1. Claims

2. A compound of Formula (ID) 5 or a stereoisomer or tautomeric form f, wherein: Each X independently represents CR7; Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, 10 Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; Rd is Hydrogen or Fluoro; 15 R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8 optionally 20 tuted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 ed mono or polycyclic saturated ring ally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C2-C6alkyl optionally being substituted with one or more substituents each independently selected from 25 the group ting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and C1-C4alkyl optionally substituted with R10; TIP 296 PCT R7 represents en, -CN, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, - CF3, C1-C3alkyl optionally substituted with methoxy, C2-C3alkenyl or C3-C4cycloalkyl; 5 R8 represents 3-7 membered saturated ring optionally ning one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 ed saturated ring optionally being substituted with one or more C1-C4alkyl optionally substituted with R10; 10 R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or lkyl; or a pharmaceutically acceptable salt or a solvate f wherein such compound is or . 20 2. A compound according to claim 1 with Formula (IB)

3. A compound according to any one of the previous claims wherein R4 is methyl.

4. A compound according to any one of the previous claims wherein R6 contains a 25 3-7 membered saturated ring optionally ning one oxygen. TIP 296 PCT

5. A compound according to any one of the previous claims wherein R6 is a 4 or 5 membered saturated ring containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with C1-C4alkyl optionally substituted with R10.

6. A compound according to any one of claims 1 to 3 wherein R6 comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl n such C3-C6cycloalkyl is substituted with one or more Fluoro or substituted with lkyl substituted with one or more Fluoro, 10 or wherein R6 comprises a C3-C6cycloalkyl ally substituted with one or more Fluoro and/or substituted with C1-C4alkyl optionally substituted with one or more Fluoro.

7. A compound according to claim 6 wherein R6 is a branched C3-C6alkyl substituted 15 with one or more Fluoro.

8. A compound according to any one of the us claims wherein Rb is Hydrogen or . 20

9. A compound according to any one of the us claims wherein Ra and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, CN and methyl.

10. A compound according to any one of the previous claims with Formula (IC) or a stereoisomer or eric form thereof, wherein: X represents CR7; TIP 296 PCT Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; 5 R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group ting of C2-C6alkyl, C1-C4alkyl-R8 optionally 10 substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic saturated ring optionally containing one or more atoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C2-C6alkyl optionally being tuted with one or more substituents each independently 15 selected from the group consisting of Hydrogen, -OH, Fluoro, oxo, R9, R10 and lkyl optionally substituted with R10; R7 represents hydrogen, -CN, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl or C3-C4cycloalkyl; R8 represents 3-7 membered saturated ring optionally containing one or more heteroatoms each ndently selected from the group ting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, ethyl, -OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; 30 R11 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof, wherein such compound is not TIP 296 PCT or .

11. A compound according to claim 10, wherein R4 is C1-C3alkyl; 5 R6 is selected from the group consisting of C2-C6alkyl ally being substituted with one or more Fluoro; and R7 represents hydrogen, Fluoro, Chloro or C1-C3alkyl.

12. A compound according to any one of the previous claims wherein R4 represents 10 methyl, R6 is C2-C6alkyl tuted with one or more fluoro, R7 represents Hydrogen and Ra, Rb and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, methyl and –CN.

13. The compound according to claim 1, n the compound is 15 or a pharmaceutically acceptable salt or a solvate f.

14. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a 20 solvate thereof. TIP 296 PCT

15. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate thereof. 5

16. The compound ing to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate thereof.

17. The compound according to claim 1, wherein the compound is 10 or a pharmaceutically acceptable salt or a solvate thereof.

18. The compound according to claim 1, n the compound is or a pharmaceutically acceptable salt or a 15 solvate thereof. TIP 296 PCT

19. The nd according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate thereof. 5

20. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate thereof.

21. The compound according to claim 1, wherein the compound is 10 or a ceutically able salt or a solvate thereof.

22. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or 15 a solvate thereof. TIP 296 PCT

23. The compound according to claim 1, n the compound is or a pharmaceutically acceptable salt or a solvate thereof. 5

24. The nd according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate thereof.

25. The compound according to claim 1, wherein the compound is 10 or a pharmaceutically able salt or a solvate thereof.

26. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or 15 a solvate thereof. TIP 296 PCT

27. The compound according to claim 1, wherein the compound is or a pharmaceutically able salt or a solvate thereof. 5

28. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or a solvate f.

29. The compound according to claim 1, wherein the compound is 10 or a pharmaceutically acceptable salt or a solvate thereof.

30. The nd according to claim 1, wherein the compound is O H N (S ) F NH S F O N N or a pharmaceutically acceptable salt 15 or a solvate thereof. TIP 296 PCT

31. The compound according to claim 1, wherein the nd is or a pharmaceutically acceptable salt or a solvate thereof. 5

32. A method for preparing a nd of Formula (ID): as defined in claim 1, wherein the method comprises the step of providing a compound of Formula (Vd): 10 ; and reacting said compound of Formula (Vd) with: (a) a compound of Formula (IV): 15 to form a compound according to Formula (VId): followed by reacting the compound ing to Formula (VId) with a TIP 296 PCT compound according to Formula (VII): or reacting said nd of Formula (Vd) with (b) a compound of Formula (IX): 5 ; or reacting said compound of Formula (Vd) with (c) a compound according to Formula (XI): 10

33. The method according to claim 32, wherein in (a) the compound of Formula (Vd) is slowly added to a refluxing solution of the compound of Formula (IV) in toluene.

34. The method according to claim 32, wherein in (a) the compound of Formula 15 (VId) is reacted with the compound of Formula (VII) in a solvent like itrile in the ce of an inorganic base like sodium bicarbonate.

35. The method according to any one of claims 32 to 34, n in (b) the compound of Formula (IX) is coupled with the compound of Formula (Vd) in the 20 presence of an activating reagent like for example HATU and an organic base like ylamine or DIPEA.

36. The method according to any one of claims 32 to 35, wherein in (c) the compound of Formula (XI) is coupled with a compound of Formula (Vd) in the 25 ce of a base like for example lithium bis(trimethylsilyl)amide, in a solvent like for example THF. TIP 296 PCT

37. The method according to claim 32, wherein the compound of Formula (IX) is obtained by: (d) reacting a compound of Formula (VIII) with a compound of Formula 5 (VII) as defined in claim 1, for example in an organic solvent like CH2Cl2 in the presence of an organic base like triethylamine or DIPEA; wherein the compound of Formula (VIII) is ; or (e) hydrolyzing a compound of Formula (XI), for example with LiOH in 10 THF/H2O, followed by acidification.

38. The method according to claim 37, wherein the compound of a (VIII) is prepared by chlorosulfonation of a nd of Formula (XIII): 15 ; n for example the chlorosulfonation is d out by either treatment of the compound of Formula (XIII) with chlorosulfonic acid at for example 0°C, optionally followed by quenching with water; or by treating the compound of Formula (XIII) with 1-1.2 equivalents of 20 sulfonic acid in CH2Cl2, resulting in a sulfonic acid derivative, and wherein the ic acid derivative is converted to the compound of Formula , for example by treatment with SOCl2 at 80°C.

39. The method according to claim 32 or 37, wherein the compound of Formula 25 (XI) is prepared by reacting a compound of Formula (X) with a compound of Formula (VII), for example in an organic t like acetonitrile in the presence of an organic base like for example triethylamine or DIPEA, or an inorganic base like for example sodium bicarbonate; wherein the compound of Formula (X) is: TIP 296 PCT Formula (X).

40. The method according to claim 39, wherein the compound of Formula (X) is 5 prepared by the sulfonation of a compound of Formula (XII): wherein for example the chlorosulfonation is carried out by either treatment of the compound of Formula (XII) with chlorosulfonic acid at for example 0°C, optionally followed by quenching with water; or 10 by treating the compound of Formula (XII) with 1-1.2 lents of chlorosulfonic acid in CH2Cl2, resulting in a sulfonic acid derivative, and wherein the sulfonic acid derivative is converted to the compound of Formula (X), for example by treatment with SOCl2 at 80°C. 15

41. The method according to claim 32, n the compound of Formula (IV) is prepared by treating a compound according to Formula (VIII) as defined in claim 6 with oxalyl chloride in .

42. The method according to claim 32, wherein the compound of Formula (ID) is , , TIP 296 PCT , , , , , or TIP 296 PCT O H N (R ) F NH S F O N N , or pharmaceutically able salt or a solvate thereof.

43. A compound ing to Formula (VId): wherein X, Ra-Rd and R4 are as defined in claim 1.

44. A compound of Formula (VId) according to claim 43, wherein the compound is 5-[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride.

45. A compound according to any one of claims 1 to 31 and 43-44 for use as a medicament.

46. The use of a nd according to any one of claims 1 to 31 and 43-44 in the 15 manufacture of a medicament in the prevention or treatment of an HBV infection in a mammal.

47. A pharmaceutical composition comprising a nd according to any one of claims 1 to 31 and 43-44, and a pharmaceutically acceptable carrier.

48. A compound according to any one of claims 1 to 31, substantially as herein described with reference to any one of the examples. TIP 296 PCT

49. The use according to claim 46, substantially as herein described with reference to any one of the examples.

50. A pharmaceutical composition according to claim 47, substantially as herein 5 described with reference to any one of the examples.

51. A method as claimed in any one of claims 32-42, substantially as herein described with nce to any one of the examples.