NZ753038B2 - Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B - Google Patents

Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B Download PDF

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NZ753038B2
NZ753038B2 NZ753038A NZ75303814A NZ753038B2 NZ 753038 B2 NZ753038 B2 NZ 753038B2 NZ 753038 A NZ753038 A NZ 753038A NZ 75303814 A NZ75303814 A NZ 75303814A NZ 753038 B2 NZ753038 B2 NZ 753038B2
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compound
pct
tip
mmol
methyl
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NZ753038A
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NZ753038A (en
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Geerwin Yvonne Paul Hache
Stefaan Julien Last
Gowan David Craig Mc
Pierre Jean Marie Bernard Raboisson
Geert Rombouts
Koen Vandyck
Wim Gaston Verschueren
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Janssen Sciences Ireland Uc
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Abstract

Inhibitors of HBV replication of Formula (IA) 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

SULPHAMOYLPYRROLAMIDE DERIVATIVES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B Background Art The Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). 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 ribed. Once encapsidated, the pregenomic RNA ), which also codes for core n 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 , and it is endemic in China. HBV has ed approximately 2 n 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 chronic 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, adefovir, 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 problems which HBV direct antivirals may encounter are ty, mutagenicity, lack of ivity, poor efficacy, poor ilability, and difficulty of synthesis.
There is a need for additional HBV inhibitors that may overcome at least one of these disadvantages or that have additional ages such as increased potency or an increased safety window. ption of the Invention The present invention and the invention of NZ 713201, from which this application was divided, relate generally to a compound of Formula (ID) 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, 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 lkyl, C1-C4alkyl-R8 optionally substituted with one or more Fluoro, C1-C4alkyl-R9 ally 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 ed saturated ring or C2-C6alkyl 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 en, -CN, Fluoro, Chloro, Bromo, -CHF2, ethyl, -CH2F, -CF3, C1-C3alkyl optionally substituted with methoxy, C2-C3alkenyl 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 tuted with one or more C1-C4alkyl optionally substituted with R10; R9 represents, lkyloxy, ethyl, -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 particular aspect, the present invention es a compound of Formula (IA) or a isomer or eric 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, C1-C3alkyl and C3-C4cycloalkyl; 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 substituted with one or more (followed by page 3a) -3asubstituents 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, ethyl, -CH2F, -CF3, C1-C3alkyl or C3-C4cycloalkyl; 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 ally being substituted with one or more C1-C4alkyl optionally substituted with R10; R9 ents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -C(=O)-N(R11)2; R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 ents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof wherein such compound is not or .
The description of the present invention and the invention of NZ 713201 are retained herein for clarity and completeness.
The invention further relates to a pharmaceutical composition sing a compound of Formula (ID), and a pharmaceutically acceptable r.
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 .
In a further aspect, the invention relates to a combination of a compound of Formula (ID), and another HBV inhibitor.
[FOLLOWED BY PAGE 3b] TIP 296 PCT -3b- The pharmaceutical composition, use and combination of compounds of Formula (ID) as provided according to the t invention includes the pharmaceutical composition, 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 hydrocarbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 3. In case C1-3alkyl is coupled to a r radical, it refers to a Formula CnH2n. C1-3alkyl groups comprise from 1 to 3 carbon atoms, more ably 1 to 2 carbon atoms. C1-3alkyl includes all linear, or branched alkyl groups with [FOLLOWED BY PAGE 4] TIP 296 PCT 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 .
The invention further s to a pharmaceutical composition comprising a compound of Formula (ID), and a ceutically acceptable carrier.
The invention also relates to the nds 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 nd of Formula (ID), and another HBV inhibitor.
The pharmaceutical composition, use and combination of compounds of Formula (ID) as provided according to the t invention includes the ceutical composition, use and combination of and .
Definitions The terms lkyl" and C1-Cxalkyl can be used interchangeably.
The term "C1-3alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 3. In case C1-3alkyl 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 , 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 ted 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 ht 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 radical 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 l having the Formula -- ORc wherein Rc is C1-3alkyl. Non-limiting examples of le C1-3alkyloxy include methyloxy (also methoxy), ethyloxy (also ), propyloxy and isopropyloxy.
As used , 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 generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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 optionally contains one or more heteroatoms, such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N 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 include oxetane, and tetrahydrofuranyl.
It should be noted that different isomers of the various heterocycles may exist within the tions as used throughout the specification. For example, if not structurally specified according to the chemical name or structure, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.
The term halo and halogen are generic 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 definitions may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl includes 2-pyridyl, 3-pyridyl and dyl; pentyl includes yl, 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 position 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 le (e.g. halogen or C1-4alkyl) occurs more than one time in any constituent, each definition is independent.
For therapeutic use, the salts of the compounds of Formula (ID) are those wherein the counter ion is pharmaceutically or physiologically able. However, salts having a pharmaceutically unacceptable counter ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of Formula (ID). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable or physiologically tolerable addition salt forms which the nds of the t invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or c acids such as, for e, , aspartic, dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, , pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, ic, , esulfonic, 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. Examples of such forms are e.g. hydrates, alcoholates and the like.
The t compounds may also exist in their tautomeric forms For example, eric forms of amide (-C(=O)-NH-) groups are iminoalcohols (-C(OH)=N-). Tautomeric 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 sequence of bonds but having different three-dimensional structures which are not TIP 296 PCT interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound.
All stereochemically isomeric forms of the compounds of the present invention 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 mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic lar structure of said compounds or intermediates. 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 isomeric 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 reomeric excess of the mixture in question.
Pure stereoisomeric forms of the nds 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 ive crystallization of their diastereomeric salts with lly active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic ques using chiral stationary phases. Said pure stereochemically ic forms may also be derived from the corresponding pure stereochemically ic forms of the appropriate ng materials, provided that the reaction occurs stereospecifically. Preferably, if a specific isomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ omerically pure ng materials.
The diastereomeric forms of a (ID) can be obtained separately by conventional methods.
Appropriate physical separation methods 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 e and without limitation, isotopes of Hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
Detailed description of the invention Whenever used hereinafter, the term unds of formula (ID)", or "the present compounds" " compounds of the present invention" or similar term is meant to include the compounds of general formula (ID), (IA), (IB), (IC), (I), (Ia), (II), (III) salts, stereoisomeric forms and racemic mixtures or any subgroups thereof.
In a first , the present invention relates to a compound of Formula (ID) 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, lkyl 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 ally containing one or more TIP 296 PCT 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, Fluoro, Chloro, Bromo, -CHF2, -CF2-methyl, -CH2F, -CF3, C1-C3alkyl optionally substituted with methoxy, C2-C3alkenyl 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 lkyl optionally tuted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -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 e thereof wherein such compound is not or .
In a further aspect, aspect, the t 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 consisting of Hydrogen, , Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; TIP 296 PCT 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 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 ndently ed 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, -CN, Fluoro, , 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, -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 one embodiment, the present invention relates to a compound Formula (IC) TIP 296 PCT or a stereoisomer or tautomeric form thereof, X represents CR7; Ra, Rb and Rc are ndently selected from the group consisting of en, Fluoro, Bromo, Chloro, -CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; R4 is Hydrogen, C1-C3alkyl or C3-C4cycloalkyl; R5 is en; 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 clic 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 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 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 tuted with one or more C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, ethyl, -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 e thereof, wherein such compound is TIP 296 PCT not or .
Of interest are compounds of the present invention wherein: Ra, Rb and Rc are independently selected from the group ting of Hydrogen, , 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 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 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; R7 represents hydrogen, -CN, Fluoro, 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 up thereof as mentioned in any of the other embodiments wherein one or more of the ing 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 represents hydrogen , Chloro or lkyl, preferably hydrogen Fluoro, Chloro or methyl. (b) Rb is Hydrogen or Fluoro. (c) Ra and Rc are independently selected from the group consisting of Hydrogen, , 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 Hydrogen, , 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 containing one oxygen, such 4 or 5 membered saturated ring optionally tuted with C1-C4alkyl optionally substituted with R10. (f) R6 comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or wherein R6 comprises 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 substituted with C1-C4alkyl optionally tuted with one or more Fluoro. (g) R6 comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or 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. More specifically, R6 is a branched C3-C6alkyl tuted with one or more . (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, Fluoro, 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, n: 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 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 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 tuents 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, CN, Fluoro or ; 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, such 3-7 ed ted ring optionally being substituted with one or more C1-C4alkyl optionally substituted with R10; R9 represents, C1-C4alkyloxy, -SO2-methyl, -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 present invention relates 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 Hydrogen, Fluoro, 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 ting of C2-C6alkyl, C1-C4alkyl-R8 ally substituted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, and a 3-7 membered mono or polycyclic 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 or C2-C6alkyl optionally being substituted with one or more substituents each independently selected from the group ting 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, 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 r , the invention relates to nd of Formula TIP 296 PCT 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, Fluoro, 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 lkyl, 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 clic 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 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 ting 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 ents, C1-C4alkyloxy, -SO2-methyl, -C(=O)-OR11 or -N(R11)2 R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; TIP 296 PCT R11 represents hydrogen or lkyl; 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 Hydrogen or Fluoro.
Furthermore, compounds according to the invention are described wherein Ra and Rc are independently selected from the group consisting of Hydrogen, Fluoro, Chloro -CN and methyl.
Preferably, Rb is en or Fluoro and Ra and Rc are independently selected from the group consisting of en, Fluoro, Chloro and -CN.
In one embodiment of compounds of the present invention, 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 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 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 ed saturated ring optionally containing one , more specifically R6 is a 5 membered ted ring containing one oxygen, such 5 membered saturated ring optionally substituted with C1-C4alkyl optionally substituted with R10.
In one embodiment of compounds of the present invention,R6 comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or R6 comprises a ycloalkyl n such C3-C6cycloalkyl is substituted with one or more Fluoro or tuted 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 compound of Formula (I) R6 O X N N S H R3 R5 O X N (I) or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents CR7; R2 is Hydrogen, CN, Chloro or ; R1 and R3 are independently selected from the group consisting of Hydrogen, Fluoro, Bromo, , -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 ed from the group ting of C2-C6alkyl, C1-C4alkyl-R8 ally tuted with one or more Fluoro, C1-C4alkyl-R9 optionally substituted with one or more Fluoro, 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 ted 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 tuted 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, -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 en or C1-C3alkyl; 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 en, CN, or Fluoro; R1 and R3 are independently selected 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; R4 is en or C1-C3alkyl; R5 is Hydrogen; R6 is selected from the group consisting 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 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; 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 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 lkyl.
In one r embodiment, compounds of Formula (I) are sed wherein: TIP 296 PCT Each X independently represents CR7; R2 is Hydrogen or Fluoro; R1 and R3 are independently ed from the group consisting of Hydrogen, Fluoro, Bromo, Chloro, 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 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 optionally being substituted with one or more tuents each independently selected from the group consisting of Hydrogen, OH, Fluoro, and C1-C4alkyl; R7 represents Hydrogen, methyl, Fluoro or Chloro; 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.
In one embodiment, for compounds according to Formula (I), at least one X represents CH.
In a further aspect, the ion provides compounds of Formula (Ia) R6 O N N S H R3 R5 N (Ia) or a stereoisomer or tautomeric form f, wherein: R2 is Hydrogen, CN or Fluoro; R1 and R3 are independently selected from the group consisting of en, Fluoro, Bromo, , -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 C1-C3alkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8, C1-C4alkyl-R9 and a 3- 7 membered saturated ring optionally containing one or more heteroatoms each ndently 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 en, -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 ndently 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 ents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 ents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salts or a e thereof.
In a sub-embodiment, compounds of Formula (I) are disclosed wherein: R2 is Hydrogen or ; R1 and R3 are independently selected from the group consisting of Hydrogen, , 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 membered saturated ring or C1-C6alkyl optionally being substituted with one or more tuents each ndently selected from the group consisting of Hydrogen, OH and C1-C4alkyl.
In another embodiment, compounds of the invention are represented by Formula (II) R6 O N N R3 S H R5 N O (II) R4 .
In yet another embodiment, nds 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 C1-C3alkyl; R5 is Hydrogen; R6 is selected from the group consisting of C2-C6alkyl, C1-C4alkyl-R8, C1-C4alkyl-R9 and a 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 membered saturated ring or -C2- l optionally being substituted with one or more substituents each independently ed from the group consisting of Hydrogen, -OH, Fluoro, oxo and C1-C4alkyl ally substituted with R10; R7 represents en, methyl, Fluoro or Chloro; TIP 296 PCT 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 tuted with one or more lkyl optionally substituted with R10; R9 ents -OR11 or -N(R11)2 R10 represents -CN, -OH, Fluoro, -CHF2, -CH2F or -CF3; R11 represents hydrogen or C1-C3alkyl.
In one embodiment, compounds of the present invention are disclosed wherein R1 is selected from either Bromo, Chloro, Fluoro or , 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 further embodiment, each of R1, R2 and R3 are n, preferably Bromo, Fluoro or Chloro, even more preferably Fluoro or Chloro.
In yet another embodiment, 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 n R6 comprises a C1-C4alkyl substituted with one or more Fluoro. In addition, compounds of the present invention are disclosed wherein R6 comprises a ed C3-C6alkyl substituted with one or more Fluoro, or n R6 comprises a C3-C6cycloalkyl n such C3-C6cycloalkyl is substituted 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 hydrogen tuent 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 ing to the invention are compound or a stereoisomer or tautomeric form f with a formula as represented in the sis of compounds section and of which the activity is displayed in Table 1.
In a further aspect, the present invention concerns a pharmaceutical composition sing a eutically or prophylactically effective amount of a compound of Formula (ID) as specified herein, and a pharmaceutically acceptable carrier. A prophylactically effective amount in this context is an amount sufficient to t HBV infection in subjects being at risk of being infected. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV ion, or to eradicate HBV infection, in infected subjects. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of Formula (ID), as specified herein.
Therefore, the compounds of the present invention or any subgroup f may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually ed for systemically administering drugs. To prepare the pharmaceutical compositions of this ion, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a ceutically 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 ion. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be ed 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 es represent the most ageous 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 included. able solutions, for example, may be prepared in which the carrier ses 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 included are solid form ations intended to be converted, shortly before use, to liquid form TIP 296 PCT preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally ed 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 tion or insufflation in the form of a solution, a suspension or a dry powder using any art-known ry system.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a ermined ty of active ingredient calculated to produce the desired eutic effect in ation 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 suspensions and the like, and segregated multiples 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 sis, 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 looded 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 infection by HBV, said method comprising 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 medicine or method of treatment comprises the systemic administration to HBV infected subjects or to subjects susceptible to HBV infection of an amount effective to combat the ions associated with HBV infection or an amount ive to prevent HBV infection.
The t 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 ive 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 ed 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 ient per unit dosage form.
The present invention also concerns combinations of a compound of Formula (ID) or any subgroup f, as ied herein with other anti-HBV agents. The term nation" 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 ion (herein designated as BV agent), as a combined preparation for simultaneous, separate or sequential use in treatment of HBV ions. In an embodiment, the invention ns combination of a nd of Formula (ID) or any subgroup thereof with at least one anti-HBV agent. In a particular embodiment, the invention concerns ation of a compound of a (ID) or any subgroup thereof with at least two anti-HBV agents. In a particular ment, the invention concerns combination of a compound 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 .
The term anti-HBV agent also includes compounds e of treating HBV infection via immunomodulation. Examples of immunomodulators are interferon-α (IFN-α), pegylated 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 compound, more specifically a ike receptor 7 and/or 8 agonist.
The combination of previously known anti-HBV agents, such as interferon-α ), pegylated interferon-α, 3TC, adefovir or a ation 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 substituent or reactive species that is suitable for transformation into any substituent according to the present invention without undue burden for the person skilled in the art.
A possible synthesis of compound of l 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 compounds 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 a (VII), resulting in a compound of general formula (I), for example in a solvent like acetonitrile in the ce of an inorganic base like sodium bicarbonate or as further 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 chloride (VIII) (for example ed according to the synthesis described for compound 2) is d 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 d 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 formula IX, is via ester X as described in scheme 3. Reaction of X with amine VII, for example in an c solvent like acetonitrile in the presence of an organic base like for example triethylamine or DIPEA, or an inorganic base like for example sodium bicarbonate, resulting in a compound of general formula XI, followed by hydrolysis of the ester, for example with LiOH in THF/H2O, followed by acidification, s in a nd of general formula IX.
A compound of l formula VIII can be converted to a compound of general formula 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 example 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 tive, for example by treatement of compound XII with 1-1.2 equiv chlorosulfonic acid in , the resulting ic acid derivative can be converted the sulfonyl chloride compound X, for e by treatement with SOCl2 at 80°C.
Scheme 5 TIP 296 PCT Scheme 5a Alternatively a compound of general formula (IA) might be obtained as described in scheme 5.
A nd of general formula XI can be coupled with a compound of general formula Va in the presence of a base like for example lithium bis(trimethylsilyl)amide, in a solvent like for example THF, resulting in the ion of a nd of l formula (IA). rly, a nd of l formula ID can be prepared as described in scheme 5a.
General procedure LCMS methods The High Performance Liquid Chromatography (HPLC) ement was performed using a LC pump, a diode-array (DAD) or a UV or 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 source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic lar weight (MW). Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]-, etc.). All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "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 mL/min; 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 Waters: 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® NH4 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 , A in 0.90min, DAD and 5% CH3CN 55 2.1*10 to 5% A in SQD B: CH3CN 0mm) 0.5min Synthesis of nds: 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 stirred for 3 hours. The reaction e was treated with 1M HCl (50 mL). The precipitate was filtered off and was tallized from hot acetonitrile (50 mL). The solid was filtered and dried ght 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 amide HN F S HN N O A e of 4-(isopropylsulfamoyl)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 triethylamine (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 sulphate, filtered and concentrated. The obtained 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- )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 e was stirred over weekend at room temperature. The reaction mixture was concentrated yielding 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride 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 chloride (3963 mg, 16.37 mmol) in toluene (200 mL) at reflux. The reaction mixture was ed 1 hour and allowed to cool to room temperature overnight. The formed precipitate was filtered and dried in vacuo at 50°C ing 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 fluoromethyl-phenyl)carbamoyl]- 1-methyl-pyrrolesulfonyl de (2250 mg). The reaction mixture was d 15 minutes.
More D-alaninol (1.5 eq) and DIPEA (2 eq) were added and the reaction mixture was stirred 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 obtained residue was purified by column chromatography on silica using a nt from 10 to 100% EtOAc in heptane. The product fractions were trated 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: N-(4-fluoromethyl-phenyl)methyl[[(3S)-tetrahydrofuranyl]- sulfamoyl]pyrrolecarboxamide O F H O (S) S N O N A e of (S)-Tetrahydrofurylamine enesulfonate 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 stirred overnight. The reaction mixture was washed with 1M HCl (3 x), water and NaHCO3 solution. The organic layer was dried over MgSO4, ed and concentrated. The residue was purified by column chromatography on silica using a nt from 10 to 100% EtOAc in heptane. The product fractions were concentrated yielding nd 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)- oyl]pyrrolecarboxamide HN S N O O A mixture of 3-methyloxetanamine hydrochloride (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 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, 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]- sulfamoyl]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 ght. 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 e was purified by column chromatography on silica using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated ng 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 reaction mixture was washed with 1M HCl (3 x), water and NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The obtained e was recrystallized by slowly adding heptanes to warm EtOAc (50 mL) solution of compound 2. Compound 2 was ed off as white solid and dried in vacuo at 50°C (357 mg).
Compound 7: luoromethyl-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 on mixture was stirred and refluxed for 1 hour. The reaction mixture was cooled to ~50°C and the solvent was removed in vacuo ing in crude 5-[(4-fluoromethylphenyl )carbamoyl]methyl-pyrrolesulfonyl chloride . Part of this crude 5-[(4-fluoro methyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl de ( 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 desired fractions were concentrated in vacuo and dried in vacuo ing 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 5-[(4-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 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 8 (557 mg) as a white . 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% iPrNH2) hold 4.00 min, up to 50% in 1 min and hold 2.00 min at 50%, ature: 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 t of the te 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 combined and the solvent d in vacuo. The obtained residue was stirred in CH2Cl2 (5 mL), ed 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).
Columns: 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 (compound 9):1.6 min. nd 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 d at room temperature for 16 hours. The volatiles were evaporated. The residue was stirred in EtOAc (50 mL) and washed with HCl 1M (25 mL). The separated organic layer was dried with Na2SO4, filtered off and evaporated. The obtained residue was dissolved in EtOAc (3 mL), and heptane (2 mL) was added. The resulting solution was left standing 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 talyzed 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 5-[(4-fluoromethyl-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (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 mixture 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 ol/Dichloromethane 2/98 to 4/96]. The d fractions were combined and the solvent was evaporated. The mixture was repurified by silica gel column chromatography using EtOAc/Heptane 50/50 to 100/0]. The desired fractions were combined and the t was evaporated. The obtained residue was recrystallized from 2-Propanol (7 mL). The obtained white solid was ed off, washed with 2-Propanol (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 filtered off. The obtained white solid was recrystallized from itrile, 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, 6)  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 d 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 yielding compound 13a (192 mg) and compound 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 d 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 stirred for 60 hour. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography nol/Dichloromethane 2/98 to 4/96). The pure fractions were combined and the solvent was evaporated and the obtained residue was crystallized from dichloromethane, resulting in compound 15 (273 mg) as a white solid after filtration and drying in 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). nd 16: 4-(tert-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). utylamine (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 washing 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 precipitate 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 ved 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 stirred for minutes. Then esulfonyl Chloride (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 ted with EtOAc (200 mL) and the combined organic layers were dried with Na2SO4.
The solvent was d in vacuo and the obtained e 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 temperature 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 t was evaporated. The obtained residue was purified by silica gel column chromatography by gradient elution with EtOAc/Heptane 0/100 to 100/0]. The desired fractions were ed and the solvent 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, ng 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, CHLOROFORM-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 3,4-difluoroaniline (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 addition, the on mixture was left to stir at reflux for 1 hour. The reaction mixture was left to cool to room temperature under nitrogen atmosphere while stirring. The grey suspension was trated 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 stirred 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 e 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 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 filtration, washing with CH2Cl2 and drying in vacuo, nd 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, 6)  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) .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 ed similarly as described for compound 19, using 3-methyl oxetanamine hydrochloride instead of tert-butylamine. After work-up 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 fluoroaniline in toluene (50 mL) was slowly added (over 1 hour) to a refluxing solution of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride in toluene (200 mL).
After on, the reaction e was left to stir at reflux for 45 minutes.
The reaction e 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 se 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 organic layer was dried on MgSO4 and was evaporated.
The obtained e was triturated in a small amount of CH2Cl2, filtered, and washed with a small amount of CH2Cl2, resulting 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 prepared 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) .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). nd 23: N-(3,4-difluorophenyl)methyl[[(1R)methylpropyl]sulfamoyl]pyrrole carboxamide Compound 23 was prepared similarly as described for nd 22, using (R)-(-)aminobutane instead of isopropylamine. After work up, the obtained residue was ated 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) 3.00-3.13 (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 d 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 on 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, filtered and evaporated.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 1 (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 residue obtained after work up was triturated in a small amount of CH2Cl2, filtered and washed with a small amount of CH2Cl2 resulting in a white powder, which was r triturated in MeOH/ CH2Cl2 5/95. After filtration, washing and drying in vacuo, compound 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 Compound 91 was prepared similarly as described for compound 19 using 3-methyloxolan amine hydrochloride instead of tert-butylamine. Compound 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, DMSO-d6) 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: here C18 ODB - 10µm, 200g, 5cm), Mobile phase: 0.5% NH4OAc solution in water + 10% CH3CN, CH3CN). The collected fractions were concentrated (to the aqueous phase). The aqueous phase was ied 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, , 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 similarly as described for compound 92 using (S)-1,1,1-trifluoro propylamine d 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 m bis(trimethylsilyl)amide in toluene (42.06 mL, 1 M, 42.06 mmol) were added and the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was quenched using ammonium chloride (sat. / 200 mL). The ing mixture was extracted using EtOAc (3 x 250 mL). The ed extracts were washed with brine (250 mL), dried on Na2SO4, filtered and trated in vacuo yielding a brown powder. This was cristallised twice out of ol/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) 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 obtained residue was crystallized out of methanol/water. The white ls were collected on a glass filter and dried in a vacuum oven at 55°C for 24 hours yielding compound 92 (4.32 g) as white needles. [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 chloride (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 ed overnight. 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 trated. The obtained residue was subjected to silica gel column chromatography using a nt from 10 to 100% EtOAc in heptane. The pure fractions were collected, concentrated and dried in vacuo at 50°C ng 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).
Compound 26: 1-methyl[[(3S)-tetrahydrofuranyl]sulfamoyl]-N-(3,4,5-trifluorophenyl lecarboxamide 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 addition, the reaction mixture was left to stir at reflux for 1 hour. The mixture was cooled and concentrated in vacuo. The obtained crude containing 1-methyl[(3,4,5- trifluorophenyl)carbamoyl]pyrrolesulfonyl chloride was used a such.A solution of (S)-(-) etrahydrofuran 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 chloride (800 mg) in CH2Cl2 (150 mL) and stirred for 1 hour. The e was diluted with dichloromethane (400 mL) and washed with 1M HCl (2x), water and saturated NaHCO3 on. The organic layer was dried over magnesium sulphate, filtered and concentrated. The obtained residue was dissolved in hot MeOH (100 mL) and water was added. The formed white precipitate was filtered off, dried in vacuo and ed 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 de (1.2 g, obtained as described for compound 26) was added and the reaction mixture was stirred for 30 minutes. The on mixture was directly loaded on silica gel column and purified by gradient elution from heptane to EtOAc, g 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 28:1-methyl[(3-methyloxetanyl)sulfamoyl]-N-[3-(trifluoromethyl)- phenyl]pyrrolecarboxamide 3-(trifluoromethyl)aniline (0.41 mL, 3.3 mmol) was added dropwise to a ing 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 mixture was d 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).
Compound 29: 1-ethyl-N-(4-fluoromethyl-phenyl)(isopropylsulfamoyl)pyrrole carboxamide TIP 296 PCT To 4-chlorosulfonylethyl-pyrrolecarboxylic acid (1 g, commercial from enamine, EN300- 43738, 4.2 mmol ) in , (10 mL ) at room temperature under N2-atmosphere, DMF (1 drop) was added followed by dropwise addition of a solution 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 dropwise to a solution of the above obtained crude 4-chlorosulfonylethyl-pyrrolecarbonyl chloride in toluene at reflux over 5 minutes. The reaction e was refluxed 30 minutes and next allowed to reach room temperature. After stirring at room temperature for 2 hours the volatiles were removed in vacuo resulting in a residue containing 1-ethyl[(4-fluoromethylphenyl )carbamoyl]pyrrolesulfonyl de that was used as such in the next step. Part of the as such obtained crude 1-ethyl[(4-fluoromethyl-phenyl)carbamoyl]pyrrolesulfonyl de (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 d with EtOAc (100 mL) and washed with 1 M HCl (2 x mL). The organic layer was dried on , filtered and concentrated resulting in a residue that was ed 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 chloride (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 mixture was diluted with EtOAc (100 mL) and washed with 1M HCl (2 x 10 mL). The organic layer was dried 4), 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).
Compound 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 rosulfonylmethyl-pyrrolecarbonylchloride (1.7 g) in toluene (100 mL) at reflux. The reaction mixture was refluxed 1 hour and next d 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 trated in vacuo. The ed residue 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 ed residue was ed by silica gel column chromatography (gradient from 20 till 100% EtOAc in heptanes). The product fractions were concentrated and the ed 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 4-fluoro-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, 6)  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 dissolved 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 on mixture was refluxed overnight. The mixture was concentrated and the obtained residue 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 mixture 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, ed and concentrated yielding 3,4-difluoro- yl-aniline as a ess 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) ved 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 refluxed 2 hours, allowed to cool to room ature 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 concentrated in vacuo. The obtained residue 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]- oyl]pyrrolecarboxamide Compound 34 (1.18 g) was ed similarly as described for compound 33, using ) 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), 3.00-3.12 (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).
Compound 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 on mixture was refluxed 2 hour, allowed to cool to room temperature and concentrated in vacuo. A mixture 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 overnight and next concentrated in vacuo. The obtained residue was dissolved in hot methanol (200 mL) and H2O was added. The formed precipitate was ed 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 toluene (20 mL) was added dropwise to a solution of rosulfonylmethyl-pyrrolecarbonylchloride (353 mg) in toluene (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 ed residue was dissolved in warm methanol (50 mL) and H2O was added. The formed precipitate was filtered off and dried in vacuo, resulting 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)-(-) etrahydrofuran p-toluenesulfonate instead of 3-methyloxetanamine hydrochloride.
After reaction, the obtained residue was ved 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. Compound 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, 6)  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 nd 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, ning 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 obtained solution containing 5-[[3-(difluoromethyl)fluoro-phenyl]carbamoyl]methyl-pyrrole yl chloride, yloxetanamine 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 stirred overnight. More DIPEA (1.14 mL, 6.6 mmol) was added and the mixture was stirred over weekend. The volatiles were removed under reduced re 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: difluoromethyl)fluoro-phenyl][[(1R)hydroxymethylethyl ]sulfamoyl]methyl-pyrrolecarboxamide Compound 40 (670 mg) was prepared similarly as described for compound 39 using D-alaninol 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 ed 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, DMSO-d6)  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 compound 41, using (S)-(-) aminotetrahydrofurantoluene-sulfonate d 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 3-methyl- 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: N-[4-fluoro(trifluoromethyl)phenyl](isopropylsulfamoyl)methyl- pyrrolecarboxamide nd 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 ropylether, 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 addition the reaction was refluxed for 4 hours. The reaction 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 hydrochloride (0.5 equiv) and DIPEA (0.5 equiv) in CH2Cl2 (2 mL) was added and the reaction mixture was stirred 2 hours more. The reaction mixture was brought to 50ºC and stirred for 2 hours. The volatiles were removed under reduced pressure and the residue was olved 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: romo-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 on of 4-chlorosulfonylmethyl-pyrrolecarbonylchloride (3100 mg, 12.8 mmol) in toluene (160 mL) at reflux. The on 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, pylamine (7.3 mL, 85.4 mmol) and DIPEA (2.2 mL, 12.8 mmol) in CH2Cl2 (70 mL) was added. The on mixture was stirred at room ature. After a few seconds the homogeneous mixture became a suspension.
The solids were ed, 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 prepared similarly as described for compound 46 using (R)-(-)aminobutane (4 equiv) instead of isopropylamine. After addition of (R)-(-)aminobutane, the mixture was d overnight. The solid was ed, washed with CH2Cl2 and dried in vacuo, resulting in compound 47 (1.17 g) as an ite 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 compound 46 using yl oxetanamine (4 equiv) instead of pylamine. 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).
Compound 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 N2-atmosphere at room temperature. The TIP 296 PCT reaction mixture was stirred for 3 hour. More DIPEA (2 mL) was added and the reaction mixture was stirred for 80 hours. Next, the reaction e was washed with 1M HCl (100 mL). The organic layer was dried on Na2SO4. After evaporation of the solvent, the residue 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 obtained 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 1-methyl[(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 another hour. The ing mixture was added drop wise to a mechanically stirred, temperature controlled, ter mixture (1500 mL) keeping the ature 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 te, 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 itrile (50 mL). diisopropylethylamine (9.06 mL, 52.6 mmol) was added, followed by 3- methyloxetanamine (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 ved 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 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 d for 72 hours. Next, it was concentrated until only water remained and extra distilled water (15 mL) was added. After neutralization with hydrochloric acid (1M / aq / 31.6 mL, 31.58 mmol). The resulting mixture was extracted using 2-methyltetrahydrofuran (3 x 20 mL). The combined extracts were dried on sodium sulphate, filtered and trated 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 d with 1-methyl[(3-methyloxetanyl)sulfamoyl]-1H-pyrrolecarboxylic acid (0.25 g, 0.91mmol) and HATU (0.36 g, 0.96 mmol). N,N-dimethylformamide (1 mL) and diisopropylethylamine (0.47 mL, 2.73 mmol) were added and the e was d 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 ted on a filter and dried in vacuo, yielding compound 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 ropylethylamine 0.38 mL, 2.19 mmol) were added and the mixture was stirred 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 resulting 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 combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo. The obtained crude was dissolved in romethane (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 desired ons were concentratcd in vacuo and dried in vacuo, resulting 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 mixture 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 ed 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 s, dissolved in methanol again and evaporated to dryness and dried in vacuo to afford compound 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, , 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 ofluorobenzonitrile (1034 mg, 7.6 mmol) ved 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 cyanofluoro-phenyl)carbamoyl] methyl-pyrrolesulfonyl chloride as a brown powder which was used as such. ). 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 solution of 5-[(3-cyano fluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (892 mg, 2.48 mmol) and tertbutylamine (544 mg, 7.44 mmol) in acetonitrile (100 mL) wer stirred overnight. Water was added untill crystallisation started. The ls were filtered of and dried ght 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 overnight. Water was added untill crystallisation started. 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: yanophenyl)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 ed 2.5 hours, decanted hot and TIP 296 PCT concentrated in vacuo yielding crude 5-[(3-cyanophenyl)carbamoyl]methyl-pyrrolesulfonyl de. 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 reaction 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 d 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 compound 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), 7.85-8.10 (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 minutes. The reaction mixture was diluted with distilled water (50 mL), alkalanised with 1M NaOH, d with brine untill product separates as oil and ted with Et2O. The c 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 reflux. The reaction mixture was refluxed 90 minutes and concentrated in vacuo ng crude 5-[(2,6-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, FORM-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 saturated NaHCO3 solution. The on 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 filtered 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 ro-4,5-difluorobenzoic acid (1011 mg, 52.5 mmol) was dissolved in utyl alcohol (200 mL). Triethylamine (8 mL, 57.8 mmol) was added followed by diphenylphosphoryl azide (14.74 g, 53.6 mmol) and the reaction mixture was refluxed overnight. The reaction mixture 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 e till 100% CH2Cl2. The product fractions were concentrated 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 residue was dissolved in water (100 mL), alkalanised with NaOH 1M and extracted with ether. The organic layer was dried over MgSO4, filtered and trated 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 minutes to a on of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (5.07 g, 20.95 mmol) in toluene (525 mL) at reflux. The reaction mixture was refluxed 90 minutes and then concentrated in vacuo yielding crude 5-[(3-chloro-4,5-difluorophenyl )carbamoyl]methyl-pyrrolesulfonyl de (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 pylamine (457 mg, 7.73 mmol) in acetonitrile (100 mL) was stirred 60 minutes. Water was added untill crystallisation began. The beige TIP 296 PCT ls were filtered off and dried in vacuo overnight at 50°C, resulting in nd 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 e of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (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)- oyl]pyrrolecarboxamide A mixture of 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.0 g, 2.57 mmol) 3-methyloxetanamine (560 mg, 6.43 mmol) and acetonitrile (100 mL) was refluxed 30 minutes. The reaction mixture was cooled to 20°C and diluted 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 de (1008 mg, 2.59 mmol), 1,1-trifluoropropylamine (1026 mg, 9.07 mmol) in acetonitrile (100 mL) was refluxed overnight. Water was added untill crystallisation d. The beige crystals were filtered 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 ly to column chromatography on a 330 g Reveleris cartridge in a Biotage system using a gradient 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 dissolved in warm methanol (150 mL) and the product crystallized upon addition of water. The product was filtered off and dried in vacuo at 50°C overnight, resulting in nd 60 (7.44 g). [α]20365= -9.5 ° (c 1.30 w/v %, MeOH). ential scanning calorimetry: From 30 to 300 °C at °C/min: peak at 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 trated and the obtained residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated. The obtained TIP 296 PCT residue was dissolved in acetonitrile (50 mL). Water was added untill precipitation was observed. The mixture was allowed to triturate further ght. The beige crystals were filtered off and dried in vacuo at 50°C, ing 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, DMSO-d6)  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 ed overnight. An equal amount of 1-(trifluoromethyl)cyclopropanamine was added and the raction mixture was further refluxed ght. The reaction e was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filtered and concentrated. The residue was purified by column tography 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 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl de (318 mg, 0.817 mmol), 1,1,1-trifluoromethoxymethyl-propanamine hydrochloride (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 e 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 on of water. The crystals were filtered off and dried overnight 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, 6)  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 lar sieves) under N2-atm. 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl] methyl-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 , 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 te was concentrated and the obtained residue was purified by silica gel chromatography (EtOAc-heptane 0/100 to 100/0) and further purified by e 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, 6)  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 se 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 arbonyldiimidazole (CDI, 0.326 g, 2.013 mmol) was added to a stirring solution of compound 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 reaction mixture was stirred for 2.5 hour at room ature. The solvent and the excess of methylamine were removed and the mixture was purified 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 methyl-phenyl)methyl-pyrrolecarboxamide 1,1'-carbonyldiimidazole (CDI, 0.149 g, 0.921 mmol) was added to a stirring e of compound 61 (0.366 g, 0.921 mmol) in acetonitrile in a sealed tube under N2 here. The resultant on 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 (323mg) 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).
Compound 64: 4-[(2-amino-1,1-dimethyloxo-ethyl)sulfamoyl]-N-(4-fluoromethyl- phenyl)methyl-pyrrolecarboxamide arbonyldiimidazole (CDI, 0.295 g, 1.820mmol) was added to a stirring e 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 t 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 solvent 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 acetonitrile (25 mL) and stirred ght.Water was added until crystallization began. The itate was filtered off and dried in vacuo at 50°C, resulting in compound 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 itrile (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 (635mg, 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). nd 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 ght. 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, 6)  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: 4-(tert-butylsulfamoyl)-N-(2,6-dideuterio-3,4,5-trifluoro-phenyl)methylpyrrolecarboxamide lamine (331 mg, 4.53 mmol) was added to a solution of 6-dideuterio-3,4,5-trifluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride (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 2,6-dideuterio-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 solution of ethyl ro-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 ied 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 ro- 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 xycarbonylfluoromethyl-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 d 1 hour at room temperature. The reaction mixture was concentrated. The obtained residue was dissolved in dichloromethane (200 mL), washed with water, dried over sodium sulphate, filtered and trated. The residue was purified by column tography 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 temperature. THF was distilled off and the mixture neutralized with 1M HCl (5.9 mL, 5.9 mmol). The e was extracted with 2- methyltetrahydrofuran (3 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The resulting 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) followed by HATU (216 mg, 0.57 mmol) and stirred 20 minutes. Then 3,4-difluoroaniline (117 mg, 0.91 mmol) was added and the reaction mixture d ght. The mixture was trated 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, filtered 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 concentrated 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). nd 75: N-(3,5-Dichlorofluorophenyl)methyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide 3,5-dichlorofluoroaniline (1534 mg, 8.5 mmol) dissolved in toluene (10 mL) was added to 4- chlorosulfonylmethyl-pyrrolecarbonyl chloride (2063 mg, 8.52 mmol) in toluene (115 mL) at reflux and refluxed 2 hours. The reaction mixture was filtered while still hot and the te was concentrated , yielding crude 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-[(3,5-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 de (792 mg) in itrile (75 mL) and stirred 2 hours. Water was added untill crystallisation began. The white crystals were filtered off and dried overnight 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 e of 1-methyl[(3-methyloxetan yl)sulfamoyl]pyrrolecarboxylic acid (0.25 g, 0.000911 mol) and CH3CN (5 mL ) under N2- here. 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 compound 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 ved in DMF (5 mL) and d for 10 minutes. 3- chlorofluoroaniline (265 mg, 1.8 mmol) and DIPEA (0.471 mL, 2.73 mmol) were added and the on mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was ed on silica using a heptane to EtOac gradient yielding compound 78 as a white powder after trituration 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 Compound 79 (1.9 g) was prepared similarly as described for compound 75, using 4-fluoro methyl(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: N-(4-Fluoro-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 ropylethylamine (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 resulting mixture 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 combined organics were washed with brine, dried on Na2SO4, filtered and concentrated in vacuo. The obtained residue was ed 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 a vacuum oven at 55°C for 24 hours ng 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, DMSO-d6 )  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 Compound 81 (129 mg) was prepared as described for compound 80 using 3-bromo fluoroaniline instead of ro-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 nd 83: N-(4-Cyanomethylphenyl)methyl[(3-methyloxetanylsulfamoyl]-1H- pyrrolecarboxamide Compound 83 (76 mg) was prepared as bed for compound 80 using 4-aminomethyl- benzonitrile instead 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, 6 )  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 ved 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 stirred 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 on 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 filtered 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 resulting 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 e was stirred at room temperature for 1 hour. Then the reaction mixture was stirred at 40°C for 80 hours. The solvent was removed, water (1 x 50 mL) was added and the e 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 d by evaporation. The crude mixture was purified by silica gel chromatography (EtOAc-heptane 0/100 to 100/0). The desired fractions were combined and evaporated. The obtained solid was crystallized by evaporation of a acetonitrile/H2O on, 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: luoro(trifluoromethoxy)phenyl]methyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 86 (127 mg) was prepared similar as described for compound 80 using 4-fluoro (trifluoromethoxy)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 chlorofluoroaniline. The reaction mixture was ed and the solids were washed with water. The grey powder was ved in ethyl acetate (300 mL) and washed with aqueous HCl (1 N, 50 mL), saturated aqueous sodium bicarbonate (30 mL) and brine, dried 4), and evaporated to dryness and dried overnight in vacuum oven at 50°C, resulting in nd 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 scanning calorimetry: From 30 to 300 °C at 10°C/min: 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 ed organic extracts were dried (Na2SO4) and concentrated resulting in crude ethyl 4-chlorosulfonyl-1,3,5- trimethyl-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 1,3,5-trimethyl[(3- methyloxetanyl)sulfamoyl]pyrrolecarboxylate was dissolved 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 reaction e was stirred at 70°C for 20 hours. NaOH (1 M in H2O, 0.61 mL) was added to the on 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 ed 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 mixture was poured into water. The dark brown precipitate was ed 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, combined with the dark brown itate, dried (Na2SO4) and evaporated. The obtained residue was purified 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 1,5-dimethyl-1H-pyrrolecarboxylate (2.5 g, 14.95 mmol) was added drop wise to chlorosulfonic acid (10 mL) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and allowed to stir overnight. The on 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, acetonitrile-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 rosulfonyl-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 e was d 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 s. The obtained crude ethyl 1,5-dimethyl[(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 methanol (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 orated with toluene (2 x 50 mL) to afford a beige powder.
Half of the above obtained powder was ved 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 d 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]- 1H-pyrrolecarboxamide 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 here. The reaction mixture was warmed to room temperature and allowed to stir 1.5 hours. The on mixture was slowly added to ice cold water, followed by extraction with CH2Cl2. The combined organic extracts were dried (Na2SO4) 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 ylate (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 mixture 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 residue was purified using silica gel column chromatography 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 dissolved in THF (40 mL) and LiOH (114.3 mg, 4.77 mmol) in water (10 mL) was added. The reaction e was stirred at room ature. Methanol (20 mL) was added to the raction TIP 296 PCT mixture. The reaction mixture was stirred at room temperature overnight. 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 d at 50°C for 2 hours.
Water was added to the reaction mixture and the mixture was extracted with yl 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. Compound 90 was ed 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 s, dissolved in methanol and evaporated to s. After drying in vacuo compound 90 was obtained as a white powder. 1 H NMR (400 MHz, 6 )  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 calorimetry: From 30 to 300 °C at in: peak at 160.5 °C.
Compound 97: N-(4-Fluoromethylphenyl)methyl{[(1R)methyl(methylsulfonyl )ethyl]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: t-Butylsulfamoyl)-N-[4-fluoro(trifluoromethoxy)phenyl]methyl-1H- pyrrolecarboxamide 4-fluoro(trifluoromethoxy)aniline (991 mg, 5.08 mmol) ved in toluene (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 H 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 dissolved in acetonitrile (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 solution 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 t was evaporated leaving yellow oil which ed 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 itate 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 yl[[(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 mixture was refluxed overnight. Then the mixture was cooled to room ature 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 te, 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- ethyl]sulfamoyl]pyrrolecarboxylate (6.6 g, 19.7 mmol) was dissolved in ydrofuran (56 mL). To this was added lithium hydroxide (1.655 g, 69.1 mmol) in distilled water (7.5 mL) followed by methanol (3 mL). The resulting mixture was stirred overnight. The mixture was concentrated until only water remained and extra distilled water (15 mL) was added. The e 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-trifluoromethylethyl moyl]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 [(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid and the corresponding aniline instead of 4-fluoro-3,5-dimethylaniline. After addition 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 purified 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, DMSO-d6)  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 ng metry: From 30 to 300 °C at 10°C/min: peak at 199.0 °C.
Compound 101: romofluorophenyl)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, DMSO-d6)  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), filtered off, and washed with CH2Cl2 (2x).
The product was crystallized from iPrOH (12.5 mL) + H2O (2.5 mL), ed 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- aminofluorobenzonitrile (2.82 g, 20.68 mmol) was added and the mixture was cooled in an ice-water bath while stirring under nitrogen. Lithium bis(trimethylsilyl)amide (1M in toluene, 47.73 mL, 47.73 mmol) was added drop wise over a period of 10 minutes. 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 ing mixture was extracted using EtOAc (3 x 150 mL). The combined ts were washed with brine (200 mL), dried on Na2SO4, filtered and concentrated in vacuo. The obtained e 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 . This powder was recrystallized out of MeOH/water. The obtained crystals were collected on a filter, rinsed with water and diisopropylether and dried in a vacuum oven at 55°C for 24 hours yielding 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% iPrNH2) @ 14.5% rate, down to 50% and hold for 2.55 min @ 50%, Temperature: 40°C: Compound 102 (first eluding), containing no detectable compound 157 d eluding). 1H NMR (600 MHz, 6) 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). nd 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 nd 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). nd 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 suspension 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 ing 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 acetonitrile, the mixture was cooled to room ature. 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 [(3-methyloxetanyl)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 ted to column chromatography using a nt from 10 till 100% EtOAc in heptane. The product fractions were combined 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 prepared 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, 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=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: hlorofluorophenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 108 (149 mg) was prepared similarly as described for compound 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 ed 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, , 7.3 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.32 (s, 1 H), 9.79 (s, 1 H). nd 110: N-(2,4-Difluoromethylphenyl)fluoromethyl[(3-methyloxetan yl)sulfamoyl]-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 prepared 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 rly 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 temperature. The on 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 e was dissolved in (CH2Cl2/MeOH (5mL, 90:10) and purified by silica gel chromatography [EtOAc-heptane 0/100 to 100/0 ] and further ed by reverse phase column tography. 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 d of 4-fluoromethylaniline but stirred 24 hours at 65°C and 48 hours at 100°C. The residue after column was crystallized from acetonitrile (10 mL) upon addition 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 (3.08ml) under N2-atm. 5-[(3-chloro-4,5-difluorophenyl )carbamoyl]methyl-pyrrolesulfonyl chloride (prepared similarly as described for nd 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 e 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 resulting in residue 1. The water layer was extracted with EtOAc (100 mL). The layers were ted and the organic layer was dried with Na2SO4 and the te was evaporated resulting in residue 2. Residue 1, 2 and precipitate 1 were ed giving methyl 1- [[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolyl]sulfonylamino]- ropanecarboxylate (2.0 g) This material was dissolved in methanol (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 [(3-chloro-4,5- difluoro-phenyl)carbamoyl]methyl-pyrrolyl]sulfonylamino]cyclopropanecarboxylic acid as a yellow residue (1164 mg) which was used as such.This material (700 mg,16.1 mmol) was stirred in CH3CN (50 mL), CDI (654 mg, 40.3 mmol) was added and the resulting on was stirred at room temperature in a sealed tube for 2.5 h [white precipitation was observed]. 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 sion was filtered off leaving a white filtercake. The filtercake was washed with CH3CN and dried in vacuo at 50°C, resulting in compound 114 (319 mg) Method A; Rt: 1.56 min. m/z: 431.0 (M-H)- Exact mass: 432.05. 1H NMR (400 MHz, 6)  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). nd 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 stirred 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 residue dissolved in 5 mL CH2Cl2/MeOH ) and purified by flash chromatography on silica using a nt EtOAcheptane 0/100 to 100/0 . The desired fractions were combined and the solvent was evaporated, 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 rly 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 reaction 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 obtained red solid was suspended in boiling diisopropyl ether (3 mL) and anol (2 mL) was added dropwise. The mixture was left standing for 90 min and then ed. The precipitate was washed with diisopropyl ether/2-propanol (4:1, 6 mL) and dried in vacuo at 50°C yielding compound 116 as a slightly rple solid (240 mg) Method A; Rt: 1.71 min. m/z: 424.0 (M-H)- 426.0 (M+H)+ Exact mass: 425.08. 1H NMR (360 MHz, DMSO-d6) 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.
Compound 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, ol). 1- (trifluoromethyl)cyclopropanamine (222mg,1.78mmol) was added under N2-atm at room temperature. The reaction e was stirred in a sealed tube at 75°C for 24 h and 110 h at 95°C. Then 1 eq of 1-(trifluoromethyl)cyclopropanamine was added and the mixture was stirred at 95° for 24 h. The solvent was evaporated leaving yellow oil which was dissolved in /Methanol (80/20; 5mL) and purified by Flash Chromatography [Biotage a 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 colored 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 stirring. 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, DMSO-d6) 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). nd 118: N-(2,4-Difluoromethylphenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide The compound was prepared 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: 439.10. 1H NMR (400 MHz, 6)  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 metry: From 30 to 300 °C at in: peak at 164.23 °C.
Compound 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: . 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 Compound 120: N-(3-Chloro-2,4-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide 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 d 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 suspended 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 ng for 2 h then left standing for 18 h, ed off and dried under vacuum at 50°C. The filtrate was left ng for 18h. The formed precipitate was filtered 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 tetrahydrofuran (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 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 , filtered and concentrated in vacuo yielding a brown powder. This powder was crystallized twice out of methanol/water. The precipitation was collected on a glass filter. The ed powder was ed by silica gel column chromatography using gradient elution from e to EtOAc (100:0 to . The obtained residue was llized 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 nd 120 (3.03 g) as a white powder. Differential scanning metry: 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 -[(3-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- ro-aniline (3.5g, 14.46 mmol) was d in dry CH3CN (10 mL). 3-methyloxetanamine (255 mg, 2.93mmol) was added under N2-atm. The reaction mixture was d in a sealed tube at room temperature for 18 h. The solvent was evaporated. The residue was stirred in CH2Cl2.
The formed precipitate was filtered off [fraction 1]. The filtrate was evaporated and the residue was dissolved in CH2Cl2/MeOH (9/1, 5 mL) and purified by Flash Chromatography [Biotage Isolera 1 // esolve Silica 12 g // EtOAc-heptane 0/100 to 100/0 ]. The desired fractions were combined and the solvent was evaporated leaving a white solid which was recrystallized 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 combined with on 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 Chlorosulfonic 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 on the mixture was allowed to reach room temperature. Then it was stirred for another 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 itation 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 d 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 Na2SO4, filtered and concentrated in vacuo. The obtained e 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 ic 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 acetate (100 mL) and the mixture partitioned with ethyl acetate (3 x 100 mL). The organic layers were combined, dried sium sulfate), the solids were removed by filtration and the ts of the filtrate 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 l/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 ic 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 on in THF/ethylbenzene) slowly via e (approx rate of 2 ). sion 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 partitioned 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 filtrate were removed under reduced pressure. The crudes were partially purified via silica column chromatography using a dichloromethane to ethylacetate gradient. The solvent of the best fractions were removed under reduced pressure.The residue was talized 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).
Compound 126: N-(3-Cyanofluorophenyl)[(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 ature 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 cs 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 fied while standing and was used as such. Methyl 4-(2,2-difluoroethylsulfamoyl)methyl-pyrrole carboxylate (5.4 g, 19.1 mmol) was dissolved in tetrahydrofuran (50 mL). To this was added an aqueous solution of lithium hydroxide (0.69 g, 28.7 mmol) in distilled water (7 mL) and a turbid mixture was ed. 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 reaction 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 hloric acid (47.8 mL, 47.83 mmol/ 1M / aq /). The resulting mixture was extracted using methyltetrahydrofuran (3 x 20 mL). The ed extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding 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 ylic 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 on mixture was stirred at room temperature for 66 hours. The reaction mixture was ly 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 evaporated 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 nd 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 similarly as described for compound 126 using 3-bromofluoroaniline d of 5-aminofluorobenzonitrile in the last step.
Method B; Rt: 1.00 min. m/z: 438 (M-H)- Exact mass: 438.98. 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=55.5, 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 ofluorobenzonitrile 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 3,4-difluoroaniline instead of 5-aminofluorobenzonitrile in the last step. Method B; Rt: 0.94 min. m/z: 378 (M-H)- Exact mass: 379.06. 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, , 4.0 Hz, 1 H), 7.34 (d, J=2.0 Hz, 1 H), 7.41 (dt, , 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 esis described in synthesis 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 tography (gradient 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 ated 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 s hydrochloric acid (2 x 150 mL, 1N). The organics were dried on sodium sulphate, filtered and trated in vacuo yielding methyl yl(2,2,2-trifluoroethyl- sulfamoyl)pyrrolecarboxylate (5.3 g) as light brown oil which solidified while ng 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 obtained.
Then methanol (3 mL) was added and the mixture 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 distilled 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 ing mixture was extracted using methyltetrahydrofuran (3 x 20 mL).
The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo ng 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 rofluoroaniline (0.48 g, 3.32 mmol) and HATU (0.76 g, 1.99 mmol) were dissolved in DMF (2 mL) ning 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 evaporated to keep ~50 mL of the solvent and 20 mL of diethyl ether was added. The formed precipitate was ed 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- pyrrolecarboxamide Compound 132 was synthesized rly as bed 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, , 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 chromatography (ethyl acetate 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 tography (methanol in CH2Cl2 from 0 to 2%) The purest fractions were combined 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: yanofluorophenyl)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 2 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 ed 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 ated to dryness, dissolved in methanol again and evaporated to dryness and dried in vacuum oven overnight to afford compound 134 (147 mg) as white powder. Method B; Rt: 0.93 min. m/z: 403 (M-H)- Exact mass: 404.06. 1H NMR (400 MHz, 6)  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: N-(3-Bromofluorophenyl)methyl[(2,2,2-trifluoroethyl)sulfamoyl]-1H- pyrrolecarboxamide Compound 135 was synthesized similarly as described for compound 134 using 3-bromo fluoroaniline (631 mg, 3.32 mmol) instead 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 00 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 e 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 (Na2SO4) 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 dissolved in DMF (3 mL). ropylethylamine (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 reaction mixture was stirred at room temperature for 68 hours and at 60°C for 2 hours. The reaction mixture was directly loaded on column. The on e was purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 80%). The desired fraction were combined and concentrated to keep ~ 100 mL of solvent. 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, DMSO-d6)  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: hloro-4,5-difluorophenyl)-1,5-dimethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide In a pressure tube, crude ethyl rosulfonyl-1,5-dimethyl-pyrrolecarboxylate (3.03 g, 11.4 mmol) (synthesis described in synthesis for compound 89) was dissolved in itrile (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 romethane (50 mL) and this was washed with aqueous hydrochloric acid (1N, 2 x 20 mL). The organics were dried on sodium sulphate, filtered and trated 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- ecarboxylate (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 ted with Me-THF (3 x 20 mL). The combined organic layers were washed with Brine, dried 4) 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) esis described in sis for compound 57) and HATU (0.73 g, 1.91 mmol) were dissolved in DMF (2 mL) containing diisopropylethylamine (0.82 mL, 4.77 mmol). The reaction mixture was stirred at 40°C for 66 hours. The reaction mixture was directly loaded on column. The reaction mixture was 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 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 ethyl]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)- 426(M+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, , 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 synthesis 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 reaction mixture was purified using silica gel column tography (ethyl acetate in e from 20 to 80%). The desired fractions 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 compound 140 using 3-bromofluoroaniline (0.20 g, 1.07 mmol) d 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 Compound 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 benzonitrile. 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 ro-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, thylpyrrolecarboxylate (10.7 g, 61.0 mmol) was added drop wise to chlorosulfonic acid (33.3 mL, 500 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was warmed to room temperature and d to stir 2 hours. The resulting mixture was added drop wise to a stirred, temperature controlled ice-water mixture (200 mL) keeping the ature under 5°C. A white precipitation was formed. The obtained aqueous suspension was ted 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 acetonitrile (30 mL). To this was added diisopropylethylamine (7.54 mL, 43.8 mmol) followed 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 concentrated. 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 sulphate, 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: e from 0 to 80%). The desired fractions were combined and ated to dryness to afford ethyl 1,3-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole- 2-carboxylate (3.05 g) as light yellow powder. 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 methyl[[(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. nd 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 ropylethylamine (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 ent elution: ethyl acetate in heptane from 10 to 70%). The desired fractions were ed and evaporated to keep ~50 mL of the solvent. The white solids were filtered 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 methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 145 (452 mg) as white powder was synthesized similarly as described for compound 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: -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 ting in 1,3-dimethyl[[(1S)-2,2,2-trifluoromethylethyl moyl]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 (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) and 3-chlorofluoroaniline instead of 3,4-difluoroaniline 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 rly 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 fractions 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). nd 149: hlorofluorophenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 149 was synthesized as compound 144 using 3-methyloxetanamine d of (R)- 1,1,1-trifluoropropylamine in Step2 and rofluoroaniline instead of 3,4- difluoroaniline in Step4. In Step4, the desired 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 petroleum 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: yanofluorophenyl)-1,3-dimethyl{[(1S)-2,2,2-trifluoro ethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 151 (420 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 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).
Compound 152: N-(3-Cyanofluorophenyl)-1,3-dimethyl[(3-methyloxetanyl)sulfamoyl]- 1H-pyrrolecarboxamide Compound 152 was synthesized similarly as described for compound 144 using 3-methyl oxetanamine d of (R)-1,1,1-trifluoropropylamine in Step2 and 5-amino TIP 296 PCT fluorobenzonitrile instead of 3,4-difluoroaniline in Step4. In Step4, the desired fractions were ated to afford light yellow oil which was ed 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- ylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 153 (270 mg) as beige solid was synthesized similarly as bed 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, DMSO-d6)  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 flushed 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 Na2SO4, 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 methanol (3 mL). The resulting mixture was stirred overnight. The mixture was concentrated until only water remained and extra distilled water (15 mL) was added. The mixture was lised with hydrochloric acid (1M, aq).
The resulting mixture was extracted using 2-methyltetrahydrofuran (3 x 20 mL). The combined ts 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. nd 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 s. 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 ature and injected directly onto a silica plug. The e 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 similarly as bed 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, 6)  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 trifluoroaniline resulting in white powder. Method B; Rt: 1.03 min. m/z : 444.11 (M-H)- Exact mass: .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 methylethyl]sulfamoyl]pyrrolecarboxamide Prepared similarly as described 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 powder (136 mg). Method B; Rt: 0.96 min. m/z : 417.13 (M-H)- Exact mass: 418.07. 1H NMR TIP 296 PCT (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 yl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylate (5.0g, 15.91mmol, prepared as in the synthesis for nd 122 ) dissolved in dioxane (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 temperature for 30'. The product was filtered off and dried in vacuo to become a pale yellow solid of 1-methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxylic acid (3.95g). This acid (700 mg, ol), 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 d at room temperature for 16 h. The mixture was poured in 100 mL ice water and was extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a silica using a gradient eluent Heptane- EtOAc 100-0 -> 50-50. The product fractions were collected and trated in vacuo. The product was crystallized from 2-propanol, filtered off and dried in vacuo, yielding nd 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 3-aminobenzonitrile 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, 6)  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 Synthesis of 2-(1,1-difluoroethyl)fluoronitro-benzene: 1-(2-fluoronitrophenyl)ethanone (19 g, 103.7mmol) was dissolved in romethane (300 mL) The mixture was stirred at -78°C under osphere. Diethylamino)sulfur trifluoride (33.4 g, 207 mmol) was added to the TIP 296 PCT mixture via cannula over a period of 30 min.The reaction mixture was stirred at 35° C for 16 h.The cold reaction mixture was poured into ice water (200mL).The aqueous layer was extracted with dichloromethane (80 mL) twice . The combined c 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: -difluoroethyl)fluoro nitrobenzene:(13 g ,63.37 mmol) was dissolved in methanol (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 purified by column chromatography to provide a yellow oil (5845 mg). sis of (1,1-difluoroethyl)fluoro-phenyl]carbamoyl]methyl-pyrrolesulfonyl chloride: -difluoroethyl)fluoro-aniline (1099.8 mg, 6.28 mmol) dissolved in toluene (10 mL) was added se during 5' to a on of 4-chlorosulfonylmethyl-pyrrolecarbonyl chloride (1520 mg, 6.28 mmol) in e (100 mL) at reflux. The reaction mixture 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: 380.02. 3-methyloxetanamine (390 mg, 4.47 mmol) was added to a solution 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 compound 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 compound 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: N-(3,5-Dichlorofluorophenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide 3,5-dichlorofluoroaniline (1534 mg,18.52 mmol) dissolved in e (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 reaction mixture was filtered while still hot and trated yielding a crude beige powder (2833 mg, 5-[(3,5-dichlorofluorophenyl )carbamoyl]methyl-pyrrolesulfonyl de) 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 ed overnight. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with 1M HCl, dried over sodium sulphate, filtered and trated. 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, DMSO-d6)  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) red as in the synthesis 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 e was concentrated. The residue was ted to column chromatography 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, ing 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 mg.12mmol) (prepared as in the synthesis for compound 57) trifluoromethylbutanamine hydrochloride (754 mg, 4.25 mmol) DIPEA (1.14 mL, 36.58 mmol) in CH3CN (31 mL)was ed 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 gradient 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: pak Diacel AD 20 x 250 mm), Mobile phase: CO2, iPrOH with 0.2% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, yielding 165a (first eluding, 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: N-(3-Chloro-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- difluorocyclopentanamine (819 mg,6.76 mmol) DIPEA (0.79 mL,4.61 mmol) in CH3CN(23 mL) was refluxed 1 hour. 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 partially concentrated untill the product started to crystallize. The white crystals were filtered off and dried overnight in vacuo at 50°C, resulting 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 in: peak at 198.05 °C.
The c 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 desired fractions were ted, evaporated, dissolved in MeOH and evaporated again, The residues were dissolved in methanol (20 mL) and crystallized upon addition of water. The white powders were ed off and dried overnight in vacuo at 50°C , resulting in compound 166a (285.5 mg, first g enantiomer), 166b (296 mg, second eluding enantiomer) Method A: Rt: 1.96 min m/z: 452.0 (M-H)- Exact mass: .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 rly as described for compound 164 using bicyclo[1.1.1]pentanamine hydrochloride d of 3,3-difluorocyclobutanamine hydrochloride. The product fractions after column chromatography were concentrated and the residue dissolved in hot methanol (25 mL). The product llized upon addition of a small amount of water. The white powder was filtered off and dried overnight in vacuo at 50°C, resulting in compound 167 (226 mg) Method A: Rt: 1.89 min m/z: 414.0 (M-H)- 416.0 (M+H)+ Exact mass: . 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 Compound 168 was prepared similarly as described for compound 164 using 3,3,3-trifluoropropylamine instead of 3,3-difluorocyclobutanamine hydrochloride but was stirred 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).
Compound 169: hloro-4,5-difluorophenyl)methyl[(3,3,3-trifluoro methylpropyl)sulfamoyl]-1H-pyrrolecarboxamide TIP 296 PCT Compound 169 was prepared similarly as compound 164 using 4,4,4-trifluorobutanamine hydrochloride instead of 3,3-difluorocyclobutanamine hloride. 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, DMSO-d6)  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: Chiralpak Diacel AD 20 x 250 mm), Mobile phase: CO2, MeOH with 0.2% ), the d fractions were collected, evaporated, solved in MeOH and evaporated again. The residue was crystallized from mL methanol upon on of water, filtered off and dried overnight in vacuo at 50°C yielding white crystals, resulting in compound 169a (first eluding enantiomer, 144 mg) and 169b d eluding enantiomer, 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 sis of 3-fluoromethyl[(3-methyloxetanyl)sulfamoyl]pyrrolecarboxylic acid for compound 74, from 5-ethoxycarbonylfluoromethyl-pyrrolesulfonic acid (heating 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 concentrated. The residue was dissolved in EtOAc (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 till 100% EtOAc in heptane. The product fractions were trated 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 ght. The reaction mixture was concentrated, 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, filtered and concentrated resulting in 3-fluoromethyl[[(1R)- 2,2,2-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 bed 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 o fluorobenzonitrile (531 mg, 3.78 mmol) instead 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: .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 e was ved in water/ EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The ed residue was ved 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 tography using a gradient from 10 to 25% EtOAc in heptane. The product fractions were concentrated 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- pyrrolecarboxylate (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 stirred 2 hours at 80°C. The on 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 ons were concentrated 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 mixture was filtered and concentrated. The residue 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 tography (2x) using a gradient from 10 to 100 % EtOAc in heptane, resulting in ethyl 3-fluoromethyl[[(1R)-2,2,2-trifluoromethylethyl moyl]pyrrolecarboxylate as a white powder which was dried overnight at 50°C in vacuo (19.1 g in total). 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 ofluoro-benzonitrile (5.11 g, 37.6 mmol)) dissolved in dry THF (200 mL) at 5°C under nitrogen atmosphere, lithium bis(trimethylsilyl)amide in e (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 sulphate, filtered and concentrated. The residue was ed by silica gel column chromatography with a gradient from 10 to 100% EtOAc in heptane. The product ons 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 chromatography (using 10 to 100% EtOAc in heptane and using dichloromethane). The resulting 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 similarly as described for ethyl romethyl[[(1R)-2,2,2-trifluoromethylethyl ]sulfamoyl]pyrrolecarboxylate starting from 5-ethoxycarbonylfluoromethylpyrrolesulfonic acid (1220 mg, 4.86 mmol), converting it to the sulphonyl chloride with thionyl 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 carboxylate (1169 mg) as a white powder. 1H NMR (400 MHz, 6)  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- ecarboxylate (1169 mg, 4.0 mmol) The reaction mixture was concentrated. The residue was dissolved in water (75 mL) and lised 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, 6)  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 compound 170 using 3- fluoro(isopropylsulfamoyl)methyl-pyrrolecarboxylic acid (594 mg, 2.25 mmol) resulting in compound 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 t 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 fractions were combined and the solvent was evaporated leaving a brown stable foam which was dissolved in a g mixture 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 t was collected as a white solid and dried in vacuo at 50°C, resulting in compound 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).
Compound 173: N-(3-Chlorofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- ecarboxamide 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 d 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 stirred at 50°C for 16 hours. Then this e was purified by silica gel column chromatography using gradient n from heptane to EtOAc. (100:0 to 0:100). The desired fractions were concentrated in vacuo and the obtained residue was crystallized 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: N-(3-Chlorofluorophenyl)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 3-chlorofluoroaniline 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). nd 175: N-(3-Cyanofluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- ecarboxamide N O S H N F N O Compound 175 (576 mg) was prepared similarly as described for nd 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: N-(3-Cyanofluorophenyl)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 Compound 177 (629 mg) was prepared similarly as bed 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).
Compound 178: N-(3-Cyano-2,4-difluorophenyl)methyl[(1-methylethyl)sulfamoyl]-1H- pyrrolecarboxamide Compound 178 (244 mg) was was prepared similarly as described for compound 173 using 3-amino-2,6-difluorobenzonitrile (0.47 g, 3.05 mmol) d of 3-chlorofluoroaniline resulting in a white powder. Method B: Rt: 0.89 min m/z: 381.1 (M-H)- Exact mass: . 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 yl)sulfamoyl]-1H-pyrrolecarboxamide Compound 179 was was prepared similarly as described 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 on mixture was stirred at 40°C for 42 hours and allowed to reach room temperature. The reaction mixture was purified using silica gel column tography (ethyl acetate in e from 10 to 70%). The desired fractions were combined and evaporated to afford light yellow oil. The yellow oil was purified using silica gel column tography (ethyl acetate in heptane from 40 to 70%) yielding nd 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 prepared 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 methanol upon on 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 (3-Cyano-2,4-difluorophenyl)fluoromethyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide nd 181 was prepared similarly as described for compound 180 using o-2,6- difluorobenzonitrile (143 mg, 0.928 mmol) instead of obenzonitrile resulting in a white powder (79 mg). Method A: Rt: 1.77 min m/z: 453.0 (M-H)- Exact mass: 454.05. 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: N-(3-Cyanofluorophenyl)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) instead 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) d 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 prepared similarly as bed 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 3-fluoromethyl[[(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 thionylchloride (heating at 80°C during 90’) and reacting this with (R)-(- )aminobutane (238.8 mg, 3.233 mmol) resulting in ethyl 3-fluoromethyl[[(1R) methylpropyl]sulfamoyl]pyrrolecarboxylate(354 mg) as a white powder. 1H NMR (400 MHz, 6)  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 (dissolved in 1 mL DMF) was purified by column tography 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 ol upon addition of water. The white crystals were filtered off and dried in vacuo at 50°C overnight, resulting in nd 186 (306 mg) Method A: Rt: 1.83 min m/z: 395.1 (M-H)- Exact mass: . 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).
Compound 187: yanofluorophenyl)[(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 aminobutane 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: yanofluorophenyl)fluoromethyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 188 (409 mg) was prepared similarly as bed for compound 186 using (2S)- 1,1,1-trifluoropropanamine instead of (R)-(-)aminobutane resulting in a white powder.
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: N-(3-Chloro-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 concentrated. The residue was purified by column chromatography on a silica using a gradient from 10 till 100 % EtOAc in heptane. The product fractions were concentrated yielding a beige . This powder was repurified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm), Mobile phase: 0.25% 3 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 te, filtered and trated 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 dissolved 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 mixture was stirred for 18 hours.
Then it was concentrated until water remained and distilled 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, ed and trated under reduced pressure resulting in 4- (tert-butylsulfamoyl)methyl-pyrrolecarboxylic acid as a white powder which was used without further purifications for the next step (10.62g). Method B: Rt: 0.83 min m/z: 258.9 (MH )- Exact mass: 260.08 und 190 (2140 mg) was prepared similarly as described for compound 158 using ofluorobenzonitrile (1348 mg, 9.604 mmol) and 4-(tertbutylsulfamoyl )methyl-pyrrolecarboxylic acid and stirring at 50°C instead of room temperature, 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, , 2.75 Hz, 1 H) 10.34 (s, 1 H).
Compound 191: t-Butylsulfamoyl)-N-(3-cyanophenyl)methyl-1H-pyrrole carboxamide TIP 296 PCT Compound 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, 6)  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) instead 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, , 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 nd 194: 4-(tert-Butylsulfamoyl)-N-(3-chloro-2,4-difluorophenyl)methyl-1H-pyrrole- 2-carboxamide Compound 194 (708 mg) was prepared similarly as described for compound 190 using 3-chloro- 2,4-difluoroaniline (628.3, 3.84 mmol) resulting in a white solid. Method B: Rt: 1.03 min m/z: 404.1 (M-H)- Exact mass: . 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). nd 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, 6)  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 toluene (6.68 mL, 6.68 mmol) over a period of 10 minutes. The resulting mixture was stirred for 1 hour while cooling was continued. 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 extracts were washed with brine (20 mL), dried on Na2SO4, filtered 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 obtained crystals were ted on a filter, rinsed with water followed by diisopropylether and dried in a vacuo at 55°C for 24 hours resulting 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 nd 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). nd 198: N-(3-Cyanofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 198 (691 mg) was prepared similarly as bed for compound 196 using 3-amino- 2-fluoro-benzonitrile (394mg, mol) 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 ethyl]sulfamoyl}-1H-pyrrolecarboxamide Sodium hydride (3.46 g, 90.2 mmol, 60 % dispersion in oil) was added portion wise, over a period of 10 minutes, to a solution of methyl 3-chloro-1H-pyrrolecarboxylate (12 g, 75.2 mmol), thane (12.8 g, 90.2 mmol) and DMF (120 mL) at 0°C under en in an ice bath. The ice bath was d 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 ved in water (100 mL)/ethyl acetate (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The e 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 reaction 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 sion was extracted using dichloromethane (3 x 100 mL). The combined organic extracts were washed with Brine and dried on sodium sulphate, filtered and concentrated 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 s under microwave irradiation. The reaction mixture 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 filtrate was concentrated in vacuo yielding brown oil. The brown oil was purified using silica gel TIP 296 PCT column chromatography (ethyl acetate in heptane from 0 to 100 %) to afford methyl ro 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 romethyl [[(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 reaction 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 extracted 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 obtained 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 10°C/min: peak at 190.1 °C.
Alternative procedure for the synthesis of methyl 3-chloromethyl[[(1R)-2,2,2-trifluoro -ethyl]sulfamoyl]pyrrolecarboxylate Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1 g, 3.68 mmol) was dissolved 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 itrile (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 les were removed under reduced pressure and the obtained e 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. nd 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 e was refluxed 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 chromatography (ethyl acetate in heptane from 0 to 100%) to afford 5-[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (5.05 g) as off white powder. cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (1.00 g, 2.93 mmol) was ved 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 ed 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: pak Diacel AD 20 x 250 mm), Mobile phase: CO2, methanol with 0.2% ), the desired ons were collected, evaporated, solved in methanol and evaporated again, yielding 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: . 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, J=56.1, 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, 6)  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 e in heptane from 10 to 70%). The desired fractions were combined and evaporated to afford a light brown oil which solidified while ng. The solid was recrystallized from ethanol (5 mL) to afford a white solid which was ed 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- R)-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) instead 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 moyl}-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). sion to product 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 ioned with ethyl acetate (3 x 100 mL).
The organic layers were combined, dried sium sulfate), the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. The crude was partially purified via silica column chromatography using a heptane to cetate gradient.
The solvent of the best fractions were removed under reduced re 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 scanning 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 bed for compound 203 using 3-chloro-2,6- difluoro-aniline mg, 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, 6)  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).
Compound 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- 4,5-difluoroaniline (970 mg, 4.663 mmol) instead of 3-aminobenzonitrile and stirring at 60°C during 18 h. The obtained residue was warmed with CH2Cl2/heptanes and the white solid collected by filtration. Method A: Rt: 1.79 min m/z: 489.9 (M-H)- Exact mass: . 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: 470.99. 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 10°C/min: peak at 216.73 °C.
Compound 207: hloro-4,5-difluoro-phenyl)[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl] methyl-pyrrolecarboxamide -[(3-chloro-4,5-difluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (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 nt from 10 till 100% EtOAc in heptane. The product fractions were concentrated. The residue was crystallized from methanol (10 mL) upon on 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]- rolecarboxamide 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 Compound 209 was prepared similarly as described for compound 146, using 3-chloro-2,4- difluoroaniline instead of 3,4-difluoroaniline.Compound 209 was recrystallized from EtOH, ing 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 nd 210 was prepared similarly as bed for compound 144 using 3-chloro-2,4- difluoroaniline instead of 3,4-difluoroaniline. The obtained solid was recrystallized from ethanol (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 ls) 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- pyrrolecarboxamide Compound 212 (396 mg, white crystals) was ed similarly as described for compound 214, using ro-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 described for nd 214, using 2,3,4-trifluoroaniline instead of 5-aminofluoro-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 scanning 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- pyrrolecarboxamide A mixture of ethyl 4-chlorosulfonylfluoromethyl-pyrrolecarboxylate (purified by column tography with 10 to 50 % EtOAc in heptane, 1.50 g, 5.6 mmol), tert-butylamine (934 mg, 12.8 mmol) and itrile (75 mL) was stirred 2 hours and then concentrated. The residue was ved 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 ls 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, DMSO-d6)  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. 4-(tert-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 e. The product 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).
Differential scanning metry: From 30 to 300 °C at 10°C/min: peak at: 198.3 °C.
Compound 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 ofluoro-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 Compound 171 (60 mg, 0.16 mmol) and potassium cyanide (102 mg, 1. 6 mmol) were dissolved in acetonitrile (2 mL, 38.3 mmol) and heated at 130°C for 8.5 hours by microwave irradiation.
The reaction mixture was ed, 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 compound 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, 6)  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: ro-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 acetonitrile (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 ated to dryness. The obtained residue was purified by silica gel column chromatography using a heptane to EtOAc gradient yielding methyl romethyl[[(1R)-2,2,2-trifluoro methyl-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 d 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 s 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 keep+/- 50 mL. A white precipitate was formed. 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 nd 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). nd 218: 3-Chloro-N-(3-chloro-2,4-difluorophenyl)methyl{[(1R)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 218 was prepared rly as described for the synthesis of compound 217 using 3- -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 acetate (20 mL) resulting 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 in: peak at 213.0 °C.
Compound 219: 3-Chloro-N-(3-chloro-2,4-difluorophenyl)methyl{[1-(trifluoro- methyl)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 rofluoro-aniline instead of 5-aminofluorobenzonitrile. Method D: Rt: 2.07min m/z: 420.1 (M-H)- Exact mass: 421.0. 1H NMR (400 MHz, DMSO-d6)  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). ential scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 195.9 °C. nd 221: 3-Chloro-N-(3-cyanofluorophenyl)methyl{[1-(trifluoro- methyl)cyclobutyl]sulfamoyl}-1H-pyrrolecarboxamide TIP 296 PCT Methyl rochlorosulfonylmethyl-pyrrolecarboxylate (2000 mg, 7.35 mmol) was sed in itrile (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 o- 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 se and the reaction 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 les 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 ite 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 compound 217 using 3- chlorofluoro-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 (4 x 50 mL). The combined organic layers were washed with brine and dried (Na2SO4) and concentrated 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). Differential scanning metry: From 30 to 300 °C at 10°C/min: peak at 218.8 °C.
TIP 296 PCT nd 223: t-Butylsulfamoyl)chloro-N-(3,4-difluorophenyl)methyl-1H-pyrrole- oxamide Compound 223 (579 mg) was prepared similarly as described for the synthesis of compound 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. nd 225: 3-Chloro-N-(3-cyanofluorophenyl)methyl{[(1S)-2,2,2-trifluoro methylethyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 225 was prepared 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 nd 226: 4-(tert-Butylsulfamoyl)chloro-N-(3-cyanofluorophenyl)methyl-1H- ecarboxamide 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 purified on silica using a heptane to EtOAc gradient ng methyl 4-(tert-butylsulfamoyl)chloromethyl-pyrrole carboxylate (3.57 g) as a white powder after trituration 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 reaction mixture was allowed to reach room temperature. More lithium bis(trimethylsilyl)amide (1 mL, 1M in THF, 1 mmol) was added and the reaction mixture was stirred for 30 s 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, ated with diisopropylether and dried, yielding 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, 6)  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 ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 207.0 °C.
Compound 227: N-(3-Cyanofluorophenyl)methyl{[1-(trifluoromethyl)cyclopropyl ]sulfamoyl}-1H-pyrrolecarboxamide cyanofluoro-phenyl)carbamoyl]methyl-pyrrolesulfonyl chloride (600 mg, 1.76 mmol) was mixed with 1-trifluoromethylcyclopropylamine (329 mg, 2.63 mmol), acetonitrile (10 mL), molecular sieves and Hunig's base (0.91 mL, 0.75 g/mL, 5.27 mmol) in a microwave TIP 296 PCT 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 concentrated to dryness. The obtained residue was purified using silica gel column chromatography (ethyl acetate 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). nd 228: N-(3-Cyanofluorophenyl)methyl{[3-(trifluoromethyl)tetrahydrofuran- 3-yl]sulfamoyl}-1H-pyrrolecarboxamide Compound 228 (153 mg) was prepared similarly 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 onary phase: Chiralpak Daicel IC 20 x 250 mm, Mobile phase: CO2, 12-50% MeOH with 0.4% iPrNH2), resulting in nd 228a (first eluding) and 228b (second eluding, 41 mg). 228a was further purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) resulting 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 mixture 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 filtrated. The filtrate was trated in vacuo and the obtained residue (63.1 g) was used directly in the next step. The ed residue (63 g) was dissolved in acetonitrile (600 mL).
Trifluoroacetic acid (45 g, 394 mmol), potassium hydrogenfluoride (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 minutes. uoromethyl)trimethylsilane (77 g, 541 mmol) was added to the reaction mixture and the mixture was d 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 e was dissolved in 2M HCl/MeOH 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 filtered and the filtrate 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 ylate (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 en atmosphere, at 0°C, lithium 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 temperature. The on e 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 crystals were ed off and dried in vacuo at 50°C overnight, resulting in nd 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 F O H F NH S Br O N 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 product ons were concentrated. The residue was dissolved 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 ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 200.9 °C.
Compound 231: N-(3-Cyano-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, 6 )  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 ng metry: From 30 to 300 °C at 10°C/min: 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 compound 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. nd 234: N-(3-Chloro-2,4-difluorophenyl)fluoromethyl[(1-methyl- ethyl)sulfamoyl]-1H-pyrrolecarboxamide Compound 234 (95 mg) was prepared 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 nd 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). Differential scanning calorimetry: From 30 to 300 °C at in: peak at 201.9 °C.
Compound 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 ed 2 hours. The reaction mixture was concentrated and the obtained residue was dissolved in EtOAc (50 mL) washed with HCl 1M, dried over sodium sulphate, filtered and concentrated. The obtained residue 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 omers 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 ) with 0.2% iPrNH2) 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: yanofluorophenyl)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 pressure tube. 2,2,2-trifluoro-1,1-dimethyl-ethylamine (139 mg, 1.1 mmol) and sodium bicarbonate (307.3 mg, 3.66 mmol) were sed 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 te was concentrated in vacuo and the obtained residue was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated under d 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: N-(3-Cyanofluorophenyl)methyl[(3,3,3-trifluoromethylpropyl moyl]-1H-pyrrolecarboxamide Compound 238 (206 mg) was prepared similarly as described for compound 237, using 4,4,4- trifluorobutanamine instead of 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 rly as described 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: N-(3-Cyanofluorophenyl)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 prepared 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), .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 nd 244 (144 mg) was ed similarly as described for compound 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]- 1-methyl-1H-pyrrolecarboxamide Compound 245 (243 mg) was prepared similarly as bed 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 hloride instead of 2,2,2-trifluoro-1,1-dimethylethylamine and 48 hours reaction time instead 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 hloride 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 (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 on 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: N-(3-cyanofluoro-phenyl){[1-ethyl(trifluoromethyl)propyl]sulfamoyl}- 1-methyl-1H-pyrrolecarboxamide nd 248 (40 mg) was prepared similarly as described for compound 237, using 3- (trifluoromethyl)pentanamine hydrochloride instead 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] -1H-pyrrolecarboxamide Compound 249 (178 mg) was prepared similarly as described for compound 237, using 1-fluoro- 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: romophenyl)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 methyl-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 on 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 organic 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 gradient from 10 till 100% EtOAc in heptane. The t fractions were concentrated and compound 251 was crystallized by dissolving the obtained liquid residue in methanol (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 ng 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 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. r tube was loaded with 1,1- difluoropropanamine (1.0 mmol) and sodium bicarbonate (284 mg, 3.39 mmol) and this was dispersed in acetonitrile (2 mL) and dried with powdered molecular sieves (4Å) over a period of minutes. This was added to the pressure tube which was d with en, 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 residue was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The ed powder was dried in a vacuum oven at 55°C for 24 hours yielding compound 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)- cyclopropyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 253 (104 mg) was prepared similarly as described for compound 252, using 1- trifluoromethylcyclopropylamine instead of 1,1-difluoropropanamine and 48 hours reaction time instead of 24 hours. An extra cation 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, 6 )  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: hloro-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 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 on 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)- oyl]-1H-pyrrolecarboxamide Compound 255 (211 mg) was prepared similarly as described for compound 252, using (1- methylcyclopropyl)amine hydrochloride d 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).
Compound 256: N-(3-chloro-2,4-difluoro-phenyl)[(3,3-difluoromethyl-cyclobutyl )sulfamoyl]methyl-1H-pyrrolecarboxamide Compound 256 (258 mg) was prepared similarly as bed for compound 252, using 3,3- difluoromethylcyclobutanamine 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 prepared 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: hloro-2,4-difluoro-phenyl)methyl[[4-(trifluoromethyl)- tetrahydropyranyl]sulfamoyl]-1H-pyrrolecarboxamide Compound 258 (29 mg) was prepared similarly as described for compound 252, using 4- (trifluoromethyl)oxanamine 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, 30x150mm, 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 hloride 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 1,1-difluoropropanamine. Method B: Rt: 1.06 min m/z: 458.1 (M-H)- Exact mass: 459.0. 1 H NMR (400 MHz, DMSO-d6)  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). nd 261: N-(3-chloro-2,4-difluoro-phenyl)[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl] methyl-1H-pyrrolecarboxamide nd 261 (143 mg) was prepared similarly as described for compound 252, using 1-fluoro- ylpropanamine instead of 1,1-difluoropropanamine. The desired fractions were concentrated 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).
Compound 262: N-(3-chloro-2,4-difluoro-phenyl)methyl{[(1S)(trifluoromethyl l]sulfamoyl}-1H-pyrrolecarboxamide nd 262 (227 mg) was prepared similarly as described for compound 252, using (S) trifluoromethyl-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 on in water, MeOH). Method B: Rt: 1.10 min m/z: 470.1 (M-H)- Exact mass: 471.0. 1 H NMR (400 MHz, DMSO-d6 )  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)- sulfamoyl}methyl-1H-pyrrolecarboxamide Compound 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 nd 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 instead 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)- tetrahydrofuranyl]sulfamoyl}-1H-pyrrolecarboxamide Compound 266 (140 mg) was prepared similarly as bed 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, DMSO-d6 )  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), .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 pressure and the residue was purified on silica using a heptane to EtOAc gradient and further by preparative HPLC (Stationary phase: RP e Prep C18 OBD-10µm, 30 x 150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN); - ing in nd 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 romethyl[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxylate (155 mg, 0.2 mmol) and 3-chlorofluoro-aniline (38 mg, 0.26 mmol) were dissolved in dry THF (10 mL) and cooled to 0ºC. Lithium imethylsilyl)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 stirred for another 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]- 1H-pyrrolecarboxamide Methyl 3-chlorochlorosulfonylmethyl-pyrrolecarboxylate (1.5 g, 5.51 mmol) was dissolved in itrile (8 mL) and dried on molecular sieves. NaHCO3 (1389 mg, 16.54 mmol) was added. Isopropylamine 1 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 filtered and washed with acetonitrile and ated 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 5-aminofluorobenzonitrile (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 mixture was stirred for 2 minutes while cooling was continued. The mixture was ed with ted ammonium de (50 mL) and extracted using EtOAc (2 X 100 mL). The combined extracts were washed with brine (50 mL), dried on Na2SO4, ed and concentrated in vacuo to afford a dark brown powder which was purified using silica gel column chromatography (ethyl acetate in heptane 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 compound 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 nd 270: 3-Chloro-N-(3-cyanofluorophenyl)methyl[(2,2,2-trifluoro-1,1- dimethylethyl)sulfamoyl]-1H-pyrrolecarboxamide Compound 270 was prepared similarly as described for compound 269, using 3 equiv 2,2,2- trifluoro-1,1-dimethyl-ethylamine, instead 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).
Compound 271: ro-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- yl-benzonitrile instead of 3-bromoaniline. ential scanning calorimetry: From 30 to TIP 296 PCT 300 °C at 10°C/min: peak at 235.1°C. Method B: Rt: 1.05 min m/z: 465.1 (M-H)- Exact mass: 466.0. 1H NMR (400 MHz, DMSO-d6)  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 Compound 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 ng metry: 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 described for compound 250, using ro uoromethyl)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 described for nd 250, using ro 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 Compound 276 was prepared similarly as bed 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: ro-N-(2,3-dichlorofluoro-phenyl)methyl[[(1R)-2,2,2-trifluoro methyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 277 was prepared similarly 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 romethane (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 s NaHCO3/ice and the aqueous phase was ted twice with ethyl acetate.
The combined c 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 ethanol (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, filtered 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). nd 278 was prepared similarly as described for compound 250, using 3-(difluoromethyl)-2,4-difluoro-aniline hydrochloride instead of 3-bromoaniline.
Differential scanning calorimetry: From 30 to 300°C at 10°C/min: peak at 189.5°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 Compound 279: 3-chloro-N-[3-(difluoromethyl)fluoro-phenyl]methyl[[(1R)-2,2,2- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide Compound 279 was prepared similarly as described for nd 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 described 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). ential scanning metry: 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 ght. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography using a nt from 10 to 100% EtOAc in e. 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 ium sulphate, ed 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. 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 ght 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 10°C/min: 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 4-chlorosulfonyl-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 sieves. 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 ed using silica gel column chromatography resulting in ethyl 1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole ylate (600 mg) as colorless sticky powder. Ethyl 1,5-dimethyl[[(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 tography (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 ro-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 chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the residue dissolved in hot methanol (10 mL). Water was added untill llisation 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 ng calorimetry: From 30 to 300 °C at 10°C/min: peak at 240.0°C.
Compound 283: N-(3-cyanofluoromethyl-phenyl)fluoromethyl[[(1R)-2,2,2- oromethyl-ethyl]sulfamoyl]pyrrolecarboxamide 2-fluoromethylbenzonitrile (18 g, 133 mmol) was added to a solution of ium 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 on mixture was poured into ice water and the pale yellow precipitate 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 ed through celite and after removal of organic solvent, 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 t 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 similarly as described for compound 229, using 5-aminofluoromethyl- TIP 296 PCT benzonitrile instead of 3,4-difluoroaniline. Method D: 5 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 scanning calorimetry: From 30 to 300 °C at 10°C/min: peak at 214.8°C.
Compound 284: N-(3-cyanofluoro-phenyl)fluoromethyl[[(1S)(trifluoromethyl )propyl]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 ng calorimetry: From 30 to 300 °C at in: 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 scanning metry: From 30 to 300 °C at 10°C/min: peak at 212.9°C. nd 286: N-[3-(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- (difluoromethyl)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). ential 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 bed for compound 229, using 3- (difluoromethyl)-2,4-difluoro-aniline instead of 3,4-difluoroaniline. Method D: Rt:1.95 min m/z: 478.3 (M-H)- Exact mass: 479.1. 1H NMR (400 MHz, DMSO-d6)  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).
Compound 288: N-(3-cyanofluoro-phenyl)fluoromethyl[[(1R)(trifluoromethyl )propyl]sulfamoyl]pyrrolecarboxamide nd 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 scanning 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. r tube was loaded with (S)trifluoromethylpropylamine (700.7 mg, 5.51 mmol) and NaHCO3 (926 mg, 11.03 mmol) and this was dispersed in acetonitrile (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 on mixture was filtered and concentrated. The e was ved in CH2Cl2 (5mL) filtered and subjected to silica gel column chromatography using a gradient from to 100% EtOAc in heptane. The t fractions were concentrated yielding methyl 3- chloromethyl[[(1S)(trifluoromethyl)propyl]sulfamoyl]pyrrolecarboxylate (829 mg) as a white solidified resin. m 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 solution (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 t fractions were concentrated and the residue dissolved in methanol (10mL). Water was added untill crystallisation began. nd 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 Compound 290 (133 mg) was ed similarly as described for compound 289 using (R)-1,1,1- trifluorobutylamine instead of (S)trifluoromethyl-propylamine. Method D: 5 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 ng 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 -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 mineral 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 se and the mixture was stirred at room temperature for 16 hours. The e was quenched with water and the mixture was extracted 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 chlorosulfonic 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 mixture was added dropwise to a stirred, temperature controlled ter mixture (100 mL) keeping the ature under 5°C. A white suspension was formed. The obtained aqueous 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 acetonitrile (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 ght at 80ºC. The reaction mixture was ed 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 using gradient eluent heptane-EtOAc; 100-0 -> 50-50. The product 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 5-aminofluorobenzonitrile 201mg, 1.43 mmol) was ved in THF (dried on molecular sieves) (10.1 mL, 124.7 mmol). lithium imethylsilyl)amide (1M in THF) (3.58 mL, 1 M, 3.583 mmol) was added drop wise and the reaction e 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 purified 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, filtered 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 -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 d 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 3-bromo 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 d. In a seperate vessel 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 les 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 resulting 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 ved 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 ed with sat. NH4Cl (5 mL). The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were ated to s and the residue was purified on silica using a heptane to EtOAc gradient resulting in compound 292 (146 mg) as a light pink powder after trituration in CH2Cl2/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 metry: 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 charged with compound 292 (94 mg, 0.189 mmol) and zinc cyanide (13.6 mg, 0.113 mmol) in DMF (0.8 mL). The mixture 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 mixture 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 e 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 ved 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: yanofluoro-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 lar 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 sed 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 stirred in a heating block at 80°C for 2 hours. Then the reaction mixture was filtered over a small path of dicalite and rinsed using dichloromethane (50 mL). The filtrate was concentrated in vacuo and the obtained residue was purified using silica gel column tography (gradient elution: 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: 3-chloro-N-(3-cyanofluoro-phenyl)methyl[[(1R)methyl- propyl]sulfamoyl]pyrrolecarboxamide TIP 296 PCT Compound 295 (515 mg) was ed similarly as described for compound 289 using (S)-(+) aminobutane instead of (S)trifluoromethyl-propylamine, stirring at70°C for 2 hours for the formation of methyl romethyl[[(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: 1 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] -pyrrolecarboxamide Compound 296 was prepared similarly as described for compound 294 using 3-amino methylbutanol 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 hydrochloride (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 mixture was poured into water (500 mL) and the formed precipitate was ed 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. Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the on mixture was stirred 16 hours at room temperature. The reaction mixture was poored into water (100 mL) and TIP 296 PCT evaporated to dryness. The e 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 . To a cooled (-78ºC) 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 c layer was washed with water, dried over Na2SO4, filtered and evaporated to s. The obtained e was purified by silica gel chromatography yielding tert-butyl )-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 minutes and then the volatiles were removed under reduced pressure yielding (2S)-3,3-difluorobutanamine hydrochloride (3.8 g) 1H NMR z, 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]- 1-methyl-pyrrolecarboxamide Compound 297 was prepared similarly as described for nd 294 using (2S)-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=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 residue 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 ved in THF (300 mL) and cooled to 0ºC. Methylmagnesium bromide 3.0 m in diethyl ether (85 mL, 255 mmol) was added drop wise and the reaction mixture was d 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 ed residue was purified via silica gel chromatography yielding tert-butyl N-[(1R)methyloxopropyl ]carbamate (18.9 g). To a cooled (-78ºC) on of tert-butyl N-[(1R)methyloxopropyl mate (10 g, 53.4 mmol) in CH2Cl2 (200 mL) bis(2-methoxyethyl)aminosulfur oride (18.9 g, 117.5 mmol) was added drop wise and stirring was continued for 2 hours at - 78ºC. The reaction 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 ated to dryness.
The residue was purified by silica gel chromatography 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 precipitate was filtered off and dried under high vacuum yielding (2R)-3,3-difluorobutanamine hydrochloride (3.5 g).
Compound 298: N-(3-cyanofluoro-phenyl)[[(1R)-2,2-difluoromethyl-propyl]- sulfamoyl]methyl-pyrrolecarboxamide Compound 298 was ed 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 allowed to reach room temperature overnight. The reaction mixture was trated and the obtained residue was dissolved in EtOAc (50mL) washed with NaHCO3 solution, dried over magnesium sulphate, filtered and concentrated, ing in ethyl 5-bromofluoromethyl[[(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 on 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 on mixture was heated at 140°C during 30 minutes by microwave irradiation. The reaction mixture was concentrated and 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 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, DMSO-d6)  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 bis(trimethylsilyl)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 ofluoro-benzonitrile (73.5 mg, 0.54 mmol) dissolved in THF (2 mL) and stirred overnight. The reaction e was quenched with NH4Cl solution (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 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 concentrated 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, ing 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 metry: 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 chromatography (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- trifluoromethyl-ethyl]sulfamoyl]pyrrolecarboxamide A mixture 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 reaction e was stirred for 4 hours. The reaction mixture was concentrated, the obtained residue dissolved in water (50 mL) and the on was neutralised with HCl (1 M in H2O). The formed white powder was filtered 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 moyl]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 on mixture was stirred over TIP 296 PCT weekend at 55°C. The solution was subjected to silica gel column chromatography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated. The e 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). nd 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. is(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 minutes 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 c 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 trated in vacuo. The product was purified using silica gel column chromatography using gradient eluent Heptane-EtOAc; 100-0 -> 0-50 and r via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN), resulting in compound 302 (10 mg).
Method B: Rt:1.10 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 organic layer was separated, dried (MgSO4), filtered and concentrated 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 3-isopropenylmethyl[[(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 osphere and the on mixture was stirred under osphere until 1 eq. H2 was absorbed. The catalyst was removed by filtration over dicalite under nitrogen atmosphere, and the solvent was removed in vacuo, resulting in crude methyl 3-isopropylmethyl[[(1R)- 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 sieves. Lithium bis(trimethylsilyl)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 t was purified by silica gel column chromatography using nt eluent Heptane-EtOAc; 100-0 to 50-50 and further by prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were collected and concentrated in vacuo. The residue was ved 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 e 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 minutes. The reaction mixture was concentrated. The residue was dissolved in EtOAc (10 mL) and water (5 mL) The organic layer was dried over magnesium te, filtered and concentrated. The residue was subjected to silica gel column tography using a gradient from 10 to 100% EtOAc in heptane. The product fractions were concentrated and the e 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, ing 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 mixture was cooled and washed with water/NH4OH. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel tography using gradient eluent Heptane-EtOAc; 100-0 -> 70-30. The product fractions were collected and concentrated 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 d 30 s. 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 . The precipatate (0.7 g) was added to SOCl2 (0.7 g, 2.503 mmol) and the e 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 itrile (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), molecular 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 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 tography (solid phase, 40g) using gradient eluent heptane-EtOAc; 100-0 -> 50-50. The product fractions were combined and concentrated in vacuo to resulting in methyl 3- chlorocyclopropyl[[(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 (48.681 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 mixture was ed with sat. sol. The organic layer was ted, dried (MgSO4), filtered and concentrated in vacuo. A purification was performed via Preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were ted 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: 478.0.1H 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 3-methyl- 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 -pyrrolecarboxylate similarly as described for compound 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 similarly as described for compound 292, using 4-fluoro -aniline instead of ofluorobenzonitrile. 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, 29.0mmol), water (distilled, 0.25 mL) during 5 minutes. Then tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added and the reaction mixture was heated at 140°C during 30 minutes by ave irradiation. The reaction 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 ed by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and further ed 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 metry: From 30 to 300 °C at 10°C/min: 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 red 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 heptane gradient from 10 to 50%. The product fractions were concentrated. The residue was dissolved in methanol (5 mL) 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 310 (45 mg). Method D: Rt: 1.91 min m/z: 460.3 (M-H)- Exact mass: 461.1. Differential scanning metry: From 30 to 300 °C at °C/min: peak at 211.4°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 d h a mixture of compound 301 (prepared rly as described in the sis of 301, but on a larger scale, 446 mg, 0.87 mmol) potassium 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 on mixture was heated at 140°C during 30 minutes by microwave irradiation. The reaction mixture was concentrated. The obtained residue was dissolved in EtOAc (50 mL) and water (25 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue was ted 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 dissolved in methanol (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 3-fluoromethyl[[(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 ght. 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 product fractions were concentrated 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 ng calorimetry: From 30 to 300 °C at in: peak at 179.4°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 on 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 temperature for 10 minutes. NH4Cl (3.29 g, 61.5 mmol) was added and the e was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was collected, washed with brine, dried and evaporated.
The crude was ed by column tography 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 filtrate was evaporated. The crude compound was purified by high-performance liquid chromatography (Column: ADIKMA Diamonsil(2) C18, 150*25*5um, Flow rate: 35 mL/min, Mobile Phase A: Purified water (containing 0.5% HCl), Mobile Phase B: CH3CN, nt: 53-83% (%B). NaHCO3 solution was added to adjust the pH to 8.The desired fraction was ted and the solvent was concentrated in vacuo ing in 5-aminochloro- 2-fluoro-benzonitrile (253 mg).
Compound 313 (118 mg) was prepared similarly as described for nd 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 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).
Compound 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 ght. The reaction 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 residue was dissolved in methanol (5mL) and the product crystallised upon addition 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), .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 nd 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 d 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 methanol (10 mL) upon addition of water. The white ls 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 ed residue was dissolved in water/EtOAc (10/20 mL) The organic layer was dried over magnesium sulphate, filtered and concentrated. The ed residue was purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated yielding ethyl 3-cyano-1,5-dimethyl[[(1R)-2,2,2-trifluoromethyl-ethyl]sulfamoyl]pyrrole carboxylate (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 toluene (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 stirred overnight. The reaction mixture was quenched TIP 296 PCT with NH4Cl solution (5 mL) and diluted with brine (5 mL), then ted with EtOAc (20 mL).
The organic 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 nt from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the residue 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 signal, 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 concentrated. The residue (1 g) was subjected to silica gel column chromatography using a gradient from 0 till 100 % EtOAc in heptane. The product fractions were trated 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). Lithium 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 dryness and the residue was ed by silica gel tography (ethyl acetate in heptane 0 to 100% and again with ethyl e in heptane 0 to 60%). The desired fractions were evaporated to dryness, the resulting residue was dissolved in refluxing isopropanol (7 mL) and ted 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 Compound 318 (111 mg) was prepared similarly as described for nd 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: yanofluoro-phenyl)fluoromethyl[[1- (trifluoromethyl)cyclobutyl]sulfamoyl]pyrrolecarboxamide A e ethyl 4-chlorosulfonylfluoromethyl-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 r 4 equiv of 1-(trifluoromethyl)cyclobutanamine were added). The reaction mixture was filtered while still hot. The te 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 fractions were concentrated in vacuo at 50°C yielding ethyl 3-fluoromethyl[[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 overnight. 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 mixture 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 mixture 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 methanol (25 mL) and water was added untill llisation began. The white crystals were filtered off and dried in vacuo at 50°C ght, 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, DMSO-d6)  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 es – 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 antiviral, assay cells were treated twice for three days with serially diluted compound in 96-well plates in duplicate. After 6 days of ent the antiviral ty was determined by quantification of purified HBV DNA from secreted virions using me PCR and an HBV specific primer set and probe.
The anti HBV ty was also measured using the HepG2.117 cell line, a stable, inducibly HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off system).
For the antiviral assay, HBV replication was induced, followed by a treatment with serially diluted compound in 96-well plates in duplicate. After 3 days of treatment, the antiviral ty 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 ce of compounds. The viability of the cells was assessed using a rin 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 (26)

Claims
1. A pharmaceutical composition comprising a ation of (a) a compound of Formula (IA) 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, -CF2-methyl, -CH2F, -CF3, -OCF3, -CN, C1-C3alkyl and C3-C4cycloalkyl; 15 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 20 substituted 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 optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered ted ring or C2-C6alkyl optionally being substituted with one or more tuents each independently selected from 25 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, 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, TIP 296 PCT such 3-7 membered ted 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; 10 or a pharmaceutically acceptable salt or a solvate thereof wherein such compound is or , and (b) at least one other HBV inhibitor, and a pharmaceutically acceptable carrier, 15 wherein the medicament is formulated for te, sequential, or simultaneous administration of (a) and (b).
2. A composition according to claim 1 with Formula (IB) 20 3. A composition according to any one of the previous claims wherein R4 in Formula
3.(IA) or (IB) is methyl.
4. A composition according to any one of the previous claims wherein R6 in Formula (IA) or (IB) contains a 3-7 membered saturated ring optionally ning one 25 oxygen.
5. A composition according to any one of the us claims wherein R6 in Formula (IA) or (IB) is a 4 or 5 membered saturated ring containing one , such 4 or 5 membered saturated ring optionally tuted with C1-C4alkyl optionally 30 substituted with R10. TIP 296 PCT
6. A composition according to any one of claims 1 to 3 wherein R6 in Formula (IA) or (IB) comprises a branched C3-C6alkyl optionally substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl wherein such C3-C6cycloalkyl 5 is substituted with one or more Fluoro or substituted with C1-C4alkyl tuted with one or more Fluoro.
7. A composition according to claim 6 n R6 is a branched C3-C6alkyl substituted with one or more Fluoro.
8. A composition according to any one of the previous claims wherein Rb in a (IA) or (IB) is Hydrogen or Fluoro.
9. A composition according to any one of the previous claims wherein Ra and Rc in 15 Formula (IA) or (IB) are independently selected from the group consisting of Hydrogen, Fluoro, , CN and methyl.
10. A composition according to any one of the previous claims, which is selected from among nds 1-285, 287 and 289-296 Compound 1: HN HN O O 25 Compound 2: HN F S HN N O Compound 3: TIP 296 PCT O O H F HO (R) O N H Compound 4: O F H O (S) S N O N Compound 5: HN S N O O nd 6: Compound 7: Compound 8: TIP 296 PCT Compound 9: 5 nd 10: Compound 11: Compound 12: Compound 13: TIP 296 PCT Compound 14: 5 Compound 15: nd 16: Compound 17: Compound 18: Compound 19: TIP 296 PCT Compound 20: nd 21: Compound 22: 10 Compound 23: Compound 24: Compound 25: TIP 296 PCT nd 91: Compound 92: Compound 93: Compound 95: TIP 296 PCT nd 26: Compound 27: Compound 28: Compound 29: Compound 30: TIP 296 PCT nd 31: Compound 32: Compound 33: Compound 34: Compound 35: 15 Compound 36: TIP 296 PCT Compound 37: Compound 38: nd 39: Compound 40: 15 Compound 41: TIP 296 PCT nd 42: Compound 43: Compound 44: Compound 45: 15 Compound 46: TIP 296 PCT Compound 47: Compound 48: nd 49: Compound 50: Compound 51: TIP 296 PCT nd 52: Compound 53: Compound 54: Compound 55: 15 Compound 56: TIP 296 PCT Compound 57: nd 58: Compound 59: Compound 60: TIP 296 PCT Compound 65: nd 66: 5 Compound 72: Compound 73: Compound 96: TIP 296 PCT nd 61: Compound 62: 5 Compound 63: Compound 64: Compound 67: Compound 68: TIP 296 PCT Compound 69: Compound 70: nd 71: Compound 74: 10 Compound 75: Compound 76: TIP 296 PCT Compound 77: nd 78: Compound 79: Compound 80: Compound 81: Compound 82: TIP 296 PCT nd 83: Compound 84: Compound 85: Compound 86: Compound 87: TIP 296 PCT Compound 88: nd 89: Compound 90: Compound 97: Compound 98: TIP 296 PCT Compound 99: Compound 100: nd 101: 10 Compound 102: Compound 103: Compound 104: TIP 296 PCT Compound 105: Compound 94: Compound 106: Compound 107: nd 108: Compound 109: TIP 296 PCT F O HN S N O N F Compound 110: 5 Compound 111: Compound 112: 10 nd 113: Compound 114: Compound 115: TIP 296 PCT Compound 116: Compound 117: Compound 118: Compound 119: nd 120: Compound 121: TIP 296 PCT Compound 122: Compound 123: Compound 124: nd 125: 10 Compound 126: Compound 127: TIP 296 PCT Compound 128: F N O S H N F N O Cl Compound 129: nd 130: Compound 131: 10 Compound 132: TIP 296 PCT Compound 133: Compound 134: 5 nd 135: Compound 136: Compound 137: Compound 138: TIP 296 PCT nd 139: Compound 140: Compound 141: Compound 142: 10 Compound 143: TIP 296 PCT Compound 144: Compound 145: nd 146: Compound 147: Compound 148: TIP 296 PCT Compound 149: 5 nd 150: Compound 151: Compound 152: TIP 296 PCT nd 153: Compound 154: 5 Compound 155: Compound 156: Compound 157: Compound 158: TIP 296 PCT nd 159: Compound 160: Compound 161: Compound 162: Compound 163: TIP 296 PCT nd 164: 5 Compound 165: Compound 166: 10 Compound 167: Compound 168: TIP 296 PCT Compound 169: 5 nd 170: Compound 171: Compound 172: Compound 173: TIP 296 PCT Compound 174: Compound 175: N O S H N F N O 5 N Compound 176: nd 177: Compound 178: TIP 296 PCT Compound 179: nd 180: Compound 181: Compound 182: Compound 183: Compound 184: TIP 296 PCT Compound 185: Compound 186: Compound 187: nd 188: Compound 189: TIP 296 PCT Compound 190: nd 191: Compound 192: Compound 193: Compound 194: TIP 296 PCT nd 195: Compound 196: Compound 197: Compound 198: Compound 199: TIP 296 PCT Compound 200: nd 201: Compound 243: Compound 202: Compound 203: TIP 296 PCT Compound 204: Compound 205: Compound 206: nd 207: Compound 208: TIP 296 PCT Compound 209: 5 nd 210: Compound 211: Compound 212: TIP 296 PCT Compound 213: Compound 214: 5 nd 215: Compound 216: 10 Compound 217: TIP 296 PCT nd 218: Compound 219: Compound 220: Compound 221: Compound 222: 15 Compound 223: TIP 296 PCT Compound 224: nd 225: Compound 226: Compound 227: 15 Compound 228: TIP 296 PCT Compound 229: 5 Compound 230: F O N F NH S Br O N Compound 231: 10 nd 232: Compound 233: TIP 296 PCT Compound 234: 5 Compound 235: Compound 236: nd 237: 15 Compound 238: TIP 296 PCT Compound 239: 5 nd 240: Compound 241: 10 Compound 242: Compound 244: TIP 296 PCT nd 245: 5 Compound 246: Compound 247: 10 Compound 248: TIP 296 PCT Compound 249: Compound 250: nd 251: Compound 252: 10 Compound 253: Compound 254: TIP 296 PCT Compound 255: Compound 256: nd 257: Compound 258: 15 Compound 259: TIP 296 PCT Compound 260: Compound 261: nd 262: Compound 263: 15 Compound 264: TIP 296 PCT Compound 265: Compound 266: nd 267: Compound 268: TIP 296 PCT Compound 269: Compound 270: nd 271: 10 Compound 272: Compound 273: TIP 296 PCT Compound 274: 5 Compound 275: Compound 276: nd 277: Compound 278: TIP 296 PCT Compound 279: 5 Compound 280: nd 281: Compound 282: TIP 296 PCT nd 283: Compound 284: Compound 285: 10 Compound 287: Compound 289: TIP 296 PCT nd 290: Compound 291: Compound 292: Compound 293: TIP 296 PCT Compound 294: Compound 295: Compound 296:
11. A composition as claimed in any one of the previous claims, wherein the at least one other HBV inhibitor of (b) is an immunomodulator selected from interferon-α (IFN-α), pegylated interferon-α and Toll-like receptor 7 and/or 8 ts. 15
12. A tion as claimed in claim 11, wherein the immunomodulator is pegylated interferon-α. TIP 296 PCT
13. A compostion as claimed in claim 11 or 12 wherein the compound of Formula (IA) is .
14. Use of (a) a compound of Formula (IA) as defined in any one of the previous 5 claims, or a stereoismeric or tautomeric form thereof, and (b) at least one other HBV inhibitor, in the manufacture of a medicament for the prevention or treatment of an HBV infection in a mammal,wherein said medicament is formulated for separate, sequential or simultaneous administration of (a) and (b). 10
15. A use as claimed in claim 14, wherein (b) the at least one other HBV tor is an immunomodulator selected from interferon-α (IFN-α), ted interferon-α and Toll-like receptor 7 and/or 8 agonists.
16. A use as claimed in claim 15, wherein the immunomodulator is pegylated 15 interferon-α.
17. A use as claimed in any one of claims 14-16 wherein the compound of Formula
18.(IA) is . 20 18. A use of (a) a nd of Formula (IA) as d in claim 1, or a stereoismeric or tautomeric form thereof, in the manufacture of a medicament for the prevention or ent of an HBV infection in a mammal, wherein said mammal is also to be administered (b) at least one other HBV inhibitor. 25
19. A use according to claim 18, wherein the at least one other HBV inhibitor is an modulator selected from interferon-α (IFN-α), pegylated interferon-α and Tolllike or 7 and/or 8 agonists.
20. A use as claimed in claim 19, wherein the immunomodulator is pegylated 30 interferon-α. TIP 296 PCT
21. A use as claimed in any one of claims 18-20 wherein the compound of Formula (IA) is . 5
22. A use according to any one of claims 18-21, wherein (a) the compound of Formula (IA) and the (b) at least one other HBV inhibitor are to be administered separately, sequentially, or simultaneously.
23. A use ing to any one of claims 18-22, wherein (a) the compound of 10 Formula (IA) and (b) at least one other HBV inhibitor are ito be administered er in a single medicament.
24. A product containing (a) a compound of Formula (IA) or (IB) as defined in any one of claims 1 to 10, and (b) another HBV inhibitor, as a combined preparation 15 for simultaneous, separate or sequential use in the ent of HBV ions.
25. The product according to claim 24, wherein said another HBV inhibitor is interferon-alpha, pegylated interferon-alpha, 3TC or adefovir. 20
26. The composition according to claim 1, substantially as herein described with reference to any one of the Examples thereof.
NZ753038A 2013-05-17 2014-05-16 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B NZ753038B2 (en)

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
EP13168291.6 2013-05-17
EP13168291 2013-05-17
EP13175181 2013-07-04
EP13175181.0 2013-07-04
EP13182281 2013-08-29
EP13182281.9 2013-08-29
EP13191209.9 2013-10-31
EP13191209 2013-10-31
EP13198160 2013-12-18
EP13198160.7 2013-12-18
EP14157900.3 2014-03-05
EP14157900 2014-03-05
NZ713201A NZ713201B2 (en) 2013-05-17 2014-05-16 Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

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NZ753038A NZ753038A (en) 2021-03-26
NZ753038B2 true NZ753038B2 (en) 2021-06-29

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