sulfamoyl-arylamides, pharmaceutical composition that comprises them and their use in the treatment

专利摘要:
SULFAMOIL-ARYLAMIDES AND THEIR USE AS DRUGS FOR THE TREATMENT OF HEPATITIS B. HBV replication inhibitors of Formula (I) including their stereochemically isomeric forms, and salts, hydrates, solvates, in which B, R1, R2 and R4 have the meaning as defined here. The present invention also relates to pharmaceutical compositions containing these inhibitors and their use, alone or in combination with other HBV inhibitors, in therapy against HBV.
公开号:BR112015004192B1
申请号:R112015004192-2
申请日:2013-08-28
公开日:2021-02-09
发明作者:Koen Vandyck；Pierre Jean-Marie Bernard Raboisson；Wim Gaston Verschueren；Stefaan Julien Last；Geert Rombouts
申请人:Janssen Sciences Ireland Uc；
IPC主号:

专利说明:

Background Technique
[0001] The Hepatitis B virus (HBV) is a partially double-stranded DNA virus (dsDNA), with an envelope from the Hepadnaviruses (Hepadnaviridae) family. Its genome contains 4 overlapping reading frames: the pre-nucleus / nucleus gene; the polymerase gene; the L, M, and S genes, which encode the 3 envelope proteins; and the X gene.
[0002] After infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted into a covalently closed circular DNA (cccDNA) in the host cell nucleus and the viral mRNAs are transcribed. Once in a capsid, the pre-genomic RNA (pgRNA), which also encodes the nucleus protein and PoI, serves as the template for reverse transcription, which partially regenerates the dsDNA (rcDNA) genome in the nucleocapsid.
[0003] HBV has caused epidemics in parts of Asia and Africa, and is endemic in China. HBV has infected approximately 2 billion people globally, of which approximately 350 million people have developed chronic infections. The virus causes hepatitis B disease, and chronic infection is related to a strongly increased risk of developing cirrhosis and hepatocellular carcinoma.
[0004] Transmission of the hepatitis B virus results from exposure to infected blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic transporters with a high titer of serum DNA.
[0005] There is an effective and well-tolerated vaccine, but direct treatment options are currently limited to interferon and the following antivirals; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
[0006] Additionally, heteroaryldihydropyrimidines (PAHs) have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54: 69-78).
[0007] WO2013 / 006394, published on January 10, 2013, and WO2013 / 096744, published on June 27, 2013 relate to subclasses of Sulfamoyl-arylamides active against HBV.
[0008] Among the problems that antivirals targeting HBV may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability and difficulty in synthesis.
[0009] There is a need for additional HBV inhibitors that can overcome at least one of these disadvantages or that have additional advantages such as increased potency or an increased safety window. Description of the Invention
[00010] The present invention relates to compounds of Formula (I)

[00011] or a stereoisomer or tautomeric form, in which:
[00012] B represents a 5- to 6-membered monocyclic aromatic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such a 5- to 6-membered aromatic ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[00013] R1 represents hydrogen or C1-C3 alkyl;
[00014] R2 represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6-R5 alkyl, C (= O) -R5, CFH2, CF2H, CF3, a dihydro-indenyl or tetrahydronaphthalenyl fraction optionally substituted by OH, or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a saturated 3-7 membered ring, C1-C6-R5 alkyl or C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00015] Or R1 and R2, together with the Nitrogen to which they are attached, form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, containing such a bridged bicyclic ring fraction or optionally saturated one or more additional heteroatoms, each independently selected from the group consisting of O, S and N, such saturated 5-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen - nio, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00016] Each R4 is independently selected from hydrogen, halogen, C1-C4oxy alkyl, C1-C4 alkyl, C1-C4 alkenyl, OH, CN, CFH2, CF2H, CF3, HC = C or a saturated 3-5 member ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N, such C1-C4 alkyl optionally substituted by OH;
[00017] R5 represents C1-C6 alkyl, CFH2, CF2H, CF3, phenyl, pyridyl or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N , with such a saturated 3-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) - C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00018] or a pharmaceutically acceptable salt or solvate thereof.
[00019] The invention further relates to a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable carrier.
[00020] The invention also relates to the compounds of Formula (I) for use as a medicine, preferably for use in the prevention or treatment of an HBV infection in a mammal.
[00021] In a further aspect, the invention relates to a combination of a compound of Formula (I), and another HBV inhibitor. Definitions
[00022] The term "C1-3 alkyl", as a group or part of a group, refers to a hydrocarbyl radical of the Formula CnH2n + 1 where n is a number ranging from 1 to 3. In the case of C1 alkyl -3 being coupled to an additional radical refers to a Formula CnH2n. C1-3 alkyl groups comprise 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C1-3 alkyl includes all linear or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes, such as, for example, methyl, ethyl, n-propyl, i-propyl.
[00023] C1-4 alkyl, as a group or part of a group, defines straight or branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms such as the group defined for C1-3 alkyl and butyl and the like.
[00024] C1-6 alkyl, as a group or part of a group, defines straight or branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms such as the groups defined for C1-4 alkyl and pentyl, hexyl, 2 -methylbutyl and the like.
[00025] C1-4 alkenyl, as a group or part of a group, defines straight or branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms with at least one double bond in any possible position. Examples of such alkenyls are ethylene, propenyl, 1-butenyl, 2-butenyl. C1-6 alkenyl, as a group or part of a group, defines straight or branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms with at least one double bond.
[00026] The term "C1-3oxyalkyl", as a group or part of a group, refers to a radical having the formula -ORbem Rbé C1-3alkyl. Non-limiting examples of suitable C1-3oxyalkyl include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.
[00027] The term oxo, C (= O), or carbonyl refers to a group consisting of a carbon atom doubly linked to an oxygen atom.
[00028] As used here, the term "3-7 membered saturated ring" means cyclic hydrocarbon saturated with 3, 4, 5, 6 or 7 carbon atoms and is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
[00029] Such a 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 N and O. Examples include oxetane, azetidine, tetra -hydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl. Preferred is saturated cyclic hydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxethane and tetrahydrofuranyl.
[00030] As used here, the term monocyclic 5- to 6-membered aromatic ring ("aryl") means a cyclic aromatic hydrocarbon with 5 or 6 carbon atoms. A preferred example of an aryl group is phenyl.
[00031] Such a saturated ring optionally contains one or more heteroatoms, each independently selected from the group consisting of O, S and N ("heteroaryl"). For the purposes of the invention, a heteroaryl group only needs to have some degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,) - and (1,2,4) -triazolyl , pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, and oxazolyl. A heteroaryl group may be unsubstituted by one or more suitable substituents.
[00032] As used here, the term 6-10 membered bicyclic ring indicates a saturated bicyclic ring with 6-7-8-9 or 10 atoms. Such a saturated bicyclic 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 N and O.
[00033] Examples of such a 6-10 membered bicyclic ring as used here are a 1,4-dioxa-8-azaspiro fraction [4,5] decyls indicating a group with structural formula
a 6-Oxa-2-azaspiro [3,4] octane fraction indicating a group with structural formula

[00034] a 2-oxa-6-azaspiro fraction [3,3] heptyl indicating a group with structural formula
[00035]
or a 6-oxa-1-azaspiro [3,3] heptyl fraction in structural form

[00036] As used here, the term 6-10 membered bridged ring indicates a saturated bridged ring with 6-7-8-9 or 10 atoms. Such a saturated bicyclic 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 N and O. An example of such a 6-ring bridge -10 members as used here is - oxyabicycle [2.2.1] heptane represented by the structure

[00037] As used here, a dihydroindenyl fraction represents a group with structural formula
Such a dihydroindenyl fraction can be optionally substituted by OH. An example as used here, a 2-hydroxy-2,3-dihydro-1H-indenyl fraction, indicates a group with a structural formula

[00038] As used here, a tetrahydronaphthalenyl fraction represents a group with structural formula

[00039] If not indicated, for any of the above fractions, the attachment to the main structure can be anywhere in such fraction as long as it is chemically stable.
[00040] It should be noted that different isomers of the various heterocycles may exist in the scope of the definitions as used throughout the specification. For example, pyrrolyl can be 1H-pyrrolyl or 2H-pyrrolyl.
[00041] The term halo and halogen is generic for fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.
[00042] It should also be noted that the positions of the radical in any molecular fraction used from the definitions can be anywhere in that fraction as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentila includes 1- pentila, 2-pentila and 3-pentila.
[00043] The positions indicated in the phenyl (for example, ortho, meta and / or para) are indicated in relation to the connection connecting the phenyl to the main structure. An example with respect to the position of R4, any location is indicated in relation to the nitrogen (*) connected to the main structure:

[00044] When any variable (for example, halogen or C1-4 alkyl) occurs more than once in any constituent, each definition is independent.
[00045] For therapeutic use, the salts of the compounds of formula (I) are those in which the counterion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counterion can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether or not pharmaceutically acceptable, are included in the scope of the present invention.
[00046] The pharmaceutically acceptable or physiologically tolerable addition salt forms that the compounds of the present invention are capable of forming can be conveniently prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, for example, acid hydrochloric or hydrobromic; sulfuric acids; hemisulfuric, nitric; phosphoric and the like; or organic acids such as, for example, acetic, aspartic, dodecylsulfuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, methanesulfonic ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoico and the like.
[00047] Conversely, said forms of addition salt can be converted by treatment with an appropriate base in the form of the free base.
[00048] The term "salts" comprises the hydrates and solvent addition forms that the compounds of the present invention are capable of forming. Examples of such forms are, for example, hydrates, alcoholates and the like.
[00049] The present compounds can also exist in their tautomeric forms, for example, tautomeric forms of amide groups (-C (= O) -NH-) are iminoalcohols (-C (OH) = N-). Tautomeric forms, although not explicitly indicated in the structural formulas depicted here, are intended to be included in the scope of the present invention.
[00050] The term stereochemically isomeric forms of compounds of the present invention, as used herein, defines all possible compounds consisting of the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, as the compounds of the present invention can own. Unless mentioned or indicated otherwise, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compound may have. 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 and in admixture with each other are intended to fall within the scope of the present invention.
[00051] The 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 molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates having a stereoisomeric excess of at least 80% (that is, a minimum of 90% of an isomer and a maximum of 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e., 100% of an isomer and none of the others), more particularly, compounds or intermediates having a stereoisomeric excess of 90% to 100%, even more particularly having a stereoisomeric excess of 94% up to 100% and the more in particular having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but then taking into account the enantiomeric excess, respectively the di-asteromeric excess, of the mixture in question.
[00052] Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by applying procedures known in the art. For example, enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples are tartaric acid, dibenzoyltartaric acid, ditoluoyl tartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, as long as the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compounds will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
[00053] The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Suitable physical separation methods that can be advantageously employed are, for example, selective crystallization and chromatography, for example, column chromatography.
[00054] The present invention is also intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, hydrogen isotopes include tritium and deuterium. Carbon isotopes include C-13 and C-14. Detailed description of the invention
[00055] Whenever used from now on, the term "compounds of formula (I)",

[00056] or "the present compounds" or similar term, is intended to include the compounds of the general formulas (I), I *), (Ia), (Ib), (Ic) and (Id), their salts, forms stereoisomeric and racemic mixtures or any subgroups.
[00057] The compounds for use in preventing or treating an HBV infection in a mammal are disclosed as compounds per se and are not limited to this use unless restricted by the claims.
[00058] The present invention relates to compounds of Formula (I)

[00059] or a stereoisomer or tautomeric form, in which:
[00060] B represents a 5- to 6-membered monocyclic aromatic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a 5- to 6-membered aromatic ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[00061] R1 represents hydrogen or C1-C3 alkyl;
[00062] R2 represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6-R5 alkyl, C (= O) -R5, CFH2, CF2H, CF3, a dihydro-indenyl or tetrahydronaphthalenyl fraction optionally substituted by OH, or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a saturated 3-7 membered ring, C1-C6-R5 alkyl or C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00063] Or R1 and R2, together with the Nitrogen to which they are attached, form a 6-10 membered bicyclic or bridged ring or a 5-7 membered saturated ring, containing such a bicyclic ring, bridged fraction or optionally saturated one or more additional heteroatoms, each independently selected from the group consisting of O, S and N, such saturated 5-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen - nio, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00064] Each R4 is independently selected from hydrogen, halogen, C1-C4oxy alkyl, C1-C4 alkyl, C1-C4 alkenyl, OH, CN, CFH2, CF2H, CF3, HC C or an optionally saturated 3-5 member ring containing one or more heteroatoms, each independently selected from the group consisting of O and N, such C1-C4 alkyl optionally substituted by OH;
[00065] R5 represents C1-C6 alkyl, CFH2, CF2H, CF3, phenyl, pyridyl or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, being such a 3-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) - C1-C3 alkyl , C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00066] or a pharmaceutically acceptable salt or solvate thereof.
[00067] In a first aspect, the invention additionally provides a compound of Formula (I)

[00068] or a stereoisomer or tautomeric form, in which:
[00069] B represents an aromatic 5- to 6-membered monocyclic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such an aromatic 5- to 6-membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[00070] R1 represents hydrogen or C1-C3 alkyl;
[00071] R2 represents C1-C6 alkyl, C1-C6 alkenyl, C1-C6-R5 alkyl, C (= O) -R5, CFH2, CF2H, CF3, a 2-hydroxy-2,3-dihydro-moiety 1H- indenyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring, C1-C6-R5 alkyl or C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1-C3 alkyl, alkyl C1-C4, OH, CN, CFH2, CF2H and CF3;
[00072] Or R1 and R2, together with the Nitrogen to which they are attached, form a 1,4-dioxa-8-azaspiro fraction [4.5] decila, a 2-oxa-6-azaspiro fraction [3.3] heptyla or a 5-7 membered saturated ring optionally containing one or more additional heteroatoms, each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00073] Each R4 is independently selected from hydrogen, halogen, C1-C4oxy alkyl, C1-C4 alkyl, C1-C4 alkenyl, OH, CN, CFH2, CF2H, CF3, HC C or an optionally saturated 3-5 member ring containing one or more heteroatoms, each independently selected from the group consisting of O and N, such C1-C4 alkyl optionally substituted by OH;
[00074] R5 represents C1-C6 alkyl, CFH2, CF2H, CF3, phenyl, pyridyl or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, being such a 3-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, oxo, C (= O) - C1-C3 alkyl , C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00075] or a pharmaceutically acceptable salt or solvate thereof.
[00076] In one embodiment, at least one R4 represents Fluorine, and another R4 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkenyl, CHF2 or cyclopropyl.
[00077] In a submodality, one R4 represents Fluorine and another R4 is selected from the group consisting of methyl or CHF2, preferably methyl, and in which the location of said Fluorine is in the position for and the location of said methyl or CHF2 is at meta position in relation to Nitrogen (*) as indicated in Formula (I *) below.

[00078] In yet another embodiment, the invention provides a compound of Formula (I) in which at least one R4 represents Fluorine, and another R4 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkenyl, CHF2 or cyclopropyl; more preferably, one R4 represents Fluorine and another R4 is selected from the group consisting of methyl or CHF2 and in which the location of said Fluorine is in the para position and the location of said methyl or CHF2 is in the meta position in relation to Nitrogen ( *) and R2 represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such a 4-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[00079] In yet another embodiment compounds are disclosed in which one R4 in the position for represents Fluorine and the other R4 in the goal position represents methyl and such a compound is not

[00080] In another embodiment of the present invention compounds according to Formula (I) are provided wherein R2 represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such a ring being saturated with 4-7 members members optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3. A preferred substituent for such a 4-7 membered saturated ring containing carbon and one or more oxygen atoms is C1-C4 alkyl. In a submodality, the saturated ring is a 4, 5 or 6 membered ring.
[00081] In another embodiment of the present invention compounds according to Formula (I) are provided in which R2 represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such a ring being saturated with 4-7 members members optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3. In an additional embodiment, R2 represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such a 4-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4oxy alkyl, C1-C4oxycarbonyl alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3 where such a compound is not

[00082] Preferably, any additional substituent on such a 3-7, 4-7 and 5-7 membered saturated ring, 6-10 membered bicyclic or bridged ring, C1-C6-R5 alkyl or C1-C6 alkyl is independently selected from the group consisting of hydrogen, fluorine, OH, C1-C3 alkyl and CF3, most preferably from the group consisting of hydrogen, C1-C3 alkyl, fluorine and CF3.
[00083] In another embodiment of the present invention compounds according to Formula (I) are provided in which B represents phenyl or thiophene, being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, alkyl C1-C3, CN, CFH2, CF2H and CF3.
[00084] In a submodality, the compounds according to the present invention are represented by Formula (Ia)

[00085] (Ia), wherein R1, R2 and R4 are defined as in any of the modalities as described.
[00086] In a submodality, such compounds are represented by Formula (Ib)

[00087] where R1, R2, R4 are defined as in any of the modalities as described and R3 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, CN, CFH2, CF2H, CF3. In a preferred embodiment, R3 represents fluorine or hydrogen, more preferably hydrogen.
[00088] In yet another submodality, the compounds are represented by Formula (Ic):

[00089] wherein R1, R2 and R4 are defined as in any of the modalities as described.
[00090] In a submodality, the compounds according to the present invention are represented by Formula (Id)

[00091] in which R1, R2 and R4 are defined as in any of the described modalities and R3 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, CH, CFH2, CF2H, CF3.
[00092] In a preferred embodiment, the compounds according to the invention are intended for use in preventing or treating HBV infection in a mammal.
[00093] In a further aspect, the present invention provides compounds that can be represented by Formula (I):

[00094] or a stereoisomer or tautomeric form, in which:
[00095] B represents a 5- to 6-membered aromatic ring monocyclic, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a 5- to 6-membered aromatic ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[00096] R1 represents hydrogen or C1-C3 alkyl;
[00097] R2 represents C1-C6 alkyl, C1-C3-R5 alkyl, benzyl, C (= O) -R5, CFH2, CF2H, CF3 or a 3-7 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such saturated 3-7 membered ring or C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1- C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00098] Or R1 and R2, together with the Nitrogen to which they are attached, form a 1,4-dioxa-8-azaspiro fraction [4.5] or a 5-7 membered saturated ring, optionally containing one or more hems additional teroatoms, each independently selected from the group consisting of O, S and N, such saturated 5-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl , oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[00099] Each R4 is independently selected from hydrogen, halo, C1-C4OXY alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3, HCC or a 3-5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
[000100] R5 represents C1-C6 alkyl, CFH2, CF2H, CF3 or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such ring being 3-7 membered saturated optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH , CN, CFH2, CF2H and CF3;
[000101] or a pharmaceutically acceptable salt or solvate thereof. These compounds are especially suitable for use in preventing or treating HBV infection in a mammal.
[000102] Still in an additional aspect, the invention relates to compounds according to Formula (I)

[000103] or a stereoisomer or tautomeric form, in which:
[000104] B represents a 5- to 6-membered aromatic monocyclic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a 5- to 6-membered aromatic ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[000105] R1 represents hydrogen or C1-C3 alkyl;
[000106] R2 represents a saturated 4-7 membered ring consisting of carbon atoms and one or more heteroatoms, each independently selected from the group consisting of O or S, such saturated 4-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) - C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000107] Each R4 is independently selected from hydrogen, halo, C1-C4OXyl alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3, HCC or a 3-5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
[000108] or a pharmaceutically acceptable salt or solvate thereof.
[000109] The present invention relates additionally to the compound of Formula (I)

[000110] or a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof.
[000111] where:
[000112] B represents a 5- to 6-membered aromatic monocyclic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such a 5- to 6-membered aromatic ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[000113] R1 represents hydrogen or C1-C3 alkyl;
[000114] R2 represents C1-C6 alkyl, C1-C3-R5 alkyl, benzyl, C (= O) -R5, CFH2, CF2H, CF3 or a 3-7 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such saturated 3-7 membered ring or C1-C6 alkyl optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1- C4oxy alkyl , oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000115] Or R1 and R2, together with the Nitrogen to which they are attached, form a 1,4-dioxa-8-azaspiro fraction [4.5] or a 5-7 membered saturated ring, optionally containing one or more he- additional teroatoms, each independently selected from the group consisting of O, S and N, such saturated 5-7 membered ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl , oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000116] Each R4 is independently selected from hydrogen, halo, C1-C4OXY alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3, HCC or a 3-5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
[000117] R5 represents C1-C6 alkyl, CFH2, CF2H, CF3 or a saturated 3-7 membered ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, with such ring being saturated 3-7 members optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000118] A submodality of the invention provides compounds that can be represented by the formula (Ia)

[000119] where R1, R2, B are defined as above and each R4 is independently selected from hydrogen, halo, C1-C4oxy alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a saturated ring of 3 -5 members optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N.
[000120] In one embodiment, R2 represents a saturated ring of 37 members, containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such saturated ring of 3-7 members optionally being replaced by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) - C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[000121] In yet another embodiment, R2 represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such a 4-7 membered saturated ring optionally substituted by one or more substituents, each independently selected. group consisting of hydrogen, halo, C1-C4oxy alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[000122] In another embodiment, R1 and R2, together with the Nitrogen to which they are attached, form a saturated ring with 5-7 members, optionally containing one or more additional heteroatoms, each independently selected from the group consisting of O, S and N, with such a 5-7 membered saturated ring optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[000123] In a preferred embodiment of the present invention, B represents phenyl or thiophene, being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, CN, CFH2, CF2H and CF3 .
[000124] In a selection of compounds according to the invention, or compounds for use in preventing or treating HBV infection in a mammal, at least one R4 represents Fluorine, C1-C3 alkyl, CHF2 or cyclopropyl.
[000125] Preferably, at least one R4 represents methyl, i-propyl or cyclopropyl. In another embodiment, one R4 represents methyl, i-propyl or cyclopropyl and the other R4 represents fluorine, or hydrogen. The position of R4 is preferably meta and / or to (position indicated from -N ~).
[000126] A specific modality is a compound of Formula (I) in which one R4 in the para position represents Fluorine and the other R4 in the meta position represents Fluorine or methyl (position indicated from - N ~).
[000127] A submodality of the invention provides compounds that can be represented by the formula (Ib)

[000128] wherein R1, R2, R4 are defined as above and R3 is selected from the group comprising hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H, CF3. In a preferred embodiment, R3 represents fluorine or hydrogen.
[000129] The invention additionally relates to compounds according to Formula (I)

[000130] or a stereoisomer or tautomeric form, in which:
[000131] B represents a 5- to 6-membered monocyclic aromatic ring, optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such a 5- to 6-membered aromatic ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H and CF3;
[000132] R1 represents hydrogen or C1-C3 alkyl;
[000133] R2 represents C1-C3-R6 alkyl or a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms, each independently selected from the group consisting of O or S, such ring being saturated with 4-7 members optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1- C4-alkyl, oxo, C (= O) -C1-C3-alkyl, C1-C4-alkyl, OH, CN , CFH2, CF2H and CF3;
[000134] Each R4 is independently selected from hydrogen, halo, C1-C4OXY alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3, HCC or a 3-5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
[000135] R6 represents a 4-7 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O or S, such a 4-7 membered saturated ring optionally substituted by one or more substituents, each one independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000136] or a pharmaceutically acceptable salt or solvate thereof.
[000137] A submodality of the invention provides compounds that can be represented by the formula (Ia)

[000138] where R1, R2, B are defined as above and each R4 is independently selected from hydrogen, halo, C1-C4oxy alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a saturated ring of 3 -5 members optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N.
[000139] In one embodiment, R2 represents C1-C3-R6 alkyl or a 4-7 membered saturated ring consisting of carbon atoms and one or more hetero atoms, each independently selected from the group consisting of O or S, with such ring being 4-7 membered saturated optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1C4 alkyl, OH, CN , CFH2, CF2H and CF3.
[000140] In a preferred embodiment for the compounds of the invention, B represents phenyl or thiophene, being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, CN, CFH2 , CF2H and CF3.
[000141] In a selection of compounds according to the invention, at least one R4 represents Fluorine, C1-C3 alkyl, CHF2 or cyclopropyl. Preferably, at least one R4 represents methyl, i-propyl or cyclopropyl. In another embodiment, one R4 represents methyl, i-propyl or cyclopropyl and the other R4 represents fluorine, or hydrogen. The position of R4 is preferably meta and / or para.
[000142] A specific modality is a compound of Formula (I) in which one R4 in the para position represents fluorine and the other R4 in the meta position represents fluorine or methyl.
[000143] A submodality of the compounds of the invention relates to compounds according to Formula (Ib)

[000144] wherein R1 represents hydrogen or C1-C3 alkyl;
[000145] R2 represents C1-C3-R6 alkyl or a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms, each independently selected from the group consisting of O or S, such ring being saturated with 4-7 members optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1- C4-alkyl, oxo, C (= O) -C1-C3-alkyl, C1-C4-alkyl, OH, CN , CFH2, CF2H and CF3;
[000146] Each R4 is independently selected from hydrogen, halo, C1-C4oxy alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a 3-5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
[000147] R6 represents a 4-7 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O or S, such a 4-7 membered saturated ring optionally substituted by one or more substituents, each one independently selected from the group consisting of hydrogen, halo, C1-C4oxy alkyl, oxo, C (= O) -C1C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3;
[000148] R3 is selected from the group comprising hydrogen, halo, C1-C3 alkyl, CN, CFH2, CF2H, CF3. In a preferred embodiment, R3 represents fluorine or hydrogen.
[000149] In one embodiment, R6 represents a 47-membered saturated ring consisting of carbon atoms and one or more heteroatoms, each independently selected from the group consisting of O or S, such a 4-7 membered saturated ring being optionally substituted by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1- C4oxyalkyl, oxo, C (= O) -C1-C3alkyl, C1-C4alkyl, OH, CN, CFH2, CF2H and CF3.
[000150] Additional combinations of any of the preferred sub- or modalities are intended to be within the scope of the present invention.
[000151] Preferred compounds according to the invention are compounds or a stereoisomer or tautomeric form with a formula or reference to a formula selected from the following tables 1 and 2: Table 2
or a pharmaceutically acceptable salt or solvate thereof.
[000152] In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of Formula (I) as specified herein, and a pharmaceutically acceptable transport. A prophylactically effective amount in this context is an amount sufficient to prevent HBV infection in subjects at risk of being infected. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV infection, or to eradicate HBV infection in infected subjects. In a still further aspect, this invention relates to a process for 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 (I), as specified. here.
[000153] Therefore, the compounds of the present invention or any subgroup thereof can be formulated in various dosage forms for administration purposes. As appropriate compositions, all compositions usually employed for systemic drug administration can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an addition salt, as the active ingredient is combined in admixture with a pharmaceutically acceptable carrier, the carrier of which can take a wide variety of forms depending on the desired form of preparation for administration. These pharmaceutical compositions are desirable in unit dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of liquid oral 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. Due to their ease of administration, tablets and capsules represent the most advantageous unitary oral dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. Injectable solutions can be prepared, for example, in which the carrier comprises saline, glucose solution or a mixture of saline and glucose. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed. Also included are preparations in solid form intended to be converted, immediately before use, into preparations in liquid form. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration-enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minimal proportions, the additives of which do not introduce a significant deleterious effect on the skin. The compounds of the present invention can also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any delivery system known in the art.
[000154] It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, suppositories, powder packs, wafers, injectable solutions and suspensions and the like, and their multiple secretions.
[000155] The compounds of Formula (I) are active as inhibitors of the HBV replication cycle and can be used in the treatment and prophylaxis of HBV infection or diseases associated with HBV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma.
[000156] Due to their antiviral properties, particularly their anti-HBV properties, the compounds of Formula (I) or any subgroup thereof are useful in inhibiting the HBV replication cycle, in particular in the treatment of warm-blooded animals, in particular infected with HBV, and for the prophylaxis of HBV infections. The present invention also relates to a method of treating a warm-blooded animal, in particular a human, infected with HBV, or being at risk of HBV infection, said method comprising the administration of a therapeutical quantity peutically effective use of a compound of Formula (I).
[000157] The compounds of Formula (I), as specified herein, can therefore be used as a medicine, in particular as a medicine to treat or prevent HBV infection. Said use as a medicine or treatment method comprises systemic administration to subjects infected with HBV or to subjects susceptible to HBV infection of an amount effective to combat conditions associated with HBV infection or an amount effective to prevent HBV infection.
[000158] The present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or prevention of infection by HBV.
[000159] In general it is contemplated that an effective antiviral daily amount would be about 0.01 to about 50 mg / kg, or about 0.01 to about 30 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four or more underdoses at appropriate intervals throughout the day. Said underdoses can be formulated as unit dosage forms, for example, containing about 1 to about 500 mg, or about 1 to about 300 mg, or about 1 to about 100 mg, or about 2 to about 50 mg of active ingredient per unit dosage form.
[000160] The present invention also relates to combinations of a compound of Formula (I) or any subgroup thereof, as specified herein, with other anti-HBV agents. The term "combination" can refer to a product or kit containing (a) a compound of Formula (I), as specified above, and (b) at least one other compound capable of treating HBV infection (hereinafter referred to as an agent anti-HBV), as a combined preparation for simultaneous, separate or sequential use in treating HBV infections. In one embodiment, the invention relates to the combination of a compound of Formula (I) or any subgroup thereof with at least one anti-HBV agent. In a particular embodiment, the invention relates to the combination of a compound of the formula (I) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the invention relates to the combination of a compound of the formula (I) or any subgroup thereof with at least three anti-HBV agents. In a particular embodiment, the invention relates to the combination of a compound of the formula (I) or any subgroup thereof with at least four anti-HBV agents.
[000161] The combination of previously known anti-HBV agents, such as interferon-α (IFN-α), pegylated interferon-α, 3TC, adefovir or a combination thereof, and a compound of the formula (I) or any either its subgroup can be used as a medicine in combination therapy. Generic synthesis:
[000162] The compound according to Formula (I) can be synthesized as described in general schemes 1 to 7.
[000163] A formula II carboxylic acid chloride can be selectively reacted with an aniline of formula III, for example in an organic solvent such as CH2Cl2 in the presence of an organic base such as triethylamine or DIPEA (N, N-diisopropylethylamine) ), or, as another example, by adding aniline III to a refluxing toluene solution of compound II, resulting in compound IV. The remaining sulfonic acid chloride functionality in compound IV is further reacted with an amine of the general formula V, resulting in a compound of the general formula (I). Alternatively, a compound of the general formula (I) could be obtained as described in scheme 2. This time, the sulfonic acid chloride VI is reacted with an amine of the general formula V, for example in an organic solvent such as CH2Cl2 in the presence of a organic base such as triethylamine or DIPEA or, as another example, in the presence of Na2CO3 in a mixture of H2O / THF. The compound VII formed is coupled with aniline of the general formula III in the presence of an activating reagent such as HATU and an organic base such as triethylamine or DIPEA.
Layout 1
Scheme 2
[000164] A general synthesis of compounds of formulas IX and X is described in scheme 3. Intermediate IV is reacted with ammonia, resulting in a compound of formula VIII. This intermediate can be further transformed into a compound of formula IX by reaction with a carbonyl chloride, for example cyclohexane carbonyl chloride in the presence of SiO2 and H2SO4 refluxed in CHCl3. The compound of the general formula IX can be further transformed into a compound of the formula X. If R1 is equal to Me, this can be done by reacting IX with TMSCHN2 in MeOH / CH2Cl2
Layout 3
[000165] In another example, compound IV can be reacted with an amino acid XI, in the presence of a base like NaOH, resulting in compound XII as described in scheme 4. Intermediate XII can be optionally cyclized to compound XIII for example by heating with acetic anhydride and KOAc in toluene, or converting the carboxylic acid to an acid chloride followed by cyclization in the presence of a base such as triethylamine. Suitable examples of amino acids of structure XI are derived from 4-aminopentanoic acid or 4-aminobutanoic acid.
Layout 4
Layout 5
[000166] A synthetic route to compounds of general formula XVI is described in Scheme 5. An aminoethanol derivative XIV, prepared as described in scheme 1 for compounds of general formula (I), is transformed into an aziridine derivative XV by treatment with diethyl Diazene-1,2-dicarboxylate and PPh3 in THF. Aziridine of general formula XV is reacted with a Nu nucleophile, resulting in a compound of general formula XVI. Examples of such nucleophiles (Nu) are, but are not limited to, morpholine and 1-methylpiperazine. Examples of a compound synthesized according to the route described in scheme 5 are compounds 116 and 117.
Layout 6
[000167] An alternative method for the synthesis of compounds of the general formula VII is through ester XVII as described in scheme 6. The reaction of XVII with amine V, for example in an organic solvent such as CH2Cl2 or THF in the presence of a base organic, such as triethylamine or DIPEA, followed by hydrolysis of the ester, for example with LiOH in THF / H2O, followed by acidification, results in a compound of the general formula VII. A compound of the general formula VII, obtained through the route in scheme 2 or scheme 6, can be transformed into an acid chloride of formula XIX, for example by treatment with oxalyl chloride or thionyl chloride. A compound of general formula XIX can then be transformed into a compound of general formula (I) by reaction with an aniline of general formula III.
[000168] A compound of the general formula VI can be converted into a compound of the general formula II, for example by treatment with oxalyl chloride in CH2Cl2.
Layout 7
[000169] Possible synthetic routes, for compounds of the general formula XVII or VI, are described in scheme 7, and additionally exemplified in the experimental section. Chlorosulfonation of carboxylic acids XXI or carboxylic esters XX may result in compounds of the general formula VI or XVII, respectively, for example by treatment with chlorosulfonic acid (for example as reviewed in Phosphorus, Sulfur, and Silicon and the Related Elements Vol. 56, Ed. 1-4, 1991). Alternatively, compounds of the general formula XXV or XXIV can be converted into compounds of the general formulas XVII and VI, respectively, by conversion to the corresponding diazonium salts (for example by NaNO2 / HCl), followed by conversion of the salt of diazonium in a sulfonyl chloride (for example by SO2 / CuCl) (for example as described in Organic Process Research & Development, 13 (5), 875-879; 2009). Alternatively, the compounds of the general formulas XXII and XXIII (with R7 equal to H, benzyl or methyl) can be converted into the compound of the general formulas XVII and VI, respectively, for example by treatment with Cl2 or N-Chlorosuccinimide in AcOH / H2O.
[000170] The substituents represented by R4 in this general synthesis are intended to include any substituent or reactive species that is suitable for transformation into any substituents of R4 according to the present invention without undue burden to the person skilled in the art.
[000171] Compounds not specifically described in the compound synthesis section below can be synthesized according to Schemes 1-7 above and have been commercially purchased.
[000172] Synthesis of compounds: LC-MS methods:
[000173] Method A: mobile phase A: H2O (0.1% TFA); B: CH3CN (0.05% TFA) Stop Time: 10 min; gradient time (min) [% A /% B] 0.0 [100/0] to 1 [100/0] to 5 [40/60] to 7.5 [40/60] to 8.0 [100 / 0]; flow: 0.8 ml / min; temp. column: 50 ° C, YMC-PACK ODS-AQ, 50x2.0 mm 5 μm
[000174] Method B: mobile phase A: H2O (0.1% TFA); B: CH3CN (0.05% TFA) Stop Time: 10 min; gradient time (min) [% A /% B] 0.0 [90/10] to 0.8 [90/10] to 4.5 [20/80] to 7.5 [20/80] to 8 , 0 [90/10]; flow: 0.8 ml / min; temp. column: 50 ° C, YMC-PACK ODS-AQ, 50x2.0 mm 5 μm
[000175] Method C: mobile phase A: H2O (0.1% TFA); B: CH3CN (0.05% TFA) Stop Time: 10 min; gradient time (min) [% A /% B] 0.0 [90/10] to 0.8 [90/10] to 4.5 [20/80] to 7.5 [20/80]; 9.5 [90/10] flow: 0.8 ml / min; temp. column: 50 ° C; Agilent TC-C18, 50x2.1 mm, 5 μm
[000176] Method D: mobile phase A: H2O (0.05% NH3.H2O); B: CH3CN Downtime: 10 min; gradient time (min) [% A /% B] 0.0 [100/0] to 1 [100/0] to 5 [40/60] to 7.5 [40/60]; 8 [100/0] flow: 0.8 ml / min; temp. column: 40 ° C, XBridge Shield-RP18, 50 * 2.1 mm 5 μm
[000177] Method E: mobile phase A: H2O (0.1% TFA); B: CH3CN (0.05% TFA) Stop Time: 10 min; Post Time: 0.5 min; gradient time (min) [% A /% B] 0 [100/0] to 1 [100/0] to 5 [40/60] to 7.5 [15/85] to 9.5 [100/0 ]; flow: 0.8 ml / min; temp. column: 50 ° C, Agilent TC-C18, 50x2.1 mm, 5 μm
[000178] Method F: LC measurement was performed using an Acquity UPLC system (Waters) with column heater (adjusted to 55 ° C). Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a C18 column of ethyl siloxane / bridged silica (BEH) (1.7 μm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml / min. Two mobile phases (10 mM ammonium acetate in H2O / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 95% and B to 5% to A to 5% and B to 95% in 1.3 minutes and maintained for 0.3 minutes. An injection volume of 0.5 μL was used. The cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
[000179] Method G: The LC measurement was performed using an UPLC Aquiquette (Waters) with column heater (adjusted to 55 ° C). Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on an Acquity UPLC HSS T3 column (1.8 μm, 2.1 x 100 mm; Waters Acquity) with a flow rate of 0.8 mL / min. Two mobile phases (A: 10 mM ammonium acetate in H2O / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 100% and B to 0% to A to 5% and B at 95% in 2.1 minutes and subsequently at A at 0% and B at 100% at 0.9 minutes at A at 0.5% and B at 95% at 0.5 min. An injection volume of 1 μL was used. The cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.
[000180] Method H: Reverse phase HPLC was carried out on a C18 Atlantis column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 mL / min. The column heater was adjusted to 45 ° C. Two mobile phases were used (mobile phase A: 70% methanol + 30% H2O; mobile phase B: 0.1% formic acid in H2O / 95/5 methanol) to operate a 100% B gradient condition a B at 5% + A at 95% in 9 minutes and maintaining these conditions for 3 minutes. An injection volume of 10 μL was used. The cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
[000181] Compounds 21, 49-55, 57-62 were purchased from Aurora Fine Chemicals.
Compound 1
[000182] 3- (Chlorosulfonyl) benzoyl chloride (207 mg, 1 mmol) was dissolved in dichloromethane (3 mL) and 4-fluoroaniline (111 mg, 1.0 mmol) and triethylamine (112 mg, 1.0 mmol) in dichloromethane (2 ml) were added to the mixture at 0 ° C. The mixture was then stirred at 20 ° C for 1 hour. To this reaction mixture containing 3- (4-fluorophenylcarbamoyl) benzene-1-sulfonyl chloride at 0 ° C, a solution of triethylamine (121 mg, 1.2 mmol) and 4-aminotetrahydropyran (88 mg, 0.861 mmol) in dichloromethane (3 mL) was added. The mixture was stirred at 20 ° C for 1 hour. The solvent was removed in vacuo. The residue was purified by high performance liquid chromatography (column: Phenomenex Synergi C18 150 * 20 mm * 5 µm. A: H2O + 0.1% TFA; B: MeCN). The product fractions were collected and the organic solvent was evaporated. The fraction was neutralized by saturated NaHCO3. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated resulting in compound 1 (85.4 mg); Method A; Rt: 4.88 min. m / z: 379.2 (M + H) + Exact mass: 378.1
[000183] The following compounds were prepared similarly to compound 1 using the corresponding amines instead of 4-aminotetrahydropyran:
Compound 2
[000184] Method B; Rt: 4.27 min. m / z: 363.1 (M + H) + Exact mass: 362.1
Compound 3
[000185] Method A; Rt: 4.64 min. m / z: 351.1 (M + H) + Exact mass: 350.1
Compound 4
[000186] Method A; Rt: 4.87 min. m / z: 365.1 (M + H) + Exact mass:
Compound 5
[000187] Method A; Rt: 5.32 min. m / z: 349.1 (M + H) + Exact mass:
79
[000188] Method A; Rt: 5.39 min. m / z: 365.2 (M + H) + Exact mass: 364.1
[000189] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (1 H, t, J = 1.5 Hz), 8.16 (1 H, s l.), 8.11 (1 H , dm, J = 8.0 Hz), 8.05 (1 H, dm, J = 8.0 Hz), 7.57 - 7.70 (3 H, m), 7.08 (2 H, t , J = 8.7 Hz), 4.78 (1 H, s), 1.55 (2 H, q, J = 7.5 Hz), 1.18 (6 H, s), 0.84 ( 3 H, t, J = 7.5 Hz).
83
[000190] Method A; Rt: 4.20 min. m / z: 415.0 (M + Na) + Exact mass: 392.1;
[000191] Purified by chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate 100/1 to 1/1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (1 H, sl), 8.33 - 8.47 (1 H, m), 8.19 (1 H, dm, J = 7.5 Hz), 8.06 (1 H, dm, J = 7.5 Hz), 7.72 - 7.85 (3 H, m), 7.66 - 7.73 (1 H, sl), 7, 12 - 7.31 (2 H, m), 3.42 - 3.58 (4 H, m), 1.71 - 1.92 (2 H, m), 1.27 - 1.50 (2 H , m), 1.06 (3 H, s).
87
[000192] Method B; Rt: 3.94 min. m / z: 363.1 (M + H) + Exact mass: 362.1
[000193] Purified by high performance liquid chromatography on RP-18 (eluent: CH3CH in water (0.1% TFA) from 25 to 55, v / v). 1H RMH (400 MHz, DMSO-d6), δ ppm 0.34-0.42 (m, 2 H), 0.460.54 (m, 2H), 0.75 (t, J = 7.3 Hz, 3 H), 1.28 (q, J = 7.3 Hz, 2 H), 7.15-7.25 (m, 2 H) 7.67-7.83 (m, 3 H), 7.97 (d, J = 8.3 Hz; 1 H), 8.14-8.25 (m, 2 H), 8.33 (s, 1 H), 10.55 (s, 1 H).
Compound 89
[000194] Method E; Rt: 4.83 min. m / z: 379.1 (M + H) + Exact mass: 378.1; 1H RMH (400 MHz, DMSO-d6), δ ppm 10.60 (s, 1H), 8.48 (s l., 1H), 8.39 (s, 1H), 8.23 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7,747.87 (m, 3 H), 7.23 (t, J = 9.0 Hz, 2 H), 4.51 (d, J = 6.5 Hz, 2 H), 4.20 (d, J = 6.5 Hz, 2 H), 1.84 (q, J = 7.3 Hz, 2 H), 0.64 (t, J = 7.3 Hz, 3 H). Prepared similarly as described for compound 1, using 3-ethyloxetan-3-amine instead of 4-aminotetrahydropyran. Synthesis of 3-ethyloxetan-3-amine: 3-ethyloxethane-3-carboxylic acid (3.0 g, 23.1 mmol), DPPA (diphenylphosphoryl azide, 7.61 g, 27.7 mmol), triethylamine (3 , 0 g, 23.1 mmol) and BnOH (2.99 g, 27.7 mmol) were dissolved in toluene (50 mL). The mixture was stirred at 110 ° C overnight. The solvent was removed in vacuo. Dichloromethane (50 ml) was added. The mixture was washed with 1 N HCl (20 ml). The aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate 100/1 to 60/40), resulting in benzyl 3-ethyloxetan-3-ylcarbamate (4.0 g). To a solution of benzyl 3-ethyloxetan-3-ylcarbamate (2.0 g, 8.5 mmol) and cyclohex-1,4-diene (1.02 g, 12.75 mmol) in MeOH (20 mL) was Pd-C (10%, 0.2 g) is added under N2. The mixture was stirred under a H2 balloon at 25 ° C for 4 hours. After filtration, the filtrate was concentrated resulting in 3-ethyloxetan-3-amine (860 mg), which was used as such in the next reaction. Synthesis of compound 6:
Compound 6
[000195] To a solution of 3- (chlorosulfonyl) benzoic acid (1 g, 4.53 mmol) in CH2Cl2 (20 mL) at 5 ° C, cyclohexanamine (0.899 g, 9.06 mmol) and triethylamine (1.38 g, 13.60 mmol) were added successively dropwise. The solution was stirred at room temperature overnight. The mixture was washed with 1 N HCl (50 ml). The organic phase was dried over MgSo4 and concentrated resulting in 3- (N-cyclohexylsulfamoyl) benzoic acid as a white solid (1.2 g), which was used in the next step without purification. To a solution of 3- (N-cyclohexylsulfamoyl) benzoic acid (1.2 g, 4.24 mmol) in DMF (15 mL) at 5 ° C, 4-fluoroaniline (0.52 g, 4.66 mmol) and DIPEA (1.64 g, 12.71 mmol) was added successively. The mixture was stirred for 20 minutes and then HATU (1.93 g, 5.08 mmol) was added. The solution was stirred at room temperature overnight. To the reaction mixture, aqueous NaHCO3 (50 ml) was added followed by EtOAc (50 ml). The organic layer was washed with HCl (5%; 50 ml) and brine. The organic layer was dried with MgSO4 and concentrated, resulting in a residue. The obtained residue was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 2: 1) resulting in compound 6 as a white solid (850 mg). Method B; Rt: 4.50 min. m / z: 377.2 (M + H) + Exact mass: 376.1 Synthesis of compound 7

[000196] To 5- (chlorosulfonyl) -2-fluorobenzoic acid (10 g, 41.91 mmol) in EtOAc (150 mL) was added cyclohexanamine (12.47 g, 125.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and washed with 1 N HCl (100 ml). The organic phase was dried over MgSO4 and concentrated resulting in 5- (N-cyclohexylsulfamoyl) -2-fluorobenzoic acid as a white solid (10.9 g), which was used in the next steps without further purification. To a solution of 5- (N-cyclohexylsulfamoyl) -2-fluorobenzoic acid (1 g, 3.32 mmol) in DMF (15 mL) was successively added 3- (trifluoromethyl) aniline (0.54 g, 3.32 mmol) ) and DIPEA (1.29 g, 9.96 mmol) at 5 ° C. The mixture was stirred for 20 minutes and then HATU (1.51 g, 3.98 mmol) was added. The solution was stirred at room temperature overnight. To the reaction mixture, aqueous NaHCO3 (50 ml) was added followed by EtOAc (50 ml). The organic layer was washed with HCl (5%) and brine. The organic layer was dried with MgSO4, concentrated in vacuo, and the obtained residue was purified by preparative HPLC resulting in compound 7 (902 mg) as a white solid. Method B; Rt: 4.85 min. m / z: 445.2 (M + H) + Exact mass: 444.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (1 H, sl), 8.15 - 8.22 (1 H, m), 8.12 (1 H, dd, J = 6.5 , 2.5 Hz), 8.03 (1 H, ddd, J = 9.0, 4.5, 2.5 Hz), 7.88 - 7.97 (1 H, m), 7.83 ( 1 H, d, J = 7.5 Hz), 7.58 - 7.67 (2 H, m), 7.46 - 7.54 (1 H, m), 2.90 - 3.07 (1 H, m), 1.51 - 1.67 (4 H, m), 1.38 - 1.51 (1 H, m), 0.96 - 1.27 (5 H, m)
[000197] Examples of compounds prepared similarly to compound 7, using the corresponding anilines instead of 3- (trifluoromethyl) aniline:
Compound 18
[000198] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (1 H, ls), 8.08 (1 H, dd, J = 6.0, 2.5 Hz), 8.01 ( 1 H, ddd, J = 8.5, 4.5, 2.5 Hz), 7.83 (1 H, sl), 7.70 - 7.77 (2 H, m), 7.60 (1 H, apparent t, J = 9.0 Hz), 7.18 - 7.27 (2H, m), 2.90 - 3.07 (1 H, m), 1.53 - 1.67 (4 H , m), 1.40 - 1.53 (1 H, m), 0.96 - 1.25 (5 H, m). Method C; TA: 4.21 min. m / z: 395.1 (M + H) + Exact mass: 394.1
19
[000199] Method C; TA: 4.17 min. m / z: 377.1 (M + H) + Exact mass: 376.1 Compound 43

[000200] Method C; TA: 4.53 min. m / z: 411.1 (M + H) + Exact mass: 410.1

[000201] To a solution of (R) -tetrahydrofuran-3-amine (0.87 g, 9.97 mmol) in THF (20 mL) was added sodium hydroxide (4 mL, 5 N) in a ice followed by 3- (chlorosulfonyl) benzoic acid (2.2 g, 9.97 mmol). After stirring at 25 ° C for 3 hours, the reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (20 ml). The aqueous layer was adjusted to pH = 3 by aq. (2 N) and then the resulting mixture was extracted with EtOAc (3 x 20 ml). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo resulting in the compound (R) -3- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (900 mg). To a solution of the compound (R) - 3- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (0.80 g, 2.95 mmol), 4-fluoroaniline (0.39 g, 3, 54 mmol), and HATU (3.36 g, 8.85 mmol) in CH2Cl2 (10 mL) cooled in an ice bath under N2 atmosphere, DIPEA (0.57 g, 0.44 mmol) was added. The resulting mixture was diluted with CH2Cl2 (15 ml) and washed with saturated aqueous NaHCO3 (15 ml) and brine (10 ml). After drying over anhydrous MgSO4, the solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O: from 40% to 80%, v / v; TFA at 0.05% as an addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with Amberlite IRA-900 ion exchange resin (OH form), filtered and lyophilized. The residue obtained was further purified by prep. (Column: Chiralpak AD-3 150x4.6 mm ID, 3 um Mobile phase: 40% methanol (0.05% diethylamine) in CO2. Flow rate: 2.5 mL / min) resulting in compound 8 (370 mg) Method A; Rt: 4.6 min. m / z: 365.2 (M + H) + Exact mass: 364.1; [a] 20 D = - 13.60 (c = 0.11, MeOH) 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (1 H, sl), 8.34 - 8.40 (1 H, m), 8.18 - 8.27 (1 H, m), 8.09 (1 H, ls), 7.99 - 8.06 (1 H, m), 7.74 - 7.84 (3 H, m), 7.13 - 7.33 (2 H, m), 3.64 - 3.83 (2 H, m), 3.50 - 3.64 (2 H, m), 3 , 35 - 3.39 (1 H, m), 1.80 - 1.99 (1 H, m), 1.51 - 1.68 (1 H, m).
Compound 9
[000202] To an ice-cooled mixture of (S) hydrochloride - tetrahydrofuran-3-amine (0.500 g, 4.41 mmol) and NaOH (0.485 g, 12.138 mmol) in H2O (5 mL) and THF ( 5 ml) 3- (chlorosulfonyl) benzoic acid (0.893 g, 4.406 mmol) was added in several portions. Then, the reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was diluted with H2O (10 ml) and extracted with ethyl acetate (10 ml). The pH value of the aqueous layer was adjusted to 3 by adding 1 N HCl and then the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure resulting in (S) -3- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (0.60 g). To an ice-cooled mixture of (S) -3- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (600 mg, 2.212 mmol), 4-fluoroaniline (270 mg, 2.433 mmol) and HATU ( 1.01 g, 2.654 mmol) in DMF (5 mL) DIPEA (1.15 mL, 6.636 mmol) was added under N2 atmosphere. The resulting mixture was stirred at 20 ° C for 2 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous citric acid (10 ml), brine and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 10/90). Pure fractions were collected and the solvent was removed in vacuo. The residue obtained was further purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O from 40% to 80%, v / v; NH4HCO3 of 0.06% as an addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 9 (0.48 g) Method A; Rt: 4.6 min. m / z: 365.2 (M + H) + Exact mass: 364.1; [α] 20 D = +15.56 (c 0.10, MeOH); 1H NMR (400 MHz, 80 ° C, DMSO-d6) δ ppm 10.35 (1 H, ls), 8.32 - 8.48 (1 H, m), 8.15 - 8.32 (1 H , m), 8.03 (1 H, ls), 7.83 - 7.94 (1 H, m), 7.68 - 7.83 (3 H, m), 7.06 - 7.31 ( 2 H, m), 3.70 - 3.87 (2 H, m), 3.51 - 3.70 (2 H, m), 3.32 - 3.48 (1 H, m), 1, 85 - 2.04 (1 H, m), 1.59 - 1.78 (1 H, m)
[000203] Compounds prepared similarly as described for compounds 8 and 9 from the corresponding amines instead of tetrahydrofuran-3-amine:

[000204] Method B; Rt: 4.24 min. m / z: 365.2 (M + H) + Exact mass: 364.1;

[000205] Using 1-methylcyclopentanamine instead of tetrahydrofuran-3-amine, purified using Gemini 250 * 20 mm * 5 µm (eluent: CH3CN in H2O (0.1% TFA) from 40% to 70% , v / v). Method B; Rt: 4.24 min. m / z: 377.2 (M + H) + Exact mass: 376.1; Synthesis of 3- (N-cyclopentylsulfamoyl) benzoic acid:
[000206] To an ice-cooled mixture of cyclopentanamine (1.93 g, 22.66 mmol) and a solution of NaOH (1.81 g, 45.32 mmol) in H2O (25 mL) and THF (25 mL) 3- (chlorosulfonyl) benzoic acid (5.0 g, 22.66 mmol) was added in portions. The reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was diluted with H2O (20 ml) and extracted with ethyl acetate (30 ml). The aqueous layer was separated and adjusted to pH = 2 by 4N HCl and extracted with dichloromethane (3 x 30 ml). The combined organic layer was washed with brine (15 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3- (N-cyclopentylsulfamoyl) benzoic acid (4.5 g).

[000207] To an ice-cooled mixture of 3- (N-cyclopentylsulfamoyl) benzoic acid (250 mg, 0.928 mmol), 4-fluoro-3-methylaniline (116.2 mg, 0.928 mmol), HATU (388.2 mg , 1.021 mmol) in CH2Cl2 (15 mL) DIPEA (359.8 mg, 2.784 mmol) was added under an atmosphere of N2. The resulting mixture was stirred at 20 ° C for 16 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous citric acid (10 ml), brine and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 10/90). Pure fractions were collected and the solvent was removed in vacuo. The residue obtained was further purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O: from 45% to 75%, v / v; 0.01% HCl as an addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with Amberlite IRA-900 ion exchange resin (OH form), filtered and lyophilized to dryness to give compound 11 (170.0 mg). Method B; Rt: 4.31 min. m / z: 377.2 (M + H) + Exact mass: 376.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (1 H, sl), 8.33-8.35 (1 H, m), 8.17 (1 H, dm, J = 8.0 ), 7.98 (1 H, dm, J = 8.0), 7.78 (1 H, d, J = 7.0 Hz), 7.74 (1 H, t, J = 8.0 Hz ), 7.62 - 7.68 (1 H, m), 7.53 - 7.61 (1 H, m), 7.13 (1 H, t, J = 9.0 Hz), 3.37 - 3.48 (1 H, m), 2.23 (3 H, d, J = 1.8 Hz), 1.44 - 1.69 (4 H, m), 1.12 - 1.45 ( 4 H, m)
[000208] Prepared similarly to compound 11 starting from the corresponding anilines instead of 4-fluoro-3-methylaniline:
Compound 12
[000209] 1H NMR (400 MHz, DMSo-d6) δ ppm 10.60 (1 H, bs), 8.36 (1 H, t, J = 1.5 Hz), 8.19 (1 H, dm , J = 7.5 Hz), 8.02 (1 H, dm, J = 7.5 Hz), 7.81 (1 H, d, J = 7.5 Hz), 7.78 (1 H, t, J = 7.5 Hz), 7.55 (1 H, dm, J = 11.0 Hz), 7.38 - 7.46 (1 H, m), 6.82 (1 H, dm, J = 9.5 Hz), 3.41 - 3.54 (1 H, m), 2.34 (3 H, s), 1.45 - 1.70 (4 H, m), 1.19 - 1.45 (4 H, m); Method B; Rt: 4.41 min. m / z: 377.2 (M + H) + Exact mass: 376.1

[000210] the residue was purified by column chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 40/60). Method B; Rt: 4.41 min. m / z: 377.2 (M + H) + Exact mass: 376.1

[000211] Method B; Rt: 4.34 min. m / z: 381.2 (M + H) + Exact mass: 380.1
[000212] 1H NMR (400 MHz, DMSo-d6) δ ppm 1.20 - 1.44 (m, 4 H), 1.44 - 1.68 (m, 4 H), 3.44 (sxt, J = 6.8 Hz, 1 H), 7.45 (dt, J = 10.6, 9.0 Hz, 1 H), 7.51 - 7.60 (m, 1 H), 7.77 (t , J = 7.8 Hz, 1 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.93 (ddd, J = 13.2, 7.5, 2.5 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 8.35 (t, J = 1.7 Hz , 1 H), 10.70 (s, 1 H)

[000213] Method B; Rt: 4.43 min. m / z: 381.2 (M + H) + Exact mass: 380.1

[000214] Method B; Rt: 5.45 min. m / z: 363.2 (M + H) + Exact mass: 362.1

[000215] purified by preparative high performance liquid chromatography (column: Phenomenex Synergi 200 mm * 77 mm, 10 µm; mobile phase: CH3CN in water (0.1% TFA) from 45% to 75%). Method A; Rt: 5.87 min. m / z: 413.2 (M + H) + Exact mass: 412.1 Compound 16

[000216] A solution of 3- (N-cyclopentylsulfamoyl) benzoic acid (500 mg, 1.73 mmol) in oxalyl dichloride (10 mL) was stirred at 45 ° C for 5 hours. The solvent was removed in vacuo. Crude 3- (N-cyclopentylsulfamoyl) benzoyl chloride (600 mg) was used as such in the next step. To an ice-cooled mixture of benzoyl 3- (N-cyclopentylsulfamoyl) chloride (600 mg, 1.74 mmol) and 4-amino-2-methylbenzonitrile (230 mg, 1.74 mmol) in CH2Cl2 (5 mL) was added pyridine (10 mL) under N2 atmosphere. The resulting mixture was stirred at 20 ° C for 16 hours. The solvent was removed in vacuo. The obtained residue was purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O from 50% to 80%, v / v; 0.05% TFA as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with ion exchange resin Amberlite IRA-900 (OH form), filtered and lyophilized resulting in compound 16 (250 mg). Method B; Rt: 4.23 min. m / z: 384.2 (M + H) + Exact mass: 383.1.
75
[000217] Prepared similarly as described for compound 16 using 3-aminobenzonitrile instead of 4-amino-2-methylbenzonitrile. Method A; Rt: 5.24 min. m / z: 370.2 (M + H) + Exact mass: 369.1.
80
[000218] Prepared similarly as described for compound 16 using 4-aminobenzonitrile instead of 4-amino-2-methylbenzonitrile. Method A; Rt: 5.32 min. m / z: 370.2 (M + H) + Exact mass: 369.1.
82
[000219] Prepared similarly as described for compound 16 using 3-amino-5-methylbenzonitrile instead of 4-amino-2-methylbenzonitrile. Method A; Rt: 5.52 min. m / z: 384.2 (M + H) + Exact mass: 383.1.

[000220] To a solution of the compound 2,4-dichloro-5- (piperidin-1-ylsulfonyl) benzoic acid (1.0 g, 2.96 mmol), m-toluidine (0.38 g, 3.55 mmol ), and HATU (1.69 g, 4.44 mmol) in CH2Cl2 (10 mL) cooled in an ice bath, DIPEA (1.15 g, 8.88 mmol) was added under the N2 atmosphere. The resulting mixture was diluted with CH2Cl2 (15 ml) and washed with saturated aqueous NaHCO3 (15 ml) and brine (10 ml), dried over anhydrous MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 40/60). The pure fractions were collected and the solvent was removed in vacuo, resulting in compound 17 (0.65 g). Method B; Rt: 4.70 min. m / z: 427.1 (M + H) + Exact mass: 426.1

[000221] To a solution of 3- (chlorosulfonyl) benzoic acid (1.10 g, 4.97 mmol) in THF (60 mL) was added sodium hydroxide (aq., 2 mL, 5 N) in a gel bath followed by the addition of N-methylcyclopentanamine (0.50 g, 4.97 mmol). After stirring at 25 ° C for 3 hours, the reaction mixture was diluted with H2O (50 ml) and extracted with EtOAc (50 ml). The aqueous layer was adjusted to pH = 3 by HCl (2 N) and extracted with EtOAc (3 x 50 ml). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo resulting in 3- (N-cyclopentyl-N-methylsulfamoyl) benzoic acid (0.8 g). To a solution of 3- (N-cyclopentyl-N-methylsulfamoyl) benzoic acid (0.80 g, 2.82 mmol), 4-fluoroaniline (0.31 g, 2.82 mmol), and HATU (1.61 g, 4.24 mmol) in CH2Cl2 (10 mL), cooled to an ice bath, DIPEA (1.09 g, 8.47 mmol) was added under N2 atmosphere. The resulting mixture was diluted with CH2Cl2 (15 ml) and washed with saturated aqueous NaHCO3 (15 ml) and brine (10 ml), dried over anhydrous MgSO4 and the solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O from 30% to 80%, v / v; 0.05% TFA as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with Amberlite IRA-900 ion exchange resin (OH form), filtered and lyophilized to dryness resulting in compound 46 (0.73 g). Method B; Rt: 4.43 min. m / z: 377.2 (M + H) + Exact mass: 376.1

[000222] 4-Fluoroaniline (0.93 g, 8.366 mmol) and DIPEA (2.91 mL, 16.732 mmol) were dissolved in CH2Cl2 (20 mL). 3- (chlorosulfonyl) benzoyl chloride (2 g, 8.366 mmol) in CH2Cl2 (20 mL) was added in one portion at 0 ° C. The mixture was stirred for 1 hour at 0 ° C. The reaction mixture (40 ml) containing 3- (4-fluorophenylcarbamoyl) benzene-1-sulfonyl chloride was used for the next step without further purification. Ammonia (2.52 g, 18 mmol, 25-28% by weight) was added to a solution of 3- (4-fluorophenylcarbamoyl) benzene-1-sulfonyl chloride (obtained as above, 6 mmol) in CH2Cl2 (30 mL ) at 0 ° C. The mixture was stirred for 1 hour at 20 ° C. 1 N HCl (30 ml) was added to the reaction mixture and the volatiles were partially removed in vacuo. The formed precipitate was filtered and coevaporated with toluene (10 ml), resulting in N- (4-fluorophenyl) -3-sulfamoyl benzamide (1.6 g). A solution of N- (4-fluorophenyl) -3-sulfamoyl benzamide (1.8 g, 6.12 mmol) and cyclohexanecarbonyl chloride (1.79 g, 12.23 mmol) in chloroform (40 mL) with SiO2 (180 mg) and H2SO4 (0.5 ml) was refluxed for 1 hour. Dichloromethane (20 ml) was added and the solid was filtered. The filtrate was washed with water (10 ml) and dried over Na2SO4. The solvent was removed in vacuo. The residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 70/30). The product obtained (1.2 g, 95% purity) was further washed with methyl ether and t-butyl (10 ml) resulting in compound 56 (500 mg, 99.7% purity). Method A; Rt: 5.51 min. m / z: 405.2 (M + H) + Exact mass: 404.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (1 H, sl), 10.62 (1 H, sl), 8.41 (1 H, t, J = 2.0 Hz), 8 , 27 (1 H, dm, J = 7.5 Hz), 8.09 (1 H, dm, J = 7.5 Hz), 7.73 - 7.82 (3 H, m), 7.07 - 7.33 (2 H, m), 2.11 - 2.31 (1 H, m), 1.43 - 1.80 (5 H, m), 0.94 - 1.32 (5 H, m) Compound 48

[000223] Compound 56 (600 mg) was dissolved in CH2Cl2 (6 mL) and MeOH (2 mL) and TMSCHN2 (3.7 mL, 7.415 mmol, 2 M in hexane) were added dropwise at 20 ° C. The mixture was stirred for 2 hours at 20 ° C. The solvent was removed in vacuo. The residue was purified by flash column (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 70/30) resulting in a residue (0.41 g). The product obtained was further purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O (0.1% TFA) from 20% to 50%, v / v). The pure fractions were collected and the volatiles were removed in vacuo. The precipitate was filtered and the residual water was removed by lyophilization resulting in compound 48 (300 mg). Method B; Rt: 4.60 min. m / z: 419.2 (M + H) + Exact mass: 418.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (1 H, sl), 8.40 - 8.45 (1 H, m), 8.28 (1 H, dm, J = 7.5 Hz), 8.13 (1 H, dm, J = 7.5 Hz), 7.66 - 7.95 (3 H, m), 7.07 - 7.33 (2 H, m), 3, 40 (3 H, s), 2.73 - 2.92 (1 H, m), 1.42 - 1.77 (5 H, m), 0.90 - 1.35 (5 H, m).
63
[000224] A mixture of ethyl 2- (chlorosulfonyl) -1H-imidazole-4-carboxylate (1 g, 4.19 mmol), Et3N (1.27 g, 12.55 mmol) and cyclohexanamine (0.623 g, 6 , 28 mmol) in THF (25 mL) was stirred at room temperature for 15 hours. The mixture was concentrated and purified by preparative HPLC (Column: C18; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 25-55% , 30 min) resulting in ethyl 2- (N-cyclohexylsulfamoyl) -1H-imidazole-4-carboxylate (0.6 g) as a light yellow solid. To a solution of ethyl 2- (N-cyclohexylsulfamoyl) -1H-imidazole-4-carboxylate (0.6 g, 1.99 mmol) in EtOH-H2O (3/1; 20 mL) was added LiOH (0.145 g , 6.055 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was neutralized with HCl (2 M), diluted with water and then extracted with EtOAc, dried over MgSO4, filtered and concentrated resulting in 2- (N-cyclohexylsulfamoyl) - 1H-imidazole-4-carboxylic acid (400 mg) like a white solid. A mixture of 2- (N-cyclohexylsulfamoyl) -1H-imidazole-4-carboxylic acid (0.3 g, 1.098 mmol), aniline (0.102 g, 1.098 mmol), DIPEA (0.284 g, 2.196 mmol) and HATU (0.501 g, 1.317 mmol) in DMF (25 ml) was stirred at room temperature for 15 hours. The mixture was purified by preparative HPLC (Column: YMC 150x30 mm.
[000225] Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Gradient: 40-70%, 8 min) resulting in compound 63 (218 mg). Method B; Rt: 3.98 min. m / z: 349.2 (M + H) + Exact mass: 348.1. 1H NMR (400 MHz, METANOL-d4) δ ppm 1.26 (s, 5 H) 1.51 - 1.62 (m, 1 H) 1.65 - 1.80 (m, 4 H) 3.23 - 3.29 (m, 1 H) 7.10 - 7.18 (m, 1 H) 7.32 - 7.39 (m, 2 H) 7.67-7.74 (m, 2 H) 7 , 86 (s, 1 H);
Compound 64
[000226] A mixture of ethyl 2- (chlorosulfonyl) thiazol-4-carboxylate (3 g, 11.73 mmol), Et3N (3.56 g, 35.2 mmol) and cyclohexanamine (1.75 g, 17, 65 mmol) in THF (100 mL) was stirred at room temperature for 15 hours. The mixture was concentrated and purified by preparative HPLC resulting in ethyl 2- (N-cyclohexylsulfamoyl) thiazol-4-carboxylate (2 g) as a white solid. To a solution of ethyl 2- (N-cyclohexylsulfamoyl) thiazol-4-carboxylate (2 g) in EtOH-THF (1/1, 60 ml) was added LiOH (0.451 g, 18.83 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was neutralized with HCl (2 M), diluted with water and then extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo resulting in 2- (N-cyclohexylsulfamoyl) thiazole-4-carboxylic acid (1.7 g ) as a white solid. A mixture of 2- (N-cyclohexylsulfamoyl) thiazole-4-carboxylic acid (1 g), aniline (0.321 g, 3.44 mmol), DIPEA (1.33 g, 10.29 mmol) and HATU (1.57 g, 4.13 mmol) in DMF (40 ml) was stirred at room temperature for 15 hours. The mixture was concentrated and purified by preparative HPLC (Column: SYNERGI 250 * 50 10 um; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile Flow rate: 80 mL / min Gradient: 35 -65%, 30 min) resulting in compound 64 (895 mg) as a white solid. Method B; Rt: 4.45 min. m / z: 366.1 (M + H) + Exact mass: 365.1
65
[000227] The mixture of 6-chloro-N-phenylpicolinamide (4 g, 17.19 mmol), phenylmethanethiol (3.23 g, 25.79 mmol) and K2CO3 (4.75 g, 34.38 mmol) in DMF it was stirred at 80 ° C for 18 hours. The reaction mixture was diluted with EtOAc (150 ml), and washed with brine (2 x 200 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc in petroleum ether) to obtain 6- (benzylthio) -N-phenylpicolinamide (2.8 g). N-Chlorosuccinimide (3.42 g, 25.6 mmol) was added to the mixture of 6- (benzylthio) -N-phenylpicolinamide (2 g, 6.24 mmol) in acetic acid (60 mL) and water (40 mL) . The reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with CH2Cl2 (100 ml). After washing with water, the organic layer was added to the mixture of cyclohexanamine (12.4 g, 125 mmol) and Et3N (50 ml) in CH2Cl2 (200 ml). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with NH4Cl (saturated), brine, dried over MgSO4, filtered and concentrated. The residue obtained was purified by preparative HPLC (Column: Synergi 150 * 30 mm * 5 µm; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 30 mL / min; Gradient: 46-76% (solvent B), 8 min) resulting in compound 65 (330 mg). Method B; Rt: 4.46 min. m / z: 360.2 (M + H) + Exact mass: 359.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.31 (m, 5 H) 1.34 - 1.47 (m, 1 H) 1.51 - 1.71 (m, 4 H ) 3.02 - 3.13 (m, 1 H) 7.15 - 7.21 (m, 1 H) 7.40 - 7.46 (m, 2 H) 7.82 - 7.88 (m, 2 H) 8.15 (dd, J = 6.3, 2.5 Hz, 1 H) 8.23 - 8.28 (m, 1 H) 8,298.36 (m, 2 H) 10.47 (s , 1 H)

[000228] A mixture of 2-chloro-N-phenylisonicotinamide (2 g, 8.6 mmol), phenylmethanethiol (2.11 g, 17 mmol) and K2CO3 (2.35 g, 17 mmol) in DMF was stirred at 80 ° C ° C for 18 hours. The reaction was diluted with water (200 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue obtained was purified by chromatography on silica gel (EtOAc 0-20% in petroleum ether) resulting in 2- (benzylthio) -N-phenylisonitoctinamide (1.7 g). N-Chlorosuccinimide (2.56 g, 19.2 mmol) was added to a mixture of 2- (benzylthio) -N-phenylisonicotinamide (1.5 g, 4.68 mmol) in acetic acid (20 mL) and water ( 10 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was diluted with CH2Cl2 (20 ml). After washing with water, the organic layer was added to the mixture of cyclohexanamine (4.641 g, 46.8 mmol) and Et3N (10 mL, 71.74 mmol) in CH2Cl2 (50 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with NH4Cl (saturated), brine, dried over MgSO4, filtered and concentrated. The residue obtained was purified by preparative HPLC (Column: C18-10 um; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 40-70% (solvent B), 25min) resulting in compound 66 (250 mg). Method B; Rt: 4.22 min. m / z: 360.2 (M + H) + Exact mass: 359.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 - 1.08 (m, 1 H) 1.08 - 1.24 (m, 4 H) 1.40 - 1.52 (m, 1 H ) 1.53 - 1.67 (m, 4 H) 3.11 - 3.22 (m, 1 H) 7.14 - 7.21 (m, 1 H) 7.37 - 7.44 (m, 2 H) 7.78 (d, J = 7.8 Hz, 2 H) 7.97 (ls, 1 H) 8.12 (dd, J = 5.0, 1.5 Hz, 1 H) 8, 40 (s, 1 H) 8.94 (d, J = 5.0 Hz, 1 H) 10.75 (s, 1 H)

[000229] 2-Chloro-N-cyclohexylpyridine-4-sulfonamide (540 mg, 1.965 mmol), PdCl2dppf (100 mg, 0.137 mmol) and Et3N (5.89 mmol) in methanol (50 mL) were stirred at 50 ° C for 18 hours under a CO atmosphere (50 psi). The solvent was removed under reduced pressure. The residue obtained (700 mg) containing methyl 4- (N-cyclohexylsulfamoyl) picolinate was used in the next step without further purification. K2CO3 (421 mg, 3.05 mmol) was added to the mixture of methyl 4- (N-cyclohexylsulfamoyl) picolinate in methanol and water. The mixture was stirred at 20 ° C for 18 hours. The solvent was removed, the residue was diluted with water (50 ml) and washed with EtOAc (2 x 50 ml). The aqueous layer was then adjusted to pH = 3 with 1 M HCl and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated resulting in 4- (N-cyclohexylsulfamoyl) picolinic acid (380 mg). HATU (0.76 g, 2.0 mmol) was then added to a mixture of 4- (N-cyclohexylsulfamoyl) picolinic acid (380 mg, 1.34 mmol), aniline (251 mg, 2.7 mmol) and DIPEA (0.517 g, 4.0 mmol) in DMF (50 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (200 ml), and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (10-20% EtOAc in petroleum ether) resulting in compound 67 as a white solid (330 mg). Method B; Rt: 4.58 min. m / z: 360.2 (M + H) + Exact mass: 359.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 - 1.26 (m, 5 H) 1.37 - 1.50 (m, 1 H) 1.50 - 1.69 (m, 4 H ) 2.98-3.12 (m, 1 H) 7.15 (t, J = 7.2 Hz, 1 H) 7.32-7.45 (m, 2 H) 7.86-7.97 (m, 2 H) 8.03 (dd, J = 5.0, 1.5 Hz, 1 H) 8.25 (d, J = 7.3 Hz, 1 H) 8.47 (d, J = 1.5 Hz, 1 H) 9.00 (d, J = 5.0 Hz, 1 H) 10.78 (s, 1 H)

[000230] Thionyl chloride (10 ml, 137 mmol) was added dropwise to water (60 ml) at 0-5 ° C. The mixture was stirred at room temperature for 16 hours. CuCl (40 mg, 0.4 mmol) was added, and the mixture (mixture A) was cooled to -5 ° C. To a mixture of 5-aminonicotinic acid in conc. (35 mL) a solution of NaNO2 (2.76 g, 40 mmol) in water (40 mL) was added at -5 ° C to 0 ° C (mixture B). Mixture B was added portion by portion to mixture A over 30 minutes, maintaining the temperature at -5 ° C to 0 ° C. After stirring at 0 ° C for 1 hour, the solid was collected by filtration, washed with water, and dried in vacuo resulting in 5- (chlorosulfonyl) nicotinic acid (1.05 g). The mixture of 5- (chlorosulfonyl) nicotinic acid (1 g, 4.5 mmol), cyclohexanamine (0.893 g, 9 mmol) and Et3N (1.37 mmol, 13.5 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was purified by HPLC (Column: C18 10 µm; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 30-60% ( solvent B), 30 min) resulting in 5- (N-cyclohexylsulfamoyl) nicotinic acid as a white solid (1 g). HATU (2.6 g, 7 mmol) was added to the mixture of 5- (N-cyclohexylsulfamoyl) nicotinic acid (1 g, 3.5 mmol), aniline (391 mg, 4.2 mmol) and DIPEA (1.36 g, 10.5 mmol) in DMF (50 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (200 ml) and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (10-100% EtOAc in petroleum ether) resulting in compound 68 (708 mg) as a white solid. Method B; Rt: 4.58 min. m / z: 360.2 (M + H) + Exact mass: 359.1

[000231] To an ice-cooled solution of 5-aminopentanoic acid (1.2 g, 3.44 mmol) and 1 N NaOH (8 mL) in THF (16 mL) was added 3- (4-fluorophenylcarbamoyl chloride) ) benzene-1-sulfonyl (0.444 g, 3.78 mmol). Then, the reaction mixture was stirred at 25 ° C overnight. The resulting mixture was diluted with 1 N HCl (10 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient: petroleum ether: ethyl acetate: from 100: 0 to 65:35) resulting in 5- (3- (4-fluorophenylcarbamoyl) phenylsulfonamido acid ) pentanoic (0.9 g). A mixture of 5- (3- (4-fluorophenylcarbamoyl) phenylsulfonamido) pentanoic acid (400 mg, 0.913 mmol), acetic anhydride (0.466 g, 4.57 mmol) and AcOK (1.79 g, 18.3 mmol) in toluene (25 ml) was heated by microwave irradiation at 150 ° C for 30 minutes. The formed precipitate was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative high performance liquid chromatography (eluent: CH3CN in H2O (HCl 0.05%) from 0% to 35%, v / v). The pure fractions were collected and adjusted to pH = 7 with Amberlite IRA-900 (OH) ion exchange resin. The resin was filtered and the filtrate was lyophilized to dryness resulting in compound 69 (200 mg). Method A; Rt: 4.97 min. m / z: 377.2 (M + H) + Exact mass: 376.1; 1H NMR (400 MHz, CHLOROPHORUM-d) δ ppm 1.78 - 1.87 (m, 2 H), 1.90 - 1.99 (m, 2 H), 2.44 (t, J = 6.8 Hz, 2 H), 3.95 (t, J = 6.0 Hz, 2 H), 7.08 (t, J = 8.7 Hz, 2 H), 7.55 - 7.70 (m, 3 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 8.26 (s l., 1 H), 8.49 (s, 1 H)

[000232] To an ice-cooled mixture of (R) -butan-2-amine (0.500 g, 6.837 mmol) and NaOH (0.547 g, 13.67 mmol) in H2O (15 mL) and THF (15 mL) 3- (chlorosulfonyl) benzoic acid (1.508 g, 6.84 mmol) is added in portions. The reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was diluted with H2O (15 ml) and extracted with ethyl acetate (15 ml). The aqueous layer was separated and the pH was adjusted to 3 by 1N HCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure resulting in (R) -3- (N-sec-butylsulfamoyl) benzoic acid (0.73 g).
[000233] To an ice-cooled mixture of (R) -3- (N-sec-butylsulfamoyl) benzoic acid (730 mg, 4 mmol), 4-fluoroaniline (347 mg, 3.121 mmol), HATU (1.294 g, 3.404 mmol) in DMF (10 mL) DIPEA (1.48 mL, 8.51 mmol) was added under N3 atmosphere. The resulting mixture was stirred at 20 ° C for 2 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous citric acid (10 ml), brine and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 55/45). Pure fractions were collected and the solvent was removed in vacuo. The residue was purified by SFC separation (Chiralcel OJ, 20 μm; Supercritical CO2: MeOH (0.2% diethylamine)). The pure fractions were collected and the solvent was removed in vacuo, resulting in compound 70 (300 mg). Method A; Rt: 5.25 min. m / z: 351.2 (M + H) + Exact mass: 350.1. I • • '= - (c = 0.2, MeOH). I • ■ '= -9.9 (c 0.435 w / v%, DMF); Column: Chiralpak AD-3 150x4.6 mm ID, 3 µm; Mobile phase: methanol (0.05% diethylamine) in CO2 from 5% to 40%; Flow rate: 2.5 mL / min; Rt: 7.58 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J = 7.4 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H), 1.30 ( quin, J = 7.2 Hz, 2 H), 3.01 - 3.18 (m, 1 H), 7.21 (t, J = 8.8 Hz, 2 H), 7.67 (d l ., J = 5.5 Hz, 1 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.78 (dd, J = 8.8, 5.1 Hz, 2 H) , 8.00 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 8.36 (s, 1 H), 10.55 (s , 1 H).
71
[000234] Prepared similarly as described for compound 70 starting from (S) -butan-2-amine instead of (R) -butan-2-amine. Method B; Rt: 4.03 min. m / z: 351.2 (M + H) + Exact mass: 350.1 (! ■■ '= + (c = 0.2, MeOH). [a] 20 D = + 9.49 (c 0.611 p / v%, DMF), Column: Chiralpak AD-3 150x4.6 mm ID, 3 µm; Mobile phase: methanol (0.05% ethylamine) in CO2 from 5% to 40%; Flow rate: 2, 5 mL / min; Rt: 7.73 min. [Α] ^ + 9.49 ° (c 0.61 w / v%, MeOH)
72
[000235] 3- (Chlorosulfonyl) benzoyl chloride (1200 mg, 5.0 mmol) was dissolved in dichloromethane (15 ml). A solution of 4-fluoro-3-methylaniline (625 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) in dichloromethane (15 mL) was added to the mixture at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was used in the next step without further purification. To the above reaction mixture was added a solution of triethylamine (606 mg, 6.0 mmol) and (S) -tetrahydrofuran-3-amine (460.0 mg, 5.3 mmol) in dichloromethane (15 mL) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The solvent was removed in vacuo. The residue was purified by high performance reverse liquid chromatography (eluent: CH3CN in water (0.1% TFA) from 25 to 55, v / v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCO3 until pH = 7-8. The mixture was extracted with dichloromethane (3 x 15 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo resulting in compound 72 (620 mg). Method A; Rt: 4.88 min. m / z: 379.2 (M + H) + Exact mass: 378.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 - 1.65 (m, 1 H), 1.85 - 1.94 (m, 1 H), 2.22 - 2.28 (m, 3 H), 3.33 - 3.39 (m, 1 H), 3.52 - 3.65 (m, 2 H), 3.65 - 3.73 (m, 1 H), 3.73 - 3.79 (m, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.67 (dd, J = 7 , 0, 2.3 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.10 ( d, J = 4.5 Hz, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 8.37 (s, 1 H), 10.49 (s, 1 H)
85
[000236] Prepared similarly as described for compound 72 using 1-ethylcyclopropanamine hydrochloride instead of (S) -tetrahydrofuran-3-amine. Compound 85 was purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O (NH4HCO3 0.5%) from 43% to 73%, v / v). Method B; Rt: 4.17 min. m / z: 377.1 (M + H) + Exact mass: 376.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.45 (m, 2 H), 0.49-0.58 (m, 2 H), 0.77 (t, J = 7, 2 Hz, 3 H), 1.31 (q, J = 7.1 Hz, 2 H), 2.26 (s, 3 H), 7.15 (t, J = 9.3 Hz, 1 H) , 7.55 - 7.64 (m, 1 H) 7.69 (d, J = 7.0 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7, 98 (d, J = 7.8 Hz, 1 H), 8.16 - 8.25 (m, 2 H), 8.35 (s, 1 H), 10.50 (s, 1 H).

[000237] Prepared similarly as described for compound 72 using 2-methylbutan-2-amine hydrochloride instead of (S) -tetrahydrofuran-3-amine. Purified by high performance liquid chromatography on RP-18 (eluent: CH3CN in water from 47% to 77%, v / v). Method D; Rt: 5.97 min. m / z: 379.1 (M + H) + Exact mass: 378.1. 1H NMR (400 MHz, DMSO-d6), δ = 0.73 (t, J = 7.5 Hz, 3 H), 1.02 (s, 6 H), 1.44 (q, J = 7, 5 Hz, 2 H), 2.23 (d, J = 1.0 Hz, 3 H), 7.12 (t, J = 9.3 Hz, 1 H), 7.52 - 7.61 (m , 2 H), 7.64 - 7.77 (m, 2 H), 8.01 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 8.36 (s, 1 H). 10.45 (s, 1 H).
[000238] Alternative synthesis of compound 72:
[000239] A mixture of 3- (chlorosulfonyl) benzoyl chloride (4.61 g, 19.28 mmol) in toluene (45 mL) was refluxed under a gentle flow of nitrogen. 4-fluoro-3-methylaniline (2.19 g, 17.53 mmol) in toluene (15 mL) was added dropwise to the reflux solution. After addition, the mixture was refluxed for another 30 minutes. The mixture was then cooled to room temperature, and a mixture of (S) -3-aminotetrahydrofuran tosylate (5 g, 19.28 mmol) and diisopropylethylamine (15 mL) in toluene (15 mL) and CH2Cl2 (10 ml) was added dropwise. After addition, the mixture was stirred for 4 hours at room temperature. The resulting mixture was washed with HCl (2 x 100 ml, 1 M aq), water (2 x 100 ml) and NaHCO3 (2 x 100 ml, sat. Aq). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (CH2Cl2-MeOH 100: 0 to 95: 5) giving 3- (4-fluoro-3-methylphenylcarbamoyl) benzene-1-sulfonyl chloride (1.07 g) during elution of CH2Cl2, followed by compound 72 (2.85 g) as a white solid after removal of the solvent (dried in a vacuum oven at 55 ° C for 20 hours). I "'= - 5.21 (c 0.67 w / v%, MeOH), Method F; Rt: 0.88 min. M / z: 379.1 (M + H) + Exact mass: 378.1 The compound was crystallized from CH2Cl2: DSC (From 30 to 300 ° C to 10 ° C / min): 149 ° C = + 3.21 (c 0.65 w / v%, DMF).

[000240] To an ice-cooled solution of 3- (chlorosulfonyl) benzoic acid (50.0 g, 226.6 mmol) in ethyl acetate (1000 mL) was added isopropylamine (67.0 g, 1.13 mol) in one serving. The reaction mixture was stirred at 25 ° C for 3 hours. The resulting mixture was diluted with 1 N HCl (500 ml) and extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with brine (400 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure resulting in 3- (N-isopropylsulfamoyl) benzoic acid (46 g). To an ice-cooled mixture of 3- (N-isopropylsulfamoyl) benzoic acid (7.0 g, 28.77 mmol), 4-fluoro-3-methylaniline (3.6 g, 28.77 mmol) and DIPEA (18 , 6 g, 143.91 mmol) in CH2Cl2 (70 mL) HATU (12.0 g, 31.56 mmol) was added under N2 atmosphere. The resulting mixture was stirred at 20 ° for 16 hours *** s. The solvent was removed in vacuo. The mixture was washed with saturated aqueous citric acid (30 ml), brine (20 ml) and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by preparative high performance liquid chromatography in SYNERGI 250 * 50 10 um (eluent: CH3CN in H2O (TFA 0.05%) from 35% to 65%, v / v). The pure fractions were collected and adjusted to pH = 7 with Amberlite IRA-900 (OH) anion exchange resin. The resin was filtered. The filtrate was lyophilized to dryness resulting in compound 73 (7.5 g). Method B; Rt: 3.44 min. m / z: 351.1 (M + H) + Exact mass: 350.1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (1 H, sl), 8.36 (1 H, t, J = 1.5 Hz), 8.19 (1 H, ddd, J = 7.8, 1.5, 1.0 Hz), 8.01 (1 H, ddd, J = 7.8, 1.5, 1.0 Hz), 7.76 (1 H, t, J = 7.8 Hz), 7.68 (1 H, dd, J = 7.0, 3.0 Hz), 7.75 (1 H , bs), 7.59 (1 H, ddd, J = 9.0, 4.5, 3.0 Hz), 7.15 (1 H, t, J = 9.0 Hz), 3.14 - 3.33 (1 H, m), 2.25 (3 H, d, J = 1.5 Hz), 0.96 (6 H, d, J = 6.5 Hz).

[000241] Prepared similarly as described for compound 73, using 4-fluoro-3- (trifluoromethyl) aniline instead of 4-fluoro-3-methylaniline. Purified on HPLC Synergi 150x30 mmx5 um (eluent: CH3CN in H2O (HCl 0.05%) from 45% to 75%, v / v). Method A; Rt: 5.62 min. m / z: 405.2 (M + H) + Exact mass: 404.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (1 H, s), 8.39 (1 H, t, J = 1.5 Hz), 8.17 - 8.30 (2 H, m), 8.07 - 8.17 (1 H, m), 8.03 (1 H, d, J = 7.8), 7.73-7.83 (2 H, m), 7.55 (1 H, t, J = 10.0 Hz), 3.20 - 3.33 (1 H, m), 0.95 (6 H, d, J = 6.5 Hz).
84
[000242] A mixture of N- (3-bromo-4-fluorophenyl) -3- (N-isopropylsulfamoyl) benzamide (prepared similarly as described for compound 73, using 3-bromo-4-fluoroaniline instead of 4-fluoro -3-methylaniline and purified by pre-parative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O (0.05% NH4HCO3) from 40% to 70%, v / v); 700 mg, 1 , 69 mmol), cyclopropylboronic acid (0.22 g, 2.529 mmol), Pd (PPh3) 4 (0.20 g, 0.169 mmol) and Na2CO3 (1.43 g, 13.49 mmol) in water (7 mL) , EtOH (7 ml) and toluene (7 ml) was heated by microwave irradiation for 40 minutes at 100 ° C under N2. The reaction mixture was filtered through celite. Water (10 ml) was added to the filtrate and the mixture was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography on RP-18 (eluent: CH3CN in H2O (0.1% TFA) from 20% to 50%, v / v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na2SO4. The solvent was removed in vacuo and the residue obtained was further purified by chromatography with supercritical fluid (Column: Chiralpak AD-3 150x4.6 mm ID, 3 µm, Mobile phase: methanol (0.05% diethylamine) in CO2 of 5 % to 40% Flow rate: 2.5 mL / min). The pure fractions were collected and the volatiles were removed in vacuo. The residue was suspended in water (5 ml) and lyophilized to dryness resulting in compound 84 (35 mg) Method B; Rt: 4.18 min. m / z: 377.1 (M + H) + Exact mass: 376.1; 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 8.34 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.97 - 8.07 (m, 2 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.36 - 7.46 (m, 1 H), 7.15 - 7.22 (m, 1 H), 7, 01 (t, J = 9.3 Hz, 1 H), 4.65 (d, J = 7.5 Hz, 1 H), 3.44 3.58 (m, 1 H), 2.04 - 2 , 16 (m, 1 H), 1.10 (d, J = 6.5 Hz, 6 H), 0.96 - 1.06 (m, 2 H), 0.71 - 0.82 (m, 2 H).

[000243] Prepared similarly as described for compound 73, using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Method E; Rt: 5.31 min. m / z: 355.1 (M + H) + Exact mass: 354.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1 H), 8.36 (t, J = 1.5 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.98 - 8.08 (m, 1 H), 7.94 (ddd, J = 13.2, 7.5, 2.4 Hz, 1 H), 7.71 - 7 , 83 (m, 2 H), 7.53 - 7.59 (m, 1 H), 7.42 - 7.51 (m, 1 H), 3.21 - 3.29 (m, 1 H) , 0.96 (d, J = 6.5 Hz, 6 H).

[000244] 3- (Chlorosulfonyl) benzoyl chloride (1200 mg, 5.0 mmol) was dissolved in dichloromethane (15 mL). A solution of 3,4-difluoroaniline (650 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) in dichloromethane (15 mL) was added to the mixture at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. To the reaction mixture obtained was added a solution of triethylamine (606 mg, 6.0 mmol) and (S) -tetrahydrofuran-3-amine (460.0 mg, 5.3 mmol) in dichloromethane (15 mL) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The solvent was removed in vacuo. The residue obtained was purified by high performance liquid chromatography on RP-18 (eluent: CH3CN in water (0.1% TFA) from 30 to 60, v / v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCO3 until pH = 7-8. The mixture was extracted with dichloromethane (3 x 15 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo resulting in compound 90 (710 mg) Method A; Rt: 4.16 min. m / z: 383.0 (M + H) + Exact mass: 382.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 - 1.63 (m, 1 H), 1.83 - 1.93 (m, 1 H), 3.32 - 3.38 (m, 1 H), 3.52 - 3.63 (m, 2 H), 3.63 - 3.77 (m, 2 H), 7.45 (dt, J = 10.5, 9.0 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.92 (ddd, J = 13.3, 7.5, 2.5 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 6.5 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 8.35 (s, 1 H), 10.70 (s, 1 H). SFC: Column: Chiralcel OJ-H 250x4.6 mm ID, 5 µm; Flow: 2.35 ml / min; Mobile phase: methanol (0.05% diethylamine) in CO2 from 5% to 40%; Rt: 5.61 Min. H = + 3.21 (c 0.624 w / v%, DMF)

[000245] N- (3-bromo-4-fluorophenyl) -3- (N-isopropylsulfamoyl) benzamide (1.5 g, 3.61 mmol), ethinyltrimethylsilane (1.77 g, 18.06 mmol), Pd ( PPh3) 2Cl2 (0.127 g, 0.181 mmol) and copper iodide (34.4 mg, 0.181 mmol) were dissolved in diisopropylamine (10 mL). The mixture was stirred at 80 ° C in the autoclave for 24 hours. The solvent was removed in vacuo and dichloromethane (30 ml) was added. The mixture was washed with water (20 ml) and the aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The residue obtained was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 100/1 to 60/40) resulting in N- (4-fluoro-3 - ((trimethylsilyl) ethynyl) phenyl ) -3- (N-isopropylsulfamoyl) benzamide (0.8 g). N- (4-fluoro-3- ((trimethylsilyl) ethynyl) phenyl) -3- (N-isopropylsulfamoyl) benzamide (0.8 g, 1.66 mmol) and TFA (4 ml) were dissolved in anhydrous CH2Cl2 (16 mL). The mixture was stirred at 25 ° C overnight and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 75/25), resulting in compound 91 (220 mg). Method A; Rt: 5.12 min. m / z: 361.3 (M + H) + Exact mass: 360.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (1 H, s), 8.35 (1 H, t, J = 1.5 Hz), 8.18 (1 H, d, J = 8.0 Hz), 8.00 (1 H, d, J = 8.0 Hz), 7.97 (1 H, dd, J = 6.5, 3.0 Hz), 7.77 - 7, 84 (1 H, m), 7.70 - 7.79 (2 H, m), 7.32 (1 H, t, J = 9.0 Hz), 4.52 (1H, s) 3.22 - 3.31 (1 H, m), 0.94 (6 H, d, J = 6.5 Hz).

[000246] N- (4-fluoro-3 - ((trimethylsilyl) ethynyl) phenyl) -3- (N-isopropylsulfamoyl) benzamide (0.8 g, 1.66 mmol) and TFA (4 ml) were dissolved in CH2Cl2 anhydrous (16 mL). The mixture was stirred at 25 ° overnight. The mixture was concentrated resulting in crude N- (3-ethynyl-4-fluorophenyl) -3- (N-isopropylsulfamoyl) benzamide which was used as such in the next step (650 mg). To a solution of N- (3-ethynyl-4-fluorophenyl) -3- (N-isopropylsulfamoyl) benzamide (0.6 g) in MeOH (20 ml) was added Pd-C (10%, 0.2 g) under N2 atmosphere. The mixture was stirred under a hydrogen atmosphere (50 psi) at 25 ° C for 4 hours. After filtration on celite, the solvent was removed in vacuo and the residue obtained was purified by preparative high performance liquid chromatography in reverse phase C-18 (eluent: CH3CN in H2O (HCl 0.05%) from 42% to 72% , v / v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was adjusted to pH = 7 with Amberlite IRA-900 anion exchange resin (OH form), filtered and lyophilized to dryness resulting in compound 92 (160 mg). Method B; Rt: 4.13 min. m / z: 365.3 (M + H) + Exact mass: 364.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (1 H, s), 8.35 (1 H, t, J = 1.5 Hz), 8.18 (1 H, d, J = 8.0 Hz), 7.99 (1 H, d, J = 8.0 Hz), 7.70 - 7.78 (2 H, m), 7.65 - 7.70 (1 H, m) , 7.57 - 7.65 (1 H, m), 7.13 (1 H, t, J = 9.0 Hz), 3.21 - 3.32 (1 H, m), 2.62 ( 2 H, q, J = 7.5 Hz), 1.18 (3 H, t, J = 7.5 Hz), 0.94 (6 H, d, J = 6.5 Hz).

[000247] To a solution of 3- (chlorosulfonyl) benzoyl chloride (0.50 g, 2.09 mmol) in CH2Cl2 (10 mL) was added DIPEA (1.35 g, 10.45 mmol) followed by slow addition of 4-fluoro-3-methylaniline (0.25 g, 1.99 mmol). After stirring at 25 ° C for 0.5 hours, 3-ethyloxetan-3-amine (0.21 g, 2.09 mmol) was added. After 1 hour, the resulting mixture was diluted with CH2Cl2 (15 mL), washed with saturated aqueous NaHCO3 (15 mL) and brine (10 mL) and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 80/70) resulting in compound 93 ( 70 mg). Method B; Rt: 3.79 min. m / z: 393.3 (M + H) + Exact mass: 392.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (1 H, s), 8.47 (1 H, sl), 8.38 (1 H, t, J = 1.5 Hz), 8 , 22 (1 H, d, J = 8.0 Hz), 8.03 (1 H, d, J = 8.0 Hz), 7.78 (1 H, t, J = 8.0 Hz), 7.68 (1 H, dd, J = 7.5, 2.5 Hz), 7.56 - 7.64 (1 H, m), 7.15 (1 H, t, J = 9.0 Hz ), 4.51 (2 H, d, J = 6.5 Hz), 4.19 (2 H, d, J = 6.5 Hz), 2.25 (3 H, d, J = 1.5 Hz), 1.84 (2 H, q, J = 7.0 Hz), 0.64 (3 H, t, J = 7.0 Hz).

[000248] 3- (Chlorosulfonyl) benzoyl chloride (1200 mg, 5.0 mmol) was dissolved in dichloromethane (15 ml). A solution of 4-fluoro-3-methylaniline (625 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) in dichloromethane (15 mL) was added to the mixture at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was used in the next step without further purification (crude, 30 ml). To the above reaction mixture was added a solution of triethylamine (606 mg, 6.0 mmol) and 1-methylcyclopropanamine (425.0 mg, 5.9 mmol) in dichloromethane (15 mL) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The solvent was removed in vacuo. The residue was purified by high performance liquid chromatography in reverse phase (eluent: CH3CN in water from 40% to 70%, v / v). The pure fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCO3 until pH = 7-8. The mixture was extracted with dichloromethane (3 x 15 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo resulting in compound 94 (365 mg). Method B; Rt: 3.40 min. m / z: 363.0 (M + H) + Exact mass: 362.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (1 H, s), 8.35 (1 H, t, J = 1.5 Hz), 8.17 - 8.23 (2 H, m), 7.99 (1 H, d, J = 8.0 Hz), 7.76 (1 H, t, J = 8.0 Hz), 7.68 (1 H, dd, J = 7, 0, 2.5 Hz), 7.56 - 7.62 (1 H, m), 7.14 (1 H, t, J = 9.0 Hz), 2.25 (3 H, d, J = 1.5 Hz), 1.06 (3 H, s), 0.58 - 0.63 (2 H, m), 0.37 - 0.42 (2 H, m)

[000249] A mixture of N- (3-bromo-4-fluorophenyl) -3- (N-isopropylsulfamoyl) benzamide (800 mg, 1.93 mmol), 4,4,5,5-tetramethyl- 2- (prop -1-en-2-yl) -1,3,2-dioxaborolane (0.65 g, 3.85 mmol), Pd (PPh3) 4 (111 mg, 0.096 mmol) and K2CO3 (0.53 g, 3 , 85 mmol) in dioxane (8 ml) and water (2 ml) was heated by microwave irradiation for 110 minutes at 120 ° C under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (20 ml) and the catalyst was filtered. The filtrate was concentrated in vacuo. Water (20 ml) was added and the aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue obtained was purified by preparative high performance liquid chromatography on C-18 reverse phase (eluent: CH3CN in H2O (0.1% TFA) from 40% to 70%, v / v) . The pure fractions were collected and the organic solvent was removed in vacuo. The aqueous layer was lyophilized to dryness resulting in N- (4-fluoro-3- (prop-1-en-2-yl) phenyl) -3- (N-isopropyl-sulfamoyl) benzamide (300 mg). N- (4-fluoro-3- (prop-1-en-2-yl) phenyl) -3- (N-isopropylsulfamoyl) benzamide (180 mg) and Pd / C (wet) (20 mg) were stirred in methanol (4 mL) under a hydrogen atmosphere at 25 ° C for 3 hours. The mixture was filtered over celite and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 70/30). The volatiles were removed in vacuo, resulting in compound 95 (175 mg). Method B; Rt: 4.33 min. m / z: 379.3 (M + H) + Exact mass: 378.1;

[000250] 3- (difluoromethyl) -4-fluoroaniline (1.20 g, 7.448 mmol), 3- (N-isopropylsulfamoyl) benzoic acid (0.90 g, 3.699 mmol) and DIPEA (1.93 mL, 11, 10 mmol) were dissolved in CH2Cl2 (10 mL) and HATU (1.41 g, 3.699 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. The mixture was diluted with CH2Cl2 (10 ml) and H2O (10 ml). The organic layer was separated, washed with saturated aqueous NaHCO3 (10 ml) and brine (10 ml) and dried over Na2SO4. The solvent was removed in vacuo and the residue obtained was purified by preparative high performance liquid chromatography on C-18 reverse phase (eluent: CH3CN in H2O (NH4HCO3 0.1% o) from 45% to 75%, v / v ). The pure fractions were collected and the organic solvent was removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 96 (0.885 g). Method A; Rt: 5.16 min. m / z: 387.3 (M + H) + Exact mass: 386.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (1 H, s), 8.38 (1 H, t, J = 1.5 Hz), 8.21 (1 H, d, J = 8.0 Hz), 8.06 - 8.13 (1 H, m), 8.02 (1 H, d, J = 8.0 Hz), 7.92 - 8.00 (1 H, m) , 7.72 - 7.82 (2 H, m), 7.40 (1 H, t, J = 9.5 Hz), 7.25 (1 H, t, J = 55 Hz), 3.23 - 3.32 (1 H, m), 0.95 (6 H, d, J = 6.5 Hz).

[000251] 3- (4-fluoro-3-methylphenylcarbamoyl) benzene-1-sulfonyl chloride (500 mg, 1.53 mmol) in toluene (10 mL) at room temperature, a solution of diisopropylethylamine ( 0.657 ml, 141.6 mmol) and 3-methyl-3-oxetanamine hydrochloride (207 mg, 1.68 mmol) in toluene (5 ml) and dichloromethane (10 ml) were added dropwise. After 2 hours, the reaction mixture was washed with 1 M hydrochloric acid (2 x 10 ml), saturated NaHCO3 (2 x 10 ml) and brine (2 x 10 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure until only toluene remained. The white precipitate formed was filtered and recrystallized from diisopropyl ether and acetonitrile. The crystals were dried in a vacuum oven at 55 ° C for 20 hours giving compound 97 (361 mg) as a white solid. Method F; Rt: 0.89 min. m / z: 379.0 (M + H) + Exact mass: 378.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3 H), 2.25 (d, J = 1.5 Hz, 3 H), 4.14 (d, J = 6.3 Hz, 2 H), 4.56 (d, J = 6.3 Hz, 2 H), 7.14 (t, J = 9.0 Hz, 1 H), 7.52 - 7.64 (m, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7.77 (t, J = 8.0 Hz, 1 H), 7.99 - 8.06 ( m, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.37 (t, J = 1.5 Hz, 1 H), 8.50 (s l., 1 H ), 10.48 (s, 1 H).

[000252] 3- (4-fluoro-3-methylphenylcarbamoyl) benzene-1-sulfonyl chloride (500 mg, 1.53 mmol) in toluene (10 mL) at room temperature, a solution of diisopropylethylamine (0.657 mL , 141.6 mmol) and (R) - (-) - 2-aminobutane (130 mg, 1.83 mmol) in toluene (5 ml) and dichloromethane (10 ml) were added dropwise. After 2 hours, the reaction mixture was washed with 1 M aqueous HCl (2 x 10 ml), NaHCO3 (2 x 10 ml) and brine (2 x 10 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure until only toluene remained. The white precipitate formed was filtered, recrystallized (diisopropyl ether and acetonitrile) and dried in vacuo at 55 ° C for 20 hours resulting in compound 98 (257 mg) as a white solid. Method F; Rt: 1.04 min. m / z: 382.1 (M + NH4) + Exact mass: 364.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J = 7.5 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 1.31 ( quin, J = 7.5 Hz, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.05-3.18 (m, 1 H), 7.14 (t, J = 9.0 Hz, 1 H), 7.55 - 7.62 (m, 1 H), 7.63 - 7.72 (m, 2 H), 7.75 (t, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 8.36 (t, J = 1, 5 Hz, 1 H), 10.46 (s, 1 H).

[000253] A mixture of 3- (N-isopropylsulfamoyl) benzoic acid (2.3 g, 9.615 mmol), 3-bromo-4,5-difluoroaniline (2 g, 9.615 mmol) and DIPEA (5 mL) in CH2Cl2 ( 30 ml) was cooled to 0 ° C and HATU (4.39 g, 11.538 mmol) was added. The mixture was stirred for 2 hours at 20 ° C. The mixture was washed with 1 N HCl (30 ml) and brine (30 ml) and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/0 to 70/30) resulting in N- (3-bromo-4,5-difluorophenyl) -3 - Crude (N-isopropylsulfamoyl) benzamide (4 g). A mixture of N- (3-bromo-4,5-difluorophenyl) -3- (N-isopropylsulfamoyl) benzamide (1 g, 2.308 mmol), methylboronic acid (1 g, 4.616 mmol), Cs2CO3 (2.26 g, 6.924 mmol), 2-Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (95 mg, 0.231 mmol) and Tris (dibenzylidenoacetone) dipaladium (0) (0.21 g, 0.221 mmol) in dioxane (15 mL) was heated by irradiation microwave for 40 minutes at 120 ° C under N2 atmosphere. After cooling, the mixture was filtered through celite and the filtrate was evaporated to dryness. The residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/0 to 70/30) and further purified by preparative high performance liquid chromatography on reverse phase C -18 (eluent: CH3CN in H2O (0.1% TFA) from 38% to 68%, v / v). Pure fractions were collected and half of the volatiles were removed in vacuo. The mixture was adjusted to pH = 7 with Amberlite IRA-900 (OH) anion exchange resin and the resin was filtered. The organic solvent was concentrated in vacuo and the aqueous layer was lyophilized to dryness. The product obtained was further purified by chromatography on silica gel (eluent gradient: petroleum ether / ethyl acetate from 100/0 to 70/30), resulting in compound 99 (190 mg). Method A; Rt: 6.09 min. m / z: 369.2 (M + H) + Exact mass: 368.1, 1H NMR (400 MHz, CHLOROPHORUM-d) δ ppm 8.35 (1 H, t, J = 1.5 Hz), 8 , 09 - 8.17 (2 H, m), 8.04 (1 H, dt, J = 8.0, 1.5 Hz), 7.66 (1 H, t, J = 8.0 Hz) , 7.54 (1 H, ddd, J = 11.5, 6.5, 3.0 Hz), 7.14 - 7.22 (1 H, m), 4.72 (1 H, d, J = 8.0 Hz), 3.43-3.60 (1 H, m), 2.32 (3 H, d, J = 2.0 Hz), 1.10 (6 H, d, J = 6 , 5 Hz).
Compound 100
[000254] 5- (Chlorosulfonyl) -1-fluorobenzoic acid (7 g, 29.3 mmol) was dissolved in dichloromethane (70 ml). DMF (0.7 mL) was added, followed by the dropwise addition of oxalyl chloride (4.46 g, 35.16 mmol) at 0 ° C. The mixture was stirred for 1 hour at 20 ° C. The mixture was concentrated in vacuo and the crude 5- (chlorosulfonyl) -2-fluorobenzoyl chloride was dissolved in dichloromethane (15 ml). A solution of 3,4-difluoroaniline (3.6 g, 27.87 mmol) and DIPEA (4.6 g, 35.20 mmol) in dichloromethane (60 mL) was added to the mixture at 0 ° C. The mixture was stirred at 25 ° C for 1 hour and used in the next step directly. To the above reaction mixture was added a solution of (R) - (-) - 2-aminobutane (2.2 g, 29.34 mmol) and DIPEA (4.6 g, 35.20 mmol) in dichloromethane (60 mL) at 0 ° C. The resulting mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (eluent: CH3CN in water (0.1% TFA) from 25% to 55%, v / v). The pure fractions were collected and the organic solvent was evaporated. The aqueous solution was adjusted to pH = 7 with saturated aqueous NaHCO3. The mixture was extracted with dichloromethane (3 x 200 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The obtained residue was suspended in water (10 ml) and the aqueous layer was lyophilized to dryness resulting in compound 100 (4.7 g). Method B; Rt: 4.70 min. m / z: 387.2 (M + H) + Exact mass: 386.1.

[000255] (S) -tetrahydrofuran-3-amine hydrochloride (5.17 g, 42 mmol) and NaOH (5 g, 126 mmol) were dissolved in THF (50 ml) and H2O (50 ml). 5- (chlorosulfonyl) -2-fluorobenzoic acid (10 g, 42 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 4 hours. The mixture was washed with ethyl acetate (3 x 20 ml). The aqueous layer was separated and adjusted to pH = 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo resulting in (S) -2-fluoro-5- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (2.1 g). (S) -2-fluoro-5- (N- (tetrahydrofuran-3-yl) sulfamoyl) benzoic acid (1 g, 3.457 mmol), 3,4-difluoroaniline (0.53 g, 4.15 mmol) and triethylamine (0.7 g, 6.9 mmol) were dissolved in DMF (400 mL) and HATU (1.57 g, 4.15 mmol) was added at 0 ° C. The mixture was then stirred at 20 ° C for 6 hours. The solvent was removed in vacuo and the residue obtained was purified by chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 5: 1) resulting in compound 101 (0.8 g). Method B; Rt: 4.15 min. m / z: 401.3 (M + H) + Exact mass: 400.1
[000256] Synthesis of 3 - [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid:
[000257] (3S) -tetrahydrofuran-3-amine hydrochloride (5.6 g, 45.3 mmol) and NaOH (5.2 g, 130 mmol) were dissolved in THF (50 mL) and H2O (50 mL). 3- (Chlorosulfonyl) benzoic acid (10 g, 45.325 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 4 hours. The aqueous layer was separated and the pH was adjusted to 2 with 1 N HCl. The mixture was washed with ethyl acetate (3 x 100 ml). The combined organic layers were concentrated in vacuo resulting in 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (11.2 g).

[000258] A mixture of (S) -tetrahydrofuran-3-amine hydrochloride (11.2 g, 90.7 mmol) and NEt3 (50.5 mL, 362.6 mmol) in dry CH2Cl2 (400 mL) it was stirred for 5 minutes at 20 ° C.
[000259] 3- (Chlorosulfonyl) benzoic acid (20 g, 90.7 mmol) was added and the mixture was stirred overnight at 20 ° C. The reaction mixture was washed with 1 N HCl (100 ml), the aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo, resulting in 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (16.3 g). 3 - [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (3 g, 11.058 mmol), 3- (difluoromethyl) -4-fluoroaniline (2.1 g, 13.3 mmol) and triethylamine (3.3 g, 33 mmol) were dissolved in DMF (400 ml). PyBrOP (132705-51-2, 6.2 g, 13.3 mmol) was added at 0 ° C. The mixture was stirred at 50 ° C for 12 hours. The solvent was removed in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 30% to 60%). The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo and the precipitate formed was filtered, washed with H2O (5 ml) and dried under high vacuum. The obtained residue was suspended in water (5 ml) and lyophilized to dryness resulting in compound 102 (2.3 g). Method A; Rt: 5.32 min. m / z: 415.2 (M + H) + Exact mass: 414.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 - 1.68 (m, 1 H) 1.82 - 1.99 (m, 1 H) 3.27 - 3.42 (m, 1 H ) 3.51 - 3.90 (m, 4 H) 7.26 (t, J = 55 Hz, 1 H) 7.36 - 7.51 (m, 1 H) 7.80 (t, J = 7 , 8 Hz, 1 H) 7.92 - 8.00 (m, 1 H) 8.01 - 8.08 (m, 1 H) 8.08 - 8.15 (m, 2 H) 8.25 ( d, J = 7.8 Hz, 1 H) 8.40 (s, 1 H) 10.75 (s, 1 H).

[000260] 3 - [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (400 mg, 1.47 mmol) was dissolved in DMF (0.5 ml) and CH2Cl2 (10 ml). (COCl) 2 (223 mg, 1.76 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. The solvent was removed in vacuo and the residue obtained was coevaporated with toluene (2 x 10 mL) resulting in crude 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoyl chloride (400 mg ). The crude product was used in the next step without purification. 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoyl chloride (200 mg) was dissolved in dichloromethane (5 ml). 4-Fluoro-3-methoxyaniline (78 mg, 0.552 mmol) and triethylamine (167 mg, 165 mmol) were added at 0 ° C. The mixture was stirred at 20 ° C for 2 hours, washed with H2O (5 ml) and the water layer extracted with dichloromethane (3 x 10 ml). The combined organic layers were concentrated in vacuo. The residue obtained was purified by reverse phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 30% to 60%). The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo. The precipitate obtained was filtered, washed with H2O (5 ml) and dried under high vacuum. The residue was suspended in water (5 ml), lyophilized to dryness resulting in compound 103 (140 mg). Method A; Rt: 4.98 min. m / z: 395.2 (M + H) + Exact mass: 394.1
[000261] Prepared similarly as described for compound 103: Compound 104

[000262] Method A; Rt: 5.17 min. m / z: 397.3 (M + H) + Exact mass: 396.1 Compound 105

[000263] Method A; Rt: 5.10 min. m / z: 389.1 (M + H) + Exact mass: 390.2 Compound 106

[000264] Method A; Rt: 5.18 min. m / z: 397.2 (M + H) + Exact mass: 396.1
[000265] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 - 1.69 (m, 1 H) 1.82 - 1.98 (m, 1 H) 2.24 (s, 3 H) 3.35 - 3.40 (m, 1 H) 3.52 - 3.66 (m, 2 H) 3.66 - 3.83 (m, 2 H) 7.32 (t, J = 10.0 Hz, 1 H) 7.49 (t, J = 8.5 Hz, 1 H) 7.79 (t, J = 7.8 Hz, 1 H) 8.04 (d, J = 8.0 Hz, 1 H) 8.07 - 8.18 (m, 1 H) 8.23 (d, J = 7.8 Hz, 1 H) 8.39 (s, 1 H) 10.40 (sl, 1 H)

[000266] 3 - [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (270 mg, 1.0 mmol) was dissolved in dichloromethane (5 ml). 3-Methyl-4-methoxyaniline (165 mg, 1.2 mmol) and triethylamine (145 mg, 1.4 mmol) were added to the mixture at 20 ° C. The mixture was stirred at 20 ° C for 5 minutes. HATU (456 mg, 1.2 mmol) was added and the mixture was further stirred at 20 ° C for 8 hours. The solvent was removed in vacuo and the residue obtained was purified by high performance liquid chromatography (Column: Phenomenex Synergi C18 150 * 20 mm * 5 µm. A: H2O + 0.1% TFA B: 30% to 60% MeCN Well). The product fractions were collected and the organic solvent was evaporated in vacuo. The aqueous layer was neutralized with saturated aqueous NaHCO3 and extracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo resulting in compound 107 (135 mg). Method A; Rt: 5.24 min. m / z: 391.3 (M + H) + Exact mass: 390.1

[000267] 5-Amino-2-fluoro-phenol (234 mg, 1.84 mmol) and 3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (500 mg, 1.84 mmol) were dissolved in dichloromethane (8 ml). PyBrOP (132705-51-2, 1030 mg, 2.21 mmol) was added followed by the dropwise addition of DIPEA (714 mg, 5.53 mmol) at 0 ° C. The mixture was stirred for 1 hour at 25 ° C. The mixture was washed with saturated aqueous citric acid (15 ml), saturated aqueous NaHCO3 (15 ml) and brine and dried over Na2SO4. The solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography of reverse phase (mobile phase: CH3CN in water (NH4HCO3 0.05%) from 29% to 39%). The pure fractions were collected and the volatiles were removed in vacuo. The residual aqueous layer was lyophilized to dryness resulting in the compost108 (60 mg). Method A; Rt: 4.47 min. m / z: 381.2 (M + H) + Exact mass: 380.1

[000268] Prepared similarly as described for compound 108, using 4-fluoro-3-methoxyaniline instead of 5-amino-2-fluoro-phenol. Method A; Rt: 5.03 min. m / z: 395.2 (M + H) + Exact mass: 394.1

[000269] DIPEA (2.85 g, 22.08 mmol) was added to a solution of 3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (3.0 g, 11.06 mmol) and HATU (4.20 g, 11.05 mmol) in DMF (100 mL) at 25 ° C. After 30 minutes, 3-bromo-4-fluoroaniline (2.1 g, 11.05 mmol) was added to the solution. The reaction mixture was stirred at 25 ° C overnight. The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate from 10/1 to 5/1). The pure fractions were collected and the solvent was removed in vacuo resulting in N- (3-bromo-4-fluoro-phenyl) -3 - [(3-methyloxetan-3-yl) sulfamoyl] benzamide (compound 160, 2.5 g). A mixture of N- (3-bromo-4-fluoro-phenyl) -3 - [(3-methyloxetan-3-yl) sulfamoyl] benzamide (0.3 g, 0.68 mmol), 4.4.5, 5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (54.2 mg, 0.35 mmol), Pd (dppf) Cl2 (50 mg, 0.068 mmol), KOAc (108 mg, 1.1 mmol) and Na2CO3 (100 mg, 0.94 mmol) in CH3CN (10 mL) and H2O (2 mL) was heated by microwave irradiation for 30 minutes at 130 oC under an N2 atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate (2 x 10 mL). The organic layer was separated from the filtrate, washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography of reverse phase (eluent: CH3CN in H2O (NH3.H2O at 0.05%) from 30% to 80%, v / v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 110 (70 mg). Method B; Rt: 4.19 min. m / z: 391.3 (M + H) + Exact mass: 390.1.

[000270] Methyl 3 - [(3-methyloxetan-3-yl) sulfamoyl] (3 g, 11.06 mmol), methyl 5-amino-2-fluoro-benzoate (2.33 g, 13.2 mmol ) and DI-PEA (2.84 g, 22 mmol) were dissolved in DMF (40 mL). HATU (5.02 g, 13.2 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3: 1) resulting in 2-fluoro-5 - [[3 - [(3 - methyloxetan-3-yl) sulfamoyl] benzoyl] amino] methyl benzoate (2.3 g). 2- Fluoro-5 - methyl [[3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoyl] amino] benzoate (0.3 g, 0.71 mmol) was dissolved in THF (5 ml) and ethanol (5 mL). NaBH4 (53 mg, 1.4 mmol) was added at 0 ° C. The mixture was stirred for 2 hours at 20 ° C. The solvent was removed in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 34% to 64%). The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo. The precipitate was filtered, washed with H2O (5 ml) and dried under high vacuum. The residue was suspended in water (5 ml) and the aqueous layer was lyophilized to dryness resulting in compound 111 (220 mg). Method A; Rt: 4.34 min. m / z: 395.3 (M + H) + Exact mass: 394.1.

[000271] (2-Fluoro-5-nitro-phenyl) methanol (4.3 g, 25.1 mmol) was dissolved in dichloromethane (50 ml). Diethylamino sulfur trifluoride (4.5 g, 27.9 mmol) was added dropwise to the mixture at -30 ° C. The mixture was stirred at 10 ° C for 4 hours. Methanol (10 ml) was added to the mixture and the mixture was further stirred at 10 ° C for 30 minutes. The mixture was washed with brine (30 ml) and the aqueous layer was extracted with CH2Cl2 (2 x 30 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo, resulting in 1-fluoro-2- (fluoromethyl) -4-nitro-benzene (3.9 g). A mixture of 1-fluoro-2- (fluoromethyl) -4-nitro-benzene (3.1 g, 17.9 mmol), iron (4.0 g, 71.6 mmol) and methanol (30 mL) was stirred at 65 ° for 8 hours. The mixture was filtered and the filtrate was concentrated in vacuo, resulting in 4-fluoro-3- (fluoromethyl) aniline (1.5 g). 3- (Chlorosulfonyl) benzoyl chloride (300 mg, 1.2 mmol) and triethylamine (150 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-Fluoro-3- (fluoromethyl) aniline (175 mg, 1.22 mmol) was added to the mixture at 0 ° C. The mixture was stirred at 10 ° C for 30 minutes. The mixture was used in the next step without further purification. Triethylamine (152 mg, 1.5 mmol) and 3-methyl-3-oxetanamine (131 mg, 1.5 mmol) were added to the reaction mixture obtained above at 0 ° C. The mixture was stirred at 20 ° C for 1 hour. The solvent was removed in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (Column: Gemini 250 * 20 mm * 5 µm. A: H2O + 0.1% TFA B: MeCN. 27% a 57% B in A). The product fractions were collected and the organic solvent was removed in vacuo. The fraction was neutralized by saturated NaHCO3. The mixture was extracted with dichloromethane (3 x 20 ml) and the combined organic layer was dried over Na2SO4 and concentrated in vacuo, resulting in compound 127 (91.1 mg). Method A; Rt: 4.95 min. m / z: 397.3 (M + H) + Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3 H) 4.14 (d, J = 6.3 Hz, 2 H) 4.56 (d, J = 6.3 Hz, 2 H) 5.52 (d, J = 48 Hz, 2 H) 7.31 (t, J = 9.4 Hz, 1 H) 7.72 - 7.89 (m, 2 H) 7.92- 7.97 (m, 1 H) 8.03 (d, J = 8.0 Hz, 1 H) 8.23 (d, J = 7.8 Hz, 1 H) 8.39 (s, 1 H) 8.55 (s, 1 H) 10.67 (s, 1 H).

[000272] Compound 123 (255 mg, 0.592 mmol) and Pd / C (50 mg) were stirred in methanol (25 mL) under an atmosphere of hydrogen for 3 hours. The reaction mixture was filtered, concentrated and the residue obtained dried in vacuo at 50 ° C resulting in compound 112 as a colorless resin (174 mg). Method G; Rt: 1.57 min. m / z: 397.1 (M + H) + Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.80 (m, 1 H), 1.91 - 2.04 (m, 1 H), 2.24 (d, J = 1, 5 Hz, 3 H), 3.43 (dd, J = 9.0, 4.6 Hz, 1 H), 3.55 - 3.79 (m, 3 H), 3.80 - 3.91 ( m, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.45 - 7.57 (m, 2 H), 7.64 (dd, J = 7.0, 2 , 4 Hz, 1 H), 7.85 - 8.02 (m, 2 H), 8.40 (d, J = 6.8 Hz, 1 H), 10.62 (s, 1 H)

[000273] 3-Methyloxetan-3-amine hydrochloride (210 mg, 1.7 mmol) and NaOH (204 mg, 5.1 mmol) were dissolved in 2-methyltetrahydrofuran (5 ml) and H2O (5 ml) . 5-Chlorosulfonyl-2-methyl-benzoic acid (400 mg, 1.7 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 4 hours. The aqueous layer was separated and adjusted to pH = 3 by aq. (1 N). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated in vacuo resulting in 2-methyl-5 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (250 mg). 2-Methyl-5 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (250 mg, 0.876 mmol), 3- (difluoromethyl) -4-fluoroaniline (178 mg, 1.1 mmol) and DIPEA (232 mg, 1.8 mmol) were dissolved in DMF (5 ml). HATU (399 mg, 1.05 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. The solvent was removed in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 34% to 64%). The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo and the precipitate formed was filtered, washed with H2O (5 ml) and dried under high vacuum. The residue was suspended in water (5 ml) and the aqueous layer was lyophilized to dryness resulting in compound 113 (220 mg). Method A; Rt: 5.28 min. m / z: 429.3 (M + H) + Exact mass: 428.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H) 2.47 (s, 3 H) 4.15 (d, J = 6.3 Hz, 2 H) 4.57 ( d, J = 6.0 Hz, 2 H) 7.24 (t, J = 54.5 Hz, 1 H) 7.40 (t, J = 9.5 Hz, 1 H) 7.56 (d, J = 8.0 Hz, 1 H) 7.71 - 7.98 (m, 3 H) 8.09 (d, J = 4.3 Hz, 1 H) 8.37 (s l., 1 H) 10.74 (s l., 1 H)

[000274] 3- (Isopropylsulfamoyl) benzoic acid (190 mg, 0.78 mmol) was dissolved in dichloromethane (5 ml). 3-Fluoro-4-methoxyaniline (139 mg, 0.94 mmol) and triethylamine (112 mg, 1 mmol) were added to the mixture at 20 ° C. The mixture was stirred at 20 ° C for 5 minutes. HATU (358 mg, 0.94 mmol) was added to the mixture at 20 ° C. The mixture was stirred at 20 ° C for 8 hours. The solvent was removed in vacuo and the residue obtained was purified by high performance liquid chromatography (Column: Phenomenex Synergi C18 150 * 20 mm * 5 µm. A: H2O + 0.1% TFA B: MeCN 30% a 60% B in A). The product fractions were collected and the organic solvent was evaporated. The aqueous layer was neutralized with saturated aqueous NaHCO3. The mixture was extracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo resulting in compound 114 (135 mg). Method A; Rt: 5.60 min. m / z: 367.2 (M + H) + Exact mass: 366.1

[000275] Prepared similarly as described for compound 127 using 4-fluoro-2,3-dimethylaniline instead of 4-fluoro-3- (trifluoromethyl) aniline. Method A; Rt: 4.98 min. m / z: 393.3 (M + H) + Exact mass: 392.1.

[000276] 4-Fluoro-3-methyl-aniline (9.04 g, 72.2 mmol) was added dropwise to a solution of 3- (chlorosulfonyl) benzoyl chloride (19.0 g, 79.47 mmol ) in toluene (300 ml) at 110 ° C. The resulting mixture was stirred at 110 ° C for 1 hour and allowed to cool to 20 ° C overnight. The precipitate was filtered and recrystallized from dry toluene resulting in 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (20 g). 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (15 g, 45.77 mmol) was added dropwise at 0 ° C to a solution of 2-aminopropan-1-ol (3,437 g, 45.77 mmol) and triethylamine (6.946 g) in THF (200 ml). The resulting mixture was stirred for 10 minutes and then allowed to warm to 20 ° C for 2 hours. The reaction mixture was quenched with 1N HCl (50 ml). The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/1 to 50/50), resulting in N- (4-fluoro-3-methyl-phenyl) - 3 - [(2-hydroxy-1-methyl-ethyl) sulfamoyl] benzamide (15.6 g). Diethyl diazene-1,2-dicarboxylate (4.91 g, 28.19 mmol) was added dropwise to a solution of N- (4-fluoro-3-methyl-phenyl) -3 - [(2-hydroxy -1-methyl-ethyl) sulfamoyl] benzamide (7.8 g, 21.29 mmol) and PPh3 (6.14 g, 23.41 mmol) in THF (500 mL) at - 70 ° C under Argon. The resulting mixture was stirred for 1 hour and then allowed to warm to 20 ° C overnight. The reaction mixture was quenched with 1 N HCl (300 ml). The mixture was extracted with dichloromethane (4 x 400 ml) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/1 to 60/40) resulting in N- (4-fluoro-3-methyl-phenyl) - 3- (2-methylazaridin-1-yl) sulfonyl-benzamide (6.5 g). A mixture of N- (4-fluoro-3-methyl-phenyl) -3- (2-methylaziridin-1-yl) sulfonyl-benzamide (300 mg, 0.861 mmol) and 1-methylpiperazine (862 mg, 8.61 mmol ) in 1,4-dioxane (3 ml) was heated by microwave irradiation at 150 ° C for 30 minutes. The volatiles were removed in vacuo. The residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/1 to 1/100). Pure fractions were collected and the solvent was removed in vacuo. The residue obtained was purified by preparative high performance liquid chromatography (column: Luna 150 * 30 mm * 5 um, mobile phase: CH3CN in water (0.1% NH4HCO3) from 44% to 74%). The pure fractions were collected, concentrated in vacuo and the residual aqueous solution was lyophilized to dryness resulting in compound 116 (250 mg). Method A; Rt: 4.26 min. m / z: 449.4 (M + H) + Exact mass: 448.2 Compound 117

[000277] Prepared similarly as described for compound 116 using morpholine instead of 1-methylpiperazine. Method A; Rt: 4.45 min. m / z: 436.3 (M + H) + Exact mass: 435.2 Compound 118

[000278] To a stirred solution of 3,4-difluoro-2-methyl-aniline (369 mg, 2.6 mmol), 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid ( 700 mg, 2.58 mmol) and N, N-diisopropylethylamine (1.35 mL, 7.74 mmol) in DMF (10 mL) was added Pybrop (132705-51-2, 1.82 g, 3, 9 mmol) at 0 ° C. The resulting mixture was stirred overnight at 18 ° C. The mixture was concentrated in vacuo, ethyl acetate (15 ml) was added and the organic layer was washed with 1 N HCl (15 ml) and saturated aqueous NaHCO3 (15 ml). After drying over Na2SO4 and concentration in vacuo, the crude residue was purified by preparative reversed phase high performance liquid chromatography (eluent: CH3CN in H2O (NH3.H2O 0.05%) from 37% to 37%, v / v ). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness, resulting in compound 118 (238 mg). Method D; Rt: 5.01 min. m / z: 396.9 (M + H) + Exact mass: 396.1 Compound 119

[000279] Prepared similarly as described for compound 127 using 4-fluoro-2,5-dimethylaniline instead of 4-fluoro-3- (fluoromethyl) aniline, and DIPEA instead of NEt3. Method A; Rt: 5.27 min. m / z: 393.3 (M + H) + Exact mass: 392.1

[000280] A mixture of 1- (2-pyridyl) propan-2-amine (207.8 mg, 1.53 mmol) and DIPEA (0.532 mL, 3.05 mmol) was dissolved in CH2Cl2 (10 mL). 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (500 mg, 1.53 mmol) was added portion by portion at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. The mixture was washed with saturated citric acid (10 ml), saturated aqueous NaHCO3 (10 ml), brine and dried over Na2SO4. The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (eluent gradient: petroleum ether / ethyl acetate 100/1 to 1/100). Pure fractions were collected and the solvent was removed in vacuo. The obtained solid was suspended in water (10 ml) and acetonitrile (10 ml) and the solution was lyophilized to dryness resulting in compound 120 (550 mg). Method B; Rt: 3.36 min. m / z: 428.3 (M + H) + Exact mass: 427.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J = 6.5 Hz, 3 H) 2.26 (d, J = 1.5 Hz, 3 H) 2.69 (dd, J = 13.6, 7.3 Hz, 1 H) 2.80 (dd, J = 13.6, 7.0 Hz, 1 H) 3.64 - 3.74 (m, 1 H) 7.08 - 7.19 (m, 3 H) 7.55-7.64 (m, 2 H) 7.64 - 7.71 (m, 2 H) 7.84 - 7.89 (m, 1 H) 7 , 89 - 7.95 (m, 1 H) 8.12 - 8.17 (m, 1 H) 8.25 (t, J = 1.5 Hz, 1 H) 8.32 - 8.36 (m , 1 H) 10.45 (s, 1 H). 224

[000281] Compound 224 was prepared similarly as described for compound 223, using 1- (4-pyridyl) propan-2-amine instead of 1- (2-pyridyl) propan-2-amine. Compound 224 was purified by preparative high performance liquid chromatography (column: Luna 150 * 30 mm * 4 um, mobile phase: CH3CN in water (0.05% NH4HCO3) from 40% to 70%).
[000282] Method A; Rt: 4.6 min. m / z: 428.3 (M + H) + Exact mass: 427.1. Synthesis of 5-chlorosulfonyl-2-methyl-benzoyl chloride and 3- [(4-fluoro-3-methyl-phenyl) carbamoyl] -4-methyl-benzenesulfonyl chloride
[000283] 5- (Chlorosulfonyl) -1-methylbenzoic acid (10 g, 42.61 mmol) was dissolved in dichloromethane (200 ml). N, N-dimethylformamide (166 μL, 2.13 mmol) was added and the mixture was stirred at room temperature under an atmosphere of nitrogen.
[000284] Oxalyl chloride (18.3 mL, 213 mmol) was added in four portions over the course of an hour.
[000285] The resulting mixture was stirred for one hour at room temperature. The mixture was concentrated in vacuo and coevaporated twice using toluene (2 x 100 ml) giving 5-chlorosulfonyl-2-methyl-benzoyl chloride as a yellow oil which was used as such. 5-Chlorosulfonyl-2-methyl-benzoyl chloride (10.7 g, 42.3 mmol) was dissolved in toluene (220 mL) and this was heated to reflux and stirred under a gentle flow of nitrogen.
[000286] 4-Fluoro-3-methylaniline (4.76 g, 38.1 mmol) in toluene (80 mL) was added dropwise using a syringe pump (0.8 mL / min). The resulting mixture was stirred for 30 minutes while heating was continued. Then, the mixture was cooled to room temperature. A precipitation was formed and collected on a glass filter. The obtained solid was dried in vacuo at 55 ° C, giving 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] -4-methyl-benzenesulfonyl chloride (10.4 g) as a solid that was used as such in the next step.

[000287] A solution of (S) -3-aminotetrahydrofuran tosylate (0.76 g, 2.93 mmol) and diisopropylethylamine (1.26 mL, 7.31 mmol) in dichloromethane (10 mL) added dropwise to a solution of 3- [(4-fluoro-3-methyl-phenyl) carbamoyl] -4-methyl-benzenesulfonyl (1 g, 2.93 mmol) in dichloromethane (10 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was quenched using HCl (aq / 14.6 ml, 14.6 mmol). The layers were separated and the water layer was extracted with dichloromethane (2 x 20 ml). The combined organics were concentrated in vacuo and purified using silica gel column chromatography (elution gradient: EtOAc-heptane 0: 100 to 100: 0). The desired fractions were concentrated in vacuo and dried in vacuo at 55 ° C to give compound 121 as a bright white solid. Method F; Rt: 0.90 min. m / z: 393.2 (M + H) + Exact mass: 392.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 - 1.69 (m, 1 H), 1.85 - 1.98 (m, 1 H), 2.24 (d, J = 1, 3 Hz, 3 H), 2.45 (s, 3 H), 3.38 (dd, J = 8.8, 4.4 Hz, 1 H), 3.53 - 3.65 (m, 2 H ), 3.66 - 3.76 (m, 2 H), 7.13 (t, J = 9.2 Hz, 1 H), 7.46 - 7.59 (m, 2 H), 7.66 (dd, J = 7.0, 2.2 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 7.96 (s l., 1 H), 10.46 (s, 1 H).

[000288] A solution of 3-methyl-3-oxetanamine hydrochloride (0.4 g, 3.22 mmol) and diisopropylethylamine (1.26 mL, 7.31 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] -4-methyl-benzenesulfonyl chloride (1 g, 2.93 mmol) in dichloromethane (10 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was quenched using HCl (aq / 14.63 ml, 14.63 mmol). The layers were separated and the water layer was extracted using dichloromethane (2 x 20 ml). The combined organic layers were concentrated in vacuo and purified using column chromatography (elution gradient: EtOAc-heptane 0: 100 to 100: 0). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55 ° C giving compound 122 as a shiny white solid. Method F; Rt: 0.90 min. m / z: 410.2 (M + NH4) + Exact mass: 392.1.1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 3 H), 2.19 - 2.29 (m , 3 H), 2.44 (s, 3 H), 4.14 (d, J = 6.4 Hz, 2 H), 4.56 (d, J = 6.2 Hz, 2 H), 7 , 13 (t, J = 9.1 Hz, 1 H), 7.42 - 7.57 (m, 2 H), 7.59 - 7.71 (m, 1 H), 7.74 - 7, 90 (m, 2 H), 8.36 (s, 1 H), 10.46 (s, 1 H). Compound 123

[000289] Compound 123 was prepared similarly as described for compound 121 starting from 5-chloro-3-chlorosulfonyl-2-fluoro-benzoic acid (Enamine commercial EN300-35191) through 5-chloro-3 chloride -chlorosulfonyl-2-fluoro-benzoyl CLO- ROFORRY-d) (1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 8.23 (dd, J = 5.4, 2.8 Hz, 1 H), 8, 37 (dd, J = 5.5, 2.6 Hz, 1 H)). After silica gel column chromatography (elution gradient: EtOAc-heptane 10:90 to 100: 0), compound 123 was crystallized by adding H2O to a hot iPrOH solution of compound 123, resulting in compound 123 as white solid (3153 mg). Method G; Rt: 1.81 min. m / z: 431.0 (M + H) + Exact mass: 430.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.79 (m, 1 H), 1.93 - 2.06 (m, 1 H), 2.25 (d, J = 1, 8 Hz, 3 H), 3.44 (dd, J = 9.0, 4.4 Hz, 1 H), 3.62 (td, J = 8.0, 5.9 Hz, 1 H), 3 , 69 (dd, J = 8.9, 6.3 Hz, 1 H), 3.71 - 3.79 (m, 1 H), 3.84 - 3.98 (m, 1 H), 7, 15 (t, J = 9.1 Hz, 1 H), 7.45 - 7.55 (m, 1 H), 7.61 (dd, J = 6.9, 2.3 Hz, 1 H), 7.91 (dd, J = 5.7, 2.6 Hz, 1 H), 8.07 (dd, J = 5.2, 2.8 Hz, 1 H), 8.57 (d, J = 6.8 Hz, 1 H), 10.68 (s, 1 H)

[000290] Compound 125 (167 mg, 0.371 mmol) and Pd / C (25 mg) were stirred in methanol (19 mL) under a hydrogen atmosphere for 80 minutes. The reaction mixture was filtered and concentrated. The obtained residue was purified by preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, MeOH with 0.2% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again resulting in compound 124 (67 mg). Method G; Rt: 1.61 min. m / z: 430.0 (M + NH4) + Exact mass: 412.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 - 1.83 (m, 1 H), 1.89 - 2.03 (m, 1 H), 2.24 (d, J = 1, 5 Hz, 3 H), 3.45 (dd, J = 8.9, 4.7 Hz, 1 H), 3.56 - 3.69 (m, 2 H), 6 3.70 - 3.86 (m, 2 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.45 - 7.55 (m, 1 H), 7.60 - 7.69 (m, 2 H ), 7.82 (dd, J = 7.6, 1.7 Hz, 1 H), 8.09 (dd, J = 7.8, 1.7 Hz, 1 H), 8.34 (s, 1 H), 10.62 (s, 1 H)

[000291] Compound 125 was prepared similarly as described for compound 126 starting from 2,6-dichloro-3-chlorosulfonyl-benzoic acid instead of 3-chlorosulfonyl-2-methyl-benzoic acid. Method G; Rt: 1.77 min. m / z: 464.0 (M + NH4) + Exact mass: 446.0.
[000292] 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.75-1.86 (m, 1 H), 2.04 - 2.16 (m, 1 H), 2.30 (d, J = 1.8 Hz, 3 H), 3.57 - 3.65 (m, 1 H), 3.66 - 3.76 (m, 2 H), 3.82 - 3.95 (m, 2 H ), 5.45 (d, J = 7.5 Hz, 1 H), 7.01 (t, J = 8.9 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 7.47 - 7.56 (m, 2 H), 7.83 (s, 1 H), 8.05 (d, J = 8.6 Hz, 1 H).

[000293] 3-Chlorosulfonyl-2-methyl-benzoic acid (Enamine commercial EN300-109516; 508.4 mg, 2.17 mmol) was dissolved in dichloromethane (50 mL). DMF (1 drop) and oxalyl chloride (1375 mg, 10.83 mmol) were added and the mixture was stirred for 4 hours under an inert atmosphere. The reaction mixture was concentrated resulting in 3-chlorosulfonyl-2-methyl-benzoyl chloride as a yellow oil (554 mg) which was used as such in the next step. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 2.92 - 3.01 (m, 3 H), 7.60 (t, J = 7.9 Hz, 1 H), 8.27 - 8.41 (m, 2 H). 4-Fluoro-3-methylaniline (227 mg, 1.98 mmol) dissolved in dichloromethane (10 mL) was added dropwise over 5 minutes to a solution of 3-chlorosulfonyl-2-methyl-benzoyl chloride (550 mg, 2.17 mmol) in toluene (50 mL) at reflux. The reaction mixture was refluxed for 30 minutes and then cooled in an ice bath. A solution of (S) -3-aminotetrahydrofuran tosylate (564 mg, 2.17 mmol) and DIPEA (0.85 mL, 4.94 mmol) dissolved in dichloromethane (10 mL) was added and the mixture obtained was stirred for 30 minutes. The resulting mixture was washed with HCl (2 x 100 ml / 1 M aq), water (2 x 100 ml) and NaHCO3 (2 x 100 ml / sat. Aq). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified using silica gel column chromatography (CH2Cl2-MeOH 100: 0 to 90:10) and repurified by applying a gradient of 10 to 100% EtOAc in heptane. The product fractions were concentrated and dried overnight in vacuo at 50 ° C giving compound 126 as a colorless oil (16.6 mg). Method G; Rt: 1.65 min. m / z: 393.1 (M + H) + Exact mass: 392.1. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.73 - 1.87 (m, 1 H), 2.06 - 2.20 (m, 1 H), 2.30 (d, J = 1, 8 Hz, 3 H), 2.69 (s, 3 H), 3.54 - 3.63 (m, 1 H), 3.65 - 3.78 (m, 2 H), 3.83 - 3 , 97 (m, 2 H), 4.99 (d, J = 8.1 Hz, 1 H), 7.01 (t, J = 8.9 Hz, 1 H), 7.31 - 7.44 (m, 2 H), 7.51 (dd, J = 6.7, 2.5 Hz, 1 H), 7.58 - 7.69 (m, 2 H), 8.06 (dd, J = 8.0, 1.2 Hz, 1 H)
[000294] Procedure S1: A solution of 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl (0.50 g, 1.52 mmol, 1 eq) in toluene (10 mL) was added to a flask containing an amine (1.1 eq). DIPEA (657 μL, 3.81 mmol, 2.5 eq) was added and the reaction mixture was stirred for 1 hour. Then, 1 N HCl (5 ml) was added to the reaction mixture.
[000295] Procedure S2: A tube was loaded with 3- [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (250 mg, 0.76 mmol) and an amine (1.1 eq) and was CH2Cl2 (5 ml) is added. The solution was stirred, DIPEA (329 μL, 1.9 mmol, 2.5 eq) was added and the mixture was further stirred for 30 minutes. Then, HCl (1 M aq / 5 ml) was added and the mixture was stirred for an additional 5 minutes.
[000296] Procedure S3: To a solution of 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl (0.50 g, 1.52 mmol, 1 eq) and DIPEA (657 μL, 3 , 81 mmol, 2.5 eq) in CH2Cl2 (10 ml) an amine (1.1 eq) was added. The reaction mixture was stirred for 1 hour. Then, 1 N HCl (5 ml) was added to the reaction mixture.
[000297] Procedure S4: 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (250 mg, 0.76 mmol) and DIPEA (329 μL, 1.9 mmol, 2.5 eq) dissolved in CH2Cl2 (5 mL) were added to a tube containing an amine (1.1 eq). The reaction mixture was stirred for 3 hours. 1 M HCl (5 ml) was added.
[000298] Processing W1: A precipitate was formed. The precipitate was filtered, rinsed with diisopropyl ether and dried in a vacuum oven at 55 ° C.
[000299] Processing W2: The organic layer was separated and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using a gradient of heptane to EtOAc as eluent.
[000300] Processing W3: The layers were separated and the organic layer was loaded onto a silica gel column for purification (with elution gradient: CH2Cl2-methanol 100: 0 to 97: 3).
[000301] Processing W4: The organic layer was separated and loaded onto a silica gel column. The mixture was purified using heptane elution gradient to EtOAc.

[000302] Synthesis following procedure S4 with 7-oxabicyclo [2.2.1] heptan-2-amine as amine, processing W4. Method F; Rt: 0.94 min. m / z: 422.1 (M + NH4) + Exact mass: 404.1.1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 - 1.48 (m, 5 H), 1.68 (dd , J = 12.5, 7.9 Hz, 1 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.25 - 3.29 (m, 1 H), 4.14 (d, J = 4.8 Hz, 1 H), 4.44 (t, J = 4.8 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7, 54 - 7.63 (m, 1 H), 7.68 (dd, J = 7.2, 2.3 Hz, 1 H), 7.74 - 7.80 (m, 1 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.98 - 8.03 (m, 1 H), 8.20 (dt, J = 7.8, 1.4 Hz, 1 H), 8 , 35 (t, J = 1.5 Hz, 1 H), 10.46 (s, 1 H).

[000303] Synthesis following procedure S3 with R - (+) - 3-aminotetrahydrofuranotoluene-4-sulfonate as amine, processing W2.
[000304] Method F; Rt: 0.89 min. m / z: 396.1 (M + NH4) + Exact mass: 378.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.56 - 1.65 (m, 1 H), 1.85 - 1.94 (m, 1 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.36 (dd, J = 9.0, 4.4 Hz, 1 H), 3.52 - 3.65 (m, 2 H), 3.65 - 3.73 (m , 1 H), 3.73 - 3.79 (m, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.67 (dd, J = 7.0, 2.3 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.99 - 8.05 (m, 1 H ), 8.08 (bs, 1 H), 8.20-8.23 (m, 1 H), 8.37 (t, J = 1.7 Hz, 1 H), 10.47 (s, 1 H), [α] 20 D = + 5.8 (c 0.61 w / v%, MeOH) Compound 130

[000305] Method F; Rt: 0.95 min. m / z: 424.2 (M + NH4) + Exact mass: 406.1.
[000306] Synthesis following procedure S3 with racemic trans-2-aminocyclohexanol hydrochloride as amine, W2 processing. 131

[000307] Synthesis following procedure S3 with (1S, 2S) -trans-2-aminocyclohexanol hydrochloride as amine, W2 processing.
[000308] Method F; Rt: 0.95 min. m / z: 424.2 (M + NH4) + Exact mass: 406.1.
[000309] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 - 1.23 (m, 4 H), 1.41 - 1.58 (m, 2 H), 1.59 - 1.70 (m, 1 H), 1.71 - 1.83 (m, 1 H), 2.25 (d, J = 1.3 Hz, 3 H), 2.77 - 2.90 (m, 1 H ), 3.15 - 3.27 (m, 1 H), 4.50 (d, J = 4.6 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.54 - 7.64 (m, 2 H), 7.64 - 7.69 (m, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 8.04 (d , J = 7.7 Hz, 1 H), 8.16 (d, J = 7.9 Hz, 1 H), 8.39 (s, 1 H), 10.43 (s, 1 H) Compound 132

[000310] Synthesis following procedure S3 with racemic cis-2-aminocyclohexanol hydrochloride as amine, W2 processing. Method F; Rt: 0.96 min. m / z: 424.1 (M + NH4) + Exact mass: 406.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 - 1.26 (m, 4 H), 1.26 - 1.36 (m, 1 H), 1.38 - 1.62 (m, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.03 - 3.14 (m, 1 H), 3.57 (s l., 1 H), 4.52 (d, J = 4.2 Hz, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7, 56 - 7.62 (m, 1 H), 7.68 (dd, J = 7.0, 2.6 Hz, 1 H), 7.73 (t, J = 7.8 Hz, 1 H), 8.05 (dt, J = 8.1, 1.2 Hz, 1 H), 8.14 - 8.19 (m, 1 H), 8.39 (t, J = 1.7 Hz, 1 H ), 10.43 (s, 1 H)

[000311] Synthesis following procedure S3 with trans-2-aminocyclohexanol hydrochloride as amine, processing W2.
[000312] Method F; Rt: 0.84 min. m / z: 424.2 (M + NH4) + Exact mass: 406.1.
[000313] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 - 1.31 (m, 4 H), 1.57 (d, J = 10.3 Hz, 2 H), 1.69 ( d, J = 12.5 Hz, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 2.84 - 3.01 (m, 1 H), 3.22 - 3, 29 (m, 1 H), 4.46 (d, J = 4.4 Hz, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.53 - 7.64 ( m, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7.72 - 7.79 (m, 2 H), 7.95 - 8.04 (m , 1 H), 8.18 (dt, J = 7.7, 1.3 Hz, 1 H), 8.36 (t, J = 1.7 Hz, 1 H), 10.46 (s, 1 H)

[000314] Method F; Rt: 0.89 min. m / z: 424.2 (M + NH4) + Exact mass: 406.1.
[000315] Synthesis following procedure S3 with 3-amino-cyclohexanol as amine, processing W2.
[000316] Compound 134 was separated into its isomers by preparative SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm), Mobile phase: CO2, iPrOH with 0.4% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, yielding 134a, 134b, 134c, 134d. SFC columns: H-ID 250 mm x 4.6 mm Flow rate: 3 mL / min Mobile phase: iPrOH 25% (containing iPrNH2 0.2%) maintenance 18.0 min.
[000317] Temperature: 30 ° C; Rt: 134a (10.0 min), 134b (11.1 min), 134c (13.6 min), 134d (14.7 min). Cis: Enantiomers 134a and 134b N- (4-fluoro-3-methyl-phenyl) -3 - [[(1R, 3S) -3-hydroxycyclohexyl] sulfamoyl] benzamide or N- (4-fluoro-3-methyl-phenyl) ) -3- [[(1S, 3R) -3-hydroxycyclohexyl] sulfamoyl] benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.14 (m, 4 H), 1.48 - 1.60 (m, 2 H), 1.60-1.72 (m, 1 H), 1.72 - 1.82 (m, 1 H), 2.26 (d, J = 1.8 Hz, 3 H), 2.93 - 3.07 (m, 1 H), 3 , 20 - 3.30 (m, 1 H), 4.58 (d, J = 4.6 Hz, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.55 - 7.64 (m, 1 H), 7.69 (dd, J = 7.0, 2.2 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7 , 83 (s l., 1 H), 7.96 - 8.06 (m, 1 H), 8.13 - 8.24 (m, 1 H), 8.38 (t, J = 1.7 Hz, 1 H), 10.47 (s, 1 H)
[000318] Trans: enantiomers 134c and 134d N- (4-fluoro-3-methyl-phenyl) - 3 - [[(1R, 3R) -3-hydroxycyclohexyl] sulfamoyl] benzamide or N- (4-fluoro-3- methyl-phenyl) -3 - [[(1S, 3S) -3-hydroxycyclohexyl] sulfamoyl] benzamide 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 - 1.20 (m, 1 H), 1, 25 - 1.42 (m, 4 H), 1.42 - 1.58 (m, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.36 - 3.45 (m, 1 H), 3.71 - 3.89 (m, 1 H), 4.38 (d, J = 3.5 Hz, 1 H), 7.14 (t, J = 9.1 Hz , 1 H), 7.51 (s l., 1 H), 7.56 - 7.63 (m, 1 H), 7.69 (dd, J = 7.2, 2.3 Hz, 1 H ), 7.73 - 7.78 (m, 1 H), 7.97 - 8.05 (m, 1 H), 8.19 (dt, J = 7.9, 1.2 Hz, 1 H) , 8.37 (t, J = 1.7 Hz, 1 H), 10.47 (s l., 1 H) Compound 135

[000319] Synthesis following procedure S3 with 2-oxa-6-azaspiro [3.3] heptane as amine, processing W2. Method F; Rt: 0.91 min. m / z: 389.1 (MH) -Exact mass: 390.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (d, J = 1.8 Hz, 3 H), 3.95 (s, 4 H), 4.44 (s, 4 H), 7 , 15 (t, J = 9.2 Hz, 1 H), 7.57 - 7.65 (m, 1 H), 7.68 (dd, J = 7.0, 2.4 Hz, 1 H) , 7.85 (t, J = 7.8 Hz, 1 H), 8.01 (dt, J = 8.0, 1.3 Hz, 1 H), 8.28 - 8.38 (m, 2 H), 10.51 (s, 1 H).

[000320] Synthesis following procedure S1 with (1R, 2S) - (+) - cis-1-aminoindan-2-ol as amine, processing W1. Method G; Rt: 1.79 min. m / z: 439.0 (MH) -Exact mass: 440.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 2.72 (d, J = 15.0 Hz, 1 H), 2.93 (dd, J = 16.1, 4.6 Hz, 1 H), 4.15 (qd, J = 4.7, 1.8 Hz, 1 H), 4.69 (dd, J = 8.7 , 4.7 Hz, 1 H), 4.96 (d, J = 4.4 Hz, 1 H), 6.87 (d, J = 7.3 Hz, 1 H), 7.04 - 7, 10 (m, 1 H), 7.10 - 7.21 (m, 3 H), 7.55 - 7.64 (m, 1 H), 7.68 (dd, J = 7.0, 2, 4 Hz, 1 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.93 (d, J = 9.0 Hz, 1 H), 8.15 (dt, J = 8 , 1, 1.2 Hz, 1 H), 8.21 (dd, J = 7.7, 1.5 Hz, 1 H), 8.48 (t, J = 1.7 Hz, 1 H), 10.44 (s, 1 H) Compound 137

[000321] Synthesis following procedure S4 with (1S, 2R) -2-aminotetralin-1-ol hydrochloride as amine, W4 processing. Method F; Rt: 1.03 min. m / z: 472.2 (M + NH4) + Exact mass: 454.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 - 1.46 (m, 1 H), 1.96 (qd, J = 11.8, 6.2 Hz, 1 H), 2.25 (d, J = 1.5 Hz, 3 H), 2.62 (ddd, J = 17.2, 10.9, 6.3 Hz, 1 H), 2.70 - 2.82 (m, 1 H), 3.34 - 3.45 (m, 1 H), 4.39 (s l., 1 H), 5.29 (d, J = 5.7 Hz, 1 H), 7.04 ( d, J = 6.8 Hz, 1 H), 7.09 - 7.24 (m, 4 H), 7.55 - 7.63 (m, 1 H), 7.62-7.70 (m , 2 H), 7.75 (t, J = 7.8 Hz, 1 H), 8.06 - 8.13 (m, 1 H), 8.19 (d, J = 8.1 Hz, 1 H), 8.43 (t, J = 1.5 Hz, 1 H), 10.44 (s, 1 H), [α] 20 D: +66 ° (c 0.55 w / v%, DMF ). DSC (From 30 to 300 ° C to 10 ° C / min): 170 ° C.
138 OH
[000322] Synthesis following procedure S1 with trans- (1S, 2S) -2-aminocyclopentanol hydrochloride as amine, W1 processing. Method F; Rt: 0.88 min. m / z: 410.4 (M + NH4) + Exact mass: 392.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 - 1.29 (m, 1 H), 1.29 - 1.40 (m, 1 H), 1.50 (quin, J = 7, 4 Hz, 2 H), 1.61 - 1.78 (m, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.16 - 3.26 (m, 1 H ), 3.74 - 3.82 (m, 1 H), 4.67 (d, J = 4.4 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.65 - 7.72 (m, 2 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.98 - 8 , 04 (m, 1 H), 8.18 (dt, J = 7.9, 1.3 Hz, 1 H), 8.36 (t, J = 1.7 Hz, 1 H), 10.45 (s, 1 H)

[000323] Synthesis following procedure S1 with cis- (1R, 2S) -2-aminocyclopentanol hydrochloride as amine, processing W1. Method F; Rt: 0.92 min. m / z: 410.1 (M + NH4) + Exact mass: 392.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 - 1.51 (m, 4 H), 1.51 - 1.67 (m, 2 H), 2.25 (d, J = 1, 5 Hz, 3 H), 3.21 - 3.28 (m, 1 H), 3.72 - 3.79 (m, 1 H), 4.63 (d, J = 4.0 Hz, 1 H ), 7.14 (t, J = 9.2 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.68 (dd, J = 7.3, 2.4 Hz, 1 H), 7.73 (t, J = 7.8 Hz, 1 H), 8.06 (dt, J = 8.1, 1.2 Hz, 1 H), 8.17 (d, J = 8.1 Hz, 1 H), 8.40 (t, J = 1.5 Hz, 1 H), 10.43 (s, 1 H)
Compound 172 0H
[000324] Synthesis following procedure S2 with cis- (1S, 2R) -2-aminocyclopentanol hydrochloride as amine. The formed precipitate was collected on a glass filter and rinsed with CH2Cl2 (2 x 5 mL). The precipitate was further purified using silica gel column chromatography (elution gradient: EtOAc-heptane 0: 100 to 100: 0). Drying in vacuo at 55 ° C resulted in compound 172 as a bright white powder. Method G; Rt: 1.65 min. m / z: 392.9 (M + H) + Exact mass: 392.1. DSC (From 30 to 300 ° C to 10 ° C / min): 145 ° C.
173
[000325] Synthesis following procedure S4 (reaction time = 20 hours instead of 3 hours) with trans- (1R, 2R) -2-aminocyclopentanol as amine, W4 processing. Method F; Rt: 0.87 min. m / z: 410.1 (M + NH4) + Exact mass: 392.1.
140
[000326] Synthesis following procedure S1 with 1,1-dioxothiolan-3-amine hydrochloride as amine, processing W1. Method F; Rt: 0.85 min. m / z: 444.2 (M + NH4) + Exact mass: 426.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.90 - 2.04 (m, 1 H), 2.16 - 2.24 (m, 1 H), 2.25 (d, J = 1 , 8 Hz, 3 H), 2.81 (dd, J = 13.4, 7.0 Hz, 1 H), 3.08 (ddd, J = 13.1, 9.1, 7.5 Hz, 1 H), 3.15 - 3.26 (m, 2 H), 3.94 - 4.06 (m, 1 H), 7.15 (t, J = 9.2 Hz, 1 H), 7 , 55 - 7.63 (m, 1 H), 7.68 (dd, J = 7.2, 2.3 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H) , 8.01 - 8.07 (m, 1 H), 8.23 (dt, J = 7.7, 1.3 Hz, 1 H), 8.38 (t, J = 1.7 Hz, 1 H), 8.40 (s l., 1 H), 10.48 (s, 1 H)

[000327] Synthesis following procedure S4 with 2-aminoindan-1-ol hydrochloride as amine, processing W4. Method F; Rt: 0.98 and 1.01 min. m / z: 458.1 (M + NH4) + Exact mass: 440.1. Compound 141 was separated into its isomers by preparative SFC (Stationary phase: Chiralcel Diacel OD 20 x 250 mm), Mobile phase: CO2, MeOH with 0.2% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. SFC, Column: OD-H (Diacel) 250 mm x 4.6 mm
[000328] Flow: 5 mL / min, Mobile phase: 30% MeOH (containing 0.2% iPrNH2) 4.00 min maintenance, up to 50% in 1 min and 2.00 min @ 50% maintenance Temperature: 40 ° C. Rt: 141a (1.8 min), 141b (2.1 min), 141c (2.5 min), 141d (2.7 min).
[000329] 141a, 141c: N- (4-fluoro-3-methyl-phenyl) -3 - [[((1S, 2S) -1- hydroxyindan-2-yl] sulfamoyl] benzamide or N- (4-fluoro- 3-methyl-phenyl) -3- [[(1R, 2R) -1-hydroxyindan-2-yl] sulfamoyl] benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.5 Hz, 3 H), 2.43-2.55 (m, 1 H), 2.83 (dd, J = 15.7, 7.8 Hz, 1 H), 3.59 - 3.70 (m, 1 H), 4.83 (d, J = 6.8 Hz, 1 H), 5.58 (s l., 1 H), 7.03 - 7.27 (m, 5 H), 7.56 - 7.65 (m, 1 H), 7.68 (dd, J = 7.0, 2.4 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 8.05 - 8.11 (m, 1 H), 8.16 (s l., 1 H), 8 , 22 (d, J = 8.1 Hz, 1 H), 8.43 (t, J = 1.7 Hz, 1 H), 10.47 (s l., 1 H) Method F; Rt: 0.98 m / z: 458.3 (M + NH4) + Exact mass: 440.1.
[000330] 141b, 141d: N- (4-fluoro-3-methyl-phenyl) -3 - [[((1R, 2S) -1- hydroxyindan-2-yl] sulfamoyl] benzamide or N- (4-fluoro- 3-methyl-phenyl) -3- [[(1S, 2R) -1-hydroxyindan-2-yl] sulfamoyl] benzamide. 1H NMR (600 MHz, ACETONE-d6, -14 ° C) δ ppm 2.25 (d, J = 1.9 Hz, 3 H), 2.80 - 2.90 (m, 2 H), 3, 94 - 3.99 (m, 1 H), 4.72 (d, J = 5.3 Hz, 1 H), 4.87 (d, J = 3.8 Hz, 1 H), 6.96 ( d, J = 5.0 Hz, 1 H), 7.08 (t, J = 9.2 Hz, 1 H), 7.14 - 7.19 (m, 2 H), 7.21 (td, J = 7.3, 1.2 Hz, 1 H), 7.29 (d, J = 7.3 Hz, 1 H), 7.65 - 7.70 (m, 1 H), 7.74 ( dt, J = 6.8, 3.1 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 8.19 (ddd, J = 7.8, 1.8, 1.1 Hz, 1 H), 8.27 (ddt, J = 7.8, 1.8, 0.9, 0.9 Hz, 1 H), 8.54 (q, J = 1.6 Hz , 1 H), 10.09 (s, 1 H) Method F; Rt: 1.00 m / z: 458.2 (M + NH4) + Exact mass: 440.1.

[000331] Synthesis following procedure S4 with (1R, 2R) -2-amino-1-phenyl-propan-1-ol as amine, W4 processing. Method F; Rt: 1.00 min. m / z: 460.1 (M + NH4) + Exact mass: 442.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76 (d, J = 6.8 Hz, 3 H), 2.25 (d, J = 1.3 Hz, 3 H), 3.37 - 3.46 (m, 1 H), 4.56 (d, J = 4.6 Hz, 1 H), 5.41 (s l., 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.18 - 7.23 (m, 1 H), 7.23 - 7.32 (m, 4 H), 7.49 (s l., 1 H), 7.56 - 7.64 (m, 1 H), 7.64 - 7.72 (m, 2 H), 7.88 - 7.96 (m, 1 H), 8.15 (d, J = 7.9 Hz , 1 H), 8.31 (t, J = 1.5 Hz, 1 H), 10.42 (s, 1 H).

[000332] Synthesis following procedure S1 with (1R, 2S) - (-) - norephedrine as amine, processing W1.
[000333] Method F; Rt: 1.01 min. m / z: 460.1 (M + NH4) + Exact mass: 442.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (d, J = 6.8 Hz, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.33 - 3.37 (m, 1 H), 4.48 (t, J = 4.6 Hz, 1 H), 5.42 (d, J = 4.6 Hz, 1 H), 7.10 - 7, 27 (m, 6 H), 7.55 - 7.63 (m, 1 H), 7.64 - 7.71 (m, 2 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.91 (dt, J = 8.2, 1.2 Hz, 1 H), 8.12 - 8.18 (m, 1 H), 8.30 (t, J = 1.7 Hz , 1 H), 10.42 (s, 1 H)

[000334] Synthesis following procedure S1 with (1S, 2R) - (+) - norephedrine as amine, processing W1. Method F; Rt: 1.01 min. m / z: 460.2 (M + NH4) + Exact mass: 442.1.
[000335] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (d, J = 6.8 Hz, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 3 , 32 - 3.38 (m, 1 H), 4.48 (t, J = 4.6 Hz, 1 H), 5.42 (d, J = 4.8 Hz, 1 H), 7.10 - 7.27 (m, 6 H), 7.56 - 7.63 (m, 1 H), 7.65 - 7.71 (m, 2 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.89 - 7.94 (m, 1 H), 8.15 (dt, J = 7.8, 1.3 Hz, 1 H), 8.30 (t, J = 1 , 7 Hz, 1 H), 10.42 (s, 1 H)

[000336] Synthesis following procedure S4 with 3-aminocyclopentanol as amine, after completion, the reaction mixture was directly loaded onto a silica gel column for purification, using a gradient from heptane to EtOAc giving compound 145 as a mixture 83 ( 145a, 145b): 17 (145c, 145d) of di-asteromers. Method F; Rt: 0.82 and 0.86 min. m / z: 410.2 (M + NH4) + Exact mass: 392.1. Compound 145 was separated into its isomers by preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, MeOH with 0.4% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again to give compounds 145a (238 mg) and 145b (236 mg) and a mixture of compounds 145c and 145d. The mixture of 145c and 145d was further purified by Preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, EtOH with 0.4% iPrNH2), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again giving 145c (29 mg) and 145d (27 mg). 145a and 145b: N- (4-fluoro-3-methyl-phenyl) -3- [[((1R, 3S) -3-hydroxycyclopentyl] sulfamoyl] benzamide or N- (4-fluoro-3-methyl-phenyl) - 3 - [[(1S, 3R) -3-hydroxycyclopentyl] sulfamoyl] benzamide.
[000337] Method F; Rt: 0.85 min. m / z: 410.2 (M + NH4) + Exact mass: 392.1.
[000338] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (ddd, J = 13.3, 7.8, 6.1 Hz, 1 H), 1.36 - 1.64 (m, 4 H), 1.84 - 1.95 (m, 1 H), 2.25 (d, J = 1.1 Hz, 3 H), 3.37 - 3.47 (m, 1 H), 3 , 85 - 3.96 (m, 1 H), 4.25-5.00 (1H, ls), 7.14 (t, J = 9.2 Hz, 1 H), 7.35-7.75 (1H, sl), 7.54 - 7.63 (m, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7.75 (t, J = 7 , 8 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 8.36 (s, 1 H ), 10.46 (s l., 1 H)
[000339] 145c and 145d: N- (4-fluoro-3-methyl-phenyl) -3 - [[((1S, 3S) -3-hydroxycyclopentyl] sulfamoyl] benzamide or N- (4-fluoro-3-methyl- phenyl) -3- [[(1R, 3R) -3-hydroxycyclopentyl] sulfamoyl] benzamide. Method F; Rt: 0.82 min. m / z: 410.2 (M + NH4) + Exact mass: 392.1.
[000340] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 - 1.35 (m, 2 H), 1.41 (ddd, J = 13.4, 8.0, 5.7 Hz, 1 H), 1.56 (ddd, J = 13.2, 7.3, 2.6 Hz, 1 H), 1.69 - 1.83 (m, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.59 - 3.72 (m, 1 H), 3.99 - 4.09 (m, 1 H), 4.43 (d, J = 3.5 Hz , 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.55 - 7.63 (m, 1 H), 7.68 (dd, J = 7.0, 2, 2 Hz, 1 H), 7.73 - 7.84 (m, 2 H), 7.96 - 8.02 (m, 1 H), 8.20 (dt, J = 7.9, 1.2 Hz, 1 H), 8.36 (t, J = 1.7 Hz, 1 H), 10.48 (s l., 1 H) 145a: [α] 20 D: +5.2 ° (c 0 , 56 w / v%, DMF); 145b: [α] 20 D: -5.4 ° (c 0.60 w / v%, DMF); 145c: [α] 20 D: -3.5 ° (c 0.46 w / v%, DMF); 145d: [α] 20 D: +2.5 ° (c 0.44 w / v%, DMF)

[000341] Synthesis following procedure S2 with 6-oxa-2-azaspiro oxalate [3.4] octane as amine, after completion, the reaction mixture was directly loaded onto a silica gel column for purification, using a heptane gradient EtOAc giving compound146. Method F; Rt: 0.93 min. m / z: 422.3 (M + NH4) + Exact mass: 404.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.81 (t, J = 6.9 Hz, 2 H), 2.26 (d, J = 1.8 Hz, 3 H), 3.46 (s , 2 H), 3.57 (t, J = 6.9 Hz, 2 H), 3.72 - 3.80 (m, 4 H), 7.15 (t, J = 9.1 Hz, 1 H), 7.58 - 7.64 (m, 1 H), 7.69 (dd, J = 7.0, 2.2 Hz, 1 H), 7.87 (t, J = 7.8 Hz , 1 H), 8.04 (dt, J = 8.0, 1.3 Hz, 1 H), 8.32 - 8.41 (m, 2 H), 10.53 (s, 1 H).

[000342] Synthesis following procedure S2 with 6-oxa-1-azaspiro [3.3] heptane as amine, after completion, the reaction mixture was directly loaded onto a silica gel column for purification, using a heptane gradient EtOAc giving rise to the composite147. Method F; Rt: 0.92 min. m / z: 408.2 (M + NH4) + Exact mass: 390.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 2.53 (t, J = 7.3 Hz, 2 H), 3.73 ( t, J = 7.4 Hz, 2 H), 4.53 (d, J = 7.9 Hz, 2 H), 5.01 (d, J = 7.9 Hz, 2 H), 7.15 (t, J = 9.1 Hz, 1 H), 7.56 - 7.64 (m, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7 , 82 (t, J = 7.8 Hz, 1 H), 8.05 - 8.11 (m, 1 H), 8.29 (dt, J = 7.8, 1.3 Hz, 1 H) , 8.40 (t, J = 1.7 Hz, 1 H), 10.51 (s, 1 H) Compound 148

[000343] Synthesis following procedure S4 with (S) - (+) - 1-cyclohexylethylamine as amine, processing W4. Method F; Rt: 1.23 min. m / z: 436.2 (M + NH4) + Exact mass: 418.2 Compound 149

[000344] Synthesis following procedure S4 with 4,4-difluorocyclohexylamine as amine, processing W4. Method F; Rt: 1.06 min. m / z: 444.5 (M + NH4) + Exact mass: 426.1. Compound 150

[000345] Synthesis following procedure S4 with 3-buten-2-amine, hydrochloride as amine, processing W4. Method F; Rt: 1.01 min. m / z: 380.3 (M + NH4) + Exact mass: 362.1. 1H NMR (400 MHz, DMSO- d6) δ ppm 1.03 (d, J = 6.8 Hz, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.74 - 3.87 (m, 1 H), 4.87 (dt, J = 10.5, 1.4 Hz, 1 H), 5.00 (dt, J = 17.3, 1.4 Hz, 1 H ), 5.61 (ddd, J = 17.3, 10.5, 6.1 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.55 - 7, 63 (m, 1 H), 7.68 (dd, J = 7.2, 2.3 Hz, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.93 ( d, J = 7.9 Hz, 1 H), 7.96 - 8.01 (m, 1 H), 8.18 (dt, J = 7.7, 1.3 Hz, 1 H), 8, 35 (t, J = 1.7 Hz, 1 H), 10.45 (s, 1 H).

[000346] Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with (S) - (+) - 2-amino-3-methylbutane as amine, W4 processing. Method F; Rt: 1.11 min. m / z: 396.2 (M + NH4) + Exact mass: 378.1. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 0.81 (d, J = 6.8 Hz, 6 H), 0.95 (d, J = 6.8 Hz, 3 H), 1.57 - 1.67 (m, 1 H), 2.28 (d, J = 1.8, 3 H), 3.13 - 3.28 (m, 1 H), 4.85 (d, J = 8, 6 Hz, 1 H), 6.98 (t, J = 9.0 Hz, 1 H), 7.36 - 7.46 (m, 1 H), 7.49 - 7.57 (m, 1 H ), 7.61 (t, J = 7.8 Hz, 1 H), 8.00 (dt, J = 7.9, 1.5 Hz, 1 H), 8.12 (dt, J = 7, 9, 1.5 Hz, 1 H), 8.25 (s, 1 H), 8.39 (t, J = 1.9 Hz, 1 H).

[000347] Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with (1R) -1-cyclopropylethylamine as amine, W4 processing. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm - 0.05 - 0.05 (m, 1 H), 0.09-0.16 (m, 1 H), 0.20 - 0.36 (m , 1 H), 0.38 - 0.51 (m, 1 H), 0.69-0.81 (m, 1 H), 1.13 (d, J = 6.6 Hz, 3 H), 2.27 (d, J = 1.8 Hz, 3 H), 2.63 - 2.85 (m, 1 H), 5.10 (d, J = 6.8 Hz, 1 H), 6, 98 (t, J = 8.9 Hz, 1 H), 7.37- 7.45 (m, 1 H), 7.52 (dd, J = 6.6, 2.4 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.98-8.02 (m, 1 H), 8.08-8.13 (m, 1 H), 8.25 (s , 1 H), 8.38 (t, J = 1.7 Hz, 1 H). Method F; Rt: 1.07 min. m / z: 394.2 (M + NH4) + Exact mass: 376.1. 174

[000348] Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with (1R) -1-cyclopropylethylamine as amine, W4 processing. The residue obtained was recrystallized from diisopropylether / acetonitrile. The precipitate was collected and dried in vacuo at 55 ° C, resulting in compound 174. 1H NMR (400 MHz, DMSO-d6) δ ppm -0.11 - -0.01 (m, 1 H), 0.07 - 0.23 (m, 2 H), 0.29 - 0.38 (m, 1 H), 0.70 - 0.82 (m, 1 H), 0.99 (d, J = 6.6 Hz , 3 H), 2.21 - 2.30 (m, 3 H), 2.66 (quin, J = 6.8 Hz, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.56 - 7.64 (m, 1 H), 7.68 (dd, J = 7.0, 2.4 Hz, 1 H), 7.75 (t, J = 7.8 Hz , 1 H), 7.85 (s l., 1 H), 7.93 - 8.07 (m, 1 H), 8.18 (d, J = 7.9 Hz, 1 H), 8, 37 (t, J = 1.7 Hz, 1 H), 10.46 (s l., 1 H)

[000349] Synthesis following procedure S4 (stirred for 20 hours instead of 3 hours) with 3-amino-1-phenylbutane as amine, W4 processing. Method F; Rt: 1.19 min. m / z: 458.2 (M + NH4) + Exact mass: 440.2. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.06 (d, J = 6.6 Hz, 3 H), 1.62 - 1.76 (m, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 2.44 - 2.64 (m, 2 H), 3.30 - 3.43 (m, 1 H), 5.05 (d, J = 8.4 Hz , 1 H), 6.96 (t, J = 8.9 Hz, 1 H), 7.00-7.04 (m, 2 H), 7.09 - 7.17 (m, 1 H), 7.17 - 7.25 (m, 2 H), 7.36-7.42 (m, 1 H), 7.50 (dd, J = 6.8, 2.4 Hz, 1 H), 7 , 57 (t, J = 7.8 Hz, 1 H), 7.95 (m, J = 7.8, 1 H), 8.10 (m, J = 7.8 Hz, 1 H), 8 , 25 (s, 1 H), 8.37 (t, J = 1.5 Hz, 1 H)

[000350] Phenyl) carbamoyl chloride] benzenesulfonyl (500 mg, 1.53 mmol) and DIPEA (657 μL, 3.8 mmol, 2.5 eq) dissolved in CH2Cl2 (15 mL) were added to a tube containing 3-amino -1-Boc-3-methyl-azetidine (1.1 eq). The reaction mixture was stirred for 20 hours. 1M HCl (5 ml) was added and the mixture was stirred for 5 minutes. The organic layer was separated and loaded onto a silica gel column. The mixture was purified using heptane elution gradient to EtOAc, resulting in compound 154 (721 mg). Method F; Rt: 1.11 min. m / z: 478.2 (M + H) + Exact mass: 477.2.

[000351] Prepared as described for compound 154 using 1-Boc-3-aminopiperidine instead of 3-amino-1-Boc-3-methyl-azetidine. Method F; Rt: 1.13 min. m / z: 492.1 (M + H) + Exact mass: 491.2.

[000352] Prepared as described for compound 154 using (+/-) -3-amino-1-N-Boc-pyrrolidine instead of 3-amino-1-Boc-3-methyl-azetidine. Method F; Rt: 1.08 min. m / z: 478.2 (M + H) + Exact mass: 477.2 1H NMR (400 MHz, CHLOROPHORUM-d) δ ppm 1.36 (s, 9 H), 1.71 - 1.92 (m , 1 H), 1.92 - 2.15 (m, 1 H), 2.28 (d, J = 1.8 Hz, 3 H), 3.103.24 (m, 1 H), 3.24- 3.44 (m, 3 H), 3.81 - 3.94 (m, 1 H), 5.50 - 6.00 (m, 1 H), 6.98 (t, J = 9.0 Hz , 1 H), 7.40 - 7.48 (m, 1 H), 7.52 - 7.71 (m, 2 H), 7.93-8.03 (m, 1 H), 8.04 - 8.17 (m, 1 H), 8.31 (s l., 1 H), 8.45 - 8.88 (m, 1 H).

[000353] Compound 154 (721 mg, 1.51 mmol) was dissolved in CH2Cl2 (10 mL) and HCl (6 M in iPrOH, 2.5 mL) was added. The mixture was stirred overnight and the volatiles were removed in vacuo, resulting in N- (4-fluoro-3-methyl-phenyl) -3 - [(3-methylazetidin-3-yl) sulfamoyl] benzamide hydrochloride as a white solid (0.57 g). N- (4-fluoro-3-methyl-phenyl) -3 - [(3-methylazetidin-3-yl) sulfamoyl] benzamide hydrochloride (150 mg) in CH2Cl2 (10 mL) were added DIPEA (263 μL, 1 , 5 mmol) and methyl chloroformate (44 μL, 0.57 mmol). The mixture was concentrated under a gentle flow of nitrogen at 55 ° C until only 2 mL remained. The residue was purified using silica gel column chromatography (elution gradient: EtOAc-heptane 0: 100 to 100: 0). The desired fractions were concentrated under reduced pressure and the product obtained was dried in a vacuum oven at 55 ° C giving compound 157 (74.2 mg) as a bright white solid. Method F; Rt: 0.93 min. m / z: 436.1 (M + H) + Exact mass: 435.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 3 H), 2.25 (d, J = 1.5 Hz, 3 H), 3.52 (s, 3 H), 3 , 56-3.68 (m, 2 H), 3.83-3.93 (m, 2 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.57 - 7, 62 (m, 1 H), 7.68 (dd, J = 6.8, 2.4 Hz, 1 H), 7.77 (t, J = 7.9 Hz, 1 H), 8.01 ( m, J = 7.9 Hz, 1 H), 8.21 (m, J = 7.9 Hz, 1 H), 8.37 (t, J = 1.5 Hz, 1 H), 8.48 (bs, 1 H), 10.49 (s, 1 H)

[000354] Prepared similarly as described for compound 157, starting from compound 156 instead of compound 154, through the intermediate of N- (4-fluoro-3-methyl-phenyl) -3- (pyrrolidin-3- ylsulfamoyl) benzamide. Method F; Rt: 0.91 min. m / z: 436.2 (M + H) + Exact mass: 435.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.77 (m, 1 H), 1.80-1.98 (m 1 H), 2.25 (d, J = 1.5 Hz, 3 H), 3.00 - 3.12 (m, 1 H), 3.14 - 3.27 (m, 1 H), 3.26 - 3.39 (m, 2 H), 3, 50-3.58 (m, 3 H), 3.67 - 3.76 (m, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.57 - 7.63 (m, 1 H), 7.68 (dd, J = 7.2, 2.3 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.97 - 8 , 04 (m, 1 H), 8.04 - 8.18 (m, 1 H), 8.18 - 8.25 (m, 1 H), 8.37 (t, J = 1.5 Hz, 1 H), 10.48 (s, 1 H)

[000355] Prepared similarly as described for compound 157, starting from compound 155 instead of compound 154, through the intermediate of N- (4-fluoro-3-methyl-phenyl) -3- (3-piperidylsulfamoyl) benzamide. Method F; Rt: 0.96 min. m / z: 467.1 (M + NH4) + Exact mass: 449.1. The racemic compound 159 was separated by Preparative SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm), Mobile phase: CO2, MeOH with 0.2% iPrNH2), the desired fractions were collected, evaporated, dissolved in methanol and evaporated again, resulting in enantiomers 159a and 159b.
[000356] Columns: ID-H (Daicel) 250 mm x 4.6 mm; Flow: 3 mL / min; Mobile phase: 20% EtOH (containing 0.2% iPrNH2) maintenance 15.00 min; Temperature: 30 ° C; Rt: 9.6 min (159a), Rt: 11.0 min (159b)

[000357] Method B; Rt: 4 min. m / z: 443.1 (M + H) + Exact mass: 442.0
[000358] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3 H) 4.14 (d, J = 6.3 Hz, 2 H) 4.56 (d, J = 6, 0 Hz, 2 H) 7.42 (t, J = 8.8 Hz, 1 H) 7.74 - 7.82 (m, 2 H) 8.04 (s, 1 H) 8.15 - 8, 24 (m, 2 H) 8.37 (t, J = 1.5 Hz, 1 H)

[000359] 1-Pyridin-4-yl-ethylamine (220 mg, 1.8 mmol) and 3- [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (500 mg, 1.53 mmol) were dissolved in CH2Cl2 (10 mL). DIPEA (6.2 mmol) was added at 0 ° C and the mixture was stirred at 25 ° C for 4 hours. The mixture was washed with water (20 ml) and the aqueous layer was extracted with CH2Cl2 (3 x 20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue obtained was purified by reverse phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 30% to 60%).
[000360] The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo and the precipitate formed was filtered, washed with H2O (5 ml) and dried under high vacuum. The obtained residue was suspended in water (5 ml) and the aqueous layer was lyophilized to dryness, resulting in compound 161 (410 mg). Method A; Rt: 4.34 min. m / z: 414.3 (M + H) + Exact mass: 413.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J = 7.0 Hz, 3 H) 2.26 (d, J = 1.5 Hz, 3 H) 4.34 - 4, 50 (m, 1 H) 7.15 (t, J = 9.3 Hz, 1 H) 7.20 - 7.24 (m, 2 H) 7.56 - 7.66 (m, 2 H) 7 , 68 (dd, J = 7.0, 2.3 Hz, 1 H) 7.86 (m, J = 7.8 Hz, 1 H) 8.13 (m, J = 7.8 Hz, 1 H ) 8.26 (t, J = 1.3 Hz, 1 H) 8.32 - 8.39 (m, 2 H) 8.55 (d, J = 8.3 Hz, 1 H) 10.41 ( s, 1 H). 162

[000361] Prepared similarly as described for compound 161, using 1- (3-pyridyl) ethanamine instead of 1-pyridin-4-yl-ethylamine. Method D; Rt: 5.16 min. m / z: 414.3 (M + H) + Exact mass: 413.1.
[000362] Compound 163

[000363] Prepared similarly as described for compound 161, using 1- (2-pyridyl) ethanamine instead of 1-pyridin-4-yl-ethylamine. Method A; Rt: 4.60 min. m / z: 414.3 (M + H) + Exact mass: 413.1. 164

[000364] Prepared similarly as described for compound 161, using 1- (1-methyl-4-piperidyl) ethanamine instead of 1-pyridin-4-ylethylamine. Method B; Rt: 3.35 min. m / z: 434.4 (M + H) + Exact mass: 433.2. 165

[000365] Prepared similarly as described for compound 161, using 4-morpholinobutan-2-amine instead of 1-pyridin-4-ylethylamine. Method B; Rt: 3.33 min. m / z: 450.3 (M + H) + Exact mass: 449.2. 166

[000366] Prepared similarly as described for compound 161, using (R) -1-phenylethanamine instead of 1-pyridin-4-yl-ethylamine. The impure compound was purified by preparative high performance liquid chromatography (column: Luna 150 * 30 mm * 5 um, mobile phase: CH3CN in water (0.1% NH4HCO3) from 40% to 70%, flow rate: 35 mL / min). Method B; Rt: 4.45 min. m / z: 413.3 (M + H) + Exact mass: 412.1. [α] 20 D: + 55 ° (c 0.12 w / v, methanol).

[000367] Prepared similarly as described for compound 166, using (S) -1-phenylethanamine instead of (R) -1-phenylethanamine. Method B; Rt: 4.45 min. m / z: 413.3 (M + H) + Exact mass: 412.1. [α] 20 D: - 57 ° (c 0.12 w / v, methanol).

[000368] Synthesis following procedure S4 (reaction time 20 hours instead of 3 hours) with 2-aminoindane as amine, W4 processing. The residue obtained was recrystallized from Diisopropylether / acetonitrile, resulting in compound 168. Method F; Rt: 1.14 min. m / z: 442.2 (M + NH4) + Exact mass: 424.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 2.72 (dd, J = 15.6, 7.0 Hz, 2 H), 2.96 (dd, J = 15.8, 7.5 Hz, 2 H), 3.95 (quin, J = 7.3 Hz, 1 H), 7.08 - 7.17 (m, 5 H ), 7.57 - 7.63 (m, 1 H), 7.68 (dd, J = 6.9, 2.3 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 8.03 - 8.12 (m, 1 H), 8.13 - 8.28 (m, 2 H), 8.41 (t, J = 1.7 Hz, 1 H), 10 , 49 (s l., 1 H)

[000369] Prepared similarly as described for compound 166, using 1-phenylpropan-2-amine instead of (R) -1-phenylethanamine. Method B; Rt: 4.60 min. m / z: 427.3 (M + H) + Exact mass: 426.1.


S4 *: reaction time of 20 hours instead of 3 hours
[000370] Compound 175. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.5 Hz, 3 H), 2.62 (dd, J = 15.7, 6.5 Hz, 1 H), 3.07 (dd, J = 15.7, 6.7 Hz, 1 H), 4.11 (quin, J = 6.2 Hz, 1 H), 4.50 (dd, J = 7.9, 6.2 Hz, 1 H), 5.14 (d, J = 5.7 Hz, 1 H), 6.92 (d, J = 7.5 Hz, 1 H), 7 , 06 - 7.24 (m, 4 H), 7.55 - 7.65 (m, 1 H), 7.69 (dd, J = 7.0, 2.4 Hz, 1 H), 7, 77 (t, J = 7.8 Hz, 1 H), 8.05 - 8.15 (m, 1 H), 8.19 - 8.26 (m, 1 H), 8.31 (d, J = 8.4 Hz, 1 H), 8.47 (t, J = 1.7 Hz, 1 H), 10.45 (s, 1 H)
[000371] Compound 178. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 - 1.72 (m, 1 H), 1.86 - 1.99 (m, 1 H), 2.22 - 2.31 (m, 3 H), 2.60-2.74 (m, 1 H), 2.74 - 2.85 (m, 1 H), 3.26 - 3.41 (m, 1 H ), 4.38 (t, J = 6.2 Hz, 1 H), 5.32 - 5.39 (m, 1 H), 6.96 - 7.09 (m, 1 H), 7.11 - 7.21 (m, 3 H), 7.28 - 7.37 (m, 1 H), 7.51 - 7.65 (m, 1 H), 7.69 (dd, J = 7.0 , 2.4 Hz, 1 H), 7.72 - 7.82 (m, 2 H), 8.05 - 8.12 (m, 1 H), 8.17 - 8.24 (m, 1 H ), 8.43 (t, J = 1.7 Hz, 1 H), 10.48 (s, 1 H)
[000372] Compound 179. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (dd, J = 5.1, 16.7 Hz, 1 H), 2.25 (d, J = 1.8 Hz, 3 H), 2.35 (dd, J = 8.4, 16.7 Hz, 1 H), 2.66 (s, 3 H), 3.10 (dd, J = 10.1, 4 , 6 Hz, 1 H), 3.47 (dd, J = 10.3, 7.3 Hz, 1 H), 3.80 - 3.92 (m, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.53 - 7.63 (m, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7.74 - 7 , 86 (m, 1 H), 7.97 - 8.08 (m, 1 H), 8.15 - 8.32 (m, 2 H), 8.37 (s, 1 H), 10.48 (s, 1 H). Racemic compound 179 was separated into enantiomers 179a and 179b by Preparative SFC (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, iPrOH with iPrNH2 0.4%). The collected fractions were concentrated in vacuo resulting in compounds 179a and 179b. Columns: AD-H (diacel) 250 mm x 4.6 mm; Flow: 5 mL / min; Mobile phase: iPrOH at 30% (containing iPrNH2 at 0.2%) maintenance 4.00 min, up to 50% in 1 min and maintenance 2.00 min @ 50%; Temperature: 40 ° C Rt: 2.2 min (179a); 2.9 min (179b). 179a: +6.1 ° (589 nm, c 0.6225 w / v%, MeOH, 20 ° C). 179b: -6.1 ° (589 nm, c 0.556 w / v%, MeOH, 20 ° C).
[000373] Compound 180. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 - 1.79 (m, 2 H), 2.01 - 2.36 (m, 5 H), 2.68 ( s, 3 H), 3.06 (dd, J = 12.3, 6.8 Hz, 1 H), 3.25 - 3.30 (m, 1 H), 3.46 - 3.58 (m , 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.52 - 7.63 (m, 1 H), 7.64 - 7.71 (m, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 8.01 - 8.09 (m, 1 H), 8.11 - 8.27 (m, 2 H), 8.39 (t , J = 1.7 Hz, 1 H), 10.47 (s, 1 H)
[000374] Compound 181. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (dq, J = 12.4, 9.3 Hz, 1 H), 1.93 - 2.16 (m, 1 H), 2.25 (d, J = 1.5 Hz, 3 H), 2.69 (s, 3 H), 3.06 - 3.24 (m, 2 H), 4.00 (t, J = 9.1 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.54 - 7.64 (m, 1 H), 7.65 - 7.71 ( m, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.99 - 8.09 (m, 1 H), 8.25 (ls, 1 H), 8.11 - 8.20 (m, 1 H), 8.44 (t, J = 1.7 Hz, 1 H), 10.42 (s, 1 H).
[000375] Compound 182. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 - 1.52 (m, 9 H), 2.26 (d, J = 1.3 Hz, 3 H), 3 , 40-3.60 (m 2 H), 3.80-4.00 (m, 2 H), 4.02 - 4.19 (m, 1 H), 7.15 (t, J = 9, 2 Hz, 1 H), 7.57 - 7.66 (m, 1 H), 7.70 (dd, J = 7.0, 2.2 Hz, 1 H), 7.80 (t, J = 7.8 Hz, 1 H), 8.01 (m, J = 8.1 Hz, 1 H), 8.26 (m, J = 7.9 Hz, 1 H), 8.38 (t, J = 1.0 Hz, 1 H), 8.51 (d, J = 8.4 Hz, 1 H), 10.50 (s, 1 H).
[000376] Compound 183. 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.19 - 1.43 (m, 4 H), 2.28 (d, J = 1.8 Hz, 3 H), 5 , 74 (s l., 1 H), 6.99 (t, J = 8.8 Hz, 1 H), 7.37 (m, J = 8.4, 3.7 Hz, 1 H), 7 , 45 - 7.54 (m, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.88 (s l., 1 H), 8.03 (m, J = 8.1 Hz, 1 H), 8.10 (m, J = 7.9 Hz, 1 H), 8.29 - 8.38 (m, 1 H)

[000377] Synthesis following procedure S4 with 3-aminocyclobutanol as amine, reaction time of 1 hour instead of 3 hours, W4 processing. Method F; Rt: 0.81 min. m / z: 396.2 (M + NH4) + Exact mass: 378.1. SFC: Columns: Diacel AD-H (250 mm x 4.6 mm); Flow: 5 mL / min Mobile phase: 30% MeOH (containing 0.2% iPrNH2) maintenance 4.00 min, up to 50% in 1 min and maintenance 2.00 min at 50%; Temperature: 40 ° C; Rt: 184a (2.5 min), 184b (3.4 min). The diastereomeric mixture of compound 184 was separated into diastereoisomers (SFC Prep (Stationary phase: Chiralpak Diacel AD 30 x 250 mm), Mobile phase: CO2, MeOH with 0.4% iPrNH2). The fractions obtained were concentrated under reduced pressure and dried in vacuo at 55 ° C, resulting in compounds 184a and 184b. 184a

[000378] 1H NMR (600 MHz, DMSO-d6) δ ppm 1.84 - 1.91 (m, 2 H), 1.92 - 1.98 (m, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.77 (quin, J = 6.9 Hz, 1 H), 4.10 - 4.14 (m, 1 H), 4.93 (d, J = 4 , 9 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.59 (ddd, J = 8.8, 4.6, 2.7 Hz, 1 H), 7.68 (dd, J = 7.1, 2.7 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7.96 (ddd, J = 7.8, 1.9, 1.1 Hz, 1 H), 8.06 (s l., 1 H), 8.20 (dt, J = 7.8, 1.5 Hz, 1 H), 8.33 ( t, J = 1.8 Hz, 1 H), 10.49 (s l., 1 H). 184b

[000379] 1H NMR (600 MHz, DMSO-d6) δ ppm 1.54 - 1.60 (m, 2 H), 2.19 - 2.24 (m, 2 H), 2.25 (d, J = 1.8 Hz, 3 H), 3.09 - 3.19 (m, 1 H), 3.62 - 3.68 (m, 1 H), 5.00 (d, J = 5.6 Hz , 1 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.59 (ddd, J = 8.5, 4.5, 2.8 Hz, 1 H), 7.68 (dd, J = 7.0, 2.2 Hz, 1 H), 7.75 (t, J = 7.8 Hz, 1 H), 7.97 (ddd, J = 7.8, 1.9 , 1.0 Hz, 1 H), 8.02 (s l., 1 H), 8.19 (ddd, J = 7.8, 1.8, 1.1 Hz, 1 H), 8.34 (t, J = 1.6 Hz, 1 H), 10.48 (s, 1 H) Compound 185

[000380] Prepared similarly as described for compound 157, starting from compound 182 instead of compound 154, through the 3- (azetidin-3-ylsulfamoyl) -N- (4-fluoro-3-methyl-) hydrochloride phenyl) benzamide. Method F; Rt: 0.89 min. m / z: 439.2 (M + NH4) + Exact mass: 421.1.1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 3, 45-3.60 (m, 5 H), 3.85-4.05 (m, 2 H), 4.07 - 4.17 (m, 1 H), 7.15 (t, J = 9, 1 Hz, 1 H), 7.53 - 7.64 (m, 1 H), 7.65 - 7.71 (m, 1 H), 7.78 (t, J = 7.8 Hz, 1 H ), 7.94 - 8.03 (m, 1 H), 8.23 (m, J = 7.9 Hz, 1 H), 8.33 (t, J = 1.7 Hz, 1 H), 8.44 - 8.63 (bs, 1 H), 10.49 (s, 1 H).

[000381] 3- (Isopropylsulfamoyl) benzoic acid (250 mg, 1.03 mmol), 4-fluoro-3,5-dimethylaniline (157 mg, 1.13 mmol) and DIPEA (398 mg, 3.08 mmol ) were mixed in acetonitrile (10 mL) at room temperature under a nitrogen atmosphere. HATU (430 mg, 1.13 mmol) was added and the mixture was stirred overnight. EtOAc (100 ml) was added and the mixture was washed with 1 M HCl, sat. NaHCO3 and brine. After drying over MgSO4 and evaporating to dryness in vacuo, the obtained residue was crystallized from MeOH (10 ml) to provide a white solid (216 mg). Method F; Rt: 1.04 min. m / z: 382.2 (M + NH4) + Exact mass: 364.1. 1H NMR (400 MHz, DMSO- d6) δ ppm 0.96 (d, J = 6.6 Hz, 6 H), 2.23 (d, J = 2.0 Hz, 6 H), 3.23 - 3.29 (m, 1 H), 7.48 (d, J = 6.6 Hz, 2 H), 7.66 - 7.80 (m, 2 H), 7.95 - 8.04 (m , 1 H), 8.18 (d, J = 7.9 Hz, 1 H), 8.35 (t, J = 1.7 Hz, 1 H), 10.37 (s, 1 H). 187

[000382] A solution of 2-fluoro-6-methylbenzoic acid (10 g, 0.0649 mol) in HOAc (300 ml) was stirred in a water bath containing a little ice. At ~ 15 ° C, HNO3 (65%, 32.7 ml) was added dropwise. After addition, H2O (30 mL) was added slowly. After addition, Br2O (3.7 mL) was added dropwise. A solution of silver nitrate (14.33 g, 0.0844 mol) in H2 O (100 ml) was added dropwise over a period of 30 minutes. After addition, the reaction mixture was stirred at room temperature for 3 hours 30 minutes. The reaction mixture was poured into H2O (850 ml), and EtOAc (300 ml) was added. The mixture was stirred vigorously for 5 minutes. Both upper liquid layers were decanted from a residue. The separated water layer was combined with the residue, and extracted with EtOAc. Both upper liquid layers were decanted from the residue. The separated water layer was combined with the residue, and extracted again with EtOAc. The organic layers were combined, washed with saturated NaCl and dried with Na2SO4, filtered, evaporated, and coevaporated with toluene. The solid residue obtained was stirred in a small amount of diisopropylether, filtered, washed with diisopropylether, resulting in 3-bromo-6-fluoro-2-methyl-benzoic acid (4 g). The filtrate was evaporated. The residue was stirred in heptane, filtered, washed with heptanes (3x), and dried at 50 ° C in vacuo, resulting in a mixture of bromo-6-fluoro-2-methyl-benzoic acid and 2-fluoro-6- acid methylbenzoic (12 g, ratio 1 / 0.4). 3-Bromo-6-fluoro-2-methyl-benzoic acid (4 g, 0.0172 mol) was added portion by portion to stirring chlorosulfonic acid (25 mL). The resulting solution was stirred at 115 ° C for 2 hours, left to stand at room temperature overnight and then stirred at 115 ° C for 3 more hours. The reaction mixture was allowed to reach room temperature, and was added dropwise to a stirring mixture of crushed ice (150 g) and H2O (50 ml). The product was extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried with Na2SO4, filtered, and evaporated, resulting in a crude mixture containing 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (4.4 g) ( Na2CO3, 1.407 g, 0.0133 mol) was dissolved in water (25 ml). A solution of (S) -3-aminotetrahydrofuran (2.312 g, 0.0265 mol) in THF (20 ml) was added, and the reaction mixture was cooled to 0 ° C in an ice bath. A solution of crude 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (44 g) in THF (30 ml) was added dropwise at 0 ° C. After addition, the reaction mixture was stirred at 0 ° C for 1 hour, and at room temperature for 2 hours. The mixture was concentrated until ~ 35 ml remained, then left to stand for 70 hours. The solid was filtered and washed with H2O (2x). The filtrate was washed with Et2O. The separated water layer was acidified with 1 N HCl (30 ml), and the product was extracted with 2-MeTHF. The separated water layer was further acidified to pH ~ 2 and extracted with 2-MeTHF. The organic layer was washed with brine, dried with Na2SO4 and filtered, resulting in crude 5-bromo-2-fluoro-6-methyl-3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (6.5 g). To a stirring solution of crude 5-bromo-2-fluoro-6-methyl-3 - [[(3S) - tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (1.3 g) in CH3CN (30 ml) under N2 atm, triethylamine (1.42 ml, 0.0102 mol), 3,4-difluoroaniline (0.446 ml, 4.42 mmol) and HATU (1.55 g, 4.08 mmol) were successively added. The reaction mixture was stirred at room temperature for 16 hours. The volatiles were evaporated and the residue obtained was purified by chromatography on silica gel (heptane-EtOAc 100/0 to 0/100], resulting in compound 187 (0.45 g). An impure fraction was further purified by Preparative HPLC ( Stationary phase: RP XBridge Prep C18 OBD-10 μm, 30x150 mm), Mobile phase: 0.25% solution of NH4HCO3 in water, CH3CN), resulting in more compound 187 (0.048 g)
[000383] Method F; Rt: 1.06 min. m / z: 491.0 (MH) -Exact mass: 492.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 - 1.76 (m, 1 H), 1.94 - 2.05 (m, 1 H), 2.41 (s, 3 H), 3.43 (dd, J = 8.9, 4.5 Hz, 1 H), 3.58 - 3.65 (m, 1 H), 3.68 (dd, J = 8.9, 6.3 Hz, 1 H), 3.71 - 3.78 (m, 1 H), 3.83 - 3.92 (m, 1 H), 7.36 - 7.42 (m, 1 H), 7, 43 - 7.52 (m, 1 H), 7.85 (ddd, J = 12.8, 7.5, 2.4 Hz, 1 H), 8.02 (d, J = 6.8 Hz, 1 H), 8.55 (s, 1 H), 11.09 (s, 1 H) Compound 188

[000384] Compound 187 (0.45 g, 0.912 mmol) was dissolved in MeOH (20 ml) and THF (30 ml). To the resulting solution, triethylamine (0.254 ml, 1.82 mmol) was added and the mixture was stirred with 10% Pd / C (0.2 g) under a hydrogen atmosphere at room temperature. After 3 hours, the catalyst was filtered over dicalite, and washed with MeOH (3x) and THF (1x). The volatiles were removed in vacuo and the residue obtained in hot MeOH (10 ml) and hot H2O (10 ml) was added. The volume was concentrated to ~ 15 ml, and left to stand for 1 hour. The precipitated product was filtered, washed with H2O (3x), and dried at 50 ° C in vacuo, resulting in compound 188 (245 mg) Method F; Rt: 0.93 min. m / z: 413.2 (MH) -Exact mass: 414.1. 19F NMR (377 MHz, DMSO-d6) δ ppm -143.7 - -143.2 (m, 1 F), -137.1 - -136.5 (m, 1 F), - 114.8 (d , J = 7.9 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 - 1.77 (m, 1 H), 1.91 - 2.03 (m, 1 H), 2.39 (s, 3 H), 3.43 (dd, J = 9.0, 4.6 Hz, 1 H), 3.57 - 3.70 (m, 2 H), 3.70 - 3.77, (m, 1 H), 3.78 - 3.86 (m, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.39 - 7.52 (m, 2 H), 7.79 (t , J = 7.8 Hz, 1 H), 7.87 (ddd, J = 12.9, 7.5, 2.1 Hz, 1 H), 8.32 (s l., 1 H), 11 , 00 (s, 1 H). 189

[000385] Compound 189 was prepared similarly as described for compound 188, using 4-fluoro-3-methylaniline instead of 3,4-difluoroaniline. Method F; Rt: 0.94 min. m / z: 409.2 (M-H) -Exact mass: 410.1. 19F NMR (377 MHz, DMSO-d66 (d, J = 7.2) δ ppm -122.40 (dtd, J = 9.3, 4.6, 4.6, 2.1 Hz, 1 F), -114.96 (d, J = 7.2 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 - 1.77 (m, 1 H), 1.92 - 2, 03 (m, 1 H), 2.24 (d, J = 1.5 Hz, 3 H), 2.38 (s, 3 H), 3.43 (dd, J = 8.8, 4.6 Hz, 1 H), 3.58 - 3.64 (m, 1 H), 3.65 - 3.70 (m, 1 H), 3.70 - 3.77 (m, 1 H), 3, 78 - 3.86 (m, 1 H), 7.14 (dd, J = 9.1 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.45 - 7.53 (m, 1 H), 7.63 (dd, J = 7.0, 2.4 Hz, 1 H), 7.77 (dd, J = 7.9 Hz, 1 H), 8, 30 (s l., 1 H), 10.72 (s, 1 H). Differential scanning calorimetry From 30 to 300 ° C to 10 ° C / min:
[000386] Peak at 157.0 ° C Compound 190

[000387] Na2CO3 (1.60 g, 0.0151 mol) was dissolved in water (25 ml). A solution of 3-methyloxetan-3-amine (2.63 g, 0.0302 mol) in THF (20 ml) was added, and the reaction mixture was cooled to 0 ° C in an ice bath. A solution of crude 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (5 g) in THF (30 ml) was added dropwise at 0 ° C. After addition, the reaction mixture was vigorously stirred at 0 ° C for 30 minutes, and at room temperature for 2 hours. The organic volatiles were evaporated, and the remaining ~ 30 ml was washed with Et2O (50 ml). The separated water layer was acidified with 1 N HCl (40 ml), and the product was extracted with 2-MeTHF (2x). The combined organic layers were washed with brine, dried with Na2SO4, filtered, evaporated, and co-evaporated in CH3CN, resulting in 5-bromo-2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl acid ) sulfamoyl] benzoic (3.6 g). To a solution of 5-bromo-2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (0.72 g, 0.00188 mol) in CH3CN (15 mL) under atm of N2 were successively added NEt3 (0.786 ml, 0.00565 mol), 4-fluoro-3-methylaniline (0.313 g, 0.00245 mol), and HATU (0.86 g, 0.00226 mol). The reaction mixture was stirred at room temperature for 20 hours. Additional 4-fluoro-3-methylaniline (0.1 g) and HATU (0.3 g) were added, and the reaction was continued for 20 hours. The volatiles were evaporated. The residue was purified by chromatography on silica gel (heptaeno-EtOAc 100/0 to 0/100). The desired fractions were combined and evaporated. The residue was stirred in diisopropyl ether, filtered, washed with diisopropyl ether (3x), and dried at 50 ° C, resulting in compound 190 (0.38 g). m / z: 486.9 (M-H) -Exact mass: 488.0. 19F NMR (377 MHz, DMSO-d6) δ ppm -122.15 - -121.89 (m, 1 F), -116.05 (d, J = 6.4 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 3 H), 2.25 (d, J = 1.5 Hz, 3 H), 2.40 (s, 3 H), 4 , 22 (d, J = 6.6 Hz, 2 H), 4.62 (d, J = 6.4 Hz, 2 H), 7.16 (dd, J = 9.2 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 7.61 (dd, J = 6.9, 2.3 Hz, 1 H), 8.01 (d, J = 6.8 Hz, 1 H ), 8.86 (s l., 1 H), 10.81 (s, 1 H) Synthesis of 2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid
[000388] A solution of 5-bromo-2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (0.9 g) and triethylamine (0.98 ml, 7, 1 mmol) in MeOH (30 mL) was stirred with 10% Pd / C (0.1 g) at room temperature under a hydrogen atmosphere. After the calculated amount of hydrogen was absorbed, the catalyst was filtered. The filtrate was concentrated in vacuo, and coevaporated with CH3CN. The residue obtained containing 2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid was used as such. Method F; Rt: 0.38 min. m / z: 302.0 (MH) -Exact mass: 303.1 Compound 191

[000389] Triethylamine (0.206 mL, 0.00149 mol) was added to a stirring mixture of 2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (0.15 g , 0.000495 mol) and CH3CN (10 mL) under N2 atm. To the resulting solution, HATU (0.207 g, 0.545 mmol) was added. After stirring for 5 minutes, 5-amino-2-fluorobenzonitrile (79.9 mg, 0.569 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then continued at 50 ° C for 4 hours. The volatiles were evaporated and the residue obtained was dissolved in CH2Cl2 (2.5 mL) and purified by chromatography on silica gel (heptane-EtOAc 100/0 to 0/100) followed by repurification with CH2Cl2-MeOH 100/0 to 98 / 2 as eluent. The desired fractions were combined and evaporated, and coevaporated with EtOAc. The residue was further dried at 50 ° C in vacuo, resulting in compound 191 (63 mg). Method F; Rt: 0.88 min. m / z: 420.1 (M-H) -Exact mass: 421.1. 1H NMR (400 MHz, DMSO-d6) d ppm 1.46 (s, 3 H), 2.40 (s, 3 H), 4.19 (d, J = 6.6 Hz, 2 H), 4 , 62 (d, J = 6.2 Hz, 2 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.58 (t, J = 9.1 Hz, 1 H), 7.80 (t, J = 7.9 Hz, 1 H), 7.96 (ddd, J = 9.1, 4.8, 2.8 Hz, 1 H), 8.22 (dd, J = 5.7, 2.6 Hz, 1 H), 8.64 (s, 1 H), 11.16 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm -115.10 (d, J = 7.9 Hz, 1 F), -113.61 (dt, J = 8.9, 5.2 Hz, 1 F ). Synthesis of 3-chloro-4,5-difluoroaniline
[000390] 3-Chloro-4,5-difluorobenzoic acid (Astatech commercial, 25.5 g, 0.132 mol) was dissolved in tert-butyl alcohol (200 ml) at 50 ° C. Et3N (20.2 mL, 0.146 mol) was added. Diphenylphosphoryl azide (30.0 mL, 0.139 mol) was added slowly, and the reaction mixture was stirred and refluxed for 18 hours. The volatiles were evaporated, and coevaporated with EtOAc. The residue was stirred in Et2O (300 ml) / NaHCO3 Sat. (300 ml) / H2O (50 ml) for 15 minutes. The separated organic layer was dried over MgSO4, filtered, and evaporated. The solid residue was stirred in diisopropyl ether (20 ml), filtered, washed with diisopropyl ether (3x) and dried at 50 ° C, resulting in N- (3-chloro-4,5-difluoro-phenyl) carbamate. tert-butyl (8.5 g). The filtrate was concentrated in vacuo. The residue was stirred in CH2Cl2 (20 mL) + heptanes (20 mL), filtered, washed with 1/2 CH2Cl2-heptane (2x) and heptanes (2x), and dried at 50 ° C in vacuo, resulting in more Tert-butyl N- (3-chloro-4,5-difluoro-phenyl) carbamate (11.8 g). N- (3-chloro-4,5-difluoro-phenyl) tert-butyl carbamate (8.5 g, 0.0322 mol) was added portion by portion to stirring HCl (40 mL, 0.16 mol, 4 M in dioxane). The mixture was stirred at room temperature for 2 hours, then left to stand for 65 hours. Stirring was continued for another 2 hours. The precipitate formed was filtered, washed with dioxane (4x) and dried at 50 ° C in vacuo, resulting in 3-chloro-4,5-difluoroaniline hydrochloride (5.95 g). A mixture of 3-chloro-4,5-difluoroaniline hydrochloride (1 g, 0.005 mol), NaOH (1 M in H2O, 10 ml, 0.01 mol) and toluene (15 ml) was stirred at room temperature for 1 hour. The separated organic layer was dried over MgSO4, filtered, and evaporated. The obtained 3-chloro-4,5-difluoroaniline (0.81 g) was used as such. 192

[000391] Compound 192 was prepared similarly as described for compound 191, using 3-chloro-4,5-difluoroaniline hydrochloride instead of 5-amino-2-fluorobenzonitrile. 19F NMR (377 MHz, DMSO-d6) d ppm -144.93 (s l., 1 F), -134.02 - -133.17 (m, 1 F), -115.09 (d, J = 7.97.3 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H), 2.38 (s, 3 H), 4.18 (d, J = 6.4 Hz, 2 H), 4 , 61 (d, J = 6.2 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.71 - 7.83 (m, 3 H), 8.64 (s l., 1 H), 11.14 (s l., 1 H). Method F; Rt: 1.05 min. m / z: 447.1 (MH) -Exact mass: 448.0. 193

[000392] Oxalyl chloride (12.3 mL, 0.143 mol) was added to a stirring solution of 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (9.5 g) and DMF ( 0.111 ml) in CH2Cl2 (100 ml). After addition, the reaction mixture was stirred at room temperature for 2 hours and 30 minutes. The volatiles were removed in vacuo, and coevaporated with toluene. The residue obtained containing 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoyl chloride was used as such. A solution of 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoyl chloride (1.75 g) in toluene (20 ml) was stirred at reflux under N2 flow. A solution of 3-chloro-4,5-difluoroaniline (0.818 g, 0.005 mol) in toluene (10 ml) was added dropwise. After addition, the reaction mixture was refluxed for 45 minutes, then allowed to reach room temperature, and left to stand for 18 hours. A precipitate (0.51 g) was filtered, washed with toluene (2 x), and dried at 50 ° C in vacuo. (R) -1,1,1-trifluoro-2-propylamine (0.181 g, 0.0016 mol) was dissolved in CH3CN (5 ml) under N2 atm. 5-Bromo-3 - [(3-chloro-4,5-difluoro-phenyl) carbamoyl] -2-fluoro-4-methyl-benzenesulfonyl chloride (0.51 g), then DIPEA (0.461 mL, 0 , 00267 mol). The mixture was stirred in a sealed tube at 80 ° C for 20 hours. The reaction mixture was allowed to reach room temperature, and was left to stand for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 (2 ml), and purified by chromatography on silica gel [heptane-EtOAc 100/0 to 0/100]. Fractions containing the desired compound were combined and evaporated, and coevaporated with EtOH, resulting in 5-bromo-N- (3-chloro-4,5-difluoro-phenyl) -2-fluoro-6-methyl-3 - [[ (1R) -2,2,2-trifluoro-1-methyl-ethyl] sulfamoyl] crude benzamide (0.12 g). To a solution of 5-bromo-N- (3-chloro-4,5-difluoro-phenyl) -2-fluoro-6-methyl-3 - [[(1R) - 2,2,2-trifluoro-1- methyl ethyl] sulfamoyl] benzamide (0.1 g) in EtOH (11 ml) H2O (3.5 ml) was added, then sol. sat. aq. K2CO3 (1.25 mL) and then Tetrakis (triphenylphosphine) palladium (0) (26.1 mg, 0.023 mmol). The mixture was stirred at 150 ° C by microwave irradiation for 45 minutes. The reaction mixture was combined with a similar reaction mixture starting from 20 mg of 5-bromo-N- (3-chloro-4,5-difluoro-phenyl) -2-fluoro-6-methyl-3- [ [(1R) -2,2,2-trifluoro-1-methyl-ethyl] sulfamoyl] benzamide), was allowed to reach room temperature and was left to stand for 15 minutes. The upper layer was isolated by means of a separating funnel, and evaporated. The residue obtained was purified by chromatography on silica gel (heptane-EtOAc 100/0 to 0/100, also CH2Cl2-MeOH 100/0 to 98/2), followed by separation by preparative HPLC (Stationary phase: RP Vydac Denali C18 - 10 μm, 200 g, 5 cm), Mobile phase: 0.25% solution of NH4HCO3 in water, CH3CN), resulting in compound 193 (11.4 mg) Method F; Rt: 1.17 min. m / z: 473.0 (MH) -Exact mass: 474.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J = 6.8 Hz, 3 H), 2.38 (s, 3 H), 4.00-4.15 (m, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.71 - 7.78 (m, 2 H), 7.82 (t, J = 7.8 Hz, 1 H) , 9.00 (br.s, 1 H), 11.13 (br, 1 H). 19F NMR (377 MHz, DMSO-d6) d ppm -145.3 to -144.5 (m, 1 F), -134.4 to -132.8 (m, 1 F), -114.9 (s l., 1 F), -76.0 (d, J = 7.2 Hz, 3 F). 194

[000393] 2-Fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid (0.15 g, 0.473 mmol) was dissolved in DMF (5 mL) and triethylamine (0.2 mL) and HATU (233 mg, 0.61 mmol) were added to the reaction mixture. The reaction mixture was stirred for 10 minutes and 3,4-difluoroaniline (123 mg, 0.945 mmol) was added. The reaction mixture was stirred at room temperature for 42 hours. The reaction mixture was poured into ice water (50 ml). The mixture was extracted with Me-THF (3 x 20 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using silica gel column chromatography (0 to 100% ethyl acetate in heptane and 0 to 2% methanol in dichloromethane) to give compound 194 (79 mg) as a white powder that was dried on vacuum oven overnight.
[000394] Method F; Rt: 0.94 min. m / z: 413.2 (MH) -Exact mass: 414.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H), 2.39 (s, 3 H), 4.18 (d, J = 6.6 Hz, 2 H), 4 , 62 (d, J = 6.2 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.39 - 7.51 (m, 2 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.87 (ddd, J = 12.9, 7.4, 2.0 Hz, 1 H), 8.64 (s l., 1 H) , 11.00 (s, 1 H) Compound 195

[000395] Compound 195 (98 mg) was prepared similarly as described for compound 194, using 3-chloro-4-fluoroaniline instead of 3,4-difluoroaniline. Method F; Rt: 0.99 min. m / z: 429.1 (MH -) - Exact mass: 430.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H), 2.39 (s, 3 H), 4.18 (d, J = 6.4 Hz, 2 H), 4 , 62 (d, J = 6.2 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.45 (t, J = 9.0 Hz, 1 H), 7.60 (ddd, J = 9.0, 4.3, 2.5 Hz, 1 H), 7.79 (t, J = 7.9 Hz, 1 H), 8.02 (dd, J = 6.8, 2.6 Hz, 1 H), 8.63 (s l., 1 H), 10.99 (s, 1 H) Compound 196

[000396] Sodium carbonate (2.07 g, 19.48 mmol) was dissolved in distilled water (30 ml). To this was added (S) -3-aminotetrahydrofuran (3.4 g, 38.97 mmol) at once followed by THF (30 ml). The obtained solution was stirred and cooled in an ice bath. 3- (Chlorosulfonyl) -2,6-difluorobenzoic acid (5 g, 19.48 mmol) was dissolved in THF (40 ml) and this was added dropwise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo until only water remained. Water (20 ml) was added and the mixture was acidified with HCl (1 M / aq; 40 ml). This was extracted using Me-THF (3 x 50 ml). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to 2,6-difluoro-3 - [[((S) -tetrahydrofuran-3-yl] sulfamoyl]] benzoic as a yellow powder (5.9 g). Method F, Rt: 0.33 min. m / z: 306.0 (MH) -Exact mass: 307.0. 2,6-Difluoro-3 - [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic acid (1 g, 2.99 mmol) was dissolved in N, N-dimethylformamide (5 ml). HATU (1.42 g, 3.74 mmol) was added followed by diisopropylethylamine (1.55 mL, 8.98 mmol). The resulting mixture was stirred for 30 minutes at room temperature. Then 3,4-difluoroaniline (0.77 g, 5.99 mmol) was added. The resulting mixture was stirred for 24 hours and then poured into water (50 ml) and extracted using Me-THF (3 x 50 ml). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using gradient elution from heptane to EtOAc (100: 0 to 0: 100). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55 ° C for 24 hours giving compound 196. Method F, Rt: 0.92 min. m / z: 417.1 (M-H) -Exact mass: 418.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 - 1.79 (m, 1 H), 1.92 - 2.07 (m, 1 H), 3.43 (dd, J = 9, 0, 4.6 Hz, 1 H), 3.56 - 3.79 (m, 3 H), 3.80 - 3.92 (m, 1 H), 7.32 - 7.43 (m, 1 H), 7.44 - 7.54 (m, 2 H), 7.84 (ddd, J = 12.7, 7.4, 2.5 Hz, 1 H), 8.01 (td, J = 8.6, 6.2 Hz, 1 H), 8.49 (s l., 1 H), 11.21 (s l., 1 H)
[000397] Compounds 197 to 201 were prepared as described for compound 196, using the corresponding aniline instead of 3,4-difluoroaniline. 197

[000398] 4-Fluoro-3-methylaniline was used as aniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 - 1.76 (m, 1 H), 1.91 - 2.05 (m, 1 H), 2.25 (d, J = 1, 8 Hz, 3 H), 3.42 (dd, J = 8.9, 4.7 Hz, 1 H), 3.56 - 3.78 (m, 3 H), 3.79 - 3.88 ( m, 1 H), 7.16 (t, J = 9.1 Hz, 1 H), 7.41 - 7.51 (m, 2 H), 7.60 (dd, J = 7.0, 2 , 2 Hz, 1 H), 7.97 (td, J = 8.6, 6.2 Hz, 1 H), 8.49 (ls, 1 H), 10.93 (s, 1 H). Method F, Rt: 0.93 min. m / z: 413.2 (MH) -Exact mass: 414.1 Compound 198

[000399] 3-Bromo-3-fluoroaniline was used as aniline. Method G, Rt: 1.74 min. m / z: 478.8 (MH) -Exact mass: 480.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 - 1.77 (m, 1 H), 1.93 - 2.05 (m, 1 H), 3.43 (dd, J = 9, 0, 4.6 Hz, 1 H), 3.57 - 3.78 (m, 3 H), 3.80 - 3.89 (m, 1 H), 7.43 (t, J = 8.7 Hz, 1 H), 7.49 (m, J = 8.7, 8.7 Hz, 1 H), 7.61 (ddd, J = 9.0, 4.4, 2.6 Hz, 1 H ), 8.00 (td, J = 8.6, 6.2 Hz, 1 H), 8.11 (dd, J = 6.3, 2.5 Hz, 1 H), 8.49 (s l ., 1 H), 11.19 (br s, 1 H) Compound 199

[000400] 5-Amino-3-fluorobenzonitrile was used as aniline
[000401] Method G, Rt: 1.56 min. m / z: 423.9 (MH) -Exact mass: 425.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 1 H), 1.94 - 2.06 (m, 1 H), 3.43 (dd, J = 9, 0, 4.6 Hz, 1 H), 3.57 - 3.78 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.49 (t, J = 8.5 Hz, 1 H), 7.59 (t, J = 9.1 Hz, 1 H), 7.94 (ddd, J = 9.2, 4.8, 2.6 Hz, 1 H), 8, 02 (td, J = 8.6, 6.2 Hz, 1 H), 8.19 (dd, J = 5.7, 2.9 Hz, 1 H), 8.50 (s l., 1 H ), 11.37 (s l., 1 H). 200

[000402] 4-Fluoro-3- (trifluoromethyl) aniline was used as aniline
[000403] Method F, Rt: 1.02 min. m / z: 467.1 (MH) -Exact mass: 468.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (ddt, J = 12.6, 7.2, 5.6, 5.6 Hz, 1 H), 1.93 - 2.08 (m , 1 H), 3.43 (dd, J = 9.0, 4.6 Hz, 1 H), 3.58 - 3.79 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.49 (t, J = 8.4 Hz, 1 H), 7.58 (t, J = 9.7 Hz, 1 H), 7.93 (s, 1 H), 8, 02 (td, J = 8.6, 6.2 Hz, 1 H), 8.16 (dd, J = 6.4, 2.6 Hz, 1 H), 8.50 (s l., 1 H ), 11.35 (s l., 1 H) Compound 201

[000404] 3-Chloro-3-fluoroaniline was used as aniline.
[000405] Method F, Rt: 0.97 min. m / z: 433.1 (M-H) -Exact mass: 434.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (ddt, J = 12.5, 7.2, 5.6, 5.6 Hz, 1 H), 1.92 - 2.12 (m , 1 H), 3.43 (dd, J = 8.8, 4.6 Hz, 1 H), 3.55 - 3.79 (m, 3 H), 3.80 - 3.91 (m, 1 H), 7.35 - 7.52 (m, 2 H), 7.53 - 7.67 (m, 1 H), 7.90 - 8.12 (m, 2 H), 8.49 ( s l., 1 H), 11.20 (s l., 1 H)
[000406] Compounds 202 and 203 were prepared similarly as described for compound 196, using isopropyl amine instead of (S) -3-aminotetrahydrofuran, and for compound 203, using 3- (trifluoromethyl) aniline instead 3,4-difluoroaniline. 202

[000407] Method G, Rt: 1.80 min. m / z: 388.9 (M-H) -Exact mass: 390.1.
[000408] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J = 6.6 Hz, 8 H), 3.34 - 3.46 (m, 1 H), 7.36 - 7.53 (m, 3 H), 7.84 (ddd, J = 12.7, 7.4, 2.5 Hz, 1 H), 8.00 (td, J = 8.6, 6.2 Hz, 1 H), 8.09 (s l., 1 H), 11.20 (s l., 1 H) Compound 203

[000409] Method G, Rt: 1.82 min. m / z: 421.1 (MH) -Exact mass: 422.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J = 6.6 Hz, 6 H), 3.34 - 3.46 (m, 1 H), 7.47 (t, J = 8.6 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 8.01 (td, J = 8.6, 6.2 Hz, 1 H), 8.11 (d, J = 7.5 Hz, 1 H), 8 , 15 (s, 1 H), 11.32 (s, 1 H). Compound 204

[000410] Compound 204 (0.19 g) was prepared starting from compound 190 (0.34 g), similarly as described for the conversion of compound 187 to compound 188. Compound 204 was crystallized from Et2O, filtered, washed with 3x Et 2 O, and dried at 50 ° C in vacuo.
[000411] Method F; Rt: 0.94 min. m / z: 409.1 (MH) -Exact mass: 410.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 3 H), 2.24 (d, J = 1.8 Hz, 3 H), 2.38 (s, 3 H), 4 , 18 (d, J = 6.6 Hz, 2 H), 4.62 (d, J = 6.2 Hz, 2 H), 7.14 (dd, J = 9.1 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 7.45 - 7.53 (m, 1 H), 7.63 (dd, J = 7.0, 2.2 Hz, 1 H ), 7.77 (t, J = 7.9 Hz, 1 H), 8.61 (s l., 1 H), 10.72 (s, 1 H). Compound 205

[000412] 3- (tert-butylsulfamoyl) -2-fluoro-6-methyl-benzoic acid was prepared similarly as described for 2-fluoro-6-methyl-3- [(3-methyloxetan-3-yl) acid sulfamoyl] benzoic, using tert-butylamine instead of 3-methyloxetan-3-amine. Compound 205 was prepared similarly as described for compound 194, using 4-fluoro-3-methylaniline instead of 3,4-difluoroaniline and starting from 3- (tert-butylsulfamoyl) -2-fluoro-6-methyl acid -benzoic instead of 2-fluoro-6-methyl-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid. Method F; Rt: 1.08 min. m / z: 395.2 (MH) -Exact mass: 396.1.1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 9 H), 2.24 (d, J = 1.8 Hz, 3 H), 2.37 (s, 3 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 1 H), 7.50 (ddd, J = 9.0, 4.7, 2.3 Hz, 1 H), 7.64 (dd, J = 6.9, 2.3 Hz, 1 H), 7.73 - 7.84 (m, 2 H), 10.70 (bs, 1 H). Compound 206

[000413] Compound 206 was prepared similarly as described for compound 194, starting from 3- (tert-butylsulfamoyl) -2-fluoro-6-methyl-benzoic acid instead of 2-fluoro-6-methyl- 3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic. Method F; Rt: 1.08 min. m / z: 399.1 (M-H) -Exact mass: 400.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 9 H), 2.31 (s, 3 H), 7.32 (d, J = 8.1 Hz, 1 H), 7 , 40 - 7.51 (m, 2 H), 7.76 - 7.82 (m, 2 H), 7.88 (ddd, J = 13.0, 7.5, 2.4 Hz, 1 H ), 10.97 (s l., 1 H) Synthesis of 6-chloro-2-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic and 2-chloro-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid
[000414] 2-Chloro-6-fluorobenzoic acid (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100 ° C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice water (1 liter). This was then extracted using dichloromethane (2 x 500 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo giving an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3-chlorosulfonyl-2-fluoro-benzoic acid (3.1 grams) as a slightly yellow powder that was used as such. Method F, Rt: 0.47 min and 0.49 min. m / z: 270.9 (M-H) - Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 ml). The obtained solution was stirred and cooled in an ice bath. An isometric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3-chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 ml) and it was added dropwise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo until only water remained.
[000415] Then water (20 ml) was added and the mixture was acidified with HCl (46 ml; 1 M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified, and the isomers were separated using preparative HPLC (Stationary phase: Uptisphere C18 ODB - 10 μm, 200 g, 5 cm), Mobile phase: 0.25% solution of NH4HCO3 in water, MeOH), giving acid 6-chloro-2-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic as a white powder. Method G, Rt: 0.40 min. m / z: 322.0 (M-H) -Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d) ppm 1.42 (s, 3 H), 4.15 (d, J = 6.6 Hz, 2 H), 4.61 (d, J = 5.9 Hz , 13 H), 7.29 (dd, J = 8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid as a white powder. Method G, Rt: 0.34 min. m / z: 321.9 (M-H) -Exact mass: 323.0
[000416] Compounds 207 to 210 were prepared similarly as described for compound 196 using 6-chloro-2-fluoro-3- [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid instead of 2,6- difluoro-3- [[((3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic and the corresponding aniline instead of 3,4-difluoroaniline. Compound 207

[000417] Using 5-amino-2-fluorobenzonitrile as aniline. Method F, Rt: 0.92 min. m / z: 440.0 (MH) -Exact mass: 441.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 2 H), 4.21 (d, J = 6.4 Hz, 2 H), 4.61 (d, J = 6.2 Hz, 2 H), 7.59 (t, J = 9.1 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.89 - 7.99 (m, 2 H), 8.18 (dd, J = 5.6, 2.8 Hz, 1 H), 8.93 (ls, 1 H), 11.37 (s l., 1 H) Compound 208

[000418] Using 4-fluoro-3- (trifluoromethyl) aniline as aniline. Method F, Rt: 1.06 min. m / z: 483 (MH) -Exact mass: 484.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 2 H), 4.20 (d, J = 6.2 Hz, 2 H), 4.61 (d, J = 6.2 Hz, 2 H), 7.58 (t, J = 9.9 Hz, 1 H), 7.66 (d, J = 8.6 Hz, 1 H), 7.94 (m, J = 8, 1, 8.1 Hz, 2 H), 8.07 - 8.25 (m, 1 H), 8.91 (ls, 1 H), 11.34 (s l., 1 H) Compound 209

[000419] Using 3,4-difluoro-5-methyl-aniline as aniline. Method F, Rt: 1.03 min. m / z: 447.1 (MH) -Exact mass: 448.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H), 2.30 (d, J = 2.0 Hz, 3 H), 4.20 (d, J = 6.4 Hz, 2 H), 4.61 (d, J = 6.2 Hz, 2 H), 7.32 (m, J = 5.9 Hz, 1 H), 7.54 - 7.69 (m, 2 H), 7.91 (t, J = 8.3 Hz, 1 H), 8.92 (ls, 1 H), 11.09 (ls, 1 H) Compound 210

[000420] Using 3-chloro-4,5-difluoroaniline hydrochloride as aniline. Method F, Rt: 1.07 min. m / z: 467.0 (MH) -Exact mass: 468.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.60 (d, J = 6.2 Hz, 2 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.67 - 7.79 (m, 2 H), 7.93 (t, J = 8.1 Hz, 1 H), 9.08 (bs, 1 H), 11.34 (s l., 1 H) Compound 211

[000421] Compound 211 was prepared similarly as described for compound 196 using 2-chloro-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid instead of 2,6-difluoro- 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic. Method F, Rt: 0.94 min. m / z: 433.1 (M-H) -Exact mass: 434.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.62 (d, J = 6.4 Hz, 2 H), 7.30 - 7.43 (m, 1 H), 7.43 - 7.54 (m, 1 H), 7.61 (t, J = 8.6 Hz, 1 H) , 7.84 (ddd, J = 12.7, 7.4, 2.3 Hz, 1 H), 8.17 (dd, J = 9.0, 5.9 Hz, 1 H), 8.75 (ls, 1 H), 11.18 (ls, 1 H).
[000422] 2-Bromo-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid and 6-bromo-2-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl acid ] benzoic acid were prepared similarly as described for 2-chloro-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid and 6-chloro-2-fluoro-3 - [(3-methyloxetan- 3-yl) sulfamoyl] benzoic, starting from 2-bromo-6-fluorobenzoic acid instead of 2-chloro-6-fluorobenzoic acid. 212

[000423] Compound 212 was prepared similarly as described for compound 196 using 2-bromo-6-fluoro-3 - [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid instead of 2,6-difluoro- 3 - [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic and 4-fluoro-3- (trifluoromethyl) aniline instead of 3,4-difluoroaniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (s, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.64 (d, J = 6.2 Hz, 2 H), 7.57 (t, J = 9.7 Hz, 1 H), 7.65 (t, J = 8.6 Hz, 1 H), 7.93 (dt, J = 8, 4, 3.7 Hz, 1 H), 8.08 - 8.31 (m, 2 H), 8.70 (s l., 1 H), 11.29 (s l., 1 H).
[000424] Compounds 213 to 216 were prepared similarly as described for compound 196 using 6-bromo-2-fluoro-3- [(3-methyloxetan-3-yl) sulfamoyl] benzoic acid instead of 2,6- difluoro-3- [[(3S) -tetrahydrofuran-3-yl] sulfamoyl] benzoic to corresponding aniline instead of 3,4-difluoroaniline. 213

[000425] Using 4-fluoro-5-methylaniline as aniline. Method F, Rt: 0.99 min. m / z: 473.0 (MH) -Exact mass: 474.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 3 H), 2.25 (d, J = 1.5 Hz, 3 H), 4.20 (d, J = 6.4 Hz, 2 H), 4.62 (d, J = 6.2 Hz, 2 H), 7.16 (t, J = 9.1 Hz, 1 H), 7.42 - 7.52 (m, 1 H), 7.60 (dd, J = 7.0, 2.4 Hz, 1 H), 7.68 - 7.93 (m, 2 H), 8.65 (ls, 1 H), 10 , 82 (bs, 1 H). 214

[000426] Using 5-amino-2-fluorobenzonitrile as aniline. Method F, Rt: 0.92 min. m / z: 484.0 (MH) -Exact mass: 485.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 - 1.55 (m, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.61 (d, J = 6.4 Hz, 2 H), 7.59 (t, J = 9.1 Hz, 1 H), 7.77 - 7.89 (m, 2 H), 7.95 (ddd, J = 9 , 2, 4.8, 2.8 Hz, 1 H), 8.18 (dd, J = 5.7, 2.6 Hz, 1 H), 8.90 (ls, 1 H), 11.34 (s l., 1 H). 215

[000427] Using 4-fluoro-3- (trifluoromethyl) aniline as aniline. Method F, Rt: 1.07 min. m / z: 527.0 (MH) -Exact mass: 528.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.61 (d, J = 6.2 Hz, 2 H), 7.58 (t, J = 9.8 Hz, 1 H), 7.74 - 7.89 (m, 2 H), 7.90 - 7.98 (m, 1 H) , 8.16 (dd, J = 6.3, 2.5 Hz, 1 H), 8.84 (ls, 1 H), 11.31 (s l., 1 H). 216

[000428] Using 3,4-difluoro-5-methyl-aniline as aniline. Method F, Rt: 1.03 min. m / z: 491.0 (MH) -Exact mass: 492.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 3 H), 2.30 (d, J = 1.8 Hz, 3 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.61 (d, J = 6.4 Hz, 2 H), 7.32 (m, J = 5.7 Hz, 1 H), 7.61 (ddd, J = 12, 3, 6.9, 2.6 Hz, 1 H), 7.72 - 7.89 (m, 2 H), 8.86 (s l., 1 H), 11.07 (s, 1 H) . 217

[000429] A solution of 3- (difluoromethyl) -4-fluoroaniline (1.02 mL, 8.58 mmol) in dry toluene (10 mL) was added dropwise (over 15 min) to a solution at reflux of 5-chloro-3-chlorosulfonyl-2-fluoro-benzoyl chloride (2500 mg, 8.576 mmol) in dry toluene (100 mL). After the addition, the reaction mixture was allowed to stir at reflux for 1 h. The reaction mixture was allowed to cool to room temperature under a nitrogen atmosphere while stirring. The brown solution containing 5-chloro-3 - [[3- (difluoromethyl) -4-fluoro-phenyl] carbamoyl] -2-fluoro-benzenesulfonyl chloride was used without further purification. 3-Methyl-3-oxetanamine (580 mg, 6.66 mmol) was added dropwise to the above solution at room temperature. Et3N (2.10 mL, 15.14 mmol) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was evaporated and the residue was taken up in EtOAc. HCl (0.5 N, 30 ml) was added to the reaction mixture and the layers were separated. The organic layer was washed again with Na-OH (0.5 N, 30 ml).
[000430] The organic layer was dried over MgSO4 and evaporated. The obtained residue was purified by silica gel column chromatography (eluent: CH2Cl2: MeOH 100: 0 -> 95: 5), resulting in compound 217 (1.8 g). 1H NMR (360 MHz, DMSO-d6) δ ppm 1.45 (s, 3 H) 4.23 (d, J = 6.2 Hz, 2 H) 4.63 (d, J = 6.2 Hz, 2 H) 7.27 (t, J = 54.3 Hz, 1 H) 7.43 (t, J = 9.7 Hz, 1 H) 7.83 (dt, J = 8.1, 4.0 Hz, 1 H) 7.95 (dd, J = 5.9, 2.6 Hz, 1 H) 8.04 (dd, J = 6.0, 2.4 Hz, 1 H) 8.13 (dd , J = 5.3, 2.7 Hz, 1 H) 8.98 (s, 1 H) 10.98 (s, 1 H)
[000431] Method F, Rt: 1.03 min. m / z: 465.1 (MH) -Exact mass: 466.0. 218

[000432] Pd / C (10%) (716 mg) was suspended in a solution of compound 217 (345 mg, 0.673 mmol) and Et3N (0.467 mL) in MeOH (100 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature under a hydrogen atmosphere until an equivalent of hydrogen was absorbed. The reaction mixture was filtered over decalite and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CH2Cl2: MeOH 100: 0 -> 95: 5) resulting in compound 218 (206 mg) as a white solid, dried in vacuo at 50 ° C.
[000433] 1H NMR (360 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H) 4.19 (d, J = 6.6 Hz, 2 H) 4.63 (d, J = 6, 2 Hz, 2 H) 7.26 (t, J = 54.3 Hz, 1 H) 7.42 (t, J = 9.5 Hz, 1 H) 7.52 (t, J = 7.7 Hz , 1 H) 7.86 (dd, J = 8.1, 3.7 Hz, 1 H) 7.93 - 8.01 (m, 2 H) 8.06 (dd, J = 6.4, 2 , 4 Hz, 1 H) 8.77 (s, 1 H) 10.92 (s, 1 H). Method F, Rt: 0.92 min. m / z: 431.1 (MH) -Exact mass: 432.1. 219

[000434] Compound 219 (828 mg) was prepared similarly as described for compounds 217 and 218. Using 4-fluoro-3- (trifluoromethyl) aniline instead of 3- (difluoromethyl) -4-fluoro-aniline. Method F, Rt: 1.00 min. m / z: 449.1 (M-H) -Exact mass: 450.1.
[000435] 1H NMR (360 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H) 4.19 (d, J = 5.9 Hz, 2 H) 4.62 (d, J = 6, 2 Hz, 2 H) 7.53 (t, J = 7.9 Hz, 1 H) 7.57 (t, J = 9.9 Hz, 1 H) 7.94 - 8.02 (m, 3 H ) 8.20 (dd, J = 6.4, 2.7 Hz, 1 H) 8.78 (s, 1 H) 11.02 (s, 1 H). 220

[000436] Compound 220 was prepared similarly as described for compounds 217 and 218, using (S) -3-aminotetrahydrofuran instead of 3-methyl-3-oxetanamine. Method F, Rt: 0.90 min. m / z: 431.1 (MH) -Exact mass: 432.1. 1H NMR (360 MHz, DMSO-d6) δ ppm 1.66 - 1.77 (m, 1 H) 1.91 - 2.03 (m, 1 H) 3.43 (dd, J = 8.8, 4.8 Hz, 1 H) 3.57 - 3.70 (m, 2 H) 3.70 - 3.78 (m, 1 H) 3.79 - 3.90 (m, 1 H) 7.26 (t, J = 54.2 Hz, 1 H) 7.42 (t, J = 9.5 Hz, 1 H) 7.53 (t, J = 7.7 Hz, 1 H) 7.81 - 7 .88 (m, 1 H) 7.94 - 8.00 (m, 2 H) 8.07 (dd, J = 6.4, 2.4 Hz, 1 H) 8.45 (d, J = 6 , 6 Hz, 1 H) 10.92 (s, 1 H). 221

[000437] Compound 221 was prepared similarly as described for compounds 217 and 218, using 2-methylpropan-2-amine instead of 3-methyl-3-oxetanamine, and 4-fluoro-3-methyl-aniline instead 3- (difluoromethyl) -4-fluoroaniline Method F, Rt: 1.06 min. m / z: 381.2 (MH) -Exact mass: 382.1. 1 H NMR (360 MHz, DMSO-d6) δ ppm 1.15 (s, 9 H) 2.24 (d, J = 1.5 Hz, 3 H) 7.15 (t, J = 9.1 Hz , 1 H) 7.47 (t, J = 7.7 Hz, 1 H) 7.43 - 7.55 (m, 1 H) 7.65 (dd, J = 7.0, 2.6 Hz, 1 H) 7.87 (ddd, J = 7.8, 6.1, 1.8 Hz, 1 H) 7.93 (s, 1 H) 7.90 - 7.99 (m, 1 H) 10 , 63 (s, 1 H). 243

[000438] Compound 243 was prepared similarly as described for compounds 217 and 218, using tert-butylamine instead of 3-methyl-3-oxetanamine. Method G, Rt: 1.76 min. m / z: 417.1 (MH) -But exact sa: 418.1. 1H NMR (360 MHz, DMSO-d6) δ ppm 1.15 (s, 9 H) 7.41 (t, J = 9.7 Hz, 1 H) 7.26 (t, J = 54.5 Hz, 1 H) 7.49 (t, J = 7.7 Hz, 1 H) 7.85 (ddd, J = 8.6, 4.4, 3.1 Hz, 1 H) 7.88 - 8.01 (m, 3 H) 8.08 (dd, J = 6.2, 2.6 Hz, 1 H) 10.90 (s, 1 H). 222

[000439] Compound 222 was prepared similarly as described for compound 221, using 3-methyl-3-oxetanamine instead of 2-methylpropan-2-amine. Method F, Rt: 0.91 min. m / z: 395.1 (MH) -Exact mass: 396.1. 1H NMR (360 MHz, DMSO-d6) δ ppm 1.44 (s, 3 H) 2.24 (d, J = 1.5 Hz, 3 H) 4.19 (d, J = 6.6 Hz, 2 H) 4.62 (d, J = 6.2 Hz, 2 H) 7.15 (t, J = 9.3 Hz, 1 H) 7.46 - 7.55 (m, 2 H) 7, 63 (dd, J = 7.0, 2.6 Hz, 1 H) 7.88 - 7.99 (m, 2 H) 8.75 (s, 1 H) 10.65 (s, 1 H). 223

[000440] 3-Methyloxolan-3-amine hydrochloride (165.9 mg, 1.21 mmol) was added to a solution of 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl (499 mg, 1.096 mmol) in dry CH2Cl2 (20 mL) at room temperature. Et3N (381 μL) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (250 ml). 0.5 N HCl (50 ml) was added and the layers were separated. The organic layer was washed again with 0.5 N NaOH (30 ml). The organic layer was dried over MgSO4 and evaporated. The residue obtained was purified by silica gel column chromatography (CH2Cl2: MeOH 100: 0 -> 95: 5) and by preparative HPLC separation (Stationary phase: RP XBridge Prep C18 OBD-10 μm, 30x150 mm), Phase mobile: 0.25% solution of NH4HCO3 in water, MeOH) resulting in compound 223 (257 mg) as a white solid after drying in vacuo at 50 ° C. Method F, Rt: 0.93 min. m / z: 391.2 (MH) -Exact mass: 392.1.1H NMR (360 MHz, DMSO-d6) ppm 1.17 (s, 3 H) 1.72 (dt, J = 12.8, 7 , 7 Hz, 1 H) 2.14 (ddd, J = 12.8, 7.1, 6.0 Hz, 1 H) 2.25 (d, J = 1.8 Hz, 3 H) 3.30 -3.40 (m, 1 H) 3.61 - 3.77 (m, 3 H) 7.15 (t, J = 9.3 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.69 (dd, J = 7.0, 2.2 Hz, 1 H) 7.75 (t, J = 7.9 Hz, 1 H) 8.04 (d, J = 8.0 Hz , 1 H) 8.10 (s l., 1 H) 8.18 (dt, J = 7.7, 1.3 Hz, 1 H) 8.39 (t, J = 1.6 Hz, 1 H ) 10.49 (br.s, 1 H). 225

[000441] 3 - [(4-fluoro-3-methyl-phenyl) carbamoyl] benzenesulfonyl chloride (0.5 g, 1.53 mmol) and (R) -1,1,1-trifluoro-2-propylamine ( 0.38 g, 3.36 mmol) were dissolved in dichloromethane (10 mL). Then diisopropylethylamine (0.66 ml, 3.81 mmol) was added and the resulting mixture was stirred for two hours. Then 1 M HCl (5 ml) was added and the organic layer was separated, loaded onto silica and subjected to silica gel column chromatography using heptane and EtOAc elution gradient (100: 0 to 0: 100). The desired fractions were concentrated in vacuo and dried in a vacuum oven at 55 ° C for 24 hours compound 225 (233 mg) as a white powder. Method F, Rt: 1.05 min. m / z: 403.1 (MH) -Exact mass: 404.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J = 6.8 Hz, 3 H), 2.25 (d, J = 1.8 Hz, 3 H), 4.06 - 4.22 (m, 1 H), 7.15 (t, J = 9.2 Hz, 1 H), 7.51 - 7.63 (m, 1 H), 7.67 (dd, J = 7 , 2, 2.3 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 8.00 - 8.10 (m, 1 H), 8.16 - 8.28 (m, 1 H), 8.40 (t, J = 1.7 Hz, 1 H), 8.66 (s l., 1 H), 10.46 (s, 1 H). 226

[000442] Compound 226 (416 mg) was prepared as described for compound 225, using (S) -1,1,1-trifluoro-2-propylamine instead of (R) -1,1,1-trifluoro- 2-propylamine. Method F, Rt: 1.05 min. m / z: 403.1 (MH) -Exact mass: 404.1. 227

[000443] Compound 227 (444 mg) was prepared similarly as described in the synthetic procedure S3 (using 2,2-difluoroethylamine as amine), processing W4. Method F, Rt: 0.93 min. m / z: 371.1 (MH) -Exact mass: 372.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 3.26 (td, J = 15.8, 3.7 Hz, 2 H), 6.00 (tt, J = 55.2, 3.5 Hz, 1 H), 7.14 (t, J = 9.0 Hz, 1 H), 7.52 - 7.62 (m, 1 H ), 7.63 - 7.70 (m, 1 H), 7.77 (t, J = 7.9 Hz, 1 H), 7.96 - 8.06 (m, 1 H), 8.14 - 8.25 (m, 1 H), 8.30-8.45 (m, 2 H), 10.46 (s, 1 H) Compound 228

[000444] Compound 228 (238 mg) was prepared similarly as described in the synthetic procedure S3 (using 2,2-difluoroethylamine as amine), W4 processing, followed by preparative HPLC (SunFire Prep C18 OBD-10 μm, 30x150 mm). Mobile phase (0.25% NH4HCO3 solution in water, MeOH). Method F, Rt: 0.97 min. m / z: 389.1 (M-H) -Exact mass: 390.1.
[000445] 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J = 1.8 Hz, 3 H), 3.74 (q, J = 9.5 Hz, 2 H), 7 , 15 (t, J = 9.2 Hz, 1 H), 7.48 - 7.62 (m, 1 H), 7.64 - 7.71 (m, 1 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.94 - 8.10 (m, 1 H), 8.20 (m, J = 8.1 Hz, 1 H), 8.37 (t, J = 1.7 Hz, 1 H), 8.49 - 9.15 (bs, 1 H), 10.45 (s, 1 H) Compound 229

[000446] Compound 243 (239 mg) was prepared similarly to the synthetic procedure S2 (using 3,3-difluoro-cyclopentanamine as amine), processing W4. Method F, Rt: 1.03 min. m / z: 411.2 (MH) - Exact mass: 412.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.165 (m, 1 H), 1.81 - 2.04 (m, 3 H), 2.04 - 2.23 (m, 2 H ), 2.25 (s, 3 H), 3.63 - 3.76 (m, 1 H), 7.14 (t, J = 9.1 Hz, 1 H), 7.59 (dt, J = 8.1, 3.9 Hz, 1 H), 7.65 - 7.72 (m, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 8.02 (d , J = 7.9 Hz, 1 H), 8.14 (d, J = 6.8 Hz, 1 H), 8.22 (d, J = 7.7 Hz, 1 H), 8.37 ( s, 1 H), 10.47 (s, 1 H). 230

[000447] 2-Methyl-3-furoic acid (4.2 g, 32.6 mmol) was dissolved in CH2 Cl2 (100 mL) and cooled with an ice bath to -5 ° C. Then chlorosulfonic (10.85 ml, 163.2 mmol) was added dropwise at a rate of 0.250 ml / min. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched on ice and extracted with 2-MeTHF. The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness giving crude 5-chlorosulfonyl-2-methyl-furan-3-carboxylic acid (420 mg) as a brown oil. 5-Chlorosulfonyl-2-methyl-furan-3-carboxylic acid (420 mg) was dissolved in CH2Cl2 (10 ml). Hunig's base (0.64 ml, 3.74 mmol) and isopropylamine (0.478 ml, 5.61 mmol) were added and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was used as such in the next step. The above residue was dissolved in CH2Cl2 (20 mL), 4-fluoro-3-methylaniline (228 mg, 1.82 mmol), HATU (830 mg, 2.18 mmol) and N, N-diisopropylethylamine (0, 94 ml, 5.46 mmol) were added and the reaction mixture was stirred for 30 minutes. The volatiles were removed under reduced pressure and the residue was purified on silica using a gradient of heptane to EtOAc resulting in compound 230 (174 mg) as a white powder. Method F, Rt: 1.00 min. m / z: 353.1 (MH) -Exact mass: 354.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J = 6.4 Hz, 6 H), 2.23 (s, 3 H), 2.64 (s, 3 H), 3 , 35 - 3.43 (m, 1 H), 7.11 (t, J = 9.2 Hz, 1 H), 7.53 (dd, J = 7.9, 4.0 Hz, 1 H) , 7.59 - 7.69 (m, 1 H), 7.72 (s, 1 H), 8.06 (d, J = 5.5 Hz, 1 H), 9.87 (s, 1 H ). 231

[000448] 3-Methyl-3-oxetanamine hydrochloride (302.6 mg, 2.45 mmol) and Hunig's base (1.15 mL, 6.68 mmol) dissolved in CH2Cl2 (2 mL) were added and a solution of methyl 5- (chlorosulfonyl) -2-furoate (Thermo scientific, 500 mg, 2.23 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue obtained was used as such.
[000449] The residue was dissolved in THF (10 ml). LiOH (60.2 mg, 2.514 mmol), dissolved in H2O (1 ml), was added to the reaction mixture, MeOH (1 ml) was added and this was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in water (25 ml). 1 M HCl (2.5 ml) was added and then 2-MeTHF (50 ml) was added. The aqueous layer was removed and the organic layer was washed with brine (50 ml). The organic layer was dried over MgSO4, filtered and evaporated to dryness giving an oil which was used as such in the next step. The oil and HATU (573 mg, 1.51 mmol) were stirred in CH2Cl2 (5 mL) and 4-fluoro-3-methylaniline (157.3 mg, 1.26 mmol) and N, N-diisopropylethylamine (0 , 65 mL, 3.77 mmol) were added. The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was purified on silica using a gradient of heptane to EtOAc followed by preparative HPLC (Stationary phase: RP Vydac Denali C18 - 10 μm, 200 g, 5 cm), Mobile phase: 0 ° solution , 25% NH4HCO3 in water, CH3CN), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again. This fraction was triturated in MeOH (4 ml), filtered and dried in the oven giving compound 231 (305 mg) as a white solid. Method F, Rt: 0.89 min. m / z: 367.1 (M-H) -Exact mass: 368.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3 H), 2.24 (d, J = 1.8 Hz, 3 H), 4.21 (d, J = 6.6 Hz, 2 H), 4.61 (d, J = 6.2 Hz, 2 H), 7.14 (t, J = 9.2 Hz, 1 H), 7.26 (d, J = 3, 7 Hz, 1 H), 7.50 (d, J = 3.7 Hz, 1 H), 7.51 - 7.57 (m, 1 H), 7.60 (dd, J = 7.0, 2.4 Hz, 1 H), 8.92 (s, 1 H), 10.34 (s, 1 H).
[000450] Compounds 232 to 239 were prepared by slowly adding an aniline to a solution refluxing toluene of a derivative of 3-chlorosulfonylbenzoyl, followed by reaction with an amine in the presence of a base such as NEt3 or DIPEA, as described above.

Differential scanning calorimetry From 30 to 300 ° C to 10 ° C / min:
[000451] Compound 232: Peak at 169.6 ° C Optical rotation:
[000452] Compound 236: [α] 20 D = - 5.83 (c 0.67 w / v%, MeOH). Compound 240

[000453] SOCl2 (20.1 ml, 277.2 mmol) was slowly added to water (125 ml) cooled to 5 ° C, maintaining the temperature between 4 and 7 ° C (the addition took about 1.5 hours) .
[000454] The solution was then kept stirring overnight while allowing the temperature to slowly reach room temperature. Copper (II) chloride (76.6 mg, 0.774 mmol) was then added to the solution and cooled to -10 ° C (dry ice / acetone bath) (resulting in solution A). In another flask cooled to 0 ° C, HCl (37% in H2O, 65 mL) was added dropwise to 3-amino-5-fluorobenzoic acid (10 g, 64.46 mmol), keeping the temperature below 20 ° C . This paste was cooled to -10 ° C (dry ice / acetone bath) and a solution of sodium nitrite (4.803 g, 69.62 mmol) in H2O (20 mL) was added very slowly (1 drop) / 5 sec) to the paste, keeping the temperature below -5 ° C.
[000455] After addition, the orange mixture was allowed to warm to -2 ° C for 5 min before cooling back to -15 ° C (solution B). Solution B was then added portion by portion (plastic pipette) to solution A, cooled to -10 ° C. After addition (~ 30 min), the reaction mixture was stirred at 0 ° C for 2 h. The resulting orange solid was filtered and rinsed with water (2 x 25 ml) resulting in 3-chlorosulfonyl-5-fluoro-benzoic acid as an orange solid (dried at 35 ° C in vacuo). Et3N (1.22 mL, 8.8 mmol) was slowly added to a solution of 3-chlorosulfonyl-5-fluoro-benzoic acid (525 mg, 2.2 mmol) in dry CH2 Cl2 (10 mL). Isopropylamine (198 μL, 2.42 mmol) was then added dropwise at room temperature to the reaction mixture. The reaction mixture was stirred at room temperature for 30 min. The brown reaction mixture was diluted with CH2Cl2 and water. 1 N HCl was added until pH 2. The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The organic layer was dried over MgSO4, filtered, and evaporated resulting in 3-fluoro-5- (isopropylsulfamoyl) benzoic acid as an orange solid, which was used without further purification. HATU (356.7 mg, 0.94 mmol) was added to a solution of crude 3-fluoro-5- (isopropylsulfamoyl) benzoic acid (190 mg), 4-fluoro-3-methylaniline (78.3 mg, 0.625 mmol) and N, N-diisopropylethylamine (326.8 μL, 1.88 mmol) in CH2 Cl2 (30 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2, washed with 0.5 N HCl, filtered on Extrelut NT3 and evaporated. The obtained residue was purified by column chromatography on silica gel (Grave Resolv 12 g, eluent: CH2Cl2: MeOH 100: 0 -> 95: 5) resulting in compound 240 (136 mg) as a white solid, dried at 50 ° C in vacuo.
[000456] Method G, Rt: 1.87 min. m / z: 366.9 (MH) -Exact mass: 368.1.1H NMR (360 MHz, DMSO-d6) δppm 0.97 (d, J = 6.2 Hz, 6 H) 2.25 (d, J = 1.5 Hz, 3 H) 3.30-3.39 (m, 1H), 7.16 (t, J = 9.3 Hz, 1 H) 7.55 - 7.62 (m, 1 H) 7.67 (dd, J = 7.1, 2.4 Hz, 1H) 7.83 (dt, J = 8.0, 1.9 Hz, 1 H) 7.88 (d, J = 7 , 0 Hz, 1 H) 8.08 (dt, J = 9.3, 1.7 Hz, 1 H) 8.22 (s, 1 H) 10.52 (s, 1 H). Compound 241

[000457] Compound 241 was prepared similarly as described for compound 240 using (S) -3-aminotetrahydrofuran tosylate instead of isopropylamine. Method G, Rt: 1.70 min. m / z: 394.9 (MH) - Exact mass: 396.1. 1H NMR (360 MHz, DMSO-d6) d ppm 1.55 - 1.67 (m, 1 H) 1.93 (dq, J = 12.8, 7.4 Hz, 1 H) 2.25 (d , J = 1.8 Hz, 3 H) 3.37 (dd, J = 9.0, 4.2 Hz, 1 H) 3.55 - 3.75 (m, 3 H) 3.75 - 3, 85 (m, 1 H) 7.16 (t, J = 9.1 Hz, 1 H) 7.56 - 7.62 (m, 1 H) 7.67 (dd, J = 7.3, 2, 6 Hz, 1 H) 7.82 - 7.88 (m, 1 H) 8.08 - 8.13 (m, 1 H) 8.20 - 8.25 (m, 2 H) 10.53 (s , 1 H). Compound 242

[000458] Compound 237 (400 mg, 0.87 mmol) was dissolved in a mixture of DMF (2.5 mL) and N-methylpyrrolidine (0.12 mL) containing Copper (I) Iodide (45.43 mg , 0.24 mmol) and 2,2-difluoro-2-fluorosulfonyl acid methyl ester (0.21 g, 1.09 mmol).
[000459] The resulting mixture was stirred at room temperature for 2 hours. An extra amount of 2,2-difluoro-2-fluorosulfonyl acid methyl ester (0.21 g, 1.09 mmol) was added and the mixture was stirred at 60 ° C for 1 hour. The mixture was stirred at 60 ° C for 18 hours. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture. This was then extracted using EtOAc (3 x 15 ml). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified using silica gel column chromatography (elution gradient: 0 to 100% ethyl acetate: heptane). All desired fractions were combined and concentrated under reduced pressure and then dried at 50 ° C in a vacuum oven overnight to give compound 242 (314 mg) as a white powder. Method G, Rt: 1.73 min. m / z: 445.0 (M-H) - Exact mass: 446.1. Biological Examples - anti-HBV activity of compounds of Formula (I)
[000460] Anti-HBV activity was measured using a stable transfected cell line, HepG2.2.15. This cell line has been reported to secrete relatively consistent high levels of HBV virion particles, which have been shown to cause acute and chronic infection and disease in chimpanzees.
[000461] For the antiviral, the test cells were treated twice for three days with compound serially diluted in duplicate 96-well plates. After 6 days of treatment, antiviral activity was determined by quantifying HBV DNA purified from secreted virions using real-time PCR and a set of HBV-specific primers and probes.
[000462] The cytotoxicity of the compounds was tested in HepG2 cells using CellTiter-Blue, with the same incubation period and dose range as in the HepG2.2.15 assay.
[000463] Anti-HBV activity was also measured using the HepG2.117 cell line, a cell line producing inducibly stable HBV that replicates HBV in the absence of doxycycline (Tet-off system). For the antiviral assay, HBV replication was induced, followed by treatment with compound diluted in series in duplicate 96-well plates. After 3 days of treatment, antiviral activity was determined by quantifying intracellular HBV DNA using real-time PCR and a set of HBV-specific primers and probe.
[000464] The cytotoxicity of the compounds was tested using HepG2 cells, incubated for 4 days in the presence of compounds. Cell viability was assessed using a Resazurin assay. The results are shown in Table 1. Table 1.

权利要求:
Claims (10)
[0001]
1. Compound, characterized by the fact that it presents Formula (Ia)
[0002]
2. Compound according to claim 1, characterized by the fact that R2 represents a saturated carbocyclic ring of 3-7 members, containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, being such a ring 3-7 membered saturated carbocyclic substituted by one or more substituents, each independently selected from the group consisting of halo, C1-C4oxy alkyl, C (= O) - C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2 , CF2H and CF3; or R1 R2, together with the Nitrogen to which they are attached, form a 5-7 membered saturated carbocyclic ring, optionally containing one or more additional heteroatoms, each independently selected from the group consisting of O, S and N, with such ring being 5-7 membered saturated carbocyclic optionally substituted by one or more substituents, each independently selected from the group consisting of halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[0003]
A compound according to claim 1 or 2, characterized by the fact that R2 represents a 4-7 membered saturated carbocyclic ring containing carbon and one or more oxygen atoms, the 4-7 membered saturated carbocyclic ring being replaced by one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[0004]
A compound according to any one of claims 1 to 3, characterized in that B represents a 6-membered monocyclic aromatic ring containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such an aromatic ring of 6 members being optionally substituted by one or more substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, CN, CFH2, CF2H and CF3.
[0005]
Compound of Formula (I) according to any one of claims 1 to 4, characterized in that R2 represents C1-C3-R6 alkyl or a 4-7 membered saturated carbocyclic ring consisting of carbon atoms and one or more heteroatoms, each independently selected from the group consisting of O or S, such a 4-7 membered saturated carbocyclic ring being replaced by one or more substituents, each independently selected from the group consisting of halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3; each R4 is independently selected from hydrogen, halo, C1-C4oxy alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a 3-5 membered saturated carbocyclic ring optionally containing one or more hetero atoms, each independently selected the group consisting of O and N; and R6 represents a 4-7 membered saturated carbocyclic ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O or S, such a 4-7 membered saturated carbocyclic ring optionally substituted by one or more substituents, each one independently selected from the group consisting of halo, C1-C4oxy alkyl, oxo, C (= O) -C1-C3 alkyl, C1-C4 alkyl, OH, CN, CFH2, CF2H and CF3.
[0006]
A compound according to any one of claims 1 to 5, characterized in that at least one R4 represents Fluorine, C1-C3 alkyl or cyclopropyl.
[0007]
A compound according to any one of claims 1 to 6, characterized in that one R4 in the para position represents fluorine and the other R4 in the meta position represents methyl.
[0008]
8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by the fact that R1 and R2, together with the nitrogen to which they are attached, form a decyl 1,4-dioxa-8 azaspiro fraction [4.5 ] or a 5-7 membered saturated carbocyclic ring, optionally containing one or more additional heteroatoms, each independently selected from the group consisting of S and N, with that 5-7 membered saturated carbocyclic ring being replaced by one or more substituents, each independently selected from the group consisting of halo, C1-C4alkyloxy, oxo, C (= O) -C1-C3alkyl, C1-C4alkyl, OH, CN, CFH2, CF2H and CF3.
[0009]
Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 8, and a pharmaceutically acceptable carrier.
[0010]
Use of a compound as defined in any one of claims 1 to 8, characterized in that it is for the preparation of a pharmaceutical composition for the prevention or treatment of an HBV infection in a mammal.

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EA201590457A1|2015-06-30|

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KR20150046089A|2015-04-29|

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CR20210079A|2021-06-10|

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GT201500021A|2017-07-24|

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EP2890375B1|2021-07-28|

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TW201920090A|2019-06-01|

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TW201422574A|2014-06-16|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-08-13| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-07| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/08/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP12182076.5|2012-08-28|

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EP12182076|2012-08-28|

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EP12185055.6|2012-09-19|

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EP12185055|2012-09-19|

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EP12190837.0|2012-10-31|

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EP12190837|2012-10-31|

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EP13157230|2013-02-28|

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EP13157230.7|2013-02-28|

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EP13169574.4|2013-05-28|

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EP13169574|2013-05-28|

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PCT/EP2013/067821|WO2014033170A1|2012-08-28|2013-08-28|Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b|

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