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    • 专利摘要:
    FUSIONED BICYCLICAL DERIVATIVE OF SULFAMOYL AND ITS USE IN THE TREATMENT AND PREVENTION OF INFECTION BY HEPATITIS B VIRUS, AS WELL AS PHARMACEUTICAL COMPOSITION AND PRODUCT THAT UNDERSTANDS IT. The present invention relates to the HBV replication inhibitors of Formula (1): including their stereochemically isomeric forms, and their salts, hydrates, solvates, in which AE, Ri, R2, Rs and Rs have the meaning as defined herein document. The present invention also relates to pharmaceutical compositions and products containing them and their use, alone or in combination with other HBV inhibitors, in therapy against HBV.
    公开号:BR112015004161B1
    申请号:R112015004161-2
    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
    申请人:Janssen Sciences Ireland Uc；
    IPC主号:
    专利说明:

    BACKGROUND TECHNIQUE
    [001] The Hepatitis B virus (HBV) is a partially double-stranded DNA (dsDNA, double-stranded DNA) virus from the Hepadnaviruses (Hepadnaviridae) family. Its genome contains 4 overlapping reading phases: the pre-core / core gene; the polymerase gene; the L, M, and S genes, which encode the 3 envelope proteins; and the X gene.
    [002] After infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA, from "relaxed circular DNA") is converted into covalently closed circular DNA (cccDNA, from "covalently closed circular DNA") in the host cell nucleus and viral mRNAs are transcribed. Once in capsid, the pre-genomic RNA (pgRNA, from the English "pregenomic RNA"), which also encodes core protein and PoI, serves as the template for reverse transcription, which regenerates the partially dsDNA (rcDNA) genome in the nucleocapsid .
    [003] 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 associated with a strongly increased risk of developing cirrhosis and liver cell carcinoma.
    [004] The transmission of the hepatitis B virus results from exposure to infected blood or body fluids, while viral DNA has been detected in saliva, tears, and urine from chronic transporters with a high titer of DNA in the serum.
    [005] 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.
    [006] 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).
    [007] Furthermore, WO2013 / 006394, published on January 10, 2013, and WO2013 / 096744, published on June 27, 2013, refer to subclasses of Sulfamoyl-arylamides active against HBV.
    [008] Among the problems that direct antivirals for HBV may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability and difficulty in synthesis.
    [009] Additional HBV inhibitors are needed that can overcome at least one of these disadvantages. DESCRIPTION OF THE INVENTION
    [0010] In one aspect, the present invention provides compounds that can be represented by Formula (I):

    [0011] or a stereoisomer or tautomeric form thereof, where:
    [0012] A represents N, C or O;
    [0013] B represents C or N;
    [0014] D represents C or N;
    [0015] E represents C or N;
    [0016] being that if A and E are N or C, they are optionally substituted with R4;
    [0017] R1 represents hydrogen or C1-C3 alkyl;
    [0018] R2 represents C1-C6 alkyl, C1-C3-R6 alkyl, benzyl, or a 3- to 7-membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, being such C1-C6 alkyl or a 3 to 7-membered saturated ring optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H or CF3;
    [0019] or R1 R2 together with the nitrogen to which they are attached form a 5- to 7-membered saturated ring that is optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyloxy , C1-C3 alkyl, OH, CN, CFH2, CF2H and CF3;
    [0020] each R3 is independently selected from hydrogen, halo, C1-C4 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a 3 to 5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N;
    [0021] R4 represents hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, - (C = O) C1-C4 alkyl, - (C = O) -C1-C3 alkyloxy or, in the case that A or E is equal to C, R4 can also be halogen;
    [0022] R5 represents hydrogen or halogen;
    [0023] R6 represents a 3 to 7-membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such a 3 to 7-membered saturated ring optionally substituted with one or more substituents , each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3;
    [0024] or a pharmaceutically acceptable salt or solvate thereof.
    [0025] The invention further relates to a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable carrier.
    [0026] The invention also relates to the compounds of Formula (I) for use as a medicament, preferably for use in the prevention or treatment of an HBV infection in a mammal.
    [0027] In a further aspect, the invention relates to a combination of a compound of Formula (I), and another HBV inhibitor. DEFINITIONS
    [0028] The term "C1-3 alkyl" or "C1-C3 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. If C1-3 alkyl is attached to an additional radical, it refers to a Formula CnH2n. The C1-C3 alkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C1-3 alkyl includes all linear or branched alkyl groups having between 1 and 3 carbon atoms, and thus includes, for example, methyl, ethyl, n-propyl and i-propyl.
    [0029] 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.
    [0030] 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.
    [0031] The term "C1-3alkoxy", as a group or part of a group, refers to a radical having the Formula --ORc where Rc is C1-3alkyl. Non-limiting examples of suitable C1-3alkoxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.
    [0032] As used herein, the term "3 to 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 cycloheptyla.
    [0033] Such a saturated ring optionally contains one or more heteroatoms, such that at least one carbon atom is replaced with a heteroatom selected from N, O and S, in particular N and O. Examples include oxethane, tetrahydro -2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl.
    [0034] As used in this document,

    [0035] means a fused bicyclic group optionally containing one or more heteroatoms, such that at least B, D or E is replaced with nitrogen or A with N or O ((hetero-) aryl). The indicated (hetero-) aryl group need only have some degree of aromatic character. Illustrative examples of (hetero-) aryl groups include, but are not limited to, benzofuran, indole, isoindole, indazole, imidazopyridine and benzisoxazole. Benzisoxazole and indazole are preferred.
    [0036] It should be noted that different isomers of the various heterocycles may exist within the scope of the definitions as used throughout the specification. For example, pyrrolyl can be 1H-pyrrolyl or 2H-pyrrolyl.
    [0037] The term halo is generic for fluoro, chloro, bromo or iodo.
    [0038] It should also be noted that the positions of the radical in any molecular fraction used in 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.
    [0039] When any variable (eg, halogen or C1-4 alkyl) occurs more than once in any constituent, each definition is independent.
    [0040] 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 within the scope of the present invention.
    [0041] 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 halide acids, for example, hydrochloric or hydrobromic acid; 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.
    [0042] Conversely, said acid addition salt forms can be converted by treatment with an appropriate base in the form of the free base.
    [0043] The term "salts" also includes 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.
    [0044] 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 shown here, are intended to be included within the scope of the present invention.
    [0045] 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 can contain all diastereoisomers 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.
    [0046] The pure stereoisomeric forms of the compounds and intermediates as mentioned in this document, are defined as isomers substantially free of other enantiomeric or diastereoisomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates that have a stereoisomeric excess of at least 80% (ie, a minimum of 90% of an isomer and a maximum of 10% of the other possible isomers) up to a stereoisomeric excess of 100% (ie, 100% of an isomer and none of the others), more particularly, compounds or intermediates that have a stereoisomeric excess of 90% to 100%, even more particularly with a stereoisomeric excess of 94% to 100% and even more particularly having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereoisomerically pure" should be understood in a similar way, but taking into account then the enantiomeric excess, respectively the diastereoisomeric excess, of the mixture in question.
    [0047] The 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 selective crystallization of their diastereoisomeric salts with optically active acids or bases. Examples of these are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. Such pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided the reaction occurs in a stereospecific manner. Preferably, if a specific stereoisomer is desired, that compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
    [0048] The diastereoisomeric racemates of formula (I) can be obtained separately by conventional methods. Suitable physical separation methods that can be advantageously used are, for example, selective crystallization and chromatography, for example, column chromatography.
    [0049] 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
    [0050] Whenever used hereinafter, the term "compounds of formula (I)",

    [0051] or "the present compounds" or similar term, is intended to include the compounds of the general formulas (I), (Ia), (Ib), (II), (I-II), their salts, stereoisomeric forms and racemic mixtures or any subgroups.
    [0052] According to the invention, in formula (I),
    [0053] A represents N, C or O;
    [0054] B represents C or N;
    [0055] D represents C or N;
    [0056] E represents C or N;
    [0057] being that if A and E are N or C, they are optionally substituted with R4;
    [0058] R1 represents hydrogen or C1-C3 alkyl;
    [0059] R2 represents C1-C6 alkyl, C1-C3-R6 alkyl, benzyl, or a 3- to 7-membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, being such C1-C6 alkyl or a 3 to 7-membered saturated ring optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H or CF3;
    [0060] or R1 R2 together with the nitrogen to which they are attached form a 5- to 7-membered saturated ring that is optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyloxy , C1-C3 alkyl, OH, CN, CFH2, CF2H and CF3;
    [0061] each R3 is independently selected from hydrogen, halo, C1-C4 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 or a 3 to 5 membered saturated ring optionally containing one or more hetero atoms, each independently selected from the group consisting of O and N;
    [0062] R4 represents hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, - (C = O) C1-C4 alkyl, - (C = O) -C1-C3 alkyloxy or, in the case that A or E is equal to C, R4 can also be halogen;
    [0063] R5 represents hydrogen or halogen and
    [0064] R6 represents a 3 to 7-membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O, S and N, such a 3 to 7-membered saturated ring optionally substituted with one or more substituents , each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3.
    [0065] In a first embodiment of the invention, R4 represents hydrogen, C3-C5 cycloalkyl, - (C = O) C1-C4 alkyl, - (C = O) -C1C3 alkyloxy or, in the case that A or E is equal to C, R4 can also be halogen.
    [0066] In an embodiment of the invention, R1 represents hydrogen or methyl. In a second embodiment of the present invention, R2 represents C1-C3-R6 alkyl or C4-C7 cycloalkyl, optionally being substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1C3 alkyloxy, C1-C4 alkyl , OH, CN, CFH2, CF2H, CF3, and where R6 represents a C4-C7 cycloalkyl, being optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1C3 alkyloxy, C1- alkyl C4, OH, CN, CFH2, CF2H, CF3.
    [0067] In a third embodiment, R2 represents a C4-C7 cycloalkyl, optionally being substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1- alkyl C4, OH, CN, CFH2, CF2H, CF3. In yet another embodiment, R2 represents C5 cycloalkyl or C6 cycloalkyl, optionally being substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo and C1-C4 alkyl.
    [0068] In another embodiment, R3 represents Fluorine, C1-C3 alkyl or cyclopropyl. Preferably, at least one R3 represents methyl, i-propyl or cyclopropyl. In another embodiment, one R3 represents methyl, i-propyl or cyclopropyl and the other R3 represents fluorine, or hydrogen.
    [0069] Preferably, R4 represents hydrogen.
    [0070] In a preferred embodiment, the compounds are represented by Formula (II) or (I-II)

    [0071] where R1, R2, R3 are as defined above.
    [0072] Additional combinations of any submodalities or preferred modalities are also intended to be within the scope of the present invention.
    [0073] The most preferred compounds are those shown in table 1.
    [0074] 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 carrier. 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 yet another additional 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 in this document.
    Therefore, the compounds of the present invention, or any subgroup thereof, can be formulated in various pharmaceutical forms for administration purposes. As appropriate compositions, all compositions normally used for the systemic administration of drugs can be cited. To prepare the pharmaceutical compositions of the present 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, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unit dosage form suitable, particularly, for administration by oral, rectal, percutaneous, or 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 vehicles 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 vehicle 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 vehicle comprises saline, glucose solution or a mixture of saline and glucose. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents and the like can be used. Also included are preparations in solid form with the intention of being converted, just before use, to preparations in liquid forms. In compositions suitable for percutaneous administration, the vehicle 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.
    [0076] It is especially advantageous to formulate the aforementioned pharmaceutical compositions 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 combination 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.
    [0077] 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 of liver disease and hepato-cellular carcinoma.
    [0078] 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 humans, 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, who is infected with HBV, or who is at risk of HBV infection, said method comprising administering a therapeutically effective amount of a compound of Formula (I).
    [0079] The compounds of Formula (I), as specified in this document, can therefore be used as a medicine, in particular as a medicine to treat or prevent HBV infection. Said use as a medication or treatment method comprises the 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.
    [0080] The present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or prevention of HBV infection.
    [0081] In general, it is contemplated that an effective daily antiviral 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 during 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.
    [0082] The present invention also relates to combinations of a compound of the 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 (referred to herein as anti-HBV agent), as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infections. In one embodiment, the invention relates to the combination of a compound of the 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.
    [0083] 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 formula (I) or any subgroup this can be used as a medicine in a combination therapy. GENERAL SYNTHETIC METHODS GENERAL SYNTHESIS:
    [0084] The compounds of the general formula (Ia) (compound I in which E is equal to nitrogen and B and D are equal to carbon, A being equal to nitrogen or oxygen, scheme 1) can be synthesized as shown in scheme 1. A 5- (chlorosulfonyl) -2-fluorobenzoic acid derivative II is coupled to an amine of structure III, resulting in sulfonamide IV. By forming an amide between carboxylic acid IV and aniline V, using, for example, HATU in the presence of an organic base such as N, N-diisopropylethylamine (DIPEA) in DMF, compound VI is obtained. Thioamide VII can be obtained by reacting VI with a thioning agent such as Lawson's reagent (2,4-bis (4-methoxyphenyl) -1,3,2,4-di-thiadiphosphethane-2,4 -disulfide). Finally, compound VII is reacted with NH2OH if A is equal to oxygen, or NH2NH2 if A is equal to nitrogen, at a higher temperature (for example, 120 ° C to 150 ° C in DMSO) resulting in compound Ia.

    Alternatively, for the synthesis of compounds of the general formula (Ia), the route described in scheme 2 can be used. Compound VIII can be reacted with an amine of the formula (III), resulting in compound IX, which undergoes cyclization to a compound of the formula X, using, for example, a hydrazine in iPrOH at 110 ° C when A is equal to NH in compound X. Compound X can be further transformed into a compound of the general formula (Ia), for example , by means of copper-catalyzed coupling using a boronic acid XI.

    [0086] Scheme 3 describes the general synthesis of compounds of the general formula (Ib). When reacting compound XII with a thioisocyanate XIII and promoting the cyclization of the intermediate formed in the compound of the general formula (Ib), for example, under the influence of N, N'-dicyclohexylmethanediimine or 2-chloro-1 iodide -methylpyridinium. The compounds of the general formula XIIa and XIIb can be prepared as shown in scheme 4 and as exemplified in the synthesis of compounds 17, 18 and 19.
    EXPERIMENTAL: LCMS conditions:
    [0087] Method A: General: mobile phase A: H2O (0.1% TFA; B: CH3CN (0.05% TFA) Downtime: 2 min; gradient time (min) [% A /% B] 0.01 [90/10] to 0.9 [20/80] to 1.5 [20/80] to 1.51 [90/10]; flow: 1.2 mL / min; temperature column height: 50 ° C, Xtimate C18 2.1 * 30 mm, 3 μm.
    [0088] Method B: General: mobile phase A: H2O (0.1% TFA; B: CH3CN (0.05% TFA) Downtime: 10 min; gradient time (min) [% A /% B] 0.0 [90/10] to 0.8 [90/10] to 4.5 [20/80] to 7.5 [20/80] to 8.0 [90/10]; flow: 0 , 8 mL / min; column temperature: 50 ° C, YMC-PACK ODS-AQ, 50x2.0 mm, 5 μm.
    [0089] Method C: General: mobile phase A: H2O (0.1% TFA; B: CH3CN (0.05% TFA) Downtime: 10 min; gradient time (min) [% A /% B] 0.0 [70/30] to 0.8 [70/30] to 4 [10/90] to 7.5 [10/90] to 8.0 [70/30]; flow: 0.8 mL / min; column temperature: 50 ° C, YMC-PACK ODS-AQ, 50x2.0 mm, 5 μm.
    [0090] Method D: General: mobile phase A: H2O (0.1% TFA; B: CH3CN (0.05% TFA) 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] to 8.0 [100/0]; flow: 0.8 mL / min; column temperature: 50 ° C, YMC-PACK ODS-AQ, 50x2.0 mm, 5 μm.
    [0091] Method E: General: mobile phase A: H2O (0.1% TFA; B: CH3CN (0.05% TFA) Downtime: 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 9.5 [90/10]; flow: 0 , 8 mL / min; column temperature: 50 ° C, Agilent TC-C18, 50x2.1 mm, 5 μm.
    [0092] Method F: The LC measurement was performed using an Acuity UPLC (Waters) with column heater (adjusted to 55 ° C). Reverse-phase UPLC (from English "Ultra Performance Liquid Chromatography") was performed on an Acquity UPLC HSS T3 (1.8 μm, 2.1 x 100 mm; Waters Acquity) column with a flow 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 to 95% in 2.1 minutes and subsequently to A to 0% and B to 100% in 0.9 minutes to A to 5% and B to 95% in 0.5 min. An injection volume of 1 μl was used. The cone voltage was 30 V for the positive ionization mode and 30 V for the negative ionization mode. SUMMARY OF COMPOUNDS:

    [0093] To 5- (chlorosulfonyl) -2-fluorobenzoic acid (5.5 g, 23.05 mmol) in EtOAc (75 mL) was added cyclohexanamine (6.86 g, 69.15 mmol) at room temperature . The reaction mixture was stirred at room temperature for 10 minutes and subsequently washed with 1 N HCl (50 ml). The organic phase was dried over MgSO4 and concentrated in vacuo, resulting in a white solid (6 g) containing 5- (N-cyclohexylsulfamoyl) -2-fluorobenzoic acid, which was used in the next steps without further purification. To a part of the solid obtained above (1.5 g), 4-fluoroaniline (553 mg, 4.98 mmol) and DIPEA (1.287 g, 9.96 mmol) in DMF (30 mL), HATU (2.27 g , 5.97 mmol) was added at room temperature. The mixture was stirred at room temperature for 15 hours. EtOAc (300 ml) and water (200 ml) were added and the mixture was washed with saline (2 x 200 ml), dried over MgSO4, filtered and concentrated resulting in compound 1. Method A; TA: 1.12 min. m / z: 395.1 (M + H) + Exact mass: 394.1;

    [0094] A mixture of compound 1 (1.5 g, 3.8 mmol) and 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphethane-2,4-disulfide (Lawes' reagent son 923 mg, 2.28 mmol) in toluene (40 mL) was stirred at 110 ° C for 15 hours. The mixture was concentrated in vacuo, resulting in a yellow solid (2.2 g). This solid, containing compound 2, was used in the next reaction.

    [0095] Part of the solid obtained above containing compound 2 (700 mg) and N2H4.H2O (546 mg, 17 mmol) in DMSO (15 mL) were stirred at 150 ° C for 5 hours. Water was added and the mixture was extracted with EtOAc (150 ml). The organic layers were washed with saline, dried and concentrated in vacuo, resulting in a residue. The obtained residue was recrystallized from MeOH-water, resulting in compound 3 as a light yellow solid (280 mg) after filtration and drying in vacuo. Method B; TA: 4.52 min. m / z: 389.2 (M + H) + Exact mass: 388.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (1 H, s), 9.26 (1 H, s), 8.60 (1 H, d, J = 1.0 Hz), 7.66 - 7.82 (3 H, m), 7.41 - 7.62 (2 H, m), 7.02 - 7.21 (2 H, m), 2.78 - 3.04 ( 1 H, m), 1.46 - 1.69 (4 H, m), 1.32 - 1.46 (1 H, m), 0.89 - 1.30 (5 H, m)

    [0096] Part of the solid obtained above containing compound 2 (1 g), Na2CO3 (2.58 g, 24.3 mmol) and NH2OH.HCl (1.69 g, 24.3 mmol) in DMSO (20 mL) and water (4 mL) were stirred at 120 ° C for 5 hours. Water was added and the mixture was extracted with EtOAc (150 ml), the organic layer was washed with brine, dried and concentrated in vacuo, resulting in a residue. This residue was purified by preparative HPLC (Phenomenex Synergi max-RP 150x30mm; Mobile phase A: purified water (0.075% TFA, V / V); Mobile phase B: acetonitrile; Flow rate: 30 mL / min; Gradient : 53 to 83% over 8 minutes, resulting in compound 4 as a white solid (120 mg) Method C; TA: 3.79 min. M / z: 390.3 (M + H) + Exact mass: 389.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (1 H, s), 8.75 (1 H, d, J = 1.5 Hz), 8.04 (1 H , dd, J = 9.0, 1.5 Hz), 7.83 (1 H, d, J = 9.0 Hz), 7.75 (1 H, d, J = 7.5 Hz), 7 , 67 - 7.73 (2 H, m), 7.16 - 7.30 (2 H, m), 2.90 - 3.02 (1 H, m), 1.48 - 1.65 (4 H, m), 1.37 - 1.49 (1 H, m), 0.95 - 1.21 (5 H, m) Compound 5

    [0097] Cyclopentanamine (17.85 g, 210 mmol) and NaOH (16.8 g, 420 mmol) were dissolved in THF (300 ml) and H2O (300 ml). 5- (chlorosulfonyl) -2-fluorobenzoic acid (50 g, 210 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 12 hours. The mixture was washed with ethyl acetate (3 x 50 ml). The aqueous layer was separated and adjusted to pH = 3 with 1 N HCl. The precipitate that formed was filtered and dried under vacuum, resulting in 5- (N-cyclopentylsulfamoyl) - 2-fluorobenzoic acid (40 g). 5- (N-cyclopentylsulfamoyl) -2-fluorobenzoic acid (40 g, 139.4 mmol), 4-fluoroaniline (19.3 g, 167.2 mmol) and triethylamine (28.2 g, 278.8 mmol) were dissolved in DMF (400 ml). HATU (63 g, 167.2 mmol) was added at 0 ° C and then the mixture was stirred at 20 ° C for 6 hours. The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5: 1) resulting in 5- (N-cyclopentylsulfamoyl) -2-fluoro-N- (4-fluorophenyl) benzamide (38 g). 5- (N-Cyclopentylsulfamoyl) -2-fluoro-N- (4-fluorophenyl) benzamide (38 g, 100 mmol) and Lawesson's reagent (40.4 g, 100 mmol) were dissolved in toluene (1000 mL). The mixture was stirred at 120 ° C for 16 hours. The volatiles were removed in vacuo and the residue obtained and N2H4-H2O (80 ml) were dissolved in 1,4-dioxane (500 ml). The mixture was stirred for 12 hours at 160 ° C. The solution was removed in vacuo and the residue obtained was purified by high performance liquid chromatography (Column: Phenomenex Synergi Diamonsil 150 * 20mm * 5um. Method: 25 to 55% B in A; A: H2O + 0.1% TFA; B: CH3CN. Flow rate (mL / min): 40). Pure fractions were collected and basified to pH = 7 with saturated aqueous NaHCO3. The organic volatiles were removed in vacuo and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, the obtained residue was suspended in water (5 ml) and the aqueous layer was lyophilized until dry resulting in compound 5 (15 g). Method B; TA: 4.14 min. m / z: 375.2 (M + H) +; Exact mass: 374.1; 1H NMR (600 MHz, DMSO-d6) δ ppm 1.26 - 1.33 (m, 2 H), 1.33 - 1.40 (m, 2 H), 1.49 - 1.56 (m , 2 H), 1.56 - 1.61 (m, 2 H), 3.40 (quin, J = 6.6 Hz, 1 H), 7.14 (t, J = 8.1 Hz, 2 H), 7.47 (ls, 1 H), 7.55 (δd, J = 8.8 Hz, 1 H), 7.73 (dd, J = 8.8, 1.8 Hz, 1 H) , 7.76 (dd, J = 9.1, 4.8 Hz, 2 H), 8.64 (d, J = 1.6 Hz, 1 H), 9.28 (s, 1 H), 12 , 37 (bs, 1 H). Compound 6

    [0098] Compound 5 (400 mg, 1 mmol) was dissolved in DMF (50 ml). CH3I (0.71 g, 5 mmol) and K2CO3 (0.69 g, 5 mmol) were added to the mixture. The mixture was stirred at 110 ° C for 12 hours. The solvent was removed in vacuo. The residue was purified by high-performance liquid chromatography (Column: Phenomenex Synergi Diamonsil 150 * 20mm * 5um. Method: 25% to 55% B in A; A: H2O + 0.1% TFA; B: CH3CN Flow rate (mL / min): 40). Pure fractions were collected and basified to pH = 7 with saturated aqueous NaHCO3. The organic solvent was removed in vacuo and the aqueous layer was extracted with ethyl acetate (3 x 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 thin layer chromatography (eluent: petroleum ether: ethyl acetate = 1: 1). The product obtained was suspended in water (5 ml) and CH3CN (2 ml) and the mixture was lyophilized until dry, resulting in compound 6 (53 mg).
    [0099] Method D; TA: 5.87 min. m / z: 389.2 (M + H) + Exact mass: 388.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (1 H, s), 8.58 (1 H, s), 7.67 - 7.81 (3 H, m), 7.58 - 7.67 (1 H, m), 7.46 (1 H, d, J = 6.5 Hz), 7.12 (2 H, t, J = 8.8 Hz), 3.93 (3 H, s), 3.33 - 3.40 (1 H, m), 1.42 - 1.66 (4 H, m), 1.16 - 1.42 (4 H, m). 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 8.26 (1 H, d, J = 1.0 Hz), 7.80 (1 H, dd, J = 8.9, 1.6 Hz) , 7.46 - 7.55 (2 H, m), 7.34 (1 H, d, J = 8.8 Hz), 7.03 (2 H, t, J = 8.7 Hz), 6 , 48 (1 H, s), 4.46 (1 H, d, J = 7.0 Hz), 3.98 (3 H, s), 3.52 - 3.66 (1 H, m), 1.69 - 1.83 (2 H, m), 1.57 - 1.66 (2 H, m), 1.45 - 1.54 (2 H, m), 1.26 - 1.45 ( 2 H, m). 7

    [00100] Compound 5 (600 mg, 1.6 mmol) was dissolved in DMF (50 ml). 2-Bromopropane (0.98 g, 8 mmol) and K2CO3 (0.45 g, 5 mmol) were added to the mixture at 0 ° C. The mixture was churned at 0 ° C for 1 hour. The solvent was removed in vacuo and the residue obtained was purified by high performance liquid chromatography (Column: Phenomenon Synergi Diamonsil 150 * 20mm * 5um. Method: 25% to 55% B in A, A: H2O + 0, 1% TFA, B: CH3CN, flow rate (mL / min): 40). Pure fractions were collected and basified to pH = 7 with saturated aqueous NaHCO3. The volatiles were removed in vacuo and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo, the residue obtained was suspended in water (5 ml) and CH3CN (2 ml) and the mixture was lyophilized until dry, resulting in compound 7 (420 mg). Method E; TA: 4.90 min. m / z: 417.1 (M + H) + Exact mass: 416.2.
    [00101] 1H NMR (600 MHz, DMSO-d6) δ ppm 1.27 - 1.41 (m, 4 H), 1.48 (d, J = 6.6 Hz, 6 H), 1.51 - 1.63 (m, 4 H), 3.38 (quin, J = 6.6 Hz, 1 H), 4.91 (spt, J = 6.5 Hz, 1 H), 7.15 (t , J = 8.9 Hz, 2 H), 7.48 (ls, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.74 (dd, J = 9.0 , 1.6 Hz, 1 H), 7.76 (dd, J = 9.0, 4.8 Hz, 2 H), 8.61 (dd, J = 1.5, 0.7 Hz, 1 H ), 9.34 (s, 1 H). Compound 8

    [00102] Compound 5 (600 mg, 1.6 mmol) was dissolved in 1,4-dioxane (50 mL), cyclopropylboronic acid (690 mg, 8 mmol), Cu (OAc) 2 (181 mg, 8 mmol) , Cs2CO3 (0.45 g, 5 mmol) and DMAP (200 mg, 1.634 mmol) were added. The mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo and the residue obtained was purified by high performance liquid chromatography (Column: Phenomenex Synergi Diamonsil 150 * 20mm * 5um. Method: From 25% to 55% B in A. A: H2O + 0.1 % TFA, B: CH3CN Flow rate (mL / min): 40). Pure fractions were collected and basified to pH = 7 with saturated aqueous NaHCO3. The volatiles were removed under vacuum. The aqueous layer was extracted with ethyl acetate (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 suspended in water (5 ml) and CH3CN (2 ml). The mixture was lyophilized until dry, resulting in compound 8 (380 mg).
    [00103] Method E; TA: 4.74 min. m / z: 415.1 (M + H) + Exact mass: 414.2. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.11 - 1.15 (m, 4 H), 1.21 - 1.41 (m, 4 H), 1.45 - 1.66 (m , 4 H), 3.39 (sxt, J = 6.7 Hz, 1 H), 3.61 - 3.68 (m, 1 H), 7.15 (t, J = 8.9 Hz, 2 H), 7.51 (d, J = 6.9 Hz, 1 H), 7.69 (dd, J = 8.9, 0.5 Hz, 1 H), 7.75 (dd, J = 9 , 0, 4.8 Hz, 1 H), 7.79 (dd, J = 8.9, 1.7 Hz, 2 H), 8.62 (dd, J = 1.8, 0.6 Hz, 1 H), 9.34 (s, 1 H). Compound 9

    [00104] Compound 5 (1.5 g, 4 mmol) was dissolved in Ac2O (50 ml). The mixture was stirred at 110 ° C for 12 hours. The solvent was removed in vacuo, the residue obtained was washed with H2O (5 ml) and dichloromethane (5 ml) and dried in vacuo, resulting in compound 9 (1.35 g). Method B; TA: 4.70 min. m / z: 417.2 (M + H) + Exact mass: 416.1.
    [00105] 1H NMR (600 MHz, DMSO-d6) δ ppm 9.81 (1 H, s), 8.80 (1 H, dd, J = 1.8, 0.5 Hz), 8.43 (1 H, dd, J = 8.8, 0.5 Hz), 8.03 (1 H, dd, J = 8.8, 1.8 Hz), 7.79 - 7.87 (2 H, m), 7.71 (1 H, d, J = 7.0 Hz), 7.18 (2 H, t, J = 9.0 Hz), 3.45 (1 H, sxt, J = 7, 0 Hz), 2.66 (3 H, s), 1.55 - 1.63 (2 H, m), 1.45 - 1.56 (2 H, m), 1.32 - 1.39 ( 2 H, m), 1.24 -1.32 (2 H, m) Compound 10

    [00106] Compound 5 (1.5 g, 4 mmol) was dissolved in DMF (20 ml). NaH (0.48 g, 20 mmol) was added to the mixture at 0 ° C. Methyl chlorocarbonate (1.89 g, 20 mmol) was added dropwise at 0 ° C. The mixture was stirred at 25 ° C for 12 hours. H2O (5 ml) was added dropwise at 0 ° C. The solvent was removed in vacuo. The residue was washed with H2O (5 ml), dichloromethane (10 ml) and N, N-dimethylformamide (5 ml) and dried in vacuo, resulting in compound 10 (1.33 g). Method B; TA: 4.54 min. m / z: 433.1 (M + H) + Exact mass: 432.1. 1H NMR (600 MHz, DMSO-d6) δ ppm 9.97 (1 H, s), 8.92 (1 H, dd, J = 1.8, 0.6 Hz), 8.28 (1 H , d, J = 8.8 Hz), 8.07 (1 H, dd, J = 8.8, 1.8 Hz), 7.88 - 7.95 (2 H, m), 7.79 ( 1 H, d, J = 7.0 Hz), 7.18 - 7.28 (2 H, m), 4.05 (3 H, s), 3.45 - 3.55 (1 H, m) , 1.58 - 1.66 (2 H, m), 1.49 - 1.58 (2 H, m), 1.23 - 1.42 (4 H, m). Compound 11

    [00107] Prepared similarly as described for compound 5 using (3S) -tetrahydrofuran-3-amine hydrochloride instead of cyclopentylamine and 3,4-difluoroaniline instead of 4-fluoroaniline. Method D; TA: 5.5 min. m / z: 395.2 (M + H) + Exact mass: 394.1. Compound 12

    [00108] Prepared similarly as described for compound 11, using 4-fluoro-3-methyl-aniline instead of 3,4-difluoroaniline. Method B; TA: 4.15 min. m / z: 391.2 (M + H) + Exact mass: 390.1. 13

    [00109] To a solution of 3-cyano-4-fluorobenzenesulfonyl chloride (3 g, 13.7 mmol) and isopropylamine (1.211 g, 20.49 mmol) in CH2Cl2 (30 mL), was added N, N-di - isopropylethylamine (3.53 g, 27.3 mmol). The resulting mixture was stirred at 18 ° C for 2 hours. The reaction mixture was washed with 1N HCl (25 ml) and saturated aqueous NaHCO3 (25 ml), dried over Na2SO4 and concentrated in vacuo, resulting in crude 3-cyano-4-fluoro-N-isopropyl-benzenesulfonamide (3.4 g). To a solution of crude 3-cyano-4-fluoro- N-isopropyl-benzenesulfonamide (2.9 g) in 2-propanol (30 mL)
    [00110] hydrazine (0.77 g, 23.9 mmol) was added. The resulting mixture was refluxed at 110 ° C for 1 hour. The mixture was concentrated under reduced pressure, resulting in crude 3-amino-N-isopropyl-1H-indazol-5-sulfonamide (4.1 g). A solution of copper (II) acetate (714 mg, 3.93 mmol) in CH2Cl2 (15 mL) was stirred for 5 minutes.
    [00111] Crude 3-amino-N-isopropyl-1H-indazol-5-sulfonamide (1 g), 3,4-difluorophenylboronic acid (620.9 mg, 3.9 mmol) and N, N-di- isopropylethylamine (508 mg, 3.9 mmol). The resulting mixture was stirred and refluxed at 50 ° C so b O2 for one night. The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, resulting in crude compound 13.
    [00112] The crude product was purified by preparative high performance liquid chromatography in reverse phase (eluent: CH3CN in H2O (0.05% NH3.H2O) from 38% to 68%, v / v). The pure fractions containing compound 13 were collected and the organics were removed under vacuum. The aqueous layer was lyophilized until dry, resulting in compound 13 (114 mg). Method B; TA: 4.23 min. m / z: 367 (M + H) + Exact mass: 366.1. Compound 14

    [00113] Prepared similarly as described for compound 12, using methyl hydrazine instead of hydrazine hydrate. Method D; TA: 5.88 min. m / z: 405.3 (M + H) + Exact mass: 404.1. 15

    [00114] Prepared similarly as described for compound 5 using isopropylamine instead of cyclopentylamine, 3- (difluoromethyl) -4-fluoroaniline instead of 4-fluoroaniline and methylhydrazine instead of hydrazine hydrate. Method B; TA: 4.71 min. m / z: 413.3 (M + H) + Exact mass: 412.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 6.5 Hz, 6 H) 3.08 - 3.28 (m, 1 H) 3.97 (s, 3 H ) 7.23 (t, J = 54.2 Hz, 1 H) 7.28 - 7.42 (m, 1 H) 7.46 (sl, 1 H) 7.63 - 7.72 (m, 1 H) 7.72 - 7.84 (m, 1 H) 7.91 - 8.04 (m, 2 H) 8.62 (s, 1 H) 9.59 (s, 1 H). 16

    [00115] Prepared similarly as described for compound 15 using (3S) -tetrahydrofuran-3-amine hydrochloride instead of isopropylamine. Method D; TA: 5.84 min. m / z: 441.2 (M + H) + Exact mass: 440.1. Compound 17

    [00116] 3- (Difluoromethyl) -4-fluoroaniline (1000 mg, 6.2 mmol), 1,1'-thiocarbonyldi-2 (1h) -pyridone (1.72 g, 7.4 mmol) were added sequentially ) and CH2Cl2 to a 20 mL flask at 25 ° C. The mixture was heated by microwave irradiation at 70 ° C for 1 hour.
    [00117] The mixture was interrupted with water, extracted with dichloromethane (20 mL).
    [00118] The organic layer was separated and concentrated in vacuo. The obtained residue (1.8 g), containing 2- (difluoromethyl) -1-fluoro-4-isothiocyanate-benzene, was used without purification. 6-Chloro-N-isopropyl-pyridine-3-sulfonamide (4 g, 17.0 mmol), zinc cyanide (4.0 g, 34 mmol), palladium (II) acetate (381 mg, 1 , 7 mmol), 1,1'-bis (diphenylphosphino) ferrocene (942 mg, 1.7 mmol) and N, N-dimethylacetamide (50 mL) at 25 ° C in a 250 mL flask. The mixture was heated to 60 ° C and stirred for 2 hours under a nitrogen atmosphere. The mixture was stopped with water, extracted with dichloromethane (50 mL). The organic layer was separated and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether and ethyl acetate (3: 1)), resulting in 6-cyano-N-isopropyl-pyridine-3-sulfonamide (3.4 g). 6-Cyano-N-isopropyl-pyridine-3-sulfonamide (2 g) and nickel (with skeletal structure, moved by molybdenum, 280 mg) were dissolved in methanol (2 mL). The mixture was stirred in an autoclave (degassed with hydrogen gas three times). The mixture was stirred at 50 ° C for 12 hours, under a hydrogen atmosphere (50 psi). The mixture was filtered and the volatiles were removed in vacuo. Crude 6- (aminomethyl) -N-isopropyl-pyridine-3-sulfonamide (1.5 g) was used in the next step without purification. 6- (Aminomethyl) -N-isopropyl-pyridine-3-sulfonamide (1.5 g) and 2- (difluoromethyl) -1-fluoro-4-isothiocyanate-benzene (1.3 g) were dissolved in toluene (20 mL ). The mixture was stirred at 120 ° C for 12 hours. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3: 1), resulting in 1- [3- (difluoromethyl) -4-fluoro-phenyl] -3 - [[ 5- (isopropylsulfamoyl) -2-pyridyl] methyl] thiourea (0.9 g). 1- [3- (Difluoromethyl) -4-fluoro-phenyl] -3 - [[5- (isopropylsulfamoyl) -2-pyridyl] methyl] thiourea (0.9 g) and DCC (0.9 g, 4.2 mmol) were dissolved in toluene. The mixture was stirred at 120 ° C for 12 hours. The solvent was removed in vacuo and the residue obtained was purified by reversed-phase high-performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 0 to 30%). The pure fractions were collected and neutralized with solid NaHCO3. The organic solvent was removed in vacuo. The precipitate that 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 until dry, resulting in compound 17 (290 mg). Method B; TA: 3.87 min. m / z: 399.3 (M + H) + Exact mass: 398.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J = 6.3 Hz, 6 H) 3.20-3.33 (m, 1 H) 6.72 (d, J = 9.5 Hz, 1 H) 7.20 (t, J = 53.5 Hz, 1 H) 7.23 - 7.37 (m, 2 H) 7.56 (d, J = 9.5 Hz, 1 H) 7.66-7.85 (m, 2 H) 7.93 (d, J = 3.3 Hz, 1 H) 8.75 (s, 1 H) 9.56 (sl, 1 H) Compound 18

    [00119] 2-Chloropyridine-5-sulfonyl chloride (10 g, 47.1 mmol) and (S) -3-aminotetrahydrofuran tosylate (3.3 g, 38 mmol) were added sequentially at 0 ° C , CH2Cl2 (200 mL), triethylamine was added slowly. The mixture was heated to 25 ° C and was stirred for 2 hours. The mixture was stopped with water, extracted with dichloromethane (100 ml). The organic layer was separated and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (3: 1), resulting in 6-chloro-N - [(3S) -tetrahydrofuran-3-yl] pyridine-3-sulfonamide . Compound 18 was prepared similarly as described for compound 17, using 6-chloro-N - [(3S) -tetrahydrofuran-3-yl] pyridine-3-sulfonamide instead of 6-chloro-N-isopropyl-pyridine -3-sulfonamide and 4-fluoro-3-methylphenyl isothiocyanate instead of 2- (difluoromethyl) -1-fluoro-4-isothiocyanate-benzene. Method B, TA: 3.35 min. m / z: 391.3 (M + H) + Exact mass: 390.1. 19

    [00120] 6-Chloro-N-isopropyl-pyridine-3-sulfonamide (1.03 g, 4.38 mmol) and hydrazine (1.54 g, 48.2 mmol) in EtOH (5 mL) were heated to 85 ° C ° C for 2 hours. The reaction mixture was cooled in an ice bath for 1 hour. The white crystals that formed were collected by filtration, washed with cold ethanol (5 mL) and dried under vacuum at 50 ° C for 2 hours, resulting in 6- hydrazine-N-isopropyl-pyridine-3-sulfonamide (694 mg) . A solution of 4-fluoro-3-methylphenyl isothiocyanate (477 mg; 2.86 mmol) in THF (10 ml) was added gradually over 3 minutes to a solution of 6-hydrazine-N-isopropyl-pyridine- 3-sulfonamide (679 mg; 2.86 mmol) in THF and stirred for 90 minutes. The reaction mixture was concentrated and the resulting white powder was crystallized from acetonitrile / water. The white crystals (844 mg) were collected by filtration and dried under vacuum at 50 ° C. To a solution of part of the white crystals (738 mg) in THF (50 ml), NEt3 (0.62 ml, 4.45 mmol) was added, followed by 2-chloro-1-methylpyridinium iodide (569 mg, 2 , 23 mmol) and stirred. The reaction mixture was left to stand overnight and then concentrated in vacuo. The obtained residue was stirred in CH2Cl2 / 1M HCl 100 ml / 100 ml. A yellow precipitate was collected by filtration, dissolved in a minimum amount of methanol and loaded into a Waters Porapak CX 5 g cartridge (eluted twice with methanol and the product eluted with 2 volumes of 7 M NH3 / CH3OH). After concentrating the product fraction under vacuum, the residue obtained was subjected to silica gel column chromatography (2 to 10% CH3OH in dichloromethane), resulting in compound 19 (75 mg). Method F, TA: 1.59 min. m / z: 364.1 (M + H) + Exact mass: 363.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.01 (d, J = 6.6 Hz, 6 H), 2.26 (d, J = 1.5 Hz, 3 H), 3.25- 3.40 (1H, proton signal under the H2O peak according to 2D-cozy), 7.12 (t, J = 9.1 Hz, 1 H), 7.36 (dd, J = 9.7 , 1.5 Hz, 1 H), 7.52 - 7.59 (m, 1 H), 7.65 (dd, J = 6.8, 2.6 Hz, 1 H), 7.76 (dd , J = 9.7, 0.9 Hz, 1 H), 8.04 (s. 1, 1 H), 9.07 (d, J = 1.1 Hz, 1 H), 9.65 (s 1, 1 H). Biological Examples - anti-HBV activity of compounds of Formula (I)
    [00121] 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 virus particles, which have been shown to cause acute and chronic infection and disease in chimpanzees. For the antiviral assay, cells were treated twice for three days with the 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 probe.
    [00122] Anti-HBV activity was also measured using the HepG2.117 cell line, a stable cell line that produces HBV inducibly that replicates HBV in the absence of doxycycline (Tet-off system). For the antiviral assay, HBV replication was induced, followed by a treatment with the compound serially diluted 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.
    [00123] The cytotoxicity of the compounds was also 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 (12)
    [0001]
    1. Compound, characterized by the fact that it presents Formula (I):
    [0002]
    2. Compound according to claim 1, characterized by the fact that R2 is C1-C3-R6 alkyl or C4-C7 cycloalkyl, being optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo, C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3 and where R6 is a C4-C7 cycloalkyl, optionally substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo , C1-C3 alkyloxy, C1-C4 alkyl, OH, CN, CFH2, CF2H, CF3.
    [0003]
    3. Compound according to claim 1 or 2, characterized by the fact that at least one R3 is independently selected from hydrogen, halogen, C1-C4 alkyl, or a 3 to 5 membered saturated ring optionally containing one or more heteroatoms, each independently selected from the group consisting of O and N.
    [0004]
    Compound according to any one of claims 1 to 3, characterized in that said compound of Formula (I) is a compound of Formula (II) or (I-II):
    [0005]
    Compound according to any one of claims 1 to 4, characterized in that R2 is C5 cycloalkyl or C6 cycloalkyl, optionally being substituted with one or more substituents, each independently selected from the group consisting of hydrogen, halo and C1 alkyl -C4.
    [0006]
    A compound according to any one of claims 1 to 5, characterized in that at least one R3 is independently selected from the group consisting of fluorine, C1-C3 alkyl and cyclopropyl.
    [0007]
    A compound according to any one of claims 1 to 6, characterized by the fact that R1 is hydrogen or methyl.
    [0008]
    A compound according to any one of claims 1 to 7, characterized by the fact that R4 is hydrogen.
    [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]
    A compound according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 9, characterized (a) in that it is for use in preventing or treating an HBV infection in a mammal.
    [0011]
    11. Product, characterized by the fact that it comprises a compound of Formula (I), as defined in any one of claims 1 to 8, and another HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of infections by HBV.
    [0012]
    12. Use of a compound, as defined in any of claims 1 to 8, characterized by the fact that it is in the manufacture of a medicament for the prevention or treatment of an HBV infection in a mammal.
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    同族专利:
    公开号 | 公开日
    PT2890683T|2017-01-17|
    PH12015500386B1|2015-04-27|
    BR112015004161A2|2017-07-04|
    EA201590453A1|2015-06-30|
    JP2015531772A|2015-11-05|
    CL2015000483A1|2015-06-12|
    AU2013307328B2|2017-10-19|
    EP2890683B1|2016-10-12|
    UA115069C2|2017-09-11|
    CA2881045A1|2014-03-06|
    IL237048A|2016-09-29|
    JP6285440B2|2018-02-28|
    WO2014033167A1|2014-03-06|
    DK2890683T3|2017-01-30|
    US9156839B2|2015-10-13|
    MY174042A|2020-03-05|
    EA026957B1|2017-06-30|
    PH12015500386A1|2015-04-27|
    US20150218159A1|2015-08-06|
    HUE031400T2|2017-07-28|
    CN104797561B|2017-03-01|
    CN104797561A|2015-07-22|
    MX2015002695A|2015-05-12|
    SG11201501360TA|2015-03-30|
    CA2881045C|2020-10-13|
    NZ704758A|2018-06-29|
    PL2890683T3|2017-06-30|
    ES2610758T3|2017-05-03|
    MX358015B|2018-08-02|
    KR102148237B1|2020-08-27|
    KR20150047136A|2015-05-04|
    HK1210156A1|2016-04-15|
    EP2890683A1|2015-07-08|
    AU2013307328A1|2015-02-19|
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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]|
    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 |
    2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-06-30| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    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 28/02/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP12182078.1|2012-08-28|
    EP12182078|2012-08-28|
    PCT/EP2013/067814|WO2014033167A1|2012-08-28|2013-08-28|Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis b|
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