N2-arylmethyl-4-haloalkyl-pyridazine-3-one compounds and uses thereof

Abstract

The present invention relates to compounds of formula I: or pharmaceutically acceptable salts or solvates thereof, and their use in treating and / or preventing diseases or disorders associated with CFTR channel activity dysfunction, in particular cystic fibrosis.

Description

Technical Field

[0001] The present invention relates to novel compounds of the N2-arylmethyl-4-haloalkyl-pyridazin-3-one type of formula I and their use in the treatment and / or prevention of diseases or disorders associated with dysfunction of CFTR channel activity, in particular cystic fibrosis. Background Art

[0002] Cystic fibrosis is caused by autosomal recessive mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which encodes the protein of the same name, a transmembrane channel that allows the exchange of ions, particularly chloride, bicarbonate, and small molecules. The disease affects many organs, including the lungs, pancreas, liver, and intestines. Respiratory and digestive problems are the main causes of morbidity and mortality in patients.

[0003] Once diagnosed, (this test is now systematically performed as part of postnatal care), people with cystic fibrosis are followed up in specialized care centers called CRCM (Centre de Ressources and de Competences de la Mucoviscidose). Currently, the treatment offered to them is symptomatic: its aim is to reduce the manifestations of the disease and its complications. It is mainly based on taking mucolytics and bronchodilators, combined with regular physiotherapy sessions. Preventive antibiotic therapy is prescribed to limit the risk of respiratory infections. When respiratory failure is over, oxygen therapy is required. To treat extrapulmonary manifestations, anti-inflammatory treatments, pancreatic extracts, vitamins and caloric supplementation are also prescribed. However, this symptomatic treatment is not satisfactory due to its inconvenient nature (almost 2 hours of care per day), its cost (treatment management, hospitalization costs...) and sometimes significant limitations on its effectiveness.

[0004] Since the discovery of the defective CFTR gene in 1989, research efforts have increased, allowing substantial progress in understanding this disease, and this has opened up several avenues for treatment development.

[0005] The first idea that emerged was to correct the genetic defect that causes the disease through gene therapy. This approach uses modified viral vectors to introduce mutant genes in lung stem cells and then replace the mutant genes with their normal forms. Clinical trials conducted so far have been disappointing because the vectors used (adenovirus, lentivirus) show immunogenicity and the success of targeting stem cells is random.

[0006] The second option (pharmacological therapy) includes the function of correcting CFTR protein. The mutation responsible for the CFTR chloride channel activity dysfunction is divided into seven categories: absence of gene expression synthesis (IA), protein (IB), absence of protein addressing at the membrane (II), absence of function at the membrane (III), reduction of function at the membrane (IV), reduction of the amount of protein at the membrane (V) and reduction of stability at the membrane (VI). The most common mutation in the colony (F508del CFTR-II class) causes the CFTR protein itself to misfold, preventing it from being integrated into the cell membrane. However, other forms of mutant proteins are dysfunctional, even if they are present in the membrane (e.g. mutation G551D-III class). In this article, the nearest goal is to develop molecules that interact with the CFTR protein to allow it to be integrated into the membrane (corrector), or to improve its function (synergist) when it exists but inactive.

[0007] Thus, in 2012, the first potentiator drug developed by the laboratory Vertex Pharmaceuticals Vertex received marketing authorization for Ivacaftor in Europe. At the time, it was intended only for patients carrying the G551D mutation (about 4% of those diagnosed), but the FDA extended the drug's approval to include seven additional mutations in July 2014 and subsequently to include 23 additional mutations in May 2017. Vertex is also developing a combination of the two molecules (one corrector and the other potentiator). (a combination of Lumacaftor, a CFTR corrector, and Ivacaftor), makes it possible to treat patients carrying the most common F508del variant (at least one allele was detected in about 80% of the 2,500 patients in France).

[0008] These molecules are innovative compared to previously available treatments because they correct some of the cellular abnormalities associated with cystic fibrosis rather than treating the symptoms of the disease. However, these treatments are very expensive ( 220,000 Euros / year, 160,000 EUR / year) and has serious side effects (diarrhea, dizziness).

[0009] US patent application US2014 / 274933A1 describes phthalazinone-type compounds and their use in the treatment of pathologies involving the CFTR protein, in particular cystic fibrosis.

[0010] Patent application WO 2016 / 066973 A1 describes fluorinated pyridazin-3-ones and their use as PDE4 inhibitors for the treatment of inflammatory components of bronchopulmonary disorders. However, these compounds do not target the CFTR channel.

[0011] However, there remains a need for new compounds that are able to restore CFTR channel activity, particularly for the treatment of cystic fibrosis. SUMMARY OF THE INVENTION

[0013] The present inventors have now been able to develop new compounds that are able to restore the activity of the CFTR channel.

[0014] Therefore, the present invention relates to compounds of formula I, pharmaceutically acceptable salts and solvates thereof, and use of these compounds or solvates or compositions thereof for treating and / or preventing diseases or conditions associated with CFTR channel activity dysfunction.

[0015] In a first aspect, the present invention relates to compounds of formula I:

[0016] [Chemical formula 1]

[0017]

[0018] or a pharmaceutically acceptable salt or solvate thereof,

[0019] in

[0020] R 1 is cycloalkyl, heteroaryl or aryl, which is optionally substituted by a group selected from alkyl, alkoxy and aralkyl;

[0021] R 2 is H or alkyl;

[0022] R 3 is cycloalkyl, heteroaryl or aryl, which is optionally substituted with one or two groups independently selected from alkyl, alkoxy and haloalkoxy;

[0023] R 4 is H or alkyl;

[0024] R F is a haloalkyl group; and

[0025] Is a single bond or a double bond.

[0026] According to another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0027] As mentioned above, the present invention further relates to the use of compounds according to the present invention or their pharmaceutically acceptable salts or solvates for restoring CFTR channel activity. Therefore, compounds of the present invention and pharmaceutically acceptable solvates thereof can be used for treating and / or preventing diseases or conditions associated with CFTR channel activity dysfunction. Therefore, the present invention further relates to compounds according to the present invention, which are used as medicines, particularly for treating and / or preventing diseases or conditions associated with CFTR channel activity dysfunction, particularly cystic fibrosis.

[0028] Finally, the present invention relates to a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent.

[0029] Further features, details and advantages are given in the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0031] As described above in detail, the present invention relates to compounds of formula I and pharmaceutically acceptable solvates thereof.

[0032] Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein R 1 , R 2 , R 3 , R 4 and R F Those defined in the following way:

[0033] R 1 is a C5-C7 cycloalkyl group, a C5-C6 heteroaryl group or a C6-C10 aryl group, which is optionally substituted by a group selected from a C1-C6 alkyl group, a C1-C4 alkoxy group and a C1-C4 aralkyl group; preferably, R 1 is a C5-C6 cycloalkyl group, a C5-C6 heteroaryl group or a C6 aryl group, which is optionally substituted by a group selected from a C1-C6 alkyl group, a C1-C2 alkoxy group and a C1-C2 aralkyl group; further preferably, R 1 is cyclohexyl, thienyl, pyridyl or phenyl, which is optionally substituted by a group selected from C1-C4 alkyl, C1-C2 alkoxy and C1-C2 aralkyl; more preferably, R 1 is cyclohexyl, thienyl or phenyl, which is optionally substituted by a group selected from methyl, methoxy and phenylethyl;

[0034] R 2 is H or C1-C6 alkyl; preferably, R 2 is H or C1-C4 alkyl; more preferably, R 2 is H or C1-C2 alkyl; more preferably, R 2 is H or methyl; even more preferably, R 2 It is H;

[0035] R 3 is C5-C7 cycloalkyl, C4-C6 heteroaryl or C6-C10 aryl, which is optionally substituted by one or two groups independently selected from C1-C6 alkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; preferably, R 3 is C5-C6 cycloalkyl, C4-C6 heteroaryl or C6 aryl, which is optionally substituted by one or two groups independently selected from C1-C6 alkyl, C1-C2 alkoxy and C1-C2 haloalkoxy; more preferably, R 3 is cyclohexyl, thienyl, pyridyl or phenyl, which is optionally substituted by one or two groups independently selected from C1-C4 alkyl, C1-C2 alkoxy and C1-C2 haloalkoxy; more preferably, R 3 is cyclohexyl, pyridyl or phenyl, which is optionally substituted with one or two groups independently selected from methoxy and difluoromethoxy;

[0036] R 4 is H or C1-C6 alkyl; preferably, R 4 is H or C1-C4 alkyl; more preferably, R 4 is H or C1-C2 alkyl; more preferably, R 4 is H or methyl; even more preferably, R 4 It is H;

[0037] R F is a C1-C6 haloalkyl group; preferably, R F is C1-C4 haloalkyl; more preferably, R F is C1-C2 haloalkyl; more preferably, R F is C1-C2 fluoroalkyl; even more preferably, R F It is trifluoromethyl.

[0038] In fact, and without wishing to be bound by any theory, the inventors believe that the ability of the compounds of the present invention to restore CFTR channel activity is due in particular to the group R 1 The pyridazinone or dihydropyridazinone nucleus is located at the benzyl position.

[0039] In a first embodiment, the compounds of the invention are those of formula II:

[0040] [Chemical formula 2]

[0041]

[0042] and pharmaceutically acceptable salts or solvates thereof,

[0043] Where R 1 , R 2 , R3 , R 4 and R F As defined above for Formula I.

[0044] Preferred compounds of formula II are those of formula IIa:

[0045] [Chemical formula 3]

[0046]

[0047] and pharmaceutically acceptable salts or solvates thereof,

[0048] Where R 1 , R 2 and R 3 As defined above for Formula I.

[0049] Other preferred compounds of formula II are those of formula IIb:

[0050] [Chemical formula 4]

[0051]

[0052] and pharmaceutically acceptable salts or solvates thereof,

[0053] Where R 1 and R 2 As defined above for Formula I, and

[0054] R 5 and R 6 are independently selected from alkoxy and haloalkoxy; preferably, R 5 and R 6 are independently selected from C1-C4 alkoxy and C1-C4 haloalkoxy; more preferably, R 5 and R 6 are independently selected from C1-C2 alkoxy and C1-C2 haloalkoxy; more preferably, R 5 and R 6 Independently selected from methoxy and difluoromethoxy.

[0055] Other preferred compounds of formula II are those of formula IIc:

[0056] [Chemical formula 5]

[0057]

[0058] and pharmaceutically acceptable salts or solvates thereof,

[0059] Where R 1 and R 2 As defined above for Formula I.

[0060] Other preferred compounds of formula II are those of formula IId:

[0061] [Chemical formula 6]

[0062]

[0063] and pharmaceutically acceptable salts or solvates thereof,

[0064] Where R 1 and R 2 As defined above for Formula I.

[0065] In a second embodiment, the compounds of the invention are those of formula III:

[0066] [Chemical formula 7]

[0067]

[0068] and pharmaceutically acceptable salts or solvates thereof,

[0069] Where R 1 , R 2 , R 3 , R 4 and R F As defined above for formula I. Other preferred compounds of formula III are those of formula IIIa:

[0070] [Chemical formula 8]

[0071]

[0072] and pharmaceutically acceptable salts or solvates thereof,

[0073] Where R 1 , R 2 and R 3 As defined above for Formula I.

[0074] Other preferred compounds of formula III are those of formula IIIb:

[0075] [Chemical formula 9]

[0076]

[0077] and pharmaceutically acceptable salts or solvates thereof,

[0078] Where R 1 and R 2 As defined above for Formula I, and

[0079] R 5 and R 6are independently selected from alkoxy and haloalkoxy; preferably, R 5 and R 6 are independently selected from C1-C4 alkoxy and C1-C4 haloalkoxy; more preferably, R 5 and R 6 are independently selected from C1-C2 alkoxy and C1-C2 haloalkoxy; more preferably, R 5 and R 6 Independently selected from methoxy and difluoromethoxy.

[0080] Other preferred compounds of formula III are those of formula IIIc:

[0081] [Chemical formula 10]

[0082]

[0083] and pharmaceutically acceptable salts or solvates thereof,

[0084] Where R 1 and R 2 As defined above for Formula I.

[0085] Other preferred compounds of formula III are those of formula IIId:

[0086] [Chemical formula 11]

[0087]

[0088] and pharmaceutically acceptable salts or solvates thereof,

[0089] Where R 1 and R 2 As defined above for Formula I.

[0090] Particularly preferred compounds of the invention are those listed in Table 1 below:

[0091] [Table 1]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097] Compounds of formula I can be prepared according to reactions known to those skilled in the art. The reaction schemes described in the "Examples" section illustrate possible synthetic methods.

[0098] In a second aspect, the present invention relates to use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for restoring CFTR channel activity.

[0099] Therefore, the compounds of the present invention can be used to treat and / or prevent diseases or conditions with CFTR channel activity dysfunction. Therefore, the present invention also relates to compounds according to the present invention or pharmaceutically acceptable salts or solvates thereof, which are used as medicines, particularly for treating and / or preventing diseases or conditions associated with CFTR channel activity dysfunction.

[0100] These diseases or conditions include cystic fibrosis and complications associated therewith.

[0101] In a preferred embodiment, the invention relates to compounds of formula I as described above for use in the treatment of cystic fibrosis.

[0102] According to another aspect, the present invention also relates to a method for treating the above-mentioned diseases and disorders, which comprises administering to a patient an effective dose of a compound according to the present invention or a pharmaceutically acceptable salt or solvate thereof. Preferably, the patient is a warm-blooded animal, more preferably a human.

[0103] According to another aspect, the present invention relates to a method for restoring CFTR channel activity in a patient in need thereof, preferably a warm-blooded animal, more preferably a human, comprising administering to the patient an effective dose of a compound according to the present invention or a pharmaceutically acceptable salt or solvate thereof.

[0104] According to one embodiment, the compounds of the invention, their pharmaceutically acceptable salts or solvates can be administered as part of a multitherapy. Thus, the scope of the invention includes embodiments comprising co-administration of a composition or medicament further containing a compound of the invention or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, one or more additional therapeutic agents and / or active ingredients. Such multiple treatment regimens, often referred to as multitherapy, can be used to treat and / or prevent cystic fibrosis.

[0105] Therefore, the treatment methods and pharmaceutical compositions of the present invention can be used as a monotherapy using a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, but these methods and compositions can also be used in a multitherapy form, wherein one or more compounds of the present invention or a pharmaceutically acceptable salt or solvate thereof are co-administered in combination with one or more other therapeutic agents. Such additional therapeutic agents include, but are not limited to, ivacaftor, rumacaftor and / or tizacaftor, preferably ivacaftor. In particular, such additional therapeutic agents are selected from ivacaftor and rumacaftor.

[0106] The present invention also relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient. The excipient is selected from conventional excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration. As described above, the present invention also relates to a pharmaceutical composition comprising, in addition to the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, one or more additional therapeutic agents and / or active ingredients.

[0107] The pharmaceutical composition of the present invention can be selected from pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, local, partial region, intratracheal, intranasal, transdermal or rectal administration. In these compositions, the active ingredient of the above-mentioned formula I or its pharmaceutically acceptable solvate can be applied to animals and humans in a unit application form mixed with conventional pharmaceutical excipients for the treatment and / or prevention of the above-mentioned diseases or conditions. Suitable unit application forms include oral forms, such as tablets, soft capsules or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal application forms, inhalation, local, transdermal, subcutaneous, intramuscular or intravenous application forms, rectal application forms and implants. For topical application, the compound according to the present invention can be used in creams, gels, ointments or lotions. In a preferred embodiment, it consists of a pharmaceutical composition for oral administration. Such suitable application forms that can be solid, semisolid or liquid forms according to the mode of administration are generally known to those skilled in the art, with reference to the latest edition of "Remington's Pharmaceutical Sciences".

[0108] definition

[0109] The definitions and explanations set out below relate to terms and expressions used in this application, including the specification and claims.

[0110] For the purpose of describing the compounds of the present invention, the terms and expressions used are to be interpreted in accordance with the following definitions unless otherwise indicated.

[0111] The term "halo" or "halogen", alone or as part of another group, refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are chlorine and fluorine, particularly preferred is fluorine.

[0112] The term "alkyl", alone or as part of another group, means a group of the formula C n H 2n+1 wherein n is an integer greater than or equal to 1.

[0113] The term "haloalkyl" or "haloalkyl", alone or as part of another group, means an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen group as defined above. The haloalkyl group according to the present invention may be linear or branched, and includes, but is not limited to, a group of formula C n F 2n+1 wherein n is an integer greater than or equal to 1, preferably an integer from 1 to 10. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, nonafluoro-n-butyl, 1,1,1-trifluoro-n-butyl, 1,1,1-trifluoro-n-pentyl and 1,1,1-trifluoro-n-hexyl, with trifluoromethyl and difluoromethyl being particularly preferred.

[0114] The term "alkoxy", alone or as part of another group, means an alkyl group as defined above attached to an oxygen atom. Preferred alkoxy groups include methoxy, ethoxy, propoxy and butoxy, with methoxy being particularly preferred.

[0115] The term "haloalkoxy" or "haloalkoxy", alone or as part of another group, refers to a haloalkyl group as defined above attached to an oxygen atom. Preferred haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloroethoxy, dichloroethoxy and trichloroethoxy, with difluoromethoxy being particularly preferred.

[0116] The term "cycloalkyl", alone or as part of another group, means a saturated monocyclic, bicyclic or tricyclic hydrocarbon radical having 3 to 12 carbon atoms, particularly 5 to 10 carbon atoms, more particularly 6 to 10 carbon atoms. Suitable cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, adamantyl, particularly adamantane-1-yl and adamantane-2-yl, 1-decalinyl. Preferred cycloalkyl radicals include cyclopropyl, cyclohexyl and cycloheptyl. A particularly preferred cycloalkyl radical is cyclohexyl.

[0117] The term "aryl", alone or as part of another group, means a polyunsaturated aromatic hydrocarbon radical having a single ring (phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms, preferably 6 to 10, wherein at least one ring is aromatic. A particularly preferred aryl group is phenyl.

[0118] The term "heteroaryl", alone or as part of another group, means but is not limited to an aromatic ring or ring system containing 1-2 rings fused together, typically containing 5-12 atoms, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, the nitrogen and sulfur heteroatoms are optionally oxides and the nitrogen heteroatom is optionally quaternized. Non-limiting preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl. Particularly preferred heteroaryls are thienyl and pyridyl.

[0119] The compounds of the present invention containing basic functional groups can be in the form of pharmaceutically acceptable salts. In particular, pharmaceutically acceptable salts of the compounds of the present invention containing one or more basic functional groups include acid addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples of salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharinate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0120] Pharmaceutically acceptable salts of compounds of formula I and its subformulae can be prepared, for example, as follows:

[0121] (i) reacting a compound of formula I or any subformula thereof with a desired acid; or

[0122] (ii) converting a salt of a compound of formula I or any subformula thereof into another by reaction with a suitable acid or passing through a suitable ion exchange column.

[0123] All of these reactions are usually carried out in solution. The salt may precipitate from solution and may be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the salt may vary from fully ionized to almost non-ionized.

[0124] The compounds of formula I may exist in the form of solvates, ie as an association or combination with one or more solvent molecules (eg ethanol or water). When the solvent is water, the term "hydrate" is used.

[0125] All references to compounds of the formula I also refer to their solvates.

[0126] The compounds of the present invention are compounds of formula I as defined above and solvates thereof, including all polymorphs and crystalline forms thereof, prodrugs and isotopically labeled compounds or solvates thereof.

[0127] The term "patient" refers to a warm-blooded animal, preferably a human, awaiting or receiving medical treatment.

[0128] The term "human" refers to subjects of both sexes and at any stage of development (ie, newborns, infants, adolescents, young adults and adults). In one embodiment, this is a young adult or an adult, preferably an adult.

[0129] The terms "treat" and "treatment" are to be understood in their ordinary sense and thus include both amelioration and elimination of the disease state.

[0130] The term "preventing" means avoiding or delaying the onset of a disease or condition and associated symptoms, thereby excluding or reducing the risk of a patient developing the disease or condition.

[0131] The term "therapeutically effective dose" or "effective dose" means a dose of the active ingredient (compound of Formula I) sufficient to achieve the desired therapeutic or prophylactic result in the patient to whom it is administered.

[0132] The term "pharmaceutically acceptable" refers to a compound or ingredient that is not deleterious to patients and, in the context of a pharmaceutical composition, is compatible with the other ingredients.

[0133] The present invention will be better understood with reference to the following examples. These examples are representative of certain embodiments of the present invention and are in no way intended to limit the scope of the present invention. These figures are used to illustrate experimental results. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Figure 1

[0135] [ Figure 1 ] show an in vitro screening of restoration of CFTR channel activity of compounds 1 and 4 according to the present invention compared to ivacaftor, rumacaftor and Orkambi.

[0136] Figure 2

[0137] [ Figure 2 ] show in vitro screening of CFTR channel activity restoration of compounds 1-6 according to the present invention.

[0138] Figure 3

[0139] [ Figure 3 ] show in vitro screening of CFTR channel activity restoration of compounds 7-11 and 13 according to the present invention.

[0140] Figure 4

[0141] [ Figure 4 ] show in vitro evaluation of restoration of CFTR channel activity of compounds according to the invention.

[0142] Figure 5

[0143] [ Figure 5 ] show an in vitro evaluation of restoration of CFTR channel activity of compounds 1-4 according to the invention in combination with ivacaftor and rumacaftor compared to Orkambi. DETAILED DESCRIPTION

[0144] Chemical synthesis

[0145] Unless otherwise indicated, all temperatures are in °C and all reactions are carried out at ambient temperature (AT).

[0146] By coating with silica gel and UV254 fluorescent indicator ( The reaction was monitored by thin layer chromatography (TLC) on ready-to-use aluminum plates (60F254 Merck, 0.2 mm thick). Visualization of the spots was performed by UV light (254 or 366 nm). The color developer used was iodine; for amines or ninhydrin solutions (0.3 g ninhydrin and 3 mL acetic acid in 100 mL butan-1-ol or 0.2 g ninhydrin in 100 mL ethanol).

[0147] Preparative column chromatography was performed by silica gel chromatography technique. 60ACC Chromagel with a particle size of 70-200 μm was used. Silica gel is used for so-called standard silica column chromatography. "Flash" silica column chromatography uses a particle size of 40-63 μm under the trade name Kieselgel 60 is made of silica gel.

[0148] NMR analysis was performed on a BRUKER 199DPX 300 spectrometer using a 7.05T superconducting magnet (1H resonates at 300MHz, 13C resonates at 75MHz). Spectra were recorded in deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as an internal standard, or in deuterated methanol (CD3OD) or in a solution in deuterated dimethyl sulfoxide (DMSO-d6). Chemical shifts are given in ppm and then in multiplicity for proton spectra, where s, d, t, q, dd, td and m represent singlet, doublet, triplet, quadrupole, doublet of doublet, triplet of doublet and multiplet (or poorly resolved mass) respectively. Where appropriate, multiplicity is followed by the value of the coupling constant, which is labeled J and represented in Hertz (Hz).

[0149] Low mass spectra (MS) and high resolution mass spectra (HREIMS) electron impact (EI) were recorded at -70 eV on a WATERS MICROMASS GCT CA 170 instrument. Electrospray ionization mass spectra (ESI) were recorded in positive mode (ESI+) or negative mode (ESI-) on a THERMOFINNIGAN MSQ instrument coupled to a quadrupole detector.

[0150] Solvents, reagents, and starting materials were purchased from well-known chemical suppliers, such as Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, Sopachem, and Polymer, and used without additional purification unless otherwise noted.

[0151] The following abbreviations are used:

[0152] ACOH: acetic acid,

[0153] EA: ethyl acetate,

[0154] TLC: Thin layer chromatography,

[0155] Eq. or equiv.: equivalent,

[0156] EP: petroleum ether,

[0157] EtOH: ethanol,

[0158] MeOH: methanol,

[0159] MS: mass spectrometry,

[0160] NMR: Nuclear Magnetic Resonance,

[0161] AT: Ambient temperature,

[0162] TBAB: Tetrabutylammonium bromide,

[0163] TFA: trifluoroacetic acid,

[0164] THF: tetrahydrofuran.

[0165] [Solution 1]

[0166]

[0167] Reagents and conditions: (i) THF, 0-25°C, 10 h; (ii) TFA, water, reflux; (iii) AcOH, reflux or EtOH, AT; (iv) CuCl2, CH3CN, reflux, 4 h; (v) K2CO3, TBAB, CH3CN, reflux, 4 h.

[0168] General method: From the R corresponding to CF3 F Starting from a fluorinated ketene dithioacetal compound of formula [a].

[0169] Compound [a] is reacted with potassium enolate in tetrahydrofuran (THF) as a solvent at a temperature of 0-25° C. for about 10 hours. Intermediate [b] is thus obtained, which is shown in the figure and corresponds to a perfluorinated dithioacetal compound.

[0170] Then, the intermediate of formula [b] is subjected to an acid hydrolysis reaction under reflux heating in the presence of trifluoroacetic acid (TFA) and water. The acid hydrolysis reaction allows the second thioester intermediate of formula [c] to be obtained.

[0171] Then, the intermediate compound [c] can be subjected to a condensation reaction with hydrazine (NH2NH2). The reaction is carried out in a reflux heater device for about 4-5 hours in the presence of glacial acetic acid. After cooling, the solvent is advantageously evaporated under vacuum. Then, the compound [d] according to the present invention is purified by column chromatography. According to a preferred embodiment, the purification of the compound [d] is advantageously carried out in the presence of a mixture of petroleum ether and ethyl acetate by silica gel chromatography.

[0172] Compound [d] in acetonitrile was mixed with cupric chloride under an argon atmosphere. The mixture was refluxed for 4 hours. After cooling, the crude product was purified by column chromatography to obtain compound [e].

[0173] Under an argon atmosphere, compound [e] in acetonitrile is mixed with potassium carbonate (K2CO3) and tetrabutylammonium bromide (TBAB). After 2 hours, benzyl halide is added to the reaction medium. The mixture is refluxed for 4 hours. After cooling, the crude reaction product is purified by a chromatographic column so that the compound according to the present invention can be obtained.

[0174] In a complementary manner, certain compounds according to the invention can be obtained after functionalized benzylhydrazine is added directly to intermediate [c]. The intermediate [f] obtained is oxidized in acetonitrile in the presence of cupric chloride. The mixture is refluxed for 4 hours. After cooling, the crude reaction product is purified by a chromatographic column so that the compound according to the invention can be obtained.

[0175] General synthetic method for synthesizing intermediate [b]

[0176] - mixing the potassium hydride solution and the acetophenone solution in the presence of a solvent, preferably tetrahydrofuran (THF), preferably under an argon atmosphere at 0° C.; this constitutes mixture 1;

[0177] - after stirring for 10-20 minutes, preferably 15 minutes, adding a solution of perfluoroethylene dithioacetal of formula [a] to said mixture 1, which constitutes mixture 2(i);

[0178] - stirring the mixture 2 at ambient temperature for 2h45 to 3h30, preferably 3h;

[0179] - the reaction is carried out while being hydrolyzed with water in the mixture 2;

[0180] - extracting the aqueous phase of mixture 2, in particular with ether;

[0181] - drying the organic phase of said mixture 2, preferably over magnesium sulfate;

[0182] - the organic phase of mixture 2 is filtered and evaporated, preferably under reduced pressure;

[0183] - Column chromatography is performed to obtain said compound [b], advantageously in the form of an oil.

[0184] 1-(3,4-dimethoxyphenyl)-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one[b1]

[0185] Compound [b1] was prepared from (perfluoroprop-1-ene-1,1-diyl)bis(ethylsulfane) [a] (500 mg, 2.13 mmol, 1 eq), 1-(3,4-dimethoxyphenyl)ethanone (471 mg, 2.56 mmol, 1.2 eq) and potassium hydride (683 mg, 4.26 mmol, 2 eq) according to the general method for synthesizing intermediate [b], and obtained as a yellow liquid after purification by flash silica gel column chromatography (EP / EA: 90 / 10). Yield: 70% (587 mg).

[0186] NMR 1 H(CDCl3):δ1.22(t, 3 J H,H =7.5Hz,3H,CH3CH2S),1.34(t,

[0187] 3 J H,H =7.5Hz,3H,CH3CH2S),2.81-2.91(m,4H,CH3CH2S),3.93(s,3H,OCH3),3.97(s,3H,OCH3),4.40(s,2H,CH2),6.92(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.56(d, 4 J H,H=1.8Hz,1H,CH Ar ),7.63(dd, 3 J H,H =8.4, 4 J H,H =2.1Hz,1H,CH Ar ).

[0188] 1-(4-difluoromethoxy)-3-methoxyphenyl)-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one[b2]

[0189] Compound [b2] was prepared from (perfluoroprop-1-ene-1,1-diyl)bis(ethylsulfane) [a] (187 mg, 0.8 mmol, 1 eq), 1-(4-(difluoromethoxy)-3-methoxyphenyl)ethanone (208 mg, 0.96 mmol, 1.2 eq) and potassium hydride (257 mg, 1.6 mmol, 2 eq) according to the general method for synthesizing intermediate [b], and obtained as colorless crystals after purification by flash silica gel column chromatography (EP / EA: 98 / 2). Yield: 85% (291 mg).

[0190] NMR 1 H(CDCl3):δ1.26(t, 3 J H,H =7.2Hz,3H,CH3CH2S),1.34(t,

[0191] 3 J H,H =7.5Hz,3H,CH3CH2S),2.81-2.91(m,4H,CH3CH2S),3.94(s,3H,OCH3),4.41(s,2H,CH2),6.65(t, 2 J H,F =74.4Hz,1H,OCHF2),7.25(d, 3 J H,H =7.2Hz,1H,CH Ar ),7.58(dd, 3 J H,H =8.4, 4 J H,H =2.1Hz,1H,CH Ar ),7.64(d, 4 J H,H =2.1Hz,1H,CH Ar ).

[0192] 1-Cyclohexyl-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one[b3]

[0193] Compound [b3] was prepared from (perfluoroprop-1-ene-1,1-diyl)bis(ethylsulfane) [a] (700 mg, 3.0 mmol, 1 eq), 1-cyclohexyl ethyl ketone (519 μL, 3.6 mmol, 1.2 eq) and potassium hydride (962 mg, 6.0 mmol, 2 eq) according to the general method for synthesizing intermediate [b], and obtained as a light yellow liquid after purification by flash silica gel column chromatography (EP / EA: 99.5 / 0.5). Yield: 74% (760 mg).

[0194] NMR 1 H(CDCl3):δ1.21(t, 3 J H,H =7.2Hz,3H,CH3CH2S),1.29(t, 3 J H,H =7.2Hz,3H,CH3CH2S),1.34-1.46(m,6H,3x CH 2环己基 ),1.65-1.92(m,4H,2x CH 2环己基 ),2.38-2.48(m,1H,CH 环己基 ),2.83(q, 3 J H,H =7.5Hz,4H,2x CH3CH2S),3.87(s,2H,CH2).

[0195] 4,4-Bis(ethylthio)-1-(pyridin-2-yl)-3-(trifluoromethyl)but-3-en-1-one[b4]

[0196] Compound [b4] was prepared from (perfluoroprop-1-ene-1,1-diyl)bis(ethylsulfane) [a] (469 mg, 2.0 mmol, 1 eq), 1-(pyridin-2-yl)ethanone (291 mg, 2.4 mmol, 1.2 eq) and potassium hydride (642 mg, 4.0 mmol, 2 eq) according to the general method for synthesizing intermediate [b], and was obtained as a yellow liquid after purification by flash silica gel column chromatography (EP / EA: 95 / 5). Yield: 70% (561 mg).

[0197] NMR 1 H(CDCl3):δ1.21(t, 3 J H,H =7.2Hz,3H,CH3CH2S),1.34(t,

[0198] 3 J H,H=7.5Hz,3H,CH3CH2S),2.80-2.91(m,4H,CH3CH2S),4.70(s,2H,CH2),7.48-7.53(m,1H,CH Ar ),7.85(dt, 3 J H,H =8.1, 4 J H,H =1.8Hz,1H,CH Ar ),8.06(d, 3 J H,H =7.8Hz,1H,CH Ar ),8.71(d, 4 J H,H =4.5Hz,1H,CH Ar ).

[0199] General synthetic method for synthetic intermediate [c]

[0200] - mixing the compound [b] with water and trifluoroacetic acid (TFA), which constitutes mixture 3(ii);

[0201] - reflux the mixture 3 for a period of about 10 h;

[0202] - after cooling, neutralize the mixture 3 with a saturated aqueous solution, preferably with NaHCO3;

[0203] - extracting the aqueous phase of mixture 3, preferably with dichloromethane;

[0204] - the organic phase of mixture 3 was dried, filtered and evaporated;

[0205] - Column chromatography is performed to obtain said compound [c], advantageously in the form of an oil.

[0206] S-4-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1]

[0207] Compound [c1] was prepared from 1-(3,4-dimethoxyphenyl)-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one [b1] (594 mg, 1.5 mmol, 1 eq), TFA (1.04 mL, 13.6 mmol, 9 eq) and water (0.082 mL, 4.53 mmol, 3 eq) according to the general method for the synthesis of intermediate [c], and obtained as a yellow oil after purification by flash silica gel column chromatography (EP / EA: 90 / 10). Yield: 89% (470 mg).

[0208] NMR 1 H(CDCl3):δ1.28(t,3 J H,H =7.5Hz,3H,CH3CH2S),

[0209] 2.85-3.10(m,2H,CH3CH2S),3.31(dd, 2 J H,H =15.0, 3 J H,H =3.0Hz,1H,CH A H B CO),3.85(dd, 2 J H,H =15.0, 3 J H,H =12.0Hz,1H,CH A H B CO),3.91(s,3H,OCH3),3.96(s,3H,OCH3),4.0-4.2(m,1H,CHCF3),6.90(d, 3 J H,H =8.3Hz,1H,CH Ar ),7.51(d, 4 J H,H =3.0Hz,1H,CH Ar ),7.61(dd, 3 J H,H =8.3, 4 J H,H =3.0Hz,1H,CH Ar ).

[0210] S-4-(4-(difluoromethoxy)-3-methoxyphenyl)-4-oxo-2-(trifluoromethyl)butanethiol ethyl ester [c2]

[0211] Compound [c2] was prepared from 1-(4-difluoromethoxy)-3-methoxyphenyl)-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one [b2] (290 mg, 0.67 mmol, 1 eq) / TFA (0.467 mL, 6.06 mmol, 9 eq) and water (0.036 mL, 2.01 mmol, 3 eq) according to the general method for synthesizing intermediate [c], and obtained as an orange liquid after purification by flash silica gel column chromatography (EP / EA: 95 / 5). Yield: 78% (200 mg).

[0212] NMR 1 H(CDCl3):δ1.29(t, 3 J H,H =7.5Hz,3H,CH3CH2S),

[0213] 2.87-3.07(m,2H,CH3CH2S),3.32(dd, 2 J H,H =18.0Hz, 3 J H,H =3.0Hz,1H,CH A H B CO),3.88(dd, 2 J H,H =18.0Hz, 3 J H,H =10.2Hz,1H,CH A H B CO),3.94(s,3H,OCH3),4.02-4.15(m,1H,CHCF3),6.65(t, 2 J H,H =74.3Hz,1H,CHCF2),7.24(d, 3 J H,H =7.8Hz,1H,CH Ar ),7.56-7.59(m,2H,2x CH Ar ).

[0214] S-4-cyclohexyl-4-oxo-2-(trifluoromethyl)thiobutyric acid ethyl ester [c3]

[0215] Compound [c3] was prepared as a brown liquid from 1-cyclohexyl-4,4-bis(ethylthio)-3-(trifluoromethyl)but-3-en-1-one [b3] (750 mg, 2.20 mmol, 1 eq), TFA (1.527 mL, 19.8 mmol, 9 eq) and water (0.119 mL, 6.60 mmol, 3 eq) according to the general method for the synthesis of intermediate [c]. Yield: 95% (618 mg).

[0216] NMR 1 H(CDCl3):δ1.27(t, 3 J H,H =7.5Hz,3H,CH3CH2S),1.23-1.42(m,4H,2xCH 2cyclohexyl ),1.66-1.94(m,6H,3x CH 2cyclohexyl ),2.33-2.42(m,1H,CH cyclohexyl ),2.82(dd, 2 J H,H =18.3Hz, 3 J H,H =3.3Hz,1H,CH A H BCO),2.95(dq, 2 J H,H =7.5Hz, 3 J H,H =3.3Hz,2H,CH3CH2S),3.32(dd, 2 J H,H =18.3Hz, 3 J H,H =10.2Hz,1H,CH A H B CO), 3.83-3.96 (m, 1H, CHCF3).

[0217] S-4-oxo-4-(pyridin-2-yl)-2-(trifluoromethyl)thiobutyric acid ethyl ester [c4]

[0218] Compound [c4] was prepared from 4,4-bis(ethylthio)-1-(pyridin-2-yl)-3-(trifluoromethyl)but-3-en-1-one [b4] (550 mg, 1.64 mmol, 1 eq), TFA (1.137 mL, 14.80 mmol, 9 eq) and water (0.088 mL, 4.92 mmol, 3 eq) according to the general method for the synthesis of intermediate [c], and obtained as a yellow lacquer after purification by flash silica gel column chromatography (EP / EA: 90 / 10). Yield: 26% (120 mg).

[0219] 1 H NMR (CDCl3): δ1.28 (t, 3 J H,H =7.5Hz,3H,CH3CH2S),2.91-3.04(m,2H,CH3CH2S),3.69(dd, 2 J H,H =18.6Hz, 3 J H,H =2.1Hz,1H,CH A H B CO), 4.02-4.20(m,2H,CH A H B CO,CHCF3),7.52(ddd, 3 J H,H =7.5Hz, 3 J H,H =4.8Hz, 4 J H,H =1.5Hz,1H,CH Ar ),7.86(dt, 3 J H,H =7.8Hz, 4 J H,H=1.8Hz,1H,CH Ar ),8.03(td, 3 J H,H =8.1Hz, 4 J H,H =1.2Hz,1H,CH Ar ),8.71(d, 3 J H,H =4.5Hz,1H,CH Ar ).

[0220] General method for the synthesis of intermediate [d]

[0221] - mixing the compound [c] with glacial acetic acid and hydrazine monohydrate; this constitutes mixture 4(iii);

[0222] - reflux the mixture 4, preferably for about 1 hour;

[0223] - After filtration, washing and vacuum drying, the product [d] is obtained in pure form or in the form of a mixture;

[0224] - If necessary, column chromatography is performed to advantageously obtain compound [d].

[0225] 6-(3',4'-Dimethoxyphenyl)-4-trifluoromethyl-4,5-dihydropyridazin-3(2H)-one[d1]

[0226] Compound [d1] was prepared from S-4-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1] (500 mg, 1.4 mmol, 1 eq) and hydrazine (35% in water) (1.616 mL, 17.8 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [d], and obtained as a white solid after purification by flash silica gel column chromatography (CH2Cl2 / MeOH: 99 / 1). Yield: 76% (320 mg).

[0227] NMR 1 H(CDCl3): δ3.09-3.43(m,3H,CH2CHCF3),3.93(brs,6H,2×OCH3),6.88(d, 3 J H,H =8.3Hz,1H,CH Ar ),7.18(d, 3 J H,H =8.3Hz,1H,CH Ar ),7.40(brs,1H,CH Ar ),8.91(brs,1H,NH).

[0228] 4-(difluoromethoxy)-3-methoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[d2]

[0229] Compound [d2] was prepared from S-4-(4-(difluoromethoxy)-3-methoxyphenyl)-4-oxo-2-(trifluoromethyl)butanethiol ethyl ester [c2] (100 mg, 0.25 mmol, 1 eq) and hydrazine (35% in water) (0.282 mL, 3.13 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [d] and obtained as a beige solid after purification by flash silica column chromatography (PE / EA: 80 / 20). Yield: 100% (086 mg).

[0230] NMR 1 H(CD3OD):δ3.17(dd, 2 J H,H =17.7Hz, 3 J H,H =9.9Hz,1H,CH A H B CHCF3),3.37(dd, 2 J H,H =17.4Hz, 3 J H,H =7.5Hz,1H,CH A H B CHCF3),3.61-3.76(m,1H,CHCF3),6.90(t, 2 J H,F =73.8Hz,1H,OCHF2),7.18(d, 3 J H,H =9.0Hz,2H,2x CH Ar ),7.84(d, 3 J H,H =9.0Hz,2H,2x CH Ar ).

[0231] General synthetic method for synthetic intermediate [e]

[0232] - Compound [d] is mixed with copper chloride in anhydrous acetonitrile under an argon atmosphere, which constitutes mixture 5(iv);

[0233] - reflux the mixture 5, preferably for about 4 hours;

[0234] - After cooling, the mixture 5 was evaporated and purified by column chromatography to obtain the product [e] in the form of a solid.

[0235] 6-(3',4'-Dimethoxyphenyl)-4-trifluoromethyl-pyridazin-3(2H)-one[e1]

[0236] Compound [e1] was prepared from 6-(3',4'-dimethoxyphenyl)-4-trifluoromethyl-4,5-dihydropyridazin-3(2H)-one [d1] (300 mg, 1.0 mmol, 1 eq) and copper (II) chloride (269 mg, 2.0 mmol, 2 eq) according to the general method for the synthesis of intermediate [e], and obtained as a dark yellow solid after purification by flash silica gel column chromatography (CH2Cl2 / MeOH: 98 / 2). Yield: 85% (256 mg).

[0237] NMR 1 H(CDCl3): δ3.95(s,3H,OCH3),3.98(s,3H,OCH3),6.95(d, 3 J H,H =8.3Hz,1H,CH Ar ),7.29(d, 3 J H,H =8.3Hz,1H,CH Ar ),7.46(brs,1H,CH Ar ),8.06(m,1H,CH pyr ),11.9(brs,1H,NH).

[0238] 6-(4-(difluoromethoxy)-3-methoxyphenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one[e2]

[0239] Compound [e2] was prepared from 6-(4-(difluoromethoxy)phenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one [d2] (16 mg, 0.05 mmol, 1 eq) and copper (II) chloride (13 mg, 0.10 mmol, 2 eq) according to the general method for the synthesis of intermediate [e], and obtained as beige crystals after purification by flash silica gel column chromatography (PE / EA: 80 / 20). Yield: 81% (13 mg).

[0240] NMR 1 H(CD3OD): δ3.96(s,3H,OCH3),6.80(t, 2 J H,F =75.0Hz,

[0241] 1H,OCHF2),7.25(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.49(dd,2 J H,H =8.4Hz, 3 J H,H =1.8Hz,1H,CH Ar ),7.65(d, 4 J H,H =2.1Hz,1H,CH Ar ),8.36(d, 5 J H,H =1.2Hz,1H,CH pyr ).

[0242] General method for the synthesis of intermediate [f]

[0243] - mixing said compound [c] with glacial acetic acid and functionalized "benzylhydrazine"; this constitutes mixture 4(iii);

[0244] - reflux the mixture 4, preferably for about 1 hour;

[0245] - After filtration, washing and vacuum drying the pure product [f] was obtained.

[0246] 2-Benzyl-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f1]

[0247] Compound [f1] was prepared from S-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1] (100 mg, 0.29 mmol, 1 eq) and dihydrochlorinated benzylhydrazine (718 mg, 3.68 mmol, 12.5 eq) according to the general method for synthesizing intermediate [f], and purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain a beige solid. Yield: 47% (54 mg).

[0248] NMR 1 H(CDCl3): δ3.05-3.23(m,2H,CH2CHCF3),3.27-3.41(m,1H,CHCF3),3.91(s,6H,2x OCH3),5.01(d, 2 J H,H =14.4Hz,1H,NCH A H B ),5.08(d, 2 J H,H =14.4Hz,1H,NCH A H B ),6.86(d, 3 J H,H =8.4Hz,1H,CH Ar),7.18(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.26-7.42(m,6H,6x CH Ar ).

[0249] 6-(3,4-dimethoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f2]

[0250] Compound [f2] was prepared from S-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1] (100 mg, 0.29 mmol, 1 eq) and dechlorinated 4-methylbenzylhydrazine (626 mg, 3.63 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f], and isolated as a white solid after purification by flash silica gel column chromatography (PE / EA: 80 / 20). Yield: 32% (40 mg).

[0251] NMR 1 H(CDCl3): δ2.33(s,3H,CH3),3.05-3.25(m,2H,CH2CHCF3),3.25-3.40(m,1H,CHCF3),3.92(s,3H,OCH3),3.93(s,3H,OCH3),4.97(d, 2 J H,H =14.3Hz,1H,NCH A H B ),5.04(d, 2 J H,H =14.3Hz,1H,NCH A H B ),6.87(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.13(d, 3 J H,H =7.8Hz,2H,2xCH Ar ),7.18(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.31(d, 3 J H,H =7.8Hz,2H,2x CH Ar ),7.38(d,4 J H,H =2.1Hz,1H,CH Ar ).

[0252] 6-(3,4-dimethoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f3]

[0253] Compound [f3] was prepared from S-4-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1] (100 mg, 0.29 mmol, 1 eq) and 4-methylbenzylhydrazine (789 mg, 3.63 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f] and isolated as a yellow solid after purification by flash silica gel column chromatography (PE / EA: 80 / 20). Yield: 51% (62 mg).

[0254] NMR 1 H(CDCl3): δ3.04-3.22(m,2H,CH2CHCF3),3.24-3.39(m,1H,CHCF3),3.79(s,3H,OCH3),3.92(s,3H,OCH3),3.93(s,3H,OCH3),4.94(d, 2 J H,H =14.1Hz,1H,NCH A H B ),5.02(d, 2 J H,H =14.1Hz,1H,NCH A H B ),6.83-6.88(m,3H,3x CH Ar ),7.18(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.33-7.39(m,3H,3x CH Ar ).

[0255] 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f4]

[0256] Compound [f4] was prepared from S-(4-(difluoromethoxy)-3-methoxyphenyl)-4-oxo-2-(trifluoromethyl)butanethiol ethyl ester [c2] (100 mg, 0.26 mmol, 1 eq) and 4-methoxybenzylhydrazine (703 mg, 3.24 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f] and isolated as a beige solid after purification by flash silica gel column chromatography (PE / EA: 80 / 20). Yield: 62% (0.074 g).

[0257] NMR 1 H(CDCl3): δ3.07-3.41(m,3H,CH2CHCF3),3.79(s,3H,OCH3),3.93(s,3H,OCH3),4.95(d, 2 J H,H =14.1Hz,1H,NCH A H B ),5.03(d, 2 J H,H =14.1Hz,1H,NCH A H B ),6.59(t, 2 J H,F =74.7Hz,1H,CHF2),6.86(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),7.19(s,2H,2x CH Ar ),7.35(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),7.42(s,1H,CH Ar ).

[0258] 2-Benzyl-6-cyclohexyl-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f5]

[0259] Compound [f5] was prepared from S-4-cyclohexyl-4-oxo-2-(trifluoromethyl)butanethiol ethyl ester [c3] (150 mg, 0.50 mmol, 1 eq) and dihydrochlorinated benzylhydrazine (1257 mg, 6.25 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f] and isolated as a beige oil after purification by flash silica gel column chromatography (PE / EA: 90 / 10). Yield: 83% (141 mg).

[0260] NMR 1 H(CDCl3):δ1.26-1.34(m,5H,5x CH环己基 ),1.68-1.82(m,5H,5x CH 环己基 ),2.22-2.30(m,1H,CH 环己基 ),2.66(s,1H,CH A H B CHCF3), 2.68(s,1H,CH A H B CHCF3),3.13-3.27(m,1H,CHCF3),4.88(d, 2 J H,H =14.6Hz,1H,NCH A H B ),4.95(d, 2 J H,H =14.6Hz,1H,NCH A H B ),7.24-7.35(m,5H,5x CH Ph ).

[0261] 2-(Cyclohexylmethyl)-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one[f6]

[0262] Compound [f6] was prepared from S-4-(3',4'-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-thiobutyric acid ethyl ester [c1] (100 mg, 0.29 mmol, 1 eq) and hydrochlorinated cyclohexylmethylhydrazine (597 mg, 3.63 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f] and isolated as a yellow oil after purification by flash silica gel column chromatography (PE / EA: 90 / 10). Yield: 25% (29 mg).

[0263] 1 H NMR(CDCl3):δ0.85-0.95(m,2H,CH 2cyclohexyl ),1.14-1.24(m,2H,CH 2cyclohexyl ),1.46-1.88(m,7H,CH cyclohexyl ,3x CH 2cyclohexyl ),3.07-3.23(m,2H,CH2),3.25-3.40(m,1H,CH-CF3),3.67(dd, 2 J H,H =13.2Hz, 3 J H,H =6.9Hz,1H,NCH2),3.80(dd, 2 J H,H =13.2Hz,3 J H,H =7.2Hz,1H,NCH2),3.93(s,3H,OCH3),3.95(s,3H,OCH3),6.90(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.22(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.40(d, 4 J H,H =2.1Hz,1H,CH Ar ).

[0264] 2-Benzyl-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one [f7]

[0265] Compound [f7] was prepared from S-oxo-4-(pyridin-2-yl)-2-(trifluoromethyl)butanethiol ethyl ester [c4] (73 mg, 0.25 mmol, 1 eq) and dihydrochlorinated benzylhydrazine (74 mg, 0.38 mmol, 12.5 eq) according to the general method for the synthesis of intermediate [f] and obtained as an orange lacquer after purification by flash silica gel column chromatography (PE / EA: 80 / 20). Yield: 100% (83 mg).

[0266] 1 H NMR (CD3OD): δ3.41 (dd, 2 J H,H =18.0Hz, 3 J H,H =9.6Hz,1H,CH A H B CH-CF3),3.64(dd, 2 J H,H =18.0Hz, 3 J H,H =7.8Hz,1H,CH A H B CH-CF3),3.72-3.87(m,1H,CH2CH-CF3),5.04(d, 2 J H,H =14.6Hz,1H,NCH A H B ),5.11(d, 2 J H,H =14.6Hz,1H,NCH A HB ),7.24-7.49(m,6H,6x CH Ar ),7.92(dt, 3 J H,H =7.5Hz, 4 J H,H =1.2Hz,1H,CH Ar ),8.11(d, 3 J H,H =7.8Hz,1H,CH Ar ),8.63(d, 3 J H,H =5.1Hz,1H,CH Ar ).

[0267] Example 1: 2-Benzyl-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0268] In an argon atmosphere, the corresponding precursor [f1] (20 mg, 0.05 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (35 mg, 0.25 mmol, 5 eq, added three times), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the reaction crude was purified by flash silica column chromatography (PE / EA: 90 / 10) to obtain compound 1 in the form of a yellow solid. Yield: 70% (10 mg).

[0269] NMR 1H(CDCl3): δ3.94(s,3H,OCH3),3.96(s,3H,OCH3),5.44(s,2H,NCH2),6.94(d,3JH,H= 8.4Hz,1H,CHAr),7.27(dd,3JH,H=8.1Hz,4JH,H=2.4Hz,1H,CHAr),7.31-7.39(m,4H,4x CHAr), 7.52 (dd, 3JH, H = 7.8Hz, 4JH, H = 1.8Hz, 1H, CHAr), 7.52 (m, 1H, CHAr), 7.93 (s, 1H, CHpyr).

[0270] Example 2: 6-(3,4-dimethoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0271] In an argon atmosphere, the corresponding precursor [f2] (25 mg, 0.062 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (34 mg, 0.24 mmol, 4 eq, added twice), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the reaction crude was purified by flash silica column chromatography (PE / EA: 85 / 15) to obtain compound 2 in the form of a yellow solid. Yield: 64% (20 mg).

[0272] NMR 1 H(CDCl3): δ2.33(s,3H,CH3),3.94(s,3H,OCH3),3.96(s,3H,OCH3),5.39(s,2H,NCH2),6.93(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.16(d, 3 J H,H =8.1Hz,2H,2x CH Ar ),7.27(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.35(d, 4 J H,H =2.1Hz,1H,CH Ar ),7.42(d, 3 J H,H =7.8Hz,2H,CH Ar ),7.92(d,1H, 4 J H,H =1.2Hz,CH pyr ).

[0273] Example 3: 6-(3,4-dimethoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0274] In an argon atmosphere, the corresponding precursor [f3] (30 mg, 0.070 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (38 mg, 0.28 mmol, 4 eq, added twice), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 3 in the form of a yellow oil. Yield: 24% (7 mg).

[0275] NMR 1H(CDCl3): δ3.79(s,3H,OCH3),3.94(s,3H,OCH3),3.97(s,3H,OCH3),5.37(s,1H,NCH2),6.87(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),6.94(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.27(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.35(d, 4 J H,H =2.1Hz,1H,CH Ar ),7.48(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),7.91(s,1H,CH pyr ).

[0276] Example 4: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0277] In an argon atmosphere, the corresponding precursor [f4] (38 mg, 0.070 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (19 mg, 0.14 mmol, 2 eq), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the crude reaction product was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 4 in the form of a yellow lacquer. Yield: 91% (30 mg).

[0278] NMR 1 H(CDCl3): δ3.78(s,3H,OCH3),3.97(s,3H,OCH3),5.38(s,2H,NCH2),6.61(t, 2 J H,F =74.4Hz,1H,OCHF2),6.87(dd, 3 J H,H =8.4Hz, 4 J H,H =1.8Hz,2H,2x CH Ar ),7.26-7.27(m,2H,2x CH Ar),7.40(d, 4 J H,H =1.5Hz,1H,CH Ar ),7.47(d, 3 J H,H =8.4Hz,2H,2x CH Ar ),7.91(s,1H,CH pyr ).

[0279] Example 5: 2-Benzyl-6-cyclohexyl-4-(trifluoromethyl)pyridazin-3(2H)-one

[0280] In an argon atmosphere, the corresponding precursor [f5] (88 mg, 0.26 mmol, 1 eq) was dissolved in anhydrous acetonitrile with cupric chloride (70 mg, 0.52 mmol, 2 eq), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the crude reaction product was purified by flash silica gel column chromatography (PE / EA: 95 / 5) to obtain compound 5 in the form of a colorless oil. Yield: 53% (50 mg).

[0281] NMR 1 H(CDCl3):δ1.18-1.35(m,5H,5x CH cyclohexyl ),1.65-1.84(m,5H,5xCH cyclohexyl ),2.46-2.54(m,1H,CH cyclohexyl ),5.23(s,2H,NCH2),7.18-7.29(m,3H,3x CH Ar ),7.34(d, 5 J H,H =0.9Hz,1H,CH pyr ),7.38-7.41(m,2H,2x CH Ar ).

[0282] Example 6: 2-(Cyclohexylmethyl)-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0283] In an argon atmosphere, the corresponding precursor [f6] (15 mg, 0.038 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (20 mg, 0.150 mmol, 4 eq, added twice), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the crude reaction product was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 6 in the form of a yellow lacquer. Yield: 61% (90 mg).

[0284] NMR 1H(CDCl3):δ1.04-1.33(m,6H,3x CH 2环己基 ),1.70-1.74(m,4H,2x CH 2环己基 ),1.98-2.10(m,1H,CH 环己基 ),3.95(s,3H,OCH3),3.98(s,3H,OCH3),4.14(d, 2 J H,H =7.2Hz,2H,NCH2),6.95(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.29(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.36(d, 4 J H,H =2.1Hz,1H,CH Ar ),7.94(s,1H,CH pyr ).

[0285] Example 7: 6-(3,4-dimethoxyphenyl)-2-(thiophen-3-ylmethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0286] Pyridazinone N2-H[e1] (50 mg, 0.17 mmol, 1 eq) was dissolved in acetonitrile together with K2CO3 (59 mg, 0.43 mmol, 2.5 eq) / Bu4NBr (3 mg, 0.009 mmol, 0.05 eq) and 3-methylthiophene chloride (25 mg, 0.18 mmol, 1.1 eq), which constituted mixture 6 (v). The mixture was heated to 60°C for about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 7 in the form of yellow crystals. Yield: 70% (47 mg).

[0287] NMR 1 H(CDCl3): δ3.94(s,3H,OCH3),3.97(s,3H,OCH3),5.44(s,2H,NCH2),6.94(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.23-7.25(m,1H,CH Ar ),7.29(dd,3 J H,H =5.1Hz, 4 J H,H =2.7Hz,2H,2xCH Ar ),7.34(d, 4 J H,H =2.1Hz,1H,CH Ar ),7.44(dd, 3 J H,H =2.7Hz, 4 J H,H =1.2Hz,1H,CH Ar ),7.93(s,1H,CH pyr ).

[0288] Example 8: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(thiophen-3-ylmethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0289] Pyridazinone N2-H[e2] (50 mg, 0.15 mmol, 1 eq) was dissolved in acetonitrile together with K2CO3 (52 mg, 0.38 mmol, 2.5 eq), Bu4NBr (3 mg, 0.009 mmol, 0.05 eq) and 3-methylthiophene chloride (23 mg, 0.17 mmol, 1.1 eq), which constituted mixture 6 (v). The mixture was heated to 60°C for a period of about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by flash silica column chromatography (PE / EA: 80 / 20) to obtain compound 8 in the form of beige crystals. Yield: 78% (50 mg).

[0290] NMR 1 H(CDCl3): δ4.00(s,3H,OCH3),5.48(s,2H,NCH2),6.64(t, 2 J H,F =74.4Hz,1H,OCHF2),7.23(dd, 3 J H,H =4.8Hz, 4 J H,H =1.5Hz,1H,CH Ar ),7.27(d, 3 J H,H =2.4Hz,2H,2x CH Ar ),7.30(dd, 3 J H,H =4.8Hz, 4 JH,H =3.3Hz,1H,CH Ar ),7.40(d, 3 J H,H =1.8Hz,1H,CH Ar ),7.44(dd, 3 J H,H =3.0Hz, 4 J H,H =1.2Hz,1H,CH Ar ),7.92(s,1H,CH pyr ).

[0291] Example 9: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(1-phenylethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0292] Pyridazinone N2-H[e2] (100 mg, 0.30 mmol, 1 eq) was dissolved in acetonitrile with K2CO3, Bu4NBr and 1-chloro-1-phenylethane (90 μL, 0.66 mmol, 2.1 eq, added twice), which constituted mixture 6 (v). The mixture was heated to 60 ° C for about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by grinding in diethyl ether to obtain compound 9 in the form of a beige solid. Yield: 50% (64 mg).

[0293] NMR 1 H(DMSO-d6):δ1.77d, 3 J H,H =6.9Hz,3H,CH3),3.90(s,

[0294] 3H,OCH3),6.27(q, 3 J H,H =6.9Hz,1H,NCHCH3),7.15(t, 2 J H,F =74.4Hz,1H,OCHF2),7.25-7.62(m,6H,6x CH Ar ),7.57(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.62(d, 4 J H,H =2.1Hz,1H,CH Ar ),8.48(s,1H,CH pyr).

[0295] Example 10: 6-(3,4-dimethoxyphenyl)-2-(4-phenylethylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0296] Pyridazinone N2-H[e1] (50 mg, 0.17 mmol, 1 eq) was dissolved in acetonitrile with K2CO3 (59 mg, 0.43 mmol, 2.5 eq), Bu4NBr (3 mg, 0.009 mmol, 0.05 eq) and 4-(chloromethyl)-1,2-diphenylethane (42 mg, 0.18 mmol, 1.1 eq), which constituted mixture 6 (v). The mixture was heated to 60°C for a period of about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 85 / 15) to obtain compound 10 in the form of a bright yellow lacquer. Yield: 65% (55 mg).

[0297] NMR 1 H(CDCl3)δ2.90(s,4H,2x CH2),3.94(s,3H,OCH3),3.96(s,3H,OCH3),5.41(s,2H,NCH2),6.94(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.16-7.21(m,5H,5x CH Ar ),7.24-7.29(m,5H,5xCH Ar ),7.35(d, 4 J H,H =2.1Hz,1H,CH Ar ),7.45(d, 3 J H,H =6.0Hz,2H,2x CH Ar ),7.93(s,1H,CH pyr ).

[0298] Example 11: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-phenylethylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0299] Pyridazinone N2-H[e2] (50 mg, 0.15 mmol, 1 eq) was dissolved in acetonitrile together with K2CO3 (52 mg, 0.38 mmol, 2.5 eq), Bu4NBr (3 mg, 0.009 mmol, 0.05 eq) and 4-(chloromethyl)-1,2-diphenylethane (38 mg, 0.16 mmol, 1.1 eq), which constituted mixture 6(v). The mixture was heated to 60°C for a period of about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 11 in the form of white crystals. Yield: 86% (69 mg).

[0300] NMR 1 H(CDCl3)δ2.89(s,4H,2x CH2),3.96(s,3H,OCH3),5.41(s,2H,NCH2),6.61(t, 2 J H,F =74.7Hz,1H,OCHF2),7.15-7.30(m,9H,9x CH Ar ),7.41-7.45(m,3H,3x CH Ar ),7.92(d, 5 J H,H =0.9Hz,1H,CH pyr ).

[0301] Example 12: 2-Benzyl-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0302] Precursor [c1] (100 mg, 0.29 mmol, 1 eq) was dissolved in glacial acetic acid and benzylhydrazine; this constituted mixture 4 (iii). The mixture 4 was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 12 in the form of a beige solid. Yield: 47% (54 mg).

[0303] NMR 1 H(CDCl3): δ3.05-3.23(m,2H,CH2CHCF3),3.27-3.41(m,1H,CHCF3),3.91(s,6H,2x OCH3),5.01(d, 2 J H,H =14.4Hz,1H,NCH A H B ),5.08(d, 2 JH,H =14.4Hz,1H,NCH A H B ),6.86(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.18(dd, 3 J H,H =8.4Hz, 4 J H,H =2.1Hz,1H,CH Ar ),7.26-7.42(m,6H,6x CH Ar ).

[0304] Example 13: 6-(3,4-dimethoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0305] The precursor [c1] (100 mg, 0.29 mmol, 1 eq) was dissolved in glacial acetic acid and 4-methylbenzylhydrazine (626 mg, 3.63 mmol, 12.5 eq), which constituted a mixture 4 (iii). The mixture 4 was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 13 in the form of a white solid. Yield: 100% (40 mg).

[0306] NMR 1 H(CDCl3): δ2.33(s,3H,CH3),3.05-3.25(m,2H,CH2CHCF3),3.25-3.40(m,1H,CHCF3),3.92(s,3H,OCH3),3.93(s,3H,OCH3),4.97(d, 2 J H,H =14.3Hz,1H,NCH A H B ),5.04(d, 2 J H,H =14.3Hz,1H,NCH A H B ),6.87(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.13(d, 3 J H,H =7.8Hz,2H,2xCH Ar ),7.18(dd, 3 J H,H =8.4Hz, 4 JH,H =2.1Hz,1H,CH Ar ),7.31(d, 3 J H,H =7.8Hz,2H,2x CH Ar ),7.38(d, 4 J H,H =2.1Hz,1H,CH Ar ).

[0307] Example 14: 2-Benzyl-6-(pyridin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (14)

[0308] In an argon atmosphere, the corresponding precursor [f7] (30 mg, 0.90 mmol, 1 eq) was dissolved in anhydrous acetonitrile with copper chloride (242 mg, 1.80 mmol, 2 eq), which constituted mixture 5 (iv). The mixture was refluxed for about 4 hours. After cooling and evaporation, the reaction crude was purified by flash silica column chromatography (PE / EA: 90 / 10) to obtain compound 14 in the form of a clear lacquer. Yield: 20% (5 mg).

[0309] NMR 1 H(CDCl3):δ5.46(s,2H,NCH2),7.32-7.39(m,4H,4x CH Ar ),7.52-7.54(m,2H,2x CH Ar ),7.83(t, 3 J H,H =7.8Hz,1H,CH Ar ),8.13(bs,1H,CH Ar ),8.65(bs,1H,CH Ar ),8.72(s,1H,CH Ar ).

[0310] Example 15: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0311] Precursor [c2] (100 mg, 0.26 mmol, 1 eq) was dissolved in glacial acetic acid and 4-methoxybenzylhydrazine (703 mg, 3.24 mmol, 12.5 eq), which constituted mixture 4 (iii). The mixture 4 was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 15 in the form of a beige solid. Yield: 62% (70 mg).

[0312] NMR 1 H(CDCl3): δ3.07-3.41(m,3H,CHCH2CF3),3.79(s,3H,OCH3),3.93(s,3H,OCH3),4.95(d, 2 J H,H =14.1Hz,1H,NCH A H B ),5.03(d, 2 J H,H =14.1Hz,1H,NCH A H B ),6.59(t, 2 J H,F =74.7Hz,1H,CHF2),6.86(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),7.19(s,2H,2x CH Ar ),7.35(d, 3 J H,H =8.7Hz,2H,2x CH Ar ),7.42(s,1H,CH Ar ).

[0313] Example 16: 2-Benzyl-6-cyclohexyl-4-(trifluoromethyl)-4,5-dihydro-pyridazin-3(2H)-one

[0314] Precursor [c3] (150 mg, 0.50 mmol, 1 eq) was dissolved in glacial acetic acid and benzylhydrazine, which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 16 in the form of a light brown oil. Yield: 43% (50 mg).

[0315] NMR 1 H(CDCl3):δ1.26-1.34(m,5H,5x CH 环己基 ),1.68-1.82(m,5H,5x CH 环己基 ),2.22-2.30(m,1H,CH 环己基 ),2.66(s,1H,CH A H B CHCF3), 2.68(s,1H,CH A H B CHCF3),3.13-3.27(m,1H,CHCF3),4.88(d, 2J H,H =14.6Hz,1H,NCH A H B ),4.95(d, 2 J H,H =14.6Hz,1H,NCH A H B ),7.24-7.35(m,5H,5x CH Ph ).

[0316] Example 17: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0317] Precursor [c2] (77 mg, 0.20 mmol, 1 eq) was dissolved in glacial acetic acid and 4-methylbenzylhydrazine (340 mg, 2.50 mmol, 12.5 eq), which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 17 in the form of a beige solid. Yield: 65% (57 mg).

[0318] NMR 1 H(CDCl3): δ2.33(s,3H,CH3),3.07-3.25(m,2H,CH2CHCF3),3.28-3.39(m,1H,CHCF3),3.92(s,3H,OCH3),4.97(d, 2 J H,H =14.1Hz,1H,NCH A H B ),5.05(d, 2 J H,H =14.1Hz,1H,NCH A H B ),6.59(t, 2 J H,F =74.7Hz,1H,CHF2),7.12-7.18(m,4H,4x CH Ar ),7.29(d, 3 J H,H =7.8Hz,2H,2x CH Ar ),7.42(s,1H,CH Ar ).

[0319] Example 18: 6-(3,4-(dimethoxyphenyl)-2-(1-phenylethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0320] Pyridazinone N2-H[e1] (50 mg, 0.16 mmol, 1 eq) was dissolved in acetonitrile together with K2CO3 (57 mg, 0.42 mmol, 2.5 eq), Bu4NBr (3 mg, 0.007 mmol, 0.05 eq) and 1-chloro-1-phenylethane (25 μL, 0.18 mmol, 1.1 eq), which constituted mixture 6 (v). The mixture was heated to 60°C for about 2 to 4 h. After cooling, the solvent was evaporated, the crude product was dissolved in water and extracted with dichloromethane. The organic phase was dried, filtered, and after evaporation under reduced pressure, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 18 in the form of a yellow lacquer. Yield: 57% (38 mg).

[0321] NMR 1 H(CDCl3):δ1.86(d, 3 J H,H =7.2Hz,3H,CH3),3.94(s,3H,OCH3),3.95(s,3H,OCH3),6.46(q, 3 J H,H =7.2Hz,1H,NCHCH3),6.94(d, 3 J H,H =8.4Hz,1H,CH Ar ),7.26-7.38(m,5H,5x CH Ar ),7.51-7.55(m,2H,2x CH Ar ),7.90(d, 4 J H,H =0.9Hz,1H,CH Ar ).

[0322] Example 19: 2-Benzyl-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0323] The precursor [c4] (73 mg, 0.25 mmol, 1 eq) was dissolved in glacial acetic acid and benzylhydrazine (74 mg, 0.38 mmol, 1.5 eq), which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 19 in the form of an orange paint. Yield: 80% (66 mg).

[0324] NMR 1 H(CD3OD):δ3.41(dd, 2 J H,H =18.0Hz, 3J H,H =9.6Hz,1H,CH A H B CHCF3),3.64(dd, 2 J H,H =18.0Hz, 3 J H,H =7.8Hz,1H,CH A H B CHCF3),3.72-3.87(m,1H,CH2CH-CF3),5.04(d, 2 J H,H =14.6Hz,1H,NCH A H B ),5.11(d, 2 J H,H =14.6Hz,1H,NCH A H B ),7.24-7.49(m,6H,6x CH Ar ),7.92(dt, 3 J H,H =7.5Hz, 4 J H,H =1.2Hz,1H,CH Ar ),8.11(d, 3 J H,H =7.8Hz,1H,CH Ar ),8.63(d, 3 J H,H =5.1Hz,1H,CH Ar ).

[0325] Example 20: 2-(4-methylbenzyl)-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0326] The precursor [c4] (44 mg, 0.15 mmol, 1 eq) was dissolved in glacial acetic acid and 4-methylbenzylhydrazine (31 mg, 0.25 mmol, 1.5 eq), which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering / washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 20 in the form of a white solid. Yield: 71% (37 mg).

[0327] NMR 1 H(CDCl3): δ2.33(s,3H,CH3),3.33-3.41(m,2H,CH2CHCF3),3.56-3.68(m,1H,CH-CF3),5.07(d,2 J H,H =14.3Hz,1H,NCH A H B ),5.05(d, 2 J H,H =14.3Hz,1H,NCH A H B ),7.14(d, 3 J H,H =7.8Hz,2H,2x CH Ar ),7.28-7.31(m,1H,CH Ar ),7.31(d, 3 J H,H =7.8Hz,2H,2x CH Ar ),7.73(dt, 3 J H,H =7.5Hz, 4 J H,H =1.2Hz,1H,CH Ar ),8.06(d, 3 J H,H =7.8Hz,1H,CH Ar ),8.59(d, 3 J H,H =5.1Hz,1H,CH Ar ).

[0328] Example 21: 2-(4-methoxybenzyl)-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0329] The precursor [c4] (73 mg, 0.25 mmol, 1 eq) was dissolved in glacial acetic acid and 4-methoxybenzylhydrazine (57 mg, 0.38 mmol, 1.5 eq), which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 90 / 10) to obtain compound 21 in the form of a white solid. Yield: 36% (33 mg).

[0330] NMR 1 H(CDCl3): δ3.26-3.40(m,2H,CH2CHCF3),3.55-3.68(m,1H,CH-CF3),3.79(s,3H,OCH3),4.96(d, 2 J H,H =14.1Hz,1H,NCH A H B ),5.03(d, 2J H,H =14.1Hz,1H,NCH A H B ),6.86(d, 3 J H,H =8.6Hz,2H,2x CH Ar ),7.29-7.33(m,1H,CH Ar ),7.36(d, 3 J H,H =8.6Hz,2H,2x CH Ar ),7.74(dt, 3 J H,H =7.5Hz, 4 J H,H =1.5Hz,1H,CH Ar ),8.07(d, 3 J H,H =8.1Hz,1H,CH Ar ),8.59(d, 3 J H,H =5.1Hz,1H,CH Ar ).

[0331] Example 22: 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one

[0332] Precursor [c2] (58 mg, 0.15 mmol, 1 eq) was dissolved in glacial acetic acid and benzylhydrazine (377 mg, 1.875 mmol, 12.5 eq), which constituted mixture 4 (iii). The mixture was refluxed for about 1 hour. After filtering, washing and vacuum drying, the reaction crude was purified by flash silica gel column chromatography (PE / EA: 80 / 20) to obtain compound 22 in the form of a beige solid. Yield: 70% (45 mg).

[0333] NMR 1 H(CDCl3): δ3.09-3.26(m,2H,CH2CH-CF3),3.31-3.45(m,2H,CH2CH-CF3),3.91(s,3H,OCH3),5.02(d, 2 J H,H =14.4Hz,1H,NCH A H B ),5.08(d, 2 J H,H =14.4Hz,1H,NCH A H B ),6.59(t, 2J H,F =74.7Hz,1H,CHF2),7.18(s,2H,2x CH Ar ),7.38-7.41(m,6H,6x CH Ar ).

[0334] Biological Assessment

[0335] In order to evaluate the effect of the compounds according to the invention on the restoration of CFTR activity, the compounds were tested in vitro using a suitable Premo HalidSensor kit (Invitrogen).

[0336] The principle is based on the measurement of the fluorescence (515-530 nm) emitted by the probe in the presence or absence of compounds of the N-benzylpyridazinone type, allowing to modulate the activity of the CFTR protein and thus restore the chloride activity of the channel.

[0337] Therefore, CFTR-dependent chloride transport was first assessed in osteoblasts using a fluorescent probe, halide-sensitive yellow fluorescent protein (YFP)-H148Q / I152L protein (Life Technologies, Saint Aubin, France). Figure 1 ).

[0338] After the probe was transfected into the cells for 48 hours, a solution consisting of forskolin, 3-isobutyl-1-methylxanthine and apigenin (each component at a concentration of 10 μM) was used to stimulate CFTR channel activity. Then, an iodine solution (140 mM) was added and the fluorescence (400 ms / point; ft) (baseline; F0) within 60 s was recorded with a plate reader. The reduction in the Ft / F0 ratio indicates the recovery of the chloride ion activity of the CFTR channel.

[0339] The signal from untreated osteoblasts was verified using a specific CFTR channel inhibitor (CFTRinh-172 (10 μM)). In the presence of this inhibitor (control), no decrease in fluorescence was observed.

[0340] For quantitative analysis, the gradient of the obtained signal was processed in a nonlinear regression and correlated to the conductivity level of chloride ions.

[0341] The results obtained for compounds 1 and 4 according to the present invention are shown in Figure 1 middle.

[0342] The measured values ​​indicate the restoration of the CFTR channel activity of compounds 1 and 4 according to the invention compared to the reference substances (ivacaftor, rumacaftor, Orkambi) (on average 150%). Figure 1It was shown that compounds 1 and 4 allowed restoration of CFTR channel activity better than those obtained with ivacaftor and rumacaftor, and that compound 1 allowed restoration of CFTR channel activity similar to that obtained with Orkambi.

[0343] Compounds 1-11 and 13 of the invention were evaluated in the lung epithelial cell model. Figure 2 and 3 Results obtained for 12 of them are shown, the efficacy of which is readable after 60 seconds of recording compared to basal conditions (DMSO). These results show an average recovery of CFTR channel activity from 102 to 132%.

[0344] Figure 4 A second analysis of CFTR channel activity was shown and confirmed the effects of compounds 1-8 and 10-18 of the invention compared to basal conditions. These results showed that CFTR channel activity was restored from an average of 102% to 152%.

[0345] Figure 5 In vitro evaluation of restoration of CFTR channel activity of compounds 1 and 4 according to the invention in combination with ivacaftor or rumacaftor compared to Orkambi is shown.

Claims

1. Compounds of formula I: [Chemical formula 1] or a pharmaceutically acceptable salt thereof, in R 1 is a C5-C6 cycloalkyl group, a C5-C6 heteroaryl group or a C6 aryl group, which is optionally substituted by a group selected from a C1-C6 alkyl group, a C1-C2 alkoxy group and a C1-C2 aralkyl group; R 2 is H or C1-C6 alkyl; R 3 is cyclohexyl, thienyl, pyridyl or phenyl, which is optionally substituted by one or two groups independently selected from C1-C4 alkyl, C1-C2 alkoxy and C1-C2 haloalkoxy; R 4 It is H; R F is trifluoromethyl; and Is a single bond or a double bond.

2. The compound or salt according to claim 1, which has formula II: [Chemical formula 2] 3. The compound or salt according to claim 1, which has formula III: [Chemical formula 7] 4. The compound or salt according to claim 1, which is selected from: 2-Benzyl-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-Benzyl-6-cyclohexyl-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-(Cyclohexylmethyl)-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(thiophen-3-ylmethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(thiophen-3-ylmethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(1-phenylethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(4-phenylethylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-phenylethylbenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-Benzyl-6-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 2-Benzyl-6-(pyridin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 2-Benzyl-6-cyclohexyl-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 6-(4-(difluoromethoxy)-3-methoxyphenyl)-2-(4-methylbenzyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 6-(3,4-dimethoxyphenyl)-2-(1-phenylethyl)-4-(trifluoromethyl)pyridazin-3(2H)-one; 2-Benzyl-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 2-(4-methylbenzyl)-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; 2-(4-methoxybenzyl)-6-(pyridin-2-yl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one; and 2-Benzyl-6-(4-(difluoromethoxy)-3-methoxyphenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one.

5. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease or condition associated with CFTR channel activity dysfunction, wherein the disease or condition associated with CFTR channel activity dysfunction is cystic fibrosis and complications associated therewith.

7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent selected from ivacaftor, rumacaftor and tezacaftor.

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