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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the subject of the present invention concerns derivatives of 2H pyridazin-3-one inhibiting the 5 activity of the SCD-I enzyme, and their application in human therapy.
• Metabolic syndrome results from increased peripheral resistance to insulin, and is characterized by obesity, intolerance to glucose, certain dyslipidaemias which may
• Stearoyl-CoA Desaturase-1 also called ⁇ 9- desaturase, is an enzyme limiting the synthesis of mono-unsaturated fatty acids under the control of the transcription factor SREBPic (Miyazaki, M., Kim, Y. C, Ntambi, J. M.
• SCD-I Stearoyl-CoA Desaturase-1
• Disablement of the SCD-I gene in mice imparts resistance to genetic or diet-induced obesity; the peripheral effects of leptin on the increase in energy expenditure, weight loss and insulin sensitivity are inversely correlated with the expression of the SCD-I gene and with enzymatic activity (Cohen, P., Miyazaki, M., Socci, N. D. et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297, 240-243 (2002), Ntambi, J. M., Miyazaki, M., Stoehr, J. P. et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity.
• SCD-I SCD-I-induced obesity
• the involvement of SCD-I in the pathogenesis of obesity is reinforced by the correlation between the plasma concentration of palmitoleic acid and abdominal adiposity in children (Okada, T., Furuhashi, N., Kuromori, Y. et al. Plasma palmitoleic acid content and obesity in children. Am J Clin Nutr 82, 747-750 (2005)), the association of SCD-I overexpression in the skeletal muscles of obese adults with poor partitioning of fatty acids leading to inhibition of hepatic ⁇ -oxidation (Hulver, M. W., Berggren, J. R., Carper, M.J. et al .
• Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans.
• Cell Metab 2, 251-261 (2005) The plasma ratio 18:1/18:0, also called “desaturation index", appears to be the biomarker of SCD-I activity in man and correlates with the plasma triglyceride level and in inverse proportional manner with the HDL level (Attie, A. D., Krauss, R. M., Gray- Keller, M. P. et al. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res 43, 1899- 1907 (2002) ) .
• SCD-I inhibitors US2008280916
• the inhibition of sebum production WO2009019566
• SCD-I inhibition appears to be a choice therapeutic target for the treatment of obesity, Type-2 diabetes and lipid disorders related to metabolic syndrome, and in dermatology for lipid disorders of the skin .
• the present invention concerns novel derivatives of 2H pyridazin-3-one inhibiting the activity of the SCD-I enzyme, their preparation and their application in human therapy. These compounds meet general formula I :
• - Ri represents one or more groups such as: trifluoromethyl, halogen such as F, Cl, Br, Ci-C 4 alkyl straight or branched, nitro, trifluoromethoxy, acetyl .
• the compounds of general formula (I) are those in which :
• - Ri represents one or more groups such as: trifluoromethyl, halogen such as F, Cl, Br, C 1 -C 3 alkyl straight or branched, trifluoromethoxy,
• R 3 represents: • a hydrogen or
• the compounds of general formula (I) are those in which:
• -Ri represents one or more groups such as: trifluoromethyl, halogen such as F, Cl,
• the compounds of general formula (I) are those in which:
• R 3 represents a hydrogen or methyl and the addition salts with the pharmaceutically acceptable bases and acids and the different isomers, and their mixtures in any proportion.
• the present invention also extends to the addition salts of the compounds of general formula (I) with the pharmaceutically acceptable bases and acids, and to the different isomers of the compounds of general formula (I) and their mixtures in any proportion.
• isomers » under the present invention, is meant the enantiomers and the isomers of cis or trans configuration.
• mixtures of the isomers in any proportion also include the racemic mixtures for the enantiomers.
• the present invention also extends to the chemical methods to prepare the compounds of general formula (D•
• the present invention also concerns the compounds of general formula (I) and the addition salts with the pharmaceutically acceptable bases and acids, and the different isomers, and their mixtures in any proportion for their use as inhibitor of the SCD-I enzyme.
• the present invention also concerns the compounds of general formula (I) and the addition salts with pharmaceutically acceptable bases and acids, and the different isomers, and their mixtures in any proportion, for their use and as medicinal product.
• the invention also concerns the compounds of general formula (I) and the addition salts with pharmaceutically acceptable bases and acids, and the different isomers, and their mixtures in any proportion for their use as medicinal product intended for the treatment and/or prevention of diseases requiring inhibitors of the activity of the SCD-I enzyme.
• the invention also concerns the compounds of general formula (I) and their addition salts with pharmaceutically acceptable bases and acid, and the different isomers, and their mixtures in any proportion for their use as medicinal product intended for the treatment and/or prevention of diseases such as obesity, diabetic dyslipidaemia, hypertriglyceridaemia, hypercholesterolemia, metabolic syndrome, atherosclerosis and its complications, hepatic steatosis, cardiovascular risks.
• the invention also concerns the compounds of general formula (I) and their addition salts with pharmaceutically acceptable bases and acids, and the different isomers, and their mixtures in any proportion, for their use as medicinal product intended for the treatment and/or prevention of dermatological diseases related to lipid disorders of the skin, and inflammatory and microbial complications related to disturbed barrier function.
• the dermatological diseases related to a lipid disorder of the skin are, for example, acne, psoriasis, hirsutism, rosacea.
• compositions characterized in that, as active ingredient, they contain a compound of general formula (I) .
• the invention also concerns a pharmaceutical composition characterized in that it contains a compound of general formula (I) in combination with any suitable excipient.
• the compounds of the present invention can be synthesized using the synthesis routes described below or using synthesis methods known to persons skilled in the art .
• Ri represents one or more groups: trifluoromethyl, Cl, F, Ci-C 4 alkyl straight or branched, trifluoromethoxy, acetyl, and R 4 , and R 5 , m, n, Y, W are such as defined in general formula I, is condensed with a derivative of general formula III
• R 3 is a Ci-C ⁇ straight or branched alkyl radical, or a C 1 -C3 alkyl radical substituted by groups such as: trifluoromethyl, phenyl, under operating conditions such as Buchwald coupling in the presence of a catalyst such as palladium acetate, a phosphine such as BINAP and a base such as caesium carbonate in a solvent such as toluene; > the derivative of general formula IV previously obtained is dehalogenated under operating conditions such as in the presence of palladium on carbon under hydrogen in a solvent such as methanol.
• a catalyst such as palladium acetate, a phosphine such as BINAP and a base such as caesium carbonate in a solvent such as toluene
• > the derivative of general formula IV previously obtained is dehalogenated under operating conditions such as in the presence of palladium on carbon under hydrogen in a solvent such as methanol.
• R 3 represents a Ci-C ⁇ straight or branched alkyl radical, or C1-C3 alkyl radical substituted by groups such as: trifluoromethyl or phenyl and R 4 and R 5 are such as defined in general formula I, are condensed with phenols of general formulas XIX: XIX in which Ri is such as defined in general formula I
• the intermediate and end compounds may be purified following one or more purification methods chosen from among extraction, filtration, silica gel chromatography, normal or reverse phase preparative HPLC, crystallisation.
• This oil is placed in 300 mL of dichloromethane in the presence of 23 mL (309 mmoles) of TFA, then this solution is agitated for 24h at ambient temperature. The medium is concentrated and the residue obtained is solubilized in AcOEt, washed with an aqueous sodium hydroxide solution
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 90:10, Rf O.63.
• This oil is placed in 35 mL 1, 2-dichloroethane in the presence of 1.73 mL (16 mmoles) of 1-chloroethylchloroformate, and this solution is then agitated for 8h at 70 0 C. 35 mL of MeOH are then added and the reaction medium is agitated overnight at 70 0 C. After concentrating to dryness, the residue obtained is triturated in petroleum ether, filtered then rinsed in petroleum ether. 1.10 g of intermediate Io are thus obtained in the form of a pale yellow solid (yield 72%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH-NH 4 OH: 95:4.5:0.5, Rf 0.38.
• reaction medium is agitated under reflux for 46h then brought to pH 8 with an aqueous HCl solution (6N). After concentrating to dryness, the residue obtained is purified by silica gel flash chromatography (CH 2 Cl 2 -MeOH-NH 4 OH, gradient 100:0:0 to 82:17:1 over 40 min) . 1.59 g of intermediate Iq are thus obtained in the form of a yellow oil (yield 64%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH-NH 4 OH: 90:9:1, Rf O.24.
• Method A 2.26 g (12.92 mmoles) of BOC-glycine are placed in the presence of 4.56 g (14.21 mmoles) TBTU in
• reaction medium is agitated for 48h at ambient temperature then concentrated to dryness.
• residue obtained is solubilized in AcOEt, washed with water then with a saturated NaCl solution. After drying over Na2SO 4 , the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH 2 Cl 2 -MeOH-NH 4 OH, gradient 100:0:0 to 98:1.8:0.2 over 35 min) . 3.9 g of colourless oil are obtained (yield 75%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH-NH 4 OH: 95:4.5:0.5, Rf O.72.
• Method B 2.43 g (12.86 mmoles) of BOC-L-alanine are placed in the presence of 6 mL (42.88 mmoles) Et3N, 1.73 g (12.86 mmoles) HOBt, 3 g (10.72 mmoles) of intermediate Ic in base form, 2.46 g (12.86 mmoles) EDCI in 150 mL CH2CI2.
• the reaction medium is agitated for 24h at ambient temperature then diluted in water and extracted with CH2CI2. After drying over Na2SO 4 , the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2CI2- MeOH, gradient 100:0 to 94:6 over 40 min) .
• 25 g (151 mmoles) of 4, 5-dichloropyridazinone are placed in a stainless steel reactor in the presence of 25.13 g (181 mmoles) K 2 CO 3 , 1 g (3.03 mmoles) of tetrabutylammonium bromide and 14.2 mL (227 mmoles) of iodomethane in 150 mL acetonitrile .
• the reaction medium is agitated for 4h at 115°C then filtered.
• the filtrate is concentrated to dryness then solubilized in AcOEt and washed in acid water (pH 1), then with NaCl- saturated water.
• reaction medium is agitated for Ih under reflux then filtered through celite. The filtrate is concentrated to dryness and the residue solubilized in
• Method B 7.3 g (34.5 mmoles) of intermediate 4d are placed in 160 mL of methanol. At 0 0 C, 41.5 mL (41.5 mmoles) of aqueous sodium hydroxide solution (IN) are added dropwise and the reaction medium is agitated for
• 1 g (5.75 mmoles) of intermediate 4b are placed in the presence of 1 mL (7.47 mmoles) of tertio-butylic ester of glycine, 0.064 g (0.29 mmoles) palladium acetate, 0.270 g (0.43 mmoles) BINAP and 3.73 g (11.5 mmoles) Cs 2 C ⁇ 3 in 58 mL toluene.
• the reaction medium is agitated for 24h at 80 0 C then 0.064 g (0.29 mmoles) of palladium acetate and 0.270 g of BINAP are added.
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 95:5, Rf 0.36. This solid is placed in 90 mL MeOH. At 0 0 C, 25 mL (23.6 mmoles) of aqueous sodium hydroxide solution (IN) are added dropwise and the reaction medium is agitated for 45 minutes at ambient temperature. After concentrating to dryness, the residue is solubilized in 50 mL water and the resulting solution is acidified (pH 2) using aqueous HCl solution
• a first batch (0.57 g) of intermediate 4k is obtained.
• the filtrate is concentrated to dryness then triturated in MeOH.
• the solid obtained is removed by filtering and, after concentrating the filtrate to dryness, a second batch (0.40 g) of intermediate 4k is obtained.
• the two batches are combined and 0.97 g of intermediate 4k are thus obtained in the form of an orange solid (yield 64%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH-AcOH: 80:20:1, Rf O.09.
• reaction medium is agitated for 15 minutes at -5°C then treated with 1OmL of aqueous HCl solution (IN) .
• aqueous HCl solution (IN)
• the organic phase is washed with water, then with aqueous NaHCO 3 solution (1%) and with NaCl-saturated water.
• the organic phases are concentrated to dryness. 12g of orange solid are obtained (quantitative yield) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 95:5, Rf O.85.
• Compound 1 is prepared following synthesis method 1: 0.87 g (2.88 mmoles) of derivative 2a and 0.51 g (2.88 mmoles) of 3a are placed in 10 mL of toluene in the presence of Pd(OAc) 2 (32 mg, 0.14 mmol) , BINAP (130 mg, 0.21 mmmol) and caesium carbonate (0.94 g, 2.88 mmol) . This mixture is agitated under reflux for 5h30. After concentrating the reaction medium to dryness, the residue obtained is solubilized in AcOEt and washed with water. After drying over MgS ⁇ 4 , the organic phase is concentrated.
• Compound 2 is prepared following synthesis method 2: 0.5Og (2.72mmol) of intermediate 4e and of intermediate Ib in base form (0.857 g, 3.26 mmol) are placed in 3OmL of CH 2 Cl 2 in the presence of EDCI (0.625 g, 3.26 mmol), HOBt (0.441 g, 3.26 mmol) and Et 3 N (1.51 mL, 10.88 mmol) .
• the reaction medium is agitated at ambient temperature overnight, then solubilized in water and extracted with CH 2 Cl 2 .
• Example 3 4- ⁇ 2- [4- (3-Fluoro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (3)
• Compound 3 is prepared following synthesis method 3: 0.7 g (2.62 mmol) of intermediate 5b are placed in 30 ml THF at 0 0 C in the presence of 1.64 g (6.28 mmol) PPh 3 and 0.943 g (5.24 mmol) of 3-fluoro, 5- trifluoromethylphenol . 1.23 ml (6.28 mmol) of DIAD are then added, the reaction medium is agitated 5mn at 0 0 C then at ambient temperature overnight.
• Compound 4 is prepared from intermediate Ic in base form and intermediate 4e following synthesis method 2 (yield: 62%) .
• Compound 5 is prepared from intermediate Ie in base form and intermediate 4e following synthesis method 2 (yield: 71%) .
• Compound 7 is prepared from intermediate Ig in base form and from intermediate 4e following synthesis method 2 (yield: 22%) .
• Example 8 4- ⁇ 2- [4- (2-Chloro-5-fluoro-phenoxy) piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (8).
• Example 10 4- ⁇ 2- [4- (3, 4-Dichloro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (10)
• Compound 10 is prepared from intermediate Ih in base form and intermediate 4e following synthesis method 2 (yield: 56%) .
• Example 11 4- ⁇ 2- [4- (2, 4-Dichloro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (11)
• Example 12 4- ⁇ 2- [4- (2, 5-Dichloro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (12)
• Compound 12 is prepared from intermediate Ij in base form and from intermediate 4e following synthesis method 2 (yield: 61%) .
• Example 13 4- ⁇ 2- [4- (2, 5-Difluoro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (13)
• Compound 13 is prepared from intermediate Ik in base form and intermediate 4e following synthesis method 2 (yield: 84%) .
• Compound 14 is prepared from intermediate 5b and from 5-fluoro-2-methyl-phenol following synthesis method 3 (yield: 15%) .
• Example 16 4- ⁇ 2- [4- (5-Isopropyl-2-methyl-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (16)
• Compound 16 is prepared from 4- (5-isopropyl-2-methyl- phenoxy) -piperidine (obtained following the method described for Ia) and from intermediate 4e following synthesis method 2 (yield: 18%) .
• Example 17 4- ( ⁇ 2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -2-oxo-ethyl ⁇ -methyl-amino) -2- methyl-2H-pyridazin-3-one (17)
• Compound 17 is prepared from intermediate Ic in base form and intermediate 4g following synthesis method 2 (yield: 63%) .
• Example 18 4- ( ⁇ 2- [4- (2-Chloro-phenoxy) -piperidin-1- yl] -2-oxo-ethyl ⁇ -methyl-amino) -2-methyl-2H-pyridazin-3- one (18)
• Compound 18 is prepared from intermediate Ig in base form and intermediate 4g following synthesis method 2 (yield: 47%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 97:3, Rf 0.15.
• Compound 19 is prepared from intermediate Ia in base form and intermediate 4h following synthesis method 2 (yield: 40%) .
• Compound 20 is prepared from intermediate Id in base form and intermediate 4h following synthesis method 2 (yield: 27%) .
• Compound 21 is prepared from intermediate 5c and 2- trifluoromethoxy-phenol following synthesis method 3 (yield: 20%) .
• Example 22 4- ⁇ 2- [4- (2-Chloro-4-fluoro-phenoxy) - piperidin-1-yl] -2-oxo-ethoxy ⁇ -2-methyl-2H-pyridazin-3- one (22)
• Compound 22 is prepared from intermediate 5c and from 2-chloro-4-fluoro-phenol following synthesis method 3 (yield: 18%) .
• Example 23 4- ⁇ 2- [4- (2-Acetyl-5-fluoro-phenoxy) - piperidin-1-yl] -2-oxo-ethoxy ⁇ -2-methyl-2H-pyridazin-3- one (23)
• Compound 27 is prepared from intermediate Io in base form and intermediate 4e following synthesis method 2 (yield: 35%) .
• Example 28 4- (2- ⁇ 4- [ (3, 4-Dichloro-benzyl) -methyl- amino] -piperidin-1-yl ⁇ -2-oxo-ethylamino) -2-methyl-2H- pyridazin-3-one (28)
• Compound 28 is prepared from intermediate Iq and intermediate 4e following synthesis method 2 (yield: 49%) .
• Example 29 4- ⁇ 2- [4- (5-Fluoro-2-trifluoromethyl- benzoyl) -piperazin-1-yl] -2-oxo-ethylamino ⁇ -2-methyl-2H- pyridazin-3-one (29)
• Compound 29 is prepared from intermediate Iu in base form and intermediate 4e following synthesis method 2 (yield: 68%) .
• Compound 30 is prepared from intermediate It in base form and from intermediate 4e following synthesis method 2 (yield: 69 %) .
• Compound 31 is prepared from intermediate Is in base form and intermediate 4e following synthesis method 2 (yield: 63%) .
• Example 32 4- (2- ⁇ 4- [ (2-Chloro-5-trifluoromethyl- phenylamino) -methyl] -piperidin-1-yl ⁇ -2-oxo-ethylaminol 2-methyl-2H-pyridazin-3-one (32)
• Example 33 4- ⁇ 2- [3- (2-Chloro-5-trifluoromethyl- phenoxymethyl) -azetidin-1-yl] -2-oxo-ethylamino ⁇ -2- methyl-2H-pyridazin-3-one (33)
• Example 34 4- ⁇ 2- [3- (2-Chloro-5-trifluoromethyl- phenoxymethyl) -pyrrolidin-1-yl] -2-oxo-ethylamino ⁇ -2- methyl-2H-pyridazin-3-one (34)
• Compound 34 is prepared from intermediate In in base form and from intermediate 4e following synthesis method 2 (yield: 16%) .
• Compound 35 is prepared from intermediate Ic in base form and from intermediate 4k following synthesis method 2 (yield: 27%) .
• Compound 36 is prepared from intermediate Ic in base form and from intermediate 4n following synthesis method 2 (yield: 82%) .
• Example 37 4- ⁇ 3- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -3-oxo-propyl ⁇ -2-methyl-2H- pyridazin-3-one (37)
• Compound 37 is prepared from intermediate Ic in base form and from intermediate 4o following synthesis method 2 (yield: 88%) .
• TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 95:5, Rf 0.45.
• Example 38 4- ⁇ (R) -2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -l-methyl-2-oxo-ethylamino ⁇ -2- methyl-2H-pyridazin-3-one (38) .
• Example 40 4- ⁇ 2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -2-oxo-ethylamino ⁇ -2H- pyridazin-3-one (40)
• Example 41 4- ⁇ 2- [4- (2, 5-dichloro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2H-pyridazin-3-one (41)
• Compound 41 is prepared from intermediate 7a and intermediate Ij following synthesis method 2 (yield: 50%) .
• Example 42 4- ⁇ 2- [4- (5-Bromo-2-Chloro-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2H-pyridazin-3-one (42)
• Compound 42 is prepared from intermediate 7a and intermediate If following synthesis method 2 (yield: 41%) .
• Example 43 4- ⁇ 2- [4- (2-Bromo-4, 5-difluoro-phenoxy) piperidin-1-yl] -2-oxo-ethylamino ⁇ -2H-pyridazin-3-one (43)
• Example 44 4- ⁇ 2- [4- (3-trifluoromethyl-phenoxy) - piperidin-1-yl] -2-oxo-ethylamino ⁇ -2H-pyridazin-3-one (44)
• Compound 44 is prepared from intermediate 7a and from 4- (3-trifluoromethyl-phenoxy) -piperidine (obtained following the method described for Ia) applying synthesis method 2 (yield: 36%) .
• Example 45 4- ⁇ 2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl ] -2-oxo-ethylamino ⁇ -2- (4,4,4- trifluoro-butyl) -2H-pyridazin-3-one (45)
• Example 47 4- ⁇ 2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -2-oxo-ethylamino ⁇ -2- (4-methyl- pentyl) -2H-pyridazin-3-one (47)
• Compound 47 is prepared from intermediate 7b and from l-bromo-4-methyl-pentane following synthesis method 6 (yield: 33%) .
• Compound 48 is prepared from (2-benzyl-3-oxo-2, 3- dihydro-pyridazin-4-ylamino) -acetic acid (obtained following the operating mode for 4e using benzyl bromide to alkylate nitrogen 2 of pyridazinone) and from intermediate Ia in base form, following synthesis method 2 (yield: 30%) .
• Compound 49 is prepared from (2-isopropyl-3-oxo-2, 3- dihydro-pyridazin-4-ylamino) - acetic acid (obtained following the operating mode for 4e using 2-iodo- propane to alkyate nitrogen 2 of pyridazinone) and from intermediate Ia in base form, following synthesis method 2 (yield: 69%) .
• Compound 50 is prepared from (2-butyl-3-oxo-2, 3- dihydro-pyridazin-4-ylamino) - acetic acid (obtained following the operating mode for 4e using 1-iodo-butane to alkylate nitrogen 2 of pyridazinone) and from intermediate Ig in base form, following synthesis method 2 (yield: 34%) .
• Example 51 4- ⁇ 2- [4- (2-Chloro-5-trifluoromethyl- phenoxy) -piperidin-1-yl] -2-oxo-ethylamino ⁇ -5-methoxy-2- methyl-2H-pyridazin-3-one (51)
• Compound 51 is prepared from intermediate Ic in base form and from intermediate 4f, following synthesis method 2 (yield: 21%) .
• Example 52 4- (2-Chloro-5-trifluoromethyl-phenoxy) - piperidine-1-carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (52)
• Example 53 4- (2-Chloro-5-fluoro-phenoxy) - piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (53)
• Example 54 4- (2-fluoro-5-trifluoromethyl-phenoxy) - piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (54)
• Compound 54 is prepared from intermediate 4c and from 4- (2-fluoro-5-trifluoromethyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia) , applying synthesis method 7 (yield: 41%) .
• Example 55 4- (2, 5-dimethyl-phenoxy) -piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3-dihydro-pyridazin- 4-yl) -amide (55)
• Compound 55 is prepared from intermediate 4c and from 4- (2, 5-dimethyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia) , applying synthesis method 7 (yield: 43%) .
• Example 56 4- (2-chloro-5-methyl-phenoxy) - piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (56)
• Compound 56 is prepared from intermediate 4c and from 4- (2-chloro-5-methyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia) applying synthesis method 7 (yield: 28%) .
• Compound 57 is prepared from intermediate 4c and from 4- (5-isopropyl-2-methyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia, ) applying synthesis method 7 (yield: 51%) .
• Compound 58 is prepared from intermediate 4c and from 4- (3-trifluoromethyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia) , applying synthesis method 7 (yield: 36%) .
• Example 60 4- (4-fluoro-5-trifluoromethyl-phenoxy) - piperidine-1-carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (60)
• Compound 60 is prepared from intermediate 4c and from 4- (4-fluoro-3-trifluoromethyl-phenoxy) -piperidine
• Example 61 4- (5-fluoro-2-trifluoromethyl-phenoxy) - piperidine-1-carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (61)
• Compound 61 is prepared from intermediate 4c and from intermediate Ib in base form, following synthesis method 7 (yield: 43%) .
• Compound 62 is prepared from intermediate 4c and from intermediate Ij in base form, following synthesis method 7 (yield: 34%) .
• Example 63 4- (2-chloro-5-bromo-phenoxy) -piperidine- 1-carboxylic acid (2-methyl-3-oxo-2, 3-dihydro- pyridazin-4-yl) -amide (63)
• Example 64 4- (2-chloro-phenoxy) -piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3-dihydro-pyridazin- 4-yl) -amide (64)
• Compound 64 is prepared from intermediate 4c and from intermediate Ig in base form, following synthesis method 7 (yield: 45%) .
• Example 65 4- (3, 4-dichloro-phenoxy) -piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3-dihydro-pyridazin- 4-yl) -amide (65)
• Example 66 4- (2, 4-dichloro-phenoxy) -piperidine-1- carboxylic acid (2-methyl-3-oxo-2, 3-dihydro-pyridazin- 4-yl) -amide (66)
• Compound 66 is prepared from intermediate 4c and from intermediate Ii in base form, following synthesis method 7 (yield: 43%) .
• Compound 67 is prepared from intermediate 4c and from 4- (3-fluoro-5-trifluoromethyl-phenoxy) -piperidine
• Compound 68 is prepared from intermediate 4c and from 4- (5-fluoro-2-methyl-phenoxy) -piperidine (obtained following the method described for intermediate Ia) , applying synthesis method 7 (yield: 46%) .
• Compound 69 is prepared from intermediate 4c and from intermediate Ik in base form, following synthesis method 7 (yield: 51%) .
• Example 70 4- (2, 4, 5-trichloro-phenoxy) -piperidine- 1-carboxylic acid (2-methyl-3-oxo-2, 3-dihydro- pyridazin-4-yl) -amide (70)
• Compound 70 is prepared from intermediate 4c and from 4- (2, 4, 5-trichloro-phenoxy) -piperidine (obtained following the method described for intermediate Ia) applying synthesis method 7 (yield: 46%).
• Example 71 4- (2-bromo-4, 5-difluoro-phenoxy) - piperidine-1-carboxylic acid (2-methyl-3-oxo-2, 3- dihydro-pyridazin-4-yl) -amide (71)
• Compound 71 is prepared from intermediate 4c and from intermediate Ie in base form, following synthesis method 7 (yield: 47%) .
• Compound 72 is prepared from 4-amino-2-benzyloxymethyl- 2H-pyridazin-3-one (prepared following the method described for intermediate 4c) and from intermediate Ic, following synthesis method 7 (yield: 49%). The compound obtained is then placed in EtOH in the presence of Pd/C under 3 bar of H 2 for Hh. After filtering and concentrating to dryness, compound 72 is obtained (yield: 61%) .
• Compound 73 is prepared from intermediate 6b and from intermediate Ic following synthesis method 7 (yield: 36%) .
• Example 74 4- (2-Chloro-5-trifluoromethyl-phenoxy) - piperidine-1-carboxylic acid (l-methyl-6-oxo-l, 6- dihydro-pyridazin-3-yl) -amide (74)
• HepG2 cells of human hepatocarcinoma are cultured at confluence then trypsinated.
• the cell residue is solubilized in 1OmM Tris buffer (pH 7.4) sucrose (250 iriM) DTT (1 iriM) then the cells are lysed by sonication.
• the microsomes are obtained after centrifuging at 10,000 g for 20 minutes at 4°C followed by centifrugation of the supernatant at 100,000 g for
• Tris buffer pH 7.4 sucrose (250 mM) at 4°C and the microsomal proteins are assayed and stored at -196°C
• the enzymatic reaction measures the conversion of stearic acid (C18:0 fatty acid) into oleic acid (C18:l fatty acid) by SCD-I.
• the enzymatic reaction is initiated by the addition of 125 ⁇ g of microsomal fraction of HepG2 cells to tubes (total reaction volume of 500 ⁇ l) containing 62 ⁇ M stearic acid (45 ⁇ M stearic acid and 17 ⁇ M [ 14 C] stearic acid) in 100 mM phosphate buffer (pH 7.16) with 7.2 mM ATP, 0.54 mM CoA, 6 mM MgCl 2 , 0.8 mM NADH and the inhibitor compound or vehicle (0.1% DMSO).
• the tubes are incubated for 20 minutes at 37°C then the enzymatic reaction is halted by the addition of KOH (12%) and saponification for 30 minutes at 80 0 C. After acidification (3N HCl), the fatty acids are extracted twice with ethyl ether, evaporated under nitrogen before being solubilized in methanol/dichloromethane (3:1). The reaction product
• Enzymatic activity is measured in picomoles of stearic acid converted to oleic acid per minute and per mg of protein. For each inhibitor compound, an IC 5 O value is determined, compared with the reference enzymatic activity (vehicle 0.1% DMSO).
• Sterculic acid is the reference inhibitor compound (Gomez F. E., Bauman D. E., Ntambi J. M., Fox B. G. Effects of sterculic acid on stearoyl-CoA desaturase in differentiating 3T3-L1 adipocytes. Biochem Biophys Res Commun . 300 316-326 (2003) .
• the results obtained show that the compounds of general formula (I) inhibit the enzymatic activity of the SCD-I enzyme.
• the compounds of general formula (I) can be used as inhibitors of the SCD-I enzyme.

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