2-CHLORO-5-TRIFLUOROMETHYL-1,3,4-THIADIAZOLE

DBU (0.135 mL, 0.901 mmol) and 11297] To a solution of intermediate B-S (71 g, 0.33 mmol) mACN (0.85 mE) was added DIPEA (0.14 mE, 0.84 mmol) followed by 2-chloro-S-(trifluoromethyl)- 1 , 3, 4-thiadiazole (73 g, 0.37 mmol). The reaction mixture was heated at 120°C. for 30 minutes using microwave. EtOAc was added and the organic phase was washed with a saturated solution of NaHCO3 followed by a saturated solution of NaC1. The organic phase was dried over MgSO4, filtered and evaporated. Purification via silica gel chromatography (0-40percent EtOAc in hexanes) gave the title compound (85 g, 70percent). 'H NMR (500 MHz, CDC13) oe 6.82 (s, 1H), 4.38-4.22 (m, 2H), 3.96-3.82 (m, 1H), 2.11-2.00(m, 1H), 1.92-1.79(m, 1H), 1.79-1.66(m, 2H), 1.43 (s, 11H). MS (ESI): mass calcd. for C, 4H, 9F3N4025, 364.1; mlz found, 365.0 [M+H].The racemic mixture of the title compounds is synthesized as described for starting from example 44c (300 mg, 0.71 mmol of the corresponding hydrochloride) instead of example 44k, 2-Chloro-5-(Trifluoromethyl)-(l, 3, 4)-thiadiazole (200 mg, 1.06 mmol) instead of 2-Chloro-5-(trifluoromethyl)pyrimidine and N, N-diisopropylethylamine (489 mu, 2.82 mmol) in 4 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 150°C during 30 minutes. The crude is partitioned between DCM and water; the organic layer is dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain 240 mg of the racemic mixture. UPLC-MS (Method 1): Rt = 1.39 min MS (ES+): m/z = 515 [M+H]+ .Nu, Nu-diisopropylethylamine (47 muL, 0.27 mmol) is added into a stirred solution of example 16a (25 mg, 0.14 mmol) and 2-Chloro-5-Trifluoromethyl-(l, 3, 4)-Thiadiazole (19.7 mu, 0.18 mmol) dissolved in 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100°C for 30 minutes. The crude is partitioned between Et2O and 5percent aqueous NaHCO3, the aqueous layer is extracted with 1 : 1 Et20/EtOAc mixture and then the collected organic phases are dried and concentrated under reduced pressure; the obtained crude intermediate is dissolved in 2 ml of anhydrous DCM, N, N-diisopropylethylamine (35 muL, 0.20 mmol) and l, l-dioxothiane-4-carbonyl chloride (40 mg, 0.20 mmol previously prepared from the corresponding carboxilic acid and oxalyl chloride in anhydrous DCM) are added and the reaction is stirred overnight. DCM is added and the reaction mixture is washed with IN aqueous HCl; the organic layer is separated, dried and concentrated under reduced pressure; the residue is purified by preparative HPLC-MS and then by Silica gel flash chromatography using Cyclohexane/EtOAc 40:60 to 0: 100 as eluent to obtain the title product (12 mg, 18 percent yield). HPLC-MS (Method 5): Rt = 2.56 MS (APCI+): m/z = 496 [M+H]+N, N-diisopropylethylamine (47 mul, 0.27 mmol) is added into a stirred solution of example 16a (25 mg, 0.14 mmol) and 2-Chloro-5-Trifluoromethyl-(1, 3, 4)-Thiadiazole (19.7 mul, 0.18 mmol) dissolved in 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100° C. for 30 minutes. The crude is partitioned between Et2O and 5percent aqueous NaHCO3, the aqueous layer is extracted with 1:1 Et2O/EtOAc mixture and then the collected organic phases are dried and concentrated under reduced pressure; the obtained crude intermediate is dissolved in 2 ml of anhydrous DCM, N, N-diisopropylethylamine (35 mul, 0.20 mmol) and 1, 1-dioxothiane-4-carbonyl chloride (40 mg, 0.20 mmol previously prepared from the corresponding carboxilic acid and oxalyl chloride in anhydrous DCM) are added and the reaction is stirred overnight. DCM is added and the reaction mixture is washed with 1N aqueous HCl; the organic layer is separated, dried and concentrated under reduced pressure; the residue is purified by preparative HPLC-MS and then by Silica gel flash chromatography using Cyclohexane/EtOAc 40:60 to 0:100 as eluent to obtain the title product (12 mg, 18percent yield). [0686] HPLC-MS (Method 5): Rt=2.56 min [0687] MS (APCI+): m/z=496 [M+H]+A mixture of 5-(1 -methanesulfonyl-1 , 2, 3, 6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl- furo[2, 3-c] pyridine (HCI salt, 70 mg), 2-chloro-5-trifluoromethyl-[1 , 3, 4]thiadiazole (35 mg), K2CO3 (55 mg), and dimethyl sulfoxide (3 mL) is stirred at 60 °C overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is triturated with methanol and then with diisopropylether to give the title compound. LC (method 1 ): tR = 0.94 min; Mass spectrum (ESI+): m/z = 514 [M+H]+.Example 26 5-(1-Methanesulfonyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-2-[1-(5-trifluoromethyl-[1, 3, 4]thiadiazol-2-yl)-piperidin-4-yl]-furo[2, 3-c]pyridine A mixture of 5-(1-methanesulfonyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2, 3-c]pyridine (HCl salt, 70 mg), To a solution of (S)-3-(2, 5-difluoro-4-(methylsulfonyl)phenoxy)-l-(piperidin- 4-yl)pyrrolidin-2-one (Preparation JJ; 0.30 g, 0.80 mmol) in DMF (2 mL) was added potassium carbonate (0.133 g, 0.96 mmol) and 2-chloro-5-(trifluoromethyl)-l, 3, 4-thiadiazole (0.181 g, 0.962 mmol). The reaction was stirred at 75 °C for 3 hours. The reaction was diluted with EtOAc and washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue purified by flash chromatography to yield (S)-3-(2, 5- dif uoro-4-(methylsulfonyl)phenoxy)- 1 -( 1 -(5 -(trif uoromethy 1)- 1 , 3 , 4-thiadiazol-2- yl)piperidin-4-yl)pyrrolidin-2-one (0.111 g, 0.211 mmol, 26.3 percent yield). Mass spectrum (apci) m/z = 527.0 (M + H).The title compound is prepared from (S)-5-(1-methanesulfonyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2, 3-dihydro-furo[2, 3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and Example 485-(1 -Methanesulfonyl-1 , 2, 3, 6-tetrahvdro-pyridin-4-yl)-2-methyl-2-[1 -(5-trifluoromethyl- [1 , 3, 41thiadiazol-2-yl)-piperidin-4-yl1-2, 3-dihvdro-furo[2, 3-clpyridineThe title compound is prepared from (S)-5-(1 -methanesulfonyl-1 , 2, 3, 6-tetrahydro- pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2, 3-dihydro-furo[2, 3-c]pyridine (Intermediate 41 ; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5- trifluoromethyl-[1 , 3, 4]thiadiazole in dimethylsulfoxide at 85°C in the presence of potassium carbonate. LC (method 4): tR = 0.98 min; Mass spectrum (EST): m/z = 530 [M+H]+.

Molecular Weight:188.56
XLogP3:2.2
Hydrogen Bond Acceptor Count:6
Exact Mass:187.9422814
Monoisotopic Mass:187.9422814
Topological Polar Surface Area:54
Heavy Atom Count:10
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes