Purine derivatives and the use thereof as medicament
20210369723 · 2021-12-02
Inventors
Cpc classification
A61K31/5377
HUMAN NECESSITIES
C07D473/00
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to novel purines of general formula A
##STR00001##
processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment or prevention of conditions having an association with NR2B negative allosteric modulating properties.
Claims
1. A compound of formula A ##STR00048## in which R.sup.1 represents phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, cyclopropyl, F.sub.2HC—, FH.sub.2C—, F.sub.3C—; R.sup.2 represents hydrogen, methyl.
2. The compound according to claim 1, wherein R.sup.2 represents hydrogen.
3. The compound according to claim 1, wherein R.sup.2 represents methyl.
4. The compound according to claim 1 wherein R.sup.1 represents phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, F.sub.2HC—.
5. The compound according to claim 1 wherein R.sup.1 represents ##STR00049##
6. The (S)-enantiomer according to claim 1 selected from the group consisting of: ##STR00050## ##STR00051## ##STR00052## ##STR00053##
7. A pharmaceutically acceptable salt of a compound according to claim 1.
8. A method of treating depression, comprising a step of administering a compound according to claim 1.
9. A method of treating bipolar disorder I depressed, hypomanic, manic and mixed form; bipolar disorder II; depressive disorders, such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, depressive disorder with postpartum onset, depressive disorders with psychotic symptoms; major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, or catatonia, said method comprising the step of administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
10. A method of treatment according to claim 9, wherein the compound is administered in addition to treatment with another antidepressant drug.
11. A method of treatment according to claim 9, wherein the compound is administered in addition to behavioural therapy.
12. A method of treatment according to claim 9, wherein the compound is in an admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
Description
EXPERIMENTAL SECTION
Abbreviations
[0078] ACN acetonitrile [0079] Alox B Aluminium oxide, basic [0080] APCI Atmospheric pressure chemical ionization [0081] Boc tert-butyloxycarbonyl [0082] CDI 1,1′-carbonyldiimidazole [0083] CO2 Carbon Dioxide [0084] d day [0085] DA Diode Array [0086] DAD Diode Array Detector [0087] DCM dichloromethane [0088] DIPE diisopropylether [0089] DIPEA diisopropylethylamine [0090] DMF dimethylformamide [0091] ee, e.e. enantiomeric excess [0092] ELSD Evaporative Light Scattering Detector [0093] ESI electrospray ionization (in MS) [0094] EtOAc ethylacetate [0095] EtOH ethanol [0096] Exp. example [0097] h hour(s) [0098] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate [0099] HPLC high performance liquid chromatography [0100] HPLC-MS coupled high performance liquid chromatography-mass spectrometry [0101] IPA Isopropanol [0102] M molar (mol/L) [0103] MeOH methanol [0104] min minute(s) [0105] MS mass spectrometry [0106] MW molecular weight [0107] NH.sub.3 ammonia [0108] NMP N-Methyl-2-pyrrolidone [0109] PSI Pound per square inch [0110] QDa Quadrupole Dalton [0111] rt room temperature [0112] R.sub.t retention time [0113] scCO2 supercritical CO2 [0114] Sol Solvent [0115] soln Solution [0116] solv solvent [0117] TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [0118] TEA triethylamine [0119] TFA trifluoroacetic acid [0120] THF tetrahydrofuran [0121] TLC thin-layer chromatography [0122] SFC Supercritical fluid chromatography
General Analytics
[0123] All of the following reactions were carried out using commercial grade reagents and solvents. NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2 p16 software. Chemical shifts are given in parts per million (ppm) downfield from internal reference trimethylsilane in 6 units. Selected data are reported in the following manner: chemical shift, multiplicity, coupling constants (J), integration. Analytical thin-layer chromatography (TLC) was carried out using Merck silica gel 60 F254 plates. All compounds were visualized as single spots using short wave UV light. Low resolution mass spectra were obtained using a liquid chromatography mass spectrometer (LCMS) that consisted of an Agilent 1100 series LC coupled to a Agilent 6130 quadrupole mass spectrometer (electrospray positive ionization).
Methods:
[0124] For solvent mixtures used for HPLC-MS methods and Chiral SFC analytical methods, % solvent are given as volume percent of the corresponding solvent.
HPLC-MS Methods:
[0125]
TABLE-US-00005 Method 1 Method Name: Z003_S05 Device description: Agilent 1200 with DA- and MS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% NH.sub.3] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 2.2 60.0 0.2 95.0 5.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0
TABLE-US-00006 Method 2 Method Name: Z011_S03 Device description: Agilent 1200 with DA- and MS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% NH.sub.3] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0
TABLE-US-00007 Method 3 Method Name: Z018_S04 Device description: Agilent 1200 with DA- and MS-Detector Column: Sunfire C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0
TABLE-US-00008 Method 5 Method Name: 004_CA02 Device description: Waters Acquity, QDa Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0
TABLE-US-00009 Method 6 Method Name: 004_CA11 Device description: Waters Acquity, QDa Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0
TABLE-US-00010 Method 7 Method Name: 003_CA11 Device description: Waters Acquity, QDa Detector Column: Sunfire C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description: % Sol Back Gradient/Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0
Chiral SFC Analytical Methods:
[0126]
TABLE-US-00011 Method 8 I_C4_20_MeOH_NH.sub.3.sub.
TABLE-US-00012 Method 9 I_C4_25_MEOH_NH.sub.3.sub.
TABLE-US-00013 Method 10: I_IB_25_IPA_NH.sub.3_001 Method Name: I_IB_25_IPA_NH.sub.3_001 Device description: Agilent 1260 SFC with DAD and MS Column: Chiralpak ® IB_4.6 × 250 mm_5 μm Column producer: Daicel % Sol Back Gradient/Solvent % Sol [IPA Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0
TABLE-US-00014 Method 11: I_IC_25_MEOH_NH.sub.3_001 Method Name: I_IC_25_MEOH_NH.sub.3_001 Device description: Agilent 1260 SFC with DAD and ELSD Column: Chiralpak ® IC_4.6 × 250 mm_5 μm Column producer: Daicel % Sol Back Gradient/Solvent % Sol [MeOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0
TABLE-US-00015 Method 12: I_IG_35_MEOH_NH.sub.3_001 Method Name: I_IG_35_MEOH_NH.sub.3_001 Device description: Agilent 1260 SFC with DAD and MS Column: Chiralpak ®-IG_4.6 × 250 mm_5 μm Column producer: Daicel % Sol Back Gradient/Solvent % Sol [EtOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 65.0 35.0 4.0 40.0 2175.0 10.0 65.0 35.0 4.0 40.0 2175.0
TABLE-US-00016 Method 13: I_SA_20_MEOH_NH.sub.3_001 Method Name: I_SA_20_MEOH_NH.sub.3_001 Device description: Agilent 1260 SFC with DAD and MS Column: CHIRAL ART ® Amylose SA_4.6 × 250 mm_5 μm Column producer: YMC % Sol Back Gradient/Solvent % Sol [MeOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0
TABLE-US-00017 Method 14: I_SA_25_MEOH_NH.sub.3_001 Method Name: I_SA_25_MEOH_NH.sub.3_001 Device description: Agilent 1260 SFC with DAD and MS Column: CHIRAL ART ® Amylose SA_4.6 × 250 mm_5 μm Column producer: YMC % Sol Back Gradient/Solvent % Sol [MeOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0
Preparation of Intermediates
Example 1b
[0127] ##STR00011##
[0128] S-Morpholine-2,4-dicarboxylic acid 4-tertbutylester (13.00 g, 56.4 mmol) and 6-Methylpyrimidine-4,5-diamine (10 g, content 70%; 56.4 mmol) were dissolved in EtOAc (200 ml); the temperature was lowered to 0° C. before the addition of TEA (19.65 ml; 140.97 mmol) followed by 1-Propanephosphonic acid (50% soln in EtOAc; 39.87 ml; 67.66 mmol) added dropwise over 1 hour. The reaction mixture was stirred 1.5 h at room temperature before the work-up: 400 ml of DCM were added followed by 100 ml of NaHCO.sub.3 (5% aqueous soln.); the phases were separated and the organic phase dried over Na.sub.2SO.sub.4; the crude obtained after evaporation of the solvents was purified by flash chromatography using a mixture EtOAc/MeOH 80/20. Obtained 5.78 g of the desired compound.
TABLE-US-00018 HPLC-MS; Method: Z011_S03; MS: 338 (M + H).sup.+ R.sub.t [min]: 0.76 Chiral SFC; Method: R.sub.t [min]: 3.31 min; I_C4_20_MEOH_NH3_001; e.e. 100%
Example 1c
[0129] ##STR00012##
[0130] S-Morpholine-2,4-dicarboxylic acid 4-tertbutylester (25.0 g, 108 mmol) was dissolved in THF (400 ml). Then TBTU (38.2 g, 119 mmol) was added, followed by Pyrimidine-4,5-diamine hydrochloride (15.9 g, 108 mmol, CAS No. 97846-32-7) and TEA (30.1 ml, 216 mmol). The reaction mixture was stirred 20 h at room temperature before the work-up: The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with 150 mL H.sub.2O and stirred for 30 min. The obtained precipitate was filtered off, washed with H.sub.2O and dried at 55° C. in the oven. Obtained 34.3 g of the desired product.
TABLE-US-00019 Chiral SFC; Method: MS: 324 (M + H).sup.+ I_C4_20_MEOH_NH3_001; ee: 100% R.sub.t [min]: 3.31 min
Example 1f
[0131] ##STR00013##
[0132] Pyrimidine-4,5-diamine hydrochloride (5.00 g, 34.1 mmol) and (S)-4-Benzyl-morpholine-2-carboxylic acid (7.75 g, 35.0 mmol) were dissolved in DMF (150 ml) and DIPEA (15 ml, 87.8 mmol). Then HATU (13.3 g, 35.0 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. Work-up: The reaction mixture was diluted with 25 ml K.sub.2CO.sub.3 solution (2M in water), filtered over Alox B and washed with a mixture of DMF/MeOH. The crude was separated via column chromatography (eluent: DCM/MeOH/NH.sub.3 9/1/0.1, volume/volume/volume). Obtained 8.81 g of the desired product.
TABLE-US-00020 HPLC-MS; Method: Z011_S03; MS: 314 (M + H)+ Rt [min]: 0.79 Chiral SFC; Method: Rt [min]: 3.23; I_IB_25_IPA_NH3_001 ee 99.1%
Example 2b
Method a (According to Scheme 1)
[0133] ##STR00014##
[0134] A mixture of example 1b (4.30 g, 12.75 mmol), potassium carbonate (1.76 g, 12.75 mmol) and isopropanol (300 ml) was stirred for 22 h at 80° C. The precipitate was filtered off, washed with isopropanol and the filtrate was concentrated in vacuo. The residue was dried overnight. Obtained 4.06 g of the desired compound used as such in the next step.
TABLE-US-00021 HPLC-MS; Method: Z011_S03; MS: 320 (M + H).sup.+ R.sub.t [min]: 0.59 Chiral SFC; Method: R.sub.t [min]: 3.05; I_IG_35_MEOH_NH.sub.3_001 ee: 94.2%
Example 2b
Method B (According to Scheme 2)
[0135] ##STR00015##
[0136] A mixture of example 1b (4.14 g; 12.27 mmol) and lithium bromide (2.13 g; 24.5 mmol) in 1-propanol (80 ml) was heated at 90° C. over 14 days. The reaction mixture was absorbed on silica gel and purified by flash chromatography; eluent: EtOAc/MeOH/NH.sub.4OH (from 9/1/0.1 to 8/2/0.2; volume/volume/volume). Obtained 3 g of the desired compound.
TABLE-US-00022 HPLC-MS; Method: Z011_S03; MS: 320 (M + H).sup.+ R.sub.t [min]: 0.59 Chiral SFC; Method: R.sub.t [min]: 3.05; I_IG_35_MEOH_NH.sub.3_001 ee: 97.4%
Example 2c
[0137] ##STR00016##
[0138] A mixture of example 1c (5.00 g, 15.5 mmol), potassium carbonate (2.14 g, 15.5 mmol) and isopropanol (50 ml) was stirred for 35 h at 80° C. The precipitate was filtered off, washed with isopropanol and the filtrate was concentrated in vacuo. The residue was dried overnight. Obtained 5.00 g of the desired product.
TABLE-US-00023 Chiral SFC; Method: MS: 306 (M + H).sup.+ I_C4_20_MEOH_NH3_001; ee: 85.4% R.sub.t [min]: 2.64 min
Example 3b
[0139] ##STR00017##
[0140] Example 2b (3.50 g, 11.0 mmol) was dissolved in DCM (120 ml), HCl in dioxane (4 M, 13.7 ml, 55.0 mmol) was added dropwise under ice cooling. The reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated in vacuo at 35° C. Obtained 3.20 g of the desired compound as a salt which was used as such in the next step.
TABLE-US-00024 Chiral SFC; Method: MS: 220 (M + H).sup.+ I_SA_25_MEOH_NH3_001; e.e. 100% R.sub.t [min]: 2.42 min
Example 3c
[0141] ##STR00018##
[0142] To a mixture of example 2c (9.40 g, 30.8 mmol) in DCM (1200 ml), HCl in dioxane (4 M, 35.0 ml, 140 mmol) was added dropwise and the reaction mixture was stirred overnight at rt. The solvents were evaporated in vacuo and the residue was re-evaporated 2× with toluene. Obtained 8.60 g of the desired product as a salt.
TABLE-US-00025 Chiral SFC; Method: MS: 206 (M + H).sup.+ I_SA_20_MEOH_NH3_001; ee: 100% R.sub.t [min]: 4.27 min
Example 5a
Method C (According to Scheme 3)
[0143] ##STR00019##
[0144] A mixture of Example 1f (8.80 g, 28.1 mmol), LiBr (3.50 g, 40.3 mmol), MeOH (100 ml) and NMP (5 ml) was stirred 1.5 days at 120° C.
[0145] The crude was separated via column chromatography (DCM/MeOH/NH.sub.3 9/1/0.1; volume/volume/volume) followed by preparative HPLC and finally chiral SFC. Obtained 650 mg of the desired product.
TABLE-US-00026 Chiral SFC; Method: ee: 100% I_C4_25_MEOH_NH3_001; R.sub.t [min]: 3.71 min
Example 6a
Method C (According to Scheme 3)
[0146] ##STR00020##
[0147] Example 5a (650 mg, 2.20 mmol) was dissolved in MeOH (30 ml) and Pd(OH).sub.2 (150 mg) was added and the reaction mixture was stirred 3 days at 50° C. and 3 bar H.sub.2 pressure. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Obtained 432 mg of the desired product.
TABLE-US-00027 Chiral SFC; Method: MS: 206 (M + H).sup.+ I_IC_25_MEOH_NH3_001; R.sub.t [min]: 3.77 min; ee >95%
Exemplary Embodiments
Example 2
[0148] (2,4-Difluorophenyl)methanol (229 μl; 2.05 mmol, CAS No. 56456-47-4), TEA (0.43 ml, 3.08 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (337 mg; 2.05 mmol) were mixed together in DMF (6 ml); the reaction mixture was heated at 50° C. for 1 h. Example 3b (300 mg; 1.03 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. After cooling down the reaction mixture was diluted with MeOH before being filtered and separated via semipreparative HPLC. Obtained 52.5 mg of the desired compound.
TABLE-US-00028 Example 2
Example 6
[0149] (2-Fluoro-4-methylphenyl)methanol (864 mg, 6.16 mmol, CAS No. 252004-38-9) and Bis-[1,2,4]triazol-1-yl-methanone (1.01 g; 6.16 mmol) were mixed together in DMF (18 ml); the reaction mixture was heated at 50° C. for 1 h. Example 3b (900 mg; 3.08 mmol) and TEA (1.29 ml, 9.24 mmol) were then added and the reaction mixture was stirred at 50° C. overnight. After cooling down the reaction mixture was concentrated in vacuo. The residue was diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was dissolved in THF before being filtered and separated via semipreparative HPLC. Obtained 180 mg of the desired compound which contained 16.5% of the R Enantiomer; consequently, the mixture was submitted to chiral SFC purification affording 130 mg of the desired S Enantiomer.
TABLE-US-00029 Example 6
Example 7
[0150] Example 7 was synthesised in analogy to Example 6. Starting materials: Example 3b (300 mg, 1.03 mmol) and (2-Fluorophenyl)methanol (221 μl, 2.05 mmol, CAS No. 446-51-5). The reaction mixture was purified via preparative HPLC. Obtained 55.0 mg of the desired compound.
TABLE-US-00030 Example 7
Example 8
[0151] (2-Fluoro-3-methylphenyl)methanol (189 mg; 1.35 mmol, CAS No. 307975-03-7), TEA (0.38 ml, 2.70 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (295 mg; 1.80 mmol) were mixed together in DMF (6 ml); the reaction mixture was heated at 50° C. for 1 h. Example 3c (250 mg; 0.90 mmol) was then added and the reaction mixture was stirred for 2 h at 50° C. The reaction mixture was diluted with 4 ml of a mixture MeOH/Water before being filtered and separated via semipreparative HPLC. Obtained 178 mg of the desired compound.
TABLE-US-00031 Example 8
Example 9
[0152] Example 9 was synthesised in analogy to Example 2. Starting materials: Example 3c (250 mg, 0.90 mmol) and (3-Fluoro-2-methylphenyl)methanol (252 mg, 1.80 mmol, CAS No. 500912-13-0). The reaction mixture was purified via preparative HPLC. Obtained 113 mg of the desired compound.
TABLE-US-00032 Example 9
Example 10
[0153] Example 10 was synthesised in analogy to Example 6. Starting materials: Example 3c (350 mg; 1.44 mmol) and (4-Methylphenyl)methanol 353.8 mg (2.88 mmol). Obtained 230 mg of a product containing approximately 20% of the R enantiomer; the mixture was therefore separated via chiral SFC affording 143 mg of the desired S enantiomer.
TABLE-US-00033 Example 10
Example 11
[0154] Example 11 was synthesised in analogy to Example 2. Starting materials: Example 3b (250 mg, 0.86 mmol) and (4-Fluorophenyl)methanol (187 μl, 1.71 mmol, CAS No. 459-56-3). The reaction mixture was purified via preparative HPLC. Obtained 43 mg of the desired compound.
TABLE-US-00034 Example 11
Example 13
[0155] (4-Fluorophenyl)methanol (194 μl; 1.80 mmol, CAS No. 459-56-3), DIPEA (548 μl, 3.15 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (295 mg; 1.80 mmol) were mixed together in DMF (5 ml); the reaction mixture was heated at 50° C. for 1 h. Example 3c (250 mg; 0.90 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. After cooling down the reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent is removed in vacuo. The residue was triturated with DIPE, the obtained precipitate was filtered, dissolved in MeOH/DMF and separated via semipreparative HPLC. Obtained 105 mg of the desired compound.
TABLE-US-00035 Example 13
Example 14
[0156] Example 14 was synthesised in analogy to Example 2. Starting materials: Example 3c (250 mg, 0.90 mmol) and (2,4-Difluorophenyl)methanol (0.20 ml, 1.80 mmol, CAS No. 56456-47-4). The reaction mixture was purified via preparative HPLC. Obtained 154 mg of the desired compound.
TABLE-US-00036 Example 14
Example 16
[0157] Example 16 was synthesised in analogy to Example 2. Starting materials: Example 3c (200 mg, 0.72 mmol) and (3-Fluorophenyl)methanol (156 μl, 1.44 mmol, CAS No. 456-47-3). The reaction mixture was purified via preparative HPLC. Obtained 131 mg of the desired compound.
TABLE-US-00037 Example 16
Example 17
[0158] (2-Fluorophenyl)methanol (155 μl; 1.44 mmol, CAS No. 446-51-5), DIPEA (438 μl, 2.52 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (236 mg; 1.44 mmol) were mixed together in DMF (5 ml); the reaction mixture was heated at 50° C. for 1.5 h. Example 3c (200 mg; 0.72 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. After cooling down the reaction mixture was diluted with H.sub.2O and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed in vacuo. The residue was dissolved in MeOH, filtered and separated via semipreparative HPLC. Obtained 98.3 mg of the desired compound.
TABLE-US-00038 Example 17
Example 18
[0159] (2,3-Difluorophenyl)methanol (162 μl; 1.44 mmol, CAS No. 75853-18-8), DIPEA (438 μl, 2.52 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (236 mg; 1.44 mmol) were mixed together in DMF (5 ml); the reaction mixture was heated at 50° C. for 1.5 h. Example 3c (200 mg; 0.72 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. The organic solvent was removed in vacuo. The residue was diluted with H.sub.2O and the obtained precipitate was filtered off. The precipitate was triturated 2× with DIPE, filtered off and dried. Obtained 138 mg of the desired compound.
TABLE-US-00039 Example 18
Example 19
[0160] (2,6-Difluorophenyl)methanol (159 μl; 1.44 mmol, CAS No. 19064-18-7), DIPEA (438 μl, 2.52 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (236 mg; 1.44 mmol) were mixed together in DMF (5 ml); the reaction mixture was heated at 50° C. for 1.5 h. Example 3c (200 mg; 0.72 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. The residue was diluted with H.sub.2O and stirred overnight at rt. The solvents were removed in vacuo. The residue was diluted with H.sub.2O, the obtained precipitate was filtered off and dried. Obtained 68.9 mg of the desired compound.
TABLE-US-00040 Example 19
Example 20
[0161] (4-Fluoro-2-methylphenyl)methanol (202 mg; 1.44 mmol, CAS No. 80141-91-9), DIPEA (0.38 ml, 2.16 mmol) and Bis-[1,2,4]triazol-1-yl-methanone (236 mg; 1.44 mmol) were mixed together in DMF (6 ml); the reaction mixture was heated at 50° C. for 1 h. Example 3c (200 mg; 0.72 mmol) was then added and the reaction mixture was stirred at 50° C. overnight. After cooling down the reaction mixture was diluted with H.sub.2O/MeOH before being filtered and separated via semipreparative HPLC. Obtained 86.0 mg of the desired compound.
TABLE-US-00041 Example 20
Example 21
[0162] Example 21 was synthesised in analogy to Example 8. Starting materials: Example 3b (250 mg, 0.86 mmol) and (4-Methylphenyl)methanol (209 mg, 1.71 mmol, CAS No. 589-18-4). The reaction mixture was purified via preparative HPLC. Obtained 50.0 mg of the desired compound.
TABLE-US-00042 Example 21
Example 24
[0163] [4-(Difluoromethyl)phenyl]methanol (24.0 mg; 0.15 mmol, CAS No. 444915-77-9) and CDI (23.0 mg; 0.14 mmol) were mixed together in DMF (0.5 ml); the reaction mixture was heated at 40° C. during 45 min. Example 3c (24.0 mg; 0.10 mmol), DIPEA (17.0 μl; 0.10 mmol) and DMF (0.5 ml) were then added in sequence and the reaction mixture was stirred overnight at 40° C. The reaction mixture was diluted with ACN/H.sub.2O/MeOH, filtered and separated via semipreparative HPLC. Obtained 20.9 mg of the desired compound.
TABLE-US-00043 Example 24
Example 25
[0164] Example 25 was synthesised in analogy to Example 24. Starting materials: Example 3c (24.0 mg, 0.10 mmol) and (4-Chlorophenyl)methanol (21.0 mg, 0.15 mmol, CAS No. 873-76-7). The reaction mixture was purified via preparative HPLC. Obtained 16.8 mg of the desired compound.
TABLE-US-00044 Example 25
Example 26
[0165] Example 3c (25.0 mg; 0.10 mmol) and DIPEA (20.0 μl, 0.12 mmol) were dissolved in dioxane (1 ml), then Benzyl chloroformate (40.0 μl, 0.12 mmol, content 50%, CAS No. 501-53-1) was added dropwise under ice cooling and the reaction mixture was stirred overnight at rt.
[0166] The reaction mixture was concentrated in vacuo, dissolved in DMF and purified via preparative HPLC. Obtained 14.0 mg of the desired compound.
TABLE-US-00045 Example 26
Example 28
[0167] (2-Chlorophenyl)methanol (21.4 mg, 0.15 mmol, CAS No. 17849-38-6) and CDI (0.14 mmol) were mixed together in DMF (1 ml); the reaction mixture was stirred at rt during 1.5 h. Example 6a (20.5 mg, 0.10 mmol) dissolved in DMF (1 ml) was then added and the reaction mixture was stirred overnight at rt. The reaction mixture was separated via semipreparative HPLC. Obtained 7.1 mg of the desired compound.
TABLE-US-00046 Example 28
Example 29
[0168] Example 29 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (3-Methylphenyl)methanol (18.3 mg, 0.15 mmol, CAS No. 587-03-1). The reaction mixture was purified via preparative HPLC. Obtained 3.4 mg of the desired compound.
TABLE-US-00047 Example 29
Example 30
[0169] Example 30 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (4-Chloro-3-fluorophenyl)methanol (24.1 mg, 0.15 mmol, CAS No. 202925-10-8). The reaction mixture was purified via preparative HPLC. Obtained 8.2 mg of the desired compound.
TABLE-US-00048 Example 30
Example 31
[0170] Example 31 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (3,4-Difluorophenyl)methanol (21.6 mg, 0.15 mmol, CAS No. 85118-05-4). The reaction mixture was purified via preparative HPLC. Obtained 5.4 mg of the desired compound.
TABLE-US-00049 Example 31
Example 32
[0171] Example 32 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (2-Chloro-4-fluorophenyl)methanol (24.1 mg, 0.15 mmol, CAS No. 208186-84-9). The reaction mixture was purified via preparative HPLC. Obtained 8.1 mg of the desired compound.
TABLE-US-00050 Example 32
Example 34
[0172] Example 34 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (3-Fluoro-4-methylphenyl)methanol (21.0 mg, 0.15 mmol, CAS No. 192702-79-7). The reaction mixture was purified via preparative HPLC. Obtained 6.2 mg of the desired compound.
TABLE-US-00051 Example 34
Example 36
[0173] Example 36 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (2-Fluoro-4-methylphenyl)methanol (21.0 mg, 0.15 mmol, CAS No. 252004-38-9). The reaction mixture was purified via preparative HPLC. Obtained 6.0 mg of the desired compound.
TABLE-US-00052 Example 36
Example 37
[0174] Example 37 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (2-Fluoro-6-methylphenyl)methanol (21.0 mg, 0.15 mmol, CAS No. 478163-35-8). The reaction mixture was purified via preparative HPLC. Obtained 5.7 mg of the desired compound.
TABLE-US-00053 Example 37
Example 38
[0175] Example 38 was synthesised in analogy to Example 28. Starting materials: Example 6a (20.5 mg, 0.10 mmol) and (2,4,6-Trifluorophenyl)methanol (24.3 mg, 0.15 mmol, CAS No. 118289-07-9). The reaction mixture was purified via preparative HPLC. Obtained 9.1 mg of the desired compound.
TABLE-US-00054 Example 38