Structure of 518057-72-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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| CAS No. : | 518057-72-2 |
| Formula : | C7H7FN2O |
| M.W : | 154.14 |
| SMILES Code : | O=C(N)C1=CC(N)=CC=C1F |
| MDL No. : | MFCD03094256 |
| InChI Key : | DGQLTQZWCJJIRU-UHFFFAOYSA-N |
| Pubchem ID : | 2778899 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319-H332-H335 |
| Precautionary Statements: | P261-P280-P305+P351+P338 |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 38.9 |
| TPSA ? Topological Polar Surface Area: Calculated from |
69.11 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.57 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.64 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.93 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.02 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.68 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.77 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.54 |
| Solubility | 4.48 mg/ml ; 0.0291 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.67 |
| Solubility | 3.32 mg/ml ; 0.0215 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.89 |
| Solubility | 1.98 mg/ml ; 0.0128 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.79 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.07 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 46% | With N,N-dimethyl-formamide; In acetonitrile; at 100℃; for 0.333333h;Microwave irradiation; | A mixture of <strong>[518057-72-2]3-amino-6-fluorobenzamide</strong> (85 mg, 0.5 mmol), 3,4-dimethoxyphenylboronic acid (91 mg, 0.5 mmol) and glyoxylic acid monohydrate (46 mg, 0.5 mmol) in acetonitrile (2.0 mL) and DMF (0.2 mL) was heated at 100 C. for 20 min. in a microwave reactor. After removal of solvent, the crude was triturated with methylene chloride. The precipitate formed was collected by filtration and washed with methylene chloride to give 13A after drying, yield: 46%. 1H NMR (400 MHz, Methanol-d4) delta ppm 3.81 (s, 3H) 3.82 (s, 3H) 4.92 (s, 1H) 6.83-6.89 (m, 1H) 6.93 (d, J=8.35 Hz, 1H) 6.96-7.02 (m, 1H) 7.03-7.07 (m, 1H) 7.10 (d, J=1.76 Hz, 1H) 7.15 (dd, J=5.93, 2.86 Hz, 1H), LCMS: 349 (M+1). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 30% | With potassium carbonate; In acetonitrile; for 4h;Reflux; | The 2-fluoro-5-aminobenzoic acid amide [<strong>[518057-72-2]2-fluoro-5-aminobenzamide</strong>] (0.20g, 1 . 3mmol) and bromo nonane (0.30g, 1 . 4mmol) solution in acetonitrile (20 ml) is evenly stirring, by adding potassium carbonate K 2 CO 3 (0.25g, 1 . 8mmol) in. Heating to reflux the reaction mixture 4 hours. In the thin-layer chromatography (TLC) display raw materials after the disappear completely, through a small section of the silicon gel layer. Reducing pressure and evaporating the solvent, the use of silica gel for rapid column chromatography. The resulting compound (0.11g) to yield of 30% |
| 30% | With potassium carbonate; In acetonitrile; for 4h;Reflux; | To a well-stirred solution of <strong>[518057-72-2]2-fluoro-5-aminobenzamide</strong> (43b)(0.20 g, 1.3 mmol) and 1-bromononane (0.30 g, 1.4 mmol) in ACN(20 mL) was added K2CO3 (0.25 g, 1.8 mmol). The reaction mixture was heated to reflux for 4 h. After the complete disappearance ofstarting material as indicated by TLC, the reaction mixture wassubjected to pass through a short pad of silica gel. The filtrate obtainedwas evaporated under reduced pressure and subjected topurification by flash column chromatography on silica gel. Thetitled compound (0.11 g) was obtained in 30% yield. 1H NMR(400 MHz, CDCl3) d 7.23e7.34 (m, 1H), 6.94 (d, J 8.8 Hz, 1H), 6.76(s, 1H), 6.62e6.71 (m, 1H), 6.28 (br. s., 1H), 3.70 (br. s., 1H), 3.11 (t,J 7.0 Hz, 2H),1.61 (quin, J 7.0 Hz, 2H),1.22e1.44 (m,12H), 0.89 (t,J 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 165.6 (s, CONH2), 153.7(d, JCF 232 Hz, C2), 145.4 (d, JCF 2.0 Hz, C5), 120.1 (d, JCF 26 Hz,C1), 117.4 (d, JCF 9.1 Hz, C4), 116.5 (dd, JCF 12 Hz, C3), 114.3 (d,JCF 9.1 Hz, C6), 44.4, 31.9, 29.5, 29.4, 29.3, 27.1, 22.7, 14.1; LRMS(ESI) m/z 281 (M H, 100), 303 (M Na, 50); HRMS (ESI) calcdfor C16H26N2OF (M H) 281.2029, found 281.2033. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 59% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of 5-amino-2-fluoro-benzamide (111 mg, 0.724 mmol) and DIEA (378 mu, 2.17 mmol) in dichloromethane (2 inL) at 0 C was added a solution of 2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride (313 mg, 0.723 mmol) in dichloromethane (2 mL) slowly, and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated by blowing down with nitrogen. The crude product was dissolved in DMSO, filtered and purified by reverse phase HPLC to yield N-(3 -carbamoyl -4-fluoro-phenyl)-2-fluoro-6- [2- methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (234 mg, 59%). ESI-MS m/z calc. 550.0775, found 551.0 (M+l)+; retention time (Method C): 2.56 minutes (5 minute run). |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 16% | 2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzoic acid (55 mg, 0.13 mmol) and HATU (49 mg, 0.13 mmol) were combined in DMF (1 mL) and DIEA (90 mu, 0.5167 mmol), stirred for 5 min, and then treated with 5-amino-2-fluoro- benzamide (24 mg, 0.16 mmol). The reaction was stirred at 45 C for 30 min. Reverse phase HPLC purification provided N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide (11.6 mg, 16%). ESI-MS m/z calc. 569.09, found 570.2 (M+l)+; retention time (Method B): 1.8 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.98 (s, 1H), 7.99 (dd, J = 6.4, 2.8 Hz, 1H), 7.78 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.59 (t, J = 9.0 Hz, 1H), 7.30 (dd, J = 9.2, 1.7 Hz, 2H), 7.22 (d, J = 2.8 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.61 (dd, J = 9.2, 1.6 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 26% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; | A solution of 5-amino-2-fluoro-benzamide (78 mg, 0.51 mmol) and DIEA (250 mu, 1.44 mmol) in THF (3 mL) at 0 C was treated with a solution of 3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2- (trifluoromethyl)pyridine-4-carbonyl chloride (200 mg, 0.496 mmol) in THF (3 mL)/dichloromethane (2 mL) under N2 atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with 1 M HC1 (2x), dried over MgSO/t, filtered and concentrated in vacuo. Silica gel chromatography (0-80% ethyl acetate/hexanes) provided N-(3-carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[4- (trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide (68 mg, 26%). ESI-MS m/z calc. 521.06, found 522.1 (M+l)+; retention time (Method B): 1.74 minutes (3 minute run). NMR (400 MHz, DMSO-d6) 5 11.18 (s, 1H), 8.43 (s, 1H), 7.90 (dd, J = 6.4, 2.8 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.50 - 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 7.30 (dd, J = 10.1, 8.9 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | Racemic fr 5-4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(2- methylcyclopropyl)pyridine-3-carboxylic acid (103 mg, 0.269 mmol) and HATU (103 mg, 0.271 mmol) were combined in DMF (1 mL) and DIEA (94 mu, 0.54 mmol) and stirred for 5 minutes. 5-Amino-2- fluoro-benzamide (62 mg, 0.40 mmol) was added in one portion and the reaction stirred at 45 C for 1 hour. The reaction was diluted with ethyl acetate and washed with 50% saturated aqueous NaHCC and brine, dried over Na2S04, filtered, and concentrated in vacuo. Silica gel chromatography (0-15% methanol/dichloromethane) provided racemic fras-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4- (trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide (135 mg, 95%). ESI-MS m/z calc. 519.14, found 520.2 (M+l)+; retention time (Method B): 1.36 minutes (3 minute run). 'H NMR(400 MHz, DMSO-d6) delta 10.38 (s, 1H), 8.54 (s, 1H), 7.99 (dd, J = 6.4, 2.8 Hz, 1H), 7.82 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.07 (ddd, J = 8.8, 2.7, 1.3 Hz, 1H), 6.55 (s, 1H), 3.80 (s, 3H), 1.81 (dt, J = 8.5, 4.4 Hz, 1H), 1.38 - 1.25 (m, 1H), 1.16 - 1.11 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H), 0.74 (ddd, J = 9.0, 5.9, 3.6 Hz, 1H) ppm. SFC purification (36% methanol/64% CO2, ChiralPak IG (250 x 21.2 mm) 5muiotaeta column, flow =70 mL/min) provided separated enantiomers re/-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6- ((lS,2S)-2-methylcyclopropyl)pyridine-3-carboxamide (113) and re/-N-(3-carbamoyl-4-fluoro-phenyl)-4- [2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((lR,2R)-2-methylcyclopropyl)pyridine-3-carboxamide (114). The absolute stereochemistry of enantiomers 113 and 114 was not determined. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 20h; | To a solution of 6-teri-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3- carboxylic acid (prepared as described in Example 67, Step 2, 200 mg, 0.519 mmol), 5-amino-2-fluoro- benzamide (80 mg, 0.52 mmol) and HATU (218 mg, 0.573 mmol) in DMF (2 inL) was added 4- methylmorpholine (200 mu, 1.82 mmol) and the reaction mixture was stirred for 20 hours. The reaction mixture was diluted with water and the aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried over MgSO/t, filtered and concentrated in vacuo. The crude material was purified by HPLC (1-99% acetonitrile/5 mM HC1)). The product fractions were neutralized with saturated aqueous NaHCC and extracted with dichloromethane. The organic layer was dried over MgSO/t, filtered and concentrated to obtain 6-fert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy- 4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (155 mg, 57%). ESI-MS m/z calc. 521.16, found 522.2 (M+l)+; retention time (Method B): 1.49 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 10.54 (s, 1H), 8.66 (s, 1H), 8.00 (dd, J = 6.5, 2.8 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.69 (d, J = 14.6 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.06 (dd, J = 9.0, 2.6 Hz, 1H), 6.55 (s, 1H), 3.78 (s, 3H), 1.21 (s, 9H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 58% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 1h; | To a solution of 4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(l- methylcyclopropyl)pyridine-3-carboxylic acid (127 mg, 0.331 mmol), 5-amino-2-fluoro-benzamide, (51 mg, 0.33 mmol) and HATU (139 mg, 0.364 mmol) in DMF (1.3 mL) was added 4-methylmorpholine (109 mu, 0.994 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was filtered and purified by HPLC (1-99% acetonitrile/5 mM HCl). Product fractions were neutralized with saturated aqueous NaHCC . The fractions were extracted with dichloromethane, dried over MgSO/t, filtered and concentrated to provide N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]- 6-(l-methylcyclopropyl)pyridine-3-carboxamide (100 mg, 58%). ESI-MS m/z calc. 519.14, found 520.1 (M+l)+; retention time (Method B): 1.52 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.43 (s, 1H), 8.60 (s, 1H), 7.98 (dd, J = 6.5, 2.8 Hz, 1H), 7.81 (ddd, J = 7.6, 4.4, 2.8 Hz, 1H), 7.69 (d, J = 13.0 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.33 - 7.22 (m, 2H), 7.07 (ddd, J = 8.7, 2.7, 1.3 Hz, 1H), 6.49 (s, 1H), 3.79 (s, 3H), 1.27 (s, 3H), 1.15 (q, J = 3.4 Hz, 2H), 0.82 (q, J = 3.6 Hz, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 38% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h; | To a solution of 5-amino-2-fluoro-benzamide (60 mg, 0.39 mmol) and DIEA (150 mu, 0.861 mmol) in THF (2 mL) at 0 C was added a suspension of 3-(difluoromemyl)-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl chloride (150 mg, 0.390 mmol) in dichloromethane (1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl (2x), dried over MgSO/t, filtered and concentrated in vacuo. Silica gel chromatography (0-50% ethyl acetate/hexanes) provided N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]benzamide (75 mg, 38%). ESI-MS m/z calc. 502.08, found 503.1 (M+l)+; retention time (Method B): 1.72 minutes ( 3 minute run). NMR (400 MHz, DMSO-d6) delta 10.98 (s, 1H), 7.96 (dd, J = 6.4, 2.8 Hz, 1H), 7.78 - 7.66 (m, 4H), 7.46 (dq, J = 7.7, 1.0 Hz, 2H), 7.42 - 7.10 (m, 4H), 6.89 (d, J = 8.7 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 46% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 10℃; for 2.16667h; | A slurry of 5-amino-2-fluoro-benzamide (42 mg, 0.27 mmol) in dichloromethane (1 mL) and DIEA (63 nL, 0.36 mmol) was cooled to 0 C. A slurry of cold l, l-difluoro-5-[4- (trifluoromethoxy)phenoxy]indane-4-carbonyl chloride (71 mg, 0.18 mmol) in dichloromethane (1 mL) was added dropwise to the stirring amine solution. The reaction mixture was stirred at 0 C for 10 minutes then allowed to warm to room temperature over 2 hours. The reaction was concentrated in vacuo and purified by HPLC (10-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-l,l- difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxamide (42.5 mg, 46%). ESI-MS m/z calc. 510.10, found 511.0 (M+l)+; retention time (Method C): 2.51 minutes (5 minute run). NMR (400 MHz, DMSO-d6) delta 10.69 (s, 1H), 7.96 (dd, J = 6.4, 2.8 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.70 - 7.62 (m, 3H), 7.55 - 7.31 (m, 2H), 7.29 - 7.17 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 3.21 - 2.98 (m, 2H), 2.78 - 2.59 (m, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.333333h; | A mixture of 6-(l-fluoro-l-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylic acid (142 mg, 0.365 mmol), 5-amino-2-fluoro- benzamide (56 mg, 0.37 mmol), HATU (140 mg, 0.368 mmol) and 4-methylmorpholine (111 mg, 1.10 mmol) in DMF (1.5 mL) was stirred at room temperature for 20 minutes. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with a saturated aqueous sodium chloride solution (2x). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. Silica gel chromatography (0-60% ethyl acetate/hexanes) provided N- (3-carbamoyl-4-fluoro-phenyl)-6-(l-fluoro-l-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (134 mg, 69%). ESI-MS m/z calc. 525.13, found 526.2 (M+l)+; retention time (method B): 1.71 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 10.65 (s, 1H), 8.70 (d, J = 1.0 Hz, 1H), 8.03 (dd, J = 6.4, 2.8 Hz, 1H), 7.83 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.70 (d, J = 14.6 Hz, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.10 (ddt, J = 7.7, 2.7, 1.3 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 3.79 (s, 3H), 1.61 (d, J = 22.3 Hz, 6H) ppm.19F NMR (376 MHz, DMSO-d6) delta -56.86, -119.01 (dt, J = 8.9, 5.5 Hz), -140.24 - -143.39 (m) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 14% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h; | A solution of 5-amino-2-fluoro-benzamide (50 mg, 0.32 mmol) and DIEA (200 mu, 1.15 mmol) in THF (2 mL) was cooled to 0 C and treated with a suspension of 3-cyclopropyl-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl chloride (120 mg, 0.3202 mmol) in THF (1 mL)/dichloromethane (1 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was diluted with water and extracted with dichloromethane. The organic layer was washed with 1 M HC1, dried over MgSO/i, filtered and concentrated in vacuo. Silica gel chromatography (0-60% ethyl acetate/hexanes) provided N-(3 -carbamoyl -4-fluoro-phenyl)-3-cyclopropyl -2 -fluoro-6- [4- (trifluoromethoxy)phenoxy]benzamide (24 mg, 14%). ESI-MS m/z calc. 492.11, found 493.1 (M+l)+; retention time (Method B): 1.83 minutes (3 minute run). 'H NMR (500 MHz, DMSO-d6) delta 10.83 (s, 1H), 7.94 (dd, J = 6.6, 2.8 Hz, 1H), 7.74 - 7.62 (m, 3H), 7.36 (d, J = 8.5 Hz, 2H), 7.23 (t, J = 9.5 Hz, 1H), 7.15 - 7.05 (m, 3H), 6.76 (d, J = 8.7 Hz, 1H), 2.05 (tt, J = 8.9, 5.2 Hz, 1H), 1.08 - 0.92 (m, 2H), 0.72 (p, J = 4.9, 4.4 Hz, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 29% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h; | A solution of 5-amino-2-fluoro-benzamide (29 mg, 0.19 mmol) and DIEA (100 mu, 0.57 mmol) in THF (1 mL) was cooled to 0 C. To this solution was added a suspension of 3- (difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride (75 mg, 0.1809 mmol) in THF (1 mL) and dichloromethane (1 mL). The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and the aqueous layer was extracted with dichloromethane. The organic phase was washed with IN HCl (2X), dried over MgSO/t, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane gradient) to afford N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2- methoxy-4-(trifluoromethoxy)phenoxy]benzamide (29 mg, 29%). ESI-MS m/z calc. 532.09, found 533.1 (M+l)+; retention time (Method B): 1.72 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.95 (s, 1H), 8.00 (dd, J = 6.4, 2.8 Hz, 1H), 7.78 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.73 (s, 1H), 7.65 (dd, J = 17.3, 9.0 Hz, 2H), 7.34 - 7.23 (m, 3H), 7.15 (t, J = 54.2 Hz, 1H), 7.03 (ddd, J = 8.8, 2.7, 1.2 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 24% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; | A solution of 5-amino-2-fluoro-benzamide (7.0 mg, 0.04 mmol), 6-(2,2- difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylic acid (15 mg, 0.04mmol) and HATU (15 mg, 0.04 mmol) in DMF (225 mu was treated with triethylamine (16 mu,, 0.11 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with DMSO (1 mL) and purified by HPLC (1-99% acetonitrile/5 mM HCl) to obtain N-(3-carbamoyl-4-fluoro-phenyl)-6-(2,2- difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (5 mg, 24%). ESI-MS m/z calc. 541.11, found 542.1 (M+l)+; retention time (Method B): 1.56 minutes (3 minute run). |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 34% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h; | 5-amino-2-fluoro-benzamide (19 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL) and DIEA (63 mu, 0.36 mmol) and treated with a solution of 3-[2-methoxy-4- (trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl chloride (50 mg, 0.12 mmol) in dichloromethane (1 mL). The reaction was stirred for 30 minutes then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and treated with water to afford a precipitate. The precipitate was filtered, then triturated and filtered sequentially with acetonitrile and diethyl ether. The resulting solid was dried under vacuum to provide N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-methoxy-4- (trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide (22 mg, 34%). ESI-MS m/z calc. 533.08, found 534.2 (M+l)+; retention time (Method B): 1.71 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.90 (s, 1H), 8.82 (dd, J = 1.9, 0.9 Hz, 1H), 8.05 (dd, J = 6.5, 2.8 Hz, 1H), 7.81 (ddd, J = 8.9, 4.5, 2.8 Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.28 (dt, J = 8.9, 5.1 Hz, 2H), 7.23 (d, J = 2.7 Hz, 1H), 7.01 (ddd, J = 8.9, 2.7, 1.3 Hz, 1H), 3.78 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48% | 2,2-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-l,3-benzodioxole-5-carboxylic acid (30 mg, 0.07 mmol) and HATU (34 mg, 0.09 mmol) were combined in DMF (500 muKappa) and DIEA (27 mu, 0.16 mmol), and stirred for 5 minutes. 5-Amino-2-fluoro-benzamide (12 mg, 0.08 mmol) was added in one portion and the reaction was stirred for 1 hour. HPLC purification (10-99% acetonitrile/5 mM HC1) provided N-(3 -carbamoyl -4-fluoro-phenyl)-2,2-difluoro-6- [2 -methoxy -4-(trifluoromethoxy)phenoxy]-l,3-benzodioxole-5-carboxamide (19 mg, 48%) as a white solid. ESI-MS m/z calc. 544.07, found 544.8 (M+l)+; retention time (Method C): 2.7 minutes (5 minute run).lNMR (400 MHz, DMSO-d6) delta 10.44 (s, 1H), 7.95 (dd, J = 6.4, 2.8 Hz, 1H), 7.80 - 7.60 (m, 4H), 7.24 (dd, J = 10.2, 9.0 Hz, 1H), 7.18 - 7.10 (m, 3H), 7.00 - 6.80 (m, 1H), 3.77 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 33% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | To 5-amino-2-fluoro-benzamide (70.54 mg, 0.4576 mmol) and diisopropylethylamine (178 mg, 1.37 mmol) in dichloromethane (2.4 mL) cooled at 0C was added dropwise a solution of 6-[2- chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl chloride (200 mg, 0.46 mmol) in dichloromethane (2.4 mL). The reaction was stirred at room temperature overnight. The crude material was purified by silica gel chromatography (ethyl acetate/hexane gradient) to obtain N-(3- carbamoyl-4-fluoro-phenyl)-6- [2-chloro-4-(trifluoromethoxy)phenoxy] -2-fluoro-3 - (trifluoromethyl)benzamide (85 mg, 33%). ESI-MS m/z calc. 554.03, found 555.0 (M+l)+; retention time (Method B): 1.9 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.06 (s, 1H), 7.98 (dd, J = 6.4, 2.8 Hz, 1H), 7.95 - 7.82 (m, 2H), 7.80 - 7.59 (m, 3H), 7.52 (d, J = 2.4 Hz, 2H), 7.30 (dd, J = 10.0, 9.1 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 551 mg | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a solution of 5-amino-2-fluoro-benzamide (37 mg, 0.24 mmol) in dichloromethane (1 mL) was added DIEA (approximately 93.06 mg, 125.4 mu, 0.7200 mmol) and the mixture was cooled to 0 C. To this solution was added a cold solution of 2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl chloride (100 mg, 0.24 mmol) in dichloromethane (1 mL) dropwise. The reaction was allowed to come to room temperature then stirred for 16 hours. The mixture was concentrated, then dissolved in 2 mL DMSO and purified by reverse phase HPLC to provide N-(3- carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide (551 mg, 48%). ESI-MS m/z calc. 534.0826, found 535.1 (M+l)+; retention time (Method B): 1.9 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.06 (s, 1H), 7.98 (dd, J = 6.4, 2.8 Hz, 1H), 7.82 (t, J = 8.7 Hz, 1H), 7.76 (ddd, J = 9.2, 4.5, 3.0 Hz, 2H), 7.70 (s, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 - 7.24 (m, 3H), 6.70 (d, J = 8.9 Hz, 1H), 2.18 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 38% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To a flask charged with 2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoic acid (205 mg, 0.495 mmol), 5-amino-2-fluoro-benzamide (81 mg, 0.53 mmol) and HATU (230 mg, 0.605 mmol) in DMF (2.5 inL) was added DIEA (300 mu, 1.72 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO/t, filtered and concentrated in vacuo. The crude material was purified by HPLC (1-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-4-methoxy-6-[4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (110 mg, 38%). ESI-MS m/z calc. 550.07, found 551.3 (M+l)+; retention time (Method B): 1.54 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.82 (s, 1H), 7.90 (dd, J = 6.4, 2.8 Hz, 1H), 7.76 - 7.62 (m, 3H), 7.44 - 7.35 (m, 2H), 7.30 - 7.19 (m, 3H), 6.69 (s, 1H), 3.83 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 20h; | To a flask charged with 4-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoic acid (90 mg, 0.18 mmol), 5-amino-2-fluoro-benzamide (34 mg, 0.22 mmol) and HATU (86 mg, 0.23 mmol) in DMF (1 mL) was added DIEA (0.100 mL, 0.574 mmol) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and the resulting precipitate was filtered and washed with water. The residue was dissolved indichloromethane, dried over MgSO/t, filtered and concentrated in vacuo. Silica gel chromatography (0- 50% ethyl acetate/hexanes) provided 4-benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (100 mg, 87%). ESI-MS m/z calc. 626.10, found 627.3 (M+l)+; retention time (Method B): 2.01 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.82 (s, 1H), 7.90 (dd, J = 6.4, 2.8 Hz, 1H), 7.73 - 7.63 (m, 3H), 7.44 - 7.32 (m, 5H), 7.29 - 7.15 (m, 5H), 6.68 (s, 1H), 5.25 (s, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 10% | 5 -[2-Methoxy-4-(trifluoromethoxy)phenoxy] -2-(trifluoromethyl)pyridine-4-carboxylic acid (150 mg, 0.378 mmol) and HATU (144 mg, 0.379 mmol) were combined in DMF (2 mL) and DIEA (0.165 mL, 0.947 mmol) and stirred for 10 minutes, followed by the addition of 5-amino-2-fluoro- benzamide (116 mg, 0.753 mmol). The reaction was stirred for 1 hour, then diluted with dichloromethane and washed with water and brine. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. HPLC purification (10-99% acetonitrile/5 mM HC1) provided N-(3-carbamoyl-4-fluoro-phenyl)- 5 -[2-methoxy-4-(trifluoromethoxy)phenoxy] -2-(trifluoromethyl)pyridine-4-carboxamide (21.8 mg, 10%). ESI-MS m/z calc. 533.08, found 534.1 (M+l)+; retention time (Method B): 1.84 minutes (3 minute run). i NMR ^OO MHz, DMSO-d6) delta 10.83 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.99 - 7.95 (m, 1H), 7.78 (ddd, J = 9.0, 4.4, 2.8 Hz, lH), 7.70 (br s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 10.1, 9.0 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.02 (ddd, J = 8.8, 2.7, 1.2 Hz, 1H), 3.78 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 10% | 2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (140 mg, 0.37 mmol) and HATU (145 mg, 0.38 mmol) were combined in N,N-dimethylformamide (1.5 mL) and DIEA (128 mu, 0.73 mmol) and stirred for 5 minutes. 5-Amino-2-fluoro-benzamide (57.1 mg, 0.3704 mmol) was added in one portion and the reaction was stirred at RT for 2.5 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (ethyl acetate/hexane gradient) and re-purified using a reverse phase HPLC to yield N- (3-carbamoyl-4-fluoro-phenyl)-2,3,4 rifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide (18.1 mg, 10%) as a white solid. ESI-MS m/z calc. 518.07, found 519.1 (M+l)+; retention time (Method B): 1.73 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 10.92 (s, 1H), 7.96 (dd, J = 6.4, 2.8 Hz, 1H), 7.80 - 7.60 (m, 3H), 7.28 (dd, J = 10.1, 8.9 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.06 - 6.90 (m, 1H), 6.90 - 6.76 (m, 1H), 3.78 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 11% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | To a solution of 5-amino-2-fluoro-benzamide (60 mg, 0.39 mmol) and DIEA (0.204 mL, 1.18 mmol) in dichloromethane (1 mL) at 0 C was added a solution of 2,3-difluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl chloride (150 mg, 0.392 mmol) in dichloromethane (1 mL) dropwise. The reaction was allowed to warm to room temperature and stirred for 2 hours. The solvent was evaporated under a stream of N2 gas. The crude product was dissolved in DMSO, filtered and purified by HPLC (1-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-2,3-difluoro-6-[2- methoxy-4-(trifluoromethoxy)phenoxy]benzamide (22.3 mg, 11%). ESI-MS m/z calc. 500.08, found 501.1 (M+l)+; retention time (Method C): 2.22 minutes (5 minute run). NMR (400 MHz, DMSO-d6) delta 10.94 (s, 1H), 7.98 (dd, J = 6.4, 2.8 Hz, 1H), 7.82 - 7.64 (m, 3H), 7.54 - 7.41 (m, 1H), 7.28 (dd, J = 10.0, 8.9 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.09 - 6.81 (m, 1H), 6.81 - 6.43 (m, 1H), 3.77 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 52% | A mixture of 6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylic acid (100 mg, 0.269 mmol), HATU (103 mg, 0.270 mmol) and 4-methylmorpholine (0.06 mL, 0.55 mmol) in DMF (0.5 mL) was stirred at room temperature for 5 minutes and then 5-amino-2-fluoro-benzamide (41 mg, 0.27 mmol) was added in one portion. The reaction was stirred for 30 minutes, then diluted to a total volume of 1 mL with DMF, filtered and purified by HPLC (30-99% acetonitrile/5 mM HCl) to provide N-(3 -carbamoyl -4-fluoro-phenyl)-6- cyclopropyl-4- [2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3 -carboxamide (72 mg, 52%). ESI-MS m/z calc. 508.15, found 509.2 (M+l)+; retention time (Method B): 1.35 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 10.61 (s, 1H), 8.67 (s, 1H), 8.00 (dd, J = 6.4, 2.8 Hz, 1H), 7.83 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 7.70 (d, J = 10.7 Hz, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.08 (ddq, J = 8.9, 2.4, 1.2 Hz, 1H), 6.69 (s, 1H), 2.18 (dt, J = 7.7, 4.6 Hz, 1H), 1.09 - 0.97 (m, 4H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 34% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | To a vial charged with 5-amino-2-fluoro-benzamide (23 mg, 0.15 mmol) and DIEA (38 mg, 0.052 mL, 0.30 mmol) in THF (0.2 mL) at 0 C was added a solution of 2-cyclopropyl-3-fluoro-5-[2- methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl chloride (60 mg, 0.15 mmol) indichloromethane dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO/i, filtered and concentrated in vacuo. The crude material was dissolved in DMF/methanol, filtered (syringe filter) and purified by HPLC (10-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-2-cyclopropyl-3-fluoro-5-[2- methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide (27 mg, 34%). ESI-MS m/z calc. 523.11, found 524.2 (M+l)+; retention time (Method B): 1.69 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.93 (s, 1H), 8.54 (s, 1H), 7.79 (dd, J = 6.4, 2.8 Hz, 1H), 7.69 (s, 2H), 7.55 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.23 (dd, J = 10.1, 8.9 Hz, 1H), 7.03 (d, J = 2.7 Hz, 1H), 6.82 (ddd, J = 8.9, 2.5, 1.2 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 3.71 (s, 3H), 2.09 (ddd, J = 13.1, 8.0, 4.9 Hz, 1H), 0.93 (qd, J = 6.2, 2.4 Hz, 2H), 0.88 - 0.82 (m, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 21% | In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of 5-amino-2-fluoro-benzamide (48 mg, 0.31 mmol) and DIEA (0.137 mL, 0.787 mmol) in anhydrous THF (1.5 mL) at 0 C under a N2 atmosphere was added a solution of 4-[3- chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carbonyl chloride (103 mg, 0.262 mmol) in dichloromethane (1.3 mL) dropwise. The reaction mixture was allowed to slowly warm to room temperature and continued to stir at room temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined organics were dried over NaaSO/t, filtered and concentrated in vacuo. Silica gel chromatography (0-60% ethyl acetate/dichloromethane) provided N-(3-carbamoyl-4- fluoro-phenyl)-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxamide (28.4 mg, 21%). ESI-MS m/z calc. 509.07, found 510.2 (M+l)+; retention time (Method B): 1.46 minutes (3 minute run). |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 17% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a mixture of 5-amino-2-fluoro-benzamide (27 mg, 0.18 mmol) and DIEA (62 mg, 0.48 mmol) in dichloromethane (0.6 inL) at 0 C was added 6-cyclopropyl-4-[3-fluoro-4- (trifluoromethoxy)phenoxy]pyridine-3-carbonyl chloride (60 mg, 0.16 mmol) as a solution indichloromethane (0.6 mL). The reaction mixture was stirred for 1 hour, then quenched with methanol and purified by HPLC (1-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-6- cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (15.8 mg, 17%). ESI-MS m/z calc. 493.10, found 494.2 (M+l)+; retention time (Method B): 1.38 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.57 (s, 1H), 8.65 (s, 1H), 7.97 (dd, J = 6.5, 2.8 Hz, 1H), 7.78 (ddd, J = 9.0, 4.4, 2.7 Hz, 1H), 7.73 - 7.63 (m, 3H), 7.54 (dd, J = 11.1, 2.8 Hz, 1H), 7.31 - 7.17 (m, 2H), 6.99 (s, 1H), 2.25 - 2.12 (m, 1H), 1.07 - 0.98 (m, 4H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 11% | With 1,4-diaza-bicyclo[2.2.2]octane trimethylalumane; In tetrahydrofuran; at 120℃; for 1h;Microwave irradiation; | A microwave vial was charged with methyl 4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6- isopropyl-pyridine-3-carboxylate (40 mg, 0.11 mmol), l,4-diazabicyclo[2.2.2]octane trimethylalumane (43 mg, 0.17 mmol) and 5-amino-2-fluoro-benzamide (17 mg, 0.11 mmol). The reaction vial was evacuated and flushed with N2. THF (800 mu) was added and the reaction again was evacuated and flushed with N2. The reaction mixture was subjected to microwave irradiation at 120 C for 60 minutes, then was cooled to room temperature and carefully quenched with 1 M HC1. The aqueous layer was extracted with dichloromethane and the organic layer was dried over MgSO/t, filtered and concentrated in vacuo. Purification by HPLC (1-99% acetonitrile/5 mM HC1) provided N-(3 -carbamoyl -4-fluoro- phenyl)-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxamide (6.1 mg, 11%). ESI-MS m/z calc. 495.12, found 496.3 (M+l)+; retention time (Method B): 1.4 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.69 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 3.1 Hz, 1H), 7.98 (dd, J = 6.4, 2.8 Hz, 1H), 7.77 (ddd, J = 7.7, 4.4, 2.9 Hz, 1H), 7.70 (t, J = 8.0 Hz, 3H), 7.54 (dd, J = 11.0, 2.8 Hz, 1H), 7.33 - 7.13 (m, 2H), 7.00 (d, J = 3.9 Hz, 1H), 3.10 (p, J = 7.2 Hz, 1H), 1.22 (dd, J = 6.9, 1.1 Hz, 6H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 52% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | A mixture of 5-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoic acid (40 mg, 0.082 mmol), 5-amino-2-fluoro-benzamide (14 mg, 0.09 mmol), HATU (38 mg, 0.10 mmol) and DIPEA (50 mu, 0.2871 mmol) in DMF (700 mu was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and the precipitated solid was filtered and washed with water. The solid was taken up in DCM, dried over MgSO/i, filtered and concentrated in vacuo. Product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford 5-benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide (28 mg, 52%). ESI-MS m/z calc. 626.11, found 627.2 (M+l)+; retention time (Method B): 2.09 minutes (3 minutes run). NMR (400 MHz, DMSO-d6) delta 11.01 (s, 1H), 7.89 (dd, J = 6.4, 2.8 Hz, 1H), 7.74 (d, J = 6.7 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.36 - 7.18 (m, 6H), 7.09 - 7.04 (m, 2H), 6.97 - 6.92 (m, 2H), 5.17 (s, 2H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 26% | In dichloromethane; at 0 - 20℃; for 1h; | To a solution of 5-amino-2-fluoro-benzamide (53 mg, 0.34 mmol) and diisopropylethylamine (179 mu, 1.03 mmol) in dichloromethane (1 mL) at 0 C was added a slurry 6-[3- chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl chloride (150 mg, 0.34 mmol) in dichloromethane (1 mL) slowly and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated by blowing down with nitrogen. The crude product was dissolved in DMSO, filtered and purified using a reverse phase HPLC to yield N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro- 4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide (49.5 mg, 26%). ESI-MS m/z calc. 554.03, found 555.0 (M+l)+; retention time (Method C): 2.58 minutes (5 minute run). l NMR (400 MHz, DMSO-d6) delta 11.02 (s, 1H), 7.94 (dd, J = 6.4, 2.8 Hz, 1H), 7.90 (t, J = 8.6 Hz, 1H), 7.76 - 7.69 (m, 3H), 7.69 - 7.64 (m, 1H), 7.63 (d, J = 2.9 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.06 (d, J = 8.8 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 45% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.166667h; | To a solution of 5-amino-2-fluoro-benzamide (23 mg, 0.15 mmol) and N-ethyl-N-isopropyl- propan-2-amine (78 mu, 0.45 mmol) in DCM (500 mu) at 0 C was added a solution of 4,5-dichloro-2-[(2- methoxy-3-pyridyl)oxy]benzoyl chloride (50 mg, 0.15 mmol) in DCM (500 mu) dropwise. The reaction mixture was warmed to room temperature and stirred for 10 minutes, resulting in a thick slurry. The slurry was filtered and the solid washed with minimal acetonitrile. The resulting solid was re-suspended in water to obtain a white solid which was filtered and air dried. The solid was rinsed with hexanes and dried under vacuum to provide N-(3-carbamoyl-4-fluoro-phenyl)-4,5-dichloro-2-[(2-methoxy-3- pyridyl)oxy]benzamide (30 mg, 45%) as a white solid. ESI-MS m/z calc. 449.03, found 450.1 (M+l)+; Retention time (Method B): 1.59 minutes (3 minutes run). NMR (400 MHz, DMSO-d6) delta 10.57 (s, 1H), 8.02 (dd, J = 4.9, 1.6 Hz, 1H), 7.97 - 7.92 (m, 2H), 7.75 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.52 (dd, J = 7.8, 1.6 Hz, 1H), 7.26 (dd, J = 10.2, 8.9 Hz, 1H), 7.15 (s, 1H), 7.04 (dd, J = 7.7, 4.9 Hz, 1H), 3.83 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In Isopropyl acetate; at 20℃; for 4h; | 6-tert-Butyl-4-chloro-pyridine-3-carboxylic acid (207 mg, 0.97 mmol), 5-amino-2-fluoro- benzamide (180 mg, 1.17 mmol), triethylamine (900 mu, 6.46 mmol) and 2,4,6-tripropyl-l, 3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (2 mL of 50 %w/v, 3.14 mmol) in isopropyl acetate (5 mL) was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and residue was partitioned between DCM and saturated aqueous sodium bicarbonate. Layers were separated and the organics dried over magnesium sulfate, filtered and concentrated in vacuo to afford 6-tert-butyl-N-(3-carbamoyl-4- fluoro-phenyl)-4-chloro-pyridine-3-carboxamide (340 mg, 100%) as a colourless oil. ESI-MS m/z calc. 349.10, found 350.2 (M+l)+;348.2 (M-l)-; Retention time (Method F): 0.8 minutes (1.5 minutes run). |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; | A vial charged with 5-amino-2-fluoro-benzamide (218 mg, 1.41 mmol) and DIEA (750 mu, 4.31 mmol) in THF (6 mL) was cooled at 0 C under an atmosphere of N2. A solution of 2-fluoro-6-[4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride (570 mg, 1.42 mmol) in THF (4 mL) and dichloromethane (3 mL) was added. The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was quenched with water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with IN HCl (4x), dried over MgSO/t, filtered and concentrated. The crude material was purified via silica gel chromatography (ethyl acetate/hexane gradient) to obtain N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (420 mg, 57%). ESI-MS m/z calc. 520.07, found 521.1 (M+l)+; retention time (Method B): 1.82 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 11.05 (s, 1H), 7.96 (dd, J = 6.3, 2.8 Hz, 1H), 7.87 (t, J = 8.6 Hz, 1H), 7.75 (ddd, J = 9.0, 4.5, 2.9 Hz, 2H), 7.69 (s, 1H), 7.49 (dq, J = 7.8, 0.9 Hz, 2H), 7.37 - 7.25 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 60% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | To 5-amino-2-fluoro-benzamide (55 mg, 0.36 mmol) and diisopropylethylamine (186 mu, 1.07 mmol) in dichloromethane (1.5 inL) cooled at 0C was added dropwise a solution of 2-fluoro-6-[3- fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride (150 mg, 0.3566 mmol) in dichloromethane (1.5 mL). The reaction was stirred at room temperature overnight. The mixture as diluted with ethyl acetate (30mL) washed with water, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to dryness. Purification by silica gel chromatography (ethyl acetate/hexane gradient) yielded N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (117.5 mg, 60%). ESI-MS m/z calc. 538.06, found 539.1 (M+l)+; retention time (Method B): 1.82 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 11.03 (s, 1H), 8.03 - 7.84 (m, 2H), 7.82 - 7.61 (m, 4H), 7.49 (dd, J = 11.0, 2.9 Hz, 1H), 7.34 - 7.22 (m, 1H), 7.19 - 7.11 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 23% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; | A solution of 5-amino-2-fluoro-benzamide (30 mg, 0.19 mmol) and diisopropylethylamine (100 mu, 0.5766 mmol) in tetrahydrofuran (1 mL) at 0 C was added to a slurry of 2-[2-methoxy-4- (trifluoromethoxy)phenoxy]-5-(l, l,2,2,2-pentafluoroethyl)benzoyl chloride (89 mg, 0.19 mmol) in tetrahydrofuran (1 mL) slowly at 0 C and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated by blowing down with nitrogen. The crude product was dissolved in DMSO, filtered and purified by reverse phase HPLC to yield N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4- (trifluoromethoxy)phenoxy]-5-(l, l,2,2,2-pentafluoroethyl)benzamide (25.7 mg, 23%). ESI-MS m/z calc. 582.08, found 583.0 (M+l)+; retention time (Method B): 2.04 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 10.62 (s, 1H), 8.00 (dd, J = 6.5, 2.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.83 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.78 - 7.62 (m, 3H), 7.44 (d, J = 8.8 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.07 (ddd, J = 8.8, 2.8, 1.3 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 42% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; | To 5-amino-2-fluoro-benzamide (212 mg, 1.38 mmol) and diisopropylethylamine (719 mu, 4.13 mmol) in dichloromethane (6 mL) cooled at 0C was added dropwise a solution of 2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl chloride (600 mg, 1.377 mmol) in THF (6 mL). The reaction was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (ethyl acetate/hexane gradient) to provide N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (329 mg, 42%). ESI-MS m/z calc. 553.0963, found 554.1 (M+l)+; Retention time (Method B): 1.83 minutes (3 minute run). l NMR (400 MHz, DMSO-d6) delta 11.02 (s, 1H), 8.00 (dd, J = 6.4, 2.8 Hz, 1H), 7.84 - 7.73 (m, 3H), 7.70 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.05 (ddd, J = 8.8, 2.7, 1.3 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | 6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00 g, 6.97 mmol) and HATU (2.65 g, 6.97 mmol) were combined in DMF (20 inL) and treated with DIEA (3.6 mL, 21 mmol). The mixture was stirred for 5 minutes then treated with 5-amino-2-fluoro-benzamide (1.08 g, 6.97 mmol). The reaction mixture was stirred for 1 hour then diluted with ethyl acetate and washed with 50% saturated NaHCC solution, water, and brine. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The resulting solid was triturated with dichloromethane, and filtered to provide crop 1 of the desired product (1.91 g). The mother liquor was concentrated and purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to provide an additional 470 mg of product. Total yield of 6-bromo-N-(3- carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide (2.38 g, 81%). ESI-MS m/z calc. 421.96, found 425.0 (M+l)+; retention time (Method B): 1.34 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.08 (s, 1H), 7.98 (dd, J = 6.3, 2.8 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.80 - 7.73 (m, 2H), 7.72 (br s, lH), 7.32 (dd, J = 10.1, 8.9 Hz, 1H) ppm. |
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice; | 5-Amino-2-fluoro-benzamide (667 mg, 4.33 mmol) in dichloromethane (14.5 mL) was treated with diisopropylethylamine (1.6 mL, 9.19 mmol) and the suspension was cooled in an ice bath and treated dropwise with the acid chloride solution. The fine suspension was stirred in the ice bath for 1 hour and at room temperature for lh. The solution was washed with water (2x50mL) and the aqueous phases were back extracted once with dichloromethane (20mL). The combined organic phases were dried, filtered and evaporated. The crude material was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide (1089 mg, 56%) as a white solid. ESI-MS m/z calc. 538.06, found 539.0 (M+l)+; retention time (Method C): 2.55 minutes (5 minute run). 'H NMR (400 MHz, DMSO-d6) delta 11.07 (s, 1H), 7.97 (dd, J = 6.3, 2.8 Hz, 1H), 7.86 (t, J = 8.6 Hz, 1H), 7.80 - 7.62 (m, 4H), 7.52 (t, J = 9.0 Hz, 1H), 7.36 (ddt, J = 8.9, 2.5, 1.3 Hz, 1H), 7.29 (dd, J = 10.1, 9.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, lH) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; | To 5-amino-2-fluoro-benzamide (441 mg, 2.86 mmol) and diisopropylethylamine (1.50 mL, 8.59 mmol) in dichloromethane (7 mL), cooled at 0C, was added dropwise a solution of 2,5-difluoro-4- (trifluoromethyl)benzoyl chloride (700 mg, 2.862 mmol) in THF (7 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (lOOmL) and washed with saturated aqueous NaHCC , water, and brine. The organic phase was dried over sodium sulfate and concentrated to dryness. The crude material was purified by silica gel chromatography (ethyl acetate/hexane gradient) to yield N-(3-carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4- (trifluoromethyl)benzamide (1 g, 89%). ESI-MS m/z calc. 362.049, found 363.2 (M+l)+; retention time (Method A): 0.55 minutes (1.2 minute run). |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 40% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 1h; | To a solution of 5-amino-2-fluoro-benzamide (0.88 g, 5.7 mmol) and DIEA (3.0 mL, 17 mmol) in THF (20 mL) and dichloromethane (10 mL) at 0 C was added a solution of 6-cyclopropyl-4- [2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonyl chloride (2.1 g, 5.4 mmol) in dichloromethane. The reaction mixture was removed from the ice bath and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was concentrated in vacuo and the resulting solid was purified using silica gel chromatography (0-60% ethyl acetate/hexanes) to provide N-(3 -carbamoyl -4-fluoro-phenyl)-6- cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (1.1 g, 40%). ESI-MS m/z calc. 505.13, found 506.2 (M+l)+; retention time (Method B): 1.4 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.41 (s, 1H), 8.55 (s, 1H), 7.99 (dd, J = 6.5, 2.8 Hz, 1H), 7.87 - 7.76 (m, 1H), 7.69 (d, J = 14.5 Hz, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.32 - 7.18 (m, 2H), 7.07 (ddd, J = 8.8, 2.8, 1.3 Hz, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 2.07 (p, J = 6.7 Hz, 1H), 0.99 - 0.87 (m, 4H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 24% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | To 5-amino-2-fluoro-benzamide (37 mg, 0.24 mmol) and diisopropylethylamine (124 mu, 0.71 mmol) in dichloromethane (390 mu) cooled at 0 C was added dropwise a solution of 2-fluoro-6-(4- fluorophenoxy)-3-(trifluoromethyl)benzoyl chloride (80 mg, 0.24 mmol) in dichloromethane (390 mu). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was concentrated to dryness. The residue was dissolved in 1ml of DMSO and purified by reverse phase HPLC to afford N-(3 -carbamoyl -4-fluoro- phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide (25.5 mg, 24%). ESI-MS m/z calc. 454.08, found 455.1 (M+l)+; retention time (Method B): 1.63 minutes (3 minute run). l NMR (400 MHz, DMSO-d6) delta 11.05 (s, 1H), 7.98 (dd, J = 6.4, 2.8 Hz, 1H), 7.89 - 7.74 (m, 3H), 7.71 (s, 1H), 7.40 - 7.25 (m, 5H), 6.79 (d, J = 8.9 Hz, 1H) ppm. |
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 4.06% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; | 5-Amino-2-fluoro-benzamide (40 mg, 0.26 mmol) was suspended in dichloromethane (1 mL) and DIEA (101 mg, 136 mu, 0.781 mmol) and cooled to 0 C, then treated with a cold solution of 6-[(6- chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoyl chloride (100 mg, 0.260 mmol) in dichloromethane (1 mL). The reaction was then allowed to warm to room temperature and stirred for 16 hours. The reaction was concentrated in vacuo, dissolved in DMSO and purified by HPLC (10-99% acetonitrile/5 mM HC1) to provide N-(3-carbamoyl-4-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3- pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide (5.3 mg, 4.06%). ESI-MS m/z calc. 501.05, found 502.0 (M+l)+; retention time (Method B): 1.66 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.03 (s, 1H), 7.98 (dd, J = 6.3, 2.8 Hz, 1H), 7.82 - 7.74 (m, 3H), 7.72 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 7.30 (dd, J = 10.1, 8.9 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H) ppm. |
[ 518057-72-2 ]
[ 749875-16-9 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In Isopropyl acetate; at 20℃; for 1h; | 5-Bromo-2-(trifluoromethyl)pyridine-4-carboxylic acid (107 mg, 0.40 mmol), 5-amino-2- fluoro-benzamide (71 mg, 0.46 mmol), triethylamine (350 mu, 2.51 mmol) and 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (800 mu^ of 50 %w/v, 1.26 mmol) in isopropyl acetate (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. Layers were separated and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to afford 5-bromo-N-(3- carbamoyl-4-fluoro-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide ( 161 mg, 100%) as a colourless oil. ESI-MS m/z calc. 404.97, found 408.1 (M+l)+; Retention time (Method F): 0.74 minutes ( 1.5 minutes run). |
[ 518057-72-2 ]
[ 749875-16-9 ]
[ 518057-72-2 ]

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 58% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To a solution of 2-fluoro-6-(trifluoromethyl)benzoyl chloride (1.00 mL, 6.49 mmol) and DIEA (3.28 mL, 18.8 mmol) in dichloromethane (15 mL) at 0 C was added a solution of 5-amino-2- fluoro-benzamide (1.00 g, 6.49 mmol) in dichloromethane (10 mL) dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 20 minutes then concentrated in vacuo. Silica gel chromatography (0-50% ethyl acetate/hexanes) provided N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- (trifluoromethyl)benzamide (1.3 g, 58%). ESI-MS m/z calc. 344.05, found 345.2 (M+l)+; retention time (Method A): 0.46 minutes (1.2 minute run). |

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