Abstract: Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO2, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP–mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties.
* 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.
Reference：
[1] Journal of the Chemical Society, 1948, p. 198
[2] Archiv der Pharmazie (Weinheim, Germany), 290<157>494,509,
2
[ 1074-98-2 ]
[ 1990-90-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With palladium 10% on activated carbon; hydrogen In ethanol at 16 - 30℃; for 36 h;
Step 2: A solution of 3-methyl-4-nitropyridine /V-oxide (30.0g, 195 mmol) and 10percent Pd-C (6.0 g) in EtOH (450 mL) was stirred at rt under H2 (5 bar) for 36 h. The RM was filtered through a pad of celite™ and the volatiles were removed under reduced pressure to yield the desired compound (20.0 g, 95percent).
83.6%
With hydrogen In water; acetic acid for 2.5 h;
3-Methyl-4-nitropyridine 1-oxide (5.85 g) was dissolved in glacial acetic acid (115 mL) and hydrogenated in a Parr hydrogenation apparatus (catalyst: 220 mg Pt02 x 2 H20, 50 psi) at ambient temperature for 2.5 h. Then the catalyst was filtered off and the solvent was evaporated. After addition of 150 mL of water the pH was adjusted to 12 by addition of 2N NaOH. The resulting solution was extracted 10 times with 100 mL of dichloromethane (containing 5 percent methanol). The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 3.81 g (83.6percent) of 4-amino-3-methylpyridine.
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2002, vol. 21, # 11-12, p. 737 - 751
[2] Patent: WO2015/22073, 2015, A1, . Location in patent: Page/Page column 39
[3] Patent: WO2005/63744, 2005, A2, . Location in patent: Page/Page column 232
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 4184
[5] Pharmaceutical Bulletin, 1956, vol. 4, p. 174,177
[6] Yakugaku Zasshi, 1955, vol. 75, p. 292,294[7] Chem.Abstr., 1956, p. 1808
[8] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[9] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[10] Journal fuer Praktische Chemie (Leipzig), 1988, vol. 330, # 1, p. 154 - 158
[11] Journal of the American Chemical Society, 1954, vol. 76, p. 4184
[12] Yakugaku Zasshi, 1955, vol. 75, p. 292,294[13] Chem.Abstr., 1956, p. 1808
3
[ 1003-73-2 ]
[ 1990-90-5 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2002, vol. 21, # 11-12, p. 737 - 751
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 4184
[3] Yakugaku Zasshi, 1955, vol. 75, p. 292,294[4] Chem.Abstr., 1956, p. 1808
[5] Yakugaku Zasshi, 1955, vol. 75, p. 292,294[6] Chem.Abstr., 1956, p. 1808
[7] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[8] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[9] Journal of the American Chemical Society, 1954, vol. 76, p. 4184
4
[ 1678-53-1 ]
[ 1990-90-5 ]
Reference：
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 1008,1010
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 4184
5
[ 86847-73-6 ]
[ 1990-90-5 ]
Reference：
[1] Synthesis, 2009, # 13, p. 2267 - 2277
6
[ 108-99-6 ]
[ 1990-90-5 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 198
7
[ 100383-06-0 ]
[ 1990-90-5 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1957, vol. 290, p. 494,508
8
[ 110178-76-2 ]
[ 1990-90-5 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1957, vol. 290, p. 494,508
9
[ 109127-89-1 ]
[ 1990-90-5 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1957, vol. 290, p. 494,508
10
[ 104915-66-4 ]
[ 1990-90-5 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 292,294[2] Chem.Abstr., 1956, p. 1808
11
[ 1990-90-5 ]
[ 1678-53-1 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 3167
12
[ 1990-90-5 ]
[ 18227-67-3 ]
Yield
Reaction Conditions
Operation in experiment
31.3%
at 20 - 60℃; for 15 h;
4-Amino-3-methylpyridine (3.00 g) was dissolved with icecooling in concentrated sulfuric acid (36 mL). Then, fuming nitric acid (4,72 g) was added dropwise. After stirring at room temperature for 1 h, the solution was heated at 60 C for 14 hours. After cooling to ambient temperature, the reaction mixture was poured on ice and the resulting solution was adjusted to pH 13 by addition of solid KOH. The precipitate was filtered off, washed with water and dried. Yield: 1. 198 g (31. 3percent) 4-amino-3- methyl-5-nitropyridine.
Reference：
[1] Patent: WO2005/63744, 2005, A2, . Location in patent: Page/Page column 232
[2] Nucleosides, Nucleotides and Nucleic Acids, 2002, vol. 21, # 11-12, p. 737 - 751
13
[ 1990-90-5 ]
[ 97944-43-9 ]
Yield
Reaction Conditions
Operation in experiment
78%
With hydrogen bromide; dihydrogen peroxide In water at 70℃; for 2 h;
Example 36 7- (2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo [4,3-c] pyridine NH2 Me step 1 Br, 97 97 98 99 Me v step step 1 ) ci ci ci C1 100 101 102 NH2 NAC2STEP 1 To a solution of 4-amino-3-picoline (97,10 g, 0.092 mmol) and HBr (50 mL) heated to 70° C was added 15percent H202 (16 mL) over a 1 h period. The reaction mixture was stirred for additional h and poured in ice (100 g). The pH of the solution was adjusted to about 5 with 50percent NAOH and the resulting red precipitate was filtered. The pH was raised to about 9 and the resulting white precipitate was collected by filtration to afford 98 (13.5 g, 78percent theory)
With palladium 10% on activated carbon; hydrogen; In ethanol; at 16 - 30℃; under 3750.38 Torr; for 36h;
Step 2: A solution of 3-methyl-4-nitropyridine /V-oxide (30.0g, 195 mmol) and 10% Pd-C (6.0 g) in EtOH (450 mL) was stirred at rt under H2 (5 bar) for 36 h. The RM was filtered through a pad of celite and the volatiles were removed under reduced pressure to yield the desired compound (20.0 g, 95%).
83.6%
With hydrogen;platinum(IV) oxide; In water; acetic acid; under 2585.81 Torr; for 2.5h;
3-Methyl-4-nitropyridine 1-oxide (5.85 g) was dissolved in glacial acetic acid (115 mL) and hydrogenated in a Parr hydrogenation apparatus (catalyst: 220 mg Pt02 x 2 H20, 50 psi) at ambient temperature for 2.5 h. Then the catalyst was filtered off and the solvent was evaporated. After addition of 150 mL of water the pH was adjusted to 12 by addition of 2N NaOH. The resulting solution was extracted 10 times with 100 mL of dichloromethane (containing 5 % methanol). The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 3.81 g (83.6%) of 4-amino-3-methylpyridine.
With hydrogen bromide; dihydrogen peroxide; In water; at 70.0℃; for 2.0h;
Example 36 7- (2,4-Dichloro-phenyl)-2-methyl-2H-pyrazolo [4,3-c] pyridine NH2 Me step 1 Br, 97 97 98 99 Me v step step 1 ) ci ci ci C1 100 101 102 NH2 NAC2STEP 1 To a solution of <strong>[1990-90-5]4-amino-3-picoline</strong> (97,10 g, 0.092 mmol) and HBr (50 mL) heated to 70 C was added 15% H202 (16 mL) over a 1 h period. The reaction mixture was stirred for additional h and poured in ice (100 g). The pH of the solution was adjusted to about 5 with 50% NAOH and the resulting red precipitate was filtered. The pH was raised to about 9 and the resulting white precipitate was collected by filtration to afford 98 (13.5 g, 78% theory)
With NaOH; hydrogen bromide; dihydrogen peroxide;
2.1 3-Bromo-5-methyl-pyridin-4-ylamine To a solution of <strong>[1990-90-5]4-amino-3-picoline</strong> (10 g, 0.092 mmol) and HBr (50 mL) heated to 70 C. was added 15% H2O2 (16 mL) over one h. The reaction mixture was stirred for an additional hour and poured into ice (100 g). The pH of the solution was adjusted to about 5 with 50% NaOH and the resulting red precipitate was filtered. The pH was raised to about 9 and the resulting white precipitate was collected by filtration to afford the title compound (13.5 g, 78%).
With sulfuric acid; nitric acid; at -8 - 50℃; for 1.0h;
4-Amino-3-methylpyridine at -8 C with stirring(3g, 27.74mmol)Add in batches to 30 ml of concentrated sulfuric acid,Slowly add fuming nitric acid when the solid is completely dissolved(1.60mL, 36.1mmol),Slowly rise to 50 C and continue to stir for 1 hour.Pour the reaction solution into 200 g of ice water.Adjust pH to 8-9 with concentrated ammonia water,The resulting yellow solid was filtered.Yellow solid recrystallized(petroleum ether / ethyl acetate = 5:1)4-amino-3-methyl-5-nitropyridine(3.5 g, yield 82.3%).
31.3%
With sulfuric acid; nitric acid; at 20 - 60℃; for 15.0h;
4-Amino-3-methylpyridine (3.00 g) was dissolved with icecooling in concentrated sulfuric acid (36 mL). Then, fuming nitric acid (4,72 g) was added dropwise. After stirring at room temperature for 1 h, the solution was heated at 60 C for 14 hours. After cooling to ambient temperature, the reaction mixture was poured on ice and the resulting solution was adjusted to pH 13 by addition of solid KOH. The precipitate was filtered off, washed with water and dried. Yield: 1. 198 g (31. 3%) 4-amino-3- methyl-5-nitropyridine.
With (R)-10-camphorsulfonic acid; In toluene;Heating / reflux;
A. 4-[2-(3-Methylpyridin-4-ylamino)-ethyl]-3-oxo-piperazine-1-carboxlic acid benzyl ester. 4-(Benzyloxycarbonyl)-piperazin-2-one (4.7 g, 20 mmol) is dissolved in THF (50 ML) and treated with 1.5M LDA (20 ML, 30 mmol) at 0 C. The reaction mixture is treated with condensed ethylene oxide (3 ML, 40 mmol) and stirred at r.t. overnight.The mixture is neutralized with 2N HCl, concentrated, and extracted with EtOAc. The EtOAc layer is washed with H2O and concentrated to a crude residue.Further extraction of the crude with Et2O and concentration of the ethereal layer gives an oil (1.5 g).The above oil is dissolved in CH2Cl2 (25 ML) and added to the solution of 2M oxalyl chloride (7.5 ML, 15 mmol) and DMSO (2.3 ML, 29.7 mmol) in CH2Cl2 (25 ML) at -60 C. After 15 minutes, Et3N (2.1 ml, 15 mmol) is added.The mixture is stirred at -50 C. for 10 minutes then warmed to r.t for 10 minutes.The reaction is quenched with 0.5 N HCl and extracted with CH2Cl2.The CH2Cl2 layer is washed with 0.5 N HCl, brine (2*), H2O, and concentrated to a residue.The residue is purified by chromatography (2% MeOH/CH2Cl2) to give 4-amino-3-methyl pyridine as an oil (0.5 g, 1.6 mmol).A solution of the oil (0.2 g, 2 mmol), and (1R)-(-)-10-camphorsulfonic acid (15 mg) in toluene (100 ml) is refluxed with a Dean Stark set up overnight.The mixture is concentrated and the residue is purified by chromatography (2-4% MeOH/CH2Cl2) to give the title imine as a white foam (0.20 g, 0.54 mmol).Ion spray MS m/z: 367, [M+1]+; 1H NMR (CDCl3, 300 MHz) delta8.20 (d, 1H), 8.14 (s, 1H), 7.35 (s, 5H), 6.60 (d, 1H), 6.18 (dd, 1H), 5.15 (s, 2H), 4.97 (d, 1H), 4.30 (s, 2H), 3.78 (t, 2H), 3.50 (bm, 2H), 2.15 (s, 3H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 15h;
To a suspension of the imino chloride [(500MG,] 1. [42MMOL)] in dioxane [(5ML)] was added Pd2 (dba) 3 (65mg, 0. [07MMOL)] followed by BINAP (66mg, [0.] [1] [LMMOL),] <strong>[1990-90-5]4-amino-3-picoline</strong> (230mg, 2. [13MMOL)] and NaO'Bu (273mg, 2. [84MMOL).] The reaction mixture was heated to [90C] for 15h. The reaction mixture was cooled to r. t. and filtered through Celite and the crude 219002029440 material purified by flash column chromatography to give (152 mg, 24% yield) as a cream colored solid. ESMS: 440 [(M+).]
2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid[ No CAS ]
2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid (3-methylpyridin-4-yl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; dichloromethane; ethyl acetate;
EXAMPLE 4 2-Methanesulfonyl-7-methoxybenzofuran-4-carboxylic Acid (3-methylpyridin-4-yl)amide Oxalyl chloride (0.27 ml) was added to 2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid (0.40 g) in dichloromethane (15 ml) under an inert atmosphere. Dimethylformamide (catalytic amount) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo to furnish the corresponding acid chloride as a yellow solid. 4-Amino-3-methylpyridine (0.32 g) was added to the acid chloride in dichloromethane (30 ml). The reaction mixture was stirred at room temperature overnight and then the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica eluding with 10% methanol in ethyl acetate to afford the title compound as an off-white solid (0.38 g). TLC Rf 0.2 (10% methanol in ethyl acetate) mp 191-193 C.
With sodium hexamethyldisilazane; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate;
EXAMPLE 1 2-Dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic Acid (3-methyl-pyridin-4-yl)amide To a stirred solution of <strong>[1990-90-5]4-amino-3-methylpyridine</strong> (200 mg) in dimethylformamide (8 ml) under an atmosphere of nitrogen at 0 C. was added sodium hexamethyldisilazide (1.0M solution in tetrahydrofuran, 1.9 ml). The reaction mixture was stirred at this temperature for 5 minutes. 2-Dimethylsulfamyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (400 mg) was then added and stirring continued for 30 minutes. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3*50 ml) and washed with brine (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluding with 10% methanol in ethyl acetate afforded the title compound as a white solid (0.3 g). TLC Rf 0.47 (10% methanol in ethyl acetate). mp 216-217 C.
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
To a solution of compound of formula (XII) (72 mg, 0.16 mmol, 1 eq) in dry dioxane (2 ml) was added Pd(OAc)2 (2 mg, 0.008 mmol, 0.05 eq) followed by BINAP (8 mg, 0.001 mmol, 0.075 eq), <strong>[1990-90-5]4-amino-3-picoline</strong> (18 mg, 0.16 mmol, 1 eq) and Cs2CO3 (80 mg, 0.24 mmol, 1.5 eq). The reaction mixture was heated to 80C for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromatography (7:3/ethyl acetate :hexane) to give compound of formula (XIII) (65 mg, 85%)
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
To a solution of compound of formula (XVII) (230 mg, 0.52 mmol, 1 eq) in dry dioxane (5 ml) was added Pd(OAc)2 (6 mg, 0.03 mmol, 0.05 eq) followed by BINAP (8 mg, 0.004 mmol, 0.075 eq), <strong>[1990-90-5]4-amino-3-picoline</strong> (67 mg, 0.62 mmol, 1.2 eq) and Cs2CO3 (271 mg, 0.83 mmol, 1.5 eq). The reaction mixture was heated to 80C for15 h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromatography (9:l/ethyl acetate:hexane) to give compound of formula (XVIII) (38 mg, 16%)
[2-(5-chloro-2-fluoro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-(3-methyl-pyridin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃;
4-Chloro-2-(5-chloro-2-fluoro-phenyl)-pyrrolo[2, 1 -fj [ 1 ,2,4]triazine (30 mg,0.106 mmole), cesium carbonate (48.5 mg, 0.149 mmole), palladium (II) acetate (1.19 mg, 0.0053 mmole), BINAP (4.96 mg, 0.0080 mmole), and 4-amino-picoline(13.8 mg, 0.128 mmole) were combined in 4 ml dioxane (anh.) and heated to 90C with stirring overnight. The reaction mixture was filtered to remove solid material, the filtrate was evaporated to dryness, the residue was dissolved in chloroform (8ml), washed with 0.5 M sodium hydroxide (1 ml), dried over sodium sulfate (anh.), evaporated to dryness, and then the residue was redissolved in dimethylformamide and purified by reversed phase HPLC. The product was isolated
[2-(5-chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 85℃; for 48h;
To a solution of 2-(5-Chloro-2-fluoro-phenyl)-4-iodo-6,6-dimethyl-6,7-dihydro-5H- cyclopentapyrimidine (100 mg, 0.25 mmol), 3-Methyl-pyridin-4-ylamine (30 mg,0.27 mmol), Pd(OAc)2 (3 mg, 12.42 mumol) and itoc-BINAP (12 mg, 18.63 mumol) in dry dioxane (3 mL) was added Cs2CO3 (121 mg, 0.37 mmol). The mixture was heated for 48 h at 85C, cooled and evaporated. HPLC purification gave, after lyophilization, the desired product of formula (60) as the TFA salt, which was a white solid (6.4 mg)
[2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-5,7-dihydrofuro[3,4-d]pyrimidine (80 mg, 0.21 mmol, 1 eq) in anhydrous dioxane (5 ml) was added Pd(OAc)2 (2 mg, 0.01 mmol, 0.05 eq) followed by BINAP (10 mg, 0.02 mmol, 0.075 eq), 4-amino-3- picoline (25 mg, 0.23 mmol, 1.2 eq) and Cs2CO3 (100 mg, 0.32 mmol, 1.5 eq). The EPO <DP n="61"/>reaction mixture was heated to 80C for 15h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromatography (9:l/ethyl acetate:hexane) to afford [2-(5-Chloro-2-fluorophenyl)-5,7- dihydrofuro[3,4-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine, compound of formula (33) (20 mg, 26%) as a white solid
[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-6,7-dihydrofuro[3,2-d]pyrimidine (106 mg, 0.28 mmol, 1 eq) in dioxane (5 ml) was added Pd(OAc)2 (3 mg, 0.01 mmol, 0.05 eq) followed by BINAP (13 mg, 0.02 mmol, 0.075 eq), <strong>[1990-90-5]4-amino-3-picoline</strong> (40 mg, 0.37 mmol, 1.3 eq) and Cs2CO3 (138 mg, 0.42 mmol, 1.5 eq). The reaction mixture was heated to 80C for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromatography (4: 1/ethyl acetate:hexane-100%ethylacetate) to afford [2-(5-chloro-2- fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine, i.e. compound of formula (39) (30 mg, 30%) as a white solid
[2-(5-Chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-5-methyl-6,7-dihydro-5H-cyclo- pentapyrimidine (275 mg, 0.71 mmol, 1 eq) in dioxane (5 ml) was added Pd(OAc)2 (8 mg, 0.04 mmol, 0.05 eq) followed by BINAP (33 mg, 0.05 mmol, 0.075 eq), <strong>[1990-90-5]4-amino-3-picoline</strong> (84 mg, 0.78 mmol, 1.1 eq) and Cs2CO3 (347 mg, 1.06 mmol, 1.5 eq). The reaction mixture was heated to 80C for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromatography (l:l/ethyl acetate:hexane-100% ethyl acetate) to afford [2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]- (3-methyl-pyridin-4-yl)-amine, compound of formula (43) (250 mg, 96%)
With caesium carbonate; sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃; for 15h;
The crude imino chloride compound of formula (VII) (210 mg, 0.76 mmol, 1 eq) was dissolved in dioxane (5 ml) and to this was added Pd(OAc)2 (9 mg, 0.04 mmol, 0.05 eq) followed by BINAP (35 mg, 0.056 mmol, 0.075 eq), <strong>[1990-90-5]4-amino-3-picoline</strong> (82 mg, 0.760 mmol, 1 eq) and Cs2CO3 (370 mg, 1.13 mmol, 1.5 eq). The reaction mixture was heated to 80C for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite and the crude material was purified by flash column chromato¬ graphy (3:2/ethyl acetate :hexane) to give compound of formula (20) (110 mg, 41%)
2-Ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid (3-methyl-pyridin-4-yl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hexamethyldisilazane; In tetrahydrofuran; water; N,N-dimethyl-formamide;
EXAMPLE 15 2-Ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid (3-methyl-pyridin-4-yl)amide A solution of <strong>[1990-90-5]4-amino-3-methylpyridine</strong> (76 mg) in dry N,N-dimethylformamide (20 ml) was stirred at 0 C. under an atmosphere of dry nitrogen. Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 0.77 ml) was added and stirring continued at 0 C. for 10 minutes. 2-Ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) was added and stirring continued at room temperature for 90 minutes. The solvent was then removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3*75 ml). The combined organic extracts were washed with water (100 ml) then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluding with ethyl acetate followed by trituration with diethyl ether gave the title compound (66 mg) as a white solid. TLC Rf 0.36 (ethyl acetate) m.p. 177-8 C.
Di-telambdat-butyldicarbonate (10.0 g, 0.0458 mol) was added slowly in portions to a solution of 3-methylpyridm-4-amine (4.13 g, 0.0382 mol) dissolved in t°rf-butyl alcohol (60 mL). Vigorous bubbling was observed during the addition. After stirring at room temperature overnight, the solvent was removed in vacuo to provide an oily residue which was partitioned between NaHCO3/water and ethyl acetate. The mixture was extracted 3x with ethyl acetate and the combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel eluting with 75% ethyl acetate/hexane to 100% ethyl acetate to provide terr-butyl (3- methylpyridm-4-yl)carbamate as a white solid (7.90 g, 99%). 1H NMR (DMSO- 6) delta 8.80 (bs, IH), 8.25 (m, 2H), 7.65 (d, IH), 2.19 (s, 3H), 1.49 (s, 9H). LC/MS: 209 (M+H)+.
80%
In tetrahydrofuran; at 16 - 30℃; for 10h;
Step 3: (Boc)20 (89.0 mL, 400 mmol) was added to a solution of the intermediate from step 2 (36.0 g, 333 mmol) in dry THF (400 mL) and the mixture was stirred at rt for 10 h. The volatiles were removedunder reduced pressure and the residue was purified by CC (silica gel, CH2CI2/MeOH) to yield the desired compound (55.0 g, 80%).
78%
In tetrahydrofuran; at 20℃; for 3h;
Example 9 Alternate Synthesis of Compound 43 Preparation of BOC-4-AMINO-3-PICOLINE : 10106L 3-METHYL-4-AMINOPYRIDINE (20. 00G, 0. 185 mol) in dry THF (150 ML) was added A solution OF DI-TERT-BUTYL DICARBONATE (Acres, 97% purity) (45. 80g, 0. 203 mol) in dry THF (50 ML). The resultant pale yellow solution was left stirred at room temperature for 3 hours before being evaporated. The solid that resulted was suspended in hexane (200 ML) and filtered. The solid was washed further with hexane (4 X 200 ML) to remove last traces of excess reagent, and dried under high vacuum. The product was A yellow crystalline solid (29. 93g, 78% yield).
16.2 g
With dmap; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a solution of <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (10 g, 92.6 mmol) in THF (100 ml.) was added TEA (14 g, 138 mmol) and DMAP (1 .12 g, 9.25 mmol) followed by addition of (Boc)20 (22.2 g, 101 mmol) at 0 C. The reaction mixture was stirred at rt for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was diluted with water (50 ml.) and extracted with DCM (3 x 70 ml_). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under vacuum to afford 16.2 g of tert-butyl A/-(3-methylpyridin-4-yl)carbamate a49, which was used in next step without further purification. LCMS (ES+): 209 (M+H)+, 96% purity. 1H NMR (400 MHz, DMSO-cfe) delta 8.76 (s, 1 H), 8.22-8.26 (m, 2H), 7.62-7.66 (m, 1 H), 2.18 (s, 3H), 1 .48 (s, 9H).
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 18h;Product distribution / selectivity;
Example 8 Synthesis of Compounds 43 and 44 43 44 [0103] This example illustrates Reaction Scheme V. Preparation of 43 : [0104] 4-chloro-2-(2-fluoro-5-chlorophenyl)pyridopyrimidine was used as the partner in the BUCHWALD coupling step, shown above, to prepare compound 43.
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 18h;
Preparation of 44 : [0105] IVD, 4-chloro-2- (3-chlorophenyl) pyridopyrimidine (294mg, Immole) was suspended in 8ML dioxan, followed by addition OF 4-AMINOPICOLINE (129mg, 1.2mmole), 2, 2BIS (diphenylphosphino)-1,1'-binaphthalene (BINAP, 4. 66mg, 0. 0075mmole). Tris (DIBENZYLIDENE acetone) dipalladium(0) (PD2 (DBA) 3 2. 2MG, 0. 0025mmole) and cesium carbonate (456mg, 1. 4mmole). The mixture was stirred at 100C under an inert atmosphere for 18 HR. Reaction mixture was FILTERED over CELITE and product was isolated by PREPARATIVE reversed phase HPLC.
To a solution [OF THE CHLOROPYRIMIDINE] 29 (43mg, 0. 12 mmol) in dry dioxane (3 mL) was added successively Pd2 (dba) 3 [(5MG,] 5mol%), Rac-BINAP (6mg, 7. 5mol%), 3, methyl-4- aminopyridine [(15MG,] 0.14 mmol, [1.] 2eq. ) and NaO'Bu (14mg, 0.14mmol, 1. 2eq. ). The mixture was heated at [50C] for 5h then cooled and evaporated. The crude residue was purified by HPLC to give the desired product 30, [LYOPHILIZED] as a TFA salt (7.4mg).
Example 1-42; {5-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-yl}-(2-methyl- pyridin-4-yl)-amine.; Combine 4-amino-3-methyl-pyridine (66 mg, 0.606 mmol) and di-imidazol-1-yl- methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir overnight. Add 2-(2,6- dichloro-phenyO-SH-benzoimidazole-delta-carboxylic acid hydrazide (150 mg, 0.466 mmol) <n="90"/>and DMF (1.5 ml_). Heat to 80 C for 1hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80 C for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Take the concentrate up in boiling toluene / EtOAc and cool to 4 C. Collect the resulting precipitate and purify by reverse-phase HPLC (20 - 45 % ACN / H2O + 5 mM NH4OH) to afford the title compound as a light yellow solid: 1 H NMR (400 MHz, DMS0-cf6, 100 C) delta ppm 2.46 (s, 3 H) 7.36 (dd, J=5.75, 2.14 Hz, 1 H) 7.42 (s, 1 H) 7.59 - 7.67 (m, 3 H) 7.81 (d, J=8.68 Hz, 1 H) 7.87 (dd, J=8.44, 1.47 Hz, 1 H) 8.16 (s, 1 H) 8.27 (d, J=5.69 Hz, 1 H); MS m/z = 437.0 (M+1).
Example 5 (4-Methyl-pyridin-3-yl)-carbamic acid tert-butyl ester To a solution of di-tert-butyl dicarbonate (11.1 g, 50.9 mmol) in THF (12.5 ml) was added <strong>[1990-90-5]4-amino-3-picoline</strong> (5.0 g, 46.2 mmol) in THF (37.5 ml). The resulting reaction mixture was stirred at room temperature for 3 hours before being concentrated in vacuo to provide a residue. The residue was triturated with heptane whereby the resultant white solid (7.34 g, 74%) was collected by filtration and dried in vacuo. LCMS (Method B): RT=1.61 min, M+H+=209.
To a mixture of <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (122; 43.3 mg, 0.4 mmol) in 3 mL of dry THF was added in one portion triethylamine (0.3 mL) followed by triphosgene (47.5 mg, 0.16 mmol). The above mixture was stirred at 50C for 2 hours and 4,4-dimethyl-7-(3-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,8-naphthyridine (61.2 mg, 0.2 mmol) was added to the reaction mixture and stirred for an additional 20 hours at 60C. Saturated sodium bicarbonate solution and dichloromethane (10 mL) were added to the reaction mixture; the organic layer was successively washed with water (10 mL) and brine, dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC to afford 4,4-dimethyl-N-(3-methylpyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydiO-l,8- aphthyridine-l(2H)-carboxamide (Compound 834) as yellow solid. Yield 23%. MS (ESI) calcd for C24H23F3N4O: 440.18; found: 441 [M+H].
Intermediate 545-Bromo-N-(3-methylpyridin-4-yl)thiophene-2-carboxamideTo a solution of 3-methylpyridine-4-amine (1.23g, 1 1.37 mmol, 1.2 eq) in DMF (5 mL) at 0 C was added solid sodium hydride (60% suspension in mineral oil, 0.44g, 18.49 mmol, 2.0 eq) and stirred for 1 h at room temperature. In a separate flask, to a solution of 5- bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol, 1.0 eq) in DCM (10 mL) was added oxalyl chloride (4.0 mL, 46.2 mmol, 5.0 eq) at 0 C and then stirred at the same temperature for 2 h. The solvent and excess of oxalyl chloride were removed by evaporation under vacuum. The residue was dissolved in DMF (2 mL) and added to the above mixture at 0 C and the resulting mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction followed by ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with water (2x20 mL), brine (20 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (silica gel, DCM:MeOH system) to afford 1.0 g of the desired product as a white solid. 1HNMR (400 MHz, CDC13) delta 8.39 (d, J = 5.5 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J = 5.5 Hz, 1H), 7.87 (s, 1H, D20 exchangeable), 7.40 (d, J= 4.0 Hz, 1H), 7.09 (d, J= 4.0 Hz, 1H), 2.29 (s, 3H); ESI-MS (m/z) 297, 299 [(MH)+ Br79' 81].
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
To a solution of 6,7-dimethoxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (0.1 g, 0.40 mmol) (from Example 15 supra) in DMF (5 mL) was added HATU (0.182 g, 0.48 mmol) (Aldrich), triethylamine (0.070 mL, 0.48 mmol) (Aldrich) and <strong>[1990-90-5]4-amino-3-methylpyridine</strong> (0.056 g, 0.52 mmol) (Chontech). The reaction mixture was stirred at room temperature for 18 hours. Then, water (5 mL), saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (10 mL) were added. After mixing, the precipitate was filtered under vacuum and washed with ethyl acetate. The resulting solid was dried under air to provide 6,7-dimethoxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (3-methyl-pyridin-4-yl)-amide. (Yield 0.07 g, 52%). HR-MS (ES+) m/z Calculated for C18H18N3O4 ([M+H]+): 340.1292. Found: 340.1291.
To a (0 C) cooled and stirred solution of 5-bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol) in DCM (20 mL) was added oxalyl chloride (4.05 mL, 46.2 mmol) followed by the addition of catalytic amount of DMF. Reaction was allowed to stir at 0 C for 2 h. The resulting reaction mixture was then concentrated under vacuum, obtained residue was dissolved in DMF (2 mL) and added to a separately prepared (0 C) cooled mixture containing <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (1.23 g, 11.37 mmol) and sodium hydride (0.444 g, 18.49 mmol) in DMF (lOmL). After stirring the reaction at RT overnight, quenched with ice cold water (20 mL), followed by the addition of ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (2x50 mL), brine (20 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, DCM-methanol system as eluent) to afford 1.10 g (40%) of the title product as a white solid. HNMR (400 MHz, CDC13) delta 8.44 (d, = 5.5 Hz, 1H), 8.40 (s, 1H), 8.14 (d, = 5.5 Hz, 1H), 7.70 (s, 1H), 7.40 (d, = 4.0 Hz, 1H), 7.13 (d, = 4.0 Hz, 1H), ESI-MS (m/z) 297, 298 [(MH)+ Br79'
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 23℃; for 2h;
To a solution of intermediate 2c (100 mg) in CH2Cl2(7 mL) were consecutively added N,N-Diisopropylethylamine (140 muL), <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (40 mg) and bromotripyrrolidinophosphonium hexafluorophosphate (230 mg) and the mixture was stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (Interchim cartridge50SiHP/25 g, Cy/EtOAc) to yield the desired compound (84% yield). [0430] LC-MS (Method 2): m/z [M+H]+=353.2 (MW calc.=352.39); Rt=0.48 min
84%
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 2h;
Synthesis example 20: 5-(2,5-Dimethoxyphenyl)-1-methyl-W-(3-methyl-pyridin-4-yl)-1H-pyrazole-3- carboxylic acid amide To a solution of intermediate 2c (100 mg) in CH2CI2 (7 mL) were consecutively added N,N- Diisopropylethylamine (140 muIota_), <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (40 mg) and bromotripyrrolidinophosphonium hexafluorophosphate (230 mg) and the mixture was stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (Interchim cartridge50SiHP / 25 g, Cy / EtOAc) to yield the desired compound (84% yield). LC-MS (Method 2): m/z [M+H]+ = 353.2 (MW calc. = 352.39); R, = 0.48 min.
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0 - 23℃;
To a solution of intermediate 23d (100 mg) in CH2Cl2 (7 mL) were at 0 C. consecutively added N,N-diisopropyl ethylamine (140 muL), <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (40 mg) and bromotripyrrolidino phosphonium hexafluorophosphate (230 mg) and the resulting mixture was stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (Interchim cartridge 15SiHP/25 g, Cy/EtOAc) to yield the desired compound (84% yield). [0490] LC-MS (Method 2): m/z [M+H]+=341.1 (MW calc.=340.81); Rt=0.57 min.
84%
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 2h;
Synthesis example 28: 5-(5-Chloro-2-methyl-phenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1 H- pyrazole-3-carboxylic acid amide To a solution of intermediate 23d (100 mg) in CH2CI2 (7 mL) were at 0 C consecutively added N,N- diisopropyl ethylamine (140 pL), <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (40 mg) and bromotripyrrolidino phosphonium hexafluorophosphate (230 mg) and the resulting mixture was stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (Interchim cartridge 15SiHP / 25 g, Cy / EtOAc) to yield the desired compound (84% yield). LC-MS (Method 2): m/z [M+H]+ = 341.1 (MW calc. = 340.81 ); R, = 0.57 min
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 20h;
To a solution of intermediate 1e (150 mg) and <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (54 mg) in dry DMF (10 mL) were consecutively added O-(7-Aza-1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (380 mg) and triethylamine (139 muL) and the mixture was stirred at rt for 20 h. The solution was concentrated under reduced pressure and was diluted in 1N NaOH and extracted with DCM. The combined organic layers were dried and the solvent was removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge 15SiHP/25 g, DCM/methanol) followed by crystallization (chloroform/heptane) to yield the title compound of example 6 (29% yield). LC-MS (Method 2): m/z [M+H]+=390.14 (MW calc.=389.47); Rt=0.55 min.
29%
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 20h;
Synthesis example 6: 1-Methyl-A/-(3-methyl-pyridin-4-yl)-5-(2-methyl-5-thiazol-2-yl-phenyl)-1H- pyrazole-3-carboxylic acid amide To a solution of intermediate 1e (150 mg) and <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (54 mg) in dry DMF (10 mL) were consecutively added 0-(7-Aza-1H-benzotriazole-1-yl)-A/,A/,/ ',//'-tetramethyluronium hexafluorophosphate (380 mg) and triethylamine (139mu) and the mixture was stirred at rt for 20 h. The solution was concentrated under reduced pressure and was diluted in 1 N NaOH and extracted with DCM. The combined organic layers were dried and the solvent was removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge15SiHP / 25 g, DCM/ methanol) followed by crystallization (chloroform / heptane) to yield the title compound of example 6 (29% yield).LC-MS (Method 2): m/z [M+Hf = 390.14 (MW calc. = 389.47); R, = 0.55 min
4-bromo-N-(3-methylpyridin-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
To a pre-washed suspension of NaH (0.164 g, 6.83 mmol) in DMF (10 mL) was added drop wise a solution of <strong>[1990-90-5]3-methylpyridin-4-amine</strong> (0.246 g, 2.28 mmol) in DMF (3 mL) at 0C. After stifling for 15 mm, a solution of 4-bromobenzoyl chloride (0.5 g, 2.278 mmol) inCH2C12 (5 mL) was added drop wise and the resulting mixture was stined at rt for 16 h. The reaction was quenched with cold water and extracted with DCM (2x15 mL). The combined organic layers were washed with water (2x15 mL), brine (15 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to give 400 mg (63%) of the desired product as a white solid. ?HNMR (400 MHz, DMSO-d6) oe 10.04 (s, 1H, D20 exchangeable), 8.44 (s, 1H),8.38(d, J= 5.5 Hz, 1H), 7.92 (d, J= 8.5 Hz, 2H), 7.78 (d, J= 8.5 Hz, 2H), 7.60 (d, J= 5.5 Hz,1H), 2.27 (s, 3H); ESI-MS (mlz) 291, 293 [(MH), Br79?81]
5-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-2-(2,6-difluorophenyl)-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester[ No CAS ]
5-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-2-(2,6-difluorophenyl)-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester[ No CAS ]
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