Patent Grant
7662832
The present invention relates to novel pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof which have an excellent inhibitory activity against gastric acid secretion, processes for the preparation thereof, and pharmaceutical compositions comprising the same.
Peptic ulcer disease occurs when offensive factors involving gastric acid secretion are strong or defensive factors of gastric mucous are weak. For the treatment of peptic ulcer disease, various drugs such as antacid, anticholinergic agent, H2-receptor antagonist, and proton pump inhibitor have been used. The advent of omeprazole as a proton pump inhibitor has rekindled research activities in this field.
However, it has been pointed out that proton pump inhibition by omeprazole is irreversible, thereby incurring long-term inhibition of gastric acid secretion, which may induce side effects. Accordingly, various attempts to develop a reversible proton pump inhibitor are being made. For example, imidazopyridine derivatives are disclosed in WO 98/37,080 (AstraZeneca AB), WO 00/17,200 (Byk Gulden Lomberg Chem.), and U.S. Pat. No. 4,450,164 (Schering Corporation) as a reversible proton pump inhibitor. Further, pyrimidine derivatives are also disclosed in European Patent No. 775,120 (Yuhan Corp.).
The present invention provides novel pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof, which have excellent proton pump inhibition effects and possess the ability to attain a reversible proton pump inhibitory effect.
According to an aspect of the present invention, there is provided a pyrrolo[2,3-c]pyridine derivative or a pharmaceutically acceptable salt thereof.
Further, according to another aspect of the present invention, there is provided a process for the preparation of the pyrrolo[2,3-c]pyridine derivative or a pharmaceutically acceptable salt thereof.
Further, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising the pyrrolo[2,3-c]pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
In accordance with an aspect of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1 is hydrogen; a straight or branched C1-C7 alkyl group, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, C3-C7 cycloalkyl, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, a straight or branched C1-C5 alkylcarbonyloxy, C1-C3 alkoxy-C1-C3 alkoxy, C1-C3 alkylsulfanyl, C2-C5 alkenyloxy, formyl, pyridyl, naphthyl, thiazolyl (the thizole ring is optionally substituted with one or more C1-C3 alkyl), thiophenyl (the thiophene ring is optionally substituted with one or more halogen), isoxazolyl (the isoxazole ring is optionally substituted with one or more C1-C3 alkyl), 1,3-dioxolanyl (the 1,3-dioxolane ring is optionally substituted with one or more C1-C3 alkyl), 1,3-dioxanyl, oxiranyl, and tetrahydropyranyl; a straight or branched C2-C6 alkenyl group optionally substituted with phenyl; a straight or branched C2-C6 alkynyl group; a C3-C6 dienyl group; or a —(CH2)p-phenyl group (p is 0, 1, 2, or 3 and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, a straight or branched C1-C5 alkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, trifluoro-C1-C3 alkyl, trifluoro-C1-C3 alkoxy, and C1-C3 alkylsulfonyl),
R2 is a straight or branched C1-C6 alkyl group,
R3 is hydrogen; a straight or branched C1-C6 alkyl group, optionally substituted with one or more substituents selected from the group consisting of hydroxy, C1-C5 alkoxy, C1-C3 alkylcarbonyloxy, cyano, morpholinyl, and mono-, di-, or tri-C1-C3 alkylamino; a halogen group; a cyano group; a formyl group; a C1-C3 alkylsulfanyl group; a C1-C3 alkylsulfonyl group; or a C1-C3 alkylsulfinyl group,
R4 is hydrogen; a straight or branched C1-C6 alkyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C5 alkylamino, C3-C6 cycloalkylamino, phenylamino (the phenyl ring is optionally substituted with one or more halogen), benzylamino (the benzyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl), morpholinyl, and piperazinyl (the piperazinyl ring is optionally substituted with C1-C3 alkyl); a straight or branched C2-C6 alkynyl group; a halogen group; a cyano group; a hydroxy group; an amino group; a morpholinyl group; a mercapto group; an aminosulfonyl group; a tetrazolyl group optionally substituted with one or more C1-C3 alkyl; a group of the formula (A)
wherein, R4′ is hydrogen, a hydroxy group, a C1-C5 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, an imidazolyl group, a morpholinyl group, a thiomorpholinyl group, a pyrrolidyl group, a tetrahydropyridyl group, a piperazinyl group (the piperazinyl ring is optionally substituted with C1-C3 alkyl or phenyl), or a piperidinyl group (the piperidinyl ring is optionally substituted with C1-C3 alkyl, hydroxy, or hydroxy-C1-C3 alkyl); or a group of formula (B)
wherein, R4″ is hydrogen or a C1-C3 alkyl group and R4′″ is hydrogen, a straight or branched C1-C5 alkyl group, a C2-C5 alkenyl group, a C3-C6 cycloalkyl group, a hydroxy-C1-C3 alkyl group, a trifluoro-C1-C3 alkyl group, a benzyl group (the benzyl ring is optionally one or more substituted with C1-C3 alkyl or halogen), or a piperonyl group, and
R5 is a 1,2,3,4-tetrahydroisoquinolinyl group, optionally substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, C1-C3 alkoxy, halogen, and C3-C6 cycloalkyl; a naphthyl group; a phenyl-C2-C5 alkenyl group; an oxo-1,2,3,4-tetrahydroisoquinolinyl group; a phenoxymethyl group (the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl); a —(CH2)q-phenyl group (q is 0, 1, 2, or 3 and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, C2-C5 alkenyl, and C1-C5 alkylsulfanyl); a group of formula (C)
wherein, Y is hydrogen or a halogen group, R5′ is hydrogen, a C1-C3 alkyl group, a benzyl group, or a cyano group, and R5″ is hydrogen, or C1-C5 alkyl group; or a group of formula (D)
wherein, r is 0, 1, 2, or 3, R5′″ is hydrogen or a C1-C3 alkyl group, and Z is a 1,3-benzodioxolyl group or a phenyl group (the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, trifluoro-C1-C3 alkoxy, and formyl).
Among the compounds of the formula (I) or its pharmaceutically acceptable salt of the present invention, preferred are those wherein:
R1 is hydrogen; a straight or branched C1-C7 alkyl group; a C1-C3 alkyl group substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, methoxycarbonyl, methylcarbonyloxy, tert-butylcarbonyloxy, methoxyethoxy, methylsulfanyl, allyloxy, formyl, pyridyl, naphthyl, methylthiazolyl, chlorothiophenyl, dimethylisoxazolyl, 1,3-dioxolanyl, 1,3-dioxanyl, oxiranyl, and tetrahydropyranyl; a chlorobutyl group; a (methyl-1,3-dioxolanyl)propyl group; a straight or branched C2-C6 alkenyl group; a phenylallyl group; a straight or branched C2-C6 alkynyl group; a propa-1,2-dienyl group; or a —(CH2)n-phenyl group (n is 1, 2, or 3 and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-C5 alkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, and methylsulfonyl),
R2 is a methyl group,
R3 is hydrogen; a straight or branched C1-C6 alkyl group; a C1-C3 alkyl group substituted with one or more substituents selected from the group consisting of hydroxy, ethoxy, methylcarbonyloxy, cyano, morpholinyl, dimethylamino, and trimethylamino; a bromo group; a cyano group; a formyl group; a methylsulfanyl group; a methylsulfonyl group; or a methylsulfinyl group,
R4 is hydrogen; a C1-C3 alkyl group substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C1-C5 alkylamino, cyclopropylamino, cyclobutylamino, fluorophenylamino, chlorobenzylamino, methylbenzylamino, morpholinyl, and methylpiperazinyl; a ethynyl group; a halogen group; a cyano group; a hydroxy group; an amino group; a morpholinyl group; a mercapto group; an aminosulfonyl group; a tetrazolyl group; a methyltetrazolyl group; an ethyltetrazolyl group; a group of the formula (A)
wherein, R4′ is hydrogen, a hydroxy group, a C1-C5 alkyl group, a C1-C3 alkoxy group, a cyclohexyl group, an imidazolyl group, a morpholinyl group, a thiomorpholinyl group, a pyrrolidyl group, a dihydropyridyl group, a piperazinyl group, a methylpiperazinyl group, an ethylpiperazinyl group, a phenylpiperazinyl group, or a piperidinyl group (the piperidinyl ring is optionally substituted with C1-C3 alkyl, hydroxy, or hydroxy-C1-C3 alkyl); or a group of formula (B)
wherein, R4″ is hydrogen or a C1-C3 alkyl group and R4′″ is hydrogen, a C1-C5 alkyl group, a C2-C5 alkenyl group, a C3-C6 cycloalkyl group, a hydroxyethyl group, a trifluoro-C1-C3 alkyl group, a chlorobenzyl group, a methylbenzyl group, or a piperonyl group, and
R5 is a 1,2,3,4-tetrahydroisoquinolinyl group, optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, and C3-C6 cycloalkyl; a naphthyl group; a phenyl-ethenyl group; a 3,4-dihydro-2H-isoquinolin-1-one-2-yl group; a phenoxymethyl group substituted with one or more substituents selected from the group consisting of halogen and C1-C3 alkyl; a —(CH2)m-phenyl group (m is 0, 1, 2, or 3 and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, C2-C5 alkenyl, and methylsulfanyl); a group of formula (C)
wherein, Y is hydrogen or a halogen group, R5′ is hydrogen, a C1-C3 alkyl group, a benzyl group, or a cyano group, and R5″ is hydrogen, or C1-C5 alkyl group; or a group of formula (D)
wherein, r is 0, 1, 2, or 3, R5′″ is hydrogen or a C1-C3 alkyl group, and Z is a 1,3-benzodioxolyl group or a phenyl group (the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, trifluoromethoxy, and formyl).
The compounds of the present invention may be pharmaceutically acceptable non-toxic salt forms. The non-toxic salts may include conventional acid addition salts used in the field of anti-ulcer agents, e.g., salts originated from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid, or trifluoroacetic acid. Further, the non-toxic salts include conventional metal salt forms, e.g., salts originated from metal such as lithium, sodium, potassium, magnesium, or calcium. Such acid addition salts or metal salts may be prepared in accordance with any of the conventional methods.
The present invention includes, within its scope, a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in accordance with the following Scheme 1:
wherein, R1, R2, R3, R4, and R5 are the same as defined in the above; X is halogen; and Q is hydrogen or B(OH)2.
Specifically, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (II) with R5-Q to obtain a compound of formula (III), reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (Ia), and reacting the compound of formula (Ia) with R1—X to obtain a compound of formula (I).
In the processes of Scheme 1, the compounds of formula (II) and (IV) are commercially available. The reaction of the compound of formula (II) and R5-Q may be performed in the presence of a base, such as sodium hydride, potassium tert-butoxide, sodium carbonate, or potassium hydroxide. Further, the reaction may be carried out in an organic solvent, such as anhydrous tetrahydrofuran and N,N-dimethylformamide, and at room temperature or under heating, e.g., at a temperature of 40° C.˜140° C. In case that Q is B(OH)2, the reaction may be carried out in the presence of potassium carbonate as a base and ligand-coupled palladium as a metallic catalyst. Further, in case that Q is B(OH)2, the reaction may be carried out in an organic solvent, e.g., 1,4-dioxane, under heating.
The compound of formula (III) is reacted with a compound of formula (IV) to obtain a compound of formula (Ia). The reaction of the compound of formula (III) and the compound of formula (IV) may be performed in an anhydrous aprotic polar organic solvent, e.g., anhydrous tetrahydrofuran. Further, the reaction may be carried out at room temperature or at a temperature of −78° C.˜0° C.
The compound of formula (Ia) is reacted with R1—X to obtain a compound of formula (I). The reaction of the compound of formula (Ia) and R1—X may be performed in the presence of a base, such as sodium hydride or potassium tert-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N,N-dimethylformamide, and at room temperature or at a temperature of 40° C.˜100° C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
In accordance with another aspect of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared in accordance with the following Scheme 2:
wherein, R1, R2, R3, R4, R5, X and Q are the same as defined in the above.
Specifically, the compound of formula (I) or its pharmaceutically acceptable salt may be prepared using a process which comprises: (a) adding a sodium nitrite solution to a compound of formula (V), followed by reducing the resulting product with tin chloride, to obtain a compound of formula (VI); (b) reacting the compound of formula (VI) with a compound of formula (VII) to obtain a compound of formula (VIII); (c) cyclizing the compound of formula (VIII) to obtain a compound of formula (Ib); (d) reacting the compound of formula (Ib) with R5-Q to obtain a compound of formula (Ia); and (e) reacting the compound of formula (Ia) with R1—X to obtain a compound of formula (I).
In the processes of Scheme 2, the compounds of formula (V) and (VII) are commercially available. The step (a) may be performed by adding a sodium nitrite solution at a temperature of −20° C.˜5° C. to a solution of the compound of formula (V) in an inorganic acid, followed by reducing the resulting product with tin chloride.
A compound of formula (VIII) may be prepared by reacting the compound of formula (VI) with a compound of formula (VII) under heating, in an organic solvent, e.g., ethanol.
The cyclization of the compound of formula (VIII) may be carried out by heating the compound of formula (VIII) in an organic solvent, e.g., diphenyl ether having a high melting point, at a temperature of 100° C.˜300° C.
The reaction of the compound of formula (Ib) and R5-Q may be performed in the presence of a base, such as sodium hydride, potassium tert-butoxide, sodium carbonate, or potassium hydroxide. Further, the reaction may be carried out in an organic solvent, such as anhydrous tetrahydrofuran and N,N-dimethylformamide, and at room temperature or at a temperature of 40° C.˜140° C.
The compound of formula (Ia) is reacted with R1—X to obtain a compound of formula (I). The reaction of the compound of formula (Ia) and R1—X may be performed in the presence of a base, such as sodium hydride or potassium tert-butoxide. Further, the reaction may be carried out in an organic solvent, such as tetrahydrofuran or N,N-dimethylformamide, and at room temperature or at a temperature of 40° C.˜100° C. In order to increase a reaction rate and/or a yield of the reaction, a catalytic amount of 18-crown-6 may be used.
In accordance with another aspect of the present invention, the compound of formulas (If) or (Ig); or its pharmaceutically acceptable salt may be prepared in accordance with the following Scheme 3:
wherein, R1, R2, R3, R4″, R4′″, R5, and X are the same as defined in the above, and Ra is a C1-C3 alkoxy group; an imidazolyl group; a morpholinyl group; a thiomorpholinyl group; a pyrrolidyl group; a tetrahydropyridyl group; a piperazinyl group optionally substituted with C1-C3 alkyl or phenyl; or a piperidinyl group optionally substituted with C1-C3 alkyl, hydroxy, or hydroxy-C1-C3 alkyl.
Specifically, the compound of formula (If) or (Ig); or its pharmaceutically acceptable salt may be prepared using a process which comprises: reacting a compound of formula (Ic) with copper cyanide to obtain a compound of formula (Id), hydrolyzing the compound of formula (Id) to obtain a compound of formula (Ie), and reacting the compound of formula (Ie) with Ra—H or R4″R4′″—NH to obtain a compound of formulas (If) or (Ig).
In the processes of Scheme 3, a compound of formula (Id) may be prepared by refluxing a mixture of a compound of formula (Ic) and copper cyanide, in an organic solvent, e.g., N,N-dimethylformamide.
The compound of formula (Id) is hydrolyzed in an acidic or basic condition to produce a compound of formula (Ie). The hydrolysis reaction may be carried out with hydrochloric acid as an acid or a potassium hydroxide solution as a base at a temperature of 50° C.˜100° C.
The reaction of the compound of formula (Ie) and Ra—H or R4″R4′″—NH may be performed in the presence of a coupling agent, e.g., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) or 1-hydroxy-7-azabenzotriazole (HOBT). The coupling reaction may be carried out in an organic solvent, e.g., dichloromethane or N,N-dimethylformamide.
In accordance with another aspect of the present invention, the compound of formula (Ij) or its pharmaceutically acceptable salt may be prepared in accordance with the following Scheme 4:
wherein, R1, R2, R4, and R5 are the same as defined in the above.
Specifically, the compound of formula (Ij) or its pharmaceutically acceptable salt may be prepared using a process which comprises: hydrolyzing a compound of formula (Ih) with a hydrolyzing agent; or performing formylation of a compound of formula (Ii), followed by reducing the resulting product, to obtain a compound of formula (Ij).
In the processes of Scheme 4, the hydrolysis reaction of a compound of formula (Ih) may be performed with a hydrolyzing agent, e.g., lithium hydroxide, in the presence of ammonium cerium (IV) nitrate and acetic acid. The formylation of a compound of formula (II) may be carried out using phosphorus oxychloride and N,N-dimethylformamide and the reduction of the resulting aldehyde group may be carried out with a reducing agent, e.g., sodium borohydride.
In accordance with another aspect of the present invention, the compound of formula (Ik) or its pharmaceutically acceptable salt may be prepared using a process which comprises: performing a Mannich reaction of a compound of formula (Ii), followed by reacting the resulting product with sodium cyanide or potassium cyanide, to obtain a compound of formula (Ik), as the following Scheme 5:
wherein, R1, R2, R4, and R5 are the same as defined in the above.
The present invention further includes, within its scope, a pharmaceutical composition comprising a therapeutically effective amount of any of the compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be used for prevention and treatment of gastrointestinal inflammatory diseases and gastric acid-related diseases in mammals including human, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. Furthermore, the compounds or their salts of the present invention may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. The compounds or their salts of the present invention may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration.
The composition of the present invention may include additives such as lactose or corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. If necessary, sweetening agents and/or flavoring agents may be added.
The composition of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral use, carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are commonly added. In the case of capsules for oral administration, lactose and/or dried corn starch can be used as a diluent. When an aqueous suspension is required for oral use, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, stertle solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The composition of the present invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, e.g., saline, at a pH level of 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
The compounds of the present invention may be administered in an effective amount ranging from about 0.1 mg/kg to about 500 mg/kg per day to a subject patient. Of course, the dosage may be changed according to the patient's age, weight, susceptibility, or symptom.
The following examples are provided for illustration purposes only, and are not intended to limit the scope of the invention.
A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methylboronic acid (8.3 g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol) and potassium carbonate (52,3 g, 0.378 mol) in anhydrous 1,4-dioxane (100 ml) was refluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 14 g of the titled compound as brown oil.
1H-NMR(400 MHz, CDCl3) δ 8.74 (d, 1H), 8.27 (d, 1H), 7.34 (t, 1H), 2.88 (s, 3H)
2,2′-azobis(isobutyronitrile) (2.7 g, 16.4 mmol) was added to a solution of 2-methyl-3-nitropyridine (12.97 g, 92.6 mmol) prepared in Step 1 and N-bromosuccinimide (23.06 g, 130 mmol) in carbon tetrachloride (100 ml) and then the reaction mixture was refluxed for 3 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml) and then washed with a saturated sodium bicarbonate solution and a saturated sodium thiosulfate solution. The organic layer was dried on anhydrous magnesium sulfate and then purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 7.5 g of the titled compound as brown oil.
1H-NMR(400 MHz, CDCl3) δ 8.82 (d, 1H), 8.39 (d, 1H), 7.56 (t, 1H), 5.07 (s, 2H)
2-Bromomethyl-3-nitropyridine (100 mg, 0.456 mmol) prepared in Step 2 was added at room temperature to a solution of 4-fluorophenol (56 mg, 0.502 mmol) and potassium carbonate (189 mg, 1.37 mmol) in N,N-dimethylformamide (3 ml) and then stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with a saturated sodium bicarbonate solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 71 mg of the titled compound as yellow solid.
1H-NMR(400 MHz, CDCl3) δ 8.85 (d, 1H), 8.34 (d, 1H), 7.52 (t, 1H), 6.97 (m, 4H), 5.53 (s, 2H)
A solution of 2-bromomethyl-3-nitropyridine (2 g, 9.13 mmol) prepared in Step 2 of Preparation 1 and 4-fluoroaniline (0.87 ml, 9.13 mmol) in ethanol (15 ml) was stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure to give 2.6 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
A solution of (4-fluorophenyl)-(3-nitropyridin-2-ylmethyl)-amine (2.28 g, 9.13 mmol) prepared in Step 1, di-tert-butyl dicarbonate (9.2 g, 23.7 mmol), and sodium bicarbonate (3.07 g, 36.6 mmol) in toluene (50 ml) was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with ethyl ether, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 1.4 g of the titled compound as yellow oil.
1H-NMR(400 MHz, CDCl3) δ 8.87 (m, 1H), 8.37 (d, 1H), 7.26 (m, 3H), 6.96 (m, 2H), 5.28 (s, 3H), 1.35 (s, 9H)
A solution of 2-methyl-3-nitropyridine (10.155 g, 72.46 mmol) prepared in Step 1 of Preparation 1 and selenium dioxide (8.84 g, 79.71 mmol) in 1,4-dioxane (80 ml) was refluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/2, v/v) to give 12.8 g of the titled compound as red oil.
1H-NMR(400 MHz, CDCl3) δ 10.27 (s, 1H), 9.00 (d, 1H), 8.28 (t, 1H), 7.76 (d, 1H)
A solution of 2-formyl-3-nitropyridine (12.8 g, 83 mmol) prepared in Step 1,1-butyl alcohol (53.1 ml, 883 mmol), and p-toluenesulfonic acid (0.32 g, 1.68 mmol) in toluene (15 ml) was refluxed for 3 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), washed with a saturated sodium bicarbonate solution (10 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 11.53 g of the titled compound as reddish brown oil.
1H-NMR(400 MHz, CDCl3) δ 8.82 (d, 1H), 8.08 (d, 1H), 7.45 (t, 1H), 5.98 (s, 1H), 3.70 (m, 2H), 3.59 (m, 2H), 1.60 (m, 4H), 1.39 (m, 4H), 0.90 (m, 6H)
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 243 ml, 121 mmol) was slowly added at −78° C. to a solution of 2-dibutoxymethyl-3-nitropyridine (11.53 g, 40 mmol) prepared in Step 2 in tetrahydrofuran (100 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution (50 ml) was added thereto. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 8 g of the titled compound as brown oil. The product was used in the subsequent step without further purification.
Sodium hydride (60%, 23 mg, 0.562 mmol) and allyl bromide (36 μl, 0.413 mmol) were added at 0° C. to a solution of 7-dibutoxymethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (0.109 g, 0.375 mmol) prepared in Step 3 in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred for 1 hour at room temperature and water (1 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (10 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. Tetrahydrofuran (10 ml) was added to the resulting residue. 0.5N hydrochloric acid (3 ml, 1.5 mmol) was added to the reaction mixture, which was then refluxed overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, basified with a saturated sodium bicarbonate solution, extracted with ethyl acetate (20 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 50 mg of the titled compound as yellow oil.
1H-NMR(400 MHz, CDCl3) δ 10.17 (s, 1H), 8.41 (d, 1H), 7.62 (d, 1H), 5.89 (m, 1H), 5.30 (d, 2H), 4.98 (d, 1H), 4.48 (d, 1H), 2.38 (s, 3H), 2.25 (s, 3H)
4-Fluorobenzylamine (5.88 ml, 51.4 mmol) was added to a solution of 2-chloro-3-nitropyridine (8.16 g, 51.4 mmol) and sodium carbonate (8.72 g, 82,3 mmol) in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then filtered to discard an insoluble solid. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution (100 ml) four times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 11.5 g of the titled compound as yellow solid.
1H-NMR(400 MHz, CDCl3) δ 8.48 (brs, 1H), 8.45 (m, 2H), 7.35 (m, 2H), 7.03 (m, 2H), 6.70 (m, 1H), 4.83 (d, 2H)
2-(4-fluorobenzyl)amino-3-nitropyridine (10.4 g, 41.9 mmol) prepared in Step 1, potassium tert-butoxide (4.71 g, 41.9 mmol), and 18-crown-6 (1.11 g, 4.19 mmol) were added to anhydrous tetrahydrofuran (100 ml). Iodomethane (3.92 ml, 62.9 mmol) was slowly added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 8.26 g of the titled compound as yellow solid. (Yield: 75%).
1H-NMR(400 MHz, CDCl3) δ 8.33 (m, 1H), 8.13 (m, 1H), 7.26 (m, 2H), 7.02 (t, 2H), 6.74 (m, 1H), 4.89 (s, 2H), 2.78 (s, 3H)
In accordance with the same procedures as in Step 1 of Preparation 4, except for using 2-chloro-3-nitropyridine and benzylamine, the titled compound was obtained as yellow solid. (Yield: 91%)
1H-NMR(400 MHz, CDCl3) δ 8.52 (brs, 1H), 8.44 (m, 2H), 7.31 (m, 5H), 6.68 (m, 1H), 4.87 (d, 2H),
Di-tert-butyl dicarbonate (36.68 ml, 160 mmol) was added to a solution of 2-benzylamino-3-nitropyridine (12.2 g, 53.2 mmol) prepared in Step 1 and 4-dimethylaminopyridine (9.75 g, 79.8 mmol) in tetrahydrofuran (100 ml). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 17.5 g of the titled compound as yellow oil.
1H-NMR(400 MHz, CDCl3) δ 8.58 (m, 1H), 8.21 (m, 1H), 7.44 (m, 2H), 7.28 (m, 2H), 7.22 (m, 2H), 5.24 (s, 2H), 1.36 (s, 9H)
5-amino-2-methoxypyridine (81.5 g, 0.657 mol) was dissolved in a mixture of concentrated hydrochloric acid (120 ml) and water (530 ml). A solution of sodium nitrate (56.5 g, 0.819 mol) in water (100 ml) was added at −5° C. to the solution. The reaction mixture was stirred for 45 minutes at room temperature and sodium nitrate (56.5 g, 0.819 mol) was further added thereto. Hexafluorophosphoric acid (132 ml) was added to the reaction mixture, which was then stirred for 20 minutes at room temperature. The reaction mixture was filtered to obtain a solid, which washed with water and ethyl ether and then dried under reduced pressure. The resulting compound was heated for 15 minutes at 150° C., dissolved in dichloromethane, and then washed with 3N sodium hydroxide solution. The organic layer was dried on anhydrous magnesium sulfate, concentrated under reduced pressure, and then fractionally distilled to give 22.6 g of the titled compound as colorless oil. (Yield: 27%).
1H-NMR(400 MHz, CDCl3) δ 7.99 (d, 1H), 7.33 (m, 1H), 6.71 (dd, 1H), 3.91 (s, 3H)
A solution of 5-fluoro-2-methoxypyridine (16.6 g, 131 mmol) prepared in Step 1 in 48% hydrobromic acid solution (250 ml) was stirred for 3 hours at 150° C. The reaction mixture was cooled to room temperature to obtain a yellow solid. The solid was dissolved in methanol (50 ml), neutralized with a sodium carbonate solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 13.1 g of the titled compound as a white solid. (Yield: 88%)
1H-NMR (400 MHz, CDCl3) δ 13.34 (brs, 1H), 7.42 (m, 1H), 7.30 (m, 1H), 6.59 (dd, 1H)
A mixture of nitric acid (70%, 15 ml) and sulfuric acid (15 ml) was slowly added at 5° C.˜10° C. to a solution of 5-fluoro-2-hydroxypyridine (13.0 g, 115 mmol) prepared in Step 2 in sulfuric acid (31 ml). The reaction mixture was heated for 2 hours at 85° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then filtered. The resulting yellow solid was dried to give 11 g of the titled compound as yellow solid. (Yield: 60%).
1H-NMR(400 MHz, DMSO-d6) δ 12.71 (brs, 1H), 8.37 (dd, 1H), 7.98 (m, 1H)
5-fluoro-2-hydroxy-3-nitropyridine (11.0 g, 69.4 mmol) prepared in Step 3 was added to a mixed solution of phosphorus oxychloride (38.8 ml, 416 mmol) and N,N-dimethylformamide (537 μl, 6.94 mmol). The reaction mixture was stirred for 5 hours at 110° C. Water (250 ml) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a sodium chloride solution (250 ml) three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate) to give 9.02 g of the titled compound as yellow solid. (Yield: 74%).
1H-NMR(400 MHz, CDCl3) δ 8.56 (d, 1H), 8.04 (dd, 1H)
2-chloro-5-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) prepared in Step 4 and sodium carbonate (1.25 g, 9.06 mmol) were added to anhydrous N,N-dimethylformamide (50 ml). 1,2,3,4-tetrahydroisoquinoline (712 μl, 5.66 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 100° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a sodium chloride solution three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 1.34 g of the titled compound as yellow solid. (Yield: 86%).
1H-NMR(400 MHz, CDCl3) δ 8.33 (d, 1H), 8.01 (dd, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 4.45 (s, 2H), 3.72 (t, 2H), 3.02 (t, 2H)
2,6-Dichloro-3-nitropyridine (10 g, 51.8 mmol) and sodium carbonate (8.8 g, 82.9 mmol) were added to anhydrous N,N-dimethylformamide (250 ml). 1,2,3,4-tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added at 0° C. to the reaction mixture, which was then stirred for 2 hours at 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 10 g of the titled compound as yellow solid. (Yield: 81%).
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 6.68 (d, 1H), 4.47 (s, 2H), 3.75 (t, 2H), 3.02 (t, 2H)
In accordance with the same procedures as in Preparation 7, except for using 2,6-dichloro-3-nitropyridine and 4-fluorobenzylamine, the titled compound was obtained as yellow solid. (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.56 (brs, 1H), 8.37 (d, 1H), 7.36 (m, 2H), 7.05 (m, 2H), 6.67 (d, 1H), 4.78 (d, 2H)
In accordance with the same procedures as in Step 2 of Preparation 4, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-amine prepared in Step 1 and iodomethane, the titled compound was obtained as yellow solid. (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.07 (d, 1H), 7.30 (m, 2H), 7.04 (m, 2H), 6.70 (d, 1H), 4.85 (s, 2H), 2.79 (s, 3H)
2-Chloro-3-nitropyridine (4.37 g, 27.6 mmol), 4-vinylphenylboronic acid (4.5 g, 30.4 mmol), tetrakis(triphenylphosphine)palladium (0) (3.19 g, 2.8 mmol), and potassium carbonate (11.4 g, 82.8 mmol) were added to anhydrous 1,4-dioxane (60 ml). The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, filtered with a Celite pad, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography and then crystallized with ethyl ether to give 4.9 g of the titled compound as a white solid. (Yield: 79%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using (4-methylthiophenyl)boronic acid, the titled compound was obtained as a white solid. (Yield: 77%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using 4-methylphenylboronic acid, the titled compound was obtained as a white solid. (Yield: 75%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using 4-chlorophenylboronic acid, the titled compound was obtained as a white solid. (Yield: 80%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using 4-fluorophenylboronic acid, the titled compound was obtained as a white solid. (Yield: 74%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using 4-methoxyphenylboronic acid, the titled compound was obtained as a white solid. (Yield: 77%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using phenylboronic acid, the titled compound was obtained as a white solid. (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.86 (d, 1H), 8.13 (d, 1H), 7.57 (m, 2H), 7.46 (m, 4H)
In accordance with the same procedures as in Preparation 9, except for using naphthalene-2-boronic acid, the titled compound was obtained as a white solid. (Yield: 72%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 9, except for using styrylboronic acid, the titled compound was obtained as a white solid. (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.80 (d, 1H), 8.24 (d, 1H), 8.09 (d, 1H), 7.78 (d, 1H), 7.65 (m, 2H), 7.37 (m, 4H)
In accordance with the same procedures as in Preparation 9, except for using benzylboronic acid, the titled compound was obtained as a white solid. (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.77 (d, 1H), 8.22 (d, 1H), 7.35 (m, 1H), 7.27 (m, 4H), 7.21 (m, 1H), 4.52 (s, 2H)
In accordance with the same procedures as in Preparation 9, except for using phenethylboronic acid, the titled compound was obtained as a white solid. (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.78 (d, 1H), 8.21 (d, 1H), 7.35 (m, 1H), 7.29 (m, 4H), 7.22 (m, 1H), 3.42 (m, 2H), 3.11 (m, 2H)
2-Chloro-3-nitropyridine (3.0 g, 18.92 mmol), 1,2,3,4-tetrahydroisoquinoline (2.37 ml, 18.92 mmol), and sodium carbonate (3.1 g, 28.62 mmol) were added to anhydrous N,N-dimethylformamide (30 ml). The reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water three times, and then washed with a saturated sodium chloride solution. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4.8 g of the titled compound as yellow oil. (Yield: 98%).
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 8.17 (d, 1H), 7.19 (m, 3H), 7.11 (m, 1H), 6.73 (m, 1H), 4.48 (s, 2H), 3.76 (t, 2H), 3.01 (t, 2H)
4-Methoxyphenethylamine (50 g, 330 mmol) was added to dichloromethane (50 ml) and then 2N sodium hydroxide solution (25 ml) was added thereto. Acetyl chloride (26 ml, 364 mmol) was slowly added at 0° C. to the reaction mixture, which was then stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 68 g of the titled compound as a white solid. The product was used in the subsequent step without further purification.
Phosphorus pentoxide (22 g, 155.24 mmol) was added to a mixture of N-[2-(4-methoxyphenyl)-ethyl]-acetamide (50 g, 258.73 mmol) prepared in Step 1 and phosphorus oxychloride (48 ml, 517.46 mmol). The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, added to ice water, basified with 2N potassium hydroxide solution, and then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 14.72 g of the titled compound as brown oil. (Yield: 32%) The product was used in the subsequent step without further purification.
Sodium borohydride (3.81 g, 100.8 mmol) was slowly added at 0° C. to a solution of 7-methoxy-1-methyl-3,4-dihydroisoquinoline (14.72 g, 84 mmol) prepared in Step 2 in anhydrous methanol (100 ml). The reaction mixture was stirred overnight at room temperature. 1N hydrochloric acid was added to the reaction mixture, which was concentrated under reduced pressure, basified with potassium hydroxide, and then extracted with dichloromethane. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 11.01 g of the titled compound as brown oil. (Yield: 74%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Preparation 20, except for using 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline prepared in Step 3, the titled compound was obtained. (Yield: 94%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 4-chlorophenethylamine and acetyl chloride, 7-chloro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 67%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 4-fluorophenethylamine and acetyl chloride, 7-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 69%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and acetyl chloride, 1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 91%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 3-fluorophenethylamine and acetyl chloride, 6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 55%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and cyclopropanecarbonyl chloride, 1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 82%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using phenethylamine and propionyl chloride, 1-ethyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 78%) The product was used in the subsequent step without further purification.
A solution of 3-amino-2-chloropyridine (5 g, 38.9 mmol) in concentrated hydrochloric acid (50 ml) was cooled to −5° C. and a solution of sodium nitrite (2.7 g, 38.9 mmol) in water (25 ml) was added thereto. The reaction mixture was stirred for 15 minutes at 0° C. and a solution of tin(II) chloride dihydrate (17.6 g, 77.8 mmol) in concentrated hydrochloric acid (17.5 ml) was slowly added thereto. The reaction mixture was stirred for 1 hour at room temperature, basified with 2N sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was crystallized with ethyl ether to give 2 g of the titled compound as a pale yellow solid. (Yield: 36%).
1H-NMR(400 MHz, CDCl3) δ 7.80 (d, 1H), 7.47 (d, 1H), 7.17 (m, 1H), 5.76 (brs, 1H), 3.65 (brs, 2H)
3-Pentanone (1.1 ml, 10.4 mmol) was added to a solution of (2-chloropyridin-3-yl)-hydrazine (1 g, 6.96 mmol) prepared in Step 1 in ethanol (35 ml). The reaction mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and then purified with silica gel column chromatography to give 1.3 g of the titled compound as pale yellow oil. (Yield: 88%).
1H-NMR(400 MHz, CDCl3) δ 7.83 (d, 1H), 7.76 (dd, 1H), 7.52 (s, 1H), 7.16 (m, 1H), 2.35 (m, 2+2H), 1.18 (m, 3+3H)
A solution of N-(2-chloropyridin-3-yl)-N′-(1-ethylpropylidene)-hydrazine (1.3 g, 6.1 mmol) prepared in Step 2 in diphenyl ether was stirred for 3 hours at 300□. The reaction mixture was cooled to room temperature and then purified with silica gel column chromatography to give 850 mg of the titled compound as a pale yellow solid. (Yield: 72%).
1H-NMR(400 MHz, CDCl3) δ 8.80 (brs, 1H), 7.98 (d, 1H), 7.32 (d, 1H), 2.82 (q, 2H), 2.21 (s, 3H), 1.31 (t, 3H)
1-Methyl-1-propenyl magnesium bromide (0.5 M in tetrahydrofuran solution, 1.7 ml, 0.851 mmol) was added at −78° C. to a solution of 2-(4-fluorophenoxymethyl)-3-nitropyridine (71 mg, 0.284 mmol) prepared in Preparation 1 in anhydrous tetrahydrofuran (5 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml). The organic layer washed with water (5 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 15 mg of the titled compound as brown oil.
1H-NMR(400 MHz, CDCl3) δ 8.46 (brs, 1H), 8.15 (d, 1H), 7.33 (d, 1H), 6.98 (m, 4H), 5.48 (s, 2H), 2.41 (s, 3H), 2.21 (s, 3H)
Allyl bromide (11.77 μl, 0.14 mmol) was added to a solution of 7-(4-fluorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (15 mg, 0.054 mmol) prepared in Example 1, potassium tert-butoxide (20.68 mg, 0.18 mmol), and 18-crown-6 (487 mg, 0.02 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/2, v/v). The residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered. The resulting solid was dried under reduced pressure to give 1.9 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.74 (d, 1H), 7.12 (m, 2H), 6.98 (t, 2H), 6.03 (m, 1H), 5.88 (s, 2H), 5.30 (d, 1H), 5.13 (s, 2H), 4.40 (d, 1H), 2.50 (s, 3H), 2.27 (s, 3H)
The titled compounds of Examples 3 to 13 were prepared, in accordance with the same procedures as in Example 2, using 7-(4-fluorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 1; and, benzyl bromide, 3-methoxybenzyl bromide, 4-methylbenzyl bromide, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, 1-iodopropane, 2-fluorobenzyl chloride, iodoethane, 4-fluorobenzyl chloride, 4-bromo-2-methyl-2-butene, or propargyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H) 7.80 (m, 1H), 7.28 (m, 3H), 6.97 (m, 4H), 6.77 (m, 2H), 5.73 (s, 2H), 5.61 (s, 2H), 2.50 (s, 3H), 2.40 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.78 (d, 1H), 7.20 (d, 1H), 6.98 (m, 4H), 6.80 (d, 1H), 6.20 (d, 1H), 6.12 (s, 1H), 5.69 (s, 2H), 5.61 (s, 2H), 3.70 (s, 3H), 2.55 (s, 3H), 2.39 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.77 (m, 1H), 7.08 (m, 2H), 6.96 (m, 4H), 6.50 (m, 2H), 5.69 (s, 2H), 5.61 (s, 2H), 2.60 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H); (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.70 (m, 1H), 7.13 (m, 2H), 7.00 (m, 2H), 6.10-5.80 (m, 2H), 4.73-4.00 (m, 2H), 3.59 (m, 2H), 3.23 (s, 3H), 2.52 (s, 3H), 2.34 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.71 (m, 1H), 7.02 (m, 2H), 6.98 (m, 2H), 6.01 (s, 2H), 4.53 (s, 2H), 2.57 (s, 3H), 2.33 (s, 3H), 1.03 (m, 1H), 0.61 (m, 2H), 0.24 (m, 2H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.71 (m, 1H), 7.15 (m, 2H), 7.01 (m, 2H), 5.93 (s, 2H), 4.36 (m, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 1.76 (m, 2H), 0.93 (t, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.81 (m, 1H), 7.30 (m, 1H), 7.11 (m, 1H), 6.96 (m, 5H), 6.12 (m, 1H), 5.79 (s, 2H), 5.68 (s, 2H), 2.48 (s, 3H), 2.39 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.72 (m, 1H), 7.15 (m, 2H), 7.00 (m, 2H), 5.96 (s, 2H), 4.52 (q, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.40 (t, 3H); (Yield: 88%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.79 (m, 1H), 7.01 (m, 6H), 6.63 (m, 2H), 5.72 (s, 2H), 5.65 (s, 2H), 2.49 (s, 3H), 2.39 (s, 3H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.70 (m, 1H), 7.12 (m, 2H), 6.97 (m, 2H), 5.93 (s, 2H), 5.08 (m, 2H), 4.96 (m, 1H), 2.52 (s, 3H), 2.32 (s, 3H), 1.71 (s, 3H), 1.65 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.74 (m, 1H), 7.14 (m, 2H), 7.00 (m, 2H), 5.97 (s, 2H), 5.44 (d, 2H), 2.56 (s, 3H), 2.33 (s, 1+3H); (Yield: 70%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-methylphenol, the titled compound was obtained as yellow solid. (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.85 (d, 1H), 8.30 (d, 1H), 7.49 (m, 1H), 7.06 (d, 2H), 6.85 (d, 2H), 5.54 (s, 2H), 2.28 (s, 3H)
In accordance with the same procedures as in Example 1, except for using 2-(4-methylphenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 20%)
1H-NMR(400 MHz, CDCl3) δ 8.60 (brs, NH), 8.15 (d, 1H), 7.31 (d, 1H), 7.07 (m, 2H), 6.93 (m, 2H), 5.48 (s, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H)
The titled compounds of Examples 15 to 31 were prepared, in accordance with the same procedures as in Example 2, using 2,3-dimethyl-7-(4-methylphenoxymethyl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 14; and, benzyl bromide, 3-methoxybenzyl bromide, 4-methylbenzyl bromide, (bromomethyl)cyclopropane, 4-fluorobenzyl chloride, 4-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 3-methylbenzyl bromide, 4-chloromethyl-2-methylthiazole, 4-bromo-2-methyl-2-butene, 2-bromoethyl methyl ether, 1-iodopropane, iodoethane, 2-methylbenzyl chloride, 4-tert-butylbenzyl chloride, 2,5-dimethylbenzyl chloride, or 4-trifluoromethylbenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.76 (d, 1H), 7.28 (m, 3H), 7.07 (d, 2H), 6.88 (d, 2H), 5.59 (m, 2H), 5.73 (s, 2H), 5.58 (s, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.76 (d, 1H), 7.19 (t, 1H), 7.09 (d, 2H), 6.90 (d, 2H), 6.79 (d, 1H), 6.18 (d, 1H), 6.11 (s, 1H), 5.69 (s, 2H), 5.57 (s, 2H), 3.69 (s, 3H), 2.50 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (t, 1H) 7.77 (d, 1H), 7.07 (m, 4H), 6.89 (d, 2H), 6.48 (d, 2H), 5.68 (s, 2H), 5.57 (s, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H); (Yield: 41%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.70 (d, 1H), 7.10 (d, 2H), 7.00 (d, 2H), 5.90 (s, 2H), 4.44 (d, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.07 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (t, 1H), 7.77 (d, 1H), 7.07 (d, 2H), 6.97 (t, 2H), 6.89 (d, 2H), 6.60 (m, 2H), 5.78 (s, 2H), 5.61 (s, 2H), 2.48 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (t, 1H), 7.77 (d, 1H), 7.24 (d, 2H), 7.07 (d, 2H), 6.86 (d, 2H), 6.55 (d, 2H), 5.70 (s, 2H), 5.61 (s, 2H), 2.47 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.07 (m, 1H), 7.58 (m, 2H), 7.43 (d, 1H), 7.33 (d, 1H), 7.06-7.01 (m, 4H), 6.98 (s, 2H), 6.00 (s, 2H), 2.60 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.76 (d, 1H), 7.16-7.07 (m, 4H), 6.88 (d, 2H), 6.41 (s, 1H), 6.35 (d, 1H), 5.68 (s, 2H), 5.56 (s, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.71 (d, 1H), 7.13-7.00 (m, 4H), 6.61 (s, 1H), 6.02 (s, 2H), 5.73 (s, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (t, 1H), 7.68 (d, 1H), 7.11 (d, 2H), 7.01 (d, 2H), 5.89 (s, 2H), 5.08 (m, 2H), 4.94 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H), 1.70 (s, 3H), 1.63 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.68 (d, 1H), 7.11-7.01 (m, 4H), 6.02 (s, 2H), 4.69 (m, 2H), 3.58 (m, 2H), 3.20 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.70 (d, 1H), 7.10 (d, 2H), 7.01 (d, 2H), 5.90 (s, 2H), 4.35 (t, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 1.72 (m, 2H), 0.90 (t, 3H); (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.70 (d, 1H), 7.11 (d, 2H), 7.03 (d, 2H), 5.93 (s, 2H), 4.50 (q, 2H), 2.55 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 1.38 (t, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (t, 1H), 7.79 (d, 1H), 7.26 (m, 1H), 7.20 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H), 5.71 (d, 1H), 5.62 (s, 2H), 5.42 (m, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.75 (d, 1H), 7.26 (d, 2H), 7.07 (d, 2H), 6.89 (d, 2H), 6.51 (d, 2H), 5.69 (s, 2H), 5.59 (s, 2H), 2.51 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.28 (s, 9H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (t, 1H), 7.79 (d, 1H), 7.08-7.00 (m, 4H), 6.82 (d, 2H), 5.53-5.58 (m, 3H), 5.44 (brs, 2H), 2.46 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); (Yield: 78%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (t, 1H), 7.79 (d, 1H), 7.53 (d, 2H), 7.07 (d, 2H), 6.84 (d, 2H), 6.74 (d, 2H), 5.80 (s, 2H), 5.62 (s, 2H), 2.50 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H); (Yield: 72%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-difluorophenol, the titled compound was obtained as yellow solid. (Yield: 98%)
1H-NMR(400 MHz, CDCl3) δ 8.87 (d, 1H), 8.38 (d, 1H), 7.54 (m, 1H), 7.00 (m, 1H), 6.86 (m, 1H), 6.78 (m, 1H), 5.60 (s, 2H)
In accordance with the same procedures as in Example 1, except for using 2-(2,4-difluorophenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 30%)
1H-NMR(400 MHz, CDCl3) δ 8.80 (brs, 1H), 8.13 (d, 1H), 7.34 (m, 1H), 7.08 (m, 1H), 6.82 (m, 2H), 5.56 (s, 2H), 2.43 (s, 3H), 2.22 (s, 3H)
The titled compounds of Examples 33 to 40 were prepared, in accordance with the same procedures as in Example 2, using 7-(2,4-difluorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 32; and, 1-iodopropane, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, iodoethane, allyl bromide, 4-bromo-2-methyl-2-butene, iodomethane, or 4-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.73 (m, 2H), 6.90-6.77 (m, 2H), 6.01 (s, 2H), 4.53 (m, 2H), 2.61 (s, 3H), 2.33 (s, 3H), 1.78 (m, 2H), 1.01 (m, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (m, 1H), 7.77-7.70 (m, 2H), 6.89 (m, 1H), 6.74 (m, 1H), 6.21 (s, 2H), 4.85 (s, 2H), 3.68 (s, 2H), 3.23 (s, 3H), 2.57 (s, 3H), 2.10 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.71 (m, 2H), 6.69-6.60 (m, 2H), 6.10 (s, 2H), 4.59 (m, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 1.10 (m, 1H), 0.63 (m, 2H), 0.29 (m, 2H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.81-7.71 (m, 2H), 6.90 (m, 1H), 6.77 (t, 1H), 6.04 (s, 2H), 4.66 (m, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 1.42 (t, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.69 (m, 2H), 6.89-6.77 (m, 2H), 6.08 (m, 1H), 5.86 (s, 2H), 5.23-5.16 (m, 4H), 4.42 (d, 1H), 2.54 (s, 3H), 2.27 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (m, 1H), 7.78-7.66 (m, 2H), 6.89-6.77 (m, 2H), 5.94 (s, 2H), 5.31 (s, 2H), 4.97 (m, 1H), 2.53 (s, 3H), 2.32 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (t, 1H), 7.78 (m, 1H), 7.70 (d, 1H), 6.90 (t, 1H), 6.78 (t, 1H), 6.14 (s, 2H), 4.23 (s, 2H), 2.56 (s, 3H), 2.33 (s, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.80 (d, 1H), 7.78 (m, 1H), 7.01 (m, 2H), 6.72 (m, 1H), 6.73 (m, 1H), 6.69 (t, 2H), 5.87 (s, 2H), 5.70 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H); (Yield: 85%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-chlorophenol, the titled compound was obtained as yellow solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.86 (d, 1H), 8.34 (d, 1H), 7.52 (m, 1H), 7.24 (m, 2H), 6.89 (m, 2H), 5.55 (s, 2H)
In accordance with the same procedures as in Example 1, except for using 2-(4-chlorophenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 24%)
1H-NMR(400 MHz, CDCl3) δ 8.48 (brs, 1H), 8.16 (d, 1H), 7.34 (d, 1H), 7.23 (m, 2H), 6.98 (m, 2H), 5.30 (s, 2H), 2.40 (s, 3H), 2.20 (s, 3H)
A solution of 7-(4-chlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 41 in ethyl acetate (10 ml) was saturated with hydrochloric acid gas and then filtered. The resulting solid was dried under reduced pressure to give the titled compound as a white solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.04 (m, 1H), 7.59 (m, 1H), 7.01 (m, 4H), 5.98 (s, 2H), 2.61 (s, 3H), 2.29 (s, 3H)
The titled compounds of Examples 43 to 52 were prepared, in accordance with the same procedures as in Example 2, using 7-(4-chlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 41; and, benzyl bromide, (bromomethyl)cyclopropane, 3-methoxybenzyl chloride, 1-iodopropane, iodoethane, 4-bromo-2-methyl-2-butene, 2-fluorobenzyl chloride, iodomethane, 4-methylbenzyl chloride, or 4-fluorobenzyl chloride
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.78 (d, 1H), 7.29-7.22 (m, 5H), 6.95 (m, 2H), 6.61 (m, 2H), 5.71 (s, 2H), 5.63 (s, 2H), 2.50 (s, 3H), 2.40 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.73 (m, 1H), 7.26 (m, 2H), 7.11 (m, 2H), 6.04 (s, 2H), 4.43 (s, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.05 (m, 1H), 0.63 (m, 2H), 0.23 (m, 2H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.79 (m, 1H), 7.26 (m, 3H), 6.98 (m, 2H), 6.82 (m, 1H), 6.12 (m, 2H), 5.63 (m, 4H), 3.65 (s, 3H), 2.52 (s, 3H), 2.39 (s, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.72 (m, 1H), 7.26 (m, 2H), 7.13 (m, 2H), 5.96 (s, 2H), 4.35 (m, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 1.74 (m, 2H), 0.93 (m, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.71 (m, 1H), 7.26 (m, 2H), 7.12 (m, 2H), 5.98 (s, 2H), 4.50 (m, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.39 (t, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (t, 1H), 7.71 (d, 1H), 7.26 (m, 2H), 7.10 (d, 2H), 5.95 (s, 2H), 5.06 (s, 2H), 4.95 (s, 1H), 1.70 (s, 3H), 1.65 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.80 (m, 1H), 7.32 (m, 2H), 7.21 (m, 2H), 7.13 (t, 1H), 7.01-6.93 (m, 3H), 6.12 (t, 1H), 5.77 (s, 2H), 5.70 (s, 2H), 2.48 (s, 3H), 2.39 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.71 (m, 1H), 7.26 (m, 2H), 7.12 (m, 2H), 6.02 (s, 2H), 4.18 (s, 3H), 2.54 (s, 3H), 2.33 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.74 (m, 1H), 7.26-6.96 (m, 6H), 6.52 (m, 2H), 5.67-5.59 (m, 4H), 2.51 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.78 (m, 1H), 7.20 (m, 2H), 6.99 (m, 4H), 6.64 (m, 2H), 5.67 (m, 4H), 2.49 (s, 3H), 2.39 (s, 3H); (Yield: 55%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2-chlorophenol, the titled compound was obtained as yellow oil. (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.85 (d, 1H), 8.37 (d, 1H), 7.50 (m, 1H), 7.38 (d, 1H), 7.10 (m, 1H), 6.97 (m, 2H), 5.64 (s, 2H)
In accordance with the same procedures as in Example 1, except for using 2-(2-chlorophenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 30%)
1H-NMR(400 MHz, CDCl3) δ 9.50 (brs, 1H), 8.13 (d, 1H), 7.33 (m, 3H), 6.92 (m, 2H), 5.41 (s, 2H), 2.43 (s, 3H), 2.22 (s, 3H)
The titled compounds of Examples 54 to 64 were prepared, in accordance with the same procedures as in Example 2, using 7-(2-chlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 53; and, allyl bromide, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, 4-methylbenzyl bromide, 4-fluorobenzyl bromide, benzyl bromide, 4-bromo-2-methyl-2-butene, 1-iodopropane, iodomethane, iodoethane, or 3-methoxybenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.81-7.73 (m, 2H), 7.35-7.26 (m, 2H), 6.95 (m, 1H), 6.12-6.03 (m, 3H), 5.32 (m, 2H), 5.16 (d, 1H), 4.31 (d, 1H), 2.57 (s, 3H), 2.37 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.26 (m, 2H), 6.92 (t, 1H), 6.28 (s, 2H), 4.90 (m, 2H), 3.64 (m, 2H), 3.21 (s, 3H), 2.55 (s, 3H), 2.32 (s, 3H); (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (t, 1H), 7.79 (m, 1H), 7.70 (m, 1H), 7.26 (m, 2H), 6.92 (t, 1H), 6.18 (s, 2H), 4.65 (m, 2H), 2.57 (s, 3H), 2.33 (s, 3H), 1.07 (m, 1H), 0.62 (m, 2H), 0.24 (m, 2H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.76-7.62 (m, 2H), 7.33-6.92 (m, 5H), 6.94 (m, 1H), 6.56 (m, 2H), 5.88 (s, 2H), 5.71 (s, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.79-7.68 (m, 2H), 7.26 (m, 1H), 6.99 (m, 4H), 6.68 (m, 2H), 5.93 (s, 2H), 5.75 (s, 2H), 2.54 (s, 3H), 2.39 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.78 (m, 1H), 7.66 (m, 1H), 7.26 (m, 5H), 6.95 (m, 1H), 6.69 (m, 2H), 5.72 (s, 2H), 5.30 (s, 2H), 2.54 (s, 3H), 2.40 (s, 3H); (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.77 (m, 1H), 7.69 (m, 1H), 7.26 (m, 2H), 6.93 (t, 1H), 6.09 (s, 2H), 5.30 (m, 2H), 4.95 (s, 1H), 2.53 (s, 3H), 2.32 (s, 3H), 1.72-1.70 (d, 6H); (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.73 (m, 2H), 7.26 (m, 2H), 6.95 (m, 1H), 6.09 (s, 2H), 4.59 (m, 2H), 2.55 (s, 3H), 2.32 (s, 3H), 1.75 (m, 2H), 0.95 (t, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (t, 1H), 7.75 (d, 1H), 7.70 (d, 1H), 7.35 (m, 2H), 6.97 (t, 1H), 6.16 (s, 2H), 4.19 (s, 3H), 2.55 (s, 3H), 2.32 (s, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (t, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.35 (m, 2H), 6.97 (t, 1H), 6.12 (s, 2H), 4.71 (m, 2H), 2.57 (s, 3H), 2.32 (s, 3H), 1.40 (t, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.78-7.63 (m, 2H), 7.26 (m, 3H), 6.97-6.79 (m, 2H), 6.24 (m, 2H), 5.90 (s, 2H), 5.72 (s, 2H), 3.70 (s, 3H), 2.54 (s, 3H), 2.32 (s, 3H); (Yield: 66%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-dimethylphenol, the titled compound was obtained as yellow solid. (Yield: 78%)
1H-NMR(400 MHz, CDCl3) δ 8.82 (d, 1H), 8.27 (d, 1H), 7.49 (m, 1H), 6.92 (m, 2H), 6.74 (d, 1H), 5.52 (s, 2H), 2.24 (s, 3H), 2.14 (s, 3H)
In accordance with the same procedures as in Example 1, except for using 2-(2,4-dimethylphenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.74 (brs, 1H), 8.16 (d, 1H), 7.33 (d, 1H), 6.95 (m, 3H), 5.49 (s, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H)
The titled compounds of Examples 66 to 77 were prepared, in accordance with the same procedures as in Example 2, using 2,3-dimethyl-7-(2,4-dimethylphenoxymethyl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 65; and, allyl bromide, benzyl bromide, 3-methoxybenzyl bromide, (bromomethyl)cyclopropane, 4-bromo-2-methyl-2-butene, 2-bromoethyl methyl ether, 1-iodopropane, 2-fluorobenzyl chloride, iodomethane, iodoethane, 4-methylbenzyl chloride, or 4-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.24 (m, 1H), 7.77 (m, 1H), 7.26 (m, 1H), 7.03 (m, 1H), 6.93 (m, 2H), 6.03-5.82 (m, 4H), 5.24-5.10 (m, 2H), 4.34 (m, 1H), 2.54 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H); (Yield: 25%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.78 (m, 1H), 7.26 (m, 2H), 7.15 (m, 1H), 6.97 (m, 3H), 6.60 (m, 2H), 5.74 (s, 2H), 5.56 (s, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (m, 1H) 7.78 (m, 1H), 7.26 (m, 2H), 6.97 (m, 2H), 6.80 (m, 1H), 6.14-6.08 (m, 2H), 5.71 (s, 2H), 5.56 (s, 2H), 3.68 (s, 3H), 2.56 (s, 3H), 2.49 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.70 (m, 1H), 7.17 (m, 1H), 7.02 (m, 1H), 6.91 (m, 1H), 6.00 (s, 2H), 4.47 (m, 2H), 2.58 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H), 2.07 (s, 3H), 1.03 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.70 (m, 1H), 7.18 (m, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 5.90 (s, 2H), 5.11 (m, 2H), 4.85 (m, 1H), 2.52 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H), 1.69 (s, 3H), 1.63 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.65 (m, 1H), 7.23 (m, 1H), 7.01 (m, 1H), 6.90 (m, 1H), 6.00 (s, 2H), 4.73 (m, 2H), 3.58 (m, 2H), 3.18 (s, 3H), 2.58 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.05 (s, 3H); (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.72 (m, 1H), 7.13 (d, 1H), 7.02 (m, 1H), 6.92 (s, 1H), 5.88 (s, 2H), 4.36 (t, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.73 (m, 2H), 0.86 (t, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.78 (m, 1H), 7.13-6.91 (m, 6H), 6.20 (m, 1H), 5.85 (s, 2H), 5.64 (s, 2H), 2.47 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.70 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 5.94 (s, 2H), 4.03 (s, 3H), 2.53 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H); (Yield: 91%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.70 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 6.92 (s, 1H), 5.91 (s, 2H), 4.50 (m, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.35 (t, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.76 (m, 1H), 7.26 (m, 2H), 7.07-6.93 (m, 4H), 6.48 (m, 1H), 5.68 (s, 2H), 5.56 (s, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (m, 1H), 7.80 (m, 1H), 6.97-6.93 (m, 5H), 6.57 (m, 2H), 5.70 (s, 2H), 5.58 (s, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H); (Yield: 86%)
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 3,4-dichlorophenol, the titled compound was obtained as yellow solid. (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.86 (d, 1H), 8.36 (d, 1H), 7.53 (d, 1H), 7.34 (d, 1H), 7.07 (s, 1H), 6.82 (d, 1H), 5.56 (s, 2H)
In accordance with the same procedures as in Example 1, except for using 2-(3,4-dichlorophenoxymethyl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.48 (brs, 1H), 8.17 (d, 1H), 7.32 (m, 1H), 7.17 (s, 1H), 6.91 (m, 2H), 5.49 (s, 2H), 2.47 (s, 3H), 2.21 (s, 3H)
In accordance with the same procedures as in Example 2, except for using 7-(3,4-dichlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 2 and 2-bromoethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.69 (m, 1H), 7.34 (m, 1H), 7.19 (m, 2H), 6.15 (s, 2H), 4.68 (s, 2H), 3.63 (s, 2H), 3.21 (s, 3H) 2.55 (s, 3H), 2.33 (s, 3H)
The titled compounds of Examples 79 to 87 were prepared, in accordance with the same procedures as in Example 2, using 7-(3,4-dichlorophenoxymethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 2 of Example 78; and, iodoethane, allyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl bromide, benzyl bromide, 4-bromo-2-methyl-2-butene, (bromomethyl)cyclopropane, 1-iodopropane, or iodomethane.
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.73 (m, 1H), 7.38 (m, 2H), 7.20 (m, 1H), 6.09 (m, 2H), 4.50 (m, 2H), 2.57 (s, 3H), 2.34 (s, 3H), 1.33 (m, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.77 (m, 1H), 7.36 (m, 2H), 7.17 (m, 1H), 6.09-5.92 (m, 2H), 5.22 (m, 2H), 5.08 (m, 2H), 4.37 (d, 1H), 2.51 (s, 3H), 2.36 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.79 (m, 1H), 7.40 (m, 2H), 7.16 (m, 3H), 6.88 (m, 2H), 6.53 (m, 2H), 5.64 (m, 2H), 2.59 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.80 (m, 1H), 7.03 (m, 5H), 6.66 (m, 2H), 5.70 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H); (Yield: 88%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.81 (m, 1H), 7.30 (m, 4H), 7.04 (m, 1H), 6.91 (s, 1H), 6.64 (m, 2H), 5.69 (m, 4H), 2.51 (s, 3H), 2.40 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.73 (m, 1H), 7.41 (m, 2H), 7.16 (s, 1H), 6.01 (s, 2H), 5.07 (s, 2H), 4.96 (m, 1H), 2.60 (s, 3H), 2.37 (s, 3H), 1.77 (s, 3H), 1.74 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.72 (m, 1H), 7.26 (m, 1H), 7.05 (m, 2H), 6.05 (s, 2H), 4.42 (s, 2H), 2.57 (s, 3H), 2.34 (s, 3H), 0.83 (m, 1H), 0.64 (m, 2H), 0.26 (m, 2H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.72 (m, 1H), 7.39 (m, 1H), 7.19 (m, 2H), 5.99 (s, 2H), 4.34 (s, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.76 (m, 2H), 0.95 (m, 3H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.70 (m, 1H), 7.36 (m, 1H), 7.22 (m, 2H), 6.07 (s, 2H), 4.08 (s, 3H), 2.55 (s, 3H), 2.33 (s, 3H); (Yield: 75%)
In accordance with the same procedures as in Example 1, except for using (4-fluorophenyl)-(3-nitropyridin-2-ylmethyl)-carbamic acid tert-butyl ester prepared in Preparation 2, the titled compound was obtained as a white solid. (Yield: 33%)
1H-NMR(400 MHz, CDCl3) δ 9.99 (brs, NH), 8.40 (d, 1H), 7.27 (d, 1H), 6.85 (m, 2H), 6.76 (m, 2H), 5.09 (s, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.37 (s, 9H)
Allyl bromide (43 μl, 0.493 mmol) was added to a solution of (2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester (150 mg, 0.328 mmol) prepared in Step 1 and sodium hydride (60%, 25 mg, 0.616 mmol) in anhydrous N,N-dimethylformamide (5 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (15 ml), washed with water (20 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/6, v/v). The resulting yellow oil was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered. The resulting solid was dried under reduced pressure to give 7.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 3H) 7.78 (m, 1H), 7.19 (m, 2H), 6.10 (m, 1H), 5.50 (s, 2H), 5.29 (d, 1H), 4.96 (s, 2H), 4.58 (d, 1H), 2.51 (s, 3H), 2.35 (s, 3H)
The titled compounds of Examples 89 to 107 were prepared, in accordance with the same procedures as in Step 2 of Example 88, using (2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester prepared in Step 1 of Example 88; and, benzyl bromide, (bromomethyl)cyclopropane, 3-fluorobenzyl bromide, 3-methoxybenzyl bromide, 4-chlorobenzyl bromide, 2-bromoethyl methyl ether, 2-methylbenzyl chloride, 4-tert-butylbenzyl chloride, 2-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 2,5-dimethylbenzyl chloride, iodoethane, 1-iodopropane, 3-methylbenzyl chloride, propargyl bromide, 4-trifluoromethylbenzyl bromide, iodomethane, 2-bromoethyl ethyl ether, or 4-methylbenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.72 (m, 1H), 7.36 (m, 4H), 6.81 (m, 5H), 5.82 (s, 2H), 4.81 (s, 2H), 2.56 (s, 3H), 2.39 (s, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.68 (d, 1H), 7.36 (m, 2H), 7.00 (t, 2H), 5.21 (s, 2H), 4.55 (m, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 1.20 (m, 1H), 0.69 (m, 2H), 0.32 (m, 2H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (d, 1H), 7.70 (d, 1H), 7.35 (q, 2H), 7.06 (t, 2H), 6.76 (t, 2H), 6.64 (d, 1H), 6.47 (m, 3H), 5.74 (s, 2H), 4.82 (s, 2H), 2.51 (s, 3H), 2.39 (s, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H), 7.66 (d, 1H), 7.31 (m, 1H), 6.88 (d, 1H), 6.71 (t, 2H), 6.47 (m, 2H), 6.32 (m, 2H), 5.69 (s, 2H), 4.84 (s, 2H), 3.76 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 7.68 (d, 1H), 7.33 (d, 2H), 6.74 (m, 4H), 6.42 (m, 2H), 5.69 (s, 2H), 4.83 (s, 2H), 2.49 (s, 3H), 2.38 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.72 (m, 3H), 7.09 (m, 2H), 5.40 (m, 2H), 4.88 (m, 2H), 3.76 (m, 2H), 3.24 (s, 3H), 2.57 (s, 3H), 2.24 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.72 (m, 2H), 6.45 (m, 2H), 6.05 (m, 1H), 5.62 (m, 2H), 4.73 (m, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H), 7.67 (d, 1H), 7.37 (d, 2H), 6.73 (m, 4H), 6.46 (m, 2H), 5.68 (s, 2H), 4.86 (s, 2H), 2.53 (s, 3H), 2.38 (s, 3H), 1.30 (s, 9H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (d, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.35 (m, 1H), 7.20 (m, 1H), 6.70 (t, 2H), 6.32 (m, 2H), 6.10 (d, 1H), 5.72 (s, 2H), 4.75 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.79 (m, 1H), 7.43 (d, 1H), 7.35 (m, 1H), 7.01 (m, 2H), 6.90 (s, 1H), 6.72 (m, 1H), 5.92 (s, 2H), 4.74 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (d, 1H), 7.70 (d, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 6.73 (t, 2H), 6.69 (m, 2H), 5.86 (s, 1H), 5.57 (s, 2H), 4.74 (s, 2H), 2.57 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (d, 1H), 7.82 (m, 2H), 7.71 (d, 1H), 7.10 (t, 2H), 5.11 (s, 2H), 4.67 (q, 2H), 2.56 (s, 3H), 2.32 (s, 3H), 1.48 (t, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (d, 1H), 7.63 (d, 1H), 7.20 (m, 2H), 6.94 (t, 2H), 5.09 (s, 2H), 4.41 (t, 2H), 2.55 (s, 3H), 2.31 (s, 3H), 1.85 (q, 2H), 1.01 (t, 3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H), 7.66 (d, 1H), 7.16 (d, 1H), 6.69 (t, 3H), 6.54 (d, 1H), 6.39 (m, 2H), 5.67 (s, 2H), 4.86 (s, 2H), 2.52 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.61 (m, 1H), 7.20 (m, 1H), 6.83 (m, 4H), 5.57 (m, 2H), 5.25 (m, 2H), 2.54 (s, 3H), 2.31 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (d, 1H), 7.77 (d, 1H), 7.60 (d, 2H), 6.93 (d, 2H), 6.85 (m, 3H), 5.90 (s, 2H), 4.78 (s, 2H), 2.51 (s, 3H), 2.40 (s, 3H); (Yield: 88%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (d, 1H), 7.68 (d, 1H), 7.46 (m, 2H), 7.01 (t, 2H), 5.19 (s, 2H), 4.22 (s, 3H), 2.55 (s, 3H), 2.32 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (d, 1H), 7.67 (d, 1H), 6.97 (t, 2H), 5.27 (s, 2H), 4.57 (m, 2H), 3.74 (m, 2H), 3.40 (q, 2H), 2.55 (s, 3H), 2.32 (s, 3H), 1.03 (t, 3H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.65 (d, 1H), 7.17 (d, 2H), 6.69 (m, 4H), 6.28 (m, 2H), 5.64 (s, 2H), 4.88 (s, 2H), 2.52 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H); (Yield: 45%)
The compound prepared in Example 88 was treated with a saturated sodium bicarbonate solution to obtain N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-4-fluorophenylamine. A solution of N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-4-fluorophenylamine (40 mg, 0.13 mmol) and sodium hydride (60%, 7.8 mg, 0.19 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (115 ml), washed with water (20 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting yellow oil was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered. The resulting solid was dried under reduced pressure to give 3.3 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.11 (d, 1H), 8.01 (m, 2H), 7.75 (d, 1H), 7.44 (d, 1H), 7.12 (t, 2H), 6.33 (m, 1H), 5.31 (d, 1H), 5.09 (d, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 1.59 (d, 3H)
In accordance with the same procedures as in Example 42, except for using (2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester prepared in Step 1 of Example 88, the titled compound was obtained as a white solid. (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.93 (d, 1H), 7.58 (d, 1H), 7.19 (m, 2H), 6.87 (t, 2H), 5.23 (s, 2H), 2.60 (s, 3H), 2.27 (s, 3H)
In accordance with the same procedures as in Step 1 of Preparation 2, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and (4-fluorophenyl)-methylamine, the titled compound was obtained as yellow solid. (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.75 (d, 1H) 8.12 (d, 1H), 7.38 (m, 1H), 6.89 (m, 2H), 6.63 (m, 2H), 4.93 (s, 2H), 3.02 (s, 3H)
In accordance with the same procedures as in Example 1, except for using (4-fluorophenyl)-methyl-(3-nitropyridin-2-ylmethyl)-amine prepared in Step 1, the titled compound was obtained as brown oil. (Yield: 27%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (d, 1H), 7.31 (d, 1H), 7.00 (m, 5H), 4.77 (s, 2H), 2.91 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H)
The titled compounds of Examples 111 to 134 were prepared, in accordance with the same procedures as in Example 2, using N-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethyl)-N-(4-fluorophenyl)-methylamine prepared in Example 110; and, benzyl bromide, (bromomethyl)cyclopropane, 4-chlorobenzyl bromide, 3-fluorobenzyl bromide, 2-fluorobenzyl bromide, 3-methoxybenzyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl bromide, 4-bromo-2-methyl-2-butene, 2-bromoethyl methyl ether, 2-chlorobenzyl bromide, 3,4-dichlorobenzyl bromide, iodoethane, 1-iodopropane, 4-methoxybenzyl chloride, 3-methylbenzyl chloride, propargyl bromide, allyl bromide, 3,4-dimethylbenzyl bromide, 2-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 2,5-dimethylbenzyl bromide, iodomethane, or 2-bromoethyl ethyl ether.
1H-NMR(400 MHz, CDCl3) δ 8.23 (m, 1H) 7.74 (d, 1H), 7.20 (m, 1H), 6.94 (t, 2H), 6.86 (m, 2H), 6.42 (d, 2H), 5.74 (s, 2H), 4.79 (s, 2H), 2.80 (s 3H), 2.44 (s, 3H), 2.39 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (t, 1H) 7.69 (d, 1H), 7.05 (m, 4H), 5.17 (s, 2H), 4.43 (d, 2H), 2.84 (s, 3H), 2.52 (s, 3H), 2.32 (s, 3H), 0.95 (m, 1H), 0.58 (q, 2H), 0.12 (q, 2H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (m, 1H), 7.77 (d, 1H), 7.19 (d, 2H), 6.97 (t, 2H), 6.35 (m, 2H), 6.33 (d, 2H), 5.69 (s, 2H), 4.79 (s, 2H), 2.77 (s, 3H), 2.41 (s, 3H), 2.38 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (m, 1H), 7.76 (d, 1H), 7.20 (m, 1H), 6.96 (m, 3H), 6.84 (m, 2H), 6.22 (d, 1H), 6.08 (d, 1H), 5.73 (s, 2H), 4.80 (s, 2H), 2.79 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (m, 1H), 7.75 (d, 1H), 7.07-6.87 (m, 7H), 6.01 (t, 1H), 5.82 (s, 2H), 4.83 (s, 2H), 2.81 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (m, 1H) 7.73 (d, 1H), 7.15 (t, 1H), 6.94 (m, 2H), 6.81 (m, 3H), 5.96 (m, 2H), 5.69 (s, 2H), 4.77 (s, 2H), 3.68 (s, 3H), 2.78 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (m, 1H), 7.73 (d, 1H), 7.03 (d, 2H), 6.96 (t, 2H), 6.85 (m, 2H), 6.29 (d, 2H), 5.69 (s, 2H), 4.78 (s, 2H), 2.80 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H), 2.17 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (m, 1H), 7.77 (d, 1H), 6.95 (m, 4H), 6.81 (m, 2H), 6.38 (t, 2H), 5.69 (s, 2H), 4.79 (s, 2H), 2.93 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.66 (d, 1H), 6.99 (m, 4H), 5.06-5.03 (m, 4H), 4.87 (m, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.04 (s, 3H), 1.66 (s, 3H), 1.41 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.66 (m, 1H), 6.98 (m, 4H), 5.23 (s, 2H), 4.66 (m, 2H), 3.53 (m, 2H), 3.21 (s, 3H), 2.81 (s, 3H), 2.51 (s, 3H), 2.32 (s, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (m, 1H), 7.77 (d, 1H), 7.37 (d, 1H), 7.10 (t, 1H), 6.91-6.80 (m, 4H), 5.84 (d, 1H), 5.78 (s, 2H), 4.76 (s, 2H), 2.78 (s, 3H), 2.39 (s, 6H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (m, 1H), 7.77 (d, 1H), 7.30 (m, 1H), 7.00 (t, 2H), 6.85 (m, 2H), 6.49 (s, 1H), 6.20 (d, 1H), 5.68 (s, 2H), 4.82 (s, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (m, 1H), 7.65 (d, 1H), 7.03 (m, 4H), 5.10 (s, 2H), 4.44 (q, 2H), 2.86 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H), 1.26 (t, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (t, 1H), 7.69 (d, 1H), 7.00 (m, 4H), 5.07 (s, 2H), 4.31 (q, 2H), 2.85 (s, 3H), 2.50 (s, 3H), 2.31 (s, 3H), 1.59 (m, 2H), 0.77 (t, 3H); (Yield: 97%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (m, 1H), 7.72 (d, 1H), 6.92 (m, 3H), 6.77 (m, 3H), 6.33 (d, 2H), 5.63 (s, 2H), 4.77 (s, 2H), 3.78 (s, 3H), 2.84 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H); (Yield: 97%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (d, 1H), 7.76 (d, 1H), 7.07 (q, 2H), 6.96 (t, 2H), 6.84 (m, 2H), 6.22 (s, 1H), 6.14 (d, 1H), 5.69 (s, 2H), 4.77 (s, 2H), 2.79 (s, 3H), 2.48 (s, 3H), 2.44 (s, 3H), 2.18 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (d, 1H), 7.68 (d, 1H), 7.35 (t, 1H), 7.00 (m, 4H), 5.40 (d, 2H), 5.13 (s, 2H), 2.90 (s, 3H), 2.57 (s, 3H), 2.32 (s, 3H); (Yield: 37%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (m, 1H), 7.71 (d, 1H), 7.01 (d, 4H), 5.80 (m, 1H), 5.16 (m, 3H), 5.00 (s, 2H), 4.25 (d, 1H), 2.83 (s, 3H), 2.45 (s, 3H), 2.34 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (m, 1H), 7.73 (d, 1H), 6.97-6.87 (m, 5H), 6.19 (s, 1H), 6.07 (d, 1H), 5.65 (s, 2H), 4.78 (s, 2H), 2.81 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (m, 1H), 7.77 (d, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 6.91 (m, 1H), 6.87 (m, 2H), 6.67 (m, 2H), 5.71 (d, 1H), 5.54 (s, 2H), 4.71 (s, 2H), 2.75 (s, 3H), 2.40 (s, 3H), 2.37 (s, 3H), 1.80 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (m, 1H), 7.74 (d, 1H), 7.22 (m, 2H), 6.98 (m, 4H), 6.33 (d, 2H), 5.71 (s, 2H), 2.85 (s, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 1.31 (s, 9H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (m, 1H), 7.80 (d, 1H), 6.98 (m, 6H), 5.60 (m, 2H), 5.48 (s, 1H), 4.80 (s, 2H), 2.90 (s, 3H), 2.41 (s, 6H), 2.04 (s, 3H), 1.85 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.65 (d, 1H), 7.05 (m, 4H), 5.12 (s, 2H), 4.00 (s, 3H), 2.84 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.04 (d, 1H), 7.60 (d, 1H), 6.97 (m, 4H), 5.30 (m, 4H), 3.48 (m, 2H), 3.01 (s, 3H), 2.53 (s, 3H), 2.28 (s, 3H), 2.10 (s, 2H), 1.28 (t, 3H); (Yield: 88%)
A solution of 1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-carbaldehyde (1.214 g, 5.67 mmol) prepared in Preparation 3 and 4-fluoroaniline (0.54 ml, 5.67 mmol) in ethanol (10 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give 2,3 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
Methylmagnesium bromide (3.0M in ethyl ether solution, 37 μl, 1.12 mmol) was added at 0° C. to a solution of N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethylene)-4-fluorophenylamine (30 mg, 0.112 mmol) prepared in Step 1 in anhydrous ethyl ether (5 ml). The reaction mixture was stirred for 2 hours at room temperature and then a saturated ammonium chloride solution (5 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting yellow oil was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered. The resulting solid was dried under reduced pressure to give 1.4 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H) 7.57 (d, 1H), 6.81-6.71 (m, 4H), 6.23 (m, 1H), 5.45 (d, 1H), 5.36 (m, 1H), 5.16 (q, 2H), 4.99 (m, 2H), 4.70 (δ, 1H), 2.51 (s, 3H), 2.32 (s, 3H), 1.91 (d, 3H)
In accordance with the same procedures as in Step 2 of Example 135, except for using N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethylene)-4-fluorophenylamine prepared in Step 1 of Example 135 and benzylmagnesium chloride, the titled compound was obtained as a white solid. (Yield: 33%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.60 (d, 1H), 7.24-7.17 (m, 5H), 6.75 (brs, 1H), 6.72-6.68 (m, 4H), 6.08 (m, 1H), 5.41 (m, 2H), 4.71 (s, 2H), 4.61 (d, 1H), 3.78 (m, 1H), 3.41 (m, 1H), 2.42 (s, 3H), 2.31 (s, 3H)
Acetic acid (0.5 ml) and potassium cyanide (10.2 mg, 0.157 mmol) was added at 0° C. to a solution of N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethylene)-4-fluorophenylamine (35 mg, 0.131 mmol) prepared in Step 1 of Example 135 in methanol (10 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was basified with a saturated sodium bicarbonate solution and then extracted with ethyl acetate (15 ml). The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v). The resulting yellow oil was dissolved in ethyl acetate and then saturated with hydrochloric acid gas to give 7.1 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3/DMSO-d6) δ 8.36 (d, 1H) 7.80 (d, 1H), 7.80-7.35 (m, 5H), 5.89 (m, 1H), 5.04 (m, 3H), 4.43 (d, 1H), 2.49 (s, 3H), 2.28 (s, 3H)
2-[N-(4-fluorobenzyl)-N-methyl]amino-3-nitropyridine (8.26 g, 31.6 mmol) prepared in Preparation 4 was dissolved in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere. 1-Methyl-1-propenylmagnesium bromide (0.5M in tetrahydrofuran solution, 190 ml, 94.8 mmol) was slowly added at −78° C. to the solution, which was then stirred for 2 hours at −20° C. 20% ammonium chloride solution (60 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 3.94 g of the titled compound as yellow oil. (Yield: 44%)
1H-NMR (400 MHz, CDCl3) δ 10.74 (brs, 1H), 7.61 (d, 1H), 7.16 (m, 2H), 6.91 (m, 3H), 5.00 (s, 2H), 3.41 (s, 3H), 2.47 (s, 3H), 2.15 (s, 3H)
In accordance with the same procedures as in Example 42, except for using 7-[N-(4-fluorobenzyl)-N-methyl]amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 138, the titled compound was obtained as a white solid. (Yield: 87%)
1H-NMR (400 MHz, CDCl3) δ 10.74 (brs, 1H), 7.61 (d, 1H), 7.16 (m, 2H), 6.91 (m, 3H), 5.00 (s, 2H), 3.41 (s, 3H), 2.47 (s, 3H), 2.15 (s, 3H); (Yield: 95%)
Potassium tert-butoxide (29 mg, 0.260 mmol) was added to a solution of 7-[N-(4-fluorobenzyl)-N-methyl]amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (49 mg, 0.173 mmol) prepared in Example 138 and 18-crown-6 (4.6 mg, 0.0171 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 1 hour at room temperature and allyl iodide (23.9 μl, 0.260 mmol) was added thereto. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting residue was dissolved in ethyl acetate and then saturated with hydrochloric acid gas to give 8.4 mg of the titled compound as a white solid. (Yield: 15%).
1H-NMR (400 MHz, CDCl3) δ 8.08 (d, 1H), 7.38 (m, 3H), 6.97 (t, 2H), 5.87 (m, 1H), 5.17 (m, 3H), 4.72 (brs, 2H), 4.52 (d, 1H), 2.97 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H)
The titled compounds of Examples 141 to 174 were prepared, in accordance with the same procedures as in Example 140, using 7-[N-(4-fluorobenzyl)-N-methyl]amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 138; and, benzyl bromide, 4-bromo-2-methyl-2-butene, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, 4-chlorobenzyl chloride, 1,3-dichlorobutane, 2-fluorobenzyl chloride, iodoethane, 1-iodo-2-methylpropane, 1-iodopropane, 3-methoxybenzyl chloride, 4-methylbenzyl chloride, propargyl bromide, 2-bromoethyl ethyl ether, 4-fluorobenzyl chloride, 4-methoxybenzyl chloride, 4-bromo-1-butene, 2-bromomethyl-1,3-dioxolane, 3-fluorobenzyl chloride, 3-methylbenzyl chloride, 1-chloro-3-methylbutane, 4-tert-butylbenzyl chloride, bromoacetonitrile, 1-bromomethoxy-2-methoxyethane, 4-trifluoromethylbenzyl chloride, iodomethane, 2-bromoethyl-1, 3-dioxane, 2-chlorobenzyl chloride, bromomethyl methyl ether, 2-chloroethanol, 5-chloro-1-pentyne, 2-(chloromethyl)tetrahydro-2H-pyran, bromomethyl acetate, or 4-chloromethyl-2-methylthiazole.
1H-NMR (400 MHz, CDCl3) δ 8.12 (d, 1H), 7.47 (d, 1H), 7.30 (m, 2H), 7.10 (m, 2H), 6.95 (m, 1H), 6.79 (t, 2H), 6.62 (d, 2H), 5.82 (s, 2H), 4.71 (s, 2H), 2.91 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H); (Yield: 25%)
1H-NMR (400 MHz, CDCl3) δ 8.06 (t, 1H), 7.38 (m, 3H), 6.96 (t, 2H), 5.16 (d, 2H), 4.88 (t, 1H), 4.79 (s, 2H), 3.04 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.75 (s, 3H), 1.72 (s, 3H); (Yield: 34%)
1H-NMR (400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.39 (brs, 3H), 7.00 (brs, 2H), 4.67 (brs, 2H), 4.66 (brs, 2H), 3.48 (m, 2H), 3.20 (brs, 3H), 3.02 (brs, 3H), 2.50 (s, 3H), 2.27 (s, 3H); (Yield: 41%)
1H-NMR (400 MHz, CDCl3) δ 8.13 (t, 1H), 7.37 (m, 3H), 7.02 (t, 2H), 4.75 (s, 2H), 4.34 (d, 2H), 3.01 (s, 3H), 2.51 (s, 3H), 2.28 (s, 3H), 0.95 (m, 1H), 0.53 (q, 2H), 0.27 (q, 2H); (Yield: 48%)
1H-NMR (400 MHz, CDCl3) δ 8.14 (t, 1H), 7.48 (d, 1H), 7.17 (t, 2H), 7.12 (m, 2H), 6.81 (t, 2H), 6.56 (d, 2H), 5.80 (s, 2H), 4.72 (s, 2H), 2.93 (s, 3H), 2.29 (s, 6H); (Yield: 24%)
1H-NMR (400 MHz, CDCl3/MeOH-d4) δ 8.01 (t, 1H), 7.44 (d, 1H), 7.33 (m, 2H), 6.99 (t, 2H), 5.09 (brs, 2H), 4.67 (s, 2H), 3.00 (s, 3H), 2.44 (s, 3H), 2.26 (m, 4H), 1.78 (m, 1H), 1.65 (d, 3H), 1.51 (m, 1H); (Yield: 19%)
1H-NMR (400 MHz, CDCl3) δ 8.14 (t, 1H) 7.49 (d, 1H), 7.30 (m, 1H), 7.13 (m, 3H), 6.96 (t, 1H), 6.81 (t, 2H), 5.97 (t, 1H), 5.86 (s, 2H), 4.71 (s, 2H), 2.90 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H); (Yield: 46%)
1H-NMR (400 MHz, CDCl3) δ 8.10 (t, 1H), 7.41 (m, 3H), 7.00 (m, 2H), 4.79 (s, 2H), 4.54 (q, 2H), 3.05 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H), 1.24 (t, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (t, 1H), 7.39 (d, 1H), 7.32 (m, 2H), 7.03 (t, 2H), 4.73 (s, 2H), 4.18 (d, 2H), 3.02 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H), 1.93 (m, 1H), 0.70 (d, 6H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3/MeOH-d4) δ 8.06 (d, 1H), 7.43 (m, 1H), 7.34 (m, 2H), 7.03 (m, 2H), 4.70 (s, 2H), 4.36 (t, 2H), 3.03 (s, 3H), 2.48 (s, 3H), 2.27 (s, 3H), 1.59 (q, 2H), 0.87 (t, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (t, 1H), 7.47 (d, 1H), 7.22 (t, 1H), 7.11 (m, 2H), 6.80 (m 3H), 6.19 (d, 1H), 6.15 (s, 1H), 5.79 (s, 2H), 4.71 (s, 2H), 3.73 (s, 3H), 2.92 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.46 (d, 1H), 7.10 (m, 4H), 6.80 (t, 2H), 6.52 (d, 2H), 5.78 (s, 2H), 4.71 (s, 2H), 2.91 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (d, 1H), 7.45 (m, 3H), 6.98 (m, 2H), 5.37 (s, 2H), 4.83 (s, 2H), 3.10 (s, 3H), 2.58 (s, 3H), 2.43 (s, 1H), 2.27 (s, 3H); (Yield: 16%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (brs, 1H), 7.41 (m, 3H), 7.00 (t, 2H), 4.77 (s, 2H), 4.66 (brs, 2H), 3.49 (brs, 2H), 3.29 (q, 2H), 3.01 (s, 3H), 2.50 (s, 3H), 2.26 (s, 3H), 1.04 (t, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 7.48 (d, 1H), 7.12 (m, 2H), 6.99 (t, 2H), 6.82 (t, 2H), 6.61 (m, 2H), 5.80 (s, 2H), 4.71 (s, 2H), 2.92 (s, 3H), 2.29 (s, 6H); (Yield: 25%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.47 (brs, 1H), 7.15 (brs, 2H), 6.81 (brs, 4H), 6.57 (brs, 2H), 5.78 (brs, 2H), 4.73 (brs, 2H), 3.78 (s, 3H), 2.96 (brs, 3H), 2.30 (brs, 6H); (Yield: 38%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.38 (m, 3H), 6.99 (t, 2H), 5.61 (m, 1H), 5.04 (m, 2H), 4.78 (s, 2H), 4.51 (t, 2H), 3.04 (s, 3H), 2.48 (s, 3H), 2.29 (m, 2H), 2.26 (s, 3H); (Yield: 33%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.44 (m, 3H), 6.70 (t, 2H), 4.94 (brs, 1H), 4.76 (brs, 2H), 4.67 (brs, 2H), 3.75 (brs, 2H), 3.47 (brs, 2H), 2.97 (s, 3H), 2.51 (s, 3H), 2.27 (s, 3H); (Yield: 39%)
1H-NMR (400 MHz, CDCl3) δ 8.15 (m, 1H), 7.49 (d, 1H), 7.28 (m, 1H), 7.11 (m, 2H), 7.01 (m, 1H), 6.81 (m, 2H), 6.40 (d, 1H), 6.32 (d, 1H), 5.82 (s, 2H), 4.72 (s, 2H), 2.92 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (brs, 1H), 7.47 (d, 1H), 7.13 (m, 4H), 6.79 (t, 2H), 6.50 (s, 1H), 6.34 (d, 1H), 5.79 (s, 2H), 4.70 (s, 2H), 2.91 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3/MeOH-d4) δ 8.06 (d, 1H), 7.41 (d, 1H), 7.33 (m, 2H), 7.00 (t, 2H), 4.69 (s, 2H), 4.42 (t, 2H), 3.06 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H), 1.61 (m, 1H), 1.40 (q, 2H), 0.97 (s, 3H), 0.95 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (t, 1H), 7.47 (d, 1H), 7.29 (m, 2H), 7.06 (m, 2H), 6.77 (t, 2H), 6.53 (d, 2H), 5.77 (s, 2H), 4.69 (s, 2H), 2.92 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H), 1.29 (s, 9H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (d, 1H), 7.50 (d, 1H), 7.41 (m, 2H), 6.99 (t, 2H), 5.60 (s, 2H), 4.83 (s, 2H), 3.12 (s, 3H), 2.59 (s, 3H), 2.29 (s, 3H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.38 (brs, 3H), 6.99 (brs, 2H), 5.83 (s, 2H), 4.80 (s, 2H), 3.48 (m, 4H), 3.32 (s, 3H), 3.09 (s, 3H), 2.53 (s, 3H), 2.26 (s, 3H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.54 (m, 3H), 7.07 (m, 2H), 6.77 (m, 4H), 5.90 (s, 2H), 4.71 (s, 2H), 2.94 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.02 (brs, 1H), 7.35 (m, 3H), 6.99 (t, 2H), 4.82 (s, 2H), 4.04 (s, 3H), 3.07 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (brs, 1H), 7.48 (brs, 3H), 7.00 (brs, 2H), 4.79 (brs, 2H), 4.62 (brs, 2H), 4.46 (brs, 1H), 4.09 (brs, 2H), 3.71 (brs, 2H), 3.08 (brs, 3H), 2.49 (brs, 3H), 2.28 (brs, 3H), 2.06 (brs, 2H), 1.84 (brs, 2H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.49 (t, 2H), 7.29 (m, 1H), 7.08 (m, 3H), 6.80 (t, 2H), 5.84-5.79 (m, 3H), 4.69 (s, 2H), 2.85 (s, 3H), 2.33 (s, 6H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.38 (m, 3H), 6.99 (m, 2H), 5.70 (s, 2H), 4.80 (s, 2H), 3.24 (s, 3H), 3.07 (s, 3H), 2.52 (s, 3H), 2.26 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.95 (m, 1H), 7.33 (m, 3H), 6.97 (t, 2H), 4.61 (brs, 4H), 3.78 (brs, 2H), 3.01 (brs, 1H), 2.91 (s, 3H), 2.53 (s, 3H), 2.25 (s, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.38 (m, 3H), 7.00 (t, 2H), 4.78 (s, 2H), 4.54 (m, 2H), 3.08 (s, 3H), 2.49 (s, 3H), 2.26 (s, 3H), 2.18 (m, 2H), 2.05 (s, 1H), 1.75 (m, 2H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.41 (m, 3H), 7.00 (t, 2H), 4.74 (m, 2H), 4.42 (m, 2H), 3.82 (m, 1H), 3.35 (m, 1H), 3.12 (m, 1H), 2.99 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H), 1.50 (m, 2H), 1.39 (m, 2H), 1.25 (m, 1H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (brs, 1H), 7.46 (d, 1H), 7.35 (m, 2H), 6.97 (t, 2H), 5.36 (s, 2H), 4.75 (s, 2H), 3.78 (s, 3H), 2.99 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (brs, 1H), 7.46 (brs, 1H), 7.22 (brs, 2H), 6.87 (m, 2H), 6.10 (s, 1H), 5.87 (s, 2H), 4.75 (s, 2H), 2.99 (s, 3H), 2.71 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H); (Yield: 60%)
1-Methyl-1-propenylmagnesium bromide (0.5M in tetrahydrofuran solution, 318 ml, 159 mmol) was slowly added at −78° C. to a solution of 2-(N-benzyl-N-tert-butoxycarbonyl)amino-3-nitropyridine (17.5 g, 53.1 mmol) prepared in Preparation 5 in anhydrous tetrahydrofuran (100 ml). The reaction mixture was stirred for 1 hour at −78° C. An ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 7.5 g of the titled compound as yellow solid.
1H-NMR(400 MHz, CDCl3) δ 7.30 (m, 2H), 7.13 (m, 2H), 7.11 (m, 1H), 7.04 (d, 1H), 6.78 (d, 1H), 4.74 (s, 2H), 2.44 (s, 3H), 2.15 (s, 3H)
A solution of 7-(N-benzyl-N-tert-butoxycarbonyl)amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (37.0 mg) prepared in Step 1 in ethyl acetate (5 ml) was saturated with hydrochloric acid gas and then filtered to give 29.0 mg of the titled compound as a white solid. (Yield: 96%)
1H-NMR(400 MHz, CDCl3/MeOH-d4) δ 7.42 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 7.14 (d, 1H), 6.84 (d, 1H), 4.74 (s, 2H), 2.44 (s, 3H), 2.15 (s, 3H)
Potassium tert-butoxide (27.1 mg, 0.242 mmol) was added to a solution of 7-(N-benzyl-N-tert-butoxycarbonyl)amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (57 mg, 0.161 mmol) prepared in Step 1 of Example 175 and 18-crown-6 (4.3 mg, 0.016 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 30 minutes at room temperature. Allyl iodide (22.1 μl, 0.242 mmol) was added at the same temperature to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then purified with silica gel column chromatography (ethyl acetate/n-hexane=1/7, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a pale yellow solid. (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 7.78 (t, 1H), 7.43-7.33 (m, 5H), 6.97 (d, 1H), 5.98 (m, 1H), 5.83 (brs, 1H), 5.26 (d, 1H), 5.05 (d, 2H), 4.84 (d, 2H), 4.73 (d, 1H), 2.33 (s, 3H), 2.21 (s, 3H)
The titled compounds of Examples 177 to 197 were prepared, in accordance with the same procedures as in Example 176, using 7-(N-benzyl-N-tert-butoxycarbonyl)amino-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 175; and, 1-iodopropane, benzyl bromide, 1-bromomethyl-2-methoxyethane, 4-methylbenzyl chloride, 4-bromo-1-butene, 2-bromoethyl methyl ether, 1,3-dichlorobutane, 1-iodo-2-methylpropane, (bromomethyl)cyclopropane, 4-chlorobenzyl chloride, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, 4-tert-butylbenzyl chloride, iodoethane, 4-bromo-2-methyl-2-butene, 2-bromoethyl-1,3-dioxane, iodomethane, 2-fluorobenzyl chloride, 3-methylbenzyl chloride, 4-fluorobenzyl chloride, or 1-bromo-3-methylbutane.
1H-NMR(400 MHz, CDCl3) δ 7.69 (t, 1H), 7.50 (d, 1H), 7.37-7.28 (m, 3H), 6.88 (d, 1H), 6.13 (brs, 1H), 5.11 (d, 2H), 4.19 (t, 2H), 2.35 (s, 3H), 2.16 (s, 3H), 1.67 (m, 2H), 0.80 (t, 3H); (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (brs, 1H), 7.33-7.18 (m, 6H), 6.94 (m, 3H), 6.76 (m, 2H), 5.86 (brs, 1H), 5.56 (brs, 2H), 4.82 (brs, 2H), 2.40 (s, 3H), 2.25 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 7.82 (t, 1H), 7.70 (brs, 1H), 7.49 (m, 2H), 7.39-7.30 (m, 3H), 6.91 (d, 1H), 5.52 (s, 2H), 5.08 (d, 2H), 3.63 (m, 2H), 3.39 (m, 2H), 3.23 (s, 3H), 2.41 (s, 3H), 2.18 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (t, 1H), 7.30-7.20 (m, 3H), 7.02-6.94 (m, 5H), 6.64 (d, 2H), 5.57 (brs, 1H), 5.42 (s, 2H), 4.80 (d, 2H), 3.40 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (m, 1H), 7.47 (m, 2H), 7.35 (m, 3H), 6.92 (d, 1H), 6.10 (brs, 1H), 5.55 (m, 1H), 5.09 (d, 2H), 4.96 (d, 1H), 4.84 (d, 1H), 4.30 (t, 2H), 2.36 (m, 5H), 2.17 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.79 (m, 2H), 7.46 (m, 2H), 7.39-7.32 (m, 3H), 6.93 (d, 1H), 5.01 (d, 2H), 4.36 (m, 2H), 3.68 (m, 2H), 3.05 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 7.76 (t, 1H), 7.43-7.34 (m, 5H), 6.65 (m, 1H), 5.99 (brs, 1H), 5.55 (m, 1H) 5.15 (m, 1H), 5.03 (m, 2H), 4.75 (m, 2H), 2.33 (s, 3H), 2.19 (s, 3H), 1.53 (d, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 7.74 (m, 1H), 7.48 (m, 2H), 7.40-7.34 (m, 3H), 6.92 (d, 1H), 5.80 (brs, 1H), 5.09 (d, 2H), 4.12 (d, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 1.93 (m, 1H), 0.75 (d, 6H); (Yield: 15%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (t, 1H), 7.51 (m, 2H), 7.38-7.31 (m, 3H), 6.91 (d, 1H), 6.29 (brs, 1H), 5.13 (d, 2H), 4.29 (d, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 0.98 (m, 1H), 0.50 (m, 2H), 0.18 (m, 2H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 7.62 (t, 1H), 7.21-7.14 (m, 5H) 6.89-6.83 (m, 3H), 6.72 (d, 2H), 6.51 (brs, 1H), 5.69 (s, 2H), 4.85 (d, 2H), 2.38 (s, 3H), 2.22 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (t, 1H), 7.26-7.13 (m, 4H), 6.98-6.92 (m, 3H), 6.83 (d, 1H), 6.31 (m, 2H), 5.71 (brs, 1H), 5.47 (s, 2H), 4.83 (d, 2H), 3.67 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.74 (t, 1H), 7.31-7.22 (m, 3H), 7.01 (d, 2H), 6.96 (d, 1H), 6.72 (d, 2H), 6.65 (d, 2H), 5.57 (brs, 1H), 5.38 (s, 2H), 4.81 (d, 2H), 3.79 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 7.78 (t, 1H), 7.35-7.22 (m, 5H), 7.02 (m, 3H), 6.64 (d, 2H), 5.36 (s, 2H), 5.30 (brs, 1H), 4.77 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.30 (s, 9H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (m, 1H), 7.52 (m, 2H), 7.36-7.29 (m, 3H), 6.86 (d, 1H), 6.47 (brs, 1H), 5.15 (d, 2H), 4.37 (q, 2H), 2.36 (s, 3H), 2.15 (s, 3H), 1.30 (t, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 7.78 (m, 1H), 7.38-7.32 (m, 5H), 6.95 (d, 1H), 5.89 (brs, 1H), 5.14 (m, 1H), 4.98 (d, 2H), 4.74 (brs, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 1.59 (s, 3H), 1.15 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 7.62 (brs, 1H), 7.35 (m, 2H), 7.18 (m, 3H), 6.84 (d, 1H), 5.91 (d, 1H), 5.58 (brs, 1H), 5.31 (d, 1H), 4.51 (m, 1H), 4.10 (m, 1H), 2.54 (m, 1H), 2.39 (s, 3H), 2.36 (m, 1H), 2.18 (s, 3H); (Yield: 50%)
1H-NMR (400 MHz, CDCl3) δ 7.57-7.44 (m, 4H), 7.29-7.20 (m, 3H), 6.70 (d, 1H), 5.12 (d, 2H), 4.12 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); (Yield: 75%)
1H-NMR (400 MHz, CDCl3) δ 7.80 (t, 1H), 7.30-7.21 (m, 4H), 7.07-7.00 (m, 4H), 6.94 (t, 1H), 6.48 (t, 1H), 5.47 (s, 2H), 5.29 (brs, 1H), 4.84 (d, 2H), 2.39 (s, 3H), 2.26 (s, 3H); (Yield: 70%)
1H-NMR (400 MHz, CDCl3) δ 7.77 (m, 1H), 7.28-7.21 (m, 3H), 7.12 (d, 2H), 6.99 (m, 3H), 6.53 (m, 2H), 5.46 (brs, 1H), 5.40 (s, 2H), 4.80 (d, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H); (Yield: 77%)
1H-NMR (400 MHz, CDCl3) δ 7.69 (t, 1H), 7.24-7.18 (m, 3H) 6.97-6.87 (m, 5H), 6.74 (m, 2H), 5.96 (brs, 1H), 5.55 (s, 2H), 4.84 (d, 2H), 2.39 (s, 3H), 2.24 (s, 3H); (Yield: 74%)
1H-NMR (400 MHz, CDCl3) δ 7.71 (m, 1H), 7.49 (m, 2H), 7.38-7.30 (m, 3H), 6.89 (d, 1H), 5.99 (brs, 1H), 5.09 (d, 2H), 4.17 (m, 2H), 2.34 (s, 3H), 2.16 (s, 3H), 1.49 (m, 3H), 0.78 (d, 6H); (Yield: 58%)
2-Chloro-3-nitropyridine (8 g, 50.46 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) at nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 252 ml, 126.15 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and 20% ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 2.73 g of the titled compound as a pale yellow solid. (Yield: 30%)
1H-NMR (400 MHz, CDCl3) δ 8.45 (brs, 1H), 7.97 (d, 1H), 7.30 (d, 1H), 2.43 (s, 3H), 2.21 (s, 3H)
Sodium hydride (60%, 33 mg, 0.83 mmol) was added to a solution of 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2.8 ml). The reaction mixture was stirred for 30 minutes at room temperature. 1-Iodo-2-methylpropane (64 t, 0.67 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/9, v/v) to give 108 mg of the titled compound as a white solid. (Yield: 86%)
1H-NMR (400 MHz, CDCl3) δ 7.94 (d, 1H), 7.29 (d, 1H), 4.25 (brs, 2H), 2.38 (s, 3H), 2.22 (m, 4H), 0.89 (d, 6H)
Cesium carbonate (97 mg, 0.317 mmol) and (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 0.0317 mmol) were added to a solution of 7-chloro-1-isobutyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (50 mg, 0.211 mmol) prepared in Step 2, tris(dibenzylideneacetone)dipalladium (0) (11 mg, 0.0106 mmol), and 4-methylbenzylamine (40 ml, 0.317 mmol) in anhydrous toluene (1.1 ml). The reaction mixture was refluxed for 40 hours and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=15/85, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 15 mg of the titled compound as a white solid. (Yield: 21%).
1H-NMR(400 MHz, CDCl3) δ 7.73 (t, 1H), 7.35 (d, 2H), 7.17 (d, 2H), 6.90 (d, 1H), 5.79 (brs, 1H), 5.03 (d, 2H), 3.97 (d, 2H), 2.34 (s, 6H), 2.17 (s, 3H), 1.93 (m, 1H), 0.76 (d, 6H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 2-bromoethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 80%)
1H-NMR (400 MHz, CDCl3) δ 7.94 (d, 1H), 7.29 (d, 1H), 4.64 (t, 2H), 3.72 (t, 2H), 3.28 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-(2-methoxyethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 7.78 (t, 1H), 7.77 (brs, 1H), 7.34 (d, 2H), 7.17 (d, 2H), 6.93 (d, 1H), 4.95 (d, 2H), 4.35 (t, 2H), 3.68 (t, 2H), 3.07 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 42%)
1H-NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.34 (d, 1H), 7.27-7.21 (m, 3H), 6.87 (d, 2H), 5.75 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 1-benzyl-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (t, 1H), 7.32-7.22 (m, 3H), 7.00 (d, 2H), 6.94 (d, 1H), 6.83 (d, 2H), 6.75 (d, 2H), 5.61 (brs, 1H), 5.49 (s, 2H), 4.73 (d, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 4-fluorobenzyl chloride, the titled compound was obtained as a pale yellow solid. (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 7.97 (d, 1H), 7.34 (d, 1H), 6.94 (dd, 2H), 6.85 (dd, 1H), 5.71 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-(4-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (t, 1H), 6.97 (d, 2H), 7.00 (d, 2H), 6.90-6.85 (m, 3H), 6.81 (d, 2H), 6.75 (dd, 2H), 6.16 (brs, 1H), 5.60 (s, 2H), 4.78 (d, 2H), 2.38 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 4-methylbenzyl chloride, the titled compound was obtained as a white solid. (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 7.93 (d, 1H), 7.29 (d, 1H), 7.07 (d, 2H), 6.79 (d, 2H), 5.71 (s, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 31%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (t, 1H), 7.01 (d, 4H), 6.93 (d, 2H), 6.85 (d, 2H), 6.64 (d, 2H), 5.56 (brs, 1H), 5.41 (s, 2H), 4.74 (d, 2H), 2.39 (s, 3H), 2.34 (s, 6H), 2.24 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and iodoethane, the titled compound was obtained as a white solid. (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 7.91 (d, 1H), 7.25 (d, 1H), 4.46 (q, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 1.33 (t, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (t, 1H), 7.41 (d, 2H), 7.12 (d, 2H), 6.82 (d, 1H), 6.59 (brs, 1H), 5.10 (s, 2H), 4.40 (brs, 2H), 2.35 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H), 1.31 (brs, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and (bromomethyl)cyclopropane, the titled compound was obtained as a white solid. (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 7.93 (d, 1H), 7.29 (d, 1H), 4.43 (d, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.26-1.21 (m, 1H), 0.53-0.48 (m, 2H), 0.40-0.36 (m, 2H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-cyclopropylmethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 7.74 (t, 1H), 7.37 (d, 2H), 7.16 (d, 2H), 6.92 (d, 1H), 6.10 (brs, 1H), 5.07 (d, 2H), 4.26 (d, 2H), 2.34 (s, 6H), 2.17 (s, 3H), 0.99 (m, 1H), 0.52 (dd, 2H), 0.18 (dd, 2H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 1-iodopropane, the titled compound was obtained as a white solid. (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 7.91 (d, 1H), 7.27 (d, 1H), 4.36 (dd, 2H), 2.36 (s, 3H), 2.20 (s, 3H), 1.75 (m, 2H), 0.96 (t, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 7.67 (t, 1H), 7.38 (d, 2H), 7.14 (d, 2H), 6.85 (d, 1H), 6.19 (brs, 1H), 5.06 (d, 2H), 4.21 (t, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H), 1.67 (m, 2H), 0.81 (t, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and allyl iodide, the titled compound was obtained as a white solid. (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 2.27 (s, 3H), 2.41 (s, 3H), 4.52 (m, 2H), 4.72 (t, 1H), 6.97 (d, 2H), 7.38 (d, 1H), 8.08 (d, 1H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 1-allyl-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 29%)
1H-NMR(400 MHz, CDCl3) δ 7.78 (t, 1H), 7.45-7.30 (m, 4H), 6.93 (d, 1H), 5.98 (m, 1H), 5.83 (brs, 1H), 5.31 (d, 1H), 5.05 (d, 2H), 4.80 (d, 2H), 4.66 (d, 1H), 2.36 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 7.98 (d, 1H), 7.35 (d, 1H), 7.27-7.21 (m, 1H), 6.92 (dd, 1H), 6.69 (d, 1H), 6.54 (d, 1H), 5.76 (s, 2H), 2.29 (s, 3H), 2.26 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-fluorobenzylamine, the titled compound was obtained as a white solid. (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.60 (t, 1H), 7.22 (dd, 1H), 6.99 (t, 1H), 6.92-6.77 (m, 5H), 6.65 (d, 1H), 6.61 (brs, —NH, 1H), 6.43 (d, 1H), 5.74 (s, 2H), 4.84 (d, 2H), 2.38 (s, 3H), 2.22 (s, 3H)
The titled compounds of Examples 208 to 210 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-1-isobutyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 2 of Example 198; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.60 (t, 1H), 7.52 (dd, 2H), 6.99 (t, 2H), 6.82 (d, 1H), 6.68 (brs, 1H), 5.07 (d, 2H), 4.15 (d, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.86 (m, 1H), 0.75 (d, 6H); (Yield: 97%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (t, 1H), 7.46 (d, 2H), 7.29 (d, 2H), 6.87 (d, 1H), 6.43 (brs, 1H), 5.09 (d, 2H), 4.11 (d, 2H), 2.35 (s, 3H), 2.16 (s, 3H), 1.89 (m, 1H), 0.77 (d, 6H); (Yield: 21%)
1H-NMR(400 MHz, CDCl3) δ 7.79 (t, 1H), 7.35 (d, 1H), 7.29-7.19 (m, 3H), 6.96 (d, 1H), 5.34 (brs, 1H), 5.07 (d, 2H), 3.88 (d, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H), 1.89 (m, 1H), 0.71 (d, 6H); (Yield: 21%)
The titled compounds of Examples 211 to 213 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-1-(2-methoxyethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 199; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.79 (d, 1H), 7.46 (dd, 2H), 7.06 (t, 2H), 6.95 (d, 1H), 5.01 (d, 2H), 4.36 (s, 2H), 3.70 (s, 2H), 3.10 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H); (Yield: 22%)
1H-NMR(400 MHz, CDCl3) δ 7.82 (brs, 1H), 7.76 (t, 1H), 7.43 (d, 2H), 7.34 (d, 2H), 6.95 (d, 1H), 5.01 (d, 2H), 4.38 (t, 2H), 3.71 (t, 2H), 3.12 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H); (Yield: 19%)
1H-NMR(400 MHz, CDCl3) δ 7.82 (t, 1H), 7.69 (brs, 1H), 7.34 (d, 1H), 7.28-7.21 (m, 3H), 6.95 (d, 1H), 4.99 (d, 2H), 4.31 (s, 2H), 3.65 (s, 2H), 2.95 (s, 3H), 2.44 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); (Yield: 29%)
The titled compounds of Examples 214 to 216 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 1-benzyl-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 200; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 13.85 (brs, 1H), 7.63 (d, 1H), 7.34-7.24 (m, 4H), 6.88-6.79 (m, 6H), 6.25 (brs, 1H), 5.66 (s, 2H), 4.82 (d, 2H), 2.40 (s, 3H), 2.23 (s, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 7.60 (t, 1H), 7.33-7.24 (m, 3H), 7.07 (d, 2H), 6.87 (d, 1H), 6.80 (d, 4H), 6.32 (brs, 1H), 5.67 (s, 2H), 4.82 (d, 2H), 2.40 (s, 3H), 2.23 (s, 3H); (Yield: 30%)
1H-NMR(400 MHz, CDCl3) δ 7.76 (t, 1H), 7.25 (m, 2H), 7.15-7.10 (m, 4H), 6.99 (brs, 1H), 6.89 (brs, 1H), 6.65 (brs, 2H), 5.40 (brs, 2H), 5.21 (brs, 1H), 4.76 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H); (Yield: 30%)
The titled compounds of Examples 217 to 219 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-1-(4-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 201; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.58 (d, 1H), 7.26 (d, 1H), 6.94-6.76 (m, 8H), 6.60 (brs, 1H), 5.71 (s, 2H), 4.84 (d, 2H), 2.38 (s, 3H), 2.22 (s, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.54 (t, 1H), 7.05 (d, 2H), 6.93 (t, 2H), 6.83-6.78 (m, 6H), 5.76 (s, 2H), 4.84 (d, 2H), 2.38 (s, 3H), 2.22 (s, 3H); (Yield: 29%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (t, 1H), 7.21 (t, 1H), 7.09 (d, 1H), 7.05 (t, 1H), 6.94 (d, 2H), 6.84-6.80 (m, 3H), 6.56 (dd, 2H), 5.51 (brs, 1H), 5.45 (s, 2H), 4.78 (d, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H); (Yield: 86%)
The titled compounds of Examples 220 to 222 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-2,3-dimethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 202; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.68 (t, 1H), 7.04 (d, 2H), 6.94 (d, 1H), 6.92 (d, 2H), 6.85 (d, 2H), 6.67 (d, 2H), 5.84 (brs, 1H), 5.49 (d, 2H), 4.81 (d, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H); (Yield: 23%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (t, 1H), 7.12 (d, 2H), 7.03 (d, 2H), 6.92 (d, 1H), 6.87 (d, 2H), 6.68 (d, 2H), 5.87 (brs, 1H), 5.51 (s, 2H), 4.79 (d, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H); (Yield: 15%)
1H-NMR (400 MHz, CDCl3) δ 7.79 (t, 1H), 7.26 (dd, 2H), 7.10 (dd, 2H), 6.99 (d, 1H), 6.91 (d, 2H), 6.53 (d, 2H), 5.30 (s, 2H), 5.13 (brs, 1H), 4.75 (d, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.05 (s, 3H); (Yield: 22%)
The titled compounds of Examples 223 to 225 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 203; and, 4-fluorobenzylamine, 4-chlorobenzylamine, or 2-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.59-7.54 (m, 3H), 7.25 (brs, 1H), 6.94 (t, 2H), 6.79 (d, 1H), 5.16 (d, 2H), 4.51 (q, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.28 (t, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.55 (t, 1H), 7.52 (d, 2H), 7.34 (brs, 1H), 7.20 (d, 2H), 6.79 (d, 1H), 5.16 (d, 2H), 4.52 (q, 2H), 2.35 (s, 3H), 2.14 (s, 3H), 1.29 (t, 3H); (Yield: 37%)
1H-NMR(400 MHz, CDCl3) δ 7.68 (t, 1H), 7.38 (d, 1H), 7.23-7.17 (m, 4H), 6.88 (d, 2H), 6.11 (brs, 1H), 5.12 (d, 2H), 4.32 (q, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H), 1.28 (t, 3H); (Yield: 76%)
The titled compounds of Examples 226 and 227 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-1-cyclopropylmethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 204; and, 4-fluorobenzylamine or 4-chlorobenzylamine.
1H-NMR (400 MHz, CDCl3) δ 7.69 (d, 1H), 7.52 (t, 2H), 7.04 (t, 2H), 6.90 (d, 1H), 6.41 (s, 1H), 5.12 (s, 2H), 4.32 (d, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 0.98 (m, 1H), 0.50 (d, 2H), 0.19 (d, 2H)
1H-NMR(400 MHz, CDCl3) δ 7.65 (t, 1H), 7.49 (d, 2H), 7.27 (d, 2H), 6.88 (d, 1H), 6.69 (brs, 1H), 5.13 (s, 2H), 4.36 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H), 0.50 (d, 2H), 0.20 (d, 2H); (Yield: 25%)
The titled compounds of Examples 228 to 236 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 7-chloro-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 205; and, 4-fluorobenzylamine, 4-chlorobenzylamine, 2-methylbenzylamine, 2-chlorobenzylamine, 3-fluorobenzylamine, 4-trifluoromethoxybenzylamine, 3-methylbenzylamine, piperonylamine, or 3-chlorobenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.60-7.52 (m, 3H), 6.97 (t, 2H), 6.81 (d, 1H), 5.11 (d, 2H), 4.35 (t, 2H), 2.34 (s, 3H), 2.14 (s, 3H), 1.66-1.60 (m, 1H), 0.82 (t, 3H); (Yield: 29%)
1H-NMR(400 MHz, CDCl3) δ 7.59 (brs, 1H), 7.48 (brs, 2H), 7.26 (brs, 2H), 6.84 (brs, 1H), 6.67 (brs, 1H), 5.12 (brs, 2H), 4.31 (brs, 2H), 2.35 (s, 3H), 2.15 (s, 3H), 1.66 (brs, 2H), 0.84 (brs, 3H); (Yield: 15%)
1H-NMR(400 MHz, CDCl3) δ 7.77 (t, 1H), 7.36 (d, 1H), 7.29-7.19 (m, 3H), 6.95 (d, 1H), 5.48 (brs, 1H), 5.09 (d, 2H), 4.07 (t, 2H), 2.42 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.65 (m, 1H), 0.73 (t, 3H); (Yield: 22%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.75 (t, 1H), 7.39 (m, 1H), 7.31-7.27 (m, 2H), 6.93 (d, 1H), 6.13 (brs, 1H), 5.33 (d, 2H), 4.17 (t, 2H), 2.36 (s, 3H), 2.17 (s, 3H), 1.73 (m, 2H), 0.88 (t, 3H); (Yield: 30%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (t, 1H), 7.33 (t, 1H), 7.29 (d, 1H), 7.20 (d, 1H), 6.96 (t, 1H), 6.85 (d, 1H), 6.73 (brs, 1H), 5.15 (d, 2H), 4.33 (t, 2H), 2.36 (s, 3H), 2.15 (s, 3H), 1.67 (m, 2H), 0.85 (t, 3H); (Yield: 22%)
1H-NMR(400 MHz, CDCl3) δ 7.59 (m, 3H), 7.13 (d, 2H), 6.84 (d, 2H), 5.19 (d, 2H), 4.33 (t, 2H), 2.35 (s, 3H), 2.14 (s, 3H), 1.62 (m, 2H), 0.82 (t, 3H); (Yield: 13%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (d, 1H), 7.28-7.22 (m, 3H), 7.13 (d, 1H), 6.88 (d, 1H), 6.09 (brs, 1H), 5.07 (d, 2H), 4.19 (t, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.68 (m, 2H), 0.82 (t, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (t, 1H), 7.02 (d, 1H), 6.96 (s, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 6.33 (brs, 1H), 5.92 (s, 2H), 5.02 (d, 2H), 4.25 (t, 2H), 2.35 (s, 3H), 2.15 (s, 3H), 1.68 (m, 2H), 0.84 (t, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (d, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 6.86 (d, 1H), 6.76 (brs, 1H), 5.13 (d, 2H), 4.33 (t, 2H), 2.36 (s, 3H), 2.16 (s, 3H), 1.65 (m, 2H), 0.87 (t, 3H); (Yield: 72%)
The titled compounds of Examples 237 to 241 were prepared, in accordance with the same procedures as in Step 3 of Example 198, using 1-allyl-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 206; and, 4-fluorobenzylamine, 4-chlorobenzylamine, 3-fluorobenzylamine, 4-trifluoromethoxybenzylamine, or 3-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.78 (t, 1H), 7.54-7.48 (m, 4H), 7.02 (d, 1H), 6.03 (m, 1H), 5.83 (brs, 1H), 5.26 (d, 1H), 5.05 (d, 2H), 4.88 (d, 2H), 4.73 (d, 1H), 2.33 (s, 3H), 2.30 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 7.80 (t, 1H), 7.44-7.40 (m, 4H), 6.97 (d, 1H), 5.98 (m, 1H), 5.90 (brs, 1H), 5.33 (d, 1H), 5.05 (d, 2H), 4.84 (d, 2H), 4.73 (d, 1H), 2.35 (s, 3H), 2.33 (s, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 7.90 (t, 1H), 7.66-7.43 (m, 4H), 6.97 (d, 1H), 5.88 (m, 1H), 5.83 (brs, 1H), 5.21 (d, 1H), 5.05 (d, 2H), 4.84 (d, 2H), 4.73 (d, 1H), 2.33 (s, 3H), 2.25 (s, 3H); (Yield: 28%)
1H-NMR(400 MHz, CDCl3) δ 8.01 (t, 1H), 7.66-7.43 (m, 4H), 6.90 (d, 1H), 5.88 (m, 1H), 5.73 (brs, 1H), 5.26 (d, 1H), 5.05 (d, 2H), 4.84 (d, 2H), 4.73 (d, 1H), 2.33 (s, 3H), 2.29 (s, 3H); (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 7.89 (t, 1H), 7.63-7.43 (m, 4H), 7.00 (d, 1H), 5.98 (m, 1H), 5.63 (brs, 1H), 5.33 (d, 1H), 5.05 (d, 2H), 4.84 (d, 2H), 4.73 (d, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); (Yield: 43%)
A solution of 3-nitro-2-(4-vinylphenyl)pyridine (4.9 g, 21.6 mmol) prepared in Preparation 9 in anhydrous tetrahydrofuran (150 ml) was cooled to −78° C. and 1-methyl-1-propenyl magnesium bromide (0.5M in anhydrous tetrahydrofuran solution; 130 ml) was slowly added thereto. The reaction mixture was stirred for 1 hour at the same temperature, slowly warmed to room temperature, and then stirred overnight. 20% (w/v) ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The reaction mixture was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography and then crystallized with ethyl ether to give 612 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.33 (d, 1H), 8.23 (brs, 1H), 7.86 (d, 2H), 7.58 (d, 2H), 7.36 (d, 1H), 6.80 (dd, 1H), 5.86 (d, 1H), 5.33 (d, 1H), 2.42 (s, 3H), 2.25 (s, 3H)
18-Crown-6 (2.5 mg, 0.0097 mmol) and potassium tert-butoxide (33 mg, 0.291 mmol) were added to a solution of 2,3-dimethyl-7-(4-vinylphenyl)-1H-pyrrolo[2,3-c]pyridine (24 mg, 0.097 mmol) prepared in Example 242 in anhydrous tetrahydrofuran (0.5 ml). The reaction mixture was stirred for 30 minutes at room temperature and 3-fluorobenzyl chloride (20 μl, 0.16 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 3.8 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.77 (d, 1H), 7.41 (d, 2H), 7.34 (d, 2H), 7.15 (m, 1H), 6.95 (m, 1H), 6.75 (dd, 1H), 6.15 (d, 1H), 6.15 (d, 1H), 5.86 (d, 1H), 5.40 (d, 1H), 5.11 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H)
The titled compounds of Examples 244 to 261 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-(4-vinylphenyl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 242; and, 4-methylbenzyl chloride, allyl bromide, benzyl bromide, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, propargyl bromide, 2,5-dimethylbenzyl chloride, iodoethane, 1-iodopropane, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, 3-methylbenzyl chloride, 1-chloro-3-methylbutane, 2-(bromomethyl)naphthalene, 4-fluorobenzyl chloride, 2-fluorobenzyl chloride, 4-tert-butylbenzyl chloride, or 4-bromo-2-methyl-2-butene.
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.74 (d, 1H), 7.39 (d, 2H), 6.97 (d, 2H), 6.73 (dd, 1H), 6.25 (d, 2H), 5.85 (d, 1H), 5.39 (d, 1H), 5.06 (s, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.72 (d, 1H), 7.58 (s, 4H), 6.78 (dd, 1H), 5.91 (d, 1H), 5.61 (m, 1H), 5.43 (d, 1H), 5.05 (d, 1H), 4.45 (s, 2H), 4.37 (d, 1H), 2.45 (s, 3H), 2.25 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (d, 1H), 7.75 (d, 1H), 7.51 (m, 4H), 7.21 (m, 3H), 6.75 (dd, 1H), 6.36 (d, 2H), 5.84 (d, 1H), 5.39 (d, 1H), 5.11 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (d, 1H), 7.67 (d, 1H), 7.56 (s, 4H), 6.77 (dd, 1H), 5.89 (d, 1H), 5.42 (d, 1H), 4.08 (t, 2H), 3.03 (t, 2H), 3.00 (s, 3H), 2.51 (s, 3H), 2.35 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.65 (m, 1+4H), 6.80 (dd, 1H), 5.93 (d, 1H), 5.44 (d, 1H), 3.87 (d, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 0.63 (m 1H), 0.26 (m, 2H), −0.17 (m, 2H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.77 (d, 2H), 7.70 (d, 2H), 7.64 (d, 2H), 6.79 (dd, 1H), 5.93 (d, 1H), 5.44 (d, 1H), 4.53 (s, 2H), 2.59 (s, 3H), 2.36 (d, 1+3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.77 (d, 1H), 7.23 (d, 2H), 7.13 (d, 2H), 6.98 (dd, 2H), 6.70 (dd, 1H), 5.77 (d, 1H), 5.68 (s, 1H), 5.35 (d, 1H), 4.87 (s, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H), 1.68 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.43 (d, 1H), 7.69 (d, 2H), 7.63 (s, 1+2H), 6.85 (dd, 1H), 5.96 (d, 1H), 5.43 (d, 1H), 3.92 (q, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 0.91 (t, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.69 (d, 1H), 7.63 (s, 3+1H), 6.80 (dd, 1H), 5.92 (d, 1H), 5.43 (d, 1H), 3.78 (t, 2H), 2.48 (s, 3H), 2.34 (s, 3H), 1.26 (m, 2H), 0.45 (t, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.74 (d, 1H), 7.34 (m, 4H), 7.06 (t, 1H), 6.74 (m, 1+1H), 5.90 (m, 2H), 5.82 (d, 1H), 5.38 (d, 1H), 5.07 (s, 2H), 3.68 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (s, 1H), 7.74 (d, 1H), 7.39 (m, 4H), 6.87 (m, 1H), 6.68 (t, 3H), 6.27 (d, 1H), 5.84 (d, 1H), 5.38 (d, 1H), 5.05 (s, 2H), 3.74 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (d, 1H), 7.75 (d, 1H), 7.40 (d, 2H), 7.34 (d, 2H), 7.02 (m, 2H), 6.76 (dd, 1H), 6.14 (s, 1H), 6.09 (d, 1H), 5.85 (d, 1H), 5.39 (d, 1H), 5.08 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.18 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.26 (d, 1H), 7.94 (d, 1H), 7.69 (m, 1H), 7.58 (dd, 2H), 7.34 (m, 1H), 6.73 (dd, 1H), 5.85 (d, 1H), 5.40 (d, 1H), 3.86 (m, 2H), 2.47 (s, 3H), 2.27 (s, 3H), 1.06 (m, 2H), 0.58 (s, 3H), 0.56 (s, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (d, 1H), 7.78 (t, H), 7.66 (d, 1H), 7.56 (d, 2H), 7.48 (m, 2H), 7.28 (s, 3H), 6.71 (s, 1H), 6.69 (dd, 1H), 6.54 (d, 1H), 5.79 (d, 1H), 5.37 (d, 1H), 5.25 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.75 (d, 1H), 7.42 (d, 2H), 7.36 (d, 2H), 6.87 (t, 2H), 6.73 (dd, 1H), 6.33 (m, 2H), 5.86 (d, 1H), 5.40 (d, 1H), 5.09 (s, 2H), 2.42 (s, 3H), 2.40 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.42 (d, 1H), 7.76 (d, 1H), 7.38 (d, 2H), 7.32 (d, 2H), 7.15 (m, 1H), 6.94 (m, 2H), 6.77 (dd, 1H), 6.03 (t, 1H), 5.83 (d, 1H), 5.39 (d, 1H), 5.12 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (d, 1H), 7.74 (d, 1H), 7.36 (dd, 4H), 7.14 (d, 2H), 6.76 (dd, 1H), 6.24 (d, 1H), 5.74 (d, 1H), 5.39 (d, 1H), 5.09 (s, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 1.25 (s, 9H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 8.29 (d, 1H), 7.68 (d, 1H), 7.59 (m, 4H), 6.74 (dd, 1H), 5.87 (d, 1H), 5.40 (d, 1H), 4.65 (s, 1H), 4.46 (s, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 1.26 (s, 3+3H); (Yield: 68%)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-methylthiophenyl)pyridine prepared in Preparation 10, the titled compound was obtained as a white solid. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (d, 1H), 8.17 (brs, 1H), 7.82 (d, 2H), 7.41 (d, 2H), 7.35 (d, 1H), 2.54 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H)
The titled compounds of Examples 263 to 275 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-(4-methylsulfanylphenyl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 262; and, allyl bromide, 2-bromoethyl methyl ether, iodoethane, 3-methoxybenzyl chloride, 4-methylbenzyl chloride, benzyl bromide, 4-bromo-2-methyl-2-butene, (bromomethyl)cyclopropane, 4-chlorobenzyl chloride, 3-fluorobenzyl chloride, 3-methylbenzyl chloride, 4-fluorobenzyl chloride, or 2-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.66 (d, 1H), 7.53 (d, 2H), 7.36 (d, 2H), 5.54 (m, 1H), 5.07 (d, 1H), 4.46 (d, 2H), 4.38 (d, 1H), 2.54 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.65 (d, 1H), 7.55 (d, 2H), 7.40 (d, 2H), 4.11 (t, 2H), 3.05 (t, 2H), 3.01 (s, 3H), 2.55 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.65 (d, 1H), 7.58 (d, 2H), 7.42 (d, 2H), 3.92 (q, 2H), 2.56 (s, 3H), 2.48 (s, 3H), 2.33 (s, 3H), 0.91 (t, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.70 (d, 1H), 7.28 (d, 2H), 7.18 (d, 2H), 7.07 (t, 1H), 6.74 (d, 1H), 5.94 (d, 1H), 5.92 (s, 1H), 5.07 (s, 2H), 3.69 (s,3H), 2.49 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.72 (d, 1H), 7.32 (d, 2H), 7.20 (m, 2H), 6.97 (d, 2H), 6.28 (d, 2H), 5.07 (s, 2H), 2.50 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.69 (d, 1H), 7.24 (d, 2H), 7.15 (m, 5H), 6.38 (d, 2H), 5.10 (s, 2H), 2.49 (s, 3H), 2.39 (s, 3+3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.30 (d, 1H), 7.65 (d, 1H), 7.55 (d, 2H), 7.34 (d, 2H), 4.65 (t, 1H), 4.47 (d, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 1.55 (s, 3H), 1.29 (s, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 7.56 (d, 2+1H), 7.40 (d, 2H), 3.83 (d, 2H), 2.55 (s, 3H), 2.46 (s, 3H), 2.32 (s, 3H), 0.61 (m, 1H), 0.24 (m, 2H), −0.16 (m, 2H); (Yield: 88%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.67 (d, 2H), 7.28 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 6.33 (d, 2H), 5.07 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3+3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (d, 1H), 7.70 (d, 1H), 7.24 (d, 3H), 7.14 (m, 2H), 6.90 (t, 1H), 6.15 (d, 1H), 6.09 (d, 1H), 5.09 (s, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 7.66 (d, 1H), 7.27 (d, 2H), 7.17 (d, 2H), 7.00 (m, 2H), 6.20 (s, 1H), 6.12 (d, 1H), 5.06 (s, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (d, 1H), 7.61 (d, 1H), 7.25 (d, 2H), 7.18 (d, 2H), 6.84 (t, 2H), 6.36 (m, 2H), 5.05 (s, 2H), 2.49 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H); (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (d, 1H), 7.65 (d, 1H), 7.22 (d, 3H), 7.16 (d, 2H), 6.92 (m, 2H), 6.06 (t, 1H), 5.09 (s, 2H), 2.49 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H); (Yield: 95%)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-methylphenyl)pyridine prepared in Preparation 11, the titled compound was obtained as a white solid. (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (d, 1H), 8.22 (brs, 1H), 7.78 (d, 2H), 7.34 (d, 2+1H), 2.43 (s, 3H), 2.40 (s, 3H), 2.24 (s 3H)
The titled compounds of Examples 277 to 298 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-(p-tolyl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 276; and, allyl bromide, 3-methoxybenzyl chloride, 4-methylbenzyl chloride, propargyl bromide, benzyl bromide, 2-bromoethyl methyl ether, 4-chlorobenzyl chloride, 3-fluorobenzyl chloride, 1-iodo-2-methylpropane, 1-iodopropane, 4-methoxybenzyl chloride, 4-fluorobenzyl chloride, (bromomethyl)cyclobutane, 2-fluorobenzyl chloride, 4-bromo-2-methyl-2-butene, 1-bromo-3-methylbutane, (bromomethyl)cyclopropane, 2,5-dimethylbenzyl bromide, 2-chlorobenzyl bromide, 3,4-dichlorobenzyl bromide, iodoethane, or 3-methylbenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.70 (d, 1H), 7.51 (d, 2H), 7.36 (d, 2H), 5.53 (m, 1H), 5.07 (d, 1H), 4.43 (s, 2H), 4.37 (d, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.73 (d, 1H), 7.28 (d, 2H), 7.18 (d, 2H), 7.08 (t, 1H), 6.72 (d, 1H), 5.91 (m, 2H), 5.06 (s, 2H), 3.69 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3+3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.72 (d, 1H), 7.31 (d, 2H), 7.19 (d, 2H), 6.97 (d, 2H), 6.27 (d, 2H), 5.05 (s, 2H), 2.39 (s, 3+3+3H), 2.19 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (brs, 1H), 7.69 (brs, 3H), 7.42 (brs, 2H), 4.52 (s, 2H), 2.60 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3+1H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.73 (d, 1H), 7.27 (m, 2H), 7.18 (m, 5H), 6.37 (d, 2H), 5.10 (s, 2H), 2.40 (s, 3+3H), 2.39 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (t, 1H), 7.67 (d, 1H), 7.52 (d, 2H), 7.38 (d, 2H), 4.08 (t, 2H), 3.04 (t, 2H), 3.02 (s, 3H), 2.48 (s, 3H), 2.45 (s, 3H), 2.34 (s, 3H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.75 (s, 1H), 7.30 (m, 1H), 7.15 (m, 4H), 6.89 (d, 1H), 6.32 (d, 2H), 5.07 (s, 2H), 2.40 (s, 3+3+3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.76 (d, 1H), 7.25 (d, 2H), 7.20 (d, 2H), 7.13 (m, 1H), 6.91 (t, 1H), 6.10 (dd, 2H), 5.10 (s, 2H), 2.42 (s, 3+3+3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (brs, 1H), 7.67 (d, 1H), 7.53 (brs, 2H), 7.40 (d, 2H), 3.76 (d, 2H), 2.49 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H), 1.25 (m, 1H), 0.39 (s, 3H), 0.37 (s, 3H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.67 (d, 1H), 7.53 (d, 2H), 7.39 (d, 2H), 3.76 (t, 2H), 2.48 (s, 3H), 2.46 (s, 3H), 2.34 (s, 3H), 1.27 (q, 2H), 0.45 (t, 3H); (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (brs, 1H), 7.31 (brs, 2H), 7.19 (brs, 2H), 6.72 (t, 2H), 6.38 (d, 1H), 6.28 (d, 1H), 5.68 (d, 2H), 3.68 (s, 3H), 2.40 (s, 3+3+3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.74 (d, 2H), 7.27 (d, 2H), 7.21 (d, 2H), 6.88 (t, 2H), 6.33 (m, 2H), 5.08 (s, 2H), 2.41 (s, 3+3+3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.66 (d, 1H), 7.56 (d, 2H), 7.40 (d, 2H), 3.96 (d, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 2.09 (m, 1H), 1.56 (m, 4H), 1.30 (m, 2H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.75 (d, 1H), 7.23 (d, 3H), 7.16 (d, 2H), 6.95 (t, 2H), 6.04 (t, 1H), 5.10 (s, 2H), 2.41 (s, 3+3+3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (t, 1H), 7.66 (d, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 4.66 (t, 1H), 4.46 (d, 2H), 2.45 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 1.47 (s, 3H), 1.22 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.66 (d, 1H), 7.56 (d, 2H), 7.40 (d, 2H), 3.86 (m, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H), 1.08 (m, 2+1H), 0.60 (s, 3H), 0.59 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (t, 1H), 7.68 (d, 1H), 7.58 (d, 2H), 7.41 (d, 2H), 3.86 (d, 2H), 2.53 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H), 1.57 (m, 1H), 0.28 (d, 2H), −0.18 (d, 2H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (t, 1H), 7.76 (d, 1H), 7.12 (d, 2H), 7.06 (d, 2H), 6.96 (s, 2H), 5.67 (s, 1H), 4.87 (s, 2H), 2.44 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 2.12 (s, 3H), 1.71 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (t, 1H), 7.77 (d, 1H), 7.29 (m, 2H), 7.23 (t, 1H), 7.09 (m, 4H), 5.92 (d, 1H), 5.04 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.75 (d, 1H), 7.26 (m, 5H), 6.42 (s, 1H), 6.10 (d, 1H), 5.07 (s, 2H), 2.44 (s, 3+3H), 2.41 (s, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.76 (d, 1H), 7.25 (d, 2H), 7.20 (d, 2H), 7.13 (m, 1H), 6.91 (t, 1H), 6.10 (dd, 2H), 5.10 (s, 2H), 2.42 (s, 3+3+3H), 1.54 (t, 3H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (brs, 1H), 7.30 (brs, 1H), 7.28 (brs, 2H), 7.18 (d, 2H), 7.03 (brs, 2H), 6.12 (m, 2H), 5.07 (s, 2H), 2.40 (s, 3+3+3H), 2.19 (s, 3H); (Yield: 75%)
In accordance with the same procedures as in Example 242, using 3-nitro-2-(4-chlorophenyl)pyridine prepared in Preparation 12, 7-(4-chlorophenyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (s, 1H), 7.47 (t, 2H), 7.05 (m, 3H), 5.46 (s, 2H), 2.33 (s, 3H), 2.13 (s, 3H)
The titled compounds of Examples 300 to 324 were prepared, in accordance with the same procedures as in Example 243, using 7-(4-chlorophenyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine obtained by treating the compound prepared in Example 299 with a saturated sodium carbonate solution; and, allyl bromide, benzyl bromide, 2-bromoethyl methyl ether, 3-fluorobenzyl chloride, 1-iodo-2-methylpropane, 4-methylbenzyl chloride, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, propargyl bromide, bromomethyl methyl ether, 4-bromo-2-methyl-2-butene, 1-bromo-3-methylbutane, (bromomethyl)cyclopropane, 2-(bromomethyl)naphthalene, 4-tert-butylbenzyl bromide, 4-chlorobenzyl chloride, epibromohydrin, 2,5-dimethylbenzyl bromide, iodoethane, 1-bromopropane, 3-methylbenzyl bromide, α-bromo-m-tolunitrile, 4-fluorobenzyl bromide, 3-chlorobenzyl chloride, or (bromomethyl)cyclobutane.
1H-NMR(400 MHz, CDCl3) δ 8.34 (brs, 1H), 7.56 (brs, 2H), 7.26 (brs, 3H), 5.60 (brs, 1H), 5.30 (brs, 1H), 4.41 (brs, 1+2H), 2.44 (d, 3+3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.79 (d, 1H), 7.29 (m, 5H), 7.20 (m, 2H), 6.35 (d, 2H), 5.09 (s, 2H), 2.44 (s, 3H), 2.42 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (s, 1H), 7.72 (s, 1H), 7.58 (brs, 4H), 4.01 (s, 2H), 3.08 (s, 2H), 3.04 (s, 3H), 2.53 (s, 3H), 2.36 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.80 (d, 1H), 7.36 (d, 2H), 7.28 (d, 2H), 7.18 (q, 1H), 6.94 (t, 1H), 6.14 (d, 1H), 6.06 (d, 1H), 5.08 (s, 2H), 2.44 (s, 3H), 2.42 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (d, 1H), 7.71 (d, 1H), 7.59 (m, 4H), 3.73 (d, 2H), 2.51 (s, 3H), 2.36 (s, 3H), 1.38 (m, 1H), 0.43 (s, 3H), 0.41 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.78 (d, 1H), 7.34 (m, 4H), 6.99 (d, 2H), 6.24 (d, 2H), 5.03 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.78 (d, 1H), 7.34 (m, 4H), 7.10 (t, 1H), 6.79 (d, 1H), 5.91 (d, 2H), 5.04 (s, 2H), 3.70 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.78 (d, 1H), 7.37 (m, 4H), 6.71 (d, 1H), 6.27 (d, 1H), 5.02 (s, 2H), 3.75 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.73 (d, 1H), 7.70 (d, 2H), 7.57 (d, 2H), 6.39 (t, 1H), 5.08 (d, 2H), 2.52 (s, 3H), 2.37 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.70 (m, 4H), 7.26 (s, 1H), 4.97 (brs, 2H), 3.42 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.71 (d, 1H), 7.60 (d, 2H), 7.55 (d, 2H), 4.66 (s, 1H), 4.44 (s, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 1.60 (s, 3+3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (t, 1H), 7.71 (d, 1H), 7.60 (m, 4H), 3.85 (m, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 1.12 (m, 3H), 0.65 (s, 3H), 0.63 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.73 (d, 1H), 7.65 (m, 4H), 3.82 (d, 2H), 2.54 (s, 3H), 2.37 (s, 3H), 0.60 (m, 1H), 0.33 (m, 2H), −0.12 (m,2H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.80 (m, 2H), 7.70 (d, 1H), 7.59 (m, 1H), 7.49 (m, 4H), 6.70 (s, 1H), 6.54 (d, 1H), 5.24 (s, 2H), 2.48 (s, 3H), 2.45 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.77 (s, 1H), 7.32 (m, 3H), 7.17 (m, 3H), 6.24 (s, 2H), 5.12 (s, 2H), 2.43 (s, 3+3H), 1.26 (s, 9H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.79 (d, 1H), 7.36 (m, 4H), 7.18 (d, 2H), 6.31 (d, 2H), 5.05 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 8.04 (d, 1H), 7.69 (t, 1H), 7.39 (m, 3H), 4.13 (d, 1H), 4.02 (d, 1H), 3.67 (s, 2H), 3.29 (m, 1H), 3.10 (m, 1H), 2.61 (s, 3H), 2.37 (s, 3H); (Yield: 37%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.81 (d, 1H), 7.22 (d, 2H), 7.15 (d, 2H), 7.00 (s, 2H), 5.66 (s, 1H), 4.86 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H), 2.12 (s, 3H), 1.76 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (t, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.64 (m, 4H), 3.89 (q, 2H), 2.50 (s, 3H), 2.35 (s, 3H), 0.93 (t, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (t, 1H), 7.72 (d, 1H), 7.61 (m, 4H), 3.76 (t, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 1.29 (q, 2H), 0.50 (t, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (t, 1H), 7.78 (d, 1H), 7.34 (d, 2H), 7.28 (d, 2H), 7.04 (s, 2H), 6.15 (s, 1H), 6.07 (d, 2H), 5.05 (s, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (d, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.47 (d, 1H), 7.33 (t, 2H), 7.32 (m, 2H), 6.62 (s, 1H), 6.58 (d, 1H), 5.11 (s, 2H), 2.42 (s, 3+3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.79 (t, 1H), 7.34 (m, 4H), 6.91 (m 2H), 6.32 (m, 2H), 5.06 (s, 2H), 2.42 (d, 3+3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.81 (d, 1H), 7.35 (d, 2H), 7.29 (d, 2H), 7.18 (q, 1H), 6.92 (t, 1H), 6.15 (d, 1H), 6.07 (d, 1H), 5.07 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (t, 1H), 7.72 (d, 1H), 7.66 (m, 4H), 3.82 (d, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 2.09 (m, 1H), 1.57 (m, 2+2H), 1.30 (t, 2H); (Yield: 57%)
In accordance with the same procedures as in Example 242, using 3-nitro-2-(4-fluorophenyl)pyridine prepared in Preparation 13, 7-(4-fluorophenyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (m, 1H), 7.95 (t, 2H), 7.73 (m, 1H), 7.59 (d, 1H), 6.90 (m, 2H), 2.64 (s, 3H), 2.32 (s, 3H)
The titled compounds of Examples 326 to 348 were prepared, in accordance with the same procedures as in Example 243, using 7-(4-fluorophenyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine obtained by treating the compound prepared in Example 325 with a saturated sodium carbonate solution; and, allyl bromide, 2-bromoethyl methyl ether, 3-fluorobenzyl chloride, benzyl chloride, bromomethyl methyl ether, 4-bromo-2-methyl-2-butene, 1-bromo-3-methylbutane, (bromomethyl)cyclopropane, 2-(bromomethyl)naphthalene, 4-tert-butylbenzyl bromide, 4-chlorobenzyl chloride, 2,5-dimethylbenzyl bromide, epibromohydrin, iodoethane, 1-iodo-2-methylpropane, 1-bromopropane, 3-methoxybenzyl bromide, 4-methoxybenzyl bromide, 3-methylbenzyl bromide, 4-methylbenzyl bromide, α-bromo-m-tolunitrile, 4-fluorobenzyl bromide, or propargyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.74 (s, 1H), 7.64 (s, 2H), 7.26 (s, 2H), 5.55 (m, 1H), 5.10 (d, 1H), 2.42 (s, 2+1H), 2.45 (s, 3H), 2.37 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (s, 1H), 7.71 (m, 3H), 7.30 (t, 2H), 4.06 (s, 2H), 3.06 (s, 2H), 3.04 (s, 3H), 2.52 (s, 3H), 2.35 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.80 (d, 1H), 7.38 (m, 2H), 7.16 (q, 1H), 7.08 (t, 2H), 6.94 (t, 1H), 6.14 (d, 1H), 6.13 (d, 1H), 5.08 (s, 2H), 2.44 (s, 3H), 2.42 (s, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.78 (d, 1H), 7.35 (m, 2H), 7.21 (m, 3H), 7.06 (t, 2H), 6.35 (d, 2H), 5.08 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 8.32 (t, 1H), 7.69 (m, 4H), 4.95 (s, 2H), 3.40 (s, 3H), 2.35 (s, 3+3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.69 (s, 3H), 7.26 (s, 2H), 4.67 (s, 1H), 4.44 (s, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 1.60 (s,3H), 1.58 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (s, 1H), 7.71 (s, 3H), 7.33 (s, 2H), 3.87 (s, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 1.14 (s, 1+2H), 0.65 (s, 3+3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (t, 1H), 7.72 (d, 3H), 7.32 (t, 2H), 3.83 (d, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 0.60 (m, 1H), 0.32 (d, 2H), 0.13 (d, 2H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.81 (d, 2H), 7.70 (t, 1H), 7.56 (t, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 7.24 (t, 2H), 6.71 (d, 1H), 6.55 (t, 1H), 5.23 (s, 2H), 2.45 (s, 3+3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.77 (t, 1H), 7.35 (m, 2H), 7.16 (t, 2H), 7.04 (m, 2H), 6.24 (t, 2H), 5.06 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.26 (s, 9H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.79 (d, 1H), 7.39 (m, 2H), 7.18 (t, 2H), 7.09 (t, 2H), 6.31 (t, 2H), 5.05 (s, 2H), 2.41 (s, 3+3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.80 (d, 1H), 7.21 (q, 2H), 6.99 (s, 2H), 6.94 (t, 2H), 5.67 (s, 1H), 4.87 (s, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H), 1.77 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3/MeOH-d4) δ 8.17 (d, 1H), 8.06 (d, 1H), 7.82 (d, 2H), 7.61 (t, 3H), 3.91 (s, 2H), 3.52 (m, 1H), 3.09 (d, 2H), 2.59 (s, 3H), 2.38 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (q, 1H), 7.68 (m, 3H), 7.33 (m, 2H), 3.87 (q, 2H), 2.50 (s, 3H), 2.35 (s, 3H), 0.91 (t, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (q, 1H), 7.71 (m, 3H), 7.33 (t, 2H), 3.74 (d, 2H), 2.51 (s, 3H), 2.36 (s, 3H), 1.39 (m, 1H), 0.44 (d, 3+3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.68 (m, 3H), 7.32 (t, 2H), 3.76 (t, 2H), 2.50 (s, 3H), 2.35 (s, 3H), 1.29 (q, 2H), 0.50 (t, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (t, 1H), 7.77 (d, 1H), 7.37 (t, 2H), 7.09 (m, 3H), 6.76 (d, 1H), 5.90 (s, 2H), 3.69 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.77 (d, 1H), 7.37 (t, 1H), 7.28 (t, 1H), 7.09 (t, 2H), 6.72 (d, 2H), 6.27 (d, 2H), 5.01 (s, 2H), 3.76 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.77 (d, 1H), 7.36 (t, 2H), 7.05 (m, 4H), 6.16 (s, 1H), 6.09 (d, 1H), 5.05 (s, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 2.21 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (t, 1H), 7.77 (d, 1H), 7.38 (m, 2H), 7.08 (t, 2H), 6.99 (d, 2H), 6.25 (d, 2H), 5.03 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3/MeOH-d4) δ 8.24 (s, 1H), 7.85 (d, 1H), 7.57 (m, 2H), 7.37 (m, 2H), 6.67 (s, 2H), 5.15 (s, 2H), 2.46 (s, 3H), 2.44 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, MeOH-d4) δ 8.17 (t, 1H), 7.97 (d, 1H), 7.48 (m, 2H), 7.26 (d,2H), 6.94 (t, 2H), 6.36 (t, 2H), 5.12 (s, 2H), 2.51 (s, 3H), 2.47 (s, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.73 (m, 3H), 7.26 (m, 2H), 6.39 (s, 1H), 5.07 (s, 2H), 2.60 (s, 3H), 2.37 (s, 3H); (Yield: 47%)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-methoxyphenyl)pyridine prepared in Preparation 14, the titled compound was obtained as a white solid. (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.30 (d, 1H), 8.19 (brs, 1H), 7.83 (d, 2H), 7.32 (d, 1H), 7.07 (d, 2H), 3.88 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H)
The titled compounds of Examples 350 to 370 were prepared, in accordance with the same procedures as in Example 243, using 7-(4-methoxyphenyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Example 349; and, benzyl bromide, (bromomethyl)cyclopropane, 3-fluorobenzyl chloride, 2-fluorobenzyl chloride, propargyl bromide, 2-bromoethyl methyl ether, 2-(bromomethyl)naphthalene, 4-chlorobenzyl bromide, 1-iodo-2-methylpropane, (bromomethyl)cyclobutane, allyl bromide, 4-bromo-2-methyl-2-butene, 1-bromo-3-methylbutane, 4-tert-butylbenzyl bromide, 2,5-dimethylbenzyl chloride, epibromohydrin, iodoethane, 1-bromopropane, 3-methoxybenzyl bromide, 4-methoxybenzyl bromide, or 4-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.72 (d, 1H), 7.34 (d, 2H), 7.18 (m, 3H), 6.88 (d, 2H), 6.40 (d, 2H), 5.13 (s, 2H), 3.88 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.54 (t, 1H), 7.83 (m, 3H), 7.28 (d, 2H), 4.07 (s, 3H), 4.05 (d, 2H), 2.69 (s, 3H), 2.52 (s, 3H), 0.77 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.75 (s, 1H), 7.33 (s, 2H), 7.15 (t, 1H), 6.91 (m, 3H), 6.15 (m, 2H), 5.14 (s, 2H), 3.85 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.38 (t, 1H), 7.73 (d, 1H), 7.30 (d, 2H), 7.22 (m, 1H), 6.96 (m, 2H), 6.87 (d, 2H), 6.04 (t, 1H), 5.14 (s, 2H), 3.84 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (d, 1H), 7.75 (d, 2H), 7.67 (d, 1H), 7.13 (d, 2H), 4.55 (s, 2H), 3.91 (s, 3H), 2.59 (s, 3H), 2.36 (s, 1H), 2.35 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (t, 1H), 7.65 (d, 1H), 7.57 (m, 2H), 7.09 (m, 2H), 4.11 (s, 2H), 3.89 (s, 3H), 3.04 (s, 2H), 3.02 (s, 3H), 2.51 (s, 3H), 2.34 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (d, 1H), 7.76 (m, 1H), 7.72 (d, 1H), 7.67 (d, 1H), 7.56 (m, 1H), 7.47 (m, 2H), 7.31 (d, 2H), 6.78 (d, 3H), 6.58 (d, 1H), 5.27 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H); (Yield: 97%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.72 (s, 1H), 7.33 (s, 2H), 7.16 (d, 2H), 6.88 (s, 2H), 6.32 (d, 2H), 5.10 (s, 2H), 3.84 (s, 3H), 2.40 (s, 3+3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.66 (m, 3H), 7.11 (d 2H), 3.90 (s, 3H), 3.79 (d, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 1.41 (m, 1H), 0.41 (s, 3H), 0.39 (s, 3H); (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 7.63 (m, 3H), 7.11 (d, 2H), 3.99 (d, 2H), 3.90 (s, 3H), 2.49 (s, 3H), 2.33 (s, 3H), 2.08 (m, 1H), 1.58 (m, 2+2H), 1.30 (t, 2H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (t, 1H), 7.69 (d, 1H), 7.57 (d, 2H), 7.07 (d, 2H), 5.55 (m, 1H), 5.09 (d, 1H), 4.47 (s, 2H), 4.39 (d, 1H), 3.90 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.63 (t, 3H), 7.07 (d, 2H), 4.68 (s, 1H), 4.49 (s, 2H), 3.89 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H), 1.59 (s, 3H), 1.33 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (t, 1H), 7.64 (m, 3H), 7.11 (d, 2H), 3.89 (s, 2+3H), 2.48 (s, 3H), 2.34 (s, 3H), 1.09 (m, 1+2H), 0.63 (s, 3H), 0.61 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 7.70 (m, 1H), 7.31 (m, 2H), 7.16 (m, 2H), 6.86 (m, 2H), 6.29 (m, 2H), 5.11 (s, 2H), 3.85 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.25 (s, 9H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.75 (s, 1H), 7.18 (s, 2H), 6.97 (s, 2H), 6.76 (s, 2H), 5.72 (s, 1H), 4.92 (s, 2H), 3.81 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H), 1.78 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 1H), 7.59 (m, 1H), 7.43 (m, 2H), 6.96 (s, 2H), 4.12 (m, 2H), 3.87 (s, 3H), 3.77 (s, 1H), 3.13 (m, 1H), 3.05 (m, 1H), 2.56 (s, 3H), 2.37 (s, 3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.66 (m, 3H), 7.08 (s, 2H), 3.90 (s, 2+3H), 2.50 (s, 3H), 2.35 (s, 3H), 0.91 (t, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.65 (d, 1H), 7.59 (s,2H), 7.10 (s, 2H), 3.90 (s, 3H), 3.82 (t, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.27 (m, 2H), 0.50 (t, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.71 (d, 1H), 7.31 (s, 2H), 7.08 (t, 1H), 6.84 (s, 2H), 6.74 (d, 1H), 5.94 (d, 2H), 5.09 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.33 (s, 1H), 7.70 (s, 1H), 7.36 (s,2H), 6.89 (s, 2H), 6.70 (d, 2H), 6.31 (d, 2H), 5.07 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (s, 1H), 7.72 (d, 1H), 7.34 (s, 2H), 6.88 (m, 4H), 6.35 (t, 2H), 5.11 (s, 2H), 3.84 (s 3H), 2.42 (s, 3H), 2.39 (s, 3H); (Yield: 50%)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-phenylpyridine prepared in Preparation 15, 2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 8.18 (brs, 1H), 7.89 (d, 2H), 7.54 (t, 2H), 7.45 (t, 1H), 7.35 (d, 1H), 2.41 (s, 3H), 2.25 (s, 3H)
The titled compounds of Examples 372 to 394 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 371; and, allyl bromide, 4-methylbenzyl bromide, iodoethane, 3-fluorobenzyl chloride, benzyl chloride, 1-iodo-2-methylpropane, bromomethyl methyl ether, 2-bromoethyl methyl ether, 4-methoxybenzyl bromide, 4-chlorobenzyl bromide, 2-chlorobenzyl bromide, 4-bromo-2-methyl-2-butene, (bromomethyl)cyclopropane, (bromomethyl)cyclohexane, 1-bromopentane, 2,5-dimethylbenzyl chloride, 3,4-dichlorobenzyl chloride, 1-bromopropane, 3-methoxybenzyl bromide, 3-methylbenzyl bromide, 4-fluorobenzyl bromide, (bromomethyl)cyclobutane, or 2-fluorobenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.64 (m, 6H), 5.52 (m, 1H), 5.08 (m, 1H), 4.42 (m, 1+2H), 2.47 (s, 3H), 2.40 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.27 (brs, 4H), 6.96 (d, 2H), 6.22 (d, 2H), 5.02 (s, 2H), 2.42 (s, 3+3H), 2.28 (s, 3H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.64 (m, 6H), 3.87 (q, 2H), 2.50 (s, 3H), 2.37 (s, 3H), 0.92 (t, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.61 (m, 1H), 7.45 (m, 1H), 7.30 (m, 4H), 7.11 (m, 1H), 6.87 (t, 1H), 6.13 (d, 1H), 6.06 (d, 1H), 5.01 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.44 (m, 1H), 7.84 (m, 1H), 7.50 (m, 1H), 7.42 (m, 4H), 7.25 (m, 3H), 6.39 (d, 2H), 5.14 (m, 2H), 2.50 (s 3H), 2.42 (s, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.70 (m, 6H), 3.76 (brs, 2H), 2.52 (s, 3H), 2.38 (s, 3H), 1.26 (m, 1H), 0.39 (s, 3+3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 8.01 (m, 1H), 7.70 (m, 2H), 7.60 (m, 3H), 4.95 (s, 2H), 2.91 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.26 (m, 1H), 7.57 (m, 6H), 4.05 (m, 2H), 3.32 (m, 2H), 3.03 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H); (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (m, 1H), 7.78 (m, 1H), 7.56 (m, 2H), 7.42 (m, 3H), 6.75 (s, 2H), 6.31 (s, 2H), 5.09 (s, 2H), 3.76 (s, 3H), 2.45 (s, 3+3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.38 (m, 4H), 7.12 (s, 2H), 6.26 (s, 2H), 5.05 (s, 2H), 2.42 (s, 3+3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.44 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.29 (m, 3H), 7.26 (m, 3H), 7.10 (s, 1H), 5.94 (s, 1H), 5.03 (s, 2H), 2.45 (s, 3H), 2.42 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.39 (brs, 1H), 7.69-7.56 (m, 6H), 4.66 (t, 1H), 4.43 (d, 3H), 2.45 (s, 3H), 2.35 (s, 3H), 1.57 (s, 3H), 1.21 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.64-7.56 (m, 6H), 3.79 (d, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 0.65 (m, 1H), 0.25 (m, 2H), −0.19 (m, 2H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (t, 1H), 7.70-7.59 (m, 6H), 3.74 (d, 2H), 2.49 (s, 3H), 2.32 (s, 3H), 1.47 (m, 2H), 1.05 (m, 1H), 0.81 (m, 4H), 0.72 (m, 2H), 0.55 (m, 2H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 7.65 (m, 6H), 3.77 (t, 2H), 2.48 (s, 3H), 2.34 (s, 3H), 1.21 (m, 2H), 1.03 (m, 2H), 0.85 (m, 2H), 0.73 (t, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.42 (t, 1H), 7.79 (d, 1H), 7.48 (t, 1H), 7.28 (m, 2H), 7.22 (m, 2H), 6.95 (m, 2H), 5.67 (s, 1H), 4.85 (s, 2H), 2.45 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H), 1.69 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.36 (d, 1H), 7.59 (m, 1H), 7.46 (m, 2H), 7.32 (m, 3H), 7.19 (d, 1H), 6.44 (s, 1H), 6.15 (d, 1H), 4.96 (s, 2H), 2.36 (s, 3H), 2.34 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (m, 1H), 8.01 (m, 1H), 7.68 (d, 1H), 7.58 (m, 4H), 3.71 (t, 2H), 2.48 (s, 3H), 2.35 (s, 3H), 0.83 (m, 2H), 0.45 (t, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (m, 1H), 7.91 (d, 1H), 7.55 (m, 1H), 7.39 (m, 1H), 7.28 (m, H), 7.04 (t, 1H), 6.70 (d, 1H), 5.96 (d, 1H), 5.91 (s, 1H), 4.96 (s, 2H), 3.66 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (t, 1H), 7.76 (d, 1H), 7.53 (m, 1H), 7.37 (m, 4H), 7.02 (m, 2H), 6.12 (s, 1H), 6.08 (d, 1H), 5.03 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (d, 1H), 7.57 (d, 1H), 7.39 (m, 1H), 7.30 (m, 4H), 6.83 (t, 2H), 6.30 (m, 2H), 4.98 (s, 2H), 2.35 (s, 3H), 2.33 (s, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.32 (m, 1H), 8.01 (m, 1H), 7.63 (m, 4H), 7.57 (m, 1H), 3.92 (d, 2H), 2.50 (s, 3H), 2.34 (s, 3H), 1.01 (m, 1H), 0.81 (m, 6H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.43 (d, 1H), 7.77 (d, 1H), 7.53 (t, 1H), 7.33 (m, 4H), 7.23 (m, 1H), 6.94 (m, 2H), 6.00 (t, 1H), 5.07 (s, 2H), 2.41 (s, 3+3H); (Yield: 48%)
The compound prepared in Example 376 was treated with a saturated sodium carbonate solution to obtain 1-benzyl-2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine. 1-Benzyl-2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine (130 mg, 0.42 mmol) was dissolved in acetic acid (4 ml) and ammonium cerium (IV) nitrate (690 mg, 1.25 mmol) was added thereto at room temperature. The reaction mixture was stirred for 3 hours at 55° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 ml) and then 2N lithium hydroxide (3 ml) was added thereto. The reaction mixture was stirred overnight at room temperature, neutralized with 1N hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/5, v/v). The resulting product was dissolved in ethyl acetate and then saturated with hydrochloric acid gas to give 2.8 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.21 (brs, 1H), 8.00 (brs, 1H), 7.54 (t, 1H), 7.37 (m, 4H), 7.16 (m, 3H), 6.35 (d, 2H), 5.08 (s, 2H), 4.99 (s, 2H), 2.52 (s, 3H)
The compound prepared in Example 376 was treated with a saturated sodium carbonate solution to obtain 1-benzyl-2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine. 1-Benzyl-2,3-dimethyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine (130 mg, 0.42 mmol) was dissolved in acetic acid (4 ml) and ammonium cerium (IV) nitrate (690 mg, 1.25 mmol) was added thereto at room temperature. The reaction mixture was stirred for 3 hours at 55□ and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 ml) and then 2N lithium hydroxide (3 ml) was added thereto. The reaction mixture was stirred overnight at room temperature, neutralized with 1N hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/4, v/v) to give 1 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 7.72 (brs, 2H), 7.60 (d, 1H), 7.54 (m, 2H), 7.23 (m, 2H), 7.13 (m, 2H), 6.39 (d, 2H), 5.37 (s, 2H), 5.01 (s, 3H), 2.38 (s, 3H), 2.09 (s, 3H)
In accordance with the same procedures as Preparation 9, except for using 1-naphthaleneboronic acid, the titled compound was obtained as a white solid. (Yield: 56%)
In accordance with the same procedures as in Example 242, except for using 2-(naphthalen-1-yl)-3-nitropyridine prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.96 (t, 2H), 7.79 (d, 1H), 7.69 (m, 2H), 7.62 (t, 1H), 7.60 (t, 1H), 7.44 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H)
The titled compounds of Examples 398 to 401 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-(naphthalen-1-yl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 397; and, benzyl bromide, 1-iodo-2-methylpropane, 1-bromopropane, or 3-methoxybenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 9.30 (brs, 1H), 8.16 (brs, 1H), 8.15 (brs, 1H), 8.01 (brs, 1H), 7.21 (m, 2H), 7.01 (m, 2H), 6.77 (m, 2H), 6.01 (s, 2H), 5.71 (d, 1H), 5.40 (d, 1H), 4.59 (d, 1H), 4.39 (d, 1H), 2.45 (s, 3H), 2.30 (s, 3H); (Yield: 37%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 7.96 (t, 2H), 7.79 (d, 1H), 7.71 (m, 2H), 7.70 (m, 1H), 7.45 (m, 1H), 7.44 (m, 1H), 3.66 (s, 2H), 2.55 (s, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 0.79 (d, 2H), 0.65 (d, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 9.02 (d, 1H), 8.24 (d, 1H), 8.05 (m, 2H), 7.86 (d, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.56 (m, 1H), 7.11 (d, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.12 (m, 1H), 3.01 (m, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 0.75 (t, 3H); (Yield: 41%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (d, 1H), 8.01 (d, 1H), 7.88 (d, 1H), 7.56 (m, 2H), 7.40 (m, 2H), 7.21 (m, 1H), 7.12 (m, 1H), 6.98 (m, 1H), 6.72 (d, 1H), 6.32 (d, 1H), 6.22 (s, 1H), 4.92 (d, 2H), 3.65 (s, 3H), 2.48 (s, 3H), 2.33 (s, 3H); (Yield: 36%)
In accordance with the same procedures as in Example 242, using 2-(naphthalen-2-yl)-3-nitropyridine prepared in Preparation 16, 2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 8.37 (d, 1H), 8.33 (s, 1H), 8.20 (d, 1H), 8.01 (s, 1H), 7.95 (m, 1H), 7.85 (m, 1H), 7.55 (m, 2H), 7.35 (d, 1H), 7.10 (d, 1H), 2.44 (s, 3H), 2.17 (s, 3H)
The titled compounds of Examples 403 to 409 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 402; and, (bromomethyl)cyclopropane, iodoethane, 3-fluorobenzyl chloride, 4-tert-butylbenzyl chloride, 1-iodopropane, propargyl bromide, or 2-fluorobenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 2H), 7.91 (m, 3H), 7.63 (m, 2H), 7.52 (m, 2H), 3.80 (d, 2H), 2.54 (s, 3H), 2.38 (s, 3H), 0.56 (m, 1H), 0.19 (m, 2H), −0.30 (m, 2H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 8.01 (m, 2H), 7.89 (m, 2H), 7.77 (m, 2H), 7.56 (m, 2H), 3.82 (q, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 1.25 (t, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (s, 1H), 8.15 (s, 1H), 7.82 (m, 2H), 7.76 (d, 2H), 7.56 (m, 3H), 7.08 (m, 1H), 6.91 (t, 1H), 5.98 (d, 1H), 5.90 (d, 1H), 5.01 (s, 2H), 2.43 (s, 3+3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.93 (m, 3H), 7.67 (m, 3H), 7.56 (m, 2H), 7.04 (d, 2H), 6.09 (d, 2H), 5.00 (s,2H), 2.45 (s, 3H), 2.43 (s, 3H), 1.25 (s, 9H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 8.05 (s, 1H), 7.92 (m, 2H), 7.61 (m, 2H), 7.55 (m,3H), 3.70 (t, 2H), 2.49 (s, 3H), 2.36 (s, 3H), 0.82 (m, 2H), 0.24 (t, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 8.28 (s, 1H), 8.25 (s, 1H), 8.01 (m, 3H), 7.82 (m, 2H), 7.52 (m, 2H), 5.16 (s, 2H), 2.55 (s, 1H), 2.41 (s, 3H), 2.11 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.98 (d, 1H), 7.89 (d, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.19 (m, 1H), 6.92 (t, 1H), 6.71 (t, 1H), 6.01 (t, 1H), 5.02 (s, 2H), 2.43 (s, 3H), 2.08 (s, 3H); (Yield: 66%)
The compound prepared in Example 402 was treated with a saturated sodium bicarbonate solution to obtain 2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine. A solution of 2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine (73.5 mg, 0.27 mmol) and sodium hydride (6.5 mg, 0.27 mmol) in anhydrous tetrahydrofuran (2 ml) was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was re-crystallized with ethyl ether to give 73 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, MeOH-d4) δ 8.48 (brs, 1H), 8.24 (m, 1H), 8.16 (m, 2H), 8.06 (m, 2H), 7.92 (m, 1H), 7.70 (m, 2H), 2.59 (s, 3H), 2.39 (s, 3H)
The compound prepared in Example 405 was treated with a saturated sodium bicarbonate solution to obtain 1-(3-fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine. 1-(3-Fluorobenzyl)-2,3-dimethyl-7-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine (225 mg, 0.59 mmol) was dissolved in acetic acid (5 ml) and ammonium cerium (IV) nitrate (973 mg, 1.77 mmol) was added thereto at room temperature. The reaction mixture was stirred for 3 hours at 55° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 ml) and then 2N lithium hydroxide (2.5 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature, neutralized with 1N hydrochloric acid solution, and then concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 45 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 8.04 (s, 1H), 7.86 (t, 2H), 7.74 (s, 1H), 7.57 (m, 3H), 7.41 (m, 1H), 7.01 (m, 1H), 6.86 (t, 1H), 6.01 (d, 1H), 5.92 (d, 1H), 5.03 (s, 2H), 4.98 (s, 2H), 2.51 (s, 3H)
18-Crown-6 (26 mg, 0.098 mmol) and potassium tert-butoxide (253 mg, 2.25 mmol) were added to a solution of 2,3-dimethyl-7-(4-methylsulfanylphenyl)-1H-pyrrolo[2,3-c]pyridine (300 mg, 0.98 mmol) prepared in Example 262 in anhydrous tetrahydrofuran (9 ml). The reaction mixture was stirred for 30 minutes at room temperature and benzyl bromide (175 μl, 1.47 mmol) was added thereto. The reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water was added thereto. The separated organic layer was dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting pale yellow solid (242 mg, 0.67 mmol) was dissolved in 6 ml of acetic acid. Ammonium cerium (IV) nitrate (1.11 g, 2.01 mmol) was added at room temperature to the resulting solution, which was stirred for 3 hours at 55° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (11 ml) and 2N lithium hydroxide (3 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature, neutralized with 1N hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to obtain 1-benzyl-3-hydroxymethyl-2-methyl-7-(4-methylsulfanylphenyl)-1H-pyrrolo[2,3-c]pyridine. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 48 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.23 (brs, 1H), 8.09 (d, 1H), 7.75 (m, 1H), 7.48 (brs, 3H), 7.20 (m, 1H), 7.15 (m, 2H), 6.31 (d, 2H), 5.09 (s, 2H), 4.93 (s, 2H), 2.79 (s, 3H), 2.55 (s, 3H)
18-Crown-6 (3 mg, 0.011 mmol) and potassium tert-butoxide (37 mg, 0.291 mmol) were added to a solution of 1-benzyl-3-hydroxymethyl-2-methyl-7-(4-methylsulfanylphenyl)-1H-pyrrolo[2,3-c]pyridine hydrochloride (48 mg, 0.11 mmol) prepared in Example 412 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 30 minutes at room temperature and iodoethane (10 μl, 0.165 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 6.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.97 (d, 1H), 7.23 (m, 7H), 6.36 (d, 2H), 5.10 (s, 2H), 4.76 (s, 2H), 3.67 (q, 2H), 2.79 (s, 3H), 2.51 (s, 3H), 1.32 (t, 3H)
In accordance with the same procedures as in Example 242, using 3-nitro-2-styrylpyridine prepared in Preparation 17 as a starting matertal, 2,3-dimethyl-7-styryl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 32%)
1H-NMR(400 MHz, CDCl3) δ 7.94 (s, 1H), 7.79 (t, 1H), 7.47 (m, 2H), 7.20 (m, 2H), 7.07 (m, 3H), 2.59 (s, 3H), 2.06 (s, 3H)
The titled compounds of Examples 415 to 427 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-styryl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 414; and, iodoethane, allyl bromide, 4-methylbenzyl chloride, benzyl bromide, 3-fluorobenzyl bromide, 2-bromoethyl methyl ether, 1-bromo-2-methylpropane, 3-methoxybenzyl chloride, (bromomethyl)cyclopropane, iodomethane, bromomethyl methyl ether, 4-methoxybenzyl bromide, or 4-chlorobenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.50 (m, 1H), 8.26 (s, 1H), 7.72 (brs, 2H), 7.52 (m, 2H), 7.41 (s, 3H), 4.50 (s, 2H), 2.53 (s, 3H), 2.30 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.07 (d, 1H), 7.89 (d, 1H), 7.70 (d, 3H), 7.50 (m, 4H), 6.23 (m, 1H), 5.33 (d, 1H), 5.16 (s, 2H), 4.68 (d, 1H), 2.54 (s, 3H), 2.39 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (d, 1H), 7.92 (d, 1H), 7.41 (brs, 7H), 7.16 (d, 2H), 6.84 (d, 2H), 5.76 (s, 2H), 2.56 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (d, 1H), 7.92 (m, 2H), 7.72 (m, 2H), 7.54 (m, 1H), 7.45 (m, 4H), 7.33 (m, 2H), 6.95 (d, 2H), 5.82 (s, 2H), 2.57 (s, 3H), 2.44 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.87 (t, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.59 (m, 2H), 7.55 (m, 3H), 7.44 (m, 5H), 5.83 (s, 2H), 2.57 (s, 3H), 2.44 (s, 3H); (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 8.03 (d, 1H), 8.08 (d, 1H), 7.86 (m, 1H), 7.75 (m,2H), 7.68 (m, 1H), 7.48 (m, 3H), 4.72 (t, 2H), 3.81 (t, 2H), 3.29 (d, 3H), 2.59 (s, 3H), 2.36 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (s, 1H), 7.87 (brs, 2H), 7.77 (m, 2H), 7.49 (m, 4H), 4.38 (brs, 2H), 2.60 (s, 3H), 2.37 (s, 3H), 2.15 (m, 1H), 0.87 (brs, 3+3H); (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 7.91 (d, 1H), 7.73 (m, 1H), 7.68 (m, 1H), 7.59 (m, 1H), 7.25 (m, 5H), 6.87 (d, 2H), 6.57 (s, 1H), 6.45 (d, 1H), 5.77 (s, 2H), 3.67 (s, 2H), 2.58 (s, 3H), 2.44 (s, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.28 (d, 1H) 7.38-7.55 (m, 7H), 3.72 (d, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 0.51 (m, 1H), 0.17 (m, 2H), −0.20 (m, 2H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.01 (s, 2H), 7.84 (d, 1H), 7.79 (d, 2H), 7.50 (m, 4H), 4.13 (s, 3H), 2.58 (s, 3H), 2.36 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.74 (d, 2H), 7.65 (d, 1H), 7.46 (m, 3H), 5.73 (s, 2H), 3.45 (s, 3H), 2.66 (s, 3H), 2.37 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.04 (d, 1H), 7.91 (d, 1H), 7.45 (m, 7H), 6.87 (s, 4H), 5.73 (s, 2H), 3.72 (s, 3H), 2.56 (s, 3H), 2.42 (s 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (d, 1H), 7.95 (m, 2H), 7.77 (m, 2H), 7.42 (brs, 4H), 7.32 (m, 2H), 6.92 (d, 2H), 5.80 (s, 2H), 2.56 (s, 3H), 2.42 (s, 3H); (Yield: 47%)
In accordance with the same procedures as in Example 242, using 2-benzyl-3-nitropyridine prepared in Preparation 18, 7-benzyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 35%)
1H-NMR(400 MHz, DMSO-d6) δ 8.11 (d, 1H), 7.83 (d, 1H), 7.44 (d, 2H), 7.34 (m, 2H), 7.25 (m, 1H), 4.64 (s, 2H), 2.56 (s, 3H), 2.26 (s, 3H)
The titled compounds of Examples 429 to 439 were prepared, in accordance with the same procedures as in Example 243, using 7-benzyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 428; and, benzyl bromide, (bromomethyl)cyclopropane, 4-chlorobenzyl chloride, 3-fluorobenzyl bromide, iodoethane, 3-methylbenzyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl chloride, allyl bromide, 3-chlorobenzyl chloride, or 4-methoxybenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.24 (s, 1H), 7.73 (s, 1H), 7.33 (s, 3H), 7.26 (s, 3H), 6.99 (s, 2H), 6.66 (s, 2H), 5.30 (s, 2H), 4.69 (s, 2H), 2.37 (s, 3+3H); (Yield: 38%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (t, 1H), 7.65 (d, 1H), 7.22 (m, 3H), 7.09 (d, 2H), 5.09 (s, 2H), 4.13 (d, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 1.01 (m, 1H), 0.63 (m, 2H), 0.24 (m, 2H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (t, 1H), 7.74 (d, 1H), 7.23 (m, 5H), 6.96 (d, 2H), 6.59 (d, 2H), 5.28 (s, 2H), 4.72 (s, 2H), 2.36 (s, 3H), 2.35 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (t, 1H), 7.75 (d, 1H), 7.24 (m, 4H), 7.02 (t, 2H), 6.97 (d, 2H), 6.46 (d, 1H), 6.32 (d, 1H), 5.29 (s, 2H), 4.72 (s, 2H), 2.37 (s, 3+3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (t, 1H), 7.65 (d, 1H), 7.27 (m, 3H), 7.09 (d, 2H), 5.02 (s, 2H), 4.21 (q, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 1.21 (t, 3H); (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (t, 1H), 7.73 (d, 1H), 7.23 (m, 4H), 7.13 (d, 1H), 6.99 (d, 2H), 6.45 (s, 1H), 6.43 (d, 1H), 5.26 (s, 2H), 4.70 (s, 2H), 2.37 (s, 3+3H), 2.29 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (t, 1H), 7.72 (d, 1H), 7.24 (m, 3H), 7.13 (d, 2H), 6.99 (d, 2H), 6.56 (d, 2H), 5.25 (s, 2H), 4.69 (s, 2H), 2.37 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (t, 1H), 7.74 (d, 1H), 7.21 (m, 3H), 7.04 (t, 2H), 6.97 (d, 2H), 6.63 (m, 2H), 5.28 (s, 2H), 4.72 (s, 2H), 2.36 (s, 3+3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (t, 1H), 7.69 (d, 1H), 7.25 (m, 3H), 7.05 (d, 2H), 5.94 (m, 1H), 5.21 (d, 1H), 4.96 (s, 2H), 4.70 (s, 2H), 4.43 (d, 1H), 2.32 (s, 3H), 2.28 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.26 (t, 1H), 7.75 (d, 1H), 7.23 (m, 5H), 6.96 (d, 2H), 6.62 (s, 1H), 6.52 (d, 1H), 5.28 (s, 2H), 4.73 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H); (Yield: 41%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (t, 1H), 7.71 (d, 1H), 7.21 (m, 2H), 6.98 (d, 2H), 6.85 (d, 2H), 6.61 (m, 2+1H), 5.23 (s, 2H), 4.70 (s, 2H), 3.81 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H); (Yield: 39%)
In accordance with the same procedures as in Example 242, using 3-phenethyl-2-nitropyridine prepared in Preparation 19, 2,3-dimethyl-7-phenethyl-1H-pyrrolo[2,3-c]pyridine was obtained. The product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 7.92 (d, 1H), 7.73 (d, 1H), 7.22 (m, 3H), 7.11 (d, 2H), 3.54 (t, 2H), 3.16 (t, 2H), 2.54 (s, 3H), 2.30 (s, 3H)
The titled compounds of Examples 441 to 462 were prepared, in accordance with the same procedures as in Example 243, using 2,3-dimethyl-7-phenethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 440; and, iodoethane, benzyl bromide, 2-bromoethyl methyl ether, 4-methylbenzyl chloride, 4-methoxybenzyl chloride, 4-chlorobenzyl chloride, 1-iodo-2-methylpropane, allyl bromide, 3-fluorobenzyl chloride, 2-fluorobenzyl chloride, 3,4-dichlorobenzyl chloride, 4-chloromethyl-2-methylthiazole, (bromomethyl)cyclopropane, cinnamyl chloride, 4-fluorobenzyl chloride, 4-chloromethyl-3,5-dimethylisoxazole, 4-bromo-2-methyl-2-butene, propargyl bromide, propargyl bromide, iodomethane, 2-chlorobenzyl chloride, or epibromohydrin.
1H-NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.58 (s, 1H), 7.31 (m, 5H), 4.27 (q, 2H), 3.82 (brs, 2H), 3.30 (brs, 2H), 2.50 (s, 3H), 2.30 (s, 3H), 1.37 (t, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.64 (brs, 1H), 7.31 (m, 3H), 7.23 (m, 3H), 7.12 (brs, 2H), 6.71 (brs, 2H), 5.40 (brs, 2H), 3.57 (brs, 2H), 3.14 (brs, 2H), 2.42 (s, 3H), 2.37 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.56 (s, 1H), 7.29 (m, 4H), 7.23 (m, 1H), 4.36 (brs, 2H), 3.85 (brs, 2H), 3.58 (s, 3H), 3.24 (brs, 2H), 3.20 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (s, 1H), 7.63 (s, 1H), 7.25 (m, 3H), 7.03 (m, 4H), 6.59 (brs, 2H), 3.58 (brs, 2H), 3.14 (brs, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.31 (s,3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 7.13 (m, 5H), 6.95 (m, 2H), 6.73 (m, 2H), 6.62 (brs, 2H), 5.34 (brs, 2H), 3.76 (brs, 3H), 3.47 (brs, 2H), 3.15 (brs, 2H), 2.42 (s, 3H), 2.36 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.71 (s, 1H), 7.26 (m, 5H), 7.04 (brs, 2H), 6.64 (brs, 2H), 5.34 (brs, 2H), 3.48 (brs, 2H), 3.17 (brs, 2H), 2.40 (s, 3H), 2.37 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 7.21 (m, 7H), 3.99 (brs, 2H), 3.81 (brs, 2H), 3.28 (brs, 2H), 2.50 (brs, 3H), 2.33 (brs, 3H), 2.10 (brs, 1H), 0.88 (brs, 6H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.60 (brs, 1H), 7.31 (m, 3H), 7.22 (m, 2H), 5.98 (m, 1H), 5.25 (d, 1H), 4.80 (s, 2H), 4.48 (d, 1H), 3.74 (brs, 2H), 3.28 (brs, 2H), 2.49 (s, 3H), 2.35 (s, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.65 (brs, 1H), 7.25 (m, 3H), 7.12 (m, 2H), 7.01 (m, 2H), 6.51 (m, 1H), 6.38 (m, 1H), 5.34 (s, 2H), 3.49 (brs, 2H), 3.16 (brs, 2H), 2.42 (s, 3H), 2.37 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.67 (brs, 1H), 7.25 (m, 3H), 7.17 (m, 3H), 7.00 (m, 2H), 6.10 (m, 1H), 5.45 (s, 2H), 3.54 (brs, 2H), 3.17 (brs, 2H), 2.42 (s, 3H), 2.37 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.66 (brs, 1H), 7.38 (brs, 1H), 7.15 (m, 3H), 7.09 (m, 2H), 6.83 (s, 1H), 6.53 (m, 1H), 5.27 (s, 2H), 3.55 (brs, 2H), 3.17 (brs, 2H), 2.40 (s, 3H), 2.37 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.62 (brs, 1H), 7.22 (m, 5H), 6.33 (brs, 1H), 5.45 (s, 2H), 3.73 (brs, 2H), 3.21 (brs, 2H), 2.67 (s, 3H), 2.48 (s, 3H), 2.34 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.58 (s, 1H), 7.28 (m, 5H), 4.17 (d, 2H), 3.90 (t, 2H), 3.28 (t, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 1.05 (m, 1H), 0.62 (m, 2H), 0.26 (m, 2H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.58 (m, 2H), 7.26 (m, 5H), 7.13 (m, 3H), 6.88 (brs, 1H), 6.28 (brs, 1H), 5.90 (s, 1H), 3.48 (brs, 2H), 3.23 (brs, 2H), 2.49 (s, 3H), 2.20 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.61 (brs, 1H), 7.26 (m, 3H), 7.13 (m, 2H), 7.02 (m, 2H), 6.68 (m, 2H), 5.36 (s, 2H), 3.48 (brs, 2H), 3.18 (brs, 2H), 2.41 (s, 3H), 2.37 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.43 (m, 1H), 8.22 (m, 1H), 7.66 (m, 1H), 7.18 (m, 3H), 6.72 (m, 1H), 5.06 (m, 2H), 3.35 (m, 2H), 3.22 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.07 (s, 3+3H); (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (s, 1H), 7.54 (s, 1H), 7.27 (m, 3H), 6.86 (brs, 2H), 4.93 (brs, 1H), 4.85 (brs, 2H), 3.76 (brs, 2H), 3.26 (brs, 2H), 2.45 (brs, 3H), 2.30 (bs. 3H), 1.69 (brs, 3+3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.58 (s, 1H), 7.40 (m, 2H), 7.15 (m, 2H), 6.70 (brs, 1H), 5.48 (brs, 2H), 3.92 (brs, 2H), 3.25 (brs, 2H), 2.46 (s, 1H), 2.31 (s, 3H), 2.17 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (s, 1H), 7.59 (s, 1H), 7.41 (m, 2H), 7.27 (m, 2H), 7.24 (m, 1H), 4.08 (brs, 2H), 3.28 (brs, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H); (Yield: 24%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (brs, 1H), 7.57 (brs, 1H), 7.23 (m, 5H), 3.88 (brs, 3+2H), 3.31 (brs, 2H), 2.48 (s, 3H), 2.31 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (brs, 1H), 7.68 (brs, 1H), 7.47 (m, 1H), 6.90 (m, 8H), 5.32 (s, 2H), 3.47 (brs, 2H), 3.01 (brs, 2H), 2.46 (brs, 6H); (Yield: 78%)
1H-NMR(400 MHz, CDCl3) δ 7.80 (s, 1H), 7.37 (s, 1H), 7.21 (m, 3H), 7.10 (m, 2H), 4.36 (m, 1H), 4.23 (m, 2H), 3.92 (m, 1H), 3.57 (m, 1H), 3.50 (m, 2H), 2.99 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H); (Yield: 77%)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-chlorophenyl)pyridine prepared in Preparation 12 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 32%)
1H-NMR(400 MHz, CDCl3) δ 8.45 (brs, 1H), 8.30 (d, 1H), 7.83 (d, 2H), 7.51 (d, 2H), 7.45 (d, 1H), 6.34 (s, 1H), 2.52 (s, 3H)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-phenylpyridine prepared in Preparation 15 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)
18-Crown-6 (2 mg, 0.006 mmol) and potassium tert-butoxide (7 mg, 0.066 mmol) were added to a solution of 2-methyl-7-phenyl-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.066 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 30 minutes at room temperature and benzyl bromide (11.8 μl, 0.099 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/8, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 10.39 (s, 1H), 8.67 (dd, 2H), 7.57 (t, 1H), 7.39 (m, 3H), 7.22 (m, 4H), 6.36 (d, 2H), 5.17 (d, 2H), 2.81 (s, 3H)
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-(4-fluorophenyl)pyridine prepared in Preparation 13 and isopropenyl magnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)
In accordance with the same procedures as in Step 2 of Example 464, except for using 7-(4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and allyl bromide, 9 mg of the titled compound was obtained as a white solid.
1H-NMR(400 MHz, CDCl3) δ 10.36 (s, 1H), 8.67 (d, 1H), 8.57 (d, 1H), 7.64 (s, 2H), 7.28 (t, 2H), 5.58 (m, 1H), 5.22 (d, 1H), 4.51 (s, 2H), 4.46 (d, 1H), 2.83 (s, 3H)
A solution of 7-(4-chlorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (170 mg, 0.07 mmol) prepared in Example 463, dimethylamine (2.0M tetrahydrofuran solution; 375 μl, 0.75 mmol), acetic acid (0.36 ml) and formaldehyde (0.68 ml) in ethanol (10 ml) was refluxed for 60 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with a sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 85 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.41 (brs, 1H), 8.34 (d, 1H), 7.79 (d, 2H), 7.50 (m, 2+1H), 4.65 (s, 2H), 3.58 (q, 2H), 2.50 (s, 3H), 1.25 (t, 3H)
18-Crown-6 (2 mg, 0.006 mmol) and potassium tert-butoxide (7 mg, 0.066 mmol) were added to a solution of 7-(4-chlorophenyl)-3-ethoxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.066 mmol) prepared in Example 466 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 30 minutes at room temperature and then benzyl bromide (11.8 μl, 0.099 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.97 (d, 1H), 7.23 (m, 7H), 6.36 (d, 2H), 5.10 (s, 2H), 4.76 (s, 2H), 3.67 (q, 2H), 2.51 (s, 3H), 1.32 (t, 3H)
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution; 112 ml) was slowly added at −78° C. to a solution of 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine (4.8 g, 18.8 mmol) prepared in Preparation 20 in anhydrous tetrahydrofuran (150 ml). The reaction mixture was stirred for 4 hours at −20° C. 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 1.3 g of the titled compound as yellow solid.
1H-NMR(400 MHz, CDCl3) δ 13.05 (brs, 1H), 11.59 (brs, 1H), 7.54 (brs, 1H), 7.08 (brs, 1H), 6.98 (m, 1H), 6.91 (brs, 1H), 6.78 (s, 2H), 5.04 (s, 2H), 3.97 (s, 2H), 2.89 (s, 2H), 2.63 (s, 3H), 2.14 (s, 3H)
Sodium hydride (60%; 40 mg, 0.999 mmol) and benzyl bromide (0.475 ml, 0.399 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92,3 mg, 0.333 mmol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature and ice was added thereto. The reaction mixture was extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 23.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.17 (brs, 1H), 7.51 (d, 1H), 7.19 (m, 4H), 7.10 (m, 2H), 6.69 (d, 1H), 6.55 (d, 2H), 5.64 (s, 2H), 4.50 (brs, 2H), 3.89 (brs, 2H), 2.86 (s, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
The titled compounds of Examples 470 to 484 were prepared, in accordance with the same procedures as in Example 469, using 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 468; and, iodomethane, 4-fluorobenzyl chloride, 2-chlorobenzyl chloride, 1-iodopropane, 4-chloromethyl-2-methyl thiazole, 4-bromo-2-methyl-2-butene, 1-iodo-2-methylpropane, 4-methylbenzyl chloride, 4-chlorobenzyl chloride, 4-(trifluoromethoxy)benzyl chloride, 3-fluorobenzyl chloride, iodoethane, 4-methoxybenzyl chloride, 2-fluorobenzyl chloride, or allyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.08 (t, 1H), 7.38 (d, 1H), 7.23 (m, 3H), 7.12 (d, 1H), 4.64 (s, 2H), 3.99 (t, 2H), 3.92 (s, 3H), 3.19 (t, 2H), 2.44 (s, 3H), 2.27 (s, 3H); (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (t, 1H), 7.51 (d, 1H), 7.19 (m, 1H), 7.12 (m, 2H), 6.89 (t, 2H), 6.74 (d, 1H), 6.52 (m, 2H), 5.61 (s, 2H), 4.43 (brs, 2H), 3.86 (brs, 2H), 2.90 (t, 2H), 2.35 (s, 3H), 2.33 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (m, 1H), 7.23 (m, 1H), 7.17 (m, 3H), 7.10 (t, 1H), 6.47 (d, 2H), 5.10 (d, 2H), 5.68 (s, 2H), 4.30 (brs, 2H), 3.85 (brs, 2H), 2.87 (brs, 2H), 2.35 (s, 3H), 2.33 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.44 (m, 1H), 7.22 (m, 2H), 7.08 (m, 2H), 4.60 (brs, 2H), 4.23 (t, 2H), 4.04 (t, 2H), 3.18 (t, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.59 (t, 2H), 0.59 (t, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (t, 1H), 7.48 (d, 1H), 7.16 (m, 2H), 7.08 (m, 1H), 6.32 (s, 1H), 5.68 (s, 2H), 4.53 (brs, 2H), 3.91 (t, 2H), 3.02 (t, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (m, 1H), 7.40 (d, 1H), 7.19 (m, 3H), 7.00 (d, 1H), 5.00 (d, 2H), 4.94 (d, 1H), 4.58 (brs, 2H), 3.97 (t, 2H), 3.13 (t, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (t, 1H), 7.42 (d, 1H), 7.18 (m, 3H), 7.06 (d, 1H), 4.52 (s, 2H), 4.02 (brs, 2+2H), 3.18 (t, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.90 (m, 1H), 0.56 (s, 3H), 0.52 (s, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 7.51 (brs, 1H), 7.11 (m, 7H), 6.49 (m, 2H), 5.76 (s, 2H), 4.65 (brs, 2H), 4.11 (brs, 2H), 2.97 (t, 2H), 2.41 (s, 3H), 2.31 (s, 3H), 1.48 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.52 (brs, 1H), 7.18 (m, 5H), 6.78 (m, 1H), 6.51 (m, 2H), 5.64 (s, 2H), 4.48 (brs, 2H), 3.91 (brs, 2H), 2.92 (brs, 2H), 2.38 (s, 3+3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (d, 1H), 7.53 (d, 1H), 7.18 (m, 5H), 6.65 (d, 1H), 6.56 (d, 2H), 5.64 (s, 2H), 4.41 (brs, 2H), 3.84 (brs, 2H), 2.89 (t, 2H), 2.36 (s, 3H), 2.34 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.53 (brs, 1H), 7.20 (m, 4H), 6.94 (brs, 1H), 6.73 (brs, 1H), 6.33 (brs, 1H), 6.24 (d, 1H), 5.65 (s, 2H), 4.41 (brs, 2H), 3.89 (brs, 2H), 2.89 (t, 2H), 2.36 (brs, 3+3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.47 (brs, 1H), 7.24 (m, 4H), 4.69 (m, 2H), 4.44 (s, 2H), 4.05 (brs, 2H), 3.21 (t, 2H), 2.51 (s, 3H), 2.33 (s, 3H), 1.23 (t, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (brs, 1H), 7.52 (brs, 1H), 7.20 (m, 3H), 6.74 (m, 3H), 6.53 (brs, 2H), 5.63 (s, 2H), 4.57 (brs, 2H), 3.81 (s, 3H), 2.96 (t, 2H), 2.38 (brs, 3+3H); (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 8.51 (brs, 1H), 7.72 (brs, 1H), 7.13 (m, 5H), 6.80 (m, 2H), 6.31 (brs, 1H), 5.72 (s, 2H), 4.58 (brs, 2H), 3.93 (brs, 2H), 2.98 (t, 2H), 2.40 (s, 3+3H); (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 7.46 (d, 1H), 7.21 (m, 3H), 7.03 (d, 1H), 5.18 (m, 1H), 5.14 (d, 1H), 5.05 (s, 2H), 4.55 (brs, 2H), 4.50 (d, 1H), 3.91 (t, 2H), 3.12 (t, 2H), 2.42 (s, 3H), 2.30 (s, 3H); (Yield: 63%)
The compound prepared in Example 484 was treated with a saturated sodium carbonate solution to obtain 1-allyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine. A solution of citric acid (11.2 t, 0.09 mmol) in ethyl acetate (0.5 ml) was added to a solution of 1-allyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (30 mg, 0.08 mmol) in ethyl acetate (3 ml). The reaction mixture was stirred overnight at room temperature. The resulting solid was filtered and then dried to give 17.3 mg of the titled compound as a pink solid.
1H-NMR(400 MHz, CDCl3) δ 8.11 (d, 1H), 7.43 (d, 1H), 7.20 (m, 3H), 7.06 (d, 1H), 5.81 (m, 1H), 5.14 (d, 1H), 5.03 (s, 2H), 4.53 (d, 1H), 4.48 (s, 2H), 3.70 (m, 2H), 3.08 (m, 2H), 2.83 (m, 4H), 2.40 (s, 3H), 2.28 (s, 3H)
The titled compounds of Examples 486 to 494 were prepared, in accordance with the same procedures as in Example 485, using 1-allyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine obtained by treating the compound prepared in Example 484 with a saturated sodium carbonate solution; and, tartaric acid, methanesulfonic acid, sulfuric acid, p-toluenesulfonic acid, nitric acid, maleic acid, phosphoric acid, benzenesulfonic acid, or hydrobromic acid.
1H-NMR(400 MHz, CDCl3) δ 8.41 (m, 1H), 7.43 (m, 1H), 7.22 (m, 3H), 7.05 (m, 1H), 5.80 (m, 1H), 5.28 (d, 1H), 5.05 (s, 2H), 4.57 (m, 1+2H), 4.21 (m, 2H), 3.61 (m, 2H), 3.10 t(m, 2H), 2.41 (s, 3H), 2.29 (s, 3H); (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 8.30 (t, 1H), 7.44 (d, 1H), 7.22 (m, 3H), 7.06 (d, 1H), 5.78 (m, 1H), 5.16 (d, 1H), 5.01 (s, 2H), 4.53 (m, 1+2H), 3.81 (m, 2H), 3.14 (m, 2H), 2.89 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (t, 1H), 7.44 (d, 1H), 7.18 (m, 3H), 7.05 (m, 1H), 5.78 (m, 1H), 5.16 (d, 1H), 4.97 (d, 2H), 4.58 (m, 1+2H), 3.83 (t, 2H), 3.13 (m, 2H), 2.40 (s, 3H), 2.26 (s, 3H); (Yield: 96%)
1H-NMR(400 MHz, CDCl3) δ 8.27 (t, 1H), 7.86 (d, 2H), 7.42 (d, 1H), 7.19 (m, 2+3H), 6.99 (d, 1H), 5.81 (m, 1H), 5.15 (d, 1H), 5.00 (s, 2H), 4.54 (m, 1+2H), 4.54 (d, 1+2H), 3.77 (s, 2H), 3.07 (m, 2H), 2.41 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.47 (d, 2H), 7.20 (m, 3H), 7.02 (d, 1H), 5.79 (m, 1H), 5.16 (d, 1H), 5.03 (s, 2H), 4.53 (m, 1+2H), 3.78 (m, 2H), 3.09 (m, 2H), 2.42 (s, 3H), 2.30 (s, 3H); (Yield: 93%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (d, 1H), 7.46 (d, 1H), 7.34 (m, 3H), 7.05 (d, 1H), 6.33 (s, 2H), 5.80 (m, 1H), 5.16 (d, 1H), 5.04 (s, 2H), 4.54 (d, 1+2H), 3.76 (m, 2H), 3.11 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, MeOH-d4) δ 7.93 (d, 1H), 7.66 (d, 1H), 7.23 (m, 3H), 7.11 (d, 1H), 5.88 (m, 1H), 5.10 (m, 1+2H), 3.71 (m, 2H), 3.14 (m, 2H), 2.47 (s, 3H), 2.33 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.26 (t, 1H), 7.98 (m, 2H), 7.43 (d, 1H), 7.36 (m, 3H), 7.34 (t, 3H), 7.01 (d, 1H), 5.78 (m, 1H), 5.15 (d, 1H), 5.00 (s, 2H), 4.54 (d, 1+2H), 3.73 (t, 2H), 3.09 (m, 2H), 2.41 (s, 3H), 2.29 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (t, 1H), 7.48 (d, 1H), 7.22 (m, 3H), 7.05 (d, 1H), 5.79 (m, 1H), 5.17 (d, 1H), 5.04 (d, 2H), 4.55 (m, 1+2H), 3.93 (m, 2H), 3.12 (m, 2H), 2.42 (s, 3H), 2.30 (s, 3H); (Yield: 75%)
The titled compounds of Examples 495 to 525 were prepared, in accordance with the same procedures as in Example 469, using 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride prepared in Example 468; and, 3,4-dichlorobenzyl chloride, bromomethyl methyl ether, (bromomethyl)cyclopropane, cyanomethyl iodide, 2-bromoethyl methyl ether, 4-trifluoromethylbenzyl chloride, methyl bromoacetate, 2-(bromomethyl)naphthalene, 2-bromoethyl ethyl ether, chloromethyl methyl sulfide, (bromomethyl)cyclobutane, propargyl bromide, 4-tert-butylbenzyl chloride, 4-chloro-1-butene, 1-bromopentane, 3-methoxybenzyl chloride, 2-chloroethyl vinyl ether, 2-bromoethyl-4-methanesulfonylbenzene, 1-bromo-3-chlorobutane, 2-chloro-5-chloromethylthiophene, 3-methylbenzyl chloride, 3-picolyl chloride, 2-picolyl chloride, 4-picolyl chloride, 2,3-dichlorobenzyl chloride, 1-bromo-3-methylbutane, α2-chloroisodurene, 2,5-dimethylbenzyl chloride, 5-chloro-1-pentyne, 4-(chloromethyl)-3,5-dimethylisoxazole, or 1-iodobutane.
1H-NMR(400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.55 (m, 2H), 7.17 (m, 3H), 6.67 (m, 2H), 6.34 (brs, 1H), 5.60 (s, 2H), 4.49 (brs, 2H), 4.08 (brs, 2H), 3.02 (t, 2H), 2.38 (s, 3+3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.42 (s, 1H), 7.23 (m, 3H), 7.10 (m, 1H), 5.71 (s, 2H), 4.64 (s, 2H), 4.04 (s, 2H), 3.18 (s, 2H), 3.05 (s, 3H), 2.51 (s, 3H), 2.28 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.44 (m, 1H), 7.19-7.30 (m, 3H), 7.05 (m, 1H), 4.53 (m, 2H), 4.20 (m, 2H), 4.02 (m, 2H), 3.18 (m, 2H), 2.52 (s, 3H), 2.30 (s, 3H), 1.21 (m, 1H), 0.33 (m, 2H), 0.03 (m, 2H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.54 (d, 1H), 7.24 (m, 3H), 7.14 (d, 1H), 5.42 (s, 2H), 4.80 (brs, 2H), 4.01 (brs, 2H), 3.24 (brs, 2H), 2.59 (s, 3H), 2.34 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.47 (s, 1H), 7.18 (m, 3H), 7.05 (d, 1H), 4.60 (brs, 2H), 4.50 (s, 2H), 3.92 (brs, 2H), 3.41 (s, 2H), 3.12 (s, 2H), 3.08 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.54 (brs, 1H), 7.45 (d, 2H), 7.29 (m, 1H), 7.22 (d, 1H), 7.18 (d, 1H), 7.06 (m, 1H), 6.65 (m, 2H), 5.71 (s, 2H), 4.39 (brs, 2H), 3.49 (brs, 2H), 2.88 (s, 2H), 2.42 (d, 3+3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (t, 1H), 7.52 (d, 1H), 7.21 (m, 3H), 7.01 (d, 1H), 5.27 (brs, 2H), 5.08 (brs, 2H), 4.16 (s, 2H), 3.49 (s, 3H), 3.12 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.54 (m, 4H), 7.27 (m, 1H), 7.15 (m, 2H), 6.98 (m, 2H), 6.73 (d, 1H), 6.56 (d, 1H), 5.81 (s, 2H), 4.46 (s, 2H), 3.84 (s, 2H), 2.83 (s, 2H), 2.38 (s, 3H), 2.36 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.46 (d, 1H), 7.21 (m, 3H), 7.05 (d, 1H), 4.51 (brs, 2H), 3.97 (brs, 4H), 3.44 (m, 2H), 3.17 (m, 4H), 2.50 (s, 3H), 2.29 (s, 3H) 1.95 (t, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.46 (s, 1H), 7.19 (m, 3H), 7.08 (d, 1H), 5.43 (s, 2H), 4.59 (s, 2H), 4.02 (s, 2H), 3.22 (s, 2H), 2.55 (s, 3H), 2.20 (s, 3H), 1.81 (s, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.40 (d, 1H), 7.23 (m, 3H), 7.09 (d, 1H), 4.58 (s, 2H), 4.29 (s, 2H), 4.03 (s, 2H), 3.21 (s, 2H), 2.46 (s, 3+1H), 2.27 (s, 3H), 1.66 (m, 4H), 1.42 (m, 2H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.43 (s, 1H), 7.25 (m, 3H), 7.13 (d, 1H), 5.22 (s, 2H), 4.73 (s, 2H), 3.98 (s, 2H), 3.22 (s, 2H), 2.58 (s, 3H), 2.42 (s, 1H), 2.18 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.48 (d, 1H), 7.16 (m, 3H), 7.13 (d, 1H), 7.04 (t, 1H), 6.60 (d, 1H), 6.47 (d, 2H), 5.60 (s, 2H), 4.38 (s, 2H), 3.87 (s, 2H), 2.91 (t, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 1.28 (s, 9H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.45 (d, 1H), 7.18 (m, 3H), 7.05 (d, 1H), 5.321 (m, 1H), 4.80 (d, 1H), 4.69 (d, 1H), 4.65 (brs, 2H), 4.36 (s, 2H), 4.01 (s, 2H), 3.17 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 2.21 (d, 2H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.44 (d, 1H), 7.22 (m, 3H), 7.06 (d, 1H), 4.70 (brs, 1H), 4.26 (m, 2H), 4.05 (brs, 2H), 3.17 (s, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.46 (m, 2H), 1.08 (m, 2H), 0.89 (m, 2H), 0.69 (m, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.13 (m, 4H), 6.78 (d, 1H), 6.68 (d, 1H), 6.09 (s, 2H), 5.62 (s, 2H), 4.44 (brs, 2H), 3.86 (brs, 2H), 3.64 (s, 3H), 2.90 (s, 2H), 2.36 (s, 3H), 2.33 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (s, 1H), 7.45 (s, 1H), 7.28 (m, 3H), 7.05 (d, 1H), 4.80 (brs, 2H), 4.47 (m, 2+1H), 3.98 (brs, 1H), 3.72 (m, 2+1H), 3.12 (m, 2+1H), 2.53 (s, 3H), 2.29 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.25 (m, 4H), 7.19 (m, 2H), 7.11 (m, 2H), 6.84 (m, 1H), 5.23 (m, 2H), 5.10 (m, 2H), 4.70 (s, 3H), 3.97 (t, 2H), 3.15 (t, 2H), 2.48 (s, 3H), 2.27 (s, 3H), 2.15 (m, 2H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.44 (s, 1H), 7.22 (m, 3H), 7.03 (m, 1H), 5.34 (m, 2H), 4.95 (m, 2H), 4.60 (s, 2H), 4.46 (d, 2H), 3.95 (t, 2H), 3.48 (m, 1H), 3.14 (t, 2H), 2.43 (s, 3H), 2.29 (s, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.48 (s, 1H), 7.21 (m, 3H), 6.98 (d, 2H), 6.64 (s, 1H), 6.33 (s, 1H), 5.61 (s, 2H), 4.52 (brs, 2H), 4.04 (brs, 2H), 3.12 (s, 2H), 2.47 (s, 3H), 2.29 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (d, 1H), 7.17 (d, 1H), 7.09 (m, 4H), 6.66 (d, 1H), 6.40 (s, 1H), 6.28 (d, 1H), 5.60 (s, 2H), 4.39 (brs, 2H), 3.85 (brs, 2H), 2.88 (t, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.51 (s, 2H), 8.19 (d, 1H), 7.62 (d, 1H), 7.24 (t, 1H), 7.13 (d, 2H), 6.88 (s, 2H), 6.66 (d, 1H), 5.87 (s, 2H), 4.52 (brs, 2H), 3.85 (brs, 2H), 2.86 (brs, 2H), 2.40 (s, 3H), 2.36 (s, 3H); (Yield: 38%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (s, 1H), 8.16 (s, 1H), 7.50 (m, 2H), 7.09 (m, 3H), 7.03 (m, 1H), 6.63 (m, 2H), 5.75 (s, 2H), 4.54 (brs, 2H), 3.85 (brs, 2H), 2.91 (brs, 2H), 2.34 (s, 3H), 2.31 (s, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.51 (s, 1H), 8.19 (d, 1H), 7.62 (d, 1H), 7.22 (m, 1H), 7.13 (d, 2H), 6.88 (s, 1H), 6.66 (d, 1H), 5.85 (s, 2H), 4.45 (m, 2H), 3.85 (m, 2H), 2.86 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.54 (m, 1H), 7.39 (d, 1H), 7.18 (m, 2H), 7.10 (m, 2H), 7.02 (m, 1H), 6.34 (d, 1H), 6.04 (s, 2H), 5.66 (brs, 2H), 3.84 (brs, 2H), 2.90 (t, 2H), 2.36 (s, 3H), 2.34 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (t, 1H), 7.43 (d, 1H), 7.21 (m, 3H), 7.06 (d, 1H), 4.65 (s, 2H), 4.27 (t, 2H), 4.03 (s, 2H), 3.18 (s, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.30 (m, 2+1H), 0.68 (s, 3H), 0.66 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.41 (m, 1H), 7.18 (m, 3H), 7.08 (m, 1H), 6.75 (s, 2H), 5.89 (brs, 2H), 4.85 (brs, 2H), 4.04 (s, 2H), 3.14 (s, 2H), 2.21 (s, 3H), 2.20 (s, 3H), 1.97 (s, 3H), 1.56 (s, 6H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.53 (s, 1H), 7.16 (m, 1H), 7.08 (m, 1H), 6.99 (m, 2H), 6.90 (m, 1H), 6.31 (d, 1H), 5.82 (s, 1H), 5.48 (brs, 2H), 4.30 (brs, 2H), 3.84 (brs, 2H), 2.81 (s, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H), 1.60 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.46 (d, 1H), 7.18 (m, 3H), 7.07 (d, 1H), 4.75 (brs, 1H), 4.42 (t, 2H), 4.00 (brs, 2H), 3.19 (s, 2H), 2.50 (s, 3H), 2.29 (s, 3H), 1.88 (m, 2H), 1.75 (m, 2+1H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.51 (d, 1H), 7.22 (m, 3H), 6.84 (d, 1H), 5.44 (s, 2H), 4.59 (brs, 2H), 4.04 (brs, 2H), 3.04 (t, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 1.73 (s, 3H), 1.54 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (m, 1H), 7.44 (d, 1H), 7.18 (m, 3H), 7.06 (d, 1H), 4.52 (s, 2H), 4.26 (t, 2H), 4.02 (s, 2H), 3.17 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 1.45 (m, 2H), 0.95 (m, 2H), 0.70 (t, 3H); (Yield: 52%)
Sodium hydride (60%; 80 mg, 1.80 mmol) and propargyl bromide (35.6 μl, 1.40 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92,3 mg, 0.33 mol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature. Ice was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.5 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.11 (t, 1H), 7.29 (d, 2H), 7.20 (m, 4H), 5.32 (d, 2H), 4.83 (s, 2H), 3.97 (t, 2H), 3.20 (t, 2H), 2.48 (s, 3H), 2.29 (s, 3H)
In accordance with the same procedures as in Example 468, except for using 7-methoxy-1-methyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 21, the titled compound was obtained as a white solid. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.75 (s, 1H), 7.92 (d, 1H), 7.03 (m, 2H), 6.73 (m, 2H), 5.22 (q, 1H), 3.68 (s, 3H), 3.61 (m, 1H), 3.49 (m, 1H), 3.35 (m, 1H), 2.72 (m, 1H), 2.32 (s, 3H), 2.18 (s, 3H), 1.31 (d, 3H)
The titled compounds of Examples 528 and 529 were prepared, in accordance with the same procedures as in Example 469, using 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 527; and, allyl bromide or 3-fluorobenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.08 (brs, 1H), 7.37 (m, 1H), 7.10 (t, 1H), 6.80 (t, 1H), 6.52 (m, 1H), 5.83 (m, 1H), 5.72 (m, 1H), 5.56 (m, 1H), 5.30 (m, 1H), 4.85 (m. 1H), 4.11 (m, 1H), 3.88 (m, 1H), 3.07 (m, 1H), 2.98 (m, 1H), 2.51 (brs, 1H), 2.33 (s, 3H), 2.27 (s, 3H), 1.33 (d, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (brs, 2H), 7.38 (m, 1H), 7.17 (m, 2H), 6.82 (m, 2H), 6.61 (m, 2H), 5.73 (m, 2H), 4.88 (m, 2H), 3.97 (m, 1H), 3.80 (s, 3H), 3.07 (m. 2H), 2.52 (s, 3H), 2.23 (s, 3H), 1.34 (brs, 3H); (Yield: 49%)
In accordance with the same procedures as in Example 468, except for using 7-chloro-1-methyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 22, the titled compound was obtained as a white solid. (Yield: 37%)
1H-NMR(400 MHz, CDCl3) δ 8.77 (s, 1H), 7.95 (d, 1H), 7.00 (m, 2H), 6.73 (m, 2H), 5.22 (q, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 3.37 (m, 1H), 2.75 (m, 1H), 2.32 (s, 3H), 2.18 (s, 3H), 1.32 (d, 3H)
The titled compounds of Examples 531 to 540 were prepared, in accordance with the same procedures as in Example 469, using 7-chloro-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 530; and, allyl bromide, iodoethane, iodomethane, 4-bromo-2-methyl-2-butene, benzyl bromide, 4-methylbenzyl chloride, bromomethyl methyl ether, 4-chloromethyl-2-methylthiazole, 3-fluorobenzyl chloride, or 4-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.08 (brs, 1H), 7.36 (s, 1H), 7.19 (d, 1H), 7.13 (d, 1H), 6.98 (s, 1H), 6.53 (d, 1H), 5.83 (s, 1H), 5.57 (t, 1H), 4.80 (m, 1H), 4.19 (m. 1H), 3.89 (m, 1H), 3.01 (brs, 2H), 2.54 (s, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 1.34 (d, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (brs, 1H), 7.45 (brs, 1H), 7.21 (m, 1H), 7.16 (t, 1H), 7.08 (m, 1H), 4.59 (m, 1H), 4.49 (m, 1H), 4.27 (m, 2H), 3.83 (m, 1H), 3.10 (brs, 2H), 2.48 (s, 3H), 2.29 (s, 3H), 1.34 (d, 3H), 1.09 (brs, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (brs, 1H), 7.41 (brs, 1H), 7.21 (d, 1H), 7.17 (d, 1H), 7.09 (brs, 1H), 4.82 (m, 1H), 4.31 (m, 1H), 3.87 (brs, 3H), 3.10 (brs, 2H), 2.45 (s. 3H), 2.29 (s, 3H), 1.38 (brs, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (brs, 1H), 7.40 (brs, 1H), 7.19 (d, 1H), 7.14 (d, 1H), 6.91 (brs, 1H), 5.19 (m, 1H), 4.98 (m, 1H), 4.50 (m, 2H), 3.81 (m, 1H), 3.07 (bs. 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H), 1.35 (brs, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 2H), 7.50 (brs, 2H), 7.15 (d, 2H), 7.05 (m, 2H), 6.62 (brs, 2H), 6.39 (m, 1H), 5.69 (m, 1H), 5.30 (m, 1H), 4.57 (m, 1H), 3.69 (m. 1H), 2.89 (m, 2H), 2.35 (s, 3+3H), 1.21 (brs, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 2H), 7.46 (m, 2H), 7.16 (d, 2H), 6.47 (d, 2H), 6.22 (m, 1H), 5.72 (m, 1H), 5.24 (m, 2H), 4.54 (m, 1H), 4.43 (m, 1H), 3.74 (m. 1H), 2.91 (m, 2H), 2.34 (s, 3+3+3H), 1.27 (brs, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.43 (m, 1H), 7.21 (m, 2H), 7.12 (m, 1H), 5.65 (m, 1H), 5.23 (m, 1H), 4.99 (m, 1H), 4.25 (m, 1H), 3.85 (m, 1H), 3.16 (brs, 2H), 3.02 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H), 1.36 (brs, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.48 (brs, 1H), 7.16 (m, 3H), 6.43 (m, 1H), 5.92 (m, 1H), 5.20 (m, 1H), 4.78 (m, 1H), 4.38 (m, 1H), 3.77 (m, 1H), 2.97 (brs, 2H), 2.66 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 1.29 (brs, 3H); (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (m, 1H), 7.52 (m, 1H), 7.18 (m, 2H), 7.08 (m, 1H), 6.98 (m, 1H), 6.42 (m, 1H), 6.27 (m, 2H), 5.70 (m, 1H), 5.30 (m, 1H), 4.49 (m. 2H), 3.63 (m, 1H), 2.91 (m, 1H), 2.80 (m, 1H), 2.35 (s, 3+3H), 1.32 (brs, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (m, 1H), 7.55 (m, 1H), 7.16 (m, 2H), 6.95 (m, 1H), 6.51 (m, 2H), 6.16 (m, 1H), 5.65 (m, 1H), 5.31 (m, 1H), 5.15 (m, 1H), 4.55 (m. 1H), 4.21 (m, 1H), 3.69 (m, 1H), 2.91 (m, 2H), 2.35 (s, 3+3H), 1.28 (brs, 3H); (Yield: 56%)
In accordance with the same procedures as in Example 468, except for using 7-fluoro-1-methyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 23, the titled compound was obtained as a white solid. (Yield: 33%)
1H-NMR(400 MHz, CDCl3) δ 8.45 (brs, 1H), 7.91 (d, 1H), 7.05 (d, 2H), 6.83 (m, 2H), 5.17 (q, 1H), 3.86 (m, 1H), 3.57 (t, 1H), 2.95 (m, 1H), 2.83 (t, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 1.32 (d, 3H)
The titled compounds of Examples 542 to 551 were prepared, in accordance with the same procedures as in Example 469, using 7-fluoro-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 541; and, 3-fluorobenzyl chloride, iodoethane, allyl bromide, 4-bromomethyl-2-methyl-2-butene, 2-bromoethyl methyl ether, benzyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl chloride, bromomethyl methyl ether, or 4-chloromethyl-2-methylthiazole.
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.52 (m, 1H), 7.19 (d, 1H), 7.10 (brs, 1H), 6.96 (m, 2H), 6.21 (m, 1+2H), 5.65 (m, 1H), 5.30 (m, 1H), 4.51 (m, 2H), 3.63 (m. 1H), 2.89 (m, 1H), 2.77 (m, 1H), 2.34 (s, 3+3H), 1.33 (brs, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (brs, 1H), 7.46 (brs, 1H), 7.18 (brs, 1H), 7.02 (s, 1H), 6.84 (m, 1H), 4.80 (m, 1H), 4.50 (m, 1H), 4.30 (m, 2H), 4.01 (m, 1H), 3.09 (brs, 2H), 2.48 (s, 3H), 2.30 (s, 3H), 1.36 (brs, 3H), 1.11 (brs, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.48 (brs, 1H), 7.17 (brs, 1H), 6.95 (brs, 1H), 6.73 (m, 1H), 5.75 (m, 2H), 5.13 (d, 2H), 4.75 (m, 2H), 4.48 (d, 1H), 3.80 (m, 1H), 3.06 (brs, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 1.35 (brs, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (brs, 1H), 7.41 (brs, 1H), 7.16 (brs, 1H), 6.95 (brs, 1H), 6.68 (m, 1H), 5.16 (m, 2H), 4.97 (brs, 1H), 4.73 (m, 2H), 4.35 (m, 1H), 3.85 (m, 1H), 3.07 (brs, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.35 (brs, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.46 (brs, 1H), 7.16 (brs, 1H), 6.95 (brs, 1H), 6.82 (m, 1H), 4.49 (m, 1H), 4.36 (brs, 2H), 4.21 (m, 1H), 3.75 (m, 1H), 3.32 (m, 2H), 3.08 (brs, 2+3H), 2.49 (s, 3H), 2.30 (s, 3H), 1.35 (brs, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (brs, 1H), 7.50 (brs, 1H), 7.24 (brs, 2H), 7.08 (brs, 1H), 6.89 (brs, 1H), 6.53 (brs, 2H), 6.14 (m, 1H), 5.65 (m, 1H), 5.37 (m, 2H), 4.55 (m, 1H), 4.38 (m, 1H), 3.67 (m, 1H), 2.89 (m, 2H), 2.34 (s, 3+3H), 1.30 (brs, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.49 (brs, 1H), 7.02 (m, 3H), 6.89 (brs, 1H), 6.44 (brs, 2H), 6.11 (brs, 2H), 5.59 (m, 1H), 5.30 (m, 1H), 4.57 (m, 1H), 4.38 (m, 1H), 3.70 (m, 1H), 2.85 (m, 2H), 2.33 (m, 3+3+3H), 1.27 (brs, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.52 (brs, 1H), 7.10 (brs, 1H), 6.93 (brs, 3H), 6.50 (brs, 2H), 6.27 (m, 1H), 5.58 (m, 1H), 5.36 (m, 1H), 4.55 (m, 1H), 4.41 (m, 1H), 3.74 (m, 1H), 2.79 (m, 2H), 2.34 (m, 3+3H), 1.33 (brs, 3H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.43 (brs, 1H), 7.19 (t, 1H), 6.97 (t, 1H), 6.80 (m, 1H), 5.79 (m, 1H), 5.15 (m, 1H), 4.99 (m, 1H), 4.34 (m, 1H), 3.87 (m, 1H), 3.09 (brs, 2H), 3.02 (brs, 3H), 2.50 (s, 3H), 2.29 (s, 3H), 1.34 (d, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (brs, 1H), 7.11 (brs, 1H), 6.96 (m, 2H), 6.79 (d, 1H), 5.85 (m, 1H), 5.25 (m, 1H), 4.35 (m, 1H), 4.11 (m, 1H), 3.92 (m, 1H), 3.72 (m, 1H), 3.09 (brs, 2H), 2.65 (brs, 3H), 2.21 (s, 3+3H), 1.51 (brs, 3H); (Yield: 42%)
In accordance with the same procedures as in Example 468, except for using 1-methyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 24, the titled compound was obtained as a white solid. (Yield: 40%)
1H-NMR(400 MHz, CDCl3) δ 8.58 (brs, 1H), 7.93 (m, 1H), 6.97 (m, 5H), 5.20 (q, 1H), 3.91 (m, 1H), 3.59 (t, 1H), 3.02 (m, 1H), 2.83 (d, 1H), 2.35 (s, 3H), 2.19 (s, 3H), 1.27 (d, 3H)
The titled compounds of Examples 553 to 559 were prepared, in accordance with the same procedures as in Example 469, using 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 552; and, allyl bromide, iodoethane, 2-bromoethyl methyl ether, benzyl bromide, 3-fluorobenzyl chloride, 4-methoxybenzyl bromide, or 4-chloromethyl-2-methylthiazole.
1H-NMR(400 MHz, CDCl3) δ 8.07 (brs, 1H), 7.52 (d, 1H), 7.19 (m, 3H), 6.99 (d, 1H), 6.52 (d, 1H), 5.83 (s, 1H), 5.51 (m, 1H), 4.85 (m, 1H), 4.19 (m, 1H), 3.89 (m. 1H), 3.13 (m, 1H), 3.05 (brs, 2H), 2.51 (d, 1H), 2.33 (s, 3H), 2.29 (s, 3H), 1.33 (d, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (brs, 1H), 7.42 (s, 1H), 7.22 (m, 3H), 7.09 (m, 1H), 4.65 (m, 1H), 4.44 (m, 1H), 4.29 (brs, 2H), 3.84 (brs, 1H), 3.12 (brs, 2H), 2.53 (s. 3H), 2.29 (s, 3H), 1.33 (d, 3H), 1.08 (brs, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.22 (s, 2H), 7.09 (s, 1H), 4.78 (m, 1H), 4.41 (m, 1H), 3.84 (s, 2H), 3.28 (s, 3H), 2.96 (m, 3H), 2.56 (s, 1H), 2.40 (s, 1H), 2.20 (s, 3+3H), 1.22 (brs, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (s, 1H), 7.61 (m, 1H), 7.44 (m, 1H), 7.30 (s, 1H), 7.21 (m, 3H), 7.11 (m, 1H), 6.85 (m, 1H), 6.48 (m, 1H), 5.82 (m, 1H), 5.39 (m, 1H), 4.72 (m, 1H), 4.35 (m, 1H), 3.75 (m, 1H), 2.98 (m, 2H), 2.43 (s, 1H), 2.33 (s, 3+3H), 1.20 (brs, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.48 (m, 1H), 7.01 (m, 3H), 6.99 (t, 1H), 6.65 (d, 1H), 6.53 (d, 1H), 6.51 (m, 2H), 5.79 (s, 1H), 5.41 (m, 1H), 4.55 (m, 1H), 4.35 (m, 1H), 3.65 (m, 1H), 2.85 (m, 1H), 2.75 (m, 1H), 2.33 (s, 3+3H), 1.26 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.57 (d, 1H), 7.17 (m, 1H), 7.12 (m, 1H), 6.81 (m, 4H), 6.73 (d, 1H), 6.43 (m, 1H), 5.73 (s, 2H), 5.39 (m, 1H), 4.65 (m, 1H), 4.41 (m, 1H), 3.81 (s, 3H), 3.61 (m, 1H), 2.98 (m, 1H), 2.31 (s, 3+3H), 1.30 (brs, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 6.64 (s, 1H), 5.80 (s, 2H), 5.76 (m, 1H), 4.40 (m, 1H), 3.96 (m, 1H), 2.88 (m, 1H), 2.62 (s, 3+3H), 2.27 (s, 3H), 2.17 (s, 3H), 1.61 (s, 3H); (Yield: 51%)
In accordance with the same procedures as in Example 410, except for using 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline obtained by treating the compound prepared in Example 552 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 91%)
1H-NMR(400 MHz, CDCl3) δ 7.94 (d, 1H), 7.90 (brs, 1H), 7.20 (s, 4H), 7.05 (d, 1H), 5.19 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.10 (m, 1H), 2.94 (dd, 1H), 2.38 (s, 3H), 2.19 (s, 3H), 1.37 (d, 3H)
In accordance with the same procedures as in Example 468, except for using 6-fluoro-1-methyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 25, the titled compound was obtained as a white solid. (Yield: 32%)
1H-NMR(400 MHz, CDCl3) δ 8.59 (brs, 1H), 7.91 (d, 1H), 7.05 (d, 1H), 6.92 (m, 1H), 6.84 (m, 1H), 6.75 (m, 1H), 5.14 (q, 1H), 3.88 (m, 1H), 3.56 (t, 1H), 2.99 (m, 1H), 2.80 (d, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 1.25 (d, 3H)
The titled compounds of Examples 562 to 566 were prepared, in accordance with the same procedures as in Example 469, using 6-fluoro-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 561; and, iodoethane, allyl bromide, 2-bromoethyl methyl ether, 3-fluorobenzyl chloride, or 4-methoxybenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.44 (s, 1H), 7.06 (m, 1H), 6.92 (m, 2H), 4.28 (m, 2H), 3.82 (m, 2H), 3.49 (m, 1H), 3.10 (m, 2H), 2.47 (s, 3H), 2.29 (s, 3H), 1.35 (m, 3H), 1.09 (m, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.43 (s, 1H), 6.91 (m, 3H), 5.70 (m, 1H), 5.13 (d, 2H), 4.72 (m, 2H), 4.49 (d, 2H), 3.78 (m, 1H), 3.01 (m, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.27 (brs, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.45 (m, 1H), 6.92 (m, 3H), 4.55 (m, 1H), 4.34 (m, 1H), 4.22 (m, 1H), 3.87 (m, 1H), 3.71 (m, 1H), 3.31 (m, 2H), 3.11 (brs, 3+2H), 2.48 (s, 3H), 2.29 (s, 3H), 1.35 (brs, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (s, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 6.98 (t, 1H), 6.82 (m, 2H), 6.51 (m, 1H), 6.22 (m, 2H), 5.55 (m, 1H), 5.35 (m, 1H), 4.44 (m, 2H), 3.59 (m, 1H), 2.75 (m, 2H), 2.35 (s, 3+3H), 1.31 (brs, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.45 (m, 1H), 6.85 (m, 3H), 6.75 (d, 1H), 6.44 (m, 3H), 5.44 (m, 1H), 5.35 (m, 1H), 4.51 (m, 1H), 4.41 (m, 1H), 3.76 (s, 3H), 3.59 (m, 1H), 2.89 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 1.22 (brs, 3H); (Yield: 43%)
The compound prepared in Example 561 was treated with a saturated sodium bicarbonate solution to obtain 6-fluoro-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline. A solution of 6-fluoro-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (73.5 mg, 0.25 mmol) and sodium hydride (6.0 mg, 0.25 mmol) in anhydrous tetrahydrofuran (2 ml) was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was recrystallized with ethyl ether to give 73 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 8.58 (brs, 1H), 7.91 (d, 1H), 7.06 (d, 1H), 6.92 (m, 1H), 6.84 (m, 1H), 6.74 (m, 1H), 5.14 (q, 1H), 3.87 (m, 1H), 3.56 (t, 1H), 2.99 (m, 1H), 2.80 (d, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.26 (d, 3H)
In accordance with the same procedures as in Example 468, except for using 1-cyclopropyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 26, the titled compound was obtained as a white solid. (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 8.31 (s, 1H), 7.91 (d, 1H), 7.19 (m, 4H), 7.04 (d, 1H), 4.45 (d, 1H), 3.86 (m, 1H), 3.77 (m, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.31 (s, 3H), 2.18 (s, 3H), 0.98 (m, 1H), 0.45 (m, 1H), 0.30 (m, 1H), 0.20 (m, 1H)
The titled compounds of Examples 569 to 573 were prepared, in accordance with the same procedures as in Example 469, using 1-cyclopropyl-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 568; and, iodoethane, allyl bromide, 2-bromoethyl methyl ether, 3-fluorobenzyl chloride, or 4-methoxybenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.11 (m, 5H), 6.30 (m, 1H), 5.84 (m, 1H), 5.67 (m, 1H), 5.26 (m, 1H), 4.37 (m, 2H), 3.82 (m, 1H), 2.83 (m, 4H), 2.29 (s, 3+3H), 1.75 (m, 1H), 0.64 (m, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (m, 1H), 7.07 (m, 5H), 6.01 (m, 1H), 4.62 (m, 1H), 4.01 (m, 2H), 3.88 (m, 2H), 3.22 (m, 2H), 3.14 (m, 2H), 2.69 (s, 3H), 2.44 (s, 3H), 1.55 (m, 1H), 0.44 (m, 2H), 0.22 (m, 2H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (s, 1H), 7.06 (m, 5H), 6.09 (m, 1H), 5.69 (m, 2H), 4.62 (m, 2H), 3.64 (m, 2H), 3.49 (m, 2H), 3.12 (m, 3H), 2.39 (s, 3H), 2.29 (s, 3H), 0.88 (m, 1H), 0.47 (m, 2+2H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (s, 1H), 7.18 (m, 9H), 6.05 (m, 1H), 4.65 (m, 1H), 4.28 (m, 2H), 3.75 (m, 2H), 3.25 (m, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 1.55 (m, 1H), 0.55 (m, 2H), 0.22 (m, 2H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (s, 1H), 7.11 (m, 9H), 6.59 (m, 2H), 6.17 (m, 2H), 5.55 (m, 1H), 5.23 (m, 1H), 2.32 (s, 3+3+3H), 1.44 (m, 1H), 0.49 (m, 2+2H); (Yield: 56%)
In accordance with the same procedures as in Example 468, except for using 1-ethyl-2-(3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 27, the titled compound was obtained as a white solid. (Yield: 33%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.86 (d, 1H), 7.15 (m, 5H), 5.12 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.35 (m, 1H), 2.84 (m, 1H), 2.35 (s, 3H), 2.12 (s, 3H), 1.23 (t, 3H)
The titled compounds of Examples 575 to 590 were prepared, in accordance with the same procedures as in Example 469, using 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-ethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Example 574; and, iodomethane, iodoethane, allyl bromide, 4-bromo-2-methyl-2-butene, benzyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl chloride, 3-fluorobenzyl chloride, 4-methoxybenzyl chloride, bromomethyl methyl ether, 2-bromoethyl methyl ether, 4-chloromethyl-2-methylthiazole, 2-chloromethoxyethyl methyl ether, 4-bromo-1-butene, 2-chloroethyl vinyl ether, or 2-fluorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.12 (m, 5H), 5.37 (m, 1H), 4.36 (m, 1H), 3.12 (m, 1H), 2.88 (m, 1H), 2.75 (m, 1H), 2.30 (s, 3+3+3H), 2.09 (m, 1H), 1.75 (m, 1H), 0.64 (brs, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.20 (m, 5H), 5.79 (s, 1H), 5.42 (m, 1H), 5.22 (m, 1H), 4.51 (m, 1H), 4.22 (m, 1H), 3.75 (m, 1H), 3.05 (m, 1H), 2.33 (s, 3+3H), 1.97 (m, 1H), 1.79 (m, 1H), 1.25 (m, 3H), 0.66 (m, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.18 (m, 5H), 5.82 (s, 1H), 5.45 (m, 1H), 5.25 (m, 1H), 4.35 (m, 1H), 3.75 (m, 1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H), 2.32 (s, 3+3H), 1.95 (m, 1H), 1.75 (m, 1H), 0.67 (s, 3H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 7.68 (s, 1H), 7.12 (m, 5H), 5.74 (s, 1H), 5.25 (m, 1H), 4.25 (m, 1H), 4.15 (m, 1H), 3.85 (m, 2H), 3.75 (s, 3+3H), 3.15 (m, 1H), 2.95 (m, 1H), 2.33 (s, 3+3H), 2.12 (m, 1H), 1.85 (m, 1H), 0.63 (m, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.06 (s, 1H), 7.25 (m, 5+5H), 5.83 (s, 1H), 5.58 (s, 1H), 5.05 (m, 1H), 4.95 (m, 1H), 4.33 (m, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.60 (s, 3H), 2.33 (s, 3H), 2.12 (m, 1H), 1.89 (m, 1H), 0.70 (m, 3H); (Yield: 32%)
1H-NMR(400 MHz, CDCl3) δ 8.06 (s, 1H), 7.27 (m, 5+4H), 6.02 (m, 1H), 5.45 (m, 1H), 5.22 (m, 1H), 4.55 (m, 1H), 3.76 (s, 3H), 3.19 (m, 1H), 2.95 (m, 1H), 2.67 (m, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.43 (m, 1H), 1.22 (m, 1H), 0.43 (m, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.02 (s, 2H), 7.29 (m, 2H), 7.23 (m, 3H), 7.15 (m, 3H), 4.02 (m, 2H), 3.74 (m, 3H), 2.96 (m, 2H), 2.42 (s, 3H), 2.30 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 0.71 (m, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 2H), 7.33 (m, 2H), 7.22 (m, 6H), 4.58 (m, 2H), 4.19 (m, 2H), 3.98 (m, 1H), 3.13 (m, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.00 (m, 1H), 1.86 (m, 1H), 0.70 (m, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (s, 1H), 7.56 (m, 2H), 7.37 (m, 2H), 7.11 (m, 5H), 6.02 (m, 2H), 5.17 (m, 2H), 4.55 (m, 2H), 3.15 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 3.33 (s, 3H), 1.12 (m, 1H), 0.82 (m, 1H), 0.65 (m, 3H); (Yield: 46%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (m, 1H), 7.42 (m, 1H), 7.17 (m, 4H), 5.11 (m, 1H), 4.82 (m, 1H), 4.55 (m, 2H), 4.01 (m, 2H), 3.11 (m, 3H), 2.89 (m, 1H), 2.45 (s, 3H), 2.22 (s, 3H), 0.69 (m, 3H); (Yield: 55%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.19 (m, 5H), 5.80 (m, 1H), 5.45 (m, 1H), 5.25 (m, 1H), 5.01 (m, 1H), 4.43 (m, 1H), 4.22 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.11 (m, 1H), 2.45 (s, 3H), 2.33 (s, 3+3H), 1.44 (m, 1H), 1.33 (m, 1H), 0.65 (m, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.07 (m, 1H), 7.92 (m, 1H), 7.22 (m, 3H), 7.14 (m, 2H), 5.05 (m, 1H), 4.72 (m, 1H), 4.33 (m, 1H), 4.22 (m, 1H), 3.95 (m, 1H), 3.70 (m, 3H), 3.22 (m, 1H), 3.12 (m, 3H), 2.55 (s, 3H), 2.05 (m, 1H), 1.86 (m, 1H), 0.82 (m, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (s, 1H), 7.19 (m, 5H), 5.85 (m, 1H), 5.04 (m, 2H), 4.72 (m, 1H), 4.58 (m, 1H), 4.44 (m, 2H), 4.22 (m, 1H), 4.01 (m, 2H), 3.12 (m, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.99 (m, 1H), 1.86 (m, 1H), 0.82 (m, 3H), 0.69 (m, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.00 (m, 1H), 7.18 (m, 5H), 6.47 (m, 1H), 6.08 (m, 1H), 5.35 (m, 1H), 5.04 (m, 1H), 4.72 (m, 1H), 4.31 (m, 1H), 4.17 (m, 1H), 4.01 (m, 1H), 3.45 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.22 (s, 3+3H), 1.55 (m, 1H), 1.33 (m, 1H), 0.83 (m, 3H); (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.03 (s, 1H), 7.11 (m, 5H), 6.45 (m, 1H), 6.22 (m, 1H), 5.66 (m, 1H), 5.22 (m, 1H), 5.05 (m, 1H), 4.55 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.33 (m, 1H), 2.95 (m, 3H), 2.55 (m, 3H), 2.33 (s, 3H), 2.22 (s, 3H), 1.88 (m, 1H), 1.66 (m, 1H), 0.76 (m, 3H); (Yield: 39%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 1H), 7.27 (m, 9H), 5.65 (m, 1H), 5.22 (m, 1H), 4.75 (m, 1H), 4.33 (m, 1H), 4.00 (m, 1H), 3.66 (m, 1H), 3.55 (m, 1H), 2.49 (s, 3H), 2.26 (s, 3H), 1.94 (m, 1H), 1.83 (m, 1H), 0.68 (m, 3H); (Yield: 39%)
1,2,3,4-Tetrahydroisoquinoline (1 ml) was added to 7-chloro-2-ethyl-3-methyl-1H-pyrrolo[2,3-c]pyridine (850 mg, 4.37 mmol) prepared in Preparation 28. The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 660 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 8.07 (brs, 1H), 7.98 (d, 1H), 7.32 (d, 1H), 2.82 (q, 2H), 2.21 (s, 3H), 1.31 (t, 3H)
18-Crown-6 (2.5 mg, 0.0097 mmol) and potassium tert-butoxide (11 mg, 0.097 mmol) was added to a solution of 2-ethyl-3-methyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[2,3-c]pyridine (28.3 mg, 0.097 mmol) prepared in Example 591 in anhydrous tetrahydrofuran (0.5 ml). The reaction mixture was stirred for 30 minutes at room temperature and benzyl bromide (17.4 μl, 0.146 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 7.8 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.52 (d, 2H), 7.16 (m, 5H), 6.72 (m, 1H), 6.46 (m, 2H), 5.55 (s, 2H), 4.43 (m, 2H), 3.72 (m, 2H), 2.87 (m, 2H), 2.75 (m, 2H), 2.41 (s, 3H), 1.17 (t, 3H)
The titled compounds of Examples 593 to 611 were prepared, in accordance with the same procedures as in Example 592, using 2-ethyl-3-methyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 591; and, 3-fluorobenzyl chloride, 3-methoxybenzyl chloride, allyl bromide, 4-bromo-2-methylbutene, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, 4-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, iodoethane, 4-methoxybenzyl chloride, 3-methylbenzyl chloride, 4-methylbenzyl chloride, propargyl bromide, 4-fluorobenzyl chloride, 4-trifluoromethylbenzyl chloride, 2-fluorobenzyl chloride, iodomethane, 3-chlorobenzyl chloride, or 1-bromopropane.
1H-NMR(400 MHz, CDCl3) δ 8.18 (d, 1H), 7.54 (d, 1H), 7.26 (m, 1H), 7.13 (m, 3H), 6.92 (t, 1H), 6.74 (d, 1H), 6.23 (d, 1H), 6.16 (d, 1H), 5.63 (s, 2H), 4.32 (m, 2H), 3.65 (m, 2H), 2.83 (m, 2H), 2.75 (m, 2H), 2.40 (s, 3H), 1.21 (t, 3H); (Yield: 35%)
1H-NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.52 (d, 1H), 7.18 (m, 1H), 7.10 (m, 3H), 6.75 (d, 1H), 6.69 (d, 1H), 6.02 (s, 2H), 5.62 (s, 2H), 4.52 (m, 2H), 3.78 (m, 2H), 3.61 (s, 3H), 2.86 (m, 2H), 2.75 (m, 2H), 2.34 (s, 3H), 1.19 (t, 3H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (d, 1H), 7.48 (d, 1H), 7.39 (m, 1H), 7.20 (m, 2H), 7.04 (d, 1H), 5.87 (m, 1H), 5.15 (d, 1H), 5.10 (s, 2H), 4.52 (m, 2H), 4.45 (d, 1H), 3.93 (s, 2H), 3.15 (s, 2H), 2.87 (m, 2H), 2.31 (s, 3H), 1.25 (t, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (s, 1H), 7.42 (d, 1H), 7.21 (m, 3H), 7.01 (d, 1H), 5.01 (s, 1H), 4.93 (s, 1H), 4.79 (s, 1H), 4.52 (m, 2H), 3.95 (m, 2H), 3.12 (m, 2H), 2.83 (q, 2H), 2.28 (s, 3H), 1.56 (s, 3H), 1.35 (s, 3H), 1.28 (t, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (d, 1H), 7.39 (d, 1H), 7.21 (m, 3H), 6.91 (d, 1H), 4.50 (s, 2H), 4.12 (s, 1H), 3.92 (s, 2H), 3.55 (m, 1H), 3.31 (t, 2H), 3.15 (t, 2H), 3.07 (s, 3H), 2.92 (q, 2H), 2.25 (s, 3H), 1.28 (t, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.44 (d, 1H), 7.24 (t, 3H), 7.07 (d, 1H), 4.51 (m, 1H), 4.21 (d, 2H), 4.01 (m, 2H), 3.48 (m, 1H), 3.17 (s, 2H), 2.90 (q, 2H), 2.29 (s, 3H), 1.29 (t, 3H), 0.89 (m, 1H), 0.33 (d, 2H), 0.04 (m, 2H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.54 (d, 1H), 7.20 (m, 2H), 7.12 (m, 3H), 6.76 (s, 1H), 6.41 (d, 2H), 5.61 (s, 2H), 4.72 (m, 1H), 4.35 (m, 1H), 3.75 (m, 2H), 2.85 (s, 2H), 2.74 (q, 2H), 2.34 (s, 3H), 1.28 (t, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (m, 1H), 7.55 (d, 1H), 7.23 (d, 2H), 7.13 (m, 2H), 6.74 (d, 1H), 6.59 (s, 1H), 6.24 (d, 1H), 5.48 (s, 2H), 4.67 (m, 1H), 3.75 (m, 1H), 3.33 (m, 1H), 3.05 (m, 1H), 2.85 (s, 2H), 2.79 (q, 2H), 2.35 (s, 3H), 1.22 (t, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.45 (d, 1H), 7.23 (m, 3H), 7.08 (d, 1H), 4.55 (m, 2H), 4.35 (q, 2H), 3.97 (m, 2H), 3.17 (s, 2H), 2.85 (q, 2H), 2.29 (s, 3H), 1.31 (t, 3H), 1.21 (t, 3H); (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.50 (d, 1H), 7.18 (m, 1H), 7.11 (m, 2H), 6.89 (m, 1H), 6.70 (d, 2H), 6.42 (d, 2H), 5.58 (s, 2H), 4.56 (m, 1H), 4.35 (m, 1H), 3.85 (m, 2H), 3.74 (s, 3H), 2.86 (s, 2H), 2.75 (q, 2H), 2.33 (s, 3H), 1.19 (t, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (m, 1H), 7.52 (d, 1H), 7.15 (m, 1H), 7.11 (m, 4H), 6.65 (d, 1H), 6.31 (s, 1H), 6.21 (d, 1H), 5.55 (s, 2H), 4.33 (m, 2H), 3.75 (m, 2H), 2.75 (m, 2H), 2.65 (q, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 1.19 (t, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (m, 1H), 7.51 (d, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.97 (d, 3H), 6.76 (d, 1H), 6.38 (d, 2H), 5.60 (s, 2H), 4.44 (m, 2H), 3.75 (m, 2H), 2.84 (t, 2H), 2.76 (q, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 1.15 (t, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (m, 1H), 7.46 (d, 1H), 7.18 (m, 2H), 7.11 (m, 2H), 5.22 (s, 2H), 4.69 (m, 1H), 4.45 (m, 1H), 3.95 (m, 2H), 3.19 (m, 2H), 2.97 (m, 2H), 2.42 (s, 3H), 2.41 (s, 1H), 1.33 (t, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (m, 1H), 7.53 (d, 1H), 7.15 (m, 2H), 6.90 (m, 2H), 6.75 (d, 2H), 6.45 (m, 1H), 5.61 (s, 2H), 4.55 (m, 1H), 4.23 (m, 1H), 3.75 (m, 2H), 2.81 (t, 2H), 2.76 (q, 2H), 2.30 (s, 3H), 1.18 (t, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (s, 1H), 7.56 (s, 1H), 7.41 (d, 2H), 7.19 (m, 1H), 7.09 (m, 2H), 6.66 (d, 1H), 6.55 (d, 2H), 5.71 (s, 2H), 4.51 (m, 2H), 3.99 (m, 1H), 3.65 (m, 1H), 3.21 (m, 1H), 2.77 (s, 2H), 2.75 (q, 2H), 2.36 (s, 3H), 1.20 (t, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.17 (d, 1H), 7.54 (d, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 7.05 (m, 2H), 6.89 (t, 1H), 6.67 (d, 1H), 6.12 (t, 1H), 5.71 (s, 2H), 4.44 (m, 2H), 3.75 (m, 2H), 2.88 (t, 2H), 2.77 (q, 2H), 2.40 (s, 3H), 1.20 (t, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (d, 1H), 7.39 (d, 1H), 7.22 (m, 3H), 7.13 (d, 1H), 4.65 (s, 2H), 3.97 (s, 2H), 3.96 (s, 3H), 3.19 (t, 2H), 2.85 (q, 2H), 2.28 (s, 3H), 1.25 (t, 3H); (Yield: 80%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 1H), 7.54 (m, 1H), 7.14 (m, 2H), 7.09 (m, 3H), 6.73 (d, 2H), 6.49 (s, 1H), 6.27 (s, 1H), 5.60 (s, 2H), 4.44 (m, 2H), 3.75 (m, 2H), 2.82 (s, 2H), 2.75 (m, 2H), 2.35 (s, 3H), 1.20 (t, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 1H), 7.55 (m, 2H), 7.19 (m, 2H), 7.05 (d, 1H), 4.56 (m, 1H), 4.19 (m, 1H), 4.09 (m, 1H), 3.91 (m, 1H), 3.51 (m, 1H), 3.25 (m, 1H), 3.15 (m, 2H), 2.85 (q, 2H), 2.28 (s, 3H), 1.29 (t, 3H), 0.79 (m, 2H), 0.60 (t, 3H); (Yield: 89%)
The compound prepared in Example 480 was treated with a saturated sodium bicarbonate solution to obtain 1-(3-fluorobenzyl)-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine. Ammonium cerium (IV) nitrate (973 mg, 1.77 mmol) was added at room temperature to a solution of 1-(3-fluorobenzyl)-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (225 mg, 0.58 mmol) in acetic acid (5 ml). The reaction mixture was stirred for 3 hours at 55□ and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydroxide solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 ml) and then 2N lithium hydroxide (2.5 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature, neutralized with 1N hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=1/3, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 35 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 9.95 (s, 1H), 8.10 (s, 1H), 7.74 (d, 1H), 7.58 (m, 2H), 7.48 (m, 1H), 7.23 (s, 1H), 6.99 (d, 1H), 6.89 (m, 2H), 6.48 (d, 1H), 5.97 (s, 2H), 3.81 (t, 2H), 3.30 (t, 2H), 2.38 (s, 3H), 2.26 (s, 3H)
In accordance with the same procedures as in Example 468, except for using 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine prepared in Preparation 20 and isopropenyl magnesium bromide, the titled compound was obtained. (Yield: 39%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Example 469, except for using 2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Step 1 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.02 (d, 1H), 7.28 (d, 1H), 7.12 (m, 4H), 6.87 (m, 2H), 6.49 (d, 1H), 6.38 (s, 1H), 6.36 (d, 1H), 5.82 (brs, 1H), 5.51 (brs, 1H), 4.33 (brs, 1H), 4.07 (brs, 1H), 3.45 (brs, 1H), 3.28 (brs, 1H), 2.91 (brs, 1H), 2.76 (brs, 1H), 2.30 (s, 3H)
In accordance with the same procedures as in Example 469, except for using (2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Step 1 of Example 613 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.25 (m, 5H), 7.12 (brs, 2H), 6.68 (m, 1H), 6.53 (s, 1H), 5.64 (brs, 2H), 4.45 (brs, 2H), 3.82 (brs, 2H), 2.84 (brs, 2H), 2.43 (s, 3H)
N-Bromosuccinimide (41 mg, 0.23 mmol) and silica gel (100 mg) were added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (88 mg, 0.23 mmol) prepared in Example 613 in dichloromethane (2 ml). The reaction mixture was stirred for 1 hour and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.10 (d, 1H), 7.27 (d, 1H), 7.12 (m, 4H), 6.91 (m, 2H), 6.52 (d, 1H), 6.44 (d, 1H), 5.88 (m, 1H), 5.72 (m, 1H), 4.42 (brs, 1H), 4.14 (brs, 1H), 3.48 (brs, 1H), 3.22 (brs, 1H), 2.92 (brs, 1H), 2.79 (brs, 1H), 2.18 (s, 3H)
Phosphorus oxychloride (44 μl, 0.47 mmol) was added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (115 mg, 0.31 mmol) prepared in Example 613 in N,N-dimethylformamide (2 ml). The reaction mixture was stirred overnight at 100° C. under heating. The reaction mixture was cooled to room temperature, added to ice water, basified with a sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 28 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 10.31 (s, 1H), 8.36 (s, 2H), 7.22 (m, 2H), 7.12 (m, 2H), 7.01 (d, 1H), 6.71 (s, 1H), 6.35 (m, 2H), 5.74 (brs, 2H), 4.45 (brs, 2H), 3.88 (brs, 2H), 2.90 (brs, 2H), 2.75 (s, 3H)
Sodium borohydride (4.7 mg, 0.124 mmol) was added to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-carbaldehyde hydrochloride (25 mg) prepared in Example 616 in methanol (2 ml). The reaction mixture was stirred for 1 hour and water was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.08 (d, 1H), 7.42 (d, 1H), 7.15 (m, 4H), 6.87 (m, 2H), 6.51 (d, 1H), 6.40 (d, 1H), 5.85 (brs, 1H), 5.69 (brs, 1H), 4.85 (s, 2H), 4.35 (brs, 1H), 4.11 (brs, 1H), 3.47 (brs, 1H), 3.29 (brs, 1H), 2.90 (brs, 1H), 2.76 (brs, 1H), 2.32 (s, 3H)
The compound prepared in Example 613 was treated with a saturated sodium bicarbonate solution to obtain 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline. Morpholine (25 μl, 0.297 mmol), acetic acid (0.13 ml), and formaldehyde (70 μl) were added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.27 mmol) in ethanol (1.5 ml). The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and then washed with a sodium bicarbonate solution. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/dichloromethane=1/1, v/v) to give the titled compound as a pale yellow solid (Yield: 65%).
1H-NMR(400 MHz, CDCl3) δ 8.07 (d, 1H), 7.42 (d, 1H), 7.13 (m, 4H), 6.88 (m, 2H), 6.47 (d, 1H), 6.35 (d, 1H), 5.84 (d, 1H), 5.70 (d, 1H), 4.32 (brs, 1H), 4.11 (brs, 1H), 3.72 (s, 2H), 3.71 (brs, 4H), 3.46 (brs, 1H), 3.29 (brs, 1H), 2.91 (brs, 1H), 2.76 (brs, 1H), 2.54 (brs, 4H), 2.28 (s, 3H)
The compound prepared in Example 613 was treated with a saturated sodium bicarbonate solution to obtain 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline. Dimethylamine (2.0M in tetrahydrofuran solution; 378 μl, 0.75 mmol), acetic acid (0.03 ml), and formaldehyde (163 μl) were added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (234 mg, 0.63 mmol) in ethanol (3.5 ml). The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and then washed with a sodium bicarbonate solution. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/dichloromethane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid (Yield: 68%).
1H-NMR(400 MHz, CDCl3) δ 8.05 (d, 1H), 7.37 (d, 1H), 7.13 (m, 4H), 6.86 (m, 2H), 6.48 (d, 1H), 6.37 (d, 1H), 5.84 (d, 1H), 5.71 (d, 1H), 4.33 (brs, 1H), 4.08 (brs, 1H), 3.62 (s, 2H), 3.47 (brs, 1H), 3.27 (brs, 1H), 2.30 (s, 6H), 2.28 (s, 3H)
The compound prepared in Example 619 was treated with a saturated sodium bicarbonate solution to obtain [7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-dimethylamine. Iodomethane (40 μl, 0.64 mmol) was added to a solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-dimethylamine (136 mg, 0.32 mmol) in ethanol (2 ml). The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered and then dried to give the titled compound as a white solid (Yield 82%).
1H-NMR(400 MHz, CDCl3) δ 8.16 (d, 1H), 7.57 (d, 1H), 7.14 (m, 4H), 6.92 (d, 2H), 6.47 (d, 1H), 6.33 (d, 1H), 5.90 (d, 1H), 5.78 (d, 1H), 5.16 (brs, 2H), 4.34 (brs, 1H), 4.10 (brs, 1H), 3.48 (brs, 1H), 3.44 (s, 9H), 3.30 (brs, 1H), 2.95 (brs, 1H), 2.81 (brs, 1H), 2.60 (s, 3H)
Sodium cyanide (34 mg, 0.72 mmol) was added to a solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-trimethylammonium iodide (100 mg, 0.27 mmol) prepared in Example 620 in N,N-dimethylformamide (3 ml). The reaction mixture was stirred for 5 hours at 100° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 17 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.28 (brs, 1H), 7.67 (brs, 1H), 7.24 (m, 3H), 7.19 (m, 1H), 7.13 (m, 2H), 6.68 (m, 2H), 5.68 (brs, 2H), 4.51 (brs, 2H), 3.92 (brs, 2H), 3.89 (brs, 2H), 2.88 (brs, 2H), 2.45 (s, 3H)
In accordance with the same procedures as in Example 619, except for using 2-(1-benzyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline obtained by treating the compound prepared in Example 614 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.52 (m, 1H), 7.17 (m, 4H), 7.11 (m, 2H), 6.85 (d, 1H), 6.65 (m, 2H), 5.78 (brs, 2H), 4.37 (s, 2H), 4.34 (brs, 2H), 3.50 (brs, 2H), 2.86 (brs, 2H), 2.82 (s, 3+3H), 2.54 (s, 3H)
In accordance with the same procedures as in Example 620, except for using [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-dimethylamine obtained by treating the compound prepared in Example 622 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (d, 1H), 7.65 (d, 1H), 7.16 (m, 4H), 7.12 (m, 2H), 6.88 (d, 1H), 6.67 (brs, 2H), 5.92 (brs, 1H), 5.75 (brs, 1H), 5.14 (s, 2H), 4.35 (brs, 1H), 4.14 (brs, 1H), 3.54 (brs, 1H), 3.45 (s, 3+3+3H), 3.26 (brs, 1H), 2.93 (brs, 1H), 2.77 (brs, 1H), 2.56 (s, 3H)
Sodium cyanide (34 mg, 0.72 mmol) was added to a solution [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-trimethylammonium iodide (100 mg, 0.18 mmol) prepared in Example 623 in N,N-dimethylformamide (3 ml). The reaction mixture was stirred for 5 hours at 100° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 15 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.27 (brs, 1H), 7.63 (brs, 1H), 7.25 (m, 3H), 7.18 (m, 1H), 7.13 (m, 2H), 6.68 (m, 1H), 6.57 (brs, 2H), 5.68 (brs, 2H), 4.50 (brs, 2H), 3.88 (brs, 2H), 3.86 (brs, 2H), 2.89 (brs, 2H), 2.45 (s, 3H)
A solution of 3-amino-2-chloropyridine (1.13 g, 8.84 mmol) in dichloromethane (22.7 ml) was cooled to −78° C. A solution of tert-butyl hyperchloride (2 ml, 17.7 mmol) in dichloromethane (6.8 ml) was added to the solution. The reaction mixture was stirred for 15 minutes and a solution of methylthioacetone (0.91 ml, 8.84 mmol) in dichloromethane (6.8 ml) was slowly added thereto. The reaction mixture was stirred for 90 minutes at the same temperature and a solution of triethylamine (1.36 ml, 8.84 mmol) in dichloromethane (6.8 ml) was added thereto. The reaction mixture was warmed to room temperature and water was added thereto. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 100 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.61 (brs, 1H), 8.07 (d, 1H), 7.52 (d, 1H), 2.61 (s, 3H), 2.26 (s, 3H)
7-Chloro-2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridine (418 mg) prepared in Step 1 was added to 1,2,3,4-tetrahydroisoquinoline (3 ml). The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 440 mg of the titled compound as pale yellow oil.
A solution of 2-(2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Step 2 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 9.64 (brs, 1H), 8.00 (d, 1H), 7.28 (d, 1H), 7.04 (m, 3H), 6.87 (d, 1H), 4.48 (s, 2H), 3.62 (t, 2H), 2.89 (t, 2H), 2.52 (s, 3H), 2.25 (s, 3H)
The titled compounds of Examples 626 to 631 were prepared, in accordance with the same procedures as in Example 592, using 2-(2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Step 2 of Example 625; and, benzyl bromide, 3-fluorobenzyl chloride, (bromomethyl)cyclopropane, 1-bromopropane, 2-bromoethyl methyl ether, or allyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.25 (d, 1H), 7.76 (d, 1H), 7.21 (m, 4H), 7.17 (m, 2H), 6.68 (d, 1H), 6.53 (d, 2H), 5.67 (s, 2H), 4.45 (brs, 2H), 3.85 (brs, 2H), 2.87 (m, 2H), 2.54 (s, 3H), 2.29 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (d, 1H), 7.63 (d, 1H), 7.09 (m, 4H), 6.93 (t, 1H), 6.78 (d, 1H), 6.40 (d, 2H), 6.33 (d, 2H), 5.73 (s, 2H), 4.33 (brs, 2H), 3.61 (brs, 2H), 2.86 (s, 2H), 2.48 (s, 3H), 2.28 (s, 3H); (Yield: 49%)
1H-NMR(400 MHz, CDCl3) δ 8.23 (d, 1H), 7.69 (d, 1H), 7.23 (m, 3H), 7.07 (d, 1H), 4.45 (brs, 2H), 4.26 (d, 2H), 4.02 (brs, 2H), 3.18 (t, 2H), 2.71 (s, 3H), 2.28 (s, 3H), 0.95 (m, 1H), 0.38 (d, 2H), 0.07 (brs, 2H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (d, 1H), 7.71 (d, 1H), 7.22 (m, 3H), 7.06 (t, 1H), 4.55 (brs, 2H), 4.26 (t, 2H), 4.05 (t, 2H), 3.16 (t, 2H), 2.66 (s, 3H), 2.26 (s, 3H), 1.57 (m, 1H), 0.59 (t, 3H); (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (t, 1H), 7.74 (d, 1H), 7.22 (m, 3H), 7.06 (d, 1H), 4.55 (m, 2+2H), 4.01 (m, 2H), 3.44 (t, 2H), 3.13 (brs, 2H), 3.08 (s, 3H), 2.69 (s, 3H), 2.26 (s, 3H); (Yield: 42%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (t, 1H), 7.73 (d, 1H), 7.20 (m, 3H), 7.03 (d, 1H), 5.82 (m, 1H), 5.20 (d, 1H), 5.08 (s, 2H), 4.57 (m, 2+1H), 3.95 (brs, 2H), 3.11 (brs, 2H), 2.62 (s, 3H), 2.27 (s, 3H); (Yield: 51%)
Hydrogen peroxide (50 wt. %, 100 μl) was added to a solution of 2-(1-allyl-2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (45 mg, 0.12 mmol) prepared in Example 631 in acetic acid (3 ml). The reaction mixture was stirred for 30 minutes at room temperature and sodium thiosulfate was added thereto. The reaction mixture was basified with a potassium carbonate solution and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 5.5 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.29 (d, 1H), 8.12 (d, 1H), 7.21 (m, 3H), 7.04 (d, 1H), 5.81 (m, 1H), 5.25 (d, 1H), 5.10 (m, 2H), 4.64 (m, 2+1H), 4.01 (brs, 2H), 3.13 (t, 2H), 3.03 (s, 3H), 2.64 (s, 3H)
The titled compounds of Examples 633 to 636 were prepared, in accordance with the same procedures as in Example 632, using the compounds prepared in Examples 627 to 630.
1H-NMR(400 MHz, CDCl3) δ 8.28 (d, 1H), 8.15 (d, 1H), 7.21 (m, 2H), 7.13 (m, 2H), 7.09 (t, 1H), 6.71 (d, 1H), 6.33 (t, 2H), 5.66 (dd, 2H), 4.55 (brs, 2H), 3.83 (brs, 2H), 3.06 (s, 3H), 2.89 (brs, 2H), 2.56 (s, 3H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.29 (d, 1H), 8.08 (d, 1H), 7.22 (m, 3H), 7.07 (d, 1H), 4.55 (brs, 2H), 4.25 (d, 2H), 4.04 (brs, 2H), 3.18 (brs, 2H), 3.04 (s, 3H), 2.74 (s, 3H), 0.92 (m, 1H), 0.40 (m, 2H), 0.07 (m, 2H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.27 (d, 1H), 8.09 (d, 1H), 7.22 (m, 3H), 7.08 (d, 1H), 4.55 (brs, 2H), 4.24 (brs, 2H), 4.04 (brs, 2H), 3.18 (brs, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 1.55 (m, 2H), 0.61 (t, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.30 (d, 1H), 8.14 (d, 1H), 7.22 (m, 3H), 7.07 (d, 1H), 4.53 (m, 2+2H), 3.97 (brs, 2H), 3.45 (brs, 2H), 3.14 (brs, 2H), 3.10 (s, 3H), 3.02 (s, 3H), 2.69 (s, 3H); (Yield: 51%)
Hydrogen peroxide (50 wt. %, 100 μl) was added to a solution of 2-(1-allyl-3-methylsulfinyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (30 mg, 0.07 mmol) prepared in Example 632 in acetic acid (3 ml). The reaction mixture was stirred for 1 hour at 60° C., cooled to room temperature, basified with a potassium carbonate solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.34 (d, 1H), 8.14 (d, 1H), 7.23 (m, 3H), 7.04 (d, 1H), 5.83 (m, 1H), 5.28 (d, 1H), 5.16 (s, 2H), 4.67 (brs, 2H), 4.62 (d, 1H), 3.97 (brs, 2H), 3.16 (s, 3H), 3.14 (brs, 2H), 2.81 (s, 3H)
The titled compounds of Examples 638 to 641 were prepared, in accordance with the same procedures as in Example 637, using the compounds prepared in Examples 633 to 636.
1H-NMR(400 MHz, CDCl3) δ 8.41 (m, 2H), 8.10 (d, 1H), 7.62 (t, 1H), 7.45 (t, 1H), 7.36 (d, 1H), 5.22 (t, 1H), 4.29 (m, 1H), 4.07 (m, 2H), 3.47 (m, 2H), 3.28 (s, 3H), 2.88 (s, 3H), 1.09 (m, 1H), 0.63 (m, 2H), 0.25 (m, 2H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 2H), 8.11 (d, 1H), 7.62 (t, 1H), 7.45 (t, 1H), 7.34 (d, 1H), 5.17 (t, 1H), 4.21 (t, 2H), 3.94 (m, 1H), 3.50 (m, 1H), 3.28 (m, 1H), 3.18 (s, 3H), 2.87 (s, 3H), 1.75 (m, 2H), 0.811 (t, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (m, 2H), 8.09 (d, 1H), 7.61 (t, 1H), 7.44 (t, 1H), 7.34 (d, 1H), 5.22 (t, 1H), 4.51 (m, 1H), 4.40 (m, 1H), 3.98 (m, 1H), 3.48 (m, 2+2H), 3.18 (s, 3+3H), 2.88 (s, 3H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 8.42 (s, 2H), 8.09 (d, 1H), 7.56 (t, 1H), 7.44 (t, 1H), 7.21 (m, 2H), 7.01 (t, 1H), 6.34 (m, 2H), 5.60 (d, 1H), 5.45 (d, 1H), 4.72 (t, 1H), 3.22 (s, 3H), 3.11 (m, 2H), 2.82 (s, 3H), 2.33 (t, 1H)
Trifluoromethanesulfonic anhydride (69.51 ml, 0.41 mol) was added to a mixture solution of tetramethylammonium nitrate (56.26 g, 0.41 mol) in dichloromethane (167 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours at room temperature and then 2,6-difluoropyridine (25 ml, 0.28 mol) and dichloromethane (50 ml) were added thereto. The reaction mixture was refluxed for 8 hours, cooled to room temperature, and then brought to pH 8 with a saturated sodium bicarbonate solution. The separated organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give 34.55 g of the titled compound as yellow oil.
1H-NMR(400 MHz, CDCl3) δ 8.69 (q, 1H), 7.04 (d, 1H)
1,2,3,4-Tetrahydroisoquinoline (34.8 ml, 0.28 mol) was added to a solution of 2,6-difluoro-3-nitropyridine (44.55 g, 0.28 mol) prepared in Step 1 in toluene (200 ml). The reaction mixture was stirred overnight at 60° C. and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=1/4, v/v) to give 5.38 g of the titled compound as yellow solid.
1H-NMR (400 MHz, CDCl3) δ 8.34 (brs, 2H), 7.49 (brs, 1H), 7.16-7.13 (m, 1H), 7.10-7.03 (m, 3H), 6.95-6.87 (m, 2H), 6.40-6.38 (d, 2H), 5.67 (s, 2H), 4.18 (brs, 2H), 4.17 (s, 2H), 3.43 (brs, 2H), 2.76 (brs, 2H), 2.18 (s, 3H), 2.14 (s, 3H)
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution; 138 ml, 68.9 mmol) was slowly added at −78° C. to a solution of 2-(6-fluoro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (5.38 g, 19.7 mmol) prepared in Step 2 in anhydrous tetrahydrofuran (150 ml). The reaction mixture was stirred for 1 hour at the same temperature, slowly warmed to room temperature, and then stirred overnight. 20% (w/v) Ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was crystallized with ethyl ether to give the titled compound as red oil. (Yield: 32%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (brs, 1H), 7.26-7.17 (m, 4H), 6.47 (brs, 1H), 4.56 (s, 2H), 3.83 (m, 2H), 3.01 (m, 2H), 2.36 (s, 3H), 2.17 (s, 3H)
A solution of 2-(5-fluoro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (117.4 mg, 0.40 mmol) prepared in Step 3, sodium hydride (60%, 23.85 mg, 0.60 mmol), and benzyl bromide (56.73 μl, 0.48 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 8.9 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 7.37-7.23 (m, 6H), 7.08 (d, 1H), 6.93 (d, 2H), 5.51 (s, 2H), 4.79 (brs, 2H), 3.87 (brs, 2H), 2.35 (s, 3H), 2.29 (s, 3H)
The titled compounds of Examples 643 to 646 were prepared, in accordance with the same procedures as in Step 4 of Example 642, using 2-(5-fluoro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Step 3 of Example 642; and, (bromomethyl)cyclopropane, 3-chlorobenzyl bromide, 3-fluorobenzyl chloride, or allyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.42 (s, 1H), 7.26-7.23 (m, 3H), 7.08 (d, 1H), 4.79 (brs, 2H), 4.17 (d, 2H), 3.87 (brs, 2H), 2.43 (s, 3H), 2.27 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, MeOH-d4) δ 7.63 (s, 1H), 7.35-7.25 (m, 6H), 6.93-6.89 (m, 2H), 5.60 (s, 2H), 4.89 (s, 2H), 4.05 (t, 2H), 3.37 (t, 2H), 2.41 (s, 3H), 2.34 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.49 (s, 1H), 7.32-7.24 (m, 4H), 7.08 (d, 1H), 6.98 (m, 1H), 6.72 (d, 1H), 6.60 (d, 1H), 5.49 (s, 2H), 4.79 (brs, 2H), 3.49 (brs, 2H), 2.35 (s, 3H), 2.30 (s, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.43 (s, 1H), 7.26-7.24 (m, 3H), 7.08 (d, 1H), 5.94 (m, 1H), 5.16 (d, 1H), 4.88 (s, 2H), 4.78 (s, 2H), 4.74 (s, 2H), 3.68 (brs, 2H), 2.38 (s, 3H), 2.27 (s, 3H); (Yield: 86%)
In accordance with the same procedures as in Step 3 of Example 642, except for using 2-(5-fluoro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 6, the titled compound was obtained as yellow oil. (Yield: 43%)
1H-NMR(400 MHz, CDCl3) δ 8.11 (brs, 1H), 7.72 (d, 1H), 7.17 (m, 4H), 4.47 (s, 2H), 3.59 (t, 2H), 3.10 (t, 2H), 2.38 (s, 3H), 2.33 (s, 3H)
A solution of 4-fluoro-2,3-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[2,3-c]pyridine (38.5 mg, 0.13 mmol) prepared in Example 647, sodium hydride (60%, 10.4 mg, 0.261 mmol), and allyl bromide (12.1 μl, 0.143 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 2.6 mg of the titled compound as a pale yellow solid. (Yield: 6%)
1H-NMR(400 MHz, CDCl3) δ 8.03 (d, 1H), 7.22 (m, 3H), 7.01 (d, 1H), 5.81 (m, 1H), 5.18-3.51 (m, 8H), 3.09 (m, 2H), 2.44 (s, 3H), 2.41 (s, 3H)
The titled compounds of Examples 649 to 651 were prepared, in accordance with the same procedures as in Example 648, using 4-fluoro-2,3-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1H-pyrrolo[2,3-c]pyridine prepared in Example 647; and, 1-bromopropane, 2-bromoethyl methyl ether, or benzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 8.02 (d, 1H), 7.20 (m, 3H), 7.04 (d, 1H), 4.79 (brs, 1H), 4.18 (m, 4H), 3.51 (brs, 1H), 3.14 (brs, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 1.55 (m, 2H), 0.60 (t, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 8.00 (d, 1H), 7.21 (m, 3H), 7.01 (d, 1H), 5.04-3.95 (m, 6H), 3.42 (m, 2H), 3.11 (m, 5H), 2.48 (s, 3H), 2.42 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 8.05 (brs, 1H), 7.16 (m, 6H), 6.54 (d, 1H), 6.54 (m, 2H), 5.69 (brs, 2H), 4.71-2.82 (m, 4H), 2.74 (brs, 2H), 2.46 (s, 3H), 2.34 (s, 3H); (Yield: 61%)
In accordance with the same procedures as in Step 3 of Example 642, except for using 5-fluoro-3-nitro-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyridine prepared in Preparation 6, the titled compound was obtained as a white solid. (Yield: 20%)
A solution of the compound (5 mg) prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 2,3 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 8.03 (brs, 1H), 7.88 (brs, 1H), 7.50 (brs, 1H), 7.31 (brs, 1H), 7.24 (brs, 1H), 4.48 (brs, 2H), 3.26 (brs, 2H), 2.44 (s, 3H), 2.40 (s, 3H)
The titled compounds of Examples 653 to 655 were prepared, in accordance with the same procedures as in Example 648, using 2-[2-(4-fluoro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylamino)-ethyl]-benzaldehyde prepared in Step 1 of Example 652; and, 1-bromopropane, benzyl bromide, or allyl iodide.
1H-NMR(400 MHz, CDCl3) δ 8.12 (d, 1H), 8.05 (d, 1H), 7.57 (t, 1H), 7.41 (t, 1H), 7.32 (d, 1H), 5.05 (m, 1H), 4.13 (m, 2H), 3.88 (m, 1H), 3.53 (m, 1H), 3.29 (m, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 1.69 (m, 2H), 0.78 (t, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.09 (m, 2H), 7.52 (t, 1H), 7.39 (t, 1H), 7.23 (m, 3H), 7.14 (d, 1H), 6.52 (d, 2H), 5.56 (d, 1H), 5.35 (d, 1H), 4.60 (m, 1H), 3.10 (m, 1H), 2.98 (m, 1H), 2.52 (s, 3H), 2.41 (s, 3H), 2.25 (m, 1H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.10 (d, 1H), 8.06 (d, 1H), 7.56 (t, 1H), 7.30 (d, 1H), 7.41 (t, 1H), 5.92 (m, 1H), 5.15 (d, 1H), 4.90 (m, 2H), 4.73 (m, 1H), 4.41 (d, 1H), 3.77 (m, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H); (Yield: 67%)
2-(6-Chloro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (16 g, 56.6 mmol) prepared in Preparation 7 was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 283 ml, 141.5 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and then 20% (w/v) ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 7.8 g of the titled compound as yellow oil. (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.15 (m, 4H), 6.98 (s, 1H), 4.60 (s, 2H), 3.71 (t, 2H), 3.04 (t, 2H), 2.36 (s, 3H), 2.13 (s, 3H)
Sodium hydride (60%, 2,3 mg, 0.075 mmol) and 3-fluorobenzyl chloride (9.2 μl, 0.075 mmol) were added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (15 mg, 0.048 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (0.5 ml). The reaction mixture was stirred for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give the titled compound as a white solid (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.52 (s, 1H), 7.21 (m, 3H), 7.07 (d, 1H), 6.98 (m, 3H), 6.88 (s, 1H), 5.68 (s, 2H), 4.35 (s, 2H), 3.49 (t, 2H), 3.15 (t, 2H), 2.54 (s, 3H), 2.27 (s, 3H)
The titled compounds of Examples 658 to 681 were prepared, in accordance with the same procedures as in Example 657, using 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Example 656; and, benzyl bromide, propargyl bromide, 2-bromoethyl methyl ether, allyl bromide, 3-fluorobenzyl bromide, 4-bromo-1-butene, 4-bromo-2-methyl-2-butene, 1-bromo-3-methylbutane, (bromomethyl)cyclopropane, 2-(bromomethyl)naphthalene, 4-tert-butylbenzyl chloride, 4-chlorobenzyl chloride, 2,5-dimethylbenzyl chloride, iodoethane, 1-iodo-2-methylpropane, 1-bromopropane, 3-methoxybenzyl bromide, 4-methoxybenzyl bromide, 3-methylbenzyl bromide, 4-methylbenzyl bromide, 4-fluorobenzyl bromide, (bromomethyl)cyclobutane, 2-fluorobenzyl chloride, or iodomethane.
1H-NMR(400 MHz, CDCl3) δ 7.12 (m, 7H), 6.88 (d, 1H), 6.71 (m, 2H), 5.67 (brs, 2H), 4.26 (brs, 2H), 3.40 (brs, 2H), 2.76 (brs, H), 2.19 (s, 3+3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.19 (m, 5H), 5.25 (brs, 2H), 4.42 (brs, 2H), 3.65 (brs, 2H), 3.15 (brs, 2H), 2.45 (s, 3H), 2.31 (s, 1H), 2.17 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 7.15 (m, 4H), 7.10 (d, 1H), 4.43 (s, 2H), 4.20 (brs, 2H), 3.49 (brs, 2H), 3.37 (t, 2H), 3.06 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.19 (m, 4H), 7.10 (d, 1H), 5.81 (m, 1H), 5.06 (d, 2+1H), 4.65 (d, 1H), 4.33 (m, 2H), 3.38 (brs, 2H), 3.05 (brs, 2H), 2.30 (s, 3H), 2.18 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.21 (s, 1H), 7.14 (m, 4H), 6.89 (d, 2H), 6.49 (d, 1H), 6.39 (d, 1H), 5.66 (brs, 2H), 4.23 (brs, 2H), 3.38 (brs, 2H), 2.84 (brs, 2H), 2.20 (s, 3+3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.16 (m, 4H), 7.10 (d, 1H), 5.40 (m, 1H), 4.78 (dd, 1+1H), 4.28 (brs, 2+2H), 3.51 (brs, 2H), 3.01 (brs, 2H), 2.34 (s, 3H), 2.17 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 7.15 (m, 4H), 7.08 (d, 1H), 5.00 (m, 2+1H), 4.35 (s, 2H), 3.45 (brs, 2H), 3.10 (brs, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.61 (s, 3H), 1.43 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) 7.17 (m, 4H), 7.08 (d, 1H), 4.31 (s, 2H), 4.26 (q, 2H), 3.49 (brs, 2H), 3.03 (brs, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 1.27 (m, 1+2H), 0.70 (s, 3H), 0.69 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.15 (m, 4H), 7.10 (d, 1H), 4.29 (brs, 2H), 4.19 (s, 2H), 3.49 (brs, 2H), 3.21 (brs, 2H), 2.39 (s, 3H), 2.17 (s, 3H), 0.86 (m, 1H), 0.25 (m, 2H), 0.09 (m, 2H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.84 (m, 4H), 7.48 (m, 4H), 7.05 (m, 4H), 5.89 (brs, 2H), 4.32 (brs, 2H), 3.45 (brs, 2H), 2.75 (brs, 2H), 2.21 (s, 3+3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.32 (d, 1H), 7.25 (d, 1H), 7.09 (m, 4H), 6.74 (d, 1H), 6.56 (d, 2H), 5.55 (s, 2H), 4.17 (brs, 2H), 3.30 (brs, 3H), 2.80 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.18 (s, 9H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.14 (m, 6H), 7.09 (d, 1H), 6.63 (d, 2H), 5.63 (brs, 2H), 4.22 (brs, 2H), 3.37 (brs, 2H), 2.84 (brs, 2H), 2.19 (s, 3+3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.14 (d, 1H), 7.07 (d, 2H), 7.02 (t, 1H), 6.54 (s, 2H), 6.54 (d, 1H), 6.01 (s, 1H), 5.56 (brs, 2H), 4.06 (brs, 2H), 3.34 (brs, 2H), 2.74 (brs, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.79 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.16 (m, 5H), 4.34 (brs, 2+2H), 3.46 (brs, 2H), 3.03 (brs, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 1.06 (t, 3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.16 (m, 4H), 7.10 (d, 1H), 4.28 (brs, 2H), 3.99 (brs, 2H), 3.48 (brs, 2H), 3.02 (brs, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 1.87 (m, 1H), 0.56 (s, 3H), 0.54 (s, 3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.16 (m, 4H), 7.10 (d, 1H), 4.30 (brs, 2H), 4.17 (m, 2H), 3.48 (brs, 2H), 3.02 (brs, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 1.43 (q, 2H), 0.60 (t, 3H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.20 (s, 1H), 7.09 (m, 4H), 6.87 (d, 1H), 6.72 (d, 1H), 6.29 (m, 2H), 5.65 (brs, 2H), 4.24 (brs, 2H), 3.63 (s, 3H), 3.41 (brs, 2H), 2.85 (brs, 2H), 2.21 (s, 3H), 2.19 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.31 (t, 2H), 7.12 (m, 1H), 6.91 (m, 2H), 6.88 (d, 2H), 6.66 (d, 2H), 5.59 (brs, 2H), 4.24 (brs, 2H), 3.74 (s, 3H), 3.38 (brs, 2H), 2.87 (brs, 2H), 2.20 (s, 3H), 2.18 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.20 (s, 1H), 7.08 (m, 4H), 7.04 (d, 1H), 6.85 (d, 1H), 6.57 (s, 1H), 6.45 (d, 1H), 5.62 (s, 2H), 4.24 (brs, 2H), 3.39 (brs, 2H), 2.83 (brs, 2H), 2.20 (s, 3+3+3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.19 (s, 1H), 7.09 (m, 3H), 6.99 (d, 2H), 6.91 (d, 1H), 6.62 (d, 2H), 5.65 (brs, 2H), 4.25 (brs, 2H), 3.37 (brs, 2H), 2.84 (brs, 2H), 2.27 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.20 (s, 1H), 7.12 (m, 3H), 6.88 (m, 3H), 6.65 (m, 2H), 5.62 (brs, 2H), 4.24 (brs, 2H), 3.47 (brs, 2H), 2.85 (brs, 2H), 2.20 (s, 3H), 2.19 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.12 (m, 2H), 7.07 (m, 1H), 7.04 (m, 2H), 4.21 (d, 2+2H), 3.52 (brs, 2H), 3.05 (brs, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 1.53 (m, 2+2H), 1.36 (brs, 2H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 7.14 (s, 1H), 7.04 (m, 4H), 6.83 (m, 2H), 6.77 (d, 1H), 6.22 (t, 1H), 5.65 (s, 2H), 4.15 (brs, 2H), 3.27 (brs, 2H), 2.78 (brs, 2H), 2.13 (s, 3+3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.14 (m, 5H), 4.38 (brs, 2H), 3.88 (brs, 3H), 3.50 (brs, 2H), 3.12 (brs, 2H), 2.32 (brs, 3H), 2.16 (brs, 3H); (Yield: 80%)
Copper(I) cyanide (9.3 g, 102.6 mmol) was added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (3.2 g, 10.3 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture washed with water. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 750 mg of the titled compound as a white solid. (Yield: 26%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (s, 1H), 7.20 (m, 4H), 4.67 (s, 2H), 3.78 (t, 2H), 3.11 (t, 2H), 2.42 (s, 3H), 2.20 (s, 3H)
The titled compounds of Examples 683 to 729 were prepared, in accordance with the same procedures as in Example 657, using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 682; and, 4-bromo-1-butene, allyl iodide, 2-chloroethyl vinyl ether, benzyl bromide, 2-bromoethyl methyl ether, propargyl bromide, 3-chlorobenzyl chloride, 4-fluorobenzyl chloride, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, 4-methylbenzyl chloride, 4-bromo-2-methyl-2-butene, 3-fluorobenzyl chloride, iodoethane, 1-bromopropane, 1-bromobutane, bromomethyl methyl ether, (bromomethyl)cyclopropane, 4-tert-butylbenzyl chloride, 4-chlorobenzyl chloride, 2-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 2,5-dimethylbenzyl chloride, 3-methylbenzyl chloride, iodomethane, 1-iodo-2-methylpropane, 1-bromo-3-methylbutane, 1-bromo-3-phenylpropane, 2-bromoethyl acetate, 2-bromoethyl-1,3-dioxane, 2-(bromoethyl)benzene, (bromomethyl)cyclobutane, (bromomethyl)cyclohexane, 2-(bromomethyl)naphthalene, 2-methylbenzyl bromide, 5-chloro-1-pentyne, 5-chloro-2-pentanone ethylene ketal, 1-chloroheptane, chloromethyl pivalate, 3-chloromethyl pentane, cis, trans-crotyl chloride, 2-fluorobenzyl chloride, 2-methoxyethoxymethyl chloride, methyl bromoacetate, methyl-(4-bromomethyl)benzoate, 4-(trifluoromethyl)benzyl bromide, or 2-methoxybenzyl bromide.
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.18 (m, 3H), 7.10 (d, 1H), 5.44 (m, 1H), 4.78 (m, 2H), 4.36 (brs, 4H), 4.26-2.96 (brs, 6H), 2.38 (s, 3H), 2.22 (s, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (s, 1H), 7.17 (m, 3H), 7.09 (m, 1H), 5.84 (m, 1H), 5.10 (d, 3H), 4.63 (d, 1H), 4.34 (brs, 2H), 3.44 (brs, 2H), 3.07 (brs, 2H), 2.33 (s, 3H), 2.17 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 7.67 (s, 1H), 7.20 (m, 3H), 7.10 (d, 1H), 6.14 (m, 1H), 4.58 (brs, 2H), 4.40-4.30 (brs, 2H), 4.18 (d, 1H), 3.96 (d, 1H), 3.84 (t, 2H), 3.58-2.99 (brs, 4H), 2.41 (s, 3H), 2.23 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (m, 7H), 6.85 (d, 1H), 6.71 (d, 2H), 5.73 (brs, 2H), 4.28 (brs, 2H), 2.84 (brs, 2H), 2.25 (s, 3H), 2.17 (s, 3H); (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (s, 1H), 7.20 (m, 3H), 7.10 (m, 1H), 4.50 (s, 2H), 3.41 (t, 2H), 3.08 (s, 3H), 4.50-3.08 (brs, 6H), 2.40 (s, 3H), 2.23 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.20 (m, 4H), 5.59 (brs, 1H), 5.12 (brs, 1H), 4.46 (m, 2H), 3.74 (brs, 1H), 3.30 (brs, 2H), 2.92 (brs, 1H), 2.43 (s, 3H), 2.38 (s, 1H), 2.23 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.15 (m, 5H), 6.84 (d, 1H), 6.74 (s, 1H), 6.53 (d, 1H), 5.72 (s, 2H), 4.26 (brs, 2H), 3.48 (brs, 2H), 2.89 (brs, 2H), 2.26 (s, 3H), 2.23 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.17 (m, 3H), 6.89 (m, 3H), 6.67 (m, 2H), 5.71 (brs, 2H), 4.13 (brs, 2H), 3.36 (brs, 2H), 2.89 (brs, 2H), 2.25 (s, 3H), 2.23 (s, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 7.69 (s, 1H), 7.13 (m, 4H), 6.85 (d, 1H), 6.74 (d, 1H), 6.28 (d, 1H), 6.25 (s, 1H), 5.72 (brs, 2H), 4.26 (brs, 2H), 3.65 (s, 3H), 3.35 (brs, 2H), 2.88 (brs, 2H), 2.25 (s, 3H), 2.23 (s, 3H); (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 7.68 (s, 1H), 7.15 (m, 3H), 6.92 (d, 1H), 6.75 (m, 2H), 6.67 (m, 2H), 5.30 (brs, 2H), 4.22 (brs, 2H), 3.80 (s, 3H), 3.52 (brs, 2H), 2.89 (brs, 2H), 2.17 (s, 6H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 7.69 (s, 1H), 7.11 (m, 3H), 7.02 (d, 2H), 6.88 (m, 1H), 6.61 (d, 2H), 5.78 (brs, 2H), 4.26 (brs, 2H), 3.40 (brs, 2H), 2.83 (brs, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H); (Yield: 70%)
1H-NMR(400 MHz, CDCl3) δ 7.82 (s, 1H), 7.18 (m, 3H), 7.08 (m, 1H), 5.09 (brs, 2H), 5.00 (brs, 1H), 4.43 (brs, 2H), 3.49 (brs, 2H), 3.06 (brs, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 1.68 (s, 3H), 1.47 (s, 3H); (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 7.83 (s, 1H), 7.15 (m, 4H), 6.90 (m, 2H), 6.49 (d, 1H), 6.38 (d, 1H), 5.74 (brs, 2H), 4.13 (brs, 2H), 3.44 (brs, 2H), 2.85 (brs, 2H), 2.26 (s, 3H), 2.23 (s, 3H); (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 4.41 (brs, 4H), 3.59-2.90 (brs, 4H), 2.39 (s, 3H), 2.23 (s, 3H), 1.12 (t, 3H); (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.18 (m, 3H), 7.10 (m, 1H), 4.27 (t, 2H), 3.70-3.00 (dr, 6H), 2.38 (s, 3H), 2.23 (s, 3H), 1.52 (m, 2H), 0.61 (t, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (s, 1H), 7.20 (m, 3H), 7.09 (m, 1H), 4.31 (t, 2H), 4.31 (brs, 2H), 3.49 (brs, 2H), 3.01 (brs, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.45 (m, 2H), 0.99 (m, 2H), 0.71 (t, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 7.63 (s, 1H), 7.18 (m, 3H), 7.12 (m, 1H), 5.72 (s, 2H), 4.35 (s, 2H), 3.55 (brs, 2H), 3.12 (brs, 2H), 3.06 (s, 3H), 2.42 (s, 3H), 2.23 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.17 (m, 3H), 7.09 (m, 1H), 5.30 (s, 2H), 4.26 (brs, 4H), 3.64-3.00 (brs, 4H), 2.44 (s, 3H), 2.25 (s, 3H), 1.11 (s, 1H), 0.28 (m, 2H), 0.15 (m, 2H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.69 (s, 1H), 7.17 (m, 5H), 6.78 (d, 1H), 6.64 (d, 2H), 5.70 (s, 2H), 4.22 (brs, 2H), 3.48 (brs, 2H), 2.93 (brs, 2H), 2.24 (s, 6H), 1.27 (s, 9H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.18 (m, 5H), 6.88 (d, 1H), 6.64 (d, 2H), 5.75 (brs, 2H), 4.20 (brs, 2H), 3.47 (brs, 2H), 2.84 (brs, 2H), 2.25 (s, 3H), 2.22 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (s, 1H), 7.17 (m, 3H), 7.07 (m, 3H), 6.70 (d, 1H), 6.14 (d, 1H), 5.80 (s, 2H), 4.17 (brs, 2H), 3.31 (s, 2H), 3.03 (brs, 2H), 2.28 (s, 3H), 2.21 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.17 (m, 4H), 6.86 (m, 2H), 6.47 (d, 1H), 5.67 (brs, 2H), 4.13 (brs, 2H), 3.39 (brs, 2H), 2.89 (brs, 2H), 2.26 (s, 3H), 224 (s, 3H); (Yield: 77%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (s, 1H), 7.14-6.96 (m, 5H), 6.94 (s, 1H), 6.48 (d, 1H), 6.01 (s, 2H), 4.06 (brs, 2H), 3.42 (brs, 2H), 2.78 (brs, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H), 1.80 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.10 (m, 4H), 7.01 (m, 1H), 6.81 (d, 1H), 6.58 (s, 1H), 6.45 (d, 1H), 5.71 (s, 2H), 4.24 (brs, 2H), 3.47 (brs, 2H), 2.84 (brs, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (s, 1H), 7.19 (m, 4H), 4.38 (s, 2H), 3.97 (s, 3H), 3.50 (brs, 2H), 3.13 (brs, 2H), 2.36 (s, 3H), 2.22 (s, 3H); (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.18 (m, 3H), 7.09 (d, 1H), 4.24 (brs, 2H), 4.11 (m, 1H), 4.11 (brs, 2H), 3.45 (brs, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.88 (m, 1H), 0.56 (d, 6H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 7.63 (s, 1H), 7.18 (m, 3H), 7.09 (d, 1H), 4.32 (m, 4H), 3.68-2.96 (brs, 4H), 2.37 (s, 3H), 2.22 (s, 3H), 0.90 (m, 3H), 0.71 (d, 6H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 7.63 (s, 1H), 7.22 (m, 3H), 7.11 (m, 4H), 6.88 (d, 2H), 4.30 (m, 2H), 4.31 (brs, 2H), 3.60-2.96 (brs, 4H), 2.34 (m, 2H), 2.33 (s, 3H), 2.21 (s, 3H), 1.78 (m, 2H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (s, 1H), 7.20 (m, 3H), 7.10 (d, 1H), 4.60 (brs, 2H), 4.38 (brs, 1H), 4.15 (brs, 1H), 4.11 (t, 2H), 3.61-2.97 (brs, 4H), 2.41 (s, 3H), 2.24 (s, 3H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.20 (m 3H), 7.12 (d, 1H), 4.41 (brs, 2H), 4.06 (t, 1H), 3.85 (m, 2H), 3.77 (m, 2H), 3.51 (t, 2H), 3.39 (brs, 2H), 2.90 (brs, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 2.09 (m, 2H), 1.86 (m, 2H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 7.66 (s, 1H), 7.22 (m, 3H), 7.12 (m, 2H), 6.99 (m, 2H), 6.65 (d, 2H), 4.50 (brs, 3H), 4.25 (brs, 1H), 3.59 (brs, 1H), 3.40 (brs, 2H), 2.96 (brs, 1H), 2.70 (brs, 2H), 2.27 (s, 3H), 2.22 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.63 (s, 1H), 7.21 (m, 3H), 7.11 (d, 1H), 4.36 (d, 2H), 4.28 (brs, 2H), 3.60 (brs, 1H), 3.28 (brs, 2H), 3.00 (brs, 1H), 2.42 (m, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.65 (m, 4H), 1.48 (m, 2H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.20 (m, 3H), 7.09 (d, 1H), 4.22 (brs, 2H) 4.10 (brs, 2H), 3.64-2.96 (brs, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.52 (m, 4H), 1.26 (m, 1H), 1.04 (m, 2H), 0.88 (brs, 2H), 0.75 (brs, 2H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 7.79 (m, 1H), 7.73 (s, 1H), 7.70 (d, 1H), 7.62 (m, 1H), 7.45 (m, 2H), 7.14-7.04 (m, 4H), 6.88 (dd, 1H), 6.77 (d, 1H), 5.93 (brs, 2H), 4.13 (brs, 2H), 3.40 (brs, 2H), 2.89 (brs, 2H), 2.27 (s, 3H), 2.25 (s, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (s, 1H), 7.20-6.98 (m, 6H), 6.48 (d, 2H), 6.15 (d, 2H), 4.05 (brs, 2H), 3.39 (brs, 2H), 2.77 (brs, 2H), 2.34 (s, 3H), 2.21 (s, 3H), 1.84 (s, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.17 (m, 3H), 7.10 (d, 1H), 4.42 (brs, 3H), 4.25 (brs, 1H), 3.63-2.96 (brs, 6H), 2.41 (s, 3H), 2.23 (s, 3H), 1.91 (t, 2H), 1.65 (s, 1H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.20 (m, 4H), 4.30 (m, 4H), 3.81 (s, 2H), 3.66 (s, 2H) 3.40 (brs, 2H), 2.99 (brs, 2H), 2.38 (s, 3H), 2.23 (s, 3H), 1.36 (t, 4H), 1.11 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.18 (m, 3H), 7.09 (m, 1H), 4.29 (t, 4H), 4.60-2.96 (brs, 4H), 2.37 (s, 3H), 2.22 (s, 3H), 1.45 (m, 2H), 1.30 (m, 2H), 1.06 (m, 6H), 0.80 (t, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.19 (m, 3H), 7.10 (m, 1H), 6.45 (brs, 2H), 4.37 (brs, 2H), 3.49 (brs, 2H), 3.03 (brs, 2H), 2.36 (s, 3H), 2.23 (s, 3H), 1.11 (s, 9H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.18 (m, 3H), 7.10 (m, 1H), 4.25 (brs, 4H), 3.80-2.90 (brs, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 0.97 (brs, 4H), 0.87 (m, 1H), 0.60 (brs, 6H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.20 (m, 3H), 7.08 (m, 1H), 5.42 (d, 1H), 5.18 (m, 1H), 5.03 (brs, 2H), 4.34 (brs, 2H), 3.80-2.90 (brs, 4H), 2.34 (s, 3H), 2.23 (s, 3H), 1.61 (d, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.13 (m, 4H), 6.94 (m, 2H), 6.82 (d, 1H), 6.29 (m, 1H), 5.81 (s, 2H), 4.23 (brs, 2H), 3.37 (brs, 2H), 2.87 (brs, 2H), 2.26 (s, 3H) 2.23 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (s, 1H), 7.18 (m, 3H), 7.11 (m, 1H), 5.85 (brs, 2H), 4.35 (s, 2H), 3.31 (s, 4H), 3.22 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H); (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 7.68 (s, 1H), 7.19 (m, 3H), 7.10 (m, 1H), 5.30 (brs, 2H), 4.10 (brs, 2H), 3.57 (s, 3H), 2.90 (brs, 2H), 2.28 (s, 3H), 2.42 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.88 (d, 2H), 7.71 (s, 1H), 7.16 (m, 1H), 7.11 (d, 2H), 6.84 (d, 2H), 6.77 (d, 2H), 4.10 (brs, 2H), 3.89 (s, 3H), 3.50 (brs, 2H), 2.80 (brs, 2H), 2.26 (s, 3H), 2.21 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (s, 1H), 7.45 (d, 2H), 7.11 (m, 3H), 6.80 (m, 3H), 5.80 (brs, 2H), 4.10 (brs, 2H), 3.40 (brs, 2H), 2.80 (brs, 2H), 2.26 (s, 3H), 2.23 (s, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.83 (s, 1H), 7.19-7.04 (m, 4H), 6.75 (m, 2H), 6.65 (d, 1H), 6.16 (d, 1H), 5.69 (brs, 2H), 4.10 (brs, 2H), 3.52 (s, 3H), 3.33 (brs, 2H), 2.80 (brs, 2H), 2.28 (s, 3H), 2.24 (s, 3H); (Yield: 69%)
In accordance with the same procedures as in Example 656, except for using 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine prepared in Preparation 20 and isopropenyl magnesium bromide, the titled compound was obtained. (Yield: 39%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Example 657, except for using 2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride prepared in Step 1 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.02 (d, 1H), 7.28 (d, 1H), 7.12 (m, 4H), 6.87 (m, 2H), 6.49 (d, 1H), 6.38 (s, 1H), 6.36 (d, 1H), 5.82 (brs, 1H), 5.51 (brs, 1H), 4.33 (brs, 1H), 4.07 (brs, 1H), 3.45 (brs, 1H), 3.28 (brs, 1H), 2.91 (brs, 1H), 2.76 (brs, 1H), 2.30 (s, 3H)
N-Bromosuccinimide (53 mg, 0.30 mmol) and silica gel (100 mg) was added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (110 mg, 0.30 mmol) prepared in Step 2 in dichloromethane (2 ml). The reaction mixture was stirred for 1 hour at 40° C. and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 110 mg of the titled compound as a white solid.
Copper(I) cyanide (107 mg, 1.2 mmol) was added to a solution of 2-[3,5-dibromo-1-(4-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (110 mg, 0.24 mmol) prepared in Step 3 in anhydrous N,N-dimethylformamide (2 ml). The reaction mixture was refluxed overnight and then cooled to room temperature. Water was added to the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 15 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.44 (s, 1H), 7.28 (d, 1H), 7.20 (m, 2H), 7.15 (d, 2H), 6.99 (t, 1H), 6.85 (d, 1H), 6.47 (t, 2H), 5.72 (s, 2H), 4.29 (brs, 2H), 3.49 (brs, 2H), 2.90 (brs, 2H), 2.52 (s, 3H)
7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.73 mmol) prepared in Example 690 was diluted with a mixture of ethanol (7 ml) and water (1 ml). Potassium hydroxide (410 mg, 7.3 mmol) was added to the solution, which was then refluxed for 72 hours. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 250 mg of the titled compound as a white solid. (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 10.13 (brs, 1H), 8.74 (s, 1H), 7.30 (m, 4H), 7.12 (m, 4H), 6.77 (s, 1H), 6.04 (s, 1H), 5.69 (s, 2H), 4.51 (brs, 2H), 3.90 (brs, 2H), 2.26 (brs, 6H)
The titled compounds of Examples 732 to 742 were prepared, in accordance with the same procedures as in Example 731, using the compounds prepared in Examples 684, 686, 687, 689, 691, 695, 696, 697, 700, 706, and 708.
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (m, 3H), 7.09 (m, 1H), 5.86 (m, 1H), 5.12 (brs, 2H), 5.09 (d, 1H), 4.65 (d, 1H), 4.36 (brs, 2H), 3.50 (brs, 2H), 3.00 (brs, 2H), 2.33 (s, 3H), 2.10 (s, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 8.34 (s, 1H), 7.22 (m, 3H), 7.12 (m, 3H), 6.87 (d, 1H), 6.71 (m, 2H), 5.75 (brs, 2H), 4.25 (brs, 2H), 3.47 (brs, 2H), 2.83 (brs, 2H), 2.29 (s, 3H), 2.24 (s, 3H); (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.22 (m, 3H), 7.13 (m, 1H), 4.52 (t, 2H), 4.30-4.10 (brs, 2H), 3.80-3.40 (brs, 2H), 3.44 (t, 2H), 3.30-2.90 (brs, 2H), 3.10 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H); (Yield: 88%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.20 (m, 1H), 7.15 (m, 4H), 6.87 (d, 1H), 6.76 (s, 1H), 6.54 (d, 1H), 5.73 (s, 2H), 4.30 (brs, 2H), 3.55-3.31 (brs, 2H), 2.93-2.82 (brs, 2H), 2.30 (s, 3H), 2.26 (s, 3H); (Yield: 91%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (s, 1H), 7.20 (m, 1H), 7.16-7.08 (m, 3H), 7.02 (d, 1H), 6.84 (d, 1H), 6.59 (s, 1H), 6.47 (d, 1H), 5.73 (s, 2H), 4.30 (brs, 2H), 3.60-3.30 (brs, 2H), 2.90-2.70 (brs, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.21 (m, 4H), 6.90 (m, 2H), 6.50 (d, 1H), 6.40 (d, 1H), 5.78 (brs, 2H), 4.32-4.18 (brs, 2H), 3.57-3.33 (brs, 2H), 2.91-2.80 (brs, 2H), 2.30 (s, 3H), 2.25 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.22 (m, 3H), 7.13 (m, 1H), 4.43 (brs, 4H), 3.69-2.97 (brs, 4H), 2.40 (s, 3H), 2.26 (s, 3H), 1.15 (t, 3H); (Yield: 93%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.22 (m, 3H), 7.13 (m, 1H), 4.36-4.28 (brs, 2H), 4.30 (t, 2H), 3.67-3.39 (brs, 2H), 3.22-2.96 (brs, 2H), 2.40 (s, 3H), 2.27 (brs, 3H), 1.54 (m, 2H), 0.64 (t, 3H); (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 4.29 (brs, 2+2H), 3.69 (brs, 1H), 3.30 (brs, 1H), 3.10 (brs, 1H), 2.90 (brs, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 0.31 (d, 2H), 0.15 (brs, 2H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.20-7.08 (m, 4H), 7.02 (d, 1H), 6.83 (d, 1H), 6.59 (s, 1H), 6.47 (d, 1H), 5.73 (s, 2H), 4.30-4.21 (brs, 2H), 3.55-3.31 (brs, 2H), 2.93-2.84 (brs, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H); (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.19 (m, 3H), 7.08 (d, 1H), 4.25 (brs, 2H), 4.10 (m, 1H), 4.11-4.09 (brs, 2H), 3.48 (brs, 4H), 2.35 (s, 3H), 2.23 (s, 3H), 1.89 (m, 1H), 0.56 (d, 6H); (Yield: 79%)
A solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733, potassium hydroxide (10.1 mg, 0.07 mmol) and iodomethane (4.3 μl, 0.07 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 10 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give the titled compound as a white solid. (Yield: 35%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.17 (m, 3H), 7.11 (m, 1H), 7.11 (m, 2H), 6.90 (d, 1H), 6.72 (d, 2H), 5.80 (brs, 2H), 4.30 (brs, 2H), 3.99 (s, 3H), 3.53 (brs, 2H), 2.90 (brs, 2H), 2.28 (s, 3H), 2.22 (s, 3H)
1-Benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (28 mg, 0.068 mmol) prepared in Example 733 and sodium hydride (2.6 mg, 0.068 mmol) were dripped into anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was re-crystallized with methanol to give the titled compound as a white solid. (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 7.91 (s, 1H), 7.04 (m, 3H), 6.92 (m, 1H), 6.76 (s, 2H), 6.54 (m, 2H), 6.31 (brs, 1H), 5.50 (brs, 2H), 4.92 (s, 2H), 3.75 (brs, 2H), 3.20 (brs, 2H), 2.6 (s, 3H), 1.94 (s, 3H)
1-Benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.76 mmol) prepared in Example 686 was diluted with a mixture of ethanol (7 ml) and water (1 ml). Potassium hydroxide (426 mg, 7.6 mmol) was added to the solution, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 260 mg of the titled compound as a white solid. (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 8.24 (brs, 1H), 7.21 (m, 3H), 7.15 (m, 1H), 713 (m, 2H), 6.88 (m, 1H), 6.73 (m, 2H), 5.81 (brs, 2H), 5.42 (brs, 1H), 4.30 (brs, 2H), 3.40 (brs, 2H), 2.90 (brs, 2H), 2.29 (s, 3H), 2.22 (s, 3H)
The titled compounds of Examples 746 to 755 were prepared, in accordance with the same procedures as in Example 745, using the compounds prepared in Example 682, 684, 687, 688, 689, 691, 695, 697, 700, and 708.
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 1H), 8.05 (brs, 1H), 7.82 (brs, 1H), 7.20 (m, 4H), 5.42 (brs, 1H), 4.63 (s, 2H), 3.77 (t, 2H), 3.08 (t, 2H), 2.42 (s, 3H), 2.23 (s, 3H); (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.79 (brs, 1H), 7.20 (m, 3H), 7.11 (d, 1H), 5.87 (m, 1H), 5.43 (s, 1H), 5.30-4.90 (brs, 2H), 5.09 (d, 1H), 4.66 (d, 1H), 4.35 (brs, 2H), 3.65-3.28 (brs, 2H), 3.20-2.90 (brs, 2H), 2.33 (s, 3H), 2.27 (s, 3H); (Yield: 89%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 8.80 (brs, 1H), 7.20 (m, 3H), 7.13 (m, 1H), 5.50 (brs, 1H), 4.52 (t, 2H), 4.52-4.20 (brs, 2H), 3.80-3.40 (brs, 2H), 3.44 (t, 2H), 3.20-2.90 (brs, 2H), 3.10 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H); (Yield: 95%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (brs, 1H), 7.20 (m, 4H), 5.41 (brs, 1H), 4.50 (s, 2H), 3.55 (brs, 2H), 3.07 (brs, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 2.05 (s, 1H); (Yield: 81%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.76 (s, —NH), 7.14 (m, 5H), 6.88 (d, 1H), 6.77 (s, 1H), 6.54 (d, 1H), 5.73 (s, 2H), 5.46 (s, —NH), 4.15 (brs, 2H), 3.49 (brs, 2H), 2.89 (brs, 2H), 2.30 (s, 3H), 2.23 (s, 3H); (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.24 (s, 1H), 7.79 (s, 1H), 7.18-7.06 (m, 4H), 7.00 (d, 1H), 6.86 (d, 1H), 6.60 (s, 1H), 6.48 (d, 1H), 5.75 (brs, 2H), 5.42 (s, 1H), 4.32-4.16 (brs, 2H), 3.55-3.24 (brs, 2H), 2.94-2.75 (brs, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H); (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.75 (brs, 1H), 7.17 (m, 4H), 6.88 (m, 2H), 6.50 (d, 1H), 6.41 (d, 1H), 5.72 (brs, 2H), 5.41 (brs, 1H), 4.23 (brs, 2H), 3.46-3.30 (brs, 2H), 2.89 (brs, 2H), 2.29 (s, 3H), 2.23 (s, 3H); (Yield: 75%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.82 (brs, 1H), 7.21 (m, 3H), 7.13 (m, 1H), 5.51 (brs, 1H), 4.39 (brs, 2H), 4.29 (t, 2H), 3.67-3.28 (brs, 2H), 3.20-2.92 (brs, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.45 (m, 2H), 0.64 (t, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.80 (s, 1H), 7.20 (m, 3H), 7.12 (d, 1H), 5.45 (s, 1H), 4.27 (m, 2+2H), 4.70 (brs, 1H), 4.40-4.10 (brs, 2H), 2.90 (brs, 1H), 2.43 (s, 3H), 2.28 (s, 3H), 0.29 (d, 2H), 0.20 (brs, 2H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.80 (s, 1H), 7.19 (m, 3H), 7.13 (m, 1H), 5.49 (s, 1H), 4.38-4.28 (m, 2H), 4.10 (s, 2H), 3.67 (brs, 1H), 3.35-3.21 (brs, 2H), 2.92 (brs, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.95 (m, 1H), 0.59 (d, 6H); (Yield: 75%)
A solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (30 mg, 0.083 mmol) prepared in Example 732, 1-hydroxybenzotriazole hydrate (16.9 mg, 0.125 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.9 mg, 0.125 mmol), diisopropylethylamine (43,4 μl, 0.25 mmol), and 4-methylbenzylamine (15.9 μl, 0.125 mmol) in dichloromethane (1 ml) was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 9.1 mg of the titled compound as a white solid. (Yield: 45%).
A solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-N-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridin-5-carboxamide prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 11.23 (brs, 1H), 8.83 (s, 1H), 7.43 (d, 2H), 7.20 (m, 3H), 7.12 (d, 2H), 7.02 (d, 1H), 5.80 (m, 1H), 5.15 (d, 1H), 5.05 (s, 2H), 4.71 (s, 2H), 4.42 (d, 1H), 4.07 (brs, 2H), 3.53 (brs, 2H), 3.07 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H)
The titled compounds of Examples 757 to 760 were prepared, in accordance with the same procedures as in Example 756, using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 732; and, monomethylamine hydrochloride, 3-chlorobenzylamine, 2,2,2-trifluoroethylamine hydrochloride, or piperonylamine.
1H-NMR(400 MHz, CDCl3) δ 10.53 (brs, 1H), 8.80 (s, 1H), 7.23 (m, 3H), 7.03 (d, 1H), 5.80 (m, 1H), 5.15 (d, 1H), 5.07 (s, 2H), 4.70 (brs, 2H), 4.45 (d, 1H), 4.18 (brs, 2H), 3.49 (brs, 2H), 3.09 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 11.22 (brs, 1H), 8.90 (brs, 1H), 7.48 (s, 1H), 7.44 (brs, 2H), 7.21 (brs, 3H), 7.04 (brs, 2H), 5.82 (m, 1H), 5.16-5.08 (m, 2H), 4.67 (s, 2H), 4.46 (d, 1H), 4.11 (m, 2H), 3.10 (s, 2H), 2.44 (s, 3H), 2.40 (s, 3H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.75 (s, 1H), 7.21 (m, 3H), 7.04 (m, 1H), 5.82 (m, 1H), 5.18 (d, 1H), 5.09 (s, 2H), 4.73 (brs, 2H), 4.45 (s, 1H), 4.18 (brs, 2H), 3.99 (brs, 2H), 3.08 (s, 3H), 2.45 (s 3H), 2.39 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.41 (brs, 1H), 7.18 (m, 3H), 7.06 (m, 1H), 6.93 (m, 2H), 6.77 (brs, 1H), 5.93 (s, 2H), 5.85 (m, 1H), 5.10 (m, 3H), 4.59 (m, 3H), 4.49 (brs, 2H), 3.62 (brs, 2H), 3.00 (brs, 2H), 2.36 (s, 3H), 2.17 (s, 3H); (Yield: 62%)
The titled compounds of Examples 761 to 763 were prepared, in accordance with the same procedures as in Step 1 of Example 756, using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 732; and, cyclopropylamine, 2,2,2-trifluoroethylamine hydrochloride, or tert-butylamine.
1H-NMR(400 MHz, CDCl3) δ 8.16 (s, 1H), 7.85 (s, 1H), 7.18 (m, 3H), 7.11 (m, 1H), 5.85 (m, 1H), 5.10 (brs, 2H), 5.05 (d, 1H), 4.62 (d, 1H), 4.30 (brs, 2H), 3.40 (brs, 2H), 3.00 (brs, 2H), 2.90 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 0.84 (t, 2H), 0.58 (t, 2H); (Yield: 79%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (s, 1H+1H), 7.20 (m, 3H), 7.12 (m, 1H), 5.87 (m, 1H), 5.16 (brs, 2H), 5.08 (d, 1H), 4.63 (d, 1H), 4.38 (m, 2H), 4.09 (m, 2H), 3.47 (brs, 2H), 2.90 (brs, 2H), 2.33 (s, 3H), 2.27 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 8.15 (s, 1H), 7.95 (s, 1H), 7.20 (m, 3H), 7.12 (s, 1H), 5.85 (m, 1H), 5.10 (brs, 2H), 5.05 (d, 1H), 4.61 (d, 1H), 4.36 (m, 2H), 4.20 (brs, 2H), 2.90 (brs, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.46 (s, 9H); (Yield: 72%)
The titled compounds of Examples 764 to 768 were prepared, in accordance with the same procedures as in Step 1 of Example 756, using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 733; and, morpholine, ethylamine, tert-butylamine, 2,2,2,-trifluoroethylamine, or 4-methylbenzylamine.
1H-NMR(400 MHz, CDCl3) δ 7.83 (s, 1H), 7.19 (m, 3H), 7.12 (m, 3H), 6.86 (d, 1H), 6.71 (d, 2H), 5.73 (brs, 2H), 5.30 (brs, 2H), 3.83 (s, 6H), 3.67 (s, 2H), 3.41 (brs, 2H), 2.73 (brs, 2H), 2.26 (s, 3H), 2.21 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.85 (t, 1H), 7.20-7.10 (m, 6H), 6.93 (d, 1H), 6.73 (d, 2H), 5.76 (brs, 2H), 4.20 (brs, 2H), 3.50 (m, 2H), 3.40 (br 2H), 2.70 (brs, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.24 (t, 3H); (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.93 (s, 1H), 7.17-7.10 (m, 6H), 6.93 (s, 1H), 6.72 (d, 2H), 5.74 (brs, 2H), 4.30 (brs, 2H), 3.40 (brs, 2H), 2.90 (brs, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 1.46 (s, 9H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (s, 1H), 8.16 (t, 1H), 7.21-7.10 (m, 6H), 6.92 (d, 1H), 6.73 (d, 2H), 5.77 (brs, 2H), 4.33 (brs, 2H), 4.09 (m, 2H), 3.40 (brs, 2H), 2.80 (brs, 2H), 2.28 (s, 3H), 2.22 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 8.20 (brs, 1H), 7.26 (m, 3H), 7.15-7.10 (m, 7H), 6.85 (d, 2H), 6.72 (m, 2H), 6.78 (brs, 2H), 4.63 (d, 2H), 4.20 (brs, 2H), 3.30 (brs, 2H), 2.70 (brs, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H); (Yield: 58%)
The titled compounds of Examples 769 to 775 were prepared, in accordance with the same procedures as in Example 756, using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 733; and, morpholine, diethylamine, dimethylamine hydrochloride, monomethylamine hydrochloride, 3-chlorobenzylamine, piperonylamine, or ethylamine.
1H-NMR(400 MHz, CDCl3) δ 7.50 (s, 1H), 7.17 (m, 4H), 7.08 (m, 2H), 6.67 (d, 1H), 6.50 (d, 2H), 5.63 (s, 2H), 4.30 (brs, 2H), 4.10-3.47 (brs, 2H), 3.90 (brs, 6H), 3.64 (brs, 2H), 2.79 (s, 2H), 2.33 (s, 3H), 2.32 (s, 3H); (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 7.72 (s, 1H), 7.15 (m, 5H), 6.89 (m, 2H), 6.38 (m, 2H), 5.74 (brs, 2H), 4.35 (brs, 2H), 3.61-3.49 (m, 6H), 2.84 (brs, 2H), 2.30 (s, 6H), 1.26 (s, 6H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.58 (s, 1H), 7.20 (m, 3H), 7.07 (m, 2H), 6.68 (d, 1H), 6.50 (d, 2H), 5.66 (s, 2H), 3.21 (s, 3H), 3.19 (s, 3H), 2.77 (s, 2H), 2.36 (s, 3H), 2.32 (s, 3H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 10.50 (s, 1H), 8.78 (s, 1H), 7.20 (m, 3H), 7.10 (m, 2H), 6.68 (d, 1H), 6.47 (d, 2H), 5.66 (s, 2H), 4.50 (brs, 2H), 4.11 (brs, 2H), 3.09 (s, 3H), 2.76 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H); (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 10.85 (brs, 1H), 8.80 (brs, 1H), 7.66-7.42 (m, 3H), 7.25 (m, 4H), 7.10 (brs, 2H), 6.72 (brs, 1H), 6.50 (s, 2H), 5.70 (brs, 2H), 4.67 (s, 2H), 4.67 (brs, 2H), 4.13 (brs, 2H), 2.78 (s, 2H), 2.43 (s, 3H), 2.37 (s, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 10.59 (brs, 1H), 8.71 (brs, 1H), 7.22 (m, 3H), 7.09 (d, 2H), 7.03 (m, 2H), 6.75 (d, 2H), 6.70 (d, 1H), 6.49 (m, 2H), 5.91 (s, 2H), 5.67 (brs, 2H), 4.51 (s, 2H), 3.84 (brs, 2H), 3.47 (brs, 2H), 2.76 (s, 2H), 2.39 (s, 3H), 2.33 (s, 3H); (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 8.89 (s, 1H), 7.21 (m, 3H), 7.11 (m, 1H), 6.68 (s, 1H), 6.45 (d, 2H), 5.67 (s, 2H), 4.62 (brs, 2H), 3.95 (brs, 2H), 3.61 (s, 2H), 2.77 (s, 2H), 2.44 (s, 3H), 2.37 (s, 3H), 1.38 (s, 3H); (Yield: 76%)
In accordance with the same procedures as in Example 731, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 682, the titled compound was obtained as a pale yellow solid. (Yield: 59%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Step 1 of Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and morpholine, the titled compound was obtained as a white solid. (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 8.04 (brs, 1H), 7.61 (s, 1H), 7.20 (m, 4H), 4.60 (s, 2H), 3.76 (m, 6H), 3.73 (t, 2H), 3.63 (brs, 2H), 3.04 (t, 2H), 2.40 (s, 3H), 2.20 (s, 3H)
The titled compounds of Examples 777 to 781 were prepared, in accordance with the same procedures as in Example 657, using [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(morpholin-4-yl)-methanone prepared in Example 776; and, allyl bromide, (bromomethyl)cyclopropane, 3-fluorobenzyl chloride, 3-methoxybenzyl bromide, or 1-iodopropane.
1H-NMR(400 MHz, CDCl3) δ 7.45 (brs, 1H), 7.22 (m, 3H), 7.00 (m, 1H), 5.79 (m, 1H), 5.17 (d, 1H), 5.03 (s, 2H), 4.75 (brs, 2H), 4.51 (d, 1H), 4.03 (brs, 2H), 3.90 (m, 6H), 3.61 (brs, 2H), 3.04 (s, 2H), 2.37 (s, 3H), 2.31 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.41 (brs, 1H), 7.21 (m, 3H), 7.16 (brs, 1H), 4.21 (s, 2H), 3.91 (m, 6H), 3.49 (m, 2H), 3.15 (brs, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 0.95 (brs, 1H), 0.35 (s, 2H), 0.32 (s, 1H); (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (brs, 1H), 7.19 (m, 2H), 7.10 (m, 2H), 6.95 (m, 1H), 6.67 (m, 1H), 6.25 (s, 1H), 6.19 (d, 1H), 5.63 (s, 2H), 3.91 (m, 6H), 3.49 (m, 2H), 2.83 (m, 2H), 2.38 (s, 3H), 2.36 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (brs, 1H), 7.17-7.05 (m, 4H), 6.78 (d, 1H), 6.62 (brs, 1H), 6.05 (m, 2H), 5.62 (brs, 2H), 3.90 (m, 6H), 3.79 (m, 2H), 3.73 (s, 3H), 2.78 (m, 2H), 2.38 (s, 3H), 2.36 (s, 3H); (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 7.44 (brs, 1H), 7.20 (m, 3H), 7.04 (brs, 1H), 3.89 (m, 6H), 3.64 (brs, 2H), 4.31 (brs, 2H), 3.10 (m, 2H), 2.49 (s, 3H), 2.39 (s, 3H), 1.46 (m, 2H), 0.58 (t, 3H); (Yield: 63%)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 738 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 56%)
1H-NMR(400 MHz, CDCl3) δ 7.38 (s, 1H), 7.24 (m, 3H), 7.08 (m, 1H), 4.88 (d, 1H), 4.70 (brs, 1H), 4.52 (brs, 1H), 4.35 (m, 3H), 4.03 (brs, 1H), 3.86 (m, 3H), 3.38 (d, 1H), 3.17 (s, 3H), 2.87 (s, 3H), 2.50 (s, 3H), 2.29 (s, 3H), 1.15 (s, 3H)
The titled compounds of Examples 783 and 784 were prepared, in accordance with the same procedures as in Example 756, using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxybenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 736; and, 1-methylpiperazine or thiomorpholine.
1H-NMR(400 MHz, CDCl3) δ 7.45 (brs, 1H), 7.21-7.07 (m, 3H), 6.80 (m, 1H), 6.60 (brs, 1H), 6.07 (s, 2H), 6.70 (brs, 1H), 6.50 (brs, 1H), 5.68 (brs, 2H), 4.86 (brs, 1H), 4.53 (brs, 3H), 4.00-3.86 (brs, 4H), 3.67 (s, 3H), 3.37 (brs, 1H), 3.10 (brs, 3H), 2.86 (s, 4H), 2.37 (s, 3H), 2.34 (s, 3H); (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 7.49 (s, 1H), 7.17-7.05 (m, 4H), 6.78 (d, 1H), 6.63 (brs, 1H), 6.07 (s, 2H), 5.63 (brs, 2H), 4.13 (brs, 2H), 3.86 (brs, 2H), 3.64 (s, 3H), 2.88-2.83 (brs, 6H), 2.35 (s, 3H), 2.32 (s, 3H); (Yield: 70%)
The titled compounds of Examples 785 and 786 were prepared, in accordance with the same procedures as in Example 756, using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 732; and, 1-methylpiperazine or piperidine.
1H-NMR(400 MHz, CDCl3) δ 7.41 (s, 1H), 7.25 (m, 3H), 7.03 (m, 1H), 5.85 (m, 1H), 5.21-5.00 (brs, 2H), 4.88 (d, 2H), 4.57 (brs, 1H), 4.30-4.00 (m, 3H), 3.88 (m, 4H), 3.30 (brs, 1H), 3.15 (brs, 1H), 3.10 (brs, 2H), 2.88 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H); (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 7.46 (brs, 1H), 7.19 (m, 3H), 7.00 (m, 1H), 5.79 (m, 1H), 5.16 (brs, 1H), 5.05 (brs, 2H), 4.80 (brs, 1H), 4.50 (brs, 1H), 4.13 (brs, 1H), 3.85 (brs, 2H), 3.55 (brs, 2H), 3.09 (brs, 2H), 2.44 (s, 3H), 2.31 (s, 3H), 1.72 (brs, 6H); (Yield: 56%)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 738 and piperidine, the titled compound was obtained as a white solid. (Yield: 47%)
1H-NMR(400 MHz, CDCl3) δ 7.47 (brs, 1H), 7.20 (m, 3H), 7.05 (m, 1H), 4.38 (brs, 2H), 3.83 (brs, 2H), 3.63 (m, 2H), 3.13 (brs, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 1.72 (m, 6H), 1.15 (s, 3H)
The titled compounds of Examples 788 and 789 were prepared, in accordance with the same procedures as in Example 756, using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 733; and, piperidine or thiomorpholine.
H-NMR(400 MHz, CDCl3) δ 7.55 (s, 1H), 7.21-7.14 (m, 4H), 7.07 (m, 2H), 6.70 (d, 1H), 6.55 (brs, 2H), 5.67 (s, 2H), 4.45 (brs, 2H), 3.96 (brs, 2H), 3.66 (brs, 2H), 2.78 (s, 2H), 2.38 (s, 6H), 1.71 (brs, 6H); (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (s, 1H), 7.22-7.15 (m, 4H), 7.09 (m, 2H), 6.68 (brs, 1H), 6.54 (s, 2H), 5.66 (s, 2H), 4.13 (brs, 2H), 3.88 (brs, 3H), 2.86 s, 3H), 2.79 (s, 3H), 2.32 (s, 6H); (Yield: 69%)
In accordance with the same procedures as in Example 756, except for using 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 737 and thiomorpholine, the titled compound was obtained as a white solid. (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.58 (s, 1H), 7.22-7.08 (m, 5H), 6.72 (m, 1H), 6.59 (s, 1H), 6.37 (m, 1H), 5.63 (s, 2H), 4.12 (brs, 2H), 3.90 (brs, 2H), 2.82 (brs, 6H), 2.32 (s, 6H)
In accordance with the same procedures as in Example 731, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 682, the titled compound was obtained. (Yield: 59%)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (450 mg, 1.4 mmol) prepared in Step 1, 1-hydroxybenzotriazole hydrate (284 mg, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (401 mg, 2.1 mmol), diisopropylethylamine (730 μl, 4.2 mmol), and piperidine (270 μl, 2.1 mmol) in dichloromethane (5 ml) was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 250 mg of the titled compound as a white solid. (Yield: 50%).
A solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(piperidin-1-yl)-methanone prepared in Step 2 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 7.58 (s, 1H), 7.22-7.08 (m, 5H), 6.72 (m, 1H), 6.59 (s, 1H), 6.37 (m, 1H), 5.63 (s, 2H), 4.12 (brs, 2H), 3.90 (brs, 2H), 2.82 (brs, 6H), 2.32 (s, 6H)
The titled compounds of Examples 792 to 802 were prepared, in accordance with the same procedures as in Example 657, using [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-piperidin-1-yl-methanone prepared in Step 2 of Example 791; and, 2-bromoethyl methyl ether, (bromomethyl)cyclopropane, 1-iodo-2-methylpropane, 4-bromo-2-methyl-2-butene, 3-fluorobenzyl chloride, 4-fluorobenzyl chloride, 3-methylbenzyl bromide, 3-chlorobenzyl chloride, bromomethyl methyl ether, 1-bromopropane, or propargyl bromide.
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.22-7.14 (m, 3H), 7.02 (m, 1H), 4.48 (brs, 2H), 3.85 (brs, 2H), 3.52 (brs, 2H), 3.39 (t, 2H), 3.12 (s, 2+3H), 2.48 (s, 3H), 2.27 (s, 3H), 1.71 (brs, 6H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.42 (s, 1H), 7.20 (m, 3H), 7.02 (m, 1H), 4.21 (d, 2H), 3.85 (brs, 2H), 3.54 (brs, 2H), 3.12 (brs, 2H), 2.50 (s, 3H), 2.28 (s, 3H), 1.69 (brs, 6H), 0.92 (m, 1H), 0.35 (m, 2H), 0.03 (m, 2H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 7.44 (s, 1H), 7.20 (m, 3H), 7.03 (m, 1H), 4.00 (brs, 2H), 3.83 (brs, 2H), 3.55 (brs, 2H), 3.12 (brs, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.90 (m, 1H), 1.70 (brs, 6H), 0.53 (d, 6H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.43 (s, 1H), 7.18 (m, 3H), 6.98 (m, 1H), 5.00 (2H), 4.90 (s, 1H), 4.80-4.50 (brs, 2H), 4.10-3.90 (brs, 2H), 3.83 (brs, 2H), 3.54 (brs, 2H), 3.08 (brs, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.70 (brs, 6H), 1.62 (s, 3H), 1.29 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (s, 1H), 7.18 (m, 2H), 7.07 (m, 2H), 6.93 (m, 1H), 6.67 (d, 1H), 6.25 (d, 1H), 6.20 (s, 1H), 5.63 (s, 2H), 3.84 (brs, 2H), 3.54 (brs, 2H), 2.79 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 1.70 (brs, 6H); (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (s, 1H), 7.17 (m, 1H), 7.08 (m, 2H), 6.91 (m, 2H), 6.72 (d, 1H), 6.47 (m, 2H), 5.61 (s, 2H), 3.84 (brs, 2H), 3.54 (brs, 2H), 2.80 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 1.70 (brs, 6H); (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 7.51 (s, 1H), 7.15 (m, 1H), 7.10-7.03 (m, 4H), 6.62 (d, 1H), 6.35 (s, 1H), 6.24 (d, 1H), 5.60 (s, 2H), 3.84 (brs, 2H), 3.55 (brs, 2H), 2.79 (s, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.20 (s, 3H), 1.70 (brs, 6H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.54 (s, 1H), 7.22-7.06 (m, 5H), 6.67 (d, 1H), 6.52 (s, 1H), 6.32 (d, 1H), 5.60 (s, 2H), 3.84 (brs, 2H), 3.54 (brs, 2H), 2.79 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 1.70 (brs, 6H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (s, 1H), 7.20 (m, 3H), 7.06 (m, 1H), 5.62 (s, 2H), 4.60 (s, 2H), 3.96-3.74 (brs, 2H), 3.81 (brs, 2H), 3.54 (brs, 2H), 3.11 (s, 2H), 3.03 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 1.71 (brs, 6H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.44 (s, 1H), 7.20 (m, 3H), 7.04 (d, 1H), 4.19 (t, 2H), 3.84 (brs, 2H), 3.49 (brs, 2H), 3.12 (brs, 2H), 2.45 (s, 3H), 2.26 (s, 3H), 1.71 (brs, 6H), 1.52 (m, 2H), 0.57 (t, 3H); (Yield: 78%)
1H-NMR(400 MHz, CDCl3) δ 7.48 (s, 1H), 7.20 (m, 3H), 7.07 (m, 1H), 5.23 (s, 2H), 3.82 (brs, 2H), 3.53 (brs, 2H), 3.17 (brs, 2H), 2.55 (s, 3H), 2.38 (s, 1H), 2.32 (s, 3H), 1.71 (brs, 6H); (Yield: 51%)
The titled compounds of Examples 803 to 810 were prepared, in accordance with the same procedures as in Example 756, using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 738; and, pyrrolidine, 4-piperidineethanol, 4-piperidinemethanol, 4-hydroxypiperidine, 3-hydroxypiperidine hydrochloride, thiomorpholine, 1,2,3,6-tetrahydropyridine, or 1-phenylpiperazine.
1H-NMR(400 MHz, CDCl3) δ 7.79 (brs, 1H), 7.21 (m, 3H), 7.14 (m, 1H), 4.46 (brs, 3H), 4.07-3.78 (brs, 6H), 3.19 (brs, 3H), 2.49 (brs, 3H), 2.35 (brs, 3H), 2.01 (brs, 3H), 2.01 (brs, 4H), 1.21 (brs, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (brs, 1H), 7.20 (m, 3H), 7.06 (m, 1H), 4.57 (m, 2H), 4.40 (m, 2H), 3.74 (s, 3H), 3.40 (brs, 2H), 3.13 (brs, 2H), 2.98 (brs, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.82 (m, 2H), 1.59 (m, 6H), 1.17 (t, 3H); (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.56 (brs, 1H), 7.20 (m, 3H), 7.07 (m, 1H), 4.77 (brs, 1H), 4.40 (brs, 3H), 3.56 (brs, 3H), 3.19-2.95 (brs, 3H), 2.46 (s, 3H), 2.28 (s, 3H), 1.84 (brs, 2H), 1.59 (m, 6H), 1.16 (t, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.20 (m, 3H), 7.11 (m, 1H), 4.42 (brs, 2H), 4.36 (brs, 2H), 4.15 (m, 1H), 3.97 (m, 1H), 3.60 (brs, 1H), 3.34 (m, 2H), 2.90 (brs, 1H), 2.38 (s, 3H), 2.23 (s, 3H), 2.02-1.94 (m, 2H), 1.64 (m, 4H), 1.12 (t, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.20 (m, 3H), 7.00 (m, 1H), 4.66 (m, 1H), 4.47 (brs, 1H), 4.37 (brs, 2H), 4.06 (brs, 1H), 3.87 (brs, 3H), 3.33 (brs, 1H), 3.15 (brs, 2H), 2.93 (brs, 1H), 2.46 (s, 3H), 2.27 (s, 3H), 2.08 (brs, 1H), 1.68-1.59 (m, 4H), 1.14 (t, 3H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 7.65 (s, 1H), 7.20 (m, 3H), 7.0 (m, 1H), 4.41 (brs, 3H), 4.14-3.96 (m, 5H), 3.60 (brs, 2H), 3.13 (brs, 2H), 2.79 (brs, 4H), 2.40 (s, 3H), 2.29 (s, 3H), 1.13 (t, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.20 (m, 3H), 7.05 (d, 1H), 5.90-5.80 (m, 2H), 4.80-4.60 (brs, 2H), 4.38 (m, 4H), 4.13 (m, 2H), 4.00 (m, 2H), 3.67 (s, 2H), 3.13 (s, 2H), 2.47 (s, 3H), 2.24 (s, 3H), 1.15 (d, 3H); (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 8.29 (d, 2H), 7.51-7.43 (m, 3H), 7.41 (s, 1H), 7.22 (m, 3H), 7.07 (d, 1H), 5.20 (brs, 1H), 4.98 (d, 1H), 4.76 (m, 2H), 4.38-4.29 (m, 4H), 4.06 (m, 1H), 3.96 (m, 1H), 3.56 (d, 1H), 3.34 (d, 1H), 3.17 (s, 2H), 2.50 (s, 3H), 2.29 (s, 3H), 1.16 (t, 3H); (Yield: 53%)
In accordance with the same procedures as in Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 732 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.22 (m, 3H), 7.06 (m, 1H), 5.75 (m, 1H), 5.21 (d, 1H), 4.99 (s, 2H), 4.70 (m, 1H), 4.60 (d, 1H), 4.27 (brs, 2H), 4.13 (brs, 2H), 3.96 (brs, 2H), 3.58 (brs, 2H), 3.43 (s, 2H), 3.14 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 733 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 67%)
1H-NMR(400 MHz, CDCl3) δ 7.76 (brs, 1H), 7.43 (s, 2H), 7.18 (m, 3H), 6.63 (brs, 2H), 5.80 (brs, 2H), 4.22 (brs, 2H), 3.65 (brs, 2H), 3.30 (brs, 3H), 3.09 (brs, 2H), 2.90 (brs, 2H), 2.83 (brs, 2H), 2.52-2.18 (brs, 5H), 1.52 (s, 3H), 1.43 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 742 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.22 (m, 3H), 7.10 (m, 1H), 4.61 (brs, 1H), 4.26 (brs, 2H), 4.18 (brs, 4H), 4.01 (brs, 2H), 3.57 (brs, 2H), 3.47 (brs, 2H), 3.18 (s, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 1.50 (m, 2H), 0.56 (t, 3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 740 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.49 (s, 1H), 7.19-7.05 (m, 5H), 6.59 (d, 1H), 6.38 (s, 1H), 6.27 (d, 1H), 5.54 (s, 2H), 4.50 (brs, 1H), 4.25-4.13 (m, 4H), 3.89 (brs, 2H), 3.59 (brs, 2H), 3.42 (brs, 2H), 2.90 (s, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-isobutyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 741 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.40 (s, 1H), 7.23 (m, 3H), 7.10 (m, 1H), 4.60 (brs, 2H), 4.26 (brs, 2H), 4.13 (brs, 4H), 3.97 (brs, 2H), 3.60 (brs, 2H), 3.45 (brs, 2H), 3.20 (s, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 1.86 (m, 1H), 0.50 (d, 6H)
The titled compounds of Examples 816 to 818 were prepared, in accordance with the same procedures as in Example 756, using 1-cyclopropylmethyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 735; and, 1-piperazin-1-carboxylic acid tert-butyl ester, 1-methylpiperazine, or 1-ethylpiperazine.
1H-NMR(400 MHz, CDCl3) δ 7.56 (brs, 1H), 7.23 (m, 4H), 4.58 (brs, 1H), 4.22 (brs, 4H), 4.05 (brs, 3H), 3.49 (brs, 4H), 3.27 (brs, 3H), 2.52 (s, 3H), 2.41 (s, 3H), 0.93 (m, 1H), 0.34 (m, 2H), 0.06 (m, 2H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (brs, 1H), 7.24 (m, 3H), 7.07 (m, 1H), 4.86 (brs, 1H), 4.67-4.58 (brs, 2H), 4.44 (m, 3H), 4.27 (m, 3H), 3.85 (m, 2H), 3.39 (brs, 1H), 3.33 (brs, 3H), 2.87 (brs, 2+3H), 2.56 (s, 3H), 2.34 (s, 3H), 0.93 (m, 1H), 0.41 (m, 2H), 0.09 (m, 2H); (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 7.47 (s, 1H), 7.21 (m, 4H), 7.04 (m, 1H), 4.85 (d, 1H), 4.60 (brs, 2H), 4.01 (brs, 4H), 3.83 (brs, 1H), 3.60 (brs, 1H), 3.44 (brs, 2H), 3.15 (s, 4H), 2.54 (s, 3H), 2.31 (s, 3H), 1.42 (s, 3H), 0.91 (m, 1H), 0.40 (m, 2H), 0.09 (m, 2H); (Yield: 51%)
In accordance with the same procedures as in Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 733 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 44%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (brs, 1H), 7.20 (m, 5H), 7.10 (m, 2H), 6.56 (m, 2H), 5.71 (brs, 2H), 4.86 (brs, 1H), 4.50-4.36 (brs, 3H), 3.82 (brs, 3H), 3.39 (brs, 2H), 2.83 (brs, 5H), 2.38 (s, 3+3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 740 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 48%)
1H-NMR(400 MHz, CDCl3) δ 7.35 (brs, 1H), 7.19-7.07 (m, 5H), 6.61 (brs, 1H), 6.44 (brs, 2H), 5.61 (brs, 2H), 4.85 (brs, 1H), 4.50-4.10 (brs, 3H), 3.82 (brs, 4H), 2.86 (brs, 5H), 2.43 (brs, 3H), 2.24 (brs, 3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxyethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 739 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 51%)
1H-NMR(400 MHz, CDCl3) δ 7.43 (s, 1H), 7.23 (m, 3H), 7.05 (m, 1H), 4.87 (d, 1H), 4.70 (brs, 1H), 4.48 (brs, 3H), 4.32 (brs, 1H), 3.92-3.80 (m, 3H), 3.39 (s, 3H), 3.10 (s, 5H), 2.86 (s, 3H), 2.51 (s, 3H), 2.34 (s, 3H)
The titled compounds of Examples 822 to 824 were prepared, in accordance with the same procedures as in Example 756, using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxybenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 736; and, 1-piperazin-1-carboxylic acid tert-butyl ester, 4-methylpiperidine, or 1-ethylpiperazine.
1H-NMR(400 MHz, CDCl3) δ 7.59 (s, 1H), 7.15 (m, 4H), 6.78 (d, 1H), 6.65 (brs, 1H), 6.12 (s, 2H), 5.59 (s, 2H), 4.44 (brs, 1H), 4.22 (brs, 3H), 3.78 (brs, 2H), 3.66 (s, 3H), 3.57-3.40 (m, 4H), 2.81 (s, 3H), 2.33 (s, 3+3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.56 (s, 1H), 7.17-7.04 (m, 4H), 6.76 (d, 1H), 6.68 (d, 1H), 6.10 (s, 2H), 5.64 (s, 2H), 4.70 (m, 1H), 3.73 (brs, 1H), 3.65 (s, 3H), 3.39 (brs, 1H), 3.00 (m, 1H), 2.81 (brs, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 1.81-1.51 (m, 5H), 1.32 (m, 1H), 0.99 (d, 3H); (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 7.42 (s, 1H), 7.22-7.11 (m, 3H), 7.07 (m, 1H), 6.80 (d, 1H), 6.60 (brs, 1H), 6.06 (s, 2H), 5.68 (d, 1H), 5.46 (d, 1H), 4.88 (d, 1H), 4.40-4.39 (m, 4H), 3.91 (m, 3H), 3.67 (s, 3H), 3.45 (d, 1H), 3.22 (m, 3H), 2.90 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 1.48 (t, 3H); (Yield: 58%)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 742 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 60%)
1H-NMR(400 MHz, CDCl3) δ 7.40 (s, 1H), 7.23 (m, 3H), 7.07 (m, 1H), 4.87 (m, 1H), 4.80-4.30 (brs, 3H), 4.24 (m, 3H), 4.14 (m, 1H), 4.02 (m, 1H), 3.85 (m, 3H), 3.37 (brs, 1H), 3.16 (s, 3H), 2.87 (s, 3H), 2.49 (s, 3H), 2.30 (s, 3H), 1.52 (m, 2H), 0.57 (t, 3H)
In accordance with the same procedures as in Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 738 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 53%)
1H-NMR(400 MHz, CDCl3) δ 7.46 (brs, 1H), 7.22 (m, 3H), 7.03 (m, 1H), 4.86 (brs, 2H), 4.59-3.80 (brs, 2H), 4.38 (m, 4H), 3.93 (brs, 4H), 3.42 (brs, 2H), 3.17 (brs, 4H), 2.55 (s, 3H), 2.35 (s, 3H), 1.47 (s, 3H), 1.20 (s, 3H)
In accordance with the same procedures as in Example 731, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 682, the titled compound was obtained as a white solid. (Yield: 59%)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (450 mg, 1.4 mmol) prepared in Step 1, 1-hydroxybenzotriazole hydrate (284 mg, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (401 mg, 2.1 mmol), diisopropylethylamine (730 μl, 4.2 mmol), and 1-methylpiperazine (234 μl, 2.1 mmol) in dichloromethane (10 ml) was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/1, v/v) to give 300 mg of the titled compound as a white solid (Yield: 53%).
A solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-methylpiperazin-1-yl)-methanone prepared in Step 2 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 12.72 (brs, 1H), 11.25 (brs, 1H), 7.20 (m, 3H), 6.94 (m, 1H), 4.84 (brs, 4H), 3.98 (brs, 5H), 3.25 (m, 2H), 3.01 (m, 3H), 2.83 (s, 3H), 2.59 (s, 3H), 2.14 (s, 3H)
The titled compounds of Examples 828 to 837 were prepared, in accordance with the same procedures as in Example 657, using [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-methylpiperazin-1-yl)-methanone prepared in Step 2 of Example 827; and, 4-methylbenzyl bromide, 4-methoxybenzyl bromide, (bromomethyl)cyclobutane, 4-fluorobenzyl chloride, 3-fluorobenzyl chloride, 1-iodo-2-methylpropane, 1-bromo-3-methylbutene, 4-tert-butylbenzyl chloride, 3-chlorobenzyl chloride, or ethanolamine.
1H-NMR(400 MHz, CDCl3) δ 7.46 (brs, 1H), 7.20 (m, 1H), 7.13 (m, 2H), 7.01 (m, 2H), 6.70 (m, 1H), 6.45 (d, 2H), 5.61-5.53 (m, 2H), 4.88 (m, 1H), 4.55 (brs, 2H), 4.25 (brs, 2H), 4.03 (brs, 2H), 3.80 (m, 3H), 3.38 (m, 2H), 3.17 (m, 2H), 2.85 (d, 3H), 2.34 (s, 3H), 2.31 (s, 6H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.47 (brs, 1H), 7.20 (m, 2H), 7.10 (m, 2H), 6.76 (d, 2H), 6.49 (m, 2H), 5.58 (m, 2H), 4.88 (m, 2H), 4.46 (brs, 2H), 4.27 (brs, 2H), 3.90 (brs, 2H), 3.81 (m, 2H), 3.73 (s, 3H), 3.38 (brs, 2H), 3.17 (brs, 2H), 2.85 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H); (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.20 (m, 3H), 7.08 (d, 1H), 4.88 (d, 1H), 4.65 (brs, 2H), 4.41 (brs, 2H), 4.29 (m, 2H), 4.04-3.90 (brs, 2H), 3.84 (m, 2H), 3.36 (brs, 2H), 3.17 (brs, 3H), 2.86 (d, 3H), 2.48 (s, 3H), 2.27 (s, 3H), 1.72 (m, 3H), 1.62 (m, 4H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.23 (m, 1H), 7.10 (m, 3H), 6.92 (m, 2H), 6.70 (brs, 1H), 6.49 (m, 1H), 5.61-5.54 (m, 2H), 4.88 (m, 1H), 4.49 (m, 2H), 4.30 (brs, 2H), 4.20-3.90 (brs, 2H), 3.82 (brs, 3H), 3.38 (brs, 2H), 3.15 (brs, 2H), 2.84 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.44 (brs, 1H), 7.22 (m, 2H), 7.15 (m, 2H), 6.99 (m, 1H), 6.66 (m, 1H), 6.27 (m, 2H), 5.71 (d, 1H), 5.50 (d, 1H), 4.88 (m, 1H), 4.58 (m, 3H), 4.33 (m, 2H), 3.87 (m, 4H), 3.37 (m, 1H), 3.19 (m, 1H), 2.87 (brs, 2+3H), 2.37 (s, 3H), 2.31 (s, 3H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.24 (m, 3H), 7.06 (d, 1H), 4.88 (d, 1H), 4.56 (brs, 3H), 4.31 (m, 2H), 4.14-4.04 (m, 3H), 3.94-3.83 (m, 4H), 3.49 (d, 1H), 3.17 (s, 2H), 2.86 (d, 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.87 (m, 1H), 0.50 (d, 6H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.22 (m, 3H), 7.00 (d, 1H), 5.09 (m, 1H), 4.87 (m, 3H), 4.65 (brs, 2H), 4.50 (brs, 1H), 4.28 (m, 1H), 3.98 (brs, 2H), 3.84 (m, 2H), 3.38 (m, 1H), 3.17 (m, 3H), 2.86 (d, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 1.64 (s, 3H), 1.29 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.21 (m, 3H), 7.13 (d, 1H), 7.05 (m, 1H), 6.55 (brs, 1H), 6.46 (d, 2H), 5.80-5.63 (m, 2H), 4.88 (d, 1H), 4.45 (brs, 2H), 4.29 (m, 2H), 3.95 (brs, 2H), 3.83 (d, 3H), 3.38 (d, 2H), 3.37 (d, 2H), 2.86 (d, 3H), 2.37 (s, 3H), 2.32 (s, 3H), 1.29 (s, 9H); (Yield: 45%)
1H-NMR(400 MHz, CDCl3) δ 7.52 (brs, 1H), 7.15 (m, 4H), 6.70 (brs, 1H), 6.58 (brs, 2H), 6.38 (brs, 1H), 5.66 (brs, 2H), 4.86 (brs, 2H), 4.45-4.11 (brs, 4H), 4.08 (brs, 2H), 3.77 (brs, 2H), 3.40 (brs, 2H), 3.17 (brs, 2H), 2.83 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H); (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 10.32 (brs, 1H), 9.03 (s, 1H), 7.25 (m, 3H), 7.07 (m, 1H), 5.83 (m, 1H), 5.20 (d, 1H), 5.06 (s, 2H), 4.71 (brs, 2H), 4.54 (d, 1H), 4.00 (brs, 2H), 3.95 (s, 2H), 3.65 (s, 2H), 3.10 (s, 2H), 2.44 (s, 3H), 2.38 (s, 3H); (Yield: 82%)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (50 mg, 0.14 mmol) prepared in Example 738 and 1,1′-carbonyldiimidazol (227 mg, 1.4 mmol) in anhydrous tetrahydrofuran (3 ml) was refluxed for 3 hours. 10% Sodium carbonate solution and water were added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 55.9 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 10.06 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.43 (s, 1H), 7.25 (m, 4H), 4.49 (m, 2H), 4.43 (s, 2H), 3.68-3.47 (brs, 2H), 3.12-2.95 (brs, 2H), 2.45 (s, 3H), 2.33 (s, 3H), 1.18 (t, 3H)
The titled compounds of Examples 839 to 843 were prepared, in accordance with the same procedures as in Example 838, using the compounds prepared in Examples 733, 743, 736, 739, and 742.
1H-NMR(400 MHz, CDCl3) δ 8.98 (s, 1H), 8.28 (s, 1H), 7.26 (s, 1H), 7.24 (m, 4H), 7.18 (d, 2H), 6.76 (m, 1H), 6.64 (s, 2H), 5.71 (s, 2H), 4.51 (brs, 2H), 3.72 (brs, 2H), 2.85 (s, 2H), 2.38 (s, 3H), 2.34 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 9.12 (s, 1H), 8.29 (s, 1H), 7.29 (s, 1H), 7.26 (m, 2H), 7.19 (m, 2H), 7.13 (m, 2H), 6.98 (m, 1H), 6.71 (d, 1H), 6.35 (d, 1H), 6.27 (d, 1H), 5.65 (s, 2H), 4.59 (brs, 2H), 3.93 (brs, 2H), 2.86 (s, 2H), 2.40 (s, 3H), 2.37 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 8.87 (s, 1H), 8.26 (s, 1H), 7.28 (s, 1H), 7.16 (m, 4H), 6.79 (d, 1H), 6.70 (d, 1H), 6.16 (s, 2H), 5.65 (s, 3H), 4.55 (brs, 2H), 3.86 (brs, 2H), 3.67 (s, 3H), 2.88 (s, 3H), 2.38-2.17 (m, 6H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 9.01 (s, 1H), 8.25 (s, 1H), 7.26 (m, 3H), 7.18 (m, 1H), 4.77 (brs, 2H), 4.52 (m, 2H), 4.36 (brs, 2H), 3.46 (m, 2H), 3.10 (m, 2+3H), 2.52 (s, 3H), 2.34 (s, 3H); (Yield: 36%)
1H-NMR(400 MHz, CDCl3) δ 9.05 (s, 1H), 8.22 (s, 1H), 7.30 (s, 1H), 7.26 (m, 3H), 7.13 (m, 1H), 4.82 (brs, 2H), 4.23 (s, 4H), 3.16 (s, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 1.54 (m, 2H), 0.57 (t, 3H); (Yield: 41%)
Morpholine (96.7 μl, 1.11 mmol) was added to a solution of 2-[5-chloro-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl-]1,2,3,4-tetrahydroisoquinoline (300 mg, 0.714 mmol) prepared in Example 662, tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (31 mg, 0.054 mmol), and cesium carbonate (326 mg, 1.0 mmol) in anhydrous 1,4-dioxane (5 ml). The reaction mixture was refluxed for 40 hours at 80° C. and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 115 mg of the titled compound as a white solid (Yield: 32%).
1H-NMR(400 MHz, CDCl3) δ 7.18 (m, 4H), 7.13 (s, 1H), 6.91 (m, 2H), 6.46 (d, 1H), 6.37 (d, 1H), 5.67 (s, 2H), 4.28 (brs, 6H), 3.61 (brs, 6H), 2.80 (brs, 2H), 2.25 (s, 3H), 2.23 (s, 3H)
A solution of 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxyethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (100 mg, 0.22 mmol) prepared in Example 737, diphenyl phosphoryl azide (71 μl, 0.33 mmol), and triethylamine (61 μl, 0.44 mmol) in a mixture of tert-butylalcohol (2 ml) and toluene (2 ml) was stirred for 1.5 hours at 60° C. under heating. The reaction mixture was stirred for 3 hours at 90° C. under heating and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 5.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.35 (m, 1H), 7.26-719 (m, 1H), 7.12 (m, 5H), 6.87 (d, 1H), 6.73 (brs, 1H), 6.53 (d, 1H), 6.40 (s, 1H), 5.53 (brs, 2H), 4.20 (brs, 2H), 3.34 (brs, 2H), 2.82 (brs, 2H), 2.17 (s, 3H), 2.15 (s, 3H)
The titled compounds of Examples 846 to 849 were prepared, in accordance with the same procedures as in Example 845, using the compounds prepared in Examples 732, 734, 736, and 738.
1H-NMR(400 MHz, CDCl3) δ 7.20 (m, 3H), 7.02 (d, 1H), 6.38 (s, 1H), 5.81 (m, 1H), 5.07 (d, 1H), 4.90 (s, 1H), 4.87 (s, 2H), 4.54 (d, 1H), 4.54-4.50 (brs, 2H), 3.80 (brs, 2H), 3.07 (brs, 2H), 2.37 (d, 1H), 2.30 (s, 3H), 2.13 (s, 3H); (Yield: 19%)
1H-NMR(400 MHz, CDCl3) δ 7.19-7.15 (m, 5H), 6.92-6.88 (m, 2H), 6.76 (m, 1H), 6.43 (s, 1H), 6.34 (d, 1H), 6.24 (d, 1H), 5.26 (s, 2H), 4.47-3.51 (brs, 4H), 2.80 (brs, 2H), 2.26 (s, 3H), 2.13 (s, 3H); (Yield: 19%)
1H-NMR(400 MHz, CDCl3) δ 7.37 (m, 1H), 7.17-7.14 (m, 2H), 7.10 (m, 3H), 6.73 (d, 2H), 6.42 (s, 1H), 6.11 (d, 2H), 5.45 (s, 2H), 4.50-4.10 (brs, 2H), 3.73-3.60 (brs, 2H), 3.61 (s, 3H), 2.81 (brs, 2H), 2.26 (s, 3H), 2.16 (s, 3H); (Yield: 18%)
1H-NMR(400 MHz, CDCl3) δ 7.38 (m, 1H), 7.21 (m, 3H), 7.05 (d, 1H), 6.35 (s, 1H), 4.50 (brs, 2H), 4.30 (m, 1H), 4.21 (brs, 2H), 3.88-3.82 (brs, 2H), 3.11 (brs, 2H), 3.35 (s, 3H), 2.10 (s, 3H), 1.09 (t, 3H); (Yield: 18%)
Hydroborane tetrahydrofuran complex (1.0M in tetrahydrofuran solution; 1 ml, 1.0 mmol) was added at 0° C. to a solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 19 mg of the titled compound as a white solid.
A solution of [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methanol prepared in Step 2 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 10.2 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.36 (s, 1H), 7.19 (m, 4H), 7.09 (m, 2H), 6.70 (d, 1H), 6.48 (d, 2H), 5.63 (s, 2H), 5.02 (s, 2H), 4.50 (brs, 2H), 3.80 (brs, 2H), 2.80 (brs, 2H), 2.34 (s, 3H), 2.31 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 850, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 734, the titled compound was obtained as a pale yellow solid. (Yield: 91%)
In accordance with the same procedures as in Step 2 of Example 850, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methanol prepared in Step 1, the titled compound was obtained as a pale yellow solid. (Yield: 92%)
1H-NMR(400 MHz, CDCl3) δ 7.37 (s, 1H), 7.22-6.95 (m, 4H), 6.93 (m, 1H), 6.73 (m, 1H), 6.25 (d, 1H), 6.16 (d, 1H), 5.62 (s, 2H), 5.03 (s, 2H), 5.00-3.00 (brs, 4H), 3.49 (s, 2H), 2.36 (s, 3H), 2.32 (s, 3H)
Sodium azide (137 mg, 2.1 mmol) was added at 0° C. to a solution of 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.7 mmol) prepared in Example 689 and ammonium chloride (74.9 mg, 1.4 mmol) in anhydrous N,N-dimethylformamide (10 ml). The reaction mixture was refluxed overnight. 6% sodium nitrite solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 110 mg of the titled compound as a white solid. (Yield: 33%).
1H-NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.19-7.11 (m, 5H), 6.92 (d, 1H), 6.78 (s, 1H), 6.55 (d, 1H), 5.74 (s, 2H), 4.35 (brs, 2H), 4.30 (brs, 2H), 3.50 (brs, 2H), 2.79 (brs, 2H), 2.31 (s, 3H), 2.26 (s, 3H)
2-[1-(3-Chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (50 mg, 0.11 mmol) prepared in Example 852 and potassium carbonate (22.1 mg, 0.16 mmol) were dripped into anhydrous N,N-dimethylformamide (1 ml). Iodomethane (10 t, 0.16 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 18 mg of the titled compound as a white solid (Yield: 34%).
1H-NMR(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.17 (m, 5H), 6.90 (d, 1H), 6.78 (s, 1H), 6.55 (d, 1H), 5.74 (s, 2H), 4.38 (s, 3H), 4.30 (brs, 2H), 3.50 (brs, 2H), 2.79 (brs, 2H), 2.31 (s, 3H), 2.27 (s, 3H)
In accordance with the same procedures as in Example 853, except for using 2-[1-(3-chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline prepared in Example 852 and iodoethane, the titled compound was obtained as a white solid. (Yield: 34%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.14 (m, 5H), 6.88 (d, 1H), 6.78 (s, 1H), 6.56 (d, 1H), 5.74 (brs, 2H), 4.98 (q, 2H), 4.32-4.17 (brs, 2H), 3.49-3.17 (brs, 2H), 2.91-2.79 (brs, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 1.51 (t, 3H)
Methyl magnesium bromide (3.0M in tetrahydrofuran solution; 244 μl, 0.74 mmol) was added at 0° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (100 mg, 0.24 mmol) prepared in Example 695 in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 95 mg of the titled compound as a white solid. (Yield: 86%).
1H-NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.18 (m, 4H), 6.91 (m, 2H), 6.49 (s, 1H), 6.36 (d, 1H), 5.76 (s, 2H), 4.38 (brs, 2H), 3.57 (brs, 2H), 2.86 (s, 2H), 2.79 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H)
In accordance with the same procedures as in Example 855, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 686 and ethyl magnesium bromide (2.0M in tetrahydrofuran solution), the titled compound was obtained as a white solid. (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.20 (m, 5H), 6.87 (brs, 1H), 6.72 (s, 2H), 5.78 (bs 2H), 4.40 (brs, 2H), 3.62 (brs, 2H), 3.31 (brs, 2H), 2.92 (brs, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 1.27 (s, 3H)
In accordance with the same procedures as in Example 855, except for using 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 689 and ethyl magnesium bromide (2.0M in tetrahydrofuran solution), the titled compound was obtained as a white solid. (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.14 (m, 5H), 6.90 (d, 1H), 6.79 (s, 1H), 6.56 (d, 1H), 5.74 (brs, 2H), 4.10 (brs, 2H), 3.49 (brs, 2H), 3.24 (q, 2H), 2.88 (brs, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 1.22 (t, 3H)
In accordance with the same procedures as in Example 855, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-ethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 696 and cyclohexyl magnesium chloride (2.0M in diethyl ether solution), the titled compound was obtained as a white solid. (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 7.97 (s, 1H), 7.21 (m, 3H), 7.10 (d, 1H), 4.81 (brs, 2H), 4.40 (q, 2H), 4.20 (brs, 2H), 3.83 (m, 1H), 3.13 (s, 2H), 2.48 (s, 3H), 2.33 (s, 3H), 1.99 (m, 2H), 1.84 (m, 2H), 1.74 (m, 1H), 1.53 (m, 4H), 1.20 (m, 1H), 1.17 (t, 3H)
In accordance with the same procedures as in Example 855, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxybenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 691 and cyclohexyl magnesium chloride (2.0M in diethyl ether solution), the titled compound was obtained as a white solid. (Yield: 61%)
1H-NMR(400 MHz, CDCl3) δ 8.08 (s, 1H), 7.16 (m, 4H), 6.81 (d, 1H), 6.76 (d, 1H), 6.24 (s, 2H), 5.73 (s, 2H), 4.50-4.20 (brs, 2H), 3.85 (m, 1H), 3.84-3.64 (brs, 2H), 3.70 (s, 3H), 2.87 (s, 2H), 2.31 (s, 3H), 2.11 (s, 3H), 1.99 (m, 2H), 1.84 (m, 2H), 1.64 (m, 1H), 1.46 (m, 4H), 1.28 (m, 1H)
Sodium borohydride (5.3 mg, 0.14 mmol) was added at 0° C. to a solution of 1-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-ethanone hydrochloride (20 mg, 0.05 mmol) prepared in Example 855 in anhydrous methanol (2 ml). The reaction mixture was stirred for 10 minutes at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v). The resulting residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 7.1 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.40 (s, 1H), 7.19-7.10 (m, 4H), 6.93 (t, 1H), 6.72 (d, 1H), 6.24 (d, 1H), 6.17 (d, 1H), 5.62 (s, 2H), 5.49 (m, 1H), 4.13-4.06 (brs, 2H), 3.56-3.49 (brs, 2H), 2.81 (s, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.82 (s, 3H)
In accordance with the same procedures as in Example 860, except for using 1-[1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-propan-1-one obtained by treating the compound prepared in Example 856 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 95%)
1H-NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.20 (m, 4H), 7.07 (m, 2H), 6.67 (d, 1H), 6.48 (d, 2H), 5.64 (s, 2H), 5.09 (brs, 1H), 4.5-3.0 (brs, 4H), 2.77 (brs, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.15 (brs, 2H), 1.40 (t, 3H)
Diisobutyl aluminum hydride (1.0M in toluene solution; 1.98 ml, 1.98 mmol) was added at −78° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 099 mmol) prepared in Example 682 in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 5 hours and then diluted with diethyl ether. Water (2 ml) and 15% sodium hydroxide solution (2 ml) were added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 50.6 mg of the titled compound as a white solid. (Yield: 16%).
1H-NMR(400 MHz, CDCl3) δ 10.04 (s, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.20 (s, 4H), 4.70 (s, 2H), 3.81 (t, 2H), 3.13 (t, 2H), 2.43 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Example 862, except for using 1-(3-chlorobenzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 689, the titled compound was obtained as a pale yellow solid. (Yield: 15%)
1H-NMR(400 MHz, CDCl3) δ 10.18 (s, 1H), 8.06 (s, 1H), 7.18-7.10 (m, 5H), 6.88 (d, 1H), 6.76 (s, 1H), 6.56 (d, 1H), 5.77 (brs, 2H), 4.42-4.11 (brs, 2H), 3.55-3.37 (brs, 2H), 2.90 (brs, 2H), 2.30 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Example 862, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 695, the titled compound was obtained as a pale yellow solid. (Yield: 15%)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbaldehyde prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 20 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 11.18 (s, 1H), 8.25 (s, 1H), 7.22-7.17 (m, 2H), 7.13-7.07 (m, 2H), 6.95 (t, 1H), 6.67 (d, 1H), 6.24 (d, 1H), 6.18 (d, 1H), 5.70 (s, 2H), 5.00-3.00 (brs, 4H), 2.83 (brs, 2H), 2.41 (s, 3H), 2.38 (s, 3H)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbaldehyde (30 mg, 0.07 mmol) prepared in Step 1 of Example 864 and 3-chlorobenzylamine (9.75 μl, 0.08 mmol) in methanol (3 ml) was refluxed for 3 hours. Titanium(IV) isopropoxide (40 μl) and sodium borohydride (5.49 mg, 0.15 mmol) were added at room temperature to the reaction mixture, which was then stirred overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 21.7 mg of the titled compound as a white solid.
A solution of (3-chlorobenzyl)-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-ylmethyl]-amine prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 15.2 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.84 (m, 2H), 7.36 (m, 2H), 7.22-7.19 (m, 4H), 7.13-7.07 (m, 1H), 6.96 (m, 1H), 6.28-6.20 (m, 2H), 5.60 (s, 2H), 4.61 (s, 2H), 4.37 (s, 2H), 4.00-3.00 (brs, 4H), 2.85 (s, 2H), 2.34 (s, 6H)
The titled compounds of Examples 866 to 873 were prepared, in accordance with the same procedures as in Example 865, using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbaldehyde prepared in Step 1 of Example 864; and, 4-fluoroaniline, 4-methylbenzylamine, ethylamine, tert-butylamine, cyclobutylamine, cyclopropylamine, morpholine, or 1-methylpiperazine.
1H-NMR(400 MHz, CDCl3) δ 8.12 (m, 2H), 7.91 (m, 1H), 7.21-7.09 (m, 6H), 6.96 (m, 1H), 6.63 (m, 1H), 6.30 (d, 1H), 6.22 (d, 1H), 5.62 (s, 2H), 4.80 (s, 2H), 4.12-3.49 (brs, 4H), 2.87 (s, 2H), 2.35 (s, 6H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 7.73 (m, 2H), 7.25-7.08 (m, 7H), 6.94 (m, 1H), 6.63 (m, 1H), 6.22 (m, 2H), 5.59 (s, 2H), 4.53 (s, 2H), 4.36 (s, 2H), 4.00-3.00 (brs, 4H), 2.83 (s, 2H), 2.34 (s, 9H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.54 (s, 1H), 7.28 (m, 1H), 7.17 (m, 3H), 6.99 (m, 2H), 6.49 (m, 2H), 5.71 (s, 2H), 4.41 (brs, 4H), 3.46 (m, 2H), 3.04 (brs, 2H), 2.85 (brs, 2H), 2.51 (brs, 2H), 2.26 (d, 6H), 1.26 (t, 3H); (Yield: 76%)
1H-NMR(400 MHz, CDCl3) δ 7.90 (brs, 1H), 7.21-7.11 (m, 4H), 6.96 (m, 1H), 6.59 (m, 1H), 6.32-6.23 (m, 2H), 5.62 (s, 2H), 4.47 (brs, 2H), 4.00-3.00 (brs, 4H), 2.85 (s, 2H), 2.33 (s, 6H), 1.68 (s, 9H); (Yield: 62%)
1H-NMR(400 MHz, DMSO-d6) 7.56 (s, 1H), 7.28-7.23 (m, 1H), 7.17 (m, 3H), 6.99 (m, 2H), 6.50 (m, 2H), 5.70 (s, 2H), 4.32 (brs, 2H), 4.20 (s, 2H), 3.76 (m, 3H), 2.86 (s, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 2.18 (m, 4H), 1.75 (m, 2H); (Yield: 61%)
1H-NMR(400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.24 (m, 1H), 7.14 (m, 3H), 7.00 (m, 2H), 6.47 (m, 2H), 5.71 (s, 2H), 4.34 (s, 4H), 3.41 (m, 3H), 2.78 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 0.83 (m, 2H), 0.73 (m, 2H); (Yield: 72%)
1H-NMR(400 MHz, CDCl3) δ 8.87 (brs, 1H), 7.23-7.07 (m, 4H), 6.94 (m, 1H), 6.65 (m, 1H), 6.26 (d, 1H), 6.21 (d, 1H), 5.66 (s, 2H), 5.20 (brs, 2H), 4.23 (brs, 2H), 4.13 (brs, 2H), 3.78 (brs, 2H), 3.20 (brs, 2H), 2.84 (s, 2H), 2.44 (m, 6H); (Yield: 69%)
1H-NMR(400 MHz, DMSO-d6/D2O) δ 7.63 (s, 1H), 7.29-7.16 (m, 4H), 7.04 (m, 1H), 6.92 (m, 1H), 6.55-6.48 (m, 2H), 5.70 (s, 2H), 4.40 (brs, 2H), 4.31 (s, 2H), 3.50 (m, 2H), 3.34-3.07 (brs, 8H), 2.83 (s, 5H), 2.00 (s, 3H), 1.96 (s, 3H); (Yield: 59%)
In accordance with the same procedures as in Step 1 of Example 865, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbaldehyde prepared in Example 862, the titled compound was obtained as a white solid. (Yield: 61%)
A solution of 2-[2,3-dimethyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and filtered. The resulting solid was dried under reduced pressure to give 3,4 mg of the titled compound as a white solid.
1H-NMR(400 MHz, MeOH-d4) δ 7.35 (m, 5H), 5.13 (s, 2H), 4.32 (brs, 2H), 4.13 (t, 2H), 3.46-3.18 (m, 8H), 3.20 (t, 2H), 2.97 (s, 3H), 2.56 (s, 3H), 2.25 (s, 3H)
Potassium tert-butoxide (15 mg, 0.12 mmol) was added to a solution of 2-[2,3-dimethyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (30 mg, 0.074 mmol) prepared in Step 1 of Example 874 and 18-crown-6 (3.1 mg, 0.012 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 1 hour at room temperature and then 3-chlorobenzyl chloride (15.2 μl, 0.12 mmol) was added thereto. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 21.0 mg of the titled compound as a white solid.
1H-NMR(400 MHz, MeOH-d4) δ 7.83 (s, 1H), 7.25-7.14 (m, 5H), 6.82 (d, 1H), 6.61 (s, 1H), 6.50 (d, 1H) 5.70 (s, 2H), 4.45 (s, 2H), 4.22 (s, 2H), 3.73 (t, 2H), 3.63 (brs, 2H), 3.30 (brs, 4H), 2.98 (brs, 2H), 2.94 (s, 3H), 2.38 (t, 2H), 2.42 (s, 3H), 2.38 (s, 3H)
The titled compounds of Examples 876 to 883 were prepared, in accordance with the same procedures as in Example 875, using 2-[2,3-dimethyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline prepared in Step 1 of Example 874; and, 3-methoxybenzyl bromide, 4-fluorobenzyl chloride, 3-methylbenzyl bromide, allyl iodide, (bromomethyl)cyclopropane, iodoethane, 1-bromopropane, or benzyl bromide.
1H-NMR(400 MHz, MeOH-d4) δ 7.87 (s, 1H), 7.23-7.11 (m, 4H), 6.78 (t, 2H), 6.18 (s, 1H), 6.11 (d, 1H), 5.69 (s, 2H), 4.88 (s, 2H), 4.37 (s, 2H), 3.75 (t, 2H), 3.61 (brs, 4H), 3.43 (brs, 4H), 2.96 (s, 3H), 2.91 (tm, 2H), 2.41 (s, 3H), 2.38 (s, 3H); (Yield: 78%)
1H-NMR(400 MHz, MeOH-d4) δ 7.84 (s, 1H), 7.24-7.16 (m, 3H), 6.96-6.86 (m, 3H), 6.68-6.64 (t, 2H), 5.69 (s, 2H), 4.48 (s, 2H), 4.29 (s, 2H), 3.75 (t, 2H), 3.34 (m, 6H), 3.13 (m, 2H), 2.95 (s, 3H), 2.88 (t, 2H), 2.41 (s, 3H), 2.37 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, MeOH-d4) δ 7.72 (s, 1H), 7.25-7.16 (m, 3H), 7.05 (m, 2H), 6.79 (d, 1H), 6.48 (s, 1H), 6.29 (d, 1H), 5.68 (s, 2H), 4.40 (s, 2H), 3.94 (s, 2H), 3.66 (t, 2H), 3.34 (m, 2H), 3.09 (m, 4H), 2.94 (s, 3H), 2.91 (m, 2H), 2.62 (m, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H); (Yield: 79%)
1H-NMR(400 MHz, MeOH-d4) δ 7.67 (s, 1H), 7.26 (m, 3H), 7.17 (m, 1H), 5.88 (m, 1H), 5.15 (m, 3H), 4.61 (s, 2H), 4.57 (d, 1H), 3.95 (s, 2H), 3.78 (t, 2H), 3.48 (m, 2H), 3.10 (m, 6H), 3.09 (s, 3H), 2.63 (m, 2H), 2.48 (s, 3H), 2.37 (s, 3H); (Yield: 74%)
1H-NMR(400 MHz, MeOH-d4) δ 7.66 (s, 1H), 7.30-7.22 (m, 4H), 4.62 (s, 2H), 4.28 (d, 2H), 4.08 (brs, 2H), 3.87 (brs, 2H), 3.51 (brs, 2H), 3.12 (brs, 4H), 2.92 (s, 3H), 2.58 (brs, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 1.23 (m, 1H), 0.34 (m, 2H), 0.11 (m, 2H); (Yield: 75%)
1H-NMR(400 MHz, MeOH-d4) δ 7.65 (s, 1H), 7.29-7.22 (m, 4H), 4.65 (s, 2H), 4.45 (q, 2H), 3.98 (s, 2H), 3.85 (t, 2H), 3.49 (brs, 2H), 3.13 (brs, 6H), 2.92 (s, 3H), 2.65 (brs, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 1.18 (t, 3H); (Yield: 76%)
1H-NMR(400 MHz, MeOH-d4) δ 7.67 (s, 1H), 7.28-7.18 (m, 4H), 4.63 (s, 2H), 4.27 (t, 2H), 3.88 (brs, 2H), 3.85 (t, 2H), 2.51 (brs, 2H), 3.15 (brs, 6H), 2.93 (s, 3H), 2.71 (brs, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.56 (q, 2H), 0.58 (t, 3H); (Yield: 74%)
1H-NMR(400 MHz, MeOH-d4) δ 7.77 (s, 1H), 7.26-7.13 (m, 6H), 6.83 (d, 1H), 6.62 (m, 2H), 5.72 (s, 2H), 4.47 (s, 2H), 4.08 (s, 2H), 3.72 (t, 2H), 3.54 (brs, 2H), 3.21 (brs, 4H), 3.01 (s, 3H), 2.87 (t, 2H), 2.84 (brs, 2H), 2.40 (s, 3H), 2.33 (s, 3H); (Yield: 81%)
Methanesulfonyl chloride (29.5 μl, 0.3 mmol) was added at 0° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methanol (50 mg, 0.12 mmol) prepared in Step 1 of Example 851 and triethylamine (46 μl, 0.33 mmol) in anhydrous dichloromethane (10 ml). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with anhydrous dichloromethane (10 ml). The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 46 mg of the titled compound as pale yellow oil.
Sodium cyanide (6.9 mg, 0.14 mmol) was added to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-ylmethanesulfonic acid methyl ester prepared in Step 1 in N,N-dimethylformamide. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 16.9 mg of the titled compound as a white solid.
1H-NMR(400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.26 (m, 1H), 7.14 (m, 3H), 7.00 (m, 2H), 6.53 (t, 2H), 5.72 (s, 2H), 5.43 (d, 2H), 4.19 (brs, 2H), 3.41 (brs, 2H), 3.00 (brs, 2H), 2.33 (d, 6H)
(Diethylamino)sulfo trifluoride was added at −78° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methanol (50 mg, 0.12 mmol) prepared in Step 1 of Example 851 in anhydrous dichloromethane (2 ml). The reaction mixture was stirred for 2 hours at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 7.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.26 (m, 1H), 7.14 (m, 3H), 7.00 (m, 2H), 6.53 (t, 2H), 5.72 (s, 2H), 5.43 (d, 2H), 4.19 (brs, 2H), 3.41 (brs, 2H), 3.00 (brs, 2H), 2.33 (d, 6H)
Diisobutyl aluminum hydride (1.0M in hexane solution; 13.8 ml, 13.8 mmol) was added at −78° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (3.8 g, 12.6 mmol) prepared in Example 682 in toluene (100 ml). The reaction mixture was stirred for 1 hour at −78° C. and then for 1 hour at 0° C. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was re-crystallized with dichloromethane to give 2.5 g of the titled compound as a pale yellow solid.
A solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methylamine (25 mg) prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 23,4 mg of the titled compound as a white solid.
1H-NMR(400 MHz, MeOH-d4) δ 7.17 (m, 4H), 6.97 (s, 1H), 4.66 (s, 2H), 3.84 (s, 2H), 3.76 (t, 2H), 3.10 (t, 2H), 2.40 (s, 3H), 2.19 (s, 3H)
Dimethylaminopyridine (12 mg, 0.098 mmol) was added to a solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-methylamine (30 mg, 0.098 mmol) prepared in Step 1 of Example 886 and di-tert-butyl dicarbonate (23.15 mg, 0.108 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 49 mg of the titled compound as a white solid.
18-Crown-6 (3.1 mg, 0.012 mmol) and potassium tert-butoxide (16.2 mg, 0.13 mmol) were added to a solution of [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-ylmethyl]-carbamic acid tert-butyl ester (49 mg, 0.12 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 30 minutes at room temperature and then allyl bromide (11.5 μl, 0.13 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 1.0 mg of the titled compound as a white solid.
1H-NMR(400 MHz, MeOH-d4) δ 7.61 (brs, 1H), 7.24 (m, 4H), 7.11 (s, 1H), 5.88 (m, 1H), 5.11 (s, 2H), 5.03 (m, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 3.70 (brs, 2H), 3.14 (brs, 2H), 2.45 (s, 3H), 2.32 (s, 3H)
In accordance with the same procedures as in Step 2 of Example 887, except for using [7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-ylmethyl]-carbamic acid tert-butyl ester prepared in Step 1 of Example 887 and 3-fluorobenzyl chloride, the titled compound was obtained as a white solid. (Yield: 36%)
1H-NMR(400 MHz, DMSO-d6) δ 8.34 (brs, 2H), 7.49 (brs, 1H), 7.13-7.16(m, 1H), 7.10-7.03 (m, 3H), 6.95-6.87 (m, 2H), 6.40-6.38 (d, 2H), 5.67 (s, 2H), 4.18 (brs, 2H), 4.17 (s, 2H), 3.43 (brs, 2H), 2.76 (brs, 2H), 2.18 (s, 3H), 2.14 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 642, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-methylamine prepared in Preparation 8, the titled compound was obtained as yellow oil. (Yield: 37%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Example 657, except for using N-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-methylamine prepared in Step 1 and 3-fluorobenzyl chloride, the titled compound was obtained as a pale yellow solid. (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.20 (m, 2H), 7.01 (m, 2H), 6.95 (m, 1H), 6.82 (m, 2H), 6.42 (d, 1H), 6.30 (d, 1H), 5.74 (s, 2H), 4.25 (brs, 2H), 2.60 (s, 3H), 2.18 (s, 6H)
The titled compounds of Examples 890 to 892 were prepared, in accordance with the same procedures as in Example 657, using N-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-methylamine prepared in Step 1 of Example 889; and, allyl bromide, (bromomethyl)cyclopropane, or 3-chlorobenzyl chloride.
1H-NMR(400 MHz, CDCl3) δ 7.32 (m, 2H), 7.13 (s, 1H), 6.97 (t, 2H), 5.83 (m, 1H), 5.10 (s, 2H), 5.02 (d, 1H), 4.55 (d, 1H), 4.32 (s, 2H), 2.65 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H); (Yield: 59%)
1H-NMR(400 MHz, CDCl3) δ 7.36 (m, 2H), 7.11 (s, 1H), 7.02 (t, 2H), 4.35 (s 2H), 4.24 (d, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 2.17 (s, 3H), 0.94 (m, 1H), 0.38 (m, 2H), 0.25 (m, 2H); (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.23 (m, 2H), 7.14 (t, 1H), 7.01 (m, 2H), 6.83 (t, 2H), 6.77 (s, 1H), 6.38 (d, 1H), 5.72 (s, 2H), 4.24 (s, 2H), 2.61 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H); (Yield: 59%)
In accordance with the same procedures as in Example 682, except for using N-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-methylamine prepared in Step 1 of Example 889, the titled compound was obtained as a white solid. (Yield: 20%)
1H-NMR(400 MHz, CDCl3) δ 7.94 (s, 1H), 7.38 (s, 1H), 7.36 (m, 2H), 7.07 (m, 2H), 4.72 (s, 2H), 3.19 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H)
The titled compounds of Examples 894 to 900 were prepared, in accordance with the same procedures as in Example 657, using 7-[(4-fluorobenzyl)-methylamino]-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 893; and, 3-fluorobenzyl chloride, (bromomethyl)cyclopropane, 2-bromoethyl methyl ether, 3-chlorobenzyl chloride, allyl bromide, 1-iodo-2-methylpropane, or iodomethane.
1H-NMR(400 MHz, CDCl3) δ 7.67 (s, 1H), 7.21 (m, 1H), 7.01 (m, 2H), 6.93 (m, 1H), 6.80 (m, 2H), 6.41 (d, 1H), 6.32 (d, 1H), 5.83 (s, 2H), 4.23 (s, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H); (Yield: 66%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (s, 1H), 7.31 (m, 2H), 7.02 (t, 2H), 4.33 (m, 2+2H), 2.63 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H), 0.99 (m, 1H), 0.42 (m, 2H), 0.26 (d, 2H); (Yield: 74%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (s, 1H), 7.32 (m, 2H), 7.00 (m, 2H), 4.58 (s, 2H), 4.35 (s, 2H), 3.41 (t, 2H), 3.17 (s, 3H), 2.64 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H); (Yield: 69%)
1H-NMR(400 MHz, CDCl3) δ 7.67 (s, 1H), 7.16 (m, 2H), 7.02 (m, 2H), 6.83 (m, 3H), 6.39 (d, 1H), 5.80 (s, 2H), 4.26 (s, 2H), 2.61 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H); (Yield: 71%)
1H-NMR(400 MHz, CDCl3) δ 7.61 (s, 1H), 7.28 (m, 2H), 6.98 (t, 2H), 5.83 (m, 1H), 5.20 (d, 2H), 5.18 (d, 1H), 4.54 (d, 1H), 4.33 (s, 2H), 2.67 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H); (Yield: 68%)
1H-NMR(400 MHz, CDCl3) δ 7.60 (s, 1H), 7.33 (m, 2H), 7.02 (m, 2H), 4.31 (s, 2H), 4.16 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H), 1.95 (m, 1H), 0.66 (s, 3H), 0.64 (s, 3H); (Yield: 65%)
1H-NMR(400 MHz, CDCl3) δ 7.58 (s, 1H), 7.31 (m, 2H), 6.99 (m, 2H), 4.40 (s, 2H), 4.03 (s, 3H), 2.73 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H); (Yield: 85%)
In accordance with the same procedures as in Example 745, except for using 1-(3-fluorobenzyl)-7-[(4-fluorobenzyl)-methylamino]-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Example 894, the titled compound was obtained as a white solid. (Yield: 90%)
1H-NMR(400 MHz, CDCl3) δ 8.22 (s, 1H), 7.78 (s, 1H), 7.20 (m, 1H), 6.97 (m, 2H), 6.92 (m, 1H), 6.82 (m, 2H), 6.42 (d, 1H), 6.38 (d, 1H), 5.83 (s, 2H), 5.46 (s, 1H), 4.28 (s, 2H), 2.66 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H)
In accordance with the same procedures as in Step 2 of Preparation 5, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-methylamine prepared in Preparation 8, the titled compound was obtained as yellow oil. (Yield: 83%)
1H-NMR(400 MHz, CDCl3) δ 8.16 (d, 1H), 7.46 (m, 2H), 7.20 (d, 1H), 6.99 (m, 2H), 5.17 (s, 2H), 1.38 (s, 9H)
In accordance with the same procedures as in Step 3 of Example 642, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 1, the titled compound was obtained as yellow oil. (Yield: 50%)
1H-NMR(400 MHz, CDCl3) δ 8.49 (brs, 1H), 7.27 (m, 2H), 6.92 (m, 2H), 5.15 (s, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.45 (s, 9H)
In accordance with the same procedures as in Example 657, except for using (5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 2 and benzyl bromide, the titled compound was obtained as yellow oil. (Yield: 70%)
A solution of (1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 3 in ethyl acetate was saturated with hydrochloric acid gas and then filtered. The resulting solid was dried under reduced pressure to give 23.5 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.29 (m, 4H), 6.78 (brs, 2H), 6.71 (m, 2H), 6.52 (s, 1H), 6.07 (brs, 2H), 5.17 (brs, 2H), 2.38 (s, 3H), 2.15 (s, 3H)
In accordance with the same procedures as in Example 682, except for using (1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 3 of Example 902, the titled compound was obtained as a white solid. (Yield: 24%)
A solution of 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 12.0 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.35 (m, 4H), 7.00 (brs, 1H), 6.77 (m, 5H), 6.04 (brs, 2H), 5.00 (brs, 2H), 2.45 (s, 3H), 2.27 (s, 3H)
In accordance with the same procedures as in Example 731, except for using 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1 of Example 903, the titled compound was obtained as a white solid. (Yield: 58%)
A solution of 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 10.5 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.53 (brs, 1H), 7.56 (brs, 1H), 7.29 (m, 4H), 6.90-6.77 (m, 5H), 6.12 (brs, 2H), 4.69 (brs, 2H), 2.44 (s, 3H), 2.25 (s, 3H)
In accordance with the same procedures as in Example 745, except for using 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1 of Example 903, the titled compound was obtained as a white solid. (Yield: 87%)
A solution of 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxamide prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 17.1 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 8.01 (s, 1H), 7.74 (brs, 1H), 7.26 (m, 3H), 6.96-6.89 (m, 6H), 5.49 (s, 2H), 5.35 (brs, 1H), 4.51 (brs, 1H), 4.40 (s, 2H), 2.33 (s, 3H), 2.28 (s, 3H)
The titled compounds of Examples 906 to 909 were prepared, in accordance with the same procedures as in Example 756, using 1-benzyl-7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 904; and, 1-methylpiperazine, 1-ethylpiperazine, piperidine, or morpholine.
1H-NMR(400 MHz, CDCl3) δ 7.31 (m, 2H), 6.91 (brs, 1H), 6.83-6.75 (m, 5H), 6.63 (brs, 2H), 5.91 (brs, 1H), 5.53 (brs, 2H), 4.88-4.72 (brs, 2H), 3.85-3.67 (brs, 5H), 3.28 (brs, 3H), 2.74 (s, 3H), 2.54 (s, 3H), 2.25 (s, 3H); (Yield: 82%)
1H-NMR(400 MHz, CDCl3) δ 7.27 (m, 2H), 7.08 (brs, 1H), 6.83-6.72 (m, 5H), 6.58 (brs, 2H), 5.99 (brs, 1H), 5.58 (brs, 2H), 4.89-4.73 (brs, 2H), 3.85-3.75 (brs, 3H), 3.47 (brs, 3H), 3.35 (brs, 3H), 2.55 (s, 3H), 2.24 (s, 3H), 1.23 (t, 3H); (Yield: 73%)
1H-NMR(400 MHz, CDCl3) δ 7.27 (m, 2H), 6.93 (m, 3H), 6.72 (m, 4H), 6.18 (brs, 2H), 5.13 (brs, 2H), 4.54 (brs, 2H), 3.54-3.13 (brs, 2+2H), 2.51 (s, 3H), 2.22 (s, 3H), 1.92 (brs, 2H), 1.78 (brs, 4H); (Yield: 52%)
1H-NMR(400 MHz, CDCl3) δ 8.74 (s, 1H), 7.26 (m, 2H), 6.92 (d, 2H), 6.77 (s, 1H), 6.70 (m, 2H), 6.58 (m, 2H), 6.11 (brs, 2H), 5.20 (brs, 2H), 3.50 (m, 6H), 3.22 (m, 2H), 2.54 (s, 3H), 2.21 (s, 3H); (Yield: 48%)
In accordance with the same procedures as in Example 682, except for using (5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 2 of Example 902, the titled compound was obtained as a white solid. (Yield: 24%)
A solution of 7-(4-fluorobenzylamino)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 3.2 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 12.27 (brs, 1H), 7.68 (s, 1H), 7.47 (m, 2H), 7.20 (m, 2H), 4.72 (s, 2H), 2.36 (s, 3H), 2.15 (s, 3H)
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658 and sodium hydrosulfide (26.7 mg, 0.48 mmol) in methanol (2 ml) was refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the resulting solid. The reaction mixture was stirred for 30 minutes and then filtered. The resulting solid washed with water 3 times and then dried to give 68 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 7.24 (s, 1H), 7.20 (m, 4H), 7.08 (m, 2H), 6.72 (d, 1H), 6.47 (d, 2H), 5.63 (s, 2H), 4.34 (brs, 2H), 3.81 (brs, 2H), 2.62 (brs, 2H), 2.35 (brs, 1H), 2.35 (s, 3H), 2.29 (s, 3H)
A solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-thiol prepared in Example 911 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 15.2 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.22 (s, 1H), 7.19 (m, 4H), 7.09 (m, 2H), 6.70 (d, 1H), 6.48 (d, 2H), 5.63 (s, 2H), 4.50 (brs, 2H), 3.80 (brs, 2H), 2.80 (brs, 2H), 2.30 (brs, 1H), 2.34 (s, 3H), 2.31 (s, 3H)
1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-thiol (500 mg, 0.24 mmol) prepared in Example 911 was added to a sodium hydroxide solution (10 ml). Excess chloramine obtained by adding sodium hyperchloride to ammonium hydroxide was slowly added at −10° C. to the reaction mixture, which was then filtered. The resulting solid was washed with water and then dried to give 150 mg of the titled compound as yellow solid.
1H-NMR(400 MHz, CDCl3) δ 7.21 (s, 1H), 7.18 (m, 4H), 7.11 (m, 2H), 6.74 (d, 1H), 6.48 (d, 2H), 5.60 (s, 2H), 4.55 (brs, 2H), 3.81 (brs, 2H), 2.90 (brs, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.15 (s, 2H)
3-Chloroperbenzoic acid (249 mg, 1.44 mmol) was added to a solution of 5-(aminosulfanyl)-2,3-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl-1H-pyrrolo[2,3-c]pyridine (150 mg, 0.36 mmol) prepared in Step 1 in dichloromethane (10 ml). The reaction mixture was stirred for 6 hours at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 54 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.34 (s, 1H), 7.20 (m, 4H), 7.11 (m, 2H), 6.74 (d, 1H), 6.49 (d, 2H), 5.69 (brs, 2H), 4.34 (brs, 2H), 3.94 (brs, 2H), 3.73 (s, 3H), 2.84 (s, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 1.98 (brs, 2H)
The compound prepared in Example 847 was treated with a saturated sodium bicarbonate solution to obtain 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine. Concentrated sulfuric acid (1 ml) and water (5 ml) were added to 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (50 mg, 0.13 mmol) and then sodium nitrite (43.1 mg, 0.63 mmol) was added thereto. The reaction mixture was stirred for 5 minutes at 100° C. under heating and then excess ammonia solution was added thereto. The reaction mixture was stirred for 2 minutes under heating at the same temperature and then filtered to discard insoluble matertals. A potassium hydroxide solution was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 28.4 mg of the titled compound as a pale yellow solid.
1H-NMR(400 MHz, CDCl3) δ 7.25 (s, 1H), 7.20-7.15 (m, 4H), 6.90-6.88(m, 2H), 6.77 (m, 1H), 6.40 (s, 1H), 6.31 (d, 1H), 6.25 (d, 1H), 5.26 (s, 2H), 4.97 (brs, 2H), 3.42 (brs, 2H), 2.99 (brs, 2H), 2.30 (s, 3H), 2.17 (s, 3H)
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-ol prepared in Example 914 in ethyl acetate was saturated with hydrochloric acid gas and then filtered to give 5.7 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.19-7.15 (m, 5H), 6.92-6.88 (m, 2H), 6.76 (m, 1H), 6.43 (s, 1H), 6.34 (d, 1H), 6.24 (d, 1H), 5.26 (s, 2H), 4.47-3.51 (brs, 4H), 2.80 (brs, 2H), 2.26 (s, 3H), 2.13 (s, 3H)
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658, bis(triphenylphosphine)palladium chloride(II) (9.4 mg, 0.013 mmol), triphenylphosphine (12.6 mg, 0.48 mmol), copper(I) iodide (2.5 mg, 0.013 mmol), trimethylsilane acetylene (42 μl, 0.3 mmol), and triethylamine (1 ml) in anhydrous N,N-dimethylformamide (2 ml) was refluxed for 8 hours at 120° C. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.1 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.17 (m, 7H), 6.84 (d, 1H), 6.71 (m, 2H), 5.74 (brs, 2H), 4.27 (brs, 2H), 2.87 (s, 2H), 2.39 (s, 1H), 2.30 (s, 3H), 2.24 (s, 3H)
In accordance with the same procedures as in Step 3 of Example 642, except for using 2-(6-chloro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 7 and isopropenylmagnesium bromide, the titled compound was obtained as yellow oil. (Yield: 35%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Example 682, except for using 2-(5-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydro-isoquinoline prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 26%)
1H-NMR(400 MHz, CDCl3) δ 8.40 (brs, 1H), 7.52 (s, 1H), 7.21 (m, 4H), 6.30 (s, 1H), 4.67 (s, 2H), 3.79 (brs, 2H), 3.11 (brs, 2H), 2.52 (s, 3H)
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 and allyl bromide, the titled compound was obtained as a white solid. (Yield: 79%)
1H-NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.20 (m, 4H), 6.30 (s, 1H), 5.84 (m, 1H), 5.10 (m, 1+2H), 4.67 (brs, 2H), 4.63 (d, 1H), 3.84 (brs, 2H), 3.11 (brs, 2H), 2.51 (s, 3H)
Phosphorus oxychloride (425 μl, 4.56 mmol) was added at room temperature to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (1 g, 3.04 mmol) prepared in Step 3 in a mixture of anhydrous dichloromethane (20 ml) and N,N-dimethylformamide (353 μl, 4.56 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, and then filtered. The resulting solid washed with water and 1M sodium acetate (30 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The resulting solid washed with water and then dried to give 350 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 10.31 (s, 1H), 7.69 (s, 1H), 7.21 (m, 4H), 5.86 (m, 1H), 5.11 (m, 1+2H), 4.67 (brs, 2H), 4.61 (d, 1H), 3.85 (brs, 2H), 3.10 (brs, 2H), 2.50 (s, 3H)
Sodium borohydride (111.2 mg, 2.94 mmol) was added to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-formyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (350 mg, 0.98 mmol) prepared in Step 4 in methanol (10 ml). The reaction mixture was stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 100 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.69 (s, 1H), 7.20 (m, 4H), 5.86 (m, 1H), 5.11 (m, 1+2H), 5.02 (s, 2H), 4.66 (brs, 2H), 4.61 (d, 1H), 3.87 (brs, 2H), 3.11 (brs, 2H), 2.71 (s, 3H)
In accordance with the same procedures as in Example 731, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 5, the titled compound was obtained as a white solid. (Yield: 86%)
1H-NMR(400 MHz, CDCl3) δ 8.12 (s, 1H), 7.25 (m, 4H), 5.87 (m, 1H), 5.10 (m, 1+2H), 5.03 (s, 2H), 4.68 (brs, 2H), 4.60 (d, 1H), 3.87 (brs, 2H), 3.10 (brs, 2H), 2.59 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 6 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 64%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.25 (m, 3H), 7.02 (m, 1H), 5.85 (m, 1H), 5.21-5.00 (brs, 2H), 5.01 (brs, 2H), 4.88 (d, 2H), 4.57 (brs, 1H), 4.30-4.00 (m, 3H), 3.88 (m, 4H), 3.30 (brs, 1H), 3.15 (brs, 1H), 3.10 (brs, 2H), 2.88 (s, 3H), 2.59 (s, 3H)
The titled compounds of Examples 918 and 919 were prepared, in accordance with the same procedures as in Example 756, using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 6 of Example 917; and, 1-ethylpiperazine or 1-piperazin-1-carboxylic acid tert-butyl ester.
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.26-7.23 (m, 3H), 7.01 (m, 1H), 5.96 (m, 1H), 5.21-5.00 (brs, 2H), 5.02 (brs, 2H), 4.89 (m, 2+2H), 4.57 (brs, 1H), 4.30-3.94 (m, 3H), 3.88 (m, 4H), 3.30 (brs, 1H), 3.15 (brs, 1H), 3.11 (brs, 2H), 2.48 (s, 3H), 1.57 (t, 3H); (Yield: 54%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.23 (m, 3H), 7.02 (m, 1H), 5.77 (m, 1H), 5.20 (d, 1H), 4.99 (m, 2+2H), 4.70 (m, 1H), 4.59 (d, 1H), 4.22 (brs, 2H), 4.12 (brs, 2H), 3.96 (brs, 2H), 3.58 (brs, 2H), 3.43 (s, 2H), 3.14 (s, 2H), 2.46 (s, 3H); (Yield: 52%)
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 of Example 917 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 87%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.19 (m, 6H), 6.87 (d, 1H), 6.71 (d, 2H), 6.25 (s, 1H), 5.72 (brs, 2H), 4.30 (brs, 2H), 3.45 (brs, 2H), 2.85 (brs, 2H), 2.32 (s, 3H)
In accordance with the same procedures as in Step 4 of Example 917, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 25%)
1H-NMR(400 MHz, CDCl3) δ 9.98 (s, 1H), 7.91 (s, 1H), 7.25-7.19 (m, 6H), 6.85 (d, 1H), 6.72 (d, 2H), 5.72 (brs, 2H), 4.30 (brs, 2H), 3.45 (brs, 2H), 2.82 (brs, 2H), 2.39 (s, 3H)
In accordance with the same procedures as in Step 5 of Example 917, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-formyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2, the titled compound was obtained as a white solid. (Yield: 95%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Example 731, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 3, the titled compound was obtained as a white solid. (Yield: 85%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (m, 3H), 7.15 (m, 3H), 6.87 (d, 1H), 6.69 (m, 2H) 5.76 (brs, 2H), 5.01 (brs, 2H), 4.24 (brs, 2H), 3.49 (brs, 2H), 2.91 (brs, 2H), 2.34 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 4 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 62%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (brs, 1H), 7.20 (m, 5H), 7.10 (m, 2H), 6.56 (m, 2H), 5.71 (brs, 2H), 4.95 (brs, 2H), 4.86 (brs, 1H), 4.50-4.36 (brs, 3H), 3.82 (brs, 3H), 3.39 (brs, 2H), 2.83 (brs, 5H), 2.58 (s, 3H)
In accordance with the same procedures as in Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 4 of Example 920 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 58%)
1H-NMR(400 MHz, CDCl3) δ 7.76 (brs, 1H), 7.43 (s, 2H), 7.18 (m, 3H), 6.63 (brs, 2H), 5.80 (brs, 2H), 4.22 (brs, 2+2H), 3.65 (brs, 2H), 3.30 (brs, 3H), 3.09 (brs, 2H), 2.90 (brs, 2H), 2.83 (brs, 2H), 2.52-2.18 (brs, 5H), 2.43 (s, 3H)
In accordance with the same procedures as in Example 731, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 3 of Example 917, the titled compound was obtained as a white solid. (Yield: 87%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (m, 3H), 7.09 (m, 1H), 6.42 (s, 1H), 5.86 (m, 1H), 5.12 (brs, 2H), 5.09 (d, 1H), 4.65 (d, 1H), 4.36 (brs, 2H), 3.50 (brs, 2H), 3.0 (brs, 2H), 2.51 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.25 (m, 3H), 7.05 (m, 1H), 5.97 (brs, 1H), 5.87 (m, 1H), 5.21-5.00 (brs, 2H), 4.89 (d, 2H), 4.57 (brs, 1H), 4.30-4.01 (m, 3H), 3.91 (m, 4H), 3.35 (brs, 1H), 3.16 (brs, 1H), 3.11 (brs, 2H), 2.87 (s, 3H), 2.49 (s, 3H)
Dimethylamine (1.05 ml, 2.1 mmol), acetic acid (0.81 ml), and formaldehyde (442 μl) were added to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-methylpiperazin-1-yl)-methanone (600 mg, 1.40 mmol) prepared in Step 2 in ethanol (5 ml). The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (methanol/dichloromethane=1/10, v/v). The resulting white solid (300 mg, 0.62 mmol) was dissolved in ethanol (2 ml) and then iodomethane (77.2 μl, 1.24 mmol) was added thereto. The reaction mixture was stirred overnight at room temperature and then filtered. The resulting residue was dried to give 100 mg of the titled compound as a white solid. The product was used in the subsequent step without further purification.
Sodium cyanide (31.4 mg, 0.64 mmol) was added to a solution of [1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-5-(4-methylpiperazin-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-trimethylammonium iodide (100 mg, 0.16 mmol) prepared in Step 3 in anhydrous N,N-dimethylformamide (3 ml). The reaction mixture was stirred for 5 hours at 100° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (methanol/dichloromethane=1/10, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 16 mg of the titled compound as a white solid.
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.26-7.22 (m, 3H), 7.04 (m, 1H), 5.87-5.61 (m, 2+1H), 5.21-5.00 (brs, 2H), 4.89 (d, 2H), 4.58 (brs, 1H), 4.30-4.06 (m, 3H), 3.88 (m, 4H), 3.36 (brs, 1H), 3.16 (brs, 1H), 3.10 (brs, 2H), 2.89 (s, 3H), 2.34 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 922 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 54%) The product was used in the subsequent step without further purification.
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.25 (m, 3H), 7.07 (m, 1H), 6.01 (s, 1H), 5.75 (m, 1H), 5.20 (d, 1H), 4.97 (s, 2H), 4.70 (m, 1H), 4.62 (d, 1H), 4.27 (brs, 2H), 4.15 (brs, 2H), 3.92 (brs, 2H), 3.59 (brs, 2H), 3.42 (s, 2H), 3.15 (s, 2H), 2.49 (s, 3H)
In accordance with the same procedures as in Steps 3 and 4 of Example 922, except for using [1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(piperazin-1-yl)-methanone prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 13%)
1H-NMR(400 MHz, CDCl3) δ 7.45 (s, 1H), 7.26-7.22 (m, 3H), 7.04 (m, 1H), 5.61 (m, 1H), 5.60 (brs, 2H), 5.21-4.98 (brs, 2H), 4.75 (d, 2H), 4.54 (brs, 1+1H), 4.30-4.05 (m, 3H), 3.89 (m, 4H), 3.37 (brs, 1H), 3.14 (brs, 1H), 3.10 (brs, 2H), 2.39 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 922 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 49%)
In accordance with the same procedures as in Steps 3 and 4 of Example 922, except for using [1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-ethylpiperazin-1-yl)-methanone prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 13%)
1H-NMR(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.26-7.22 (m, 3H), 7.04 (m, 1H), 5.83 (brs, 2H), 5.61 (m, 2+1H), 5.21-5.00 (brs, 2H), 4.89-4.74 (m, 2+2H), 4.50 (brs, 1H), 4.30-4.06 (m, 3H), 3.92 (m, 4H), 3.37 (brs, 1H), 3.20 (brs, 1H), 3.10 (brs, 2H), 2.37 (s, 3H), 1.57 (t, 3H)
In accordance with the same procedures as in Example 731, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 1 of Example 920, the titled compound was obtained as a white solid. (Yield: 84%)
1H-NMR(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.25 (m, 3H), 7.11 (m, 3H), 6.87 (d, 1H), 6.71 (m, 2H), 6.32 (s, 1H), 5.75 (brs, 2H), 4.25 (brs, 2H), 3.47 (brs, 2H), 2.83 (brs, 2H), 2.29 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 57%)
1H-NMR(400 MHz, CDCl3) δ 7.57 (brs, 1H), 7.20 (m, 5H), 7.10 (m, 2H), 6.56 (m, 2H), 6.12 (brs, 1H), 5.71 (brs, 2H), 4.86 (brs, 1H), 4.50-4.36 (brs, 3H), 3.82 (brs, 3H), 3.39 (brs, 2H), 2.83 (brs, 5H), 2.51 (s, 3H)
In accordance with the same procedures as in Steps 3 and 4 of Example 922, except for using [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-methylpiperazin-1-yl)-methanone prepared in Step 2, the titled compound was obtained as a white solid. (Yield: 15%)
1H-NMR(400 MHz, CDCl3) δ 7.53 (brs, 1H), 7.20 (m, 5H), 7.10 (m, 2H), 6.56 (m, 2H), 5.71 (brs, 2H), 4.86-4.61 (brs, 2+1H), 4.50-4.36 (brs, 3H), 3.82 (brs, 3H), 3.39 (brs, 2H), 2.83 (brs, 5H), 2.46 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 925 and 1-piperazin-1-carboxylic acid tert-butyl ester, the titled compound was obtained as a white solid. (Yield: 63%)
1H-NMR(400 MHz, CDCl3) δ 7.75 (brs, 1H), 7.43 (s, 2H), 7.15 (m, 3H), 6.63 (brs, 2H), 6.01 (brs, 1H), 5.84 (brs, 2H), 4.20 (brs, 2H), 3.66 (brs, 2H), 3.28 (brs, 3H), 3.07 (brs, 2H), 2.95 (brs, 2H), 2.83 (brs, 2H), 2.52-2.18 (brs, 5H), 1.43 (s, 3H)
In accordance with the same procedures as in Steps 3 and 4 of Example 922, except for using [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(piperazin-1-yl)-methanone prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 16%)
1H-NMR(400 MHz, CDCl3) δ 7.74 (brs, 1H), 7.40 (s, 2H), 7.15 (m, 3H), 6.63 (brs, 2H), 5.81 (brs, 2H), 4.58-4.21 (brs, 2+2H), 3.65 (brs, 2H), 3.31 (brs, 3H), 3.05 (brs, 2H), 2.91 (brs, 2H), 2.81 (brs, 2H), 2.51-2.18 (brs, 3+2H), 1.43 (s, 3H)
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 925 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 63%) The product was used in the subsequent step without further purification.
In accordance with the same procedures as in Steps 3 and 4 of Example 922, except for using [1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-(4-ethylpiperazin-1-yl)-methanone prepared in Step 1, the titled compound was obtained as a white solid. (Yield: 19%)
1H-NMR(400 MHz, CDCl3) δ 7.71 (brs, 1H), 7.40 (m, 2H), 7.15 (m, 3H), 6.63 (brs, 2H), 5.81 (brs, 2H), 5.12 (d, 2H), 4.58-4.21 (brs, 2+2H), 3.65 (brs, 2H), 3.31 (brs, 3H), 3.05 (brs, 2H), 2.91-2.85 (brs, 2H), 2.79 (brs, 2H), 2.50 (s, 3H), 1.54 (t, 3H)
1-1. Preparation of Gastric Proton Pump Vesicles
The hog fundic regions containing parietal and peptic cells were scraped with slide-glass. The collected cells were suspended in 10 ml of 0.25M sucrose buffer and homogenized using a tight-fitting Teflon-glass homogenizer. The homogenate was centrifuged for 35 min at 8,000 rpm and the pellet was discarded. The supernatant was further centrifuged for 75 min at 25,000 rpm. The resulting pellets were re-suspended in the sucrose buffer (10 ml), and then the suspension was laid onto discontinuous density gradients consisting of 0.25M sucrose buffer and isolation medium containing 9% Ficoll (w/w). After being centrifuged for 3 hours and 15 minutes at 100,000×g, the matertal at the interface of sucrose buffer and Ficoll solution was collected and then centrifuged for 40 minutes at 100,000×g. The resulting pellets were re-suspended in 1 ml of 5 mM Hepes/Tris buffer (pH 6.1). This matertal was lyophilized and stored at −70° C. and used as an enzyme source of the in vitro enzyme reaction assay of proton pump.
1-2. Measurement of Inhibitory Effects on Proton Pump (H+/K+-ATPase) Activity
The inhibitory effects of the compounds of the present invention against proton pump activity were evaluated in 96-well plate. In this assay, the K+ specific H+/K+-ATPase activity was calculated based on the difference between the activity of H+/K+-ATPase activity with K+ and without K+ ion. In 96-well plate, 1% dimethylsulfoxide (DMSO) in buffer was added to negative and positive control groups and the diluted compounds of the present invention in buffer were added to test group. All assays were performed in 100 μl reaction volume at room temperature, and the hog gastric vesicle was kept in ice before use. At the beginning of the reaction, 10 μl of reaction buffer containing 1% DMSO was added to the negative and positive control groups and to each concentration of compounds in the test group. Then lyophilized vesicle in 5 mM Pipes/Tris buffer (pH 6.1) was pre-incubated in the presence of various concentrations of test compounds. After 5 minutes incubation, negative and positive buffers were respectively added to the previous reaction mixture. As the substrate, ATP was added to the reaction buffer, and incubated for 30 minutes at 37° C. Enzymatic activity was stopped by the addition of calorimetric reagent (2× malachite green, 1× ammonium molybdate, 1× polyvinyl alcohol, 2× H2O) and the amount of mono phosphate (Pi) in the reaction was measured at 620 nm using the micro plate reader (Genios Pro, TECAN). The difference between the Pi production with K+ and without K+ is taken as K+ stimulated H+/K+-ATPase activity. The IC50s of test compounds were calculated from each % inhibition value of compounds using the method of Litchfield-Wilcoxon (J. Pharmacol. Exp. Ther. (1949) 96, 99). The results are shown in Table 1.
As shown in Table 1, the compounds of the present invention have excellent inhibitory effects on gastric H+/K+-ATPase.
Inhibitory effects of the compounds of the present invention on basal gastric acid secretion were performed according to Shay's rat model (Shay, H., et al., 1945, gastroenterology, 5, 43-61). Male Sprague Dawley (SD) rats (200±10 g body weight) were divided into 3 groups (n=5) and fasted for 24 hours with free access to water. Control group was orally administered with 0.5% methylcellulose alone and the other groups were orally administered with test compounds suspended in 0.5% methylcellulose solution at doses of 1, 3 and 10 mg/kg/5 ml one hour before pylorus ligation.
Under ether anesthesia, the abdomens of the rats were incised and then the pylorus was ligated. 5 hours after ligation, the animals were sacrificed, and the gastric contents were collected. The collected contents were centrifuged at 1,000×g for 10 minutes to obtain the gastric juice. Total acid output was measured by 0.01N NaOH volume (ueq/ml) for automatic titration of the gastric juice to pH 7.0 and the ED50s of test compounds were calculated using the Litchfield-Wilcoxon method. % inhibitory activity was calculated from the following equation and the results are shown in Table 2.
% inhibitory activity of test compound=(total acid output of control group−total acid output of the group treated with test compounds)/total acid output of control group×100
As shown in Table 2, the compounds of the present invention have potent inhibition activities against basal gastric acid secretion in pylorus-ligated rats.
3-1. Preparation of Gastric Vesicles
Gastric vesicles were prepared from hog fundic mucosa using the method of Saccomani et al. (Saccomani G, Stewart H B, Shqw D, Lewin M and Sachs G, Charactertzation of gastric mucosal membranes. IX. Fraction and purification of K-ATPase-containing vesicles by zonal centrifugation and free-flow electrophoresis techinque. Biochem. Biophy. Acta. (BBA)-Biomembranes 465, 311-330, 1977). This matertal was lyophilized and stored at −70° C. The protein content of gastric vesicles was determined by the Bradford method using bovine serum albumin as a standard (Bradford M M, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 72, 248-254, 1976).
3-2. Determination of Reversible Inhibition of Hog Gastric H+/K+-ATPase
Activity of H+/K+-ATPase in hog microsome (lyophilized vesicle) was measured by the inorganic phosphate released from ATP using an one-step calorimetric detection method at the concentration at which the test compounds have 50% inhibition of the proton pump (Chan K M, Delfert D, and Junger K D, A direct calorimetric assay for Ca2+-stimulated ATPase activity. Anal Biochem, 157, 375-380, 1986). The mode of action of test compounds on H+/K+-ATPase was investigated according to the Washout method (Beil W, Staar U, and Sewing K F, Substituted thieno[3,4-d]imidazoles, a novel group of H+/K+-ATPase inhibitors. Differentiation of their inhibition charactertstics from those of omeprazole. Eur. J. Pharmacol., 187, 455-67, 1990).
Lyophilized vesicle in the solution of 5 mM Pipes/Tris buffer was pre-incubated in the presence of the test compound (the compound of Example 480) at the concentration at which it has 50% inhibition of the proton pump. The previous reaction buffer was added with 2 mM MgCl2, 50 mM KCl, 5 uM Valinomycin, and 0.5 mM ATP and then incubated for 30 minutes at 37° C. The H+/K+-ATPase activity was measured using the calorimetric detection method and then the test sample was centrifuged at 100,000×g for 1 hr. The vesicles are present in the form of pellets in the test sample. The supernatant thereof was replaced with the same buffer not having the test compound. The test sample was pre-incubated for 5 minutes at room temperature and then incubated further for 30 minutes at 37° C. The H+/K+-ATPase activity was also measured using the colorimetric detection method. The H+/K+-ATPase activity before washout and after washout in the test sample was analyzed, in comparison with those in the non-treated group.
As a result, the compound of Example 480 inhibited H+/K+-ATPase activity by 50% before washout and did not inhibit H+/K+-ATPase activity after washout; the gastric H+/K+-ATPase activity by the compound of Example 480 was completely recovered to non-treated group level after washout. These results confirm that the compounds of formula (I) exhibited reversible inhibition of the gastric H+/K+-ATPase.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2004-0070533 | Sep 2004 | KR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/KR2005/002927 | 9/3/2005 | WO | 00 | 2/27/2007 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2006/025716 | 3/9/2006 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20070219230 A1 | Sep 2007 | US |
