HK1105978B

HK1105978B - Pyrrolo[3,2-c]pyridine derivatives and processes for the preparation thereof

Info

Publication number: HK1105978B
Application number: HK07114271.4A
Authority: HK
Inventors: 金在圭; 安秉乐; 李赫雨; 尹锡湲; 尹永爱; 崔铉浩; 姜熙日
Original assignee: 株式会社柳韩洋行
Priority date: 2004-09-03
Filing date: 2005-09-03
Publication date: 2010-04-30

Abstract

The publication number of the designated patent applied for is CN101010322A.

Description

Pyrrolo [3, 2-C ] pyridine derivatives and process for their preparation

Technical Field

The present invention relates to a novel pyrrolo [3, 2-c ] pyridine derivative or a pharmaceutically acceptable salt thereof having an excellent inhibitory activity against gastric acid secretion, a process for the preparation thereof and a pharmaceutical composition containing the same.

Background

Peptic ulcer disease occurs when the offensive factor involved in gastric acid secretion is strong or the defensive factor of gastric mucosa is weak. Various drugs such as antacids, anticholinergics, H2-receptor antagonists and proton pump inhibitors have been used for the treatment of peptic ulcer diseases. The advent of omeprazole, a proton pump inhibitor, has renewed research activity in this field.

However, it has been pointed out that the proton pump inhibition of omeprazole is irreversible and thus leads to a long-term inhibition of gastric acid secretion, which can produce side effects. Therefore, various attempts are being made to develop reversible proton pump inhibitors. For example, imidazopyridine derivatives as reversible proton pump inhibitors are disclosed in WO 98/37,080(AstraZeneca AB), WO00/17,200(Byk Gulden Lomberg Chem.), and U.S. Pat. No.4,450,164(Schering Corporation). Furthermore, European patent No.775,120(Yuhan Corp.) discloses pyrimidine derivatives.

Disclosure of Invention

Technical problem

The present invention provides a novel pyrrolo [3, 2-c ] pyridine derivative or a pharmaceutically acceptable salt thereof having an excellent proton pump inhibiting effect and having the ability to achieve a reversible proton pump inhibiting effect.

Technical scheme

According to one aspect of the present invention, there is provided a pyrrolo [3, 2-c ] pyridine derivative or a pharmaceutically acceptable salt thereof.

Further, according to another aspect of the present invention, there is provided a method for preparing a pyrrolo [3, 2-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 a pyrrolo [3, 2-c ] pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

Detailed Description

According to one aspect of the present invention, there is provided a compound of general formula (I):

wherein:

R₁is hydrogen; optionally with one or more substituents selected from C₁-C₅Alkoxy radical, C₃-C₇Cycloalkyl, 1, 3-dioxolanyl, cyano, naphthyl, C₂-C₅Alkenyloxy and 2, 3-dihydrobenzo [1, 4]]Straight-chain or branched C substituted by substituents of dioxinyl₁-C₆An alkyl group; c₂-C₆An alkenyl group; c₂-C₆An alkynyl group; or optionally with one or more substituents selected from halogen, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, cyano, C₁-C₃Alkoxycarbonyl and trifluoro-C₁-C₃A benzyl group substituted with a substituent of an alkyl group,

R₂is straight or branched C₁-C₆An alkyl group, a carboxyl group,

R₃is hydrogen; straight or branched chain C optionally substituted with hydroxy or cyano₁-C₆Alkyl, and

R₄is optionally halogen or C₁-C₅Alkyl mono-or polysubstituted 1, 2, 3, 4-tetrahydroisoquinolinyl; optionally with halogen or C₁-C₅Alkyl mono-or polysubstituted benzyloxy; or benzylamino optionally substituted with halogen.

Among the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts, those are preferred in which:

R₁is hydrogen; straight or branched C₁-C₆An alkyl group; with one or more groups selected from methoxy, cyclopropyl, cyclobutyl, 1, 3-dioxolanyl, cyano, naphthyl, C₂-C₅Alkenyloxy and 2, 3-dihydrobenzo [1, 4]]Substituent-substituted C of dioxin radical₁-C₃An alkyl group; c₂-C₆An alkenyl group; c₂-C₆An alkynyl group; or benzyl optionally substituted with one or more substituents selected from the group consisting of halogen, methyl, methoxy, cyano, methoxycarbonyl and trifluoromethyl,

R₂is a methyl group, and the compound is,

R₃is hydrogen; a methyl group; a hydroxymethyl group; cyanomethyl, and

R₄is 1, 2, 3, 4-Tetrahydroisoquinolinyl; 1-methyl-6-fluoro-1, 2, 3, 4-tetrahydroisoquinolinyl; benzyloxy optionally mono-or polysubstituted with halogen or methyl; or benzylamino optionally substituted with one or more halogens.

More preferred compounds of formula (I) or pharmaceutically acceptable salts thereof according to the invention are:

7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -2, 3-dimethyl-1- (prop-2-ynyl) -1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-ethyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-cyclopropylmethyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-allyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (3-fluorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -1- (3-methoxybenzyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -2, 3-dimethyl-1- (4-methylbenzyl) -1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (4-fluorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -2, 3-dimethyl-1- (4-trifluoromethylbenzyl) -1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -1-isobutyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-benzyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (2, 5-dimethylbenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (2-chlorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (2-fluorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -2, 3-dimethyl-1-propyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzyloxy) -1- (2-methoxyethyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-benzyl-7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (2, 4-dichlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7-benzyloxy-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (2-methylbenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7- (4-fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-benzyl-7- (4-fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

7-benzylamino-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

2- [1- (4-fluorobenzyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl ] -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

1- (4-methoxycarbonylbenzyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

2- [1- (2, 3-dihydrobenzo [1, 4] dioxin-6-ylmethyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl ] -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

1- (2-methoxyethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (2-naphthylmethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (2-vinyloxyethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1- (1, 3-dioxolan-2-ylmethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-isobutyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

1-cyclobutylmethyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

2- (2, 3-dimethyl-1-propyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

2- (1-cyclopropylmethyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

2- (1-ethyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

3- [7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 3-dimethylpyrrolo [3, 2-c ] pyridin-1-ylmethyl ] benzonitrile hydrochloride;

[7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 3-dimethylpyrrolo [3, 2-c ] pyridin-1-yl ] -acetonitrile hydrochloride;

1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -3-hydroxymethyl-2-methyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride;

2- (1-benzyl-2-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride;

1-benzyl-7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2-methyl-1H-pyrrolo [3, 2-c ] pyridine-3-carbonitrile hydrochloride.

Among them, particularly preferred compounds of the general formula (I) or pharmaceutically acceptable salts thereof are:

3- [7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 3-dimethylpyrrolo [3, 2-c ] pyridin-1-ylmethyl ] -benzonitrile hydrochloride;

the compounds of the present invention may be in the form of pharmaceutically acceptable non-toxic salts. The non-toxic salts may include conventional acid addition salts used in the field of antiulcer drugs, for example salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid and organic acids 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. These acid addition salts may be prepared according to any conventional method.

Included within the scope of the present invention is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to scheme 1 below:

scheme 1.

Wherein R is₁、R₂、R₃And R₄As defined above, X is halogen.

In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by a method comprising the following processes: reacting a compound of formula (II) with R₄-H to give a compound of the general formula (III), reacting a compound of the general formula (III) with a compound of the general formula (IV) to give a compound of the general formula (Ia), and reacting a compound of the general formula (Ia) with R₁-X to give the compound of formula (I).

In the course of scheme I, the compounds of general formulae (II) and (IV) are commercially available. A compound of the formula (II) with R₄The reaction of-H can be carried out in the presence of a base, such as sodium hydride, tert-butanolPotassium, sodium carbonate, or potassium hydroxide. Further, the reaction may be carried out in an organic solvent such as anhydrous tetrahydrofuran and N, N-dimethylformamide at room temperature or under heating such as at a temperature of 40 ℃ to 140 ℃.

The cyclization reaction of the compound of formula (III) with the compound of formula (IV) can be carried out in an organic solvent such as anhydrous tetrahydrofuran. The reaction may be carried out at-78 ℃ to-20 ℃ or at room temperature.

A compound of the formula (Ia) with R₁-X to give the compound of formula (I). A compound of the formula (Ia) with R₁The reaction of-X can be carried out in the presence of a base, such as sodium hydride or potassium tert-butoxide. Furthermore, the reaction can be carried out in an organic solvent such as tetrahydrofuran or N, N-dimethylformamide at room temperature or at a temperature of 40 ℃ to 100 ℃. In order to increase the reaction rate and/or reaction yield, a catalytic amount of 18-crown-6 may be used.

According to another aspect of the present invention, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof may be prepared according to scheme 2 below:

scheme 2.

Wherein R is₁、R₂And R₄As defined above.

In particular, the compound of formula (Ic) or a pharmaceutically acceptable salt thereof may be prepared by a process comprising: the compound of formula (Ib) is hydrolysed in the presence of cerium (IV) ammonium nitrate and acetic acid.

According to another aspect of the present invention, the compound of formula (Ie) or a pharmaceutically acceptable salt thereof may be prepared by a method comprising the following process: mannich reaction of the compound of formula (Id) was carried out followed by reaction of the resulting product with sodium or potassium cyanide to give the compound of formula (Ie) as shown in scheme 3:

scheme 3.

Wherein R is₁、R₂And R₄As defined above.

The present invention further includes within its scope pharmaceutical compositions comprising a therapeutically effective amount of a compound of any of the general formulae (I) or a pharmaceutically acceptable salt thereof as described above and a pharmaceutically acceptable carrier. The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in the prevention and treatment of gastrointestinal inflammation and gastric acid related diseases such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and zollinger ellison syndrome in mammals including humans. In addition, the compounds of the present invention or their salts may be used for the treatment of other gastrointestinal disorders requiring antisecretory action of the stomach, such as in gastrinoma patients and patients with acute upper gastrointestinal bleeding. The compounds of the invention or their salts can also be used in patients in intensive care, as well as before and after surgery to prevent acid inhalation and stress ulcers.

The compositions 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. Sweetening agents and/or flavouring agents may be added if desired.

The compositions of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Thus, the compositions of the present invention may be formulated in a wide variety of forms such as tablets, capsules, aqueous solutions or suspensions. For oral tablets, carriers such as lactose, corn starch, and lubricants such as magnesium stearate are typically added. For capsules for oral use, lactose and/or dried corn starch may be used as diluents. When an oral aqueous suspension is desired, 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, sterile solutions of the active ingredient are generally prepared and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled so that the formulation is isotonic. The compositions of the invention may be in the form of an aqueous solution, e.g., saline, containing a pharmaceutically acceptable carrier, at a pH level of 7.4. The solution may be introduced into the patient's intramuscular blood flow by a topical bolus.

An effective dose of the compounds of the invention administered to a subject patient is from about 0.1mg/kg to about 500mg/kg per day. Of course, the dosage may be varied according to the age, weight, susceptibility or symptoms of the patient.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

Preparation 1.3- (4-Fluorobenzyloxy) -4-nitropyridine

Step 1: 3-bromopyridine-N-oxides

30% hydrogen peroxide (41ml) was added to a solution of 3-bromopyridine (32g, 0.202mol) in acetic acid (120 ml). The reaction mixture was stirred at 70-80 ℃ for 9 h, concentrated under reduced pressure, basified with excess sodium carbonate and then diluted with dichloromethane (100 ml). The reaction mixture was filtered to remove insoluble inorganic substances. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was used in the next reaction without further purification.

Step 2: 3-bromo-4-nitropyridine-N-oxide

Concentrated nitric acid (128ml) and concentrated sulfuric acid (77ml) were slowly added to a solution of 3-bromopyridine-N-oxide (31.9g, 181.0mmol) prepared in step 1 in concentrated sulfuric acid (77ml) while maintaining the temperature at 0 ℃ to 5 ℃. The reaction mixture was stirred at 90 ℃ for 2 hours and then cooled to room temperature. The reaction mixture was added to 1000ml of ice water and then adjusted to pH8 with 50% sodium hydroxide solution. The resulting precipitate was filtered and dried to give the title compound as a yellow solid (29.3g, 72.0%).

TLC; n-hexane/ethyl acetate 1/1 (v/v); rf is 0.3

¹H-NMR(CDCl₃)δ8.6(s，1H)8.4-7.9(m，2H)

And step 3: 3- (4-Fluorobenzyloxy) -4-nitropyridine-N-oxide

3-bromo-4-nitropyridine-N-oxide obtained in step 2 (2.0g, 9.05mmol), 4-fluorobenzyl alcohol (1.48ml, 13.57mmol), potassium carbonate (1.25g, 9.05mmol) and potassium hydroxide (2.03g, 36.2mmol) were added to 500ml of anhydrous toluene. Tris [2- (2-methoxyethoxy) ethyl ] amine (0.29ml, 0.90mmol) was added to the reaction mixture, which was then stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 1/1(v/v)) to give the title compound as a white solid (500mg, 14.6%).

TLC; n-hexane/ethyl acetate 1/1 (v/v); rf is 0.2

¹H-NMR(CDCl₃)δ8.5(s，1H)，8.33(d，1H)，8.20(m，2H)，8.17(d，1H)，8.15(m，2H)，5.21(s，2H)

And 4, step 4: 3- (4-Fluorobenzyloxy) -4-nitropyridine

Phosphorus trichloride (3.65ml, 41.80mmol) was slowly added to a solution of 3- (4-fluorobenzyloxy) -4-nitropyridine-N-oxide (7.72g, 27.87mmol) prepared in step 3 in 500ml of ethyl acetate at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour and then basified with 2N sodium hydroxide solution. The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was used in the next reaction without further purification.

Preparation 2.2- (4-Nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline

Step 1: 2- (4-nitro-1-oxopyridyl-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline

3-bromo-4-nitropyridine-N-oxide (1.0g, 4.53mmol), prepared in step 2 of preparation 1, was added to a mixture of t-butanol (30ml), potassium t-butoxide (507mg, 4.53mmol) and 1, 2, 3, 4-tetrahydroisoquinoline (0.79ml, 6.34 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (10ml) was added to the reaction mixture, which was then extracted with ethyl acetate (100 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 1/1(v/v)) to give the title compound as a yellow solid (600 mg).

TLC; n-hexane/ethyl acetate 1/1 (v/v); rf is 0.2

¹H-NMR(CDCl₃)δ8.13(s，1H)，7.83(d，1H)，7.71(d，1H)，7.24(m，3H)，7.09(m，1H)，4.32(s，2H)，3.46(t，2H)，3.06(t，2H)

Step 2: 2- (4-Nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline

Phosphorus trichloride (3.81ml, 28.9mmol) was slowly added to a solution of 2- (4-nitro-1-oxopyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline (8.5g, 25.3mmol) prepared in step 1 in 100ml of ethyl acetate at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour and then basified with 2N sodium hydroxide solution. The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound as a yellow solid (5.26g, 65.3%). The product was used in the next reaction without further purification.

Example 1.7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

3- (4-Fluorobenzyloxy) -4-nitropyridine (6.6g, 26.59mmol) prepared in preparation 1 was dissolved in anhydrous tetrahydrofuran (300ml) under a nitrogen atmosphere. 1-methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80ml) was added to the solution at-78 ℃ and then stirred at-20 ℃ for 5 hours. 20ml of a 20% ammonium chloride solution was added to the reaction mixture, which was then extracted 2 times with ethyl acetate (200 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol-10/1 (v/v)), and then concentrated to remove the solvent. The residue obtained is dissolved in 10ml of ethyl acetate and saturated with hydrogen chloride gas. The resulting precipitate was filtered to give the title compound as a white solid (910mg, 13.5%).

TLC; ethyl acetate/methanol 10/1 (v/v); rf is 0.2

¹H-NMR(CDCl₃)δ8.46(s，1H)，8.20(s，1H)，7.94(s，1H)，7.43(m，2H)，7.09(m，2H)，5.18(s，2H)，2.36(s，3H)，2.25(s，3H)

Example 2.7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1- (prop-2-ynyl) -1H-pyrrolo [3, 2-c]Pyridine hydrochloride

The compound prepared in example 1 (25.0mg, 0.072mmol) was treated with saturated sodium bicarbonate solution to give 7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine (20.0mg, 0.073 mmol). 7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine (20.0mg, 0.073mmol), potassium tert-butoxide (11.0mg, 0.109mmol) and a catalytic amount of 18-crown-6 were dissolved in anhydrous tetrahydrofuran (2 ml). Propargyl bromide (0.08ml, 0.109mmol) was added to the solution. The reaction mixture was stirred at room temperature for 12 hours, then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol-10/1 (v/v)), and then concentrated to remove the solvent. The residue obtained is dissolved in 1ml of ethyl acetate and saturated with hydrogen chloride gas. The resulting precipitate was filtered to give the title compound as a white solid (8.5mg, 40.1%).

TLC; ethyl acetate/dichloromethane/methanol 10/1/1 (v/v); rf is 0.4

¹H-NMR(CDCl₃)δ8.55(s，1H)，7.94(s，1H)，7.49(d，2H)，7.14(d，2H)，5.30(s，2H)，5.21(s，2H)，2.50(s，3H)，2.42(s，1H)，2.32(s，3H)

Examples 3 to 17

The title compounds of examples 3 to 17 were prepared according to the same method as in example 2, using 7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine obtained by treating the compound of example 1 with a saturated sodium bicarbonate solution, and iodoethane, (bromomethyl) cyclopropane, allyl bromide, 3-fluorobenzyl chloride, 3-methoxybenzyl chloride, 4-methylbenzyl chloride, 4-fluorobenzyl bromide, 4- (trifluoromethyl) benzyl bromide, 1-iodo-2-methylpropane, benzyl bromide, 2, 5-dimethylbenzyl chloride, 2-chlorobenzyl chloride, 2-fluorobenzyl chloride, 1-iodopropane or 2-bromoethyl methyl ether.

Example 3.1-Ethyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.55(d, 1H), 7.90(d, 1H), 7.44(t, 2H), 7.14(t, 2H), 5.21(s, 2H), 4.40(m, 2H), 2.41(s, 3H), 2.30(s, 3H), 1.32(t, 3H); (yield: 56.5%)

Example 4.1-cyclopropylmethyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.55(s, 1H), 7.95(s, 1H), 7.46(d, 2H), 7.17(d, 2H), 5.28(s, 2H), 4.29(d, 2H), 2.44(s, 3H), 2.32(s, 3H), 1.21(m, 1H), 0.48(d, 2H), 0.22(d, 2H); (yield: 58.4%)

Example 5.1-allyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.89(s, 1H), 8.51(s, 1H), 7.55(m, 2H), 7.08(m, 2H), 5.89(m, 1H), 5.60(s, 2H), 5.56(s, 2H), 5.49(d, 1H), 5.18(d, 1H), 2.37(s, 3H), 2.35(s, 3H); (yield: 69.7%)

Example 6.1- (3-fluorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.62(s, 1H), 8.01(m, 2H), 7.61(m, 2H), 6.79(m, 4H), 6.49(m, 1H), 5.62(s, 2H), 5.01(s, 2H), 2.25(s, 6H); (yield: 85.4%)

Example 7.7- (4-Fluorobenzyloxy) -1- (3-methoxybenzyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.60(s, 1H), 7.89(m, 1H), 7.48(m, 1H), 6.96(m, 5H), 6.27(s, 2H), 5.62(s, 2H), 5.11(s, 2H), 3.73(s, 3H), 2.34(s, 6H); (yield: 45.8%)

Example 8.7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1- (4-methylbenzyl) -1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.61(s, 1H), 7.51(s, 1H), 7.10(s, 4H), 6.98(s, 2H), 6.65(s, 2H), 5.62(s, 2H), 5.30(s, 2H), 2.34(s, 6H); (yield: 35.7%)

Example 9.1- (4-Fluorobenzyl) -7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.60(d, 1H), 7.91(s, 1H), 7.10(m, 2H), 7.00(m, 4H), 6.71(m, 2H), 5.60(s, 2H), 5.09(s, 2H), 2.34(s, 3H), 2.33(s, 3H); (yield: 66.2%)

Example 10.7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1- (4-trifluoromethylbenzyl) -1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃)δ8.63(d，1H)，7.92(d，1H)，7.55(d，2H)，7.02(m，4H)，6.82(d，2H)，5.67(s，2H)，5.06(s, 2H), 2.36(s, 3H), 2.33(s, 3H); (yield: 33.2%)

Example 11.7- (4-Fluorobenzyloxy) -1-isobutyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.53(d, 1H), 7.91(d, 1H), 7.44(t, 2H), 7.15(t, 2H), 5.16(s, 2H), 4.11(d, 2H), 2.38(s, 3H), 2.30(s, 3H), 2.04(m, 1H), 0.72(s, 3H), 0.70(s, 3H); (yield: 34.1%)

Example 12.1-benzyl-7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.34(s, 1H), 7.52(s, 1H), 7.37(m, 2H), 7.09(m, 2H), 7.04(m, 3H), 6.97(m, 2H), 5.66(s, 2H), 5.26(s, 2H), 2.36(s, 3H), 2.34(s, 3H); (yield: 45.8%)

Example 13.1- (2, 5-dimethylbenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.62(d, 1H), 7.85(d, 1H), 7.45(m, 1H), 7.07(m, 2H), 6.92(m, 4H), 5.46(s, 2H), 4.98(s, 2H), 2.48(s, 3H), 2.31(s, 3H), 2.12(s, 3H), 2.02(s, 3H); (yield: 49.8%)

Example 14.1- (2-chlorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.62(s, 1H), 7.89(s, 1H), 7.41(d, 2H), 7.14(t, 2H), 6.95(d, 4H), 6.07(s, 1H), 5.66(s, 2H), 5.03(s, 2H), 2.37(s, 3H), 2.31(s, 3H); (yield: 58.9%)

Example 15.1- (2-fluorobenzyl) -7- (4-fluorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.62(s, 1H), 7.92(s, 1H), 7.31(m, 1H), 7.05(m, 6H), 6.31(s, 1H), 5.69(s, 2H), 5.10(s, 2H), 2.36(s, 3H), 2.34(s, 3H); (yield: 49.8%)

Example 16.7- (4-Fluorobenzyloxy) -2, 3-dimethyl-1-propyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.34(s, 1H), 8.11(s, 1H), 7.61(m, 2H), 7.17(m, 2H), 5.32(s, 2H), 4.39(s, 2H), 2.53(s, 3H), 2.33(s, 3H), 1.81(m, 2H), 0.79(d, 3H); (yield: 61.1%)

Example 17.7- (4-Fluorobenzyloxy) -1- (2-methoxyethyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.54(s, 1H), 7.91(s, 1H), 7.44(d, 2H), 7.15(d, 2H), 5.30(s, 2H), 5.21(t, 2H), 3.57(d, 2H), 3.21(s, 3H), 2.46(s, 3H), 2.05(s, 3H); (yield: 54.3%)

Example 18.7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

Step 1: 3- (4-chlorobenzyloxy) -4-nitropyridine

Following the same procedure as steps 3 and 4 of preparation 1, except using 3-bromo-4-nitropyridine-N-oxide prepared in step 2 of preparation 1 and 4-chlorobenzyl alcohol, the title compound was obtained as a white solid. (yield: 25.3%)

¹H-NMR(CDCl₃)δ8.40(s，1H)，8.31(d，1H)，8.25(m，2H)，8.19(d，1H)，8.13(m，2H)，5.20(s，2H)

Step 2: 7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride

The title compound was obtained as a white solid by following the same procedure as in example 1, except for using 3- (4-chlorobenzyloxy) -4-nitropyridine obtained in step 1. (yield: 13.4%)

¹H-NMR(CDCl₃)δ8.43(s，1H)，8.19(s，1H)，7.93(s，1H)，7.44(m，2H)，7.10(m，2H)，5.15(s，2H)，2.37(s，3H)，2.24(s，3H)

Example 19.1-benzyl-7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

The title compound was obtained as a white solid by following the same procedure as in example 2, except for using 7- (4-chlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine and benzyl bromide obtained by treating the compound of example 18 with a saturated sodium bicarbonate solution. (yield: 38.8%)

¹H-NMR(CDCl₃)δ8.33(s，1H)，7.50(s，1H)，7.35(m，2H)，7.08(m，2H)，7.01(m，3H)，6.89(m，2H)，5.63(s，2H)，5.21(s，2H)，2.34(s，3H)，2.32(s，3H)

Example 20.7- (2, 4-Dichlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

Step 1: 3- (2, 4-dichlorobenzyloxy) -4-nitropyridine

The title compound was obtained following the same procedure as in steps 3 and 4 of preparation 1, except that 3-bromo-4-nitropyridine-N-oxide prepared in step 2 of preparation 1 and 2, 4-dichlorobenzyl alcohol were used. (yield: 68.2%)

¹H-NMR(CDCl₃)δ8.40(s，1H)，8.38(s，1H)，8.31(d，1H)，8.25(m，1H)，8.22(m，1H)，8.19(d，1H)，5.20(s，2H)

Step 2: 7- (2, 4-Dichlorobenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride

The title compound was obtained as a white solid by following the same procedure as in example 1, except for using 3- (2, 4-dichlorobenzyloxy) -4-nitropyridine prepared in step 1. (yield: 11.3%)

¹H-NMR(CDCl₃)δ8.43(s，1H)，8.32(s，1H)，8.19(s，1H)，7.93(s，1H)，7.10(m，2H)，5.15(s，2H)，2.37(s，3H)，2.24(s，3H)

Examples 21 and 22

The title compounds of examples 21 and 22 were prepared according to the same procedures as in example 20 using 3-bromo-4-nitropyridine-N-oxide prepared in step 2 of preparation 1, and benzyl alcohol or 2-methylbenzyl alcohol.

Example 21.7-benzyloxy-2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.42(s, 1H), 8.15(s, 1H), 8.00(s, 1H), 7.44(m, 3H), 7.10(m, 2H), 5.13(s, 2H), 2.35(s, 3H), 2.25(s, 3H); (yield: 15.3%)

Example 22.7- (2-Methylbenzyloxy) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.45(s, 1H), 8.13(s, 1H), 7.98(s, 1H), 7.44(m, 4H), 5.13(s, 2H), 2.35(s, 3H), 2.25(s, 3H), 1.58(s, 3H); (yield: 14.7%)

Example 23.7- (4-Fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

Step 1: 3- (4-Fluorobenzylamino) -4-nitropyridine

Following the same procedure as in preparation 2, except using 3-bromo-4-nitropyridine-N-oxide obtained in step 2 of preparation 1 and 4-fluorobenzylamine, the title compound was obtained as a yellow solid. (yield: 35.8%)

¹H-NMR(CDCl₃)δ8.43(s，1H)，8.29(d，1H)，8.21(m，2H)，8.11(d，1H)，8.19(m，2H)，5.84(d，2H)

Step 2: (4-Fluorobenzyl) - (4-Nitropyridin-3-yl) -carbamic acid tert-butyl ester

Di-tert-butylbicarbonate (4.06g, 18.62mmol) and N, N-dimethylaminopyridine (1.14g, 9.31mmol) were added to a solution of 3- (4-fluorobenzylamino) -4-nitropyridine (1.53g, 6.21mmol) obtained in step 1 in 60ml of tetrahydrofuran. The reaction mixture was stirred for 24 hours and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane: 1/1(v/v)) to give the title compound as a yellow oil (1.5g, 75.8%).

¹H-NMR(CDCl₃)δ8.61(s，1H)，7.31(m，3H)，7.17(m，2H)，6.72(d，1H)，5.11(s，2H)，1.2(s，9H)

And step 3: 7- (4-Fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride

(4-Fluorobenzyl) - (4-Nitropyridin-3-yl) -carbamic acid tert-butyl ester (5.1g) prepared in step 2 was dissolved in anhydrous tetrahydrofuran (100ml) under a nitrogen atmosphere. 1-methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 55.0ml, 65.2mmol) was added to the solution at-78 ℃ and then stirred at-20 ℃ for 5 hours. 20ml of a 20% ammonium chloride solution was added to the reaction mixture, which was then extracted 2 times with ethyl acetate (200 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol 10/1(v/v)), dissolved in 1ml of ethyl acetate and saturated with hydrogen chloride gas. The resulting precipitate was filtered to give the title compound as a pale yellow solid (2.1g, 35.0%).

¹H-NMR(CDCl₃)δ8.41(brs，1H)，8.13(s，1H)，7.48(s，1H)，7.15(d，2H)，7.01(d，2H)，5.14(s，2H)，2.51(s，3H)，2.48(s，3H)

Example 24.1-benzyl-7- (4-fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3 ]，2-c]Pyridine hydrochloride

The title compound was obtained as a white solid by following the same procedure as in example 2, except for using 7- (4-fluorobenzylamino) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine and benzyl bromide obtained by treating the compound of example 23 with a saturated sodium bicarbonate solution. (yield: 15.8%)

¹H-NMR(CDCl₃)δ8.31(s，1H)，7.52(s，1H)，7.28(m，2H)，7.07(m，2H)，7.00(m，3H)，6.87(m，2H)，5.60(s，2H)，5.20(s，2H)，2.33(s，3H)，2.30(s，3H)

Example 25.7-benzylamino-2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

The title compound was obtained as a white solid by following the same procedures as in example 23, except for using 3-bromo-4-nitropyridine-N-oxide obtained in step 2 of preparation 1 and benzylamine. (yield: 11.3%)

¹H-NMR(CDCl₃)δ8.43(brs，1H)，8.12(s，1H)，7.85(s，1H)，7.13(m，3H)，7.02(m，2H)，5.56(s，2H)，2.53(s，3H)，2.47(s，3H)

Example 26.2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

Step 1: 6-fluoro-1-methyl-2- (4-nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline

Following the same procedure as in preparation 2, except for using 6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline prepared according to the method disclosed in WO 94/14,795, the title compound was obtained as a pale yellow solid. (yield: 59.8%) the product was used in the next reaction without further purification.

Step 2: 2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -6-fluoro-1-methyl-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

The title compound was obtained as a white solid according to the same procedure as in example 1, except for using 6-fluoro-1-methyl-2- (4-nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline prepared in the step 1. (yield: 14.8%)

¹H-NMR(CDCl₃)δ10.21(s，1H)，8.50(s，1H)，7.88(s，1H)，7.21(m，2H)，7.07(s，1H)，4.35(s，2H)，3.49(t，1H)，3.15(t，2H)，2.38(d，3H)，2.54(s，3H)，2.27(s，3H)

Example 27.2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

2- (4-Nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline (2.0g, 7.835mmol) obtained in preparation 2 was dissolved in anhydrous tetrahydrofuran (100ml) under a nitrogen atmosphere. 1-methyl-1-propenyl magnesium bromide (0.5M solution in tetrahydrofuran, 9.4ml) was added to the solution at-78 ℃ and then stirred at the same temperature for 20 minutes. 10ml of a 20% ammonium chloride solution was added to the reaction mixture, which was then extracted 2 times with ethyl acetate (100 ml). The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol-10/1 (v/v)), dissolved in 5ml of ethyl acetate and then saturated with hydrogen chloride gas. The resulting precipitate was filtered to give the title compound as a white solid (850mg, 19.5%).

¹H-NMR(CDCl₃)δ10.21(s，1H)，8.50(s，1H)，7.88(s，1H)，7.21(m，3H)，7.07(d，1H)，4.35(s，2H)，3.49(t，2H)，3.15(t，2H)，2.54(s，3H)，2.27(s，3H)

Examples 28 to 42

The title compounds of examples 28 to 42 were prepared according to the same procedures as in example 2, using 2- (2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline obtained by treating the compound of example 27 with a saturated sodium bicarbonate solution, and 4-fluorobenzyl chloride, methyl-4- (bromomethyl) benzoate, 6-chloromethyl-2, 3-dihydrobenzo [1, 4] dioxin, 2-bromoethyl methyl ether, 2-bromomethylnaphthalene, 2-chloroethyl vinyl ether, 2-bromomethyl-1, 3-dioxolane, benzyl bromide, 1-iodo-2-methylpropane, (bromomethyl) cyclobutane, 1-iodopropane, (bromomethyl) cyclopropane, iodoethane, 3-bromomethylbenzonitrile or bromoacetonitrile.

Example 28.2- [1- (4-fluorobenzyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl]-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

¹H-NMR(CDCl₃) δ 8.50(s, 1H), 7.88(s, 1H), 7.21(m, 3H), 7.10(m, 2H), 7.07(d, 1H), 6.98(m, 2H), 5.65(s, 2H), 4.35(s, 2H), 3.49(t, 2H), 3.15(t, 2H), 2.54(s, 3H), 2.27(s, 3H); (yield: 25.8%)

Example 29.1- (4-methoxycarbonylbenzyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.74(s, 1H), 8.16(s, 1H), 7.91(m, 2H), 7.22(m, 2H), 7.19(m, 2H), 6.74(m, 2H), 5.91(m, 2H), 4.04(s, 2H), 3.96(s, 3H), 3.31(m, 2H), 2.79(m, 2H), 2.38(s, 3H), 2.29(s, H); (yield: 38.8%)

Example 30.2- [1- (2, 3-dihydrobenzo [1, 4]]Dioxine-6-ylmethyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridin-7-yl]-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

¹H-NMR(CDCl₃) δ 8.36(s, 1H), 7.58(m, 4H), 7.15(s, 1H), 7.10(m, 3H), 5.16(s, 2H), 4.69(s, 2H), 4.33(m, 2H), 3.57(m, 2H), 3.01(m, 2H), 2.57(s, 3H), 2.47(s, 3H); (yield: 35.3%)

Example 31.1- (2-methoxyethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.69(s, 1H), 8.14(s, 1H), 7.22(m, 3H), 7.06(m, 1H), 4.64(m, 2H), 4.19(m, 2H), 3.50(m, 2H), 3.34(m, 2H), 3.13(s, 3H), 2.49(s, 3H), 2.36(s, 3H); (yield: 58.9%)

Example 32.1- (2-naphthylmethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.35(s, 1H), 8.20(m, 1H), 7.73(m, 6H), 7.18(m, 5H), 5.89(s, 2H), 4.06(s, 2H), 3.27(m, 2H), 2.87(m, 2H), 2.38(s, 3H), 2.32(s, 3H); (yield: 63.2%)

Example 33.1- (2-ethyleneoxyethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.63(s, 1H), 8.13(s, 1H), 7.25(m, 3H), 7.12(m, 1H), 4.58(m, 2H), 4.20(m, 2H), 3.81(m, 2H), 3.52(m, 3H), 3.39(m, 1H), 3.18(m, 1H), 2.96(m, 1H), 2.49(s, 3H), 2.34(s, 3H); (yield: 66.3%)

Example 34.1- (1, 3-Dioxolan-2-ylmethyl) -7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.35(s, 1H), 8.10(s, 1H), 7.85(m, 2H), 7.23(m, 3H), 5.91(d, 2H), 4.35(s, 2H), 4.04(m, 4H), 3.96(s, 2H), 2.79(m, 2H), 2.38(s, 3H), 2.29(s, H); (yield: 55.8%)

Example 35.1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃)δ8.76(s，1H)，8.14(s，1H)7.11(m, 4H), 6.74(m, 4H), 5.83(m, 2H), 4.16(m, 2H), 3.26(m, 2H), 2.90(m, 2H), 2.46(s, 3H), 2.38(s, 3H); (yield: 59.1%)

Example 36.1-isobutyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.75(s, 1H), 8.17(s, 1H), 7.33(m, 2H), 7.08(m, 2H), 4.25(m, 4H), 3.47(m, 2H), 3.25(m, 2H), 2.54(s, 3H), 2.37(s, 3H), 1.97(m, 1H), 1.60(d, 6H); (yield: 65.3%)

Example 37.1-cyclobutylmethyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

¹H-NMR(CDCl₃) δ 8.70(s, 1H), 8.03(s, 1H), 7.23(m, 2H), 7.08(m, 2H), 4.52(d, 2H), 4.30(m, 2H), 3.43(m, 2H), 3.10(m, 2H), 2.43(s, 3H), 2.33(s, 3H), 1.74(m, 4H), 1.67(m, 1H), 1.57(m, 2H); (yield: 55.4%)

Example 38.2- (2, 3-dimethyl-1-propyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

¹H-NMR(CDCl₃) δ 8.66(s, 1H), 8.15(s, 1H), 7.22(m, 3H), 7.08(m, 1H), 4.37(m, 4H), 3.49(m, 2H), 3.30(m, 1H), 3.01(m, 1H), 2.48(s, 3H), 2.34(s, 3H), 1.56(m, 2H), 0.68(t, 3H); (yield: 59.9%)

Example 39.2- (1-Cyclopropylmethyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

¹H-NMR(CDCl₃)δ8.15(s，1H)，7.57(s，1H)，7.32(m，3H)，7.09(m，H)，4.43(m，4H)，3.49(m，4H)，2.58(s，3H)，2.39(s，3H)，1.21(m，1H)0.39(m, 2H), 0.14(m, 2H); (yield: 65.8%)

Example 40.2- (1-ethyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

¹H-NMR(CDCl₃) δ 8.65(s, 1H), 8.13(s, 1H), 7.23(m, 3H), 7.08(m, 1H), 4.59(m, 2H), 4.23(m, 2H), 3.51(m, 2H), 3.23(m, 2H), 2.45(s, 3H), 2.34(s, 3H), 1.25(d, 3H); (yield: 65.8%)

Example 41.3- [7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 3-dimethylpyrrolo [3, 2-c)]Pyridin-1-ylmethyl]Benzonitrile hydrochloride salt

¹H-NMR(CDCl₃) δ 8.36(s, 1H), 7.58(m, 4H), 7.10(s, 1H), 7.08(m, 3H), 6.98(s, 1H), 5.68(s, 2H), 4.39(s, 2H), 3.68(m, 2H), 2.98(m, 2H), 2.56(s, 3H), 2.50(s, 3H); (yield: 55.7%)

Example 42.[7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 3-dimethylpyrrolo [3, 2-c ]]Pyridine-1]-acetonitrile hydrochloride

¹H-NMR(CDCl₃) δ 8.35(s, 1H), 7.58(m, 4H), 7.10(s, 1H), 4.38(s, 2H), 4.35(s, 2H), 3.61(m, 2H), 2.89(m, 2H), 2.58(s, 3H), 2.54(s, 3H); (yield: 65.3%)

Example 43.1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -3-hydroxymethyl-2-methyl-1H-pyrrolo [3, 2-c)]Pyridine hydrochloride

The compound prepared in example 35 (250.4mg, 0.62mmol) was treated with saturated sodium bicarbonate solution to give 1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine (216.8mg, 0.59 mmol). Cerium (IV) ammonium nitrate (973mg, 1.77mmol) was added to a solution of 1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine (216.8mg, 0.59mmol) in acetic acid (3ml) at room temperature, followed by stirring at 55 ℃ for 4 hours. The reaction mixture was cooled to room temperature, added to water, and then extracted with ethyl acetate. The separated organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml). 2N lithium hydroxide (2.5ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1-benzyl-7- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -3-hydroxymethyl-2-methyl-1H-pyrrolo [3, 2-c ] pyridine, which was then dissolved in 10ml of ethyl acetate and saturated with hydrogen chloride gas. The resulting precipitate was filtered to give the title compound as a white solid (200mg, 76.8%).

¹H-NMR(CDCl₃)δ8.77(s，1H)，8.18(s，1H)，7.12(m，4H)，6.75(m，5H)，5.82(s，2H)，4.15(m，2H)，4.09(s，2H)，3.25(m，2H)，2.89(m，2H)，2.38(s，3H)

Example 44.2- (1-benzyl-2-methyl-1H-pyrrolo [3, 2-c)]Pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

Step 1: 2- (2-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

The title compound was obtained as a white solid according to the same procedure as in example 27, except for using 2- (4-nitropyridin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline and isopropenylmagnesium bromide obtained in preparation 2. (yield: 18.4%) the product was used in the next reaction without further purification.

Step 2: 2- (1-benzyl-2-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride

The title compound was obtained as a white solid according to the same procedure as in example 2, except for using 2- (2-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline and benzyl bromide obtained by treating the compound of step 1 with saturated sodium bicarbonate solution. (yield: 25.3%)

¹H-NMR(CDCl₃)δ8.36(s，1H)，7.54(m，4H)，7.24(m，5H)，7.18(d，1H)，7.10(d，1H)，6.15(s，1H)，5.24(s，2H)，4.36(s，2H)，3.65(m，2H)，2.69(m，2H)，2.34(s，3H)

Example 45.1-benzyl-7- (3, 4-dihydro-1H-isoquinolin-2-yl) -2-methyl-1H-pyrrolo [3, 2-c)]Pyridine-3-carbonitrile hydrochloride

Dimethylamine (1.05ml, 2.1mmol), acetic acid (0.81ml) and formaldehyde (0.042ml) were added to a solution of 2- (1-benzyl-2-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (600mg, 1.71mmol) in ethanol (5ml) prepared in example 44. The resulting mixture was refluxed overnight with stirring and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained compound (300mg, 0.73mmol) was dissolved in ethanol (2 ml). Methyl iodide (0.091ml, 0.46mmol) was added to the solution and stirred at room temperature overnight. The resulting white product (100mg, 0.18mmol) was dissolved in N, N-dimethylformamide (3 ml). Sodium cyanide (34mg, 0.72mmol) was added to the solution and stirred at 100 ℃ for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, dissolved in ether, and then saturated with hydrogen chloride gas to give the title compound as a white solid (25mg, 34.0%).

¹H-NMR(CDCl₃)δ8.23(d，1H)，7.54(m，4H)，7.24(m，5H)，7.18(d，1H)，5.81(s，2H)，5.23(s，2H)，4.34(s，2H)，3.66(m，2H)，2.70(m，2H)，2.33(s，3H)

Test example 1. pairProton pump (H)⁺/K⁺-ATPase) activity

1-1. preparation of gastric proton pump vesicles

The fundus region (fundic region) of the pig containing parietal and digestive cells was scraped with a glass slide. The collected cells were suspended in 10ml of 0.25M sucrose buffer and homogenized with a close-fitting Teflon-glass homogenizer. The homogenate was centrifuged at 8,000rpm for 35min to remove pellet clumps. The supernatant was further centrifuged at 25,000rpm for 75 min. The resulting pellet was resuspended in sucrose buffer (10ml) and the suspension was then placed in a discontinuous density gradient consisting of 0.25M sucrose buffer and separation medium containing 9% Ficoll (w/w). After centrifugation at 100,000Xg for 3 hours and 15 minutes, the material at the interface of sucrose buffer and Ficoll solution was collected, followed by centrifugation at 100,000Xg for 40 minutes. The resulting pellet was resuspended in 1ml of 5mM Hepes/Tris buffer (pH 6.1). The material was lyophilized and stored at-70 ℃ for use as an enzyme source for enzymatic reaction analysis outside the proton pump cartridge.

1-2 proton pump (H)⁺/K⁺Measurement of the inhibition of the Activity of ATPase)

The inhibition of proton pump activity by the compounds of the present invention was evaluated using 96-well plates. In this analysis, the base contains K⁺And does not contain K⁺H of (A) to (B)⁺/K⁺Differential Activity of ATPase Activity K⁺Specificity H⁺/K⁺-ATPase activity. In a 96-well plate, 1% Dimethylsulfoxide (DMSO) in buffer was added to the negative and positive control groups, and the diluted compounds of the present invention in buffer were added to the test groups. All assays were performed in a 100 μ l reaction volume at room temperature, and prior to use, the porcine gastric vesicles were stored in ice. At the beginning of the reaction, 10. mu.l of reaction buffer containing 1% DMSO was added to the negative and positive control groups and the test group at each compound concentration. Lyophilized vesicles in 5mM PIPES/Tris buffer (pH6.1) were then pre-incubated in the presence of various concentrations of test compound. After 5min of incubation, negative and positive buffers were added to the previous reaction mixture, respectively. ATP as a substrate was added to the reaction buffer and incubated at 37 ℃ for 30 min. Adding colorimetric reagent (2X malachite green, 1X molybdenum)Ammonium salt, 1X polyvinyl alcohol, 2X H₂O) terminating the enzyme activity and detecting the amount of monophosphate (Pi) in the reaction at 620nm using a microwell reading plate (GeniosPro, TECAN). Will contain K⁺And does not contain K⁺Pi yield difference of (b) is regarded as K⁺Excited H⁺/K⁺-ATPase activity. IC of test compounds was calculated from each% inhibition value of the compound using the Litchfield-wilicoson method (j. pharmacol. exp. ther. (1949)96, 99)₅₀. The results are shown in Table 1.

Table 1.

Examples	IC(uM)	Examples	IC(uM)
Examples	IC(uM)	Examples	IC(uM)	1	0.12	2	0.01
3	0.04	4	0.01	1	0.12	2	0.01
3	0.04	4	0.01	5	0.28	6	0.03

7	0.06	8	0.06
7	0.06	8	0.06	9	0.05	10	0.34
11	0.01	12	0.01	9	0.05	10	0.34
11	0.01	12	0.01	13	1.02	14	0.46
15	0.19	16	0.01	13	1.02	14	0.46
15	0.19	16	0.01	17	0.01	27	046
28	0.19	29	0.32	17	0.01	27	046
28	0.19	29	0.32	30	0.17	31	0.17
32	0.29	33	0.41	30	0.17	31	0.17
32	0.29	33	0.41	34	0.19	35	0.06
36	0.31	37	0.75	34	0.19	35	0.06
36	0.31	37	0.75	38	0.19	39	0.24
40	0.03	41	1.81	38	0.19	39	0.24

As shown in Table 1, the compounds of the present invention showed H in stomach⁺/K⁺The ATPase has excellent inhibitory effect.

Test example 2.Inhibiting effect on basic gastric acid secretion of pylorus ligation rat

The inhibitory effect of the compounds of the invention on basal gastric acid secretion was performed according to the Shay's rat model (Shay, H., et al., 1945, gastroenterology, 5, 43-61). Male sprague dawley (sd) rats (200 ± 10g body weight) were divided into 3 groups (n ═ 5), ad libitum with water, fasted for 24 h. The 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 10mg/kg/5ml 1h before pyloric ligation.

Under ether anesthesia, the abdomen of the rat was incised and then the pylorus was ligated. 5h after ligation, the animals were sacrificed and the gastric contents were collected. The collected contents were centrifuged at 1,000Xg for 10min to obtain gastric juice. The total acid production was determined by auto-titrating the gastric juice to pH7.0 with a 0.01N NaOH volume (ueq/ml) and calculating the ED of the test compound using the Litchfield-Wilicoxon method₅₀. The% inhibitory activity was calculated by the following formula and the results are shown in table 2.

The% inhibitory activity of the test compound (total yield of acid of control group-total yield of acid of test compound treatment group)/total yield of acid of control group × 100

Table 2.

Examples	ED(mg/kg)
Examples	ED(mg/kg)	2	1.1
12	3.3	2	1.1
12	3.3	16	1.8
17	3.3	16	1.8

As shown in table 2, the compounds of the present invention have potent inhibitory activity on basic gastric acid secretion in pylorus-ligated rats.

Test example 3.For pig stomach H⁺/K⁺Reversible inhibition of ATPase

3-1 preparation of gastric vesicles

Gastric vesicles are prepared from porcine basal mucosa using the method of Sacconmani et al (Saccomani G, Stewart HB, Shqw D, Lewis M and Sachs G, Characterisation of structural mucosalmembrane. IX. Fraction and purification of K-ATPase-associating with vehicles by zonal transfection and free-flow electrophoresis technique. biochem. Bioph. acta. (BBA) -biomembranans 465, 311- "330, 1977.). The material was lyophilized and stored at-70 ℃. The protein content of the gastric vesicles was determined by the Bradford method using bovine serum albumin as standard (Bradford MM, Arapid and reactive method for the identification of microorganisms of protein digestion. anal biochem.72, 248-254, 1976).

3-2. of pig stomach H⁺/K⁺Determination of the reversible inhibition of the ATPase

Detection of H of porcine microsomes (lyophilized vesicles) by inorganic phosphate released by ATP using a one-step colorimetric assay at a concentration of test compound with 50% proton pump inhibition⁺/K⁺ATPase Activity (Chan KM, Delfert D, and Junger KD, A directcolorometric assay for Ca²⁺Stimulated ATPase activity, anal Biochem, 157, 375-380, 1986). Investigation of test Compound Pair H according to the Washout method⁺/K⁺Mode of action of the ATPase (Beil W, Staar U, and Sewing KF, Substitedthieno [3, 4-d)]imidazoles，a novel group of H⁺/K⁺-ATPase inhibitors.Differentiation of their inhibition characteristics from those ofomeprazole.Eur.J.Pharmacol，187，455-67，1990)。

Lyophilized vesicles in 5mM PIPES/Tris buffer solution were pre-incubated in the presence of a test compound (compound of example 38) at a concentration with 50% proton pump inhibition. 2mM MgCl was added to the reaction buffer described above₂50mM KCl, 5. mu.M vanlinmycin and 0.5mM ATP, followed by incubation at 37 ℃ for 30 min. Detection of H using a colorimetric assay⁺/K⁺ATPase activity, then centrifugation of the test samples for 1h at 100,000 Xg. The vesicles were present in the test samples as pellet-shaped pellets. The supernatant was replaced with the same buffer without the test compound. The test samples were pre-incubated for 5min at room temperature, followed by further incubation for 30min at 37 ℃. Detection of H also Using a colorimetric assay⁺/K⁺-ATPase activity. Analysis of H in Pre-and post-Wash test samples⁺/K⁺ATPase activity, compared with those of the untreated group.

As a result, the compound of example 38 inhibited H prior to washing⁺/K⁺50% of ATPase activity, no inhibition after washingH⁺/K⁺-an atpase activity; after washing, stomach H of the Compound of example 38⁺/K⁺The ATPase activity was fully restored to the level of the untreated group. These results demonstrate that the compounds of formula (I) exhibit reversible gastric H⁺/K⁺-ATPase inhibition.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R₂is straight or branched C₁-C₆An alkyl group, a carboxyl group,

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁Is hydrogen; straight or branched C₁-C₆An alkyl group; with one or more groups selected from methoxy, cyclopropyl, cyclobutyl, 1, 3-dioxolanyl, cyano, naphthyl, C₂-C₅Alkenyloxy and 2, 3-dihydrobenzo [1, 4]]Substituent-substituted C of dioxin radical₁-C₃An alkyl group; c₂-C₆An alkenyl group; c₂-C₆An alkynyl group; or benzyl optionally substituted with one or more substituents selected from the group consisting of halogen, methyl, methoxy, cyano, methoxycarbonyl and trifluoromethyl,

R₂is a methyl group, and the compound is,

R₃is hydrogen; a methyl group; a hydroxymethyl group; cyanomethyl, and

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

2- (1-ethyl-2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride; and

4. a compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from:

7- (4-fluorobenzyloxy) -1- (2-methoxyethyl) -2, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridine hydrochloride; and

2- (2, 3-dimethyl-1-propyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride.

5. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of formula (II) with R₄-H to give a compound of the general formula (III),

reacting a compound of formula (III) with a compound of formula (IV) to give a compound of formula (Ia), and

reacting a compound of formula (Ia) with R₁-X reaction to give a compound of general formula (I):

wherein R is₁、R₂、R₃And R₄As defined in claim 1, and X is halogen.

6. A pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.