KR101142363B1 - A composition for treating a cancer comprising pyrrolopyridine derivatives - Google Patents

Abstract

The present invention provides an anticancer composition comprising a compound of Formula 1 or a salt thereof and a pharmaceutically acceptable carrier:

<Formula 1>

Wherein A, B, and D each independently represent N or CH, any one of A, B, and D is N, and the others are CH;

R ₁ is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Straight or branched C ₁ -C ₃ alkyl substituted with a group selected from the group consisting of C ₁ -C ₃ alkoxy, C ₃ -C ₇ cycloalkyl, acetoxy, and 1,3-dioxolaneyl; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkenyl substituted with C ₁ -C ₃ alkyl; C ₂ -C ₅ alkynyl; Benzyl, provided that benzyl may be substituted with halogen, straight or branched C ₁ -C ₄ alkyl, or straight or branched C ₁ -C ₄ alkoxy; Or 2,3-dihydro-benzo [1,4] dioxinylmethyl,

R ₂ is C ₁ -C ₃ alkyl,

R ₃ is C ₁ -C ₃ alkyl or benzyl,

R ₄ is hydrogen; Aminocarbonyl; Or C ₃ -C ₇ cycloalkyl-aminocarbonyl, and

R ₅ is naphthyl; 1,2,3,4-tetrahydroisoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl substituted with C ₁ -C ₃ alkyl; Benzylamino; Benzylamino substituted one or two with halogen; Benzyloxy, provided that the benzyl group may be substituted one or two with halogen, trifluoromethyl, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; Phenyl-C ₁ -C ₃ alkyl; Phenyl; Methylsulfanylphenyl; Or benzo [1,3] dioxylylmethoxy.

Pyrrolopyridine, anticancer agent

Description

A composition for treating a cancer comprising pyrrolopyridine derivatives}

The present invention relates to an anticancer agent composition, and more particularly to an anticancer agent composition comprising a pyrrolopyridine derivative or salt thereof and a pharmaceutically acceptable carrier.

Various anticancer agents currently known and used have mechanisms that target DNA and alkylate the DNA, inhibit the synthesis of DNA, or act as metabolic agents to kill cells. However, this mechanism is not only specific for cancer cells but also acts the same for normal cells, resulting in low selectivity between normal and cancer cells, resulting in toxicity and side effects such as hair loss, bone marrow dysfunction, gastric mucosal injury, and pain. , Causing vomiting. Therefore, there is a need for developing an anticancer agent having fewer side effects and more safety.

On the other hand, the present inventors have completed the patent application by developing a compound useful as an acid pump antagonist (Reciprocal acid gas inhibitory action mechanism) that has a reversible mechanism of gastric acid secretion. The compounds developed by the present inventors are pyrrolopyridine derivatives or salts thereof, pyrrolo [2,3-c] pyridine derivatives or salts thereof (Korean Patent Application No. 2004-70533, filed Sep. 3, 2004), Pyrrolo [3,2-c] pyridine derivatives or salts thereof (Korean Patent Application No. 2004-70534, filed Sep. 3, 2004), pyrrolo [3,2-b] pyridine derivatives or salts thereof (Korea Patent Application 2004-70535, filed Sep. 3, 2004) and pyrrolo [3,2-c] pyridine derivatives or salts thereof (Korean Patent Application No. 2004-70536, filed Sep. 3, 2004).

The present inventors have surprisingly found that the pyrrolopyridine derivatives or salts thereof have excellent anticancer effects while studying the pyrrolopyridine derivatives or salts thereof.

Accordingly, an object of the present invention is to provide an anticancer agent composition comprising a pyrrolopyridine derivative or a salt thereof.

According to one aspect of the present invention, there is provided an anticancer composition comprising a compound of formula 1 or a salt thereof and a pharmaceutically acceptable carrier:

Wherein A, B, and D each independently represent N or CH, any one of A, B, and D is N, and the others are CH;

R ₁ is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Straight or branched C ₁ -C ₃ alkyl substituted with a group selected from the group consisting of C ₁ -C ₃ alkoxy, C ₃ -C ₇ cycloalkyl, acetoxy, and 1,3-dioxolaneyl; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkenyl substituted with C ₁ -C ₃ alkyl; C ₂ -C ₅ alkynyl; Benzyl, provided that benzyl may be substituted with halogen, straight or branched C ₁ -C ₄ alkyl, or straight or branched C ₁ -C ₄ alkoxy; Or 2,3-dihydro-benzo [1,4] dioxinylmethyl,

R ₂ is C ₁ -C ₃ alkyl,

R ₃ is C ₁ -C ₃ alkyl or benzyl,

R ₄ is hydrogen; Aminocarbonyl; Or C ₃ -C ₇ cycloalkyl-aminocarbonyl, and

R ₅ is naphthyl; 1,2,3,4-tetrahydroisoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl substituted with C ₁ -C ₃ alkyl; Benzylamino; Benzylamino substituted one or two with halogen; Benzyloxy, provided that the benzyl group may be substituted one or two with halogen, trifluoromethyl, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; Phenyl-C ₁ -C ₃ alkyl; Phenyl; Methylsulfanylphenyl; Or benzo [1,3] dioxylylmethoxy.

The anticancer agent composition of the present invention, R ₁ is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Methyl substituted with C ₃ -C ₇ cycloalkyl or 1,3-dioxolaneyl; C ₂ -C ₆ alkenyl substituted with C ₁ -C ₃ alkyl; C ₂ -C ₅ alkynyl; Benzyl, provided that benzyl may be substituted with halogen, straight or branched C ₁ -C ₄ alkyl, or straight or branched C ₁ -C ₄ alkoxy; Or 2,3-dihydro-benzo [1,4] dioxinylmethyl,

R ₂ and R ₃ are each methyl,

R ₄ is hydrogen, and

R ₅ is naphthyl; 1,2,3,4-tetrahydroisoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl substituted with C ₁ -C ₃ alkyl; Benzylamino; Benzyloxy, provided that the benzyl group may be substituted one or two with halogen, or C ₁ -C ₃ alkyl; Or phenyl-C ₁ -C ₃ alkyl

It may preferably comprise a compound of formula (1) or a salt thereof.

Compounds of formula (1) or salts thereof that may be more preferably included in the anticancer agent compositions of the present invention are as follows:

1- (3-methyl-buten-2-yl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - 1 H -pyrrolo [ 3,2-b] pyridine hydrochloride;

(1-allyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -amine hydrochloride;

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

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

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

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

7- (4-fluorobenzyloxy) -2,3-dimethyl-1- (3-methyl-2-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

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

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

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

7- (4-chlorophenyl) -2,3-dimethyl-1- (3-methyl-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

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

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

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

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

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

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

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

7- (benzo [1,3] dioxol-5-ylmethoxy) -1- (4-methylbenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

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

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

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

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

2,3-Dimethyl-1-ethyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

2,3-Dimethyl-1-propyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

L-allyl-2,3-dimethyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

1-cyclopropylmethyl-7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

1- (3-methoxybenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

1- (3-fluorobenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

1-cyclobutylmethyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

1-benzyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride;

2,3-dimethyl-1- (4-methylbenzyl) -7- (4-benzyloxy-trifluoromethyl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

2,3-dimethyl-1- (3-methoxybenzyl) -7- (4-benzyloxy-trifluoromethyl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

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

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

2- (1- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridine-7- Il) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

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

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

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

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

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

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

3-benzyl-2-methyl-4- (1,2,3,4-tetrahydro-isoquinolin-2-yl) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride;

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

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

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

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

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

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

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

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

2,3-Dimethyl-7- (4-methylsulfanyl-ylphenyl) - 1 H- pyrrolo [2,3-c] pyridine;

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

L- (3-fluorobenzyl) -2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride;

1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine-5-carboxylic acid cyclo Propylamide.

In addition, compounds of formula (1) or salts thereof that may be particularly preferably included in the anticancer agent compositions of the present invention are as follows:

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

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

7- (4-chlorophenyl) -2,3-dimethyl-1- (3-methyl-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

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

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

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

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

2,3-Dimethyl-1-propyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride;

2- (1- (2,3-dihydro-benzo [1, 4] dioxin-6-ylmethyl) -2,3-dimethyl-1 H- pyrrolo [3,2-c] pyridine-7 Il) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

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

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

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

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

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

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

L- (3-fluorobenzyl) -2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride.

The compound of formula (1) or a salt thereof may be in the form of a pharmaceutically acceptable salt, which salts include non-toxic salts commonly used in the field of anticancer agents, for example salts of alkali metal salts or salts produced from non-toxic inorganic or organic acids. It may be in the form. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, mal Salts prepared from organic acids such as lonic acid, methanesulfonic acid, tartaric acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid And salts made from alkaline metals such as lithium, sodium, potassium, magnesium, calcium and the like. In general, salts may be prepared by reacting an organic base in a stoichiometric amount or in excess of the desired salt-forming inorganic or organic acid, or metal hydroxide or metal hydride with various solvents or suitable combinations of solvents.

The compound of Formula 1 or a salt thereof included in the anticancer agent composition of the present invention is a Korean patent application No. 2004-70533, a Korean patent application No. 2004-70534, a Korean patent application filed by the present inventors on September 3, 2004 It can be prepared by the manufacturing method disclosed in the application 2004-70535, and the Republic of Korea Patent Application 2004-70536.

For example, the compound of Formula 1 or a salt thereof may be prepared by reacting a compound of Formula 2 with a compound of Formula 3 to prepare Formula 1a, and then reacting with R ₁ -X, which is represented by the following Scheme Same as 1.

In Formula 2, Formula 3, and Scheme 1, A, B, D, R ₁ , R ₂ , R ₃ , R _4, and R ₅ are the same as defined above, and X represents halogen.

Compounds of Formula 2 are known methods ( Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and J. Med. Chem. 1995, 38 (20), 4131 ), And the compound of formula 3 can be purchased commercially.

The reaction of the compound of Formula 2 with the compound of Formula 3 may be carried out in anhydrous polar aprotic solvent, preferably anhydrous tetrahydrofuran may be used. The reaction temperature can be reacted at low temperature (-78 ° C to 0 ° C) or at room temperature.

The compound of formula 1a obtained as an intermediate may be reacted with R ₁ -X under appropriate base and solvent conditions to produce the compound of formula 1. The base usable here includes metal salts such as sodium hydride, tert -butoxylated potassium and the like, and the usable solvents include tetrahydrofuran, N, N -dimethylformamide and the like. The reaction temperature may be reacted at 40 ° C to 100 ° C or at room temperature. In addition, a catalytic amount of 18-crown-6-ether can be used for improving the progress rate and yield of the reaction.

In another method, the compound of Formula 1 or a salt thereof is cyclized to a compound of Formula 4 to prepare a compound of Formula 5, and a halogenated compound of Formula 5 to prepare a compound of Formula 6, and then a compound of Formula 6 To react with R ₅ -Y to prepare a compound of formula (1a), it can be prepared by reacting with R ₁ -X, represented by the reaction scheme shown in Scheme 2 below.

In Formulas 4 to 6 and Scheme 2, A, B, D, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and X are the same as defined above, and Y represents hydrogen or boronic acid.

The compound of formula 4 can be easily prepared by applying a known method ( Tetrahedron, 1976, 32 (12), 1383).

The compound of formula 4 may be refluxed in an organic solvent having a high boiling point such as diphenyl ether to prepare the compound of formula 5.

The compound of formula 5 may be converted to the compound of formula 6 using a halogenating agent such as phosphorus oxychloride. It is preferable to make reaction temperature react on reflux condition.

Compounds of Formula 6 are known in the art ( Tetrahedron 1987, 43, 2557, Tetrahedron 1990, 54, 6311, Eur. J. Med. Chem. 1996, 31,359 and J. Med. Chem. 1995, 38 (20), 4131) The compound of Formula 1a may be prepared by reaction with R ₅ -Y.

The compound of formula 1a may be reacted with R ₁ -X under appropriate base and solvent conditions to produce the compound of formula 1. The base usable here includes metal salts such as sodium hydride, tert -butoxylated potassium and the like, and the usable solvents include tetrahydrofuran, N, N -dimethylformamide and the like. The reaction temperature may be reacted at 40 ° C to 100 ° C or at room temperature. In addition, a catalytic amount of 18-crown-6-ether can be used for improving the progress rate and yield of the reaction.

Compositions of the present invention may include excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, tonicity agents, and the like which are well known and can be used, and may be sweetening and / or flavoring agents. It may include.

The compositions of the present invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. The compositions of the present invention may be administered in the form of tablets or capsules, or as aqueous solutions or suspensions. In the case of oral tablets, excipients may include lactose and corn starch and lubricants such as magnesium stearate. In the case of capsule form it may comprise lactose and dry corn powder as diluents. Aqueous suspensions for oral use may include emulsifiers and suspending agents, and may optionally include certain sweetening and / or flavoring agents. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared and may contain a buffer that can suitably adjust the pH of the solution, and for intravenous administration, the isotonicity of the formulation It may include isotonic agents to be imparted. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

The composition of the present invention can be effectively administered to cancer patients, such as gastric cancer, colon cancer, colon cancer, rectal cancer, pancreatic cancer, or myeloid leukemia, by effectively inhibiting the growth of cancer cells, the dosage is usually the age, weight and patient of each patient It may be administered at a dose that can be varied according to the symptoms of, for example, about 0.1 mg / kg to about 20 mg / kg per day, preferably 0.5 mg / kg to about 10 mg / kg per day.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are described for illustrative purposes and do not limit the scope of the present invention.

Reference Example 1. 2- (3-nitropyridin-4-yl) -1,2,3,4-tetrahydroisoquinoline

<Step 1> 4-chloro-3-nitropyridine

4-hydroxy-3-nitropyridine (10 g, 71.38 mmol) was added to 100 ml of phosphorus oxytrichloride and refluxed and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was added to 500 ml of ice water and neutralized with a 2N aqueous sodium hydroxide solution. The organic layer extracted with 300 ml of methylene chloride and separated was dried over anhydrous magnesium sulfate, reduced pressure and concentrated to give the title compound (9.2 g, 92.0%) as a slightly yellow solid.

Rf (n-hexane / ethyl acetate = 2/1 (v / v)) = 0.5

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.12 (s, 1H), 8.69 (d, 1H), 7.55 (d, 1H)

<Step 2> 2- (3-nitropyridin-4-yl) -1,2,3,4-tetrahydroisoquinoline

1,2,3,4-tetrahydroisoquinoline (1.06ml, 8.05mmol) was dissolved in N, N-dimethylformamide (30ml) and sodium hydride (386.4mg, 9.66mmol) was added at 0 ° C and the same temperature Stir at 10 min. 4-chloro-3-nitropyridine (1.124g, 7.09mmol) prepared in step 1 was added dropwise to the reaction mixture, stirred at room temperature for 2 hours, diluted with 10 ml of water and 100 ml of ethyl acetate and washed with water ( 100 ml X 2). The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.13 g, 89.3%) as a yellow solid.

Rf (n-hexane / ethyl acetate = 2/1 (v / v)) = 0.3

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.86 (s, 1H), 8.36 (d, 2H), 7.22 (m, 3H), 7.12 (m, 1H), 6.96 (d, 1H), 4.35 (s, 2H), 3.53 (t, 2H), 3.03 (t, 2H)

Reference Example 2. 4- (4-fluorobenzyloxy) -3-nitropyridine

4-chloro-3-nitropyridine (2.0 g, 12.62 mmol) prepared in Step 1 of Reference Example 1 was dissolved in 100 ml of anhydrous toluene with 4-fluorobenzyl alcohol (2.04 ml, 18.92 mmol) and potassium carbonate (1.74 g). , 12.62 mmol) and potassium hydroxide (2.38 g, 50.48 mmol) were added dropwise, and a catalytic amount of tris (2- (2-methoxyethoxy) ethyl) amine was added, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered and the concentrated residue under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1 (v / v)) to give the title compound (2.5 g, 86.3%) as a white solid. .

Rf (n-hexane / ethyl acetate = 2/1 (v / v)) = 0.4

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.57 (s, 1H), 7.28 (m, 3H), 7.16 (m, 2H), 6.70 (d, 1H), 5.05 (s, 2H)

Reference Example 3. (2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -carbamic acid t-butylester

Step 1 (4-fluorobenzyl)-(3-nitropyridin-4-yl) -amine

4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in step 1 of Reference Example 1 was dissolved in 30 ml of anhydrous N, N-dimethylformamide, and sodium carbonate (3.20 g, 30.27 mmol), 4- Fluorobenzylamine (2.14 ml, 18.92 mmol) was added and warmed and stirred at 80 ° C. for 1 hour. 10 ml of water and 100 ml of ethyl acetate were added to the reaction mixture, and the mixture was washed with water (100 ml × 2). The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (3.01 g, 83.5%) as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.60 (s, 1H), 7.29 (m, 3H), 7.18 (m, 2H), 6.70 (d, 1H), 5.20 (s, 2H)

<Step 2> (4-fluorobenzyl)-(3-nitropyridin-4-yl) -carbamic acid t-butylester

(4-fluorobenzyl)-(3-nitropyridin-4-yl) -amine (3.07 g, 12.42 mmol) prepared in step 1 was dissolved in 100 ml of tetrahydrofuran and di-tert-butyl dicarbonate (8.13 g) , 37.25 mmol) and N, N-dimethylaminopyridine (2.27 g, 18.63 mmol) were added and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1 (v / v)) to give the title compound (2.9 g, 75.6%) in a yellow fluid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.60 (s, 1H), 7.29 (m, 3H), 7.18 (m, 2H), 6.70 (d, 1H), 5.10 (s, 2H), 1.3 (s, 9H)

<Step 3> (2,3-dimethyl-1 H- pyrrolo [3,2-b] pyridin-7-yl) - (4-fluorobenzyl) -carbamic acid t- butyl ester

(4-fluorobenzyl)-(3-nitropyridin-4-yl) -carbamic acid t-butyl ester (10.2 g) prepared in <Step 2> was dissolved in anhydrous tetrahydrofuran (200 ml) under a stream of nitrogen. 1-methyl-1-propenyl magnesium bromide (110 ml of tetrahydrofuran 0.5M solution, 130.5 mmol) was added at -78 ° C. After stirring at −20 ° C. for 5 hours, 20 ml of 20% (w / v) ammonium chloride solution was added thereto, and extracted with ethyl acetate (200 ml × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1 (v / v)) to give the title compound (3.8 g, 28.9%) as a slightly yellow solid. Prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.31 (d, 1H), 8.12 (s, 1H), 7.40 (m, 1H), 7.18 (d, 2H), 7.09 (d, 2H), 3.16 (s, 3H), 2.53 (s, 3H), 2.48 (s, 3H), 1.41 (s, 9H)

Reference Example 4. 2- (4-nitropyridin-3-yl) -1,2,3,4-tetrahydroisoquinoline

<Step 1> 3-bromopyridine-N-oxide

3-bromopyridine (32 g, 0.202 mol) was dissolved in 120 ml of acetic acid and then 30% hydrogen peroxide (41 ml) was added. The reaction mixture was stirred at 70-80 ° C. for 9 hours, concentrated under reduced pressure, basified with excess sodium carbonate, and diluted with 100 ml of methylene chloride. Insoluble inorganics were filtered off, the organic layer was dried over anhydrous magnesium sulfate, and the residue was concentrated under reduced pressure and used in step 2 without further separation and purification.

<Step 2> 3-bromo-4-nitropyridine-N-oxide

3-bromopyridine-N-oxide (31.9 g, 0.181 mol) prepared in step 1 was dissolved in 77 ml of concentrated sulfuric acid, and 128 ml of concentrated nitric acid and 77 ml of concentrated sulfuric acid were slowly added while maintaining 0-5 ° C. The reaction mixture was stirred at 90 ° C. for 2 hours, then cooled to room temperature, and the reaction mixture was added to 1 L of ice water and adjusted to pH 8 with 50% aqueous sodium hydroxide solution. The resulting precipitate was filtered, separated and dried to give the title compound (29.3 g, 72.0%) as a yellow solid.

Rf (n-hexane / ethylacetate = 1/1 (v / v)) = 0.3

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.9-8.4 (m, 2H), 8.6 (s, 1H)

<Step 3> 2- (4-nitro-1-oxy-pyridin-3-yl) -1,2,3,4-tetrahydroisoquinoline

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

Rf (n-hexane / ethylacetate = 1/1 (v / v)) = 0.2

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.13 (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 4 2- (4-nitropyridin-3-yl) -1,2,3,4-tetrahydroisoquinoline

2- (4-nitro-1-oxy-pyridin-3-yl) -1,2,3,4-tetrahydroisoquinoline (8.5 g, 25.3 mmol) synthesized in step 3 was dissolved in 100 ml of ethyl acetate. Phosphorus trichloride (3.81 ml, 28.9 mmol) was slowly added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour, basified with 2N aqueous sodium hydroxide solution, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (65.3%) as a yellow solid. Used in the next step without further separation and purification.

Reference Example 5. 3- (4-fluorobenzyloxy) -4-nitropyridine

<Step 1> 3- (4-fluorobenzyloxy) -4-nitropyridine-N-oxide

The title compound was prepared in the same manner as in Reference Example 2 using the 3-bromo-4-nitropyridine-N-oxide and 4-fluorobenzyl alcohol prepared in Step 2 of Reference Example 4 in a yield of 14.6%. .

Rf (n-hexane / ethylacetate = 1/1 (v / v)) = 0.2

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.5 (s, 1H), 8.33 (d, 1H), 8.20 (m, 2H), 8.17 (d, 1H), 8.15 (m, 2H), 5.21 (s, 2H)

<Step 2> 3- (4-fluorobenzyloxy) -4-nitropyridine

Using the 3- (4-fluorobenzyloxy) -4-nitropyridine-N-oxide prepared in Step 1 in the same manner as in Step 4 of Reference Example 4, the title compound was prepared in the next reaction without further purification. Used.

Reference Example 6. 4-Chloro-2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridine

Step 1 4-hydrazino - 1 H- pyridin-2-one

2,4-Dihydroxypyridine (20.3 g, 183.0 mmol) was added dropwise to the reaction mixture of 2-methoxyethanol (400 ml) and hydrazine solution (35 wt.%, 80 ml) at room temperature. The reaction mixture was refluxed for 24 hours, and the residue was concentrated under reduced pressure after stirring, and recrystallized with ethanol to obtain the title compound (20.1 g, 88.3%) as a white solid.

Rf (methylene chloride / methanol = 10/1 (v / v)) = 0.1

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.30 (brs, 1H), 7.67 (s, 1H), 7.10 (d, 1H), 5.79 (d, 1H), 5.54 (s, 1H), 3.91 (brs, 2H)

<Step 2> 4- (N'-sec- butyl this DEN-hydrazino) - 1 H- pyridin-2-one

4-Hyrazino - 1 H- pyridin-2-one (20.1 g, 161.0 mmol) and 2-butanone (21.6 ml, 241.0 mmol) prepared in Step 1 were added to 400 ml ethanol and refluxed and stirred for 4 hours. . After cooling to 0 ° C., the resulting solid was filtered, separated and washed with cold ethanol to give the title compound as a white solid in a yield of 75.0%.

Rf (methylene chloride / methanol = 10/1 (v / v)) = 0.3

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.48 (brs, 1H), 9.05 (s, 1H), 7.03 (d, 1H), 6.00 (d, 1H), 5.65 (s, 1H), 2.18 (q, 2H), 1.97 (s, 3H), 0.99 (t, 3H)

<Step 3> 2,3-dimethyl-1,5-dihydro-pyrrolo [3,2-c] pyridin-4-one

4- prepared in step 2 (this N'-sec- butyl Baden-hydrazino) - 1 H- pyridin-2-one (16.6g, 92.6 mmol) was added to diphenyl ether of 200ml was refluxed for 5 hours. Stirred. The reaction mixture was cooled to room temperature, 200 ml of n-hexane was added thereto, stirred, and the resulting solid was separated by filtration and recrystallized with methanol to obtain the title compound (10.9 g, 73.2%) as a pale yellow solid.

Rf (ethyl acetate (100%)) = 0.2

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.99 (brs, 1H), 10.55 (brs, 1H), 6.84 (d, 1H), 6.24 (d, 1H), 2.24 (s, 3H), 2.17 (s, 3H)

<Step 4> 4-Chloro-2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridine

2,3-dimethyl-1,5-dihydro-pyrrolo [3,2-c] pyridin-4-one (6.0 g, 37.0 mmol) prepared in step 3 was added to phosphorus oxytrichloride (230 ml). It was added to reflux and stirred for 6 hours. The reaction mixture was cooled and the resulting solid was separated by filtration, dissolved in methanol and basified with saturated ammonia methanol solution. The concentrated residue under reduced pressure was filtered through a silica gel layer and recrystallized to obtain the title compound (2.87 g, 43.0%) as a pale yellow solid.

Rf (ethyl acetate / n-hexane = 1/1 (v / v) 0 = 0.4

¹ H-NMR (400 MHz, CDCl ₃ ) d 11.55 (brs, 1H), 7.82 (d, 1H), 7.25 (d, 1H), 2.36 (s, 3H), 2.33 (s, 3H)

Reference Example 7. 1-Methyl-1,2,3,4-tetrahydroisoquinoline

<Step 1> N- (2-phenylethyl) -acetamide

Phenethylamine (50 g, 413 mmol) was added to dichloromethane (50 ml), and 2N aqueous sodium hydroxide solution (30 ml) was added to the solution, followed by the slow dropwise addition of acetyl chloride (33 ml, 457 mmol) at 0 ° C. The mixture was stirred overnight. Diluted with dichloromethane, washed with water and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate, reduced pressure and concentrated to give the title compound (59g) as a white solid. This compound was used in the next reaction without further purification.

<Step 2> 1-methyl-3,4-dihydro-isoquinoline

The mixture of N- (2-phenylethyl) -acetamide (12 g, 73.5 mmol) and polyphosphoric acid (200 ml) prepared in step 1 was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water, basified with 2N aqueous potassium hydroxide solution and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (4.1 g, 38%) as a brown oil. This compound was used in the next reaction without further purification.

<Step 3> 1-methyl-1,2,3,4-tetrahydroisoquinoline

Dissolve 1-methyl-3,4-dihydro-isoquinoline (4.1 g, 28 mmol) prepared in step 2 in methanol (100 ml) and add sodium borohydride (2.12 g, 56 mmol) at 0 ° C. slowly The mixture was stirred overnight at room temperature. To the reaction mixture was added 1N hydrochloric acid, reduced pressure, concentrated, basified with potassium hydroxide, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a brown oil (3.8). g, 92%) was prepared. This compound was used in the next reaction without further purification.

Example 1. 1- (3-Methyl-buten-2-yl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 2- (2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline

2- (3-nitropyridin-4-yl) -1,2,3,4-tetrahydroisoquinoline (5 g, 19.58 mmol) prepared in Reference Example 1 was added to anhydrous tetrahydrofuran (200 ml) under a stream of nitrogen. It was dissolved and 1-methyl-1-propenylmagnesium bromide (80 ml of tetrahydrofuran 0.5M solution, 117.5 mmol) was added at -78 ° C. After stirring at −20 ° C. for 5 hours, 20% (w / v) aqueous ammonium chloride solution (20 ml) was added thereto, and extracted with ethyl acetate (200 ml × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methylene chloride / methanol = 10/10/1 (v / v / v)), and concentrated to give a pale yellow solid. Phosphorus title compound (2.1 g, 25.3%) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.26 (d, 1H), 7.77 (s, 1H), 7.19 (m, 4H), 6.59 (d, 1H), 4.46 (s, 2H), 3.64 (t, 2H), 3.04 (t, 2H), 2.41 (s, 3H), 2.30 (s, 3H)

<Step 2> 1- (3-Methyl-buten-2-yl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride

2- (2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline (30 mg, 0.108 prepared in step 1 mmol), tert-butoxylated potassium (13.6 mg, 0.162 mmol), and a catalytic amount of 18-crown-6-ether in anhydrous tetrahydrofuran (2 ml) and 4-bromo-2-methyl-2-butene ( 0.07 ml, 0.162 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by short silica gel column chromatography (ethyl acetate / methylene chloride / methanol = 10/10/1 (v / v / v)), concentrated and dissolved in 1 ml of ethyl acetate, followed by hydrochloric acid. The precipitate produced by saturating the gas was filtered and separated to obtain the title compound (6.9 mg, 15.8%) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.35 (s, 1H), 7.51 (m, 4H), 7.10 (s, 1H), 4.86 (d, 2H), 4.39 (s, 2H), 4.10 (m, 1H), 3.57 (m, 2H), 2.95 (m, 2H), 2.56 (s, 3H), 2.35 (s, 3H), 1.89 (s, 6H)

Example 2. (1-allyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -amine hydrochloride

<Step 1> (1-allyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -carbamic acid t-butylester hydrochloride

(2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -carbamic acid t-butylester and allyl bromide prepared in Reference Example 3 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 88.6%. It was used for the next reaction without further separation and purification.

<Step 2> (1-allyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -amine hydrochloride

(1-allyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -carbamic acid t-butylester prepared in step 1 Hydrochloride (101.3 mg) was dissolved in 5 ml of ethyl acetate, the hydrochloric acid gas was saturated for 5 minutes, stirred at room temperature for 1 hour, and the resulting precipitate was separated by filtration and dried to prepare the title compound (35.3 mg) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.91 (t, 1H), 7.11 (m, 2H), 6.48 (s, 1H), 6.48 (m, 1H), 6.35 (m, 1H), 6.11 (m, 1H), 5.26 (d, 1H), 5.05 (s, 2H), 4.71 (d, 1H), 4.56 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H)

Example 3. 7- (4-fluorobenzyloxy) -1-isobutyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Step 1 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

4- (4-fluorobenzyloxy) -3-nitropyridine (4.8 g, 19.34 mmol) prepared in Reference Example 2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen stream and 1-methyl at -78 ° C. -1-propenyl magnesium bromide (116 ml of tetrahydrofuran 0.5 M solution, 58.02 mmol) was added. After stirring at −20 ° C. for 5 hours, 20 ml of 20% (w / v) ammonium chloride aqueous solution was added thereto, and extracted with ethyl acetate (200 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, and the residue was concentrated under reduced pressure. 2.45 g, 28.3%) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.29 (d, 1H), 7.97 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.60 (d, 1H), 5.18 (s, 2H), 2.39 (s, 3H), 2.30 (s, 3H)

<Step 2> 7- (4-fluorobenzyloxy) -1-isobutyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine) and 1-iodo-2-methylpropane prepared in step 1 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 86.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.34 (d, 1H), 7.25 (m, 5H), 5.68 (s, 2H), 4.85 (d, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.78 (m, 1H), 1.58 (d, 6H)

Example 4. 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-prop-2-ynyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Example 1 using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and propazyl bromide prepared in step 1 of Example 3 In the same manner as in step 2, the title compound was prepared as a pale yellow solid in a yield of 58.6%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.37 (s, 3H), 7.53 (m, 2H), 7.16 (m, 2H), 6.94 (s, 1H), 5.41 (s, 2H), 5.12 (s, 2H), 2.56 (s, 3H), 2.50 (s, 3H), 2.38 (s, 1H)

Example 5. 1-benzyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Example 7 using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and benzyl bromide prepared in step 1 of Example 3 In the same manner as in Step 2, the title compound was prepared as a white solid in a yield of 89.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.37 (s, 1H), 7.29 (m, 3H), 7.01 (m, 4H), 6.84 (s, 1H), 6.66 (m, 2H), 5.56 (s, 2H), 5.22 (s, 2H), 2.61 (s, 3H), 2.38 (s, 3H)

Example 6. 1-cyclobutylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and (bromomethyl) cyclobutane prepared in Step 1 of Example 3 were prepared. In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 78.6%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.37 (s, 1H), 7.50 (m, 2H), 7.18 (m, 3H), 5.37 (s, 2H), 4.28 (s, 2H), 2.54 (m, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 1.79 (m, 3H), 1.57 (m, 3H)

Example 7. 7- (4-fluorobenzyloxy) -2,3-dimethyl-1- (3-methyl-2-buten-2-yl) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-bromo-2-methyl- prepared in Step 1 of Example 3 Using the 2-butene to give the title compound as a white solid in a yield of 59.8% in the same manner as in step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.35 (s, 1H), 7.43 (m, 2H), 7.14 (m, 2H), 6.85 (s, 1H), 5.36 (s, 2H), 5.04 (m, 1H), 4.94 (s, 2H), 2.54 (s, 3H), 2.39 (s, 3H), 1.58 (s, 6H)

Example 8. 7- (4-fluorobenzyloxy) -1-propyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 1-iodopropane prepared in Step 1 of Example 3 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 78.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.36 (s, 1H), 7.48 (m, 2H), 7.17 (m, 2H), 6.89 (s, 1H), 5.34 (s, 2H), 4.17 (t, 2H), 2.54 (s, 3H), 2.40 (s, 3H), 1.66 (m, 2H), 0.72 (t, 3H)

Example 9. 1- (tert-Butylbenzyl) -7- (4-fluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-tert-butylbenzyl chloride prepared in step 1 of Example 3 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 68.2%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.35 (s, 1H), 7.29 (d, 2H), 6.99 (m, 4H), 6.90 (s, 1H), 6.61 (s, 2H), 5.60 (s, 2H), 5.22 (s, 2H), 2.60 (s, 3H), 2.38 (s, 3H), 1.32 (s, 9H)

Example 10. 1- (2-fluorobenzyl) -7- (4-fluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine) and 2-fluorobenzyl chloride prepared in step 1 of Example 3 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 86.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.43 (s, 1H), 7.53 (m, 2H), 7.27 (m, 1H), 7.05 (m, 4H), 6.23 (m, 2H), 5.61 (s, 2H), 5.30 (s, 2H), 2.63 (s, 3H), 2.49 (s, 3H)

Example 11. 1-benzyl-7- (4-chlorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (4-chlorobenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 4-chlorobenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a white solid in a yield of 78.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.04 (s, 1H), 8.62 (d, 1H), 7.40 (m, 4H), 7.04 (d, 1H), 5.28 (d, 1H)

<Step 2> 7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

Using the 4- (4-chlorobenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in step 1 in the same manner as in step 1 of Example 1, white in a yield of 23.8% The title compound was prepared as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.28 (d, 1H), 8.02 (s, 1H), 7.38 (m, 4H), 6.58 (d, 1H), 5.19 (s, 2H), 2.40 (s, 3H), 2.30 (s, 3H)

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

The same method as Step 2 of Example 1 using 7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and benzyl bromide prepared in Step 2 To give the title compound as a white solid in a yield of 69.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.36 (d, 1H), 7.30 (m, 5H), 6.98 (d, 2H), 6.84 (d, 1H), 6.68 (d, 2H), 5.57 (s, 2H), 5.23 (s, 2H), 2.60 (s, 3H), 2.38 (s, 3H)

Example 12. 7- (4-Chlorobenzyloxy) -2,3-dimethyl-1- (3-methyl-buten-2-yl) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-bromo-2-methyl-2 prepared in step 2 of Example 11 Using butene to prepare the title compound as a white solid in a yield of 58.6% in the same manner as in Step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.41 (m, 4H), 6.85 (d, 1H), 5.39 (s, 2H), 5.05 (m, 1H), 4.95 (d, 2H), 2.54 (s, 3H), 2.32 (s, 3H), 1.41 (s, 6H)

Example 13. 1- (2-acetoxyethyl) -7- (4-chlorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 2-bromoethyl acetate prepared in Step 2 of Example 11 were used. In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 77.6%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.45 (m, 4H), 6.92 (d, 1H), 5.38 (s, 2H), 4.59 (d, 2H), 4.25 (d, 23H), 2.62 (s, 3H), 2.45 (s, 3H), 2.06 (s, 3H)

Example 14. 1-cyclopropylmethyl-7- (4-chlorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and (bromomethyl) cyclopropane prepared in step 2 of Example 11 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 88.1%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.34 (d, 1H), 7.44 (m, 4H), 6.89 (d, 1H), 5.36 (s, 2H), 4.22 (d, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 1.10 (m, 1H), 0.48 (d, 2H), 0.20 (d, 2H)

Example 15. 7- (4-Chlorobenzyloxy) -1-([1,3] dioxolan-2-ylmethyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 2-bromomethyl-1,3- prepared in Step 2 of Example 11 Using the dioxolane to give the title compound as a white solid in the yield of 58.4% in the same manner as in step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.28 (d, 1H), 7.44 (m, 4H), 6.86 (d, 1H), 5.38 (s, 2H), 5.09 (m, 1H), 4.53 (s, 2H), 3.76 (s, 2H), 3.60 (s, 2H), 2.58 (s, 3H), 2.46 (s, 3H)

Example 16. 7- (4-Chlorobenzyloxy) -1- (4-chlorobenzyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Example using 7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-chlorobenzyl bromide prepared in step 2 of Example 11 In the same manner as in Step 2 of 1, the title compound was prepared in a yield of 85.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.36 (s, 1H), 7.30 (m, 4H), 7.04 (d, 2H), 6.88 (s, 1H), 6.60 (d, 2H), 5.51 (s, 2H), 5.23 (s, 2H), 2.59 (s, 3H), 2.37 (s, 3H)

Example 17. 7- (4-Chlorobenzyloxy) -1- (2-fluorobenzyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 2-fluorobenzyl bromide prepared in step 2 of Example 11 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 86.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.38 (s, 1H), 7.28 (m, 3H), 6.99 (m, 4H), 6.73 (s, 1H), 6.13 (s, 1H), 5.62 (s, 2H), 5.30 (s, 2H), 2.61 (s, 3H), 2.38 (s, 3H)

Example 18. 7- (4-Chlorobenzyloxy) -1-ethyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Example 1 was prepared by using 7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and iodoethane prepared in Step 2 of Example 11. In the same manner as in Step 2, the title compound was prepared as a white solid in a yield of 88.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (s, 1H), 7.44 (m, 4H), 6.89 (s, 1H), 5.38 (s, 2H), 4.35 (d, 2H), 2.53 (s, 3H), 2.42 (s, 3H), 1.29 (t, 3H)

Example 19. 7- (4-Chlorobenzyloxy) -1- (3-methoxybenzyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 3-methoxybenzyl chloride prepared in step 2 of Example 11 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 79.8%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.35 (s, 1H), 7.39 (m, 1H), 7.27 (s, 1H), 7.18 (t, 1H), 7.00 (d, 2H), 6.82 (d, 2H), 6.22 (d, 2H), 5.52 (s, 2H), 5.22 (s, 2H), 3.77 (s, 3H), 2.59 (s, 3H), 2.37 (s, 3H)

Example 20. 7- (Benzo [1,3] dioxol-5-ylmethoxy) -1- (4-methylbenzyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (benzo [1,3] dioxol-5-ylmethoxy) -3-nitropyridine

In the same manner as in Reference Example 2, 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) and piperonyl alcohol (3.45 ml, 18.92 mmol) prepared in Step 1 of Reference Example 1 were used. The title compound (3.08 g, 88.6%) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.02 (s, 1H), 8.60 (d, 1H), 7.06 (d, 1H), 6.91 (t, 2H), 6.84 (d, 1H), 5.99 (s, 2H), 5.21 (s, 2H)

<Step 2> 7- (benzo [1,3] dioxol-5-ylmethoxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

Same as step 1 of Example 1 using 4- (benzo [1,3] dioxol-5-ylmethoxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in step 1 The title compound was prepared as a white solid in a yield of 28.9% by the method.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.28 (d, 1H), 7.94 (s, 1H), 6.94 (m, 2H), 6.82 (d, 1H), 6.60 (d, 1H), 5.99 (s, 2H), 5.11 (s, 2H), 2.39 (s, 3H), 2.21 (s, 3H)

<Step 3> 7- (benzo [1, 3] dioxol-5-ylmethoxy) -1- (4-methylbenzyl) -2,3-dimethyl - 1 H- pyrrolo [3,2-b] Pyridine hydrochloride

The 1 H- pyrrole in [3,2-b] pyridine and 4-methylbenzyl chloride-one prepared in Step 2 7- (benzo [1, 3] dioxol-5-ylmethoxy) -2,3-dimethyl In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 66.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.08 (d, 2H), 6.88 (m, 2H), 6.63 (m, 3H), 6.42 (s, 1H), 5.99 (s, 2H), 5.52 (s, 2H), 5.16 (s, 2H), 2.58 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H)

Example 21. 1-benzyl-7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (2,4-dichlorobenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 2,4-dichlorobenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a white solid in a yield of 89.3%. .

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.05 (s, 1H), 8.60 (d, 1H), 7.13 (d, 1H), 5.29 (d, 1H)

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

Using the 4- (2,4-dichlorobenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in step 1 in 28.6% The title compound was prepared as a white solid in yield.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.29 (d, 1H), 8.01 (s, 1H), 7.52 (m, 3H), 6.53 (d, 1H), 5.18 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H)

Step 3 1-benzyl-7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride

Example 2 step 2 using 7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and benzyl bromide prepared in step 2 In the same manner as the title compound was prepared as a white solid in a yield of 86.4%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.43 (s, 3H), 7.11 (m, 2H), 6.89 (m, 1H), 6.67 (m, 2H), 5.58 (s, 2H), 5.32 (s, 2H), 2.64 (s, 3H), 2.41 (s, 3H)

Example 22. 7- (2,4-Dichlorobenzyloxy) -1-cyclopropylmethyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (2,4-Dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and (bromomethyl) cycloprop prepared in Step 2 of Example 21 Pain was used to prepare the title compound as a white solid in the same manner as in Step 2 of Example 1 in a yield of 78.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.41 (d, 1H), 7.60 (m, 2H), 7.52 (m, 1H), 7.38 (m, 1H), 5.45 (s, 2H), 4.33 (d, 2H), 2.56 (s, 3H), 2.47 (s, 3H), 1.11 (m, 1H), 0.48 (m, 2H), 0.19 (m, 2H)

Example 23. 7- (2,4-Dichlorobenzyloxy) -1-ethyl-2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and iodoethane prepared in Step 2 of Example 21 In the same manner as in Step 2 of Example 1, the title compound was prepared as a light yellow solid in a yield of 75.9%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.37 (d, 1H), 7.55 (s, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 6.93 (d, 1H), 5.45 (s, 2H), 4.34 (m, 2H), 2.58 (s, 3H), 2.42 (s, 3H), 1.11 (t, 3H)

Example 24. 7- (2,4-Dichlorobenzyloxy) -1- (4-fluorobenzyl) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-fluorobenzyl bromide prepared in step 2 of Example 21 were prepared. In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 75.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.40 (d, 1H), 7.44 (s, 1H), 7.19 (m, 2H), 6.90 (m, 3H), 6.38 (m, 2H), 5.52 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H), 2.39 (s, 3H)

Example 25. 2,3-dimethyl-1-ethyl-7- (3-methylbenzyloxy) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (3-methylbenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 3-methylbenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a yellow solid in a yield of 89.8%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.03 (s, 1H), 8.62 (d, 1H), 7.45 (m, 4H), 7.09 (d, 1H), 5.35 (d, 1H), 1.53 (s, 3H)

<Step 2> 7- (3-methylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

In the same manner as in Step 1 of Example 1, using 4- (3-methylbenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in Step 1, the pale yellow color was obtained in a yield of 28.3%. The title compound was prepared as a solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.29 (d, 1H), 8.01 (s, 1H), 7.40 (m, 4H), 6.58 (d, 1H), 5.23 (s, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.55 (s, 1H)

<Step 3> 2,3-Dimethyl-1-ethyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride

Same as Step 2 of Example 1 using 7- (3-methylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and iodoethane prepared in Step 2 The title compound was prepared as a white solid in a yield of 69.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.31 (s, 1H), 7.34 (m, 4H), 6.86 (d, 1H), 5.37 (s, 2H), 4.38 (m, 2H), 2.53 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 1.29 (t, 3H)

Example 26. 2,3-dimethyl-1-propyl-7- (3-methylbenzyloxy) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (3-methylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 1-iodopropane prepared in step 2 of Example 25 In the same manner as in Step 2 of Example 1, the title compound was prepared as a pale yellow solid in a yield of 78.2%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.34 (s, 1H), 7.34 (m, 4H), 6.881 (s, 1H), 5.33 (s, 2H), 4.20 (t, 2H), 2.40 (s, 3H), 2.17 (s, 3H), 1.69 (m, 2H), 0.75 (t, 3H)

Example 27. 1-allyl-2,3-dimethyl-7- (3-methylbenzyloxy) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Example 1 step using 7- (3-methylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and allyl bromide prepared in step 2 of Example 25 In the same manner as in the 2, the title compound was prepared as a white solid in a yield of 72.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.31 (m, 3H), 6.85 (d, 1H), 5.90 (m, 1H), 5.35 (s, 2H), 5.15 (d, 1H), 4.97 (s, 2H), 4.57 (d, 1H), 2.57 (s, 3H), 2.39 (s, 6H)

Example 28. 1-cyclopropylmethyl-7- (2-ethoxybenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (2-ethoxybenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 2-ethoxybenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a yellow solid in a yield of 65.9%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.04 (s, 1H), 8.62 (d, 1H), 7.32 (m, 4H), 7.04 (d, 1H), 5.33 (d, 1H), 2,87 ( m, 2H), 1.2 (t, 3H)

Step 2 7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

Using 4- (2-ethoxybenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in Step 1 in the same manner as in Step 1 of Example 1 in a yield of 25.5% The title compound was prepared as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.30 (d, 1H), 8.01 (s, 1H), 7.25 (m, 4H), 6.58 (d, 1H), 5.30 (s, 2H), 3.12 (m, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.21 (t, 3H)

Step 3 1-cyclopropylmethyl-7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride

Example using 7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and (bromomethyl) cyclopropane prepared in step 2 In the same manner as in Step 2 of 1, the title compound was prepared as a white solid in a yield of 82.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (t, 1H), 7.39 (m, 2H), 6.96 (m, 3H), 5.44 (s, 2H), 4.23 (d, 2H), 4.12 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 1.41 (t, 3H), 1.12 (m, 1H), 0.43 (m, 2H), 0.20 (m, 2H)

Example 29. 1- (3-methoxybenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 3-methoxybenzyl bromide prepared in step 2 of Example 28 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 79.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.32 (t, 1H), 7.31 (m, 1H), 7.16 (t, 1H), 6.92 (d, 2H), 6.84 (m, 3H), 6.26 (s, 2H), 5.57 (s, 2H), 5.35 (s, 2H), 4.01 (m, 2H), 3.68 (s, 3H), 2.57 (s, 3H), 2.35 (s, 3H), 1.34 (t, 3H )

Example 30. 1- (3-fluorobenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 3-fluorobenzyl bromide prepared in step 2 of Example 28 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 86.7%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.33 (d, 1H), 7.33 (t, 1H), 7.19 (m, 1H), 6.94 (t, 3H), 6.85 (m, 2H), 6.43 (m, 2H), 5.55 (s, 2H), 5.34 (s, 2H), 3.99 (m, 2H), 2.59 (s, 3H), 2.36 (s, 3H), 1.34 (t, 3H)

Example 31. 1-Cyclobutylmethyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (3,5-difluorobenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 3,5-difluorobenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a yellow solid in a yield of 78.0% It was.

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.06 (s, 1H), 8.73 (s, 1H), 8.65 (d, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.04 (d, 1H), 5.28 (d, 1H)

<Step 2> 7- (3,5-Difluoro-benzyl) -2,3-dimethyl - 1 H- pyrrolo [3,2-b] pyridine

20.4% in the same manner as in Step 1 of Example 1, using 4- (3,5-difluorobenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in Step 1 To afford the title compound as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.75 (s, 1H), 8.66 (d, 1H), 8.01 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.04 (d, 1H), 5.28 (d, 1H), 2.11 (s, 3H), 2.35 (s, 3H)

<Step 3> 1-cyclobutyl-7- (3,5-Difluoro-benzyl) -2,3-dimethyl - 1 H- pyrrolo [3,2-b] pyridine hydrochloride

Using 7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and (bromomethyl) cyclobutane prepared in step 2 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 70.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.36 (s, 1H), 7.02 (m, 2H), 6.91 (m, 1H), 6.82 (m, 1H), 5.36 (s, 2H), 4.35 (d, 2H), 2.67 (m, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.73 (m, 2H), 1.67 (m, 2H)

Example 32. 1-benzyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-b] pyridine hydrochloride

By using 7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and benzyl bromide prepared in step 2 of Example 31 In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 80.9%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.35 (d, 1H), 7.42 (m, 4H), 6.80 (m, 4H), 6.55 (d, 1H), 5.60 (s, 2H), 5.25 (s, 2H), 2.62 (s, 3H), 2.45 (s, 3H)

Example 33. 2,3-dimethyl-1- (4-methylbenzyl) -7- (4-trifluoromethylbenzyloxy) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

<Step 1> 4- (4-trifluoromethylbenzyloxy) -3-nitropyridine

Using the 4-chloro-3-nitropyridine and 4-trifluoromethylbenzyl alcohol prepared in Step 1 of Reference Example 1 to give the title compound as a yellow solid in a yield of 89.5%. .

¹ H-NMR (400 MHz, CDCl ₃ ) d 9.03 (s, 1H), 8.66 (d, 1H), 7.38 (m, 4H), 7.02 (d, 1H), 5.29 (d, 1H)

Step 2 7- (4-Trifluoromethylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine

In the same manner as in Step 1 of Example 1, using 4- (4-trifluoromethylbenzyloxy) -3-nitropyridine and 1-methyl-1-propenylmagnesium bromide prepared in Step 1 The title compound was prepared as a white solid in yield.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.28 (d, 1H), 8.01 (s, 1H), 7.36 (m, 4H), 6.57 (d, 1H), 5.20 (s, 2H), 2.41 (s, 3H), 2.31 (s, 3H)

<Step 3> 2,3-dimethyl-1- (4-methylbenzyl) -7- (4-trifluoromethyl-benzyloxy) - 1 H- H-pyrrolo [3,2-b] pyridine hydrochloride

Example 1 using 7- (4-trifluoromethylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 4-methylbenzyl bromide prepared in step 2 In the same manner as in Step 2, the title compound was prepared as a white solid in a yield of 88.6%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.37 (d, 1H), 7.55 (d, 2H), 7.16 (m, 2H), 7.13 (d, 2H), 6.81 (m, 1H), 6.58 (d, 2H), 5.55 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H)

Example 34. 2,3-dimethyl-1- (3-methoxybenzyl) -7- (4-trifluoromethylbenzyloxy) - One H- Pyrrolo [3,2-b] pyridine hydrochloride

7- (4-trifluoromethylbenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine and 3-methoxybenzyl bromide prepared in step 2 of Example 33 were prepared. In the same manner as in Step 2 of Example 1, the title compound was prepared as a white solid in a yield of 89.0%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.34 (t, 1H), 7.55 (d, 2H), 7.18 (m, 3H), 6.83 (d, 2H), 6.22 (s, 2H), 5.54 (s, 2H), 5.30 (s, 2H), 3.70 (s, 3H), 2.60 (s, 3H), 2.38 (s, 3H)

Example 35. 1- (1,3-dioxolan-2-ylmethyl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridine hydrochloride

<Step 1> 2- (2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline

Using 2- (4-nitropyridin-3-yl) -1,2,3,4-tetrahydroisoquinoline prepared in Reference Example 4 in the same manner as in Step 1 of Example 1 in a yield of 19.5% The title compound was prepared as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.21 (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)

<Step 2> 1- (1, 3-dioxolan-2-ylmethyl) - [7- (1,2,3,4-tetrahydro-isoquinolin-2-yl)] - 2,3-dimethyl- 1 H -pyrrolo [3,2-c] pyridine hydrochloride

2- (2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline and 2-bromine prepared in step 1 The title compound was prepared as a white solid in the yield of 55.8% by the same method as Step 2 of Example 1 using mother methyl-1,3-dioxolane.

¹ H-NMR (400 MHz, CDCl ₃ ) d 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)

Example 36. 2- (1-ethyl-2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

2- (2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline prepared in step 1 of Example 35 Using Iodoethane to prepare the title compound as a white solid in a yield of 65.8% in the same manner as in Step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) d 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)

Example 37. 2- (1- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

2- (2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline prepared in step 1 of Example 35 And 2-bromomethyl-1,4-dibenzooxalane were prepared in the same manner as in Step 2 of Example 1, to obtain a white solid title compound in a yield of 35.3%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 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)

Example 38. 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-prop-2-ynyl - One H- Pyrrolo [3,2-c] pyridine hydrochloride

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

3- (4-fluorobenzyloxy) -4-nitropyridine (6.6 g, 26.59 mmol) prepared in Reference Example 5 was dissolved in anhydrous tetrahydrofuran (300 ml) under nitrogen stream and 1-methyl at -78 ° C. -1-propenylmagnesium bromide (80 ml of tetrahydrofuran 0.5 M solution) was added. After stirring at −20 ° C. for 5 hours, 20 ml of 20% (w / v) ammonium chloride aqueous solution was added thereto, and extracted with ethyl acetate (200 ml × 2). The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1 (v / v)), concentrated, dissolved in 10 ml of ethyl acetate and saturated with hydrochloric acid gas. The precipitate thus produced was filtered and separated to obtain the title compound (910 mg, 13.5%) as a white solid.

Rf (ethyl acetate / methanol = 10/1 (v / v)) = 0.2

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.46 (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)

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

A handle 7 of the compound prepared in Step 1 with a saturated aqueous solution of sodium bicarbonate (4-fluorobenzyloxy) -2,3-dimethyl - 1 H- pyrrolo [3,2-c] pyridine (20.0mg, 0.073 mmol) and propazyl bromide (0.08 ml, 0.109 mmol) were used to prepare the title compound as a white solid in a yield of 40.1% in the same manner as in Step 2 of Example 1.

Rf (ethylacetate / methylenechloride / methanol = (10/1/1)) = 0.0.4

¹ H-NMR (400 MHz, CDCl ₃ ) d 8.55 (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)

Example 39. 7- (4-fluorobenzyloxy) -1- (2-methoxyethyl) -2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridine hydrochloride

7- (4-fluorobenzyloxy) -2,3-dimethyl - l H -pyrrolo [3,2-c] pyridine, treated with a saturated sodium bicarbonate solution prepared from step 1 of Example 38 And 2-bromoethylmethyl ether to give the title compound as a white solid in a yield of 54.3% in the same manner as in Step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) d 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)

Example 40. 1-Cyclopropylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - One H- Pyrrolo [3,2-c] pyridine hydrochloride

7- (4-fluorobenzyloxy) -2,3-dimethyl - l H -pyrrolo [3,2-c] pyridine, treated with a saturated sodium bicarbonate solution prepared from step 1 of Example 38 To give the title compound as a pale yellow solid in the yield of 58.4% in the same manner as in step 2 of Example 1 using (bromomethyl) cyclopropane.

¹ H-NMR (400 MHz, CDCl ₃ ) d 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)

Example 41. 1-cyclopropylmethyl-2,3-dimethyl-4- (4-fluorobenzylamino) - One H- Pyrrolo [3,2-c] pyridine hydrochloride

<Step 1> 2,3-dimethyl-4- (4-fluorobenzylamino) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride

Reference Example 6 A 4-Chloro-2,3-dimethyl-manufactured - a 1 H- pyrrolo [3,2-c] pyridine (1.16g, 6.43mmol) and benzylamine (3ml) with 4-160 ℃ Stir at 12 h. The reaction mixture was cooled to room temperature, purified and purified by silica gel column chromatography (ethyl acetate: 100%), dissolved in 10 ml of ethyl acetate, and the resulting precipitate was filtered and separated by saturation of hydrochloric acid gas to give the title compound as a white solid. (1.47 g, 85.0%) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ / CD ₃ OD) d 7.44 (brs, 3H), 7.06 (brs, 2H), 6.90 (brs, 1H), 4.87 (brs, 2H), 2.33 (brs, 6H)

<Step 2> 1-cyclopropyl-2,3-dimethyl-4- (4-fluorobenzylamino) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride

2,3-dimethyl-4 obtained by treating the compound with saturated aqueous sodium hydrogen carbonate solution prepared in Step 1 (4-fluoro-benzylamino) - 1 H- pyrrolo [3,2-c] pyridine (20mg, 0.065 mmol) was dissolved in 1 ml of N, N-dimethylformamide and sodium hydride (60%, 4.9 mg, 0.118 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, (bromomethyl) cyclopropane (0.046 ml, 0.0515 mmol) was added dropwise and stirred at room temperature for 1 hour. 10 ml of ethyl acetate was added, diluted, and washed three times with 10 ml of water. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated, dissolved in 1 ml of ethyl acetate, saturated gaseous hydrochloric acid, and the resulting precipitate was filtered and separated to obtain the title compound as a white solid in a yield of 65.5%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.79 (brs, 1H), 7.50 (brs, 2H), 7.07 (brs, 2H), 6.81 (brs, 1H), 5.87 (brs, 1H), 5.12 (brs, 2H), 3.97 (brs, 2H), 2.39 (brs, 3H), 2.35 (brs, 3H), 1.12 (brs, 1H), 0.62 (m, 2H), 0.34 (m, 2H)

Example 42. 1-benzyl-2,3-dimethyl-4- (4-fluorobenzylamino) - One H- Pyrrolo [3,2-c] pyridine hydrochloride

Example 2,3-dimethyl-41 To a solution of the compound prepared in step 1 is obtained by treatment with a saturated aqueous solution of sodium hydrogencarbonate-4- (4-fluoro-benzylamino) - 1 H- pyrrolo [3,2-c] Using the pyridine and benzyl bromide the title compound was prepared in the same manner as in Step 2 of Example 41 in a yield of 58.4%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.73-6.78 (m, 11H), 6.07 (brs, 1H), 5.28 (brs, 2H), 5.12 (brs, 2H), 2.42 (brs, 3H), 2.25 ( brs, 3H)

Example 43. 2,3-dimethyl-1- (2-fluorobenzyl) -4- (4-fluorobenzylamino) - One H- Pyrrolo [3,2-c] pyridine hydrochloride

Example 2,3-dimethyl-41 To a solution of the compound prepared in step 1 is obtained by treatment with a saturated aqueous solution of sodium hydrogencarbonate-4- (4-fluoro-benzylamino) - 1 H- pyrrolo [3,2-c] The title compound was prepared in the same manner as in Step 2 of Example 41 using pyridine and 2-fluorobenzyl bromide in a yield of 35.4%.

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.78 (brs, 1H), 7.52 (brs, 2H), 7.31 (brs, 2H), 7.08 (m, 3H), 6.79 (brs, 1H), 6.53 (brs, 1H), 6.07 (brs, 1H), 5.32 (brs, 2H), 5.15 (brs, 2H), 2.43 (brs, 3H), 2.27 (brs, 3H)

Example 44. 3-benzyl-2-methyl-4- (1,2,3,4-tetrahydroisoquinolin-2-yl) -  One H- Pyrrolo [3,2-c] pyridine hydrochloride

<Step 1> 4- [N '- ( 1- methyl-3-phenylpropyl The Den) - hydrazino] - 1 H- pyridin-2-one

Step 2 of Reference Example 6 was prepared using 4-hydrazino - 1H - pyridin-2-one (5.39 g, 43.1 mmol) and benzylacetone (9.70 ml, 64.6 mmol) prepared in Step 1 of Reference Example 6. In the same manner, the title compound (7.30 g, 66.5%) as a white solid was prepared and used in the next reaction without further separation and purification.

<Step 2> 3-benzyl-2-methyl-1,5-dihydro-pyrrolo [3,2-c] pyridin-4-one

A 4- [N '- (1- methyl-3-phenylpropyl The Den) - hydrazino] - prepared in Step 1 1 H- pyridin-2-one (7.30g, 28.6mmol) the step of Reference Example 6 In the same manner as in the 3, the title compound (6.41 g, 94%) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.99 (brs, 1H), 10.55 (brs, 1H), 7.33 (m, 5H), 6.86 (d, 1H), 6.25 (d, 1H), 5.10 (s, 2H), 2.25 (s, 3H)

<Step 3> 3-benzyl-4-chloro-2-methyl - 1 H -pyrrolo [3,2-c] pyridine

Step 4 of Reference Example 6 using 3-benzyl-2-methyl-1,5-dihydro-pyrrolo [3,2-c] pyridin-4-one (4.82 g, 20.2 mmol) prepared in step 2 In the same manner as the title compound (1.74 g, 33%) as a slightly yellow solid was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) d 10.54 (brs, 1H), 7.32 (m, 5H), 7.12 (d, 1H), 6.28 (d, 1H), 5.11 (s, 2H), 2.28 (s, 3H)

<Step 4> 3-benzyl-2-methyl-4- (1,2,3,4-tetrahydro-isoquinolin-2-yl) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride

Example 41 using 3-benzyl-4-chloro-2-methyl - 1 H -pyrrolo [3,2-c] pyridine and 1,2,3,4-tetrahydroisoquinoline prepared in step 3 In the same manner as in step 1, the title compound (89.7%) was obtained as a pale yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) d 7.82 (brs, 1H), 7.55 (brs, 1H), 7.26-7.02 (m, 6H), 6.90 (brs, 2H), 6.44 (m, 1H), 4.55 ( brs, 2H), 4.13 (brs, 2H), 3.84 (brs, 2H), 2.94 (brs, 2H), 2.42 (s, 3H)

Example 45. 1-allyl-7- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

<Step 1> 2- (1,2,3,4-tetrahydroisoquinolin-2-yl) -3-nitropyridine

In the same manner as in Step 1 of Reference Example 3, using 2-chloro-3-nitropyridine (3.0 g, 18.92 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.37 ml, 18.92 mmol) 4.8 g of the title compound was prepared as a yellow solid in% yield.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

<Step 2> 7- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride

2- (1,2,3,4-tetrahydroisoquinolin-2-yl) -3-nitropyridine (4.8 g, 18.8 mmol) and 1-methyl-1-propenyl magnesium bromide prepared in step 1 7- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2,3-di obtained in the same manner as in step 1 of Example 1 using 0.5M tetrahydrofuran solution, 112 ml) methyl- by dissolving 1 H- pyrrolo [2,3-c] pyridine in ethyl acetate, filtered, the resulting solid was saturated with hydrochloric acid gas to give the titled compound as 1.3 g of a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

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

7- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride (92.3 mg) prepared in step 2 , 0.333 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and sodium hydride (60%, 40 mg, 0.999 mmol), allyl bromide (0.385 ml, 0.399 mmol) was added at 0 ° C. and 12 h at room temperature. Stirred. 1-allyl-7- (1,2,3,4-tetrahydroisoquinolin-2-yl) obtained by adding ice, drying with anhydrous magnesium sulfate, filtration, and separating and purifying by silica gel column chromatography. -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine was dissolved in ethyl acetate and the resulting solid was filtered to give 23.7 mg of the title compound as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (br, 2H), 4.50 (d, 1H), 3.91 (t, 2H), 3.12 (t, 2H), 2.42 (s, 3H), 2.30 (s, 3H )

Example 46. 2- (2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

<Step 1> 1-methyl-2- (3-nitropyridin-2-yl) -1,2,3,4-tetrahydroisoquinoline

In the same manner as in Step 1 of Reference Example 3, using 2-chloro-3-nitropyridine and 1-methyl-1,2,3,4-tetrahydroisoquinoline prepared in Reference Example 7, it was pale yellow in a yield of 97%. The title compound as a fluid was prepared. This compound was used in the next reaction without further purification.

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

The same method as Step 1 of Example 1 using 1-methyl-2- (3-nitropyridin-2-yl) -1,2,3,4-tetrahydroisoquinoline prepared in Step 1 as a starting material obtained with the compound 2- (2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridin-7-yl) ethyl-1-methyl-1, & hydro isoquinoline The resulting solid was dissolved in acetate and saturated with hydrochloric acid gas and filtered to give the title compound as a white solid in 40% yield.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.58 (bs, 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)

Example 47. 2- (2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline sodium salt

Example 46 A two-handle compound prepared with a saturated sodium hydrogen carbonate in the (2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1, Anhydrous tetrahydrofuran solution (2 ml) of 2,3,4-tetrahydroisoquinoline (78.5 mg, 0.27 mmol) and sodium hydride (6.5 mg, 0.27 mmol) was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was recrystallized to give 75 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) 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)

Example 48. 7- (4-Chlorobenzylamino) -1-isobutyl-2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

<Step 1> 7-chloro-2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridine

2-chloro-3-nitropyridine (8 g, 50.46 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) under nitrogen filling, followed by 1-methyl-1-propenyl magnesium bromide (-78 ° C). 0.5M tetrahydrofuran solution, 252 ml, 126.15 mmol) was added slowly. The reaction solution was stirred at -20 ° C for 2 hours and 20% aqueous ammonium chloride solution was added. After extraction with ethyl acetate and concentration of the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3, v / v) to give the title compound 2.73 as a pale yellow solid in a yield of 30%. g was prepared

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (brs, 1H), 7.97 (d, 1H), 7.30 (d, 1H), 2.43 (s, 3H), 2.21 (s, 3H)

<Step 2> 7-chloro-1-isobutyl-2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridine

7-Chloro-2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine (100 mg, 0.53 mmol) prepared in step 1 was dissolved in anhydrous tetrahydrofuran (2.8 ml) and sodium hydroxide Ride (60%, 33 mg, 0.83 mmol) was added and stirred at room temperature for 30 minutes. 1-iodo-2-methylpropane (64 ml, 0.67 mmol) was added to the reaction solution, stirred at room temperature overnight, water was added thereto, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/9, v / v) to give a white color in a yield of 86%. 108 mg of the title compound as a solid was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, 1H), 7.29 (d, 1H), 4.25 (s, br, 2H), 2.38 (s, 3H), 2.22 (m, 4H), 0.89 (d, 6H)

<Step 3> 7- (4-chlorobenzylamino) -1-isobutyl-2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride

Cesium carbonate (97 mg, 0.317 mmol) in a solution of toluene (1.1 mL) of tris (dibenzylidecetone) dipalladium (0) (11 mg, 0.0106 mmol), 4-chlorobenzyl amine (40 ml, 0.317 mmol), (S) -2,2'bis (diphenylphosphino) -1,1'binapryl (20 mg, 0.0317 mmol) and 7-chloro-1-isobutyl-2,3-di prepared in Step 2 Methyl - 1 H -pyrrolo [2,3-c] pyridine (50 mg, 0.211 mmol) was added. The reaction solution was refluxed for 40 hours, and the reaction solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 15/85, v / v), and the obtained residue was dissolved in ethyl acetate and saturated with hydrochloric acid gas. The resulting solid was filtered to give a yield of 21%. 15 mg of the title compound as a white solid was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.64 (t, 1H), 7.46 (d, 2H), 7.29 (d, 2H), 6.87 (d, 1H), 6.43 (br, 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)

Example 49. 7- (benzylamino) -2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

<Step 1> 2-benzylamino-3-nitropyridine

Using the 2-chloro-3-nitropyridine and benzyl amine to give the title compound as a yellow solid in the yield of 91% in the same manner as in Step 1 of Reference Example 3.

Rf (ethyl acetate / n-hexane = 1/5, v / v) = 0.5

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.52 (brs, 1H), 8.44 (m, 2H), 7.31 (m, 5H), 6.68 (m, 1H), 4.87 (d, 2H)

<Step 2> 2- ( N -benzyl- N - tert -butoxycarbonyl) amino-3-nitropyridine

In the same manner as in Step 2 of Reference Example 3, using 2-benzylamino-3-nitropyridine (12.2 g, 53.2 mmol) and di- tert -butyldicarbonate (36.68 ml, 160 mmol) prepared in Step 1 17.5 g of the title compound as a yellow oil was prepared.

Rf (ethyl acetate / n-hexane = 1/5, v / v) = 0.4

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

7- ( N -benzyl- N -tert-butyloxycarbonyl) amino-2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine

2- ( N -benzyl- N - tert -butyloxycarbonyl) amino-3-nitropyridine (17.5 g, 53.1 mmol) and 1-methyl-1-propenylmagnesium bromide (0.5M) prepared in step 2 Tetrahydrofuran solution, 318 ml, 159 mmol) was used to prepare 7.5 g of the title compound as a yellow solid in the same manner as in Step 1 of Example 1.

Rf (ethyl acetate / n-hexane = 1/1, v / v) = 0.1

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

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

7-1 prepared in Step 3 (N - benzyl - N - tert - butyloxycarbonyl) amino-2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridine acetate (37.0 mg) acetate The resulting solid was dissolved in and saturated with hydrochloric acid gas and the resulting solid was filtered to give 29.0 mg of the title compound as a white solid in 96% yield.

¹ H-NMR (400 MHz, CDCl ₃ / MeOD) 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)

Example 50. 1-benzyl-2,3-dimethyl-7-phenethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

<Step 1> 3-phenethyl-2-nitropyridine

2-chloro-3-nitropyridine (4.37 g, 27.6 mmol) in 1,4-dioxane (60 ml), phenethylboronic acid (4.6 g, 30.4 mmol), tetrakis (triphenylphosphine) palladium (0 ) (3.19 g, 2.76 mmol) and potassium carbonate (11.4 g, 82.8 mmol) were added and refluxed for 24 hours, then cooled to room temperature and filtered over a pad of celite. The solvent was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography, and then crystallized with ethyl ether to obtain 4.1 g of the title compound as a white solid in 55% yield. This compound was used in the next reaction without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

<Step 2> 2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine

Using the 3-phenethyl-2-nitropyridine prepared in step 1 as a starting material to prepare the title compound as a white solid in a yield of 43% in the same manner as in step 1 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

Step 3 1-benzyl-2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride

52% yield in the same manner as Step 2 of Example 1, using 2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine and benzyl bromide prepared in step 2 To give the title compound as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (bs, 1H), 7.64 (bs, 1H), 7.31 (m, 3H), 7.23 (m, 3H), 7.12 (bs, 2H), 6.71 (bs, 2H), 5.40 (bs, 2H), 3.57 (bs, 2H), 3.14 (bs, 2H), 2.42 (s, 3H), 2.37 (s, 3H)

Example 51. 1- (2-methoxyethyl) -2,3-dimethyl-7-phenethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

Example 1 step using 2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine and 2-bromoethyl methyl ether prepared in step 2 of Example 50 In the same manner as in the 2, the title compound was prepared in a yield of 49%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.56 (s, 1H), 7.29 (m, 4H), 7.23 (m, 1H), 4.36 (bs, 2H), 3.85 (bs, 2H), 3.58 (s, 3H), 3.24 (bs, 2H), 3.20 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H)

Example 52. 2,3-Dimethyl-1- (4-methylbenzyl) -7-phenethyl - One H- Pyrrolo [2,3-c] pyridine hydrochloride

Example 2 step 2 of Example 1 using 2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine and 4-methylbenzyl chloride prepared in Step 2 of Example 50; In the same manner, the title compound was prepared as a white solid in a yield of 56%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.63 (s, 1H), 7.25 (m, 3H), 7.03 (m, 4H), 6.59 (bs, 2H), 3.58 (bs, 2H), 3.14 (bs, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H)

Example 53. 2,3-dimethyl-7- (4-methylsulfanylphenyl) - One H- Pyrrolo [2,3-c] pyridine

<Step 1> 3-nitro-2- (4-methylthiophenyl) pyridine

77% of 77% in the same manner as in Example 1, using 2-chloro-3-nitropyridine (4.37 g, 27.6 mmol), (4-methylthiophenyl) boronic acid (5.8 g, 30.4 mmol) 6.3 g of the title compound was prepared as a white solid in yield. This compound was used in the next reaction without further purification.

<Step 2> 2,3-Dimethyl-7- (4-methylsulfanyl-ylphenyl) - 1 H- pyrrolo [2,3-c] pyridine

Using the 3-nitro-2- (4-methylthiophenyl) pyridine prepared in Step 1 as a starting material to prepare the title compound as a white solid in a yield of 35% in the same manner as in Step 1 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, 1H), 8.17 (bs, 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)

Example 54. 2,3-dimethyl-7- (naphthalen-2-yl) - One H- Pyrrolo [2,3-c] pyridine hydrochloride

<Step 1> 2- (naphthalen-2-yl) -3-nitropyridine

Using the 2-naphthalenyl boronic acid, the title compound was prepared in the same manner as in Step 1 of Example 50, in a yield of 72%. This compound was used in the next reaction without further purification.

<Step 2> 2,3-dimethyl-7- (naphthalen-2-yl) -1 H -pyrrolo [2,3-c] pyridine hydrochloride

Compound 2,3-dimethyl-7- (naphthalene-2) obtained by the same method as Step 1 of Example 1 using 2- (naphthalen-2-yl) -3-nitropyridine prepared in Step 1 as a starting material - yl) - 1 H- pyrrolo [2,3-c] to yield the title compound as a white solid in 46% pyridine was dissolved in ethyl acetate, filtered, the resulting solid was saturated with hydrochloric acid gas were produced.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

Example 55. 1- (3-fluorobenzyl) -2,3-dimethyl-7- (naphthalen-2-yl) - One H- Pyrrolo [2,3-c] pyridine hydrochloride

Example 54 treated with the compound prepared with a saturated sodium hydrogen carbonate 2,3-Dimethyl-7- (naphthalen-2-yl) at - 1 H- pyrrolo [2,3-c] pyridine and 3-fluoro- Using the benzyl chloride to give the title compound as a white solid in the yield of 43% in the same manner as in step 2 of Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

Example 56. 1-allyl-7- (3,4-dihydro - One H- Isoquinolin-2-yl) -2,3-dimethyl - One H- Pyrrolo [2,3-c] pyridine-5-carboxylic acid cyclopropylamide

<Step 1> 2- (6-chloro-3-nitropyridin-2-yl) -1,2,3,4-tetrahydroisoquinoline

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) and 1, at 0 ° C. 2,3,4-tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added slowly and then stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/5, v / v). Isolation and purification gave 10 g of the title compound as a yellow solid (yield: 81%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

<Step 2> Synthesis of methyl 2- (5-chloro-2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline

The 2- (6-chloro-3-nitropyridin-2-yl) -1,2,3,4-tetrahydroisoquinoline prepared in Step 1 was prepared in the same manner as in Step 1 of Example 1 in a yield of 37%. The title compound in the yellow oil was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

<Step 3> 7- (3, 4-dihydro - 1 H- isoquinolin-2-yl) -2,3-dimethyl - 1 H- pyrrolo [2,3-c] pyridine-5-carbonitrile

2- (5-chloro-2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline prepared in step 2 (1.8 g, 3.94 mmol) and copper cyanide (I) (705 mg, 7.88 mmol) were dissolved in anhydrous N, N -dimethylformamide (30 ml) and refluxed for 48 hours, and then the reaction solution was cooled to room temperature. Ethyl acetate was added to the reaction solution, and the insoluble solid was filtered off. Water was added to the solution, followed by extraction with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3, v / v) to obtain 120 mg of the title compound as a white solid in a yield of 15%. .

¹ H-NMR (400 MHz, CDCl ₃ ) 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)

<Step 4> 1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine- 5-carbonitrile

7- (3,4-hydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine-5-carbonitrile prepared in step 3 Using the allyl iodide and the title compound as a white solid in 56% yield in the same manner as in step 2 of Example 41.

¹ H-NMR (400 MHz, CDCl ₃ ) 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), 4.341 (br, 2H), 3.44 (br, 2H), 3.07 (br, 2H), 2.33 (s, 3H), 2.17 (s, 3H)

Step 5 1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine- 5-carboxylic acid

1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine prepared in step 4 To the reaction solution diluted 5-5-carbonitrile (300 mg, 0.89 mmol) in ethanol (7 ml) and water (1 ml) was added potassium hydroxide (502 mg, 8.9 mmol) and refluxed for 72 hours. Water was added to the mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1, v / v) to give 210 mg of the title compound as a white solid in 73% yield.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.21 (m, 3H), 7.09 (m, 1H), 5.86 (m, 1H), 5.12 (br, 2H), 5.09 (d, 1H), 4.65 (d, 1H), 4.36 (brs, 2H), 3.50 (br, 2H), 3.0 (br, 2H), 2.33 (s, 3H), 2.10 (s, 3H)

<Step 6> 1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine- 5-carboxylic acid cyclopropylamide

1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine prepared in step 5 -5-carboxylic acid (20 mg, 0.056 mmol) with 1-hydroxybenzotriazole hydrate (11.4 mg, 0.085 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (16.3 mg , 0.085 mmol), and cyclopropyl amine (5.8 μl, 0.085 mmol) were dissolved in dichloromethane (1 ml), stirred for 2 hours, and the reaction solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3, v / v) was purified to give 9.1 mg of the title compound as a white solid in a yield of 65%.

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (br, 2H), 3.40 (br, 2H), 3.00 (br, 2H), 2.90 (m, 1H), 2.32 (s, 3H ), 2.27 (s, 3H), 0.84 (t, 2H), 0.58 (t, 2H)

Test Example 1. Effect of Cancer Cell Growth Inhibition

The cancer cell proliferation inhibitory effect of pyrrolopyridine derivatives or salts thereof was measured on human lung cancer cell H460 (ATCC HTB-177), colon cancer cell HCT116 (ATCC CCL-247), and human breast cancer cell MCF-7 (ATCC HTB-22). . Lung cancer cells H460 and colorectal cancer cells HCT116 1,000 each, and breast cancer cells MCF-7 each 2,000 cells were suspended in Dulbecco's modified Eagle's medium (DMEM) containing 100ul medium [5% FBS (fetal bovine serum)] Cells were stabilized by aliquoting into well plates and incubating for 24 hours at 37 ° C., 5% CO ₂ . Test compounds were treated to cancer cells by concentration (as a comparative compound, 5-FU (5-Fluorouracil) was used), and then cultured for 4 days (3- (4,5-dimethylthiazol-2-yl)- Live cancer cells were stained by treatment with 2,5-diphenyl tetrazolium bromide (MTT, Sigma) The effect of the test compound on cancer cell proliferation was measured by lysing the stained cells with dimethylsulfoxide. Based on the measured values, the concentration of inhibiting cell growth by 50% (IC ₅₀ ) was determined.

Example IC ₅₀ (uM) H460 HCT116 MCF-7 6 2.0 1.2 2.9 8 1.9 0.1 2.7 12 0.4 0.4 3.7 15 0.7 0.8 4.7 19 1.9 2.0 2.5 22 1.2 0.7 3.1 24 1.9 1.3 4.6 26 0.6 0.6 2.9 37 1.6 3.3 0.6 38 0.8 0.7 1.6 40 2.0 0.9 3.4 46 0.4 1.0 2.7 49 1.4 2.8 1.9 52 1.9 1.3 3.4 54 0.4 0.4 3.4 55 3.7 1.1 3.3 5-FU 5.9 3.7 > 10

From the results of Table 1, it can be seen that the compound of Formula 1 or a salt thereof has an excellent growth inhibitory effect on human cancer cells.

The compound of formula (1) or a salt thereof has an excellent cancer cell growth inhibitory effect, thereby having an effect as an excellent anticancer agent.

Claims (4)

delete An anticancer composition comprising a compound of Formula 1 or a salt thereof and a pharmaceutically acceptable carrier: <Formula 1>

Wherein A, B, and D each independently represent N or CH, any one of A, B, and D is N, and the others are CH; R ₁ is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Methyl substituted with C ₃ -C ₇ cycloalkyl or 1,3-dioxolaneyl; C ₂ -C ₆ alkenyl substituted with C ₁ -C ₃ alkyl; C ₂ -C ₅ alkynyl; Benzyl, provided that benzyl may be substituted with halogen, straight or branched C ₁ -C ₄ alkyl, or straight or branched C ₁ -C ₄ alkoxy; Or 2,3-dihydro-benzo [1,4] dioxinylmethyl, R ₂ and R ₃ are each methyl, R ₄ is hydrogen, and R ₅ is naphthyl; 1,2,3,4-tetrahydroisoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl substituted with C ₁ -C ₃ alkyl; Benzylamino; Benzyloxy, provided that the benzyl group may be substituted one or two with halogen, or C ₁ -C ₃ alkyl; Or phenyl-C ₁ -C ₃ alkyl. 1- (3-methyl-buten-2-yl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - 1 H -pyrrolo [ 3,2-b] pyridine hydrochloride; (1-allyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridin-7-yl)-(4-fluorobenzyl) -amine hydrochloride; 7- (4-fluorobenzyloxy) -1-isobutyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-prop-2-ynyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-benzyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-cyclobutylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-fluorobenzyloxy) -2,3-dimethyl-1- (3-methyl-2-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 1- (tert-butylbenzyl) -7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1- (2-fluorobenzyl) -7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-benzyl-7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorophenyl) -2,3-dimethyl-1- (3-methyl-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 1- (2-acetoxyethyl) -7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-cyclopropylmethyl-7- (4-chlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1-([1,3] dioxolan-2-ylmethyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1- (4-chlorobenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1- (2-fluorobenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1-ethyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1- (3-methoxybenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (benzo [1,3] dioxol-5-ylmethoxy) -1- (4-methylbenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-benzyl-7- (2,4-dichlorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (2,4-dichlorobenzyloxy) -1-cyclopropylmethyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (2,4-dichlorobenzyloxy) -1-ethyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (2,4-dichlorobenzyloxy) -1- (4-fluorobenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 2,3-Dimethyl-1-ethyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 2,3-Dimethyl-1-propyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; L-allyl-2,3-dimethyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 1-cyclopropylmethyl-7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1- (3-methoxybenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1- (3-fluorobenzyl) -7- (2-ethoxybenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-cyclobutylmethyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 1-benzyl-7- (3,5-difluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 2,3-dimethyl-1- (4-methylbenzyl) -7- (4-benzyloxy-trifluoromethyl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 2,3-dimethyl-1- (3-methoxybenzyl) -7- (4-benzyloxy-trifluoromethyl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 1- (1,3-dioxolan-2-ylmethyl)-[7- (1,2,3,4-tetrahydroisoquinolin-2-yl)]-2,3-dimethyl - 1 H -pi Rolo [3,2-c] pyridine hydrochloride; 2- (1-ethyl-2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (1- (2,3-dihydro-benzo [1, 4] dioxin-6-ylmethyl) -2,3-dimethyl-1 H- pyrrolo [3,2-c] pyridine-7 Il) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-prop-2-ynyl - 1 H -pyrrolo [3,2-c] pyridine hydrochloride; 7- (4-fluorobenzyloxy) -1- (2-methoxyethyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridine hydrochloride; 1-cyclopropylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridine hydrochloride; 1-Cyclopropyl-2,3-dimethyl-4- (4-fluorobenzylamino) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride; 1-benzyl-2,3-dimethyl-4- (4-fluorobenzylamino) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride; 2,3-dimethyl-1- (2-fluorobenzyl) -4- (4-fluoro-benzylamino) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride; 3-benzyl-2-methyl-4- (1,2,3,4-tetrahydro-isoquinolin-2-yl) - 1 H- pyrrolo [3,2-c] pyridine hydrochloride; 1-allyl-7- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 2- (2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline sodium salt; 7- (4-chlorobenzylamino) -1-isobutyl-2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 7- (benzylamino) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 1-benzyl-2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 1- (2-methoxyethyl) -2,3-dimethyl-7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 2,3-dimethyl-1- (4-methylbenzyl) -7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 2,3-Dimethyl-7- (4-methylsulfanyl-ylphenyl) - 1 H- pyrrolo [2,3-c] pyridine; 2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride; L- (3-fluorobenzyl) -2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride; And 1-allyl-7- (3,4-dihydro - 1 H -isoquinolin-2-yl) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine-5-carboxylic acid cyclo Propylamide An anticancer agent composition comprising a compound selected from the group consisting of pharmaceutically acceptable carriers. 1-cyclobutylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-fluorobenzyloxy) -1-propyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorophenyl) -2,3-dimethyl-1- (3-methyl-butene-2-yl) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1-([1,3] dioxolan-2-ylmethyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (4-chlorobenzyloxy) -1- (3-methoxybenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (2,4-dichlorobenzyloxy) -1-cyclopropylmethyl-2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 7- (2,4-dichlorobenzyloxy) -1- (4-fluorobenzyl) -2,3-dimethyl - 1 H -pyrrolo [3,2-b] pyridine hydrochloride; 2,3-Dimethyl-1-propyl-7- (3-methyl-benzyloxy) - 1 H- pyrrolo [3,2-b] pyridine hydrochloride; 2- (1- (2,3-dihydro-benzo [1, 4] dioxin-6-ylmethyl) -2,3-dimethyl-1 H- pyrrolo [3,2-c] pyridine-7 Il) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-prop-2-ynyl - 1 H -pyrrolo [3,2-c] pyridine hydrochloride; 1-cyclopropylmethyl-7- (4-fluorobenzyloxy) -2,3-dimethyl - 1 H -pyrrolo [3,2-c] pyridine hydrochloride; 2- (2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride; 7- (benzylamino) -2,3-dimethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 2,3-dimethyl-1- (4-methylbenzyl) -7-phenethyl - 1 H -pyrrolo [2,3-c] pyridine hydrochloride; 2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride; And L- (3-fluorobenzyl) -2,3-dimethyl-7- (naphthalen-2-yl) - 1 H- pyrrolo [2,3-c] pyridine hydrochloride An anticancer agent composition comprising a compound selected from the group consisting of pharmaceutically acceptable carriers.