WO1998030548A1

WO1998030548A1 - 5-HT2c RECEPTOR AGONISTS AND AMINOALKYLINDAZOLE DERIVATIVES

Info

Publication number: WO1998030548A1
Application number: PCT/JP1998/000071
Authority: WO
Inventors: Kyoichi Maeno; Hideki Kubota; Itsuro Shimada; Shuichi Sakamoto; Shin-Ichi Tsukamoto; Fumikazu Wanibuchi
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1997-01-13
Filing date: 1998-01-12
Publication date: 1998-07-16
Also published as: JP3560986B2; AU5343298A

Abstract

Drugs containig as the active ingredient aminoalkylindazole derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof, which have high affinity and selectivity to 5-HT2c receptors and are useful in treating central nervous system diseases such as sexual disorders, genital insufficiency, appetite regulation disorders, anxiety, depression, and sleep disorders, wherein each symbol has the following meaning: A represents optionally substituted, linear or branched C2-6 alkylene or cycloalkane; R?1 and R2¿ are the same or different and each represents hydrogen or lower alkyl, or R?1 and R2¿ may form together with A a nitrogen-containing saturated heterocycle; and R?3 and R4¿ are the same or different and each represents hydrogen, lowr alkyl, halogeno, hydroxy, lower alkoxy, aryl-substituted lower alkoxy, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro or cyano.

Description

Specification

5-HT _{2 c} receptor agonists and aminoalkylindazole derivatives

The present invention relates to a 5-HT _2c receptor agonist comprising, as an active ingredient, an aminoalkylindazole derivative or a pharmaceutically acceptable salt thereof. Further regarding aminoalkyl indazoles derivative or a pharmaceutically acceptable salt thereof is a 5-HT _{2 c} receptor work for drugs. Background art

With the advent of an aging society, the improvement and improvement of the lives of the elderly has been reviewed, and the prevention or treatment of sexual disorders, sexual dysfunctions, and other diseases that have been abandoned until now are not diseases. Is becoming more focused.

5— Η Τ _{2 ϋ} receptors are mainly centrally distributed and their role is not fully understood, but central nervous system disorders such as sexual disorders, sexual dysfunction, anorexia, anxiety It is thought to be involved in depression, sleep disorders, etc. Therefore, 5-HT _{2 C} receptor agonists are useful for the prevention or treatment of the above-mentioned diseases, and in particular, there is no effective treatment method that has been abandoned as a non-disease such as sexual dysfunction and sexual dysfunction. It is considered that it is also useful.

For such 5-HT _{2 C} receptor agonists, several compounds have been known so far. For example, EP 655440, EP 657426, EP 700905, J. Med. Chem., 40, 2762 (1997) in 5 HT _{2 c} receptor compounds central nervous system disorders having an affinity, for example, sexual dysfunction, anxiety, It is disclosed that it is useful for depression, sleep disorders, and the like. The compounds disclosed therein are only indole derivatives, tricyclic pial derivatives and tricyclic pyrazole derivatives.

On the other hand, some aminoalkylindazole derivatives have been reported (FR 7631; Zhur. Obshchei. Khim., 29, 1012 (1959); Bull. Soc. Chim. Fr., 1969, 2064, etc.). Has an affinity for 5-HT _{2 C} receptors and discloses and suggests central nervous system diseases such as sexual disorders, sexual dysfunction, appetite regulation disorders, anxiety, depression, sleep disorders, etc. Not. Disclosure of the invention

The present inventors have, 5-HT _{2 C} receptor agonists result of intense study regarding, amino alkyl fin Dazo Ichiru derivative Shi pairs 5-HT ₂ c receptor compared to Indoru derivatives mightier, affinity have sex, and completed also found present invention to have a selectivity for 5-HT _{2 a} and 5-HT receptors. Furthermore, it has been found that these aminoalkylindazole derivatives have high activity even in animal models. That is, the present invention relates to a medicament comprising, as an active ingredient, an aminoalkylindazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which has strong affinity and selectivity for 5-HT _{2 C} receptor. Preferably, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, which is a therapeutic agent for central nervous system diseases such as sexual disorders, sexual dysfunction, anorexia dysfunction, anxiety, depression or sleep disorders, is used as an active ingredient. The object of the present invention is to provide a drug comprising the compound (I) of the present invention, which is preferably a therapeutic agent for sexual dysfunction or sexual dysfunction, or a pharmaceutically acceptable salt thereof as an active ingredient. is there.

(The symbols in the formula have the following meanings

A: may have a substituent having 2 to 6 carbon atoms, and may be a linear or branched alkylene group or cycloalkane

! ^ And scale ² : same or different, hydrogen atom, lower alkyl group or R ¹ may combine with R ² or A to form a nitrogen-containing saturated ring

R ³ and R ^{4 are the} same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino Group, nitro group or cyano group) Further, the present invention provides a general compound having strong affinity and selectivity for 5-HT _{2 C} receptor as follows: The aminoalkylindazole derivative AI represented by the formula (II) is a pharmaceutically acceptable salt thereof, or the compound (II) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. It is intended to provide a pharmaceutical composition comprising a carrier.

(The symbols in the formula have the following meanings

A: may have a substituent having 2 to 6 carbon atoms t, linear or branched alkylene group or cycloalkane

R ¹ and R ² : the same or different, and a hydrogen atom, a lower alkyl group or R ¹ may combine with R ² or A to form a nitrogen-containing saturated heterocycle

R ³ and R ^{4 are the} same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino Group, nitro group or cyano group, provided that when R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkanoylamino group or a nitro group, R ¹ is hydrogen Indicates the meaning of the atom)

Preferred compounds are the compounds (II) of the present invention wherein A is an ethylene or propylene group, and more preferably the compounds of the present invention wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a lower alkoxy group or a halogen atom. (II), more preferably the compound of the present invention (II) wherein R ¹ and R ² are hydrogen atoms, and particularly preferably 2- (5,6-dichloro-1H-indazole-11-yl) ethylamine Or a pharmaceutically acceptable salt thereof; (S) —2- (6-fluoro-1H-indazole-11-yl) -11-methylethylamine or a pharmaceutically acceptable salt thereof. . Hereinafter, the compound of the present invention (1, II) will be described in detail.

“5-HT _2C receptor agonist” is a compound that has an affinity for 5-HT _2C receptor and has an agonistic or antagonistic action. In the definition of the general formula herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.

Specific examples of the “linear or branched alkylene group having 2 to 6 carbon atoms” include ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, Ethil Echire

A ethylene group.

And particularly preferably an ethylene or propylene group.

"Cycloalkane" means a monocyclic hydrocarbon ring group having 3 to 8 ring atoms, and specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. And preferably pentane and pentane, and particularly preferably pentane.

As the "lower alkyl group", specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or isohexyl A hexyl group and the like can be mentioned, preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl or ethyl group, and particularly preferably a methyl group.

The term "nitrogen-containing saturated heterocycle" means a 3- to 8-membered nitrogen-containing saturated heterocycle, specifically, for example, aziridine, azetidine, pyrrolidine, piperidine, hexahydroazepine or octahydroazosine. Preferred are pyrrolidine and piperidine, and particularly preferred is pyrrolidine.

The “halogen atom” includes a fluorine, chlorine, bromine or iodine atom, and is preferably a fluorine or chlorine atom.

“Lower alkoxy group” means an oxy group substituted by the lower alkyl group.

“Aryl lower alkoxy group” means the above lower alkoxy group substituted by the aryl group.

The term "aryl group" means a carbon ring aryl group having 6 to 14 carbon atoms, specifically, for example, phenyl, trithyl, xylyl, biphenyl, naphthyl, anthryl or And a phenyl group. A phenyl group is preferred.

The “mono- or di-lower alkylamino group” means an amino group in which the above lower alkyl group is substituted by 1 or 2 groups.

"Lower alkanoylamino" means a carbonylamino group substituted by the lower alkyl.

The substituent “may have a substituent” means the above-mentioned halogen atom or lower alkoxy group.

The compound (III) of the present invention may have an asymmetric carbon atom depending on the type of the group. Therefore, the compound (III) of the present invention includes a mixture of optical isomers and an isolated one.

The compound (III) of the present invention can form an acid addition salt. The compounds of the present invention also include these salts. Specific examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and the like. Organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.

Furthermore, the compound (III) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as various solvates such as hydrates and ethanolates, or as polymorphic substances thereof. The compounds of the present invention also include various hydrates and solvates of the above-mentioned type.

(Manufacturing method)

The compound of the present invention represented by the general formula (II) can be synthesized, for example, by the following method, but the production method of the compound of the present invention is not limited thereto.

First production method (raw material synthesis)

(iv) ^ ϊζMiddle, Κ. ( ⁴⁾ is as described above, (D) is a straight chain or branched alkylene group having 6 carbons, and (E) is a halogen atom, a tosyloxy group or a mesyloxy group. And the like, or a group which can be easily converted to an amino group such as a cyano group, an azido group, a nitro group, an amino group protected with a commonly used protecting group, or a hydroxyl group.

However, D and E may combine to form a nitrogen-containing saturated ring.)

The raw material (IV) of the compound of the present invention can be easily produced by subjecting the indazole derivative (III) to a conventional alkylation reaction. For example, an alkylation reaction using an alkyl halide, an alkyl tosylate, an alkyl mesylate or an epoxide derivative can be performed. When E is a hydroxyl group, esters of tosylic acid and mesylic acid can be easily produced by using a standard esterification reaction, and phthalimid derivatives can be easily produced by using Mitsunobu reaction or the like.

Second manufacturing method

(Wherein, RR ² , R ³ , R ⁴ and A are as described above, and X represents a leaving group such as a halogen atom, a tosyloxy group, a mesyloxy group, etc.)

The compound (I, II) of the present invention can be produced by converting the compound represented by the general formula (IVa) into a corresponding amino compound.

This reaction can be carried out in the presence or absence of a suitable solvent, in the presence of a suitable base if necessary, under cooling or heating, or, if necessary, in a sealed reaction vessel.

Third manufacturing method

(IVb) A, K \ Κ ⁴ and Α are as described above, and G means a linear or branched alkylene group having 5 urinary cords.

The compounds (Ia, IIa) of the present invention can be produced by reducing the nitrile compound represented by the general formula (IVb) and converting it into the corresponding amino compound.

This reaction is carried out in the presence or absence of a suitable inert solvent, preferably in tetrahydrofuran, if necessary, in the presence or absence of a suitable Lewis acid, using a suitable reducing agent, under cooling or heating. , Preferably at room temperature. Examples of the Lewis acid include aluminum chloride, and examples of the reducing agent include a hydride complex such as lithium aluminum hydride.

This reaction can also be carried out by catalytic hydrogenation on a metal catalyst using a suitable solvent such as ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof.

Fourth manufacturing method

(IVc) (la'lla)

(Wherein RRR ⁴ and A are as described above, and Y represents a group that can be easily converted to an amino group such as an azido group, a nitro group, or an amino group protected with a commonly used protecting group.

However, A and Y may combine to form a nitrogen-containing saturated heterocycle.)

The compounds (Ia, IIa) of the present invention can be produced by converting the compound represented by the general formula (IVc) to the corresponding amino compound.

When Y represents an azide group, etc., this reduction reaction is carried out in the presence or absence of a suitable inert solvent, and if necessary, in the presence or absence of a suitable Lewis acid, by cooling or heating using a reducing agent. Can be done below. As the reducing agent, a hydride complex such as lithium aluminum hydride or the like can be used. In addition, the present reduction reaction is carried out in a suitable solvent, for example, ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid, water or The reaction can also be carried out by using catalytic hydrogenation on a metal catalyst using these mixtures or by using triphenylene.

When Y represents a nitro group or the like, the present reduction reaction can be carried out by catalytic hydrogenation on a metal catalyst using an appropriate solvent, for example, ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof. . Alternatively, the reaction can be carried out in the presence or absence of a suitable solvent, using a metal (eg, iron, tin) or the like, in the presence of an acid catalyst, and under cooling or heating.

When Y represents an amino group protected by a commonly used protecting group, the amino group can be converted into an amino group by deprotection according to a conventional method. For example, when the protecting group is a phthalimid group, a similar method described in Protecting Groups in Organic Synthesis, John Wiley & Sons, INC. Can be used. If the protecting group is a normal acyl group, it can be easily deprotected under acidic or basic conditions.

Fifth manufacturing method

(Where RR ² , R ³ , R ⁴ and A are as described above)

The compound (I, II) of the present invention can be produced by N-alkylating the compound represented by the general formula (Ia, IIa) produced by the second to fourth processes.

This reaction is carried out in the presence or absence of a suitable solvent, in the presence of a suitable alkylating agent, preferably a lower alkyl halide (eg, propyl iodide), and if necessary, a suitable base as a deoxidizing agent, and then cooling or heating. Can be done below.

A reductive alkylation reaction can also be performed as the present alkylation reaction. In the presence or absence of a suitable inert solvent, a reducing agent such as a borohydride reagent (for example, sodium borohydride) is used, and if necessary, an acid catalyst, preferably a mineral acid or In the presence of an organic acid, under cooling or heating, an appropriate lower alkyl aldehyde (eg, (Propanal) can be reacted.

Sixth manufacturing method

(Wherein, RR ² , R ³ , R \ A, D and X are as described above, and Z means the aforementioned E or the formula NR ¹ R ^2. )

The compound (I, II) of the present invention is obtained by reacting the compound represented by the general formula (V) with a hydrazine derivative (VI) to lead to a hydrazone (VII), and further converted to (VIII) by an intramolecular cyclization reaction. If necessary, it can be produced via desired functional group conversion.

The reaction for producing the hydrazone compound (VII) is carried out in the presence or absence of a suitable solvent, preferably in an alcohol, and, if necessary, in the presence or absence of a suitable acid or base, with a suitable substituted hydrazine (VI) (Eg, 2-hydrazinoethanol) under cooling or heating, preferably at room temperature.

The intramolecular cyclization reaction is carried out in the presence or absence of a suitable solvent, preferably in dimethylformamide, and, if necessary, in the presence or absence of a suitable acid or base (for example, in carbon dioxide lime). The reaction can be carried out at room temperature to 100 ° C. under cooling or heating.

The (VIII) thus obtained can be produced, if necessary, by converting it to the compound (1, II) of the present invention by a method similar to Production Methods 1 to 5.

Further, the salt of the compound of the present invention (I, II) can also be produced by subjecting the salt to a conventional salt-forming operation.

The compound of the present invention (1, II) thus produced is isolated and purified as a salt, a hydrate, a solvate, or a polymorphic substance of the compound as free. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, reconstituted products, and valley chromatography.

Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, the optical isomers can be sterically selected by selecting an appropriate raw material or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active acid or base). It can lead to scientifically pure isomers.

Hereinafter, in addition to those described in the examples, the above-mentioned production methods, the production methods of the examples, the production methods known to those skilled in the art, and modifications thereof are used without any special experiment. The following compounds can be obtained:

2- (7-Fluoro-1H-indazolu-1-yl) ethylamine; 2- (6,7-difluoro-1H-indazo-1-1-1inoethyl) ethylamine; 2- (5,7-difluoro-1H) —Indazo-1-ru) -Echilamine; 2— (4,7—Difluoro- 1 H—Indazo-1-1-yl) Echilamine; (R) — 2— (6 —Full-orle 1 fi—Indazo-lu 1-yl) 1-methylethylamine; (S) — 2— (6-Fluoro-1H-indazolone) 1-ethylethylethylamine; (S) 1 2 — (6—Fluoro 1 H indazole-1 —inole) 1 1—Isopropylletylamine; 3— (6—Fluoro1 fiindazoyl 1 1yl) — 1-Methylpropylamine; 3— (5— Fluoro-1H-indazolu-l-inole 1-methyl-1-propylamine 2 _ (7 -Bromo-6-fluoro-1 H-indazole-1 1-yl) ethylamine; 2- (6 -Fluoro-7-methoxy-1 1-indazo-Lu 1 -yl) ethylamine; 2- (5 -Fluoro-6 —Methoxy 1 H—Indazole—1 yl) ethylamine; 2— (7—Cro mouth—6—Fluoro-1H-indazole—1 yl) ethylamine; 2— (7—Chloro-5 —Fluoro 1 H—Indazolu 1—Innole) ethylamine; (S) — 2— (6—black 1—fluo 1—ff—indazo 1—1) — 1—Methylethylamine 2— (4-chloro-6-fluoro-1H-indazole-1-1-inole) ethylamine; 2- (4,6 dichroic mouth—1-indazo-1l-1yl) ethylamine; 2 -— (4,7—dic Rollo-1H-Indazole-1-yl) ethylamine; —2— (4,5-dichloro mouth-1 fi-indazole-1-1-yl) 1-1-methylethylamine; 2 — (5—Cyano 1 H-indazo 1-yl) ethylamine; 2- (5-dimethylamino 1 H—indazo 1-yl) ethylamine; 2- (5-methylamino 1 H-indazo) 1-ru) Etilamine Possibility of industrial use

The compound of the present invention has a strong affinity and selectivity for 5-HT _2C receptor and is also effective in animal models, so that it can be used in central nervous system diseases such as sexual disorders, sexual dysfunction, and appetite regulation. It is useful for treating disorders, anxiety, depression, sleep disorders, etc.

The selectivity and affinity of the compound of the present invention for 5-HT _{2 C} receptor and the evaluation by an animal model using a rat were confirmed by the following methods.

A. Combination experiment

5-HT _{2 c} and 5 -HT _{2 A} receptor:... A. Pazos et al , Eur J. Pharmacol, ] 06, 539-546 (1985) or, S. havlik and SJ Peroutka, Brain Res,. 584, was performed by ^[3 H] 5- HT binding assay according to the method of 191-196 (1992).

5 -HT! ; ^ Receptor: SJ Peroutka, J. Neurochem.47, was carried out by the method according to ^{[3 H] 8 -OH-DP} AT binding assay 529-540 (1986).

Using the above method, the concentration of the drug that inhibits 50% of the receptor-binding ligand (IC ₅₀ value) was determined, and the Ki value representing the affinity for the receptor was calculated by the following formula: Ki = IC ₅ . Z (1+ [L] / [Kd]) ([L]: ligand concentration, [Kd]: dissociation constant) The results are shown in Table 1. Table 1 Binding experiments (K i, nM)

Known compound: 2- (5-Fluoroin'-Lu-11-yl) ethylamine fumarate (Example 1 of 655655440) The compounds of the present invention 5 compared to Indoru derivatives - have a strong parent Oro against HT _{2 C} '' trough body, 5-HT _{2 A} receptor and 5 - has a selectivity for HTA receptor.

B. Animal model using rat

Rat penile erection-inducing action: 5-—The ability to induce penile erection by HT _{2 C} receptor stimulation is known (Berendsen & Broekkamp, Eur. J. Pharmacol., 135, 179-184 (1987) ). The test compound was administered to the rat. Immediately after the administration, the number of penile erections for 30 minutes was measured and compared with the minimum effective dose at which a statistically significant response was observed. Table 2 shows the results. Table 2 Animal model using rat

Known compound: 2- (5-fluoroindole-l-yl) ethylamine fumarate (Example 1 of EP 655440) The indazole derivative of the present invention is an animal compared to the indole derivative of EP 655440. The model showed a much higher activity of 10 times or more.

As described above, the compound of the present invention is effective in animal models using rats, and is therefore useful for treating central nervous system diseases such as sexual dysfunction or sexual dysfunction.

Pharmaceutical compositions containing one or more of the compound (I, 11) of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, etc. as an active ingredient are usually used. Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., using the carriers used in formulation, excipients and other additives It is prepared and administered orally (including sublingually) or parenterally.

The clinical dose of the compound of the present invention (I, II) for humans is appropriately determined according to the individual case in consideration of the patient's symptoms, body weight, age, sex, administration route, and the like. Normally, per adult, 10 mg to 100 mg per day, preferably in the range of 50 mg to 200 ^ ^ orally once or several times a day, or adult Per person Or from 1 mg to 500 mg, preferably 5 mg to 100 mg per day, administered intravenously once to several times a day, or 1 hour to 24 hours a day It is administered intravenously over a period of time. Of course, as described above, since the dose varies under various conditions, a smaller amount of t or less than the above dose may be sufficient.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. Mixed with magnesium aluminate metasilicate. The composition may contain, in a conventional manner, additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose. A solubilizing agent such as glutamate or aspartic acid may be contained. Tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a gastric or enteric film, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavors, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). is there. Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. . These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. these Alternatively, a sterile solid composition can be produced and dissolved in sterile water or a sterile injection solvent before use. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described in more detail with reference to examples. The present invention is not limited to these examples. The starting compounds used in the examples will be described as reference examples.

Reference example 1

Under an argon stream, 1.86 g of sodium hydride was washed with hexane, and 100 ml of dimethylformamide was added. Under ice-cooling, 5.27 g of 4-fluoro-indazole dissolved in 10 ml of dimethylformamide was gradually added thereto, followed by stirring for 30 minutes. Further, 3.50 g of chloroacetonitrile was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 5) (4-funoleolol 1H-indazolyl-1-yl) acetonitrile 3.3 3 g was obtained as a pale yellow solid.

In the same manner as in Reference Example 1, the compounds of Reference Examples 2 to 24 were obtained.

Reference Example 2: (6-Fluoro-1H-indazo-1-yl) acetonitrile Reference Example 3: (4,5-difluoro-1 fi-indazolyl-1-1-yl) acetonitrile Reference Example 4: (5 —Fluoro-4 —Methyl— 1 H—Indazo-1-yl

Reference Example 5: (6-Nitro 1 H— ^ f Dazo 1-Ru 1-inole) acetonitrile Reference Example 6: (5-Nitro-1 f / -indazole-1-yl) acetonitrile Reference Example 7: (5— Chloro I f / —Indazo 1-yl) Acetonitrile Reference Example 8: (5—Bromo 1 H—Indazo 1-yl 1-yl) Acetonitrile Reference Example 9: (5—N-do 1 fi-Indazo 1-ru 1 —Yl) acetonitrile Reference Example 10 0: (5-methyl-1H-indazolu-l 1 —yl) acetonitrile Reference Example 1 1: (5-Butyl 1 H-Indazolu-l-Il-Acetonitrile Reference Example 1 2: (5-Methoxy 1 fi-Indazo-l-Ru 1-yl) Acetonitrile Reference Example 1 3 : (5,6-Dichloro-1-indazo-1-yl-1) acetate ditolyl Reference Example 14: (5-bromo-6-fluoro-1 fi-indazole-1-11) acetate nitrile

Reference Example 15: (6-chloro-5-fluoro-1H-indazo-1-yl) acetate nitrile

Reference Example 16: (5-black mouth _ 6-fluoro-1 H-indazo 1-yl) acetate ditril

Reference Example 17: (4-chloro-5-fluoro-1 fi-indazole-1-yl) aceto nitrile

Reference Example 18: (6-Bromo-5-fluoro-1H-indazo-1-yl)

Reference Example 19: (5,6-Difluoro-1H-Indazo-1-yl) Acetonitrile

Reference Example 20: (6-Methoxy Iff-Indazo-1-ru) Acetonitrile Reference Example 21: 2- (6-Fluoro-1H-Indazo-1-ru) Propionnitrile

Reference Example 22: 2- (6-Fluoro-1H-indazole-1-yl)

Reference Example 23: (5-Fluoro-1H-indazolu-1-yl) Ethyl acetate Reference Example 24: (7-Bromo-6-methoxy-1H-indazo-1-ru 1-1yl) acetonitrile

Reference Example 25

Dissolve 1.40 g of 5-fluoro-1H-indazole in 10 ml of dibromoethane, add 1 · 38 g of ert ert potassium monobutoxide, stir at 100 ° C for 1 hour, and further add ί er 1.38 g of potassium butoxide and 10 ml of dibromoethane were added, and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with chloroform. Organic layer Was washed with water and dried over anhydrous magnesium sulfate. After solvent distillation, 饯渔 was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4), and 0.41 g of 1-bromoethyl-5-fluoro-1H-indazole was converted to a yellow solid. As obtained. Reference Example 26

Under an argon atmosphere, 0.24 g of lithium aluminum hydride was suspended in 30 ml of tetrahydrofuran, and a solution of (5-fluoro-1H-indazo-1-yl) ethyl acetate (1.4 g of tetrahydrofuran in 10 m) was added. Was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and chloroform was added. After removing insolubles by celite filtration, the filtrate was extracted with chloroform. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After distilling off a part of the solvent, the residue is purified by silica gel gel chromatography (eluent: ethyl tolueneacetate = 2Z1), and 2- (5-fluoro-1-if-dazo-1-yl) ethanol 1.03 g was obtained.

Reference Example 27

By a method similar to that of Reference Example 26, 2- (6-fluoro-1H-indazo-1-yl) cyclopentanoyl was obtained.

Reference Example 28

2- (5-Fluoro-1H-indazolu-1-yl) Dissolve 1.03 g of ethanol in 20 ml of methylene chloride, add 2.40 ml of triethylamine, 0.66 m of methanesulfonyl chloride 1 was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with a black form. The organic layers were combined, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure to obtain 1.43 g of methanesulfonic acid 2_ (5-funoleo-1H-indazole-1-inole) ethyl.

Reference Example 29

0.33 g of sodium cyanide was suspended in 15 ml of dimethylformamide, and 0.53 g of 2- (5-fluoro-1H-indazo-1-yl) ethyl methanesulfonate was added to 0.58 g of dimethylforma A mid solution (5 ml) was added, and the mixture was stirred at 50 ° C for 4 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. Filter off the desiccant Thereafter, the solution was reduced in concentration to obtain 0.40 g of 3- (5-fluorene 1 ff / intersol / poly) propiononitrile.

Reference example 30

Under an argon stream, sodium hydride (0.32 g) was washed with hexane, and dimethylformamide (10 m) was added. To this, 2 ml of a dimethylformamide solution of 5-fluoro-1-indazole 1.OOg was added dropwise under ice-cooling, and the mixture was stirred for 20 minutes. Further, 0.59 ml of propylene oxide was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 48 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: toluene Z-ethyl acetate = 4), and purified with 1- (5-fluoro-1H-indazo-1-yl) propane-2-ol 0.64 g was obtained.

In the same manner as in Reference Example 30, the compounds of Reference Examples 31 to 42 were obtained.

Reference Example 3 1: (R) — 1— (5—Fluoro—1 H—Indazo 1-Ru 1-Il) Propane 2—All

Reference example 3 2: (S) — 1— (5—Funolero 1 —Indazo mono 1-yl) Propane 21

Reference Example 3 3: (R) -1-1 (6-fluoro-1H-indazole-1-yl) propane_2-one

Reference Example 34: (R) -1-1 (6-Methoxy 1 H-indazole-1-yl) Propan-2-ol

Reference Example 35: (R) -1-1 (6-benzyloxy 1 H-indazo-1-ru-1) propane-1-2-ol

Reference Example 3 6: 1-(6-Fluoro-1H-Indazo-1-yl) 1-3-Fluoropropane-1--2-ol

Reference Example 37: 1 — (6-Fluo mouth — 1 H—Indazo 1-yl 1 —yl) — 3—Methoxy cyproha. No 2—All

Reference Example 38: (R)-1-(6,7-Dichro mouth-1 J / Indazole-1 -yl) Bronon 2 Ginseng example 3 9: K-1-(5, 6—: Loro 1 — Indazol 1 1) Propane 2 1 1

Reference Example 40: (R) — 1 (6—Methoxy 7—Nitro 1 H—Indazo 1 1 1 1) Prono. N-one 21-all

Reference Example 4 1: (R)-1-(7-chloro-6-methoxy-1 Η-indazo 1-1 yl) Propane 1-2-ol

Reference Example 4 2: (R) -1-1 (7-bromo-6-methoxy-1Η-indazo-1-yl) propane-1-2-ol

Reference example 4 3

Dissolve 0.64 g of 1- (5-fluoro-1-indazole-1 l-fol) propane-2-ol in 15 ml of methylene chloride, add 1.38 ml of triethylamine, and add 0.38m] and stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with black-mouthed form. The organic layers were combined, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the dried precipitate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain 0.92 g of methanesulfonic acid 2- (5-fluoro-1fi-indazo-l-yl) -11-methylethyl. Dissolve 0.90 g of methanesulfonic acid 2- (5-fluoro-1-indazole-1 T) in methyl dimethylformate in 15 ml of dimethylformamide and add 0.64 g of sodium azide to this The mixture was stirred at 70 ° C for 17 hours. After cooling, the reaction mixture was poured into ice water and extracted with ether. The organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the solvent was concentrated under reduced pressure to obtain 0.63 g of 1- (2-azidopropyl) -15-fluoro 1H-indazole.

The compounds of Reference Examples 44 to 54 were obtained in the same manner as in Reference Example 43.

Reference Example 44: (S) -1-1 (2-azidopropyl) -1-5-fluoro-1H-indazo

—Le

Reference Example 45: (R) -1 (2-azidopropyl) -1-5-fluoro-1-indazole

Reference Example 4 6: (S) 1 (2-azidopropyl) -1-6-fluoro-1ff-indazole Reference Example 4 7 (2-Azido 6-benzyloxy 1 H-indazo-norre

Reference Example 4 8 (S) — 1— (2-azidopropyl) 1 6—Methoxy 1 Iff 1 Indazole

Reference Example 4 9 1 1 (2-azidocyclopentyl) 1 6-fluoro-1-indazole

Reference Example 50 1- (2-azido 3-fluoro 6-fluoro-1H-indazole

Reference Example 5 1 1 1 (2-azi 3-methoxypropyl) 6-fluoro-1H-indazo

Reference Example 5 2 (S) -1-1 (2-azi 6-methoxy 7-nitro 1 H-indazole

Reference Example 5 3: (S) — 1 — (2-Azido- 1 7 —Chloro-1- 6—Methoxy 1 // Indazole

Reference Example 54: (S) -11- (2-azidopropyl) 7-bromo-6-methoxy 1H-indazole

Reference Example 5 5

To a solution of 0.83 g of 1,4-dioxane (80 ml) in 2- (5-nitro-1-fi-indazo-l-l-yl) ethylamine, 0.97 g of di-tert-butyl dicarbonate was added. In addition, the mixture was stirred at 80 ° C for 4 hours. After allowing the reaction solution to cool to room temperature, it was poured into water and extracted with ethyl acetate. The extracted organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 1.19 g. This 1.16 g was dissolved in tetrahydrofuran (50 ml), 10% palladium carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-form 7 methanol = 100/3), and [2- (5-amino-1H-indazo-l-u-inole) ethyl] capillamide was purified. 0.81 g of tert-butyl ester of acid was obtained.

Example 1 Under an argon stream, 0.30 g of lithium aluminum hydride was suspended in 0 ml of tetrahydrofuran, and 0.97 g of aluminum chloride was added thereto under ice-cooling, followed by stirring for 15 minutes. To this suspension, a tetrahydrofuran solution (5 ml) of 1.28 g of (4-fluoro-1H-indazo-1-yl) acetonitrile was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. . Methanol was added to the reaction solution, and the excess reagent was separated by ft. Further, 0.5 ml of water, 0.5 m of a 15% aqueous sodium hydroxide solution and 1.5 m of water were sequentially added, and the mixture was stirred for 1 hour. The resulting insoluble matter was removed by filtration through a silica gel, and the filtrate was concentrated. The resulting residue was subjected to silica gel gel chromatography (eluent: chloroform Z methanol Z saturated ammonium water = 10/1. Purification by 1) gave 0.56 g of 2- (4-fluoro-1H-indazo-1-yl) ethylamine. The obtained 2- (4-fluoro-1-indazolu-1-ethyl) ethylamine was dissolved in ethanol, and a 4N solution of ethyl acetate in hydrochloric acid was added thereto. The resulting crystals were collected by filtration, dried under reduced pressure, and dried under reduced pressure. 4-Fluoro-1H-indazo-1-yl) ethylamine hydrochloride 0.28 g was obtained as a white solid.

Example 2

To a solution consisting of 7 ml of water and 7 ml of concentrated hydrochloric acid was added 3.50 g of 4-fluoro-2,5-dimethylaniline, and 1.9 sodium nitrite dissolved in 1 ml of water was added under ice cooling. 0 g was added dropwise and stirred for 1 hour. After removing the insoluble matter by filtration, 3.86 g of sodium borohydride dissolved in 5 ml of water was added to the filtrate under ice cooling and stirred for 30 minutes. The resulting precipitate was collected by filtration and air-dried. The obtained boroboronate was suspended in 50 ml of chloroform, and 0.13 g of 18-crown 6-etherenol was added thereto at room temperature under a stream of argon at room temperature. 11 g were added sequentially. After reacting at room temperature for 1 hour, insolubles in the reaction solution were removed by filtration, and the filtrate was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: toluene Z-ethyl acetate = 5) to obtain 0.36 g of 5-fluoro-6-methyl-1H-indazole. Under an argon stream, 0.14 g of sodium hydride was washed with hexane, and 10 ml of dimethylformamide was added. Under ice-cooling, 0.36 g of 5-funoleol 6-methyl-1ff-indazol dissolved in 1 ml of dimethylformamide was gradually added thereto, followed by stirring for 30 minutes. Further, 20 g of chloroacetonitrile was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. Was. The reaction solution was poured into ice water and extracted with ether. The organic layers were combined, washed with water and brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: hexane Z-ethyl acetate = 5) (5-fluoro-6-methinole 1 H-indazole-1 -yl) acetonitrile 0.08 g Was obtained as a white solid. Under argon gas flow, 0.3 g of hydrogen aluminum lithium aluminum was suspended in 5 ml of tetrahydrofuran, and 0.12 g of aluminum chloride was added thereto under ice cooling, followed by stirring for 15 minutes. To this suspension, a tetrahydrofuran solution (5 ml) of 0.08 g of (5-fluoro-6-methyl-1H-indazo-1-yl-1-yl) acetonitrile was added under ice-cooling, followed by stirring at room temperature for 1 hour. Methanol was added to the reaction solution to decompose excess reagents, and then 10 ml of a 40% aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: chloroform Z methyl alcohol Z saturated aqueous ammonia = 10/1 / 0.1). Purification gave 0.07 g of 2- (5-fluoro-6-methyl-1 ff-indazo-l-l-yl) ethylamine. The obtained 2- (5-fluoro-6-methyl-1H-indazo-1-yl) ethylamine was dissolved in ethanol, and a 4 N ethyl acetate solution of hydrochloric acid was added thereto. The resulting crystals were collected by filtration. Thereafter, the residue was dried under reduced pressure to obtain 0.07 g of 2- (5-fluoro-6-methyl-1H-indazo-1-yl-1-ethyl) ethylamine hydrochloride as a white solid. In the same manner as in Example 1, the compound of Example 3 was obtained.

Example 3: 21- (6-fluoro-1H-indazolu-l-yl) ethylamine hydrochloride

■ * -πfeτrι ·

Ingredients: (6-Fluoro-1Η-indazo-l-l-inole) acetonitrile Example 4: 2- (4,5-difluoro-1 fi-1 ^ T-dazol-1-inole) ethylamin hydrochloride

Ingredients: (4,5-difluoro-1 fi-indazole-1-yl) acetate nitrile Example 5: 2-(5_fluoro- 4-methyl-11 / indazole-1) Yl) ethylamine hydrochloride

Ingredients: (5-Fluoro-4-methyl-1H-indazo-1-yl) acetonitrile Example 6: 2- (6-nitro-indazole-1-ylenalamine diphosphate) Raw material: (6-nitro-1-indazolu-l-yl) acetonitrile

Example 7: 2- (5-nitro-1 1 / -1-indazole-1-yl) ethylamine hydrochloride Raw material: (5-nitro-1 indazole-1-yl) acetonitrile

Example 8: 2- (5-Chloro-1-indazo-1-yl) ethylamine hydrochloride Raw material: (5-chloro-1-H-indazol-1-inole) acetonitrile

Example 9: 2- (5-Bromo-1Η-indazo 1-l-inole) ethylamine hydrochloride Raw material: (5-bromo-1 1-indazo 1-l 1-inole) acetonitrile

Example 10 0: 2 — (5—1—1—1—1) Echilamine hydrochloride is

Ingredients: (5—Edodo 1 Indazolu Ro 1—Ir) Acetonitrile

Example 11 1: 2 (5-bromo-6-fluoro-1H-indazo-1-ru-1-yl) ethylamine hydrochloride

Ingredients: (5-Bromo 6-Fluoro mouth-1H-Indazo-1-ru 1-yl)

Example 1 2: 2-(5-methoxy-1-indazole) 1-ethylenethylamine hydrochloride

Ingredients: (5-Methoxy 1H-Indazo-l-yl) Acetonitrile Example 13: 2- (5-Methyl-lH-Indazo-l-l-yl) Ethylamine hydrochloride (5-Methyl-1H-Indazo-1-yl) Acetonitrile

Example 14: 2- (5-butyl-1H-indazole-1-inole) Ethylamine hydrochloride Raw material: (5-butyl-1H-indazo-1-ru-1-yl) acetate : 2- (5, 6-dichloro-Iff-indazole-1-yl) ethylamine hydrochloride

Ingredients: (5, 6-dichloro-indazole-1-1-yl) acetonitrile Example 16: 2-(5-chloro-port-6-fluoro-1H-indazo-l-yl) Tilamine hydrochloride

Ingredients: (5—black mouth—6—fluor—1 fi—indazole—1—yl) acetonitrile

Example 17: 2- (4-chloro-5-fluoro-1H-indazo-l-l-^-l) -ethylamine hydrochloride

Ingredients: (4-chloro-5-fluoro-1—indazo-1-yl) acetate nitrile

Example 18: 2- (6-chloro-5-fluoro-1 fi-indazo-l-l-yl) -ethylamine hydrochloride

Ingredients: (6—Black mouth—5—Fluoro-1 fi_Indazo-1ru 1-yl) Acetonitrile

Example 19: 2- (6-bromo-5-fluoro-1H-indazo-1-yl) ethylamine hydrochloride

Ingredients: (6-bromo-5-fluoro-1H-indazolu-1-yl) acetonitrile

Example 20: 2- (5,6-difluoro-1H-indazo-1-yl) ethylamine hydrochloride

Ingredients: (5,6-Difluoro-1H-indazo-1-yl-1) acetonitrile Example 21: 3- (5-fluoro-1H-indazo-1-yl-1yl) propylamine hydrochloride

Ingredients: 3- (5-Fluoro-1H-indazo-1-yl) propionitol Example 22: 2- (6-Methoxy-1-indazo-1-yl) ethylamine feiic acid ίπιι

Ingredients: (6-Methoxy-Indazo-1-yl) acetonitrile Example 23: 2- (6-Fluoro-1H-indazole-1-yl) — 2-Methylethylamine hydrochloride

Ingredients: 2-(6-Fluoro mouth _ 1 H-indazo 1-yl) 1-propionitrile Example 24: 2-(7-bromo-6-methoxy-1H-indazo- 1- Ill) Ethylamine 0.5 fumarate

Ingredients: (7-bromo-6-methoxy-1 fi-indazole-1-yl) acetitol

Example 25

2- (6,7-Dichloro-1-H-indazo-1-ru-1-yl) ethylamine 0.5 fumarate from 6,7-dichloro-Iff-monoindazole in the same manner as in Reference Example 1 and Example 1. I got

Example 26

0.40 g of 1-bromoethyl-5-fluoro-1H-indazole was dissolved in 10 ml of dimethyl honolemamide, 0.32 g of sodium azide was added, and the mixture was stirred at 80 for 2 hours. After cooling the reaction solution to room temperature, it was poured into ice water and extracted with ethyl acetate. The extracted organic layers were combined, washed with water and brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: hexane Z ethyl acetate = 3-1) to give 11- (2-azidoethyl) -15-fluoro-1fi-indazole in yellow. Obtained as a solid. Then, under a stream of argon, 0.08 g of lithium aluminum hydride was suspended in 5 ml of tetrahydrofuran, and a solution of 1- (2-azidoethyl) -15-fluoro-1H-indazole in tetrahydrofuran (1 ml) was added. ) Was added at room temperature and stirred for 30 minutes. Methanol is added to the reaction solution to decompose excess lithium aluminum hydride, and then 0.08 ml of water, 15 ml of 15¾ sodium hydroxide aqueous solution 8 8 ml of water, and 0.24 ml of water are sequentially added for 1 hour. Stirred. The resulting insolubles were removed by filtration through celite, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform / methanol / saturated aqueous ammonia = 10Z1Z0.1) to give 2- (5-Fluoro-1-indazo-1-yl) ethylamine was obtained. The obtained 2- (5-fluoro-1H-indazo-1-yl) ethylamine was dissolved in ethanol, a 4N ethyl acetate solution of hydrochloric acid was added thereto, and the resulting crystals were collected by filtration and dried under reduced pressure. (5-Fluoro 1 H-indazo-1-yl) 0.04 g of ethylamine hydrochloride was obtained. Example 27

Under an argon atmosphere, 0.21 g of hydrogen aluminum lithium tetrahydrofuran The suspension was suspended in 10 ml, and a solution of 11- (2-azidopropyl) -15-fluoro-1H-indazole in tetrahydrofuran (5 ml) was added at room temperature under ice-cooling, followed by stirring for 1 hour. Methanol was added to the reaction solution to decompose excess lithium aluminum hydride, and 0.2 1 ml of water, 0.2 lml of 15% aqueous sodium hydroxide solution, and 0.63 mj of water were sequentially added for 30 minutes. Stirred. The resulting insolubles were removed by filtration through Celite, and the concentrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform Z solvent = 9Z1) to give 2- (5-fluoro- 1-Indazole-1-yl) 1-Methylethylamine was obtained. The resulting 2- (5-fluoro-1U-indazo-l-l-yl) -l-methylethylamine is dissolved in a mixed solvent of ethanol and ethyl acetate, and a 4N ethyl acetate hydrochloride solution is added thereto. The resulting crystals were collected by filtration and dried under reduced pressure to obtain 0.48 g of 2- (5-fluoro-1H-indazo-l-yl-1-yl) -1-methylethylamine hydrochloride.

By a method similar to that in Example 27, the compounds of Examples 28 to 30 were obtained.

Example 28: (S) —2— (5-fluoro—1 fi—indazole—11-yl) —1-methylethylamine hydrochloride

Ingredients: (S) —1— (2-azidopropyl) -5-fluorene 1 ff-indazo mono Example 29: (R) —2— (5-fluoro-1H—indazo-1-ru 1-yl) I 1-Methylethylamine hydrochloride

Ingredients: (R) — 1— (2-azidopropyl) — 5-fluoro-1 indazolone Example 30: (S) — 2— (6-fluoro-1H-indazolyl 1_yl) Methylethylamine hydrochloride

Ingredients: (S) — 1— (2-azidopropyl) 1 6-fluoro 1 fi-indazo-mono Example 3 1

Dissolve 0.07 g of lithium aluminum hydride in 5 ml of tetrahydrofuran and, under ice-cooling, (S) -11- (2-azidopropyl) -16-methoxy-1H-indazole 0.19 g of tetrahydrofuran After the solution was added dropwise, the mixture was stirred at room temperature for 1 hour under an atmosphere of argon. Add a small amount of methanol to the reaction solution, add 0.5 ml of 30% aqueous sodium hydroxide solution, stir at room temperature for 1 hour, and add celite and magnesium sulfate. And dried. This was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. 17 g of the obtained amine was dissolved in ethanol, and 0.09 g of fumaric acid was added, followed by stirring for 10 minutes. Ethyl acetate was added thereto, and the precipitated crystals were collected by filtration, washed with a mixed solvent of ethyl ethanol and ethyl acetate, and washed with (S) -2- (6-methoxy-1H-indazo-1-yl) -1-ethyl. 1-methylethylamine fumarate 0.

20 g were obtained.

The compounds of Examples 32 to 35 were obtained in the same manner as in Example 31.

Example 32: (S) _2- [6-benzyloxy 1H-indazo-l-l-inole) 1-1-methylethylamine fumarate

Ingredients: (S) — 1- (2-azidopropyl) 1-6-benzyloxy 1 H-indazole

Example 33: Trans-2- (6-fluoro-1H-indazo-1-yl) cyclopentylamine 0.5 fumarate

Ingredients: 1- (2-azidocyclopentyl) -1-6-fluoro-1H-indazole Example 34: 2- (6-fluoro-1H-indazolu-1-yl) 1-1-methoxymethyl Tilamine 0.5 fumarate

Ingredients: 1- (2-azido-3-methoxypropyl) 1-6-fluoro-1H-indona zone

Example 35: (S) -2- (5,6-dichloro-1-indazo-1-yl) -1-methylethylamine fumarate

Ingredients: (S) —1— (2-azidopropyl) -1,5,6-dichloro-1H—indazole

Example 36

(S) —2- (6,7-dichloro-1-one-indazo-1-ru) 1 1 from 6, 7-dichroic mouth—If-indazole by the same method as in Reference Example 43 and Example 31. -Methylethylamine 0.5 fumarate was obtained.

Example 37

Methanesulfonic acid 2- (5-fluoro-1Η-indazole-1-yl) ethyl A mixture of U.2 g and getylamine 2.O ml was placed in a 10 mj sealed vessel and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was made basic by adding a 1N aqueous solution of sodium hydroxide, and then extracted with chloroform. The combined organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is purified by silica gel column chromatography (eluent: toluene 7 ethyl acetate = 2/1), and Ν, Ν-I-Jetyl 2-— (5-Fluoro-1 Η-Indazo-1 ルー 1-Inole) Echilamine 10 was obtained. The obtained N, N-Jetyl-2- (5-fluoro-1-indazole-1-inole) ethylamine was dissolved in ethanol, 4N ethyl acetate hydrochloride solution was added thereto, and the resulting crystals were collected by filtration and dried under reduced pressure. 0.06 g of N, N-getyl-2- (5-fluoro-1H-indazol-1-yl) ethylamine hydrochloride was obtained as a white solid. The compounds of Examples 38 to 40 were obtained in the same manner as in Example 37.

Example 3 8: 5-Fluoro-1- (2-pyrrolidine-1-ylethyl) -1H-indazole hydrochloride

Ingredients: methanesulfonic acid 2- (5-fluoro-1ff / indazo-1ru 1-yl) ethyl and pyrrolidine

Example 3 9: 5_Fluoro-11- (2-piperidine-1-1-ylethyl) -Iff-Indazole hydrochloride

Ingredients: Methanesulfonic acid 2 — (5-Fluoro-1 fi-Indazo-1-ru 1-yl) Ethyl and piperidine

Example 40: 2- (5-Fluoro-1H-indazol-1-yl) -N, N-dipolepyruethylamine hydrochloride

Ingredients: methanesulfonic acid 2- (5-fluoro-1 fi-1 indazo-1 ru-1 yl) 1-1-methylethyl and dipropylamine

Example 4 1

Under an argon atmosphere, 15 ml of dimethylformamide was added to 0.16 g of sodium hydride. Under ice-cooling, 0.50 g of 5-funoleo mouth-l-fi-indazole dissolved in 5 ml of dimethylformamide was added dropwise thereto, and the mixture was stirred for 30 minutes. Further, chloroacetonitrile (0.27 ml) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 4 hours. Ice water Drained and extracted with ethyl acetate. The extracted organic layers were combined, washed with water and brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: toluene Z-ethyl acetate = 8) (5-fluoro-Iff-indazo-1-yl). 41 g were obtained. Under an argon atmosphere, 0.10 g of lithium aluminum hydride was suspended in 10 ml of tetrahydrofuran, and 5 ml of a tetrahydrofuran solution of 0.37 g of aluminum chloride was added thereto, followed by stirring for 30 minutes. To this suspension was added a solution of 0.41 g of (5-fluoro-1H-indazole-1-yl) acetonitrile in tetrahydrofuran (5 m), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution to decompose excess reagents, and further a 1N aqueous sodium hydroxide solution was added to make the solution basic. The resulting insolubles were removed by filtration through celite, and the filtrate was extracted with black hole form. The combined organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (eluent: chloroform Zmethanol = 9-1) to obtain 0.32 g of 2- (5-fluoro-1fi-indazole-1-yl) ethylamine. Was. 0.32 g of this 2- (5-fluoro-1H-indazole-1-yl) ethynoleamine was dissolved in 1 Om1 of dichloromethane, and 0.30 ml of acetic acid and 0.15 ml of propionaldehyde were added thereto. The mixture was stirred at room temperature for 30 minutes. 0.75 g of sodium triacetoxyhydrogenboronate was added to the reaction mixture under ice cooling, and the mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was made basic by further adding a 1 N aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: chloroform Z-methyl = 9/1) to give N- [2- (5-fluoro-1 indazo-1-yl) ) Ethyl] Propylamine 0.06 g was obtained. The obtained TV- [2- (5-fluoro-1H-indazo-l-l-l-l-ethyl)] propinoleamine was dissolved in a mixed solvent of ethanol and ethyl acetate, and a 4 N ethyl acetate solution of hydrochloric acid was added thereto to form crystals. After filtration, the filtrate was dried under reduced pressure to obtain 0.05 g of IV- [2- (5-fluoro-1H-indazo-1-yl) ethyl] propylamine hydrochloride as a white solid.

Example 42 Dissolve 0.20 g of tert-butyl canolebamic acid in 20 ml of ethanol, and add 4N ethyl acetate solution of hydrochloric acid acetate (1 Om). The mixture was stirred at room temperature for 19 hours. The resulting crystals were collected by filtration and then recrystallized from ethanol to obtain 0.15 g of 2- (5-amino-indazo-1-yl) ethylamine hydrochloride.

Example 43

[2- (5-Amino-1-i-indazo-l--1-yl) ethyl] Canolebamic acid teri monobutyl ester (0.59 g) was dissolved in toluene (3 Om1), and acetic anhydride dissolved in toluene (2 ml) 0.20 ml was added, and the mixture was stirred at 0 ° C for 1 hour. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel gel chromatography (eluent: toluene / ethyl acetate = 271). [2- (5-acetylamino 1H-indazolone) L-yl) ethyl] canolebamic acid ίerί-butyl ester 64 g was obtained. This [2- (5-acetylamine 1H-indazole-1_yl) ethyl] carbamic acid ererί-butyl ester 0.20 g is mixed solvent of ethyl acetate 5 ml and ethanol 5 ml 1 , And thereto was added 4 N of a 4 N solution of hydrochloric acid in ethyl acetate, and the mixture was stirred at room temperature for 17 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 0.10 g of N- [111- (2-aminoethyl) -11H-indazo-1-yl] acetamido hydrochloride. Was.

Example 44

6 Using monofluorindazole and (S) -2-methanesulfonyloxymethylpyrrolidine-111-benzyl ruvonic acid ester as starting materials, the same method as in Reference Example 1 was used to synthesize (S ) — 2— (6-Fluoro 1 —indazo-1-ylmethyl) pyrrolidine—11-hydroxybenzyl ester of sorbonic acid 0.66 g of ethanol solution, add 10% of 10% palladium on carbon and 5 Omg under hydrogen atmosphere The mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. This was dissolved in ethyl acetate, 0.45 ml of 4 N ethyl acetate hydrochloride was added, and the mixture was stirred for 1 hour. The precipitated crystals are collected by filtration and washed with ethyl acetate. There was obtained 0.40 g of monofluoro-1-[(S) -pyrrolidine-12-ilmenal]-丄 -indosasol hydrochloride.

Example 45

6-Fluoro 1- (1-benzo-1-pyrrolidine) was synthesized in the same manner as in Reference Example 1, using 6-fluorindazole and 1-benzoylpyrrolidine-13-yl methanesulfonate as starting materials. Dissolve 0.38 g of 1H-indazole in 10 ml of acetic acid, add 5 ml of 6 N hydrochloric acid, heat to reflux for 6 hours, and remove the solvent under reduced pressure. Distilled off. After adding saturated aqueous ammonia, the solvent was again distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. This was dissolved in ethanol, and 67 mg of fumaric acid was added, followed by stirring for 10 minutes. Ethyl acetate was added thereto, and the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 0.13 g of 6-fluoro-11- (pyrrolidine-13-yl) -11H-indazolfumarate. Was.

Example 46

(S) 1 2— (6-benzyloxy 1 H—indazoyl 11-yl) — 1-methylethylamine 10% in 0.14 g of ethanol solution 10% —palladium on carbon 15 mg, concentrated hydrochloric acid 0.5 m 1 In addition, the mixture was stirred for 6 days under a hydrogen atmosphere at 3 atm. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel gel chromatography. This was dissolved in ethanol, an ethanol solution of fumaric acid was added and the mixture was stirred, and then the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethanol to obtain 0.04 g of (S) -2- (6-hydroxy-1H-indazole-11-yl) -1-methylethylamine fumarate.

Example 47

(S) — 11- (2-azidopropyl) 17-chloro-6-methoxyl 1 H-indazole To a solution of 0.26 g of tetrahydrofuran, add 0.31 g of triphenylphenylphosphine, and add 50 ° The mixture was stirred at C for 5 hours. After adding a few drops of water to the reaction solution and further stirring at 50 ° C for 15 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel gel chromatography. This was dissolved in ethanol, a solution of 0.11 g of fumaric acid in ethanol was added, and the mixture was stirred for 1 hour under ice cooling. The crystals formed are filtered off and washed with ethanol. (S) 12- (7-chloro-1-6-methoxy-1H-indazolu-l-l-Ilk-dimethylmethylethylamine fumarate; 22 g was obtained.

The compounds of Examples 48 to 50 were obtained in the same manner as in Example 47.

Example 48: 2- (6-Fluoro-1H-indazole-11-yl) 1-1-fluoromethylethylamine fumarate

Ingredients: 1— (2-azido-3-fluoropropyl) 1-fluoro-1H-ingzole

Example 49: (S) — 2— (7—promo 6—methoxy 1 H-indazo 1-yl 1-yl) 1-1-methylethylamine fumarate

Ingredients: (S) — 1— (2-azidopropyl) 1 7-bromo-6-methoxy-indazo

Example 50: (S) 1 2— (6—Methoxy 7—2 troth 1 H—Indazole—1 1 1) 1-Methylethylamine 0.9 fumarate

Ingredients: (S) — 1— (2-azidopropyl) 16-methoxy 7-nitro 1 H-indazo

Example 5 1

(S) — 2— (6-Methoxy 7-Nitro- 1 H-Indazo-l-yl) 11-Methylethylamine Add 10% -palladium-carbon to a 17 g ethanol solution, and add The mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. This was dissolved in ethanol, a solution of 0.08 g of fumaric acid in ethanol was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with a mixed solvent of ethanol and diisopropyl ether. (S) — 2— (7-amino-6-methoxy-1-H-indazo-1-yl) 1-1 —0.117 g of methylethylamine fumarate was obtained.

Example 52

To a solution of 0.26 g of (6-nitro-1H-indazole-11-yl) acetonitrile was added 10% -palladium-carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction solution was filtered through celite, the solvent was distilled off under reduced pressure, and (6-amino-If / (Dazol-l-yl) Acetonitrile was obtained. Separately, in another solution, 0.029 g of aluminum aluminum hydrate was added to a solution of 0.08 g of tetrahydrofuran under ice-cooling, and 0.29 g of aluminum chloride was added thereto. A tetrahydrofuran solution of (6-nitro-1-1-indazo-1-inole) acetonitrile was added, and the mixture was stirred under ice-cooling for 2 hours and further at room temperature for 2 hours. To the reaction solution was added methanol and a small amount of a 30% aqueous sodium hydroxide solution, and the mixture was stirred for 30 minutes, dried over magnesium sulfate, and filtered through celite. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography. This was dissolved in ethanol, a solution of 0.07 g of fumaric acid in ethanol was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with ethanol to obtain 0.09 g of 2- (6-amino-1H-indazo-1-yl) ethylamine fumarate.

The chemical structural formulas and physicochemical properties of the compounds obtained in Reference Examples and Examples are shown in the following table.

The symbols in the table have the following meanings.

Rf .: Reference example number

Ex .: Example number

mp: melting point

顺R: nuclear magnetic resonance scan Bae spectrum (unless otherwise specified MSO- d _6, TMS internal standard) δ: m / z: Mass spectrometry value (m / z)

Ms: Mesinole group

Me: methyl group

Et: ethyl group

Pr: propyl group

Ac: acetyl group

Bn: benzyl group Table 3

Rf.

1 NMR: 5.86 (2H, s), 7.01 ^ 7.07 (lH, ra), 7.49-7.55 (lH, m), 7.63-7.68 (1H, m),

8.37 (lH, s)

2 NMR: 5.77 (2H, s), 7.13 (1H, ddd), 7.7K1H, dd), 7.88 (1H, dd), 8.26 (1H, s)

3 NMR: 5.86C2H, s), 7.61-7.72 (2H, m), 8.45 (1H, s)

4 NMR: 2.46-2.48C3H, m), 5.80 (2H, s), 7.347.40 (1H, m :), 7,6 7.66 (1H, ra),

8.33-8.35 (1H, m)

_{5 MR (CDC1 3) 5.42C2H,} s), 7.93 (lH, d), 8.15 (1H, dd), 8.24 (lH, d), 8.48C1H, s)

6 negation _{R (CDC1 3) 5.39 (2H} , s), 7.60 (lH, d), 8.30 (lH, d), 8.4K1H, dd), 8.78 (lH, d)

7 layers _{R (CDC1 3) 5, 30} (2H, s), 7.42-7.48 (2H, m), 7.76 (lH, d), 8.02 (lH, s)

_{8 NR (CDC1 3) 5.29 (} 2H, s), 7.38 (lH, d), 7.58 (1H, dd), 7.92 (lH, d), 8.02 (lH, s)

9 negation _{R (CDC1 3) 5.28 (2H} , s), 7.28 (lH, d), 7.73 (1H, dd), 7.99 (lH, s), 8.14 (lH, d)

10 Marauder R (CDC1 ₃ ) 2.48 (3H, s), 5.28 (2H, s), 7.31-7.38 (2H, m), 7.54 (lH, s),

7.98 (LH, d)

11 negation _{R (CDC1 3): 0.94C3H,} t), 1. 2-1.42 (2H, m), 1.61-1.68 (2H, m), 2.73 (2H, t),

5.27 (2H, s), 7.327.40 (2H, m), 7.53 (lH, s), 7.99 (lH, s)

12 Keio _{_{R (CDC1 3): 3.87 (}} 3H, s), 5.27 (2H, s), 7. ll (lH, d), 7.17 (1H, dd),

7.38 (lH, d), 7.97 (lH, d)

_{13 NR (CDC1 3) 5.27 (} 2H, s), 7.65 (lH, s), 7.89 (lH, s), 8.02 (lH, s)

14 negation _{R (CDC1 3) 5.26 (2H} , s), 7.26 (lH, d), 7.99 (lH, d), 8.02 (lH, s)

15 notes (CDC1 ₃ ) 5.28 (2H, s), 7.51 (lH, d), 7.58 (lH, d), 8.03 (lH, d)

_{16 NMR (CDC1 3) 5.26C2H,} s), 7.28 (lH, d), 7.83 (lH, d), 8.02 (lH, s)

_{17 MR (CDC1 3) 5.30 (} 2H, s), 7.34-7.37 (2H, m), 8.15 (1H, s)

18 negation _{R (CDC1 3) 5.28 (2H} , s), 7.49 (lH, d), 7.74 (lH, d), 8.03 (lH, s)

_{19 NMR (CDC1 3) 5.27 (} 2H, s), 7.27-7.31 (lH, m), 7.53 (1H, dd), 8.04C1H, d)

20 NMR: 3.86 (3H, s), 5.73 (2H, s), 6.85 (1H, dd), 7.32 (lH, d),

7.67 (lH, d), 8.09 (1H, s)

21 NMR: 2.00 (3H, d), 5.54 (lH, q), 6.98 7.06 (1H, m), 7.17-7.21 (1H, m),

7.69-7.74 (1H, m), 8.04 8.06 (1H, m)

22 NMR: 1.89-2.28C2H, m), 2.32-2.54 (4H, m), 5.44 (1H, dd),

6.99-7.08C1H, m), 7.46-7.52 (1H, m), 7.8K1H, dd), 8.12 (1H, s)

_{23 MR (CDC1 3): 1.25} (3H, t), 4.22 (2H, q), 5.14 (2H, s), 7.16- 7.22 (1H, m),

7.27-7.30 (1H, m), 7.37 (1H, dd), 7.667.69 (1H, m), 8.01 (lH, d)

24 NMR: 3.97 (3H, s), 5.92 (2H, s), 7.18 (1H, d), 7.83 (1H, d), 8.24C1H, s

25 NMR: 3.94C2H, t), 5.04 (2H, t), 7.3K1H, ddd), 7.55 (1H, dd), 7.79 (1H, dd),

8.12 (lH, s)

26 Anonymous _{R (CDC1 3): 4.09- 4.13} (2H, m), 4.45 (2H, t), 7.15-7.20 (lH, m), 7.35 (1H, dd),

7.39 (1H, dd), 7.96 (lH, s) Table 4

Rf.

27 丽 R: l.57-178 (2Η, m), 1.80-2.20C4H, m), 4.244.35 (1Η, m), 4.55C1H, d),

4, 79-4.88 (1H, m), 6.95-7.04 (1H, m), 7.49-7.56 (1H, m), 7.76 (1H, dd), 8.04 (lH, s)

28 Awakening: _{R (CDC1 3): 2.72 (} 3H, s), 4.664.72 (4H, m), 7.18- 7.23 (1H, m), 7.35 (1H, dd),

7.43 (1H, dd), 8.01 (lH, d)

_{29 NMR (CDC1 3): 3.01} (2H, t), 4.65 (2H, t), 7.18- 7.25 (1H, m), 7.37 (1H, dd),

7.4K1H, dd), 8.01 (lH, d)

_{30 NMR (CDC1 3): 1.28} (3H, d), 3.16 (lH, d), 4.20- 4.27 (lH, m), 4.304.39 (2H, m),

7.15-7.20 (1H, m), 7.34- 7.40 (2H, m), 7.98C1H, d)

_{31 NR (CDC1 3): 1.28C3H} , d), 3.18 (lH, d), 4.20-4.25 (lH, m), 4.294.39 (2H, m),

7.157.20 (lH, m), 7.337.40 (2H, m), 7.97 (lH, d)

32丽_{R (CDC1 3): 1.29 (} 3H, d), 3. ll (lH, d), 4.20-4.26 (1H, m), 4.314.40 (2H, m),

7.16-7.2K1H, m), 7.34-7.4K2H, m), 7.99 (lH, d)

33丽_{R (CDC1 3): 1.28C3H,} d), 3.18 (1H, d), 4.15- 4.21 (1H, m), 4.30 ~ 4.38 (2H, m),

6.92 6.97 (1H, m), 7.07- 7.10 (1H, m), 7.68 (1H, dd), 8.00C1H, m)

34 NMR: 1.06 (3H, d), 3.83 (3H, s), 4.054.16 (lH, m), 4.104.30 (2H, m),

4.85 (lH, d), 6.73 (1H, dd), 7.087.1K1H, m), 7.58 (lH, d), 8.22 (lH, s)

35 NMR: 1.04 (3H, d), 4.004.31 (3H, m), 4.85 (lH, d), 5.17 (2H, s),

6.82 (1H, dd), 7.30 ~ 7.65 (7H, m), 7.92 (lH, s)

36 Anonymous: 4.06-4.58 (5H, m), 5.42 (lH, d), 6.93-7.06C1H, m), 7.46 7.52 (1H, m),

7.78 (1H, dd), 8.10 (lH, s)

37 NMR: 3.22-3.33 (5H, m), 3.97-4.08 (lH, m), 4.25- 4.45 (2H, m), 5.08 (1H, d),

6.95 ^ 7.04 (1H, m), 7.42 7.48 (lH, m), 7.77 (1H, dd), 8.08 (lH, s)

38 MR: 1.04 (3H, d), 4.01-4.ΙΚΙΗ, ιη), 4.53C1H, dd), 4.72 (1H, dd), 4.88 (lH, d)

7.34 (1H, d), 7.78 (lH, d), 8.21 (lH, s)

39 NMR: 1.08C3H, d), 4.00-4.08 (1H, m), 4.30-4.32 (2H, m), 4.85C1H, d),

8.04 8.08 (3H, m)

40 NMR: 0.94 (3H, d), 3.77-3.86 (1H, m), 3.98C3H, s), 4.09-4.13 (2H, m),

4.83 (1H, d), 7.23C1H, d), 8.02 (1H, d), 8.23 (1H, s)

41 NMR: 1.00 (3H, d), 3.94C3H, s), 4.04-4.09 (1H, m), 4.464.50 (1H, m), 4.65- 4.70

(1H, m), 4.84 (1H, d), 7.10 (1H, d), 7.7K1H, d), 8.06 (1H, s)

42 NMR: 1.0K3H, d), 3.93 (3H, s), 4.06-4.14 (1H, m), 4.53-4.58 (1H, m),

4.71- 4.75 (1H, m), 4, 82 (1H, d), 7.07 (1H, d), 7.75 (1H, d), 8.06 (1H, s)

43-field _{R (CDC1 3): 1.33 (} 3H, d), 4.074.15C1H, m), 4.29- 4.40 (2H, m),

7.17-7.22 (lH, m), 7.35 (1H, dd), 7.4K1H, dd), 8.00 (lH, d)

44 negation _{R (CDC1 3): 1.33 (} 3H, d), 4.074.15 (1H, m), 4.294.40 (2H, m),

7.17-7.22 (1H, m), 7.35 (1H, dd), 7.4K1H, dd), 8.OO (lH'd)

Table 6-1

Table 6-2

Table 6-3

Table 7-1

Table 7-3

Table 9

Table 10-1

Ex. AR ³ R ⁴

35 5- CI 6- CI m / z: 244 (FAB, M ⁴ + l)

NMR: 1.12 (3H, d), 3.50 3.6K1H, m), 4.42

-4.59 (2H, m), 6.49 (2H, s), 8.ll (lH, s), 8.16 (lH, s), 8.21 (lH, s)

36 -CH ₂ CH (Me)-6- CI 7- CI m / z: 244CFAB, MM1)

(S) -form NMR: 1.01 (3H, d), 3.25- 4.25 (4H, m), 4.60

-4.72 (2H, m), 6.43 (lH, s), 7.37 (lH, d), 7.80 (lH, d), 8.25 (lH, s)

47 C¾CH (Me)-6 -MeO 7- CI m / z: 240 (FAB, M ⁺ + l)

(S) form NMR: 1.04 (3H, d), 3.51-3.6K1H, m), 3.95 (3H, s),

4.68-4.78 (2H, m), 6.47 (2H, s), 7.14 (lH, d), 7.75 (lH, d), 8.13 (lH, s)

49 C CH (Me)-6 -MeO 7 Br mp: 178 179 ° C

(S) -form NMR: 1.06 (3H, d), 3.53-3.62 (lH, m), 3.94 (3H, s),

4.72 4.83 (2H, m), 6.46 (2H, s), 7.ll (lH, d), 7.79 (lH, d), 8.13 (lH, s) 1 0— 2

Claims

The scope of the claims

1. 5-HT _{2 c} agonists to aminoalkyl fin indazole derivative or the pharmaceutically acceptable salt thereof as an active ingredient represented by the following general formula (I).

(The symbols in the formula have the following meanings

1 ^ ³ and 1 ^: same or different, hydrogen atom, lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, aryl lower alkoxy group, amino group, mono- or di-lower alkylamino group, lower alkanol Mino group, nitro group or cyano group)

2. An aminoalkylindazole derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings

R ¹ and R ² : the same or different, a hydrogen atom, a lower alkyl group or R ¹ may form a nitrogen-containing saturated heterocyclic ring together with R ² or A R ³ and R ^{4 are the} same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino When R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkanoylamino group or a nitro group, R ¹ is hydrogen Indicates the meaning of the atom)

3. The compound according to claim 2, wherein A is an ethylene or propylene group.

4. The compound according to claim ^3, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a lower alkoxy group or a halogen atom.

5. The compound according to claim 4, wherein R ¹ and R ² are hydrogen atoms.

6.2— (5, 6—dichroic mouth—1 indazole—1—yl) ethylamine; Chilamine or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 2 to 6 and a pharmaceutically acceptable carrier.