JPWO2015152196A1 - Imidazoline derivatives and their pharmaceutical use - Google Patents

Abstract

An object of the present invention is to provide a compound that strongly activates α1L adrenergic receptor and is useful for treating or preventing stress urinary incontinence. The present invention provides an imidazoline derivative represented by the following or a pharmaceutically acceptable acid addition salt thereof.

Description

  The present invention relates to an imidazoline derivative and a pharmaceutical use thereof.

  Stress urinary incontinence means urine leaks when transient abdominal pressure rises in daily life, such as when sneezing or coughing, laughing, running, lifting heavy objects, etc. It is a disease characterized by symptoms. The cause is considered to be trauma, ischemia, denervation, etc. of the pelvic floor muscle group and external urethral sphincter, which are urethral closure tissues, due to childbirth, menopause, aging, etc. Many have been reported (Non-Patent Document 1).

  As a treatment method for stress urinary incontinence, exercise therapy, surgical operation or drug therapy is known. Pelvic floor muscle training, which is exercise therapy, can be effective after several weeks to several months by performing it continuously every day (Non-patent Document 2). Not reported (Non-patent Document 3). Moreover, although it has been shown that a surgical operation has a certain effect, it is reported that there are few patients who receive an operation (nonpatent literature 4). With regard to drug therapy, examples of drugs for which stress urinary incontinence is indicated include duloxetine and clenbuterol. Duloxetine contracts the urethra by suppressing the reuptake of serotonin and noradrenaline at the nerve endings, thereby providing a therapeutic effect. Clenbuterol has been reported to stimulate the β2 adrenergic receptor of the external urethral sphincter and contract the urethra to produce a therapeutic effect (Non-patent Document 5).

So far, drug research targeting α1 adrenergic receptors has been conducted for the purpose of treating and preventing stress urinary incontinence by increasing urethral resistance when abdominal pressure increases. α1 adrenergic receptors are classified into α1A adrenergic receptors, α1B adrenergic receptors, α1D adrenergic receptors and α1L adrenergic receptors. In recent years, the receptor responsible for urethral contraction is α1L adrenergic receptor, and α1L adrenergic receptor agonists are expected to be expected as therapeutic agents for stress urinary incontinence (Patent Documents 1 and 2 and Non-patent documents 6 to 8). Patent Document 2 discloses a compound represented by the following formula (A) that activates the α1L adrenergic receptor as a specific compound.

  On the other hand, examples of the compound having an imidazoline ring include a compound having an imidazoline ring that acts on an amine receptor (Patent Document 3), a compound having an imidazoline ring having insecticidal activity (Patent Document 4), and an imidazoline that acts on an adrenergic receptor. A compound having a ring (Patent Document 5) has been reported.

International Publication No. 2009/128479 International Publication No. 2012/008565 International Publication No. 2007/085558 International Publication No. 2003/092374 US Pat. No. 4,634,705

Irwin et al., BJU Int. 2011, Vol. 108, No. 7, p. 1132-1138 Sampselle et al., J Obstet Gynecol Neural Nurs. 1997, Vol. 26, No. 4, p. 375-385 Bishop et al., J Obstet Gynecol Neonatal Nurs. 1992, Vol. 21, No. 5, p. 401-406 L. Elaine Waetjen et al., OBSTETRICS & GYNECOLOGY, 2003, 101, p. 671-676 Vella et al., Int Urogenecol J Pelvic Floor Dysfunct. 2008, Vol. 19, No. 7, p. 961-964 Muramatsu et al., British Journal of Pharmacology, 2013, 170, p. 1242-1252 Muramatsu et al., The Journal of Urology, 2010, 183, p. 812-819 Muramatsu et al., Journal of Pharmaceutical Science, 2010, 113, p. 169-181 Female lower urinary tract symptom guidelines, Japan Urinary Function Society

  However, it has been reported that the drugs described in Non-Patent Document 5 have side effects (Non-Patent Document 9), and safer therapeutic agents are currently required. In addition, the α1L adrenergic receptor agonists described in Patent Documents 1 and 2 and Non-Patent Documents 6 to 8 have not exhibited sufficient medicinal effects, and a more potent α1L adrenergic receptor agonist is required for reducing the effective dose. It has been demanded.

  Furthermore, Patent Documents 3 to 5 describe compounds having an imidazoline ring, but do not describe at all whether these compounds act on α1L adrenergic receptors.

  Therefore, an object of the present invention is to provide a compound that strongly activates α1L adrenergic receptor and is useful for treating or preventing stress urinary incontinence.

［式中、Ａは、以下の一般式（ＩＩ）又は（ＩＩＩ）で示される基を表す。

（式中、Ｒ^１は、ハロゲン、炭素数１〜６のアルキル又は炭素数１〜６のアルコキシを表し、Ｒ^２及びＲ^３は、それぞれ独立して炭素数１〜６のアルキルを表すか、又は、一緒になって炭素数２〜５のアルキレンを表し、Ｒ^４は、水素、ハロゲン又は炭素数１〜６のアルコキシを表し、Ｒ^５は、水素又は炭素数１〜６のアルコキシを表し、ｍ及びｎは、１又は２を表し、Ｘは、ＣＨ_２、ＮＲ^６又はＯを表し、Ｙは、ＣＨ_２、ＮＨ又はＯを表し、Ｒ^６は、水素又は炭素数１〜６のアルキルを表し、波線は、結合位置を表す）。］As a result of intensive studies to achieve the above object, a novel imidazoline derivative that activates the α1L adrenergic receptor at a lower concentration than the existing compounds has been found, and the present invention has been completed. That is, the present invention provides an imidazoline derivative represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof.

[Wherein, A represents a group represented by the following general formula (II) or (III).

(In the formula, R ¹ represents halogen, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms, and R ² and R ³ each independently represent alkyl having 1 to 6 carbon atoms, or Or together, it represents alkylene having 2 to 5 carbon atoms, R ⁴ represents hydrogen, halogen or alkoxy having 1 to 6 carbon atoms, R ⁵ represents hydrogen or alkoxy having 1 to 6 carbon atoms, m and n represent 1 or 2, X represents CH ₂ , NR ⁶ or O, Y represents CH ₂ , NH or O, R ⁶ represents hydrogen or alkyl having 1 to 6 carbon atoms. And the wavy line represents the binding position). ]

In the imidazoline derivative or a pharmaceutically acceptable acid addition salt thereof, A represents a group represented by the general formula (II), R ¹ represents chlorine, bromine or methyl, and R ⁶ represents hydrogen or It represents methyl, m preferably represents 2, more preferably R ¹ represents chlorine, X represents NR ⁶ and R ⁶ represents hydrogen.

A represents a group represented by the general formula (III), R ² and R ³ represent methyl, or together represent ethylene or propylene, and R ⁴ represents hydrogen or chlorine. , R ⁵ represents hydrogen or methoxy, n represents 1 or 2, Y represents CH ₂ or NH, and R ² and R ³ together represent ethylene, R It is particularly preferred that ⁴ represents hydrogen, R ⁵ represents methoxy and n represents 2.

  In addition, the present invention provides a medicine containing an imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  Furthermore, the present invention provides a therapeutic or prophylactic agent for stress urinary incontinence containing an imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  The present invention also provides an α1L adrenergic receptor agonist containing the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  The imidazoline derivative of the present invention and a pharmaceutically acceptable acid addition salt thereof have a potent α1L adrenergic receptor agonistic activity and are particularly useful for drugs against diseases caused by α1L adrenergic receptor signaling, particularly stress urinary incontinence. It can be used as a therapeutic agent and a preventive agent for.

［式中、Ａは、以下の一般式（ＩＩ）又は（ＩＩＩ）で示される基を表す。

（式中、Ｒ^１は、ハロゲン、炭素数１〜６のアルキル又は炭素数１〜６のアルコキシを表し、Ｒ^２及びＲ^３は、それぞれ独立して炭素数１〜６のアルキルを表すか、又は、一緒になって炭素数２〜５のアルキレンを表し、Ｒ^４は、水素、ハロゲン又は炭素数１〜６のアルコキシを表し、Ｒ^５は、水素又は炭素数１〜６のアルコキシを表し、ｍ及びｎは、１又は２を表し、Ｘは、ＣＨ_２、ＮＲ^６又はＯを表し、Ｙは、ＣＨ_２、ＮＨ又はＯを表し、Ｒ^６は、水素又は炭素数１〜６のアルキルを表し、波線は、結合位置を表す）。］The imidazoline derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein, A represents a group represented by the following general formula (II) or (III).

(In the formula, R ¹ represents halogen, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms, and R ² and R ³ each independently represent alkyl having 1 to 6 carbon atoms, or Or together, it represents alkylene having 2 to 5 carbon atoms, R ⁴ represents hydrogen, halogen or alkoxy having 1 to 6 carbon atoms, R ⁵ represents hydrogen or alkoxy having 1 to 6 carbon atoms, m and n represent 1 or 2, X represents CH ₂ , NR ⁶ or O, Y represents CH ₂ , NH or O, R ⁶ represents hydrogen or alkyl having 1 to 6 carbon atoms. And the wavy line represents the binding position). ]

  “Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  “C1-C6 alkyl” means a monovalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms composed of carbon and hydrogen, such as methyl, ethyl , N-propyl, 2-propyl, n-butyl, 2-methylpropan-2-yl, n-pentyl or n-hexyl.

  The term “C 1-6 alkoxy” means a group in which the above C 1-6 alkyl is bonded to an oxygen atom. For example, methoxy, ethoxy, n-propyloxy, 2-propyloxy, n- Examples include butyloxy, 2-methylpropan-2-yloxy, n-pentyloxy or n-hexyloxy.

  “Alkylene having 2 to 5 carbon atoms” means a divalent linear saturated hydrocarbon group having 2 to 5 carbon atoms composed of carbon and hydrogen, and includes ethylene, n-propylene, and n-butylene. , N-hexylene.

Preferred specific examples of R ¹ , m and X in the general formula (II) are shown below.
R ¹ preferably represents chlorine, bromine or methyl, and more preferably represents chlorine. m preferably represents 2. X preferably represents NR ⁶ , and R ⁶ preferably represents hydrogen or methyl, and more preferably represents hydrogen.

Preferred specific examples of R ^{2 to} R ⁵ , n and Y in the above general formula (III) are shown below. R ² and R ³ are preferably methyl or taken together to represent ethylene or propylene, and more preferably taken together to represent ethylene. R ⁴ preferably represents hydrogen or chlorine, and more preferably represents hydrogen. R ⁵ preferably represents hydrogen or methoxy, and more preferably represents methoxy. n preferably represents 2. Y preferably represents CH ₂ or NH, and more preferably represents CH ₂ .

  Examples of the pharmaceutically acceptable acid addition salt of the imidazoline derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate. Inorganic acid salts such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate And organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, etc., but hydrochloride, hydrogen bromide Acid salts, phosphate salts, tartrate salts or methanesulfonate salts are preferred, and hydrochloride salts, tartrate salts or methanesulfonate salts are more preferred.

Of the imidazoline derivatives represented by the following general formula (I), preferred specific examples of A in the formula are shown in Tables 1 and 2. However, these do not limit the present invention.

  The starting materials and reagents used for the production of the imidazoline derivatives represented by the above general formula (I) are generally available and can be synthesized by known methods.

［式中、Ｒ^１は、上記定義に同じであり、ＰＭＢは、パラメトキシベンジルを表す。］(Production method 1)
Among the imidazoline derivatives represented by the above general formula (I), the imidazoline derivative represented by the general formula (IV) is produced from the imidazoline derivative represented by the general formula (V) as shown in the following scheme 1, for example. can do.

[Wherein, R ¹ is as defined above, and PMB represents paramethoxybenzyl. ]

  The deprotection reaction of the imidazoline derivative represented by the general formula (V) is generally a method using an acid in a solvent.

  As the acid used for the deprotection reaction, for example, trifluoroacetic acid, hydrochloric acid or sulfuric acid can be used, but trifluoroacetic acid or hydrochloric acid is preferred. Although 1-500 equivalent can be used for an acid with respect to an imidazoline derivative, 1-100 equivalent is preferable. As the solvent, for example, dichloromethane, 1,4-dioxane, methanol or ethanol can be used, but dichloromethane or methanol is preferable.

  0-60 degreeC is preferable and, as for the reaction temperature of deprotection reaction, 10-40 degreeC is more preferable. The reaction time of the deprotection reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 24 hours, more preferably 30 minutes to 12 hours.

  The concentration at the start of the reaction of the imidazoline derivative represented by the above general formula (V) in the deprotection reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^１は、上記定義に同じであり、Ｒ^７は、炭素数１〜６のアルキル又はパラメトキシベンジルを表す。］(Production method 2)
The imidazoline derivative represented by the general formula (VI) including a part of the imidazoline derivative represented by the above general formula (I) and the imidazoline derivative represented by the general formula (V) is exemplified in the following scheme 2. As shown, it can be produced from a nitrile derivative represented by the general formula (VII).

[Wherein, R ¹ is as defined above, and R ⁷ represents alkyl having 1 to 6 carbon atoms or paramethoxybenzyl. ]

  The cyclization reaction of the nitrile derivative represented by the general formula (VII) is generally a method using ethylenediamine together with phosphorus pentasulfide.

  The phosphorus pentasulfide can be used in an amount of 0.01 to 10 equivalents, preferably 0.1 to 2 equivalents, relative to the nitrile derivative.

  The reaction temperature of the cyclization reaction is preferably 0 to 110 ° C, more preferably 70 to 100 ° C. The reaction time of the cyclization reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 1 to 24 hours.

  The concentration at the start of the reaction of the nitrile derivative represented by the general formula (VII) in ethylenediamine in the cyclization reaction is preferably 0.001 to 5M, and more preferably 0.01 to 1M.

［式中、Ｒ^１及びＲ^７は、上記定義に同じである。］(Production method 3-1)
The nitrile derivative represented by the above general formula (VII) can be produced, for example, from the dihydroquinolinone derivative represented by the general formula (VIII) as shown in the following scheme 3.

[Wherein, R ¹ and R ⁷ are the same as defined above. ]

Conversion of the dihydroquinolinone derivative represented by the above general formula (VIII) to a nitrile derivative is generally a method using p-toluenesulfonylmethyl isocyanide together with a base and methanol in a tetrahydrofuran solvent.

  Although 1-10 equivalent can be used for p-toluenesulfonylmethyl isocyanide used for nitrification reaction with respect to a dihydroquinolinone derivative, 1-5 equivalent is preferable. Methanol can be used in an amount of 1 to 100 equivalents relative to the dihydroquinolinone derivative, but preferably 1 to 10 equivalents. As the base, for example, t-butoxy potassium, t-butoxy sodium, potassium hydroxide or sodium hydroxide can be used, and t-butoxy potassium is preferable. Although 1-10 equivalent can be used for a base with respect to p-toluenesulfonylmethyl isocyanide, 1-5 equivalent is preferable.

  The reaction temperature of the nitrification reaction is preferably -100 ° C to 66 ° C, more preferably -80 ° C to 60 ° C. The reaction time of the nitrification reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours.

  The concentration of the dihydroquinolinone derivative represented by the above general formula (VIII) in the nitrification reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.01 to 0.5M.

［式中、Ｒ^１及びＲ^７は、上記定義に同じである。］(Production method 3-2)
The nitrile derivative represented by the above general formula (VII) can be produced from the dihydroquinolinone derivative represented by the above general formula (VIII) by the method shown in the following scheme 4, for example.

[Wherein, R ¹ and R ⁷ are the same as defined above. ]

  The conversion of the dihydroquinolinone derivative represented by the above general formula (VIII) to a nitrile derivative is carried out by reacting with trimethylsilylcyanide with diiodozinc in dichloromethane solvent, followed by unsaturated nitrile using acid in toluene solvent. It is common to synthesize derivatives and then reduce with sodium borohydride in a solvent.

  The trimethylsilyl cyanide used in the unsaturated nitrification reaction can be used in an amount of 1 to 30 equivalents relative to the dihydroquinolinone derivative, but is preferably 1 to 5 equivalents. Although diiodo zinc can use 0.05-10 equivalent with respect to a dihydroquinolinone derivative, 0.1-5 equivalent is preferable. As the acid, for example, Amberlyst 15 (H) or p-toluenesulfonic acid can be used, but Amberlyst 15 (H) is preferable. Although 0.1-30 equivalent can be used for an acid with respect to a dihydroquinolinone derivative, 1-5 equivalent is preferable.

  0-40 degreeC is preferable and, as for the reaction temperature of unsaturated nitrification reaction, 20-40 degreeC is more preferable. The reaction time of the unsaturated nitrification reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours.

  The concentration of the dihydroquinolinone derivative represented by the above general formula (VIII) in the unsaturated nitrification reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

  Sodium borohydride used for the reduction reaction can be used in an amount of 0.25 to 10 equivalents relative to the unsaturated nitrile derivative, but 1 to 5 equivalents are preferred. As the solvent, for example, tetrahydrofuran, methanol, ethanol or propanol can be used, but methanol or ethanol is preferable.

  The reaction temperature of the reduction reaction is preferably −20 ° C. to 80 ° C., more preferably 0 to 40 ° C. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 1 minute to 24 hours, and more preferably 5 minutes to 2 hours.

  The concentration of the unsaturated nitrile derivative in the reduction reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^１及びＲ^７は、上記定義に同じである。］(Production Method 4)
The dihydroquinolinone derivative represented by the above general formula (VIII) can be produced, for example, from the dihydroquinolinone derivative represented by the general formula (IX) as shown in the following scheme 5.

[Wherein, R ¹ and R ⁷ are the same as defined above. ]

  The alkylation reaction of the dihydroquinolinone derivative represented by the general formula (IX) is generally a method using an alkylating agent together with a base in a solvent or a method using a reducing agent together with an aldehyde in a solvent.

  As the alkylating agent used in the alkylation reaction, for example, alkyl halide or benzyl halide can be used, but methyl iodide or paramethoxybenzyl bromide is preferable. Although 1-10 equivalent can be used for an alkylating agent with respect to a dihydroquinolinone derivative, 1-3 equivalent is preferable. As the base, for example, potassium carbonate, sodium carbonate, sodium hydroxide or sodium hydride can be used, but potassium carbonate is preferred. Although 1-10 equivalent can be used for a base with respect to a dihydroquinolinone derivative, 1-3 equivalent is preferable. As the solvent, for example, dichloromethane, DMF, DMSO or acetonitrile can be used, but DMF is preferable.

  As the aldehyde used in the alkylation reaction, for example, formaldehyde or paramethoxybenzaldehyde can be used, but paraformaldehyde is preferable. Although 1-20 equivalent can be used for an aldehyde with respect to a dihydroquinolinone derivative, 1-10 equivalent is preferable. As the reducing agent, for example, sodium borohydride, sodium cyanoborohydride or sodium acetoxyborohydride can be used, but sodium acetoxyborohydride is preferable. Although 1-10 equivalent can be used for a reducing agent with respect to a dihydroquinolinone derivative, 1-5 equivalent is preferable. As the solvent, for example, dichloromethane or 1,2-dichloroethane can be used, but 1,2-dichloroethane is preferable.

  The reaction temperature of the alkylation reaction is preferably 0 to 120 ° C, more preferably 10 to 80 ° C. The reaction time of the alkylation reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 24 hours, more preferably 1 hour to 15 hours.

  The concentration at the start of the reaction of the dihydroquinolinone derivative represented by the above general formula (IX) in the alkylation reaction is preferably 0.001 to 5M, and more preferably 0.1 to 1M.

［式中、Ｒ^８は、水素、フッ素、塩素、炭素数１〜６のアルキル又は炭素数１〜６のアルコキシを表す。］(Production method 5)
The dihydroquinolinone derivative represented by the general formula (X) including a part of the dihydroquinolinone derivative represented by the above general formula (IX) is represented by, for example, the general formula (XI) as shown in the following scheme 6. It can manufacture from the dihydroquinolinone derivative shown by these.

[Wherein, R ⁸ represents hydrogen, fluorine, chlorine, alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons. ]

  The reduction reaction of the dihydroquinolinone derivative represented by the above general formula (XI) is generally a method using hydrogen together with a metal catalyst in a solvent.

  As the metal catalyst used in the reduction reaction, for example, a Wilkinson complex, platinum oxide or palladium carbon can be used, but a Wilkinson complex or platinum oxide is preferable. Although 0.001-0.99 equivalent can be used for a metal catalyst with respect to a dihydroquinolinone derivative, 0.1-0.99 equivalent is preferable. As the solvent, for example, dichloromethane, methanol or ethanol can be used, but dichloromethane or methanol is preferable.

  0-60 degreeC is preferable and, as for the reaction temperature of a reductive reaction, 5-40 degreeC is more preferable. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 10 minutes to 24 hours.

  The concentration at the start of the reaction of the dihydroquinolinone derivative represented by the above general formula (XI) in the reduction reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^８は、上記定義に同じである。］(Production method 6)
The dihydroquinolinone derivative represented by the above general formula (XI) can be produced, for example, from the dihydroquinolinone derivative represented by the general formula (XII) as shown in the following scheme 7.

[Wherein R ⁸ is the same as defined above. ]

  The coupling reaction of the dihydroquinolinone derivative represented by the general formula (XII) is generally a method using potassium isopropenyl trifluoroborate together with a base, a palladium catalyst and a ligand in a solvent.

Potassium isopropenyl trifluoroborate used for the coupling reaction can be used in an amount of 1 to 10 equivalents with respect to the dihydroquinolinone derivative, but preferably 1 to 5 equivalents. As the base, for example, potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate can be used, but cesium carbonate is preferred. Although 0.5-10 equivalent can be used for a base with respect to a dihydroquinolinone derivative, 1-5 equivalent is preferable. As the palladium catalyst, for example, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, PdCl ₂ (PPh ₃ ) ₂ or palladium acetate can be used, and palladium acetate is preferable. Although 0.001-0.99 equivalent can be used for a palladium catalyst with respect to a dihydroquinolinone derivative, 0.1-0.99 equivalent is preferable. As the ligand, for example, triphenylphosphine, tricyclohexylphosphine, diphenylphosphinoferrocene or tri-t-butylphosphine can be used, but triphenylphosphine is preferable. Although 1-5 equivalent can be used for a ligand with respect to a palladium catalyst, 1-3 equivalent is preferable. As the solvent, for example, 1,4-dioxane, DMSO, water, DMF, n-propanol, toluene, tetrahydrofuran, or a mixed solvent thereof can be used, but a mixed solvent of water and tetrahydrofuran is preferable.

  0-110 degreeC is preferable and, as for the reaction temperature of a coupling reaction, 20-66 degreeC is more preferable. The reaction time of the coupling reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, and more preferably 1 hour to 24 hours.

  The concentration of the dihydroquinolinone derivative represented by the above general formula (XII) in the coupling reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The dihydroquinolinone derivative represented by the general formula (XII) used for the coupling reaction may be a commercially available product or a compound synthesized from a commercially available product.

(Production method 7)
Among the dihydroquinolinone derivatives represented by the above general formula (IX), the dihydroquinolinone derivative represented by the formula (XIII) is, for example, a dihydroquinolone represented by the general formula (XIV) as shown in the following scheme 8. It can be produced from a quinolinone derivative.

  The bromination reaction of the dihydroquinolinone derivative represented by the above general formula (XIV) is generally performed by using a brominating agent together with an acid in a solvent.

  As the brominating agent used in the bromination reaction, for example, bromine or N-bromosuccinimide can be used, and any of them can give a good result. Although 1-10 equivalent can be used for a brominating agent with respect to a dihydroquinolinone derivative, 1-5 equivalent is preferable. As the acid, for example, aluminum chloride or gold chloride can be used, and in either case, good results can be obtained. Although 0.05-10 equivalent can be used for an acid with respect to a dihydroquinolinone derivative, 0.1-2 equivalent is preferable. As the solvent, for example, water, DMF, tetrahydrofuran, dichloromethane or 1,2-dichloroethane can be used, but water, DMF or 1,2-dichloroethane is preferable.

  The reaction temperature of the bromination reaction is preferably −20 ° C. to 150 ° C., more preferably 0 to 110 ° C. Although the reaction time of bromination reaction changes with substrates or reaction conditions, 10 minutes-48 hours are preferable and 1 hour-24 hours are more preferable.

  The concentration of the dihydroquinolinone derivative represented by the above general formula (XIV) in the bromination reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The dihydroquinolinone derivative represented by the above general formula (XIV) used for the bromination reaction may be a commercially available product or a compound synthesized from a commercially available product.

［式中、Ｒ^８は、上記定義に同じであり、Ｒ^９は、臭素又はイソプロピルを表す。］(Production method 8)
The dihydroquinolinone derivative represented by the general formula (XV) including the dihydroquinolinone derivative represented by the above general formula (XII) and the dihydroquinolinone derivative represented by the above general formula (XIV) is, for example, As shown in Scheme 9, it can be produced from an aniline derivative represented by the general formula (XVII).

[Wherein, R ⁸ has the same definition as above, and R ⁹ represents bromine or isopropyl. ]

  The conversion of the aniline derivative represented by the above general formula (XVII) into the dihydroquinolinone derivative is carried out by using 3-bromopropionyl chloride together with a base in a dichloromethane solvent and a β-lactam derivative represented by the above general formula (XVI). Is generally followed by rearrangement using an acid in a solvent.

  Although 3-bromopropionyl chloride used for amidation reaction can use 1-10 equivalent with respect to an aniline derivative, 1-3 equivalent is preferable. As the base, for example, triethylamine, sodium carbonate or potassium carbonate can be used, but potassium carbonate is preferable. Although 1-10 equivalent can be used for a base with respect to an aniline derivative, 1-5 equivalent is preferable.

  The reaction temperature of the amidation reaction is preferably −20 ° C. to 40 ° C., more preferably 0 to 40 ° C. The reaction time of the amidation reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 24 hours, and more preferably 1 hour to 12 hours.

  The concentration at the start of the reaction of the aniline derivative represented by the above general formula (XVII) in the amidation reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The aniline derivative represented by the general formula (XVII) used for the amidation reaction may be a commercially available product or a compound synthesized from a commercially available product.

  As the acid used for the rearrangement reaction, for example, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid can be used, but trifluoromethanesulfonic acid is preferred. Although 0.1-100 equivalent can be used for an acid with respect to (beta) lactam derivative, 1-10 equivalent is preferable. As the solvent, for example, 1,2-dichloroethane or dichloromethane can be used, but 1,2-dichloroethane is preferable.

  The reaction temperature of the rearrangement reaction is preferably −20 ° C. to 80 ° C., more preferably 0 to 80 ° C. The reaction time of the rearrangement reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 48 hours, more preferably 30 minutes to 5 hours.

  The concentration at the start of the reaction of the β-lactam derivative represented by the above general formula (XVI) in the rearrangement reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^１は、上記定義に同じである。］(Production method 9)
Among the imidazoline derivatives represented by the above general formula (I), an imidazoline derivative represented by the general formula (XVIII) is produced from a nitrile derivative represented by the general formula (XIX) as shown in the following scheme 10, for example. can do.

[Wherein R ¹ is the same as defined above. ]

  The cyclization reaction of the nitrile derivative represented by the above general formula (XIX) can be performed by the same method as Production Method 2.

［式中、Ｒ^１は、上記定義に同じである。］(Production method 10)
The nitrile derivative represented by the above general formula (XIX) can be produced, for example, from a chromanone derivative represented by the general formula (XX) as shown in the following scheme 11.

[Wherein R ¹ is the same as defined above. ]

  Conversion of the chromanone derivative represented by the above general formula (XX) to a nitrile derivative can be carried out in the same manner as in Production Method 3-2.

［式中、Ｒ^８は、上記定義に同じである。］(Production method 11)
The chromanone derivative represented by the general formula (XXI) including a part of the chromanone derivative represented by the above general formula (XX) is, for example, the chromanone represented by the general formula (XXII) as shown in the following scheme 12. It can be produced from a derivative.

[Wherein R ⁸ is the same as defined above. ]

  The reduction reaction of the chromanone derivative represented by the above general formula (XXII) can be performed in the same manner as in Production Method 5.

［式中、Ｒ^８は、上記定義に同じである。］(Production method 12)
The chromanone derivative represented by the above general formula (XXII) can be produced, for example, from the chromanone derivative represented by the general formula (XXIII) as shown in the following scheme 13.

[Wherein R ⁸ is the same as defined above. ]

  The coupling reaction of the chromanone derivative represented by the above general formula (XXIII) can be performed in the same manner as in Production Method 6.

［式中、Ｒ^８は、上記定義に同じである。］(Production method 13)
The chromanone derivative represented by the above general formula (XXIII) can be produced from, for example, a phenol derivative represented by the general formula (XXV) as shown in the following scheme 14.

[Wherein R ⁸ is the same as defined above. ]

  The conversion of the phenol derivative represented by the above general formula (XXV) to the chromanone derivative is performed by synthesizing the nitrile derivative represented by the above general formula (XXIV) using acrylonitrile together with potassium carbonate and t-butanol, In general, a method of cyclization using an acid is used.

  Potassium carbonate used for the alkylation reaction can be used in an amount of 0.1 to 10 equivalents with respect to the phenol derivative, but is preferably 1 to 5 equivalents. Although t-butanol can use 0.1-10 equivalent with respect to a phenol derivative, 1-5 equivalent is preferable.

  The reaction temperature of the alkylation reaction is preferably −20 ° C. to 77 ° C., more preferably 20 to 70 ° C. The reaction time for the alkylation reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, more preferably 1 hour to 35 hours.

  The concentration at the start of the reaction of the phenol derivative represented by the above general formula (XXV) in acrylonitrile in the alkylation reaction is preferably 0.01 to 5M, more preferably 0.05 to 2M. In addition, the phenol derivative shown by said general formula (XXV) used for alkylation reaction may be a commercial item, and may use the compound synthesize | combined from the commercial item.

  As the acid used for the cyclization reaction, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a mixture thereof can be used, but a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid is preferable.

  The reaction temperature of the cyclization reaction is preferably -20 ° C to 100 ° C, more preferably 0 to 60 ° C. The reaction time of the cyclization reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.

  The concentration at the start of the reaction of the nitrile derivative represented by the above general formula (XXIV) in the acid in the cyclization reaction is preferably 0.01 to 5M, and more preferably 0.05 to 2M.

［式中、Ｒ^１及びｍは、上記定義に同じである。］(Production method 14)
Among the imidazoline derivatives represented by the above general formula (I), an imidazoline derivative represented by the general formula (XXVI) is produced from an imidazoline derivative represented by the general formula (XXVII) as shown in the following scheme 15, for example. can do.

[Wherein, R ¹ and m are the same as defined above. ]

  The reduction reaction of the imidazoline derivative represented by the above general formula (XXVII) can be performed in the same manner as in Production Method 5.

［式中、Ｒ^１及びｍは、上記定義に同じである。］(Production method 15)
The imidazoline derivative represented by the above general formula (XXVII) can be produced, for example, from a nitrile derivative represented by the general formula (XXVIII) as shown in the following scheme 16.

[Wherein, R ¹ and m are the same as defined above. ]

  The cyclization reaction of the nitrile derivative represented by the above general formula (XXVIII) can be performed in the same manner as in Production Method 2.

［式中、Ｒ^１及びｍは、上記定義に同じである。］(Production Method 16)
The nitrile derivative represented by the above general formula (XXVIII) can be produced from, for example, a ketone derivative represented by the general formula (XXIX) as shown in the following scheme 17.

[Wherein, R ¹ and m are the same as defined above. ]

  Conversion of the ketone derivative represented by the above general formula (XXIX) to a nitrile derivative can be carried out in the same manner as in Production Method 3-1.

［式中、Ｒ^８及びｍは、上記定義に同じである。］(Production Method 17)
The ketone derivative represented by the general formula (XXX) including a part of the ketone derivative represented by the general formula (XXIX) is, for example, a ketone represented by the general formula (XXXI) as shown in the following scheme 18. It can be produced from a derivative.

[Wherein R ⁸ and m are the same as defined above. ]

  The coupling reaction of the ketone derivative represented by the above general formula (XXXI) can be performed in the same manner as in Production Method 6.

［式中、Ｒ^８及びｍは、上記定義に同じである。］(Production method 18)
The ketone derivative represented by the above general formula (XXXI) can be produced, for example, from the ketone derivative represented by the general formula (XXXII) as shown in the following scheme 19.

[Wherein R ⁸ and m are the same as defined above. ]

  The bromination reaction of the ketone derivative represented by the above general formula (XXXII) can be performed in the same manner as in Production Method 7.

［式中、Ｒ^８及びｍは、上記定義に同じである。］(Production Method 19)
The ketone derivative represented by the above general formula (XXXII) can be produced, for example, from a carboxylic acid derivative represented by the general formula (XXXIV) as shown in the following scheme 20.

[Wherein R ⁸ and m are the same as defined above. ]

  The conversion of the carboxylic acid derivative represented by the above general formula (XXXIV) into the ketone derivative is performed by synthesizing the carboxylic acid derivative represented by the above general formula (XXXIII) using hydrazine in a solvent together with a base, In general, a method of converting to an acid chloride using a chlorinating agent in a solvent and then cyclizing using an aluminum chloride in a solvent is common.

  Although 1-10 equivalent can be used for the hydrazine used for a reductive reaction with respect to a carboxylic acid derivative, 1-5 equivalent is preferable. As the base, sodium hydroxide or potassium hydroxide can be used, but potassium hydroxide is preferred. Although 1-10 equivalent can be used for a base with respect to a carboxylic acid derivative, 1-5 equivalent is preferable. As the solvent, for example, ethylene glycol or DMSO can be used, and in either case, good results can be obtained.

  The reaction temperature of the reduction reaction is preferably 30 ° C to 180 ° C, more preferably 100 to 180 ° C. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 1 hour to 36 hours, and more preferably 2 hours to 24 hours.

  The concentration at the start of the reaction of the carboxylic acid derivative represented by the above general formula (XXXIV) in the reduction reaction is preferably 0.05 to 5M, and more preferably 0.1 to 2M. The carboxylic acid derivative represented by the general formula (XXXIV) used for the reduction reaction may be a commercially available product or a compound synthesized from a commercially available product.

  As the chlorinating agent used in the chlorination reaction, for example, thionyl chloride or oxalyl chloride can be used, and thionyl chloride is preferable. Although 1-100 equivalent can be used for a chlorinating agent with respect to a carboxylic acid derivative, 1-10 equivalent is preferable. As the solvent, for example, dichloromethane or 1,2-dichloroethane can be used, but dichloromethane is preferable.

  The reaction temperature of the chlorination reaction is preferably -20 ° C to 80 ° C, more preferably 0 to 40 ° C. The reaction time of the chlorination reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, and more preferably 1 hour to 24 hours.

  The concentration at the start of the reaction of the carboxylic acid derivative represented by the above general formula (XXXIII) in the chlorination reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The carboxylic acid derivative represented by the above general formula (XXXIII) used for the cyclization reaction may be a commercially available product or a compound synthesized from a commercially available product.

  The aluminum chloride used in the cyclization reaction can be used in an amount of 0.3 to 10 equivalents relative to the acid chloride, but is preferably 1 to 5 equivalents. As the solvent, for example, dichloromethane or 1,2-dichloroethane can be used, but dichloromethane is preferable.

The reaction temperature of the cyclization reaction is preferably -50 ° C to 80 ° C, more preferably -10 ° C to 40 ° C. The reaction time of the cyclization reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
The concentration of acid chloride at the start of the reaction in the cyclization reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^４及びＲ^５は、上記定義に同じであり、Ｒ^１０は、パラメトキシベンジル又はｔ−ブトキシカルボニルを表し、ｐは、１〜４の整数を表す。］(Production method 20)
Among the imidazoline derivatives represented by the above general formula (I), an imidazoline derivative represented by the general formula (XXXV) is produced from an imidazoline derivative represented by the general formula (XXXVI) as shown in the following scheme 21, for example. can do.

[Wherein, R ⁴ and R ⁵ are the same as defined above, R ¹⁰ represents paramethoxybenzyl or t-butoxycarbonyl, and p represents an integer of 1 to 4.] ]

  The deprotection reaction of the imidazoline derivative represented by the above general formula (XXXVI) can be performed in the same manner as in Production Method 1.

［式中、Ｒ^４、Ｒ^５、Ｒ^１０及びｐは、上記定義に同じである。］(Production method 21)
The imidazoline derivative represented by the above general formula (XXXVI) can be produced, for example, from a nitrile derivative represented by the general formula (XXXVII) as shown in the following scheme 22.

[Wherein R ⁴ , R ⁵ , R ¹⁰ and p are the same as defined above. ]

  The cyclization reaction of the nitrile derivative represented by the above general formula (XXXVII) can be performed in the same manner as in Production Method 2.

［式中、Ｒ^５、Ｒ^１０及びｐは、上記定義に同じであり、Ｒ^１１は、水素、フッ素、塩素又は炭素数１〜６のアルコキシを表す。］(Production method 22)
The nitrile derivative represented by the general formula (XXXVIII), which is a part of the nitrile derivative represented by the above general formula (XXXVII), is, for example, an indoline represented by the general formula (XLI) as shown in the following scheme 23. It can be produced from a derivative.

[In formula, R < ⁵ >, R < ¹⁰ > and p are the same as the said definition, and R < ¹¹ > represents hydrogen, a fluorine, chlorine, or a C1-C6 alkoxy. ]

  The conversion of the indoline derivative represented by the above general formula (XLI) to the nitrile derivative is carried out by synthesizing the formyl derivative represented by the above general formula (XL) using DMF together with a base in a tetrahydrofuran solvent, followed by the solvent. A method using a reducing agent to reduce to the benzyl alcohol derivative represented by the above general formula (XXXIX), further chlorinating with a chlorinating agent in a dichloromethane solvent, and then using a nitrating agent in a DMSO solvent Is common.

  DMF used for the formylation reaction can be used in an amount of 1 to 100 equivalents with respect to the indoline derivative, but 1 to 10 equivalents are preferable. As the base, for example, n-butyl lithium, s-butyl lithium, t-butyl lithium or isopropyl magnesium bromide can be used, but n-butyl lithium or isopropyl magnesium bromide is preferable. Although 1-10 equivalent can be used for a base with an indoline derivative, 1-5 equivalent is preferable.

  The reaction temperature of the formylation reaction is preferably -100 ° C to 60 ° C, more preferably -80 ° C to 30 ° C. The reaction time of the formylation reaction varies depending on the substrate or reaction conditions, but is preferably 1 minute to 48 hours, and more preferably 10 minutes to 5 hours.

  The concentration of the indoline derivative represented by the above general formula (XLI) in the formylation reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

  As the reducing agent used in the reduction reaction, for example, sodium borohydride, sodium cyanoborohydride, or lithium aluminum hydride can be used, but sodium borohydride is preferable. Although 0.25-10 equivalent can be used for a reducing agent with respect to a formyl derivative, 1-5 equivalent is preferable. As the solvent, for example, methanol, ethanol, tetrahydrofuran or diethyl ether can be used, but methanol is preferable.

The reaction temperature of the reduction reaction is preferably −20 ° C. to 80 ° C., more preferably 0 to 40 ° C. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 1 minute to 24 hours, and more preferably 5 minutes to 2 hours.
The concentration at the start of the reaction of the formyl derivative represented by the above general formula (XL) in the reduction reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

  As the chlorinating agent used in the chlorination reaction which is the first stage of the nitrification reaction, for example, thionyl chloride, methanesulfonyl chloride or oxalyl chloride can be used, but thionyl chloride or methanesulfonyl chloride is preferred. Although 1-100 equivalent can be used for a chlorinating agent with respect to a benzyl alcohol derivative, 1-10 equivalent is preferable.

  The reaction temperature of the chlorination reaction is preferably −20 ° C. to 40 ° C., more preferably 0 to 40 ° C. The reaction time of the chlorination reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours.

  The concentration at the start of the reaction of the benzyl alcohol derivative represented by the above general formula (XXXIX) in the chlorination reaction is preferably 0.001 to 5M, more preferably 0.05 to 1M.

  As the nitrifying agent used in the nitrification reaction, for example, sodium cyanide or potassium cyanide can be used, but sodium cyanide is preferable. Although 1-10 equivalent can be used for a nitrifying agent with respect to a chlorine body, 1-5 equivalent is preferable.

20-80 degreeC is preferable and, as for the reaction temperature of nitrification reaction, 20-60 degreeC is more preferable. The reaction time of the nitrification reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 24 hours, more preferably 30 minutes to 15 hours.
The concentration of the chlorine body at the start of the reaction in the nitrification reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^５、Ｒ^１１及びｐは、上記定義に同じであり、Ｂｏｃは、ｔ−ブトキシカルボニルを表す。］(Production Method 23)
The indoline derivative represented by the general formula (XLII), which is a part of the indoline derivative represented by the above general formula (XLI), is, for example, an indoline represented by the general formula (XLIII) as shown in the following scheme 24. It can be produced from a derivative.

[Wherein, R ⁵ , R ¹¹ and p are the same as defined above, and Boc represents t-butoxycarbonyl. ]

The Boc reaction of the indoline derivative represented by the above general formula (XLIII) is generally a method using Boc ₂ O together with N, N-dimethylaminopyridine in a solvent.

Boc ₂ O used in the Boc-forming reaction can be used in an amount of 1 to 10 equivalents relative to the indoline derivative, but is preferably 1 to 3 equivalents. N, N-dimethylaminopyridine can be used in an amount of 0.05 to 1 equivalent, preferably 0.1 to 1 equivalent, relative to the indoline derivative. As the solvent, for example, DMF, tetrahydrofuran, dichloromethane or 1,2-dichloroethane can be used, but tetrahydrofuran is preferred.

  The reaction temperature of the Boc reaction is preferably 0 ° C to 66 ° C, more preferably 20 to 60 ° C. The reaction time of the Boc reaction varies depending on the substrate or reaction conditions, but is preferably 1 hour to 48 hours, and more preferably 1 hour to 24 hours.

  The concentration of the indoline derivative represented by the above general formula (XLIII) in the Boc reaction at the start of the reaction is preferably 0.01 to 2M, more preferably 0.05 to 1M. As the indoline derivative represented by the above general formula (XLIII) used for the Boc reaction, a compound synthesized from a commercially available product can be used.

［式中、Ｒ^５、Ｒ^１１及びｐは、上記定義に同じである。］(Production method 24)
The indoline derivative represented by the above general formula (XLIII) can be produced, for example, from the indoline derivative represented by the general formula (XLIV) as shown in the following scheme 25.

[Wherein R ⁵ , R ¹¹ and p are the same as defined above. ]

  The bromination reaction of the indoline derivative represented by the above general formula (XLIV) can be performed in the same manner as in Production Method 7.

［式中、Ｒ^５、Ｒ^１１及びｐは、上記定義に同じである。］(Production method 25)
The indoline derivative represented by the above general formula (XLIV) can be produced, for example, from the oxindole derivative represented by the general formula (XLVI) as shown in the following scheme 26.

[Wherein R ⁵ , R ¹¹ and p are the same as defined above. ]

  The conversion of the oxindole derivative represented by the above general formula (XLVI) into the indoline derivative is performed by synthesizing the oxindole derivative represented by the above general formula (XLV) using a dibromoalkane together with a base in a solvent. A method using a reducing agent in a solvent is generally used.

  As the dibromoalkane used in the cycloalkylation reaction, for example, 1,2-dibromoethane or 1,4-dibromobutane can be used, and any of them gives good results. Although 1-10 equivalent can be used for dibromoalkane with respect to an oxindole derivative, 1-5 equivalent is preferable. As the base, for example, sodium hydride, isopropyl magnesium bromide, or n-butyl lithium can be used, but sodium hydride or n-butyl lithium is preferable. Although 2-10 equivalent can be used for a base with respect to an oxindole derivative, 2-5 equivalent is preferable. As the solvent, for example, DMF or tetrahydrofuran can be used, and good results can be obtained in any case.

  The reaction temperature of the cycloalkylation reaction is preferably -90 ° C to 100 ° C, more preferably -80 ° C to 40 ° C. The reaction time of the cycloalkylation reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 24 hours, more preferably 30 minutes to 4 hours.

  The concentration at the start of the reaction of the oxindole derivative represented by the above general formula (XLVI) in the cycloalkylation reaction is preferably 0.001M to 5M, and more preferably 0.05M to 1M. The oxindole derivative represented by the above general formula (XLVI) used for the cycloalkylation reaction may be a commercially available product or a compound synthesized from a commercially available product.

  As the reducing agent used in the reduction reaction, for example, borane / tetrahydrofuran complex or lithium aluminum hydride can be used, and any of them can give a good result. Although 0.5-10 equivalent can be used for a reducing agent with respect to an oxindole derivative, 0.5-5 equivalent is preferable. As the solvent, for example, tetrahydrofuran or diethyl ether can be used, but tetrahydrofuran is preferred.

  The reaction temperature of the reduction reaction is preferably -90 ° C to 66 ° C, more preferably -80 ° C to 66 ° C. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours.

  The concentration at the start of the reaction of the oxindole derivative represented by the above general formula (XLV) in the reduction reaction is preferably 0.001M to 5M, and more preferably 0.05M to 1M.

［式中、Ｒ^５、Ｒ^１１及びｐは、上記定義に同じである。］(Production Method 26)
The indoline derivative represented by the general formula (XLVII), which is a part of the indoline derivative represented by the above general formula (XLI), is, for example, an indoline represented by the general formula (LII) as shown in Scheme 27 below. It can be produced from a -2,3-dione derivative.

[Wherein R ⁵ , R ¹¹ and p are the same as defined above. ]

  The conversion of the indoline-2,3-dione derivative represented by the above general formula (LII) to the indoline derivative is carried out in the same manner as in Production Method 7 and the indoline-2,3- A dione derivative is synthesized, and subsequently converted into the indoline-2,3-dione derivative represented by the above general formula (L) in the same manner as in Production Method 4, followed by the reduction reaction in Production Method 19 An oxindole derivative represented by the above general formula (XLIX) can be synthesized by the same method, and further, the same method as in Production Method 25 can be used.

［式中、Ｒ^２〜Ｒ^５は、上記定義に同じである。］(Production Method 27)
Among the imidazoline derivatives represented by the above general formula (I), an imidazoline derivative represented by the general formula (LIII) is produced from a nitrile derivative represented by the general formula (LIV) as shown in the following scheme 28, for example. can do.

[Wherein R ^{2 to} R ⁵ are the same as defined above. ]

  The cyclization reaction of the nitrile derivative represented by the above general formula (LIV) can be performed by the same method as in Production Method 2.

［式中、Ｒ^２、Ｒ^３、Ｒ^５及びＲ^１１は、上記定義に同じである。］(Production method 28)
The nitrile derivative represented by the general formula (LV), which is a part of the nitrile derivative represented by the above general formula (LIV), is, for example, a chroman represented by the general formula (LVI) as shown in the following scheme 29. It can be produced from a derivative.

[Wherein R ² , R ³ , R ⁵ and R ¹¹ are the same as defined above. ]

  Conversion of the chroman derivative represented by the above general formula (LVI) to a nitrile derivative is carried out in a solvent with 4- (4,4,5,5-tetramethyl-1,3,2 together with a base, a palladium catalyst and a ligand. A method by a coupling reaction using -dioxaboran-2-yl) isoxazole is common.

4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) isoxazole used for the coupling reaction can be used in an amount of 1 to 10 equivalents based on the chroman derivative. However, 1 to 5 equivalents are preferable. As the base, for example, potassium fluoride, potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate can be used, but potassium fluoride is preferable. Although 1-20 equivalent can be used for a base with respect to a chroman derivative, 1-5 equivalent is preferable. As the palladium catalyst, for example, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, PdCl ₂ (PPh ₃ ) ₂ or palladium acetate can be used, but dichloro [1,1′-bis ( Diphenylphosphino) ferrocene] palladium is preferred. Although 0.001-0.99 equivalent can be used for a palladium catalyst with respect to a chroman derivative, 0.1-0.99 equivalent is preferable. As the ligand, for example, triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene or tri-t-butylphosphine can be used, but 1,1′-bis (diphenylphosphino) ferrocene is preferable. Although 1-10 equivalent can be used for a ligand with respect to a palladium catalyst, 1-3 equivalent is preferable. As the solvent, for example, DMSO, water, DMF, n-propanol, toluene, tetrahydrofuran, or a mixed solvent thereof can be used, but a mixed solvent of DMSO and water is preferable.

  0-180 degreeC is preferable and, as for the reaction temperature of a coupling reaction, 20-140 degreeC is more preferable. The reaction time of the coupling reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, and more preferably 1 hour to 20 hours.

  The concentration at the start of the reaction of the chroman derivative represented by the above general formula (LVI) in the coupling reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^５及びＲ^１１は、上記定義に同じである。］(Production Method 29)
The chroman derivative represented by the general formula (LVII), which is a part of the chroman derivative represented by the above general formula (LVI), is, for example, a chromanone represented by the general formula (LVIII) as shown in the following scheme 30 It can be produced from a derivative.

[Wherein R ⁵ and R ¹¹ are the same as defined above. ]

  The dimethylation reaction of the chromanone derivative represented by the above general formula (LVIII) is generally performed by using dimethylzinc together with titanium tetrachloride in a dichloromethane solvent.

  The dimethylzinc used in the dimethylation reaction can be used in an amount of 0.5 to 10 equivalents relative to the chromanone derivative, with 1 to 5 equivalents being preferred. Although titanium tetrachloride can use 0.1-10 equivalent with respect to a chromanone derivative, 1-5 equivalent is preferable.

  The reaction temperature of the dimethylation reaction is preferably -90 ° C to 40 ° C, more preferably -80 ° C to 30 ° C. The reaction time of the dimethylation reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 48 hours, and more preferably 1 hour to 20 hours.

  The concentration at the start of the reaction of the chromanone derivative represented by the above general formula (LVIII) in the dimethylation reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The chromanone derivative represented by the above general formula (LVIII) used for the dimethylation reaction may be a commercially available product or a compound synthesized from a commercially available product.

［式中、Ｒ^５及びＲ^１１は、上記定義に同じである。］(Manufacturing method 30)
The chroman derivative represented by the general formula (LIX), which is a part of the chroman derivative represented by the general formula (LVI), is represented by the above general formula (LVIII) as shown in the following scheme 31, for example. Can be produced from the chromanone derivative.

[Wherein R ⁵ and R ¹¹ are the same as defined above. ]

  The conversion of the chromanone derivative represented by the above general formula (LVIII) to the chroman derivative is carried out by converting the olefin derivative represented by the above general formula (LX) by a Wittig reaction using methyltriphenylphosphonium bromide together with a base in a tetrahydrofuran solvent. And then using a dihalogenated methane together with diethylzinc and acid in a solvent.

  The methyltriphenylphosphonium bromide used for the Wittig reaction can use 1 to 10 equivalents with respect to the chromanone derivative, but 1 to 5 equivalents are preferable. As the base, for example, t-butoxy potassium, sodium hydride or sodium bis (trimethylsilyl) amide can be used, but t-butoxy potassium is preferable. Although 1-10 equivalent can be used for a base with respect to methyltriphenylphosphonium bromide, 1-5 equivalent is preferable.

  The reaction temperature of the Wittig reaction is preferably −80 ° C. to 66 ° C., more preferably 0 to 60 ° C. The reaction time of the Wittig reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 20 minutes to 5 hours.

  The concentration at the start of the reaction of the chromanone derivative represented by the above general formula (LVIII) in the Wittig reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M. The chromanone derivative represented by the above general formula (LVIII) used for the Wittig reaction may be a commercially available product or a compound synthesized from a commercially available product.

  Although diethyl zinc used for cyclopropanation reaction can use 1-10 equivalent with respect to an olefin derivative, 1-5 equivalent is preferable. As the dihalogenated methane, for example, chloroiodomethane or diiodomethane can be used, and good results are obtained in either case. The dihalogenated methane can be used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, based on the olefin derivative. As the acid, for example, trifluoroacetic acid or acetic acid can be used, but trifluoroacetic acid is preferred. Although 1-10 equivalent can be used for an acid with respect to an olefin derivative, 1-5 equivalent is preferable. As the solvent, for example, dichloromethane or 1,2-dichloroethane can be used, and any of them gives good results.

  The reaction temperature of the cyclopropanation reaction is preferably -80 ° C to 84 ° C, more preferably 0 to 40 ° C. The reaction time of the cyclopropanation reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 48 hours, more preferably 30 minutes to 18 hours.

  The concentration at the start of the reaction of the olefin derivative represented by the above general formula (LX) in the cyclopropanation reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^２〜Ｒ^５及びｎは、上記定義に同じである。］(Production method 31)
Among the imidazoline derivatives represented by the above general formula (I), an imidazoline derivative represented by the general formula (LXI) is produced from a nitrile derivative represented by the general formula (LXII) as shown in the following scheme 32, for example. can do.

[Wherein R ^{2 to} R ⁵ and n are the same as defined above. ]

  The cyclization reaction of the nitrile derivative represented by the above general formula (LXII) can be carried out by the same method as Production Method 2.

［式中、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production method 32-1)
The nitrile derivative represented by the general formula (LXIII), which is a part of the nitrile derivative represented by the above general formula (LXII), is, for example, as shown in the following scheme 33, the cyclohexane represented by the general formula (LXVI) It can be produced from an alkylbenzene derivative.

[Wherein R ² , R ³ , R ⁵ , R ¹¹ and n are the same as defined above. ]

  The conversion of the cycloalkylbenzene derivative represented by the above general formula (LXVI) into a nitrile derivative can be performed by the same method as Production Method 22.

［式中、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production method 32-2)
The nitrile derivative represented by the above general formula (LXIII), which is a part of the nitrile derivative represented by the above general formula (LXII), can be obtained, for example, by the method shown in the following scheme 34, LXVI) can be produced from the cycloalkylbenzene derivative.

[Wherein R ² , R ³ , R ⁵ , R ¹¹ and n are the same as defined above. ]

  Conversion of the cycloalkylbenzene derivative represented by the above general formula (LXVI) to a nitrile derivative can be carried out in the same manner as in Production Method 28.

［式中、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production Method 33)
The cycloalkylbenzene derivative represented by the general formula (LXVII), which is a part of the cycloalkylbenzene derivative represented by the general formula (LXVI), is represented by the general formula (LXVIII) as shown in the following scheme 35, for example. It can be produced from a ketone derivative.

[Wherein, R ⁵ , R ¹¹ and n are the same as defined above. ]

  The dimethylation reaction of the ketone derivative represented by the above general formula (LXVIII) can be carried out by the same method as Production method 29.

［式中、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production Method 34)
The cycloalkylbenzene derivative represented by the general formula (LXIX), which is a part of the cycloalkylbenzene derivative represented by the above general formula (LXVI), is represented by the above general formula (LXVIII) as shown in the following scheme 36, for example. It can manufacture from the ketone derivative shown by these.

[Wherein, R ⁵ , R ¹¹ and n are the same as defined above. ]

  Conversion of the ketone derivative represented by the above general formula (LVIII) to a cycloalkylbenzene derivative can be carried out in the same manner as in Production Method 30.

［式中、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production method 35)
The cycloalkylbenzene derivative represented by the general formula (LXXI), which is a part of the cycloalkylbenzene derivative represented by the above general formula (LXVI), is represented by the above general formula (LXVIII) as shown in the following scheme 37, for example. It can manufacture from the ketone derivative shown by these.

[Wherein, R ⁵ , R ¹¹ and n are the same as defined above. ]

  The conversion of the ketone derivative represented by the above general formula (LXVIII) to the cycloalkylbenzene derivative is performed by using cyclopropyldiphenylsulfonium tetrafluoroborate together with a base in a DMSO solvent and the cyclobutanone derivative represented by the above general formula (LXXV). Followed by reduction to the alcohol derivative of general formula (LXXIV) using sodium borohydride in methanol solvent, then using methanesulfonyl chloride with triethylamine in dichloromethane solvent Then, a mesyl derivative represented by the above general formula (LXXIII) was synthesized, and further an olefin derivative represented by the above general formula (LXXII) was synthesized by E2 elimination reaction using t-butoxypotassium in a DMSO solvent. , Finally, metal in solvent How to reduction with medium and hydrogen is common.

  The cyclopropyldiphenylsulfonium tetrafluoroborate used in the cyclobutanonation reaction can be used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, based on the ketone derivative. As the base, for example, n-butyllithium, potassium hydroxide or sodium hydroxide can be used, but potassium hydroxide is preferred. Although 1-10 equivalent can be used for a base with respect to cyclopropyl diphenylsulfonium tetrafluoroborate, 1-5 equivalent is preferable.

  The reaction temperature of the cyclobutanone reaction is preferably 20 to 100 ° C, more preferably 20 to 40 ° C. The reaction time of the cyclobutanation reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 20 minutes to 5 hours.

  The concentration of the ketone derivative represented by the above general formula (LXVIII) in the cyclobutanation reaction at the start of the reaction is preferably 0.001 mM to 5M, and more preferably 0.05 mM to 1M.

  The sodium borohydride used for the reduction reaction can be used in an amount of 0.25 to 10 equivalents relative to the cyclobutanone derivative, but 1 to 5 equivalents are preferred.

  0-60 degreeC is preferable and, as for the reaction temperature of a reductive reaction, 0-40 degreeC is more preferable. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 1 minute to 24 hours, and more preferably 10 minutes to 5 hours.

  The concentration of the cyclobutanone derivative represented by the above general formula (LXXV) in the reduction reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

  Although 1-10 equivalent can be used for the methanesulfonyl chloride used for a mesylation reaction with respect to an alcohol derivative, 1-5 equivalent is preferable. Although triethylamine can use 1-10 equivalent with respect to methanesulfonyl chloride, 1-5 equivalent is preferable.

  0-40 degreeC is preferable and, as for the reaction temperature of a mesylation reaction, 10-40 degreeC is more preferable. The reaction time of the mesylation reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 24 hours, and more preferably 1 hour to 12 hours.

The concentration of the alcohol derivative represented by the general formula (LXXIV) in the mesylation reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.
Although 1-10 equivalent can be used for t-butoxy potassium used for E2 elimination reaction with respect to a mesyl derivative, 1-5 equivalent is preferable.

  The reaction temperature for the E2 elimination reaction is preferably 20 to 150 ° C, more preferably 20 to 80 ° C. The reaction time for the E2 elimination reaction varies depending on the substrate or reaction conditions, but is preferably 30 minutes to 24 hours, more preferably 30 minutes to 3 hours.

  The concentration of the mesyl derivative represented by the above general formula (LXXIII) in the E2 elimination reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

  As the metal catalyst used in the reduction reaction, for example, a Wilkinson complex, platinum oxide or palladium carbon can be used, but a Wilkinson complex or platinum oxide is preferable. Although 0.001-0.99 equivalent can be used for a metal catalyst with respect to an olefin derivative, 0.1-0.99 equivalent is preferable. As the solvent, for example, dichloromethane, methanol or ethanol can be used, but dichloromethane or methanol is preferable.

  0-60 degreeC is preferable and, as for the reaction temperature of a reductive reaction, 5-40 degreeC is more preferable. The reaction time of the reduction reaction varies depending on the substrate or reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 10 minutes to 24 hours.

  The concentration of the olefin derivative represented by the general formula (LXXII) in the reduction reaction at the start of the reaction is preferably 0.001 to 5M, and more preferably 0.05 to 1M.

［式中、Ｒ^５、Ｒ^１１及びｎは、上記定義に同じである。］(Production method 36)
The ketone derivative represented by the above general formula (LXVIII) can be produced, for example, from the ketone derivative represented by the general formula (LXXVI) as shown in the following scheme 38.

[Wherein, R ⁵ , R ¹¹ and n are the same as defined above. ]

  The bromination reaction of the ketone derivative represented by the above general formula (LXXVI) can be carried out by the same method as Production Method 7.

  The fact that the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has α1L receptor agonist activity is described in, for example, Nishimune et al. (Journal of Pharmaceutical Sciences, 2010, No. 1). 113, p.169-181), and can be evaluated in an in vitro experimental system using cells expressing human α1L adrenergic receptor. Specifically, for example, human α1L adrenergic receptor is expressed in Chinese hamster ovary-derived CHO-K1 cells, and the increase in intracellular calcium concentration by the action of the compound is measured, whereby the agonistic activity of the compound on the receptor Can be evaluated.

  Since the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has α1L adrenergic activity, it can be used as a medicine, and in particular, a signal of α1L adrenergic receptor. It can be used as a therapeutic or prophylactic agent for diseases caused by transmission.

  Examples of diseases caused by α1L adrenergic receptor signal transduction include urinary incontinence, and urinary incontinence includes stress urinary incontinence, urge incontinence, mixed urinary incontinence, mixed urinary incontinence, persistent urinary incontinence and the like. Although included, the medicament is preferably a therapeutic or prophylactic agent for stress urinary incontinence.

  The fact that the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is effective for treating or preventing stress urinary incontinence is, for example, known literature (American Journal of Physiology- Renal Physiology, 2008, Vol. 295, p.F264-271) or the method described in the patent literature (International Publication No. 2007/018234), that is, the urethral pressure-increasing effect after administration of the compound in the rat urethral pressure measurement system Can be confirmed.

  The medicament containing the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is not only effective for humans but also mammals other than humans, such as mice and rats. It is also effective against hamsters, rabbits, cats, dogs, cows, sheep and monkeys.

  When the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is used clinically as a medicine, the drug may be a free base or the acid addition salt itself, For example, additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents, or tonicity agents may be appropriately mixed. Examples of the dosage form include oral administration such as tablets, capsules, granules, powders or syrups, parenteral administration such as injections, suppositories or liquids, and local administration such as ointments, creams or patches. Can be mentioned.

  The medicament preferably contains 0.00001 to 90% by weight of the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. It is more preferable to contain 70% by weight. The dosage is appropriately selected according to the patient's symptoms, age and body weight, administration method, etc., but for adults, the amount of active ingredient is 0.1 μg to 1 g per day in the case of injections, oral preparations In the case of 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day is preferable, and each can be administered once or divided into several times.

  EXAMPLES Hereinafter, although an Example is shown and this invention is explained in full detail, this invention is not limited to these.

  In addition, about the compound which is not described in the synthesis method among the compounds used for the synthesis | combination of a compound, the commercially available compound was used. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), brs (wide single line), d (double line), t (triple line), dd, respectively. (Double double line), dt (double quadruple line), td (triple double line), qq (quadruple quadruple line), and m (multiple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). The silica gel used was TLC Silica gel 60 F254 (Merck KGaA), and the chromatography was YFLC W-prep2XY (Yamazen).

Reference Example 1 Synthesis of 4-bromo-6-chloro-2,3-dihydro-1H-inden-1-one:
To a solution of 500 mg (2.7 mmol) of 3- (4-chlorophenyl) propionic acid in 1,2-dichloroethane (10 mL), N-bromosuccinimide (530 mg, 3.0 mmol) and gold chloride (80 mg, 0.27 mmol) were added. In addition, the mixture was stirred at 70 ° C. for 26 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Dichloromethane (10 mL) and thionyl chloride (1.3 g, 11 mmol) were added to the obtained intermediate and stirred at room temperature for 23 hours. The reaction solution was concentrated, dichloromethane (10 mL) and aluminum chloride (720 mg, 5.4 mmol) were added to the resulting concentrate, and the mixture was heated to reflux for 4 hours. Ice and water were added to the reaction solution at 0 ° C., followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 1 (153 mg, white solid, yield 22%) Got.

Reference Example 2 Synthesis of 6-chloro-4- (prop-1-en-2-yl) -2,3-dihydro-1H-inden-1-one:
To a solution of the compound of Reference Example 1 (100 mg, 0.41 mmol) in tetrahydrofuran (4.0 mL) and water (0.4 mL), palladium acetate (14 mg, 0.061 mmol), triphenylphosphine (32 mg, 0.12 mmol) , Potassium isopropenyl trifluoroborate (130 mg, 0.90 mmol), and cesium carbonate (360 mg, 1.1 mmol) were added, and the mixture was stirred at 70 ° C. for 17 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 2 (75 mg, pale yellow oil, yield 89%) )

Reference Example 3 Synthesis of 6-chloro-4- (prop-1-en-2-yl) -2,3-dihydro-1H-indene-1-carbonitrile:
To a solution of t-butoxypotassium (42 mg, 0.38 mmol) in tetrahydrofuran (1.0 mL) was added p-toluenesulfonylmethyl isocyanide (48 mg, 0.25 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 25 minutes. Subsequently, a solution of the compound of Reference Example 2 (30 mg, 0.15 mmol) in tetrahydrofuran (1.5 mL) was added, and the mixture was stirred at −78 ° C. for 80 minutes. Further, methanol (0.18 mL) was added at −78 ° C., followed by stirring at 60 ° C. for 80 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 3 (18 mg, brown oil, yield 56%) Got.

Reference Example 4 2- (6-Chloro-4- (prop-1-en-2-yl) -2,3-dihydro-1H-inden-1-yl) -4,5-dihydro-1H-imidazole Synthesis of:
To a solution of the compound of Reference Example 3 (17 mg, 0.078 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (8.7 mg, 0.039 mmol), and the mixture was stirred at 100 ° C. for 50 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 4 (15 mg, white solid, yield 76%).

Example 1 Synthesis of 2- (6-chloro-4-isopropyl-2,3-dihydro-1H-inden-1-yl) -4,5-dihydro-1H-imidazole hydrochloride:
To a methanol (1.0 mL) solution of the compound of Reference Example 4 (14 mg, 0.054 mmol), platinum oxide (2.4 mg, 0.011 mmol) was added, followed by hydrogen substitution, and then stirred at room temperature for 20 minutes. The reaction solution was filtered through celite and concentrated. The obtained crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (9.0 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (35 μL), followed by concentration to give the compound of Example 1 (8.1 mg, white solid, yield 64%). Got.

Reference Example 5 Synthesis of 4- (4-chlorophenyl) butyric acid:
To a solution of 4- (4-chlorophenyl) -4-oxobutyric acid (10 g, 47 mmol) in ethylene glycol (42 mL), potassium hydroxide (7.0 g, 130 mmol) and hydrazine monohydrate (5.1 g, 100 mmol) And a Dean-Stark device was attached to the reaction vessel and heated to reflux for 7 hours. Water (50 mL) and 2.5 N hydrochloric acid (60 mL) were added to the reaction solution, and the precipitated yellow solid was collected by filtration. A saturated potassium carbonate aqueous solution (100 mL) and a water (40 mL) solution of the obtained crude product were dropped into 2.5 N hydrochloric acid (200 mL) at 0 ° C., and the precipitated solid was collected by filtration to give Reference Example 5 (9.6 g, white solid, quantitative) was obtained.

Reference Example 6 Synthesis of 7-chloro-3,4-dihydronaphthalen-1 (2H) -one:
To a solution of the compound of Reference Example 5 (700 mg, 3.5 mmol) in dichloromethane (13 mL) was added thionyl chloride (840 mg, 7.1 mmol) at 0 ° C., and the mixture was stirred at room temperature for 15 hours. Dichloromethane (15 mL) and aluminum chloride (470 mg, 3.5 mmol) were added to the concentrate obtained by concentrating the reaction solution, and the mixture was heated to reflux for 4 hours. Ice and water were added to the reaction solution at 0 ° C., followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 6 (540 mg, white solid, yield 84%) Got.

Reference Example 7 Synthesis of 5-bromo-7-chloro-3,4-dihydronaphthalen-1 (2H) -one:
A mixture of the compound of Reference Example 6 (400 mg, 2.2 mmol) and powdered aluminum chloride (830 mg, 6.2 mmol) was stirred at 110 ° C. for 20 minutes. Subsequently, bromine (390 mg, 2.4 mmol) was slowly added and stirred at 110 ° C. for 30 minutes. Ice and water were added to the reaction solution at 0 ° C., followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 7 (310 mg, light brown solid, 53% yield). )

Reference Example 8 Synthesis of 7-chloro-5- (prop-1-en-2-yl) -3,4-dihydronaphthalen-1 (2H) -one:
To a solution of the compound of Reference Example 7 (40 mg, 0.15 mmol) in tetrahydrofuran (2.0 mL) and water (0.20 mL), palladium acetate (5.2 mg, 0.023 mmol) and triphenylphosphine (12 mg, 0.25 mL) were added. 046 mmol), potassium isopropenyl trifluoroborate (50 mg, 0.34 mmol), and cesium carbonate (140 mg, 0.42 mmol) were added, and the mixture was stirred at 70 ° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 8 (27 mg, yellow oil, yield 79%). Got.

Reference Example 9 Synthesis of 7-chloro-5- (prop-1-en-2-yl) -1,2,3,4-tetrahydronaphthalene-1-carbonitrile:
To a solution of potassium t-butoxy (36 mg, 0.32 mmol) in tetrahydrofuran (1.5 mL) was added p-toluenesulfonylmethyl isocyanide (41 mg, 0.21 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 25 minutes. Subsequently, a solution of the compound of Reference Example 8 (27 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) was added, and the mixture was stirred at −78 ° C. for 3 hours. Further, methanol (150 μL) was added and stirred at 60 ° C. for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 9 (8.7 mg, light yellow oil, yield) 31%).

Example 2 Synthesis of 2- (7-chloro-5-isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 9 (6 mg, 0.026 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (2.9 mg, 0.013 mmol), and the mixture was stirred at 100 ° C. for 1 hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain a white solid (2.0 mg). To a solution of the obtained white solid in methanol (1.0 mL), platinum oxide (0.60 mg, 0.0026 mmol) was added and replaced with hydrogen, followed by stirring at room temperature for 30 minutes. The reaction solution was filtered through celite and concentrated. The obtained crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (1.0 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (30 μL), followed by concentration to give the compound of Example 2 (1.0 mg, white solid, yield 14%). Got.

Reference Example 10 Synthesis of 6-chloro-8- (prop-1-en-2-yl) chroman-4-one:
To a solution of 8-bromo-6-chlorochroman-4-one (480 mg, 1.8 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL) was added palladium acetate (62 mg, 0.28 mmol), triphenylphosphine (140 mg). 0.55 mmol), potassium isopropenyl trifluoroborate (630 mg, 4.2 mmol), and cesium carbonate (1600 mg, 5.0 mmol) were added, and the mixture was stirred at 70 ° C. for 18 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 10 (370 mg, pale yellow oil, 91% yield). )

Reference Example 11 Synthesis of 6-chloro-8-isopropylchroman-4-one:
Wilkinson complex (140 mg, 0.15 mmol) was added to a solution of the compound of Reference Example 10 (370 mg, 1.5 mmol) in dichloromethane (15 mL), and after hydrogen substitution, the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 11 (370 mg, light yellow solid, yield 96%) )

Reference Example 12 Synthesis of 6-chloro-8-isopropyl-2H-chromene-4-carbonitrile:
To a solution of the compound of Reference Example 11 (200 mg, 0.89 mmol) in dichloromethane (9.0 mL) were added diiodozinc (57 mg, 0.18 mmol) and trimethylsilylcyanide (120 mg, 1.2 mmol), and 6 Stir for 5 hours. The reaction solution was concentrated, toluene (9.0 mL) and Amberlyst 15 (H) (200 mg) were added to the resulting crude product, and the mixture was heated to reflux for 90 minutes. The reaction solution was filtered through celite, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 12 (81 mg, white solid, yield 39%) Got.

Reference Example 13 Synthesis of 6-chloro-8-isopropylchroman-4-carbonitrile:
To a solution of the compound of Reference Example 12 (76 mg, 0.33 mmol) in ethanol (3.5 mL) was added sodium borohydride (12 mg, 0.33 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 13 (75 mg, colorless transparent oil, yield 97%) )

Example 3 Synthesis of 2- (6-chloro-8-isopropylchroman-4-yl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 13 (75 mg, 0.32 mmol) in ethylenediamine (3.0 mL) was added phosphorus pentasulfide (35 mg, 0.16 mmol), and the mixture was stirred at 100 ° C. for 4.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (84 mg). To a solution of the obtained white solid in methanol (3.0 mL), 10% hydrogen chloride-methanol (300 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 3 (90 mg). , White solid, 94%).

Reference Example 14 Synthesis of 3- (2-bromo-4-methylphenoxy) propanenitrile:
To a solution of 2-bromo-p-cresol (500 mg, 2.7 mmol) in acrylonitrile (1.8 mL, 27 mmol), potassium carbonate (740 mg, 5.4 mmol) and t-butanol (510 μL, 2.7 mmol) were added, The mixture was stirred at 77 ° C. for 28 hours. Phosphoric acid and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 14 (200 mg, white solid, yield 32%). Got.

Reference Example 15 Synthesis of 8-bromo-6-methylchroman-4-one:
To a solution of the compound of Reference Example 14 (400 mg, 1.7 mmol) in trifluoroacetic acid (600 μL) was added trifluoromethanesulfonic acid (900 μL, 10 mmol) at 0 ° C., and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 15 (190 mg, white solid, yield 47%). Got.

Reference Example 16 Synthesis of 6-methyl-8- (prop-1-en-2-yl) chroman-4-one:
To a solution of the compound of Reference Example 15 (190 mg, 0.79 mmol) in tetrahydrofuran (3.0 mL) and water (0.30 mL), palladium acetate (88 mg, 0.39 mmol), triphenylphosphine (52 mg, 0.20 mmol). , Potassium isopropenyl trifluoroborate (350 mg, 2.4 mmol), and cesium carbonate (690 mg, 2.1 mmol) were added, and the mixture was stirred at 70 ° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 16 (160 mg, white solid, yield 99%) Got.

Reference Example 17 Synthesis of 8-isopropyl-6-methylchroman-4-one:
Wilkinson complex (72 mg, 0.78 mmol) was added to a solution of the compound of Reference Example 16 (160 mg, 0.78 mmol) in dichloromethane (10 mL), purged with hydrogen, and then stirred at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 17 (120 mg, white solid, yield 75%). Got.

Reference Example 18 Synthesis of 8-isopropyl-6-methyl-2H-chromene-4-carbonitrile To a solution of the compound of Reference Example 17 (62 mg, 0.30 mmol) in dichloromethane (2.0 mL) was added diiodozinc (64 mg, 0.20 mmol) and trimethylsilylcyanide (400 μL, 3.0 mmol) were added, and the mixture was stirred at 40 ° C. for 10 hours. The reaction solution was concentrated, toluene (5.0 mL) and Amberlyst 15 (H) (200 mg) were added to the obtained crude product, and the mixture was heated to reflux for 1 hour. The reaction solution was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 18 (4.6 mg, yellow oil, yield 7) 0.1%).

Reference Example 19 Synthesis of 8-isopropyl-6-methylchroman-4-carbonitrile:
Sodium borohydride (1.0 mg, 0.22 mmol) was added to a solution of the compound of Reference Example 18 (4.6 mg 0.21 mmol) in ethanol (2.0 mL), and the mixture was stirred at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33), and the compound of Reference Example 19 (4.5 g, colorless transparent oil, yield) 97%).

Example 4 Synthesis of 2- (8-isopropyl-6-methylchroman-4-yl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 19 (4.0 mg, 0.019 mmol) in ethylenediamine (2.0 mL) was added phosphorus pentasulfide (4.1 mg, 0.019 mmol), and the mixture was stirred at 100 ° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / chloroform / methanol = 46/46/8), and the free form of the title compound was converted into a white solid (2.0 mg, 42%). Obtained. To a solution of the obtained white solid in methanol (1.0 mL), 10% hydrogen chloride-methanol (50 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 4 (3 0.0 mg, white solid, quantitative).

Reference Example 20 Synthesis of 8-isopropyl-2,3-dihydroquinolin-4 (1H) -one:
To a solution of 2-isopropylaniline (10 g, 74 mmol) in dichloromethane (100 mL) was added potassium carbonate (12 g, 89 mmol) and 3-bromopropionyl chloride (8.9 mL, 89 mmol) at 0 ° C., and the mixture was stirred at room temperature for 4 hours. . A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the obtained concentrate (20 g), DMF (100 mL) was added, followed by sodium t-butoxy (8.5 g, 89 mmol) at 0 ° C., and the mixture was stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the resulting intermediate (13 g, yellow oil) was added 1,2-dichloroethane (100 mL), followed by trifluoromethanesulfonic acid (9.9 mL, 110 mmol) at 0 ° C. and stirred at room temperature for 16 hours. The reaction solution was added to 1N aqueous sodium hydroxide solution at 0 ° C., followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 20 (8.0 g, yellow solid, yield 57). %).

Reference Example 21 Synthesis of 6-bromo-8-isopropyl-2,3-dihydroquinolin-4 (1H) -one:
N-bromosuccinimide (6.1 g, 34 mmol) was added to a solution of the compound of Reference Example 20 (6.5 g, 34 mmol) in dichloromethane (200 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 21 (6.8 g, yellow solid, yield 74). %).

Reference Example 22 Synthesis of 6-bromo-8-isopropyl-1- (4-methoxybenzyl) -2,3-dihydroquinolin-4 (1H) -one:
To a solution of the compound of Reference Example 21 (5.7 g, 21 mmol) in DMF (6.0 mL), potassium carbonate (8.9 g, 64 mmol), sodium iodide (3.2 g, 21 mmol), and p-methoxybenzyl chloride ( (5.9 mL, 43 mmol) was added, and the mixture was stirred at 50 ° C. for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 80/20) to give the compound of Reference Example 22 (8.3 g, yellow solid, yield 93). %).

Reference Example 23 Synthesis of 6-bromo-8-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinoline-4-carbonitrile:
To a solution of t-butoxypotassium (430 mg, 3.9 mmol) in tetrahydrofuran (15 mL) was added p-toluenesulfonylmethyl isocyanide (500 mg, 2.6 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the compound of Reference Example 22 (500 mg, 1.3 mmol) in tetrahydrofuran (5.0 mL) was added, and the mixture was stirred at −30 ° C. for 4 hours. Furthermore, methanol (4.0 mL) was added, and the mixture was stirred at 60 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 80/20) to give the compound of Reference Example 23 (230 mg, white solid, yield 45%). Got.

Reference Example 24 6-Bromo-4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinoline Synthesis of:
To a solution of the compound of Reference Example 23 (10 mg, 0.025 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (2.8 mg, 0.013 mmol), and the mixture was stirred at 100 ° C. for 5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 24 (7.4 mg, white solid, 67%). Obtained.

Example 5 Synthesis of 6-bromo-4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1,2,3,4-tetrahydroquinoline dihydrochloride:
Trifluoroacetic acid (0.50 mL) was added to a solution of the compound of Reference Example 24 (7.0 mg, 0.016 mmol) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / methanol = 90/10) to give the free form of the title compound as a colorless transparent oil (5.6 mg). Obtained. To a solution of the obtained colorless transparent oil in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (35 μL), followed by concentration, recrystallization from methanol / diethyl ether, and the compound of Example 5 (5.0 mg). , A brown solid, 88%).

Reference Example 25 Synthesis of 2-bromo-4-methoxyaniline:
N-bromosuccinimide (15 g, 850 mmol) was added to a DMF (160 mL) solvent of p-anisidine (10 g, 810 mmol), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 80/20) to give the compound of Reference Example 25 (2.0 g, brown oil, yield 12). %).

Reference Example 26 Synthesis of 8-bromo-6-methoxy-2,3-dihydroquinolin-4 (1H) -one:
To a solution of the compound of Reference Example 25 (2.0 g, 9.9 mmol) in dichloromethane (33 mL) was added potassium carbonate (1.6 g, 12 mmol) and 3-bromopropionyl chloride (1.1 mL, 11 mmol), and at room temperature. Stir for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a DMF (20 mL) solution of the obtained concentrate (3.3 g, brown oil) was added t-butoxy sodium (1.1 g, 12 mmol), and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a 1,2-dichloroethane (25 mL) solution of the obtained intermediate (2.5 g, brown oil) was added trifluoromethanesulfonic acid (2.6 mL, 30 mmol), and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 26 (900 mg, yellow solid, yield 35%). Got.

Reference Example 27 Synthesis of 6-methoxy-8- (prop-1-en-2-yl) -2,3-dihydroquinolin-4 (1H) -one:
To a solution of the compound of Reference Example 26 (200 mg, 0.78 mmol) in tetrahydrofuran (7.8 mL) and water (0.78 mL), palladium acetate (26 mg, 0.12 mmol), triphenylphosphine (62 mg, 0.23 mmol) , Potassium isopropenyl trifluoroborate (280 mg, 1.9 mmol), and cesium carbonate (690 mg, 2.1 mmol) were added, and the mixture was stirred at 70 ° C. for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: n-hexane → n-hexane / ethyl acetate = 80/20) to give the compound of Reference Example 27 (140 mg, yellow oil, yield 82%). )

Reference Example 28 Synthesis of 8-isopropyl-6-methoxy-2,3-dihydroquinolin-4 (1H) -one:
Wilkinson complex (60 mg, 0.064 mmol) was added to a solution of the compound of Reference Example 27 (140 mg, 0.64 mmol) in dichloromethane (6.4 mL), purged with hydrogen, and then stirred at room temperature for 21 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 28 (130 mg, yellow oil, yield 73%). )

Reference Example 29 Synthesis of 4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-6-methoxyquinoline:
To a solution of Reference Example 28 (130 mg, 0.59 mmol) in toluene (5.9 mL), zinc iodide (95 mg, 0.30 mmol) and trimethylsilylcyanide (180 mg, 1.8 mmol) were added, and the mixture was heated at 80 ° C. for 5 hours. Stir. Subsequently, p-toluenesulfonic acid monohydrate (51 mg, 0.30 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a solution of the obtained concentrate (130 mg, yellow oil) in ethylenediamine (1.9 mL) was added phosphorus pentasulfide (130 mg, 0.59 mmol), and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 29 (10 mg, yellow solid, 6%).

Example 6 Synthesis of 4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-6-methoxy-1,2,3,4-tetrahydroquinoline dihydrochloride:
To a solution of the compound of Reference Example 29 (10 mg, 0.028 mmol) in ethanol (9.3 mL), concentrated hydrochloric acid (0.14 mL, 1.7 mmol) and platinum oxide (1.3 mg, 0.0056 mmol) are added, and hydrogen is added. After the replacement, the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and concentrated. The obtained crude product was recrystallized from acetonitrile / diethyl ether to obtain the compound of Example 6 (12 mg, white solid, yield 95%).

Reference Example 30 Synthesis of 3-bromo-N- (2-bromo-4-chlorophenyl) propanamide:
To a solution of 2-bromo-4-chloroaniline (3.6 g, 18 mmol) in dichloromethane (20 mL) at 0 ° C. was added potassium carbonate (2.9 g, 21 mmol) and 3-bromopropionyl chloride (2.1 mL, 21 mmol). And stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the compound of Reference Example 30 (6.2 g, white solid).

Reference Example 31 Synthesis of 1- (2-bromo-4-chlorophenyl) azetidin-2-one:
To a DMF (3.0 mL) solution of the compound of Reference Example 30 (6.2 g), t-butoxy sodium (2.0 g, 21 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 31 (3.3 g, white solid, yield 72). %).

Reference Example 32 Synthesis of 8-bromo-6-chloro-2,3-dihydroquinolin-4 (1H) -one:
To a 1,2-dichloroethane (20 mL) solution of the compound of Reference Example 31 (3.2 g, 12 mmol) was added trifluoromethanesulfonic acid (2.2 mL, 25 mmol) at 0 ° C., and the mixture was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 32 (720 mg, yellow solid, yield 34%). Got.

Reference Example 33 Synthesis of 6-chloro-8- (prop-1-en-2-yl) -2,3-dihydroquinolin-4 (1H) -one:
To a mixed solvent solution of the compound of Reference Example 32 (630 mg, 2.4 mmol) in tetrahydrofuran (2.0 mL) and water 0.20 mL), palladium acetate (81 mg, 0.36 mmol), triphenylphosphine (190 mg, 0 .72 mmol), potassium isopropenyl trifluoroborate (850 mg, 5.8 mmol) and cesium carbonate (2.1 g, 6.5 mmol) were added and stirred at 70 ° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 33 (430 mg, yellow solid, yield 85%). Got.

Reference Example 34 Synthesis of 6-chloro-8-isopropyl-2,3-dihydroquinolin-4 (1H) -one:
Wilkinson complex (190 mg, 0.20 mmol) was added to a solution of the compound of Reference Example 33 (450 mg, 2.0 mmol) in dichloromethane (22 mL), and after hydrogen substitution, the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 80/20), and the compound of Reference Example 34 (450 mg, yellow solid, yield 99%) Got.

Reference Example 35 Synthesis of 6-chloro-8-isopropyl-1-methyl-2,3-dihydroquinolin-4 (1H) -one:
To a 1,2-dichloroethane (3.0 mL) solution of the compound of Reference Example 34 (35 mg, 0.16 mmol), paraformaldehyde (47 mg, 1.6 mmol), sodium triacetoxyborohydride (170 mg, 0.78 mmol), and Acetic acid (9.4 mg, 0.16 mmol) was added and stirred at 80 ° C. for 14 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 35 (23 mg, yellow oil, yield 62%). Got.

Reference Example 36 Synthesis of 6-chloro-8-isopropyl-1-methyl-1,2,3,4-tetrahydroquinoline-4-carbonitrile:
To a solution of t-butoxypotassium (28 mg, 0.25 mmol) in tetrahydrofuran (2.0 mL) was added p-toluenesulfonylmethyl isocyanide (32 mg, 0.16 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 40 minutes. Subsequently, a solution of the compound of Reference Example 35 (23 mg, 0.097 mmol) in tetrahydrofuran (1.5 mL) was added, and the mixture was stirred at −78 ° C. for 2 hours. Further, methanol (0.12 mL) was added and stirred at 60 ° C. for 45 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 36 (14 mg, pale yellow solid, yield 58%). )

Example 7 Synthesis of 6-chloro-4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1-methyl-1,2,3,4-tetrahydroquinoline dihydrochloride :
To a solution of the compound of Reference Example 36 (14 mg, 0.056 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (6.3 mg, 0.028 mmol), and the mixture was stirred at 100 ° C. for 3.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / chloroform / methanol = 46/46/8) to obtain a free form of the title compound as a white solid (12 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol solution (82 μL), concentrated, and recrystallized with methanol / diethyl ether to give the compound of Example 7 ( 15 mg, white solid, yield 75%).

Reference Example 37 Synthesis of 6-chloro-8-isopropyl-1- (4-methoxybenzyl) -2,3-dihydroquinolin-4 (1H) -one:
To a solution of Reference Example 34 (20 mg, 0.090 mmol) in DMF (0.20 mL), potassium carbonate (25 mg, 0.18 mmol), p-methoxybenzyl chloride (18 μL, 0.13 mmol) and sodium iodide (13 mg, 0 0.089 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 37 (14 mg, yellow oil, yield 47%). Got.

Reference Example 38 Synthesis of 6-chloro-8-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinoline-4-carbonitrile:
To a solution of t-butoxypotassium (24 mg, 2.2 mmol) in tetrahydrofuran (7.0 mL) was added p-toluenesulfonylmethyl isocyanide (280 mg, 1.4 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the compound of Reference Example 37 (250 mg, 0.72 mmol) in tetrahydrofuran (4.0 mL) was added, and the mixture was stirred at −78 ° C. for 4 hours. Furthermore, methanol (0.89 mL) was added and stirred at 60 ° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 38 (150 mg, yellow oil, yield 60%). Got.

Reference Example 39 6-Chloro-4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinoline Synthesis of:
To a solution of the compound of Reference Example 38 (140 mg, 0.39 mmol) in ethylenediamine (3.0 mL) was added phosphorus pentasulfide (43 mg, 0.19 mmol), and the mixture was stirred at 100 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 39 (140 mg, white solid, yield 91%). Obtained.

Example 8 Synthesis of 6-chloro-4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1,2,3,4-tetrahydroquinoline dihydrochloride:
To a solution of the compound of Reference Example 39 (140 mg, 0.35 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL, 26 mmol), and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction solution, followed by extraction with ammonia-saturated chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ammonia saturated chloroform / methanol = 90/10) to give a free form of the title compound as a white solid (99 mg). To a solution of the obtained white solid in methanol (3.0 mL) was added 10% hydrogen chloride-methanol solution (700 μL), followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 8 ( 90 mg, white solid, 73% yield).

Reference Example 40 Synthesis of 4-bromo-6-chloro-1,1-dimethyl-2,3-dihydro-1H-indene:
To a solution of titanium tetrachloride (460 mg, 2.4 mmol) in dichloromethane (2.4 mL) was added dimethylzinc (230 mg, 1.04 M, n-hexane solution, 2.4 mmol) at −78 ° C., and 15 at −78 ° C. Stir for minutes. Subsequently, a solution of the compound of Reference Example 1 (100 mg, 0.41 mmol) in dichloromethane (2.0 mL) was added, and the mixture was stirred at 0 ° C. for 3 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to obtain the compound of Reference Example 40 (88 mg, colorless transparent oil, 83%). Obtained.

Reference Example 41 Synthesis of 2- (6-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl) acetonitrile:
To a solution of the compound of Reference Example 40 (85 mg, 0.33 mmol) in DMSO (3.2 mL) and water (0.98 mL) was added 4- (4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl) isoxazole (77 mg, 0.39 mmol), potassium fluoride (160 mg, 0.98 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (24 mg, 0.033 mmol) ) And stirred at 130 ° C. for 13 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 41 (2.1 mg, colorless transparent oil, yield) 3.0%).

Example 9 Synthesis of 2-((6-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl) methyl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 41 (2.1 mg, 0.0096 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (1.5 mg, 0.0068 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative silica gel chromatography (developing solvent: chloroform / ammonia saturated chloroform / methanol = 46/46/8) to obtain the free form of the title compound as a colorless transparent oil (2.5 mg). It was. To a solution of the obtained colorless transparent oil in methanol (1.0 mL), 10% hydrogen chloride-methanol (10 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 9 ( 2.5 mg, white solid, 89% yield).

Reference Example 42 Synthesis of 4-bromo-6-chloro-1-methylene-2,3-dihydro-1H-indene:
To a solution of methyltriphenylphosphonium bromide (660 mg, 1.8 mmol) in tetrahydrofuran (6.0 mL) was added t-butoxypotassium (210 mg, 1.9 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Subsequently, a tetrahydrofuran (3.0 mL) solution of the compound of Reference Example 1 (150 mg, 0.61 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give the compound of Reference Example 42 (140 mg, white solid, yield 95%). Got.

Reference Example 43 Synthesis of 4′-bromo-6′-chloro-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene]:
Diethyl zinc (61 mg, 1.09 M, n-hexane solution, 0.49 mmol) was added to a solution of chloroiodomethane (170 mg, 0.99 mmol) in dichloromethane (2.0 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 35 minutes. did. Subsequently, a dichloromethane (1.0 mL) solution of the compound of Reference Example 42 (60 mg, 0.25 mmol) was added, and the mixture was stirred at 0 ° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to obtain the compound of Reference Example 43 (65 mg, colorless transparent oil, quantitative). Obtained.

Reference Example 44 Synthesis of 2- (6′-chloro-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-yl) acetonitrile Compound of Reference Example 43 (65 mg, 0 .25 mmol) in DMSO (3.0 mL) and water (1.5 mL) was added to 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) isoxazole ( 59 mg, 0.30 mmol), potassium fluoride (44 mg, 0.76 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (18 mg, 0.025 mmol) were added, and 17 hours at 130 ° C. Stir. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 44 (13 mg, colorless transparent oil, yield 24%). )

Example 10 2-((6′-Chloro-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-yl) methyl) -4,5-dihydro-1H— Synthesis of imidazole hydrochloride:
To a solution of the compound of Reference Example 44 (13 mg, 0.060 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (6.6 mg, 0.030 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative silica gel chromatography (developing solvent: chloroform / ammonia saturated chloroform / methanol = 46/46/8) to obtain the free form of the title compound as a colorless transparent oil (15 mg). To a solution of the obtained colorless transparent oil in methanol (1.0 mL), 10% hydrogen chloride-methanol (57 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 10 ( 13 mg, white solid, 89% yield).

Reference Example 45 Synthesis of 5-bromo-7-chloro-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene:
To a solution of titanium tetrachloride (290 mg, 1.5 mmol) in dichloromethane (3.0 mL) was added dimethylzinc (150 mg, 1.04 M, n-hexane solution, 1.5 mmol) at −78 ° C., and 20 at −78 ° C. Stir for minutes. Subsequently, a solution of the compound of Reference Example 7 (80 mg, 0.31 mmol) in dichloromethane (1.5 mL) was added, and the mixture was stirred at 0 ° C. for 3 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 45 (74 mg, colorless transparent oil, yield 88%). )

Reference Example 46 Synthesis of 2- (3-chloro-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl) acetonitrile:
To a solution of the compound of Reference Example 45 (73 mg, 0.27 mmol) in DMSO (3.9 mL) and water (1.2 mL) was added 4- (4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl) isoxazole (62 mg, 0.32 mmol), potassium fluoride (47 mg, 0.80 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (20 mg, 0.027 mmol) ) And stirred at 110 ° C. for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 46 (14 mg, colorless transparent oil, yield 19%). )

Example 11 Synthesis of 2-((3-chloro-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl) methyl) -4,5-dihydro-1H-imidazole hydrochloride :
To a solution of the compound of Reference Example 46 (13 mg, 0.056 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (6.2 mg, 0.028 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (13 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (47 μL), followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 11 (11 mg White solid, yield 87%).

Reference Example 47 Synthesis of 5-bromo-7-chloro-1-methylene-1,2,3,4-tetrahydronaphthalene:
To a solution of methyltriphenylphosphonium bromide (910 mg, 2.5 mmol) in tetrahydrofuran (8.0 mL) was added t-butoxypotassium (290 mg, 2.5 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of the compound of Reference Example 7 (220 mg, 0.85 mmol) in tetrahydrofuran (3.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give the compound of Reference Example 47 (210 mg, white solid, yield 97%). Got.

Reference Example 48 Synthesis of 5′-bromo-7′-chloro-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalene]:
Diethyl zinc (120 mg, 1.09 M, n-hexane solution, 0.93 mmol) was added to a solution of chloroiodomethane (330 mg, 1.9 mmol) in dichloromethane (4.5 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 35 minutes. did. Subsequently, a solution of the compound of Reference Example 47 (120 mg, 0.47 mmol) in dichloromethane (2.0 mL) was added, and the mixture was stirred at 0 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 48 (100 mg, colorless transparent oil, yield 80%). )

Reference Example 49 Synthesis of 2- (7′-chloro-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalen] -5′-yl) acetonitrile:
To a solution of the compound of Reference Example 48 (100 mg, 0.37 mmol) in DMSO (3.7 mL) and water (1.1 mL) was added 4- (4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl) isoxazole (86 mg, 0.44 mmol), potassium fluoride (180 mg, 1.1 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (27 mg, 0.037 mmol) ) And stirred at 130 ° C. for 7 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 49 (22 mg, white solid, yield 19%). Got.

Example 12 2-((7′-Chloro-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalene] -5′-yl) methyl) -4,5 Synthesis of dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 49 (22 mg, 0.095 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (11 mg, 0.047 mmol), and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (25 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (90 μL), followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 12 (25 mg , White solid, 86%).

Reference Example 50 Synthesis of 4-bromo-5-methoxy-2,3-dihydro-1H-inden-1-one:
To a suspension of 5-methoxyindanone (3.0 g, 19 mmol) in water (190 mL) was added N-bromosuccinimide (3.3 g, 19 mmol), followed by 40% aqueous sulfuric acid (4.9 mL, 37 mmol) was added, and the mixture was stirred at 60 ° C. for 14 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was recrystallized with ethyl acetate to obtain the compound of Reference Example 50 (1.9 g, white solid, yield 41%).

Reference Example 51 Synthesis of 7-bromo-6-methoxy-3-methyl-1H-indene:
To a solution of methyltriphenylphosphonium bromide (3.9 g, 11 mmol) in tetrahydrofuran (15 mL) was added t-butoxypotassium (1.2 g, 10 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 min. Subsequently, a solution of the compound of Reference Example 50 (1.0 g, 4.2 mmol) in tetrahydrofuran (5.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give the compound of Reference Example 51 (0.90 g, white solid, yield 91). %).

Reference Example 52 Synthesis of 4′-bromo-5′-methoxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene]:
Diethylzinc (900 mg, 1.04 M, n-hexane solution, 7.3 mmol) was added to a solution of diiodomethane (2500 mg, 9.4 mmol) in dichloromethane (16 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 35 minutes. Subsequently, a solution of the compound of Reference Example 51 (500 mg, 2.1 mmol) in dichloromethane (4.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 52 (500 mg, white solid, 94% yield). Got.

Reference Example 53 Synthesis of 5′-methoxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-carbaldehyde:
N-Butyllithium (240 mg, 2.64 M, n-hexane solution, 3.8 mmol) was added to a solution of the compound of Reference Example 52 (480 mg, 1.9 mmol) in tetrahydrofuran (18 mL) at −78 ° C., and −78 ° C. For 30 minutes. Subsequently, DMF (830 mg, 11 mmol) was added and stirred at 0 ° C. for 25 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give the compound of Reference Example 53 (370 mg, white solid, yield 97%). Got.

Reference Example 54 Synthesis of (5′-methoxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-yl) methanol:
To a solution of the compound of Reference Example 53 (200 mg, 1.0 mmol) in methanol (9.0 mL) was added sodium borohydride (75 mg, 2.0 mmol) at 0 ° C., and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and then the precipitated white solid was collected by filtration to obtain the compound of Reference Example 54 (170 mg, white solid, yield 85%).

Reference Example 55 Synthesis of 2- (5′-methoxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-yl) acetonitrile:
To a solution of the compound of Reference Example 54 (170 mg, 0.84 mmol) in dichloromethane (8.0 mL) was added triethylamine (510 mg, 5.1 mmol) and mesyl chloride (290 mg, 2.5 mmol) at 0 ° C. Stir for hours. The reaction solution was concentrated, DMSO (4.0 mL) and sodium cyanide (330 mg, 6.7 mmol) were added to the resulting concentrate, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 55 (65 mg, white solid, yield 36%). Got.

Example 13 2-((5′-Methoxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -4′-yl) methyl) -4,5-dihydro-1H— Synthesis of imidazole hydrochloride:
To a solution of the compound of Reference Example 55 (13 mg, 0.061 mmol) in ethylenediamine (1.0 mL), 6.8 mg (0.030 mmol) of phosphorus pentasulfide was added and stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (16 mg). To a solution of the obtained white solid in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (63 μL), followed by concentration to obtain the compound of Example 13 (16 mg, white amorphous, quantitative).

Reference Example 56 Synthesis of 5-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H) -one:
To a solution of 6-methoxytetralone (300 mg, 1.9 mmol) in 1,2-dichloroethane (9.0 mL), N-bromosuccinimide (330 mg, 1.9 mmol) and gold chloride (5.6 mg, 0.018 mmol) were added. In addition, the mixture was stirred at 60 ° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was recrystallized from ethyl acetate / hexane to obtain the compound of Reference Example 56 (190 mg, white solid, yield 42%).

Reference Example 57 Synthesis of 5-bromo-6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene:
Dimethyl zinc (900 mg, 1.04 M, n-hexane solution, 9.4 mmol) was added to a solution of titanium tetrachloride (1800 mg, 9.4 mmol) in dichloromethane (23 mL) at −78 ° C., and the mixture was stirred at −78 ° C. for 20 minutes. did. Subsequently, a solution of the compound of Reference Example 56 (600 mg, 2.4 mmol) in dichloromethane (4.0 mL) was added, and the mixture was stirred at 0 ° C. for 6 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was recrystallized with n-hexane to obtain the compound of Reference Example 57 (430 mg, white solid, yield 68%).

Reference Example 58 Synthesis of 2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carbaldehyde:
N-Butyllithium (340 mg, 2.64 M, n-hexane solution, 5.4 mmol) was added to a solution of the compound of Reference Example 57 (720 mg, 2.7 mmol) in tetrahydrofuran (18 mL) at −78 ° C., and −78 ° C. For 45 minutes. Subsequently, DMF (1200 mg, 16 mmol) was added and stirred at 0 ° C. for 50 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 58 (590 mg, white solid, yield 95%) Got.

Reference Example 59 Synthesis of (2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl) methanol:
To a solution of the compound of Reference Example 58 (280 mg, 1.3 mmol) in methanol (12 mL) was added sodium borohydride (96 mg, 2.5 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 59 (280 mg, colorless transparent oil, yield 99%) )

Reference Example 60 Synthesis of 2- (2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl) acetonitrile:
To a solution of the compound of Reference Example 59 (280 mg, 1.2 mmol) in dichloromethane (12 mL) was added thionyl chloride (300 mg, 2.5 mmol) at 0 ° C., and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated, DMSO (2.5 mL) and sodium cyanide (180 mg, 3.7 mmol) were added to the obtained concentrate, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 60 (260 mg, colorless transparent oil, yield 91%) )

Example 14 Synthesis of 2-((2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl) methyl) -4,5-dihydro-1H-imidazole:
To a solution of the compound of Reference Example 60 (260 mg, 1.1 mmol) in ethylenediamine (5.0 mL) was added phosphorus pentasulfide (120 mg, 0.56 mmol), and the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Example 14 (290 mg, white solid, yield 94%). Obtained.

Reference Example 61 Synthesis of 5-bromo-6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene:
To a solution of methyltriphenylphosphonium bromide (1800 mg, 5.1 mmol) in tetrahydrofuran (14 mL) was added t-butoxypotassium (550 mg, 4.9 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of the compound of Reference Example 56 (500 mg, 2.0 mmol) in tetrahydrofuran (5.0 mL) was added, and the mixture was stirred at room temperature for 50 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give the compound of Reference Example 61 (460 mg, white solid, 93% yield). Got.

Reference Example 62 Synthesis of 5′-bromo-6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalene]:
Diethylzinc (900 mg, 1.04 M, n-hexane solution, 7.3 mmol) was added to a solution of diiodomethane (2400 mg, 9.1 mmol) in dichloromethane (13 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 35 minutes. Subsequently, a solution of the compound of Reference Example 61 (460 mg, 1.8 mmol) in dichloromethane (5.0 mL) was added, and the mixture was stirred at room temperature for 80 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to obtain the compound of Reference Example 62 (490 mg, white solid, quantitative). It was.

Reference Example 63 Synthesis of (6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalene] -5′-yl) methanol:
N-Butyllithium (230 mg, 2.64 M, n-hexane solution, 3.6 mmol) was added to a solution of the compound of Reference Example 62 (480 mg, 1.8 mmol) in tetrahydrofuran (17 mL) at −78 ° C., and −78 ° C. For 40 minutes. Subsequently, DMF (790 mg, 11 mmol) was added and stirred at 0 ° C. for 35 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a solution of the obtained concentrate (390 mg, light yellow oil) in methanol (17 mL) was added sodium borohydride (140 mg, 3.6 mmol) at 0 ° C., and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 63 (300 mg, white solid, yield 77%). Got.

Reference Example 64 Synthesis of 2- (6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclopropane-1,1′-naphthalene] -5′-yl) acetonitrile:
To a solution of the compound of Reference Example 63 (300 mg, 1.4 mmol) in dichloromethane (13 mL) was added triethylamine (830 mg, 8.3 mmol) and mesyl chloride (470 mg, 4.1 mmol) at 0 ° C., and the mixture was stirred at room temperature for 17 hours. . Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. DMSO (7.5 mL) and sodium cyanide (350 mg, 7.2 mmol) were added to the resulting concentrate, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 64 (130 mg, colorless transparent oil, yield 42%). )

Example 15 2-((6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclopropa-1,1′-naphthalene] -5′-yl) methyl) -4,5- Synthesis of dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 64 (130 mg, 0.57 mmol) in ethylenediamine (3.0 mL) was added phosphorus pentasulfide (64 mg, 0.29 mmol), and the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain the free form of the title compound as a white solid (160 mg, quantitative). . To a solution of the obtained white solid (160 mg) in methanol (3.0 mL), a 10% hydrogen chloride-methanol solution (600 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether. (77 mg, white solid, 53% yield) was obtained.

Reference Example 65 Synthesis of 5′-bromo-6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalen] -2-one:
To a solution of cyclopropyldiphenylsulfonium tetrafluoroborate (1000 mg, 3.2 mmol) in DMSO (6.0 mL), powdered potassium hydroxide (300 mg, 5.3 mmol) and the compound of Reference Example 64 (680 mg, 2.7 mmol) were added. ) In DMSO (2.0 mL) was added and stirred at room temperature for 13 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 65 (400 mg, white solid, yield 51%). Got.

Reference Example 66 Synthesis of 5′-bromo-6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalen] -2-ylmethanesulfonate:
To a solution of the compound of Reference Example 65 (30 mg, 0.10 mmol) in methanol (2.0 mL) was added sodium borohydride (7.7 mg, 0.20 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to obtain a crude product (20 mg, colorless transparent oil, yield 67%). Obtained. To a solution of the obtained intermediate (65 mg, 0.22 mmol) in dichloromethane (3.0 mL) was added mesyl chloride (75 mg, 0.66 mmol) and triethylamine (130 mg, 1.3 mmol) at 0 ° C. Stir for minutes. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 66 (76 mg, white solid, yield 93%). Got.

Reference Example 67 Synthesis of 5′-bromo-6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobu [2] ene-1,1′-naphthalene]:
To a solution of the compound of Reference Example 66 (76 mg, 0.27 mmol) in DMSO (2.0 mL) was added t-butoxypotassium (68 mg, 0.61 mmol), and the mixture was stirred at 65 ° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 67 (11 mg, brown oil, yield 19%). Got.

Reference Example 68 Synthesis of 5′-bromo-6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalene]:
To a solution of the compound of Reference Example 67 (10 mg, 0.036 mmol) in methanol (1.0 mL) was added platinum oxide (0.81 mg, 0.0036 mmol), and after hydrogen substitution, the mixture was stirred at room temperature for 20 minutes. The reaction solution was filtered through celite and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to obtain the compound of Reference Example 68 (11 mg, colorless transparent oil, quantitative). Obtained.

Reference Example 69 Synthesis of 6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalene] -5′-carbaldehyde:
N-Butyllithium (30 μL, 2.64 mM, n-hexane solution, 0.078 mmol) was added to a solution of the compound of Reference Example 68 (11 mg, 0.039 mmol) in tetrahydrofuran (2.0 mL) at −78 ° C., and − Stir at 78 ° C. for 20 minutes. Subsequently, DMF (17 mg, 0.24 mmol) was added and stirred at 0 ° C. for 30 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 69 (6.5 mg, colorless transparent oil, yield) 72%).

Reference Example 70 Synthesis of (6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalene] -5′-yl) methanol:
To a solution of the compound of Reference Example 69 (6.5 mg, 0.028 mmol) in methanol (1.0 mL) was added sodium borohydride (2.1 mg, 0.056 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 70 (4.3 mg, colorless transparent oil, yield) 66%).

Reference Example 71 Synthesis of 2- (6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalene] -5′-yl) acetonitrile:
To a solution of the compound of Reference Example 70 (4.3 mg, 0.019 mmol) in dichloromethane (2.0 mL) was added triethylamine (11 mg, 0.011 mmol) and mesyl chloride (6.4 mg, 0.056 mmol) at 0 ° C. And stirred at room temperature for 14 hours. The reaction solution was concentrated, DMSO (1.0 mL) and sodium cyanide (14 mg, 0.30 mmol) were added to the obtained concentrate, and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 71 (1.7 mg, colorless transparent oil, yield) 38%).

Example 16 2-((6′-methoxy-3 ′, 4′-dihydro-2′H-spiro [cyclobutane-1,1′-naphthalen] -5′-yl) methyl) -4,5- Synthesis of dihydro-1H-imidazole:
To a solution of the compound of Reference Example 71 (1.7 mg, 0.0041 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (0.92 mg0.0041 mmol), and the mixture was stirred at 100 ° C. for 3.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by preparative silica gel chromatography (developing solvent: chloroform / ammonia saturated chloroform / methanol = 46/46/8) to obtain the compound of Example 16 (1.9 mg, white solid, quantitative). Got.

Reference Example 72 Synthesis of 8-bromo-6-chloro-4,4-dimethylchroman:
To a solution of titanium tetrachloride (440 mg, 2.3 mmol) in dichloromethane (4.0 mL) was added dimethylzinc (220 mg, 1.04 M, n-hexane solution, 2.3 mmol) at −78 ° C., and 20 at −78 ° C. Stir for minutes. Subsequently, a solution of 8-bromo-6-chlorochroman-4-one (100 mg, 0.38 mmol) in dichloromethane (2.0 mL) was added, and the mixture was stirred at 0 ° C. for 2.5 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 72 (89 mg, pale yellow oil, yield 85%) )

Reference Example 73 Synthesis of 2- (6-chloro-4,4-dimethylchroman-8-yl) acetonitrile:
To a solution of the compound of Reference Example 72 (47 mg, 0.17 mmol) in DMSO (1.7 mL) and water (0.52 mL), 4- (4,4,5,5-tetramethyl-1,3,2) was added. -Dioxaboran-2-yl) isoxazole (40 mg, 0.21 mmol), potassium fluoride (30 mg, 0.51 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (12 mg, 0.2 mg). 017 mmol) was added, and the mixture was stirred at 120 ° C. for 3 hours. The reaction solution was filtered through celite, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 73 (13 mg, colorless transparent oil, yield 31%). )

Example 17 Synthesis of 2-((6-chloro-4,4-dimethylchroman-8-yl) methyl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 73 (12 mg, 0.051 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (5.7 mg, 0.0025 mmol), and the mixture was stirred at 100 ° C. for 2.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / chloroform / methanol = 46/46/8) to obtain the free form of the title compound as a colorless transparent oil (13 mg). To a solution of the obtained colorless transparent oil in methanol (1.0 mL) was added 10% hydrogen chloride-methanol (47 μL), followed by concentration to obtain the compound of Example 17 (13 mg, white solid, yield 92%). Obtained.

Reference Example 74 Synthesis of 8-bromo-6-chloro-4-methylenechroman:
To a solution of triphenylphosphonium bromide (1000 mg, 2.9 mmol) in tetrahydrofuran (8.0 mL) was added t-butoxypotassium (320 mg, 2.9 mmol) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. Subsequently, a solution of 8-bromo-6-chlorochroman-4-one (300 mg, 1.1 mmol) in tetrahydrofuran (4.0 mL) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by amine silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 74 (46 mg, colorless transparent oil, yield 15). %).

Reference Example 75 Synthesis of 8-bromo-6-chlorospiro [chroman-4,1′-cyclopropane]:
Diethyl zinc (110 mg, 1.09 M, n-hexane solution, 0.87 mmol) in 1,2-dichloroethane (1.7 mL) was added at 0 ° C. with 1,2-trifluoroacetic acid (99 mg, 0.87 mmol) in 1,2- Dichloroethane (0.50 mL) solution was added and stirred at 0 ° C. for 20 minutes. Subsequently, a solution of diiodomethane (230 mg, 0.87 mmol) in 1,2-dichloroethane (0.50 mL) was added and stirred at 0 ° C. for 40 minutes. Furthermore, a 1,2-dichloroethane (1.5 mL) solution of the compound of Reference Example 74 (45 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 90 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 75 (30 mg, white solid, yield 64%). Got.

Reference Example 76 Synthesis of 2- (6-chlorospiro [chroman-4,1′-cyclopropane] -8-yl) acetonitrile:
To a solution of the compound of Reference Example 75 (30 mg, 0.11 mmol) in DMSO (1.1 mL) and water (0.33 mL), 4- (4,4,5,5-tetramethyl-1,3,2) was added. -Dioxaboran-2-yl) isoxazole (26 mg, 0.13 mmol), potassium fluoride (19 mg, 0.33 mmol), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (8.0 mg, 0.010 mmol) was added, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was filtered through celite, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 76 (4.0 mg, colorless transparent oil, yield) 16%).

Example 18 Synthesis of 2-((6-chlorospiro [chroman-4,1′-cyclopropane] -8-yl) methyl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 76 (4.0 mg, 0.017 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (1.9 mg, 0.0086 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / chloroform / methanol = 46/46/8) to obtain a free form of the title compound as a colorless transparent oil (2.3 mg). . To a solution of the obtained colorless transparent oil in methanol (1.0 mL), 10% hydrogen chloride-methanol (10 μL) was added, followed by concentration, and recrystallization from methanol / diethyl ether to obtain the compound of Example 18 ( 2.3 mg, white solid, yield 49%).

Reference Example 77 Synthesis of 7-bromo-5-methoxyindoline-2,3-dione:
Bromine (3.5 mL) was added to a solution of 5-methoxyindoline-2,3-dione (10 g, 57 mmol) in dichloromethane (120 mL) and ethanol (60 mL), and the mixture was stirred at room temperature for 20 hours. Subsequently, toluene (180 mL) was added, and the mixture was stirred at 0 ° C. for 2 hours. The precipitated solid was collected by filtration to obtain the compound of Reference Example 77 (8.2 g, red solid, yield 57%).

Reference Example 78 Synthesis of 7-bromo-5-methoxy-1- (4-methoxybenzyl) indoline-2,3-dione:
To a DMF (50 mL) solution of the compound of Reference Example 77 (3.8 g, 15 mmol), p-methoxybenzyl chloride (2.2 mL, 16 mmol) and sodium hydride (0.84 g, 19 mmol) were added at 0 ° C. Stir at room temperature for 20 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was recrystallized with ethyl acetate / n-hexane to obtain the compound of Reference Example 78 (4.1 g, brown solid, yield 73%).

Reference Example 79 Synthesis of 7′-bromo-5′-methoxy-1 ′-(4-methoxybenzyl) spiro [cyclopropane-1,3′-indoline]:
Hydrazine monohydrate (0.33 mL, 11 mmol) was added to a solution of the compound of Reference Example 78 (2.0 g, 5.3 mmol) in DMSO (3.5 mL), and the mixture was stirred at 150 ° C. for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a solution of the obtained concentrate (1.9 g, brown oil) in DMF (10 mL) was added sodium hydride (0.46 g, 10 mmol) and 1,2-dibromoethane (0.49 mL, 5.8 mmol). And stirred at room temperature for 3 hours. After adding methanol (20 mL) to the reaction solution at −78 ° C., water was added at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Borane-tetrahydrofuran complex (20 mL, 1.0 M tetrahydrofuran solution, 20 mmol) was added to a solution of the obtained intermediate (2.0 g, brown oil) in tetrahydrofuran (10 mL), and the mixture was stirred at 70 ° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 79 (0.83 g, brown solid, yield 43). %).

Reference Example 80 Synthesis of 2- (5′-methoxy-1 ′-(4-methoxybenzyl) spiro [cyclopropane-1,3′-indoline] -7′-yl) acetonitrile:
N-Butyllithium (0.98 mL, 1.64 M, n-hexane solution, 1.6 mmol) was added to a solution of the compound of Reference Example 79 (400 mg, 1.1 mmol) in tetrahydrofuran (5.3 mL) at −78 ° C. And stirred at 0 ° C. for 1 hour. Subsequently, DMF (0.50 mL, 6.4 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a solution of potassium t-butoxy (220 mg, 1.9 mmol) in tetrahydrofuran (6.5 mL) was added p-toluenesulfonylmethyl isocyanide (360 mg, 3.2 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the obtained concentrate (350 mg, brown oil) in tetrahydrofuran (4.0 mL) was added, and the mixture was stirred at −78 ° C. for 1 hour. Furthermore, methanol (10 mL) was added and stirred at 60 ° C. for 1 hour. The crude product obtained by concentrating the reaction solution was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 80 (80 mg, red) An oil, yield 22%) was obtained.

Example 19 Synthesis of 7 ′-((4,5-dihydro-1H-imidazol-2-yl) methyl) -5′-methoxyspiro [cyclopropane-1,3′-indoline] dihydrochloride:
To a solution of the compound of Reference Example 80 (70 mg, 0.21 mmol) in ethylenediamine (2.1 mL) was added phosphorus pentasulfide (140 mg, 0.63 mmol), and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. A solution of the obtained concentrate (50 mg, brown oil) in trifluoroacetic acid (2.6 mL) was stirred at 80 ° C. for 3 hours. A 1N aqueous sodium hydroxide solution was added to the reaction solution at 0 ° C. until the pH reached 8 or higher, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a yellow oil (10 mg, yield 30%). To the yellow oil was added 5% hydrogen chloride-methanol (1.0 mL), followed by concentration and further recrystallization from acetonitrile / diethyl ether to give the compound of Example 19 (9.0 mg, white solid, yield 70%). )

Reference Example 81 Synthesis of 5′-chlorospiro [cyclopropane-1,3′-indoline] -2′-one:
To a solution of 5-chlorooxindole (0.50 g, 3.0 mmol) in tetrahydrofuran (30 mL) was added tetramethylethylenediamine (0.98 mL, 6.6 mmol) at −78 ° C. with n-butyllithium (3.7 mL, 1. mL). 64M, n-hexane solution, 6.0 mmol) and 1,2-dibromoethane (0.31 mL, 3.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 50/50), and the compound of Reference Example 81 (250 mg, brown solid, yield 44%) Got.

Reference Example 82 Synthesis of 5′-chlorospiro [cyclopropane-1,3′-indoline]:
To a solution of the compound of Reference Example 81 (50 mg, 0.26 mmol) in tetrahydrofuran (2.6 mL) was added lithium aluminum hydride (49 mg, 1.3 mmol), and the mixture was stirred at 50 ° C. for 2 hours. A saturated aqueous Rochelle salt solution was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 82 (39 mg, brown oil, 84% yield). Got.

Reference Example 83 Synthesis of 7′-bromo-5′-chlorospiro [cyclopropane-1,3′-indoline]:
Bromine (0.34 mL, 6.9 mmol) was added to a solution of the compound of Reference Example 82 (0.82 g, 4.6 mmol) in dichloromethane (18 mL), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium thiosulfate solution and a 1N aqueous sodium hydroxide solution were added to the reaction solution at 0 ° C., followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 83 (1.2 g, brown oil, yield 98). %).

Reference Example 84 Synthesis of t-butyl-7′-bromo-5′-chlorospiro [cyclopropane-1,3′-indoline] -1′-carboxylate:
Boc ₂ O (51 mg, 0.23 mmol) and N, N-dimethylaminopyridine (14 mg, 0.12 mmol) were added to a solution of the compound of Reference Example 83 (30 mg, 0.12 mmol) in tetrahydrofuran (1.2 mL). , And stirred at 70 ° C. for 24 hours. The crude product obtained by concentrating the reaction solution was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 84 (31 mg, brown) Solid, yield 75%) was obtained.

Reference Example 85 Synthesis of t-butyl-5′-chloro-7 ′-(cyanomethyl) spiro [cyclopropane-1,3′-indoline] -1-carboxylate:
To a solution of the compound of Reference Example 84 (500 mg, 1.4 mmol) in tetrahydrofuran (4.6 mL) was added isopropylmagnesium bromide (2.1 mL, 2.0 M tetrahydrofuran solution, 4.2 mmol) at 0 ° C., and 2 at 0 ° C. Stir for hours. Subsequently, DMF (0.44 mL, 7.0 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (n-hexane → n-hexane / ethyl acetate = 75/25) to obtain an intermediate (210 mg, yellow oil). To a solution of potassium t-butoxy (110 mg, 0.98 mmol) in tetrahydrofuran (3.2 mL) was added p-toluenesulfonylmethyl isocyanide (127 mg, 0.65 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the obtained intermediate (100 mg) in tetrahydrofuran (1.0 mL) was added, and the mixture was stirred at -78 ° C for 1 hour. Furthermore, methanol (5.0 mL) was added, and the mixture was stirred at 60 ° C. for 1 hour. The crude product obtained by concentrating the reaction solution was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 85 (81 mg, yellow) Oil, yield 78%).

(Reference Example 86) t-butyl-5′-chloro-7 ′ ((4,5-dihydro-1H-imidazol-2-yl) methyl) spiro [cyclopropane-1,3′-indoline] -1′- Carboxylate synthesis:
To a solution of the compound of Reference Example 85 (40 mg, 0.13 mmol) in ethylenediamine (1.3 mL) was added phosphorus pentasulfide (14 mg, 0.063 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 86 (10 mg, yellow oil, yield 22%).

Example 20 Synthesis of 5′-chloro-7 ′ ((4,5-dihydro-1H-imidazol-2-yl) methyl) spiro [cyclopropane-1,3′-indoline] dihydrochloride:
To the compound of Reference Example 86 (10 mg, 0.028 mmol) was added 5% hydrogen chloride-methanol (1.0 mL), and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution was concentrated and subsequently recrystallized from acetonitrile / diethyl ether to obtain the compound of Example 20 (6.0 mg, white solid, yield 67%).

Reference Example 87 Synthesis of 5′-chlorospiro [cyclopentane-1,3′-indoline] -2′-one:
To a solution of 5-chlorooxindole (1.0 g, 6.0 mmol) in tetrahydrofuran (60 mL) at −78 ° C., tetramethylethylenediamine (2.0 mL, 13 mmol), n-butyllithium (7.9 mL, 1.64 mM, n-Hexane solution, 13 mmol) and 1,4-dibromobutane (0.93 mL, 7.8 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 50/50), and the compound of Reference Example 87 (450 mg, brown solid, yield 34%) Got.

Reference Example 88 Synthesis of t-butyl-7′-bromo-5′-chlorospiro [cyclopentane-1,3′-indoline] -1′-carboxylate:
To a solution of the compound of Reference Example 87 (400 mg, 1.8 mmol) in tetrahydrofuran (6.0 mL) was added lithium aluminum hydride (140 mg, 3.6 mmol), and the mixture was stirred at 50 ° C. for 4 hours. Saturated Rochelle salt aqueous solution was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Bromine (0.14 mL, 2.7 mmol) was added to a solution of the obtained concentrate (380 mg, brown oil) in dichloromethane (7.2 mL), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium thiosulfate solution and a 1N aqueous sodium hydroxide solution were added to the reaction solution at 0 ° C., followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a solution of the obtained intermediate (520 mg, brown solid) in tetrahydrofuran (9.0 mL), Boc ₂ O (790 mg, 3.6 mmol) and N, N-dimethylaminopyridine (110 mg, 0.90 mmol) were added, Stir at 60 ° C. for 16 hours. The crude product obtained by concentrating the reaction solution was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 88 (510 mg, white) Solid, yield 73%) was obtained.

Reference Example 89 Synthesis of t-butyl-5′-chloro-7 ′-(cyanomethyl) spiro [cyclopentane-1,3′-indoline] -1′-carboxylate:
To a solution of the compound of Reference Example 88 (340 mg, 0.88 mmol) in tetrahydrofuran (2.9 mL) was added isopropylmagnesium bromide (1.3 mL, 2.0 M tetrahydrofuran solution, 2.6 mmol) at 0 ° C., and 2 at 0 ° C. Stir for hours. Subsequently, DMF (1.1 mL, 18 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution at 0 ° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to obtain an intermediate (200 mg, yellow oil). To a solution of potassium t-butoxy (220 mg, 1.9 mmol) in tetrahydrofuran (6.5 mL) was added p-toluenesulfonylmethyl isocyanide (250 mg, 1.3 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the obtained intermediate in tetrahydrofuran (2.0 mL) was added, and the mixture was stirred at -78 ° C for 1 hour. Furthermore, methanol (5.0 mL) was added, and the mixture was stirred at 60 ° C. for 1 hour. The crude product obtained by concentrating the reaction solution was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 89 (74 mg, yellow) Oil, yield 78%).

Reference Example 90 t-butyl-5′-chloro-7 ′-((4,5-dihydro-1H-imidazol-2-yl) methyl) spiro [cyclopentane-1,3′-indoline] -1 ′ -Synthesis of carboxylates:
To a solution of the compound of Reference Example 89 (40 mg, 0.12 mmol) in ethylenediamine (1.2 mL) was added phosphorus pentasulfide (78 mg, 0.36 mmol), and the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia saturated chloroform / methanol = 90/10) to obtain the compound of Reference Example 90 (28 mg, yellow oil, yield 62%).

Example 21 Synthesis of 5′-chloro-7 ′-((4,5-dihydro-1H-imidazol-2-yl) methyl) spiro [cyclopentane-1,3′-indoline] dihydrochloride:
5% Hydrogen chloride-methanol (1.0 mL) was added to the compound of Reference Example 90 (28 mg, 0.072 mmol), and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was concentrated and subsequently recrystallized from acetonitrile / diethyl ether to obtain the compound of Example 21 (23 mg, light brown solid, yield 88%).

Reference Example 91 Synthesis of 1- (2-bromo-4-methylphenyl) azetidin-2-one:
To a solution of 2-bromo-4-methylaniline (3.0 g, 16 mmol) in dichloromethane (50 mL) was added potassium carbonate (4.5 g, 16 mmol) and 3-bromopropionyl chloride (3.5 mL, 16 mmol) at 0 ° C. The mixture was further stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To a DMF (50 mL) solution of the obtained concentrate (5.2 g, white solid), t-butoxy sodium (2.4 g, 26 mmol) was added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 50/50) to give the compound of Reference Example 91 (1.5 g, white solid, yield 50). %).

Reference Example 92 Synthesis of 8-bromo-6-methyl-2,3-dihydroquinolin-4 (1H) -one:
Trifluoromethanesulfonic acid (850 μL, 9.6 mmol) was added to a solution of the compound of Reference Example 91 (770 mg, 3.2 mmol) in 1,2-dichloroethane (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 67/33), and the compound of Reference Example 92 (550 mg, yellow oil, yield 72%) Got.

Reference Example 93 Synthesis of 6-methoxy-8- (prop-1-en-2-yl) -2,3-dihydroquinolin-4 (1H) -one:
To a solution of the compound of Reference Example 92 (550 mg, 2.3 mmol) in tetrahydrofuran (3.0 mL) and water (0.30 mL), palladium acetate (210 mg, 0.92 mmol), triphenylphosphine (120 mg, 0.46 mmol). , Potassium isopropenyl trifluoroborate (750 mg, 4.6 mmol), and cesium carbonate (2.2 g, 6.9 mmol) were added, and the mixture was stirred at 70 ° C. for 18 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane → n-hexane / ethyl acetate = 67/33) to give the compound of Reference Example 93 (330 mg, yellow solid, 71% yield). Got.

Reference Example 94 Synthesis of 8-isopropyl-6-methyl-2,3-dihydroquinolin-4 (1H) -one:
Wilkinson complex (190 mg, 0.20 mmol) was added to a solution of the compound of Reference Example 93 (330 mg, 1.6 mmol) in dichloromethane (10 mL), purged with hydrogen, and then stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 80/20) to give the compound of Reference Example 94 (250 mg, yellow solid, yield 75%). Got.

Reference Example 95 Synthesis of 8-isopropyl-1- (4-methoxybenzyl-6-methyl-2,3-dihydroquinolin-4 (1H) -one:
To a solution of Reference Example 94 (190 mg, 0.94 mmol) in DMF (1.6 mL), potassium carbonate (260 mg, 1.9 mmol), p-methoxybenzyl chloride (220 mg, 1.4 mmol), and sodium iodide (170 mg, 170 mg, 1.1 mmol) was added and the mixture was stirred at 50 ° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 95 (290 mg, yellow oil, yield 95%). Got.

Reference Example 96 Synthesis of 8-isopropyl-1- (4-methoxybenzyl) -6-methyl-1,2,3,4-tetrahydroquinoline-4-carbonitrile:
To a solution of t-butoxypotassium (290 mg, 2.6 mmol) in tetrahydrofuran (8.6 mL) was added p-toluenesulfonylmethyl isocyanide (340 mg, 1.7 mmol) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Subsequently, a solution of the compound of Reference Example 95 (280 mg, 0.87 mmol) in tetrahydrofuran (8.6 mL) was added, and the mixture was stirred at −78 ° C. for 2 hours. Furthermore, methanol (1.1 mL) was added and stirred at 60 ° C. for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25) to give the compound of Reference Example 96 (130 mg, colorless transparent oil, yield 43%). )

Reference Example 97 4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-1- (4-methoxybenzyl) -6-methyl-1,2,3,4-tetrahydroquinoline Synthesis of:
To a solution of the compound of Reference Example 96 (130 mg, 0.37 mmol) in ethylenediamine (2.0 mL) was added phosphorus pentasulfide (42 mg, 0.19 mmol), and the mixture was stirred at 100 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10), and the compound of Reference Example 97 (120 mg, light yellow solid, yield 83%) Got.

Comparative Example 1 Synthesis of 4- (4,5-dihydro-1H-imidazol-2-yl) -8-isopropyl-6-methyl-1,2,3,4-tetrahydroquinoline dihydrochloride:
To a solution of the compound of Reference Example 97 (120 mg, 0.31 mmol) in methanol (2.0 mL) and chloroform (1.0 mL) was added palladium on carbon (3.3 mg), and after hydrogen substitution, the mixture was stirred at room temperature for 5 hours. did. The reaction solution was filtered through celite and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ammonia saturated chloroform → ammonia saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a white solid (85 mg). A 10% hydrogen chloride-methanol solution (660 μL) was added to a methanol (2.0 mL) solution of the obtained white solid, followed by concentration, recrystallization with methanol / diethyl ether, and the compound of Comparative Example 1 ( 79 mg, white solid, 91% yield).

Reference Example 98 Synthesis of methyl 5-chloro-3-cyclopropyl-2-methylbenzoate:
N-iodosuccinimide (1.3 g, 5.9 mmol) was divided into three portions of a solution of 5-chloro-2-methylbenzoic acid (1.0 g, 5.9 mmol) in concentrated sulfuric acid (3.0 mL) at 0 ° C. And stirred at 0 ° C. for 2 hours. The reaction solution was added to water at 0 ° C., and the precipitated solid was collected by filtration. Concentrated sulfuric acid (0.31 mL, 5.9 mmol) was added to a methanol (20 mL) solution of the obtained solid (1.7 g, white solid), and the mixture was heated to reflux for 9 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give a colorless transparent oil (1.5 g, colorless transparent oil, 83%). Obtained. To a solution of the obtained colorless transparent oil (340 mg) in toluene (10 mL) and water (1.0 mL), palladium acetate (24 mg, 0.11 mmol), tricyclohexylphosphine (61 mg, 0.22 mmol), cyclopropylboronic acid (120 mg, 1.4 mmol) and potassium phosphate (800 mg, 3.8 mmol) were added, and the mixture was stirred at 100 ° C. for 15 hours. The reaction solution was filtered through celite, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to obtain the compound of Reference Example 98 (240 mg, pale yellow oil, 83%). Obtained.

Reference Example 99 Synthesis of (5-chloro-3-cyclopropyl-2-methylphenyl) methanol:
To a solution of the compound of Reference Example 98 (240 mg, 1.1 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (61 mg, 1.6 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. Water (60 μL), 15% aqueous sodium hydroxide solution (60 μL), and water (180 μL) were added to the reaction solution at 0 ° C., and the mixture was filtered through celite and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10), and the compound of Reference Example 99 (61 mg, colorless transparent oil, yield 29%). )

Reference Example 100 Synthesis of 2- (5-chloro-3-cyclopropyl-2-methylphenyl) acetonitrile:
To a solution of the compound of Reference Example 99 (61 mg, 0.31 mmol) in dichloromethane (3.0 mL) was added thionyl chloride (150 mg, 1.3 mmol) and DMF (one drop) at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. . The reaction solution was concentrated, DMSO (1.5 mL) and sodium cyanide (23 mg, 0.46 mmol) were added to the obtained crude product, and the mixture was stirred at 40 ° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 75/25), and the compound of Reference Example 100 (62 mg, colorless transparent oil, yield 97%) )

Comparative Example 2 Synthesis of 2- (5-chloro-3-cyclopropyl-2-methylbenzyl) -4,5-dihydro-1H-imidazole hydrochloride:
To a solution of the compound of Reference Example 100 (30 mg, 0.15 mmol) in ethylenediamine (1.0 mL) was added phosphorus pentasulfide (39 mg, 0.17 mmol), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by preparative chromatography (developing solvent: ammonia-saturated chloroform / methanol = 90/10) to obtain a free form of the title compound as a colorless transparent oil (20 mg). To a solution of the obtained colorless transparent oil in methanol (10 mL), 10% hydrogen chloride-methanol (200 μL) was added, followed by concentration, recrystallization from methanol / diethyl ether, and the compound of Comparative Example 2 (20 mg, White solid, yield 49%) was obtained.

  The spectral data and melting points of the compounds of Examples, Reference Examples and Comparative Examples are shown in Tables 3 to 13 below.

Example 22 Human α1L adrenergic receptor operability test:
Using a cell stably expressing human α1L adrenergic receptor (hereinafter, human α1L adrenergic receptor expressing cell), the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is human. α1L adrenergic receptor agonism was assessed.

  According to a standard method, human α1L adrenergic receptor-expressing cells were prepared by stably expressing a human α1A adrenergic receptor gene and a Cistine-Rich Epidermal Growth Factor-Like Domain 1α gene in CHO-K1 cells derived from Chinese hamster ovary. The α1A adrenergic receptor and α1L adrenergic receptor are phenotypes derived from the same gene.

Human α1L adrenergic receptor-expressing cells include 10% fetal bovine serum, 4-6 mM L-Glutamine, 100 μM MEM non-essential amino acids, 100 U / mL penicillin, 100 μg / mL streptomycin, 800 μg / mL Geneticin and 2 μg / mL Puromycin The culture was maintained in a 37 ° C., 5% CO ₂ incubator using Dulbecco's Modified Eagle's Medium as the culture medium.

Human α1L adrenergic receptor-expressing cells were suspended in the above culture solution, seeded at 5 × 10 ⁴ cells in each well of a 96-well black plate (Corning), and cultured overnight at 37 ° C. and 5% CO ₂ . After overnight culture, the medium of the plate on which the cells were seeded was removed, and 100 μL of the above culture solution (but not containing Puromycin or Geneticin) was added to each well, and the cells were cultured overnight under the same conditions, and used for the following evaluation.

  Evaluation of human α1L adrenergic receptor operability was performed by measuring an increase in intracellular calcium concentration due to activation of human α1L adrenergic receptor. For the measurement of intracellular calcium concentration, FLIPR (registered trademark) Calcium 5 Assay Kit (Molecular Devices) was used. As an assay buffer, Hank's balanced salt solution containing 20 mM HEPES (pH 7.4) added with 2.5 mM probenecid (SIGMA) was used.

The medium of the plate seeded with human α1L adrenergic receptor-expressing cells was removed, and 150 μL of Component A (fluorescent indicator; contained in the Kit) dissolved in the assay buffer was added to the Kit according to the instructions attached to the Kit. The cells were cultured at 5% CO ₂ for 45 minutes, and further allowed to stand at room temperature for 15 minutes under light shielding. Using FLIPR (registered trademark) TETRA (Molecular Devices), 50 μL of the test compound was automatically added, and the fluorescence intensity was measured at an excitation wavelength of 470-495 nm and a fluorescence wavelength of 515-575 nm for 5 minutes. Since human α1L adrenergic receptor-expressing cells also express human α1A adrenergic receptor, the operability was evaluated in the presence of 10 nM α1 adrenergic receptor antagonist (prazosin; SIGMA).

Each test compound was evaluated at triplicate for each concentration at a common ratio of 3 or 10. The fluorescence intensity when the test compound is not added is defined as 0% response value, and the fluorescence intensity when noradrenaline (SIGMA) (final concentration: 10 or 100 μM) exhibiting human α1L adrenergic receptor agonist activity is added instead of the test compound is 100. The reaction rate (%) at each concentration of each test compound was determined as a% response value. Using the response rate (%) at each concentration of each test compound, the EC ₅₀ value of each test compound (concentration showing 50% response to the 100% response value of noradrenaline) was determined by non-linear regression. In addition, a value obtained by dividing the EC ₅₀ value of each test compound by the EC ₅₀ value of noradrenaline (hereinafter, noradrenaline ratio) was calculated. In addition, prazosin, each test compound and noradrenaline were dissolved in DMSO and then diluted with assay buffer, and the final concentration of DMSO in the reaction system was 0.2% or less.

The EC ₅₀ values for each test compound are shown in Table 14. As is clear from the results in Table 14, the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof had potent human α1L adrenergic receptor agonist activity.

(Example 23) Rat urethral pressure measurement test:
In accordance with the method described in the patent literature (International Publication No. 2007/018234) that can evaluate the effect on stress urinary incontinence, the intraurethral pressure of anesthetized rats was measured, and the effect of intravenous administration of the test compound was evaluated.

1. Measurement of rat urethral pressure An SD female rat (Charles River Japan) weighing 200-300 g was anesthetized with isoflurane (Mylan Pharmaceutical), the lower abdomen was incised, the ureters on both sides were ligated, and the kidney side was cut. Further, a catheter (PE-10; Becton & Dickinson) was placed in the jugular vein as an intravenous administration route. Immediately before waking up from anesthesia, urethane (SIGMA) was additionally anesthetized in the abdominal cavity, and then the abdominal muscles and skin incisions were sutured. A 3.5 Fr microchip transducer (SPR-524; Millar) was inserted from the external urethral orifice and placed at a site where the maximum urethral pressure could be measured. The signal of the 3.5 Fr microchip transducer is passed through a control unit (TCB-600; LMS), an amplifier (blood pressure amplification unit AP-641G; Nihon Kohden) and a data analysis device (PowerLab; AD Instruments Inc). The urethral pressure over time was recorded on the hard disk.

2. Evaluation of drug efficacy After a stable intraurethral pressure was obtained, the test compound or its solvent was administered through a catheter placed in the jugular vein at a volume of 0.5 mL / kg. A change value (Delta cmH2O) of the maximum value of urethral pressure 3 minutes after administration with respect to the maximum value of urethral pressure 1 minute before administration of the test compound or solvent was calculated and used as an evaluation value.

  As the test compound, the compound of Example 8 was used. The compound of Example 8 was dissolved in physiological saline and administered at 0.1 μg / kg, 0.3 μg / kg or 1 μg / kg. In addition, the group which administered the same volume of the same solvent as a test compound administration liquid was provided as control with respect to test compound administration.

The group administered with 0.1 μg / kg of the compound of Example 8 was “0.1 μg / kg group”, the group administered 0.3 μg / kg was “0.3 μg / kg group”, and the group administered 1 μg / kg was “ The 1 μg / kg group ”was designated, and the group administered with the solvent was designated as the“ solvent group ”.
3. result

  Table 15 shows the change value (Delta cmH2O) (average value ± standard error; N = 4) of the maximum value of the rat urethral pressure by administration of the test compound or the solvent. * Mark in a table | surface shows that it is statistically significant compared with a solvent group (p <0.05, Williams test).

  The administration of the compound of Example 8 increased the urethral pressure depending on the dose. In addition, the action of increasing the urethral pressure was statistically significant in the 1 μg / kg group of the compound of Example 8 as compared to the solvent group.

  From these results, the imidazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an action of increasing urethral pressure, and is useful for the treatment or prevention of stress urinary incontinence. It was shown that it can be expected as a new compound.

  Since the imidazoline derivative of the present invention or a pharmaceutically acceptable acid addition salt thereof has strong α1L adrenergic receptor agonist activity, it is particularly useful as a medicament for diseases caused by α1L adrenergic receptor signal transduction. It can be used as a therapeutic or prophylactic for urinary incontinence.

Claims (8)

An imidazoline derivative represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof:

[Wherein, A represents a group represented by the following general formula (II) or (III).

(In the formula, R ¹ represents halogen, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms, and R ² and R ³ each independently represent alkyl having 1 to 6 carbon atoms, or Or together, it represents alkylene having 2 to 5 carbon atoms, R ⁴ represents hydrogen, halogen or alkoxy having 1 to 6 carbon atoms, R ⁵ represents hydrogen or alkoxy having 1 to 6 carbon atoms, m and n represent 1 or 2, X represents CH ₂ , NR ⁶ or O, Y represents CH ₂ , NH or O, R ⁶ represents hydrogen or alkyl having 1 to 6 carbon atoms. And the wavy line represents the binding position). ] The imidazoline according to claim 1, wherein A represents a group represented by the general formula (II), R ¹ represents chlorine, bromine or methyl, R ⁶ represents hydrogen or methyl, and m represents 2. A derivative or a pharmaceutically acceptable acid addition salt thereof. The imidazoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 2, wherein R ¹ represents chlorine, X represents NR ⁶ and R ⁶ represents hydrogen. A represents a group represented by the general formula (III), R ² and R ³ are methyl or together represent ethylene or propylene, R ⁴ represents hydrogen or chlorine, R ^{4 5.} The imidazoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein ⁵ represents hydrogen or methoxy, n represents 1 or 2, and Y represents CH ₂ or NH. R ² and R ³ together represent ethylene, R ⁴ represents hydrogen, R ⁵ represents methoxy, and n represents 2, The imidazoline derivative according to claim 4, or a pharmaceutically acceptable derivative thereof. Acceptable acid addition salt.   The pharmaceutical which contains the imidazoline derivative as described in any one of Claims 1-5, or its pharmaceutically acceptable acid addition salt as an active ingredient.   A therapeutic or prophylactic agent for stress urinary incontinence comprising the imidazoline derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. An α1L adrenergic receptor agonist containing the imidazoline derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.