JP2004091486A - Condensed benzene derivative and its use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound shown as general formula (I) useful for an androgen receptor modulator (especially agonist) having a non-steroid structure. <P>SOLUTION: The compound or the salt is shown by general formula (I) and useful for an androgen receptor modulator. In the general formula, A ring is a (substituted) 5-membered or 8-membered hydrocarbon, B ring is a (substituted) 4-membered or 10-membered hydrocarbon, C ring is a (substituted) benzene ring, X<SP>1</SP>is carbon, X<SP>2</SP>is carbon, oxygen, etc., W is nitrogen, etc., Y<SP>11</SP>is shown as CR<SP>2</SP>R<SP>3</SP>' (R<SP>2</SP>is hydrogen, a cyano group, a nitro group, or the like, R<SP>3</SP>' is hydrogen, a cyano group, a nitro group, or the like), Y<SP>21</SP>is shown as CR<SP>4</SP>R<SP>5</SP>' (R<SP>4</SP>is hydrogen, a cyano group, a nitro group, or the like, R<SP>5</SP>' is hydrogen, a cyano group, a nitro group, or the like), and R<SP>1</SP>is an electron attractive group. Straight continuous-and-broken double line of the figure denotes a single bond or a double bond. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a fused benzene derivative useful as an androgen receptor modulator, a method for producing the same, and the like.

Androgens are synthesized in the testis and adrenal cortex, bind to androgen receptors in target organs, and exert various biological activities. All natural androgens chemically belong to the C19 steroid. The main androgen among them is testosterone, which is mainly synthesized in the testis, and has strong uptake into target cells and strong bioactivity. In women, the adrenal cortex is the major source of androgens.
Androgens are responsible for the development and maintenance of reproductive organs (prostate, seminal vesicles, epididymis, vas deferens, etc.), sexual differentiation during fetal life, spermatogenesis, and expression of secondary sexual characteristics (musculoskeletal, voice, fat distribution, etc. Induction, etc.), the action of promoting protein assimilation in muscles, etc., and the action on bone metabolism. Therefore, if androgen is deficient due to testicular dysfunction, castration, or the like, such effects become insufficient, leading to various diseases and deterioration in quality of life (QOL). In response to this, a therapy for supplementing androgen is usually performed. In addition to testosterone, synthetic androgens with a different balance of androgen action have been studied and used clinically.
On the other hand, when androgen is involved in the progression of the disease state, treatment for reducing androgen is performed. For example, in androgen-dependent prostate cancer, testosterone is reduced by castration or administration of a GnRH agonist to increase the therapeutic effect.

When supplementing androgens, testosterone and synthetic androgens are usually used. However, they have a steroid skeleton, and may exert a heavy burden on the liver and may exhibit other steroid hormone actions. Therefore, an androgen receptor modulator (especially an agonist) having a nonsteroidal skeleton can be used to improve conditions with androgen deficiency (hypogonadism, male climacteric disorder, etc.) or conditions that can be expected to be improved by the effects of androgens (osteoporosis) Etc.).
In addition, the present inventors have examined that when testosterone is reduced by castration or administration of a GnRH agonist, some cancers acquire the ability to proliferate even with low testosterone.In such cancers, conversely, androgen agonists have antitumor activity. It has been found to work.
Therefore, an object of the present invention is to provide an androgen receptor modulator (particularly an agonist) having a nonsteroidal skeleton, and to solve these problems.

〔式中、A環は置換されていてもよい５ないし８員環を、B環はさらに置換されていてもよい４ないし１０員環を、C環はさらに置換されていてもよいベンゼン環を、X¹は置換されていてもよい炭素原子を、X²は置換されていてもよい炭素原子、酸素原子または式S(O)_ｋ（式中、ｋは０、１または２を示す。）で表される基をそれぞれ示す。Wは窒素原子を示すか、またはA環が置換されていてもよいベンゼン環の場合、式CR^a（式中、R^aは結合手、水素原子、水酸基または置換されていてもよいアルコキシ基を示す。）で表される基を示す。Y¹¹は式CR²R^3’（式中、R²は水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基を、R^3’は結合手、水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基を、Y²¹は１）Wが窒素原子の場合、式CR⁴R^5’（式中、R⁴は水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基を、R^5’は結合手、水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基、置換されていてもよい窒素原子、酸素原子または式S(O)_ｍ（式中、ｍは０、１または２を示す。）で表される基を、２）Wが式CR^a（式中の記号は前記定義に同じ。）で表される基の場合、式CR⁴R^5’（式中の各記号は前記定義に同じ。）で表される基または窒素原子を（但し、Y²¹が窒素原子であり、Wが式CR^a（式中の記号は前記定義に同じ。）で表される基の場合、CR^aとY²¹との結合は二重結合を示す。）それぞれ示し、B環がさらに置換されていてもよい二環式の環の場合、Y¹¹におけるCR²またはY²¹におけるCR⁴もしくは窒素原子はB環の一部を構成していてもよい。R¹は電子吸引性基を示す。式

は単結合または二重結合を示す。〕で表される化合物またはその塩。但し、
１）Wが窒素原子であり、B環が置換されていてもよいピペラジン環である場合、
２）A環が置換されていてもよいベンゼン環であり、R¹がニトロ基または置換されていてもよいスルファモイル基であり、Wが窒素原子であり、B環がオクタヒドロ[１,２−a]ピラジン環、窒素原子がアルキル基で置換されていてもよいホモピペラジン環または窒素原子がアルキル基で置換されていてもよい２,５−ジアザビシクロ[２,２,１]ヘプタン環である場合、
３）A環が置換されていてもよく飽和されていてもよいフラン環またはピラン環であり、R¹がハロゲン原子であり、Wが窒素原子であり、B環が３位が置換されていてもよいアミノ基で置換されたピロリジン環である場合、
４）Wが式CR^a（式中の記号は前記定義に同じ。）で表される基であり、B環がその４位でC環と結合した置換されていてもよいピペリジン環またはその４位でC環と結合した置換されていてもよい１,２,５,６−テトラヒドロピリジン環である場合、ならびに
５）１−[４−（１−ピペリジニル）−１−ナフチル]エタノン、４−（１−ピペリジニル）−１−ニトロナフタレン、４−（１−ピペリジニル）−１−ナフトニトリルおよび４−（１−ピロリジニル）−１−ニトロナフタレンを除く；
［２］一般式

〔式中、A環は置換されていてもよい５ないし８員環を、B環はさらに置換されていてもよい４ないし１０員環を、C環はさらに置換されていてもよいベンゼン環を、X¹は置換されていてもよい炭素原子を、X²は置換されていてもよい炭素原子、酸素原子または式S(O)_ｋ（式中、ｋは０、１または２を示す。）で表される基をそれぞれ示す。Y¹は式CR²R³（式中、R²およびR³は同一または異なって水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基を、Y²は式CR⁴R⁵（式中、R⁴およびR⁵は同一または異なって水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基、置換されていてもよい窒素原子、酸素原子または式S(O)_ｍ（式中、ｍは０、１または２を示す。）で表される基をそれぞれ示し、B環がさらに置換されていてもよい二環式の環の場合、Y¹におけるCR²またはY²におけるCR⁴もしくは窒素原子はB環の一部を構成していてもよい。R¹は電子吸引性基を示す。〕で表される前記［１］記載の化合物。但し、
１）B環が置換されていてもよいピペラジン環である場合、
２）A環が置換されていてもよいベンゼン環であり、R¹がニトロ基または置換されていてもよいスルファモイル基であり、B環がオクタヒドロ[１,２−a]ピラジン環、窒素原子がアルキル基で置換されていてもよいホモピペラジン環または窒素原子がアルキル基で置換されていてもよい２,５−ジアザビシクロ[２,２,１]ヘプタン環である場合、
３）A環が置換されていてもよく飽和されていてもよいフラン環またはピラン環であり、R¹がハロゲン原子であり、B環が３位が置換されていてもよいアミノ基で置換されたピロリジン環である場合、ならびに
４）１−[４−（１−ピペリジニル）−１−ナフチル]エタノン、４−（１−ピペリジニル）−１−ニトロナフタレン、４−（１−ピペリジニル）−１−ナフトニトリルおよび４−（１−ピロリジニル）−１−ニトロナフタレンを除く；
［３］A環が置換されていてもよいベンゼン環、置換されていてもよいチオフェン環または置換されていてもよいフラン環である前記［１］記載の化合物；
［４］B環が置換されていてもよいピロリジン環、置換されていてもよいピペリジン環、置換されていてもよいモルホリン環、置換されていてもよいチオモルホリン環、置換されていてもよいピラゾリン環、置換されていてもよいピラゾリジン環、置換されていてもよいイソオキサゾリン環、置換されていてもよいシクロペンタン環、置換されていてもよいシクロペンテン環または置換されていてもよいパーヒドロアゼピン環である前記［１］記載の化合物；
［５］R¹がシアノ基、ニトロ基、ハロゲン原子、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または１ないし５個のハロゲン原子で置換されたC_1-6アルキル基である前記［１］記載の化合物；
［６］A環上またはB環上のR^a、R²、R^3’、R⁴およびR^5’以外の置換基が（１）水素原子、（２）ハロゲン原子、（３）シアノ基、（４）ニトロ基、（５）水酸基、（６）置換されていてもよいアミノ基、（７）エステル化もしくはアミド化されていてもよいカルボキシル基、（８）置換されていてもよいC_1-6アルキル基、（９）置換されていてもよいC_1-6アシル基、（１０）置換されていてもよいC_1-6アルコキシ基、（１１）式R⁶S(O)_p（式中、R⁶は置換されていてもよいC_1-6アルキル基を、pは０、１または２をそれぞれ示す。）で表される基、（１２）オキソ基、（１３）ヒドロキシイミノ基、（１４）置換されていてもよいC_1-6アルコキシイミノ基および（１５）置換されていてもよいC_1-4アルキレンジオキシ基からなる群より選ばれる１ないし６つの基である前記［１］記載の化合物；
［７］一般式

〔式中、R⁷はシアノ基、ニトロ基、ハロゲン原子、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または１ないし５個のハロゲン原子で置換されたC_1-6アルキル基を、R⁸およびR⁹は同一または異なって（１）水素原子、（２）シアノ基、（３）ニトロ基、（４）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（５）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基または（７）エステル化もしくはアミド化されていてもよいカルボキシル基を、qは０、１または２を、Z¹はカルボニル基、ヒドロキシイミノ基もしくは置換されていてもよいC_1-6アルコキシイミノ基で置換された炭素原子、C_1-4アルキレンジオキシ基で置換された炭素原子または式

（式中、R¹⁰およびR¹¹は同一または異なって（１）水素原子、（２）ハロゲン原子、（３）シアノ基、（４）ニトロ基、（５）水酸基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（７）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（８）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基、（９）C_1-6アルキル基および／もしくはC_1-6アシル基で置換されていてもよいアミノ基または（１０）エステル化もしくはアミド化されていてもよいカルボキシル基をそれぞれ示す。）で表される基を、Z²は酸素原子、硫黄原子、SO、SO₂、カルボニル基、ヒドロキシイミノ基もしくは置換されていてもよいC_1-6アルコキシイミノ基で置換された炭素原子、C_1-6アルキル基もしくはC_1-6アシル基で置換されていてもよいアミノ基、C_1-4アルキレンジオキシ基で置換された炭素原子または式

（式中、R¹²およびR¹³は同一または異なって（１）水素原子、（２）ハロゲン原子、（３）シアノ基、（４）ニトロ基、（５）水酸基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（７）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（８）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基、（９）C_1-6アルキル基および／もしくはC_1-6アシル基で置換されていてもよいアミノ基または（１０）エステル化もしくはアミド化されていてもよいカルボキシル基をそれぞれ示す。）で表される基をそれぞれ示す。〕で表される化合物またはその塩。但し、
１−[４−（１−ピペリジニル）−１−ナフチル]エタノン、４−（１−ピペリジニル）−１−ニトロナフタレン、４−（１−ピペリジニル）−１−ナフトニトリルおよび４−（１−ピロリジニル）−１−ニトロナフタレンを除く；
［８］一般式

〔式中、X³は硫黄原子または酸素原子を、R⁷はシアノ基、ニトロ基、ハロゲン原子、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または１ないし５個のハロゲン原子で置換されたC_1-6アルキル基を、R⁸およびR⁹は同一または異なって（１）水素原子、（２）シアノ基、（３）ニトロ基、（４）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（５）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基または（７）エステル化もしくはアミド化されていてもよいカルボキシル基を、qは０、１または２を、Z¹はカルボニル基、ヒドロキシイミノ基もしくは置換されていてもよいC_1-6アルコキシイミノ基で置換された炭素原子、C_1-4アルキレンジオキシ基で置換された炭素原子または式

（式中、R¹⁰およびR¹¹は同一または異なって（１）水素原子、（２）ハロゲン原子、（３）シアノ基、（４）ニトロ基、（５）水酸基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（７）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（８）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基、（９）C_1-6アルキル基および／もしくはC_1-6アシル基で置換されていてもよいアミノ基または（１０）エステル化もしくはアミド化されていてもよいカルボキシル基をそれぞれ示す。）で表される基を、Z²は酸素原子、硫黄原子、SO、SO₂、カルボニル基、ヒドロキシイミノ基もしくは置換されていてもよいC_1-6アルコキシイミノ基で置換された炭素原子、C_1-6アルキル基もしくはC_1-6アシル基で置換されていてもよいアミノ基、C_1-4アルキレンジオキシ基で置換された炭素原子または式

（式中、R¹²およびR¹³は同一または異なって（１）水素原子、（２）ハロゲン原子、（３）シアノ基、（４）ニトロ基、（５）水酸基、（６）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルキル基、（７）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アシル基、（８）ハロゲン原子、水酸基もしくはC_1-6アルコキシ基で置換されていてもよいC_1-6アルコキシ基、（９）C_1-6アルキル基および／もしくはC_1-6アシル基で置換されていてもよいアミノ基または（１０）エステル化もしくはアミド化されていてもよいカルボキシル基をそれぞれ示す。）で表される基をそれぞれ示す。〕で表される化合物またはその塩。但し、
X³が酸素原子であり、R⁷がハロゲン原子であり、ｑが０であり、R⁸およびR⁹が水素原子であり、Z¹が式

（式中、R¹⁰およびR¹¹の一方が水素原子を、他方がC_1-6アルキル基および／もしくはC_1-6アシル基で置換されていてもよいアミノ基を示す。）で表される基であり、Z²がメチレン基である場合を除く；
［９］４−［４−（ヒドロキシメチル）−１−ピペリジニル］−１−ナフトニトリル、４−［３−（ヒドロキシメチル）−１−ピペリジニル］−１−ナフトニトリル、４−［３−（ヒドロキシメチル）−３−メチル−１−ピペリジニル］−１−ナフトニトリル、４−（２−メチル−１−ピロリジニル）−１−ナフトニトリル、４−（２−エチル−１−ピロリジニル）−１−ナフトニトリル、４−（２−ビニル−１−ピロリジニル）−１−ナフトニトリル、４−（２−イソプロピル−１−ピロリジニル）−１−ナフトニトリル、４−（３−ヒドロキシ−２−メチル−１−ピロリジニル）−１−ナフトニトリル、４−（３−メトキシ−２−メチル−１−ピロリジニル）−１−ナフトニトリル、４−（４−メトキシ−２−メチル−１−ピロリジニル）−１−ナフトニトリル４−［３−（ヒドロキシメチル）−２−メチル−１−ピロリジニル］−１−ナフトニトリル、４−［３−（１-ヒドロキシ-１-メチルエチル）−２−メチル−１−ピロリジニル］−１−ナフトニトリル、１−（４−シアノ−１−ナフチル）−２−メチルピロリジン−３−カルボキサミド、１−（４−シアノ−１−ナフチル）−２−メチルピロリジン−３−カルボニトリル、４−（２−メチル−１−ピロリジニル）−１−ベンゾチオフェン−７−カルボニトリル、４−（３−ヒドロキシ−２−メチル−１−ピロリジニル）−１−ベンゾチオフェン−７−カルボニトリル、４−（４−ヒドロキシ−２−メチル−１−ピロリジニル）−１−ベンゾチオフェン−７−カルボニトリルもしくはその光学活性体またはその塩；
［１０］一般式

〔式中、A^a環は置換されていてもよい５ないし８員環を、C^a環はさらに置換されていてもよいベンゼン環を、X^1aは置換されていてもよい炭素原子を、X^2aは置換されていてもよい炭素原子、酸素原子または式S(O)_ｋ ^a（式中、ｋ^aは０、１または２を示す。）で表される基を、R^1aは電子吸引性基を、Mは脱離基をそれぞれ示す。〕で表される化合物またはその塩と、一般式

［式中、B^a環はさらに置換されていてもよい４ないし１０員環を示す。Y^1aは式CR^2aR^3a（式中、R^2aおよびR^3aは同一または異なって水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基を、Y^2aは式CR^4aR^5a（式中、R^4aおよびR^5aは同一または異なって水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基、置換されていてもよい窒素原子、酸素原子または式S(O)_m ^a（式中、m^aは０、１または２を示す。）で表される基をそれぞれ示すか、またはB^a環がさらに置換されていてもよい二環式の環の場合、Y^1aにおけるCR^2aまたはY^2aにおけるCR^4aもしくは窒素原子はB^a環の一部を構成していてもよい。］で表される化合物またはその塩とを反応させ、所望により保護基を除去する前記［２］記載の化合物またはその塩の製造方法；
［１１］前記［１］、［７］または［８］記載の化合物のプロドラッグ；
［１２］前記［１］、［７］もしくは［８］記載の化合物またはその塩あるいはそのプロドラッグを含有する医薬；
［１３］アンドロゲン受容体モジュレーターである前記［１２］記載の医薬；
［１４］アンドロゲン受容体アゴニストである前記［１２］記載の医薬；
［１５］一般式

〔式中、A環は置換されていてもよい５ないし８員環を、B環はさらに置換されていてもよい４ないし１０員環を、C環はさらに置換されていてもよいベンゼン環を、X¹は置換されていてもよい炭素原子を、X²は置換されていてもよい炭素原子、酸素原子または式S(O)_ｋ（式中、ｋは０、１または２を示す。）で表される基をそれぞれ示す。W¹は窒素原子または式CR^a（式中、R^aは結合手、水素原子、水酸基または置換されていてもよいアルコキシ基を示す。）で表される基を示す。Y¹¹は式CR²R^3’（式中、R²は水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基を、R^3’は結合手、水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基を、Y²¹は式CR⁴R^5’（式中、R⁴は水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基を、R^5’は結合手、水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。）で表される基、置換されていてもよい窒素原子、酸素原子または式S(O)_ｍ（式中、ｍは０、１または２を示す。）で表される基をそれぞれ示し、B環がさらに置換されていてもよい二環式の環の場合、Y¹¹におけるCR²またはY²¹におけるCR⁴もしくは窒素原子はB環の一部を構成していてもよい。R¹は電子吸引性基を示す。式

は単結合または二重結合を示す。〕で表される化合物もしくはその塩またはそのプロドラッグを含有するアンドロゲン受容体モジュレーター；
［１６］アンドロゲン受容体アゴニストである前記［１５］記載のモジュレーター；
［１７］前記［１５］記載のモジュレーターを含有してなるハイポゴナディズムまたは男性更年期障害の予防・治療剤；
［１８］前記［１５］記載のモジュレーターを含有してなる骨粗しょう症の予防・治療剤；
［１９］前記［１５］記載のモジュレーターを含有してなるホルモン抵抗性癌の予防・治療剤；
［２０］ホルモン抵抗性癌がＬＨＲＨアゴニスト抵抗性癌である前記［１９］記載の剤；
［２１］癌が前立腺癌である前記［１９］または［２０］記載の剤；
［２２］哺乳動物に対して、アンドロゲン受容体アゴニストを有効量投与することを特徴とするホルモン抵抗性癌の予防・治療方法；
［２３］アンドロゲン受容体アゴニストを含有してなるホルモン抵抗性癌の予防・治療剤；
［２４］アンドロゲン受容体アゴニストが非ステロイド化合物である前記［２３］記載の剤；
［２５］アンドロゲン受容体アゴニストを製造するための前記［１］記載の化合物もしくはその塩またはそのプロドラッグの使用；および
［２６］癌の予防・治療剤を製造するための前記［１］記載の化合物もしくはその塩またはそのプロドラッグの使用などに関する。 The present inventors have conducted intensive studies in view of the above circumstances, and as a result, have found that the compound represented by the general formula (I) has an excellent action as an androgen receptor modulator, and can achieve the above object. Thus, the present invention has been completed.
That is, the present invention
[1] General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by W represents a nitrogen atom, or, in the case where the ring A is a benzene ring which may be substituted, a group represented by the formula CR ^a (wherein R ^a represents a bond, a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group; Is shown.). Y ¹¹ is a group represented by the formula CR ² R ^{3 ′} (wherein R ² is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated carboxyl group or a substituted An optionally substituted hydrocarbon group, R ^{3 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, or a substituted Y ²¹ represents 1) when W is a nitrogen atom, the formula CR ⁴ R ^{5 ′} (wherein, R ⁴ represents a hydrogen atom, a cyano group, or a nitro group) An optionally substituted acyl group, an optionally esterified or amidated carboxyl group or an optionally substituted hydrocarbon group, R ^{5 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, Acyl group which may be substituted, esterification Or a carboxyl group which may be amidated or a hydrocarbon group which may be substituted.), A nitrogen atom which may be substituted, an oxygen atom or a formula S (O) _m ( In the formula, m represents 0, 1 or 2.) 2) When W is a group represented by the formula CR ^a (the symbols in the formula are the same as defined above), the group represented by the formula CR ⁴ R ^{5 ′} (each symbol in the formula is the same as defined above) or a nitrogen atom (provided that Y ²¹ is a nitrogen atom and W is a formula CR ^a (the symbols in the formula are as defined above. In the case of a group represented by the formula, a bond between CR ^a and Y ²¹ represents a double bond.) In the case of a bicyclic ring in which ring B may be further substituted, Y CR ^{2 at 11} or CR ⁴ or the nitrogen atom at Y ²¹ may form part of the B ring. R ¹ represents an electron-withdrawing group. formula

Represents a single bond or a double bond. Or a salt thereof. However,
1) When W is a nitrogen atom and ring B is an optionally substituted piperazine ring,
2) ring A is an optionally substituted benzene ring, R ¹ is a nitro group or an optionally substituted sulfamoyl group, W is a nitrogen atom, and ring B is octahydro [1,2-a A pyrazine ring, a homopiperazine ring in which a nitrogen atom may be substituted with an alkyl group or a 2,5-diazabicyclo [2,2,1] heptane ring in which a nitrogen atom may be substituted with an alkyl group,
3) A ring is a furan ring or a pyran ring which may be substituted or saturated, R ¹ is a halogen atom, W is a nitrogen atom, and ring B is substituted at the 3-position. When a pyrrolidine ring substituted with a good amino group,
4) W is a group represented by the formula CR ^a (the symbols in the formula are the same as defined above), and the optionally substituted piperidine ring wherein ring B is bonded to ring C at the 4-position or 4 And optionally substituted 1,2,5,6-tetrahydropyridine ring bonded to ring C, and 5) 1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- Excluding (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1-naphthonitrile and 4- (1-pyrrolidinyl) -1-nitronaphthalene;
[2] General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by Y ¹ is a group represented by the formula CR ² R ^{3 wherein} R ² and R ³ are the same or different and each may be a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated A group represented by a carboxyl group or a hydrocarbon group which may be substituted; Y ² is a group represented by the formula CR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a cyano group, A nitro group, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a hydrocarbon group which may be substituted.) A nitrogen atom, an oxygen atom or a group represented by the formula S (O) _m (where m represents 0, 1 or 2), and the ring B may be further substituted. for cyclic ring, CR ⁴ in CR ² or Y ² in Y ¹ Properly nitrogen atom may constitute a part of the B ring. R ¹ represents an electron-withdrawing group. ] The compound according to the above [1], which is represented by the formula: However,
1) When ring B is an optionally substituted piperazine ring,
2) ring A is an optionally substituted benzene ring; R ¹ is a nitro group or an optionally substituted sulfamoyl group; ring B is an octahydro [1,2-a] pyrazine ring; When a homopiperazine ring optionally substituted with an alkyl group or a 2,5-diazabicyclo [2,2,1] heptane ring wherein a nitrogen atom is optionally substituted with an alkyl group,
3) Ring A is a furan ring or pyran ring which may be substituted or saturated, R ¹ is a halogen atom, and ring B is substituted with an amino group which may be substituted at the 3-position. And 4) 1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1- Except naphthonitrile and 4- (1-pyrrolidinyl) -1-nitronaphthalene;
[3] The compound of the above-mentioned [1], wherein the ring A is an optionally substituted benzene ring, an optionally substituted thiophene ring or an optionally substituted furan ring;
[4] ring B optionally substituted pyrrolidine ring, optionally substituted piperidine ring, optionally substituted morpholine ring, optionally substituted thiomorpholine ring, optionally substituted pyrazoline Ring, optionally substituted pyrazolidine ring, optionally substituted isoxazoline ring, optionally substituted cyclopentane ring, optionally substituted cyclopentene ring or optionally substituted perhydroazepine ring The compound according to the above [1], which is
[5] R ¹ is a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, C ₁ to better carboxyl group or 1 may be esterified or amidated substituted with five halogen atoms The compound of the above-mentioned [1], which is a _-6 alkyl group;
[6] The substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B are (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) nitro group, (5) hydroxyl group, (6) optionally substituted amino group, (7) optionally carboxyl group which may be esterified or amidated, (8) optionally substituted C _{1 -6} alkyl group, (9) optionally substituted C _1-6 acyl group, (10) optionally substituted C _1-6 alkoxy group, (11) formula R ⁶ S (O) _p (formula Wherein R ⁶ represents a C _1-6 alkyl group which may be substituted, p represents 0, 1 or 2, respectively)), an oxo group, (13) a hydroxyimino group, (14) at least one selected from the group consisting of an optionally substituted C _1-6 alkoxyimino group and (15) an optionally substituted C _1-4 alkylenedioxy group The compound according to the above [1], which is six groups;
[7] General formula

[In the formula, R ⁷ represents a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a C substituted with 1 to 5 halogen atoms. _1-6 alkyl group, R ⁸ and R ⁹ are the same or different and are (1) hydrogen atom, (2) cyano group, (3) nitro group, (4) halogen atom, hydroxyl group or C _1-6 alkoxy group. An optionally substituted C _1-6 alkyl group, (5) a halogen atom, a hydroxyl group or a C _1-6 acyl group optionally substituted with a C _1-6 alkoxy group, (6) a halogen atom, a hydroxyl group or C _1-6 substituted alkoxy group a C _1-6 alkoxy group, or also (7) esterified or amidated carboxyl group which may be, q and is 0, 1 or 2, Z ¹ is a carbonyl group A hydroxyimino group or Conversion to carbon atoms which is substituted in a C _1-6 alkoxyimino group optionally, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹⁰ and R ¹¹ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group Z ² represents an oxygen atom, a sulfur atom, SO, SO ₂ , a carbonyl group, a hydroxy group or a carboxyl group which may be esterified or amidated. It may be imino group or substituted C _1-6 alkoxy Substituted carbon atom in the imino group, C _1-6 alkyl or C _1-6 acyl amino group which may be substituted with a group, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹² and R ¹³ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group An amino group or (10) a carboxyl group which may be esterified or amidified, respectively). Or a salt thereof. However,
1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1-naphthonitrile and 4- (1-pyrrolidinyl) Excluding -1-nitronaphthalene;
[8] General formula

Wherein X ³ is a sulfur atom or an oxygen atom, R ⁷ is a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, an esterified or amidated carboxyl group or 1 to A C _1-6 alkyl group substituted with 5 halogen atoms, R ⁸ and R ⁹ being the same or different, and (1) hydrogen atom, (2) cyano group, (3) nitro group, (4) halogen atom , hydroxyl or C _1-6 alkoxy optionally substituted by C _1-6 alkyl group group, (5) halogen atom, a hydroxyl group or a C _1-6 optionally substituted alkoxy group C _1-6 acyl group (6) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group which may be substituted with a C _1-6 alkoxy group, or (7) a carboxyl group which may be esterified or amidated, q represents 0, 1 or 2, Z ¹ is carbonyl , Hydroxyimino group or substituted carbon atom substituted in a C _1-6 alkoxyimino group optionally, C _1-4 carbon atoms substituted with an alkylenedioxy group or formula

(Wherein R ¹⁰ and R ¹¹ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group Z ² represents an oxygen atom, a sulfur atom, SO, SO ₂ , a carbonyl group, a hydroxy group or a carboxyl group which may be esterified or amidated. It may be imino group or substituted C _1-6 alkoxy Substituted carbon atom in the imino group, C _1-6 alkyl or C _1-6 acyl amino group which may be substituted with a group, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹² and R ¹³ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group An amino group or (10) a carboxyl group which may be esterified or amidified, respectively). Or a salt thereof. However,
X ³ is an oxygen atom, R ⁷ is a halogen atom, q is 0, R ⁸ and R ⁹ are hydrogen atoms, and Z ¹ is a group represented by the formula

(In the formula, one of R ¹⁰ and R ^{11 represents} a hydrogen atom, and the other represents an amino group optionally substituted with a C _1-6 alkyl group and / or a C _1-6 acyl group.) Excluding the case where Z ² is a methylene group;
[9] 4- [4- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3- (hydroxy Methyl) -3-methyl-1-piperidinyl] -1-naphthonitrile, 4- (2-methyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-ethyl-1-pyrrolidinyl) -1-naphthonitrile , 4- (2-vinyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-isopropyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (3-hydroxy-2-methyl-1-pyrrolidinyl) -1-Naphthonitrile, 4- (3-methoxy-2-methyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (4-methoxy-2-methyl-1-pyrrolidinyl -1-Naphthonitrile 4- [3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile, 4- [3- (1-hydroxy-1-methylethyl) -2-methyl-1 -Pyrrolidinyl] -1-naphthonitrile, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxamide, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carbo Nitrile, 4- (2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- (3-hydroxy-2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- (4-hydroxy-2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile or an optically active form thereof or a salt thereof;
[10] General formula

[In the formula, ring A ^a represents ^a 5- to 8-membered ring which may be substituted, ring C ^a represents ^a benzene ring which may be further substituted, X ^1a represents a carbon atom which may be substituted, ^2a is an optionally substituted carbon atom, oxygen atom or a group represented by the formula S (O) _k ^a (where k ^a is 0, 1 or 2), and R ^1a is an electron withdrawing property And M represents a leaving group. A compound represented by the general formula

[In the formula, the ^Ba ring represents ^a 4- to 10-membered ring which may be further substituted. Y ^1a has the formula CR ^2a R ^3a (wherein R ^2a and R ^3a are the same or different and each may be a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated A group represented by a carboxyl group or a hydrocarbon group which may be substituted; Y ^2a is a group represented by the formula CR ^4a R ^5a (wherein R ^4a and R ^5a are the same or different and are a hydrogen atom, a cyano group, A nitro group, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a hydrocarbon group which may be substituted.) a nitrogen atom which may, (wherein, m ^a is. for 0, 1 or 2) an oxygen atom or a group represented by formula S (O) _m ^a or respectively a group represented by or B ^a ring, is further substituted In the case of an optionally bicyclic ring, CR ^2a in Y ^1a Alternatively, CR ^4a or a nitrogen atom in Y ^2a may form part of ^a Ba ring. The method for producing a compound or a salt thereof according to the above-mentioned [2], wherein the compound or a salt thereof is reacted with a compound represented by the formula [2];
[11] A prodrug of the compound of the above-mentioned [1], [7] or [8];
[12] A medicament containing the compound according to the above [1], [7] or [8], a salt thereof, or a prodrug thereof;
[13] the medicament of the above-mentioned [12], which is an androgen receptor modulator;
[14] the medicament of the above-mentioned [12], which is an androgen receptor agonist;
[15] General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by W ¹ represents a nitrogen atom or a group represented by the formula CR ^a (where R ^a represents a bond, a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group). Y ¹¹ is a group represented by the formula CR ² R ^{3 ′} (wherein R ² is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated carboxyl group or a substituted An optionally substituted hydrocarbon group, R ^{3 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, or a substituted Y ²¹ is a group represented by the formula CR ⁴ R ^{5 ′} (wherein R ⁴ is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group) A carboxyl group that may be esterified or amidated or a hydrocarbon group that may be substituted, R ^{5 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an acyl group that may be substituted, Esterified or amidated It indicates a hydrocarbon group which may optionally be also be a carboxyl group or substituted, respectively.) Or a group represented by optionally substituted nitrogen atom, an oxygen atom or a group represented by formula S (O) _{m (wherein,} m is 0, 1 or 2). In the case of a bicyclic ring in which ring B may be further substituted, CR ² in Y ¹¹ or CR ⁴ or a nitrogen atom in Y ²¹ May form a part of the B ring. R ¹ represents an electron-withdrawing group. formula

Represents a single bond or a double bond. An orrogen receptor modulator comprising the compound represented by the formula (I) or a salt thereof or a prodrug thereof;
[16] the modulator of the above-mentioned [15], which is an androgen receptor agonist;
[17] A prophylactic / therapeutic agent for hypogonadism or male climacteric disorder comprising the modulator according to the above [15];
[18] a prophylactic / therapeutic agent for osteoporosis comprising the modulator according to the above [15];
[19] a prophylactic / therapeutic agent for a hormone-resistant cancer comprising the modulator according to the above [15];
[20] the agent of the above-mentioned [19], wherein the hormone-resistant cancer is an LHRH agonist-resistant cancer;
[21] the agent of the above-mentioned [19] or [20], wherein the cancer is prostate cancer;
[22] a method for preventing and treating hormone-resistant cancer, which comprises administering an effective amount of an androgen receptor agonist to a mammal;
[23] a prophylactic / therapeutic agent for hormone-resistant cancer comprising an androgen receptor agonist;
[24] the agent of the above-mentioned [23], wherein the androgen receptor agonist is a non-steroid compound;
[25] use of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof for producing an androgen receptor agonist; and [26] a use of the above-mentioned [1] for producing a prophylactic / therapeutic agent for cancer. It relates to the use of a compound or a salt thereof or a prodrug thereof.

The present invention also provides [27] a medicament comprising a combination of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof and an anticancer agent;
[28] A medicament obtained by combining the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof with a hormonal therapeutic agent;
[29] the medicament of the above-mentioned [28], wherein the hormone therapy agent is an LH-RH modulator;
[30] the medicament of the above-mentioned [29], wherein the LH-RH modulator is a LH-RH agonist;
[31] the medicament of the above-mentioned [30], wherein the LH-RH agonist is leuprorelin or a salt thereof;
[32] a method for preventing or treating cancer, which comprises administering an effective amount of the compound according to [1], a salt thereof, or a prodrug thereof to a mammal;
[33] A method for preventing or treating cancer, which comprises administering to a mammal a combination of an effective amount of the compound according to [1] or a salt thereof or a prodrug thereof and an effective amount of another anticancer agent. ;
[34] A method for preventing or treating cancer, which comprises administering to a mammal a combination of an effective amount of the compound according to [1] or a salt thereof or a prodrug thereof and an effective amount of a hormonal therapeutic agent. ;
[35] the method of the above-mentioned [34], wherein the hormone therapy agent is an LH-RH modulator;
[36] The method of the above-mentioned [35], wherein the LH-RH modulator is an LH-RH agonist;
[37] the method of the above-mentioned [36], wherein the LH-RH agonist is leuprorelin or a salt thereof;
[38] A method for preventing or treating cancer, which comprises administering an effective amount of the compound according to [1] or a salt thereof or a prodrug thereof after administration of another anticancer agent;
[39] Effectiveness of the compound according to [1] or a salt thereof or a prodrug thereof against a mammal before applying surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy and / or laser burn therapy. A method for preventing or treating cancer, which comprises administering an amount of the cancer;
[40] An effective amount of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof to a mammal after applying surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy and / or laser burn therapy. A method for preventing or treating cancer;
[41] a medicament obtained by combining the agent of the above-mentioned [13] with an anticancer agent;
[42] A medicine comprising a combination of the agent of the above-mentioned [13] and a hormonal therapy agent;
[43] the medicament of the above-mentioned [42], wherein the hormone therapy agent is an LH-RH modulator;
[44] the medicament of the above-mentioned [43], wherein the LH-RH modulator is an LH-RH agonist;
[45] the medicament of the above-mentioned [44], wherein the LH-RH agonist is leuprorelin or a salt thereof;
[46] a method for preventing or treating cancer, which comprises administering an effective amount of the agent according to [13] to a mammal;
[47] A method for preventing or treating cancer, which comprises administering to a mammal an effective amount of the agent described in [13] and an effective amount of another anticancer agent in combination;
[48] a method for preventing or treating cancer, which comprises administering to a mammal a combination of an effective amount of the agent described in [13] and an effective amount of a hormonal therapy agent;
[49] the method of the above-mentioned [48], wherein the hormonal therapeutic agent is an LH-RH modulator;
[50] the method of the above-mentioned [49], wherein the LH-RH modulator is an LH-RH agonist;
[51] The method of the above-mentioned [50], wherein the LH-RH agonist is leuprorelin or a salt thereof;
[52] a method for preventing or treating cancer, which comprises administering an effective amount of the agent according to the above [13] after administering another anticancer agent;
[53] Before applying surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy and / or laser burn therapy, a mammal is administered an effective amount of the agent described in [13] above. [54] The agent according to [13] above, which is applied to a mammal after applying surgery, radiation therapy, gene therapy, hyperthermia therapy, cryotherapy and / or laser burn therapy. A method for preventing or treating cancer, comprising administering an effective amount of And so on.

Further, the present invention provides the compound of the above-mentioned [2], wherein the ring [55] is an optionally substituted benzene ring;
[56] ring B optionally substituted pyrrolidine ring, optionally substituted piperidine ring, optionally substituted piperazine ring, optionally substituted morpholine ring, optionally substituted thiomorpholine The compound of the above-mentioned [2], which is a ring or a perhydroazepine ring which may be substituted;
[57] the medicament of the above-mentioned [12], which is a preventive / therapeutic agent for hypogonadism;
[58] The pharmaceutical according to [12], which is an agent for preventing or treating osteoporosis; and [59] The pharmaceutical according to [12], which is an agent for preventing or treating hormone-resistant cancer.

Hereinafter, the contents of the present invention will be described in detail.
First, terms used in the present invention will be described.
R ² , R ^2a , R ³ , R ^{3 ′} , R ^3a , R ⁴ , R ^4a , R ⁵ , R ^{5 ′} and the `` hydrocarbon group '' in the `` optionally substituted hydrocarbon group ^{'' represented by} R ^5a , For example, an "aliphatic hydrocarbon group", an "alicyclic hydrocarbon group" and an "aromatic hydrocarbon group" can be used.
As the “aliphatic hydrocarbon group” as an example of the hydrocarbon group, a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group is used.
Examples of the “alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,1 -Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl And C _1-10 alkyl groups such as nonyl, etc., but preferably C _1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like) ) Can be used.
Examples of the “alkenyl group” include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 2-ethyl-1- Butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, A C _2-10 alkenyl group such as 3-hexenyl, 4-hexenyl, 5-hexenyl and the like can be used. Preferably, it is a C _2-6 alkenyl group.
Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, hexynyl, 3-hexynyl, 4-hexynyl, and _{C 2-10} alkynyl groups such as 5-hexynyl used. Preferably, it is a C _2-6 alkynyl group.

Examples of the “alicyclic hydrocarbon group” as an example of the hydrocarbon group include, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkanedienyl group, and a C _6-14 aryl group (for example, benzene or the like). A saturated or unsaturated, monocyclic or fused polycyclic, alicyclic hydrocarbon group such as a bicyclic or tricyclic fused ring is used.
As the “cycloalkyl group”, for example, C _3-10 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like are used.
Examples of the “cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, A C _3-10 cycloalkenyl group such as 1-cyclopenten-1-yl and the like are used.
Examples of the “cycloalkanedienyl group” include, for example, C _4-6 cycloalkyl such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexanedien-1-yl. An alkanedienyl group or the like is used.
As the “aromatic hydrocarbon group” as an example of the hydrocarbon group, a monocyclic or condensed polycyclic aromatic hydrocarbon group is used and is not particularly limited, but is preferably a C _6-22 aromatic hydrocarbon group. And more preferably a C _6-18 aromatic hydrocarbon group, further preferably a C _6-10 aromatic hydrocarbon group. Specifically, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, 2,3-xylyl, 2,4-xylyl, mesityl, o-cumenyl, m-cumenyl, p-cumenyl, α-methylbenzyl , Benzhydryl, o-biphenyl, m-biphenyl, p-biphenylyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, azulenyl, phenanthryl, fluorenyl, etc., among which phenyl, 1-naphthyl, 2- Naphthyl, 2-anthryl and the like are preferred.

The `` electron-withdrawing group '' represented by R ¹ and R ^1a generally refers to a group that tends to attract electrons from others when hydrogen is used as a standard in a molecule. Without limitation, for example, a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or C ₁ substituted with 1 to 5 halogen atoms _{A -6} alkyl group or the like can be used.

R ⁶ and the `` optionally substituted C <sub>1-6</sub> alkyl group <sup>'' represented</sup> by `` a substituent other than R ^a , R ² , R ^{3 '} , R ⁴ and R ^5' on the ring A or B ^'' In the above, the “C _1-6 alkyl group” is the same as defined above.
`` C on the optionally substituted C <sub>1-6</sub> alkoxy group '' represented by `` substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B ^'' <sub>As the `</sub> ` _1-6 alkoxy group '', for example, methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, n -Hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy and the like can be used. Preferred are methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy and the like.
As the “alkoxy group” in the “optionally substituted alkoxy group” for Ra, ^a C _1-6 alkoxy group is preferable, for example, methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy , Sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3 -Dimethylbutyloxy, 2-ethylbutyloxy and the like can be used. Preferred are methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy and the like.
R ¹ , R ^1a , R ⁷ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , `` Substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on the A ring or the B ring ", A fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like can be used. Preferably it is a fluorine atom or a chlorine atom.

R ¹ , R ^1a , R ² , R ^2a , R ³ , R ^{3 ′} , R ^3a , R ⁴ , R ^4a , R ⁵ , R ^{5 ′} , R ^5a and R ⁷ `` may be substituted Examples of the “acyl group” in the “acyl group” include lower (C <sub>1-6</sub> ) alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl; acryloyl, methacryloyl, crotonoyl, and isocrotonoyl A lower (C <sub>3-7</sub> ) alkenoyl group; a C <sub>4-7</sub> cycloalkanecarbonyl group such as a cyclopropanecarbonyl group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, or a cyclohexanecarbonyl group; a lower (C <sub>3-7</sub> ) C <sub>1-4</sub> ) alkanesulfonyl group; benzoyl, p-toluoyl, 1-naph C <sub>7-14</sub> aroyl groups such as toyl and 2-naphthoyl; C <sub>6-10</sub> aryl lower (C <sub>2-4</sub> ) alkanoyl groups such as phenylacetyl, phenylpropionyl, hydroatropoyl and phenylbutyryl; cinnamoyl and atropoyl A C <sub>6-10</sub> aryl lower (C <sub>3-5</sub> ) alkenoyl group; a C <sub>6-10</sub> arene sulfonyl group such as a benzenesulfonyl group and a p-toluenesulfonyl group can be used.
`` C in the optionally substituted C _1-6 acyl group '' represented by `` substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B ^'' _{Examples of the} " _1-6 acyl group" include lower (C _1-6 ) alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl; _3-6 ) Alkenoyl group; C _4-6 cycloalkanecarbonyl group such as cyclopropanecarbonyl group, cyclobutanecarbonyl group and cyclopentanecarbonyl group can be used.

^{R 1, R 1a, R 2} , R 2a, R 3, R 3 ', R 3a, R 4, R 4a, R 5, R 5', R 5a, R 7, R 8, R 9, R 10, R ¹¹ , R ¹² , R ¹³ and `` esterification or amidation represented by substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B ^'' Examples of the "carboxyl group which may be used" include a carboxyl group, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl.
Here, as the "alkoxycarbonyl", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl pentyl lower (C _1-6) such as oxycarbonyl alkoxycarbonyl, or the like can be used, inter alia methoxycarbonyl, etc. C _1-3 alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl are preferred. The “lower alkoxycarbonyl” may have a substituent, and the substituent may be a hydroxyl group, an amino group which may be substituted [The amino group is, for example, 1 to 5 halogen atoms (eg, fluorine , Chlorine, bromine, iodine, etc.) and lower alkyl groups which may be substituted (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.). Represents one or two substituents such as methyl, ethyl, etc.), an acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, and benzoyl), a carboxyl group, and C _1-6 alkoxycarbonyl. You may have. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a lower alkoxy group optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (For example, C _1-6 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably methoxy, ethoxy, etc.). Further, these substituents are preferably the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).
Here, as the “aryloxycarbonyl”, for example, C _6-14 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, 1-phenanthoxycarbonyl and the like are preferable. The “aryloxycarbonyl” may have a substituent. As the substituent, the same number of the same substituents as those in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “aralkyloxycarbonyl”, for example, C _7-14 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. The “aralkyloxycarbonyl” may have a substituent, and as the substituent, the same number of the same substituents as in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “N-monosubstituted carbamoyl”, for example, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like), lower alkenyl ( examples include vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, _{C 2-6} alkenyl hexenyl, etc.), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, _{C 3-6} cycloalkyl such as cyclohexyl, etc.), Aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (e.g., _{C 8-10} Arirua of cinnamyl etc. Kenyir, preferably phenyl -C _2-4 alkenyl, etc.), using the same "heterocyclic group" and the like) and the like in the "optionally substituted heterocyclic group" as the Hajime Tamaki (e.g., below substituent be able to. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and the substituent may be a substituent in “alkoxycarbonyl” as the substituent described above. A similar number of similar elements can be used.
Here, “N, N-disubstituted carbamoyl” means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is “N-monosubstituted carbamoyl” as the above-mentioned substituent. The same substituents as those in "carbamoyl" can be used, and examples of the substituent include lower alkyl (eg, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.). Alkyl), C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg, benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc.) and the like. Can be used. Further, two substituents may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, Piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), 1-pipe which may have aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl and the like), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl) and the like. A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as radinylcarbonyl can be used.

As the “C _1-6 alkyl group substituted with 1 to 5 halogen atoms” represented by R ¹ , R ^1a and R ⁷ , 1 to 5, preferably 1 to 3 halogen atoms (eg, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having fluorine, chlorine, bromine, iodine, etc. And specifically, for example, fluoromethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl , 2-fluoropropyl, 1,2-difluoropropyl, 3,3,3-trifluoropropyl, 1-fluorobutyl, 4,4,4-trifluoro Robuchiru, 1-fluoropentyl, 5,5,5-trifluoro-pentyl, 1-fluoro-hexyl, 3,3-difluoro-hexyl, and the like can be used 6,6,6-trifluoro hexyl.

The `` optionally substituted amino group <sup>'' represented</sup> by `` substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B ^'' is defined below. The same groups as the “optionally substituted amino group” in the “substituent” can be used.
`` C <sub>1- of the</sub> optionally substituted C <sub>1-6</sub> alkoxyimino group '' in the `` carbon atom substituted with an optionally substituted C _1-6 alkoxyimino group '' represented by Z ¹ and Z ² ₆ alkoxyimino group '' and `` optionally substituted C <sub>1-6 represented</sub> by `` a substituent on the A ring or the B ring other than R ^a , R ² , R ^{3 '} , R ⁴ and R ^5''' As the "C _1-6 alkoxyimino group" in the "alkoxyimino group", for example, methoxyimino, ethoxyimino, n-propoxyimino, isopropyloxyimino, n-butoxyimino, isobutyloxyimino, sec-butyloxyimino, tert- Butyloxyimino, n-pentyloxyimino, isopentyloxyimino, neopentyloxyimino, n-hexyloxyimino, isohexyloxyimino, 1,1-dimethylbutyloxy Imino, 2,2-dimethylbutyloxyimino, 3,3-dimethylbutyloxyimino, 2-ethylbutyloxyimino and the like can be used. Preferred are methoxyimino, ethoxyimino, n-propoxyimino, isopropyloxyimino, n-butoxyimino and the like.

`` C <sub>1-4</sub> alkylenedioxy group '' in `` carbon atom substituted by C _1-4 alkylenedioxy group '' represented by Z ¹ and Z ² and `` R <sup>a</sup> , R <sup>2</sup> on ring A or ring B As the `` C _1-4 alkylenedioxy group '' in the `` optionally substituted C <sub>1-4</sub> alkylenedioxy group <sup>'' represented</sup> by ``, a substituent other than R ^{3 ′} , R ⁴ and R ^{5 ′ ''} , for example, Methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy and the like can be used. Preferred are a methylenedioxy group and an ethylenedioxy group.

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , represented by `` a halogen atom, a hydroxyl group or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group '', 0 to 5, preferably 0 to 3 of the above-defined "C _1-6 alkyl group" at the substitutable site, "Halogen atom", hydroxyl group, and the above-defined "C _1-6 alkoxy group" ] Can be used. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2 0 to 5, preferably 0 to 3 at a substitutable site of a C _1-6 alkyl group such as -dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, etc. A fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a hydroxyl group; methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy , Neopentyloxy, n-hexyloxy, isohexyloxy, 1,1-dimethylbutyi Oxy, 2,2-dimethyl-butyloxy, 3,3-dimethyl-butyloxy, those substituted with C _1-6 alkoxy groups such as 2-ethyl-butyloxy is used. Specifically, methyl, fluoromethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, pentyloxymethyl, ethyl, 1-fluoroethyl, 2-bromoethyl, 1,2 -Dichloroethyl, 1,2-dichloro-1-hydroxyethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, n-propyl, isopropyl, -Hydroxypropyl, ethoxypropyl, 2-fluoropropyl, 1,2-difluoropropyl, 3,3,3-trifluoropropyl, n-butyl, isobutyl, 1-chlorobutyl, 4,4,4-trifluorobutyl, fluoro Methoxybutyl, 1,1-dimethyl N-butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-hydroxy-2-fluoro-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-fluoropentyl , 5,5,5-trifluoropentyl, n-hexyl, isohexyl, 1-fluorohexyl, 3,3-difluorohexyl, 6,6,6-trifluorohexyl and the like can be used.

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , represented by `` a halogen atom, a hydroxyl group or a C _1-6 acyl group optionally substituted with a C _1-6 alkoxy group '', 0 to 5, preferably 0 to 3 of the above-defined "C _1-6 acyl group" at the substitutable site of the above-defined "halogen atom", hydroxyl group, "C _1-6 alkoxy group" ] Can be used. For example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclopropanecarbonyl group, cyclobutanecarbonyl group, a C _1-6 acyl group such as cyclopentane group 0 to 5, preferably 0 to 3, fluorine, chlorine, bromine and iodine atoms at the substitutable site; hydroxyl group; methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy 3,3-dimethyl-butyloxy, those substituted with C _1-6 alkoxy groups such as 2-ethyl-butyloxy is used.

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , represented by `` a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted with a C _1-6 alkoxy group '', 0 to 5, preferably 0 to 3 of the above-defined "C _1-6 alkoxy group" at the substitutable site of the "C _1-6 alkoxy group", a hydroxyl group, a "C _1-6 alkoxy group" as defined above ] Can be used. For example, methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 1,1-dimethyl-butyloxy, 2,2-dimethyl-butyloxy, 3,3-dimethyl-butyloxy, 0 to the substitutable positions of a C _1-6 alkoxy group such as 2-ethyl-butyloxy 5, preferably 0 to 3 fluorine, chlorine, bromine and iodine; hydroxyl; methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy , Isopentyloxy, neopentyloxy, n-hexyl Those substituted with a C _1-6 alkoxy group such as loxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy and 2-ethylbutyloxy are used. It is.

Examples of the “amino group optionally substituted with a C _1-6 alkyl group and / or a C _1-6 acyl group” represented by R ¹⁰ , R ¹¹ , R ¹² and R ¹³ include methyl, ethyl and , propyl, isopropyl, butyl, isobutyl, tert- butyl, _{C 1-6} alkyl groups as well as formyl, such as pentyl and hexyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl And those substituted with 0 to 2 groups selected from C _1-6 acyl groups such as cyclopropanecarbonyl group, cyclobutanecarbonyl group and cyclopentanecarbonyl group.

The `` amino group optionally substituted with a C _1-6 alkyl group or C _1-6 acyl group '' represented by Z ² includes, as an amino group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- Substituted by 0 to 2 groups selected from C _1-6 alkyl groups such as butyl, pentyl and hexyl, or formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, Those substituted with 0 to 2 groups selected from C _1-6 acyl groups such as crotonoyl, isocrotonoyl, cyclopropanecarbonyl group, cyclobutanecarbonyl group and cyclopentanecarbonyl group can be used.

k, m, p, q, k a, m a is 0, 1 or 2. Thus, the formula S (O) k, S ( O) m, S (O) p, S (O) k a, k in ^{S (O) m a, m} , p, k a, m a represents 0 case, the S; formula S (O) k, S ( O) m, S (O) p, S (O) k a, k in ^{S (O) m a, m} , p, k a, m a There values to indicate 1, S (O) a; formula S (O) k, S ( O) m, S (O) p, S (O) k a, S (O) m a in k, m, p, k ^a, when m ^a represents 2 shows S (O) _2, respectively. When q represents 0, it represents a chemical bond; when q represents 1, it represents a methylene group; and when q represents 2, it represents an ethylene group.

As "5- to 8-membered ring" of the "substituted 5- or may be 8-membered ring" represented by ring A and A ^a ring, for example, "alicyclic hydrocarbon", "aromatic hydrocarbon", " Heterocycle "and the like can be used.
Examples of the "4- to 10-membered ring" of the "further 4 to optionally substituted 10-membered ring" represented by ring B and B ^a ring, can be used, for example, "non-aromatic heterocyclic ring".

"Alicyclic hydrocarbon" includes, for example, saturated or unsaturated, monocyclic or fused polycyclic, such as cycloalkane, cycloalkene, cycloalkanediene and bicyclic fused ring thereof and benzene, C _5-8 or _C4-10 alicyclic hydrocarbons are used.
As the “cycloalkane”, for example, C _3-10 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane and the like are used.
As the “cycloalkene”, for example, C _3-10 cycloalkene such as cyclopentene, cyclohexene and cyclobutene is used.
As the “cycloalkanediene”, for example, C _4-6 cycloalkanediene such as cyclopentadiene, cyclohexadiene and cyclohexanediene is used.
As the “aromatic hydrocarbon”, a monocyclic or condensed polycyclic aromatic hydrocarbon is used and is not particularly limited, but is preferably a C _6-8 aromatic hydrocarbon, more preferably a C ₆ aromatic hydrocarbon. And so on. Specifically, for example, benzene, toluene, xylene, mesitylene, cumene, styrene, 1,2,3-trimethylbenzene, pentalene and the like are preferable, and benzene, toluene and the like are preferably used.

As the “heterocycle”, for example, at least one or three (preferably one or two) heteroatoms selected from oxygen, sulfur and nitrogen atoms as atoms (ring atoms) constituting a ring system are used. (Preferably 1 to 4, more preferably 1 to 2) aromatic heterocycles, saturated or unsaturated non-aromatic heterocycles (aliphatic heterocycles), and the like are used. Is a 4- to 10-membered or 5- to 8-membered heterocycle.
Specific examples of the “aromatic heterocycle” include a 5- to 10-membered aromatic heterocycle, for example, a 5- to 6-membered aromatic monocyclic heterocycle (eg, furan, thiophene, pyrrole, oxazole, iso- Oxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), and 8 to 10-membered condensed aromatic heterocycle (for example, 1H-pyrrolo [1,2-c] imidazole, pyrrolo [1,2-a] imidazole-4-ium, pyro B [1,2-c] imidazole-4-ium, pyrrolo [2,3-c] pyrazole, pyrrolo [3,2-c] pyrazole, pyrrolo [3,4-c] pyrazole, 1H-pyrrolo [3 2-c] pyrazole, pyrrolo [1,2-b] pyrazole-7-ium, 1H-furo [2,3-d] imidazole, 1H-furo [3,4-d] imidazole, 1H-furo [2, 3-c] pyrazole, 1H-furo [2,3-d] imidazole, 1H-furo [3,2-c] pyrazole, 1H-furo [3,4-c] pyrazole, 1H-thieno [2,3- d] imidazole, thieno [2,3-b] furan, 4H-imidazo [4,5-d] thiazole, imidazo [2,1-b] thiazole, 5H-pyrrolo [1,2-c] imidazole, benzofuran, Isobenzofuran, benzothio Ene, indole, isoindole, 1H-indazole, benzoxazole, 1,2-benzoisoxazole, benzothiazole, benzopyran, 1,2-benzoisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline Phthalazine, naphthyridine, purine, buteridine, indolizine, pyrrolo [1,2- b ] pyridazine, pyrazolo [1,5- a ] pyridine, imidazo [1,2- a ] pyridine, imidazo [1,5- a ] Pyridine, imidazo [1,2- b ] pyridazine, imidazo [1,2- a ] pyrimidine, 1,2,4-triazolo [4,3- a ] pyridine, 1,2,4-triazolo [4,3- b] pyridazine and the like (preferably, 5 to the to 6-membered aromatic monocyclic heterocyclic group is benzene Heterocyclic, etc.)) are used to two same or different heterocyclic aromatic monocyclic heterocyclic group having 5 heterocycle or with the fused 6-membered condensed with.
Specific examples of the "non-aromatic heterocycle" include, for example, oxetane, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, quinuclidine, aziridine, oxirane, azetidine, pyrrolidine, tetrahydrofuran, thiolane, piperidine, tetrahydropyran, dioxolane, thiazane , Morpholine, thiomorpholine, piperazine, azepan, perhydroindole, perhydropyrrolo [2,3-d] pyridine, perhydropyrrolo [3,2-d] pyridine, 7-azabicyclo [2,2,1] heptane, and the above aromatics A 4- to 10-membered or 5- to 8-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic ring (aliphatic heterocyclic ring) such as a compound in which part or all of the heterocyclic ring is saturated is used.
Here, in the case where the ring B is a bicyclic ring which may be further substituted, CR ² in Y ¹ or CR ⁴ or a nitrogen atom in Y ² may form a part of the ring B.
Also, in the case of B ^a ring further also be bicyclic optionally substituted ring, CR ^4a or the nitrogen atom in the CR ^2a or Y ^2a in Y ^1a may constitute a part of the B ^a ring.
Further, in the case where the ring B is a bicyclic ring which may be further substituted, CR ² in Y ¹¹ or CR ⁴ or a nitrogen atom in Y ²¹ may form a part of the ring B.

A substituent in the “optionally substituted hydrocarbon group” represented by R ² , R ^2a , R ³ , R ^{3 ′} , R ^3a , R ⁴ , R ^4a , R ⁵ , R ^{5 ′} and R ^5a ; A Substituents in the “optionally substituted 5- to 8-membered ring” represented by the ring and A ^a ring; substitution in the “optionally substituted 4- to 10-membered ring” represented by the ring B and the ^Ba ring "substituted in the B ring; substituents of the" benzene ring which may be substituted "for ring a; substituents of the" further optionally substituted benzene ring "represented by ring C and C ^a ring: group Optionally substituted pyrrolidine ring "," optionally substituted piperidine ring "," optionally substituted piperazine ring "," optionally substituted morpholine ring "," optionally substituted thiomorpholine ring " Or a substituent in the "optionally substituted perhydroazepine ring" The substituent in the present invention is not particularly limited, for example, (i) optionally substituted alkyl group, (ii) optionally substituted alkenyl group, (iii) optionally substituted alkynyl group (Iv) optionally substituted aryl group, (v) optionally substituted aralkyl group, (vi) optionally substituted cycloalkyl group, (vii) optionally substituted cycloalkenyl group (Viii) an optionally substituted heterocyclic group, (ix) an optionally substituted amino group, (x) an optionally substituted imidoyl group (for example, a compound of the formula -C (U ') = N- U (wherein, U and U ′ each represent a hydrogen atom or a substituent (U preferably represents a hydrogen atom) or the like); (xi) an optionally substituted amidino group (for example, Formula -C (NE'E ") = NE [where E, E 'and E" are each a hydrogen atom Or a group represented by a substituent (E preferably represents a hydrogen atom)], (xii) an optionally substituted hydroxyl group, (xiii) an optionally substituted thiol group, (xiv) Optionally substituted alkylsulfinyl group, (xv) carboxyl group which may be esterified or amidated, (xvi) optionally substituted thiocarbamoyl group, (xvii) optionally substituted sulfamoyl group A, (xviii) a halogen atom (eg, fluorine, chlorine, bromine, iodine or the like, preferably chlorine, bromine or the like), (xix) cyano group, (xx) isocyano group, (xxi) cyanate group, (xxii) isocyanate group, (xxiii) thiocyanate group, (xxiv) isothiocyanate group, (xxv) nitro group, (xxvi) nitroso group, (xxvii) acyl group derived from sulfonic acid, (xxviii) acyl group derived from carboxylic acid, (xxix) oxo group , (xxx) thioxo group, _{(xxxi) C 1-4} alkyl Njiokishi group or the like is used, 1 to 5 of these optional substituents at substitutable positions (preferably 1 to 3) may be substituted.

Examples of the alkyl group in the `` optionally substituted alkyl group '' as the substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, C _1-6 alkyl such as isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc. Can be used. Here, the substituent of the alkyl group includes a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (Eg, C _1-6 alkyl such as methyl, ethyl, propyl, etc.), lower alkenyl group (eg, C _2-6 alkenyl such as vinyl, allyl, etc.), lower alkynyl group (eg, C ₂ such as ethynyl, propargyl, etc.) _-6 alkynyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a cyano group, an optionally substituted amidino group, a carboxy group, a lower alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) C _1-6 alkoxycarbonyl, etc.) etc., optionally substituted carbamoyl group (e.g., 5 to 6 membered monocyclic aromatic double Ring group (e.g., pyridyl) optionally substituted C _1-6 alkyl group or an acyl group (e.g., a formyl, C _2-6 alkanoyl, benzoyl, a C _1-6 alkoxycarbonyl which may be halogenated , A carbamoyl group which may be substituted with an optionally halogenated C _1-6 alkylsulfonyl, benzenesulfonyl, etc.), 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl , 1-piperazinylcarbonyl and the like), and one or three of these optional substituents may be substituted at substitutable positions.

As the `` optionally substituted amino group '' as a substituent of the `` optionally substituted alkyl group '', `` optionally substituted hydroxyl group '', and `` optionally substituted amidino group '' Are `` optionally substituted amino group '', `` optionally substituted hydroxyl group '', and `` optionally substituted amidino '' The same groups as those described above can be used.

Examples of the alkenyl group in the “optionally substituted alkenyl group” as the substituent include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, -Butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, it may be used _{C 2-6} alkenyl such as 5-hexenyl. Here, as the substituent of the alkenyl, the same number and the same substituents as those of the “optionally substituted alkyl group” as the substituent can be used.

Examples of the alkynyl group in the “optionally substituted alkynyl group” as the substituent include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, may be used _{C 2-6} alkynyl 5-hexynyl and the like. Here, as the substituent of the alkynyl group, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

As the aryl group in the “optionally substituted aryl group” as the substituent, for example, C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used. Here, as the substituent of the aryl group, the same number and similar substituents as those of the “optionally substituted alkyl group” as the above-mentioned substituent can be used.

As the aralkyl group in the “optionally substituted aralkyl group” as the substituent, for example, C _7-11 aralkyl such as benzyl, phenethyl and naphthylmethyl can be used. Here, as the substituent of the aralkyl group, the same number and similar substituents as those of the “optionally substituted alkyl group” as the substituent can be used.

As the cycloalkyl group in the “optionally substituted cycloalkyl group” as the substituent, for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl can be used. Here, as the substituent of the cycloalkyl group, the same number of the same substituents as those of the “optionally substituted alkyl group” as the substituent can be used.

As the cycloalkenyl group in the “optionally substituted cycloalkenyl group” as the substituent, for example, C _3-7 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl can be used. Here, as the substituent of the cycloalkenyl group which may be substituted, the same number of the same substituent as the substituent in the above-mentioned "alkyl group which may be substituted" as the substituent can be used. .

Examples of the heterocyclic group in the “optionally substituted heterocyclic group” as the substituent include, for example, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system. An aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) atoms, a saturated or unsaturated non-aromatic heterocyclic ring Groups (aliphatic heterocyclic groups) and the like can be used.
Here, the "aromatic heterocyclic group" includes, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 1,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl 5- or 6-membered monocyclic aromatic heterocyclic group such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolo Ryl, benzoxazolyl, 1,2-benzoisooxy Sazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1, 2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3 - a] pyridyl, 1,2,4-triazolo [4,3- b] can be used such as 8-12 membered fused polycyclic aromatic heterocyclic group pyridazinyl, and the like.

Here, as the "non-aromatic heterocyclic group", for example, 3 to 8 members (preferably 5 Or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4 -Use a non-aromatic heterocyclic group or the like in which a part or all of the above-mentioned monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group is saturated, such as tetrahydroisoquinolyl or the like. be able to.
Examples of the substituent which the “optionally substituted heterocyclic group” may have include a lower alkyl group (eg, C _1-6 alkyl such as methyl, ethyl and propyl), a lower alkenyl Groups (eg, C _2-6 alkenyl such as vinyl and allyl), lower alkynyl groups (eg, C _2-6 alkynyl such as ethynyl, propargyl, etc.), and acyl groups (eg, formyl, acetyl, propionyl, pivaloyl, etc.) C _1-6 alkanoyl, benzoyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), An imidoyl group which may be substituted, an amidino group which may be substituted and the like can be used. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions.
"Optionally substituted amino group", "optionally substituted hydroxyl group", "optionally substituted hydroxyl group", "optionally substituted heterocyclic group" As the `` imidoyl group '' and `` optionally substituted amidino group '', `` optionally substituted amino group '' and `` substituted The same as those described for the "optionally substituted hydroxyl group", "optionally substituted imidoyl group", and "optionally substituted amidino group" can be used.

As the substituent, "optionally substituted amino group", "optionally substituted imidoyl group", "optionally substituted amidino group", "optionally substituted hydroxyl group", "substituted As the substituent in the optionally substituted thiol group, for example, an optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloro Methoxy, 2,2,2-trichloroethoxy, etc.) and C _7-11 alkylaryl groups (eg, o-toluyl, m-toluyl, p-toluyl, xylyl, mesityl, etc., preferably C _1-5 alkyl-phenyl, etc.) Lower alkyl groups which may be substituted with a substituent selected from (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, C _1-6 alkyl such as tert-butyl, pentyl, hexyl, etc., acyl group (C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, C _1-6 alkylsulfonyl (eg, methane Sulfonyl, etc.), benzenesulfonyl, etc.), optionally halogenated C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxy) Carbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), a C _1-6 alkoxycarbonyl group (eg, benzyloxycarbonyl, etc.) which may be substituted with a phenyl group, aryl (eg, phenyl, 1-naphthyl, 2 -C _6-10 aryl such as naphthyl, etc.), Aralkyl (eg, C _7-10 aralkyl such as benzyl and phenethyl, preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (eg, C _8-10 arylalkenyl such as cinnamyl, preferably phenyl-C _2-4) Alkenyl), a heterocyclic group (the same as the “heterocyclic group” in the “optionally substituted heterocyclic group” as the substituent, preferably pyridyl, more preferably 4-pyridyl) and the like are used. be able to. These optional substituents may be substituted one to three times at substitutable positions.

The “amino group” in the “optionally substituted amino group” as the substituent is an imidoyl group which may be substituted (for example, C _1-6 alkylimidoyl (eg, formyl imidoyl, acetyl Imidyl, etc.), C _1-6 alkoxyimidoyl, C _1-6 alkylthioimidoyl, amidino, etc.), substituted with one or two amino groups which may be substituted with one to two C _1-6 alkyl groups. You may. One or two of these optional substituents may be substituted at substitutable positions. In addition, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, Morpholino, 1-piperazinyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), aralkyl (eg, benzyl, phenethyl and the like) C _7-10 aralkyl, etc.), aryl (e.g., phenyl, 1-naphthyl, _{2-C 6-10} may have an aryl, etc.) and 1-piperazinyl of naphthyl, 1-pyrrolyl, 1-imidazolyl, etc. And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino or the like can be used.

Examples of the alkylsulfinyl group in the `` optionally substituted alkylsulfinyl group '' as the substituent include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl And C _1-6 alkylsulfinyl such as pentylsulfinyl and hexylsulfinyl. Here, as the substituent of the alkylsulfinyl, the same number and the same substituents as those of the above-mentioned “optionally substituted alkyl” as the substituent can be used.

Examples of the “carboxyl group that may be esterified or amidated” as the substituent include a carboxyl group, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted Carbamoyl can be used.
Here, as the "alkoxycarbonyl", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl C _1-6 alkoxycarbonyl (lower alkoxycarbonyl) such as pentyloxycarbonyl and the like can be used, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is preferable. The “lower alkoxycarbonyl” may have a substituent, and the substituent may be a hydroxyl group, an amino group which may be substituted [The amino group is, for example, 1 to 5 halogen atoms (eg, fluorine , Chlorine, bromine, iodine, etc.) and lower alkyl groups which may be substituted (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.). Represents one or two substituents such as methyl, ethyl, etc.), an acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, and benzoyl), a carboxyl group, and C _1-6 alkoxycarbonyl. You may have. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a lower alkoxy group optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (For example, C _1-6 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably methoxy, ethoxy, etc.). Further, these substituents are preferably the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).

Here, as the “aryloxycarbonyl”, for example, C _6-14 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, 1-phenanthoxycarbonyl and the like are preferable. The “aryloxycarbonyl” may have a substituent. As the substituent, the same number of the same substituents as those in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “aralkyloxycarbonyl”, for example, C _7-14 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. The “aralkyloxycarbonyl” may have a substituent, and as the substituent, the same number of the same substituents as in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “N-monosubstituted carbamoyl”, for example, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like), lower alkenyl ( examples include vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, _{C 2-6} alkenyl hexenyl, etc.), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, _{C 3-6} cycloalkyl such as cyclohexyl, etc.), Aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (e.g., _{C 8-10} Arirua of cinnamyl etc. Kenyir, preferably phenyl -C _2-4 alkenyl, etc.), using the same "heterocyclic group" and the like) and the like in the "optionally substituted heterocyclic group" as the Hajime Tamaki (e.g. the substituent be able to. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and the substituent may be a substituent in “alkoxycarbonyl” as the substituent described above. A similar number of similar elements can be used.

Here, “N, N-disubstituted carbamoyl” means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is “N-monosubstituted carbamoyl” as the above-mentioned substituent. The same substituents as those in "carbamoyl" can be used, and examples of the substituent include lower alkyl (eg, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.). Alkyl), C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg, benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc.) and the like. Can be used. Further, two substituents may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, Piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), 1-pipe which may have aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl and the like), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl) and the like. A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as radinylcarbonyl can be used.

Examples of the substituent of the `` optionally substituted thiocarbamoyl group '' and the `` optionally substituted sulfamoyl group '' as the substituent include `` an optionally esterified or amidated carboxyl group '' as the substituent. The same substituents as those for "N-monosubstituted carbamoyl" and "N, N-disubstituted carbamoyl" in "group" can be used.

As the `` acyl derived from sulfonic acid '' as the substituent, for example, those in which the above-mentioned `` N-monosubstituted carbamoyl '' has one substituent on the nitrogen atom bonded to a sulfonyl can be used, Preferably, acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl can be used.

Examples of the “acyl derived from carboxylic acid” as a substituent include those in which a hydrogen atom or the above-mentioned “N-monosubstituted carbamoyl” has one substituent on a nitrogen atom bonded to carbonyl, and the like. Preferably, acyl such as C _1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and benzoyl can be used.

As the “C _1-4 alkylenedioxy group” as a substituent, a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, a butylenedioxy group, or the like can be used. And it may be substituted on a different carbon.

R ⁶ and the `` optionally substituted C <sub>1-6</sub> alkyl group <sup>'' represented</sup> by `` a substituent other than R ^a , R ² , R ^{3 '} , R ⁴ and R ^5' on the ring A or B ^'' And the same number of the same substituents as those used in the “optionally substituted alkyl group” as the substituent can be used.
A substituent in the “optionally substituted C _1-6 alkoxy group” represented by “a substituent other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on ring A or ring B” And the same number of the same substituents as those used in the “optionally substituted alkyl group” as the substituent can be used.
As the substituent in the `` optionally substituted alkoxy group '' represented by <sup>Ra</sup> , the same number of similar substituents as those used in the `` optionally substituted alkyl group '' as the substituent may be used. Can be used.
^{R 1, R 1a, R 2} , R 2a, R 3, R 3 ', R 3a, R 4, R 4a, R 5, R 5', represented by R ^5a and R ⁷ 'may be substituted As the substituent for the “acyl group”, the same number of the same substituents as those used for the “optionally substituted alkyl group” as the substituent can be used.
A substituent in the “optionally substituted C _1-6 acyl group” represented by “a substituent other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on the A ring or the B ring”; And the same number of the same substituents as those used in the “optionally substituted alkyl group” as the substituent can be used.
Z ¹ and Z ² "C _1-6 optionally substituted alkoxyimino group" of the "substituted carbon atom substituted in a C _1-6 alkoxyimino group optionally" represented by as well as "on the A ring Or a substituent on the `` optionally substituted C <sub>1-6</sub> alkoxyimino group <sup>'' represented</sup> by R <sup>a</sup> , R <sup>2</sup> , R <sup>3 ′</sup> , a substituent other than R <sup>4</sup> and R <sup>5 ′</sup> on the B ring, The same number of the same substituents as those used in the “optionally substituted alkyl group” as the substituent can be used.
In the `` optionally substituted C _1-4 alkylenedioxy group ^{'' represented} by `` Substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on A ring or B ring ^'' As the substituent, the same number and similar substituents as those used in the “optionally substituted alkyl group” as the substituent can be used.

As the “leaving group” represented by ΔM, for example, halogen such as fluorine, chlorine, bromine, and iodine, trifluoromethanesulfonate, p-toluenesulfonate, and methanesulfonyl can be used.

A ring and A ^a ring and B ring and B ^a ring may be substituted.
X ¹ , X ² , X ^1a and the substituent in the `` optionally substituted carbon atom '' represented by X <sup>2a</sup> include the aforementioned R <sup>2</sup> , R <sup>2a</sup> , R <sup>3</sup> , R <sup>3 ′</sup> , R <sup>3a</sup> , R <sup>4</sup> , One or two substituents similar to the substituents in the “optionally substituted hydrocarbon group” represented by R <sup>4a</sup> , R <sup>5</sup> , R <sup>5 ′</sup> and R <sup>5a</sup> can be used. Here, when the “optionally substituted carbon atom” has no substituent, the carbon atom has one or two hydrogen atoms, and the “optionally substituted carbon atom” has one When it has a substituent, the carbon atom has 0 or 1 hydrogen atom in addition to the substituent.
Examples of the substituent in the `` optionally substituted nitrogen atom '' represented by Y ² , Y ²¹ and Y ^2a include `` R ^a , R ² , R ^{3 ′} , R ⁴ and As the substituent in the definition of the “substituent other than R ^{5 ′} ”, the same substituent as the “optionally substituted amino group” can be used. Here, when the “optionally substituted nitrogen atom” has no substituent, the nitrogen atom has 0 or 1 hydrogen atom.

W and W ¹ represent a nitrogen atom or a group represented by the formula CR ^a (wherein the symbols represent the same groups as defined above). However, when the ring A represents an optionally substituted benzene ring, W represents a group represented by the formula CR ^a (wherein the symbols represent the same groups as defined above).
Y ¹ represents a group represented by the formula CR ² R ³ (wherein each symbol represents the same group as defined above), and Y ² represents a group represented by the formula CR ⁴ R ⁵ (wherein each symbol has the same definition as the above.) And a group represented by a nitrogen atom, an oxygen atom or a formula S (O) _m (wherein each symbol has the same meaning as defined above).
Y ¹¹ is the formula CR ² R ^{3 '(wherein} each symbol. Indicate the same groups as defined above) a group represented by, Y ²¹ is 1) when W is a nitrogen atom, the formula CR ⁴ R ^5' (Wherein each symbol represents the same group as defined above), a nitrogen atom, an oxygen atom or a formula S (O) _m (wherein the symbols have the same meanings as defined above). When the group represented by 2) W is a group represented by the formula CR ^a (the symbols in the formula are the same as defined above), the formula CR ⁴ R ^{5 ′} (each symbol in the formula is the same as defined above) . the group or a nitrogen atom represented by) (where, Y ²¹ is a nitrogen atom, W is the symbols in the formula CR ^a (wherein the same. as defined above) in the case of a group represented by the CR ^a The bond to Y ²¹ represents a double bond.)
Y ^1a is a group represented by the formula CR ^2a R ^3a (wherein each symbol is the same as defined above), and Y ^2a is a group represented by the formula CR ^4a R ^5a (wherein each symbol is the same as defined above) A nitrogen atom, an oxygen atom or a group represented by the formula S (O) _m ^a (wherein each symbol has the same meaning as defined above).

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩であり、より好ましくは、一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩であり、さらに好ましくは、
一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩、あるいは一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩である。 The compound of the present invention has the general formula

Wherein each symbol is as defined above. Or a salt thereof, more preferably a compound of the general formula

Wherein each symbol is as defined above. Or a salt thereof, more preferably,
General formula

Wherein each symbol is as defined above. Or a salt thereof, or a general formula

Wherein each symbol is as defined above. Or a salt thereof.

A ring or ^Aa ring is particularly preferably an optionally substituted benzene ring, an optionally substituted furan ring, an optionally substituted dihydrofuran ring, an optionally substituted cyclopentadiene ring , A cyclopentene ring, an optionally substituted cyclohexene ring, an optionally substituted cyclohexadiene ring, an optionally substituted dihydropyran ring, an optionally substituted pyran ring, an optionally substituted thiophene ring It is possible to use an optionally substituted pyrrole ring, an optionally substituted pyridine ring, an optionally substituted pyrroline ring, an optionally substituted pyrrolidine ring, an optionally substituted piperidine ring, and the like. it can.
The B ring or B ^a ring, particularly preferably, may pyrroline ring which may be substituted, an optionally substituted pyrrolidine ring, optionally piperidine ring which may be substituted, may morpholine ring which may be substituted, substituted An optionally substituted thiomorpholine ring or an optionally substituted perhydroazepine ring can be used.
As R ¹ , R ^1a and R ⁷ , a cyano group, a nitro group, a halogen atom, a fluoromethyl group, a trifluoromethyl group and the like can be particularly preferably used.
The substituent other than R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on the B ring is particularly preferably a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxyl group, an optionally substituted C _{1 -6} alkyl group (eg, methyl group, ethyl group, propyl group, fluoromethyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, methoxymethyl group, etc.), carbamoyl group and the like can be used.

The compound of the present invention is preferably a compound represented by the above general formula (I), and specifically, for example, 4- [4- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3 -(Hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3- (hydroxymethyl) -3-methyl-1-piperidinyl] -1-naphthonitrile, 4- (2-methyl-1-pyrrolidinyl) ) -1-Naphthonitrile, 4- (2-ethyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-vinyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-isopropyl-1- Pyrrolidinyl) -1-naphthonitrile, 4- (3-hydroxy-2-methyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (3-methoxy-2-methyl-1-pyrrolidinyl ) -1-Naphthonitrile, 4- (4-methoxy-2-methyl-1-pyrrolidinyl) -1-naphthonitrile 4- [3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile , 4- [3- (1-hydroxy-1-methylethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3- Carboxamide, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carbonitrile, 4- (2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- (3 -Hydroxy-2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- (4-hydroxy-2-methyl-1-pyrrolidinyl) -1-benzo Thiophene-7-carbonitrile, an optically active form thereof, or a salt thereof can be suitably used.

〔式中、各記号は前記と同意義を示す。〕で表される本発明化合物において、「B環がさらに置換されていてもよい二環式の環の場合、Y¹¹におけるCR²またはY²¹におけるCR⁴もしくは窒素原子はB環の一部を構成していてもよい」とは、例えば一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物または、一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物もしくは、一般式

〔式中、各記号は前記と同意義を示す。〕で表される化合物などを示す。
　「B^a環がさらに置換されていてもよい二環式の環の場合、Y^1aにおけるCR^2aまたはY^2aにおけるCR^4aもしくは窒素原子はB^a環の一部を構成していてもよい」および「B環がさらに置換されていてもよい二環式の環の場合、Y¹¹におけるCR²またはY²¹におけるCR⁴もしくは窒素原子はB環の一部を構成していてもよい」についても同様である。 The following general formula

Wherein each symbol is as defined above. In the compound of the present invention represented by the following formula: `` In the case of a bicyclic ring in which ring B may be further substituted, CR ² in Y ¹¹ or CR ⁴ or a nitrogen atom in Y ²¹ is a part of ring B. May be composed of, for example, a general formula

Wherein each symbol is as defined above. Or a compound represented by the general formula:

Wherein each symbol is as defined above. Or a compound represented by the general formula:

Wherein each symbol is as defined above. And the like.
`` If the <sup>Ba</sup> ring is <sup>a</sup> bicyclic ring which may be further substituted, CR <sup>2a</sup> in Y <sup>1a</sup> or CR <sup>4a</sup> or a nitrogen atom in Y <sup>2a</sup> may form part of the <sup>Ba</sup> ring '' and The same applies to `` in the case where the ring B is a bicyclic ring which may be further substituted, CR ² in Y ¹¹ or CR ⁴ or a nitrogen atom in Y ²¹ may form a part of the ring B '' It is.

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩と、式

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩とを反応させ、保護基を有する場合は保護基を除去することにより製造することができる。Mで示される「脱離基」としては、例えばフッ素、塩素、臭素、ヨウ素等のハロゲン、トリフルオロメタンスルホナート、p−トルエンスルホナート、メタンスルホニル等を用いることができる。
　化合物（IV）またはその塩は化合物（III）１モルに対して通常１から３モル用いる。この反応は必要に応じ、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素ナトリウム、水酸化ナトリウム、ナトリウムt-ブトキシド、カリウムt-ブトキシド、トリエチルアミン、ジイソプロピルアミン（DIEA）、ピリジン、４−（ジメチルアミノ）ピリジン（DMAP）、１,８−ジアザビシクロ［５,４,０］ウンデク−７−エン（DBU）、１,５−ジアザビシクロ［４,３,０］ノン−５−エン（DBN）等の塩基を添加することにより、円滑に反応を進行させることもできる。更に触媒として遷移金属触媒（例えば、J.O.C., 1997, 62, pp1264-1267）を用いることも好適である。
　反応は、不活性溶媒、例えばメタノール、エタノール、プロパノール、イソプロパノール、n−ブタノール、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、アセトン、酢酸エチル、１，２−ジメトキシエタン、１，４−ジオキサン、トルエン、ベンゼン、キシレン、ジクロロメタン、クロロホルム、１，２−ジクロルエタン、DMF、ジメチルスルホキシド（DMSO）等、あるいはこれらの混合溶媒中で行うことができる。反応は約０℃ないし１８０℃の温度範囲で行われる。反応時間は特に限定されないが、通常0.1時間から100時間、好ましくは、0.5時間から72時間である。 [General manufacturing method]
Compounds according to the present invention (compounds represented by general formulas I, Ia, IIa, IIb, I ′, etc .; hereinafter, compound (I), compound (Ia), compound (IIa), compound (IIb), compound (II )) Can be produced by using a general organic synthesis method or by a known synthesis method. For example, it can be synthesized by the following method.
In the compound (I) or the compound (I ′), the compound in which W or W ¹ represents a nitrogen atom is, for example, a compound represented by the formula

Wherein each symbol is as defined above. A compound represented by the formula:

Wherein each symbol is as defined above. And a salt thereof, and when the compound has a protecting group, the compound can be produced by removing the protecting group. As the "leaving group" represented by M, for example, halogen such as fluorine, chlorine, bromine, and iodine, trifluoromethanesulfonate, p-toluenesulfonate, and methanesulfonyl can be used.
Compound (IV) or a salt thereof is usually used in an amount of 1 to 3 mol per 1 mol of compound (III). This reaction may be performed, if necessary, with potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium t-butoxide, potassium t-butoxide, triethylamine, diisopropylamine (DIEA), pyridine, 4- (dimethylamino) Bases such as pyridine (DMAP), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) and 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) The addition allows the reaction to proceed smoothly. It is also preferable to use a transition metal catalyst (for example, JOC, 1997, 62 , pp1264-1267) as a catalyst.
The reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, acetonitrile, acetone, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene , Dichloromethane, chloroform, 1,2-dichloroethane, DMF, dimethylsulfoxide (DMSO) or the like, or a mixed solvent thereof. The reaction is carried out in a temperature range from about 0 ° C to 180 ° C. The reaction time is not particularly limited, but is usually 0.1 hour to 100 hours, preferably 0.5 hour to 72 hours.

〔式中、各記号は前記と同意義を示す。〕で表される化合物またはその塩と、式

〔式中、B^bは前記式(V)のアミノ基と反応し閉環した後B^a環となる鎖状部分を、L¹およびL²は同一または異なって脱離基を示す。他の各記号は前記と同意義を示す。〕で表される化合物とを反応させ、保護基を有する場合は保護基を除去することにより製造することができる。L¹およびL²で示される「脱離基」としては、同一または異なって、例えばフッ素、塩素、臭素、ヨウ素等のハロゲン、トリフルオロメタンスルホニル、p−トルエンスルホニル、メタンスルホニル等のスルホニル基を用いることができる。
　化合物（VI）は化合物（V）またはその塩１モルに対して通常１から３モル用いる。この反応は必要に応じ、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素ナトリウム、水酸化ナトリウム、トリエチルアミン、ジイソプロピルアミン（DIEA）、ピリジン、４−（ジメチルアミノ）ピリジン（DMAP）、１,８−ジアザビシクロ［５,４,０］ウンデク−７−エン（DBU）、１,５−ジアザビシクロ［４,３,０］ノン−５−エン（DBN）等の塩基やヨウ化ナトリウム等を添加することにより、円滑に反応を進行させることもできる。
　反応は、不活性溶媒、例えばメタノール、エタノール、プロパノール、イソプロパノール、n−ブタノール、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、アセトン、酢酸エチル、１，２−ジメトキシエタン、１，４−ジオキサン、トルエン、ベンゼン、キシレン、ジクロロメタン、クロロホルム、１，２−ジクロルエタン、DMF、ジメチルスルホキシド（DMSO）等、あるいはこれらの混合溶媒中で行うことができる。反応は約０℃ないし１８０℃の温度範囲で行われる。反応時間は特に限定されないが、通常0.1時間から100時間、好ましくは、0.5時間から24時間である。 In the compound (I) or the compound (I ′), the compound in which W or W ¹ represents a nitrogen atom is also, for example, a compound represented by the formula

Wherein each symbol is as defined above. A compound represented by the formula:

[In the formula, B ^b is ^a chain-like portion that reacts with the amino group of the formula (V) to form ^a Ba ring after ring closure, and L ¹ and L ² are the same or different and represent a leaving group. Other symbols are as defined above. And a compound represented by the formula (1): As the `` leaving group '' represented by L ¹ and L ² , the same or different, for example, a halogen such as fluorine, chlorine, bromine and iodine, and a sulfonyl group such as trifluoromethanesulfonyl, p-toluenesulfonyl and methanesulfonyl are used. be able to.
Compound (VI) is usually used in an amount of 1 to 3 mol per 1 mol of compound (V) or a salt thereof. This reaction may be carried out, if necessary, with potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylamine (DIEA), pyridine, 4- (dimethylamino) pyridine (DMAP), 1,8-diazabicyclo By adding a base such as [5,4,0] undec-7-ene (DBU), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) or sodium iodide, The reaction can also proceed smoothly.
The reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, acetonitrile, acetone, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene , Dichloromethane, chloroform, 1,2-dichloroethane, DMF, dimethylsulfoxide (DMSO) or the like, or a mixed solvent thereof. The reaction is carried out in a temperature range from about 0 ° C to 180 ° C. Although the reaction time is not particularly limited, it is generally 0.1 hour to 100 hours, preferably 0.5 hour to 24 hours.

〔式中、各記号は前記と同意義を示す。〕で表される化合物である場合は、例えば式

〔式中、M¹は脱離基またはニトリルオキシドを示し、他の記号は前記と同意義を示す。〕で表される化合物またはその塩と、式

〔式中、Q^aはカルボニル基またはCM²（M²は脱離基を示す。）を示し、他の各記号は前記と同意義を示す。〕または式

〔式中、R^BおよびR^Cは同一または異なって水素原子、シアノ基、ニトロ基、置換されていてもよいアシル基、エステル化もしくはアミド化されていてもよいカルボキシル基または置換されていてもよい炭化水素基をそれぞれ示す。〕で表される化合物またはその塩とを反応させ、保護基を有する場合は保護基を除去することにより製造することができる。
　M¹、M²で示される「脱離基」としては、例えばフッ素、塩素、臭素、ヨウ素等のハロゲン、アルカリ金属、アルカリ土類金属またはそれらのハロゲン化金属、ハロゲン化亜鉛、ハロゲン化錫、トリフルオロメタンスルホナート、p−トルエンスルホナート、メタンスルホニル、ジヒドロキシボラン、ジアルコキシボラン、等を用いることができる。
　R^BおよびR^Cで示される「置換されていてもよいアシル基」、「エステル化もしくはアミド化されていてもよいカルボキシル基」および「置換されていてもよい炭化水素基」としては、前記R¹等で示される「置換されていてもよいアシル基」、「エステル化もしくはアミド化されていてもよいカルボキシル基」の定義、および前記R²等で示される「置換されていてもよい炭化水素基」の定義と同様なものを用いることができる。
　化合物（IX）、(X)またはその塩は化合物（VIII）１モルに対して通常１から３モル用いる。この反応は必要に応じ、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素ナトリウム、水酸化ナトリウム、ナトリウムt-ブトキシド、カリウムt-ブトキシド、トリエチルアミン、ジイソプロピルアミン（DIEA）、ピリジン、４−（ジメチルアミノ）ピリジン（DMAP）、１,８−ジアザビシクロ［５,４,０］ウンデク−７−エン（DBU）、１,５−ジアザビシクロ［４,３,０］ノン−５−エン（DBN）等の塩基を添加することにより、円滑に反応を進行させることもできる。更に触媒として遷移金属触媒（例えば、J.O.C., 1997, 62, pp1264-1267）を用いることも好適である。
　反応は、不活性溶媒、例えばメタノール、エタノール、プロパノール、イソプロパノール、n−ブタノール、テトラヒドロフラン、ジエチルエーテル、アセトニトリル、アセトン、酢酸エチル、１，２−ジメトキシエタン、１，４−ジオキサン、トルエン、ベンゼン、キシレン、ジクロロメタン、クロロホルム、１，２−ジクロルエタン、DMF、ジメチルスルホキシド（DMSO）等、あるいはこれらの混合溶媒中で行うことができる。反応は約−８０℃ないし１８０℃の温度範囲で行われる。反応時間は特に限定されないが、通常0.1時間から100時間、好ましくは、0.5時間から72時間である。 Compound (I) or compound (I ') has the formula

Wherein each symbol is as defined above. Is a compound represented by the formula

[Wherein, M ¹ represents a leaving group or a nitrile oxide, and the other symbols have the same meanings as described above. A compound represented by the formula:

Wherein Q ^a represents a carbonyl group or CM ² (M ² represents a leaving group), and other symbols have the same meanings as described above. ] Or expression

Wherein R ^B and R ^C are the same or different and are a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated carboxyl group, or a substituted Shown below are good hydrocarbon groups. And a salt thereof, and when the compound has a protecting group, the compound can be produced by removing the protecting group.
As the `` leaving group '' represented by M <sup>1</sup> and M <sup>2</sup> , for example, fluorine, chlorine, bromine, halogen such as iodine, alkali metal, alkaline earth metal or a halide thereof, zinc halide, tin halide, Trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonyl, dihydroxyborane, dialkoxyborane, and the like can be used.
As the `` optionally substituted acyl group '', `` optionally esterified or amidated carboxyl group '' and `` optionally substituted hydrocarbon group '' represented by R ^B and R ^C , The definition of the `` optionally substituted acyl group '' represented by <sup>1 and the</sup> like, the `` optionally esterified or amidated carboxyl group '', and the `` optionally substituted hydrocarbon '' represented by the aforementioned R ^{2 and the} like The same ones as defined in "group" can be used.
Compound (IX), (X) or a salt thereof is generally used in 1 to 3 mol per 1 mol of compound (VIII). This reaction may be performed, if necessary, with potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium t-butoxide, potassium t-butoxide, triethylamine, diisopropylamine (DIEA), pyridine, 4- (dimethylamino) Bases such as pyridine (DMAP), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) and 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) The addition allows the reaction to proceed smoothly. It is also preferable to use a transition metal catalyst (for example, JOC, 1997, 62 , pp1264-1267) as a catalyst.
The reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, acetonitrile, acetone, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene , Dichloromethane, chloroform, 1,2-dichloroethane, DMF, dimethylsulfoxide (DMSO) or the like, or a mixed solvent thereof. The reaction is carried out in a temperature range from about -80C to 180C. The reaction time is not particularly limited, but is usually 0.1 hour to 100 hours, preferably 0.5 hour to 72 hours.

Further, one or more substituents on ring B in compound (I) or compound (I ') can be converted to other substituents. For example, the carbonyl group can be reduced to an alcohol, the alcohol can be dehydrated to an olefin, or the alcohol can be alkylated to an ether according to a method known per se.
Compounds (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) used as starting materials should be synthesized by a known method or a method analogous thereto. And can be produced, for example, by the method described in Reference Examples below.
Further, the compounds (Ia), (IIa) and (IIb) can also be synthesized by the above-mentioned method or a known method or a method analogous thereto.
Here, the group in the above formula may be protected with a protecting group used in general organic synthesis, and after the reaction, the protecting group can be removed by a known method if desired after the reaction.

The thus-obtained compound represented by the general formula (I), (Ia), (IIa), (IIb) or (I ′) (hereinafter also referred to as compound (I) or the like) is separated by a known separation method. It can be isolated and purified by means such as concentration, concentration under reduced pressure, solvent extraction, liquid conversion, salting out, crystallization, recrystallization, phase transfer, chromatography and the like.
When the compound (I) or the like is obtained in a free form, it can be converted to a target salt by a method known per se or a method analogous thereto. The compound can be converted into a free form or another desired salt by a method or a method analogous thereto.
Compound (I) or the like may be a hydrate or a non-hydrate.
When the compound (I) or the like is obtained as a mixture of optically active substances, it can be separated into the desired (R) -form or (S) -form by a known optical resolution means.
The compound (I) and the like may be labeled with an isotope (eg, ³ H, ¹⁴ C, etc.).

化合物 The compounds in the present invention may form a salt. The salt of the compound is not particularly limited as long as it does not inhibit the reaction.For example, a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with an amino acid Are used. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine And the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Salts with acids, p-toluenesulfonic acid and the like are used. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

A prodrug of the compound (I) or the like or a salt thereof (hereinafter abbreviated as the compound (I)) is a compound that is converted into the compound (I) by a reaction with an enzyme or gastric acid under physiological conditions in a living body, that is, an enzymatic compound. A compound which changes to the compound (I) by causing oxidation, reduction, hydrolysis or the like, or a compound which changes to the compound (I) by causing hydrolysis or the like by gastric acid or the like. As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Compound, dimethylaminomethylcarbonylated compound etc.); carboxyl group of compound (I) is esterified, amide (E.g., the carboxyl group of compound (I) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalate Jil esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like are used. These compounds can be produced from compound (I) by a method known per se.
The prodrug of compound (I) changes into compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals," Vol. 7, Molecular Design, pp. 163 to 198. There may be.

The compound (I) of the present invention or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention) has an androgen receptor modulator action, particularly an androgen receptor agonist action, and has an androgen receptor agonist in mammals. Can be used for the prevention or treatment of diseases for which administration of is effective. Diseases for which administration of androgen receptor agonists are effective include hypogonadism, osteoporosis, hormone-resistant cancer (particularly LHRH agonist-resistant cancer), menopause (particularly male menopause), anemia, arteriosclerosis, Alzheimer's disease, erection Deficiency, depression or debilitating diseases and the like.
The compounds of the present invention prevent or treat breast cancer, prostate cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, thyroid cancer, bone tumor, penis cancer, which have acquired hormone resistance among various cancers. It can be used as an agent, and is particularly useful as an agent for preventing or treating prostate cancer.
Examples of the hormone-resistant cancer include LHRH derivative-resistant cancer, and are preferably LHRH agonist-resistant cancer.
The compound of the present invention has low toxicity and can be used as a medicament as it is or as a mixture with a pharmaceutically acceptable carrier known per se, for example, a mammal (eg, human, horse, cow, dog, cat, rat, mouse, rabbit) , Pigs, monkeys, etc.) as a pharmaceutical composition.
In a pharmaceutical composition, together with the compound of the present invention, other active ingredients, such as the following hormonal therapeutic agents, anticancer agents (eg, chemotherapeutic agents, immunotherapeutic agents, or cell growth factors and agents that inhibit the action of its receptor, etc.) ) And the like.

When administering the compound of the present invention as a medicine to a mammal such as a human, the method of administration is usually oral, such as tablets, capsules (including soft capsules and microcapsules), powders, granules, etc. It can be administered parenterally as agents, pellets and the like. "Parenteral" includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, vaginal and intraperitoneal, intratumoral, proximal to tumors, etc. Including administration directly to the lesion.
The dose of the compound of the present invention varies depending on the administration route, symptoms and the like. For example, when orally administered to a patient (body weight 40 to 80 kg) having breast cancer or prostate cancer as an anticancer agent, for example, 0.1 to 200 mg / kg daily. The body weight is preferably 1 to 100 mg / kg body weight per day, and more preferably 1 to 50 mg / kg body weight per day. This amount can be administered once or in two or three portions a day.

The compound of the present invention is mixed with a pharmaceutically acceptable carrier and administered orally or parenterally as a solid preparation such as tablets, capsules, granules and powders; or as a liquid preparation such as syrups and injections. be able to.
As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, and disintegrants in solid preparations; It is formulated as an auxiliary, suspending agent, isotonic agent, buffer, soothing agent and the like. If necessary, additives for preparations such as preservatives, antioxidants, coloring agents, sweeteners and the like can also be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like.
Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.
Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
Suitable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, For example, hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose are used.
Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.
Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
Preferred examples of the soothing agent include benzyl alcohol and the like.
Suitable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The pharmaceutical composition may vary depending on the dosage form, administration method, carrier and the like, but may be produced in a usual manner by containing the compound of the present invention usually in an amount of 0.1 to 95% (w / w) based on the total amount of the preparation. Can be.
(1) administering an effective amount of the compound of the present invention; (2) administering an effective amount of (i) another anticancer agent; (ii) administering an effective amount of a hormonal therapy agent; (iii) Cancer can be more effectively prevented and treated by combining with 1 to 3 types selected from the group consisting of non-drug therapies. As the non-drug therapy, for example, surgery, radiation therapy, gene therapy, hyperthermia, cryotherapy, laser burn, and the like are used, and two or more of these can be combined.
For example, the compound of the present invention can be used in combination with other hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors), antiemetic agents, etc. Abbreviated) can be used in combination.
Although the compound of the present invention exhibits excellent anticancer activity even when used as a single agent, it can be further enhanced or used in combination with one or several of the above concomitant drugs (multiple drug combination) to further enhance its effect. QOL can be improved.

Examples of the `` hormone therapeutic agent '' include, for example, phosphestrol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, guestrinone, Mepaltricin, raloxifene, olmeloxifene, revolmeloxifene, antiestrogen (eg, tamoxifen citrate, toremifene citrate, etc.), pill preparation, mepithiostane, testolactone, aminoglutethimide, droloxifene, epithiostanol, sulfonic acid Ethinylestradiol, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane, etc.), antiandrogen Eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone) And the like, retinoids, drugs that delay the metabolism of retinoids (eg, rialosol, etc.), LH-RH derivatives, and the like. Preferred are LH-RH derivatives.
As the "chemotherapeutic agent", for example, an alkylating agent, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent and the like are used.
Examples of the "alkylating agent" include, for example, nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, Phalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemus Prednismin, bumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, Roh statins scan Chima Lamar, carboquone, adozelesin, system scan Chin, Bizereshin or the like is used.
Examples of “antimetabolites” include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine octophosphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, mititefur, etc.), aminopterin, leucovorin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, mititefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxiurizine, idoxiuridine, idoxiuridine And ambamustine are used.
Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocarzinostatin, mythramycin, sarcomycin, carcinophilin, mitotane, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like.
As the "plant-derived anticancer agent", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine and the like are used.
Examples of the "immunotherapeutic agent (BRM)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, coryne Bacterium parvum, levamisole, polysaccharide K, procodazole and the like are used.
The “cell growth factor” in the “drug that inhibits the action of cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000. In the following peptides, factors which exert an effect at a low concentration by binding to a receptor are used. Specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity as that [ (Eg, EGF, hallegulin (HER2 ligand), etc.), (2) insulin or a substance having substantially the same activity as it (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), ( 3) FGF (fibroblast growth factor) or a substance having substantially the same activity as that (eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.), (4) Other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth growth) factorβ), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor) and the like].
The “cell growth factor receptor” may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2) , Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2.
Examples of the “agent that inhibits the action of cell growth factor” include trastuzumab (Herceptin (trademark); HER2 antibody), imatinib mesylate, ZD1839, cetuximab, and the like.
In addition to the above drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercury hematoporphyrin sodium, topoisomerase I inhibitors (eg, irinotecan, nogitecan, exatecan (DX-8951f, DE-310), Rubitecan, T-0128, etc.), topoisomerase II inhibitors (eg, sobuzoxane, etc.), differentiation inducers (eg, retinoids, vitamins D, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.), TZT -1027 can also be used.
The "antiemetic", ondansetron, hydrochloric tropisetron, azasetron, ramosetron, granisetron, Dora cell Tron mesylate, 5-HT ₃ antagonists such as palonosetron, domperidone, mosapride, 5-HT ₄ antagonist such as metoclopramide Gastrointestinal motility-promoting agents such as trimebutine; phenothiazines such as prochlorperazine maleate, promethazine and thiethylperazine; tranquilizers such as haloperidol, chlorpromazine phenolphthaleinate, diazepam and droperidol; Steroid agents such as dexamethasone, prednisolone, betamethasone, and triamcinolone; and dimethylhydrinic acid, diphenhydramine, hyoscine, hyoscine hydrobromide, tetrabenazine and the like can also be used.

Examples of the LH-RH derivative include hormone-dependent diseases, particularly sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, liver cancer, etc.), benign prostatic hyperplasia, endometriosis, uterine fibroids, Sex hormone-dependent diseases such as precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multilocular ovary syndrome, and contraception (or infertility if the rebound effect after withdrawal is used) An LH-RH derivative or a salt thereof effective for the disease is used. Furthermore, LH-RH derivatives or salts thereof which are effective for benign or malignant tumors which are sex hormone-independent but LH-RH sensitive are also used.
Specific examples of the LH-RH derivative or a salt thereof include, for example, Treatment with GnRH analog: Treatment with GnRH analogs: Controversies and perspectives [Parthenon Publishing Group Ltd. ) 1996], JP-A-3-503165, JP-A-3-101695, JP-A-7-97334, and JP-A-8-259460.

Examples of LH-RH derivatives include LH-RH agonists and LH-RH antagonists. Examples of LH-RH antagonists include compounds of the formula
X-D2Nal-D4ClPhe-D3Pal-Ser-AB-Leu-C-Pro-DAlaNH ₂
Wherein X is N (4H ₂ -furoyl) Gly or NAc, A is a residue selected from NMeTyr, Tyr, Aph (Atz), NMeAph (Atz), B is DLys (Nic), DCit, DLys (AzaglyNic), DLys (AzaglyFur), DhArg (Et ₂ ), a residue selected from DAph (Atz) and DhCi, and C represents Lys (Nisp), Arg or hArg (Et ₂ ), respectively. Active peptides or salts thereof are used, particularly preferably abarelix, ganirelix, cetrolelix, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- ( 3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2 , 6-Difluorobenzyl) -6- [4- (3-ethylureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N- Benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-ethyluree De) phenyl] -3-phenyl-thieno [2,3-d] pyrimidine -2,4 (1H, 3H) - such as dione hydrochloride salt is used.
As the LH-RH agonist, for example,
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
Wherein, Y is DLeu, DAla, DTrp, DSer ( tBu), a residue selected from D2Nal and DHis (ImBzl), Z denotes a NH-C ₂ H ₅ or Gly-NH _2] represented by A physiologically active peptide or a salt thereof is used. For example, goserelin acetate, buserelin and the like. In particular, Y is at DLeu, Z is NH-C ₂ H ₅ in which the peptide (i.e., in 5-oxo-Pro-His- Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 Peptide A represented; leuprorelin) or a salt thereof (eg, acetate) is preferred.

When amino acids, peptides, protecting groups, and the like in the polypeptides described in the present specification are indicated by abbreviations, they shall be based on the abbreviations by the IUPAC-IUB Commission on Biochemical Nomenclature or commonly used abbreviations in the art. When there is an optical isomer, the L-form is indicated unless otherwise specified.
Examples of abbreviations are shown below.
Abu: aminobutyric acid Aibu: 2-aminobutyric acid Ala: alanine Arg: arginine Gly: glycine His: histidine Ile: isoleucine Leu: leucine Met: methionine Nle: norleucine Nval: norvaline Phe: phenylalanine PhgPly: glyphine Glu: pyroglutamic acid Ser: serine Thr: threonine Trp: tryptophan Tyr: tyrosine Val: valine D2Nal: D-3- (2-naphthyl) alanine residue DSer (tBu): O-tert-butyl-D-serine DHis (ImBzl ): N ^im - benzyl -D- histidine PAM: phenyl acetamidomethyl Boc: t-butyloxycarbonyl F oc: 9--fluorenylmethyloxycarbonyl Cl-Z: 2-chloro - benzyloxycarbonyl Br-Z: 2-bromo-over benzyloxycarbonyl Bzl: benzyl _Cl 2 -Bzl: 2,6-dichlorobenzyl Tos: p- Toluenesulfonyl HONb: N-hydroxy-5-norbornene-2,3-dicarboximide HOBt: 1-hydroxybenzotriazole HOOBt: 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine MeBzl: 4-methylbenzyl Bom: benzyloxymethyl Bum: t-butoxymethyl Trt: trityl DNP: dinitrophenyl DCC: N, N'-dicyclohexylcarbodiimide

中 で も Among the above, LH-RH agonists (eg, goserelin acetate, buserelin, leuprorelin, etc.) are preferable as the concomitant drug.

When the compound of the present invention and a concomitant drug are used in combination, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to a subject to be administered. It may be administered with a time lag. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination, and the like.
The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing a compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and a concomitant drug. (2) Simultaneous administration of the two preparations obtained in the same administration route by the same administration route, and (3) a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Separate preparation of the compound of the present invention and the concomitant drug For example, administration of two types of preparations obtained in different times at different administration routes (for example, administration of the compound of the present invention → concomitant drug or administration in the reverse order) and the like are used. Hereinafter, these administration forms are collectively abbreviated as the concomitant drug of the present invention.

The concomitant drug of the present invention has low toxicity. For example, a compound of the present invention or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, and a pharmaceutical composition such as a tablet ( Sugar-coated tablets, film-coated tablets), powders, granules, capsules, (including soft capsules), solutions, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, topically, rectally, Intravenous administration, etc.). Injectables can be administered intravenously, intramuscularly, subcutaneously, intra-organically, intranasally, intradermally, instilled, intracerebrally, rectally, intravaginally and intraperitoneally, inside tumors, proximal to tumors, etc. or directly into lesions Can be administered.
As the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention, the same carriers as those used in the above-mentioned pharmaceutical composition of the present invention can be used.

The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention in the combination preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. And more preferably about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.1 to 50% by weight, based on the whole preparation. It is about 0.5 to 20% by weight.
The content of additives such as a carrier in the concomitant preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. .
The same content may be used when the compound of the present invention and the concomitant drug are separately formulated.

These preparations can be produced by a method known per se which is generally used in the preparation process.
For example, the compound of the present invention or the concomitant drug is used as a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose) , Dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solvents (eg, glycerin, ethanol, etc.), buffers (eg, Phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc., tonicity agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide) Etc.), preservatives (eg, ethyl parahydroxybenzoate, benzoic acid, Aqueous solution together with solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) An injection can be prepared by dissolving, suspending or emulsifying in an injection or a vegetable oil such as olive oil, sesame oil, cottonseed oil and corn oil, or a dissolution aid such as propylene glycol to form an oily injection.

In order to prepare a preparation for oral administration, the compound of the present invention or the concomitant drug is used in accordance with a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.) , A binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), and compression-molded. If necessary, a preparation for oral administration can be prepared by coating with a method known per se for the purpose of taste masking, enteric coating or sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween # 80, Pluronic # F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (ROHM) Co., Ltd., Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, bengara, titanium dioxide, etc.) are used. The preparation for oral administration may be any of a quick release preparation and a sustained release preparation.

For example, in order to prepare a suppository, the compound of the present invention or the concomitant drug can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsol (manufactured by Dynamite Nobel, Germany), etc.), and intermediate fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany) ) And vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
As the sustained release preparation, a sustained release microcapsule or the like is used.
A method known per se can be used to obtain sustained release microcapsules. For example, it is preferable to administer the composition by shaping into a sustained release preparation shown in the following [2].
The compound of the present invention is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository. In particular, preparations for oral administration are preferred.
The concomitant drug can be in the above-mentioned dosage form depending on the type of the drug.

Hereinafter, (1) an injection of the compound of the present invention or the concomitant drug and its preparation, (2) a sustained-release or immediate-release preparation of the compound of the present invention or the concomitant drug and its preparation, and (3) a preparation of the present invention. The sublingual tablet, buccal or oral rapid disintegrating agent of the compound or the concomitant drug and the preparation thereof will be specifically described.
[1] Injection and its preparation An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate.
The injection can be obtained by dissolving both the compound of the present invention or the concomitant drug and, if desired, a benzoate and / or a salicylate in water.
Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and organic acid salts such as trometamol.
The concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of the benzoate and / or salicylate is 0.5 to 50 w / v%, preferably 3 to 20 w / v%.

In addition, this agent contains additives generally used for injections, such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), and solvents (glycerin, ethanol, etc.). , Buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin), pH adjusters (hydrochloric acid) , Sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (glucose, benzyl alcohol, etc.) ) Etc. can be appropriately compounded. These additives are generally blended in a ratio usually used for an injection.
The injection is preferably adjusted to 2 to 12, preferably 2.5 to 8.0 by adding a pH adjuster.
An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, if desired, a benzoate and / or a salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
The aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, sterilization by filtration, high-pressure heat sterilization, etc. in the same manner as an ordinary injection.
The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes.
Further, a formulation having antibacterial properties of the solution may be used so that it can be used as a multiple-dose formulation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof Sustained-release preparation comprising a core containing the compound of the present invention or the concomitant drug optionally coated with a film-forming agent such as a water-insoluble substance or a swellable polymer. Is preferred. For example, a once-daily sustained release preparation for oral administration is preferable.
Examples of the water-insoluble substance used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose; cellulose esters such as cellulose acetate and cellulose propionate; polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate; Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially oil Ragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / methacrylated trimethyl / ammonium ethyl copolymer), Eudragit NE- Acrylic polymers such as Eudragits (Rohm Pharma Co., Ltd.) such as 30D (methyl methacrylate-ethyl acrylate copolymer), and hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Corporation), etc.); Waxes such as carnauba wax, fatty acid glycerin ester and paraffin, and polyglycerin fatty acid ester are used.

As the swellable polymer, a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable.Swelling is small in an acidic region such as in the stomach and large in a neutral region such as the small intestine and large intestine. Polymers having acidic dissociating groups are preferred.
Examples of a polymer having such an acidic dissociating group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, etc., polycarbophil, calcium polycarbophil ( Cross-linked polyacrylic acid polymers such as carcium polycarbophil (all of which are manufactured by BF Gudrich) and Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.) are used.

The coating agent used in the sustained release preparation may further contain a hydrophilic substance.
Examples of the hydrophilic substance include pullulan, dextrin, a polysaccharide which may have a sulfate group such as an alkali metal salt of alginic acid, a hydroxyalkyl group or a carboxyalkyl group such as hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose. , A polysaccharide having the above, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used.
The content of the water-insoluble substance in the film of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), and more preferably about 40 to 75% (w / w). w / w), the content of swellable polymer is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The coating agent may further include a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w). Here, the above-mentioned% (w / w) indicates the weight% based on the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent liquid.

Sustained-release preparations are prepared by preparing a nucleus containing a drug as exemplified below, and then heating and dissolving the obtained nucleus with a water-insoluble substance or a swellable polymer in a solvent solution or dispersing or dispersing in a solvent. Manufactured by coating.
I. Preparation of core containing drug.
The form of the nucleus containing the drug to be coated with the coating agent (hereinafter, may be simply referred to as nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules.
When the core is granules or fine granules, the average particle size is preferably about 150 to 2,000 μm, more preferably about 500 to about 1,400 μm.
The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer and the like, and is prepared by wet extrusion granulation, fluidized bed granulation, or the like.
The drug content of the core is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w). It is.

As the excipient contained in the core, for example, sugars such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferred.
As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred. For example, talc, magnesium stearate and its inorganic salts are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol and the like are used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

The nucleus can be prepared by spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) onto inert carrier particles serving as the center of the nucleus, for example, by spraying a drug or It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method, in which a mixture of this and an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable.
In order to separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substance, water-insoluble substance and the like are used. As the protective agent, polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group is preferably used, and more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose is used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w) based on the core. w / w).
The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.

II. Coating of nucleus with coating agent The nucleus obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. Produces a sustained-release preparation.
As a method for coating the nucleus with the coating agent solution, for example, a spray coating method or the like is used.
The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably, about the core (not including the protective agent). About 5 to 35% (w / w).

As a solvent for the coating agent solution, water or an organic solvent may be used alone or in a mixture of both. The mixing ratio of water and the organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, and is preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance.For example, methyl alcohol, ethyl alcohol, isopropyl alcohol, lower alcohols such as n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution for stabilizing the coating agent solution.
The operation in the case of coating by spray coating can be performed by a usual coating method. Specifically, the coating is performed by spray-coating a coating agent solution onto a core by, for example, a fluidized bed coating method or a pan coating method. Can be. At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. are plasticized. It may be added as an agent.
After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.

The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.). Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred.
The quick-release preparation may generally contain, in addition to the drug as the active ingredient, carriers, additives, and excipients (hereinafter, sometimes abbreviated as excipients) commonly used in the field of formulation. . The formulation excipient used is not particularly limited as long as it is a commonly used excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Abicel PH101, etc., manufactured by Asahi Kasei Corporation), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate , L-cysteine and the like, and preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to about 9% w / w% based on the whole amount of the immediate release preparation. 97 w / w%.
The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60% based on the total amount of the immediate release preparation.

When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (e.g., Aczisol, manufactured by Asahi Kasei Corporation), and crospovidone (e.g., BASF Corporation, Kollidon CL) , Low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), sodium carboxymethyl starch (Exprotab, manufactured by Kimura Sangyo), partially pregelatinized starch (manufactured by Asahi Kasei Corporation) , PCS) and the like, for example, those which disintegrate the granules by absorbing water, swelling upon contact with water, or forming a channel between the excipient and the excipient constituting the core can be used. . These disintegrants can be used alone or in combination of two or more. The blending amount of the disintegrant is appropriately selected depending on the kind and blending amount of the drug to be used, the design of the release preparation, and the like. For example, about 0.05 to about 30 w / w%, preferably, Is from about 0.5 to about 15% w / w.

When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, in addition to the above-mentioned composition, if necessary, the solid preparation may further contain conventional additives. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants (for example, , Polyethylene glycol, magnesium stearate, talc, light silicic anhydride (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and polyoxyethylene) Nonionic surfactants such as sorbitan fatty acid esters and polyoxyethylene castor oil derivatives, etc.), coloring agents (for example, tar dyes, caramel, red pepper, titanium oxide, riboflavins), In addition, bridging agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. are used, and tartaric acid, citric acid, succinic acid, fumaric acid, etc. as stabilizers. May be added.
As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
The immediate-release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation production technique. The mixing is performed by a commonly used method, for example, mixing, kneading, and the like. Specifically, for example, when the rapid-release preparation is formed into particles, a vertical granulator, a universal kneading machine (manufactured by Hata Iron Works), a fluid It can be prepared by mixing using a layer granulator FD-5S (manufactured by Powrex) or the like, and then granulating by wet extrusion granulation, fluidized bed granulation, or the like.
The thus obtained immediate-release preparation and sustained-release preparation can be administered as they are or as appropriate, separately and separately in a usual manner together with excipients, etc., and then administered simultaneously or in combination at an arbitrary administration interval. The preparation may be formulated into a single oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with preparation excipients. Both preparations may be made into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.

[3] Sublingual tablet, buccal or oral rapid disintegrating agent and preparation thereof Sublingual tablet, buccal preparation, oral rapid disintegrating agent may be a solid preparation such as a tablet or a tablet (film) for oral mucosa patch. There may be.
As the sublingual tablet, buccal or intraoral quick disintegrant, a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer may be contained. Further, β-cyclodextrin or a β-cyclodextrin derivative (eg, hydroxypropyl-β-cyclodextrin and the like) may be contained to facilitate absorption and increase the bioavailability.
As the excipient, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like are used. As the lubricant, magnesium stearate, calcium stearate, talc, colloidal silica and the like are used, and particularly, magnesium stearate and colloidal silica are preferable. As the tonicity agent, sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like are used, and mannitol is particularly preferable. As the hydrophilic carrier, a swelling hydrophilic carrier such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, etc. is used. In particular, crystalline cellulose (eg, microcrystalline cellulose, etc.) Is preferred. Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin Water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbic acid palmitate, etc., and hydroxypropyl methylcellulose, polyacrylic acid, alginate. , Gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferred. Particularly, hydroxypropyl methylcellulose is preferable. As the stabilizer, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like are used, and citric acid and ascorbic acid are particularly preferable.

下 The sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a colorant, a sweetener, and a preservative may be mixed. The sublingual tablet, buccal tablet or orally rapidly disintegrating tablet can be obtained by mixing the above components at the same time or with a time interval and then press-molding. In order to obtain an appropriate hardness, the tablet may be produced by humidifying / wetting using a solvent such as water or alcohol as necessary before and after the tableting process, followed by molding and drying.

When molded into a mucoadhesive tablet (film), the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient, and the like are dissolved in a solvent such as water. The resulting solution is cast into a cast film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added. Contains glycols such as polyethylene glycol and propylene glycol to impart appropriate elasticity to the film, and contains bioadhesive polymers (eg, polycarbophil, carbopol) to enhance the adhesion of the film to the mucosal lining of the oral cavity Or you may be. Casting is performed by pouring the solution onto the non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved. The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.

Preferred rapid intraoral disintegrants include solid rapid diffusion administration consisting of a network of the compound or concomitant drug of the present invention and a water-soluble or water-diffusible carrier inactive with the compound or concomitant drug of the present invention. Agent is used. The network can be obtained by sublimating a solvent from the solid composition comprising a solution of the compound of the present invention or the concomitant drug in an appropriate solvent.
The composition of the oral disintegrating agent preferably contains a matrix forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.
Examples of the matrix-forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat, and psyllium seed proteins; gums such as gum arabic, guar gum, agar, and xanthan; polysaccharides Alginic acids; carboxymethyl celluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex. Furthermore, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- It includes amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine.
One or more of the matrix-forming agents can be introduced into a solution or suspension before solidification. Such a matrix-forming agent may be present in addition to the surfactant, or may be present without the surfactant. In addition to forming the matrix, the matrix-forming agent can help maintain the compound of the present invention or the concomitant drug in a diffusion state in the solution or suspension.

Secondary components such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners or taste masking agents may be included in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everard. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, terry and grape flavor and combinations thereof. Suitable pH adjusters include citric, tartaric, phosphoric, hydrochloric and maleic acids. Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
The formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, of the compound of the present invention or the concomitant drug, and are used for about 1 minute to about 60 minutes, preferably about 1 minute. A formulation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (see above, sublingual tablets) , Buccal, etc.), and a rapid disintegrating agent in the oral cavity which disintegrates within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity.

含有 The content of the excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant relative to the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The preparation may further contain additives such as a coloring agent, a sweetening agent and a preservative, if necessary.

The dose of the concomitant drug of the present invention varies depending on the type, age, body weight, symptom, dosage form, administration method, administration period and the like of the compound of the present invention. Usually, about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg per day, as the compound of the present invention and the concomitant drug, respectively. In particular, about 0.1 to about 50 mg / kg, particularly about 1.5 to about 30 mg / kg, is intravenously administered once to several times a day. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range.
The concomitant drug can be used in any amount as long as side effects do not matter. The daily dose as a concomitant drug depends on the degree of symptoms, age, gender, weight, sensitivity difference, timing of administration, interval of administration, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of a mammal by oral administration, for example. Is usually administered 1 to 4 times a day.

When administering the concomitant drug of the present invention, the concomitant drug may be administered at the same time, but after administering the concomitant drug first, the compound of the present invention may be administered, or the compound of the present invention may be administered first. Thereafter, the concomitant drug may be administered. When the administration is carried out with a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form and the administration method. For example, when the concomitant drug is administered first, within 1 minute to 3 days after administration of the concomitant drug, preferably A method of administering a compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is used. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention. A method is used.
As a preferred administration method, for example, about 0.001 to 200 mg / kg of a concomitant drug formed into an oral administration preparation is orally administered, and about 15 minutes later, about 0.1 to about 0.2% of the compound of the present invention formed into an oral administration preparation. 005-100 mg / kg is orally administered as a daily dose.

In addition, the pharmaceutical composition of the present invention or the concomitant drug of the present invention may be used, for example, for (1) surgery, (2) vasopressor chemotherapy using angiotensin II or the like, (3) gene therapy, (4) hyperthermia, (5) freezing. It can also be combined with non-drug therapies such as therapy, (6) laser ablation, (7) radiation therapy.
For example, the use of the pharmaceutical composition of the present invention or the concomitant drug of the present invention before or after surgery or the like, or before or after treatment of a combination of these two or three types, can prevent the onset of resistance and prevent disease-free disease (Disease- Free Survival is prolonged, cancer metastasis or recurrence is suppressed, and effects such as life extension are obtained.
In addition, treatment with the pharmaceutical composition of the present invention or the concomitant drug of the present invention, and supportive treatment [(i) antibiotics against complications of various infectious diseases (eg, β-lactams such as pansporin, macrolides such as clarithromycin, etc.) System)), (ii) high-calorie infusion for improving nutritional disorders, administration of amino acid preparations and multivitamin preparations, (iii) morphine administration for pain relief, (iv) nausea, vomiting, anorexia, diarrhea Administration of drugs that improve side effects such as leukopenia, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver injury, kidney injury, DIC, fever, and (v) administration of drugs for suppressing multidrug resistance of cancer Etc.] can be combined.
Drugs for such purpose, for example, 5-HT3 antagonists such as ondansetron, tropisetron hydrochloride, azasetron, ramosetron, granisetron, dolasetron mesylate, palonosetron, and the like as specific examples of the "antiemetic"; NK1 receptor antagonists such as sendide, CP-99994, CP-100263, CP-122721-1, CP-96345, FK224, RPR100893, NKP608, aprepitant (EMEND (trademark)); NK1 receptor antagonists such as domperidone, mosapride, metoclopramide Gastrointestinal motility enhancers such as -HT4 antagonists; gastrointestinal motility regulants such as trimebutine; phenothiazines such as prochlorperazine maleate, promethazine and thiethylperazine; haloperidol, phenol chlorphthalate Mental stabilizers such as promazine, diazepam, and droperidol; steroids such as dexamethasone, prednisolone, betamethasone, and triamcinolone; and dimethylhydrinic acid, diphenhydramine, hyostine, hyoscine bromide, and tetrabenazine can also be used.
Before or after the above treatment, the pharmaceutical composition of the present invention or the concomitant drug of the present invention is orally administered (including sustained release), intravenous administration (including bolus, infusion, clathrate), subcutaneous It is preferably administered by intramuscular injection (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
The time when the pharmaceutical composition of the present invention or the concomitant drug of the present invention is administered before surgery or the like may be, for example, administration once about 30 minutes to 24 hours before surgery or the like, or surgery. About 3 to 6 months before the administration can be divided into 1 to 3 cycles. As described above, by administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention before surgery or the like, for example, cancer tissue can be reduced, so that surgery or the like can be easily performed.
The time when the pharmaceutical composition of the present invention or the concomitant drug of the present invention is administered after surgery or the like can be repeated about 30 minutes to 24 hours after the surgery or the like, for example, several weeks to 3 months. . Thus, by administering the pharmaceutical composition of the present invention or the concomitant drug of the present invention after surgery or the like, the effects of surgery or the like can be enhanced.

The present inventors have surprisingly found that an androgen receptor agonist suppresses the growth of hormone-resistant cancer, and that an androgen receptor agonist having a nonsteroidal skeleton such as the compound of the present invention is used for prevention and treatment of hormone-resistant cancer. I found it useful.
It is another object of the present invention to provide a method for preventing and treating hormone-resistant cancer by administering an androgen receptor agonist, and an agent for preventing and treating hormone-resistant cancer comprising an androgen receptor agonist.
As the androgen receptor agonist, a steroidal androgen receptor agonist and a non-steroidal androgen receptor agonist can be used.
Steroidal androgen receptor agonists include endogenous androgens such as dehydroepiandrosterone (testosterone), testosterone (testosterone), dihydrotestosterone (DHT: dihydrotestosterone), androstenedione (androstendione), and mestanolone (Mestanolone) and oxymesterone. (Oxymesterone), Methandrostenolone (Methandrostenolone), Fluoxymesterone, Chlorotestosterone acetate, Methenolone acetate (Methenolone acetate), Oxymetholone (Oxymetholone), Stanozolol, Frazabol (Furazabol), Frazabol (Furazabol) Oxandrolone, 19-Nortestosterone, Norrethandrolone, Ethylestreno l), synthetic androgens (anabolic steroids) such as norbolethone and the like can be used.
As the nonsteroidal androgen receptor agonist, LGD-2226 and the like can be used in addition to the compound (I) of the present invention.
As the androgen receptor agonist, the above-mentioned compounds can be used alone or in combination of two or more compounds, and a non-steroidal androgen receptor agonist is particularly preferred.

Cancer includes prostate cancer and the like.
Examples of the hormone-resistant cancer include LHRH derivative-resistant cancer. Preferably, it is an LHRH derivative-resistant prostate cancer, more preferably, an LHRH agonist-resistant cancer, even more preferably, an LHRH agonist-resistant prostate cancer.
Here, as the LHRH derivative and the LHRH agonist, the same compounds as defined above can be used.

As a method for preventing and treating hormone-resistant cancer by administering an androgen receptor agonist,
(A) administering an effective amount of an androgen receptor agonist (particularly a non-steroidal androgen receptor agonist) or a salt thereof to a mammal having hormone-resistant prostate cancer cells,
(B) An effective amount of an LHRH derivative or a salt thereof is administered to a mammal having prostate cancer cells, and after the prostate cancer cells become hormone-resistant, an androgen receptor agonist (particularly, a nonsteroidal androgen receptor agonist) ) Or a salt thereof, in an effective amount;
(C) administering to a mammal having prostate cancer cells an effective amount of an LHRH derivative or a salt thereof in combination with an effective amount of an androgen receptor agonist (particularly a nonsteroidal androgen receptor agonist) or a salt thereof. ,
(D) administering to a mammal having prostate cancer cells an effective amount of an LHRH derivative or a salt thereof in combination with an effective amount of an androgen receptor agonist (particularly a nonsteroidal androgen receptor agonist) or a salt thereof; Performing surgery or radiation therapy after reducing prostate cancer;
(E) 1) When an androgen receptor agonist (particularly a nonsteroidal androgen receptor agonist) or a salt thereof is administered to a hormone-resistant prostate cancer cell for a certain period of time, and 2) After that, the cancer cell becomes hormone-dependent. Administers an effective amount of one or more compounds selected from LHRH derivatives, lyase inhibitors, aromatase inhibitors and antiandrogens or salts thereof, and when the cancer cells become hormone-resistant, androgen receptor agonists ( In particular, administering an effective amount of a non-steroidal androgen receptor agonist) or a salt thereof, and 3) repeating the step 2) as necessary until the therapeutic purpose for cancer is achieved.
(F) 1) androgen receptor agonist (especially non-steroidal androgen receptor agonist) or a salt thereof and 2) one or more compounds selected from LHRH derivatives, lyase inhibitors, aromatase inhibitors and antiandrogens, or a compound thereof Alternately administering an effective amount of the salt (eg, at intervals of 3 months to 5 years) and the like.

Administration of an effective amount of an LHRH derivative, lyase inhibitor, aromatase inhibitor or antiandrogen or a salt thereof for a certain period of time (eg, 3 months to 5 years) may increase the hormone resistance of prostate cancer cells. Thereafter, by administering an effective amount of an androgen receptor agonist (particularly a nonsteroidal androgen receptor agonist) or a salt thereof, the growth of prostate cancer cells can be suppressed or the cancer can be reduced. Continue administration of androgen receptor agonists (especially non-steroidal androgen receptor agonists), and the hormone resistance of prostate cancer cells returns to normal cell levels again, or the prostate cancer begins to grow (tumor volume etc. Increased), switch to administration of one or more compounds or salts thereof selected from LHRH derivatives, lyase inhibitors, aromatase inhibitors and antiandrogens, and then depending on the degree of hormone resistance of such cancers , LHRH derivatives, lyase inhibitors, aromatase inhibitors and antiandrogens, or one or two compounds thereof or a salt thereof (cells having normal hormone resistance of cancer cells [eg LNCaP 104-S cells (Cancer Res, 54, p1566-1573), LNCaP-FGC cells, etc.) or an androgen receptor agonist ( Non-steroidal androgen receptor agonist) or its salt (if the hormone resistance of cancer cells is higher than normal cells [eg LNCaP 104-R2 cells (Cancer Res, 54, p1566-1573), LNCaP-hr cells, etc.) ]) It is possible to perform optimal treatment for prostate cancer by switching between administration and selection.
The timing of switching these administrations can be set as appropriate for each treatment, and is, for example, in a range of 3 months to 5 years, preferably 6 months to 4 years, more preferably 1 year to 3 years, and still more preferably 1 year to 2 years. Can be done with
Therefore, when MAB (Maximum androgen blockade) therapy or the like is performed by administration of an LHRH derivative (for example, an LHRH agonist), a lyase inhibitor, an aromatase inhibitor, or an antiandrogen for a certain period of time, the hormone resistance of prostate cancer increases. It is highly likely that the therapeutic method using the androgen receptor agonist of the present invention (particularly, a nonsteroidal androgen receptor agonist) or a salt thereof in combination is effective. In this case, an androgen receptor agonist (particularly, a non-steroidal androgen receptor agonist) can be administered while the administration of the LHRH derivative is continued, or an androgen receptor agonist (particularly, a non-steroidal androgen (Receptor agonist) administration, and both cases are included in the present invention.
The hormone resistance of cancer can be measured by a method of observing the reactivity of cancer cells to androgens, but can also be estimated by increasing or decreasing tumor markers, physiological indices, tumor volumes, etc. under certain drug administration.

Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.
Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, a Kieselgel 60F ₂₅₄ plate manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As the silica gel for the column, Kieselgel 60F ₂₅₄ (70 to 230 mesh) also manufactured by Merck & Co. was used. The NMR spectrum shows proton NMR, using VARIAN Gemini-200 (200 MHz type spectrometer), VARIAN Mercury-300 (300 MHz) or JEOL JMTCO 400/54 (400 MHz) using tetramethylsilane as an internal standard. It was measured and the δ value was expressed in ppm.
The infrared absorption spectrum (IR) was measured using Paragon 1000 manufactured by PerkinElmer.
The specific rotation ([α] _D ) was measured with a HIGH SENSITIVE POLARIMETER manufactured by HORIBA or a DIP-370 polarimeter manufactured by JASCO.
The abbreviations used in Reference Examples and Examples have the following meanings.
s: Singlet br: Broad (wide)
d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet dt: double triplet m: multiplet J: coupling constant Hz: Hertz Reference Example 1

Sodium iodide (13.9 g) was added to a mixture of copper sulfate (11.4 g) and water (80 mL) at room temperature, and the mixture was stirred at 0 ° C for 10 minutes. Sulfuric acid (3.0 mL) and nitric acid (3.0 mL) were added, and after 5 minutes, 4-nitro-1-naphthylamine (5.00 g) was added. After 5 minutes, a mixture of sodium nitrite (2.57 g) and water (5.0 mL) was added at 0 ° C. for 1 hour. The mixture was extracted with ethyl acetate, and the extract was washed with a sodium thiosulfate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-iodo-4-nitronaphthalene (1.70 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.69-7.80 (2H, m), 7.87 (1H, d, J = 8.1 Hz), 8.22 (1H, d, J = 8.1 Hz), 8.25-8.28 (1H, m), 8.46-8.49 (1H, m).
Reference Example 2

1-iodo-4-nitronaphthalene (1.70 g), sodium trifluoroacetate (3.07 g), copper (I) iodide (2.10 g), 1-methyl-2-pyrrolidone (40 mL) Was stirred at 160 ° C. for 5 hours under an argon atmosphere. After cooling to room temperature, water and ethyl acetate were added, and insolubles were removed by filtration using Celite. The mother liquor was partitioned, and the organic layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-nitro-4- (trifluoromethyl) naphthalene (897 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.74-7.83 (2H, m), 7.96 (1H, d, J = 7.8 Hz), 8.09 (1H, d, J = 7.8 Hz), 8.28-8.32 (1H, m), 8.39-8.45 (1H, m).
Reference Example 3

A mixture of 1-nitro-4- (trifluoromethyl) naphthalene (813 mg), 10% palladium on carbon (50% water content, 717 mg), and methanol (16 mL) was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. Palladium carbon was removed by filtration using Celite. The residue obtained by concentrating the mother liquor was purified by silica gel column chromatography to obtain 4- (trifluoromethyl) -1-naphthylamine (634 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.46 (2H, br.s), 6.71 (1H, d, J = 8.1 Hz), 7.49-7.62 (2H, m), 7.66 (1H, d, J = 8.1 Hz), 7.82-7.85 (1H, m), 8.12-8.16 (1H, m).
Reference example 4

Bromine (75 μL) was added to a mixture of 4-amino-1-naphthonitrile (250 mg) and dichloromethane (10 mL) at room temperature. After stirring for 2.5 hours, sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a sodium thiosulfate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-amino-3-bromo-1-naphthonitrile (301 mg).
¹ H-NMR (CDCl ₃ ) δ: 5.23 (2H, br.s), 7.59 (1H, ddd, J = 8.4, 6.8 and 1.4 Hz), 7.68 (1H , ddd, J = 8.4, 6.8 and 1.4 Hz), 7.93 (1H, s), 8.14-8.18 (1H, m).
IR (KBr) 3366, 2215, 1632 cm ^-1
Reference example 5

Lithium aluminum hydride (278 mg) was added at 0 ° C. to a mixture of (S) -ethyl nipecotinate (1.15 g) and tetrahydrofuran (16 mL). The mixture was stirred for 3 hours while warming to room temperature. Water (0.28 mL), 25% potassium hydroxide solution (0.28 mL), and water (0.84 mL) were sequentially added, and the mixture was stirred for 15 hours. The mother liquor was concentrated after removing the insolubles by filtration using Celite to obtain (S) -3- (hydroxymethyl) piperidine (797 mg).
[α] _D = -11.3 ° (c = 0.730, MeOH).
¹ H-NMR (300 Hz, CDCl ₃ ) δ: 1.07-1.20 (1H, m), 1.40-1.54 (1H, m), 1.61-1.82 (3H, m ), 2.39 (1H, dd, J = 12.0 and 9.9 Hz), 2.54-2.62 (3H, m), 2.95-3.01 (1H, m), 3. 13-3.18 (1H, m), 3.40-3.54 (2H, m).
Reference Example 6

Lithium aluminum hydride (278 mg) was added at 0 ° C. to a mixture of (R) -ethyl nipecotate (1.15 g) and tetrahydrofuran (16 mL). The mixture was stirred for 3 hours while warming to room temperature. Water (0.28 mL), 25% potassium hydroxide solution (0.28 mL), and water (0.84 mL) were sequentially added, and the mixture was stirred for 15 hours. The mother liquor was concentrated after filtering off the insolubles using celite to obtain (R) -3- (hydroxymethyl) piperidine (852 mg).
[α] _D = + 11.7 ° (c = 0.730, MeOH).
¹ H-NMR (300 Hz, CDCl ₃ ) δ: 1.07-1.20 (1H, m), 1.40-1.54 (1H, m), 1.61-1.82 (3H, m ), 2.39 (1H, dd, J = 12.0 and 9.9 Hz), 2.54-2.62 (3H, m), 2.95-3.01 (1H, m), 3. 13-3.18 (1H, m), 3.40-3.54 (2H, m).
Reference Example 7

To a mixture of 4-amino-1-nitronaphthalene (5.00 g) and dichloromethane (120 mL) was added a mixture of bromine (4.25 g) and dichloromethane (10 mL) at room temperature. After stirring for 3 hours, a sodium sulfite solution was added, followed by extraction with ethyl acetate. The extract was washed with a sodium carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-amino-3-bromo-1-nitronaphthalene (1.33 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.55 (2H, br.s), 7.61 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.79 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 8.45-8.48 (1H, m), 8.56 (1H, s), 8.78- 8.81 (1H, m).
Reference Example 8

A mixture of 4-amino-3-bromo-1-nitronaphthalene (500 mg) and acetic acid (3.5 mL) was added to a mixture of sodium nitrite (336 mg) and sulfuric acid (1.7 mL) at 0 ° C. . After stirring for 30 minutes, diethyl ether was added. The resulting precipitate was collected by filtration and washed with 95% ethanol at 0 ° C. The obtained solid was added to water at 0 ° C., and immediately added to a mixture of potassium cyanide (792 mg), copper (I) chloride (463 mg), and water (25 mL). After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 2-bromo-4-nitro-1-naphthonitrile (141 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.84-7.92 (2H, m), 8.32 (1H, s), 8.36-8.47 (2H, m).
IR (KBr) 2236, 1532 cm ^-1
Reference Example 9

A mixture of 2-bromo-4-nitro-1-naphthonitrile (141 mg), iron (134 mg), ammonium chloride (12 mg), ethanol (5.0 mL), and water (1.5 mL) was heated at 90 ° C. For 30 minutes. The reaction was cooled to room temperature and poured into brine. After extraction with ethyl acetate, the extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-amino-2-bromo-1-naphthonitrile (81 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.79 (2H, br.s), 6.93 (1H, s), 7.56 (1H, ddd, J = 8.4, 6.9) and 1.2 Hz), 7.68 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.77 (1H, d, J = 8.4 Hz), 8.15 (1H, d, J = 8.4 Hz).
IR (KBr) 2215, 1572, 1514 cm ^-1
Reference Example 10

To a mixture of 2- (hydroxymethyl) piperidine (10.0 g), 1 M potassium carbonate solution (250 mL) and tetrahydrofuran (150 mL) was added benzyloxycarbonyl chloride (16.3 g) at 0 ° C. The temperature was raised to room temperature and stirred for 24 hours. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 2- (hydroxymethyl) -1-piperidinecarboxylate (15.2 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.70 (6H, m), 2.91-2.99 (1H, m), 3.63 (1H, dt, J = 11) .1 and 6.0 Hz), 3.84 (1H, ddd, J = 11.1, 9.0 and 6.0 Hz), 4.01-4.05 (1H, m), 4.32- 4.39 (2H, m), 5.13 (2H, ABq, J = 12.3 Hz), 7.27-7.38 (5H, m).
Reference Example 11

Chloromethyl methyl ether (80%, 2.42 g) was added to a mixture of benzyl 2- (hydroxymethyl) -1-piperidinecarboxylate (3.00 g), diisopropylethylamine (6.3 mL) and dichloromethane (30 mL). Was added at 0 ° C. The temperature was raised to room temperature and stirred for 14 hours. The reaction solution was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 2- (methoxymethoxymethyl) -1-piperidinecarboxylate (3.43 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-1.78 (6H, m), 2.83-1.92 (1H, m), 3.31 (3H, s), 3. 59 (1H, dd, J = 9.9 and 7.2 Hz), 3.67 (1H, dd, J = 9.9 and 7.2 Hz), 4.06-4.11 (1H, m) , 4.46-4.52 (1H, m), 5.13 (2H, ABq, J = 12.3 Hz), 7.27-7.37 (5H, m).
Reference Example 12

A mixture of benzyl 2- (methoxymethoxymethyl) -1-piperidinecarboxylate (3.23 g), 10% palladium-carbon (50% water content, 1.17 g), and methanol (50 mL) was added under a hydrogen atmosphere at room temperature. For 5 hours. The catalyst was removed by filtration using Celite, and the mother liquor was concentrated to give 2- (methoxymethoxymethyl) piperidine (1.27 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04-1.83 (6H, m), 2.23 (1H, br.s), 2.58-2.81 (2H, m), 3.06-3.12 (1H, m), 3.30-3.39 (1H, m), 3.36 (3H, s), 3.50 (1H, dd, J = 9.2 and 5) .2 Hz), 4.63 (2H, s).
Reference Example 13

Sodium hydride (60% oily, 5.28 g) was washed with hexane and suspended in tetrahydrofuran (150 mL). 5-Hydroxy-2-nitrobenzaldehyde (14.7 g) was added at room temperature and stirred for 20 minutes. Chloromethyl methyl ether (80%, 15.9 g) was added and stirred for 1 hour. The reaction solution was poured into water and extracted with diethyl ether. The extract was washed with 1N sodium hydroxide solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 5-methoxymethoxy-2-nitrobenzaldehyde (16.5 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.49 (3H, s), 5.29 (2H, s), 7.29 (1H, dd, J = 9.0 and 3.0 Hz) , 7.47 (1H, d, J = 3.0 Hz), 8.15 (1H, d, J = 9.0 Hz), 10.46 (1H, s).
Reference Example 14

To a mixture of 5-methoxymethoxy-2-nitrobenzaldehyde (17.0 g) and methanol (150 mL) was added sodium borohydride (910 mg) at room temperature. After stirring for 20 minutes, the mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 5-methoxymethoxy-2-nitrobenzyl alcohol (15.6 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.73 (1H, t, J = 6.6 Hz), 3.49 (3H, s), 4.98 (2H, d, J = 6. 6 Hz), 5.28 (2H, s), 7.05 (1H, dd, J = 8.8 and 3.0 Hz), 7.36 (1H, d, J = 3.0 Hz), 8 .17 (1H, d, J = 8.8 Hz).
Reference Example 15

Methanesulfonyl chloride (3.77 mL) was added at 0 ° C. to a mixture of 5-methoxymethoxy-2-nitrobenzyl alcohol (8.65 g), triethylamine (8.48 mL), and tetrahydrofuran (130 mL). After stirring for 30 minutes, the mixture was concentrated, and acetone (150 mL) and sodium iodide (21.2 g) were added to the obtained residue. After stirring at room temperature for 1 hour, the mixture was concentrated, and the obtained residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated. The obtained residue was subjected to silica gel column chromatography to obtain a pale yellow solid (10.8 g). Sodium hydride (60% oily, 2.00 g) was added to a mixture of diethyl malonate (8.00 g) and dimethyl sulfoxide (80 mL) at room temperature, followed by stirring for 20 minutes. The above pale yellow solid (10.8 g) was added and stirred for 5 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain diethyl 2- [5- (methoxymethoxy) -2-nitrobenzyl] malonate (10.4 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22 (6H, t, J = 7.2 Hz), 3.47 (3H, s), 3.53 (2H, d, J = 7. 8 Hz), 3.88 (1H, t, J = 7.8 Hz), 4.18 (4H, q, J = 7.2 Hz), 5.22 (2H, s), 6.98 (1H , d, J = 2.4 Hz), 7.01 (1H, dd, J = 9.0 and 2.4 Hz), 8.10 (1H, d, J = 9.0 Hz).
Reference Example 16

A mixture of diethyl 2- [5- (methoxymethoxy) -2-nitrobenzyl] malonate (8.68 g), trifluoroacetic acid (30 mL), and dichloromethane (30 mL) was stirred at room temperature for 4 hours. The residue obtained by concentrating the reaction solution was subjected to silica gel column chromatography to obtain a pale yellow oily substance (7.44 g). A mixture of this substance (7.28 g), methyl iodide (3.65 g), potassium carbonate (3.88 g), and N, N-dimethylformamide (80 mL) was stirred at room temperature under an argon atmosphere for 1 hour. . The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain diethyl 2- (5-methoxy-2-nitrobenzyl) malonate (6.30 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22 (6H, t, J = 7.2 Hz), 3.53 (2H, d, J = 7.8 Hz), 3.86 (3H , s), 3.88 (1H, t, J = 7.8 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.17 (2H, q, J = 7.2 Hz) ), 6.83-6.87 (2H, m), 8.10-8.13 (1H, m).
Reference Example 17

A mixture of diethyl 2- (5-methoxy-2-nitrobenzyl) malonate (6.04 g) and hydrochloric acid (80 mL) was stirred at 105 ° C for 21 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 3- (5-methoxy-2-nitrophenyl) propionic acid (3.30 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.80 (2H, t, J = 7.8 Hz), 3.27 (2H, t, J = 7.8 Hz), 3.88 (3H , s), 6.82-6.85 (2H, m), 8.07-8.10 (1H, m).
Reference Example 18

3- (5-Methoxy-2-nitrophenyl) propionic acid (3.23 g) was added to polyphosphoric acid (32 g) at 80 ° C, and the mixture was stirred for 20 minutes. After cooling to room temperature, the mixture was poured into ice water and extracted with ethyl acetate. The resulting insolubles were filtered off using celite, and the organic layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-methoxy-4-nitro-1-indanone (1.60 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.74-2.78 (2H, m), 3.56-3.60 (2H, m), 4.08 (3H, s), 6. 96 (1H, d, J = 9.0 Hz), 8.47 (1H, d, J = 9.0 Hz).
Reference Example 19

A mixture of 7-methoxy-4-nitro-1-indanone (1.60 g) and dichloromethane (50 mL) was cooled to −78 ° C., and a 1M boron tribromide-dichloromethane solution (10.7 mL) was added for 30 minutes. Added in. After stirring for 30 minutes, the temperature was raised to room temperature, and the mixture was stirred for 1.5 hours. The reaction solution was poured into ice water, and the insolubles were removed by filtration using Celite. The organic layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-hydroxy-4-nitro-1-indanone (1.26 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.83-2.87 (2H, m), 3.63-3.67 (2H, m), 6.94 (1H, d, J = 9.0 Hz), 8.42 (1H, d, J = 9.0 Hz), 10.03 (1H, s).
Reference Example 20

Diisopropylamine (2.83 g) was dissolved in anhydrous ether (40 mL), and a 1.6 M n-butyllithium solution (15 mL) was added dropwise at −60 ° C. under cooling and stirring. Then, 1-benzyl-5-methylpyrrolidin-2-one (3.78 g) was dissolved in anhydrous ether (15 mL) and added dropwise while maintaining the temperature at -60 ° C, and then returned to 5 ° C and stirred for 2 hours. The cooling bath was removed and dry carbon dioxide was introduced for 30 minutes. Ice water was added to the mixture, the aqueous layer was separated, and the organic layer was extracted twice with 2N-sodium hydroxide. The aqueous layers were combined, washed with ether, and then made acidic with concentrated hydrochloric acid under cooling. The aqueous layer was extracted twice with ethyl acetate, and the extract was washed with water, dried and concentrated to give 1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid (3.45 g) as a pale yellow oil. Obtained as a product.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21 (1.5 H, d, J = 6.6 Hz), 1.27 (1.5 H, d, J = 5.2 Hz), 1.80 -2.20 (1H, m), 2.39-2.70 (1H, m), 3.40-3.76 (2H, m), 4.00-4.20 (1H, m), 4.98 (1H, dd, J = 4.0 and 15.0Hz), 7.10-7.50 (5H, m).
Reference Example 21

Lithium aluminum hydride (1 mL) in anhydrous tetrahydrofuran (80 mL) was stirred with 1-benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid (3.45 g) dissolved in anhydrous tetrahydrofuran (40 mL). .2 g). After the reaction solution was heated to reflux for 5 hours, water (2 mL), 4N-sodium hydroxide (1.5 mL), and water (5.0 mL) were added dropwise in this order under water cooling. The resulting precipitate was collected by filtration and washed with tetrahydrofuran. After the filtrate was concentrated to dryness, the residue was purified by basic silica gel column chromatography, and cis- (1-benzyl-5-methylpyrrolidin-3-yl) methanol (0.8 g) and trans- (1- Benzyl-5-methylpyrrolidin-3-yl) methanol (0.75 g) was obtained as a colorless oil.
Cis form ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24 (3H, d, J = 5.8 Hz), 1.36-1.52 (1H, m), 2.10-2.60 (4H, m), 2.80 (1H, d, J = 10.0 Hz), 3.01 (1H, d, J = 12.8 Hz), 7.16-7.42 (5H, m).
Trans-form ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.16 (3H, d, J = 6.2 Hz), 1.50-1.82 (2H, m), 1.95 (1H, dd) , J = 8.0 and 8.2 Hz), 2.20-2.40 (2H, m), 3.03 (1H, dd, J = 7.2 and 7.4 Hz), 3.15 (1H, d, J = 12.8 Hz), 3.40-3.64 (2H, m), 4.00 (1H, d, J = 12.8 Hz), 7.12-7.40 (5H, m).
Reference Example 22

Mixture of cis- (1-benzyl-5-methylpyrrolidin-3-yl) methanol (350 mg), methyl alcohol (10 mL), 1N-hydrochloric acid (1.5 mL), 10% palladium on carbon (hydrous 300 mg) Was stirred under a stream of hydrogen for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to obtain cis- (5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg).
¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.30-1.55 (1H, m) 1.42 (3H, d, J = 6.6 Hz), 2.20-2.40 (1H , m), 2.48-2.72 (1H, m), 3.10-3.22 (1H, 3.30-3.48 (1H, m), 3.48-3.80 (3H, m).
Reference Example 23

A mixture of trans- (1-benzyl-5-methylpyrrolidin-3-yl) methanol (350 mg), methyl alcohol (10 mL), 1N hydrochloric acid (1.5 mL), and 10% palladium on carbon (containing 300 mg of water) Was stirred under a stream of hydrogen for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to give trans- (5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg).
¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.39 (3H, d, J = 6.6 Hz), 1.70-1.90 (1H, m), 1.98-2.16 ( 1H, m), 2.54-2.80 (1H, m), 3.02-3.20 (1H, m).
Reference Example 24

To a mixture of nipecotic acid (10.0 g) and a 1N sodium hydroxide solution (77 mL) were added benzyloxycarbonyl chloride (13.2 g) and a 1N sodium hydroxide solution (77 mL) at 0 ° C. The temperature was raised to room temperature and stirred for 14 hours. The reaction was washed with diethyl ether and acidified with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with water, dried and concentrated to give 1-[(benzyloxy) carbonyl] -3-piperidinecarboxylic acid (20.1 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42-1.76 (3H, m), 2.05-2.11 (1H, m), 2.48-2.53 (1H, m), 2 .89-3.44 (2H, m), 3.94-4.00 (1H, m), 4.05-4.64 (1H, m), 5.14 (2H, ABq, J = 12. 6 Hz), 7.27-7.37 (5H, m).
Reference Example 25

1-[(benzyloxy) carbonyl] -3-piperidinecarboxylic acid (20.0 g), iodoethane (14.2 g), potassium carbonate (15.7 g), N, N-dimethylformamide (150 mL) The mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl 1-[(benzyloxy) carbonyl] -3-piperidinecarboxylate (20.0 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.5 Hz), 1.45-1.74 (3H, m), 2.02-2.08 ( 1H, m), 2.42-2.48 (1H, m), 2.85-3.13 (2H, m), 3.95-4.02 (1H, m), 4.12 (2H, m) q, J = 7.5 Hz), 4.18-4.30 (1H, m), 5.12 (2H, s), 7.27-7.36 (5H, m).
Reference Example 26

Tetrahydrofuran (5.0 mL) was added to a 15% potassium hexamethyldisilazide-toluene solution (31 mL) under an argon atmosphere, and the mixture was cooled to -78 ° C. A mixture of ethyl 1-[(benzyloxy) carbonyl] -3-piperidinecarboxylate (4.00 g) and tetrahydrofuran (3.0 mL) was added, and the mixture was stirred for 20 minutes. A mixture of iodomethane (1.3 mL) and tetrahydrofuran (2.0 mL) was added, and the temperature was raised to room temperature. After stirring for 12 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl 1-[(benzyloxy) carbonyl] -3-methyl-3-piperidinecarboxylate (3.76 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.16 to 1.26 (6H, m), 1.40 to 1.49 (1H, m), 1.52-1.65 (2H, m ), 2.03-2.10 (1H, m), 3.11-3.30 (2H, m), 3.52-3.64 (1H, m), 3.98-4.13 (3H , m), 5.12 (2H, s), 7.27-7.37 (5H, m).
Reference Example 27

A mixture of ethyl 1-[(benzyloxy) carbonyl] -3-methyl-3-piperidinecarboxylate (3.57 g), 10% palladium-carbon (50% aqueous, 1.24 g), and methanol (50 mL) was prepared. The mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The catalyst was removed by filtration using Celite, and the mother liquor was concentrated to give ethyl 3-methyl-3-piperidinecarboxylate (1.86 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, s), 1.27 (3H, t, J = 7.2 Hz), 1.33-1.82 (3H, m) , 2.14-2.22 (1H, m), 2.40 (1H, d, J = 12.9 Hz), 2.53-2.62 (1H, m), 2.89-2.95 (1H, m), 3.31 (1H, dd, J = 12.9 and 1.5 Hz), 4.09-4.24 (2H, m).
Reference Example 28

Lithium aluminum hydride (372 mg) was added at 0 ° C to a mixture of ethyl 3-methyl-3-piperidinecarboxylate (1.68 g) and tetrahydrofuran (21 mL). The mixture was stirred for 3 hours while warming to room temperature. Water (0.37 mL), 25% potassium hydroxide solution (0.37 mL), and water (1.10 mL) were sequentially added, and the mixture was stirred for 15 hours. The mother liquor was concentrated after filtering off the insolubles using Celite to obtain 3- (hydroxymethyl) -3-methylpiperidine (1.01 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.81 (3H, s), 1.27-1.37 (1H, m), 1.49-1.68 (2H, m), 1. 80-1.93 (1H, m), 2.54 (1H, d, J = 11.7 Hz), 2.60-2.69 (1H, m), 2.85-3.11 (3H, m m), 3.58 (2H, s).
Reference Example 29

A mixture of 5,6,7,8-tetrahydro-1-naphthol (4.96 g), benzyl bromide (4.3 mL), potassium carbonate (6.94 g), and N, N-dimethylformamide (70 mL) Was stirred at room temperature for 21 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 5- (benzyloxy) -1,2,3,4-tetrahydronaphthalene (7.85 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.84 (4H, m), 2.72-2.78 (4H, m), 5.05 (2H, s), 6. 68-6.72 (2H, m), 7.04 (1H, d, J = 7.8 Hz), 7.27-7.45 (5H, m).
Reference Example 30

A mixture of 5- (benzyloxy) -1,2,3,4-tetrahydronaphthalene (6.30 g), dichloromethyl methyl ether (4.8 mL) and dichloromethane (50 mL) was added to titanium tetrachloride (7.3). mixture) and dichloromethane (5.0 mL) were added dropwise at 0 ° C. over 30 minutes. After stirring for 15 minutes, the reaction was poured into ice water and stirred vigorously for 30 minutes. The organic layer was washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4- (benzyloxy) -5,6,7,8-tetrahydro-1-naphthalenecarbaldehyde (4.86). g) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.77-1.81 (4H, m), 2.74-2.77 (2H, m), 3.18-3.22 (2H, m ), 5.15 (2H, s), 6.86 (1H, d, J = 8.4 Hz), 7.32-7.45 (5H, m), 7.63 (1H, d, J = 8.4 Hz), 10.09 (1H, s).
Reference Example 31

To a mixture of 4- (benzyloxy) -5,6,7,8-tetrahydro-1-naphthalenecarbaldehyde (4.64 g) and dichloromethane (50 mL) was added a 0.5 M boron tribromide-dichloromethane solution (40 mL). ) Was added dropwise at -78 ° C over 30 minutes. After stirring for 40 minutes, the temperature was raised to room temperature. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarbaldehyde (2.73 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.77-1.87 (4H, m), 2.65-2.68 (2H, m), 3.19-3.22 (2H, m ), 5.93 (1H, s), 6.76 (1H, d, J = 8.1 Hz), 7.58 (1H, d, J = 8.1 Hz), 10.08 (1H, s) ).
Reference Example 32

4-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarbaldehyde (2.72 g), hydroxylamine hydrochloride (1.29 g), sodium acetate (1.90 g), ethanol (60 mL) ) And water (30 mL) were stirred at room temperature for 1 hour. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated to give a tan solid. A mixture of this solid and acetic anhydride (50 mL) was stirred at 150 ° C. for 12 hours. The residue obtained by concentrating the reaction product was treated with a silica gel column to obtain a colorless solid. A mixture of this solid, a 1N sodium hydroxide solution (28 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 1.5 hours. Neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give 4-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarbonitrile (2.24 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79-1.88 (4H, m), 2.60-2.64 (2H, m), 2.90-2.94 (2H, m ), 5.65 (1H, s), 6.66 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.4 Hz). IR (KBr) 3256, 2938 , 2228, 1584 cm ^-1
Reference Example 33

To a mixture of 4-hydroxy-5,6,7,8-tetrahydro-1-naphthalenecarbonitrile (300 mg), triethylamine (0.72 mL) and dichloromethane (3.0 mL) was added trifluoromethanesulfonic anhydride (0 mL). (44 mL) and dichloromethane (1.0 mL) were added dropwise at -40 ° C. After stirring for 15 minutes, the mixture was heated to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-cyano-5,6,7,8-tetrahydro-1-naphthalenyltrifluoromethanesulfonate (500 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.81-1.93 (4H, m), 2.81 (2H, t, J = 5.4 Hz), 3.01 (2H, t, J = 5.4 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz).
Reference Example 34

1.6M was added to a mixture of 1-methoxy-3- (methoxymethoxy) benzene (5.00 g), N, N, N ', N',-tetramethylethylenediamine (5.20 mL) and tetrahydrofuran (250 mL). An n-butyllithium-hexane solution (21.4 mL) was added at 0 ° C for 20 minutes. After heating to room temperature and stirring for 2 hours, it was cooled to -78 ° C. Copper (I) iodide (6.82 g) was added, and the mixture was stirred for 2 hours while heating to -40 ° C. The mixture was cooled to -78 ° C, and a mixture of methallyl bromide (3.81 mL) and tetrahydrofuran (20 mL) was added in 30 minutes. The temperature was raised to room temperature and stirred for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with a sodium hydrogen carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-methoxy-3- (methoxymethoxy) -2- (2-methyl-2-propenyl) benzene (4.77 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79 (3H, d, J = 0.6 Hz), 3.37 (2H, s), 3.45 (3H, s), 3.79 (3H, s), 4.44-4.45 (1H, m), 4.65-4.67 (1H, m), 5.15 (2H, s), 6.58 (1H, dd, J = 8.4 and 0.6 Hz), 6.73 (1H, dd, J = 8.4 and 0.6 Hz), 7.12 (1H, t, J = 8.4 Hz).
Reference Example 35

1-methoxy-3- (methoxymethoxy) -2- (2-methyl-2-propenyl) benzene (4.50 g), N, N, N ', N',-tetramethylethylenediamine (3.36 mL), To a mixture of hexane (250 mL) was added a 1.6 M n-butyllithium-hexane solution (13.9 mL) at 0 ° C. for 15 minutes. After heating to room temperature and stirring for 3 hours, the mixture was cooled to -78 ° C. N, N-dimethylformamide (3.92 mL) was added, and the mixture was stirred for 1 hour, further heated to room temperature, and stirred for 13 hours. The reaction solution was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-methoxy-2- (methoxymethoxy) -3- (2-methyl-2-propenyl) benzaldehyde (3.20 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.82 (3H, s), 3.38 (2H, s), 3.58 (3H, s), 3.89 (3H, s), 4 .37 (1H, br.s), 4.71-4.74 (1H, m), 5.05 (2H, s), 6.81 (1H, d, J = 8.7 Hz), 7. 81 (1H, d, J = 8.7 Hz), 10.19 (1H, s).
Reference Example 36

A mixture of 4-methoxy-2- (methoxymethoxy) -3- (2-methyl-2-propenyl) benzaldehyde (3.20 g), 4N hydrochloric acid (50 mL) and 2-propanol (50 mL) was added at room temperature for 18 minutes. Stirred for hours. The reaction solution was concentrated, and the residue was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a sodium hydrogen carbonate solution and a saline solution, dried and concentrated. The obtained residue was treated with a silica gel column to give a yellow substance. A mixture of this substance, Amberlyst 15 (3.00 g) and toluene (30 mL) was vigorously stirred at room temperature for 3 days. The mixture was filtered using celite, and the residue was washed with toluene. The mother liquor and the washings were combined and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (1.72 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53 (6H, s), 2.92 (2H, s), 3.88 (3H, s), 6.47 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 8.4 Hz), 10.05 (1H, s).
Reference Example 37

To a mixture of tert-hexadecanethiol (2.16 g) and hexamethylphosphoric triamide (HMPA) (9.0 mL) was added a 1.6 M n-butyllithium-hexane solution (5.7 mL) at 0 ° C. Added in. After stirring for 20 minutes, the mixture was added to a mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (860 mg) and HMPA (20 mL) at the same temperature. The temperature was raised to room temperature and stirred for 13 hours. The reaction solution was poured into a 1N sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (860 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55 (6H, s), 2.96 (2H, s), 6.39 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 10.01 (1H, s).
Reference Example 38

4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg), hydroxylamine hydrochloride (217 mg), sodium acetate (320 mg), ethanol (10 mL) And a mixture of water (5.0 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated to give a brown oil. A mixture of this substance and acetic anhydride (7.5 mL) was stirred at 150 ° C. for 12 hours. The residue obtained by concentrating the reaction product was treated with a silica gel column to obtain a pale yellow oily substance. A mixture of this substance, a 1N sodium hydroxide solution (4.7 mL) and tetrahydrofuran (9.0 mL) was stirred at room temperature for 2.5 hours. Neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give 4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonitrile (431 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54 (6H, s), 2.98 (2H, s), 5.57 (1H, br.s), 6.34 (1H, d, J = 8.7 Hz), 7.22 (1H, d, J = 8.7 Hz).
IR (KBr) 2230, 1609, 1453 cm ^-1
Reference Example 39

To a mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonitrile (250 mg), triethylamine (552 μL) and dichloromethane (5.0 mL) was added trifluoromethanesulfonic anhydride. (333 μL) and dichloromethane (2.0 mL) were added dropwise at −40 ° C. After stirring for 15 minutes, the mixture was heated to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-cyano-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yltrifluoromethanesulfonate (405 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58 (6H, s), 3.17 (2H, s), 6.80 (1H, d, J = 8.7 Hz), 7.42 (1H, d, J = 8.7 Hz).
Reference Example 40

Toluene (4 mL) and tetrahydrofuran (1 mL) were added and dissolved in 4-bromo-1-naphthonitrile (0.232 g) and triisopropyl borate (2.8 mL), and the mixture was cooled and stirred at -70 ° C. Then, 1.6 M n-butyllithium (hexane solution, 0.75 mL) was added, and the mixture was kept at -70 ° C and stirred for 1.5 hours. After the temperature was lowered to -50 ° C, 3N-hydrochloric acid (2 mL) was added, and the temperature was raised to room temperature. Ethyl acetate was added, extracted, washed with water, dried and concentrated. Acetonitrile was added to the obtained residue for crystallization to obtain 4-cyano-1-naphthylboronic acid (0.102 g).
¹ H-NMR (200 MHz, CDCl ₃ + CD ₃ OD) δ: 7.50-8.00 (5H, m), 8.20-8.40 (1H, m).
Reference Example 41

A mixture of ethyl 3- (2-methyl-2-oxiranyl) butyrate (400 mg), benzylamine (2.76 mL), and ethanol (4.0 mL) was stirred at 90 ° C. for 14 hours. After cooling to room temperature, the residue obtained by concentration was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with 1N hydrochloric acid and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-benzyl-5-hydroxy-5-methyl-2-piperidinone (120 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, s), 1.83-1.89 (2H, m), 2.47 (1H, ddd, J = 18.0, 6) 2.0 and 4.2 Hz), 2.72 (1H, ddd, J = 18.0, 10.2 and 7.5 Hz), 3.05-3.09 (1H, m), 3.20 ( 1H, d, J = 12.6 Hz), 4.59 (2H, ABq, J = 14.4 Hz), 7.23-7.35 (5H, m).
Reference Example 42

To a mixture of methanesulfonamide (1.96 g), triethylamine (3.2 mL), 4- (dimethylamino) pyridine (252 mg) and dichloromethane (30 mL) was added ditertbutyl dicarbonate (5.17 g). A mixture of dichloromethane (40 mL) was added at room temperature for 30 minutes. After stirring for 2 hours, the mixture was concentrated, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl methylsulfonylcarbamate (2.44 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.52 (9H, s), 3.28 (3H, s).
Reference Example 43

To a mixture of 2-bromo-5-methoxyphenol (22.0 g), 1,8-diazabicyclo [2,2,2] octane (24.3 g) and N, N-dimethylformamide (120 mL) was added N, N-Dimethylthiocarbamoyl chloride (26.8 g) was added at room temperature for 30 minutes. After stirring for 13 hours, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained solid was washed with methanol to obtain O- (2-bromo-5-methoxyphenyl) dimethylthiocarbamate (26.6 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.39 (3H, s), 3.47 (3H, s), 3.79 (3H, s), 6.69-6.72 (2H, m), 7.43-7.47 (1H, m).
Reference Example 44

A mixture of O- (2-bromo-5-methoxyphenyl) dimethylthiocarbamate (26.4 g) and diethylaniline (66 mL) was stirred at 240 ° C for 4 hours. After cooling to room temperature, the mixture was poured into 1N hydrochloric acid under ice cooling and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give S- (2-bromo-5-methoxyphenyl) dimethylthiocarbamate (22.2 g). ) Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.06 (3H, br.s), 3.11 (3H, br.s), 3.79 (3H, s), 6.82 (1H, dd, J = 8.7 and 3.0 Hz), 7.19 (1H, d, J = 3.0 Hz), 7.55 (1H, d, J = 8.7 Hz).
Reference Example 45

To a mixture of potassium hydroxide (85%, 17.1 g) and methanol (70 mL) was added S- (2-bromo-5-methoxyphenyl) dimethylthiocarbamate (10.0 g), and the mixture was heated to 85 ° C under an argon atmosphere. For 2 hours. After cooling to room temperature, 6N hydrochloric acid was added to the mixture under ice cooling to make it acidic, and the mixture was extracted with hexane. After washing with hexane, drying and concentration gave a colorless oil. A mixture of this substance, potassium carbonate (9.53 g) and N, N-dimethylformamide (80 mL) was stirred at room temperature for 20 minutes under an argon atmosphere. 1-Brom-2,2-dimethoxyethane (10.5 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with hexane. The extract was washed with water, dried and concentrated. The residue obtained was purified by silica gel column chromatography to give 1-bromo-2-[(2,2-dimethoxyethyl) sulfanyl] -4-methoxybenzene (9.37 g). ) Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.12 (2H, d, J = 5.7 Hz), 3.39 (6H, s), 3.78 (3H, s), 4.59 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 8.7 and 3.0 Hz), 6.90 (1H, d, J = 3.0 Hz), 7 .41 (1H, d, J = 8.7 Hz).
Reference Example 46

A mixture of 1-bromo-2-[(2,2-dimethoxyethyl) sulfanyl] -4-methoxybenzene (9.37 g), polyphosphoric acid (18.7 g) and xylene (200 mL) was added at 150 ° C for 1 hour. Stirred for hours. After cooling to room temperature, insolubles were removed by decanting, and the supernatant was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-bromo-4-methoxy-1-benzothiophene (7.07 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.95 (3H, s), 6.66 (1H, d, J = 8.1 Hz), 7.38-7.41 (2H, m) , 7.58 (1H, d, J = 5.4 Hz).
Reference Example 47

7-bromo-4-methoxy-1-benzothiophene (3.00 g), zinc cyanide (1.09 g), tetrakis (triphenylphosphine) palladium (0) (1.43 g), N, N- A mixture of dimethylformamide (75 mL) was stirred at 100 ° C. under an argon atmosphere for 12 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The insoluble matter was removed by filtration using Celite, and the organic layer was washed with brine. The residue obtained by drying and concentrating was purified by silica gel column chromatography to obtain 4-methoxy-1-benzothiophene-7-carbonitrile (2.25 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.02 (3H, s), 6.79 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 5. 4 Hz), 7.53 (1H, d, J = 5.4 Hz), 7.66 (1H, d, J = 8.1 Hz).
IR (KBr) 2215, 1561 cm ^-1
Reference Example 48

To a mixture of 2-methyl-2-pentadecanethiol (6.12 g) and hexamethylphosphoric triamide (25 mL) was added a 1.6 M n-butyllithium-hexane solution (15.5 mL) at 0 ° C. After stirring for 20 minutes, the mixture was added to a mixture of 4-methoxy-1-benzothiophene-7-carbonitrile (2.24 g) and hexamethylphosphoric triamide (50 mL) at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction solution was poured into 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain 4-hydroxy-1-benzothiophene-7-carbonitrile (1.93 g). .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.88 (1 H, d, J = 8.4 Hz), 7.57 (1 H, d, J = 5.4 Hz), 7.76 (1 H , d, J = 8.4 Hz), 7.78-7.81 (1H, m), 11.32 (1H, br.s).
IR (KBr) 3326, 2220, 1566 cm ^-1
Reference Example 49

To a mixture of 4-hydroxy-1-benzothiophene-7-carbonitrile (1.43 g), triethylamine (3.4 mL) and dichloromethane (25 mL) was added trifluoromethanesulfonic anhydride (2.1 mL) and dichloromethane. (13 mL) was added dropwise at -50 ° C. After stirring for 15 minutes and concentration, the residue obtained was purified by silica gel column chromatography to obtain 7-cyano-1-benzothien-4-yltrifluoromethanesulfonate (2.36 g).
^{1 H-NMR (300 MHz,} CDCl 3) δ: 7.43 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 5.4 Hz), 7.77 (1H , dd, J = 5.4 and 0.6 Hz), 7.79 (1H, dd, J = 8.4 and 0.6 Hz).
IR (KBr) 2226, 1427, 1221, 1140 cm ^-1
Reference example 50

To a mixture of 2-bromo-5-fluorophenol (19.4 g), 1,8-diazabicyclo [2,2,2] octane (22.8 g) and N, N-dimethylformamide (130 mL) was added N, N-Dimethylthiocarbamoyl chloride (25.1 g) was added at room temperature for 30 minutes. After stirring for 4 hours, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained solid was washed with methanol to obtain O- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (27.1 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.39 (3H, s), 3.47 (3H, s), 6.86-6.95 (2H, m), 7.51-7. 56 (2H, m).
Reference Example 51

A mixture of O- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (21.9 g) and diethylaniline (60 mL) was stirred at 240 ° C for 4 hours. After cooling to room temperature, the mixture was poured into 1N hydrochloric acid under ice cooling and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give S- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (21.2 g). ) Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.06 (3H, br.s), 3.11 (3H, br.s), 6.98 (1H, ddd, J = 9.0, 7) .8 and 3.0 Hz), 7.38 (1H, dd, J = 8.4 and 3.0 Hz), 7.62 (1H, dd, J = 9.0 and 5.4 Hz).
Reference Example 52

S- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (20.0 g) was added to a mixture of potassium hydroxide (85%, 35.6 g) and methanol (150 mL), and the mixture was heated to 85 ° C. under an argon atmosphere. For 2 hours. After cooling to room temperature, 6N hydrochloric acid was added to the mixture under ice cooling to make it acidic, and the mixture was extracted with hexane. After washing with hexane, drying and concentration gave a pale yellow oil. A mixture of this substance, potassium carbonate (19.9 g) and N, N-dimethylformamide (160 mL) was stirred at room temperature for 20 minutes under an argon atmosphere. 1-Brom-2,2-dimethoxyethane (21.9 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with hexane. The extract was washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 1-bromo-2-[(2,2-dimethoxyethyl) sulfanyl] -4-fluorobenzene (19.9 g). ) Got.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.12 (2H, d, J = 5.4 Hz), 3.40 (6H, s), 4.60 (1H, t, J = 5. 4 Hz), 6.75 (1H, ddd, J = 8.4, 7.8 and 3.0 Hz), 7.03 (1H, dd, J = 9.3 and 3.0 Hz), 7. 43 (1H, dd, J = 8.4 and 5.4 Hz).
Reference Example 53

A mixture of 1-bromo-2-[(2,2-dimethoxyethyl) sulfanyl] -4-fluorobenzene (19.9 g), polyphosphoric acid (33.0 g) and xylene (400 mL) was added at 150 ° C. for 5 hours. Stirred for hours. After cooling to room temperature, insolubles were removed by decanting, and the supernatant was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-bromo-4-fluoro-1-benzothiophene (9.52 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.95 (1H, dd, J = 9.6 and 8.4 Hz), 7.42 (1H, ddd, J = 8.4, 4.2) and 0.3 Hz), 7.50 (1H, dt, J = 5.4 and 0.3 Hz), 7.54 (1H, d, J = 5.4 Hz).
Reference Example 54

7-bromo-4-fluoro-1-benzothiophene (4.50 g), zinc cyanide (1.37 g), tetrakis (triphenylphosphine) palladium (0) (2.25 g), N, N- A mixture of dimethylformamide (120 mL) was stirred at 100 ° C. under an argon atmosphere for 2.5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The insoluble matter was removed by filtration using Celite, and the organic layer was washed with brine. The residue obtained by drying and concentrating was purified by silica gel column chromatography to obtain 4-fluoro-1-benzothiophene-7-carbonitrile (3.30 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.12 (1H, dd, J = 9.6 and 8.4 Hz), 7.52 (1H, dt, J = 5.4 Hz), 7 .60 (1H, d, J = 5.4 Hz), 7.69 (1H, dd, J = 8.4 and 4.8 Hz).
IR (KBr) 2224, 1568, 1464, 1366, 1248 cm ^-1
Reference Example 55

2-bromo-5-fluorophenol (14.6 g), 1-bromo-2,2-dimethoxyethane (32.2 g), potassium carbonate (21.1 g), N, N-dimethylformamide (200 mL) )) Was stirred at 100 ° C. for 5 hours. After cooling to room temperature, the reaction was poured into water and extracted with hexane. The extract was washed with 1N sodium hydroxide and brine. The residue obtained after drying and concentration was purified by silica gel column chromatography to obtain 1-bromo-2- (2,2-dimethoxyethoxy) -4-fluorobenzene (20.6 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.51 (6H, s), 4.02 (2H, d, J = 5.1 Hz), 4.74 (1H, t, J = 5. 1 Hz), 6.56-6.67 (2H, m), 7.46 (1H, dd, J = 8.4 and 6.0 Hz).
Reference Example 56

A mixture of 1-bromo-2- (2,2-dimethoxyethoxy) -4-fluorobenzene (20.6 g), polyphosphoric acid (45.1 g) and xylene (500 mL) was added at 150 ° C. for 7.5 hours. Stirred. After cooling to room temperature, insolubles were removed by decanting, and the supernatant was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7-bromo-4-fluoro-1-benzofuran (5.30 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.86 (1H, d, J = 8.7 Hz), 6.93 (1H, d, J = 2.1 Hz), 7.38 (1H , dd, J = 8.7 and 4.5 Hz), 7.66 (1H, d, J = 2.1 Hz).
Reference Example 57

7-bromo-4-fluoro-1-benzofuran (5.30 g), zinc cyanide (1.74 g), tetrakis (triphenylphosphine) palladium (0) (2.85 g), N, N-dimethyl A mixture of formamide (160 mL) was stirred at 100 ° C. under an argon atmosphere for 2.5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The insoluble matter was removed by filtration using Celite, and the organic layer was washed with brine. The residue obtained by drying and concentrating was purified by silica gel column chromatography to obtain 4-fluoro-1-benzofuran-7-carbonitrile (3.63 g).
^{1 H-NMR (300 MHz,} CDCl 3) δ: 6.96 (1H, d, J = 2.4 Hz), 7.03 (1H, d, J = 8.7 Hz), 7.60 (1H , dd, J = 8.7 and 5.1 Hz), 7.74 (1H, d, J = 2.4 Hz).
IR (KBr) 2232, 1497, 1271 cm ^-1
Reference Example 58

A mixture of tert-butyl hydroxycarbamate (5.00 g), 1,4-dibromobutane (3.18 g), potassium hydroxide (85%, 2.92 g), and ethanol (30 mL) was heated under reflux for 7 hours. . After filtering off the insolubles, the residue was washed with ethanol, and the mother liquor was concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 1,2-oxadinane-2-carboxylate (2.24 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.50 (9H, s), 1.64-1.82 (4H, m), 3.60-3.66 (2H, m), 3. 92-3.97 (2H, m).
Reference Example 59

4N Hydrogen chloride-ethyl acetate (7.5 mL) was added to tertbutyl 1,2-oxadinane-2-carboxylate (2.18 g), and the mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration and washed with diethyl ether to give 1,2-oxadinane hydrochloride (1.24 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.70-1.77 (2H, m), 1.83-1.90 (2H, m), 3.25-3.29 (2H , m), 4.20-4.24 (2H, m).
Reference Example 60

To a mixture of isonipecotic acid (10.0 g) and 1N sodium hydroxide (77 mL) was added benzyloxycarbonyl chloride (13.2 g) and 1N sodium hydroxide (77 mL) simultaneously at 0 ° C. over 10 minutes. After stirring for 14 hours, the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give 1-[(benzyloxy) carbonyl] -4-piperidinecarboxylic acid (18.3 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.72 (2H, m), 1.91-1.95 (2H, m), 2.46-2.56 (1H, m ), 2.91-2.99 (2H, m), 4.04-4.14 (2H, m), 5.12 (2H, s), 7.27-7.36 (5H, m).
Reference Example 61

1-[(benzyloxy) carbonyl] -4-piperidinecarboxylic acid (18.3 g), ethyl iodide (12.9 g), potassium carbonate (14.3 g), N, N-dimethylformamide (160 mL) )) Was stirred at room temperature for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 1-benzyl 4-ethyl 1,4-piperidinedicarboxylate (16.5 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.5 Hz), 1.58-1.71 (2H, m), 1.84-1.94 ( 2H, m), 2.46 (1H, tt, J = 8.1 and 3.9 Hz), 2.88-2.96 (2H, m), 4.04-4.16 (2H, m) , 4.14 (2H, q, J = 7.5 Hz), 7.30-7.39 (5H, m).
Reference Example 62

In a mixture of potassium hexamethyldisilazide (20% toluene solution, 23.1 mL) and tetrahydrofuran (5 mL), 1,4-piperidinedicarboxylic acid-1-benzyl 4-ethyl (4.00 g) and tetrahydrofuran (4 mL) at −78 ° C. and stirred for 20 minutes. A mixture of methyl iodide (2.92 g) and tetrahydrofuran (15 mL) was added, and the mixture was stirred for 10 minutes, heated to room temperature, and stirred for 19 hours. . The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4-benzyl-1,4-piperidinedicarboxylate-1-benzyl 4-ethyl (3.66 g). Was.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.20 (3H, s), 1.26 (3H, t, J = 7.2 Hz), 1.32-1.41 (2H, m) , 2.06-2.10 (2H, m), 3.01-3.09 (2H, m), 3.84-3.88 (2H, m), 4.16 (2H, q, J = 7.2 Hz), 5.11 (2H, s), 7.27-7.35 (5H, m).
Reference Example 63

A mixture of 1-benzyl 4-ethyl 4-methyl-1,4-piperidinedicarboxylate (3.60 g), 10% palladium on carbon (50% water content, 1.25 g) and methanol (50 mL) was placed in a hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The palladium carbon was removed by filtration using Celite and washed with methanol. The mother liquor was concentrated to give ethyl 4-methyl-4-piperidinedicarboxylate (1.76 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19 (3H, s), 1.26 (3H, t, J = 7.2 Hz), 1.39 (2H, ddd, J = 13. 5, 10.2 and 3.9 Hz), 2.06-2.12 (2H, m), 2.65-2.78 (3H, m), 2.94 (2H, dt, J = 12. 9 and 3.9 Hz), 4.19 (2H, q, J = 7.2 Hz).
Reference Example 64

Lithium aluminum hydride (376 mg) was added to a mixture of ethyl 4-methyl-4-piperidinedicarboxylate (1.70 g) and tetrahydrofuran (22 mL) at 0 ° C., and the mixture was stirred for 4 hours. Water (0.4 mL), 25% potassium hydroxide solution (0.4 mL), and water (1.2 mL) were sequentially added, and the mixture was stirred for 3 hours. The mother liquor was concentrated after removing the insoluble matter by filtration using Celite to obtain (4-methyl-4-piperidinyl) methanol (1.28 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98 (3H, s), 1.24-1.34 (2H, m), 1.35-1.49 (2H, m), 1. 75 (2H, br.s), 2.75-2.90 (4H, m), 3.36 (2H, s).
Reference Example 65

Sodium cyanotrihydroborate (4.00 g) was added to a mixture of ethyl isonipecotate (10.0 g), benzaldehyde (6.75 g) and ethanol (100 mL) at room temperature. After stirring for 3 hours, the mixture was concentrated and partitioned with hexane and water. The organic layer was extracted with 1N hydrochloric acid, the aqueous layer was made alkaline with sodium hydrogen carbonate, and then extracted with hexane. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain ethyl 1-benzyl-4-piperidinecarboxylate (2.34 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 1.68-1.91 (5H, m), 2.02 (2H, td, J = 11.4 and 2.7 Hz), 2.27 (2H, tt, J = 10.8 and 4.2 Hz), 2.82-2.88 (2H, m), 3.49 (2H , s), 4.12 (2H, q, J = 7.2 Hz), 7.25-7.38 (5H, m).
Reference Example 66

To a mixture of ethyl 1-benzyl-4-piperidinecarboxylate and tetrahydrofuran (50 mL) was added a 1 M solution of methylmagnesium bromide-tetrahydrofuran (1.2 mL) at -78 ° C for 1 hour. After stirring for 6 hours, the temperature was raised to room temperature, and the mixture was stirred for 14 hours. The reaction was poured into ammonium chloride solution and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 2- (1-benzyl-4-piperidinyl) -2-propanol (820 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.16-1.45 (4H, m), 1.17 (6H, s), 1.68-1.73 (2H, m), 1. 87-1.95 (2H, m), 2.94-2.99 (2H, m), 3.49 (2H, s), 7.24-7.32 (5H, m).
Reference Example 67

To a mixture of Boc L-prolinol (2.10 g) and dimethyl sulfoxide (14 mL) was added triethylamine (5.1 mL) and pyridine sulfur trioxide (5.81 g) at 10 ° C. After stirring for 2.5 hours, the mixture was poured into ice water and extracted with dichloromethane. The extract was washed with a 50% citric acid solution, a sodium hydrogen carbonate solution and water, dried and concentrated to obtain a pale yellow oily substance. A mixture of sodium hydride (60% oily, 416 mg) and dimethylsulfoxide (10 mL) was stirred at 55 ° C. for 1 hour. A mixture of methyltriphenylphosphonium bromide (3.72 g) and dimethylsulfoxide (15 mL) was added, and the mixture was stirred for 45 minutes. After cooling to room temperature, the mixture was added to a mixture of the above oily substance and dimethyl sulfoxide (30 mL), and the mixture was stirred for 15 hours. The reaction was poured into water and extracted with dichloromethane. The extract was washed with water, dried and concentrated, and the residue obtained was purified by silica gel column chromatography to obtain tert-butyl (2S) -2-vinyl-1-pyrrolidinecarboxylate (490 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.64-2.10 (4H, m), 3.34-3.45 (2H, m), 4. 20-4.38 (1H, m), 5.03-5.06 (2H, m), 5.66-5.80 (1H, m).
Reference Example 68

A mixture of (2S) -2-tert-butyl-2-vinyl-1-pyrrolidinecarboxylate (200 mg), 10% palladium on carbon (50% water, 216 mg), and methanol (3.0 mL) was added at room temperature under a hydrogen atmosphere for 20 hours. Stirred. The palladium carbon was removed by filtration using Celite and washed with methanol. The mother liquor was concentrated to give tert-butyl (2R) -2-ethyl-1-pyrrolidinecarboxylate (170 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (3H, t, J = 7.5 Hz), 1.25-1.37 (1H, m), 1.46 (9H, s) , 1.59-1.99 (5H, m), 3.26-3.74 (3H, m).
Reference Example 69

To a mixture of ethyl diethoxyphosphoryl acetate (2.69 g), lithium chloride (509 mg), diisopropylethylamine (1.74 mL) and acetonitrile (100 mL) was added benzyl 4-formylpiperidine-1-carboxylate (2.47). g) was added and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried and concentrated, and the residue obtained was purified by silica gel column chromatography to give 4-[(1E) -3-ethoxy-3-oxoprop-1-en-1-yl. ] Benzyl piperidine-1-carboxylate (2.45 g) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 1.31-1.42 (2H, m), 1.73-1.77 ( 2H, m), 2.25-2.37 (1H, m), 2.85 (2H, t, J = 12.0 Hz), 4.16-4.24 (4H, m), 5.80 (1H, dd, J = 15.9 and 1.8 Hz), 6.88 (1H, dd, J = 15.9 and 6.6 Hz), 7.29-7.40 (5H, m).
Reference example 70

Benzyl 4-[(1E) -3-ethoxy-3-oxo-1-en-1-yl] piperidine-1-carboxylate (2.38 g), 10% palladium on carbon (50% aqueous, 1.60 g) ) And ethanol (50 mL) were stirred at room temperature under a hydrogen atmosphere for 2 days. The palladium carbon was removed by filtration using Celite, and washed with ethanol. The mother liquor was concentrated to give ethyl 3- (4-piperidinyl) butyrate (1.09 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03-1.17 (2H, m), 1.26 (3H, t, J = 7.2 Hz), 1.23-1.43 ( 2H, m), 1.57 (2H, dt, J = 15.0 and 7.5 Hz), 1.65-1.69 (2H, m), 2.31 (2H, t, J = 7. 5 Hz), 2.57 (1H, td, J = 12.0 and 2.7 Hz), 3.04-3.08 (2H, m), 4.12 (2H, q, J = 7.2 Hz).
Reference Example 71

To a mixture of Boc D-prolinol (5.10 g) and dimethylsulfoxide (35 mL) was added triethylamine (12.1 mL) and pyridine sulfur trioxide (13.8 g) at 10 ° C. After stirring for 2.5 hours, the mixture was poured into ice water and extracted with dichloromethane. The extract was washed with a 50% citric acid solution, a sodium hydrogen carbonate solution and water, dried and concentrated to give a pale yellow oil (2.30 g). A mixture of sodium hydride (60% oily, 402 mg) and dimethylsulfoxide (10 mL) was stirred at 55 ° C. for 1 hour. A mixture of methyltriphenylphosphonium bromide (3.59 g) and dimethylsulfoxide (15 mL) was added, and the mixture was stirred for 45 minutes. After cooling to room temperature, the mixture was added to a mixture of the above oily substance (2.00 g) and dimethyl sulfoxide (30 mL), and the mixture was stirred for 15 hours. The reaction was poured into water and extracted with dichloromethane. The extract was washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain tert-butyl (2R) -2-vinyl-1-pyrrolidinecarboxylate (191 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.64-2.10 (4H, m), 3.34-3.45 (2H, m), 4. 20-4.38 (1H, m), 5.03-5.06 (2H, m), 5.66-5.80 (1H, m).
Reference Example 72

A mixture of tert-butyl (2R) -2-vinyl-1-pyrrolidinecarboxylate (110 mg), 10% palladium-carbon (50% water-containing, 119 mg), and methanol (3.0 mL) was added under a hydrogen atmosphere at room temperature for 20 hours. Stirred. The palladium carbon was removed by filtration using Celite and washed with methanol. The mother liquor was concentrated to give tert-butyl (2S) -2-ethyl-1-pyrrolidinecarboxylate (80 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (3H, t, J = 7.5 Hz), 1.25-1.37 (1H, m), 1.46 (9H, s) , 1.59-1.99 (5H, m), 3.26-3.74 (3H, m).
Reference Example 73

To a mixture of 1-bromo-4-fluoronaphthalene (1.57 g) and tetrahydrofuran (30 mL) was added a 1.6 M n-butyllithium-hexane solution (4.8 mL) at -78 ° C. After stirring for 20 minutes, the mixture was added to a mixture of ethyl trifluoroacetate (1.7 mL) and tetrahydrofuran (20 mL) at the same temperature. After stirring for 20 minutes, the mixture was stirred for 30 minutes while heating to room temperature. The reaction was poured into brine and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 2,2,2-trifluoro-1- (4-fluoro-1-naphthyl) ethanone ( 865 mg).
^{1 H-NMR (300 MHz,} CDCl 3) δ: 7.25 (1H, dd, J = 9.6 and 8.4 Hz), 7.69 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.79 (1H, ddd, J = 8.4, 6.9 and 1.8 Hz), 8.21-8.27 (2H, m), 8.95-8. 99 (1H, m).
Reference Example 74

To a mixture of 1-fluoronaphthalene (2.50 g), aluminum chloride (2.74 g) and dichloromethane (13 mL) was added a mixture of acetyl chloride (1.22 mL) and dichloromethane (2.0 mL) at 0 ° C. Added in 15 minutes. The temperature was raised to room temperature and stirred for 4 hours. The reaction was poured into water and extracted with hexane. The extract was washed with sodium carbonate solution and brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 1- (4-fluoro-1-naphthyl) ethanone (1.20 g). Obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.73 (3H, s), 7.15 (1H, dd, J = 9.9 and 8.1 Hz), 7.56-7.69 ( 2H, m), 7.96 (1H, dd, J = 8.1 and 5.4 Hz), 8.13-8.16 (1H, m), 8.86-8.90 (1H, m) .
Reference example 75

Hydrazine monohydrate (0.45 mL) was added to a mixture of 4-fluoro-1-naphthonitrile (865 mg) and N, N-dimethylacetamide (5.0 mL), and the mixture was stirred at 30 ° C for 40 minutes. Water was added to the reaction product, and the resulting precipitate was collected by filtration. After washing with water, the residue was dissolved in ethyl acetate, dried and concentrated to obtain 4-hydrazino-1-naphthonitrile (530 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 4.47 (2H, br.s), 7.05 (1H, d, J = 8.4 Hz), 7.49 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.66 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.89-7.92 (1H, m), 8.23-8.26 (1H, m), 8.59 (1H, br.s).
IR (KBr) 3312, 2205, 1578 cm ^-1
Reference Example 76

To a mixture of 2-bromo-5-fluorophenol (10.3 g), potassium carbonate (11.2 g) and N, N-dimethylformamide (60 mL) was added propargyl bromide (8.64 g) and N, N- A mixture of dimethylformamide (6 mL) was added at room temperature in 10 minutes. After stirring for 2 hours, the mixture was poured into water and extracted with hexane. The extract was washed with water, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 1-bromo-4-fluoro-2- (2-propynyloxy) benzene (9.27 g).
^{1 H-NMR (300 MHz,} CDCl 3) δ: 2.58 (1H, t, J = 2.4 Hz), 4.77 (2H, d, J = 2.4 Hz), 6.64 (1H , ddd, J = 8.7, 7.8 and 2.7 Hz), 6.84 (1H, dd, J = 10.5 and 2.7 Hz), 7.49 (1H, dd, J = 8) .7 and 6.3 Hz).
Reference Example 77

A mixture of 1-bromo-4-fluoro-2- (2-propynyloxy) benzene (9.00 g), cesium carbonate (8.36 g), and diethylaniline (60 mL) was stirred at 240 ° C. for 2.5 hours. did. It was cooled to room temperature, diluted with diethyl ether, and washed with 1N hydrochloric acid and brine. The residue obtained by drying and concentrating was purified by silica gel column chromatography to obtain 7-bromo-4-fluoro-2-methyl-1-benzofuran (7.06 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.50 (3H, d, J = 0.9 Hz), 6.52 (1H, q, J = 0.9 Hz), 6.79 (1H , t, J = 8.7 Hz), 7.26 (1H, dd, J = 8.7 and 4.8 Hz).
Reference Example 78

7-bromo-4-fluoro-2-methyl-1-benzofuran (4.50 g), zinc cyanide (1.38 g), tetrakis (triphenylphosphine) palladium (0) (2.27 g), N , N-dimethylformamide (120 mL) was stirred at 100 ° C. for 2.5 hours under an argon atmosphere. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The insoluble matter was removed by filtration using Celite, and the organic layer was washed with brine. The residue obtained by drying and concentration was purified by silica gel column chromatography to obtain 4-fluoro-2-methyl-1-benzofuran-7-carbonitrile (3.34 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.53 (3H, d, J = 0.9 Hz), 6.55 (1H, q, J = 0.9 Hz), 6.97 (1H , t, J = 8.7 Hz), 7.49 (1H, dd, J = 8.7 and 4.8 Hz).
IR (KBr) 2234, 1605, 1505 cm ^-1
Reference Example 79

To a mixture of benzyl 3-hydroxy-1-pyrrolidinecarboxylate (5.00 g) and pyridine (50 mL) was added p-toluenesulfonyl chloride (4.74 g) at 0 ° C. After stirring at room temperature for 20 hours, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, a sodium hydrogen carbonate solution, and a saline solution. The residue obtained by drying and concentrating was purified by silica gel column chromatography to obtain benzyl 3-[[(4-methylphenyl) sulfonyl] oxy] -1-pyrrolidinecarboxylate (4.98 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.95-2.24 (2H, m), 2.45 (3H, d, J = 2.7 Hz), 3.45-3.64 ( 4H, m), 5.05-5.12 (3H, m), 7.33-7.36 (7H, m), 7.77-7.80 (2H, m).
Reference Example 80

A mixture of benzyl 3-[[(4-methylphenyl) sulfonyl] oxy] -1-pyrrolidinecarboxylate (3.92 g), potassium fluoride (3.64 g) and ethylene glycol (16 mL) was placed under an argon atmosphere. Stirred at 85 ° C. for 24 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 3-fluoro-1-pyrrolidinecarboxylate (1.32 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.88-2.32 (2H, m), 3.44-3.85 (4H, m), 5.12-5.32 (1H, m ), 5.14 (2H, s), 7.29-7.37 (5H, m).
Reference Example 81

A mixture of benzyl 3-fluoro-1-pyrrolidinecarboxylate (1.32 g), 10% palladium on carbon (containing 50% water, 503 mg), and acetic acid (13 mL) was stirred at room temperature under a hydrogen atmosphere for 2 days. The palladium carbon was removed by filtration using Celite and washed with methanol. To the mother liquor was added 4N hydrogen chloride-ethyl acetate (4.5 mL) and concentrated. The obtained residue was washed with diethyl ether to obtain 3-fluoropyrrolidine hydrochloride (711 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.95-2.28 (2H, m), 3.15-3.50 (4H, m), 5.43 (1H, dt, J = 52.5 and 3.6 Hz), 9.58 (2H, br.s).
Reference Example 82

A mixture of benzyl 3-hydroxy-1-pyrrolidinecarboxylate (10.0 g), pyridinium dichromate (14.6 g), and dichloromethane (150 mL) was stirred at room temperature for 3 days. The insoluble material was removed by filtration using Celite, and washed with dichloromethane. The residue obtained by concentrating the mother liquor was purified by silica gel column chromatography to obtain benzyl 3-oxo-1-pyrrolidinecarboxylate (4.39 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.61 (2H, t, J = 7.5 Hz), 3.83-3.89 (4H, m), 5.18 (2H, s) , 7.33-7.39 (5H, m).
Reference Example 83

A mixture of benzyl 3-oxo-1-pyrrolidinecarboxylate (4.00 g), diethylaminosulfur trifluoride (90%, 10.0 g), and toluene (50 mL) was stirred at room temperature for 4 days. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 3,3-difluoro-1-pyrrolidinecarboxylate (3.23 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.27-1.41 (2H, m), 3.62-3.80 (4H, m), 5.15 (2H, s), 7. 32-7.38 (5H, m).
Reference Example 84

A mixture of benzyl 3,3-difluoro-1-pyrrolidinecarboxylate (3.00 g), 10% palladium on carbon (50% water content, 1.06 g), and acetic acid (30 mL) was stirred at room temperature under a hydrogen atmosphere for 2 days. did. The palladium carbon was removed by filtration using Celite and washed with methanol. To the mother liquor was added 4N hydrogen chloride-ethyl acetate (5.0 mL) and concentrated. The obtained residue was washed with ethyl acetate to obtain 3,3-difluoropyrrolidine hydrochloride (1.65 g).
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.37-1.59 (2H, m), 3.42 (2H, t, J = 7.6 Hz), 3.63 (2H, t, J = 12.4 Hz).
Reference Example 85

A mixture of [1- (tert-butoxycarbonyl) -4-piperidinyl] acetic acid (500 mg), ethyl iodide (385 mg), potassium carbonate (926 mg), and N, N-dimethylformamide (5.0 mL) was added at room temperature. For 3 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4- (2-ethoxy-2-oxoethyl) -1-piperidinecarboxylate (558 mg). .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.08-1.22 (2H, m), 1.26 (3H, t, J = 7.2 Hz), 1.45 (9H, s) , 1.66-1.71 (2H, m), 1.86-2.00 (1H, m), 2.23 (2H, d, J = 7.2 Hz), 2.67-2.76 (2H, m), 4.00-4.16 (4H, m).
Reference Example 86

A mixture of 4-bromo-1-naphthaldehyde (1.00 g), hydroxylamine hydrochloride (355 mg), sodium acetate (523 mg), ethanol (16 mL), and water (8.0 mL) was added at room temperature for 2 hours. Stirred. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain 4-bromo-1-naphthaldehyde oxime (1.05 g). To a mixture of this substance (800 mg) and N, N-dimethylformamide (8.0 mL) was added 4N hydrogen chloride-ethyl acetate (0.96 mL) and OXONE (2.36 g), and the mixture was stirred at room temperature for 20 hours. did. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with 0.5N hydrochloric acid and water, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 4-bromo-N-hydroxynaphthalene-1-carboximidoyl chloride (660 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.54 (1H, d, J = 7.8 Hz), 7.60-7.68 (2H, m), 7.83 (1H, d, J = 7.8 Hz), 8.12 (1H, s), 8.21-8.24 (1H, m), 8.30-8.33 (1H, m).
Reference Example 87

To a mixture of methyl acetoacetate (10.0 g), potassium carbonate (29.8 g) and acetone (145 mL) was added 1,2-dibromoethane (21.0 g) at room temperature, and the mixture was heated under reflux for 8 hours. The reaction product was cooled to room temperature and concentrated, and the residue obtained was purified by silica gel column chromatography to obtain methyl 1-acetylcyclopropanecarboxylate (1.90 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49 (4H, s), 2.47 (3H, s), 3.75 (3H, s).
Reference Example 88

A mixture of methyl 1-acetylcyclopropanecarboxylate (1.40 g), [(1S) -1-phenylethyl] amine (1.26 mL) and toluene (18 mL) was heated under reflux for 12 hours. The reaction product was cooled to room temperature and concentrated, and the residue obtained was purified by silica gel column chromatography to give 2-methyl-1-[(1S) -1-phenylethyl] -4,5-dihydro-1H-pyrrole-3. -Methyl carboxylate (1.29 g) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54 (3H, d, J = 7.2 Hz), 2.33 (3H, s), 2.64-2.72 (2H, m) , 3.10-3.20 (1H, m), 3.37-3.48 (1H, m), 3.63 (3H, s), 4.88 (1H, q, J = 7.2 Hz) ), 7.21-7.38 (5H, m).
Reference Example 89

To a mixture of sodium triacetoxyhydroborate (2.02 g), acetic acid (4.7 mL) and acetonitrile (4.7 mL) was added 2-methyl-1-[(1S) -1-phenylethyl] -4, A mixture of methyl 5-dihydro-1H-pyrrole-3-carboxylate (780 mg) and acetonitrile (1.7 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. The reaction was poured into sodium carbonate solution and extracted with ethyl acetate. The extract was washed successively with a sodium carbonate solution and brine, dried and concentrated, and methyl (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate (778) mg).
[Α] _D = −28.4 ° (c = 2.08, EtOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.79 (3H, d, J = 6.3 Hz), 1.35 (3H, d, J = 6.9 Hz), 1.82-1 .93 (1H, m), 2.11-2.24 (1H, m), 2.54 (1H, t, J = 7.2 Hz), 2.70 (1H, td, J = 9.3) and 3.9 Hz), 3.02-3.15 (1H, m), 3.44-3.62 (2H, m), 3.67 (3H, s), 7.21-7.36 ( 5H, m).
Reference Example 90

Lithium aluminum hydride (160) was added to a mixture of methyl (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate (1.04 g) and tetrahydrofuran (11 mL). mg) at 0 ° C. and stirred for 3 hours. Water (0.16 mL), a 25% potassium hydroxide solution (0.16 mL) and water (0.48 mL) were sequentially added, and the mixture was stirred at room temperature for 16 hours. The insolubles were filtered off using Celite, and the mother liquor was concentrated to give [(2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidin-3-yl] methanol (920 mg). Obtained. This compound was used for the next reaction without further purification.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.14 (3H, d, J = 6.3 Hz), 1.29 (3H, d, J = 6.9 Hz), 1.67-1 .79 (1H, m), 1.85-1.97 (1H, m), 2.04-2.09 (1H, m), 2.36-2.46 (1H, m), 2.62 (1H, td, J = 9.9 and 3.6 Hz), 2.87-2.95 (1H, m), 3.47 (1H, dd, J = 9.9 and 3.3 Hz), 3.86-3.99 (2H, m), 7.22-7.33 (5H, m).
Reference Example 91

10% palladium carbon (containing 895 mg of 50% water) was washed with methanol, suspended in methanol (15 mL), and [(2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine. -3-yl] methanol (920 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The palladium carbon was removed by filtration using Celite and washed with methanol. The mother liquor was concentrated to give (2S, 3S) -3-hydroxymethyl-2-methylpyrrolidine (483 mg). This compound was used for the next reaction without further purification.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23 (3H, d, J = 6.6 Hz), 1.76-1.87 (1H, m), 1.96-2.10 ( 2H, m), 2.82-2.90 (1H, m), 3.06-3.23 (2H, m), 3.56 (1H, dd, J = 10.2 and 4.2 Hz) , 3.81 (1H, dd, J = 10.2 and 4.2 Hz).
Reference Example 92

A mixture of Boc-L-alanine (20.0 g), Meldrum's acid (16.0 g), 4-dimethylaminopyridine (29.7 g) and dichloromethane (460 mL) was added to a mixture of isopropenyl chloroformate (12.5 g). and a mixture of dichloromethane (40 mL) was added at −5 ° C. for 1 hour and stirred for 3 hours. A 5% potassium hydrogen sulfate solution (500 mL) at 0 ° C. was added and partitioned. The organic layer was washed with brine, dried and concentrated to give a yellow oil. A mixture of this substance and ethyl acetate (500 mL) was heated under reflux for 30 minutes. After cooling to room temperature, the mixture was extracted with a 5% sodium hydrogen carbonate solution (500 mL). The extract was adjusted to about PH3 with citric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated, and the resulting residue was washed with ethyl acetate to give (2S) -3-hydroxy-2-methyl-5-oxo-2,5-dihydro-1H-pyrrole. Tert-Butyl-1-carboxylate (15.2 g) was obtained.
[Α] _D = + 86.8 ° (c = 0.515, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51 (3H, d, J = 6.9 Hz), 1.56 (9H, s), 3.15-3.31 (2H, m) , 4.42 (1H, qd, J = 6.9 and 0.9 Hz).
Reference Example 93

(2S) -3-Hydroxy-2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate tertbutyl (15.0 g), acetic acid (35 mL), dichloromethane (70 mL) To this mixture was added sodium tetrahydroborate (985 mg) at 0 ° C. for 1 hour and stirred for 20 hours. After adding water and stirring at 0 ° C. for 10 minutes, the organic layer was separated. The organic layer was washed with brine, dried and concentrated to give a pale yellow oil. To a mixture of this oil, acetic acid (4.7 mL) and dichloromethane (70 mL) was added sodium tetrahydroborate (985 mg) at 0 ° C for 1 hour, and the mixture was stirred for 20 hours. After adding water and stirring at 0 ° C. for 10 minutes, the organic layer was separated. After washing with a saline solution, the residue obtained by drying and concentrating was washed with a mixed solution of diisopropyl ether and hexane to give (2S, 3S) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylic acid. Tert butyl (2.25 g) was obtained.
[Α] _D = −24.6 ° (c = 0.735, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (3H, d, J = 6.6 Hz), 1.53 (9H, s), 2.58 (1H, dd, J = 17. 1 and 9.0 Hz), 2.72 (1H, dd, J = 17.1 and 7.8 Hz), 4.26 (1H, qui, J = 6.6 Hz), 4.47-4. 54 (1H, m).
Reference Example 94

To trifluoroacetic acid (4.0 mL) was added tertbutyl (2S, 3S) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate (3.00 g) at 0 ° C, and the mixture was added at room temperature for 15 minutes. For a minute. The reaction was concentrated and tetrahydrofuran (5.0 mL) was added to the residue. The mixture was neutralized with potassium carbonate, and the insolubles were removed by filtration using Celite. Concentration gave a colorless solid (1.56 g). A mixture of this solid and tetrahydrofuran (13 mL) was added to a mixture of lithium aluminum hydride (1.29 g) and tetrahydrofuran (35 mL) at room temperature for 15 minutes and stirred at 70 ° C. for 24 hours. After cooling to 0 ° C., water (1.3 mL), 25% potassium hydroxide solution (1.3 mL) and water (4.0 mL) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. The insoluble matter was removed by filtration using Celite. Tetrahydrofuran (13 mL) was added to the residue obtained by concentrating the mother liquor, and the resulting mixture was added to a mixture of lithium aluminum hydride (1.03 g) and tetrahydrofuran (35 mL) at room temperature for 15 minutes. For 18 hours. After cooling to 0 ° C., water (1.0 mL), 25% potassium hydroxide solution (1.0 mL) and water (3.0 mL) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. The insoluble matter was removed by filtration using Celite. The mother liquor was concentrated to give (2S, 3S) -3-hydroxy-2-methylpyrrolidine (1.19 g). This compound was used for the next reaction without further purification.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.99 (3H, d, J = 6.6 Hz), 1.50-1.60 (1H, m), 1.78-1. 89 (1H, m), 2.49-2.66 (2H, m), 2.89-2.97 (1H, m), 3.83-3.87 (1H, m).
Reference example 95

A mixture of Boc-D-alanine (4.78 g), Meldrum's acid (3.78 g), 4-dimethylaminopyridine (7.02 g) and dichloromethane (120 mL) was added to isopropenyl chloroformate (2.95 g). A mixture of (mL) and dichloromethane (10 mL) was added at -5 ° C for 1 hour and stirred for 3 hours. A 5% potassium hydrogen sulfate solution (100 mL) at 0 ° C. was added and partitioned. The organic layer was washed with brine, dried and concentrated to give a yellow oil. A mixture of this substance and ethyl acetate (120 mL) was heated under reflux for 30 minutes. After cooling to room temperature, the mixture was extracted with a 5% sodium hydrogen carbonate solution (100 mL). The extract was adjusted to about pH 3 with citric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated, and the resulting residue was washed with ethyl acetate to give (2R) -3-hydroxy-2-methyl-5-oxo-2,5-dihydro-1H-pyrrole. Tert-Butyl-1-carboxylate (3.11 g) was obtained.
[Α] _D = -86.5 ° (c = 0.204, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51 (3H, d, J = 6.9 Hz), 1.56 (9H, s), 3.15-3.31 (2H, m) , 4.42 (1H, qd, J = 6.9 and 0.9 Hz).
Reference Example 96

(2R) -3-Hydroxy-2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate tertbutyl (3.00 g), acetic acid (4.7 mL), dichloromethane (70 mL) Sodium tetrahydroborate (985 mg) was added to the mixture at 0 ° C. for 1 hour and stirred for 20 hours. After adding water and stirring at 0 ° C. for 10 minutes, the organic layer was separated. The organic layer was washed with brine, dried and concentrated to give a pale yellow oil. To a mixture of this oil, acetic acid (4.7 mL) and dichloromethane (70 mL) was added sodium tetrahydroborate (985 mg) at 0 ° C for 1 hour, and the mixture was stirred for 20 hours. After adding water and stirring at 0 ° C. for 10 minutes, the organic layer was separated. After washing with brine, the residue obtained by drying and concentration was washed with a mixture of diisopropyl ether and hexane to give (2R, 3R) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylic acid. Tert butyl (2.25 g) was obtained.
[Α] _D = + 24.0 ° (c = 0.515, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (3H, d, J = 6.6 Hz), 1.53 (9H, s), 2.58 (1H, dd, J = 17. 1 and 9.0 Hz), 2.72 (1H, dd, J = 17.1 and 7.8 Hz), 4.26 (1H, qui, J = 6.6 Hz), 4.47-4. 54 (1H, m).
Reference Example 97

To a mixture of tert-butyl (2R, 3R) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate (2.20 g) and ethyl acetate (18 mL) was added 4N hydrogen chloride-ethyl acetate (6. 0 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to give a yellow oil. To a mixture of this substance and tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.15 g) at room temperature for 15 minutes, and the mixture was stirred at 70 ° C for 12 hours. After cooling to 0 ° C., water (1.0 mL), 25% potassium hydroxide solution (1.0 mL) and water (3.0 mL) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. The insoluble matter was removed by filtration using Celite. The mother liquor was concentrated to give (2R, 3R) -3-hydroxy-2-methylpyrrolidine (1.00 g). This compound was used for the next reaction without further purification.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.99 (3H, d, J = 6.6 Hz), 1.50-1.60 (1H, m), 1.78-1. 89 (1H, m), 2.49-2.66 (2H, m), 2.89-2.97 (1H, m), 3.83-3.87 (1H, m).
Reference Example 98

(4R) -1- (tert-Butoxycarbonyl) -4-hydroxy-D-proline (0.94 g) was dissolved in anhydrous tetrahydrofuran (6 mL), and a 1 M tetrahydrofuran-borane tetrahydrofuran solution (20 mL) was stirred with ice cooling. ) Was added dropwise, and the mixture was stirred for 1 hour, returned to room temperature, and further stirred for 1 hour. After ice water was added to the reaction solution to decompose it, saturated saline was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated, and tert-butyl (2R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.99 g) was obtained as a colorless oil. Obtained.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.20-2.50 (2H, m), 3.30-4.40 (6H, m).
Reference Example 99

1-Benzyl-5-methyl-2-oxopyrrolidine-3-carboxylic acid (2.34 g) was dissolved in N, N-dimethylformamide (40.0 mL), and sodium hydride (60 mL) was added under ice cooling. % Oily, 0.99 g) and further stirred at room temperature for 1 hour. Then, after adding methyl iodide (3 mL) under ice-cooling and stirring, the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from hexane: ethyl acetate = 8: 1 to give methyl 1-benzyl-3,5-dimethyl-2-oxopyrrolidine-3-carboxylate. (1.40 g) was obtained.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.22 (3H, d, J = 6.4 Hz), 1.44 (3H, s), 1.95-2.25 (2H, m) , 3.36-3.55 (1H, m), 3.78 (3H, s), 4.00 (1H, d, J = 15.0 Hz), 5.00 (1H, d, J = 15 2.0 Hz), 7.22-7.40 (5H, m).
_{.. Anal Calcd for C 15 H} 19 N 2 O 3: C, 68.94; H, 7.33; N, 5.36.
Found: C, 68.80; H, 7.08; N, 5.24.
Reference example 100

The mixture was stirred under ice-cooling, lithium aluminum hydride (0.784 g) was suspended in tetrahydrofuran (60 mL) and methyl 1-benzyl-3,5-dimethyl-2-oxopyrrolidine-3-carboxylate (2.7) was added. g) was dissolved in tetrahydrofuran (50 mL), added little by little, returned to room temperature, stirred for 1 hour, and further heated under reflux for 20 hours. After the reaction solution was ice-cooled, 4N-sodium hydroxide (20 mL) and water (20 mL) were added to decompose. Tetrahydrofuran was added and the mixture was decanted three times, and the tetrahydrofuran layers were combined and concentrated to dryness. A saturated saline solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated, and the residue was purified by basic silica gel column chromatography (Chromatorex NH Fuji Silysia) to give 1-benzyl-4-hydroxymethyl-2,4-dimethylpyrrolidine (1.88 g). Obtained.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.92 (3H, s), 1.24 (3H, d, J = 6.2 Hz), 1.64-1.95 (2H, m) , 2.05 (1H, dd, J = 2.2 Hz and 9.2 Hz), 2.46-2.68 (1H, m), 2.79 (1H, d, J = 9.2 Hz) , 2.95 (1H, d, J = 12.8 Hz), 3.26 (1H, dd, J = 2.2 Hz and 9.4 Hz), 3.43 (1H, d, J = 9. 4 Hz), 4.05 (1H, d, J = 12.8 Hz), 7.20-7.40 (5H, m).
Reference Example 101

Dissolve (4R) -1- (tert-butoxycarbonyl) -4-hydroxy-D-proline (0.93 g) in N, N-dimethylformamide (12.0 mL) and hydrogenate under ice-cooling Sodium (60% oily, 400 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, after adding methyl iodide (1 mL) under ice-cooling and stirring, the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Methyl alcohol (30 mL) was added to the obtained residue for dissolution, 4N-sodium hydroxide (4 mL) was added, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution and washing the aqueous layer with ether, the aqueous layer was adjusted to pH = 2 with aqueous potassium hydrogen sulfate and extracted with ethyl acetate. The extract was dried and concentrated to give (4R) -1- (tert-butoxycarbonyl) -4-methoxy-D-proline (0.85 g). This was dissolved in anhydrous tetrahydrofuran (6 mL), and a 1 M tetrahydrofuran-borane-tetrahydrofuran solution (10 mL) was added dropwise with stirring under ice-cooling, and the mixture was stirred for 1 hour, returned to room temperature, and stirred for 2 hours. After decomposing by adding ice water, saturated saline was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give tert-butyl (2R, 4R) -2- (hydroxymethyl) -4-methoxypyrrolidine-1-carboxylate (0.7 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 2.00-2.40 (2H, m), 3.33 (3H, s), 3.40-4. 20 (6H, m), 4.30-4.60 (1H, m).
Reference example 102

Acetyl chloride (10.0 mL) was added to 2-phenylsuccinic acid (3.88 g), and the mixture was heated under reflux for 2 hours. After toluene was added to the reaction solution, the mixture was concentrated to dryness, dissolved in toluene (10 mL), benzylamine (2.2 g) was added, and the mixture was stirred at room temperature for 15 minutes. Then, acetyl chloride (10 mL) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-benzyl-3-phenylpyrrolidine-2,5-dione (4.1 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.82 (1 H, dd, J = 4.8 Hz and J = 18.2 Hz), 3.21 (1 H, dd, J = 9.6 Hz) and 18.2 Hz), 4.02 (1H, dd, J = 4.8 Hz and 9.6 Hz), 4.60-4.85 (2H, m), 7.10-7.50 (10H , m).
Reference Example 103

Stir under ice-cooling, suspend lithium aluminum hydride (1.15 g) in tetrahydrofuran (50 mL), and add 1-benzyl-3-phenylpyrrolidine-2,5-dione (4.1 g) to tetrahydrofuran (30 mL). Then, the mixture was added dropwise to the solution, and the mixture was returned to room temperature, stirred for 1 hour, and further heated under reflux for 12 hours. After the reaction solution was ice-cooled, 4N-sodium hydroxide (10 mL) and water (10 mL) were added to decompose. Tetrahydrofuran was added and the mixture was decanted three times, and the tetrahydrofuran layers were combined and concentrated to dryness. Saturated saline was added to the residue, and extracted with dichloromethane. The extract was dried and concentrated, and the residue was purified by basic silica gel column chromatography to obtain 1-benzyl-3-phenylpyrrolidine (2.35 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.80-2.00 (1H, m), 2.22-2.45 (1H, m), 2.87 (1H, dd, J = 1) 2.4 Hz and 7.8 Hz), 2.60-2.92 (2H, m), 3.04 (1H, dd, J = 1.4 Hz and 7.8 Hz), 3.28-3. 47 (1H, m), 3.62 (2H, s), 7.12-7.40 (10H, m).
Reference Example 104

Acetyl chloride (25 mL) was added to D-malic acid (8 g), and the mixture was heated under reflux for 2.5 hours, concentrated and dried, and toluene was added and concentrated twice to dryness. Toluene (25 ml) was added to the residue, benzylamine (6.7 g) was added dropwise with ice cooling and stirring, and the mixture was returned to room temperature and stirred for 30 minutes. Then, acetyl chloride (25 mL) was added, and the mixture was heated under reflux for 2.5 hours, concentrated and dried, and toluene was added and concentrated twice to dryness. The residue was purified by silica gel column chromatography to obtain (3R) -3-acetoxy-1-benzyl-2,5-dioxopyrrolidine (14.9 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.16 (1 H, s), 2.67 (1 H, dd, J = 4.6 Hz and 18.4 Hz), 3.17 (1 H, d) , J = 8.8, 18.4 Hz), 4.70 (2H, s), 5.45 (1H, dd, J = 4.4 Hz and 8.8 Hz), 7.28-7.45 ( 5H, m).
Reference Example 105

(3R) -3-Acetoxy-1-benzyl-2,5-dioxopyrrolidine (14.9 g) was dissolved in ethyl alcohol (150 mL), acetyl chloride (8 mL) was added dropwise at room temperature, and the temperature was raised to 50 ° C. Stir for 4 hours while heating. After cooling, the mixture was concentrated to dryness, toluene was added, and the mixture was again concentrated to dryness. Crystallization from toluene gave (3R) -1-benzyl-3-hydroxypyrrolidine-2,5-dione (7.85 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.68 (1 H, dd, J = 4.8 Hz, and 18.2 Hz), 3.06 (1 H, dd, J = 8.4 Hz, and 18.2 Hz), 3.5 (1H, d, J = 2.8 Hz), 4.52-4.70 (1H, m), 4.65 (2H, s), 5.45 (1H , dd, J = 4.4 Hz and 8.8 Hz), 7.20-7.50 (5H, m).
Reference Example 106

(3R) -1-benzyl-3-hydroxypyrrolidine-2,5-dione (19.7 g) was dissolved in diethyl ether (600 mL), benzyl bromide (49.3 g) and silver (I) oxide (66) were dissolved. .8 g) and stirred at room temperature for 3 days under light shielding. The insolubles were collected by filtration, washed with diethyl ether, and the filtrates were combined and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain (3R) -1-benzyl-3-benzyloxypyrrolidine-2,5-dione (25.5 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.66 (1 H, dd, J = 4.4 Hz and 18.4 Hz), 2.96 (1 H, dd, J = 8.0 Hz and 8) 4.6 Hz), 4.36 (1H, dd, J = 8.0 Hz and 8.6 Hz), 4.66 (2H, s), 4.78 (1H, d, J = 11.8 Hz) , 4.99 (1H, d, J = 11.8 Hz), 7.20-7.40 (10H, m).
Reference Example 107

(3R) -1-benzyl-3-benzyloxypyrrolidine-2,5-dione (12 g) was dissolved in dehydrated tetrahydrofuran (200 mL), cooled to -70 ° C under a nitrogen stream, and 1M-methylmagnesium bromide (THF) Solution, 100 mL), and the mixture was stirred at −70 ° C. for 3 hours. After adding a saturated ammonium chloride aqueous solution (200 mL) to the reaction solution, the mixture was extracted twice with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. Hexane: ethyl acetate = 4: 1 was added to the residue to obtain (4R) -1-benzyl-4- (benzyloxy) -5-hydroxy-5-methylpyrrolidin-2-one (9.5 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.29 (3 H, s), 2.50-2.80 (2 H, m), 3.72 (1 H, s), 3.87 (1 H, s) dd, J = 4.2 Hz and 5.4 Hz), 4.42 (1H, d, 15.4 Hz), 4.57 (1H, d, J = 11.8 Hz), 4.59 (1H , d, 15.4 Hz), 4.70 (1H, d, 11.8 Hz), 7.20-7.45 (10H, m).
Reference Example 108

Dissolve (4R) -1-benzyl-4- (benzyloxy) -5-hydroxy-5-methylpyrrolidin-2-one (12.43 g) in dichloromethane (200 mL) and triethylsilane (13.93 g) Was added, and the mixture was cooled to -70 ° C under a nitrogen stream, and boron trifluoride diethyl ether complex (6 mL) was added thereto, followed by stirring for 10 minutes. Then, the mixture was returned to ice-cooling and stirred for 1 hour. A saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain (4R, 5S) -1-benzyl-4- (benzyloxy) -5-methylpyrrolidin-2-one (11.3 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.14 (3H, d, J = 6.6 Hz), 2.53 (1H, dd, J = 3.2 Hz and 17.2 Hz), 2. 77 (1H, ddd, J = 0.8 Hz and 6.6 Hz and 17.2 Hz), 3.56 (1H, dq, J = 2.6 Hz and 6.6 Hz), 3.79 (1H , ddd, J = 2.6 Hz and 3.2 Hz and 6.6 Hz), 3.98 (1H, d, J = 15.4 Hz), 4.42 (1H, d, J = 11.8) Hz), 4.50 (1H, d, J = 11.8 Hz), 5.03 (1H, d, J = 15.4 Hz), 7.10-7.501 (10H, m).
Reference Example 109

(4R, 5S) -1-Benzyl-4- (benzyloxy) -5-methylpyrrolidin-2-one (11.7 g) was dissolved in methyl alcohol (300 mL), 10% palladium on carbon (50% aqueous, 8 g) and stirred under a stream of hydrogen for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain (4R, 5S) -1-benzyl-4- (hydroxy) -5-methylpyrrolidin-2-one (7.48 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.14 (3H, d, J = 6.6), 2.11 (1H, d, J = 4.4 Hz), 2.40 (1H, dd, J = 3.2 Hz and 17.2 Hz), 2.81 (1H, ddd, J = 1.0 Hz and 6.6 Hz and 17.2 Hz), 3.38 (1H, m), 3. 98 (1H, d, J = 15.0 Hz), 4.00-4.15 (1H, m), 4.99 (1H, d, J = 15.0 Hz), 7.15-7.40 (5H, m).
Reference Example 110

When lithium aluminum hydride (6.9 g) was suspended in tetrahydrofuran (containing 100 mL of a stabilizer), (4R, 5S) -1-benzyl-4- (hydroxy) -5-methylpyrrolidine-2- A solution of ON (12.4 g) in tetrahydrofuran (100 mL) was added dropwise at room temperature, and the mixture was refluxed for 4.5 hours. While stirring the reaction mixture under ice-cooling, a 4N-sodium hydroxide aqueous solution (75 mL) was added dropwise (reacted vigorously), and water (50 mL) was added, followed by stirring for 30 minutes. Decant to separate the tetrahydrofuran layer, add tetrahydrofuran (containing stabilizer) to the residue, repeat decant three times, combine and concentrate the tetrahydrofuran solution, add dichloromethane to the residue, extract twice, wash with saturated brine, wash the extract with sulfuric anhydride. After drying over sodium, it was concentrated to dryness. The residue was purified by basic silica gel column chromatography to obtain (2S, 3R) -1-benzyl-2-methylpyrrolidin-3-ol (10.1 g).
[α] _D + 68.61 ° (C = 3.0, CHCl ₃ ).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.14 (3 H, d, J = 6.6 Hz), 2.11 (1 H, d, J = 4.4 Hz), 2.40 (1 H , dd, J = 3.2 Hz and 17.2 Hz), 2.81 (1H, ddd, J = 1.0 Hz and 6.6 Hz and 17.2 Hz), 3.38 (1H, m) , 3.98 (1H, d, J = 15.0 Hz), 4.00-4.15 (1H, m), 4.99 (1H, d, J = 15.0 Hz), 7.15- 7.40 (5H, m).
Reference Example 111

Ethyl (diethoxyphosphoryl) acetate (3.54 g) was dissolved in anhydrous tetrahydrofuran (20 mL), sodium hydride (60% oily, 0.63 g) was added under ice-cooling and stirring, and the temperature was returned to room temperature. Stirred for minutes. Then, tert-butyl 3-oxopyrrolidine-1-carboxylate (1.47 g) dissolved in anhydrous tetrahydrofuran (6 mL) was added under ice-cooling and stirring, and the mixture was stirred at room temperature for 1.5 hours. Water was poured into the reaction mixture, the pH was adjusted to 2 with aqueous potassium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and tert-butyl 3- (2-ethoxy-2-oxoethylidene) pyrrolidine-1-carboxylate and 3- (2 A mixture of tert-butyl- (ethoxy-2-oxoethyl) -2,5-dihydro-1H-pyrrole-1-carboxylate (1.78 g) was obtained. The whole amount was dissolved in methyl alcohol (50 mL), 10% palladium on carbon (containing water) (0.9 g) was added, and the mixture was stirred for 11 hours under a hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to obtain tert-butyl 3- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate (1.75 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.38-1.68 (1H, m), 1.46 (9H, s) , 1.96-2.18 (1H, m), 2.34-2.43 (2H, m), 2.44-2.68 (1H, m), 2.84-3.04 (1H, m), 3.16-3.68 (3H, m), 4.14 (2H, q, J = 7.2 Hz).
Reference Example 112

Sodium hydride (60% oil, 0.6 g) was added to dimethyl sulfoxide (20 mL) at room temperature, and the mixture was stirred at 55 ° C. for 1 hour. Then, ethyl (triphenyl) phosphonium bromide (5.57 g) was added, and the mixture was stirred at 55 ° C. for 45 minutes. The reaction solution was returned to room temperature, tert-butyl (2R) -2-formylpyrrolidine-1-carboxylate (2 g) was dissolved in dimethyl sulfoxide (4 mL), and the mixture was stirred for 16 hours. Ice water was poured into the reaction product, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 2-[(1E) -prop-1-enyl] pyrrolidine-1-carboxylate (1.6 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.50-2.20 (7H, m), 3.30-3.50 (2H, m), 4. 10-4.65 (1H, m), 5.20-5.60 (2H, m).
Reference Example 113

Dissolve methyl (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate (1.0 g) in dehydrated tetrahydrofuran (10 mL), The mixture was cooled to 50 ° C, 1M-methylmagnesium bromide (THF solution, 12 mL) was added dropwise, and the mixture was returned to room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution (8 mL) was added to the reaction solution, which was then extracted twice with ethyl acetate, and washed with saturated saline. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by basic silica gel column chromatography to give 2-[(2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidin-3-yl] propan-2-ol ( 0.9 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.03 (3H, d, J = 6.6 Hz), 1.21 (3H, s), 1.32 (3H, s), 1.33 (3H, d, J = 6.6 Hz), 1.60-1.90 (3H, m), 2.05-2.25 (1H, m), 2.40-2.64 (2H, m ), 3.30-3.70 (2H, m), 7.15-7.40 (5H, m).
Reference Example 114

Benzyl 1-acetylcyclopropanecarboxylate (13 g) and (1R) -1-phenylethylamine (7.6 g) were dissolved in toluene (100 mL), and the mixture was refluxed under dehydration for 22 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel column chromatography, and benzyl 2-methyl-1-[(1S) -1-phenylethyl] -4,5-dihydro-1H-pyrrole-3-carboxylate (13 .2 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.55 (3H, d, J = 6.8 Hz), 2.34 (3H, s), 2.65-2.85 (2H, m) , 3.05-3.55 (2H, m), 4.89 (1H, q, J = 6.8 Hz), 5.15 (2H, s), 7.20-7.50 (10H, m ).
Reference Example 115

Acetic acid (70 mL) was maintained at 15 to 20 ° C., sodium borohydride (4.66 g) was added little by little, and the mixture was stirred at this temperature for 30 minutes. Then, acetonitrile (35 mL) was added, and the mixture was cooled to 5 ° C. and stirred with benzyl 2-methyl-1-[(1S) -1-phenylethyl] -4,5-dihydro-1H-pyrrole-3-carboxylate. (13.2 g) was dissolved in acetonitrile (35 mL) and added dropwise. The mixture was kept at 0 to 8 ° C and stirred for 3 hours. After the reaction solution was concentrated to dryness, the residue was made alkaline with saturated aqueous sodium carbonate. Extracted twice with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by basic silica gel column chromatography to obtain benzyl (11.7 g) (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate. Was.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, d, J = 6.6 Hz), 1.33 (3H, d, J = 6.6 Hz), 1.80-2 .35 (2H, m), 2.45-2.85 (2H, m), 3.00-3.22 (1H, m), 3.40-3.70 (2H, m), 5.00 −5.20 (2H, m), 7.20-7.40 (10H, m).
Reference Example 116

Dissolve benzyl (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate (11.7 g) in methyl alcohol (100 mL), 10% palladium on carbon ( (Water-containing) (3.0 g), and the mixture was stirred under a hydrogen stream for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness and crystallized from acetone to obtain (2S, 3S) -2-methylpyrrolidine-3-carboxylic acid (4.77 g). This compound (2.0 g) was dissolved in water (40 mL), sodium carbonate (2.65 g) and acetone (10 mL) were added, and then di-t-butyl dicarbonate (5.07 g) was added. The mixture was stirred at room temperature for 16 hours. After the acetone was distilled off, water was added, the pH was adjusted to 2 with potassium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, concentrated, and crystallized from hexane to give (2S, 3S) -1- (tert-butoxycarbonyl) -2-methylpyrrolidine-3-carboxylic acid (3.19 g). Got.
[α] _D = + 13.3 ° (c = 0.328, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.13 (3H, d, J = 6.6 Hz), 1.47 (9H, s), 1.95-2.40 (2H, m) , 3.00-3.60 (3H, m), 4.05-4.40 (1H, m).
Reference Example 117

(2S, 3S) -1- (tert-butoxycarbonyl) -2-methylpyrrolidine-3-carboxylic acid (0.917 g) was dissolved in dioxane (20 mL), and pyridine (0.2 mL) was added. Then, di-t-butyl dicarbonate (1.14 g) was added and the mixture was stirred for 10 minutes. Then, ammonium carbonate (0.4 g) was added, and the mixture was stirred at room temperature for 20 hours. After dioxane was distilled off, water was added, the pH was adjusted to 2 with potassium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain tert-butyl (2S, 3S) -3- (aminocarbonyl) -2-methylpyrrolidine-1-carboxylate (0.76 g).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.12 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 1.90-2.45 (2H, m) , 2.85-3.10 (1H, m), 3.20-3.60 (2H, m), 4.10-4.30 (1H, m), 4.45 (1H, br.s) , 5.10 (1H, br.s).
Example 1 (Production of Compound 1)

Sodium hydride (60% oily, 1.25 g) was added to a mixture of 4-amino-1-naphthonitrile (1.75 g) and N, N-dimethylformamide (20 mL) at room temperature, followed by stirring for 20 minutes. . After adding 1,4-dibromobutane (2.24 g), the mixture was stirred at 50 ° C. for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-pyrrolidinyl) -1-naphthonitrile (1.76 g) (Compound 1).
mp 109-110 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.01-2.08 (4H, m), 3.59-3.66 (4H, m), 6.69 (1H, d, J = 8) .4 Hz), 7.39-7.48 (1H, m), 7.55-7.62 (1H, m), 7.72 (1H, d, J = 8.0 Hz), 8.13 -8.17 (1H, m), 8.26 (1H, d, J = 8.2 Hz).
IR (KBr) 2203, 1563, 1518 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₄ N ₂ : C, 81.05; H, 6.35; N, 12.60.
Found: C, 80.99; H, 6.33; N, 12.47.
Example 2 (Production of Compound 2)

A mixture of 4- (1-pyrrolidinyl) -1-naphthonitrile (1.76 g), 2N potassium hydroxide solution (2.7 mL), and ethanol (2.7 mL) was stirred at 100 ° C. for 2 days. The insolubles were collected by filtration and washed with water. The washing solution and the mother liquor were combined, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give 4- (1-pyrrolidinyl) -1-naphthoic acid (17 mg) (Compound 2).
mp 194 ° C (dec).
¹ H-NMR (200 MHz, DMSO-d6) δ: 1.94-2.00 (4H, m), 3.48-3.54 (4H, m), 6.82 (1H, d, J = 8.4 Hz), 7.38-7.47 (1H, m), 7.50-7.58 (1H, m), 8.09 (1H, d, J = 8.4 Hz), 8. 22-8.26 (1H, m), 9.05-9.09 (1H, m), 12.27 (1H, br.s).
Example 3 (Production of compound 3)

Sodium hydride (60% oily, 346 mg) was added to a mixture of 4-amino-1-naphthonitrile (500 mg) and N, N-dimethylformamide (5.5 mL) at room temperature, followed by stirring for 20 minutes. After adding 1,5-dibromopentane (663 mg), the mixture was stirred at 50 ° C for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-piperidinyl) -1-naphthonitrile (597 mg) (Compound 3).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.73 (2H, m), 1.82-1.90 (4H, m), 3.11-1.14 (4H, m ), 6.98 (1H, d, J = 8.1 Hz), 7.52-7.58 (1H, m), 7.60-7.66 (1H, m), 7.80 (1H, d, J = 8.1 Hz), 8.14-8.19 (2H, m).
IR (KBr) 2938, 2215, 1572 cm ^-1
Example 4 (Production of compound 4)

4N Hydrogen chloride-ethyl acetate (1.5 mL) was added to 4- (1-piperidinyl) -1-naphthonitrile (130 mg), and the mixture was stirred at room temperature for 1 hour. The precipitated compound was collected by filtration and washed with diethyl ether to obtain 4- (1-piperidinyl) -1-naphthonitrile hydrochloride (120 mg) (Compound 4).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.62-1.67 (2H, m), 1.76-1.84 (4H, m), 3.08-3.11 (2H , m), 7.14 (1H, d, J = 7.8 Hz), 7.67 (1H, ddd, J = 8.4, 6.6 and 1.2 Hz), 7.75 (1H, ddd, J = 8.4, 6.6 and 1.2 Hz), 8.02-8.06 (2H, m), 8.13-8.16 (1H, m).
Example 5 (Production of compound 5)

Sodium hydride (60% oily, 262 mg) was added to a mixture of 4-bromo-1-naphthylamine (500 mg) and N, N-dimethylformamide (6.0 mL) at room temperature, followed by stirring for 20 minutes. After adding 1,5-dibromopentane (502 mg), the mixture was stirred at 50 ° C for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- (4-bromo-1-naphthyl) piperidine (120 mg) (Compound 5).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.68 (2H, br.s), 1.84 (4H, qui, J = 5.4 Hz), 3.03 (4H, br.s) , 6.91 (1H, d, J = 8.2 Hz), 7.48-7.68 (3H, m), 8.17-8.24 (2H, m).
Example 6 (Production of compound 6)

4- (trifluoromethyl) -1-naphthylamine (200 mg), 1,5-dibromopentane (544 mg), potassium carbonate (654 mg), sodium iodide (710 mg), N, N-dimethylformamide ( (3.0 mL) was stirred at 90 ° C. for 13 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- [4- (trifluoromethyl) -1-naphthyl] piperidine (108 mg) (Compound 6).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68 (2H, br.s), 1.85 (4H, qui, J = 5.4 Hz), 3.08 (4H, br.s) , 6.99 (1H, d, J = 8.1 Hz), 7.50-7.60 (2H, m), 7.75 (1H, dd, J = 8.1 and 0.9 Hz), 8.10-8.15 (1H, m), 8.22-8.25 (1H, m).
IR (KBr) 2938, 1582, 1516 cm ^-1
Example 7 (Production of compound 7)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), morpholine (0.10 mL), potassium carbonate (162 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4-morpholinyl) -1-naphthonitrile (113 mg) (Compound 7).
mp 128-129 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.17-3.20 (4H, m), 3.99-4.02 (4H, m), 7.05 (1H, d, J = 7) .8 Hz), 7.57-7.70 (2H, m), 7.86 (1H, d, J = 7.8 Hz), 8.19-8.24 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₄ N ₂ O: C, 75.61; H, 5.92; N, 11.76.
Found: C, 75.69; H, 6.15; N, 11.65.
Example 8 (Production of compound 8)

A mixture of 4-fluoro-1-naphthonitrile (500 mg), thiomorpholine (0.57 mL), potassium carbonate (808 mg), and dimethylsulfoxide (5.0 mL) was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4-thiomorpholinyl) -1-naphthonitrile (560 mg) (Compound 8).
mp 130-131 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.94-2.97 (4H, m), 3.41-3.45 (4H, m), 7.06 (1H, d, J = 8) .1 Hz), 7.60 (1H, ddd, J = 8.4, 6.6 and 1.2 Hz), 7.68 (1H, ddd, J = 8.4, 6.6 and 1.2) Hz), 7.85 (1H, d, J = 8.1 Hz), 8.13-8.17 (1H, m), 8.20-8.23 (1H, m).
IR (KBr) 2216, 1574 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₄ N ₂ S: C, 70.83; H, 5.55; N, 11.01.
Found: C, 70.84; H, 5.60; N, 10.87.
Example 9 (Production of compound 9)

A mixture of 4- (4-thiomorpholinyl) -1-naphthonitrile (500 mg) and dichloromethane (3.0 mL) in a mixture of m-chloroperbenzoic acid (70%, 242 mg) and dichloromethane (3.0 mL) Was added at -78 ° C and stirred for 1 hour. After adding a sodium sulfite solution, the temperature was raised to room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with sodium carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-oxide-4-thiomorpholinyl) -1-naphthonitrile (239 mg) (Compound 9).
mp 183-184 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.13-1.14 (4H, m), 3.34-3.40 (2H, m), 3.85-3.93 (2H, m ), 7.18 (1H, d, J = 8.1 Hz), 7.62 (1H, ddd, J = 8.1, 6.6 and 1.2 Hz), 7.70 (1H, ddd, J = 8.1, 6.6 and 1.2 Hz), 7.87 (1H, d, J = 8.1 Hz), 8.10-8.13 (1H, m), 8.22-8 .25 (1H, m).
IR (KBr) 2218, 1574 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₄ N ₂ OS: C, 66.64; H, 5.22; N, 10.36.
Found: C, 66.63; H, 4.98; N, 10.21.
Example 10 (Production of compound 10)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), azepan (116 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-azepanyl) -1-naphthonitrile (116 mg) (Compound 10).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.77-1.92 (8H, m), 3.40-3.44 (4H, m), 7.02 (1H, d, J = 8) .1 Hz), 7.52 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.62 (1H, ddd, J = 8.4, 6.9 and 1.2) Hz), 7.77 (1H, d, J = 8.1 Hz), 8.15-8.18 (1H, m), 8.19-8.23 (1H, m).
IR (KBr) 2930, 2213, 1568 cm ^-1
Example 11 (Production of compound 11)

A mixture of 4-fluoro-1-naphthonitrile (300 mg), 4-hydroxypiperidine (355 mg), potassium carbonate (485 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4-hydroxy-1-piperidinyl) -1-naphthonitrile (380 mg) (Compound 11).
mp 126-127 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.85-1.96 (2H, m), 2.05-2.20 (2H, m), 2.94-3.02 (2H, m ), 3.40-3.47 (2H, m), 3.95-4.03 (1H, m), 7.02 (1H, d, J = 7.8 Hz), 7.58 (1H, m) ddd, J = 8.1, 6.6 and 1.5 Hz), 7.65 (1H, ddd, J = 8.1, 6.6 and 1.5 Hz), 7.81 (1H, d, J = 7.8 Hz), 8.13-8.21 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₆ N ₂ O: C, 76.16; H, 6.39; N, 11.10.
Found: C, 76.01; H, 6.29; N, 10.92.
Example 12 (Production of compound 12)

A mixture of 4- (4-thiomorpholinyl) -1-naphthonitrile (150 mg) and dichloromethane (2.0 mL) in a mixture of m-chloroperbenzoic acid (70%, 291 mg) and dichloromethane (2.0 mL) Was added at -78 ° C, and the mixture was stirred for 5 hours while heating to 0 ° C. After adding a sodium sulfite solution, the mixture was extracted with ethyl acetate. The extract was washed with sodium carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1,1-dioxide-4-thiomorpholinyl) -1-naphthonitrile (112 mg) (Compound 12).
mp 265 ° C (dec).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.36-3.39 (4H, m), 3.68-3.71 (4H, m), 7.17 (1H, d, J = 7 .8 Hz), 7.65-7.77 (2H, m), 7.89 (1H, d, J = 7.8 Hz), 8.11-8.14 (1H, m), 8.25 -8.29 (1H, m).
IR (KBr) 2218, 1574 cm ^-1
_{.. Anal Calcd for C 15 H} 14 N 2 O 2 S: C, 62.92; H, 4.93; N, 9.78.
Found: C, 62.83; H, 5.05; N, 9.71.
Example 13 (Production of compound 13)

4-Fluoro-1-naphthonitrile (1.00 g), 1,4-dioxa-8-azaspiro [4,5] decane (1.67 g), potassium carbonate (1.62 g), dimethyl sulfoxide (10 g) mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1-naphthonitrile (1.42 g). (Compound 13).
mp 142-143 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.02 (4H, t, J = 5.7 Hz), 3.26-3.29 (4H, m), 4.04 (4H, s) , 7.05 (1H, d, J = 7.8 Hz), 7.59 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.83 (1H, d, J = 7.8 Hz), 8.16-8.22 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
_{.. Anal Calcd for C 18 H} 18 N 2 O 2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.34; H, 6.19; N, 9.40.
Example 14 (Production of compound 14)

4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1-naphthonitrile (423 mg), p-toluenesulfonic acid monohydrate (410 mg), acetone (17 mL) and water (2.5 mL) were stirred at 75 ° C. for 3.5 hours. The reaction solution was concentrated, a sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4-oxo-1-piperidinyl) -1-naphthonitrile (105 mg) (Compound 14).
mp 143-144 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.77 (4H, t, J = 6.0 Hz), 3.49 (4H, t, J = 6.0 Hz), 7.09 (1H , d, J = 7.8 Hz), 7.62-7.73 (2H, m), 7.85 (1H, d, J = 7.8 Hz), 8.22-8.26 (2H, m).
IR (KBr) 2216, 1717, 1574 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₄ N ₂ O: C, 76.78; H, 5.64; N, 11.19.
Found: C, 76.63; H, 5.87; N, 10.98.
Example 15 (Production of Compound 15)

A mixture of 4-fluoro-1-naphthonitrile (500 mg), isonipecotamide (749 mg), potassium carbonate (808 mg), and dimethyl sulfoxide (5.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- (4-cyano-1-naphthyl) -4-piperidinecarboxamide (651 mg) (Compound 15).
mp 249-250 ° C.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.88-1.94 (4H, m), 2.29-2.40 (1H, m), 2.78-2.87 (2H , m), 3.45-3.49 (2H, m), 6.85 (1H, br.s), 7.16 (1H, d, J = 7.8 Hz), 7.35 (1H, br.s), 7.68 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.76 (1H, ddd, J = 8.4, 6.9 and 1.2) Hz), 8.02-8.06 (2H, m), 8.13-8.16 (1H, m).
IR (KBr) 2211, 1663 cm ^-1
_{.. Anal Calcd for C 17 H} 17 N 3 O: C, 73.10; H, 6.13; N, 15.04.
Found: C, 72.92; H, 6.22; N, 14.87.
Example 16 (Production of compound 16)

Sodium hydride (60% oil, 121 mg) was added to a mixture of 4-amino-3-bromo-1-naphthonitrile (250 mg) and N, N-dimethylformamide (3.0 mL) at room temperature, and the mixture was added for 20 minutes. Stirred. After adding 1,5-dibromopentane (233 mg), the mixture was stirred at 50 ° C for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 3-bromo-4- (1-piperidinyl) -1-naphthonitrile (198 mg) (Compound 16).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.90 (6H, m), 3.14 (2H, br), 3.49 (2H, br), 7.59-7. 70 (2H, m), 7.80 (1H, s), 8.14-8.17 (1H, m), 8.38-8.43 (1H, m).
IR (KBr) 2934, 2222, 1551 cm ^-1
Example 17 (Production of compound 17)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 1-methylpiperazine (117 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4-methyl-1-piperazinyl) -1-naphthonitrile (100 mg) (Compound 17).
mp 128-129 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.43 (3H, s), 2.73 (4H, br.s), 3.22 (4H, br.s), 7.03 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.4, 6.6 and 1.2 Hz), 7.65 (1H, ddd, J = 8.4, 6. 6 and 1.2 Hz), 7.83 (1H, d, J = 7.8 Hz), 8.16-8.21 (2H, m).
IR (KBr) 2795, 2215, 1574 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₇ N ₃ : C, 76.46; H, 6.82; N, 16.72.
Found: C, 76.29; H, 6.62; N, 16.48
Example 18 (Production of compound 18)

A mixture of 4-fluoro-1-naphthonitrile (400 mg), 3-hydroxypyrrolidine (467 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-hydroxy-1-pyrrolidinyl) -1-naphthonitrile (447 mg) (Compound 18).
mp 138-139 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93 (1 H, d, J = 6.6 Hz), 2.08-2.29 (2H, m), 3.49-3.56 ( 2H, m), 3.84-3.98 (2H, m), 4.62-4.68 (1H, m), 6.73 (1H, d, J = 8.1 Hz), 7.46 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.60 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.72 (1H , d, J = 8.1 Hz), 8.13-8.16 (1H, m), 8.22-8.25 (1H, m).
IR (KBr) 3434, 2205, 1561 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₄ N ₂ O: C, 75.61; H, 5.92; N, 11.76.
Found: C, 75.37; H, 5.90; N, 11.57.
Example 19 (Production of compound 19)

A mixture of 4-fluoro-1-naphthonitrile (400 mg), 3- (hydroxymethyl) piperidine (539 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 ° C. for 3 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (560 mg) (Compound 19).
¹ H-NMR (300 Hz, CDCl ₃ ) δ: 1.20-1.32 (1H, m), 1.59 (1H, br.s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J = 10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 ( 1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.1, 6. 9 and 1.2 Hz), 7.62 (1H, ddd, J = 8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J = 7.8 Hz), 8. 13-8.18 (2H, m).
IR (KBr) 2932, 2216, 1572 cm ^-1
Example 20 (Production of compound 20)

4N Hydrogen chloride-ethyl acetate (2.0 mL) was added to 4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (560 mg), and the mixture was stirred at room temperature for 5 minutes. The residue obtained by concentration was treated with diethyl ether to obtain 4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile hydrochloride (631 mg) (Compound 20).
¹ H-NMR (300 Hz, DMSO-d ₆ ) δ: 1.10-1.24 (1H, m), 1.74-2.04 (4H, m), 2.54 (1H, t, J = 10.8 Hz), 2.76-2.84 (1H, m), 3.29-3.52 (4H, m), 7.14 (1H, d, J = 8.1 Hz), 7 .67 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.75 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 8.02 -8.06 (2H, m), 8.14-8.17 (1H, m).
Example 21 (Production of compound 21)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), (S) -3- (hydroxymethyl) piperidine (135 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was added at 100 ° C. Stir for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3S) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (133 mg) (Compound 21).
[Α] _D = + 4.9 ° (c = 0.460, MeOH).
¹ H-NMR (300 Hz, CDCl ₃ ) δ: 1.20-1.32 (1H, m), 1.59 (1H, br.s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J = 10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 ( 1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.1, 6. 9 and 1.2 Hz), 7.62 (1H, ddd, J = 8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J = 7.8 Hz), 8. 13-8.18 (2H, m).
Compound 21 was obtained by optical resolution shown in Example 23 as an alternative.
Example 22 (Production of compound 22)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), (R) -3- (hydroxymethyl) piperidine (135 mg), potassium carbonate (161 mg), and dimethyl sulfoxide (1.0 mL) was added at 100 ° C. Stir for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3R) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (139 mg) (Compound 22).
[Α] _D = -4.4 ° (c = 0.460, MeOH).
¹ H-NMR (300 Hz, CDCl ₃ ) δ: 1.20-1.32 (1H, m), 1.59 (1H, br.s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J = 10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 ( 1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.1, 6. 9 and 1.2 Hz), 7.62 (1H, ddd, J = 8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J = 7.8 Hz), 8. 13-8.18 (2H, m).
Compound 22 was obtained as an alternative by optical resolution as described in Example 23.
Example 23 (Production of compounds 21 and 22)

4- [3- (Hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (3.53 g) was optically resolved using CHILALCEL OD (50 × 500 mm) to give 4-[(3S) -3-. (Hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (compound 21, 1.77 g) and 4-[(3R) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (compound 22 1.77 g).
Example 24 (Production of compound 23)

4N Hydrogen chloride-ethyl acetate (2.0 mL) was added to 4-[(3S) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (1.66 g), and the mixture was stirred at room temperature for 5 minutes. . The precipitated compound was collected by filtration and washed with ethyl acetate to obtain 4-[(3S) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile hydrochloride (1.71 g) ( Compound 23).
mp 179-180 ° C.
[α] _D = + 1.3 ° (c = 0.535, MeOH).
¹ H-NMR (300 Hz, DMSO-d ₆ ) δ: 1.10-1.24 (1H, m), 1.74-2.04 (4H, m), 2.54 (1H, t, J = 10.8 Hz), 2.76-2.84 (1H, m), 3.29-3.52 (4H, m), 7.14 (1H, d, J = 8.1 Hz), 7 .67 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.75 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 8.02 -8.06 (2H, m), 8.14-8.17 (1H, m).
_{.. Anal Calcd for C 17 H} 18 N 2 O · HCl: C, 67.43; H, 6.32; N, 9.25.
Found: C, 67.21; H, 6.40; N, 9.07.
Example 25 (Production of compound 24)

To 4-[(3R) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (1.66 g) was added 4N hydrogen chloride-ethyl acetate (2.0 mL), and the mixture was stirred at room temperature for 5 minutes. . The precipitated compound was collected by filtration and washed with ethyl acetate to obtain 4-[(3R) -3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile hydrochloride (1.72 g) ( Compound 24).
mp 178-179 ° C.
[α] _D = -0.45 ° (c = 0.520, MeOH).
¹ H-NMR (300 Hz, DMSO-d ₆ ) δ: 1.10-1.24 (1H, m), 1.74-2.04 (4H, m), 2.54 (1H, t, J = 10.8 Hz), 2.76-2.84 (1H, m), 3.29-3.52 (4H, m), 7.14 (1H, d, J = 8.1 Hz), 7 .67 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.75 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 8.02 -8.06 (2H, m), 8.14-8.17 (1H, m).
_{.. Anal Calcd for C 17 H} 18 N 2 O · HCl: C, 67.43; H, 6.32; N, 9.25.
Found: C, 67.32; H, 6.30; N, 9.01.
Example 26 (Production of compound 25)

A mixture of 4-fluoro-1-naphthonitrile (500 mg), tert-butyl 3-pyrrolidinylcarbamate (1.09 g), potassium carbonate (808 mg), and dimethylsulfoxide (10 mL) was added at 100 ° C. for 3 hours. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 1- (4-cyano-1-naphthyl) -3-pyrrolidinylcarbamate (765 mg) (Compound 25).
mp 157-158 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.92-2.08 (1H, m), 2.26-2.43 (1H, m), 3. 41-3.61 (2H, m), 3.72-3.87 (2H, m), 4.35-4.45 (1H, m), 4.78 (1H, br.s), 6. 74 (1H, d, J = 8.0 Hz), 7.48 (1H, ddd, J = 8.8, 6.8 and 1.2 Hz), 7.62 (1H, ddd, J = 8. 8, 6.8 and 1.2 Hz), 7.75 (1H, d, J = 8.0 Hz), 8.15-8.22 (2H, m).
IR (KBr) 2978, 2209, 1694cm ^-1
_{.. Anal Calcd for C 20 H} 23 N 3 O 2: C, 71.19; H, 6.87; N, 12.45.
Found: C, 70.56; H, 6.93; N, 12.20.
Example 27 (Production of compound 26)

Sodium hydride (60% oil, 134 mg) was added to a mixture of 4-amino-2-bromo-1-naphthonitrile (70 mg) and N, N-dimethylformamide (3.5 mL) at room temperature, and the mixture was added for 20 minutes. Stirred. 1,5-Dibromopentane (93 mg) was added, and the mixture was stirred for 30 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-bromo-4- (1-piperidinyl) -1-naphthonitrile (58 mg) (Compound 26).
mp 179-180 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.74 (2H, m), 1.82-1.90 (4H, m), 3.12-1.16 (4H, m ), 7.13 (1H, s), 7.55 (1H, ddd, J = 8.4, 7.2 and 1.5 Hz), 7.64 (1H, ddd, J = 8.4, 7) .2 and 1.5 Hz), 8.07-8.10 (1H, m), 8.12-8.16 (2H, m).
IR (KBr) 2938, 2218, 1570 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₅ BrN ₂ : C, 60.97; H, 4.80; N, 8.89.
Found: C, 60.89; H, 4.70; N, 8.90.
Example 28 (Production of compound 27)

Oxalyl chloride (60 μL) was added to a mixture of dimethyl sulfoxide (0.10 mL) and dichloromethane (3.0 mL) at −78 ° C. Five minutes later, a mixture of 4- (3-hydroxy-1-pyrrolidinyl) -1-naphthonitrile (150 mg), dichloromethane (3.0 mL) and dimethylsulfoxide (0.20 mL) was added, and the mixture was stirred for 15 minutes. . Triethylamine (0.44 mL) was added, and the mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, sodium carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-oxo-1-pyrrolidinyl) -1-naphthonitrile (83 mg) (Compound 27).
mp 153-154 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.76 (2H, t, J = 7.2 Hz), 3.73 (2H, t, J = 7.2 Hz), 3.77 (2H , s), 7.04 (1H, d, J = 8.1 Hz), 7.61 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.69 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.85 (1H, d, J = 8.1 Hz), 8.16-8.18 (1H, m), 8.22 -8.25 (1H, m).
IR (KBr) 2215, 1759, 1572 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₂ N ₂ O: C, 76.25; H, 5.12; N, 11.86.
Found: C, 75.89; H, 5.13; N, 11.69.
Example 29 (Production of compound 28)

To tert-butyl 1- (4-cyano-1-naphthyl) -3-pyrrolidinylcarbamate (600 mg) was added 4N hydrogen chloride-ethyl acetate (3.0 mL) at room temperature, and the mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with ethyl acetate to give 4- (3-amino-1-pyrrolidinyl) -1-naphthonitrile dihydrochloride (558 mg) (Compound 28).
mp 161-163 ° C.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.11-2.21 (1H, m), 2.29-2.40 (1H, m), 3.48-3.55 (1H , m), 3.67 (1H, dd, J = 10.8 and 3.6 Hz), 3.82-3.96 (3H, m), 6.89 (1H, d, J = 8.4) Hz), 7.57-7.62 (1H, m), 7.71-7.76 (1H, m), 7.95 (1H, d, J = 8.4 Hz), 8.01-8 .04 (1H, m), 8.38 (1H, d, J = 8.4 Hz), 8.58 (3H, br.s).
IR (KBr) 2209, 1518 cm ^-1
Example 30 (Production of compound 29)

Sodium hydride (60% oily, 40 mg) was washed with hexane and suspended in N, N-dimethylformamide (1.0 mL). 4- (3-Hydroxy-1-pyrrolidinyl) -1-naphthonitrile (100 mg) was added, and the mixture was stirred for 10 minutes. After adding methyl iodide (78 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-methoxy-1-pyrrolidinyl) -1-naphthonitrile (102 mg) (Compound 29).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.10-2.24 (2H, m), 3.37 (3H, s), 3.52 (1H, ddd, J = 12.0, 7) 4.5 and 4.5 Hz), 3.57-3.62 (1H, m), 3.76-3.85 (2H, m), 4.09-4.14 (1H, m), 6. 72 (1H, d, J = 8.1 Hz), 7.46 (1H, ddd, J = 8.7, 6.9 and 1.5 Hz), 7.60 (1H, ddd, J = 8. 7, 6.9 and 1.5 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.14-8.18 (1H, m), 8.22-8.25 (1H , m).
IR (KBr) 2205, 1563, 1518 cm ^-1
Example 31 (Production of compound 30)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 4- (hydroxymethyl) piperidine (135 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 3 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (150 mg) (Compound 30).
mp 135-136 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (1H, t-like), 1.58-1.80 (3H, m), 1.93-1.98 (2H, m), 2.79-2.87 (2H, m), 3.55 (1H, dt-like, J = 12.3 Hz), 3.65 (2H, t, J = 5.4 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J = 8.4) , 6.9 and 1.5 Hz), 7.81 (1H, d, J = 7.8 Hz), 8.13-8.20 (2H, m).
IR (KBr) 2915, 2216, 1572 cm ^-1
Anal. Calcd. For C ₁₇ H ₁₈ N ₂ O: C, 76.66; H, 6.81; N, 10.52.
Found: C, 76.35; H, 6.88; N, 10.42.
Example 32 (Production of compound 31)

A mixture of 4-fluoro-1-naphthonitrile (300 mg), ethyl (S) -nipecotinate (551 mg), potassium carbonate (485 mg), and dimethyl sulfoxide (3.0 mL) was stirred at 100 ° C. for 3 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl (3S) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylate (508 mg) (Compound 31).
[α] _D = + 49.6 ° (c = 0.580, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.70-2.03 (3H, m), 2.14-2.20 ( 1H, m), 2.79-2.95 (2H, m), 3.07 (1H, t, J = 10.6 Hz), 3.35-3.41 (1H, m), 3.57 -3.62 (1H, m), 4.17 (2H, q, J = 7.0 Hz), 7.06 (1H, d, J = 8.2 Hz), 7.54-7.70 ( 2H, m), 7.84 (1H, d, J = 8.2 Hz), 8.13-8.23 (2H, m).
IR (KBr) 2216, 1730, 1574 cm ^-1
Example 33 (Production of compound 32)

A mixture of 4-fluoro-1-naphthonitrile (300 mg), ethyl (R) -nipecotinate (551 mg), potassium carbonate (485 mg), and dimethyl sulfoxide (3.0 mL) was stirred at 100 ° C. for 3 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl (3R) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylate (451 mg) (Compound 32).
[α] _D = -56.4 ° (c = 0.475, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.70-2.03 (3H, m), 2.14-2.20 ( 1H, m), 2.79-2.95 (2H, m), 3.07 (1H, t, J = 10.6 Hz), 3.35-3.41 (1H, m), 3.57 -3.62 (1H, m), 4.17 (2H, q, J = 7.0 Hz), 7.06 (1H, d, J = 8.2 Hz), 7.54-7.70 ( 2H, m), 7.84 (1H, d, J = 8.2 Hz), 8.13-8.23 (2H, m).
IR (KBr) 2216, 1730, 1574 cm ^-1
Example 34 (Production of compound 33)

A mixture of ethyl (3S) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylate (396 mg), 1N sodium hydroxide solution (2.6 mL), and tetrahydrofuran (4.4 mL) was added at room temperature. For 20 hours. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give (3S) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylic acid (351 mg) (Compound 33).
[α] _D = + 60.9 ° (c = 0.495, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-2.24 (4H, m), 2.86-3.00 (2H, m), 3.04-3.14 (1H, m ), 3.29-3.36 (1H, m), 3.58-3.62 (1H, m), 7.05 (1H, d, J = 7.8 Hz), 7.55-7. 68 (2H, m), 7.83 (1H, d, J = 7.8 Hz), 8.12-8.15 (1H, m), 8.18-8.21 (1H, m).
IR (KBr) 2947, 2216, 1705, 1474 cm ^-1
Example 35 (Production of compound 34)

A mixture of ethyl (3R) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylate (340 mg), 1N sodium hydroxide solution (2.2 mL), and tetrahydrofuran (4.0 mL) was added at room temperature. For 20 hours. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated to give (3R) -1- (4-cyano-1-naphthyl) -3-piperidinecarboxylic acid (287 mg) (Compound 34).
[α] _D = -63.9 ° (c = 0.500, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-2.24 (4H, m), 2.86-3.00 (2H, m), 3.04-3.14 (1H, m ), 3.29-3.36 (1H, m), 3.58-3.62 (1H, m), 7.05 (1H, d, J = 7.8 Hz), 7.55-7. 68 (2H, m), 7.83 (1H, d, J = 7.8 Hz), 8.12-8.15 (1H, m), 8.18-8.21 (1H, m).
IR (KBr) 2947, 2216, 1705, 1474 cm ^-1
Example 36 (Production of compound 35)

A mixture of 4-fluoro-1-naphthonitrile (400 mg), 2- (methoxymethoxymethyl) piperidine (744 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 ° C. for 60 hours. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give a tan oil. A mixture of this substance and trifluoroacetic acid (2.0 mL) was stirred at room temperature for 10 hours. The reaction solution was made alkaline with a 1N sodium hydroxide solution and extracted with diethyl ether. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [2- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (37 mg) (Compound 35).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42-1.92 (6H, m), 1.96-2.06 (1H, m), 2.88-2.96 (1H, m ), 3.30-3.37 (1H, m), 3.52-3.62 (3H, m), 7.21 (1H, d, J = 8.1 Hz), 7.55-7. 67 (2H, m), 7.82 (1H, d, J = 8.1 Hz), 8.17 (1H, d, J = 8.1 Hz), 8.29 (1H, d, J = 8 .1 Hz).
IR (KBr) 2935, 2216, 1570, 1508 cm ^-1
Example 37 (Production of compound 36)

A mixture of 7-hydroxy-4-nitro-1-indanone (1.02 g), triethylamine (2.21 mL) and dichloromethane (20 mL) was cooled to −25 ° C., and trifluoromethanesulfonic anhydride (1. A mixture of 33 mL) and dichloromethane (5.0 mL) was added in 15 minutes. After stirring at the same temperature for 10 minutes, the temperature was raised to room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography to obtain a brown solid (1.42 g). A mixture of this solid (140 mg), 3- (hydroxymethyl) piperidine (99 mg), potassium carbonate (119 mg), and dimethylsulfoxide (1.5 mL) was stirred at room temperature for 30 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7- [3- (hydroxymethyl) -1-piperidinyl] -4-nitro-1-indanone (95 mg) (Compound 36).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.13-1.18 (1H, m), 1.76-1.91 (4H, m), 2.03-2.18 (1H, m ), 2.69-2.73 (2H, m), 2.94 (1H, dd, J = 12.6 and 9.6 Hz), 3.11 (1H, ddd, J = 12.6, 9) .6 and 3.3 Hz), 3.52-3.70 (5H, m), 3.77-3.83 (1H, m), 6.85 (1H, d, J = 9.0 Hz) , 8.28 (1H, d, J = 9.0 Hz).
IR (KBr) 1699, 1586, 1319 cm ^-1
Example 38 (Production of compound 37)

Sodium borohydride (5.9 mg) was added to a mixture of 7- [3- (hydroxymethyl) -1-piperidinyl] -4-nitro-1-indanone (91 mg) and methanol (2.0 mL) at room temperature. added. After stirring for 30 minutes, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 7- [3- (hydroxymethyl) -1-piperidinyl] -4-nitro-1-indanol (92 mg). (Compound 37).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19-1.31 (1H, m), 1.64-2.18 (6H, m), 2.49-2.81 (2H, m ), 2.93-3.04 (1H, m), 3.16-3.67 (6H, m), 4.28 (1H, br.s), 5.51 (1H, t, J = 6) .6 Hz), 6.94 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 9.0 Hz).
Example 39 (Production of compounds 38 and 39)

A mixture of 7- [3- (hydroxymethyl) -1-piperidinyl] -4-nitro-1-indanol (79 mg), 0.5 N hydrochloric acid (9.0 mL), and ethanol (4.0 mL) was treated at 100 ° C. For 6 hours. After cooling to room temperature, the mixture was concentrated, the residue was neutralized with a sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography, and [1- (7-nitro-1H-inden-4-yl) -3-piperidinyl] methanol (37 mg) (compound 38) and [1- (4- [Nitro-1H-inden-7-yl) -3-piperidinyl] methanol (20 mg) (Compound 39).
Compound 38
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21-1.33 (1H, m), 1.71-2.07 (5H, m), 2.77 (1H, dd, J = 12) 2.0 and 9.6 Hz), 2.87-2.96 (1H, m), 3.49-3.70 (4H, m), 3.89 (2H, t, J = 1.8 Hz) , 6.64 (1H, dt, J = 5.7 and 1.8 Hz), 6.86 (1H, d, J = 8.7 Hz), 6.97 (1H, dt, J = 5.7) and 1.8 Hz), 8.02 (1H, d, J = 8.7 Hz).
IR (KBr) 2928, 1582, 1327 cm ^-1
Compound 39
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24-1.35 (1H, m), 1.62-2.04 (5H, m), 2.81 (1H, dd, J = 12) .3 and 9.6 Hz), 2.93-3.01 (1H, m), 3.49 (2H, t, J = 1.8 Hz), 3.56-3.71 (3H, m) , 3.75-3.80 (1H, m), 6.78 (1H, d, J = 9.0 Hz), 6.81 (1H, dt, J = 5.7 and 1.8 Hz), 7.68 (1H, dt, J = 5.7 and 1.8 Hz), 8.09 (1H, d, J = 9.0 Hz).
IR (KBr) 2936, 1584, 1318 cm ^-1
Example 40 (Production of compound 40)

A mixture of 4-fluoro-1-naphthonitrile (200 mg), 3-hydroxypiperidine (236 mg), potassium carbonate (322 mg), and dimethylsulfoxide (2.5 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-hydroxy-1-piperidinyl) -1-naphthonitrile (259 mg) (Compound 40).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.28 (5H, m), 3.02-3.16 (3H, m), 3.22-3.36 (1H, m ), 4.08-4.15 (1H, m), 7.03 (1H, d, J = 7.8 Hz), 7.59 (1H, ddd, J = 8.1, 6.6 and 1) 7.5 Hz), 7.66 (1H, ddd, J = 8.1, 6.6 and 1.5 Hz), 7.82 (1H, d, J = 7.8 Hz), 8.18-8 .21 (2H, m).
IR (KBr) 2216, 1572 cm ^-1
Example 41 (Production of compound 41)

Sodium hydride (60% oily, 84 mg) was washed with hexane and suspended in N, N-dimethylformamide (2.5 mL). 4- (3-Hydroxy-1-piperidinyl) -1-naphthonitrile (220 mg) was added, and the mixture was stirred for 10 minutes. After adding methyl iodide (160 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-methoxy-1-piperidinyl) -1-naphthonitrile (220 mg) (Compound 41).
mp 92-93 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.60 (1H, m), 1.79-2.03 (2H, m), 2.14-2.27 (1H, m ), 2.82-2.90 (2H, m), 3.28-3.34 (1H, m), 3.44 (3H, s), 3.51-3.64 (2H, m), 7.02 (1H, d, J = 7.8 Hz), 7.57 (1H, ddd, J = 8.4, 6.6 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6.6 and 1.5 Hz), 7.82 (1H, d, J = 7.8 Hz), 8.17-8.20 (2H, m).
IR (KBr) 2215, 1574 cm ^-1
Anal. Calcd. For C ₁₇ H ₁₈ N ₂ O: C, 76.66; H, 6.81; N, 10.52.
Found: C, 76.44; H, 6.73; N, 10.44.
Example 42 (Production of compound 42)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), N-pyrrolidin-3-ylacetamide (240 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C. for 16 hours. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from hexane: ethyl acetate = 4: 1 to give N- [1- (4-cyano-1-naphthyl) pyrrolidin-3-yl] acetamide. (136 mg) was obtained (compound 42).
mp 154-155 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.90-2.15 (1H, m), 2.02 (3H, s), 2.35-2.48 (1H, m), 3. 40-3.60 (2H, m), 3.70-3.92 (2H, m), 4.55-4.78 (1H, m), 5.90 (1H, d, J = 5.0) Hz), 6.72 (1H, d, J = 5.0 Hz), 7.42-7.68 (2H, m).
IR (KBr) 2203, 1649, 1563, 1518 cm ^-1
_{.. Anal Calcd for C 17 H} 17 N 3 O: C, 73.10; H, 6.13; N, 15.04.
Found: C, 72.92; H, 6.04; N, 14.85.
Example 43 (Production of compound 43)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), (2S) -pyrrolidin-2-ylmethanol (177 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was added at 100 ° C for 16 hours. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). The residue was dissolved in ethyl acetate, 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was crystallized to give 4-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -1-naphtho. The nitrile hydrochloride (148 mg) was obtained (compound 43).
mp 123-125 ° C.
[α] _D = + 119.7 ° (c = 0.870, MeOH).
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.60-2.05 (3H, m), 2.15-2.32 (1H, m), 3.25-3.57 (3H , m), 3.90-4.20 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 7.48-7.55 (2H, m), 7.89 (1H , d, J = 8.4 Hz), 7.98 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 8.4 Hz).
IR (KBr) 2225, 1522, 772 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₆ N ₂ O.HCl: C, 66.55; H, 5.93; N, 9.70.
Found: C, 66.27; H, 5.88; N, 9.58.
Example 44 (Production of compound 44)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), (2R) -pyrrolidin-2-ylmethanol (117 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was added at 100 ° C for 16 hours. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). The residue was dissolved in ethyl acetate, a 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was concentrated to dryness. Methyl) pyrrolidin-1-yl] -1-naphthonitrile hydrochloride (148 mg) was obtained (Compound 44).
mp 125-127 ° C.
[α] _D = -117.5 ° (c = 0.922, MeOH).
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.60-2.09 (3H, m), 2.14-2.34 (1H, m), 3.25-3.55 (3H , m), 3.85-4.20 (2H, m), 7.01 (1H, d, J = 8.4 Hz), 7.48-7.74 (2H, m), 7.89 (1H , d, J = 8.4 Hz), 7.98 (1H, dd, J = 1.2 and 8.4 Hz), 8.26 (1H, d, J = 8.4 Hz).
IR (KBr) 2225, 1522, 772 cm ^-1
Anal. Calcd. For
_{C 16 H 16 N 2 O ·} HCl · 0.2H 2 O: C, 65.73; H, 6.00; N, 9.58.
Found: C, 65.96; H, 5.93; N, 9.52.
Example 45 (Production of compound 45)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), (2R) -2- (methoxymethyl) pyrrolidine (200 mg), potassium carbonate (87 mg), and dimethyl sulfoxide (2.0 mL) was added at 100 ° C. Stirred for 16 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). The residue was dissolved in ethyl acetate, 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was concentrated to dryness and crystallized from hexane: ethyl acetate = 1: 1 to give 4-[(2R) -2- (methoxy). Methyl) pyrrolidin-1-yl] -1-naphthonitrile hydrochloride (63 mg) was obtained (Compound 45).
mp 88-89 ° C.
[α] _D = -136.6 ° (c = 0.696, MeOH).
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.65-2.05 (3H, m), 2.12-2.34 (1H, m), 3.15 (3H, s), 3.20-3.46 (2H, m), 3.93-4.05 (1H, m), 4.15-4.36 (1H, m), 7.06 (1H, d, J = 8 .4Hz), 7.50-7.76 (2H, m), 7.90 (1H, d, J = 8.4Hz), 8.00 (1H, dd, J = 1.0 and 8.4Hz) , 8.23 (1H, d, J = 8.4Hz).
IR (KBr) 2218, 1598, 1519, 1386, 773 cm ^-1
Anal. Calcd. For
_{C 17 H 18 N 2 O ·} HCl · 0.1H 2 O: C, 67.03; H, 6.35; N, 9.20.
Found: C, 66.97; H, 6.35; N, 9.05.
Example 46 (production of compound 46)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), L-prolinamide (200 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C for 15 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) and crystallized from hexane: ethyl acetate = 1: 2 to give 1- (4-cyano-1-naphthyl) -L-. Prolinamide (101 mg) was obtained (compound 46).
mp 177-178 ° C.
[α] _D = + 218.7 ° (c = 0.608, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.80-2.30 (3H, m), 2.30-2.72 (1H, m), 3.28-3.46 (1H, m ), 4.10-4.30 (1H, m), 4.38 (1H, t, J = 8.0Hz), 5.32 (1H, brs), 6.39 (1H, brs), 6. 97 (1H, d, J = 8.0 Hz), 7.52-7.75 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.18-8.32 (2H , m).
IR (KBr) 2210, 1691, 1323 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₅ N ₃ O: C, 72.43; H, 5.70; N, 15.84.
Found: C, 72.25; H, 5.52; N, 15.68.
Example 47 (Production of compound 47)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 2-methylpyrrolidine (150 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C for 15 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1). The residue was dissolved in ethyl acetate, 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was concentrated to dryness to give 4- (2-methylpyrrolidin-1-yl) -1-naphthonitrile hydrochloride as a hygroscopic amorphous substance. The salt (150 mg) was obtained (compound 47).
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (3H, d, J = 5.8 Hz), 1.58-2.10 (3H, m), 2.20-2.40 (1H, m), 3.20-3.60 (1H, m), 3.95-4.20 (2H, m), 6.92 (1H, d, J = 8.4 Hz), 7.49 -7.76 (2H, m), 7.90 (1H, d, J = 8.4 Hz), 7.99 (1H, d, J = 8.4 Hz), 8.25 (1H, d, J = 8.4Hz).
IR (KBr) 2209, 1566, 1515, 1328, 764 cm ^-1
Example 48 (Production of compound 48)

A mixture of 4-fluoro-1-naphthonitrile (400 mg), 2-methylpyrrolidine (410 mg), potassium carbonate (350 mg), and dimethylsulfoxide (8.0 mL) was stirred at 100 ° C for 5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain 4- (2-methylpyrrolidin-1-yl) -1-naphthonitrile (516 mg) (compound 48).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18 (3H, d, J = 5.8 Hz), 1.60-2.15 (3H, m), 2.20-2.40 (1H , m), 3.25-3.40 (1H, m), 3.90-4.15 (2H, m), 6.82 (1H, d, J = 8.0 Hz), 7.40- 7.70 (2H, m) 7.76 (1H, d, J = 8.0 Hz), 8.15-8.25 (2H, m).
IR (KBr) 2209, 1565, 1514, 1327, 763 cm ^-1
Example 49 (Production of compound 49)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), N-methyl-N-pyrrolidin-3-ylacetamide (249 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was treated at 100 ° C. For 15 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) and crystallized from hexane: ethyl acetate = 1: 1 to give N- [1- (4-cyano-1-naphthyl). Pyrrolidin-3-yl] -N-methylacetamide (130 mg) was obtained (Compound 49).
mp 144-145 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.00-2.40 (2H, m), 2.15 (2.1 H, s), 2.20 (0.9 H, s), 3. 03 (0.9H, s), 3.08 (2.1H, s), 3.40-3.78 (4H, m), 4.52-4.62 (0.3H, m), 5. 28-5.50 (0.7H, m), 6.80 (0.7H, d, J = 8.4Hz), 6.84 (0.3H, d, J = 8.4Hz), 7.45 -7.70 (2H, m), 7.77 (0.7H, J = 8.4Hz), 7.79 (0.3H, d, J = 8.4Hz), 8.12 (2H, d, J = 8.4Hz).
IR (KBr) 2199, 1655, 1565 cm ^-1
Anal. Calcd. For C ₁₈ H ₁₉ N ₃ O: C, 73.69; H, 6.53; N, 14.32.
Found: C, 73.48; H, 6.56; N, 14.12.
Example 50 (Production of compound 50)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), pyrrolidin-3-ylmethanol hydrochloride (240 mg), potassium carbonate (330 mg), and dimethyl sulfoxide (2.0 mL) was stirred at 100 ° C. for 3 hours. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The residue was dissolved in ethyl acetate, 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was concentrated to dryness. 4- [3- (hydroxymethyl) pyrrolidin-1-yl] -1-naphthonitrile hydrochloride (153 mg) was obtained as a hygroscopic amorphous (compound 50).
¹ H-NMR (200 MHz, CDCl ₃ + CD ₃ OD + D ₂ O) δ: 1.75-2.00 (1H, m), 2.05-2.38 (1H, m), 2.45 -2.80 (1H, m), 3.40-3.90 (6H, m), 6.81 (1H, d, J = 8.4Hz), 7.40-7.80 (3H, m) , 8.14 (1H, d, J = 8.4Hz), 8.29 (1H, d, J = 8.4Hz).
IR (KBr) 2205, 1561 cm ^-1
Example 51 (Production of compound 51)

4- (3- (Hydroxymethyl) pyrrolidin-1-yl) -1-naphthonitrile hydrochloride (85 mg) was dissolved in N, N-dimethylformamide (2.0 mL) and sodium hydride (60% oily, 28 mg) at room temperature and stirred for 1 hour. Then, after adding methyl iodide (0.1 mL), the mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 4- [3- (methoxymethyl) pyrrolidin-1-yl] -1-naphthonitrile (77 mg). (Compound 51).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.70-1.96 (1H, m), 2.06-2.30 (1H, m), 3.39 (3H, s), 3. 42-3.78 (6H, m), 6.72 (1H, d, J = 8.2 Hz), 7.40-7.68 (2H, m), 7.73 (1H, d, J = 8 .2Hz), 8.12-8.30 (2H, m).
IR (KBr) 2206, 1569 cm ^-1
Example 52 (Production of compound 52)

Mixture of 4-fluoro-1-naphthonitrile (100 mg), cis- (5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg), potassium carbonate (330 mg), dimethylsulfoxide (2.0 mL) Was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain cis-4- [4- (hydroxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (139 mg) (Compound 52). .
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 (3H, d, J = 6.2 Hz), 1.40-1.70 (1H, m), 2.28-2.58 (2H , m), 3.30-3.45 (1H, m), 3.62-4.20 (4H, m), 6.85 (1H, d, J = 8.4Hz), 7.44-7 .68 (2H, m), 7.77 (1H, d, J = 8.4Hz), 8.18 (2H, t, J = 8.4Hz).
IR (KBr) 2209, 1566, 1514, 1327 cm ^-1
Example 53 (Production of compound 53)

Mixture of 4-fluoro-1-naphthonitrile (100 mg), trans- (5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg), potassium carbonate (330 mg), dimethylsulfoxide (2.0 mL) Was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain trans-4- [4- (hydroxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (148 mg) (Compound 53). .
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 5.8 Hz), 1.18-1.99 (1H, m), 2.10-2.30 (1H , m), 2.40-2.70 (1H, m), 3.10-3.20 (1H, m), 3.40-3.70 (2H, m), 4.00-4.20 (2H, m), 6.86 (1H, d, J = 8.0 Hz), 7.48-7.70 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 8 .12-8.24 (2H, m).
IR (KBr) 2210, 1566, 1514, 1327 cm ^-1
Example 54 (Production of compound 54)

Dissolve cis-4- [4- (hydroxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (120 mg) in N, N-dimethylformamide (3.0 mL) and add sodium hydride (60% oily, 35 mg) was added at room temperature and stirred for 1 hour. After adding methyl iodide (0.2 mL), the mixture was stirred at room temperature for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain cis-4- [4- (methoxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (78 mg) (Compound 54). .
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.36 (3H, d, J = 6.2 Hz), 1.60-1.82 (1H, m), 2.44-2.76 (2H , m), 3.44-3.78 (3H, m), 3.56 (3H, s), 4.01 (1H, t, J = 8.8 Hz), 4.10-4.34 (1H , m), 7.01 (1H, d, J = 8.4 Hz), 7.60-7.86 (2H, m), 7.94 (1H, d, J = 8.0 Hz), 8.28 -8.42 (2H, m).
IR (KBr) 2210, 1567, 1514, 1330 cm ^-1
Example 55 (Production of compound 55)

Trans-4- [4- (hydroxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (129 mg) was dissolved in N, N-dimethylformamide (3.0 mL), and sodium hydride ( 60% oily, 32 mg) was added at room temperature and stirred for 1 hour. After adding methyl iodide (0.2 mL), the mixture was stirred at room temperature for 15 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain trans-4- [4- (methoxymethyl) -2-methylpyrrolidin-1-yl] -1-naphthonitrile (100 mg) (Compound 55). .
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.12 (3H, d, J = 5.8 Hz), 1.80-1.97 (1H, m), 2.08-2.22 (1H , m), 2.55-2.75 (1H, m), 3.03-3.40 (3H, m), 3.29 (3H, s), 4.00-4.20 (2H, m ), 6.86 (1H, d, J = 8.6Hz), 7.42-7.64 (2H, m), 7.77 (1H, d, J = 8.0Hz), 8.12-8 .24 (2H, m).
IR (KBr) 2211, 1566, 1515, 1332 cm ^-1
Example 56 (Production of compound 56)

A mixture of 4-fluoro-1-naphthonitrile (200 mg), 3- (hydroxymethyl) -3-methylpiperidine (301 mg), potassium carbonate (322 mg), and dimethyl sulfoxide (2.5 mL) was added at 100 ° C. Stir for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3-hydroxymethyl) -3-methyl-1-piperidinyl] -1-naphthonitrile (264 mg) (Compound 56).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.13 (3H, s), 1.40-1.48 (1H, m), 1.63-2.04 (4H, m), 2. 86-3.20 (4H, m), 3.63-3.76 (2H, m), 7.03 (1H, d, J = 8.1 Hz), 7.54-7.67 (2H, m m), 7.81 (1H, d, J = 8.1 Hz), 8.17-8.22 (2H, m).
IR (KBr) 2216, 1572 cm ^-1
Example 57 (Production of compound 57)

Sodium hydride (60% oily, 34 mg) was washed with hexane and suspended in N, N-dimethylformamide (1.0 mL). 4-[(3-Hydroxymethyl) -3-methyl-1-piperidinyl] -1-naphthonitrile (100 mg) was added, and the mixture was stirred for 10 minutes. After adding methyl iodide (66 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3-methoxymethyl) -3-methyl-1-piperidinyl] -1-naphthonitrile (100 mg) (Compound 57).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.14 (3H, s), 1.37-1.45 (1H, m), 1.62-1.70 (1H, m), 1. 84-1.94 (2H, m), 2.78-2.82 (1H, m), 3.04-3.14 (3H, m), 3.31 (1H, d, J = 9.0 Hz), 3.37 (3H, s), 3.48 (1H, d, J = 9.0 Hz), 7.02 (1H, d, J = 7.8 Hz), 7.57 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.80 (1H, d, J = 7.8 Hz), 8.16-8.19 (1H, m), 8.21-8.24 (1H, m).
IR (KBr) 2934, 2216, 1574 cm ^-1
Example 58 (Production of compound 58)

A mixture of 4-fluoro-1-naphthonitrile (150 mg), 3,5-dimethylpiperidine (198 mg), potassium carbonate (362 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3,5-dimethyl-1-piperidinyl) -1-naphthonitrile (223 mg) (Compound 58).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.72-0.84 (1H, m), 0.95 (6H, d, J = 6.6 Hz), 1.91-2.12 ( 3H, m), 2.32 (2H, t, J = 11.4 Hz), 3.39-3.44 (2H, m), 6.98 (1H, d, J = 7.8 Hz), 7.55 (1H, ddd, J = 8.4, 6.6 and 1.5 Hz), 7.63 (1H, ddd, J = 8.4, 6.6 and 1.5 Hz), 7. 80 (1H, d, J = 7.8 Hz), 8.11-8.14 (1H, m), 8.16-8.19 (1H, m).
IR (KBr) 2953, 2216, 1574 cm ^-1
Example 59 (Production of compound 59)

Pyrrolidine (16 μL), palladium acetate (1.9 mg), rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (15 mg), sodium t-butoxide (22 mg), toluene (1.5 mL) to a mixture of 4-cyano-5,6,7,8-tetrahydro-1-naphthalenyltrifluoromethanesulfonate (50 mg) and toluene (0.5 mL) at 80 ° C. Added in 50 minutes. After stirring for 1 hour, the mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-pyrrolidinyl) -5,6,7,8-tetrahydro-1-naphthalenecarbonitrile (12 mg) (Compound 59).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.75 (2H, m), 1.78-1.87 (2H, m), 1.92-1.96 (4H, m ), 2.61 (2H, t, J = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz), 3.25-3.29 (4H, m), 6.65 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 8.4 Hz).
IR (KBr) 2938, 2209, 1588 cm ^-1
Example 60 (Production of compound 60)

Piperidine (39 μL), palladium acetate (3.7 mg), rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (33 mg), sodium t-butoxide (44 mg), toluene (3.0 mL) to a mixture of 4-cyano-5,6,7,8-tetrahydro-1-naphthalenyltrifluoromethanesulfonate (100 mg) and toluene (1.0 mL) at 80 ° C. Added in 50 minutes. After stirring for 2 hours, the mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1-piperidinyl) -5,6,7,8-tetrahydro-1-naphthalenecarbonitrile (5.0 mg) (Compound 60).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.56-1.63 (2H, m), 1.67-1.77 (6H, m), 1.81-1.89 (2H, m ), 2.67 (2H, t, J = 6.0 Hz), 2.84-2.87 (4H, m), 2.96 (2H, t, J = 6.0 Hz), 6.83 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz).
IR (KBr) 2934, 2220, 1587 cm ^-1
Example 61 (Production of compounds 61 and 62)

4- (3-oxo-1-pyrrolidinyl) -1-naphthonitrile (159 mg), hydroxylamine hydrochloride (70.1 mg), sodium acetate (99.4 mg), ethanol (4.0 mL), water (2.0 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain 4- [3- (hydroxyimino) -1-pyrrolidinyl] -1-naphtho having a large Rf value. Nitrile (76.5 mg) (compound 61) and 4- [3- (hydroxyimino) -1-pyrrolidinyl] -1-naphthonitrile (20.4 mg) (compound 62) consisting of a small Rf value were obtained.
Compound 61
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.94 (2H, t, J = 6.9 Hz), 3.57 (2H, t, J = 6.9 Hz), 4.03 (2H , s), 7.00 (1H, d, J = 8.1 Hz), 7.37 (1H, br.s), 7.58 (1H, ddd, J = 8.4, 6.9 and 1) 0.5 Hz), 7.67 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.17-8 .23 (2H, m).
IR (KBr) 2216, 1572 cm ^-1
Compound 62
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.86-2.90 (2H, m), 3.57 (2H, t, J = 6.9 Hz), 4.22 (2H, s) , 7.01 (1H, d, J = 8.1 Hz), 7.23 (1H, br.s), 7.58 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz) ), 7.67 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.17-8.23 ( 2H, m).
IR (KBr) 2215, 1572 cm ^-1
Example 62 (Production of compound 63)

Pyrrolidine (31 μL), palladium acetate (3.5 mg), rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (29 mg), sodium t-butoxide (42 mg), toluene (1.5 mL) to a mixture of 7-cyano-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yltrifluoromethanesulfonate (100 mg) and toluene (0.8 mL). Was added at 80 ° C for 30 minutes. After stirring for 1.5 hours, the mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-4- (1-pyrrolidinyl) -2,3-dihydro-1-benzofuran-7-carbonitrile (30 mg) (compound 63).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49 (6H, s), 1.93-1.98 (4H, m), 3.27 (2H, s), 3.45-3. 49 (4H, m), 6.03 (1H, d, J = 8.7 Hz), 7.13 (1H, d, J = 8.7 Hz).
IR (KBr) 2201, 1613 cm ^-1
Example 63 (Production of compound 64)

4-cyano-1-naphthylboronic acid (760 mg), 2-methyl-3-oxocyclopenta-1-en-1-yl trifluoromethanesulfonate (940 mg) and tetrakistriphenylphosphine (90 mg) were added to dioxane. (24 mL) and a 2N-sodium carbonate solution (3.5 mL) were heated to reflux for 2.5 hours under a nitrogen stream. After cooling to room temperature, the mixture was concentrated, water was poured into the reaction product, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (2-methyl-3-oxocyclopenta-1-en-1-yl) -1-naphthonitrile (622 mg) (Compound 64). .
mp 163-165 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.59 (3H, dd, J = 1.8 Hz and 2.2 Hz), 2.65-2.75 (2H, m), 2.90-3 .01 (2H, m), 7.40 (1H, d, J = 7.4 Hz), 7.60-7.95 (3H, m), 7.99 (1H, d, J = 7.4 Hz), 8.30-8.40 (1H, m).
IR (KBr) 2223, 1689, 1644 cm ^-1
Anal. Calcd. For
C ₁₇ H ₁₃ NO · 0.1 H ₂ O: C, 81.97; H, 5.33; N, 5.62.
Found: C, 81.99; H, 5.33; N, 5.49.
Example 64 (Production of compound 65)

4- (2-Methyl-3-oxocyclopenta-1-en-1-yl) -1-naphthonitrile (125 mg) was dissolved in methyl alcohol (5 mL), and sodium borohydride (50 mg) was dissolved in methyl alcohol (5 mL). The mixture was stirred at room temperature for 15 minutes. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-hydroxy-2-methylcyclopenta-1-en-1-yl) -1-naphthonitrile (63 mg) (Compound 65). .
mp 113-114 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.53-1.65 (3H, m), 1.80-2.05 (2H, m), 2.45-2.98 (3H, m ), 4.85-5.05 (1H, m), 7.33 (1H, d, J = 7.6 Hz), 7.55-7.76 (2H, m), 7.85-7. 96 (2H, m), 8.22-8.35 (1H, m).
IR (KBr) 3505, 2222 cm ^-1
Anal. Calcd. For C ₁₇ H ₁₅ NO: C, 81.90; H, 6.06; N, 5.62.
Found: C, 81.84; H, 6.25; N, 5.40.
Example 65 (Production of compound 66)

4- (3-Hydroxy-2-methylcyclopenta-1-en-1-yl) -1-naphthonitrile (50 mg) was dissolved in N, N-dimethylformamide (2 mL) and stirred under ice-cooling. . Then, sodium hydride (60% oily, 15 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, methyl iodide (0.1 mL) was added, and the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-methoxy-2-methylcyclopenta-1-en-1-yl) -1-naphthonitrile (19 mg) (Compound 66) ).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.50-1.60 (3H, s), 1.19-2.10 (1H, m), 2.30-2.50 (2H, m ), 3.46 (3H, m), 4.40-4.60 (1H, m), 7.32 (1H, d, J = 7.2 Hz), 7.50-7.80 (2H, m) m), 7.90 (2H, d, J = 7.2 Hz), 8.20-8.35 (1H, m).
IR (KBr) 2222, 1102 cm ^-1
Example 66 (Production of compound 67)

Sodium hydride (60% oil, 28 mg) was added to a mixture of 4- [4- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (80 mg) and N, N-dimethylformamide (1.0 mL). Was added at room temperature. After stirring for 20 minutes, methyl iodide (60 μl) was added, and the mixture was stirred for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (methoxymethyl) -1-piperidinyl] -1-naphthonitrile (79 mg) (Compound 67).
mp 96-97 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.70 (2H, m), 1.78-1.95 (3H, m), 2.82 (2H, td, J = 12) 2.0 and 2.1 Hz), 3.37 (2H, d, J = 6.0 Hz), 3.40 (3H, s), 3.51-3.55 (2H, m), 7.01 (1H, d, J = 8.1 Hz), 7.56 (1H, ddd, J = 8.4, 6.6 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4) , 6.6 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.17-8.21 (2H, m).
IR (KBr) 2213, 1570 cm ^-1
Anal. Calcd. For C ₁₈ H ₂₀ N ₂ O: C, 77.11; H, 7.19; N, 9.99.
Found: C, 77.00; H, 7.11; N, 9.77.
Example 67 (Production of compound 68)

Lithium aluminum hydride (16 mg) was added to a mixture of 1-benzyl-5-hydroxy-5-methyl-2-piperidinone (95 mg) and tetrahydrofuran (2.5 mL) at room temperature, and the mixture was stirred at 75 ° C for 5 hours. . After cooling to room temperature, water (16 μl), a 25% potassium hydroxide solution (16 μl) and water (48 μl) were sequentially added, followed by stirring for 1 hour. The insolubles were filtered off using celite, and the mother liquor was concentrated to obtain a yellow oily substance. A mixture of this substance, 10% palladium on carbon (containing 50% water, 92 mg), 4N hydrochloric acid (0.12 mL), and methanol (1.4 mL) was stirred at room temperature under a hydrogen atmosphere for 12 hours. Palladium carbon was removed by filtration using Celite. The mother liquor was concentrated to give a pale orange oil. A mixture of this substance, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (120 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-hydroxy-3-methyl-1-piperidinyl) -1-naphthonitrile (15 mg) (Compound 68).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (3H, s), 1.49-1.59 (1H, m), 1.78-1.89 (2H, m), 2. 05-2.22 (1H, m), 2.70-2.85 (2H, m), 3.02 (1H, br.s), 3.22-3.26 (1H, m), 3. 40-3.53 (1H, m), 7.05 (1H, d, J = 7.8 Hz), 7.60-7.70 (2H, m), 7.83 (1H, d, J = 7.8 Hz), 8.20-8.29 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
Example 68 (Production of compound 69)

To a mixture of 4- (3-amino-1-pyrrolidinyl) -1-naphthonitrile (120 mg), triethylamine (0.22 mL) and N, N-dimethylformamide (1.5 mL) was added methanesulfonyl chloride (45 μL). ) Was added at room temperature and stirred for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain N- [1- (4-cyano-1-naphthyl) -3-pyrrolidinyl] methanesulfonamide (93 mg) (Compound 69).
mp 128-129 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05-2.16 (1H, m), 2.39-2.50 (1H, m), 3.03 (3H, s), 3. 47-3.57 (2H, m), 3.74-3.84 (2H, m), 4.17-4.29 (1H, m), 4.80 (1H, d, J = 7.8 Hz), 6.78 (1H, d, J = 8.4 Hz), 7.52 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.64 (1H, ddd) , J = 8.4, 6.9 and 1.2 Hz), 7.75 (1H, d, J = 8.4 Hz), 8.15-8.19 (2H, m).
IR (KBr) 2207, 1564, 1329, 1152 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₇ N ₃ O ₂ S: C, 60.93; H, 5.43; N, 13.32.
Found: C, 60.98; H, 5.57; N, 13.15.
Example 69 (Production of compound 70)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 1,2,3,4-tetrahydroisoquinoline (150 mg), potassium carbonate (161 mg) and dimethyl sulfoxide (1.5 mL) was added at 100 ° C. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3,4-dihydro-2 (1H) -isoquinolinyl) -1-naphthonitrile (140 mg) (Compound 70).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.15 (2H, t, J = 6.0 Hz), 3.55 (2H, t, J = 6.0 Hz), 4.39 (2H , s), 7.10-7.14 (2H, m), 7.18-7.26 (3H, m), 7.57 (1H, ddd, J = 8.1, 6.9 and 1. 2 Hz), 7.66 (1H, ddd, J = 8.1, 6.9 and 1.2 Hz), 7.84 (1H, d, J = 7.8 Hz), 8.20-8. 24 (2H, m).
IR (KBr) 2216, 1572 cm ^-1
Example 70 (Production of compound 71)

4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile (120 mg), tertbutyl methylsulfonylcarbamate (106 mg), triphenylphosphine (142 mg), and tetrahydrofuran (2.0 mL) )) At 0 ° C. was added diethyl azodicarboxylate (40% toluene solution, 0.25 mL). After stirring for 1.5 hours and concentrating, the residue obtained was purified by silica gel column chromatography to give [tert-butyl [[1- (4-cyano-1-naphthyl) -3-piperidinyl] methyl] (methylsulfonyl) carbamate. (195 mg) was obtained (Compound 71).
mp 139-140 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.20-1.36 (1H, m), 1.51 (9H, s), 1.87-1.98 (3H, m), 2. 30-2.42 (1H, m), 2.59 (1H, t, J = 10.8 Hz), 2.77-2.84 (1H, m), 3.28 (3H, s), 3 .39-3.50 (2H, m), 3.60-3.75 (2H, m), 7.00 (1H, d, J = 7.8 Hz), 7.55 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.63 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.81 (1H, d, J = 7 .8 Hz), 8.10-8.19 (2H, m).
IR (KBr) 2215, 1726, 1352 cm ^-1
Anal. Calcd. For C ₂₃ H ₂₉ N ₃ O ₄ S: C, 62.28; H, 6.59; N, 9.47.
Found: C, 62.06; H, 6.50; N, 9.33.
Example 71 (Production of compound 72)

A mixture of tert-butyl 1- (4-cyano-1-naphthyl) -3-piperidinyl] methyl (methylsulfonyl) carbamate (127 mg, trifluoroacetic acid (0.4 mL) and dichloromethane (1.0 mL) was added at room temperature. The reaction mixture was diluted with diethyl ether, washed with 1N sodium hydroxide and brine, dried and concentrated to give N-[[1- (4-cyano-1-naphthyl) -3. -Piperidinyl] methyl] methanesulfonamide (86 mg) was obtained (Compound 72).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18-1.35 (1H, m), 1.83-2.04 (3H, m), 2.09-2.21 (1H, m ), 2.64 (1H, t, J = 10.2 Hz), 2.81-2.88 (1H, m), 2.95 (3H, s), 3.10-3.24 (2H, m), 3.35-3.39 (1H, m), 3.44-3.52 (1H, m), 4.45 (1H, t, J = 6.6 Hz), 7.01 (1H , d, J = 7.8 Hz), 7.57 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6) .9 and 1.5 Hz), 7.81 (1H, d, J = 7.8 Hz), 8.10-8.13 (1H, m), 8.17-8.19 (1H, m) IR (KBr) 2215, 1572, 1316, 1154 cm ^-1
Example 72 (Production of compound 73)

A mixture of 7-cyano-1-benzothien-4-yltrifluoromethanesulfonate (150 mg) and piperidine (0.45 mL) was stirred at room temperature for 2 hours. The reaction was partitioned between ethyl acetate and water. The residue obtained by drying and concentrating the organic layer was purified by silica gel column chromatography to obtain 4- (1-piperidinyl) -1-benzothiophene-7-carbonitrile (35 mg) (Compound 73).
mp 99-100 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.71 (2H, m), 1.77-1.84 (4H, m), 3.20-3.24 (4H, m ), 6.83 (1H, d, J = 8.1 Hz), 7.40 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 8.1 Hz).
IR (KBr) 2938, 2213, 1568 cm ^-1
Anal. Calcd. For C ₁₄ H ₁₄ N ₂ S: C, 69.39; H, 5.82; N, 11.56.
Found: C, 69.27; H, 5.71; N, 11.40.
Example 73 (Production of compound 74)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), nipecotamide (150 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- (4-cyano-1-naphthyl) -3-piperidinecarboxylic acid amide (140 mg) (Compound 74).
mp 187-188 ° C.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.51-1.64 (1H, m), 1.76-1.87 (2H, m), 1.96-2.02 (1H , m), 2.65-2.81 (2H, m), 2.90 (1H, t, J = 11.1 Hz), 3.38-3.48 (2H, m), 6.90 ( 1H, br.s), 7.17 (1H, d, J = 8.4 Hz), 7.40 (1H, br.s), 7.68 (1H, ddd, J = 8.1, 6. 6 and 1.2 Hz), 7.76 (1H, ddd, J = 8.1, 6.6 and 1.2 Hz), 8.02-8.07 (1H, m), 8.15-8 .17 (1H, m).
IR (KBr) 3422, 2216, 1661 cm ^-1
Anal. Calcd. For
C ₁₇ H ₁₇ N ₃ O · 0.1 H ₂ O: C, 72.63; H, 6.17; N, 14.95.
Found: C, 72.56; H, 6.16; N, 14.64.
Example 74 (production of compound 75)

1,2-oxadinane hydrochloride (300 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorin (polystyrene supported, about 2.2 mmol / g) ) (1.20 g) and dichloromethane (6.0 mL) were stirred at room temperature for 3 hours. The resin was filtered off, washed with dichloromethane and concentrated to give a colorless oil. A mixture of this substance, 4-fluoro-1-naphthonitrile (225 mg), potassium carbonate (336 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100 ° C for 27 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1,2-oxadinan-2-yl) -1-naphthonitrile (34 mg) (Compound 75).
mp 111-112 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.77-1.85 (2H, m), 2.03-2-1.10 (2H, m), 3.32-3.36 (2H, m ), 4.28 (2H, t, J = 5.4 Hz), 7.44 (1H, d, J = 7.8 Hz), 7.57 (1H, ddd, J = 8.4, 6. 9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.86 (1H, d, J = 7.8 Hz), 8. 09-8.12 (1H, m), 8.17-8.20 (1H, m).
IR (KBr) 2220, 1576 cm ^-1
Anal. Calcd. For
C ₁₅ H ₁₄ N ₂ O · 0.2H ₂ O: C, 74.48; H, 6.00; N, 11.58.
Found: C, 74.69; H, 5.87; N, 11.45.
Example 75 (Production of compound 76)

A mixture of 4-fluoro-1-benzothiophene-7-carbonitrile (349 mg), 2-methylpyrrolidine (252 mg), potassium carbonate (544 mg), and dimethyl sulfoxide (4.0 mL) was added at 100 ° C. for 1 hour. Stirred. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile (466 mg) (Compound 76).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.26 (3H, d, J = 6.0 Hz), 1.70-1.81 (1H, m), 1.86-2.30 ( 3H, m), 3.64-3.71 (1H, m), 3.86-3.94 (1H, m), 4.14-4.23 (1H, m), 6.50 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 6.0 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 6.0 Hz).
IR (KBr) 2205, 1566 cm ^-1
Example 76 (Production of compound 77)

A mixture of 4-fluoro-1-naphthonitrile (200 mg), (4-methyl-4-piperidinyl) methanol (242 mg), potassium carbonate (332 mg), and dimethylsulfoxide (3.0 mL) was added at 100 ° C. for 3 hours. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (hydroxymethyl) -4-methyl-1-piperidinyl] -1-naphthonitrile (256 mg) (Compound 77).
mp 136-137 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, s), 1.48 (1H, t, J = 6.0 Hz), 1.55-1.61 (2H, m) , 1.90 (2H, ddd, J = 13.2, 10.2 and 4.2 Hz), 3.04-3.12 (2H, m), 3.24-3.31 (2H, m) , 3.53 (2H, d, J = 6.0 Hz), 7.04 (1H, d, J = 8.1 Hz), 7.57 (1H, ddd, J = 8.1, 6.9) and 1.5 Hz), 7.65 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.83 (1H, d, J = 8.1 Hz), 8.15 -8.21 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
Anal. Calcd. For C ₁₈ H ₂₀ N ₂ O: C, 77.11; H, 7.19; N, 9.99.
Found: C, 76.88; H, 7.12; N, 9.72.
Example 77 (Production of compound 78)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 4-piperidineethanol (151 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (2-hydroxyethyl) -1-piperidinyl] -1-naphthonitrile (149 mg) (Compound 78).
mp 128-129 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (1 H, t, J = 5.1 Hz), 1.59-1.73 (5H, m), 1.90-1.94 ( 2H, m), 2.78-2.86 (2H, m), 3.49-3.53 (2H, m), 3.77-3.83 (2H, m), 7.01 (1H, d, J = 8.1 Hz), 7.56 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6. 9 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.14-8.20 (2H, m).
IR (KBr) 2924, 2216, 1572 cm ^-1
Anal. Calcd. For C ₁₈ H ₂₀ N ₂ O: C, 77.11; H, 7.19; N, 9.99.
Found: C, 76.89; H, 7.03; N, 9.71
Example 78 (Production of compound 79)

To a mixture of 4- [4- (2-hydroxyethyl) -1-piperidinyl] -1-naphthonitrile (80 mg) and N, N-dimethylformamide (1.0 mL) was added sodium hydride (60% oil, 34%). .1 mg) at room temperature and stirred for 20 minutes. After adding methyl iodide (66 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (2-methoxyethyl) -1-piperidinyl] -1-naphthonitrile (79 mg) (Compound 79).
mp 95-96 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.69 (5H, m), 1.88-1.92 (2H, m), 2.77-2.85 (2H, m ), 3.37 (3H, s), 3.48-3.52 (4H, m), 7.00 (1H, d, J = 7.8 Hz), 7.56 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J = 8.1, 6.9 and 1.5 Hz), 7.81 (1H, d, J = 7. 8 Hz), 8.14-8.20 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
_{.. Anal Calcd for C 19 H} 22 N 2 O: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.37; H, 7.31; N, 9.40.
Example 79 (Production of compound 80)

A mixture of 2- (1-benzyl-4-piperidinyl) -2-propanol (790 mg), 10% palladium on carbon (50% water content, 720 mg), and methanol (20 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. . The palladium carbon was removed by filtration using Celite and washed with methanol. The mother liquor was concentrated to give a colorless solid (485 mg). A mixture of this solid (151 mg), 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (1-hydroxy-1-methylethyl) -1-piperidinyl] -1-naphthonitrile (150 mg) (Compound 80).
mp 133-134 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (6H, s), 1.48-1.59 (1H, m), 1.66-1.80 (2H, m), 1. 94-1.98 (2H, m), 2.74-2.82 (2H, m), 3.58-3.62 (2H, m), 7.00 (1H, d, J = 8.1) Hz), 7.56 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz) , 7.81 (1H, d, J = 8.1 Hz), 8.14-8.20 (2H, m).
IR (KBr) 2216, 1574 cm ^-1
_{.. Anal Calcd for C 19 H} 22 N 2 O: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.31; H, 7.28; N, 9.24.
Example 80 (production of compounds 81 and 82)

A mixture of tert-butyl (2R) -2-vinyl-1-pyrrolidinecarboxylate (70 mg) and 4N hydrogen chloride-ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated and treated with diethyl ether to give a colorless solid. A mixture of the solid, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R) -2-vinyl-1-pyrrolidinyl] -1-naphthonitrile (36 mg). The enantiomeric excess of this compound was 24.8% ee.
A mixture of tert-butyl (2S) -2-vinyl-1-pyrrolidinecarboxylate (185 mg) and 4N hydrogen chloride-ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated and treated with diethyl ether to give a colorless solid. A mixture of this solid, 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (242 mg), and dimethyl sulfoxide (1.5 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S) -2-vinyl-1-pyrrolidinyl] -1-naphthonitrile (90 mg). The enantiomeric excess of this compound was 22.7% ee.
The above 4-[(2R) -2-vinylpyrrolidinyl] -1-naphthonitrile (25 mg) and the above 4-[(2S) -2-vinylpyrrolidinyl] -1-naphthonitrile (70 mg) were used. Combined and subjected to optical resolution using CHIRALPAK AS (50 × 500 mm) to give 4-[(2R) -2-vinyl-1-pyrrolidinyl] -1-naphthonitrile (compound 81) (43 mg) and 4- [ (2S) -2-vinyl-1-pyrrolidinyl] -1-naphthonitrile (compound 82) (50 mg) was obtained.

Compound 81
[Α] _D = -267.0 ° (c = 0.295, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-1.35 (1H, m ), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J = 10.2 and 1.2 Hz), 5.23 (1H, dt, J = 17.1 and 1.2 Hz), 5.70 (1H, ddd, J = 17.1, 10.2 and 7) .2 Hz), 6.78 (1H, d, J = 8.4 Hz), 7.46 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.59 (1H , ddd, J = 8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J = 8.4 Hz), 8.13-8.16 (1H, m), 8. 21-8.24 (1H, m).
IR (KBr) 2209, 1566 cm ^-1

Compound 82
[Α] _D = + 267.9 ° (c = 0.345, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-1.35 (1H, m ), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J = 10.2 and 1.2 Hz), 5.23 (1H, dt, J = 17.1 and 1.2 Hz), 5.70 (1H, ddd, J = 17.1, 10.2 and 7) .2 Hz), 6.78 (1H, d, J = 8.4 Hz), 7.46 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.59 (1H , ddd, J = 8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J = 8.4 Hz), 8.13-8.16 (1H, m), 8. 21-8.24 (1H, m).
IR (KBr) 2209, 1566 cm ^-1
Example 81 (Production of compounds 83 and 84)

A mixture of tert-butyl (2S) -2-ethyl-1-pyrrolidinecarboxylate (70 mg) and 4N hydrogen chloride-ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated and treated with diethyl ether to give a colorless solid. A mixture of the solid, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S) -2-ethyl-1-pyrrolidinyl] -1-naphthonitrile (33 mg). The enantiomeric excess of this compound was 24.4% ee.
A mixture of tert-butyl (2R) -2-ethyl-1-pyrrolidinecarboxylate (130 mg) and 4N hydrogen chloride-ethyl acetate (1.5 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated and treated with diethyl ether to give a colorless solid. A mixture of this solid, 4-fluoro-1-naphthonitrile (75 mg), potassium carbonate (182 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R) -2-ethyl-1-pyrrolidinyl] -1-naphthonitrile (85 mg). The enantiomeric excess of this compound was 21.0% ee.
The 4-[(2S) -2-ethyl-1-pyrrolidinyl] -1-naphthonitrile (80 mg) and the 4-[(2R) -2-ethyl-1-pyrrolidinyl] -1-naphthonitrile (19 mg) ) Were combined and subjected to optical resolution using CHIRALPAK AS (50 × 500 mm) to give 4-[(2S) -2-ethyl-1-pyrrolidinyl] -1-naphthonitrile (compound 83) (44 mg) and 4 -[(2R) -2-Ethyl-1-pyrrolidinyl] -1-naphthonitrile (Compound 84) (51 mg) was obtained.

Compound 83
[Α] _D = -294.6 ° (c = 0.330, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 ( 3H, m), 1.95-2.05 (1H, m), 2.26-1.34 (1H, m), 3.32-2.38 (1H, m), 3.83-3.3. 92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J = 8.1 Hz), 7.45 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.13-8.18 (2H, m).
IR (KBr) 2963, 2209, 1564 cm ^-1

Compound 84
[Α] _D = + 294.9 ° (c = 0.380, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 ( 3H, m), 1.95-2.05 (1H, m), 2.26-1.34 (1H, m), 3.32-2.38 (1H, m), 3.83-3.3. 92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J = 8.1 Hz), 7.45 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.13-8.18 (2H, m).
IR (KBr) 2963, 2209, 1564 cm ^-1
Example 82 (Production of compound 85)

Tert-butyl (2S) -2-methylpyrrolidine-1-carboxylate ([α] _D = + 32.7 ° (c = 2.17, CHCl ₃ )) (1250 mg) synthesized by a known method was dissolved in toluene ( 2.0 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (855 mg), potassium carbonate (2800 mg), and dimethyl sulfoxide (10.0 mL), and the mixture was stirred at 100 ° C. for 5.5 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (780 mg) (Compound 85).
[Α] _D = -244.4 ° (c = 0.448, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18 (3H, d, J = 5.8 Hz), 1.60-2.15 (3H, m), 2.20-2.40 (1H , m), 3.25-3.40 (1H, m), 3.90-4.15 (2H, m), 6.82 (1H, d, J = 8.0 Hz), 7.40- 7.70 (2H, m) 7.76 (1H, d, J = 8.0 Hz), 8.15-8.25 (2H, m).
Example 83 (Production of compounds 85 and 86)

4- (2-Methyl-1-pyrrolidinyl) -1-naphthonitrile (1.68 g) was subjected to optical resolution using CHIRALPAK AS (50 × 500 mm) to give 4-[(2S) -2-methyl- 1-Pyrrolidinyl] -1-naphthonitrile (compound 85) (804 mg) and 4-[(2R) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (compound 86) (805 mg) were obtained.

Compound 85
mp 73-74 ° C.
[Α] _D = -251.5 ° (c = 0.470, MeOH).
NMR was consistent with that of compound 85 described in Example 81.
IR (KBr) 2209, 1565, 1514, 1327, 763 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₆ N ₂ : C, 81.32; H, 6.82; N, 11.85.
Found: C, 81.35; H, 6.87; N, 11.84.

Compound 86
[Α] _D = + 257.7 ° (c = 0.410, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18 (3H, d, J = 5.8 Hz), 1.60-2.15 (3H, m), 2.20-2.40 (1H , m), 3.25-3.40 (1H, m), 3.90-4.15 (2H, m), 6.82 (1H, d, J = 8.0 Hz), 7.40- 7.70 (2H, m) 7.76 (1H, d, J = 8.0 Hz), 8.15-8.25 (2H, m).
IR (KBr) 2209, 1565, 1514, 1327, 763 cm ^-1
Example 84 (Production of compound 87)

A mixture of 4-fluoro-1-naphthonitrile (70 mg), ethyl 3- (4-piperidinyl) butyrate (91 mg), potassium carbonate (78 mg) and dimethylsulfoxide (1.0 mL) was added at 100 ° C. for 1 hour. Stirred. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl 3- [1- (4-cyano-1-naphthyl) -4-piperidinyl] butyrate (110 mg) (Compound 87).
mp 106-107 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.2 Hz), 1.54-1.62 (2H, m), 1.69-1.77 ( 2H, m), 1.88-1.91 (2H, m), 2.41 (2H, t, J = 7.5 Hz), 2.79 (2H, t, J = 11.1 Hz), 3.46-3.52 (2H, m), 4.16 (2H, q, J = 7.2 Hz), 6.99 (1H, d, J = 7.8 Hz), 7.55 (1H , ddd, J = 8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.80 (1H, d , J = 7.8 Hz), 8.12-8.19 (2H, m).
IR (KBr) 2216, 1732, 1574 cm ^-1
Anal. Calcd. For C ₂₁ H ₂₄ N ₂ O ₂ : C, 74.97; H, 7.19; N, 8.33.
Found: C, 74.71; H, 7.08; N, 7.99.
Example 85 (Production of compound 88)

Lithium aluminum hydride (178 mg) was added to a mixture of ethyl 3- (4-piperidinyl) butyrate (870 mg) and tetrahydrofuran (10 mL) at 0 ° C, and the mixture was stirred for 6 hours. Water (0.18 mL), 25% potassium hydroxide solution (0.18 mL), and water (0.54 mL) were sequentially added, and the mixture was stirred for 14 hours. The insolubles were filtered off using celite and the mother liquor was concentrated to give a pale yellow oil (590 mg). A mixture of this substance (167 mg), 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (202 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 3 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (3-hydroxypropyl) -1-piperidinyl] -1-naphthonitrile (105 mg) (Compound 88).
mp 114-115 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (1 H, t, J = 5.4 Hz), 1.43-1.54 (4H, m), 1.57-1.72 ( 3H, m), 1.90-1.92 (2H, m), 2.80 (2H, t, J = 11.7 Hz), 3.49-3.54 (2H, m), 3.70 (2H, td, J = 6.6 and 5.4 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.56 (1H, ddd, J = 8.4, 6.9) and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.14 -8.20 (2H, m).
IR (KBr) 2932, 2216, 1572 cm ^-1
_{.. Anal Calcd for C 19 H} 22 N 2 O: C, 75.92; H, 7.65; N, 8.85.
Found: C, 75.79; H, 7.71; N, 8.69.
Example 86 (production of compound 89)

2,2,2-trifluoro-1- (4-fluoro-1-naphthyl) ethanone (100 mg), 2-methylpyrrolidine (85 mg), potassium carbonate (138 mg), dimethyl sulfoxide (1.0 mL) Was stirred at 100 ° C. for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2,2,2-trifluoro-1- [4- (2-methyl-1-pyrrolidinyl) -1-naphthyl] ethanone (86 mg) ( Compound 89).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, d, J = 6.0 Hz), 1.66-1.84 (2H, m), 1.97-2.04 ( 1H, m), 2.29-1.42 (1H, m), 3.54-3.60 (1H, m), 4.05-4.16 (2H, m), 6.75 (1H, m) d, J = 9.0 Hz), 7.44 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.63 (1H, ddd, J = 8.4, 6. 9 and 1.5 Hz), 8.09-8.16 (2H, m), 9.24 (1H, d, J = 9.0 Hz).
IR (KBr) 1669, 1559, 1518 cm ^-1
Example 87 (Production of compound 90)

A mixture of 1- (4-fluoro-1-naphthyl) ethanone (141 mg), 2-methylpyrrolidine (96 mg), potassium carbonate (207 mg) and dimethylsulfoxide (1.5 mL) was added at 100 ° C for 1.5 hours. Stirred for hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- [4- (2-methyl-1-pyrrolidinyl) -1-naphthyl] ethanone (50 mg) (Compound 90).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.17 (3H, d, J = 6.0 Hz), 1.67-1.88 (2H, m), 1.97-2.05 ( 1H, m), 2.26-1.34 (1H, m), 2.70 (3H, s), 3.20-3.26 (1H, m), 3.95-4.04 (2H, m), 6.83 (1H, d, J = 8.1 Hz), 7.43 (1H, ddd, J = 8.7, 6.9 and 1.5 Hz), 7.56 (1H, ddd , J = 8.7, 6.9 and 1.5 Hz), 7.97 (1H, d, J = 8.1 Hz), 8.15-8.19 (1H, m), 9.06- 9.09 (1H, m).
IR (KBr) 1653, 1566, 1512 cm ^-1
Example 88 (Production of compound 91)

A mixture of 4-hydrazino-1-naphthonitrile (560 mg), acrylamide (304 mg), sodium ethoxide (20%, 1.5 mL), ethanol (15 mL), and toluene (15 mL) was added at 1000 ° C. for 2 hours. Stirred for hours. After cooling to room temperature, the mixture was concentrated. The residue was acidified with a potassium hydrogen sulfate solution, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-oxo-1-pyrazolidinyl) -1-naphthonitrile (102 mg) (Compound 91).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.43 (2H, t, J = 8.1 Hz), 4.02 (2H, t, J = 8.1 Hz), 7.30 (1H, d, J = 8.1 Hz), 7.72 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.81 (1H, ddd, J = 8.4) , 6.9 and 1.5 Hz), 8.07-8.10 (2H, m), 8.18-8.21 (1H, m), 10.22 (1H, s).
IR (KBr) 2218, 1707 cm ^-1
Example 89 (Production of compounds 92 and 93)

Sodium hydride (60% oil, 17 mg) was added to a mixture of 4- (3-oxo-1-pyrazolidinyl) -1-naphthonitrile (72 mg) and N, N-dimethylformamide (4.0 mL) at room temperature. The mixture was stirred for 15 minutes. After adding methyl iodide (26 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give 4- (3-methoxy-4,5-dihydro-1H-pyrazol-1-yl) -1-naphthonitrile (compound 92) (18 mg) and (2-Methyl-3-oxo-1-pyrazolidinyl) -1-naphthonitrile (compound 93) (43 mg) was obtained.

Compound 92
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.95 (2H, t, J = 9.3 Hz), 3.94 (2H, t, J = 9.3 Hz), 3.99 (3H , s), 7.03 (1H, d, J = 8.1 Hz), 7.52 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.63 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.77 (1H, d, J = 8.1 Hz), 8.16-8.19 (1H, m), 8.55 -8.58 (1H, m).
IR (KBr) 2205, 1640, 1568, 1518 cm ^-1

Compound 93
mp 192-193 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.4-2.8 (2H, br), 3.09 (3H, s), 3.7-4.3 (2H, br), 6. 98 (1H, d, J = 7.8 Hz), 7.67 (1H, ddd, J = 8.4, 6.6 and 1.2 Hz), 7.74 (1H, ddd, J = 8. 4, 6.6 and 1.2 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.16-8.19 (1H, m), 8.25-8.28 (1H , m).
IR (KBr) 2218, 1698 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₃ N ₃ O: C, 71.70; H, 5.21; N, 16.72.
Found: C, 71.55; H, 5.31; N, 16.59.
Example 90 (Production of compound 94)

A mixture of 4-fluoro-1-benzothiophene-7-carbonitrile (100 mg), 4- (2-hydroxyethyl) piperidine (109 mg), potassium carbonate (156 mg), and dimethylsulfoxide (2.0 mL) was prepared. Stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (2-hydroxyethyl) -1-piperidinyl] -1-benzothiophene-7-carbonitrile (145 mg) (Compound 94). .
mp 134-135 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.26 (1 H, t, J = 5.1 Hz), 1.46-1.76 (5H, m), 1.88-1.92 ( 2H, m), 2.85 (2H, td, J = 12.0 and 1.8 Hz), 3.63-3.67 (2H, m), 3.77 (2H, td, J = 6. 3 and 5.1 Hz), 6.83 (1H, d, J = 8.1 Hz), 7.39 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 8.1 Hz).
IR (KBr) 2928, 2215, 1566, 1462 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₈ N ₂ OS: C, 67.10; H, 6.33; N, 9.78.
Found: C, 67.01; H, 6.28; N, 9.76.
Example 91 (production of compound 95)

A mixture of 4-fluoro-1-benzofuran-7-carbonitrile (400 mg), 2-methylpyrrolidine (317 mg), potassium carbonate (686 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 ° C. for 1 hour. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (2-methyl-1-pyrrolidinyl) -1-benzofuran-7-carbonitrile (542 mg) (Compound 95).
mp 82-83 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.26 (3H, d, J = 6.3 Hz), 1.76-1.83 (1H, m), 2.01-2.20 ( 3H, m), 3.54-3.63 (1H, m), 3.74-3.81 (1H, m), 4.20-4.29 (1H, m), 6.27 (1H, m) d, J = 8.7 Hz), 6.95 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.1 Hz).
IR (KBr) 2211, 1607, 1508 cm ^-1
Anal. Calcd. For C ₁₄ H ₁₄ N ₂ O: C, 74.31; H, 6.24; N, 12.38.
Found: C, 74.10; H, 6.34; N, 12.20.
Example 92 (Production of compound 96)

A mixture of 4-fluoro-1-benzofuran-7-carbonitrile (100 mg), 4- (2-hydroxyethyl) piperidine (120 mg), potassium carbonate (172 mg), and dimethyl sulfoxide (2.0 mL) was added to 100 parts. Stirred at C for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (2-hydroxyethyl) -1-piperidinyl] -1-benzofuran-7-carbonitrile (135 mg) (Compound 96).
mp 103-104 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (1 H, t, J = 5.4 Hz), 1.39-1.80 (5H, m), 1.86-1.91 ( 2H, m), 2.94 (2H, td, J = 12.3 and 2.4 Hz), 3.74-3.84 (4H, m), 6.63 (1H, d, J = 8. 4 Hz), 6.82 (1H, d, J = 2.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 2.4 Hz) ).
IR (KBr) 2926, 2218, 1607, 1503 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₈ N ₂ O ₂ : C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.13; H, 6.67; N, 10.38.
Example 93 (production of compound 97)

A mixture of 4-fluoro-2-methyl-1-benzofuran-7-carbonitrile (100 mg), 2-methylpyrrolidine (73 mg), potassium carbonate (158 mg), and dimethyl sulfoxide (2.0 mL) was heated at 100 ° C. For 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-methyl-4- (2-methyl-1-pyrrolidinyl) -1-benzofuran-7-carbonitrile (88 mg) (Compound 97).
mp 78-80 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24 (3H, d, J = 6.6 Hz), 1.75-1.80 (1H, m), 1.96-2.22 ( 3H, m), 2.45 (3H, d, J = 0.9 Hz), 3.51-3.59 (1H, m), 3.71-3.78 (1H, m), 4.18 -4.27 (1H, m), 6.24 (1H, d, J = 8.4 Hz), 6.54-6.55 (1H, m), 7.30 (1H, d, J = 8 .4 Hz).
IR (KBr) 2209, 1605, 1512 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₆ N ₂ O: C, 74.97; H, 6.71; N, 11.66.
Found: C, 74.85; H, 6.67; N, 11.82.
Example 94 (Production of compound 98)

4-fluoro-2-methyl-1-benzofuran-7-carbonitrile (100 mg), 4- (2-hydroxyethyl) piperidine (111 mg), potassium carbonate (158 mg), dimethylsulfoxide (2.0 mL) Was stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (2-hydroxyethyl) -1-piperidinyl] -2-methyl-1-benzofuran-7-carbonitrile (149 mg) ( Compound 98).
mp 106-107 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (1 H, t, J = 4.8 Hz), 1.37-1.50 (2H, m), 1.57-1.74 ( 3H, m), 1.84-1.89 (2H, m), 2.48 (3H, d, J = 1.2 Hz), 2.88 (2H, td, J = 12.0 and 2. 4 Hz), 3.73-3.79 (4H, m), 6.40-6.41 (1H, m), 6.58 (1H, d, J = 8.4 Hz), 7.37 ( 1H, d, J = 8.4 Hz).
IR (KBr) 2924, 2220, 1607 cm ^-1
_{.. Anal Calcd for C 17 H} 20 N 2 O 2: C, 71.81; H, 7.09; N, 9.85.
Found: C, 71.62; H, 7.29; N, 9.99.
Example 95 (Production of compound 99)

A mixture of 4-fluoro-1-naphthonitrile (40 mg), 3-fluoropyrrolidine hydrochloride (29 mg), potassium carbonate (81 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 ° C. for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-fluoro-1-pyrrolidinyl) -1-naphthonitrile (32 mg) (Compound 99).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.11-2.46 (2H, m), 3.48-3.55 (1H, m), 3.66-4.00 (3H, m ), 5.39 (1H, dt, J = 53.7 and 3.9 Hz), 6.78 (1H, d, J = 8.1 Hz), 7.49 (1H, ddd, J = 8. 4, 6.9 and 1.5 Hz), 7.62 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.75 (1H, d, J = 8.1 Hz) ), 8.16-8.22 (2H, m).
IR (KBr) 2207, 1566 cm ^-1
Example 96 (Production of compound 100)

A mixture of 4-fluoro-1-benzothiophene-7-carbonitrile (40 mg), 3-fluoropyrrolidine hydrochloride (28 mg), potassium carbonate (78 mg) and dimethylsulfoxide (1.0 mL) was added at 100 ° C. Stir for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-fluoro-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile (39 mg) (Compound 100).
mp 151-152 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05-2.34 (1H, m), 2.41-2.54 (1H, m), 3.77-4.08 (4H, m ), 5.43 (1H, dt, J = 52.8 and 3.3 Hz), 6.46 (1H, d, J = 8.7 Hz), 7.37 (1H, d, J = 5. 7 Hz), 7.53 (1H, d, J = 5.7 Hz), 7.68 (1H, d, J = 8.7 Hz).
IR (KBr) 2201, 1570 cm ^-1
Anal. Calcd. For C ₁₃ H ₁₁ FN ₂ S: C, 63.39; H, 4.50; N, 11.37.
Found: C, 63.30; H, 4.64; N, 11.39.
Example 97 (Production of compound 101)

4-Fluoro-1-benzothiophene-7-carbonitrile (100 mg), 3- (2-hydroxyethyl) pyrrolidine hydrochloride (163 mg), potassium carbonate (275 mg), dimethylsulfoxide (1.0 mL) The mixture was stirred at 100 ° C. for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [3- (2-hydroxyethyl) -1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (49 mg) (Compound 101). .
mp 109-111 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (1 H, t, J = 4.8 Hz), 1.68-1.83 (3H, m), 2.22-2.31 ( 1H, m), 2.41-2.48 (1H, m), 3.39 (1H, t, J = 9.0 Hz), 3.67-3.88 (5H, m), 6.40 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 5.7 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.70 (1H , d, J = 5.7 Hz).
IR (KBr) 2199, 1570, 1476 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₆ N ₂ OS: C, 66.15; H, 5.92; N, 10.29.
Found: C, 66.10; H, 5.92; N, 10.30.
Example 98 (Production of compound 102)

To a mixture of 4- [3- (2-hydroxyethyl) -1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (43 mg) and N, N-dimethylformamide (1.0 mL) was added sodium hydride ( 60% oily, 30.0 mg) was added at room temperature and stirred for 20 minutes. After adding methyl iodide (60 μl), the mixture was stirred for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [3- (2-methoxyethyl) -1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (43 mg) (Compound 102). .
mp 88-89 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.82 (3H, m), 2.18-2.26 (1H, m), 2.39-2.49 (1H, m ), 3.32-3.39 (1H, m), 3.36 (3Hs), 3.48 (2H, t, J = 6.3 Hz), 3.69-3.84 (3H, m ), 6.40 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 6.0 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.69 (1H, d, J = 6.0 Hz).
IR (KBr) 2201, 1570, 1474 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₈ N ₂ OS: C, 67.10; H, 6.33; N, 9.78.
Found: C, 66.91; H, 6.29; N, 9.79.
Example 99 (Production of compound 103)

A mixture of 4-fluoro-1-naphthonitrile (100 mg), 3,3-difluoropyrrolidine hydrochloride (92 mg), potassium carbonate (202 mg), and dimethyl sulfoxide (1.0 mL) was stirred at 100 ° C. for 1 hour. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3,3-difluoro-1-pyrrolidinyl) -1-naphthonitrile (39 mg) (Compound 103).
mp 68-69 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.50-2.64 (2H, m), 3.64 (2H, t, J = 7.2 Hz), 3.81 (2H, t, J = 12.6 Hz), 6.90 (1H, d, J = 8.1 Hz), 7.58 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7. 68 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J = 8.1 Hz), 8.14-8.17 (1H, m) , 8.21-8.24 (1H, m).
IR (KBr) 2213, 1574 cm ^-1
_{.. Anal Calcd for C 15 H} 12 F 2 N 2: C, 69.76; H, 4.68; N, 10.85.
Found: C, 69.95; H, 4.95; N, 10.91.
Example 100 (Production of compound 104)

A mixture of 4-fluoro-1-benzothiophene-7-carbonitrile (100 mg), 3,3-difluoropyrrolidine hydrochloride (134 mg), potassium carbonate (240 mg), and dimethyl sulfoxide (2.0 mL) was added to 100 parts. Stirred at C for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3,3-difluoro-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile (51 mg) (Compound 104).
mp 169-170 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.48-2.62 (2H, m), 3.86 (2H, t, J = 7.2 Hz), 4.06 (2H, t, J = 12.6 Hz), 6.47 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 5.4 Hz).
IR (KBr) 2203, 1570 cm ^-1
_{.. Anal Calcd for C 13 H} 10 F 2 N 2 S: C, 59.08; H, 3.81; N, 10.60.
Found: C, 59.09; H, 4.11; N, 10.68.
Example 101 (Production of Compound 105)

A mixture of tert-butyl 4- (2-ethoxy-2-oxoethyl) -1-piperidinecarboxylate (450 mg) and 4N hydrogen chloride-ethyl acetate (1.5 mL) was stirred at room temperature for 1 hour. The reaction was concentrated to give a colorless solid (330 mg). A mixture of this solid (146 mg), 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (218 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl [1- (4-cyano-1-naphthyl) -4-piperidinyl] acetate (113 mg) (Compound 105).
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 1.60-1.72 (2H, m), 1.92-2.12 (3H, m ), 2.38 (2H, d, J = 6.9 Hz), 2.84 (2H, td, J = 12.0 amd 1.8 Hz), 3.48-3.52 (2H, m) , 4.17 (2H, q, J = 7.2 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.55 (1H, ddd, J = 8.4, 6.9) and 1.5 Hz), 7.64 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.81 (1H, d, J = 8.1 Hz), 8.11 -8.20 (2H, m).
IR (KBr) 2216, 1732, 1574 cm ^-1
Example 102 (Production of compound 106)

A mixture of ethyl [1- (4-cyano-1-naphthyl) -4-piperidinyl] acetate (80 mg), a 0.67 M sodium carbonate solution (1.5 mL), and methanol (1.5 mL) was added at 70 ° C. Stir for 1 hour. After cooling to room temperature, the reaction was poured into water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The obtained residue was washed with dichloromethane to obtain [1- (4-cyano-1-naphthyl) -4-piperidinyl] acetic acid (30 mg) (Compound 106).
mp 195-196 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.75 (2H, m), 1.97-2.12 (3H, m), 2.46 (2H, d, J = 6) 2.6 Hz), 2.82-2.89 (2H, m), 3.47-3.54 (2H, m), 7.02 (1H, d, J = 8.1 Hz), 7.57 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.83 (1H , d, J = 8.1 Hz), 8.13-8.21 (2H, m).
IR (KBr) 2216, 1705, 1574 cm ^-1
Anal. Calcd. For
C ₁₈ H ₁₈ N ₂ O ₂ .0.5H ₂ O: C, 71.27; H, 6.31; N, 9.23.
Found: C, 70.91; H, 6.24; N, 8.86.
Example 103 (Production of compound 107)

To a mixture of sodium triacetoxyhydroborate (2.02 g), acetic acid (4.7 mL) and acetonitrile (3.0 mL) was added 2-methyl-1-[(1S) -1-phenylethyl] -4, A mixture of methyl 5-dihydro-1H-pyrrole-3-carboxylate (780 mg) and acetonitrile (1.7 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. The reaction was poured into sodium carbonate solution and extracted with ethyl acetate. The extract was washed with a sodium carbonate solution and brine, dried and concentrated to give a colorless oil (778 mg). Lithium aluminum hydride (114 mg) was added to a mixture of this oil (740 mg) and tetrahydrofuran (8.0 mL) at 0 ° C., and the mixture was stirred for 3 hours. Water (0.11 mL), a 25% potassium hydroxide solution (0.11 mL) and water (0.33 mL) were sequentially added, and the mixture was stirred at room temperature for 15 hours. The insolubles were removed by filtration using Celite, and the mother liquor was concentrated to give a pale yellow oil (656 mg). A mixture of this oily substance (581 mg), 10% palladium carbon (50% water content, 564 mg), and methanol (9.0 mL) was stirred at room temperature under a hydrogen atmosphere for 20 hours. The palladium carbon was removed by filtration using Celite and washed with methanol. After concentration of the mother liquor, ethyl acetate was added to the residue, dried and concentrated to give a pale yellow oil (260 mg). A mixture of the oily substance (117 mg), 4-fluoro-1-naphthonitrile (171 mg), potassium carbonate (207 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C. for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was washed with dichloromethane to obtain 4-[(2S, 3S) -3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (80 mg) (Compound 107). .
mp 158-159 ° C.
[Α] _D = -258.9 ° (c = 0.320, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (3H, d, J = 6.3 Hz), 1.99-2.20 (3H, m), 2.55-2.66 ( 1H, m), 3.01-3.09 (1H, m), 3.79-4.02 (3H, m), 4.11 (1H, qui, J = 6.3 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.54 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J = 8.4) , 6.9 and 1.5 Hz), 7.82 (1H, d, J = 8.4 Hz), 8.14-8.21 (2H, m).
IR (KBr) 2211, 1568, 1323 cm ^-1
Anal. Calcd. For
_{C 17 H 18 N 2 O ·} 0.2H 2 O: C, 75.64; H, 6.87; N, 10.38.
Found: C, 75.77; H, 6.83; N, 10.46.
Example 104 (production of compound 108)

To a mixture of sodium triacetoxyhydroborate (2.02 g), acetic acid (4.7 mL) and acetonitrile (3.0 mL) was added 2-methyl-1-[(1S) -1-phenylethyl] -4, A mixture of methyl 5-dihydro-1H-pyrrole-3-carboxylate (780 mg) and acetonitrile (1.7 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. The reaction was poured into sodium carbonate solution and extracted with ethyl acetate. The extract was washed with a sodium carbonate solution and brine, dried and concentrated to give a colorless oil (778 mg). Lithium aluminum hydride (114 mg) was added to a mixture of this oil (740 mg) and tetrahydrofuran (8.0 mL) at 0 ° C., and the mixture was stirred for 3 hours. Water (0.11 mL), a 25% potassium hydroxide solution (0.11 mL) and water (0.33 mL) were sequentially added, and the mixture was stirred at room temperature for 15 hours. The insolubles were removed by filtration using Celite, and the mother liquor was concentrated to give a pale yellow oil (656 mg). A mixture of this oily substance (581 mg), 10% palladium carbon (50% water content, 564 mg), and methanol (9.0 mL) was stirred at room temperature under a hydrogen atmosphere for 20 hours. The palladium carbon was removed by filtration using Celite and washed with methanol. After concentration of the mother liquor, ethyl acetate was added to the residue, dried and concentrated to give a pale yellow oil (260 mg). A mixture of this oily substance (100 mg), 4-fluoro-1-benzothiophene-7-carbonitrile (154 mg), potassium carbonate (180 mg), and dimethyl sulfoxide (2.0 mL) was stirred at 100 ° C. for 30 minutes. did. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was washed with diethyl ether to give 4-[(2S, 3S) -3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (109 mg). (Compound 108).
mp 109-111 ° C.
[Α] _D = + 17.8 ° (c = 0.320, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21 (3H, d, J = 6.6 Hz), 1.84-1.98 (1H, m), 2.11-2.20 ( 1H, m), 2.52-2.66 (1H, m), 3.64-3.98 (4H, m), 4.51 (1H, qui, J = 6.6 Hz), 6.47 (1H, d, J = 8.7 Hz), 7.33 (1H, d, J = 5.7 Hz), 7.49 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.7 Hz) , d, J = 5.7 Hz).
IR (KBr) 2205, 1568, 1472 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₆ N ₂ OS: C, 66.15; H, 5.92; N, 10.29.
Found: C, 65.83; H, 5.98; N, 10.05.
Example 105 (production of compound 109)

Trifluoroacetic acid (1.5 mL) was added to a mixture of tert-butyl (2S, 4R) -4-hydroxy-2-methylpyrrolidine-1-carboxylate (200 mg) and dichloromethane (1.5 mL) at room temperature. Stir for 30 minutes. The reaction was concentrated to give a colorless oil. A mixture of this oily substance, 4-fluoro-1-benzothiophene-7-carbonitrile (159 mg), potassium carbonate (622 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C. for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography to obtain 4-[(2S, 4R) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (184 mg). (Compound 109).
mp 102-103 ° C.
[Α] _D = -78.4 ° (c = 0.305, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, d, J = 6.0 Hz), 1.81-2.00 (2H, m), 2.49-2.58 ( 1H, m), 3.82-3.92 (1H, m), 4.17-4.28 (2H, m), 4.53 (1H, qui, J = 6.3 Hz), 6.53 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.51 (1H, d, J = 8.7 Hz), 7.60 (1H , d, J = 5.7 Hz).
IR (KBr) 2207, 1568, 1470 cm ^-1
Anal. Calcd. For C ₁₄ H ₁₄ N ₂ OS: C, 65.09; H, 5.46; N, 10.84.
Found: C, 64.82; H, 5.47; N, 10.54.
Example 106 (production of compound 110)

Hydrogen was added to a mixture of 4-[(2S, 3S) -3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (40 mg) and N, N-dimethylformamide (1.0 mL). Sodium chloride (60% oily, 29 mg) was added at room temperature. After stirring for 20 minutes, methyl iodide (60 μl) was added, and the mixture was stirred for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S, 3S) -3- (methoxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (36 mg) ( Compound 110).
[Α] _D = -144.6 ° (c = 0.280, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (3 H, d, J = 6.6 Hz), 1.84-1.94 (1 H, m), 2.01-2.13 ( 1H, m), 2.69-2.81 (1H, m), 3.15-3.23 (1H, m), 3.41 (3H, s), 3.51-3.54 (2H, m), 3.89-3.98 (1H, m), 4.24 (1H, qui, J = 6.3 Hz), 6.89 (1H, d, J = 8.4 Hz), 7. 51 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.62 (1H, ddd, J = 8.4, 6.9 and 1.5 Hz), 7.78 ( 1H, d, J = 8.4 Hz), 8.16-8.19 (2H, m).
IR (KBr) 2211, 1568 cm ^-1
Example 107 (Production of compound 111)

4-[(2S, 4R) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (184 mg), p-nitrobenzoic acid (286 mg), triphenylphosphine ( 449 mg) and tetrahydrofuran (3.5 mL) were added with diethyl azodicarboxylate (40% toluene solution, 0.75 mL) at 0 ° C, and the mixture was stirred for 2 hours. After further stirring at room temperature for 18 hours, the reaction product was concentrated, and the residue was purified by silica gel column chromatography to obtain an orange oily substance. To a mixture of this oily substance and methanol (2.5 mL) was added 1N sodium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction was poured into brine and extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4-[(2S, 4S) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1. -Benzothiophene-7-carbonitrile (68 mg) was obtained (Compound 111).
[Α] _D = −65.7 ° (c = 0.235, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, d, J = 6.0 Hz), 1.63 (1H, d, J = 3.9 Hz), 1.90 (1H , ddd, J = 13.2, 9.0 and 3.9 Hz), 2.30-2.38 (1H, m), 3.60-3.64 (1H, m), 4.15 (1H , dd, J = 10.8 and 3.6 Hz), 4.32-4.43 (1H, m), 4.55-4.60 (1H, m), 6.62 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 6.0 Hz), 7.51-7.53 (2H, m).
IR (KBr) 2209, 1566 cm ^-1
Example 108 (production of compound 112)

Oxalyl chloride (0.14 mL) was added to a mixture of dimethyl sulfoxide (0.22 mL) and dichloromethane (4.0 mL) at -78 ° C, and the mixture was stirred for 10 minutes. A mixture of 4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (207 mg) and dichloromethane (2.0 mL) was added, and the mixture was stirred for 15 minutes. Triethylamine (0.57 mL) was added, and the mixture was stirred for 10 minutes and further stirred at room temperature for 30 minutes. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue obtained was purified by silica gel column chromatography to give 4-[(2S) -2-methyl-3-oxo-1-pyrrolidinyl] -1-naphthonitrile (150 mg) (Compound 112).
mp 113-114 ° C.
[Α] _D = -253.9 ° (c = 0.270, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.17 (3H, d, J = 6.6 Hz), 2.69 (1H, ddd, J = 18.0, 7.5 and 4.2) Hz), 2.79 (1H, dt, J = 18.0 and 7.8 Hz), 3.15 (1H, ddd, J = 9.9, 7.8 and 7.5 Hz), 3.89 (1H, q, J = 6.6 Hz), 4.07 (1H, ddd, J = 9.9, 7.8 and 4.2 Hz), 7.09 (1H, d, J = 8.1) Hz), 7.63 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.71 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz) , 7.89 (1H, d, J = 8.1 Hz), 8.24-8.28 (2H, m).
IR (KBr) 2216, 1759, 1574 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₄ N ₂ O: C, 76.78; H, 5.64; N, 11.19.
Found: C, 76.52; H, 5.63; N, 11.30.
Example 109 (Production of compound 113)

Dissolve (2S, 3R) -1-benzyl-2-methylpyrrolidin-3-ol (820 mg) in methyl alcohol (30 mL), 1N hydrochloric acid (4.3 mL), 10% palladium on carbon (containing water) ( (500 mg), and the mixture was stirred under a hydrogen stream for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (582 mg), potassium carbonate (890 mg), and dimethyl sulfoxide (12.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 15 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography and basic silica gel column chromatography (Chromatorex NH manufactured by Fuji Silysia) to give 4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl]-. 1-Naphthonitrile (540 mg) was obtained (Compound 113).
[Α] _D = −268.6 ° (c = 0.515, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.15 (3H, d, J = 6.2 Hz), 1.80-2.20 (2H, m), 2.30-2.50 ( 1H, m), 3.20-3.38 (1H, m), 3.77-4.00 (2H, m), 4.10-4.30 (1H, m), 6.89 (1H, m) d, J = 8.0 Hz), 7.46-7.68 (2H, m), 7.19 (1H, d, J = 8.0 Hz), 8.14-8.26 (2H, m ).
IR (KBr) 2211, 1567, 1514 cm ^-1 .
Example 110 (Production of Compound 114)

Methanesulfonic acid (72 μL) was added to a mixture of 4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (280 mg) and tetrahydrofuran (about 1 mL) at room temperature. added. Crystallization was performed by adding diethyl ether to obtain 4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile methanesulfonate (205 mg) (Compound 114).
mp 107-108 ° C.
[Α] _D = -174.5 ° (c = 0.350, MeOH).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 6.3 Hz), 2.40-2.50 (1H, m), 2.80-2.90 (1H, m ), 2.89 (3H, s), 3.98-4.36 (3H, m), 4.58-4.64 (1H, m), 7.83-7.94 (3H, m), 8.02 (1H, d, J = 7.8 Hz), 8.37-8.40 (1H, m), 8.68-8.71 (1H, m).
IR (KBr) 3320, 2228, 1194 cm ^-1
Anal. Calcd. For
_{C 16 H 16 N 2 OCH 3} SO 3 H · 0.1H 2 O: C, 58.30; H, 5.81; N, 8.00.
Found: C, 58.13; H, 5.77; N, 7.97.
Example 111 (production of compound 115)

4-Fluoro-1-benzothiophene-7-carbonitrile (100 mg), (2S, 3R) -2-methyl-3-pyrrolidinol hydrochloride (93 mg), potassium carbonate (195 mg), dimethylsulfoxide (1. 5 mL) was stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography to obtain 4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (108 mg). (Compound 115).
mp 145-146 ° C.
[Α] _D = + 30.6 ° (c = 0.345, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, d, J = 6.6 Hz), 1.80 (1H, d, J = 4.5 Hz), 2.01-2 .14 (1H, m), 2.31-2.43 (1H, m), 3.82-3.98 (2H, m), 4.11-4.19 (1H, m), 4.23 -4.28 (1H, m), 6.49 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 5.7 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 5.7 Hz).
IR (KBr) 2207, 1568 cm ^-1
Anal. Calcd. For C ₁₄ H ₁₄ N ₂ OS: C, 65.09; H, 5.46; N, 10.84.
Found: C, 65.03; H, 5.58; N, 10.90.
Example 112 (Production of compound 116)

4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (254 mg), acetic acid (175 mg) and triphenylphosphine (510 mg) in toluene (12 mL) , And added with diethyl azodicarboxylate (40% toluene solution, 0.8 mL) under a nitrogen stream, followed by stirring at room temperature for 16 hours. The precipitated insolubles were removed by filtration, washed with toluene, then water was poured into the filtrate, and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and water in that order, dried and concentrated. The obtained residue was purified by silica gel column chromatography, and the target product fraction was concentrated. The residue was dissolved in methyl alcohol (10 mL), potassium carbonate (280 mg) was added, and the mixture was stirred at room temperature for 1.0 hour. The reaction solution was concentrated, the residue was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (105 mg) (Compound 116).
[Α] _D = -270.2 ° (c = 0.618, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 (3H, d, J = 6.2 Hz), 1.93 (1H, d-like), 2.00-2.20 (2H, m), 3.18-4.02 (1H, m), 4.20-4.40 (1H, m), 4.40-4.58 (1H, m), 6.86 (1H, d, J = 8.0 Hz), 7.46-7.70 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.12-8.28 (2H, m).
IR (KBr) 2211, 1565, 1515 cm ^-1
Example 113 (Production of compound 116)

A mixture of 4-fluoro-1-naphthonitrile (166 mg), (2S, 3S) -2-methyl-3-pyrrolidinol (98 mg), potassium carbonate (202 mg), and dimethylsulfoxide (1.5 mL) was added to 100 parts. Stirred at 40 ° C. for 40 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (160 mg) (Compound 116). .
NMR was consistent with the value of compound 116 described in Example 111.
Example 114 (production of compound 117)

A mixture of 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (20 mg) and ethyl acetate (about 1 mL) was added with sulfuric acid (0.5 mL) and acetic acid. A mixture (0.3 mL) of ethyl (35.5 mL) was added at room temperature and crystallized to give 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile sulfate. The salt (18 mg) was obtained (Compound 117).
mp 111-112 ° C.
[Α] _D =-144.0 ° (c = 0.270, MeOH).
¹ H-NMR (DMSO-d ₆ ) δ: 1.10 (3H, d, J = 6.3 Hz), 1.86-1.93 (2H, m), 3.25-3.31 (1H , m), 3.96-4.04 (1H, m), 4.21-4.32 (2H, m), 6.89 (1H, d, J = 8.4 Hz), 7.55 ( 1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.70 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz), 7.89 (1H, d, J = 8.4 Hz), 7.97-8.00 (1H, m), 8.23-8.26 (1H, m).
IR (KBr) 2228, 1223 cm ^-1
Anal. Calcd. For
_{C 16 H 16 N 2 OH 2} SO 4 · 1.2H 2 O: C, 51.66; H, 5.53; N, 7.53.
Found: C, 51.60; H, 5.52; N, 7.62.
Example 115 (Production of compound 118)

4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (600 mg), p-nitrobenzoic acid (1.55 g), triphenyl To a mixture of phosphine (2.44 g) and tetrahydrofuran (18 mL) was added diethyl azodicarboxylate (40% solution in toluene, 4.0 mL) at 0 ° C, and the mixture was stirred at room temperature for 12 hours. The reaction was concentrated and the residue was purified by silica gel column chromatography to give an orange oil. To a mixture of the oily substance and methanol (15 mL) was added 1N sodium hydroxide (3.0 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction was poured into brine and extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1. -Benzothiophene-7-carbonitrile (228 mg) was obtained (Compound 118).
[Α] _D = −52.0 ° (c = 0.450, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, d, J = 6.6 Hz), 2.07-2.11 (3H, m), 3.61-3.68 ( 1H, m), 4.09-4.18 (2H, m), 4.49-4.53 (1H, m), 6.54 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 5.7 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 5.7 Hz).
IR (KBr) 2207, 1568 cm ^-1
Example 116 (production of compound 118)

4-fluoro-1-benzothiophene-7-carbonitrile (100 mg), (2S, 3S) -2-methyl-3-pyrrolidinol (86 mg), potassium carbonate (156 mg), dimethylsulfoxide (1.5 mL) )) Was stirred at 100 ° C. for 40 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography to obtain 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (113 mg). (Compound 118).
NMR was consistent with the value of compound 118 described in Example 114.
Example 117 (production of compound 119)

Sulfuric acid (1.0) was added to a mixture of 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (175 mg) and ethyl acetate (10 mL). (35 mL) and ethyl acetate (35 mL) at room temperature. After stirring for several minutes, the supernatant was removed, and the residue was crystallized from diethyl ether-ethanol (9: 1) to give 4-[(2S, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzo. Thiophene-7-carbonitrile sulfate (53 mg) was obtained (Compound 119).
mp 128-129 ° C.
[Α] _D = -37.4 ° (c = 0.200, MeOH).
¹ H-NMR (DMSO-d ₆ ) δ: 1.14 (3H, d, J = 6.3 Hz), 1.87-2.06 (2H, m), 3.53-3.61 (1H , m), 3.96-4.16 (2H, m), 4.29 (1H, q, J = 5.1 Hz), 6.61 (1H, d, J = 8.4 Hz), 7 .63 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 5.4 Hz).
IR (KBr) 2226, 1221 cm ^-1
Anal. Calcd. For
_{C 14 H 14 N 2 OS ·} H 2 SO 4 · H 2 O: C, 44.91; H, 4.85; N, 7.48.
Found: C, 44.92; H, 5.01; N, 7.52.
Example 118 (production of compound 120)

To a mixture of tert-butyl (2R, 3R) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate (2.20 g) and ethyl acetate (18 mL) was added 4N hydrogen chloride-ethyl acetate (6. 0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a pale yellow oily substance. Lithium aluminum hydride (1.15 g) was added to a mixture of this substance and tetrahydrofuran (50 mL) at room temperature, and the mixture was heated under reflux for 18 hours. After cooling to 0 ° C., water (1.0 mL), 25% potassium hydroxide solution (1.0 mL), and water (3.0 mL) were sequentially added, followed by stirring for 1 hour. The insolubles were removed by filtration using Celite, and the mother liquor was concentrated to give a pale brown oil (1.0 g). A mixture of this substance (107 mg), 4-fluoro-1-benzothiophene-7-carbonitrile (170 mg), potassium carbonate (199 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 ° C. for 30 minutes. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography to obtain 4-[(2R, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (172 mg). (Compound 120).
[Α] _D = + 51.8 ° (c = 0.265, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, d, J = 6.6 Hz), 2.07-2.11 (3H, m), 3.61-3.68 ( 1H, m), 4.09-4.18 (2H, m), 4.49-4.53 (1H, m), 6.54 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 5.7 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 5.7 Hz).
IR (KBr) 2207, 1568 cm ^-1
Example 119 (Production of compound 121)

4-[(2R, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-benzothiophene-7-carbonitrile (125 mg), p-nitrobenzoic acid (323 mg), triphenylphosphine ( 508 mg) and tetrahydrofuran (4.5 mL) were added with diethyl azodicarboxylate (40% toluene solution, 0.84 mL) at 0 ° C, and the mixture was stirred at room temperature for 12 hours. The reaction was concentrated and the residue was purified by silica gel column chromatography to give an orange oil. 1N Sodium hydroxide (3.0 mL) was added to a mixture of the oily substance and methanol (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was poured into brine and extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4-[(2R, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1. -Benzothiophene-7-carbonitrile (61 mg) was obtained (Compound 121).
mp 145-146 ° C.
[Α] _D = -29.2 ° (c = 0.353, MeOH).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, d, J = 6.6 Hz), 1.80 (1H, d, J = 4.5 Hz), 2.01-2 .14 (1H, m), 2.31-2.43 (1H, m), 3.82-3.98 (2H, m), 4.11-4.19 (1H, m), 4.23 -4.28 (1H, m), 6.49 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 5.7 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 5.7 Hz).
IR (KBr) 2207, 1568 cm ^-1
Example 120 (Production of compound 122)

To a mixture of tert-butyl (2R, 3R) -3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate (2.20 g) and ethyl acetate (18 mL) was added 4N hydrogen chloride-ethyl acetate (6. 0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a pale yellow oily substance. Lithium aluminum hydride (1.15 g) was added to a mixture of this substance and tetrahydrofuran (50 mL) at room temperature, and the mixture was heated under reflux for 18 hours. After cooling to 0 ° C., water (1.0 mL), 25% potassium hydroxide solution (1.0 mL), and water (3.0 mL) were sequentially added, followed by stirring for 1 hour. The insolubles were removed by filtration using Celite, and the mother liquor was concentrated to give a pale brown oil (1.0 g). A mixture of this substance (330 mg), 4-fluoro-1-naphthonitrile (500 mg), potassium carbonate (606 mg), and dimethylsulfoxide (5.0 mL) was stirred at 100 ° C for 30 minutes. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (473 mg) (Compound 122). .
[Α] _D = + 271.5 ° (c = 0.555, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 (3H, d, J = 6.2 Hz), 1.93 (1H, d-like), 2.00-2.20 (2H, m), 3.18-4.02 (1H, m), 4.20-4.40 (1H, m), 4.40-4.58 (1H, m), 6.86 (1H, d, J = 8.0 Hz), 7.46-7.70 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.12-8.28 (2H, m).
IR (KBr) 2211, 1565, 1515 cm ^-1
Example 121 (Production of compound 123)

4-[(2R, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (272 mg), p-nitrobenzoic acid (719 mg), triphenylphosphine (1.13 g) Then, diethyl azodicarboxylate (40% toluene solution, 1.9 mL) was added to a mixture of the mixture and tetrahydrofuran (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The reaction was concentrated and the residue was purified by silica gel column chromatography to give an orange oil. To a mixture of the oily substance and methanol (15 mL) was added 1N sodium hydroxide (3.0 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction was poured into brine and extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to give 4-[(2R, 3S) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1. -Naphthonitrile (102 mg) was obtained (Compound 123).
[Α] _D = + 269.8 ° (c = 0.590, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.15 (3H, d, J = 6.2 Hz), 1.80-2.20 (2H, m), 2.30-2.50 ( 1H, m), 3.20-3.38 (1H, m), 3.77-4.00 (2H, m), 4.10-4.30 (1H, m), 6.89 (1H, m) d, J = 8.0 Hz), 7.46-7.68 (2H, m), 7.19 (1H, d, J = 8.0 Hz), 8.14-8.26 (2H, m ).
IR (KBr) 2211, 1567, 1514 cm ^-1
Example 122 (Production of compound 124)

Triethylamine (0.10 mL) was added to a mixture of 4-bromo-N-hydroxynaphthalene-1-carboximidoyl chloride (200 mg), allyl alcohol (48 μl) and diethyl ether (20 mL) at room temperature for 3 days. Stirred. The insolubles were removed by filtration, and the residue obtained by concentrating the mother liquor was purified by silica gel column chromatography to give [3- (4-bromo-1-naphthyl) -4,5-dihydroisoxazol-5-yl. ] Methanol (188 mg) was obtained (Compound 124).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.01 (1 H, t, J = 6.6 Hz), 3.41-3.64 (2H, m), 3.69-3.81 ( 1H, m), 3.91-4.02 (1H, m), 4.84-4.97 (1H, m), 7.37 (1H, d, J = 7.8 Hz), 7.60 -7.69 (2H, m), 7.80 (1H, d, J = 7.8 Hz), 8.31-8.35 (1H, m), 8.91-8.97 (1H, m ).
Example 123 (production of compound 125)

[3- (4-Brom-1-naphthyl) -4,5-dihydroisoxazol-5-yl] methanol (70 mg), zinc cyanide (16 mg), tetrakis (triphenylphosphine) palladium (0) ( A mixture of 26 mg) and N, N-dimethylformamide (3.0 mL) was stirred at 100 ° C. for 15 hours under an argon atmosphere. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The insoluble matter was removed by filtration using Celite, and the organic layer was washed with brine. The residue obtained by drying and concentration was purified by silica gel column chromatography, and 4- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1-naphthonitrile (46 mg) was obtained. (Compound 125).
mp 138-139 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93 (1H, dd, J = 8.1 and 5.4 Hz), 3.49-3.65 (2H, m), 3.74- 3.80 (1H, m), 3.97-4.03 (1H, m), 4.93-4.97 (1H, m), 7.59 (1H, d, J = 7.5 Hz) , 7.70-7.80 (2H, m), 7.93 (1H, d, J = 7.5 Hz), 8.30-8.33 (1H, m), 9.01-9.04 (1H, m).
IR (KBr) 2924, 2224 cm ^-1
Anal. Calcd. For C ₁₅ H ₁₂ N ₂ O ₂ : C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.22; H, 4.86; N, 11.06.
Example 124 (production of compound 126)

Sodium hydride was added to a mixture of 4- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1-naphthonitrile (46 mg) and N, N-dimethylformamide (1.0 mL). (60% oily, 35 mg) was added at room temperature. After stirring for 20 minutes, methyl iodide (70 μl) was added, and the mixture was stirred for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [5- (methoxymethyl) -4,5-dihydroisoxazol-3-yl] -1-naphthonitrile (38 mg) (Compound 126) ).
mp 110-111 ° C.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.47 (3H, s), 3.47 (1H, dd, J = 16.5 and 7.8 Hz), 3.59 (1H, dd, J = 16.5 and 10.8 Hz), 3.66 (2H, d, J = 4.5 Hz), 4.94-5.03 (1H, m), 7.58 (1H, d, J = 7.8 Hz), 7.70-7.79 (2H, m), 7.93 (1H, d, J = 7.8 Hz), 8.30-8.33 (1H, m), 9 .06-9.09 (1H, m).
IR (KBr) 2222, 1514 cm ^-1
Anal. Calcd. For C ₁₆ H ₁₄ N ₂ O ₂ : C, 72.16; H, 5.30; N, 10.52.
Found: C, 71.91; H, 5.19; N, 10.65.
Example 125 (Production of compound 127)

4- [4- (Hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (1.12 g) was dissolved in ethyl acetate (10.0 mL), and 4N-hydrogen chloride-ethyl acetate ( (2 mL) was added at room temperature and the mixture was crystallized to give 4- [4- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile hydrochloride (1.06 g) (Compound 127). .
mp 114-116C.
¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (3H, d, J = 5.8 Hz), 1.30-1.60 (1H, m), 2.10-2. 40 (2H, m), 3.25-4.20 (6H, m), 6.92 (1H, d, J = 8.4 Hz), 7.50-7.80 (2H, m), 7 .91 (1H, d, J = 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz), 8.24 (1H, d, J = 8.4 Hz).
IR (KBr) 2225, 1521, 1389 cm- ¹ .
Anal. Calcd. For
_{C 17 H 18 N 2 O ·} HCl · 0.1AcOEt: C, 67.07; H, 6.40; N, 8.99.
Found: C, 67.00; H, 6.30; N, 9.20.
Example 126 (Production of compound 128)

Dissolve tert-butyl (2R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate (700 mg) in toluene (2.0 mL) and add trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (440 mg), potassium carbonate (1.34 g), and dimethyl sulfoxide (10.0 mL), and the mixture was stirred at 100 ° C for 4 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 4-[(2R, 4R) -4-hydroxy-2- (hydroxymethyl) -1-pyrrolidinyl] -1-naphthonitrile (119 mg) (119 mg). Compound 128).
mp 146-147 ° C.
[α] _D = -284.7 ° (c = 0.364, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.05-2.40 (2H, m), 2.46-2.70 (1H, m), 3.10-3.24 (1H, m ), 3.35-3.80 (3H, m), 3.96-4.10 (1H, m), 4.16-4.30 (1H, m), 4.35-4.55 (1H , m), 7.13 (1H, d, J = 8.2 Hz), 7.50-7.75 (2H, m), 7.80 (1H, d, J = 8.2 Hz), 8 .12-8.40 (2H, m).
IR (KBr) 2214, 1570 cm ^-1
Anal. Calcd. For
C ₁₆ H ₁₆ N ₂ O ₂ .0.1AcOEt: C, 70.08; H, 6.11; N, 10.11.
Found: C, 70.00; H, 6.14; N, 9.96.
Example 127 (production of compound 129)

Dissolve tert-butyl (2R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate (700 mg) in toluene (2.0 mL) and add trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (440 mg), potassium carbonate (1340 mg), and dimethyl sulfoxide (10.0 mL), and the mixture was stirred at 100 ° C for 4 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue is purified by silica gel column chromatography, and 4-{[(2R, 4R) -1- (4-cyano-1-naphthyl) -4-hydroxypyrrolidin-2-yl] methoxy} -1-naphtho. The nitrile (50 mg) was obtained (Compound 129).
mp 123-126 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.12-2.30 (2H, m), 2.76-1.94 (1H, m), 3.48-3.52 (1H, m ), 3.88-4.00 (1H, m), 4.15-4.38 (2H, m), 4.60-4.76 (2H, m), 6.64 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.40-7.85 (7H, m), 8.04-8.30 (3H, m).
IR (KBr) 2214, 1570 cm- ¹ .
Anal. Calcd. For
_{C 27 H 21 N 3 O 2} · 0.2AcOEt: C, 76.39; H, 5.21; N, 9.61.
Found: C, 76.25; H, 5.18; N, 9.87.
Example 128 (Production of compound 130)

(1-benzyl-3,5-dimethylpyrrolidin-3-yl) methanol (1.88 g), methanol (60 mL), 1N hydrochloric acid (8.6 mL), 10% palladium on carbon (containing water) (1. The mixture of 10 g) was stirred under a stream of hydrogen for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (1.10 g), potassium carbonate (3.55 g) and dimethylsulfoxide (30.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 4 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [4- (hydroxymethyl) -2,4-dimethyl-1-pyrrolidinyl] -1-naphthonitrile (480 mg) (Compound 130).
mp 100-101 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.02 (3H, s), 1.20 (3H, d, J = 5.8 Hz), 1.65-2.04 (3H, m) , 2.98 (1H, dd, J = 1.0 Hz and 9.8 Hz), 3.66 (2H, d, J = 5.4 Hz), 4.00-4.26 (2H, m) , 6.88 (1H, d, J = 8.4 Hz), 7.42-7.70 (2H, m), 7.23 (1H, d, J = 8.0 Hz), 8.12- 8.26 (2H, m).
IR (KBr) 2211, 1564, 1515cm ^-1
_{.. Anal Calcd for C 18 H} 20 N 2 O: C, 77.11; H, 7.19; N, 9.99.
Found: C, 77.09; H, 7.25; N, 9.90.
Example 129 (Production of compound 131)

A mixture of 4-fluoro-1-naphthonitrile (300 mg), isoindoline (250 mg), potassium carbonate (270 mg), and dimethylsulfoxide (6.0 mL) was stirred at 100 ° C. for 5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1,3-dihydro-2H-isoindol-2-yl) -1-naphthonitrile (195 mg) (Compound 131).
mp 156-158 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.00 (4H, s), 6.94 (1H, d, J = 8.2 Hz), 7.30-7.41 (4H, m) , 7.48-7.72 (2H, m), 7.82 (1H, d, J = 8.2 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.48 ( (1H, d, J = 8.0Hz).
IR (KBr) 2201, 1561, 1413 cm ^-1
Example 130 (Production of compound 132)

Dissolve tert-butyl (2R, 4R) -2- (hydroxymethyl) -4-methoxypyrrolidine-1-carboxylate (700 mg) in toluene (2.0 mL) and add trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (300 mg), potassium carbonate (730 mg), and dimethylsulfoxide (6.0 mL), and the mixture was stirred at 100 ° C for 16 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R, 4R) -2- (hydroxymethyl) -4-methoxy-1-pyrrolidinyl] -1-naphthonitrile (334 mg). (Compound 132).
[α] _D = -212 ° (c = 0.316, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.00-2.30 (2H, m), 2.40-2.60 (1H, m), 3.20-3.40 (1H, m ), 3.44 (3H, s), 3.50-3.76 (2H, m), 3.92-4.26 (3H, m), 7.09 (1H, d, J = 8.6) Hz), 7.50-7.74 (2H, m) 7.80 (1H, d, J = 8.0 Hz), 8.16-8.30 (2H, m).
IR (KBr) 3437, 2212, 1568 cm ^-1
Example 131 (production of compound 133)

Dissolve 4-[(2R, 4R) -4-hydroxy-2- (hydroxymethyl) -1-pyrrolidinyl] -1-naphthonitrile (310 mg) in N, N-dimethylformamide (6.0 mL). After adding sodium hydride (60% oil, 100 mg) under ice-cooling, the mixture was returned to room temperature and stirred for 1 hour. Then, methyl iodide (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R, 4R) -4-methoxy-2- (methoxymethyl) -1-pyrrolidinyl] -1-naphthonitrile (303 mg). (Compound 133).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.90-2.50 (1H, m), 2.50-2.70 (1H, m), 3.25 (3H, s), 3. 25-3.55 (3H, m), 3.41 (3H, s), 3.80-4.27 (3H, m), 7.00 (1H, d, J = 8.0 Hz), 7 .48-7.70 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.14-8.26 (2H, m).
IR (KBr) 2212, 1568 cm ^-1
Example 132 (production of compound 134)

Dissolve 1-benzyl-2,2-dimethylpyrrolidine (1.00 g) in methyl alcohol (30 mL), add 1N-hydrochloric acid (5.5 mL), 10% palladium on carbon (containing water) (500 mg), and add hydrogen. The mixture was stirred under a stream of air for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. A mixture of 4-fluoro-1-naphthonitrile (256 mg), potassium carbonate (825 mg) and dimethylsulfoxide (6.0 mL) was stirred in the residue at 100 ° C. for 20 hours. Then, imidazole (210 mg) and potassium carbonate (280 mg) were added, and the mixture was stirred at 100 ° C for 3 hours. Then, after cooling to room temperature, water was poured into the reaction product, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (2,2-dimethyl-1-pyrrolidinyl) -1-naphthonitrile (46 mg) (Compound 134).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17 (6H, s), 1.90-2.15 (4H, m), 7.34 (1H, d, J = 8.0 Hz) , 7.48-7.70 (2H, m), 7.83 (1H, d, J = 8.0 Hz), 8.14-8.22 (1H, m), 8.42-8.49 (1H, m).
IR (KBr) 2218, 1570 cm ^-1
Example 133 (production of compound 135)

Dimethyl sulfoxide (15.0 mL) was added to D-prolinamide (800 mg), 4-fluoro-1-naphthonitrile (1000 mg) and potassium carbonate (1000 mg), and the mixture was stirred at 100 ° C for 23 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Hexane: ethyl acetate = 1: 2 was added to the resulting residue for crystallization to give 1- (4-cyano-1-naphthyl) -D-prolinamide (570 mg) (Compound 135).
mp 176-177 ° C.
[α] _D = -194.6 ° (c = 0.380, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.82-2.30 (3H, m), 2.50-2.72 (1H, m), 3.30-3.42 (1H, m ), 4.10-4.48 (2H, m), 5.29 (1H, br.s), 6.38 (1H, br.s), 6.97 (1H, d, J = 8.0) Hz), 7.50-7.75 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.20-8.32 (2H, m).
IR (KBr) 2210, 1690, 1568 cm ^-1
Example 134 (production of compound 136)

1- (4-Cyano-1-naphthyl) -D-prolinamide (160 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic anhydride (0.25 mL) and triethylamine (0.56 mL) were added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was made alkaline with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain (2R) -1- (4-cyano-1-naphthyl) pyrrolidine-2-carbonitrile (113 mg) (Compound 136).
[α] _D = + 92.3 ° (c = 0.39, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.00-2.72 (4H, m), 3.35-3.50 (1H, m), 3.65-3.82 (1H, m ), 4.70-4.80 (1H, m), 7.88 (1H, d, J = 8.0 Hz), 8.04-8.15 (1H, m), 8.20-8. 32 (1H, m).
IR (KBr) 2216, 1573cm ^-1
Example 135 (Production of compound 137)

Dissolve 1-benzyl-3-phenylpyrrolidine (2.35 g) in methyl alcohol (30 mL), add 1N hydrochloric acid (10 mL), 10% palladium on carbon (water-containing) (1200 mg), and add 15 Stirred for hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (600 mg), potassium carbonate (1500 mg) and dimethyl sulfoxide (15.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 15 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-phenyl-1-pyrrolidinyl) -1-naphthonitrile (628 mg) (Compound 137).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.01-2.57 (2H, m), 3.40-4.02 (5H, m), 6.73 (1H, d, J = 8) .4 Hz), 7.20-7.50 (5H, m), 7.57-7.70 (1H, m), 7.75 (1H, d, J = 8.4 Hz), 8.12 −8.32 (2H, m).
IR (KBr) 2205, 1563, 1518 cm ^-1
Example 136 (production of compound 138)

4- (3-Hydroxy-1-pyrrolidinyl) -1-naphthonitrile (220 mg), phenol (175 mg) and triphenylphosphine (290 mg) were dissolved in toluene (6 mL) and tetrahydrofuran (2 mL). Diethyl azodicarboxylate (40% toluene solution, 1.2 mL) was added under a stream of air, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain 4- (3-phenoxy-1-pyrrolidinyl) -1-naphthonitrile (180 mg) (Compound 138).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.20-2.50 (2H, m), 3.50-4.10 (4H, m), 5.00-5.15 (1H, m ), 6.80 (1H, d, J = 8.0 Hz), 6.82-7.06 (3H, m), 7.22-7.38 (2H, m), 7.42-7. 70 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 8.12-8.30 (2H, m).
IR (KBr) 2213, 1568, cm ^-1
Example 137 (Production of compound 139)

4-[(2S, 3R) -3-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (110 mg) was dissolved in N, N-dimethylformamide (2 mL) and stirred under ice-cooling. . Then, sodium hydride (60% oily, 35 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, methyl iodide (0.10 mL) was added, and the mixture was stirred at room temperature for 15 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S, 3R) -3-methoxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (110 mg) (Compound 139) ).
[α] _D = -221 ° (c = 0.45, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.14 (3H, d, J = 6.2 Hz), 1.80-2.20 (1H, m), 2.28-2.46 ( 1H, m), 3.20-3.38 (1H, m), 3.47 (3H, s), 3.50-3.98 (3H, m), 6.90 (1H, d, J = 8.2 Hz), 7.46-7.68 (2H, m), 7.79 (1H, d, J = 8.2 Hz), 8.14-8.24 (2H, m).
IR (KBr) 2211, 1568, 1514 cm- ¹
Example 138 (Production of compound 140)

Dissolve tert-butyl 3- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate (510 mg) in toluene (2.0 mL), add trifluoroacetic acid (2.0 mL), and add Stirred for hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (171 mg), potassium carbonate (410 mg), and dimethylsulfoxide (4.0 mL), and the mixture was stirred at 100 ° C for 1.5 hours. . After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl [1- (4-cyano-1-naphthyl) pyrrolidin-3-yl] acetate (300 mg) (Compound 140).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.28 (3H, d, J = 7.2 Hz), 1.64-1.88 (1H, m), 2.20-2.40 ( 1H, m), 2.53 (2H, d, J = 7.8 Hz), 2.62-2.70 (1H, m), 3.40 (1H, dd, J = 7.6 Hz and 7.7 Hz) ), 3.55-3.84 (3H, m), 4.17 (2H, q, J = 7.2 Hz), 6.70 (1H, d, J = 8.4 Hz), 7.40 −7.68 (2H, m), 7.72 (1H, d, J = 8.4 Hz), 8.12-8.28 (2H, m).
IR (KBr) 2199, 1732, 1556, 1522 cm ^-1
Example 139 (Production of compound 141)

The solution was dissolved in tert-butyl 3- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate (1200 mg) in 4N hydrochloric acid (ethyl acetate solution) (10 mL) and stirred for 1.5 hours. Toluene was added and concentrated to dryness. Tetrahydrofuran (35 mL) was added to the residue, and the mixture was stirred under ice-cooling. After lithium aluminum hydride (530 mg) was added little by little, the mixture was returned to room temperature and stirred for 3 hours. After the reaction solution was ice-cooled, 4N-sodium hydroxide (6 mL) and water (6 mL) were added to decompose. Tetrahydrofuran was added and the mixture was decanted three times, and the tetrahydrofuran layers were combined and concentrated to dryness. Saturated saline (5 mL) was added to the residue, and the mixture was extracted with dichloromethane. 4-Fluoro-1-naphthonitrile (340 mg), potassium carbonate (410 mg), and dimethyl sulfoxide (6.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 3.0 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- [3- (2-hydroxyethyl) -1-pyrrolidinyl] -1-naphthonitrile (223 mg) (Compound 141).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45 (3H, t, J = 5.0 Hz), 1.62-1.90 (3H, m), 2.10-2.60 ( 2H, m), 3.41 (1H, J = 9.2 Hz), 3.52-3.90 (5H, m), 6.65 (1H, d, J = 8.4 Hz), 7. 36-7.68 (2H, m), 7.71 (1H, d, J = 8.4 Hz), 8.10-8.30 (2H, m).
IR (KBr) 2204, 1562 cm ^-1
Example 140 (production of compound 142)

Dissolve tert-butyl 2-[(1E) -prop-1-enyl] pyrrolidine-1-carboxylate (1600 mg) in methanol (50 mL), acetic acid (2 mL) and 10% palladium on carbon (containing water) (1600 mg). ) And stirred under a hydrogen stream for 19 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was dissolved in toluene (2.0 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and 4-fluoro-1-naphthonitrile (520 mg), potassium carbonate (1450 mg), and dimethylsulfoxide (10.0 mL) were added to the residue, and the mixture was stirred at 100 ° C. for 3.5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (2-propyl-1-pyrrolidinyl) -1-naphthonitrile (310 mg) (Compound 142).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t, J = 7.0 Hz), 1.20-1.45 (3H, m), 1.60-2.10 ( 4H, m), 2.20-2.40 (2H, m), 3.28-3.40 (1H, m), 3.80-4.10 (2H, m), 6.80 (1H, m) d, J = 8.8 Hz), 7.40-7.70 (2H, m), 7.75 (1H, d, J = 8.8 Hz), 8.10-8.30 (2H, m ).
IR (KBr) 2209, 1560 cm ^-1
Example 141 (production of compound 143)

Dissolve benzyl (2R) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylate (1200 mg) in methyl alcohol (30 mL), acetic acid (2.0 mL), 10% palladium carbon ( (Water-containing) (600 mg), and the mixture was stirred under a hydrogen stream for 2.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (390 mg), potassium carbonate (940 mg) and dimethylsulfoxide (10.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 17 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography and basic silica gel column chromatography (Chromatorex NH manufactured by Fuji Silysia), and 4-[(2R) -2- (1-hydroxy-1-methylethyl) -1-) was obtained. [Pyrrolidinyl] -1-naphthonitrile (120 mg) was obtained (Compound 143).
[α] _D = -337.2 ° (c = 0.776, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10 (3H, s), 1.60-2.30 (5H, m), 3.10-3.22 (1H, m), 3. 70-3.90 (1H, m), 4.23 (1H, t, J = 7.6 Hz), 7.26 (1H, d, J = 8.8 Hz), 7.50-7.26 (2H, m), 7.72 (1H, d, J = 8.8 Hz), 8.14-8.28 (2H, m).
IR (KBr) 2212, 1568 cm ^-1
Example 142 (Production of compound 144)

Dissolve benzyl (2R) -2-isopropylpyrrolidine-1-carboxylate (1700 mg) in methanol (30 mL), add acetic acid (2.0 mL), 10% palladium on carbon (containing water) (1700 mg), and add a hydrogen stream. Stirred under for 17 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (510 mg), potassium carbonate (1380 mg), and dimethyl sulfoxide (15.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 9 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R) -2-isopropyl-1-pyrrolidinyl] -1-naphthonitrile (220 mg) (Compound 144).
[α] _D = -337.2 ° (c = 0.776, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.81 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 7.0 Hz), 1.60-2 .20 (5H, m), 3.30-3.46 (1H, m), 3.88-4.08 (2H, m), 6.85 (1H, d, J = 8.8 Hz), 7.40-7.68 (2H, m), 7.73 (1H, d, J = 8.8 Hz), 8.10-8.22 (2H, m).
IR (KBr) 2210, 1560 cm ^-1
Example 143 (Production of compound 145)

4- (3-Hydroxy-1-pyrrolidinyl) -1-naphthonitrile (240 mg) was dissolved in N, N-dimethylformamide (5 mL) and stirred under ice cooling. Then, sodium hydride (60% oily, 100 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, benzyl bromide (0.17 mL) was added, and the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography and crystallized from ether to give 4- [3- (benzyloxy) -1-pyrrolidinyl] -1-naphthonitrile (311 mg) (Compound 145).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.10-2.35 (2H, m), 3.50-3.95 (4H, m), 4.26-4.40 (1H, m ), 4.57 (2H, q, J = 11.8 Hz), 6.73 (1H, d, J = 8.0 Hz), 7.30-7.68 (7H, m), 7.74 (1H, d, J = 8.0 Hz), 8.12-8.28 (2H, m).
IR (KBr) 2201, 1562 cm ^-1
Example 144 (Production of compound 146)

4- [3- (2-Hydroxyethyl) -1-pyrrolidinyl] -1-naphthonitrile (130 mg) was dissolved in N, N-dimethylformamide (5 mL) and stirred under ice cooling. Then, sodium hydride (60% oily, 30 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, methyl iodide (0.05 mL) was added, and the mixture was stirred at room temperature for 15 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give 4- [3- (2-methoxyethyl) -1-pyrrolidinyl] -1-naphthonitrile (85 mg) as a pale yellow oil (Compound 146). ).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.60 (3H, m), 2.10-2.55 (2H, m), 3.35 (3H, s), 3.38-3. 85 (6H, m), 6.66 (1H, d, J = 8.4 Hz), 7.29-7.63 (2H, m), 7.71 (1H, d, J = 8.4 Hz) ), 8.10-8.30 (2H, m).
IR (KBr) 2207, 1563 cm- ¹
Example 145 (production of compound 147)

1,4-Dibromonaphthalene (2.86 g) was dissolved in anhydrous tetrahydrofuran (100 mL), stirred at −78 ° C. while cooling, and 1.6 M n-butyllithium (hexane solution, 6.25 mL) was added. The mixture was stirred for 15 minutes. Then, 2-methylcyclopentanone (1.07 mL) was added, and the mixture was stirred for 15 minutes. After adding saturated ammonium chloride, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1- (4-bromo-1-naphthyl) -2-methylcyclopentanol (1.35 g) (Compound 147).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.26 (3H, d, J = 6.6 Hz), 1.80-2.50 (6H, m), 2.60-3.00 ( 2H, m), 7.54 (1H, d, J = 8.0 Hz), 7.60-7.81 (2H, m), 7.85 (1H, d, J = 8.0 Hz), 8.45-8.56 (2H, m), 8.85-8.90 (1H, m).
Example 146 (production of compound 148)

1- (4-Bromo-1-naphthyl) -2-methylcyclopentanol (310 mg), zinc cyanide (72 mg) and tetrakistriphenylphosphine (120 mg) were combined with N, N-dimethylformamide (6 mL). And heated to 100 ° C. under a nitrogen stream and stirred for 2 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography, and crystallized from hexane to obtain 4- (1-hydroxy-2-methylcyclopentyl) -1-naphthonitrile (174 mg) (Compound 148).
mp 121-122 ° C.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.06 (3H, d, J = 6.6 Hz), 1.60-2.15 (5H, m), 2.15-2.38 ( 1H, m), 2.42-2.85 (2H, m), 7.56-7.72 (3H, m), 7.86 (1H, d, J = 7.6 Hz), 8.24 −8.34 (1H, m), 8.72−8.80 (1H, m).
IR (KBr) 3493, 2965, 2217, 764 cm ^-1
Anal. Calcd. For C ₁₇ H ₁₇ NO: C, 81.24; H, 6.82; N, 5.57.
Found: C, 81.89; H, 6.92; N, 5.48.
Example 147 (Production of compound 149)

1-bromo-4- (5-methylcyclopent-1-en-1-yl) -naphthalene and 1-bromo-4- (2-methylcyclopent-1-en-1-yl) -naphthalene (about 6 : A mixture of 4) (290 mg), zinc cyanide (71 mg) and tetrakistriphenylphosphine (120 mg) were dissolved in N, N-dimethylformamide (6 mL), and heated to 100 ° C under a nitrogen stream. Stir for 1 hour. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give 4- (5-methylcyclopent-1-en-1-yl) -1-naphthonitrile and 4- (2-methylcyclopent-1-en-1). -Yl) -1-Naphthonitrile (mixture of about 6: 4) (224 mg) was obtained (Compound 149).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.93 (1.8 H, d, J = 7.0 Hz), 1.48-1.55 (1.2 H, m), 1.60-2 .85 (4.8H, m), 3.20-3.40 (0.6H, m), 5.85-5.95 (0.6H, m), 7.25-8.50 (6H, m m).
IR (KBr) 2220, 766 cm ^-1
Example 148 (Production of compound 150)

A mixture of 4-fluoro-1-naphthonitrile (514 mg), [1,4] oxepane (506 mg), potassium carbonate (420 mg), and dimethylsulfoxide (5.0 mL) was stirred at 100 ° C for 1 hour. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (1,4-oxazepan-4-yl) -1-naphthonitrile (281 mg) (Compound 150).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.10-2.30 (2H, m), 3.40-3.60 (4H, m), 3.90-4.10 (4H, m ), 7.09 (1H, d, J = 8.0 Hz), 7.50-7.75 (2H, m), 7.82 (1H, d, J = 8.0 Hz), 8.18 −8.28 (2H, m).
IR (KBr) 2215, 1571, 1512 cm ^-1
Example 149 (Production of compounds 151 and 152)

4- (5-methylcyclopent-1-en-1-yl) -1-naphthonitrile and 4- (2-methylcyclopent-1-en-1-yl) -1-naphthonitrile (about 6: 4 The mixture was dissolved in methyl alcohol (20 mL), 10% palladium on carbon (containing water) (100 mg) was added, and the mixture was stirred under a hydrogen stream for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was dissolved in dichloromethane (6 mL), m-chloroperbenzoic acid (170 mg) was added at room temperature, and the mixture was stirred for 1 hour. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and water in that order, dried and concentrated. The obtained residue was purified by silica gel column chromatography, and 4- (2-methylcyclopentyl) -1-naphthonitrile (compound 151) (38 mg) and 4- (5-methyl-6-oxabicyclo [3, [1,0] Hex-1-yl) -1-naphthonitrile (compound 152) (62 mg) was obtained.

Compound 151
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.39 (3H, d, J = 7.4 Hz), 1.35-1.58 (1H, m), 1.60-2.40 (5H , m), 2.52-2.80 (1H, m), 3.80-4.00 (1H, m), 7.43 (1H, d, J = 7.6 Hz), 7.58- 7.74 (2H, m), 7.87 (1H, d, J = 7.6 Hz), 8.20-8.32 (2H, m).
IR (KBr) 2221, 1579, 1514 cm ^-1

Compound 152
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, s), 1.60-2.40 (6H, m), 7.50-7.90 (4H, m), 7. 93 (1H, d, J = 7.4 Hz), 8.22-8.35 (1H, m).
IR (KBr) 2223, 1514, 1390 cm ^-1
Example 150 (production of compound 153)

Dissolve tert-butyl (2S, 4R) -4-hydroxy-2-methylpyrrolidine-1-carboxylate (2.01 g) in toluene (4.0 mL) and add trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (1.71 g), potassium carbonate (2.77 g), and dimethylsulfoxide (15.0 mL). Stir for 5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S, 4R) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (119 mg) (Compound 153). ).
[α] _D = -263.9 ° (c = 0.462, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23 (3H, d, J = 6.4 Hz), 1.70-1.90 (1H, m), 2.04 (1H, d, J = 6.0 Hz), 2.56-2.74 (1H, m), 3.25-3.39 (1H, m), 3.85-4.10 (2H, m), 4.35 -4.55 (1H, m), 6.90 (1H, d, J = 8.4 Hz), 7.48-7.69 (2H, m), 7.79 (1H, d, J = 8 .4 Hz), 8.16-8.30 (2H, m).
IR (KBr) 2212, 1567 cm ^-1
Example 151 (Production of compound 154)

4-[(2S, 4R) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (310 mg), acetic acid (210 mg) and triphenylphosphine (645 mg) in toluene (8 mL) And diethyl azodicarboxylate (40% toluene solution, 1 mL) was added thereto under a nitrogen stream, followed by stirring at room temperature for 15 hours. Hexane (20 mL) was added to the reaction solution, the precipitated insolubles were removed by filtration, water was poured into the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and water in that order, dried and concentrated. The obtained residue was purified by silica gel column chromatography, and the target product fraction was concentrated. The residue was dissolved in methyl alcohol (15 mL), potassium carbonate (680 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, the residue was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 4-[(2S, 4S) -4-hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (119 mg) (Compound 154).
mp 149-151 ° C.
[α] _D = -211.8 ° (c = 0.51, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, d, J = 5.8 Hz), 1.66 (1H, d, J = 3.6 Hz), 1.80-2 .00 (1H, m), 2.20-2.40 (1H, m), 3.28 (1H, dd, J = 1.8 Hz and 11.0 Hz), 4.18-4.60 ( 3H, m), 6.90 (1H, d, J = 8.4 Hz), 7.40-7.68 (2H, m), 7.76 (1H, d, J = 8.4 Hz), 8.08-8.20 (2H, m).
IR (KBr) 3480, 2214, 1564 cm ^-1
Example 152 (Production of compound 155)

4-[(2S, 4R) -4-Hydroxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (73 mg) was dissolved in N, N-dimethylformamide (2 mL) and stirred under ice-cooling. . Then, sodium hydride (60% oily, 17 mg) was added, and the mixture was further stirred at room temperature for 0.5 hour. Then, methyl iodide (0.1 mL) was added, and the mixture was stirred at room temperature for 15 hours. Water was poured into the reaction and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S, 4R) -4-methoxy-2-methyl-1-pyrrolidinyl] -1-naphthonitrile (72 mg) (Compound 155). .
mp 88-89 ° C.
[α] _D = -225.1 ° (c = 0.386, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20 (3H, d, J = 6.2 Hz), 1.70-1.90 (1H, m), 2.50-2.70 ( 1H, m), 3.28-3.44 (1H, m), 3.40 (3H, s), 3.84-4.08 (3H, m), 6.88 (1H, d, J = 8.2 Hz), 7.48-7.70 (2H, m), 7.79 (1H, d, J = 8.2 Hz), 8.14-8.30 (2H, m).
IR (KBr) 2210, 1569 cm ^-1
Example 153 (production of compound 156)

Methyl (2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidine-3-carboxylate (1.00 g) methanol (20 mL), acetic acid (1.0 mL), 10 % Palladium on carbon (water) (350 mg) was stirred under a stream of hydrogen for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (680 mg), potassium carbonate (1.66 g) and dimethyl sulfoxide (10.0 mL) were added to the residue, and the mixture was stirred at 100 ° C for 1.5 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give methyl (2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxylate (262 mg) ( Compound 156).
[α] _D = -236.3 ° (c = 0.408, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35 (3H, d, J = 6.4 Hz), 2.00-2.52 (2H, m), 3.10-3.48 ( 2H, m), 3.76 (1H, s), 4.05-4.45 (2H, m), 6.93 (1H, d, J = 8.6 Hz), 7.50-7.70 (2H, m), 7.80 (1H, d, J = 8.0 Hz), 8.14-8.28 (2H, m).
IR (KBr) 2213, 1737, 1570 cm ^-1
Example 154 (production of compound 157)

Dissolve methyl (2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxylate (62 mg) in methyl alcohol (2 mL) and add 1N sodium hydroxide (0.1 mL). 63 mL) and stirred at room temperature for 5 hours. After adjusting the pH to 2 with acetic acid, the mixture was concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain (2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxylic acid (8.8 mg). (Compound 157).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.15 (3H, d, J = 6.2 Hz), 2.08-2.55 (2H, m), 3.08-3.24 (1H , m), 3.35-3.50 (1H, m), 4.05-4.40 (2H, m), 6.98 (1H, d, J = 8.0 Hz), 7.50- 7.76 (2H, m), 7.82 (1H, d, J = 8.0 Hz), 8.16-8.30 (2H, m).
IR (KBr) 2213, 1708, 1570 cm ^-1
Example 155 (Production of compound 158)

Dissolve 2-{(2S, 3S) -2-methyl-1-[(1S) -1-phenylethyl] pyrrolidin-3-yl} propan-2-ol (1.08 g) in methanol (20 mL) Then, acetic acid (1.0 mL) and 10% palladium carbon (containing water) (500 mg) were added, and the mixture was stirred under a hydrogen stream for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. 4-Fluoro-1-naphthonitrile (750 mg), potassium carbonate (1.81 g), and dimethyl sulfoxide (20.0 mL) were added to the residue, and the mixture was stirred at 100 ° C. for 3.0 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give 4-[(2S, 3S) -3- (1-hydroxy-1-methylethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile ( 543 mg) (Compound 158).
[α] _D = -225.5 ° (c = 0.20, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.98 (3H, d, J = 6.6 Hz), 1.34 (3H, s), 1.39 (3H, s), 1.57 (1H, s), 2.05-2.16 (2H, m), 2.45-2.65 (1H, m), 3.20-3.40 (1H, m), 3.70-3 .92 (1H, s), 4.35-4.55 (1H, m), 6.89 (1H, d, J = 8.0 Hz), 7.45-7.70 (2H, m), 7.77 (1H, d, J = 8.0 Hz), 8.06-8.24 (2H, m).
IR (KBr) 2211, 1569 cm ^-1
Example 156 (Production of compound 159)

Dissolve 4-[(2S, 3S) -3- (1-hydroxy-1-methylethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile (130 mg) in dichloromethane (2 mL), -40 Chlorosulfonyl isocyanate (0.10 mL) was added to the mixture under cooling with stirring and the mixture was stirred for 30 minutes. Water (10 mL) and dichloromethane (2 mL) were added to the reaction solution, and the mixture was heated under reflux for 30 minutes. After making the reaction solution alkaline with aqueous sodium carbonate, it was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to give 1-[(2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidin-3-yl] -1-methylcarbamate. Ethyl (19 mg) was obtained (compound 159).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94 (3H, d, J = 6.6 Hz), 1.63 (3H, s), 1.68 (3H, s), 2.10 -2.30 (2H, m), 2.68-2.85 (1H, m), 3.70-3.90 (1H, m), 4.35-4.60 (3H, m), 6 .90 (1H, d, J = 8.0 Hz), 7.46-7.70 (2H, m), 7.78 (1H, d, J = 8.0 Hz), 8.06-8. 24 (2H, m).
IR (KBr) 2212, 1715, 1568 cm ^-1
Example 157 (Production of compound 160)

Dissolve tert-butyl (2S, 3S) -3- (aminocarbonyl) -2-methylpyrrolidine-1-carboxylate (760 mg) in toluene (4.0 mL) and add trifluoroacetic acid (4.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and to the residue were added 4-fluoro-1-naphthonitrile (570 mg), potassium carbonate (1370 mg), and dimethylsulfoxide (12 mL), and the mixture was stirred at 100 ° C for 5 hours. After cooling to room temperature, water was poured into the reaction product, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Hexane: ethyl acetate = 1: 2 was added to the residue for crystallization to obtain (2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxamide (158 mg). The mother liquor was purified by silica gel column chromatography to obtain the same compound (289 mg) (Compound 160).
mp 204-206 ° C.
[α] _D = -276.7 ° (c = 0.388, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) δ: 1.17 (3H, d, J = 6.2 Hz), 2.00-2.50 (2H, m), 3.06- 3.30 (2H, m), 4.05-4.30 (2H, m), 5.84 (1H, br.s), 6.51 (1H, br.s), 6.98 (1H, d, J = 8.0 Hz), 7.50-7.71 (2H, m), 7.82 (1H, d, J = 8.0 Hz), 8.12-8.30 (2H, m ).
IR (KBr) 2210, 1664, 1567 cm ^-1
Anal. Calcd. For C ₁₇ H ₁₇ N ₃ O: C, 73.10; H, 6.13; N, 15.04.
Found: C, 72.82; H, 6.03; N, 15.09.
Example 158 (Production of compound 161)

(2S, 3S) -1- (4-Cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxamide (160 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic anhydride (0.2 mL) was added. The mixture was stirred at room temperature for 5 hours. The reaction solution was made alkaline with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain (2S, 3S) -1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carbonitrile (124 mg) (compound 161).
mp 143-145 ° C.
[α] _D = -192.6 ° (c = 0.34, MeOH).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.36 (3H, d, J = 5.8 Hz), 2.20-2.50 (2H, m), 3.08-3.25 ( 1H, m), 3.38-3.50 (1H, m), 4.00-4.22 (2H, m), 6.96 (1H, d, J = 8.0 Hz), 7.50 −7.78 (2H, m), 7.83 (1H, d, J = 8.0 Hz), 8.18-8.30 (2H, m).
IR (KBr) 2249, 2213, 1567 cm ^-1

The structural formulas of the compounds obtained in the above Examples are shown in Tables 1 to 12 below. "Real" in the table indicates the embodiment number. In the table, the notations such as `` HCl '', `` H ₂ SO ₄ '', and `` MsOH '' in the B ring column indicate that the compound is `` hydrochloride '', `` sulfate '' and `` methane sulfonate '', respectively. Show.

実験例１　AR結合阻害試験（野生型，LNCaP型）

Experimental Example 1 AR binding inhibition test (wild type, LNCaP type)

実験例２　Cos７細胞を用いたレポーターアッセイ系での化合物評価 To a solution containing an androgen receptor (AR) having a wild-type or LNCaP-type mutation, 3 nM of radiolabeled mibolerone and 100 nM of a compound were added, and the mixture was incubated at 4 ° C. for 3 hours, followed by dextran / charcoal method. (Bound) / F (Free) separated. The label count of B was measured, and the compound inhibition rate was calculated. Table 13 shows the results.
[Table 13]

Experimental Example 2 Evaluation of Compounds in Reporter Assay System Using Cos7 Cells

実験例３　ヒト前立腺癌細胞株におけるPSA産生試験 Cos-7 was seeded in a 150 cm ² flask at 5,000,000 cells and cultured in a culture solution (10% Dextran Charcoal (DCC) -Fetal Bovine Serum (FBS), a DMEM medium containing 2 mM glutamine) for 24 hours. And a vector DNA having a luciferase gene linked downstream of an androgen-responsive promoter prepared by linking two PSA promoter regions in tandem were cotransfected by a liposome method. After 2 hours, the medium was replaced and the cells were cultured for 3 hours, 1 μM of 5α-dihydrotestosterone or 100 nM of the compound was added, and the cells were further cultured for 24 hours. Then, the luciferase activity was measured. The luciferase activity induced when 1 μM of 5α-dihydrotestosterone was added was defined as 100, and the compound induction rate was determined. Table 14 shows the results.
[Table 14]

Experimental Example 3 PSA production test in human prostate cancer cell line

実験例４　アンドロゲン受容体アゴニストのホルモン抵抗性癌細胞増殖率に対する影響 The human prostate cancer cell line LNCaP-FGC was seeded at 5,000 cells / 100 μL / well in a 96-well plate, and the next day, the test compound (final concentration 100 nM) or vehicle or testosterone as a control (final concentration 0.35 to 350 nM), and the culture supernatant is collected 3 days after the addition of the drug. The concentration of PSA (Prostate Specific Antigen) produced in an androgen-dependent manner in the culture supernatant was measured by ELISA, and the PSA production by the test compound when the group added with the vehicle was set to 0 and the group added with 350 nM testosterone was set to 100 The promotion rate was calculated. Table 15 shows the results.
[Table 15]

Experimental Example 4 Effect of androgen receptor agonist on growth rate of hormone-resistant cancer cells

1) Establishment of hormone-resistant cell lines (LNCaP-hr and MDA PCa 2b-hr cell lines) A culture solution from LNCaP-FGC and MDA PCa 2b cell lines without androgen (LNCaP-FGC is RPMI1640 + 10% Dextran Charcoal ( DCC) -Fetal Bovine Serum (FBS), MDA PCa 2b is Ham's F-12K + 25 ng / ml cholera toxin + 10 ng / ml EGF + 0.005 mM phosphoethanol amine + 100 pg / ml hydrocortisone + 45 nM selenious acid + 0.005 mg / ml insulin + 20% DCC-FBS). It did not proliferate at first, but began to proliferate after more than 3 to 8 months of culture. The cells were named LNCaP-hr and MDA PCa 2b-hr, respectively.
2) Effect on cell proliferation rate in the presence of androgen receptor agonist
(Method) LNCaP-hr (cultured in a culture solution without androgen for 60 weeks) was seeded at 40,000 cells / mL / well in a 24-well plate, and the next day, 0.01 to 10 nmol / L of the test compound was added, followed by addition for 3 days. Later, the number of cells was counted. Also, cells of MDA PCa 2b-hr (cultured in a culture solution without androgen for 61 weeks) were seeded at 40,000 cells / mL / well in a 24-well plate, and the following day, 0.01 to 10 μmol / L of the test compound was added. The number of cells was counted after one day.
(Results) The proliferation of LNCaP-hr and MDA PCa 2b-hr cells was suppressed by the compound of the present invention.
Formulation Example 1 Microcapsules containing leuprorelin acetate

5.8 g of leuprorelin acetate was dissolved in 6.7 ml of distilled water. 138 g of a dichloromethane solution containing 51.6 g of polylactic acid (weight average molecular weight: 15,000), which was separately dissolved and filtered, was added thereto, and the mixture was stirred and emulsified (rotational speed: about 6000 rpm) for 9 minutes with an auto mini mixer, and then heated at 15 ° C. Was adjusted to This was dissolved, filtered, and emulsified by adding it to 13.5 L of a 0.1% polyvinyl alcohol (PVA) aqueous solution adjusted to the same temperature. In this case, using a homomic line flow (specialized machine), the number of revolutions of the mixer was about 7,000 rpm to emulsify. This W / O / W emulsion was desolvated for about 3 hours while being gently stirred (in-water drying method).
The obtained microcapsules were passed through a 74 μm sieve to remove coarse particles, and then separated by filtration or centrifugation. This was washed with distilled water to remove free drug and PVA, redispersed with a small amount of water to dissolve 8.7 g of D-mannitol, sieved, and freeze-dried. The shelf temperature at the time of drying was gradually increased, and drying was performed at a final temperature of 52 ° C. for 69 hours. This was sieved and pulverized to obtain microcapsule powder. By this operation, 58 g of microcapsule powder containing 15% D-mannitol was obtained.
Formulation Example 2 Compound-containing injection described in Example 1

(1) 5.0 mg of the compound described in Example 1
(2) Salt 20.0mg
(3) Distilled water Make the total volume 2 ml 5.0 mg of the compound described in Example 1 and 20.0 mg of common salt are dissolved in distilled water, and water is added to make a total volume of 2.0 ml. The solution is filtered and filled under aseptic conditions into 2 ml ampules. After sterilizing the ampoule, seal it to obtain a solution for injection.
Formulation Example 3 Testosterone-containing tablet

(1) Testosterone 50mg
(2) Lactose 34mg
(3) Corn starch 10.6mg
(4) Corn starch (paste-like) 5mg
(5) 0.4 mg of magnesium stearate
(6) carboxymethylcellulose calcium 20mg
120mg in total
According to a conventional method, the above (1) to (6) were mixed and tableted with a tableting machine to obtain tablets.
Formulation Example 4

The formulation obtained in Formulation Example 1 and the formulation obtained in Formulation Example 2 are combined.
Formulation Example 5
The formulation obtained in Formulation Example 1 and the formulation obtained in Formulation Example 3 are combined.
Formulation Example 6
The formulation obtained in Formulation Example 1, the formulation obtained in Formulation Example 2, and the formulation obtained in Formulation Example 3 are combined.

The compound of the present invention has an excellent action as an androgen receptor modulator (especially an agonist), and hypogonadism, male climacteric disorder, osteoporosis, hormone-resistant cancer (especially LHRH derivative-resistant prostate cancer) for which androgen administration is effective. Useful for prevention and treatment of

Claims (26)

General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by W represents a nitrogen atom, or, in the case where the ring A is a benzene ring which may be substituted, a group represented by the formula CR ^a (wherein R ^a represents a bond, a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group; Is shown.). Y ¹¹ is a group represented by the formula CR ² R ^{3 ′} (wherein R ² is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated carboxyl group or a substituted An optionally substituted hydrocarbon group, R ^{3 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, or a substituted Y ²¹ represents 1) when W is a nitrogen atom, the formula CR ⁴ R ^{5 ′} (wherein, R ⁴ represents a hydrogen atom, a cyano group, or a nitro group) An optionally substituted acyl group, an optionally esterified or amidated carboxyl group or an optionally substituted hydrocarbon group, R ^{5 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, Acyl group which may be substituted, esterification Or a carboxyl group which may be amidated or a hydrocarbon group which may be substituted.), A nitrogen atom which may be substituted, an oxygen atom or a formula S (O) _m ( In the formula, m represents 0, 1 or 2.) 2) When W is a group represented by the formula CR ^a (the symbols in the formula are the same as defined above), the group represented by the formula CR ⁴ R ^{5 ′} (each symbol in the formula is the same as defined above) or a nitrogen atom (provided that Y ²¹ is a nitrogen atom and W is a formula CR ^a (the symbols in the formula are as defined above. In the case of a group represented by the formula, a bond between CR ^a and Y ²¹ represents a double bond.) In the case of a bicyclic ring in which ring B may be further substituted, Y CR ^{2 at 11} or CR ⁴ or the nitrogen atom at Y ²¹ may form part of the B ring. R ¹ represents an electron-withdrawing group. formula

Represents a single bond or a double bond. Or a salt thereof. However,
1) When W is a nitrogen atom and ring B is an optionally substituted piperazine ring,
2) ring A is an optionally substituted benzene ring, R ¹ is a nitro group or an optionally substituted sulfamoyl group, W is a nitrogen atom, and ring B is octahydro [1,2-a A pyrazine ring, a homopiperazine ring in which a nitrogen atom may be substituted with an alkyl group or a 2,5-diazabicyclo [2,2,1] heptane ring in which a nitrogen atom may be substituted with an alkyl group,
3) A ring is a furan ring or a pyran ring which may be substituted or saturated, R ¹ is a halogen atom, W is a nitrogen atom, and ring B is substituted at the 3-position. When a pyrrolidine ring substituted with a good amino group,
4) W is a group represented by the formula CR ^a (the symbols in the formula are the same as defined above), and the optionally substituted piperidine ring wherein ring B is bonded to ring C at the 4-position or 4 And optionally substituted 1,2,5,6-tetrahydropyridine ring bonded to ring C, and 5) 1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- Excludes (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1-naphthonitrile and 4- (1-pyrrolidinyl) -1-nitronaphthalene. General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by Y ¹ is a group represented by the formula CR ² R ^{3 wherein} R ² and R ³ are the same or different and each may be a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated A group represented by a carboxyl group or a hydrocarbon group which may be substituted; Y ² is a group represented by the formula CR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a cyano group, A nitro group, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a hydrocarbon group which may be substituted.) A nitrogen atom, an oxygen atom or a group represented by the formula S (O) _m (where m represents 0, 1 or 2), and the ring B may be further substituted. for cyclic ring, CR ⁴ in CR ² or Y ² in Y ¹ Properly nitrogen atom may constitute a part of the B ring. R ¹ represents an electron-withdrawing group. The compound according to claim 1, which is represented by the formula: However,
1) When ring B is an optionally substituted piperazine ring,
2) ring A is an optionally substituted benzene ring; R ¹ is a nitro group or an optionally substituted sulfamoyl group; ring B is an octahydro [1,2-a] pyrazine ring; When a homopiperazine ring optionally substituted with an alkyl group or a 2,5-diazabicyclo [2,2,1] heptane ring wherein a nitrogen atom is optionally substituted with an alkyl group,
3) Ring A is a furan ring or pyran ring which may be substituted or saturated, R ¹ is a halogen atom, and ring B is substituted with an amino group which may be substituted at the 3-position. And 4) 1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1- Excludes naphthonitrile and 4- (1-pyrrolidinyl) -1-nitronaphthalene. The compound according to claim 1, wherein the ring A is an optionally substituted benzene ring, an optionally substituted thiophene ring or an optionally substituted furan ring. B ring optionally substituted pyrrolidine ring, optionally substituted piperidine ring, optionally substituted morpholine ring, optionally substituted thiomorpholine ring, optionally substituted pyrazoline ring, substituted An optionally substituted pyrazolidine ring, an optionally substituted isoxazoline ring, an optionally substituted cyclopentane ring, an optionally substituted cyclopentene ring or an optionally substituted perhydroazepine ring. Item 7. The compound according to Item 1. R ¹ is a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a C _1-6 alkyl substituted with 1 to 5 halogen atoms. The compound according to claim 1, which is a group. Substituents other than R ^a , R ² , R ^{3 ′} , R ⁴ and R ^{5 ′} on the A ring or the B ring are (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) Nitro group, (5) hydroxyl group, (6) optionally substituted amino group, (7) optionally esterified or amidified carboxyl group, (8) optionally substituted C _1-6 alkyl A group, (9) an optionally substituted C _1-6 acyl group, (10) an optionally substituted C _1-6 alkoxy group, (11) a formula R ⁶ S (O) _p , wherein R ⁶ represents a C _1-6 alkyl group which may be substituted, p represents 0, 1 or 2), (12) an oxo group, (13) a hydroxyimino group, and (14) 1 to 6 selected from the group consisting of an optionally substituted C _1-6 alkoxyimino group and (15) an optionally substituted C _1-4 alkylenedioxy group The compound according to claim 1, which is a group of General formula

[In the formula, R ⁷ represents a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a C substituted with 1 to 5 halogen atoms. _1-6 alkyl group, R ⁸ and R ⁹ are the same or different and are (1) hydrogen atom, (2) cyano group, (3) nitro group, (4) halogen atom, hydroxyl group or C _1-6 alkoxy group. An optionally substituted C _1-6 alkyl group, (5) a halogen atom, a hydroxyl group or a C _1-6 acyl group optionally substituted with a C _1-6 alkoxy group, (6) a halogen atom, a hydroxyl group or C _1-6 substituted alkoxy group a C _1-6 alkoxy group, or also (7) esterified or amidated carboxyl group which may be, q and is 0, 1 or 2, Z ¹ is a carbonyl group A hydroxyimino group or Conversion to carbon atoms which is substituted in a C _1-6 alkoxyimino group optionally, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹⁰ and R ¹¹ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group Z ² represents an oxygen atom, a sulfur atom, SO, SO ₂ , a carbonyl group, a hydroxy group or a carboxyl group which may be esterified or amidated. It may be imino group or substituted C _1-6 alkoxy Substituted carbon atom in the imino group, C _1-6 alkyl or C _1-6 acyl amino group which may be substituted with a group, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹² and R ¹³ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group An amino group or (10) a carboxyl group which may be esterified or amidified, respectively). Or a salt thereof. However,
1- [4- (1-piperidinyl) -1-naphthyl] ethanone, 4- (1-piperidinyl) -1-nitronaphthalene, 4- (1-piperidinyl) -1-naphthonitrile and 4- (1-pyrrolidinyl) Except for -1-nitronaphthalene. General formula

Wherein X ³ is a sulfur atom or an oxygen atom, R ⁷ is a cyano group, a nitro group, a halogen atom, an optionally substituted acyl group, an esterified or amidated carboxyl group or 1 to A C _1-6 alkyl group substituted with 5 halogen atoms, R ⁸ and R ⁹ being the same or different, and (1) hydrogen atom, (2) cyano group, (3) nitro group, (4) halogen atom , hydroxyl or C _1-6 alkoxy optionally substituted by C _1-6 alkyl group group, (5) halogen atom, a hydroxyl group or a C _1-6 optionally substituted alkoxy group C _1-6 acyl group (6) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group which may be substituted with a C _1-6 alkoxy group, or (7) a carboxyl group which may be esterified or amidated, q represents 0, 1 or 2, Z ¹ is carbonyl , Hydroxyimino group or substituted carbon atom substituted in a C _1-6 alkoxyimino group optionally, C _1-4 carbon atoms substituted with an alkylenedioxy group or formula

(Wherein R ¹⁰ and R ¹¹ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group Z ² represents an oxygen atom, a sulfur atom, SO, SO ₂ , a carbonyl group, a hydroxy group or a carboxyl group which may be esterified or amidated. It may be imino group or substituted C _1-6 alkoxy Substituted carbon atom in the imino group, C _1-6 alkyl or C _1-6 acyl amino group which may be substituted with a group, C _1-4 carbon atoms or formula substituted with an alkylenedioxy group

(Wherein R ¹² and R ¹³ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro group, (5) hydroxyl group, (6) halogen atom, hydroxyl group Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group, (7) a C _1-6 acyl group optionally substituted with a halogen atom, a hydroxyl group or a C _1-6 alkoxy group, 8) a halogen atom, a hydroxyl group or a C _1-6 alkoxy group optionally substituted C _1-6 alkoxy group, optionally substituted with (9) C _1-6 alkyl group and / or a C _1-6 acyl group An amino group or (10) a carboxyl group which may be esterified or amidified, respectively). Or a salt thereof. However,
X ³ is an oxygen atom, R ⁷ is a halogen atom, q is 0, R ⁸ and R ⁹ are hydrogen atoms, and Z ¹ is a group represented by the formula

(In the formula, one of R ¹⁰ and R ^{11 represents} a hydrogen atom, and the other represents an amino group optionally substituted with a C _1-6 alkyl group and / or a C _1-6 acyl group.) Excluding the case where Z ² is a methylene group. 4- [4- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3- (hydroxymethyl) -1-piperidinyl] -1-naphthonitrile, 4- [3- (hydroxymethyl)- 3-methyl-1-piperidinyl] -1-naphthonitrile, 4- (2-methyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-ethyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-vinyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (2-isopropyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (3-hydroxy-2-methyl-1-pyrrolidinyl) -1- Naphthonitrile, 4- (3-methoxy-2-methyl-1-pyrrolidinyl) -1-naphthonitrile, 4- (4-methoxy-2-methyl-1-pyrrolidinyl) -1 Naphthonitrile 4- [3- (hydroxymethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile, 4- [3- (1-hydroxy-1-methylethyl) -2-methyl-1-pyrrolidinyl] -1-naphthonitrile, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carboxamide, 1- (4-cyano-1-naphthyl) -2-methylpyrrolidine-3-carbonitrile, 4 -(2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- (3-hydroxy-2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, 4- ( 4-hydroxy-2-methyl-1-pyrrolidinyl) -1-benzothiophene-7-carbonitrile, an optically active form thereof, or a salt thereof. General formula

[In the formula, ring A ^a represents ^a 5- to 8-membered ring which may be substituted, ring C ^a represents ^a benzene ring which may be further substituted, X ^1a represents a carbon atom which may be substituted, ^2a is an optionally substituted carbon atom, oxygen atom or a group represented by the formula S (O) _k ^a (where k ^a is 0, 1 or 2), and R ^1a is an electron withdrawing property And M represents a leaving group. A compound represented by the general formula

[In the formula, the ^Ba ring represents ^a 4- to 10-membered ring which may be further substituted. Y ^1a has the formula CR ^2a R ^3a (wherein R ^2a and R ^3a are the same or different and each may be a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated A group represented by a carboxyl group or a hydrocarbon group which may be substituted; Y ^2a is a group represented by the formula CR ^4a R ^5a (wherein R ^4a and R ^5a are the same or different and are a hydrogen atom, a cyano group, A nitro group, an optionally substituted acyl group, a carboxyl group which may be esterified or amidated, or a hydrocarbon group which may be substituted.) a nitrogen atom which may, (wherein, m ^a is. for 0, 1 or 2) an oxygen atom or a group represented by formula S (O) _m ^a or respectively a group represented by or B ^a ring, is further substituted In the case of an optionally bicyclic ring, CR ^2a in Y ^1a Alternatively, CR ^4a or a nitrogen atom in Y ^2a may form part of ^a Ba ring. The method for producing a compound or a salt thereof according to claim 2, wherein the reaction is carried out with a compound represented by the formula A prodrug of the compound according to claim 1, 7 or 8. A medicament comprising the compound according to claim 1, 7 or 8, or a salt thereof, or a prodrug thereof. 13. The medicament according to claim 12, which is an androgen receptor modulator. 13. The medicament according to claim 12, which is an androgen receptor agonist. General formula

[Wherein, ring A is an optionally substituted 5- to 8-membered ring, ring B is an optionally substituted 4- to 10-membered ring, and ring C is an optionally substituted benzene ring. , X ¹ represents an optionally substituted carbon atom, X ² represents an optionally substituted carbon atom, an oxygen atom or a formula S (O) _k (where k represents 0, 1 or 2) And the groups represented by W ¹ represents a nitrogen atom or a group represented by the formula CR ^a (where R ^a represents a bond, a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group). Y ¹¹ is a group represented by the formula CR ² R ^{3 ′} (wherein R ² is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an esterified or amidated carboxyl group or a substituted An optionally substituted hydrocarbon group, R ^{3 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, or a substituted Y ²¹ is a group represented by the formula CR ⁴ R ^{5 ′} (wherein R ⁴ is a hydrogen atom, a cyano group, a nitro group, an optionally substituted acyl group) A carboxyl group that may be esterified or amidated or a hydrocarbon group that may be substituted, R ^{5 ′} is a bond, a hydrogen atom, a cyano group, a nitro group, an acyl group that may be substituted, Esterified or amidated It indicates a hydrocarbon group which may optionally be also be a carboxyl group or substituted, respectively.) Or a group represented by optionally substituted nitrogen atom, an oxygen atom or a group represented by formula S (O) _{m (wherein,} m is 0, 1 or 2). In the case of a bicyclic ring in which ring B may be further substituted, CR ² in Y ¹¹ or CR ⁴ or a nitrogen atom in Y ²¹ May form a part of the B ring. R ¹ represents an electron-withdrawing group. formula

Represents a single bond or a double bond. And a salt thereof or a prodrug thereof. The modulator according to claim 15, which is an androgen receptor agonist. An agent for preventing or treating hypogonadism or male climacteric disorder, comprising the modulator according to claim 15. An agent for preventing or treating osteoporosis, comprising the modulator according to claim 15. An agent for preventing or treating hormone-resistant cancer, comprising the modulator according to claim 15. The agent according to claim 19, wherein the hormone-resistant cancer is an LHRH agonist-resistant cancer. 21. The agent according to claim 19, wherein the cancer is prostate cancer. A method for preventing or treating hormone-resistant cancer, which comprises administering an effective amount of an androgen receptor agonist to a mammal. An agent for preventing and treating hormone-resistant cancer, comprising an androgen receptor agonist. The agent according to claim 23, wherein the androgen receptor agonist is a non-steroid compound. Use of the compound according to claim 1, a salt thereof or a prodrug thereof for producing an androgen receptor agonist. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a prophylactic / therapeutic agent for cancer.