JP2005060375A - Oxygen-containing heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new oxygen-containing heterocyclic compound having phosphodiesterase (PDE)-IV inhibitory action. <P>SOLUTION: This oxygen-containing heterocyclic compound expressed by general formula (I) (W is -OR<SP>5</SP>or the like; R<SP>4</SP>is H, a substituted or unsubstituted lower alkyl or the like; R<SP>1</SP>is a substituted or unsubstituted lower alkyl or the like; R<SP>2</SP>and R<SP>3</SP>are identical to or different from each other and are each H, a substituted or unsubstituted lower alkyl or the like; and m is 0, 1 or 2) or its pharmacologically acceptable salt is provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention has a phosphodiesterase (PDE) -IV inhibitory action, for example, inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, nephritis, chronic obstructive pulmonary disease, rheumatism, multiple sclerosis, Autoimmune diseases such as Crohn's disease, psoriasis and systemic lupus erythematosus, diseases of the central nervous system such as gonorrhea, amnesia, dementia, organ damage associated with ischemia-reperfusion caused by heart failure, shock, cerebrovascular disorder, The present invention relates to an oxygen-containing heterocyclic compound useful as a therapeutic agent for insulin-resistant diabetes, wounds, AIDS, osteoporosis, urinary calculus, urinary incontinence, etc., and an improving agent for fatigue, fatigue and the like.

Conventionally, many hormones and neurotransmitters have concentrations of adenosine 3 ′, 5′-cyclic monophosphate (cAMP) or guanosine 3 ′, 5′-cyclic monophosphate (cGMP), which are intracellular second messengers. It is known to exert its action by raising The intracellular concentrations of cAMP and cGMP are controlled by their production and degradation, and these degradations are performed by PDE. Thus, inhibiting PDE increases the concentration of these intracellular second messengers. It has been clarified that there are 8 types of isozymes in PDE so far, and isozyme-selective PDE inhibitors exhibit pharmacological effects based on the physiological significance and distribution in the body of the isozyme ["Trends in Pharmacological Science", 1990, Vol. 11, p. 150, 1991, Vol. 12, p. 19, “Biochemical & Biophysical Research Communications”, 1998, vol. 250, p. 751].
It is known that when the intracellular cAMP concentration of inflammatory white blood cells is increased, their activation can be suppressed. Activation of white blood cells leads to secretion of inflammatory cytokines such as tumor necrosis factor (TNF), expression of cell adhesion molecules such as intercellular adhesion molecule (ICAM) and subsequent cell invasion [“Journal of "Molecular and Cellular Cardiology", 1989, Volume 12 (Suppl. II), S61].
Increasing cAMP concentration in tracheal smooth muscle cells is known to be able to suppress the contraction ["TJ Tofy in Directions for New Anti-Azuma Drugs (TJ Torphy"). in Directions for New Anti-Asthma Drugs), SR O'Donell et al., 1988, p. 37, Birkhauser-Verlag]. Tracheal smooth muscle contraction is a major pathology of bronchial asthma. In ischemia-reperfusion organ disorders such as myocardial ischemia, infiltration of inflammatory leukocytes such as neutrophils is observed in the lesion. In these inflammatory cells and tracheal smooth muscle cells, it has been revealed that PDE-IV is mainly involved in cAMP degradation. Therefore, a PDE-IV selective inhibitor can be expected to have a therapeutic and / or preventive effect on inflammatory diseases, airway obstructive diseases, ischemic diseases and the like.
The PDE-IV inhibitor suppresses the secretion of inflammatory cytokines such as TNFα and interleukin (IL) -8 due to the increase in cAMP, and further prolongs the progress of inflammatory reactions and the like transmitted by these cytokines. It is expected that it can be prevented. For example, TNFα has been reported to reduce the mechanism of insulin receptor phosphorylation in muscle and adipocytes and contribute to insulin-resistant diabetes ["Journal of Clinical Investigation (Journal of Clinical (Clinical Investigation), 1994, 94, p. 1543] Similarly, TNFα is involved in the development of autoimmune diseases such as rheumatism, multiple sclerosis, Crohn's disease, and PDE- It has been suggested that IV inhibitors may be effective ["Nature Medicine", 1995, Vol. 1, p. 211, 1995, Vol. 1, p. 244].
In addition, it has been reported that THFα is involved in fatigue feeling after dialysis and cancer patients [“International Journal of Artificial Organs”, 1998, Vol. 21, p. 83, “Oncology Nursing Forum”, 1992, Vol. 19, p. 419]. Therefore, the PDE-IV inhibitor can be expected to be effective in improving fatigue, fatigue and the like.
It has been reported that drugs that increase cAMP promote wound healing [The 68th Annual Meeting of the Japanese Pharmacological Society (Nagoya), 1995, Title P3-116).
It has been suggested that PDE-IV inhibitors show therapeutic effects in cancer osteogenesis models, sciatic nerve resection models, and ovariectomy models, which are animal models of osteoporosis, and may be therapeutic drugs for osteoporosis [“Japanese”・ Journal of Pharmacology ”, 1999, vol. 79, p. 477].
Although relaxation of the ureter is known to promote stone excretion, PDE-IV inhibitors are effective in the treatment and / or prevention of urinary calculi because they suppress the peristaltic movement of the ureter. A possibility has been suggested ["Journal of Urology", 1998, vol. 160, p. 920].
However, PDE-IV inhibitors known so far have been reported to also exhibit side effects such as emetic action [Current Pharmaceutical Design, 2002, 8th. Volume, p. 1255].
On the other hand, oxygen-containing heterocyclic compounds having a PDE-IV inhibitory action are known (see Patent Documents 1 to 4).
International Publication No. 98/22455 Pamphlet WO99 / 16766 pamphlet International Publication No. 00/14085 Pamphlet International Publication No. 01/64666 Pamphlet

  An object of the present invention is to provide a novel oxygen-containing heterocyclic compound having a PDE-IV inhibitory action.

The present invention relates to the following (1) to (15).
(1) General formula (I)

［式中、ｍは０、１または２を表し、Ｗは−ＯＲ^５（式中、Ｒ^５は水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニルまたはアラルキルを表す）または−ＮＲ^６Ｒ^７（式中、Ｒ^６およびＲ^７は同一または異なって、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、または置換もしくは非置換の低級アルキニルを表すか、Ｒ^６とＲ^７が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）を表し、
Ｒ^４は水素原子、ヒドロキシ、置換もしくは非置換の低級アルキル、または置換もしくは非置換の低級アルコキシを表し、
Ｒ^２およびＲ^３は、同一または異なって、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のポリシクロアルキル、置換もしくは非置換の脂環式複素環基、多環式複素環基、置換もしくは非置換の低級アルケニル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換の芳香族複素環基または置換もしくは非置換のアラルキルを表すか、Ｒ^２およびＲ^３が同一炭素原子上に存在し、その炭素原子と一緒になって置換もしくは非置換のスピロシクロアルカン、置換もしくは非置換のスピロ脂環式複素環、置換もしくは非置換のスピロポリシクロアルカン、または置換もしくは非置換のスピロ多環式複素環を形成し、
Ｒ^１は、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルカノイル、ホルミルまたは−ＮＲ^８Ｒ^９（式中、Ｒ^８およびＲ^９は同一または異なって、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、ホルミル、または置換もしくは非置換の低級アルカノイルを表すか、Ｒ^８とＲ^９が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）を表すか、
あるいは、Ｒ^２およびＲ^３の一方が水素原子を表し、他方が多環式複素環基を表すか、Ｒ^２およびＲ^３が同一炭素上に存在し、その炭素原子と一緒になって、置換もしくは非置換のスピロ脂環式複素環、置換もしくは非置換のスピロポリシクロアルカンまたは置換もしくは非置換のスピロ多環式複素環を形成するとき、
Ｒ^１はヒドロキシまたは置換もしくは非置換の低級アルコキシを表す］で表される含酸素複素環化合物またはその薬理学的に許容される塩。
（２） Ｒ^１が置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルカノイル、ホルミルまたは−ＮＲ^８Ｒ^９（式中、Ｒ^８およびＲ^９はそれぞれ前記と同義である）である（１）記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（３） Ｒ^２およびＲ^３が水素原子である（１）または（２）記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（４） Ｒ^１が置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニルまたは置換もしくは非置換の低級アルキニルである（１）〜（３）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（５） Ｒ^１がヒドロキシまたは置換もしくは非置換の低級アルコキシである（１）記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（６） Ｒ^２およびＲ^３が同一炭素上に存在し、その炭素原子と一緒になって置換もしくは非置換のスピロ脂環式複素環、置換もしくは非置換のスピロポリシクロアルカンまたは置換もしくは非置換のスピロ多環式複素環を形成し、Ｒ^１が置換もしくは非置換の低級アルコキシである（１）記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（７） Ｒ^２およびＲ^３が同一炭素上に存在し、その炭素原子と一緒になって置換もしくは非置換のスピロ脂環式複素環または置換もしくは非置換のスピロポリシクロアルカンを形成し、Ｒ^１が置換もしくは非置換の低級アルコキシである（１）記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（８） Ｒ^４が水素原子である（１）〜（７）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（９） Ｗが−ＯＲ^５（式中、Ｒ^５は前記と同義である）である（１）〜（８）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（１０） Ｗがヒドロキシである（１）〜（８）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（１１） Ｗが−ＮＲ^７Ｒ^８（式中、Ｒ^７およびＲ^８はそれぞれ前記と同義である）である（１）〜（８）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（１２） ｍが１である（１）〜（１１）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（１３） ｍが０である（１）〜（１１）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩。
（１４） （１）〜（１３）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩を含有する医薬。
（１５） （１）〜（１３）のいずれかに記載の含酸素複素環化合物またはその薬理学的に許容される塩を含有するホスホジエステラーゼ（ＰＤＥ）−ＩＶ阻害剤。

[Wherein m represents 0, 1 or 2; W represents —OR ⁵ (wherein R ⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted; Lower alkynyl or aralkyl) or —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or Represents an unsubstituted lower alkynyl, or R ⁶ and R ⁷ together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group),
R ⁴ represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
R ² and R ³ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted polycycloalkyl, substituted or unsubstituted alicyclic heterocycle A group, a polycyclic heterocyclic group, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aralkyl. R ² and R ³ are present on the same carbon atom and together with the carbon atom are substituted or unsubstituted spirocycloalkanes, substituted or unsubstituted spiroalicyclic heterocycles, substituted or unsubstituted A spiropolycycloalkane, or a substituted or unsubstituted spiropolycyclic heterocycle,
R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, formyl, or —NR ⁸ R ⁹ (wherein R ⁸ and R ^{9 s} are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, formyl, or substituted or unsubstituted lower alkanoyl, or nitrogen in which R ⁸ and R ⁹ are adjacent to each other. Together with the atom to form a substituted or unsubstituted heterocyclic group)
Alternatively, one of R ² and R ³ represents a hydrogen atom and the other represents a polycyclic heterocyclic group, or R ² and R ³ are present on the same carbon, together with the carbon atom, substituted Or when forming an unsubstituted spiroalicyclic heterocycle, a substituted or unsubstituted spiropolycycloalkane or a substituted or unsubstituted spiropolycyclic heterocycle,
R ¹ represents hydroxy or substituted or unsubstituted lower alkoxy], or a pharmacologically acceptable salt thereof.
(2) R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, formyl, or —NR ⁸ R ⁹ (wherein R 1 ⁸ and R ⁹ are the same as defined above, respectively, and the oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to (1).
(3) The oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to (1) or (2), wherein R ² and R ³ are hydrogen atoms.
(4) The oxygen-containing heterocyclic compound according to any one of (1) to (3), wherein R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl. Its pharmacologically acceptable salt.
(5) The oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to (1), wherein R ¹ is hydroxy or substituted or unsubstituted lower alkoxy.
(6) R ² and R ³ are present on the same carbon and together with the carbon atom are substituted or unsubstituted spiroalicyclic heterocycles, substituted or unsubstituted spiropolycycloalkanes, or substituted or unsubstituted The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1), wherein the spiro polycyclic heterocyclic ring is formed and R ¹ is substituted or unsubstituted lower alkoxy.
(7) R ² and R ³ are present on the same carbon and together with the carbon atom form a substituted or unsubstituted spiroalicyclic heterocycle or a substituted or unsubstituted spiropolycycloalkane; ^1. The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1), wherein ¹ is substituted or unsubstituted lower alkoxy.
(8) The oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of (1) to (7), wherein R ⁴ is a hydrogen atom.
(9) The oxygen-containing heterocyclic compound according to any one of (1) to (8) or pharmacologically acceptable thereof, wherein W is —OR ⁵ (wherein R ⁵ has the same meaning as described above). salt.
(10) The oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of (1) to (8), wherein W is hydroxy.
(11) The oxygen-containing heterocyclic compound or the drug thereof according to any one of (1) to (8), wherein W is —NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above). Physically acceptable salt.
(12) The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein m is 1.
(13) The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein m is 0.
(14) A medicine containing the oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of (1) to (13).
(15) A phosphodiesterase (PDE) -IV inhibitor comprising the oxygen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (13).

  According to the present invention, it has a PDE-IV inhibitory action, such as bronchial asthma, allergic rhinitis, atopic dermatitis, nephritis and other inflammatory allergic diseases, chronic obstructive pulmonary disease, rheumatism, multiple sclerosis, Crohn's disease, Autoimmune diseases such as psoriasis, systemic lupus erythematosus, central nervous system diseases such as depression, forgetfulness, dementia, organ diseases associated with ischemia-reperfusion caused by heart failure, shock, cerebrovascular disorder, insulin resistance To provide an oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof useful as a therapeutic agent for diabetes, wounds, AIDS, osteoporosis, urinary calculus, urinary incontinence, etc., an improving agent for fatigue, fatigue, etc. it can.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of general formula (I):
(I) Lower alkyl part of lower alkyl, lower alkoxy and lower alkanoyl includes, for example, linear or branched alkyl having 1 to 10 carbon atoms, and more specifically methyl, ethyl, propyl, isopropyl, Examples include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl and the like.
(Ii) Examples of lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3- Butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 1-decenyl, 2-decenyl, etc. Is given.
(Iii) Examples of lower alkynyl include linear or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl Etc.
(Iv) Examples of the cycloalkyl and the cycloalkyl part of the spirocycloalkane formed by R ² and R ³ existing on the same carbon atom together with the carbon atom include cycloalkyl having 3 to 10 carbon atoms More specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, cyclodecanyl and the like can be mentioned.
Examples of (v) cycloalkenyl include cycloalkenyl having 4 to 10 carbon atoms, and more specifically, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
(Vi) Polycycloalkyl, a polycycloalkyl part of a spiro polycycloalkane formed by R ² and R ³ existing on the same carbon atom together with the carbon atom, for example, a polycycloalkyl having 8 to 12 carbon atoms More specifically, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [4.3.2] undecyl. , Adamantyl, noradamantyl and the like.
(Vii) Examples of the aryl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, anthryl and the like.
(Viii) Aralkyl includes, for example, aralkyl having 7 to 15 carbon atoms, and more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
(Ix) As the alicyclic heterocyclic group part of the spiro alicyclic heterocyclic group formed by R ² and R ³ existing on the same carbon atom together with the carbon atom, A 4- to 7-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from, for example, a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic or tricyclic condensed 3- to 8-membered ring And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, tetrahydrothienyl, tetrahydrothiopyranyl, imidazolidinyl, pyrrolidinyl, Piperidino, piperidinyl, piperazinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, homopiperidino, homopiperidinyl, homopiperazinyl, tetrahydro Lysinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzofuranyl, azetidinyl and the like.
(X) As the aromatic heterocyclic group, for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom; Examples thereof include condensed bicyclic or tricyclic condensed ring aromatic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. More specifically, pyridyl, pyrazinyl , Pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiazodiazolyl, thiazodiazolyl Le, Ba Zochiazoriru, benzoxazolyl, such as purinyl and the like.
(Xi) a polycyclic heterocyclic group, and a polycyclic heterocyclic group part of a spiro polycyclic heterocyclic ring formed by R ² and R ³ existing on the same carbon atom together with the carbon atom, Examples thereof include a polycyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, quinuclidinyl and the like.
(Xii) Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 4 to 7-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3 to 8 membered rings and containing at least one nitrogen atom ( The condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, 1-pyrrolyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino , Homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, azetidinyl and the like.
(Xiii) Substituent (a) in substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy and substituted lower alkanoyl is the same or different, for example, having 1 to 3 substituents, specifically halogen, hydroxy , Oxo, carboxy, cyano, nitro, lower alkyl, lower alkenyl, lower alkoxycarbonyl, lower alkanoyl, cycloalkyl, substituted or unsubstituted aryl [substituent (b) in the substituted aryl includes halogen, hydroxy, carboxy, Cyano, nitro, lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino (the two lower alkyl groups in the di-lower alkylamino may be the same or different), etc.], substituted or non-substituted Replacement Cyclic heterocyclic group [substituent (c) in the substituted alicyclic heterocyclic group includes halogen, hydroxy, oxo, carboxy, cyano, nitro, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, amino, Lower alkylamino, di-lower alkylamino (the two lower alkyl groups in the di-lower alkylamino may be the same or different), substituted or unsubstituted aromatic heterocyclic groups (the substituted aromatic The substituent in the heterocyclic group has the same meaning as the substituent (b) in the substituted aryl), -NR ¹⁰ R ¹¹ [wherein R ¹⁰ and R ¹¹ are the same or different and represent a hydrogen atom, lower alkyl, Lower alkenyl, formyl, lower alkanoyl, lower alkoxycarbonyl, substituted or unsubstituted aralkyl (The substituent in the substituted aralkyl has the same meaning as the substituent (b) in the substituted aryl), substituted or unsubstituted aryl (the substituent in the substituted aryl has the same meaning as the substituent (b) in the substituted aryl. Or a substituted or unsubstituted aromatic heterocyclic group (the substituent in the substituted aromatic heterocyclic group has the same meaning as the substituent (b) in the substituted aryl)], substituted or unsubstituted [Substituent (d) in the substituted lower alkoxy includes halogen, hydroxy, oxo, carboxy, cyano, lower alkoxy, amino, lower alkylamino, di-lower alkylamino (two lower groups of the di-lower alkylamino) Alkyl groups may be the same or different), substituted or unsubstituted aralkyl (the substituted aralkyl And the substituent in the substituted aryl is the same as the substituent (b) in the substituted aryl), substituted or unsubstituted aryl (the substituent in the substituted aryl is the same as the substituent (b) in the substituted aryl) Substituted or unsubstituted aromatic heterocyclic groups (the substituent in the substituted aromatic heterocyclic group is the same as the substituent (b) in the substituted aryl) and the like], substituted or unsubstituted aralkyl (The substituent in the substituted aralkyl has the same meaning as the substituent (b) in the substituted aryl). The lower alkyl part of lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylamino and di-lower alkylamino shown here has the same meaning as the above lower alkyl, and lower alkenyl, cycloalkyl, aralkyl, aryl, An alicyclic heterocyclic group and an aromatic heterocyclic group have the same meanings as the above-mentioned lower alkenyl, cycloalkyl, aralkyl, aryl, alicyclic heterocyclic group and aromatic heterocyclic group, respectively, halogen is fluorine, It means each atom of chlorine, bromine and iodine.
(Xiv) The substituent (e) in the substituted aryl, substituted aralkyl, and substituted aromatic heterocyclic group is the same or different, for example, having 1 to 3 substituents, specifically halogen, hydroxy, carboxy, cyano, nitro Substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl has the same meaning as the substituent (a) in the substituted lower alkyl), substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is substituent in the substituted lower alkyl (a) as ^{synonymous), -} NR ^{10a R 11a (wherein, R 10a} and ^{R 11a} are the same meanings as the ^{R 10} and ^{R 11), - CONR 10b R} 11b ^{(wherein, R 10b} and ^{R 11b} are the same meanings as the ^{R 10} and ^{R 11),} substituted Or an unsubstituted lower alkoxycarbonyl (the substituent in the substituted lower alkoxycarbonyl has the same meaning as the substituent (a) in the substituted lower alkyl), a substituted or unsubstituted aryl (the substituent in the substituted aryl is The same as the substituent (b) in the substituted aryl), a substituted or unsubstituted aromatic heterocyclic group (the substituent in the substituted aromatic heterocyclic group has the same meaning as the substituent (b) in the substituted aryl). ), A substituted or unsubstituted alicyclic heterocyclic group (the substituent in the substituted alicyclic heterocyclic group has the same meaning as the substituent (c) in the substituted alicyclic heterocyclic group), substituted or non-substituted And substituted aralkyl (the substituent in the substituted aralkyl has the same meaning as the substituent (b) in the substituted aryl). The lower alkyl part of lower alkyl, lower alkoxy and lower alkoxycarbonyl shown here has the same meaning as the above lower alkyl, and aryl, aromatic heterocyclic group, alicyclic heterocyclic group, aralkyl and halogen are the same as defined above. Synonymous with aryl, aromatic heterocyclic group, alicyclic heterocyclic group, aralkyl and halogen.
(Xv) substituted alicyclic heterocyclic group, substituted spiroalicyclic heterocyclic ring formed by R ² and R ³ existing on the same carbon atom together with the carbon atom, R existing on the same carbon atom A substituted spiro polycyclic heterocycle formed by combining ² and R ³ with the carbon atom, a heterocyclic group formed with an adjacent nitrogen atom, substituted cycloalkyl, substituted cycloalkenyl, substituted polycyclo alkyl, substituted spirocycloalkane R ² and R ³ are on the same carbon atom to form together with the carbon atoms, and R ² and R ³ are present on the same carbon atom together with the carbon atoms Examples of the substituent in the substituted spiropolycycloalkane formed in this manner include oxo and the like in addition to the groups mentioned in the substituent (e) in the substituted aryl and the like.
The pharmacologically acceptable salt of compound (I) includes, for example, a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, amino acid addition salt and the like.
Examples of the pharmacologically acceptable acid addition salt of Compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, fumarate, citrate, and the like. Examples of the pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of the pharmacologically acceptable ammonium salt include salts such as ammonium and tetramethylammonium. Examples of the pharmacologically acceptable organic amine addition salt include addition salts such as morpholine and piperidine. Examples of pharmacologically acceptable amino acid addition salts include addition salts such as glycine, phenylalanine, lysine, aspartic acid, and glutamic acid. That.
Next, the manufacturing method of compound (I) is demonstrated.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, protection of a functional group, Deprotection [e.g., Protective Groups in Organic Synthesis, third edition, by John Wiley and Sons, Inc., by TW Greene] (e.g., Protective Groups in Organic Synthesis, third edition). John Wiley & Sons Inc. (1999)] can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
Compound (I) can be produced, for example, according to the following steps.
Manufacturing method 1
In the compound (I), W is —OR ^5a (wherein R ^5a is substituted or unsubstituted lower alkyl as defined above, substituted or unsubstituted lower alkenyl as defined above, substituted or unsubstituted as defined above) Compound (Ia) which is a substituted lower alkynyl or aralkyl as defined above or —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are each as defined above) is prepared according to the following steps. Can be manufactured.

［式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ前記と同義であり、Ｗ^ａは−ＯＲ^５ａ（式中、Ｒ^５ａは前記と同義である）または−ＮＲ^６Ｒ^７（式中、Ｒ^６およびＲ^７はそれぞれ前記と同義である）を表す］
工程１−１
原料化合物（ＩＩ）は公知の方法（国際公開第９８／２２４５５号、国際公開第００／１４０８５号など）に準じて、または参考例に記載した方法でもしくはそれらに準じて得ることができ、化合物（ＩＩＩ）としては市販のものを用いることができる。
化合物（ＩＶ）は、化合物（ＩＩ）を反応に不活性な溶媒中、１〜５当量の塩基の存在下、−１００℃〜６０℃の間の温度で、５分間〜２４時間処理した後、１〜５当量の化合物（ＩＩＩ）と−１００℃〜６０℃の間の温度で、５分間〜４８時間反応させることにより製造することができる。必要に応じ、化合物（ＩＩ）を塩基で処理した後に、同温度で１〜５当量の塩化セリウム、塩化トリイソプロポキシチタンなどを添加した後、次いで化合物（ＩＩＩ）と反応させてもよい。また、反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
塩基としては、例えばｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウムなどがあげられる。反応に不活性な溶媒としては、例えばジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、ｎ−ヘキサン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程１−２
化合物（Ｉ−ａ）は、化合物（ＩＶ）を反応に不活性な溶媒中、０．０１〜５０当量の適当な酸の存在下、１〜５０当量のシアン化トリメチルシリルと−７８℃〜６０℃の間の温度で反応させることにより製造することができる。
適当な酸としては、例えば塩酸、硫酸、１０−カンファースルホン酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸、四塩化チタン、三フッ化ホウ素、塩化アルミニウムなどがあげられる。反応に不活性な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、１，２−ジメトキシエタン（ＤＭＥ）、ジクロロメタン、１，２−ジクロロエタンなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法２
化合物（Ｉ−ａ）のうち、Ｒ^１が置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニルまたは置換もしくは非置換の低級アルキニルである化合物（Ｉ−ｂ）は、以下の工程によっても製造することができる。

[Wherein, m, R ¹ , R ² , R ³ and R ⁴ are each as defined above, and W ^a is —OR ^5a (wherein R ^5a is as defined above) or —NR ⁶ R ⁷ (Wherein R ⁶ and R ⁷ are as defined above)]
Step 1-1
The starting compound (II) can be obtained according to a known method (International Publication No. 98/22455, International Publication No. 00/14085, etc.), or by the method described in Reference Examples or according to them. As (III), a commercially available product can be used.
Compound (IV) is obtained by treating Compound (II) in a solvent inert to the reaction in the presence of 1 to 5 equivalents of base at a temperature between −100 ° C. and 60 ° C. for 5 minutes to 24 hours, It can manufacture by making it react for 5 minutes-48 hours at the temperature between -100 degreeC-60 degreeC with 1-5 equivalent compound (III). If necessary, after treating compound (II) with a base, 1 to 5 equivalents of cerium chloride, triisopropoxytitanium chloride and the like may be added at the same temperature, and then reacted with compound (III). Moreover, it is preferable to implement reaction in inert gas atmosphere, such as nitrogen and argon.
Examples of the base include n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like. Examples of the solvent inert to the reaction include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, n-hexane, toluene and the like, and these can be used alone or in combination.
Step 1-2
Compound (Ia) is a compound obtained by reacting Compound (IV) with 1 to 50 equivalents of trimethylsilyl cyanide and -78 ° C to 60 ° C in the presence of 0.01 to 50 equivalents of an appropriate acid in a solvent inert to the reaction. It can manufacture by making it react at the temperature between.
Examples of suitable acids include hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, boron trifluoride, aluminum chloride and the like. Examples of the solvent inert to the reaction include THF, 1,4-dioxane, 1,2-dimethoxyethane (DME), dichloromethane, 1,2-dichloroethane, etc., and these may be used alone or in combination. Can do.
Manufacturing method 2
Among compounds (Ia), compound (Ib) in which R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl is also obtained by the following steps. Can be manufactured.

（式中、Ｒ^１ａは前記と同義の置換もしくは非置換の低級アルキル、または前記と同義の置換もしくは非置換の低級アルケニルを表し、Ｒ^１２は前記と同義の置換もしくは非置換の低級アルキルを表し、Ｒ^１３は前記と同義の低級アルキルまたは前記と同義のアリールを表し、ｍ、Ｒ^２、Ｒ^３、Ｒ^４およびＷ^ａはそれぞれ前記と同義である）
工程２−１
化合物（Ｖｂ）または（Ｉ−ｃｂ）は、国際公開第００／１４０８５号などに記載の方法で、またはそれらに準じて得られる化合物（Ｖａ）または（Ｉ−ｃａ）を、反応に不活性な溶媒中、１当量〜１００当量のチオール化合物、酸、ヨウ化トリメチルシリルまたは硫化ナトリウムの存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜６０時間処理することにより製造することができる。
チオール化合物としては、例えばチオフェノール、メタンチオール、エタンチオールなどがあげられ、これらのアルカリ金属塩、例えばナトリウムチオフェノキシド、ナトリウムチオメトキシド、ナトリウムチオエトキシドなどもまた用いることができる。酸としては、例えば臭化水素／酢酸、塩化ピリジニウム、三臭化ホウ素、三塩化ホウ素、臭化アルミニウム、塩化アルミニウムなどがあげられる。反応に不活性な溶媒としては、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン（ＮＭＰ）などがあげられ、これらを単独でまたは混合して用いることができる。
工程２−２
化合物（ＶＩ）は、化合物（Ｖｂ）または（Ｉ−ｃｂ）を無溶媒もしくは適当な溶媒中、１〜３０当量のトリフルオロメタンスルホン酸無水物と、必要に応じ１〜３０当量の適当な塩基の存在下、−３０℃〜６０℃の間の温度で５分間〜４８時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
適当な塩基としては、例えばピリジン、２，６−ルチジン、２，４，６−コリジン、Ｎ，Ｎ−ジメチルアミノピリジン（ＤＭＡＰ）、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、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）などがあげられる。適当な溶媒としては、例えばピリジン、ＤＭＦ、ＮＭＰ、ＴＨＦ、ジクロロメタン、１，２−ジクロロエタン、１，４−ジオキサンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程２−３
化合物（Ｉ−ｂ）は、化合物（ＶＩ）と化合物（ＶＩＩ）とをスティルカップリング反応（Ｓｔｉｌｌｅ Ｃｏｕｐｌｉｎｇ）に付すことにより製造することができる。
すなわち、化合物（Ｉ−ｂ）は、反応に不活性な溶媒中、化合物（ＶＩ）と１〜２０当量の化合物（ＶＩＩ）とを、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒の存在下、必要に応じて０．０１〜２０当量の適当な添加剤を添加し、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜１００時間反応させることにより製造することができる。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な添加剤としては、例えばヨウ化銅、塩化亜鉛、塩化リチウム、フッ化セシウム、炭酸リチウム、炭酸ナトリウム、トリエチルアミン、２，６−ジ−ｔｅｒｔ−ブチル−４−メチルフェノール、４−ｔｅｒｔ−ブチルカテコール、トリフェニルホスフィンなどがあげられ、これらを単独でまたは混合して用いることができる。反応に不活性な溶媒としては、例えばＴＨＦ、ＤＭＦ、ＮＭＰ、ＤＭＥ、１，４−ジオキサン、ベンゼン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法３
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＣＯＣＨＲ^１４Ｒ^１５（式中、Ｒ^１４およびＲ^１５は、同一または異なって水素原子または前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉ−ｄ）は以下の工程によっても製造することができる。

Wherein R ^1a represents a substituted or unsubstituted lower alkyl as defined above, or a substituted or unsubstituted lower alkenyl as defined above, and R ¹² represents a substituted or unsubstituted lower alkyl as defined above. , ^{R 13} represents an aryl lower alkyl or as defined above of the same ^{meaning, m, R 2, R 3} , R 4 and ^{W a} are the same meanings as defined above, respectively)
Step 2-1
Compound (Vb) or (I-cb) is obtained by reacting compound (Va) or (I-ca) obtained by the method described in International Publication No. 00/14085 or the like in an inert manner. It can be produced by treatment in a solvent in the presence of 1 equivalent to 100 equivalents of a thiol compound, acid, trimethylsilyl iodide or sodium sulfide at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 60 hours. it can.
Examples of the thiol compound include thiophenol, methanethiol, ethanethiol and the like, and alkali metal salts thereof such as sodium thiophenoxide, sodium thiomethoxide, sodium thioethoxide and the like can also be used. Examples of the acid include hydrogen bromide / acetic acid, pyridinium chloride, boron tribromide, boron trichloride, aluminum bromide, aluminum chloride and the like. Examples of the solvent inert to the reaction include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like. These may be used alone or in combination. Can be used.
Step 2-2
Compound (VI) is obtained by mixing compound (Vb) or (I-cb) with 1-30 equivalents of trifluoromethanesulfonic anhydride and 1-30 equivalents of an appropriate base in a solvent-free or appropriate solvent. It can manufacture by making it react for 5 minutes-48 hours at the temperature between -30 degreeC-60 degreeC in presence. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Suitable bases include, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, N, N-dimethylaminopyridine (DMAP), triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo [5. 4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), and the like. Examples of suitable solvents include pyridine, DMF, NMP, THF, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, and the like, and these can be used alone or in combination.
Step 2-3
Compound (Ib) can be produced by subjecting compound (VI) and compound (VII) to a Still coupling reaction (Still Coupling).
That is, compound (Ib) requires compound (VI) and 1 to 20 equivalents of compound (VII) in a solvent inert to the reaction in the presence of 0.01 mol% to 30 mol% of a palladium catalyst. Depending on the conditions, 0.01 to 20 equivalents of an appropriate additive can be added and reacted at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 100 hours.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable additives include, for example, copper iodide, zinc chloride, lithium chloride, cesium fluoride, lithium carbonate, sodium carbonate, triethylamine, 2,6-di-tert-butyl-4-methylphenol, 4-tert-butyl. Catechol, triphenylphosphine and the like can be mentioned, and these can be used alone or in combination. Examples of the solvent inert to the reaction include THF, DMF, NMP, DME, 1,4-dioxane, benzene, toluene and the like, and these can be used alone or in combination.
Production method 3
Of the compounds (Ia), R ¹ is —COCHR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl as defined above) A certain compound (Id) can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１４、Ｒ^１５およびＷ^ａはそれぞれ前記と同義である）
化合物（Ｉ−ｄ）は、製造法２で得られる化合物（ＶＩ）と化合物（ＶＩＩＩ）または（ＩＸ）とをパラジウム触媒の存在下反応させた後、酸で処理することにより製造することができる。
すなわち、製造法２で得られる化合物（ＶＩ）を１〜１００当量の化合物（ＶＩＩＩ）または（ＩＸ）と、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒の存在下、無溶媒でまたは反応に不活性な溶媒中、必要に応じて、０．０１〜５０当量の適当な塩基および／または適当な添加剤の存在下、−３０℃から１５０℃の間の温度で、５分間〜１００時間反応させ、次いで、該反応混合物を０℃〜１５０℃の間の温度で、１〜３００当量の適当な酸で処理することにより、化合物（Ｉ−ｄ）を製造することができる。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な塩基としては、例えばトリエチルアミン、炭酸カリウム、炭酸ナトリウムなどがあげられ、適当な添加剤としては、例えば塩化リチウム、１，３−ビス（ジフェニルホスフィノ）プロパン、トリ（ｏ−トリル）ホスフィン、トリフェニルホスフィン、トリエチルアミン、２，６−ジ−ｔｅｒｔ−ブチル−４−メチルフェノール、４−ｔｅｒｔ−ブチルカテコールなどがあげられ、これらを単独でまたは混合して用いることができる。適当な酸としては、例えば塩酸、硫酸などがあげられる。反応に不活性な溶媒としては、例えばＤＭＦ、ＴＨＦ、ＮＭＰ，１，４−ジオキサン、ベンゼン、トルエン、アセトニトリルなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法４
化合物（Ｉ−ａ）のうち、Ｒ^１が−Ｃ（ＣＨＲ^１４Ｒ^１５）＝ＣＨＲ^１６（式中、Ｒ^１４およびＲ^１５は前記と同義であり、Ｒ^１６は前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉ−ｅ）は、製造法３で得られる化合物（Ｉ−ｄ）より、以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 14, R 15 and ^{W a} are the same meanings as defined above, respectively)
Compound (Id) can be produced by reacting compound (VI) obtained in Production Method 2 with compound (VIII) or (IX) in the presence of a palladium catalyst and then treating with an acid. .
That is, Compound (VI) obtained by Production Method 2 is inert to the reaction in the presence of 1 to 100 equivalents of Compound (VIII) or (IX) and 0.01 mol% to 30 mol% of a palladium catalyst without solvent. In a suitable solvent, if necessary, in the presence of 0.01 to 50 equivalents of a suitable base and / or a suitable additive at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 100 hours, The compound (Id) can then be prepared by treating the reaction mixture at a temperature between 0 ° C. and 150 ° C. with 1 to 300 equivalents of a suitable acid.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable bases include, for example, triethylamine, potassium carbonate, sodium carbonate and the like, and suitable additives include, for example, lithium chloride, 1,3-bis (diphenylphosphino) propane, tri (o-tolyl) phosphine, Examples thereof include triphenylphosphine, triethylamine, 2,6-di-tert-butyl-4-methylphenol, 4-tert-butylcatechol, and these can be used alone or in combination. Examples of suitable acids include hydrochloric acid and sulfuric acid. Examples of the solvent inert to the reaction include DMF, THF, NMP, 1,4-dioxane, benzene, toluene, acetonitrile and the like, and these can be used alone or in combination.
Manufacturing method 4
Of the compounds (Ia), R ¹ is —C (CHR ¹⁴ R ¹⁵ ) ═CHR ¹⁶ (wherein R ¹⁴ and R ¹⁵ are as defined above, and R ¹⁶ is substituted or unsubstituted as defined above). Compound (Ie), which represents lower alkyl of the above, can also be produced from compound (Id) obtained by Production Method 3 by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１４、Ｒ^１５、Ｒ^１６およびＷ^ａはそれぞれ前記と同義であり、Ｐｈはフェニルを表し、Ｙは塩素、臭素またはヨウ素の各原子を表す）
化合物（Ｘ）を反応に不活性な溶媒中、１〜２当量の塩基の存在下、−７８℃〜用いる溶媒の沸点の間の温度で、５分間〜２４時間処理した後、０．２〜２当量の化合物（Ｉ−ｄ）と−７８℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させることにより、化合物（Ｉ−ｅ）を製造することができる［ウィッティッヒ（Ｗｉｔｔｉｇ）反応］。反応は、窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
化合物（Ｘ）は市販品として、または公知の方法［例えば、「ネーム・リアクションズ・アンド・リエイジェンツ・イン・オーガニック・シンセシス（Ｎａｍｅ Ｒｅａｃｔｉｏｎｓ ａｎｄ Ｒｅａｇｅｎｔｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ）、マンディ（Ｂｒａｄｆｏｒｄ Ｐ．Ｍｕｎｄｙ）、エラード（Ｍｉｃｈａｅｌ Ｇ．Ｅｌｌｅｒｄ）著、ｐ．２２６、ジョン・ワイリー・サンズ・インコーポレイテッド（Ｊｏｈｎ Ｗｉｌｅｙ＆Ｓｏｎｓ Ｉｎｃ．）（１９８８年）」など］で、もしくはそれらに準じて得ることができる。
塩基としては、例えばｎ−ブチルリチウム、リチウムジイソプロピルアミド（ＬＤＡ）、リチウムヘキサメチルジシラジド（ＬｉＨＭＤＳ）、ナトリウムヘキサメチルジシラジド（ＮａＨＭＤＳ）などがあげられる。反応に不活性な溶媒としては、例えばジエチルエーテル、ＴＨＦ、１，４−ジオキサンなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法５
化合物（Ｉ−ａ）のうち、Ｒ^１が置換もしくは非置換の低級アルキルである化合物（Ｉ−ｆ）は、以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 14, R 15, R 16 and ^{W a} have the same meanings as defined above, Ph represents phenyl, Y is chlorine, each atom of bromine or iodine Represents
Compound (X) is treated in a solvent inert to the reaction in the presence of 1 to 2 equivalents of base at a temperature between −78 ° C. and the boiling point of the solvent used for 5 minutes to 24 hours, and then 0.2 to The compound (Ie) can be produced by reacting with 2 equivalents of the compound (Id) at a temperature between −78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours [Wittig )reaction]. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Compound (X) is a commercially available product, or a known method [for example, “Name Reactions and Reagents in Organic Synthesis”, Bradford P. Mundy, Michael G. Ellerd), p. 226, John Wiley & Sons Inc. (1988) etc.], or the like.
Examples of the base include n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), and the like. Examples of the solvent inert to the reaction include diethyl ether, THF, 1,4-dioxane and the like, and these can be used alone or in combination.
Manufacturing method 5
Among compounds (Ia), compound (If) in which R ¹ is substituted or unsubstituted lower alkyl can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４およびＷ^ａはそれぞれ前記と同義であり、Ｒ^１ｂは前記と同義の置換もしくは非置換の低級アルケニルを表し、Ｒ^１ｃは前記と同義の置換もしくは非置換の低級アルキルを表す）
化合物（Ｉ−ｆ）は、製造法１、２または４で得られる化合物（Ｉ−ｇ）を反応に不活性な溶媒中、０．０１〜３０当量の例えばパラジウム炭素、ラネーニッケルなどの存在下、水素気流中、常圧〜５０，０００ｋＰａの圧力下で、０℃〜溶媒の沸点の間の温度で５分間〜４８時間処理するか、または１〜２００当量の例えばギ酸、ギ酸アンモニウム、ヒドラジン、シクロヘキセン、シクロヘキサンジエン、トリエチルシランなどの水素供与体の存在下、必要に応じ例えばアンモニア、酢酸、塩酸、硫酸などの存在下で、−２０℃〜溶媒の沸点の間の温度で５分間〜１００時間処理することによって製造することができる。
反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、ＴＨＦ、１，４−ジオキサン、水などがあげられ、これらを単独でまたは混合して用いることができる。
製造法６
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＣＨ（ＯＨ）ＣＨＲ^１４Ｒ^１５（式中、Ｒ^１４およびＲ^１５はそれぞれ前記と同義である）である化合物（Ｉ−ｈ）は以下の工程によっても製造することができる

^{(Wherein, m, R 2, R 3} , R 4 and ^{W a} have the same meanings as defined ^{above, R 1b} represents a substituted or unsubstituted lower alkenyl as defined ^{above, R 1c} is substituted as defined above Or represents an unsubstituted lower alkyl)
Compound (If) is prepared by subjecting compound (Ig) obtained by Production Method 1, 2 or 4 to 0.01 to 30 equivalents of palladium carbon, Raney nickel, etc. in a solvent inert to the reaction, Treatment in a hydrogen stream under normal pressure to 50,000 kPa at a temperature between 0 ° C. and the boiling point of the solvent for 5 minutes to 48 hours, or 1 to 200 equivalents of, for example, formic acid, ammonium formate, hydrazine, cyclohexene Treatment in the presence of a hydrogen donor such as cyclohexanediene or triethylsilane, for example, in the presence of ammonia, acetic acid, hydrochloric acid, sulfuric acid or the like, at a temperature between −20 ° C. and the boiling point of the solvent for 5 minutes to 100 hours. Can be manufactured.
Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Manufacturing method 6
Among the compounds (Ia), the compound (Ih) in which R ¹ is —CH (OH) CHR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ have the same meanings as described above) has the following steps. Can also be manufactured by

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１４、Ｒ^１５およびＷ^ａはそれぞれ前記と同義である）
化合物（Ｉ−ｈ）は、製造法３で得られる化合物（Ｉ−ｄ）を反応に不活性な溶媒中、０．５〜２０当量の還元剤で、−７８℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間処理することにより製造することができる。処理は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
還元剤としては、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウムなどがあげられる。反応に不活性な溶媒としては、例えばメタノール、エタノール、ジエチルエーテル、ＴＨＦ、１，４−ジオキサン、ジクロロメタン、１，２−ジクロロエタン、ベンゼン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法７
化合物（Ｉ−ａ）のうち、Ｒ^１がホルミル、−ＣＨ_２ＯＨまたは−ＣＨ_２ＯＲ^１７（式中Ｒ^１７は前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉ−ｍ）、（Ｉ−ｉ）および（Ｉ−ｊ）は以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 14, R 15 and ^{W a} are the same meanings as defined above, respectively)
Compound (Ih) is a compound obtained by the production method 3 (Id) in a solvent inert to the reaction, with 0.5 to 20 equivalents of a reducing agent, between -78 ° C. and the boiling point of the solvent used. It can manufacture by processing for 5 minutes-48 hours at the temperature of this. The treatment is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like. Examples of the solvent inert to the reaction include methanol, ethanol, diethyl ether, THF, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene and the like, and these are used alone or in combination. be able to.
Manufacturing method 7
Of the compounds (Ia), R ¹ is formyl, —CH ₂ OH or —CH ₂ OR ¹⁷ (wherein R ¹⁷ represents a substituted or unsubstituted lower alkyl as defined above) (I— m), (Ii) and (Ij) can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１７およびＷ^ａはそれぞれ前記と同義である）
工程７−１
化合物（Ｉ−ｍ）は、製造法１または２で得られる化合物（Ｉ−ｋ）を適当な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％の四酸化オスミウムと１〜３０当量の適当な酸化剤の存在下、−７８℃〜６０℃の間の温度で、５分間〜４８時間処理することにより製造することができる。
適当な酸化剤としては、例えば過ヨウ素酸ナトリウム、オルト過ヨウ素酸、過ヨウ素酸カリウムなどがあげられる。適当な溶媒としては、例えばメタノール、エタノール、ｔｅｒｔ−ブタノール、ジエチルエーテル、ＴＨＦ、１，４−ジオキサン、ピリジン、ベンゼン、トルエン、水などがあげられ、これらを単独でまたは混合して用いることができる。
工程７−２
化合物（Ｉ−ｉ）は、化合物（Ｉ−ｍ）を用い、製造法６に記載の方法と同様にして製造することができる。
工程７−３
化合物（Ｉ−ｊ）は、化合物（Ｉ−ｉ）を無溶媒でまたは適当な溶媒中、１〜２００当量の適当なハロゲン化剤またはスルホニル化剤で、−３０〜１５０℃の間の温度で、５分間〜４８時間処理した後、適当な溶媒中、−３０〜１５０℃の間の温度で、１〜２００当量の金属アルコキシドと５分間〜４８時間反応させることにより製造することができる。
適当なハロゲン化剤としては、例えば塩化チオニル、オキシ塩化リン、塩化オキザリル、塩化水素、オキシ臭化リンなどがあげられ、スルホニル化剤としては、塩化ｐ−トルエンスルホニル、塩化メタンスルホニル、無水メタンスルホン酸、無水トリフルオロメタンスルホン酸などがあげられる。ハロゲン化剤またはスルホニル化剤での処理に用いられる溶媒としては、例えばジクロロメタン、１，２−ジクロロエタン、クロロホルム、ピリジン、酢酸エチル、ＴＨＦ、１，４−ジオキサンなどがあげられる。また、金属アルコキシドとしては、Ｒ^１７ＯＨのアルカリ金属塩またはアルカリ土類金属塩であれば特に限定されないが、例えば、ナトリウム、カリウム、リチウム、マグネシウムなどの金属塩があげられる。金属アルコキシドとの反応において用いられる溶媒としては、例えばＲ^１７ＯＨ、ＴＨＦ、１，４−ジオキサン、トルエン、アセトニトリルなどがあげられ、これらを単独でまたは混合して用いることができるが、中でもＲ^１７ＯＨが含有されているものが好ましい。
また、ハロゲン化剤またはスルホニル化剤との反応は、必要に応じ１〜２０当量の例えばトリエチルアミン、ジイソプロピルエチルアミン、Ｎ，Ｎ−ジメチルアニリン、ピリジン、ピコリン、コリジン、ルチジン、ＤＭＡＰなどの塩基および／または０．０１〜１当量のＤＭＦなどの存在下で実施することもできる。
製造法８
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＣＨＦＣＨ_２Ｂｒ、−ＣＦ＝ＣＨ_２または−ＣＨＦＣＨ_３である化合物（Ｉ−ｎ）、（Ｉ−ｏ）、（Ｉ−ｐ）は、以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 17 and ^{W a} are the same meanings as defined above, respectively)
Step 7-1
Compound (Im) is compound (Ik) obtained by production method 1 or 2 in an appropriate solvent in an amount of 0.01 mol% to 30 mol% of osmium tetroxide and 1 to 30 equivalents of an appropriate oxidizing agent. It can manufacture by processing for 5 minutes-48 hours at the temperature between -78 degreeC-60 degreeC in presence.
Suitable oxidizing agents include, for example, sodium periodate, orthoperiodic acid, potassium periodate and the like. Examples of suitable solvents include methanol, ethanol, tert-butanol, diethyl ether, THF, 1,4-dioxane, pyridine, benzene, toluene, water and the like, and these can be used alone or in combination. .
Step 7-2
Compound (Ii) can be produced in the same manner as in Production Method 6 using Compound (Im).
Step 7-3
Compound (Ij) is obtained by reacting Compound (Ii) in the absence of a solvent or in a suitable solvent with 1 to 200 equivalents of a suitable halogenating agent or sulfonylating agent at a temperature between −30 to 150 ° C. After the treatment for 5 minutes to 48 hours, it can be produced by reacting with 1 to 200 equivalents of metal alkoxide for 5 minutes to 48 hours in a suitable solvent at a temperature of -30 to 150 ° C.
Suitable halogenating agents include, for example, thionyl chloride, phosphorus oxychloride, oxalyl chloride, hydrogen chloride, phosphorus oxybromide, and the sulfonylating agents include p-toluenesulfonyl chloride, methanesulfonyl chloride, anhydrous methanesulfone. Examples thereof include acid and trifluoromethanesulfonic anhydride. Examples of the solvent used for the treatment with the halogenating agent or sulfonylating agent include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, ethyl acetate, THF, 1,4-dioxane and the like. The metal alkoxide is not particularly limited as long as it is an alkali metal salt or alkaline earth metal salt of R ¹⁷ OH, and examples thereof include metal salts such as sodium, potassium, lithium, and magnesium. Examples of the solvent used in the reaction with the metal alkoxide include R ¹⁷ OH, THF, 1,4-dioxane, toluene, acetonitrile, and the like. These can be used alone or in combination, and among them, R ¹⁷ Those containing OH are preferred.
The reaction with the halogenating agent or sulfonylating agent may be carried out according to necessity with 1 to 20 equivalents of a base such as triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, picoline, collidine, lutidine, DMAP and / or It can also be carried out in the presence of 0.01 to 1 equivalent of DMF or the like.
Manufacturing method 8
Among the compounds (Ia), compounds (In), (Io) and (Ip) in which R ¹ is —CHFCH ₂ Br, —CF═CH ₂ or —CHFCH ₃ are It can also be manufactured by a process.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４およびＷ^ａはそれぞれ前記と同義である）
工程８−１
化合物（Ｉ−ｎ）は、製造法１または２で得られる化合物（Ｉ−ｋ）を用い、テトラへドロン（Ｔｅｔｒａｈｅｄｒｏｎ）、１９９０年、第４６巻、ｐ．４２５５などに記載の方法に準じて製造することができる。すなわち、化合物（Ｉ−ｋ）を反応に不活性な溶媒中、１〜１０当量のＮ−ブロモスクシンイミドおよび１〜１０当量のトリエチルアミン・三フッ化水素の存在下、−７８℃〜６０℃の間の温度で、５分間〜４８時間処理することにより、化合物（Ｉ−ｎ）を製造することができる。
反応に不活性な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程８−２
化合物（Ｉ−ｏ）は、化合物（Ｉ−ｎ）を無溶媒でまたは適当な溶媒中、１〜１００当量の適当な塩基の存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間処理することにより製造することができる。
適当な塩基としては、例えばＤＢＵ、ＤＢＮ、ｔｅｒｔ−ブトキシカリウム、ＬＤＡ、ＬｉＨＭＤＳ、ＮａＨＭＤＳなどがあげられる。適当な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、ＤＭＦ、ジメチルスルホキシド（ＤＭＳＯ）などがあげられ、これらを単独でまたは混合して用いることができる。
工程８−３
化合物（Ｉ−ｐ）は、化合物（Ｉ−ｏ）を用い、製造法５に記載の方法と同様にして製造することができる。
製造法９
化合物（Ｉ−ａ）のうち、Ｒ^１が−Ｃ≡Ｃ−Ｒ^１８（式中、Ｒ^１８は水素原子、または前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉ−ｑ）は、以下の工程によっても製造することができる。

(Wherein m, R ² , R ³ , R ⁴ and W ^a are as defined above)
Step 8-1
Compound (In) uses Compound (Ik) obtained by Production Method 1 or 2, and is prepared according to Tetrahedron, 1990, Vol. 46, p. 4255 or the like. That is, in the presence of 1 to 10 equivalents of N-bromosuccinimide and 1 to 10 equivalents of triethylamine / hydrogen trifluoride in a solvent inert to the reaction, the compound (Ik) is between −78 ° C. and 60 ° C. Compound (In) can be produced by treating at a temperature of 5 minutes to 48 hours.
Examples of the solvent inert to the reaction include dichloromethane and 1,2-dichloroethane, and these can be used alone or in combination.
Step 8-2
Compound (Io) is obtained by reacting Compound (In) in the absence of a solvent or in the presence of 1 to 100 equivalents of a suitable base at a temperature between −30 ° C. and the boiling point of the solvent used. It can manufacture by processing for 48 minutes for 48 minutes.
Suitable bases include DBU, DBN, tert-butoxypotassium, LDA, LiHMDS, NaHMDS, and the like. Suitable solvents include, for example, THF, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO) and the like, and these can be used alone or in combination.
Step 8-3
Compound (Ip) can be produced in the same manner as in Production Method 5 using compound (Io).
Manufacturing method 9
Among the compounds (Ia), a compound in which R ¹ is —C≡C—R ¹⁸ (wherein R ¹⁸ represents a hydrogen atom or a substituted or unsubstituted lower alkyl as defined above) (I— q) can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１８およびＷ^ａはそれぞれ前記と同義である）
化合物（Ｉ−ｑ）は、製造法２で得られる化合物（ＶＩ）と１〜２０当量の化合物（ＸＩ）とを、反応に不活性な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒および１〜２０当量の適当な塩基の存在下、−２０℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な塩基としては、例えば炭酸リチウム、炭酸ナトリウム、トリエチルアミンなどがあげられる。反応に不活性な溶媒としては、例えばＤＭＦ、ＮＭＰ、ＴＨＦ、ＤＭＥ、１，４−ジオキサン、ベンゼン、トルエンなどがあげられる。
また、化合物（ＸＩ）としては、市販品を用いることができる。
製造法１０
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＮＲ^８ａＲ^９ａ［式中、Ｒ^８ａおよびＲ^９ａは、それぞれ前記Ｒ^８およびＲ^９と同義である（ただし、同時に水素にはならない）］である化合物（Ｉ−ｒ）およびＲ^１がアミノである化合物（Ｉ−ｓ）は以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 18 and ^{W a} are the same meanings as defined above, respectively)
Compound (Iq) is obtained by reacting Compound (VI) obtained in Production Method 2 and 1 to 20 equivalents of Compound (XI) in a solvent inert to the reaction with 0.01 mol% to 30 mol% of a palladium catalyst and It can be produced by reacting in the presence of 1 to 20 equivalents of a suitable base at a temperature between −20 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable bases include, for example, lithium carbonate, sodium carbonate, triethylamine and the like. Examples of the solvent inert to the reaction include DMF, NMP, THF, DME, 1,4-dioxane, benzene, toluene and the like.
Moreover, as a compound (XI), a commercial item can be used.
Manufacturing method 10
Of the compounds (I-a), ^{[wherein, R 8a} and ^{R 9a} are each synonymous with the ^{R 8} and ^{R 9} (provided that at the same time not hydrogen)] ^{R 1} is ^-NR 8a ^{R 9a} in A certain compound (Ir) and a compound (Is) in which R ¹ is amino can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^８ａ、Ｒ^９ａ、Ｗ^ａおよびＰｈはそれぞれ前記と同義である）
工程１０−１
化合物（Ｉ−ｒ）は、製造法２で得られる化合物（ＶＩ）を用い、例えばジャーナル・オブ・オーガニック・ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ）、１９９７年、第６２巻、ｐ．１２６８などに記載の方法に準じて製造することができる。すなわち、化合物（ＶＩ）と１〜２０当量のＲ^８ａＲ^９ａＮＨを、反応に不活性な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒および１〜２０当量の適当な塩基の存在下、必要に応じ０．１〜２０当量の適当な添加剤の存在下、０℃〜用いる溶媒の沸点の間の温度で、５分間〜７２時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
パラジウム触媒としては、例えば酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウムなどがあげられる。適当な塩基としては、例えばリン酸カリウム、炭酸カリウム、炭酸セシウム、ｔｅｒｔ−ブトキシナトリウム、トリエチルアミンなどがあげられる。適当な添加剤としては、例えば２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（ＢＩＮＡＰ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（ＤＰＰＦ）などがあげられる。反応に不活性な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、ＤＭＥ、トルエン、アセトニトリル、グライムなどがあげられる。
工程１０−２
化合物（ＸＩＩ）は、製造法２で得られる化合物（ＶＩ）とＰｈ_２Ｃ＝ＮＨを用い、工程１０−１に記載の方法と同様にして製造することができる。
工程１０−３
化合物（Ｉ−ｓ）は、化合物（ＸＩＩ）を用い、製造法５に記載の方法と同様にして製造することができる。
工程１０−４
化合物（Ｉ−ｒ）は、化合物（Ｉ−ｓ）を、０．５〜２当量のＲ^８ａＺ（式中、Ｚは塩素、臭素またはヨウ素の各原子を表す）と反応に不活性な溶媒中、必要に応じて１〜２０当量の適当な塩基の存在下、−３０℃〜用いる溶媒の沸点の間の温度で反応させた後、無溶媒でまたは反応に不活性な溶媒中、１〜５０当量のＲ^９ａＺ^ａ（式中、Ｚ^ａは塩素、臭素またはヨウ素の各原子を表す）と、必要に応じて１〜１００当量の適当な塩基の存在下、−３０℃〜１５０℃の間の温度で反応させることによっても製造することができる。
各反応において用いられる反応に不活性な溶媒としては、同一でも異なってもよく、例えばジクロロメタン、クロロホルム、ＴＨＦ、酢酸エチル、アセトニトリル、トルエン、ＤＭＦ、ＮＭＰ、ピリジンなどがあげられる。適当な塩基としては、各反応で同一でも異なってもよく、例えばトリエチルアミン、ジイシプロピルエチルアミン、ＤＢＵ、ピリジン、炭酸カリウム、水酸化カリウム、水素化ナトリウムなどがあげられる。
製造法１１
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＮＲ^２１（ＣＨＲ^１９Ｒ^２０）または−Ｎ（ＣＨＲ^１９Ｒ^２０）（ＣＨＲ^２２Ｒ^２３）［式中、Ｒ^１９、Ｒ^２０、Ｒ^２２およびＲ^２３はそれぞれ前記と同義の置換もしくは非置換の低級アルキルを表し、Ｒ^２１は水素原子または−ＣＨＲ^１９Ｒ^２０（式中、Ｒ^１９およびＲ^２０はそれぞれ前記と同義である）を表す］である化合物（Ｉ−ｔ）および（Ｉ−ｕ）は、以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 8a, R 9a, W a and Ph each have the same meanings as defined above)
Step 10-1
As the compound (Ir), the compound (VI) obtained by the production method 2 is used. For example, Journal of Organic Chemistry, 1997, Vol. 62, p. 1268 or the like. That is, compound (VI) and 1 to 20 equivalents of R ^8a R ^9a NH in the presence of 0.01 mol% to 30 mol% of a palladium catalyst and 1 to 20 equivalents of an appropriate base in a solvent inert to the reaction, If necessary, it can be produced by reacting at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours in the presence of 0.1 to 20 equivalents of an appropriate additive. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Examples of the palladium catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, and tris (dibenzylideneacetone) dipalladium. Suitable bases include, for example, potassium phosphate, potassium carbonate, cesium carbonate, tert-butoxy sodium, triethylamine and the like. Suitable additives include, for example, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 1,1′-bis (diphenylphosphino) ferrocene (DPPF), and the like. Examples of the solvent inert to the reaction include THF, 1,4-dioxane, DME, toluene, acetonitrile, glyme and the like.
Step 10-2
Compound (XII) can be produced in the same manner as in Step 10-1, using Compound (VI) obtained in Production Method 2 and Ph ₂ C═NH.
Step 10-3
Compound (Is) can be produced in the same manner as in Production Method 5 using Compound (XII).
Step 10-4
Compound (Ir) is a solvent inert to the reaction of Compound (Is) with 0.5 to 2 equivalents of R ^8a Z (wherein Z represents each atom of chlorine, bromine or iodine). In the presence of 1 to 20 equivalents of a suitable base, if necessary, the reaction is carried out at a temperature between −30 ° C. and the boiling point of the solvent used, and then in the absence of solvent or in a solvent inert to the reaction, 50 (wherein, ^{Z a} chlorine, represents each atom of bromine or iodine) equivalents of ^R 9a ^{Z a} and, the presence of optionally 1 to 100 equivalents of a suitable base, of -30 ° C. to 150 DEG ° C. It can also be produced by reacting at a temperature between.
The solvent inert to the reaction used in each reaction may be the same or different, and examples thereof include dichloromethane, chloroform, THF, ethyl acetate, acetonitrile, toluene, DMF, NMP, and pyridine. Suitable bases may be the same or different in each reaction, and examples thereof include triethylamine, diisopropylpropylamine, DBU, pyridine, potassium carbonate, potassium hydroxide, sodium hydride and the like.
Manufacturing method 11
Among the compounds (Ia), R ¹ is —NR ²¹ (CHR ¹⁹ R ²⁰ ) or —N (CHR ¹⁹ R ²⁰ ) (CHR ²² R ²³ ) [wherein R ¹⁹ , R ²⁰ , R ²² and R ²³ represents a substituted or unsubstituted lower alkyl as defined above, and R ²¹ represents a hydrogen atom or —CHR ¹⁹ R ²⁰ (wherein R ¹⁹ and R ²⁰ are each as defined above). Compounds (It) and (Iu) can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１９、Ｒ^２０、Ｒ^２１、Ｒ^２２、Ｒ^２３およびＷ^ａはそれぞれ前記と同義である）
工程１１−１
化合物（Ｉ−ｔ）は、製造法１０で得られる化合物（Ｉ−ｓ）と等量のＲ^１９ＣＯＲ^２０を、反応に不活性な溶媒中、適当な還元剤の存在下、必要により０．０１〜５０当量の塩基または酸の存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜１００時間反応させることにより製造することができる。
適当な還元剤としては、例えばシアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウムなどがあげられる。塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミン、アンモニアなどがあげられ、酸としては、例えば酢酸、塩酸、硫酸などがあげられる。反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、酢酸ブチル、ＤＭＦ、ジクロロメタン、１，２−ジクロロエタン、水などがあげられ、これらを単独でまたは混合して用いることができる。
また別法として、化合物（Ｉ−ｓ）と等量のＲ^１９ＣＯＲ^２０とを、上記と同様の反応に不活性な溶媒中、必要により０．０１〜５０当量の上記と同様の塩基または酸の存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜１００時間反応させることによりイミンを生成させた後に、得られた生成物を適当な還元反応に付すことによっても化合物（Ｉ−ｔ）を製造することができる。イミン形成の際には、モレキュラーシーブスなどの脱水剤を共存させてもよい。
適当な還元反応としては、製造法５に記載した反応（接触還元反応）、０．５〜３０当量のシアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウムなどを用いた還元反応などがあげられる。
さらに、上記の製造法において、Ｒ^１９ＣＯＲ^２０を２当量以上用いることにより、Ｒ^２１が−ＣＨＲ^１９Ｒ^２０である化合物（Ｉ−ｔ）を製造することができる。
工程１１−２
化合物（Ｉ−ｕ）は、Ｒ^２１が水素原子である化合物（Ｉ−ｔ）と１〜３０当量のＲ^２２ＣＯＲ^２３を用い、工程１１−１に記載の方法と同様にして製造することができる。
製造法１２
化合物（Ｉ−ａ）のうち、Ｒ^１が−ＮＨＣＯＲ^２４（式中、Ｒ^２４は前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（ＩＩ−ｖ）は、以下の工程によっても製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 19, R 20, R 21, R 22, R 23 and ^{W a} are the same meanings as defined above, respectively)
Step 11-1
Compound (It) is prepared by subjecting compound (Is) obtained in Production Method 10 to an equal amount of R ¹⁹ COR ²⁰ in a solvent inert to the reaction, in the presence of a suitable reducing agent, if necessary, in an amount of 0. It can be produced by reacting in the presence of 01 to 50 equivalents of base or acid at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 100 hours.
Suitable reducing agents include, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. Examples of the base include triethylamine, diisopropylethylamine, ammonia and the like, and examples of the acid include acetic acid, hydrochloric acid, sulfuric acid and the like. Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, butyl acetate, DMF, dichloromethane, 1,2-dichloroethane, water and the like, and these can be used alone or in combination.
Alternatively, compound (I-s) and an equivalent amount of R ¹⁹ COR ²⁰ may be combined with 0.01 to 50 equivalents of the same base or acid as described above in a solvent inert to the same reaction as necessary. In the presence of the compound, an imine is formed by reacting at a temperature between −30 ° C. and the boiling point of the solvent to be used for 5 minutes to 100 hours, and then the resulting product is subjected to an appropriate reduction reaction. It) can be produced. In the formation of imine, a dehydrating agent such as molecular sieves may coexist.
As the appropriate reduction reaction, the reaction described in Production Method 5 (catalytic reduction reaction), reduction reaction using 0.5 to 30 equivalents of sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like Etc.
Furthermore, in the above production method, by using 2 equivalents or more of R ¹⁹ COR ²⁰ , compound (It) in which R ²¹ is —CHR ¹⁹ R ²⁰ can be produced.
Step 11-2
Compound (Iu) can be produced in the same manner as in Step 11-1, using Compound (It) wherein R ²¹ is a hydrogen atom and 1 to 30 equivalents of R ²² COR ^23. it can.
Production method 12
Among compounds (Ia), compound (II-v) wherein R ¹ is —NHCOR ²⁴ (wherein R ²⁴ represents a substituted or unsubstituted lower alkyl having the same meaning as described above) is produced by the following steps. Can also be manufactured.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^２４およびＷ^ａはそれぞれ前記と同義である）
化合物（Ｉ−ｖ）は、無溶媒でまたは反応に不活性な溶媒中、必要により０．５〜１００当量の塩基の存在下、製造法１０で得られる化合物（Ｉ−ｓ）と１〜１００当量のＲ^２４ＣＯＸ（式中、Ｘは塩素または臭素の各原子を表す）または（Ｒ^２４ＣＯ）_２Ｏ（式中、Ｒ^２４は前記と同義である）とを、−３０〜１５０℃の間の温度で、５分間〜４８時間反応させることにより製造することができる。
塩基としては、例えばピリジン、２，６−ルチジン、２，４，６−コリジン、ＤＭＡＰ、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、ＤＢＮ、Ｎ−メチルモルホリンなどがあげられる。反応に不活性な溶媒としては、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、ＴＨＦ、１，４−ジオキサン、アセトニトリル、ＤＭＦ、ＮＭＰなどがあげられ、これらを単独でまたは混合して用いることができる。
また、別法として、化合物（Ｉ−ｓ）と１〜３０当量のＲ^２４ＣＯＯＨ（式中、Ｒ^２４は前記と同義である）とを、適当な溶媒中、１〜３０当量の適当な縮合剤の存在下、必要により１〜３０当量の適当な添加剤の存在下、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させることによっても化合物（Ｉ−ｖ）を製造することができる。
用いられる適当な縮合剤としては、例えばジシクロヘキシルカルボジイミド（ＤＣＣ）、カルボニルジイミダゾール（ＣＤＩ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）などがあげられる。適当な添加剤としては、例えば１−ヒドロキシベンゾトリアゾール、Ｎ−メチルモルホリンなどがあげられる。適当な溶媒としては、例えばジクロロメタン、トルエン、ＤＭＦ、ＮＭＰなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法１３
化合物（Ｉ）のうち、Ｗがヒドロキシである化合物（Ｉ−ｗ）は、化合物（Ｉ）のうち、Ｗが−ＯＲ^５ａ（式中、Ｒ^５ａは前記と同義である）である化合物（Ｉ−ｘ）から以下の工程に従い製造することができる。

^{(Wherein, m, R 2, R 3} , R 4, R 24 and ^{W a} are the same meanings as defined above, respectively)
Compound (Iv) is compounded with Compound (Is) obtained by Production Method 10 in the presence of 0.5 to 100 equivalents of a base in the absence of a solvent or in an inert solvent for the reaction, if necessary. An equivalent amount of R ²⁴ COX (wherein X represents each atom of chlorine or bromine) or (R ²⁴ CO) ₂ O (wherein R ²⁴ is as defined above), It can be produced by reacting at a temperature between 5 minutes and 48 hours.
Examples of the base include pyridine, 2,6-lutidine, 2,4,6-collidine, DMAP, triethylamine, tributylamine, diisopropylethylamine, DBU, DBN, N-methylmorpholine and the like. Examples of the solvent inert to the reaction include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, acetonitrile, DMF, NMP and the like, and these can be used alone or in combination. .
Alternatively, the compound (Is) and 1 to 30 equivalents of R ²⁴ COOH (wherein R ²⁴ has the same meaning as described above) and 1 to 30 equivalents of an appropriate condensation can be obtained. Compound (Iv) can also be obtained by reacting in the presence of an agent, optionally in the presence of 1 to 30 equivalents of an appropriate additive, at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. Can be manufactured.
Examples of suitable condensing agents to be used include dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), and the like. Examples of suitable additives include 1-hydroxybenzotriazole, N-methylmorpholine, and the like. Suitable solvents include, for example, dichloromethane, toluene, DMF, NMP and the like, and these can be used alone or in combination.
Production method 13
Among the compounds (I), the compound (Iw) in which W is hydroxy is the compound (I) in which W is —OR ^5a (wherein R ^5a is as defined above). -X) can be produced according to the following steps.

（式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５ａはそれぞれ前記と同義である）
化合物（Ｉ−ｗ）は、製造法１で得られる化合物（Ｉ−ｘ）を無溶媒でまたは水を含む溶媒中、１〜２００当量の塩基、または触媒量から２００当量の酸で、−２０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間処理することにより製造することができる。
塩基としては、例えば水酸化ナトリウム、水酸化カリウム、水酸化リチウムなどがあげられ、酸としては、例えば塩酸、硫酸、酢酸、ギ酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸、四塩化チタン、三フッ化ホウ素などがあげられる。溶媒としては、例えばメタノール、エタノール、１−プロパノール、アセトン、メチルエチルケトン、ジエチルエーテル、ＴＨＦ、１，４−ジオキサン、ＤＭＦ、ジクロロメタン、１，２−ジクロロエタンなどがあげられ、これらを単独でまたは混合して用いることができる。
また、Ｒ^５ａが置換もしくは非置換のアラルキルである場合は、化合物（Ｉ−ｘ）を接触還元反応に付すことにより化合物（Ｉ−ｗ）を製造することもできる。
すなわち、Ｒ^５ａが置換もしくは非置換のアラルキルである化合物（Ｉ−ｘ）を反応に不活性な溶媒中、触媒量〜３０当量の例えばパラジウム炭素、ラネーニッケルなどの存在下、水素気流中、常圧〜５０，０００ｋＰａの圧力下で、０℃〜溶媒の沸点の間の温度で５分間〜４８時間処理するか、または１〜２００当量の例えばギ酸、ギ酸アンモニウム、ヒドラジン、シクロヘキセン、シクロヘキサンジエン、トリエチルシランなどの水素供与体の存在下、必要に応じ１〜２００当量のアンモニア、酢酸、塩酸、硫酸などを添加し、−２０℃〜溶媒の沸点の間の温度で５分間〜４８時間処理することにより化合物（Ｉ−ｗ）を製造することができる。
反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、ＴＨＦ、１，４−ジオキサン、水などがあげられ、これらを単独でまたは混合して用いることができる。
製造法１４
化合物（Ｉ）のうち、Ｗが−ＮＲ^６Ｒ^７（式中、Ｒ^６およびＲ^７はそれぞれ前記と同義である）である化合物（Ｉ−ｙ）は以下の工程に従い製造することもできる。

(Wherein, m, R ¹ , R ² , R ³ , R ⁴ and R ^5a are as defined above)
Compound (I-w) is the compound (I-x) obtained in Production Method 1 without solvent or in a solvent containing water, 1 to 200 equivalents of base, or catalytic amount to 200 equivalents of acid, −20 It can manufacture by processing for 5 minutes-48 hours at the temperature between the boiling point of the solvent to be used.
Examples of the base include sodium hydroxide, potassium hydroxide and lithium hydroxide. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, tetrachloride. Examples thereof include titanium and boron trifluoride. Examples of the solvent include methanol, ethanol, 1-propanol, acetone, methyl ethyl ketone, diethyl ether, THF, 1,4-dioxane, DMF, dichloromethane, 1,2-dichloroethane, and these can be used alone or in combination. Can be used.
In addition, when R ^5a is substituted or unsubstituted aralkyl, compound (Iw) can also be produced by subjecting compound (Ix) to a catalytic reduction reaction.
That is, R ^5a is a substituted or unsubstituted aralkyl compound (Ix) in a solvent inert to the reaction, in the presence of a catalytic amount to 30 equivalents of, for example, palladium carbon, Raney nickel, etc., in a hydrogen stream, at atmospheric pressure Treat for 5 minutes to 48 hours at a temperature between 0 ° C. and the boiling point of the solvent under a pressure of ˜50,000 kPa, or 1 to 200 equivalents of formic acid, ammonium formate, hydrazine, cyclohexene, cyclohexanediene, triethylsilane In the presence of a hydrogen donor such as 1 to 200 equivalents of ammonia, acetic acid, hydrochloric acid, sulfuric acid and the like, and treatment at a temperature between −20 ° C. and the boiling point of the solvent for 5 minutes to 48 hours. Compound (Iw) can be produced.
Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Production method 14
Among compounds (I), compound (Iy) in which W is —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are as defined above) can also be produced according to the following steps.

（式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^６およびＲ^７はそれぞれ前記と同義である）
化合物（Ｉ−ｙ）は、製造法１３で得られる化合物（Ｉ−ｗ）を、無溶媒でまたは反応に不活性な溶媒中、１〜３０当量のＨＮＲ^６Ｒ^７と、１〜３０当量の適当な縮合剤の存在下、必要により１〜３０当量の適当な添加剤の存在下、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させることにより製造することができる。
適当な縮合剤としては、例えばＤＣＣ、ＣＤＩ、ＥＤＣ・ＨＣｌなどがあげられる。適当な添加剤としては、例えば１−ヒドロキシベンゾトリアゾールなどがあげられる。反応に不活性な溶媒としては、例えばジクロロメタン、トルエン、ＤＭＦ、ＮＭＰなどがあげられ、これらを単独でまたは混合して用いることができる。
また、化合物（Ｉ−ｗ）を上記と同様の反応に不活性な溶媒中、１〜３０当量の上記と同様の適当な縮合剤の存在下、１〜３０当量のＨＮＲ^６Ｒ^７の１−ヒドロキシベンゾトリアゾール塩（ＨＯＢｔ・ＮＨＲ^６Ｒ^７）と反応させることによっても化合物（Ｉ−ｙ）を製造することができる。
製造法１５
化合物（Ｉ）のうち、Ｒ^２およびＲ^３が同一炭素上に存在し、その炭素原子と一緒になって含窒素シクロアルカン（該含窒素シクロアルカンの窒素原子上に前記と同義の置換もしくは非置換の低級アルキル、前記と同義の置換もしくは非置換のアラルキルまたは前記と同義の置換もしくは非置換のアリールが置換してもよい）を形成する化合物（Ｉ−ｚ）および（Ｉ−ａａ）は、以下の工程によっても製造することができる。

(Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as defined above)
Compound (Iy) is obtained by reacting Compound (Iw) obtained by Production Method 13 with 1 to 30 equivalents of HNR ⁶ R ⁷ in the absence of a solvent or in a solvent inert to the reaction, and 1 to 30 equivalents. It can be prepared by reacting in the presence of a suitable condensing agent, optionally in the presence of 1 to 30 equivalents of a suitable additive, at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. it can.
Suitable condensing agents include, for example, DCC, CDI, EDC · HCl and the like. Examples of suitable additives include 1-hydroxybenzotriazole. Examples of the solvent inert to the reaction include dichloromethane, toluene, DMF, NMP and the like, and these can be used alone or in combination.
In addition, in the presence of 1 to 30 equivalents of a suitable condensing agent similar to the above, 1 to 30 equivalents of HNR ⁶ R ⁷ 1- Compound (I-y) can also be produced by reacting with a hydroxybenzotriazole salt (HOBt · NHR ⁶ R ⁷ ).
Production method 15
Among the compounds (I), R ² and R ³ are present on the same carbon, and together with the carbon atom, a nitrogen-containing cycloalkane (on the nitrogen atom of the nitrogen-containing cycloalkane, Compounds (Iz) and (I-aa) forming a substituted lower alkyl, a substituted or unsubstituted aralkyl as defined above or a substituted or unsubstituted aryl as defined above may be substituted, It can also be manufactured by the following steps.

［式中、Ｒ^１、Ｒ^４およびＷはそれぞれ前記と同義であり、Ｒ^２５は前記と同義の置換もしくは非置換の低級アルキル、前記と同義の置換もしくは非置換のアラルキルまたは前記と同義の置換もしくは非置換のアリールを表し、ｍ１およびｍ２は０〜２の整数を表し（ただし、ｍ１とｍ２の合計は２以下である）、ｎ１およびｎ２は０〜６の整数を表す（ただし、ｎ１とｎ２の合計は１以上である）］
工程１５−１
化合物（ＩＩ−ｂ）は、公知の方法（国際公開第９８／２２４５５号、国際公開第００／１４０８５号など）に準じて、または参考例に記載した方法でもしくはそれらに準じて得ることができる化合物（ＩＩ−ａ）を、無溶媒でまたは適当な溶媒中、２〜５０当量のスルホニル化剤と、必要に応じ、１〜１００当量の適当な塩基の存在下、−３０℃〜１５０℃の間の温度で、５分間〜７２時間反応させた後、無溶媒でまたは適当な溶媒中、１〜３００当量のＲ^２５ＮＨ_２（式中、Ｒ^２５は前記と同義である）と、必要に応じ、１〜１００当量の適当な塩基の存在下、−３０℃〜１５０℃の間の温度で、５分間〜７２時間反応させることにより製造することができる。
スルホニル化剤としては、例えば塩化メタンスルホニル、塩化ｐ−トルエンスルホニル、塩化ベンゼンスルホニル、塩化トリフルオロメタンスルホニル、無水トリフルオロメタンスルホン酸、無水メタンスルホン酸などがあげられる。各反応で用いられる適当な溶媒としては、例えば水、エタノール、ジクロロメタン、クロロホルム、ＴＨＦ、トルエン、酢酸エチル、ＤＭＦ、ＮＭＰ、ピリジンなどがあげられ、これらを単独でまたは混合して用いることができる。各反応で用いられる適当な塩基としては、例えば炭酸カリウム、水酸化カリウム、水酸化ナトリウム、トリエチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、ＤＢＮなどがあげられる。
工程１５−２
化合物（Ｉ−ｚ）は、化合物（ＩＩ−ｂ）を用い、製造法１に記載の方法と同様にして製造することができる。
工程１５−３
化合物（Ｉ−ａａ）は、化合物（Ｉ−ｚ）のうちＲ^２５がベンジルである化合物を用い、製造法５に記載の方法と同様にして製造することができる。
また別法として、化合物（Ｉ−ａａ）は、化合物（Ｉ−ｚ）のうちＲ^２５がベンジルである化合物を適当な溶媒中、１〜３０当量のクロロギ酸１−クロロエチルと、０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させ、次いで無溶媒でまたは適当な溶媒中、１〜５００当量の低級アルコールの存在下、０℃〜１５０℃の間の温度で、５分間〜４８時間処理することにより製造することもできる。
クロロギ酸１−クロロエチルとの反応、および低級アルコールでの処理に用いられる適当な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタン、ＴＨＦ、トルエン、酢酸エチル、アセトニトリル、ピリジンなどがあげられ、これらを単独でまたは混合して用いることができる。低級アルコールとしては、例えばメタノール、エタノール、プロパノールなどがあげられる。
製造法１６
化合物（Ｉ−ｚ）のうち、Ｒ^２５がＣＨ_２Ｒ^２６（式中、Ｒ^２６は前記と同義の置換もしくは非置換の低級アルキルのうち、１位がメチレンである該置換もしくは非置換の低級アルキルから該メチレンを除いた基を表す）である化合物（Ｉ−ｂｂ）は、以下の工程によっても製造することができる。

[Wherein R ¹ , R ⁴ and W are as defined above, and R ²⁵ is a substituted or unsubstituted lower alkyl as defined above, a substituted or unsubstituted aralkyl as defined above, or a substitution as defined above. Or it represents an unsubstituted aryl, m1 and m2 represent an integer of 0 to 2 (provided that the sum of m1 and m2 is 2 or less), and n1 and n2 represent an integer of 0 to 6 (provided that n1 and The sum of n2 is 1 or more)]
Step 15-1
Compound (II-b) can be obtained according to a known method (International Publication No. 98/22455, International Publication No. 00/14085, etc.), or by the method described in Reference Examples or according thereto. Compound (II-a) is used in the presence of 2 to 50 equivalents of a sulfonylating agent and optionally 1 to 100 equivalents of a suitable base in the absence of solvent or in a suitable solvent at −30 ° C. to 150 ° C. After reacting at a temperature between 5 minutes and 72 hours, 1 to 300 equivalents of R ²⁵ NH ₂ (wherein R ²⁵ is as defined above) without solvent or in a suitable solvent, as required Accordingly, it can be produced by reacting at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 72 hours in the presence of 1 to 100 equivalents of a suitable base.
Examples of the sulfonylating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, and the like. Examples of suitable solvents used in each reaction include water, ethanol, dichloromethane, chloroform, THF, toluene, ethyl acetate, DMF, NMP, pyridine and the like, and these can be used alone or in combination. Examples of suitable bases used in each reaction include potassium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropylethylamine, DBU, DBN and the like.
Step 15-2
Compound (Iz) can be produced in the same manner as in Production Method 1 using Compound (II-b).
Step 15-3
Compound (I-aa) can be produced in the same manner as in Production Method 5, using the compound (Iz) wherein R ²⁵ is benzyl.
In another method, compound (I-aa) is a compound (Iz) in which R ²⁵ is benzyl, and 1 to 30 equivalents of 1-chloroethyl chloroformate is used at 0 ° C. in an appropriate solvent. The reaction is carried out at a temperature between the boiling points of the solvents for 5 minutes to 48 hours, and then in the absence of solvent or in the presence of 1 to 500 equivalents of a lower alcohol in a suitable solvent at a temperature between 0 ° C. and 150 ° C. It can also be produced by treating for from min to 48 hours.
Suitable solvents used for the reaction with 1-chloroethyl chloroformate and the treatment with lower alcohols include, for example, dichloromethane, 1,2-dichloroethane, THF, toluene, ethyl acetate, acetonitrile, pyridine and the like. They can be used alone or in combination. Examples of the lower alcohol include methanol, ethanol, propanol and the like.
Production method 16
Among the compounds (Iz), R ²⁵ is CH ₂ R ²⁶ (wherein R ²⁶ is a substituted or unsubstituted lower alkyl having the same meaning as described above, wherein the 1-position is methylene. Compound (I-bb) which is a group obtained by removing methylene from alkyl) can also be produced by the following steps.

（式中、Ｒ^１、Ｒ^４、Ｒ^２６、Ｗ、ｍ１、ｍ２、ｎ１およびｎ２はそれぞれ前記と同義である）
工程１６
化合物（Ｉ−ｂｂ）は、製造法１〜１５で得られる化合物（Ｉ−ａａ）と１〜３０当量のＲ^２６ＣＨＯ（式中、Ｒ^２６は前記と同義である）を、反応に不活性な溶媒中、適当な還元剤の存在下、必要により０．０１〜５０当量の塩基または酸の存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜１００時間反応させることにより製造することができる。
適当な還元剤としては、例えばシアン化水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウムなどがあげられる。塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミン、アンモニアなどがあげられ、酸としては、例えば酢酸、塩酸、硫酸などがあげられる。反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、酢酸ブチル、ＤＭＦ、ジクロロメタン、１，２−ジクロロエタン、水などがあげられ、これらを単独でまたは混合して用いることができる。
製造法１７
化合物（Ｉ−ｚ）のうち、Ｒ^２５が前記と同義の置換もしくは非置換の低級アルキルである化合物（Ｉ−ｃｃ）は、以下の工程によっても製造することができる。

(Wherein R ¹ , R ⁴ , R ²⁶ , W, m1, m2, n1 and n2 are as defined above)
Step 16
Compound (I-bb) is inert to the reaction between Compound (I-aa) obtained in Production Method 1-15 and 1-30 equivalents of R ²⁶ CHO (wherein R ²⁶ has the same meaning as described above). By reacting in a suitable solvent in the presence of a suitable reducing agent, optionally in the presence of 0.01 to 50 equivalents of a base or acid, at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 100 hours. Can be manufactured.
Suitable reducing agents include, for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. Examples of the base include triethylamine, diisopropylethylamine, ammonia and the like, and examples of the acid include acetic acid, hydrochloric acid, sulfuric acid and the like. Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, butyl acetate, DMF, dichloromethane, 1,2-dichloroethane, water and the like, and these can be used alone or in combination.
Manufacturing method 17
Among compounds (Iz), compound (I-cc) in which R ²⁵ is substituted or unsubstituted lower alkyl as defined above can also be produced by the following steps.

（式中、式中、Ｒ^１、Ｒ^４、Ｗ、ｍ１、ｍ２、ｎ１およびｎ２はそれぞれ前記と同義であり、Ｒ^２７は前記と同義の置換もしくは非置換の低級アルキルを表し、Ｌは塩素原子、臭素原子、ヨウ素原子、トリフルオロメタンスルホニルオキシ、メタンスルホニルオキシ、ベンゼンスルホニルオキシまたはｐ−トルエンスルホニルオキシを表す）
化合物（Ｉ−ｃｃ）は、製造法１〜１５で得られる化合物（Ｉ−ａａ）を１〜３０当量のＲ^２７Ｌ（式中、Ｒ^２７およびＬはそれぞれ前記と同義である）と無溶媒でまたは反応に不活性な溶媒中、必要に応じて１〜３０当量の適当な塩基の存在下、−３０℃〜１５０℃の間の温度で、５分間〜７２時間反応させることにより製造することができる。
反応に不活性な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタン、クロロホルム、ＴＨＦ、酢酸エチル、アセトニトリル、トルエン、ＤＭＦ、ＮＭＰ、ピリジンなどがあげられる。適当な塩基としては、例えばトリエチルアミン、ジイシプロピルエチルアミン、ＤＢＵ、ピリジン、炭酸カリウム、水酸化カリウム、水素化ナトリウムなどがあげられる。
製造法１８
化合物（Ｉ−ｚ）のうち、Ｒ^２５が前記と同義の置換もしくは非置換のアリールまたは置換もしくは非置換の芳香族複素環基である化合物（Ｉ−ｄｄ）は、以下の工程によっても製造することができる。

Wherein R ¹ , R ⁴ , W, m1, m2, n1 and n2 are as defined above, R ²⁷ represents a substituted or unsubstituted lower alkyl as defined above, and L represents chlorine. Atom, bromine atom, iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy)
Compound (I-cc) is compound (I-aa) obtained by production methods 1 to 15 and 1 to 30 equivalents of R ²⁷ L (wherein R ²⁷ and L are as defined above) and no solvent Or in a solvent inert to the reaction, optionally in the presence of 1 to 30 equivalents of a suitable base, at a temperature between -30 ° C and 150 ° C for 5 minutes to 72 hours. Can do.
Examples of the solvent inert to the reaction include dichloromethane, 1,2-dichloroethane, chloroform, THF, ethyl acetate, acetonitrile, toluene, DMF, NMP, pyridine and the like. Suitable bases include, for example, triethylamine, diisopropylethylamine, DBU, pyridine, potassium carbonate, potassium hydroxide, sodium hydride and the like.
Production method 18
Among the compounds (Iz), the compound (I-dd) in which R ²⁵ is substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group as defined above is also produced by the following steps. be able to.

（式中、式中、Ｒ^１、Ｒ^４、Ｗ、ｍ１、ｍ２、ｎ１およびｎ２はそれぞれ前記と同義であり、Ｒ^２８は前記と同義の置換もしくは非置換のアリールまたは置換もしくは非置換の芳香族複素環基を表し、Ｚはフッ素原子、塩素原子、臭素原子、ヨウ素原子、トリフルオロメタンスルホニルオキシ、メタンスルホニルオキシ、ベンゼンスルホニルオキシまたはｐ−トルエンスルホニルオキシを表す）
工程１８
化合物（Ｉ−ｄｄ）は、製造法１〜１５で得られる化合物（Ｉ−ａａ）と１〜３０当量のＲ^２８Ｚ（式中、Ｚは前記と同義である）を、反応に不活性な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒および１〜３０当量の適当な塩基の存在下、必要に応じ０．０１〜３０当量の適当な添加剤の存在下、０℃〜用いる溶媒の沸点の間の温度で、５分間〜１００時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
パラジウム触媒としては、例えば酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウムなどがあげられる。適当な塩基としては、例えばリン酸カリウム、炭酸カリウム、炭酸セシウム、ｔｅｒｔ−ブトキシナトリウム、トリエチルアミンなどがあげられる。適当な添加剤としては、例えば２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（ＢＩＮＡＰ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（ＤＰＰＦ）などがあげられる。反応に不活性な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、ＤＭＥ、トルエン、キシレン、アセトニトリル、グライムなどがあげられ、これらを単独でまたは混合して用いることができる。
また別法として、化合物（Ｉ−ｄｄ）は、化合物（Ｉ−ａａ）を１〜１００当量のＲ^２８Ｚ（式中、Ｚは前記と同義である）と無溶媒でまたは反応に不活性な溶媒中、必要に応じて１〜５０当量の適当な塩基の存在下、−３０℃〜２００℃の間の温度で反応させることにより製造することもできる。
反応に不活性な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタン、クロロホルム、ＴＨＦ、酢酸エチル、アセトニトリル、トルエン、ＤＭＦ、ＮＭＰ、ピリジンなどがあげられる。適当な塩基としては、例えばトリエチルアミン、ジイシプロピルエチルアミン、ＤＢＵ、ピリジン、炭酸カリウム、水酸化カリウム、水素化ナトリウムなどがあげられる。
製造法１９
化合物（Ｉ−ｚ）のうち、Ｒ^２５が前記と同義の置換もしくは非置換の低級アルカノイルである化合物（Ｉ−ｅｅ）は、以下の工程によっても製造することができる。

Wherein R ¹ , R ⁴ , W, m1, m2, n1 and n2 are as defined above, and R ²⁸ is substituted or unsubstituted aryl or substituted or unsubstituted aromatic as defined above. Z represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy)
Step 18
Compound (I-dd) is an inactive compound obtained by reacting compound (I-aa) obtained in Production Methods 1-15 with 1-30 equivalents of R ²⁸ Z (wherein Z is as defined above). In a solvent, in the presence of 0.01 mol% to 30 mol% of a palladium catalyst and 1 to 30 equivalents of an appropriate base, and optionally in the presence of 0.01 to 30 equivalents of an appropriate additive, 0 ° C to It can manufacture by making it react for 5 to 100 hours at the temperature between boiling points. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Examples of the palladium catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, and tris (dibenzylideneacetone) dipalladium. Suitable bases include, for example, potassium phosphate, potassium carbonate, cesium carbonate, tert-butoxy sodium, triethylamine and the like. Suitable additives include, for example, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 1,1′-bis (diphenylphosphino) ferrocene (DPPF), and the like. Examples of the solvent inert to the reaction include THF, 1,4-dioxane, DME, toluene, xylene, acetonitrile, glyme and the like, and these can be used alone or in combination.
In another method, compound (I-dd) is compound (I-aa) with 1 to 100 equivalents of R ²⁸ Z (wherein Z is as defined above) without solvent or inert to the reaction. It can also be produced by reacting in a solvent at a temperature between −30 ° C. and 200 ° C. in the presence of 1 to 50 equivalents of a suitable base as necessary.
Examples of the solvent inert to the reaction include dichloromethane, 1,2-dichloroethane, chloroform, THF, ethyl acetate, acetonitrile, toluene, DMF, NMP, pyridine and the like. Suitable bases include, for example, triethylamine, diisopropylethylamine, DBU, pyridine, potassium carbonate, potassium hydroxide, sodium hydride and the like.
Production method 19
Among compounds (Iz), compound (I-ee) in which R ²⁵ is a substituted or unsubstituted lower alkanoyl as defined above can also be produced by the following steps.

（式中、Ｒ^１、Ｒ^４、Ｗ、Ｌ、ｍ１、ｍ２、ｎ１およびｎ２はそれぞれ前記と同義であり、Ｒ^２９は前記と同義の置換もしくは非置換の低級アルカノイルから１位のＣＯを除いた基を表す。）
工程１９
化合物（Ｉ−ｅｅ）は、製造法１〜１５で得られる化合物（Ｉ−ａａ）を、無溶媒でまたは適当な溶媒中、１〜１００当量のＲ^２９ＣＯＬ（式中、Ｒ^２９およびＬはそれぞれ前記と同義である）または（Ｒ^２９ＣＯ）_２Ｏ（式中、Ｒ^２９は前記と同義である）と、必要により０．５〜１００当量の適当な塩基の存在下、−３０℃〜１５０℃の間の温度で、５分間〜７２時間反応させることにより製造することができる。
適当な塩基としては、例えばピリジン、２，６−ルチジン、２，４，６−コリジン、ＤＭＡＰ、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、ＤＢＮ、Ｎ−メチルモルホリンなどがあげられる。反応に不活性な溶媒としては、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、ＴＨＦ、１，４−ジオキサン、アセトニトリル、ＤＭＦ、ＮＭＰなどがあげられ、これらを単独でまたは混合して用いることができる。
また、別法として、化合物（Ｉ−ｅｅ）は、化合物（Ｉ−ａａ）を、適当な溶媒中、１〜３０当量のＲ^２９ＣＯＯＨ（式中、Ｒ^２９は前記と同義である）と、１〜３０当量の適当な縮合剤の存在下、必要により１〜３０当量の適当な添加剤の存在下、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜７２時間反応させることにより製造することもできる。
適当な縮合剤としては、例えばＤＣＣ、ＣＤＩ、ＥＤＣ・ＨＣｌなどがあげられる。適当な添加剤としては、例えば１−ヒドロキシベンゾトリアゾールなどがあげられる。適当な溶媒としては、例えばジクロロメタン、トルエン、ＤＭＦ、ＮＭＰなどがあげられ、これらを単独でまたは混合して用いることができる。
化合物（Ｉ）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４またはＷに含まれる官能基の変換は、上記工程以外にも公知の他の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ）、Ｒ．Ｃ．ラロック（Ｌａｒｏｃｋ）著（１９８９年）などに記載の方法］またはそれらに準じて行うこともできる。
また、上記の方法を適宜組み合わせて実施することにより、所望の位置に所望の官能基を有する化合物（Ｉ）を得ることができる
上記各製造方法における中間体および目的化合物は、有機合成化学で常用される分離精製法、例えば、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィーなどに付して単離精製することができる。また、中間体においては特に精製することなく次の反応に供することも可能である。
化合物（Ｉ）の中には、幾何異性体、光学異性体、互変異性体などの立体異性体が存在し得るものもあるが、本発明は、これらを含め、全ての可能な異性体およびそれらの混合物を包含する。
化合物（Ｉ）の塩を取得したいとき、化合物（Ｉ）が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物（Ｉ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて単離、精製すればよい。
また、化合物（Ｉ）およびその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含される。
本発明によって得られる化合物（Ｉ）の具体例を第１表および第２表に示す。

(Wherein R ¹ , R ⁴ , W, L, m1, m2, n1 and n2 have the same meanings as described above, and R ²⁹ excludes CO at the 1-position from the substituted or unsubstituted lower alkanoyl as defined above. Represents a group.
Step 19
Compound (I-ee) is compound (I-aa) obtained by production method 1-15, without solvent or in a suitable solvent, 1 to 100 equivalents of R ²⁹ COL (wherein R ²⁹ and L are Each having the same meaning as above) or (R ²⁹ CO) ₂ O (wherein R ²⁹ is as defined above), and optionally in the presence of 0.5 to 100 equivalents of a suitable base, It can manufacture by making it react for 5 minutes-72 hours at the temperature between 150 degreeC.
Suitable bases include, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, DMAP, triethylamine, tributylamine, diisopropylethylamine, DBU, DBN, N-methylmorpholine and the like. Examples of the solvent inert to the reaction include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, acetonitrile, DMF, NMP and the like, and these can be used alone or in combination. .
Alternatively, compound (I-ee) is compound (I-aa) with 1-30 equivalents of R ²⁹ COOH (wherein R ²⁹ is as defined above) in a suitable solvent; The reaction is carried out in the presence of 1 to 30 equivalents of a suitable condensing agent and optionally in the presence of 1 to 30 equivalents of a suitable additive at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours. Can also be manufactured.
Suitable condensing agents include, for example, DCC, CDI, EDC · HCl and the like. Examples of suitable additives include 1-hydroxybenzotriazole. Suitable solvents include, for example, dichloromethane, toluene, DMF, NMP and the like, and these can be used alone or in combination.
The conversion of the functional group contained in R ¹ , R ² , R ³ , R ⁴ or W in the compound (I) may be carried out by other known methods [eg, Comprehensive Organic Transformations (for example, Complementary Organic Transformations ( Comprehensive Organic Transformations), R.C. C. The method described in Larock (1989)] or the like can also be performed.
In addition, by appropriately combining the above methods, a compound (I) having a desired functional group at a desired position can be obtained. Intermediates and target compounds in each of the above production methods are commonly used in organic synthetic chemistry. It can be isolated and purified by subjecting it to separation and purification methods such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. The intermediate can be subjected to the next reaction without any particular purification.
Some compounds (I) may have stereoisomers such as geometrical isomers, optical isomers, tautomers and the like, and the present invention includes all possible isomers including these, Including mixtures thereof.
When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be dissolved or suspended and isolated and purified by adding acid or base.
Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
Specific examples of the compound (I) obtained by the present invention are shown in Tables 1 and 2.

次に、代表的な化合物（Ｉ）の薬理作用について試験例により具体的に説明する。
試験例：組み換えヒトＰＤＥ−ＩＶ酵素阻害試験
ヒトＰＤＥｃＤＮＡ（ＨＳＰＤＥ４Ａ）を、ＨＬ−６０細胞より単離した。予想されるアミノ酸配列は、ボルガー（Ｂｏｌｇｅｒ，Ｇ．）ら［「モレキュラー・アンド・セルラー・バイオロジー（Ｍｏｌ．Ｃｅｌｌ．Ｂｉｏｌ．）」、１９９３年、１３巻、ｐ．６５５８］の報告した配列（ＨＳＰＤＥ４Ａ４）と同一である。この組み換えタンパク質を、Ｓｆ９昆虫細胞を用いて発現させた。ＰＤＥ活性は、Ｋｉｎｃａｉｄ Ｒ．Ｌ．およびＭａｎｇａｎｉｅｌｌｏ Ｖ．Ｃ．の方法［「メソッズ・イン・エンザイモロジー（Ｍｅｔｈｏｄｓ Ｅｎｚｙｍｏｌ．）」、１９８８年、１５９巻、ｐ．４５７］に従い、次の二段階過程により測定した。基質には［^３Ｈ］ｃＡＭＰ（最終濃度１μｍｏｌ／Ｌ）を用い、反応は、Ｎ，Ｎ−ビス（２−ヒドロキシエチル）−２−アミノエタンスルホン酸（５０ｍｍｏｌ／Ｌ，ｐＨ ７．２）、ＭｇＣｌ_２（１ｍｍｏｌ／Ｌ）およびＳｏｙｂｅａｎ ｔｒｙｐｓｉｎ ｉｎｈｉｂｉｔｏｒ（０．１ｍｇ／ｍＬ）を含む標準混合液中で行った。反応は酵素の添加により開始し、３０℃で１０〜３０分間インキュベーションした。塩酸により反応を停止し、生成した５’−ＡＭＰを５’−ヌクレオチダーゼによって完全に分解した。ＤＥＡＥ−Ｓｅｐｈａｄｅｘ Ａ−２５でクロマトグラフィーによる処理を行い、溶出した［^３Ｈ］アデノシンをシンチレーションカウンターでカウントした。薬物はＤＭＳＯに溶解して（濃度１．７％）添加した。
本試験において、化合物２、４、５、１１、１４、１７、１８、１９、２５、２８、３５、３７、３８、４０、４２、４４および４６は、薬物濃度１μｍｏｌ／Ｌにおいて５０％以上の酵素阻害活性を示した。
化合物（Ｉ）またはその薬理学的に許容される塩は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが望ましい。また、それら医薬製剤は、動物および人に使用されるものである。
本発明に係わる医薬製剤は、活性成分として化合物（Ｉ）またはその薬理学的に許容される塩を単独で、あるいは任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬理学的に許容される一種もしくはそれ以上の担体と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。
投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば静脈内、気管内、経皮などの非経口をあげることができる。
投与形態としては、例えば錠剤、注射剤、吸入剤、外用剤などがあげられる。徐放的な適応もまた利用できる。
経口投与に適当な、例えば錠剤などは、乳糖、マンニットなどの賦形剤、澱粉などの崩壊剤、ステアリン酸マグネシウムなどの滑沢剤、ヒドロキシプロピルセルロースなどの結合剤、脂肪酸エステルなどの界面活性剤、グリセリンなどの可塑剤、安息香酸、ｐ−ヒドロキシ安息香酸エステル類などの防腐剤などを用いて製造できる。
非経口投与に適当な、例えば注射剤は、好ましくは受容者の血液と等張である活性化合物を含む滅菌水性剤からなり、例えば、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合物からなる担体などを用いて注射用の溶液を調製する。
吸入剤は、活性成分を粉末または液状にして、吸入噴霧剤または担体中に配合し、例えば、定量噴霧式吸入器、ドライパウダー吸入器などの吸入容器に充填することにより製造される。吸入噴射剤としては、従来公知のものを広く使用することができ、例えばフロン−１１、フロン−１２、フロン−２１、フロン−２２、フロン−１１３、フロン−１１４、フロン−１２３、フロン−１４２ｃ、フロン−１３４ａ、フロン−２２７、フロン−Ｃ３１８、１，１，１，２−テトラフルオロエタンなどのフロン系ガス、ＨＦＡ−２２７、ＨＦＡ−１３４ａなどの代替フロンガス、プロパン、イソブタン、ｎ−ブタンなどの炭化水素系ガス、ジエチルエーテル、窒素ガス、炭酸ガスなどがあげられる。担体としては、従来公知のものを広く使用でき、例えば糖類、糖アルコール類、アミノ酸類などがあげられ、乳糖、Ｄ−マンニトールなどが好ましい。
外用剤としては、特に限定されるものではないが、例えば基剤に活性成分を溶解または混合分散しクリーム状、ペースト状、ゼリー状、ゲル状、乳液状、液状などの形状になされたもの（軟膏剤、ローション剤など）、基剤に活性成分および経皮吸収促進剤を溶解または混合分散させたものを例えばポリエチレンなどの支持体上に展延したもの（パップ剤、テープ剤など）などがあげられる。上記基剤としては、薬理学的に許容しうるものであればいずれでもよく、軟膏剤、リニメント剤、ローションなどの基剤として従来公知のものを用いることができ、例えば、アルギン酸ナトリウム；ゼラチン、コーンスターチ、トラガントガム、メチルセルロース、キサンタンガム、デキストリン、ポリビニルアルコールなどのポリマー；オリーブ油、ラノリンなどの油脂類；白色ワセリン；パラフィン；ステアリン酸などの高級脂肪酸；セチルアルコールなどの高級アルコール；ポリエチレングリコール；水などがあげられる。上記経皮吸収促進剤としては、薬理学的に許容しうるものであればいずれでもよく、例えばエタノール、ジエチレングリコールなどのアルコール類；ドデシルピロリドンなどの極性溶剤；尿素；ラウリル酸エチル；エイゾン；オリーブ油などがあげられる。さらに必要に応じて、カオリン、ベントナイト、酸化亜鉛、酸化チタンなどの無機充填剤；粘度調節剤；老化防止剤；ｐＨ調節剤；グリセリン、プロピレングリコールなどの保湿剤などを添加してもよい。
また、これら非経口剤においても、経口剤で例示した賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤、防腐剤などから選択される１種もしくはそれ以上の補助成分を添加することもできる。
化合物（Ｉ）またはその薬理学的に許容される塩の投与量および投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度などにより異なるが、通常経口の場合、成人一人当り０．０１ｍｇ〜１ｇ、好ましくは０．０５〜５０ｍｇを一日１回ないし数回投与する。静脈内投与などの非経口投与の場合、成人一人当り０．００１〜１００ｍｇ 、好ましくは０．０１〜５０ｍｇを一日１回ないし数回投与する。気管内投与（吸入剤）の場合、成人一人当たり、０．００１ｍｇ〜１ｇ、好ましくは０．０１ｍｇ〜１００ｍｇ、より好ましくは０．５ｍｇ〜２０ｍｇを一日１回ないし数回投与する。しかしながら、これら投与量および投与回数に関しては、前述の種々の条件により変動する。
以下に、本発明の態様を実施例、参考例および製剤例で説明する。

Next, the pharmacological action of a typical compound (I) will be specifically described with reference to test examples.
Test Example: Recombinant human PDE-IV enzyme inhibition test Human PDE cDNA (HSPDE4A) was isolated from HL-60 cells. The predicted amino acid sequence is described in Bolger, G. et al. ["Mole. Cell. Biol.", 1993, 13, p. 6558] is the same as the reported sequence (HSPDE4A4). This recombinant protein was expressed using Sf9 insect cells. PDE activity was determined by Kincaid R. L. And Manganello V. C. [Methods Enzymol.], 1988, 159, p. 457] according to the following two-step process. [ ³ H] cAMP (final concentration 1 μmol / L) was used as the substrate, and the reaction was performed using N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (50 mmol / L, pH 7.2), It was carried out in a standard mixture containing MgCl ₂ (1 mmol / L) and Soybean trypsin inhibitor (0.1 mg / mL). The reaction was started by addition of enzyme and incubated at 30 ° C. for 10-30 minutes. The reaction was stopped with hydrochloric acid, and the produced 5′-AMP was completely decomposed with 5′-nucleotidase. Chromatographic treatment was performed with DEAE-Sephadex A-25, and the eluted [ ³ H] adenosine was counted with a scintillation counter. The drug was dissolved in DMSO (concentration 1.7%) and added.
In this test, compounds 2, 4, 5, 11, 14, 17, 18, 19, 25, 28, 35, 37, 38, 40, 42, 44, and 46 were not less than 50% at a drug concentration of 1 μmol / L. Enzyme inhibitory activity was demonstrated.
Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
The pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration, intratracheal administration and transdermal administration.
Examples of the dosage form include tablets, injections, inhalants, and external preparations. Sustained release indications are also available.
Suitable for oral administration, such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and surface activity such as fatty acid esters Agent, plasticizer such as glycerin, benzoic acid, and preservatives such as p-hydroxybenzoic acid esters.
Suitable for parenteral administration, for example injections, comprise a sterile aqueous agent containing an active compound, preferably isotonic with the blood of the recipient, for example a carrier consisting of a salt solution, a glucose solution or a mixture of saline and glucose solution A solution for injection is prepared using such as.
An inhalant is produced by making an active ingredient into a powder or liquid and blending it into an inhalation spray or carrier and filling the inhalation container such as a metered dose inhaler or a dry powder inhaler. As the inhalation propellant, conventionally known ones can be widely used. For example, chlorofluorocarbon-11, chlorofluorocarbon-12, chlorofluorocarbon-21, chlorofluorocarbon-22, chlorofluorocarbon-113, chlorofluorocarbon-114, chlorofluorocarbon-123, chlorofluorocarbon-142c. , Freon gases such as Freon-134a, Freon-227, Freon-C318, 1,1,1,2-tetrafluoroethane, alternative Freon gases such as HFA-227, HFA-134a, propane, isobutane, n-butane, etc. Hydrocarbon gas, diethyl ether, nitrogen gas, carbon dioxide gas and the like. As the carrier, conventionally known ones can be widely used, and examples thereof include sugars, sugar alcohols, amino acids and the like, and lactose, D-mannitol and the like are preferable.
Although it does not specifically limit as an external preparation, For example, the active ingredient is melt | dissolved or mixed-dispersed in the base, and it was made into shapes, such as cream form, paste form, jelly form, gel form, emulsion, and liquid ( Ointments, lotions, etc.) and active ingredients and percutaneous absorption accelerators dissolved or mixed and dispersed in a base, for example, spread on a support such as polyethylene (paps, tapes, etc.) can give. The base may be any pharmacologically acceptable, and conventionally known bases such as ointments, liniments, and lotions can be used, such as sodium alginate; gelatin, Polymers such as corn starch, tragacanth gum, methylcellulose, xanthan gum, dextrin, polyvinyl alcohol; fats and oils such as olive oil and lanolin; white petrolatum; paraffin; higher fatty acids such as stearic acid; higher alcohols such as cetyl alcohol; polyethylene glycol; It is done. As the transdermal absorption enhancer, any pharmacologically acceptable one may be used. For example, alcohols such as ethanol and diethylene glycol; polar solvents such as dodecylpyrrolidone; urea; ethyl laurate; Can be given. Furthermore, if necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide; viscosity modifiers; anti-aging agents; pH regulators; humectants such as glycerin and propylene glycol may be added.
In these parenterals, one or more auxiliary components selected from excipients, disintegrants, lubricants, binders, surfactants, plasticizers, preservatives and the like exemplified in the oral preparations. Can also be added.
The dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc. In addition, 0.01 mg to 1 g, preferably 0.05 to 50 mg per adult is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 50 mg per adult is administered once to several times a day. In the case of intratracheal administration (inhalation agent), 0.001 mg to 1 g, preferably 0.01 mg to 100 mg, more preferably 0.5 mg to 20 mg is administered once or several times a day per adult. However, the dose and the number of doses vary depending on the various conditions described above.
Below, the aspect of this invention is demonstrated with an Example, a reference example, and a formulation example.

Cis-4-cyano-4- (8-methyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 1)
To DMF (1.8 mL), 4-cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester obtained in Reference Example 1 ( 150 mg, 0.325 mmol), lithium chloride (41.3 mg, 0.974 mmol), tetramethyltin (41.3 mg, 0.487 mmol), dichlorobis (triphenylphosphine) palladium (11.4 mg, 0.0162 mmol) and 2,6-ditert- Butyl-4-methylphenol (catalytic amount) was suspended and heated to reflux for 4 hours under an argon atmosphere. After the reaction solution was cooled to room temperature, an aqueous ammonium fluoride solution and ethyl acetate were added and stirred at room temperature. The obtained suspension was filtered through celite, and the organic layer of the filtrate was washed with an aqueous ammonium fluoride solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 1 (78.4 mg, 73%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.79 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.31 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 2.46-1.81 (m, 9H), 2.18 (s, 3H), 1.27 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-methyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (compound 2)
Compound 1 (31.7 mg, 0.0962 mmol) obtained in Example 1 was dissolved in ethanol (0.80 mL), 6 mol / L aqueous potassium hydroxide solution (0.20 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction solution was ice-cooled, water (0.80 mL) and 4 mol / L hydrochloric acid (0.45 mL) were added, and the mixture was stirred at that temperature for 1 hr. The precipitated solid was collected by filtration, and the obtained solid was recrystallized from ethanol-water to obtain Compound 2 (23.6 mg, 81%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.21 (br, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.29 (m , 4H), 2.33-1.63 (m, 9H), 2.11 (s, 3H).

Cis-4-cyano-4- (8-ethenyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (compound 3)
Cis-4-cyano-4- (8-hydroxy-2,3-dihydrobenzo-1,4-dioxin-5) prepared in accordance with the method described in JP-A-12-57381 or the like in dichloromethane (100 mL) -Iyl) cyclohexanecarboxylic acid ethyl ester (6.00 g, 18.2 mmol) and triethylamine (7.6 mL, 55 mmol) were added and dissolved, and then cooled to -10 ° C under an argon atmosphere. Trifluoromethanesulfonic anhydride (9.2 mL, 55 mmol) was added dropwise to the resulting solution, and the mixture was stirred at −10 ° C. for 1 hour. Water was added to the reaction solution to stop the reaction, followed by extraction with chloroform. The organic layer was washed with 0.5 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (250 mL), lithium chloride (2.31 g, 54.6 mmol), vinyltri-n-butyltin (8.66 g, 27.3 mmol), tetrakis (triphenylphosphine) palladium (1.05 g, 0.910 mmol) and 2, 6-Ditert-butyl-4-methylphenol (catalytic amount) was added, and the mixture was heated to reflux for 9 hours under an argon atmosphere. After the reaction solution was cooled to room temperature, an aqueous ammonium fluoride solution and ethyl acetate were added and stirred at room temperature. The obtained suspension was filtered through celite, and the organic layer of the filtrate was washed with an aqueous ammonium fluoride solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 3 (2.72 g, 44%, 2 steps) as a pale yellow solid. .
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.04 (d, J = 8.5 Hz, 1H), 6.92 (dd, J = 17.9, 11.2 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H ), 5.75 (dd, J = 17.9, 1.4 Hz, 1H), 5.30 (dd, J = 11.2, 1.4 Hz, 1H), 4.34 (m, 4H), 4.17 (q, J = 7.3 Hz, 2H), 2.47 -1.82 (m, 9H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-ethenyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (compound 4)
The compound 3 (2.72 g, 8.68 mmol) obtained in Example 3 was hydrolyzed in the same manner as in Example 2 to obtain compound 4 (1.93 g, 6.16 mmol, 77%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.29 (br, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 17.8, 11.4 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.81 (dd, J = 17.8, 1.5 Hz, 1H), 5.30 (dd, J = 11.4, 1.5 Hz, 1H), 4.33 (m, 4H), 2.34-1.64 ( m, 9H).

Cis-4-cyano-4- (8-ethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 5)
Compound 4 (1.93 g, 6.16 mmol) was dissolved in ethyl acetate (400 mL), 10% palladium carbon (50% water-containing product; 300 mg) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was recrystallized from ethanol-water to obtain Compound 5 (1.69 g, 5.37 mmol, 87%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.24 (br, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.29 (m , 4H), 2.51 (q, J = 7.4 Hz, 2H), 2.34-1.63 (m, 9H), 1.11 (t, J = 7.4 Hz, 3H).

Cis-4-cyano-4- [8- (2-propenyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid ethyl ester (Compound 6)
To DMF (3.6 mL), 4-cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester obtained in Reference Example 1 ( 300 mg, 0.649 mmol), lithium chloride (82.6 mg, 1.95 mmol), allyltri-n-butyltin (322 mg, 0.972 mmol), dichlorobis (triphenylphosphine) palladium (22.8 mg, 0.0325 mmol) and 2,6-ditert -Butyl-4-methylphenol (catalytic amount) was suspended and stirred at 100 ° C. for 4 hours under an argon atmosphere. After the reaction solution was cooled to room temperature, an aqueous ammonium fluoride solution and ethyl acetate were added and stirred at room temperature. The obtained mixture was filtered through celite, and the organic layer of the filtrate was washed with an aqueous ammonium fluoride solution, water and saturated brine in this order, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 6 (98.7 mg, 43%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.83 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 5.95 (m, 1H), 5.09-5.02 (m , 2H), 4.32 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 3.33 (d, J = 6.6 Hz, 2H), 2.46-1.80 (m, 9H), 1.27 (t, J = (7.3 Hz, 3H).

Cis-4-cyano-4- [8- (2-propenyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid (Compound 7)
The compound 6 (28.2 mg, 0.0793 mmol) obtained in Example 6 was hydrolyzed in the same manner as in Example 2 to obtain Compound 7 (21.4 mg, 82%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.22 (br, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.91 (m , 1H), 5.07-5.00 (m, 2H), 4.29 (m, 4H), 3.26 (d, J = 5.1 Hz, 1H), 2.05-1.64 (m, 9H).

Cis-4-cyano-4- (8-propyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 8)
Compound 6 (40.0 mg, 0.113 mmol) obtained in Example 6 was subjected to catalytic reduction in the same manner as in Example 5 to obtain cis-4-cyano-4- (8-propyl-2,3-dihydrobenzo-1 , 4-Dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (42.3 mg) was obtained. Subsequently, 34.5 mg was hydrolyzed in the same manner as in Example 2 to obtain Compound 8 (28.2 mg, 94%, 2 steps) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.22 (br, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.29 (m , 4H), 2.48 (t, J = 7.4 Hz, 2H), 2.34-1.63 (m, 9H), 1.52 (td, J = 7.4, 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H) .

Cis-4- (8-acetyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) -4-cyanocyclohexanecarboxylic acid ethyl ester (compound 9)
4-cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (250) obtained in Reference Example 1 was added to DMF (2.5 mL). mg, 0.541 mmol), triethylamine (110 mg, 1.08 mmol), n-butyl vinyl ether (434 mg, 4.69 mmol), palladium acetate (14.6 mg, 0.0649 mmol) and 1,3-bis (diphenylphosphino) propane (26.8 mg, 0.0649 mmol) was suspended, and heated and stirred at 80 ° C. for 5 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 2 mol / L hydrochloric acid (5 mL) was added, and the mixture was stirred for 40 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give compound 9 (173 mg, 90%) as a pale yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.31 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.41 (m, 4H), 4.17 (q, J = 7.3 Hz, 2H), 2.60 (s, 3H), 2.48-1.79 (m, 9H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4- (8-acetyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) -4-cyanocyclohexanecarboxylic acid (Compound 10)
The compound 9 (29.6 mg, 0.0820 mmol) obtained in Example 9 was hydrolyzed in the same manner as in Example 2 to obtain Compound 10 (22.1 mg, 81%) as a pale yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.26 (br, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.40 (m , 4H), 2.53 (s, 3H), 2.36-1.66 (m, 9H).

Cis-4-cyano-4- [8- (1-hydroxyethyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid (Compound 11)
Compound 9 (40.0 mg, 0.112 mmol) obtained in Example 9 was dissolved in a mixed solvent of ethanol (2 mL) and THF (0.80 mL), cooled to −20 ° C., and then sodium borohydride (15.3 mg, 0.404). mmol) was added, and the mixture was stirred at -10 ° C for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). Next, hydrolysis was carried out in the same manner as in Example 2 to obtain Compound 11 (25.3 mg, 68%, 2 steps) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.26 (br, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.91 (m , 1H), 4.30 (m, 4H), 2.35-1.65 (m, 9H), 1.26 (d, J = 6.4 Hz, 3H).

Cis-4-cyano-4- (8-isopropenyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 12)
Dissolve methyltriphenylphosphonium bromide (482 mg, 1.35 mmol) in THF (8 mL) under argon flow, add tert-butoxypotassium (151 mg, 1.35 mmol) under ice-cooling, and stir for 30 minutes did. Compound 9 (200 mg, 0.562 mmol) obtained in Example 9 was added to the obtained solution, and the mixture was stirred at room temperature for 1.3 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 12 (128 mg, 64%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.85 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.18 (m, 1H), 5.09 (m, 1H ), 4.21 (m, 4H), 4.17 (q, J = 7.3 Hz, 2H), 2.48-1.81 (m, 9H), 2.10 (m, 3H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-isopropenyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 13)
The compound 11 (40.0 mg, 0.113 mmol) obtained in Example 11 was hydrolyzed in the same manner as in Example 2 to obtain Compound 13 (35.2 mg, 95%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.26 (br, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.14 (m , 1H), 5.06 (m, 1H), 4.31 (m, 4H), 2.36-1.64 (m, 9H), 2.04 (m, 3H).

Cis-4-cyano-4- (8-isopropyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 14)
Compound 12 (41.9 mg, 0.118 mmol) obtained in Example 12 was subjected to catalytic reduction in the same manner as in Example 5 to obtain cis-4-cyano-4- (8-isopropyl-2,3-dihydrobenzo-1 , 4-Dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (48.1 mg) was obtained. Subsequently, 39.2 mg was hydrolyzed in the same manner as in Example 2 to obtain Compound 14 (29.9 mg, 94%, 2 steps) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.25 (br, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 4.30 (m , 4H), 3.16 (septd, J = 6.9 Hz, 1H), 2.35-1.63 (m, 9H), 1.15 (d, J = 6.9 Hz, 6H).

Cis-4-cyano-4- [8- (2-bromo-1-fluoroethyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid ethyl ester (Compound 15)
Compound 3 (2.0 g, 5.9 mmol) obtained in Example 3 was dissolved in dichloromethane (20 mL), N-bromosuccinimide (1.3 g, 7.0 mmol) was added, and further triethylamine, trifluoride was added under ice cooling. A solution of hydrogen halide (1.9 mL, 12 mmol) in dichloromethane (5 mL) was slowly added dropwise. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 15 (2.6 g, 99%).
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 7.00 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 5.87 (ddd, J = 47, 7.7, 3.1 Hz, 1H), 4.35 (brs, 4H), 4.17 (q, J = 7.1 Hz, 2H), 3.80-3.50 (m, 2H), 2.55-2.25 (m, 3H), 2.23-1.75 (m, 6H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [8- (1-fluoroethenyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid ethyl ester (Compound 16)
Compound 15 (2.5 g, 5.7 mmol) obtained in Example 15 was dissolved in THF (50 mL), and a solution of tert-butoxypotassium in THF (1 mol / L; 21 mL, 21 mmol) was added under ice cooling. And stirred at 0 ° C. for 4.5 hours. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 16 (2.2 g, quantitative).
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 7.12 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.33 (dd, J = 53, 2.6 Hz, 1H) , 5.07 (dd, J = 21, 2.6 Hz, 1H), 4.39 (brs, 4H), 4.17 (q, J = 7.1 Hz, 2H), 2.50-1.75 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [8- (1-fluoroethenyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid (Compound 17)
Compound 16 (2.2 g, 6.1 mmol) obtained in Example 16 was dissolved in ethanol (40 mL), 2 mol / L aqueous sodium hydroxide solution (6 mL, 12 mmol) was added under ice cooling, and at room temperature. Stir for 1 hour and then at 40 ° C. for 1 hour. The reaction solution was cooled to 0 ° C., adjusted to pH 2-3 with 2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 100 → 80: 20) to obtain Compound 17 (0.93 g, 46%).
¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 12.3 (brs, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.38 (dd, J = 55, 2.8 Hz, 1H), 5.13 (dd, J = 21, 3.0 Hz, 1H), 4.39 (brs, 4H), 2.40-2.25 (m, 3H), 2.15-1.60 (m, 6H).

Cis-4-cyano-4- [8- (1-fluoroethyl) -2,3-dihydrobenzo-1,4-dioxin-5-yl] cyclohexanecarboxylic acid (Compound 18)
Compound 17 (400 mg, 1.2 mmol) obtained in Example 17 was dissolved in ethyl acetate (12 mL), 10% palladium carbon (50% water-containing product; 80 mg) was added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stir for hours. Celite was added to the reaction solution and stirred, followed by filtration through celite. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from acetonitrile to obtain Compound 18 (142 mmg, 44%).
¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 12.2 (brs, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.84 (dq, J = 47, 6.6 Hz, 1H), 4.34 (brs, 4H), 2.40-2.25 (m, 3H), 2.15-1.60 (m, 6H), 1.54 (dd, J = 24, 6.4 Hz, 3H).

Cis-4-cyano-4- (8-ethynyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 19)
Step 1:
To DMF (1.0 mL), 4-cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester obtained in Reference Example 1 ( 200 mg, 0.433 mmol), triethylamine (175 mg, 1.73 mmol), trimethylsilylacetylene (255 mg, 2.60 mmol) and dichlorobis (triphenylphosphine) palladium (30.4 mg, 0.0433 mmol) are suspended in an argon atmosphere at 70 ° C. And stirred for 4 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give cis-4-cyano-4- (8-trimethylsilylethynyl-2,3-dihydro Benzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (177 mg, quantitative) was obtained as a red-brown oil.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.01 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.36 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 2.45-1.79 (m, 9H), 1.27 (t, J = 7.3 Hz, 3H), 0.25 (s, 9H).
Step 2:
The compound (50.6 mg, 0.123 mmol) obtained above was hydrolyzed in the same manner as in Example 2 to obtain compound 19 (34.0 mg, 89%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.17 (br, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 4.29 (m , 4H), 3.21 (s, 1H), 2.28-1.58 (m, 9H).

Cis-4-cyano-4- (8-formyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 20)
Compound 3 (2.0 g, 5.9 mmol) obtained in Example 3 was dissolved in a mixed solvent of THF (60 mL) and water (2.0 mL), and a 2.5% tert-butanol solution of osmium tetroxide (2.2%) was cooled with ice. (mL, 0.18 mmol) and sodium periodate (2.5 g, 12 mmol) were added, followed by stirring at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 100 → 80: 20) to give compound 20 (1.3 g, 65%).
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 10.36 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.43 (s, 4H) , 4.17 (q, J = 7.1 Hz, 2H), 2.55-1.75 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- (8-hydroxymethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 21)
Compound 20 (100 mg, 0.29 mmol) obtained in Example 20 was dissolved in a mixed solvent of ethanol (1.0 mL) and THF (1.0 mL), and sodium borohydride (17 mg, 0.44 mmol) was added under ice cooling. After the addition, the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 21 (100 mg, quantitative).
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 6.89 (s, 2H), 4.66 (brs, 2H), 4.36 (s, 4H), 4.12 (q, J = 7.3 Hz, 2H), 2.50-1.75 ( m, 9H), 1.26 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-methoxymethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid methyl ester (Compound 22)
Step 1:
Compound 21 (100 mg, 0.29 mmol) obtained in Example 21 was dissolved in chloroform (3.0 mL), methanesulfonyl chloride (0.034 mL, 0.43 mmol) and triethylamine (0.061 mL, 0.43 mmol) were added, and at room temperature. Stir for 1.5 hours. 2 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain cis-4-cyano-4- (8-methanesulfonyloxymethyl-2,3-dihydrobenzo-1,4-dioxin-5- Yl) cyclohexanecarboxylic acid ethyl ester (100 mg, 82%) was obtained.
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 6.98 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 4.37 (s, 4H) , 4.17 (q, J = 7.1 Hz, 2H), 3.00 (s, 3H), 2.50-1.75 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).
Step 2:
The compound (100 mg, 0.24 mmol) obtained above was dissolved in methanol (5.0 mL), 28% sodium methoxide-methanol solution (0.15 mL, 0.71 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 22 (71 mg, 87%).
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 4.44 (s, 2H), 4.34 (s, 4H) , 3.71 (s, 3H), 3.41 (s, 3H), 2.55-1.75 (m, 9H).

Cis-4-cyano-4- (8-methoxymethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 23)
Compound 22 (70 mg, 0.20 mmol) obtained in Example 22 was dissolved in methanol (4.0 mL), 2 mol / L aqueous sodium hydroxide solution (0.20 mL, 0.41 mmoL) was added, and the mixture was stirred at 40 ° C. for 2 hours. did. The reaction mixture was concentrated under reduced pressure, 2 mol / L hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to obtain Compound 23 (14 mg, 22%).
¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 6.91 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 4.36 (s, 2H), 4.31 (s, 4H), 3.30 (s, 3H), 2.45-1.60 (m, 9H).

Cis-4-cyano-4- (8-fluoromethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 24)
The cis-4-cyano-4- (8-hydroxymethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (510 mg, 1.5 mmol) obtained in Example 21 was used. Dissolved in dichloromethane (8.0 mL) and cooled to −78 ° C. under an argon atmosphere. To this solution was added a solution of [bis (2-methoxymethyl) amino] sulfatrifluoride (0.30 mL, 1.6 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at −78 ° C. for 1 hour. After returning the reaction solution to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 24 (513 mg, quantitative).

Cis-4-cyano-4- (8-fluoromethyl-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 25)
Compound 24 (513 mg, 1.5 mmol) obtained in Example 24 was dissolved in ethanol (10 mL), 1 mol / L aqueous sodium hydroxide solution (3.2 mL, 3.2 mmol) was added, and the mixture was stirred at 40 ° C. for 5 hours. did. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. 2 mol / L hydrochloric acid was added to the aqueous layer, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from acetonitrile to obtain Compound 25 (40 mg, 8%).
¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 12.3 (brs, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.37 (d, J = 48 Hz, 2H), 4.35 (s, 4H), 2.45-1.60 (m, 9H).

Cis-4- (8-amino-2,3-dihydrobenzo-1,4-dioxin-5-yl) -4-cyanocyclohexanecarboxylic acid ethyl ester (Compound 26)
To THF (2 mL), 4-cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester obtained in Reference Example 1 ( 200 mg, 0.433 mmol), palladium acetate (11.6 mg, 0.0517 mmol), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (48.4 mg, 0.0777 mmol), cesium carbonate (198 mg, 0.608 mmol) and benzophenone imine (94.1 mg, 0.597 mmol) were added, and the mixture was heated to reflux for 12 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was divided into two equal parts. Methanol (3 mL), 10% palladium carbon (50% water-containing product; 32 mg) and ammonium formate (406 mg, 6.44 mmol) were added to one of them and heated under reflux for 4 hours. After extraction with chloroform, the organic layer was washed with 0.1 mol / L aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give compound 26 (25.1 mg, 35%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.69 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 4.33 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 3.76 (br, 2H), 2.45-1.76 (m, 9H), 1.27 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-methylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 27)
In ethyl acetate (0.5 mL), compound 26 (10.0 mg, 0.0303 mmol) obtained in Example 26, 10% palladium carbon (50% water-containing product; catalytic amount) and 38% formaldehyde aqueous solution (23.9 mg, 0.0302 mmol) were added. In addition, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give compound 27 (9.6 mg, 92%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.79 (d, J = 8.6 Hz, 1H), 6.18 (d, J = 8.6 Hz, 1H), 4.31 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 2.85 (s, 3H), 2.46-1.77 (m, 9H), 1.27 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-methylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 28)
Compound 28 (4.9 mg, 56%) was obtained as a white solid by hydrolyzing the compound 27 (9.5 mg, 0.028 mmol) obtained in Example 27 in the same manner as in Example 2.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 12.26 (br, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.19 (d, J = 8.6 Hz, 1H), 4.33 (m, 4H ), 2.85 (s, 3H), 2.47-1.80 (m, 9H).

Cis-4-cyano-4- (8-dimethylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 29)
In ethyl acetate (1.0 mL), compound 26 (20.0 mg, 0.0605 mmol) obtained in Example 26, 10% palladium carbon (50% water-containing product; catalytic amount) and 38% formaldehyde aqueous solution (95.6 mg, 1.21 mmol) were added. In addition, the mixture was stirred at room temperature for 83 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give compound 29 (20.1 mg, 93%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.82 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 4.36 (m, 4H), 4.16 (q, J = 7.3 Hz, 2H), 2.78 (s, 6H), 2.47-1.79 (m, 9H), 1.27 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- (8-dimethylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 30)
The compound 29 (19.0 mg, 0.0530 mmol) obtained in Example 29 was hydrolyzed in the same manner as in Example 2 to obtain compound 30 (14.3 mg, 82%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.24 (br, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 4.29 (m , 4H), 2.68 (s, 6H), 2.34-1.63 (m, 9H).

Cis-4-cyano-4- (8-formylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester (Compound 31)
Under an argon atmosphere, formic acid (100 mg, 2.17 mmol) was dissolved in dichloromethane (2 mL), and EDC · HCl (209 mg, 1.09 mmol) was added under ice cooling, followed by stirring for 15 minutes. The compound 26 (30.0 mg, 0.0909 mmol) obtained in Example 26 and N-methylmorpholine (91.9 mg, 0.909 mmol) were added here, and it stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain Compound 31.

Cis-4-cyano-4- (8-formylamino-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid (Compound 32)
Compound 31 obtained in Example 31 was hydrolyzed in the same manner as in Example 2 to obtain Compound 32 (12.5 mg, 42%, 2 steps from Example 31) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 12.22 (br, 1H), 9.68 (s, 1H), 8.27 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.35 (m, 4H), 2.34-1.64 (m, 9H).

Cis-4-cyano-4- [2 ', 3', 5 ', 6'-tetrahydrospiro (7-methoxy-1,3-benzodioxol-2,4'-thiopyran) -4-yl] cyclohexane Carboxylic acid ethyl ester (Compound 33)
Step 1:
2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro (4-bromo-7-methoxy-1,3-benzodioxol-2,4′-thiopyran) obtained in Reference Example 3 (1.50 g, 4.75 mmol) was dissolved in THF (15 mL) and cooled to −78 ° C., and then n-butyllithium (1.56 mol / L n-hexane solution 3.26 mL, 5.22 mmol) was added dropwise under a nitrogen stream. After stirring at the same temperature for 30 minutes, the obtained mixture was added dropwise to a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (808 mg, 4.75 mmol) in THF (8 mL) at −78 ° C. under a nitrogen stream. After stirring at the same temperature for 1.5 hours, the mixture was poured into a mixed aqueous solution of ice and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give 4-hydroxy-4- [2 ', 3', 5 ', 6' -Tetrahydrospiro (7-methoxy-1,3-benzodioxol-2,4'-thiopyran) -4-yl] cyclohexanecarboxylic acid ethyl ester (1.06 g, 52.2%) was obtained as a white amorphous.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.90-6.80 (m, 1H), 6.52-6.44 (m, 1H), 4.22-4.10 (m, 2H), 3.88 (s, 3H), 2.97-2.75 (m, 4H), 2.66-2.58 (m, 0.5H), 2.40-2.15 (m, 5H), 2.10-1.83 (m, 6.5H), 1.72-1.60 (m, 1H), 1.34-1.22 (m, 3H).
Step 2:
The compound obtained above (300 mg, 73.4 mmol) was dissolved in dichloromethane (6 mL) and cooled to −78 ° C. under a nitrogen stream. Trimethylsilyl cyanide (0.685 mL, 514 mmol) and then boron trifluoride diethyl ether complex (0.051 mL, 58.7 mmol) were added thereto, and the mixture was stirred for 10 minutes and then heated to 0 ° C. After stirring at the same temperature for 2 hours, boron trifluoride diethyl ether complex (0.045 mL, 51.4 mmol) was further added. After further stirring at the same temperature for 3 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain Compound 33 (0.164 g, 53.6%) as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.90 (d, J = 9.0 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H ), 3.89 (s, 3H), 2.92-2.84 (m, 4H), 2.35-2.10 (m, 9H), 2.07-1.92 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 ', 1'-dioxide-2', 3 ', 5', 6'-tetrahydrospiro (7-methoxy-1,3-benzodioxole-2,4'- Thiopyran) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 34)
Compound 33 (0.361 g, 0.866 mmol) obtained in Example 33 was dissolved in ethyl acetate (12 mL), cooled to 0 ° C., 3-chloroperbenzoic acid (0.505 g, 1.91 mmol) was added, and room temperature was reached. The temperature rose. After stirring at the same temperature for 12 hours, an aqueous sodium sulfite solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium sulfite solution, an aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from acetone-diisopropyl ether to obtain Compound 34 (0.359 g, 92.4%) as white crystals.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.90 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H ), 3.90 (s, 3H), 3.36-3.28 (m, 4H), 2.67-2.60 (m, 4H), 2.40-2.26 (m, 3H), 2.22-2.15 (m, 2H), 2.17-1.82 (m , 4H), 1.29 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 ', 1'-dioxide-2', 3 ', 5', 6'-tetrahydrospiro (7-methoxy-1,3-benzodioxole-2,4'- Thiopyran) -4-yl] cyclohexanecarboxylic acid (Compound 35)
Compound 34 (0.340 g, 0.757 mmol) obtained in Example 34 was suspended in 1,4-dioxane (6 mL), 1 mol / L aqueous potassium hydroxide solution (3.02 mL, 3.03 mmol) was added, and 5 at room temperature was added. Stir for hours. After the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1 mol / L hydrochloric acid, and the precipitated crystals were collected by filtration to give compound 35 (0.290 g, 87.1%) as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.91 (d, J = 9.0 Hz, 1H), 6.57 (d, J = 9.0 Hz, 1H), 3.91 (s, 3H), 3.38-2.98 (m, 4H), 2.68-2.60 (m, 4H), 2.47-2.28 (m, 3H), 2.28-2.17 (m, 2H), 2.12-1.84 (m, 4H).

Cis-4-cyano-4- [4 ', 5'-dihydrospiro (7-methoxy-1,3-benzodioxol-2,3'-thiophene) -4-yl] cyclohexanecarboxylic acid ethyl ester (compound 36)
Step 1:
4 ', 5'-dihydrospiro (4-bromo-7-methoxy-1,3-benzodioxole-2,3'-thiophene (2.66 g, 8.77 mmol) obtained in Reference Example 2 was added to THF (40 mL). ) And then cooled to −70 ° C. under a nitrogen atmosphere, where n-butyllithium (1.56 mol / L n-hexane solution, 6.19 mL, 9.65 mmol) was added dropwise at an internal temperature of −60 ° C. or lower. The mixture was stirred for 30 minutes at −70 ° C. The obtained mixture was added dropwise to a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (1.40 mL, 8.77 mmol) in THF (30 mL) at −70 ° C. over 1.5 hours. The resulting mixture was stirred at −70 ° C. for 2 hours and then quenched with saturated aqueous ammonium chloride, and 2 mol / L hydrochloric acid (4.40 mL, 2.20 mmol) was added to bring the solution to near neutrality. After adjustment, the mixture was extracted 3 times with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 4-hydroxy-4- [4 ', 5'-dihydrospiro (7-methoxy-1,3-benzodioxole-) by purification by chromatography (n-hexane: ethyl acetate = 4: 1) 2,3′-thiophen) -4-yl] cyclohexanecarboxylic acid ethyl ester (1.76 g, 51%) was obtained as a mixture of cis: trans = 1: 1.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.89 (d, J = 8.8 Hz, 0.5H), 6.86 (d, J = 8.8 Hz, 0.5H), 6.51 (d, J = 9.2 Hz, 0.5 H), 6.50 (d, J = 8.8 Hz, 0.5H), 4.19-4.08 (m, 2H), 3.88 (s, 3H), 3.28-3.16 (m, 2H), 3.05-3.00 (m, 2H), 2.65-2.55 (m, 0.5H), 2.46-2.40 (m, 2H), 2.35-1.72 (m, 8.5H), 1.29-1.24 (m, 3H).
Step 2:
The compound obtained above (1.76 g, 4.46 mmol) was dissolved in dichloromethane (35 mL), trimethylsilyl cyanide (2.97 mL, 22.3 mmol) was added, and the reaction solution was cooled to −70 ° C. under a nitrogen atmosphere. . Boron trifluoride diethyl ether complex (0.55 mL, 4.46 mmol) was added, and the temperature was gradually raised to 0 ° C., followed by stirring at 0 ° C. for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 6: 1) and then triturated with ethanol to give Compound 36 (0.67 g, 37%) as a white solid. .
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.96 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.28 (d, J = 12.0 Hz, 1H), 3.21 (d, J = 11.9 Hz, 1H), 3.03 (t, J = 6.9 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.40-2.00 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [4 ′, 5′-dihydrospiro (7-methoxy-1,3-benzodioxol-2,3′-thiophene) -4-yl] cyclohexanecarboxylic acid (Compound 37)
Compound 36 (0.67 g, 1.66 mmol) obtained in Example 36 was dissolved in ethanol (10 mL), 4 mol / L aqueous potassium hydroxide solution (1.7 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction solution was cooled to 0 ° C., water (11 mL) and 2 mol / L hydrochloric acid (5 mL) were added, and the mixture was stirred at the same temperature for 30 min. The precipitated solid was collected by filtration to give compound 37 (0.63 g, quantitative) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.88 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.20 (s , 2H), 3.01-2.92 (m, 2H), 2.39 (t, J = 6.9 Hz, 2H), 2.35-1.65 (m, 9H).

Cis-4-cyano-4- [1 ', 1'-dioxide-4', 5'-dihydrospiro (7-methoxy-1,3-benzodioxol-2,3'-thiophene) -4-yl ] Cyclohexanecarboxylic acid (Compound 38)
Compound 37 (0.11 g, 0.29 mmol) obtained in Example 37 was dissolved in dichloromethane (3 mL), 3-chloroperbenzoic acid (65%, 0.17 g, 0.64 mmol) was added, and the mixture was stirred overnight at room temperature. did. The reaction solution was cooled to 0 ° C., 0.5 mol / L aqueous sodium sulfite solution (3.0 mL) was added, and 2 mol / L hydrochloric acid was further added to acidify the reaction solution. The resulting solution was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue, and the precipitated crystals were collected by filtration to give compound 38 (0.027 g, 23%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.95 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 3.89-3.77 (m, 2H), 3.83 (s, 3H), 3.61-3.49 (m, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.37-1.59 (m, 9H).

Cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 39)
Step 1:
4-Bromo-7-methoxy-1'-benzylspiro (1,3-benzodioxole-2,3'-pyrrolidine (1.67 g, 4.45 mmol) obtained in Reference Example 4 was dissolved in THF (40 mL). After cooling to −78 ° C. under an argon atmosphere, n-butyllithium (1.58 mol / L n-hexane solution; 3.4 mL, 5.4 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. To a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (0.83 g, 4.9 mmol) in THF (40 mL) was added dropwise at −78 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 1.5 hours and further at room temperature for 1 hour. On the other hand, the same reaction was repeated using 4-bromo-7-methoxy-1'-benzylspiro (1,3-benzodioxole-2,3'-pyrrolidine (1.67 g, 4.45 mmol). Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and both were combined, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). Spiro (7-methoxy-1,3-benzodioxol-2,3′-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (2.19 g) was used in the next reaction without purification.
Step 2:
The compound (2.08 g) obtained above and trimethylsilyl cyanide (7.1 mL, 53 mmol) were dissolved in dichloromethane (30 mL), cooled to −78 ° C., and boron trifluoride diethyl ether complex ( 1.2 mL, 9.8 mmol) was added, and the mixture was stirred at 0 ° C. for 1.5 hours. To the reaction solution was added 0.5 mol / L aqueous sodium hydroxide solution (30 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 39 (0.70 g, 14%, 2 steps) as a yellow oily liquid. .
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33-7.26 (m, 5H), 6.93 (d, J = 8.8 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.17 (q , J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.70 (d, J = 13.2 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.01 (d, J = 10.9 Hz, 1H ), 2.94 (d, J = 10.9 Hz, 1H), 2.90-2.72 (m, 2H), 2.44-1.89 (m, 11H), 1.29 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 40)
Compound 39 (0.063 g, 0.13 mmol) obtained in Example 39 was dissolved in ethanol (1.0 mL), 6 mol / L aqueous potassium hydroxide solution (0.20 mL) was added, and the mixture was stirred at room temperature for 9 hr. The reaction solution was cooled to 0 ° C., 4 mol / L hydrochloric acid was added to adjust the pH to 6.7, and the solvent was evaporated under reduced pressure. Chloroform was added to the residue, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give compound 40 (0.031 g, 53%) as a white solid.
¹ H NMR (270 MHz, CD ₃ OD) δ (ppm) 7.38-7.25 (m, 5H), 6.88 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 9.0 Hz, 1H), 3.85 ( s, 3H), 3.69 (s, 2H), 2.98 (d, J = 11.1 Hz, 1H), 2.94 (d, J = 11.1 Hz, 1H), 2.82 (t, J = 7.2 Hz, 2H), 2.39 ( t, J = 7.2 Hz, 2H), 2.24-1.85 (m, 9H).

Cis-4-cyano-4- [spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 41)
Compound 39 (0.69 g, 1.4 mmol) obtained in Example 39 was dissolved in 1,2-dichloroethane (50 mL), and (1-chloroethyl) chloroformate (0.46 g, 3.2 mmol) was added under an argon atmosphere. The mixture was heated to reflux for 1 hour. After the solvent was distilled off under reduced pressure, methanol (40 mL) was added to the resulting residue, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to obtain Compound 41 (0.29 g, 51%) as a red oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.94 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.38-3.26 (m, 4H), 2.40-1.98 (m, 11H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 42)
Compound 41 (0.31 g, 0.80 mmol) obtained in Example 41 was hydrolyzed in the same manner as in Example 40 to obtain Compound 42 (0.29 g, quantitative) as a white solid.
¹ H NMR (270 MHz, CD ₃ OD) δ (ppm) 6.89 (d, J = 8.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H), 3.64 (s, 2H), 3.56 (t, J = 7.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 2.36-1.71 (m, 9H).

Cis-4-cyano-4- [1'-methylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 43)
Compound 41 (0.52 g, 1.4 mmol) obtained in Example 41 was dissolved in ethyl acetate (40 mL), and 10% palladium on carbon (50% water-containing product; catalytic amount) and 38% aqueous formaldehyde solution (0.85 g, 11 mmol). ) Was added and stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give compound 43 (0.39 g, 72%) as a red-brown oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.07 (d, J = 10.9 Hz, 1H), 2.89 (d, J = 10.9 Hz, 1H), 2.87-2.63 (m, 2H), 2.44-1.98 (m, 11H), 2.40 (s, 3H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1'-methylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 44)
Compound 43 (0.39 g, 0.98 mmol) obtained in Example 43 was hydrolyzed in the same manner as in Example 40, and triturated with ethanol to obtain Compound 44 (0.19 g, 52%) as a white solid. It was.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.92 (d, J = 8.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H), 3.69 (s , 2H), 3.11 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.96-2.80 (m, 2H), 2.48-1.79 (m, 9H), 2.46 (s, 3H).

Cis-4-cyano-4- [spiro (7-methoxy-1,3-benzodioxole-2,2'-bicyclo [2.2.1] heptane) -4-yl] cyclohexanecarboxylic acid ethyl ester (compound 45 )
Step 1:
Spiro (4-bromo-7-methoxy-1,3-benzodioxole-2,2'-bicyclo [2.2.1] heptane) (6.00 g) obtained in Reference Example 5 was dissolved in THF (48 mL). After cooling to −68 ° C. under an argon atmosphere, n-butyllithium (1.58 mol / L n-hexane solution; 9.0 mL, 14 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Triisopropoxytitanium chloride (1.0 mol / L n-hexane solution; 19 mL, 19 mmol) was added dropwise to the resulting reaction solution at the same temperature, followed by stirring at −20 to −4 ° C. for 1 hour, and then 4- Oxocyclohexanecarboxylic acid ethyl ester (1.85 mL, 11.6 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was ice-cooled and then poured into a mixture of 0.4 mol / L hydrochloric acid (113 mL) and ice to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed 3 times with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2.5: 1). The resulting cis-4-hydroxy-4- [spiro (7-methoxy-1,3-benzodioxole-2,2'-bicyclo [2.2.1] heptane) -4-yl] cyclohexanecarboxylic acid ethyl ester (3.48 g) was used in the next reaction without purification.
Step 2:
The compound (3.48 g) obtained above and trimethylsilyl cyanide (2.3 mL, 17 mmol) were dissolved in dichloromethane (60 mL), cooled to −78 ° C., and then boron trifluoride diethyl ether complex ( 1.1 mL, 8.7 mmol) was added, and the mixture was stirred at the same temperature for 55 minutes, and further stirred at 0 ° C. for 1.5 hours. To the reaction solution was added 1 mol / L aqueous sodium hydroxide solution (40 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1 mol / L aqueous sodium hydroxide solution, three times with water and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to obtain Compound 45 (1.54 g, 18%, 3 steps) as a pale yellow oily liquid. It was.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) {6.92 (d, J = 8.9 Hz, major isomer), 6.90 (d, J = 8.8 Hz, minor isomer) (total 1H)}, {6.48 (d, J = 8.8 Hz, minor isomer), 6.48 (d, J = 8.9 Hz, major isomer) (total 1H)}, {4.17 (q, J = 7.2 Hz, minor isomer), 4.17 (q , J = 7.2 Hz, main isomer) (total 2H)}, {3.89 (s, main isomer), 3.88 (s, minor isomer) (total 3H)}, 2.46-1.36 (m, 19H), { 1.28 (t, J = 7.2 Hz, minor isomer), 1.28 (t, J = 7.2 Hz, main isomer) (total 3H)}.

Cis-4-cyano-4- [spiro (7-methoxy-1,3-benzodioxole-2,2'-bicyclo [2.2.1] heptane) -4-yl] cyclohexanecarboxylic acid (Compound 46)
Compound 45 (307 mg, 0.75 mmol) obtained in Example 45 was dissolved in ethanol (7.0 mL), 4 mol / L aqueous potassium hydroxide solution (0.75 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was cooled to 0 ° C., 6 mol / L hydrochloric acid was added, water (9.5 mL) was added, and the mixture was stirred for 1.3 hr. The precipitated solid was collected by filtration, and the obtained solid was washed with water and dried under reduced pressure to obtain Compound 46 (272 mg, 95%, diastereomer ratio 3: 1) as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 12.27 (brs, 1H), 6.83 (d, J = 8.8 Hz, 0.75H), 6.82 (d, J = 8.8 Hz, 0.25H), 6.65 (d, J = 8.8 Hz, 0.25H), 6.64 (d, J = 8.8 Hz, 0.75H), 3.81 (s, 2.25H), 3.80 (s, 0.75H), 2.38-1.37 (m, 19H).

Cis-4-cyano-4- [1 '-(2-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 47)
Compound 41 (0.090 g, 0.23 mmol) obtained in Example 41 was dissolved in 1,2-dichloroethane (1.5 mL), o-anisaldehyde (0.038 g, 0.28 mmol) and sodium triacetoxyborohydride (0.099 g). , 0.46 mmol) and stirred at room temperature for 7 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain Compound 47 (0.070 g, 61%) as a colorless oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 7.67 (td, J = 7.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.8, 1.2 Hz, 1H), 7.17 (ddd, J = 7.8, 4.8, 1.2 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.15-2.87 (m, 3H), 2.47-2.41 (m, 3H), 2.20-1.97 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 48)
Compound 47 (0.070 g, 0.14 mmol) obtained in Example 47 was treated according to the method described in Example 40 to give Compound 48 (0.047 g, 71%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33-7.20 (m, 2H), 7.10 (d, J = 8.9 Hz, 1H), 6.97-6.88 (m, 2H), 6.51 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.99-3.82 (m, 2H), 3.52-3.37 (m, 2H), 2.82-1.93 (m, 13H).

Cis-4-cyano-4- [1 '-(4-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 49)
Using compound 41 (0.104 g, 0.27 mmol) obtained in Example 41 and p-anisaldehyde (0.044 g, 0.32 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 2: 1) gave Compound 49 (0.079 g, 58%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.30 (dd, J = 2.2, 8.8 Hz, 2H), 6.90 (dd, J = 2.2, 8.8 Hz, 2H), 6.85 (dd, J = 1.8, 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 4.17 (dd, J = 7.4, 14.3 Hz, 2 H), 3.88 (s, 3H), 3.79 (s , 3H), 3.61 (brd, J = 2.2 Hz, 2H), 2.96 (dd, J = 1.0, 13.9 Hz, 2H), 2.84-2.72 (m, 2H), 2.43-2.33 (m, 3H), 2.22- 2.08 (m, 2H), 2.04-1.93 (m, 2H), 1.69-1.62 (m, 2H), 1.29 (t, J = 7.4 Hz, 3H).

Cis-4-cyano-4- [1 '-(4-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 50)
Compound 49 (0.079 g, 0.16 mmol) obtained in Example 49 was treated according to the method described in Example 40 and triturated with diethyl ether to give Compound 50 (0.057 g, 75%). Obtained as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.18 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.9 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.75 (dd, J = 12.6, 38.1 Hz, 1H), 3.48 (dd, J = 7.1, 14.1 Hz , 1H), 3.44 (d, J = 11.2 Hz, 1H), 3.41-3.35 (m, 1H), 2.71 (d, J = 11.2 Hz, 1H), 2.61-2.42 (m, 4H), 2.26-2.15 ( m, 4H), 2.07-1.94 (m, 4H).

Cis-4-cyano-4- [1 '-(3-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 51)
Using compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and m-anisaldehyde (0.044 g, 0.32 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 2: 1) gave Compound 51 (0.080 g, 57%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.36 (t, J = 8.1 Hz, 1H), 6.94-6.90 (m, 2H), 6.81-6.78 (m, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.68 (d, J = 12.8 Hz, 1H), 3.62 (d, J = 12.8 Hz, 1H), 3.04-2.76 (m, 3H), 2.44-2.36 (m, 3H), 2.20-1.93 (m, 9H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(3-methoxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 52)
Compound 51 (0.036 g, 48%) was obtained as a white solid by treating Compound 51 (0.080 g, 0.16 mmol) obtained in Example 51 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.28-7.22 (m, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.87-6.83 (m, 3H), 6.51 (d, J = 8.9 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.83-3.67 (m, 4H), 3.46-3.38 (m, 2H), 2.75-1.94 (m, 11H).

Cis-4-cyano-4- [1 '-(2-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 53)
Reaction was carried out according to the method described in Example 47 using Compound 41 (0.10 g, 0.26 mmol) and 2-fluorobenzaldehyde (0.033 mL, 0.31 mmol) obtained in Example 41, and silica gel column chromatography (n By purifying with -hexane: ethyl acetate = 5: 1 to 3: 1), Compound 53 (0.11 g, 85%) was obtained as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.43-7.37 (m, 1H), 7.29-7.21 (m, 1H), 7.13-7.00 (m, 2H), 6.93 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.76 (brs, 2H), 3.06 (d, J = 11.0 Hz, 1H), 2.98 (d, J = 10.9 Hz, 1H), 2.88-2.79 (m, 2H), 2.43-1.92 (m, 11H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 54)
The compound 53 (0.11 g, 0.22 mmol) obtained in Example 53 was treated according to the method described in Example 40 to obtain a compound 54 (0.080 g, 78%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33-7.28 (m, 2H), 7.16-7.04 (m, 3H), 6.51 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H) , 3.95-3.84 (m, 2H), 3.49-3.38 (m, 2H), 2.79-1.93 (m, 13H).

Cis-4-cyano-4- [1 '-(3-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester Hydrochloride (Compound 55)
The reaction was performed according to the method described in Example 47, using Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and 3-fluorobenzaldehyde (0.039 g, 0.31 mmol). The obtained crude product is dissolved in ethyl acetate, hydrochloric acid (4 mol / L ethyl acetate solution, 0.5 mL, 2.0 mmol) is added, the solvent is distilled off, diethyl ether is added and the precipitated solid is collected by filtration. This gave compound 55 (0.11 g, 35%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.45 (m, 1H), 7.30 (m, 2H), 7.18 (m, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.68 (d , J = 8.9 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.65-3.25 (m, 6H), 2.65-1.83 (m, 11H), 1.27 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(3-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 56)
Compound 56 (0.079 g, 80%) was obtained as a white solid by treating compound 55 (0.10 g, 0.20 mmol) obtained in Example 55 according to the method described in Example 40.
¹ H NMR (270 MHz, CD ₃ OD) δ (ppm) 7.43 (m, 1H), 7.28 (m, 2H), 7.17 (m, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.42 ( d, J = 8.9 Hz, 1H), 4.43 (s, 2H), 3.78 (s, 3H), 3.78 (s, 2H), 3.62 (t, J = 7.3 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.36-1.70 (m, 9H).

Cis-4-cyano-4- [1 '-(4-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 57)
Reaction was performed according to the method described in Example 47 using Compound 41 (0.10 g, 0.26 mmol) and 4-fluorobenzaldehyde (0.33 mL, 0.31 mmol) obtained in Example 41, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 5: 1 to 3: 1) gave Compound 57 (0.10 g, 77%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33-7.25 (m, 2H), 7.03-6.94 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.48 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.63 (brs, 2H), 2.97 (d, J = 10.9 Hz, 1H), 2.95 (d, J = 10.9 Hz, 1H), 2.82-2.74 (m, 2H), 2.44-1.98 (m, 11H), 1.29 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(4-fluorobenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 58)
Compound 58 (0.089 g, 95%) was obtained as a white solid by treating Compound 57 (0.10 g, 0.20 mmol) obtained in Example 57 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.26-7.22 (m, 2H), 7.10-7.00 (m, 3H), 6.52 (d, J = 9.2 Hz, 1H), 3.89 (s, 3H) , 3.84 (d, J = 12.8 Hz, 1H), 3.70 (d, J = 12.8 Hz, 1H), 3.43-3.34 (m, 2H), 2.74-1.94 (m, 13H).

Cis-4-cyano-4- [1 '-(2-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 59)
The reaction was conducted according to the method described in Example 47 using Compound 41 (0.32 g, 0.83 mmol) and 2-hydroxybenzaldehyde (0.121 g, 0.99 mmol) obtained in Example 41, and silica gel column chromatography (chloroform ) To obtain Compound 59 (0.36 g, 87%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.21-7.13 (m, 1H), 7.02-6.94 (m, 2H), 6.87-6.73 (m, 2H), 6.50 (d, J = 8.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.94 (d, J = 12.7 Hz, 1H), 3.88 (s, 3H), 3.79 (d, J = 12.7 Hz, 1H), 3.18-2.79 ( m, 4H), 2.56-2.41 (m, 3H), 2.27-1.88 (m, 8H), 1.29 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 114)
The compound 59 (0.34 g, 0.69 mmol) obtained in Example 59 was treated according to the method described in Example 40, whereby Compound 60 (0.14 g, 44%) was obtained as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.19-7.04 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.81-6.72 (m, 2H), 6.68 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 2H), 2.95 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 2.86-2.70 ( m, 2H), 2.40-2.16 (m, 5H), 2.10-1.85 (m, 4H), 1.76-1.63 (m, 2H).

Cis-4-cyano-4- [1 '-(3-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 61)
Using compound 41 (0.090 g, 0.23 mmol) and 3-hydroxybenzaldehyde (0.034 g, 0.28 mmol) obtained in Example 41, the reaction was carried out according to the method described in Example 47, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 1: 1) gave Compound 61 (0.053 g, 46%).
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.12 (t, J = 7.7 Hz, 1H), 7.06 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.75-6.67 (m , 2H), 6.48 (d, J = 8.8 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (s, 3H), 2.75-1.89 (m, 11H), 1.29 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(3-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 62)
The compound 61 (0.053 g, 0.11 mmol) obtained in Example 61 was treated according to the method described in Example 40, whereby Compound 62 (0.047 g, 92%) was obtained as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.10 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.77-6.61 (m, 4H), 3.80 (s, 3H), 3.55 (s, 2H), 2.92-2.80 (m, 2H), 2.77-2.65 (m, 2H), 2.39-2.17 (m, 5H), 2.10-2.00 (m, 2H), 1.97 -1.81 (m, 2H), 1.76-1.63 (m, 2H).

Cis-4-cyano-4- [1 '-(4-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 63)
The reaction was performed according to the method described in Example 47 using Compound 41 (0.100 g, 0.26 mmol) and 4-hydroxybenzaldehyde (0.038 g, 0.31 mmol) obtained in Example 41, and silica gel column chromatography (chloroform : Compound 63 (0.068 g, 54%) was obtained by purification with methanol = 9: 1).
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.13 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.8 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.60 (s, 2H), 3.07 (d, J = 11.0 Hz, 1H), 2.98-2.84 (m, 2H), 2.82-2.70 (m, 1H), 2.47-1.86 (m, 11H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(4-hydroxybenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 64)
The compound 63 (0.068 g, 0.14 mmol) obtained in Example 63 was treated according to the method described in Example 40, whereby Compound 64 (0.039 g, 60%) was obtained as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.10 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.74-6.64 (m, 3H), 3.80 (s, 3H), 3.51 (s, 2H), 2.83 (s, 2H), 2.76-2.63 (m, 2H), 2.36-2.17 (m, 5H), 2.10-1.99 (m, 2H), 1.95-1.82 (m, 2H), 1.76-1.63 (m, 2H).

Ethyl cis-4-cyano-4- [1 '-(2-hydroxymethylbenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 65)
Compound 41 (0.15 g, 0.39 mmol) obtained in Example 41 and the method described in Journal of Organic Chemistry, 1990, Vol. 55, No. 8, p.2325-2332, etc. Using 2-hydroxymethylbenzaldehyde (0.038 g, 0.031 mmol) prepared according to the procedure described above, the reaction was conducted according to the method described in Example 47, and silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) To obtain Compound 65 (0.10 g, 51%).
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.38-7.22 (m, 4H), 6.98 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 4.66 (d , J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.87 (s, 3H), 3.84 (d, J = 12.3 Hz, 1H ), 3.77 (d, J = 12.3 Hz, 1H), 3.06 (d, J = 10.8 Hz, 1H), 3.10-2.94 (m, 1H), 2.87 (d, J = 10.8 Hz, 1H), 2.81-2.70 (m, 1H), 2.62-2.30 (m, 3H), 2.20-1.83 (m, 8H), 1.29 (t, J = 6.9 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-hydroxymethylbenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 66)
Compound 65 (0.050 g, 52%) was obtained as a white solid by treating the compound 65 (0.10 g, 0.20 mmol) obtained in Example 65 according to the method described in Example 40.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.42-7.20 (m, 4H), 7.03 (d, J = 9.0 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 4.72 (d , J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 3.84 (d, J = 12.0 Hz, 1H), 3.75 (d, J = 12.0 Hz, 1H ), 3.18 (d, J = 11.1 Hz, 1H), 3.15-3.05 (m, 1H), 2.76 (d, J = 11.1 Hz, 1H), 2.70-2.50 (m, 2H), 2.33-2.50 (m, 2H), 2.23-1.83 (m, 8H).

Ethyl cis-4-cyano-4- [1 '-(4-hydroxymethylbenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 67)
Compound 41 (0.15 g, 0.39 mmol) obtained in Example 41 and the method described in Journal of Organic Chemistry, 2001, Vol. 66, No. 13, p.4476-4486, etc. Using 4-hydroxymethylbenzaldehyde (0.063 g, 0.47 mmol) prepared according to the procedure described above, the reaction was carried out according to the method described in Example 47, and silica gel column chromatography (n-hexane: ethyl acetate = 2: 3) To obtain Compound 67 (0.13 g, 67%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33 (s, 4H), 6.92 (d, J = 8.9 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 4.68 (s, 2H ), 4.18 (q, J = 7.4 Hz, 2H), 3.88 (s, 3H), 3.70 (d, J = 12.1 Hz, 1H), 3.64 (d, J = 12.1 Hz, 1H), 3.01 (d, J = 8.9 Hz, 1H), 2.94 (d, J = 8.9 Hz, 1H), 2.91-2.72 (m, 2H), 2.47-2.33 (m, 3H), 2.28-1.92 (m, 6H), 1.80-1.59 ( m, 2H), 1.29 (t, J = 7.4 Hz, 3H).

Cis-4-cyano-4- [1 '-(4-hydroxymethylbenzyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 68)
Compound 67 (0.13 g, 0.26 mmol) obtained in Example 67 was treated with an aqueous sodium hydroxide solution according to the method described in Example 40, and then the reaction solution was neutralized with dilute hydrochloric acid to give compound 68 ( 0.039 g, 31%) was obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.35 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.70 (s, 2H), 3.89 (s, 3H), 3.84 (d, J = 12.7 Hz, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.49-3.36 (m, 4H), 2.73 (d, J = 11.0 Hz, 1H), 2.65-1.83 (m, 10H).

Ethyl cis-4-cyano-4- [1 '-(pyridin-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 69)
Using compound 41 (0.099 g, 0.26 mmol) obtained in Example 41 and 2-pyridinecarboxaldehyde (33.4 mg, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 2: 1) gave Compound 69 (0.11 g, 89%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.54 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.67 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.19-7.15 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H) , 3.88 (s, 3H), 3.84 (s, 2H), 3.15-2.81 (m, 3H), 2.57-2.35 (m, 3H), 2.24-1.89 (m, 9H), 1.29 (t, J = 7.1 Hz , 3H).

Cis-4-cyano-4- [1 '-(pyridin-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 70)
Compound 70 (0.080 g, 75%) was obtained as a white solid by treating compound 69 (0.11 g, 0.24 mmol) obtained in Example 69 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.59 (brd, J = 5.1 Hz, 1H), 7.72 (td, J = 1.7, 7.7 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H ), 7.27-7.23 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.89 (s , 3H), 3.81 (d, J = 13.2 Hz, 1H), 3.43-3.27 (m, 2H), 3.00-2.71 (m, 2H), 2.51-1.87 (m, 11H).

Ethyl cis-4-cyano-4- [1 '-(pyridin-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 71)
Using compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and 3-pyridinecarboxaldehyde (33.7 mg, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 3: 1) gave Compound 71 (0.072 g, 58%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 8.56 (d, J = 1.8 Hz, 1H), 8.51 (br d, J = 4.8 Hz, 1H), 7.71 (brd, J = 7.7 Hz, 1H) , 7.29-7.25 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.68 (s, 2H), 3.03-2.78 (m, 3H), 2.45-1.98 (m, 12H), 1.29 (t, J = 7.0 Hz, 3H).

Cis-4-cyano-4- [1 '-(pyridin-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 72)
Compound 71 (0.049 g, 74%) was obtained as a white solid by treating compound 71 (0.072 g, 0.24 mmol) obtained in Example 71 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.60-8.55 (m, 2H), 7.68-7.65 (m, 1H), 7.34-7.29 (m, 1H), 7.04 (d, J = 9.1 Hz, 1H), 6.51 (d, J = 9.1 Hz, 1H), 3.89 (s, 3H), 3.85 (d, J = 12.9 Hz, 1H), 3.71 (d, J = 12.9 Hz, 1H), 3.35-3.23 ( m, 2H), 2.79-2.61 (m, 2H), 2.51-1.95 (m, 11H).

Ethyl cis-4-cyano-4- [1 '-(pyridin-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 73)
Using compound 41 (0.10 g, 0.26 mmol) and 4-pyridinecarboxaldehyde (33.4 mg, 0.31 mmol) obtained in Example 41, the reaction was performed according to the method described in Example 47, and silica gel column chromatography ( Purification by chloroform: methanol = 9: 1) gave Compound 73 (0.14 g, quantitative) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.55 (d, J = 6.1 Hz, 2H), 7.30 (d, J = 6.1 Hz, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.68 (s, 2H), 3.05-2.80 (m, 4H), 2.47-1.99 (m, 11H), 1.29 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(pyridin-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 74)
Compound 73 (0.080 g, 61%) was obtained as a white solid by treating Compound 73 (0.14 g, 0.30 mmol) obtained in Example 73 according to the method described in Example 40.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 8.60 (d, J = 5.0 Hz, 1H), 8.56 (dd, J = 1.5, 5.0 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H ), 7.31 (dd, J = 5.0, 7.7 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 3.83 (d , J = 13.6 Hz, 1H), 3.70 (d, J = 13.6 Hz, 1H), 3.29-3.15 (m, 2H), 2.85-2.67 (m, 2H), 2.51-2.20 (m, 3H), 2.16- 1.94 (m, 8H).

Ethyl cis-4-cyano-4- [1 '-(pyrimidin-5-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 75)
3 prepared according to the method described in Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and SYNTHETIC COMMUNICATIONS, 1994, Vol. 24, No. 2, p.253-256, etc. -Pyrimidinecarboxaldehyde (0.034 g, 0.31 mmol) was used in accordance with the method described in Example 47 and purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give compound 75 ( 0.11 g, 85%).
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 9.14 (s, 1H), 8.74 (s, 2H), 6.93 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H ), 4.17 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.70 (s, 2H), 3.02 (s, 2H), 2.93-2.77 (m, 2H), 2.53-2.31 (m, 3H), 2.28-2.10 (m, 4H), 2.08-1.92 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(pyrimidin-5-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 76)
Compound 75 (0.055 g, 55%) was obtained as a white solid by treating Compound 75 (0.11 g, 0.22 mmol) obtained in Example 75 according to the method described in Example 40.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 9.10 (s, 1H), 8.77 (s, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.68 (d, J = 9.2 Hz , 1H), 3.80 (s, 3H), 3.74 (d, J = 13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.94 (s, 2H), 2.82-2.70 (m, 2H) , 2.40-2.17 (m, 5H), 2.10-1.98 (m, 2H), 1.97-1.82 (m, 2H), 1.77-1.60 (m, 2H).

Ethyl cis-4-cyano-4- [1 '-(furan-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 77)
The reaction was conducted according to the method described in Example 47 using Compound 41 (0.10 g, 0.26 mmol) and 2-furaldehyde (0.026 mL, 0.31 mmol) obtained in Example 41, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 1: 0 to 5: 1) gave Compound 77 (0.10 g, 82%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.38-7.37 (m, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 6.33-6.31 (m, 1H), 6.22-6.20 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.71 (brs, 2H), 3.13 (d, J = 10.9 Hz, 1H), 2.99 (d, J = 11.0 Hz, 1H), 2.91-2.77 (m, 2H), 2.43-1.92 (m, 11H), 1.28 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(furan-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 78)
Compound 77 (0.073 g, 79%) was obtained as a white solid by treating compound 77 (0.10 g, 0.21 mmol) obtained in Example 77 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.39-7.38 (m, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.35-6.34 (m, 1H), 6.27-6.26 (m, 1H), 3.89 (s, 3H), 3.89-3.85 (m, 2H), 3.50-3.39 (m, 2H), 2.81-1.93 (m, 13H).

Ethyl cis-4-cyano-4- [1 '-(furan-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 79)
The reaction was conducted according to the method described in Example 47 using Compound 41 (0.10 g, 0.27 mmol) and 3-furaldehyde (0.031 g, 0.32 mmol) obtained in Example 41, and silica gel column chromatography (n Purification by -hexane: ethyl acetate = 2: 1) gave Compound 79 (0.052 g, 41%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.38 (t, J = 1.8 Hz, 1H), 7.36 (brs, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 6.41 (dd, J = 0.7, 11.8 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2 H), 3.88 (s, 3H), 3.54 (s, 2H), 3.04 ( d, J = 11.0 Hz, 1H), 2.94 (d, J = 11.0 Hz, 1H), 2.90-2.83 (m, 1H), 2.79-2.71 (m, 1H), 2.44-2.33 (m, 3H), 2.25 -2.18 (m, 2H), 2.16-1.90 (m, 6H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(furan-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 80)
Compound 79 (0.052 g, 0.11 mmol) obtained in Example 79 was treated according to the method described in Example 40 and triturated with diethyl ether to give Compound 80 (0.045 g, 92%). Obtained as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.40 (brt, J = 1.6 Hz, 1H), 7.37 (brs, 1H), 7.11 (d, J = 8.8 Hz, 1 H), 6.52 (d, J = 8.8 Hz, 1H), 6.37 (m, 1H), 3.89 (s, 3H), 3.76 (d, J = 3.3 Hz, 1H), 3.71 (d, J = 3.3 Hz, 1H), 3.49 (d, J = 11.4 Hz, 1H), 3.49-3.43 (m, 1H), 2.68 (d, J = 11.4 Hz, 1H), 2.60-2.41 (m, 4H), 2.30-2.15 (m, 4H), 2.08-1.94 (m, 4H).

Ethyl cis-4-cyano-4- [1 '-(thiophen-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 81)
Using compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and 2-thiophenecarboxaldehyde (0.029 mL, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 1: 0 to 5: 1) gave Compound 81 (0.12 g, 96%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.24-7.22 (m, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.95-6.92 (m, 2H), 6.49 (d, J = 8.7 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.90 (brs, 2H), 3.88 (s, 3H), 3.08 (d, J = 10.9 Hz, 1H), 2.97 (d, J = 11.0 Hz, 1H), 2.95-2.79 (m, 2H), 2.43-1.94 (m, 11H), 1.31 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(thiophen-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 82)
Compound 82 (0.085 g, 75%) was obtained as a white solid by treating compound 81 (0.12 g, 0.25 mmol) obtained in Example 81 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.29-7.27 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.00-6.96 (m, 2H), 6.51 (d, J = 8.9 Hz, 1H), 4.11 (d, J = 14.0 Hz, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.88 (s, 3H), 3.49-3.44 (m, 2H), 2.77-1.96 ( m, 13H).

Ethyl cis-4-cyano-4- [1 '-(thiophen-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 83)
Using compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and 3-thiophenecarboxaldehyde (0.030 mL, 0.34 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 5: 1) gave Compound 83 (0.11 g, 81%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.29-7.26 (m, 1H), 7.18-7.15 (m, 1H), 7.09-7.07 (m, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.19 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.69 (brs, 2H), 3.03 (d, J = 10.8 Hz, 1H), 2.95 (d, J = 10.8 Hz, 1H), 2.87-2.74 (m, 2H), 2.64-1.93 (m, 11H), 1.29 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(thiophen-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 84)
Compound 84 (0.075 g, 71%) was obtained as a white solid by treating compound 83 (0.11 g, 0.23 mmol) obtained in Example 83 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.34-7.31 (m, 2H), 7.10-7.06 (m, 2H), 6.53 (d, J = 8.9 Hz, 1H), 4.01-3.86 (m, 2H), 3.89 (s, 3H), 3.55-3.45 (m, 2H), 2.79-1.89 (m, 13H).

Cis-4-cyano-4- [1 '-{(1-methyl-1H-pyrrol-2-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 85)
Using compound 41 (0.14 g, 0.36 mmol) obtained in Example 41 and 1-methylpyrrole-2-carboxaldehyde (0.047 mL, 0.43 mmol), the reaction was carried out according to the method described in Example 47, and silica gel Purification by column chromatography (n-hexane: ethyl acetate = 6: 1) gave Compound 85 (0.11 g, 64%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.92 (d, J = 8.9 Hz, 1H), 6.61-6.59 (m, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.01-5.98 (m, 2H), 4.16 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 3.60 (brs, 2H), 2.93 (d, J = 10.8 Hz, 1H) , 2.92 (d, J = 10.8 Hz, 1H), 2.80-2.70 (m, 2H), 2.42-1.93 (m, 11H), 1.29 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-{(1-methyl-1H-pyrrol-2-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid (Compound 86)
Compound 85 (0.11 g, 0.23 mmol) obtained in Example 85 was treated according to the method described in Example 40 to give compound 86 (0.082 g, 79%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.06 (d, J = 8.9 Hz, 1H), 6.62-6.60 (m, 1H), 6.51 (d, J = 8.9 Hz, 1H), 6.07-6.06 (m, 2H), 3.90-3.79 (m, 2H), 3.63 (s, 3H), 3.41-3.28 (m, 2H), 2.84-1.93 (m, 13H).

Cis-4-cyano-4- [1 '-{(1-methyl-1H-pyrrol-3-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 87)
Using compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and 1-methylpyrrole-3-carboxaldehyde (34.2 mg, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel Purification by column chromatography (n-hexane: ethyl acetate = 1: 1) gave Compound 87 (0.073 g, 59%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 9.0 Hz, 2H), 6.63-6.52 (m, 2H), 6.48 (d, J = 8.8 Hz, 2H), 6.07-6.06 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.61 (s, 3H), 3.56 (brs, 2H), 3.10-2.90 (m, 2H), 2.41- 1.97 (m, 13H), 1.28 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-{(1-methyl-1H-pyrrol-3-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid (Compound 88)
Compound 88 (0.039 g, 58%) was obtained as a white solid by treating Compound 87 (0.073 g, 0.15 mmol) obtained in Example 87 according to the method described in Example 40.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.10 (d, J = 8.8 Hz, 1H), 6.54-6.49 (m, 3H), 6.03-6.02 (m, 1H), 3.88 (s, 3H) , 3.75 (d, J = 13.3 Hz, 1H), 3.67 (d, J = 13.3 Hz, 1H), 3.63 (s, 3H), 3.53-3.41 (m, 2H), 2.77-1.92 (m, 13H).

Cis-4-cyano-4- [1 '-(1H-pyrrol-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid ethyl ester (Compound 89)
Using compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and pyrrole-2-carboxaldehyde (0.030 g, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography. Purification by (n-hexane: ethyl acetate = 1: 1) gave Compound 89 (0.089 g, 74%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.53 (brs, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.75-6.73 (m, 1H), 6.49 (d, J = 8.8 Hz , 1H), 6.12-6.09 (m, 1H), 6.04-6.01 (m, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.66 (brs, 2H), 2.98 ( d, J = 10.6 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H), 2.85-2.75 (m, 2H), 2.46-1.94 (m, 11H), 1.29 (t, J = 7.3 Hz, 3H ).

Cis-4-cyano-4- [1 '-(1H-pyrrol-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid (Compound 90)
Compound 90 (0.070 g, 84%) was obtained as a white solid by treating compound 89 (0.089 g, 0.19 mmol) obtained in Example 89 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 9.79 (brs, 1H), 7.07 (d, J = 8.9 Hz, 1H), 6.80-6.79 (m, 1H), 6.52 (d, J = 8.9 Hz , 1H), 6.09-6.08 (m, 2H), 3.98 (d, J = 13.3 Hz, 1H), 3.89 (s, 3H), 3.70 (d, J = 13.2 Hz, 1H), 3.49-3.40 (m, 2H), 2.79-1.96 (m, 13H).

Cis-4-cyano-4- [1 '-(1H-pyrrol-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid ethyl ester (Compound 91)
Using compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and pyrrole-3-carboxaldehyde (30.6 mg, 0.32 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography. Purification by (chloroform: methanol = 9: 1) gave Compound 91 (0.12 g, 99%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.13 (brs, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.75-6.73 (m, 2H), 6.48 (d, J = 8.8 Hz , 1H), 6.20-6.18 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.64 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 12.8 Hz, 1H), 3.10-2.70 (m, 4H), 2.42-1.93 (m, 11H), 1.26 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(1H-pyrrol-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid (Compound 92)
Compound 91 (0.081 g, 71%) was obtained as a white solid by treating Compound 91 (0.12 g, 0.26 mmol) obtained in Example 91 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.23 (s, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.76-6.74 (m, 2H), 6.51 (d, J = 8.8 Hz , 1H), 6.16-3.14 (m, 1H), 3.88 (s, 3H), 3.81 (d, J = 13.5 Hz, 1H), 3.71 (d, J = 13.5 Hz, 1H), 3.55-3.41 (m, 2H), 2.77-1.91 (m, 13H).

Cis-4-cyano-4- [1 '-(1H-pyrazol-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid ethyl ester (Compound 93)
Using compound 41 (0.099 g, 0.26 mmol) obtained in Example 41 and pyrazole-3-carboxaldehyde (29.9 mg, 0.31 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography. Purification by (n-hexane: ethyl acetate = 1: 1) gave Compound 93 (0.088 g, 73%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.53 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.49 (d, J = 9.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.81 (d, J = 13.8 Hz, 1H), 3.75 (d, J = 13.8 Hz, 1H), 3.07 (d, J = 11.0 Hz, 1H), 3.00 (d, J = 10.8 Hz, 1H), 2.95-2.78 (m, 2H), 2.51-1.89 (m, 11H), 1.28 (t , J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(1H-pyrazol-3-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid (Compound 94)
Compound 93 (0.039 g, 47%) was obtained as a white solid by treating compound 93 (0.088 g, 0.19 mmol) obtained in Example 93 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.61 (brs, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 9.0 Hz, 1H), 6.27 (brs, 1H ), 3.95 (d, J = 13.4 Hz, 1H), 3.89 (s, 3H), 3.80 (d, J = 13.4 Hz, 1H), 3.43-3.31 (m, 2H), 2.81-1.91 (m, 13H) .

Cis-4-cyano-4- [1 '-(1,3-thiazol-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 95)
Using compound 41 (0.10 g, 0.26 mmol) and 2-formylthiazole (35.4 mg, 0.31 mmol) obtained in Example 41, the reaction was carried out according to the method described in Example 47, and silica gel column chromatography (n -Hexane: ethyl acetate = 1: 1) to obtain Compound 95 (0.13 g, 95%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.71 (d, J = 3.1 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.07 (brs, 1H), 4.06 (brs, 1H), 3.89 (s, 3H), 3.20 (d, J = 10.8 Hz, 1H), 3.10 (d, J = 10.8 Hz, 1H), 3.06-2.90 (m, 2H), 2.51-1.91 (m, 11H), 1.29 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(1,3-thiazol-2-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 96)
Compound 95 (0.033 g, 28%) was obtained as a white solid by treating compound 95 (0.13 g, 0.26 mmol) obtained in Example 95 according to the method described in Example 40.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.76 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 4.20 (d, J = 14.5 Hz, 1H), 4.13 (d, J = 14.5 Hz, 1H), 3.88 (s, 3H), 3.42 (d, J = 11.0 Hz, 1H), 3.27-3.35 (m, 1H), 2.98 (d, J = 11.0 Hz, 1H), 2.91-2.82 (m, 1H), 2.52-2.44 (m, 3H), 2.26-1.91 (m, 8H).

Cis-4-cyano-4- [1 '-(1,2,3-thiadiazol-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- Yl] cyclohexanecarboxylic acid ethyl ester (Compound 97)
Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 was dissolved in DMF (2.0 mL), and 1,2,3-thiadiazol-4-yl methanesulfonate obtained according to the method described in EP284174 Methyl ester (0.060 g, 0.31 mmol), potassium carbonate (0.86 g, 0.31 mmol) and sodium iodide (catalytic amount) were added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Water and ethyl acetate were added to the reaction solution, and then the organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 97 (0.040 g, 32%) as a reddish brown oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.53 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.27 (s, 2H ), 4.17 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.18-2.80 (m, 4H), 2.49-1.93 (m, 11H), 1.28 (t, J = 7.2 Hz, 3H) .

Cis-4-cyano-4- [1 '-(1,2,3-thiadiazol-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- Yl] cyclohexanecarboxylic acid (compound 98)
Compound 97 (0.025 g, 67%) was obtained as a white solid by treating compound 97 (0.040 g, 0.083 mmol) obtained in Example 97 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 9.11 (s, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 4.22 (s , 2H), 3.83 (s, 3H), 3.03-2.76 (m, 4H), 2.40-1.60 (m, 11H).

Cis-4-cyano-4- [1 '-{(3,5-dimethylisoxazol-4-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 99)
The reaction was performed according to the method described in Example 97, using Compound 41 (0.080 g, 0.21 mmol) obtained in Example 41 and 4-chloromethyl-3,5-dimethylisoxazole (0.036 g, 0.25 mmol). And purification by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) gave Compound 99 (0.056 g, 55%) as a colorless oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.43 (d, J = 13.3 Hz, 1H), 3.36 (d, J = 13.3 Hz, 1H), 2.95 (d, J = 10.7 Hz, 1H), 2.90 (d, J = 10.7 Hz, 1H), 2.82-2.66 (m, 2H), 2.42-1.98 (m, 11H), 2.36 (s, 3H), 2.28 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-{(3,5-dimethylisoxazol-4-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid (Compound 100)
Compound 99 (0.035 g, 72%) was obtained as a white solid by treating compound 99 (0.052 g, 0.10 mmol) obtained in Example 99 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.84 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.46 (d , J = 13.3 Hz, 1H), 3.39 (d, J = 13.3 Hz, 1H), 2.86 (s, 2H), 2.69 (m, 2H), 2.34 (s, 3H), 2.30-1.60 (m, 11H) , 2.19 (s, 3H).

Cis-4-cyano-4- [1'-phenylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 101)
Compound 41 (0.020 g, 0.052 mmol) obtained in Example 41 was dissolved in toluene (0.5 mL), cesium carbonate (0.024 g, 0.72 mmol), iodobenzene (0.012 g, 0.057 mmol), palladium acetate (0.0035 g). , 0.016 mmol) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (0.015 g, 0.023 mmol) were added, and the mixture was stirred at 100 ° C. for 8 hours in an argon atmosphere. The reaction solution was cooled and then purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 101 (0.017 g, 69%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.26 (m, 2H), 6.98 (d, J = 9.0 Hz, 1H), 6.76 (t, J = 7.1 Hz, 1H), 6.59-6.53 (m , 3H), 4.15 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.82 (d, J = 10.9 Hz, 1H), 3.75 (d, J = 10.9 Hz, 1H), 3.60 (t , J = 6.1 Hz, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.34-1.92 (m, 9H), 1.26 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1'-phenylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 102)
Compound 101 (0.078 g, 48%) was obtained as a white solid by treating compound 101 (0.017 g, 0.036 mmol) obtained in Example 101 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.20 (m, 2H), 6.90 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 7.1 Hz, 1H), 6.71-6.61 (m, 3H), 3.82 (s, 3H), 3.74 (d, J = 11.5 Hz, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.51 (d, J = 7.1 Hz, 2H), 2.25 -1.68 (m, 11H).

Cis-4-cyano-4- [1 '-(4-cyanophenyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 103)
Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 was dissolved in dimethyl sulfoxide (1.0 mL), and potassium carbonate (0.38 g, 0.27 mmol) and 4-fluorocyanobenzene (0.033 g, 0.27 mmol) were added. The mixture was stirred at 100 ° C. for 8 hours under an argon atmosphere. Subsequently, potassium carbonate (0.38 g, 0.27 mmol) and 4-fluorocyanobenzene (0.033 g, 0.27 mmol) were added, and the mixture was further stirred at 120 ° C. for 12 hours. The reaction solution was cooled and water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 103 (0.55 g, 44%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.61 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 8.9 Hz, 2H), 4.25 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 3.95 (d, J = 11.2 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.78 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.44-2.02 (m, 9H), 1.36 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(4-cyanophenyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 104)
Compound 103 (0.032 g, 65%) was obtained as a white solid by treating compound 103 (0.052 g, 0.11 mmol) obtained in Example 103 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.57 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H ), 6.71 (d, J = 8.4 Hz, 2H), 3.85 (d, J = 11.7 Hz, 1H), 3.82 (s, 3H), 3.78 (d, J = 11.7 Hz, 1H), 2.95 (t, J = 7.4 Hz, 2H), 2.55 (m, 2H), 2.35-1.87 (m, 9H).

Cis-4-cyano-4- [1'-phenethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 105)
The reaction was carried out according to the method described in Example 47 using compound 41 (0.15 g, 0.38 mmol) obtained in Example 41 and phenylacetaldehyde (60.3 mg, 0.50 mmol), and silica gel column chromatography (n-hexane). : Ethyl acetate = 2: 1) gave Compound 105 (0.18 g, 97%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.31-7.19 (m, 5H), 6.95 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.17 (q , J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.15 (d, J = 10.9 Hz, 1H), 3.00 (d, J = 10.9 Hz, 1H), 2.97-2.73 (m, 5H), 2.49 -2.33 (m, 3H), 2.25-1.94 (m, 9H), 1.28 (t, J = 7.0 Hz, 3H).

Cis-4-cyano-4- [1'-phenethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 106)
Compound 105 (0.13 g, 80%) was obtained as a white solid by treating compound 105 (0.17 g, 0.35 mmol) obtained in Example 105 according to the method described in Example 40.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.33-7.17 (m, 5H), 7.11 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 3.90 (s , 3H), 3.88-3.55 (m, 2H), 2.96-1.92 (m, 17H).

Cis-4-cyano-4- [1 '-(1-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 107)
Using compound 41 (0.10 g, 0.26 mmol) and (1-bromoethyl) benzene (52.7 mg, 0.29 mmol) obtained in Example 41, the reaction was performed according to the method described in Example 97, and silica gel column chromatography was performed. Purification by (n-hexane: ethyl acetate = 4: 1) gave Compound 107 (0.094 g, 74%, diastereomer ratio 1: 1) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.34-7.20 (m, 5H), 6.92 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 8.6 Hz, 0.5H), 6.47 ( d, J = 8.6 Hz, 0.5H), 4.18 (brq, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.37-3.28 (m, 1H), 3.05-2.78 (m, 3H), 2.69- 2.56 (m, 1H), 2.43-1.80 (m, 11H), 1.38 (d, J = 5.9 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(1-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (compound 108)
The compound 107 (0.094 g, 0.19 mmol) obtained in Example 107 was treated according to the method described in Example 40, whereby the compound 108 (0.063 g, 72%, diastereomer ratio 1: 1) was obtained. Obtained as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.36-7.26 (m, 5H), 7.08 (d, J = 8.8 Hz, 0.5H), 7.06 (d, J = 8.8 Hz, 0.5H), 6.52 (d, J = 8.8 Hz, 0.5H), 6.49 (d, J = 8.8 Hz, 0.5H), 3.89 (s, 1.5H), 3.86 (s, 1.5H), 3.73-3.55 (m, 2H), 3.15-2.99 (m, 1.5H), 2.84-2.80 (m, 0.5H), 2.65-1.98 (m, 12H), 1.50 (d, J = 6.7 Hz, 3H).

Cis-4-cyano-4- [1 '-{1- (2-hydroxyphenyl) ethyl} spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 109)
Using compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and 2′-hydroxyacetophenone (0.045 mL, 0.37 mmol), the reaction was carried out according to the method described in Example 47, and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 3: 2) gave Compound 109 (0.099 g, 70%, diastereomeric ratio 1: 1) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.16 (d, J = 8.8 Hz, 0.5H), 7.11 (d, J = 8.8 Hz, 0.5H), 6.99-6.92 (m, 2H), 6.84 -6.73 (m, 2H), 6.51 (d, J = 8.8 Hz, 0.5H), 6.49 (d, J = 9.2 Hz, 0.5H), 4.18 (q, J = 7.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 1H), 3.89 (s, 1.5H), 3.87 (s, 1.5H), 3.61-3.52 (m, 1H), 3.20-2.77 (m, 4H), 2.52-1.94 (m, 11H) , 1.44 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 7.2 Hz, 1.5H), 1.29 (t, J = 7.2 Hz, 1.5H).

Cis-4-cyano-4- [1 '-{1- (2-hydroxyphenyl) ethyl} spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 110)
Compound 109 (0.049 g, 54%, diastereomer ratio 1: 1) was obtained by treating compound 109 (0.099 g, 0.19 mmol) obtained in Example 109 according to the method described in Example 40. Obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.16-6.80 (m, 5H), 6.52 (d, J = 8.8 Hz, 0.5H), 6.51 (d, J = 9.0 Hz, 0.5H), 3.89 (s, 1.5H), 3.88 (s, 1.5H), 3.45-2.80 (m, 3H), 2.65-1.90 (m, 13H), 1.53 (brs, 3H).

Cis-4-cyano-4- [1 '-(2-hydroxy-1-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexane Carboxylic acid ethyl ester (Compound 111)
Using compound 41 (0.15 g, 0.39 mmol) obtained in Example 41 and 2-hydroxy-1-phenylethanone (0.063 g, 0.47 mmol), the reaction was carried out according to the method described in Example 47, and silica gel Purification by column chromatography (n-hexane: ethyl acetate = 1: 1) gave Compound 111 (0.070 g, 35%, diastereomer ratio 1: 1) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.34-7.28 (m, 5H), 6.91 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.17 (q , J = 7.1 Hz, 2H), 3.90-3.70 (m, 2H), 3.86 (s, 3H), 3.54 (t, J = 5.6 Hz, 1H), 3.08-2.70 (m, 4H), 2.53-1.96 ( m, 11H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-hydroxy-1-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexane Carboxylic acid (Compound 112)
Compound 111 (0.048 g, 79%, diastereomeric ratio 1: 1) was obtained by treating compound 111 (0.065 g, 0.13 mmol) obtained in Example 111 according to the method described in Example 40. Obtained as a white solid.
¹ H NMR (270 MHz, CD ₃ OD) δ (ppm) 7.42-7.25 (m, 5H), 6.89 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 3.93- 3.77 (m, 2H), 3.85 (s, 3H), 3.53 (m, 1H), 3.25-2.76 (m, 4H), 2.40-1.80 (m, 11H).

Cis-4-cyano-4- [1 '-(2-hydroxy-2-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexane Carboxylic acid ethyl ester (Compound 113)
Step 1:
Using compound 41 (0.11 g, 0.27 mmol) obtained in Example 41 and 2-bromoacetophenone (0.065 g, 0.33 mmol), the reaction was carried out according to the method described in Example 97, and silica gel column chromatography (n -Hexane: ethyl acetate = 2: 1) to give cis-4-cyano-4- [1 '-(2-oxo-2-phenylethyl) spiro (7-methoxy-1,3-benzodio Xol-2,3′-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (0.091 g, 66%) was obtained as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 8.00-7.97 (m, 2H), 7.61-7.55 (m, 1H), 7.50-7.44 (m, 2H), 6.96 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.17 (dd, J = 7.3, 14.3 Hz, 2 H), 4.05 (d, J = 9.6 Hz, 2H), 3.89 (s, 3H), 3.40 (d, J = 11.2 Hz, 1H), 3.16-3.12 (m, 1H), 3.12 (d, J = 11.2 Hz, 1H), 2.93 (dt, J = 7.6, 1.3 Hz, 1H), 2.46 (t, J = 6.7 Hz, 2H), 2.37 (dd, J = 3.3, 11.6 Hz, 1H), 2.24-1.93 (m, 8H), 1.28 (t, J = 7.3 Hz, 3H).
Step 2:
The compound obtained above (0.091 g, 0.18 mmol) was dissolved in ethanol (1.0 mL), cooled to −40 ° C. under a nitrogen atmosphere, sodium borohydride (8.0 mg, 0.22 mmol) was added, and −30 Stir for 3 hours at ° C. Acetone was added to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 113 (0.067 g, 74%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.40-7.27 (m, 5H), 6.96 (d, J = 8.8 Hz, 0.5H), 6.94 (d, J = 8.8 Hz, 0.5H), 6.54 (d, J = 8.8 Hz, 0.5H), 6.51 (d, J = 8.8 Hz, 0.5H), 4.74 (t, J = 2.6 Hz, 0.5H), 4.71 (t, J = 2.6 Hz, 0.5H) , 4.17 (dd, J = 7.0, 14.3 Hz, 1 H), 4.16 (dd, J = 7.0, 14.3 Hz, 1 H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 3.27 (d , J = 10.8 Hz, 1H), 3.05 (d, J = 10.8 Hz, 1H), 3.09-2.99 (m, 1H), 2.93-2.76 (m, 2H), 2.63 (t, J = 3.1 Hz, 0.5H ), 2.59 (t, J = 3.1 Hz, 0.5H), 2.51-2.34 (m, 3H), 2.28-2.21 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.95 (m, 4H) , 1.28 (t, J = 7.0 Hz, 1.5H), 1.27 (t, J = 7.0 Hz, 1.5H).

Cis-4-cyano-4- [1 '-(2-hydroxy-2-phenylethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexane Carboxylic acid (compound 114)
Compound 113 (0.067 g, 0.13 mmol) obtained in Example 113 was treated according to the method described in Example 40 and triturated with diethyl ether to give Compound 114 (0.034 g, 54%). Obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.38-7.28 (m, 5H), 7.06 (d, J = 8.8 Hz, 0.5H), 7.03 (d, J = 8.8 Hz, 0.5 H), 6.55 (d, J = 8.8 Hz, 0.5H), 6.52 (d, J = 8.8 Hz, 0.5H), 4.92 (dd, J = 2.8, 10.3 Hz, 0.5H), 4.84 (dd, J = 2.8, 10.3 Hz , 0.5H), 3.91 (s, 1.5H), 3.90 (s, 1.5 H), 3.66 (d, J = 11.9 Hz, 1H), 3.46-3.33 (m, 1H), 3.70-2.72 (m, 5H) , 2.68-2.43 (m, 3H), 2.21-2.17 (m, 5H), 2.03-1.96 (m, 2H).

Cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,4'-piperidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 115)
Step 1:
4-Bromo-7-methoxy-1′-benzylspiro (1,3-benzodioxole-2,4′-piperidine) (1.00 g, 2.56 mmol) obtained in Reference Example 6 was added to THF (10 mL). After dissolution and cooling to −78 ° C. under an argon atmosphere, n-butyllithium (1.57 mol / L n-hexane solution; 1.8 mL, 2.83 mmol) was added, and the mixture was stirred at the same temperature for 20 minutes. The obtained mixture was added dropwise to a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (0.44 g, 2.56 mmol) in THF (10 mL) at −78 ° C. over 1 hour under an argon atmosphere, and the mixture was stirred at the same temperature. After stirring for 45 minutes, the temperature was raised to room temperature. Water was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give cis-4-hydroxy-4- [1'-benzylspiro (7-methoxy- 1,3-Benzodioxol-2,4′-piperidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (0.79 g, 64%) was obtained.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.35-7.26 (m, 5H), 6.83 (d, J = 8.8 Hz, 0.5H), 6.80 (d, J = 8.8 Hz, 0.5H), 6.47 (d, J = 8.8 Hz, 0.5H), 6.46 (d, J = 8.8 Hz, 0.5H), 4.12 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.60 (s, 2H) , 2.79-2.71 (m, 2H), 2.64-2.54 (m, 3H), 2.28-1.64 (m, 12H), 1.31-1.24 (m, 3H).
Step 2:
Cis-4-hydroxy-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,4'-piperidin) -4-yl] cyclohexanecarboxylic acid ethyl ester obtained above (0.79 g, 1.63 mmol) and trimethylsilyl cyanide (1.8 mL, 13.4 mmol) were dissolved in dichloromethane (8.2 mL), cooled to −78 ° C., and then boron trifluoride diethyl ether complex (0.41 mL) under an argon atmosphere. , 3.35 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. To the reaction solution was added 0.5 mol / L aqueous sodium hydroxide solution (9 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 115 (0.46 g, 56%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.34-7.25 (m, 5H), 6.91 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.18 (q , J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.61 (s, 2H), 2.79-2.72 (m, 2H), 2.61-2.53 (m, 2H), 2.34-1.91 (m, 13 H) , 1.30 (t, J = 7.0 Hz, 3H).

Cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,4'-piperidin) -4-yl] cyclohexanecarboxylic acid (Compound 116)
Compound 115 (0.071 g, 0.145 mmol) obtained in Example 115 was dissolved in ethanol (1.5 mL), 1 mol / L aqueous sodium hydroxide solution (0.43 mL) was added, and the mixture was stirred at room temperature for 4 hr. The solvent was distilled off under reduced pressure, and 1 mol / L hydrochloric acid was added to adjust the pH to 6.5. The precipitated solid was collected by filtration, washed with water, and dried to give compound 116 (0.041 g, 62%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.37-7.32 (m, 5H), 6.99 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 3.89 (s , 3H), 3.50 (s, 2H), 2.92-2.87 (m, 2 H), 2.76-2.67 (m, 2 H), 2.47-1.90 (m, 13 H).

Cis-4-cyano-4- [1'-ethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 117)
Using compound 41 (0.080 g, 0.21 mmol) and acetaldehyde (0.091 g, 2.1 mmol) obtained in Example 41, the reaction was carried out according to the method described in Example 43, and silica gel column chromatography (chloroform: methanol = 19: 1) gave Compound 117 (0.040 g, 46%) as an orange oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.10 (d, J = 11.0 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 2.92-2.66 (m, 2H), 2.55 (q, J = 7.3 Hz, 2H ), 2.43-1.92 (m, 11H), 1.28 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1'-ethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 118)
Compound 117 (0.018 g, 50%) was obtained as a white solid by treating Compound 117 (0.039 g, 0.094 mmol) obtained in Example 117 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.84 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H), 2.89 (s , 2H), 2.69 (m, 2H), 2.44 (d, J = 7.3 Hz, 2H), 2.36-1.65 (m, 11H), 1.03 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1′-cyclopropylmethylspiro (7-methoxy-1,3-benzodioxol-2,3′-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 119 )
The reaction was carried out according to the method described in Example 97 using Compound 41 (0.32 g, 0.83 mmol) obtained in Example 41 and cyclopropylmethyl bromide (0.13 g, 1.0 mmol), and silica gel column chromatography ( Purification by n-hexane: ethyl acetate = 2: 1) gave Compound 119 (0.11 g, 29%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.82 (d, J = 9.8 Hz, 1H), 6.38 (d, J = 9.8 Hz, 1H), 4.03 (q, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.05 (d, J = 11.1 Hz, 1H), 2.85 (d, J = 11.1 Hz, 1H), 2.82-2.56 (m, 2H), 2.29-1.80 (m, 13H), 1.15 (d, J = 7.3 Hz, 3H), 0.78 (m, 1H), 0.38 (m, 2H), -0.01 (m, 2H).

Cis-4-cyano-4- [1'-cyclopropylmethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 120)
Compound 120 (0.057 g, 57%) was obtained as a white solid by treating the compound 119 (0.11 g, 0.24 mmol) obtained in Example 119 according to the method described in Example 40.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.84 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.81 (s, 3H), 2.94 (s , 2H), 2.74 (m, 2H), 2.35-1.60 (m, 13H), 0.86 (m, 1H), 0.45 (m, 2H), 0.09 (m, 2H).

Cis-4-cyano-4- [1'-cyanomethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 121)
Reaction was carried out according to the method described in Example 97 using Compound 41 (0.32 g, 0.83 mmol) and cyanomethyl bromide (0.12 g, 1.0 mmol) obtained in Example 41, and silica gel column chromatography (n- Purification with hexane: ethyl acetate = 2: 1) gave Compound 121 (0.19 g, 53%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.96 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.70 (s, 2H), 3.17 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 10.5 Hz, 1H), 2.98 (m, 2H), 2.58-1.86 (m , 11H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(2-amino-2-oxoethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid (compound 122) and cis-4-cyano-4- [1'-cyanomethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 123)
Compound 121 (0.19 g, 0.44 mmol) obtained in Example 121 was treated according to the method described in Example 40, and the obtained solid was purified by silica gel column chromatography (chloroform: methanol = 9: 1). As a result, Compound 122 (0.075 g, 42%) and Compound 123 (0.022 g, 12%) were obtained as white solids, respectively.
Compound 122
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.23 (br, 1H), 7.08 (br, 1H), 6.85 (d, J = 9.1 Hz, 1H), 6.68 (d, J = 9.1 Hz , 1H), 3.81 (s, 3H), 3.08 (s, 2H), 3.03 (s, 2H), 2.81-1.65 (m, 13H).
Compound 123
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.03 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 2H ), 3.26 (d, J = 10.6 Hz, 1H), 3.11 (d, J = 10.6 Hz, 1H), 3.20-2.90 (m, 2H), 2.57-1.97 (m, 11H).

Cis-4-cyano-4- [1 '-(cyclohexylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (compound 124)
The reaction was carried out according to the method described in Example 47 using compound 41 (0.100 g, 0.26 mmol) obtained in Example 41 and cyclohexanecarbaldehyde (0.037 g, 0.33 mmol), and silica gel column chromatography (n- Purification by hexane: ethyl acetate = 4: 1) gave Compound 124 (0.13 g, 99%).
¹ H NMR (270 MHz, CD ₃ OD) δ (ppm) 6.89 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H) , 3.86 (s, 3H), 2.99 (d, J = 10.9 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H), 2.85-2.68 (m, 2H), 2.50-1.62 (m, 16H), 1.55-1.38 (m, 1H), 1.37-1.18 (m, 6H), 1.02-0.83 (m, 2H).

Cis-4-cyano-4- [1 '-(cyclohexylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 125)
Compound 125 (0.060 g, 49%) was obtained as a white solid by treating the compound 124 (0.18 g, 0.27 mmol) obtained in Example 123 according to the method described in Example 40.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.84 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 3.81 (s, 3H), 2.84 (s , 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.38-2.17 (m, 7H), 2.10-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.82-1.55 (m, 7H ), 1.48-1.33 (m, 1H), 1.29-1.08 (m, 3H), 0.93-0.76 (m, 2H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-thiopyran-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 126)
The reaction was performed according to the method described in Example 47, using Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and tetrahydro-2H-thiopyran-4-carbaldehyde (0.044 g, 0.34 mmol). Purification by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) gave Compound 126 (0.090 g, 69%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.95 (brs, 2H), 2.75-2.62 (m, 5H), 2.40-1.93 (m, 15H), 1.52-1.30 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-thiopyran-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 127)
The compound 126 (0.090 g, 0.18 mmol) obtained in Example 125 was treated according to the method described in Example 40, whereby Compound 127 (0.084 g, 99%) was obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.05 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H), 3.50-3.32 (m , 2H), 2.74-1.94 (m, 22H), 1.56-1.36 (m, 2H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-pyran-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 128)
Reaction was performed according to the method described in Example 47, using Compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and tetrahydro-2H-pyran-4-carbaldehyde (0.049 g, 0.43 mmol). Purification by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1.3) gave Compound 128 (0.12 g, 88%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.99-3.94 (m, 2H), 3.89 (s, 3H), 3.41-3.32 (m, 2H), 2.98 (brs, 1H), 2.97 (brs, 1H), 2.77-2.72 (m, 1H), 2.41- 1.93 (m, 15H), 1.73-1.68 (m, 2H), 1.31-1.26 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-pyran-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 129)
Compound 128 (0.080 g, 70%) was obtained as a white solid by treating compound 128 (0.12 g, 0.25 mmol) obtained in Example 127 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.07 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 3.98-3.90 (m, 2H), 3.90 (s , 3H), 3.59-3.32 (m, 4H), 2.73-1.64 (m, 18H), 1.35-1.26 (m, 2H).

Cis-4-cyano-4- [1 '-{[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'- Pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 130)
According to the method described in Example 47, using Compound 41 (0.057 g, 0.15 mmol) obtained in Example 41 and 4-formylpiperidine-1-carboxylic acid-tert-butyl ester (0.22 g, 1.01 mmol). The reaction was performed, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2) to obtain Compound 130 (0.056 g, 64%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.7 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.13-4.08 (m, 2H), 3.89 (s, 3H), 2.97 (brs, 2H), 2.77-2.68 (m, 4H), 2.38-1.74 (m, 16H), 1.45 (s, 9H), 1.28 ( t, J = 7.1 Hz, 3H), 1.12-1.07 (m, 2H).

Cis-4-cyano-4- [1 '-{[1- (tert-butoxycarbonyl) piperidin-4-yl] methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'- Pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 131)
The compound 130 (0.050 g, 0.090 mmol) obtained in Example 129 was treated according to the method described in Example 40 to give compound 131 (0.021 g, 42%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.06 (d, J = 8.7 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.10-4.05 (m, 2H), 3.90 (s , 3H), 3.55-3.37 (m, 2H), 2.74-1.94 (m, 18H), 1.74-1.70 (m, 2H), 1.45 (s, 9H), 1.21-1.11 (m, 2H).

Cis-4-cyano-4- [1 '-{(1-acetylpiperidin-4-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- Yl] cyclohexanecarboxylic acid ethyl ester (compound 132)
Compound 134 (0.090 g, 0.19 mmol) obtained in Example 133 was dissolved in dichloromethane (3 mL), cooled to 0 ° C., triethylamine (0.039 mL, 0.28 mmol) and acetic anhydride (0.023 mL, 0.24 mmol) were added. The mixture was further stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 0: 1) to obtain Compound 132 (0.097 g, 97%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95-6.90 (m, 1H), 6.51 (d, J = 9.0 Hz, 1H), 4.60 (br, 1H), 4.17 (q, J = 7.2 Hz , 2H), 3.89 (s, 3H), 3.83-3.71 (m, 1H), 3.00-2.91 (m, 3H), 2.78-2.73 (m, 2H), 2.54-1.60 (m, 16H), 2.09 (s , 3H), 1.28 (t, J = 7.2 Hz, 1.5H), 1.24 (t, J = 7.2 Hz, 1.5H), 1.30-1.11 (m, 3H).

Cis-4-cyano-4- [1 '-{(1-acetylpiperidin-4-yl) methyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- Yl] cyclohexanecarboxylic acid (compound 133)
Compound 132 (0.093 g, 0.18 mmol) obtained in Example 131 was treated according to the method described in Example 40, and triturated with acetonitrile to give Compound 133 (0.054 g, 42%) as white. Obtained as a solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.01-6.97 (m, 1H), 6.51 (d, J = 9.2 Hz, 1H), 4.62-4.58 (m, 2H), 3.89 (s, 3H) , 3.83-3.71 (m, 2H), 3.34-1.77 (m, 19H), 2.09 (s, 3H), 1.28-1.14 (m, 3H).

Ethyl cis-4-cyano-4- [1 '-(piperidin-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 134)
Compound 130 (0.30 g, 0.51 mmol) obtained in Example 129 was dissolved in dichloromethane (12 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 134 (0.26 g, quantitative) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.17 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 3.10-3.06 (m, 2H), 3.00 (d, J = 11.0, 1H), 2.93 (d, J = 11.0 Hz, 1H), 2.80-2.54 (m, 4H), 2.40- 1.76 (m, 14H), 1.60-1.50 (m, 1H), 1.28 (t, J = 7.3 Hz, 3H), 1.30-1.11 (m, 3H).

Cis-4-cyano-4- [1 '-(piperidin-4-ylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid ( Compound 135)
The compound 134 (0.090 g, 0.19 mmol) obtained in Example 133 was treated according to the method described in Example 40 and triturated with acetonitrile to give Compound 135 (0.032 g, 37%) as white. Obtained as a solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.83 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H), 3.21-3.16 (m, 2H), 2.87 (brs, 2H), 2.80-2.67 (m, 4H), 2.31-2.20 (m, 7H), 2.07-1.58 (m, 9H), 1.29-1.17 (m, 2H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-thiopyran-4-yl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 136)
Reaction was performed according to the method described in Example 47 using Compound 41 (0.10 g, 0.27 mmol) obtained in Example 41 and tetrahydro-2H-thiopyran-4-one (0.038 g, 0.32 mmol), and silica gel Purification by column chromatography (n-hexane: ethyl acetate = 2: 1) gave Compound 136 (0.091 g, 70%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.94 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.09 (dd, J = 10.9, 14.3 Hz, 2H), 2.92-2.74 (m, 4H), 2.64-2.52 (m, 2H), 2.46-1.90 (m, 14H), 1.71 ( ddd, J = 3.2, 9.4, 22.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-thiopyran-4-yl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 137)
Compound 136 (0.091 g, 0.19 mmol) obtained in Example 135 was treated according to the method described in Example 40 and triturated with diethyl ether to give Compound 137 (0.065 g, 76%). Obtained as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.08 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H), 3.60 (d, J = 11.1 Hz, 1H), 3.51-3.47 (m, 1H), 2.82 (d, J = 11.1 Hz, 1H), 2.72-2.64 (m, 4H), 2.63-2.54 (m, 1H), 2.52-2.28 ( m, 5H), 2.21-2.06 (m, 7H), 2.03-1.93 (m, 2H), 1.75-1.64 (m, 2H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-pyran-4-yl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid ethyl ester (Compound 138)
Reaction was performed according to the method described in Example 47 using Compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and tetrahydro-2H-pyran-4-one (0.034 g, 0.34 mmol), and silica gel Purification by column chromatography (n-hexane: ethyl acetate = 2: 1) gave Compound 138 (0.11 g, 81%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.93 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 4.17 (dd, J = 7.2, 14.4 Hz, 2H ), 4.03-3.95 (m, 2H), 3.89 (s, 3H), 3.40 (dt, J = 1.8, 11.5 Hz, 2H), 3.13 (d, J = 10.9 Hz, 1H), 3.04 (d, J = 10.9 Hz, 1H), 2.90 (dd, J = 7.3, 13.5 Hz, 1H), 2.78 (dd, J = 7.3, 15.9 Hz, 1H), 2.51 (t, J = 6.0 Hz, 1H), 2.45-2.31 ( m, 3H), 2.24 (brd, J = 10.5 Hz, 2H), 2.14 (brd, J = 12.1 Hz, 2H), 2.05-1.93 (m, 4H), 1.82-1.71 (m, 2H), 1.59 (ddd , J = 3.5, 11.5, 23.4 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(tetrahydro-2H-pyran-4-yl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] Cyclohexanecarboxylic acid (Compound 139)
Compound 139 (0.076 g, 77%) was obtained by treating compound 138 (0.11 g, 0.22 mmol) obtained in Example 137 according to the method described in Example 40 and triturating with diethyl ether. Obtained as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.09 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.11-3.96 (m, 2H), 3.90 (s , 3H), 3.64 (d, J = 11.4 Hz, 1H), 3.57-3.54 (m, 1H), 3.41-3.34 (m, 2H), 2.77 (d, J = 11.4 Hz, 1H), 2.58-2.47 ( m, 4H), 2.41-2.33 (m, 1H), 2.27-2.08 (m, 6H), 1.98 (dt, J = 4.0, 12.9 Hz, 2H), 1.86 (brd, J = 13.3 Hz, 1H), 1.76 -1.60 (m, 3H).

Cis-4-cyano-4- [1 '-(pyridin-3-ylcarbonyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid Ethyl ester (Compound 140)
Compound 41 (0.15 g, 0.39 mmol) obtained in Example 41 was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. To this solution were added triethylamine (0.17 mL, 1.2 mmol) and nicotinoyl chloride hydrochloride (0.079 g, 0.43 mmol), and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound 140 (0.12 g, 63%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 8.83-8.66 (m, 2H), 7.93-7.86 (m, 1H), 7.43-7.30 (m, 1H), 6.97 (d, J = 9.0 Hz, 0.5H), 6.93 (d, J = 9.0 Hz, 0.5H), 6.58 (d, J = 9.0 Hz, 0.5H), 6.54 (d, J = 9.0 Hz, 0.5H), 4.12 (q, J = 7.2 Hz, 2H), 4.04-3.82 (m, 6H), 2.58-2.45 (m, 2H), 2.34-1.83 (m, 10H), 1.26 (t, J = 7.2 Hz, 3H).

Cis-4-cyano-4- [1 '-(pyridin-3-ylcarbonyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 141)
The compound 140 (0.12 g, 0.24 mmol) obtained in Example 139 was treated according to the method described in Example 40 and triturated with diethyl ether to give Compound 141 (0.087 g, 75%). Obtained as a yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.88-8.68 (m, 2H), 7.98-7.93 (m, 1H), 7.47-7.39 (m, 1H), 6.96 (brt, J = 8.4 Hz, 1H), 6.55 (br t, J = 8.4 Hz, 1H), 4.15-3.82 (m, 6H), 2.57-1.98 (m, 12H).

Cis-4-cyano-4- [1 '-{[1- (tert-butoxycarbonyl) piperidin-4-yl] carbonyl} spiro (7-methoxy-1,3-benzodioxole-2,3'- Pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 142)
Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 was dissolved in 1,2-dichloroethane (3 mL), and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.059 g, 0.26 mmol) was dissolved. , Triethylamine (0.11 mL, 0.78 mmol), 1-hydroxybenzotriazole (0.079 g, 0.52 mmol) and WSC · HCl (0.099 g, 0.52 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 6) to obtain Compound 142 (0.12 g, 77%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95 (d, J = 8.9 Hz, 0.5H), 6.94 (d, J = 8.7 Hz, 0.5H), 6.56 (d, J = 8.9 Hz, 0.5 H), 6.55 (d, J = 9.1 Hz, 0.5H), 4.17 (q, J = 7.3 Hz, 2H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 4.18-3.80 (m, 4H), 2.71-1.71 (m, 20H), 1.46 (s, 4.5H), 1.45 (s, 4.5H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-{[1- (tert-butoxycarbonyl) piperidin-4-yl] carbonyl} spiro (7-methoxy-1,3-benzodioxole-2,3'- Pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 143)
Compound 142 (0.071 g, 62%) was obtained as a white solid by treating Compound 142 (0.12 g, 0.20 mmol) obtained in Example 141 according to the method described in Example 40.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 9.0 Hz, 0.5H), 6.56 (d, J = 9.0 Hz, 0.5H ), 3.91 (s, 1.5H), 3.90 (s, 1.5H), 4.18-3.77 (m, 9H), 2.73-1.72 (m, 15H), 1.46 (s, 4.5H), 1.45 (s, 4.5H ).

Cis-4-cyano-4- [1 '-(piperidin-4-ylcarbonyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid Hydrochloride (Compound 144)
The compound 143 (0.066 g, 0.12 mmol) obtained in Example 142 was treated according to the method described in Example 134 and triturated with acetonitrile to give Compound 144 (0.041 g, 68%) as white. Obtained as a solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 8.90 (brs, 0.5H), 8.55 (brs, 0.5H), 6.90 (d, J = 8.9 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 4.07-3.35 (m, 8H), 3.82 (s, 3H), 2.86-1.03 (m, 16H).

Cis-4-cyano-4- [1 '-(N, N-dimethylglycyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid ethyl ester (Compound 145)
Step 1:
Compound 41 (0.18 g, 0.47 mmol) obtained in Example 41 was dissolved in dichloromethane (5 mL), cooled to 0 ° C., and then chloroacetyl chloride (0.041 mL, 0.51 mmol) and triethylamine (0.13 mL, 0.93 mmol). ) Was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give cis-4-cyano-4- [1 '-(chloroacetyl) spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- [Il] cyclohexanecarboxylic acid ethyl ester (0.23 g, quantitative) was obtained as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.97 (d, J = 8.9 Hz, 0.5H), 6.95 (d, J = 8.8 Hz, 0.5H), 6.57 (d, J = 8.9 Hz, 0.5 H), 6.56 (d, J = 8.9 Hz, 0.5H), 4.17 (q, J = 7.1 Hz, 2H), 4.07 (s, 1H), 3.99 (s, 1H), 3.91 (s, 1.5H), 3.90 (s, 1.5H), 4.05-3.82 (m, 4H), 2.57-1.98 (m, 11H), 1.28 (t, J = 7.1 Hz, 3H).
Step 2:
The compound (0.11 g, 0.24 mmol) obtained above was dissolved in THF (1 mL), dimethylamine (2.0 mol / L THF solution, 1.4 mL, 2.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain Compound 145 (0.096 g, 85%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.97 (d, J = 8.7 Hz, 0.5H), 6.95 (d, J = 8.9 Hz, 0.5H), 6.56 (d, J = 8.9 Hz, 0.5 H), 6.55 (d, J = 8.9 Hz, 0.5H), 4.17 (q, J = 7.3 Hz, 2H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 4.01-3.68 (m, 6H), 3.12 (d, J = 2.6 Hz, 1H), 3.05 (d, J = 2.6 Hz, 1H), 2.48-1.98 (m, 9H), 2.33 (s, 3H), 2.28 (s, 3H), 1.30-1.22 (m, 3H).

Cis-4-cyano-4- [1 '-(N, N-dimethylglycyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarbon Acid (Compound 146)
Compound 146 (0.034 g, 38%) was obtained by treating compound 145 (0.096 g, 0.20 mmol) obtained in Example 144 according to the method described in Example 40 and triturating with diethyl ether. Was obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.95 (d, J = 8.9 Hz, 1H), 6.56 (d, J = 8.9 Hz, 0.5H), 6.54 (d, J = 9.0 Hz, 0.5H ), 3.99-3.82 (m, 10H), 3.45-3.11 (m, 2H), 2.48 (s, 3H), 2.43 (s, 3H), 2.41-1.94 (m, 8H).

Ethyl cis-4-cyano-4- [1 '-(morpholin-4-ylacetyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylate Ester (Compound 147)
Cis-4-cyano-4- [1 '-(chloroacetyl) spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4- obtained in Step 1 of Example 144 [Il] cyclohexanecarboxylic acid ethyl ester (0.12 g, 0.26 mmol) and morpholine (0.025 mL, 0.29 mmol) were used according to the method described in Step 2 of Example 144, followed by silica gel column chromatography (chloroform: Purification with methanol = 30: 1) gave Compound 147 (0.074 g, 55%) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.97 (d, J = 8.9 Hz, 0.5H), 6.95 (d, J = 8.9 Hz, 0.5H), 6.57 (d, J = 8.9 Hz, 0.5 H), 6.55 (d, J = 8.9 Hz, 0.5H), 4.17 (q, J = 7.3 Hz, 2H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 4.01-3.70 (m, 8H), 3.18 (brs, 1H), 3.11 (brs, 1H), 2.53-1.98 (m, 15H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(morpholin-4-ylacetyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid Salt (Compound 148)
Compound 147 (0.074 g, 0.14 mmol) obtained in Example 146 was treated according to the method described in Example 40 and treated with a 4 mol / L hydrogen chloride-dioxane solution to give compound 148 (0.051 g , 70%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.98 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.42-4.29 (m, 2H), 4.13 -3.82 (m, 13H), 3.63 (brs, 2H), 2.40-1.71 (m, 10H), 1.30-1.13 (m, 1H).

Cis-4-cyano-4- [1 '-{(2R) -2-[(tert-butoxycarbonyl) amino] -2-phenylacetyl} spiro (7-methoxy-1,3-benzodioxole-2 , 3′-Pyrrolidin) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 149)
The reaction was performed according to the method described in Example 141, using Compound 41 (0.10 g, 0.26 mmol) obtained in Example 41 and 2R-[(tert-butoxycarbonyl) amino] phenylacetic acid (0.071 g, 0.28 mmol). And purification by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) gave Compound 149 (0.12 g, 74%, diastereomer ratio 1: 1) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.43-7.26 (m, 5H), 6.97-6.94 (m, 1H), 6.54 (d, J = 8.9 Hz, 0.5H), 6.53 (d, J = 8.9 Hz, 0.5H), 5.92 (brs, 1H), 5.46-5.28 (m, 1H), 4.20-4.14 (m, 2H), 3.89 (s, 3H), 4.02-3.46 (m, 6H), 2.44 -1.88 (m, 9H), 1.42 (brs, 9H), 1.33-1.24 (m, 3H).

Cis-4-cyano-4- [1 '-{(2R) -2-[(tert-butoxycarbonyl) amino] -2-phenylacetyl} spiro (7-methoxy-1,3-benzodioxole-2 , 3′-Pyrrolidin) -4-yl] cyclohexanecarboxylic acid (Compound 150)
Compound 150 (0.087 g, 77%, diastereomeric ratio 1: 1) was obtained by treating compound 149 (0.12 g, 0.19 mmol) obtained in Example 148 according to the method described in Example 40. Obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.39-7.30 (m, 5H), 7.00-6.93 (m, 1H), 6.54 (d, J = 9.1 Hz, 0.5H), 6.53 (d, J = 8.9 Hz, 0.5H), 5.98-5.93 (m, 1H), 5.48-5.26 (m, 1H), 4.04-3.71 (m, 6H), 3.53-3.04 (m, 2H), 2.42-1.95 (m, 10H), 1.42 (s, 4.5H), 1.41 (s, 4.5H).

Cis-4-cyano-4- [1 '-{(2R) -2-amino-2-phenylacetyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4 -Yl] cyclohexanecarboxylic acid hydrochloride (Compound 151)
Compound 151 (0.060 g, 81%, diastereomer) was obtained by treating compound 150 (0.080 g, 0.14 mmol) obtained in Example 149 according to the method described in Example 134 and triturating with acetonitrile. Mer ratio 1: 1) was obtained as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.58-7.55 (m, 5H), 6.96 (d, J = 8.9 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.82 -6.76 (m, 1H), 5.55-5.40 (m, 1H), 4.34-4.08 (m, 1H), 3.88-3.63 (m, 6H), 3.35-3.05 (m, 1H), 2.49-1.72 (m, 10H).

Cis-4-cyano-4- [1 '-{N- (tert-butoxycarbonyl) -L-phenylalanyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid ethyl ester (Compound 152)
The reaction was performed according to the method described in Example 141, using Compound 41 (0.11 g, 0.28 mmol) obtained in Example 41 and N- (tert-butoxycarbonyl) -L-phenylalanine (0.083 g, 0.31 mmol). Purification by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) gave Compound 152 (0.13 g, 73%, diastereomer ratio 1: 1) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.33-7.21 (m, 5H), 7.00-6.87 (m, 1H), 6.54 (d, J = 8.9 Hz, 0.5H), 6.53 (d, J = 8.9 Hz, 0.5H), 5.37-5.33 (m, 1H), 4.70-4.60 (m, 2H), 4.24-4.11 (m, 2H), 3.92-3.64 (m, 7H), 3.09-2.96 (m, 2H), 2.27-1.92 (m, 9H), 1.43-1.40 (m, 9H), 1.31-1.22 (m, 3H).

Cis-4-cyano-4- [1 '-{N- (tert-butoxycarbonyl) -L-phenylalanyl} spiro (7-methoxy-1,3-benzodioxole-2,3'-pyrrolidine) -4-yl] cyclohexanecarboxylic acid (Compound 153)
Compound 152 (0.10 g, 79%, diastereomeric ratio 1: 1) was obtained by treating compound 152 (0.13 g, 0.21 mmol) obtained in Example 151 according to the method described in Example 40. Obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.32-7.18 (m, 5H), 7.00-6.87 (m, 1H), 6.54 (d, J = 8.9 Hz, 0.5H), 6.53 (d, J = 8.9 Hz, 0.5H), 5.46-5.44 (m, 1H), 4.67-4.47 (m, 2H), 3.98-3.71 (m, 5H), 3.15-2.77 (m, 4H), 2.41-1.96 (m, 9H), 1.44-1.40 (m, 9H).

Cis-4-cyano-4- [1 '-(L-phenylalanyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid Salt (Compound 154)
Compound 153 (0.090 g, 0.15 mmol) obtained in Example 152 was treated according to the method described in Example 134, and triturated with a mixed solvent of diethyl ether: ethyl acetate = 1: 1. Compound 154 (0.057 g, 70%, diastereomeric ratio 1: 1) was obtained as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 8.49 (brs, 2H), 7.38-7.24 (m, 5H), 6.90-6.87 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.39-4.28 (m, 1H), 4.08-4.02 (m, 1H), 3.84-3.57 (m, 5H), 3.17-2.76 (m, 4H), 2.26-1.63 (m, 11H).

Cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide hydrochloride (Compound 155)
Compound 40 (0.12 g, 0.24 mmol) obtained in Example 40 was dissolved in DMF (1.0 ml), cooled to 0 ° C. in a nitrogen atmosphere, 1-hydroxybenzotriazole ammonium salt (0.054 g, 0.36 mmol) and WSC · HCl (0.068 g, 0.36 mmol) was added and stirred at room temperature for 18.5 hours. Water was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3 -Benzodioxole-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide was obtained. Next, the obtained cis-4-cyano-4- [1'-benzylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide was converted to acetic acid. After dissolving in ethyl and cooling to 0 ° C., 4 mol / L hydrogen chloride-ethyl acetate solution (0.18 ml, 0.71 mmol) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain Compound 155 (0.099 g, 86%) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.35-7.22 (m, 5H), 6.93 (d, J = 9.0 Hz, 1H), 6.49 (d, J = 9.0 Hz, 1H), 6.24 (s , 1H), 5.93 (s, 1H), 3.87 (s, 3H), 3.67 (dd, J = 13.2, 13.9 Hz, 2H), 3.03 (d, J = 11.0 Hz, 1H), 2.94 (d, J = 11.0 Hz, 1H), 2.86 (dt, J = 1.6, 7.1 Hz, 1H), 2.76 (dd, J = 7.3, 16.1 Hz, 1H), 2.41 (dd, J = 6.4, 13.4 Hz, 2H), 2.36- 2.19 (m, 3H), 2.11-1.91 (m, 6H).

Cis-4-cyano-4- [spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide (Compound 156)
Compound 155 (0.099 g, 0.20 mmol) obtained in Example 154 was dissolved in ethanol (1.0 mL), 10% palladium carbon (50% water-containing product, 0.010 g) was added under a nitrogen atmosphere, and then in a hydrogen stream. And stirred at room temperature for 6 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain Compound 156 (0.078 g, quantitative).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.43 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J = 8.8 Hz , 1H), 3.88 (s, 3H), 3.73-3.50 (m, 4H), 3.21 (s, 1H), 2.58-2.43 (m, 2H), 2.37-2.13 (m, 3H), 2.17-1.86 (m , 4H), 1.84-1.69 (m, 2H).

Cis-4-cyano-4- [1 '-(ethoxycarbonylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide (compound 157)
Compound 156 (0.078 g, 0.22 mmol) obtained in Example 155 was dissolved in dimethyl sulfoxide (1.0 mL), and 2-bromoacetic acid ethyl ester (0.029 mL, 0.26 mmol) and potassium carbonate (0.061) at room temperature under a nitrogen atmosphere. g, 0.44 mmol) was added and the mixture was heated to reflux for 9 hours. The reaction solution was returned to room temperature, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain Compound 157 (0.041 g, 45%, two steps from Compound 155) as a yellow oily liquid. .
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.98 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.90 (brd, J = 18.7 Hz, 2H), 4.19 (q, J = 7.3 Hz, 2 H), 3.89 (s, 3H), 3.40 (d, J = 6.6 Hz, 1H), 3.38 (d, J = 11.0 Hz, 1H), 3.15-3.10 (m, 1H), 3.04 (d, J = 11.0 Hz, 1H), 2.84 (dd, J = 7.7, 16.5 Hz, 1H), 2.46-2.41 (m, 2H), 2.39-2.21 (m, 3H), 2.15-1.95 (m, 5H), 1.28 (t, J = 7.3 Hz, 3H).

Cis-4-cyano-4- [1 '-(carboxymethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide hydrochloride ( Compound 158)
Compound 157 (0.041 g, 0.090 mmol) obtained in Example 156 was treated according to the method described in Example 40, and triturated with ethyl acetate to obtain a solid. The obtained solid was dissolved in methanol, water was added, and the mixture was extracted with chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain cis-4-cyano-4- [1'-carboxymethylspiro (7-methoxy-1,3-benzodioxole-2, 3′-Pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide was obtained. The resulting cis-4-cyano-4- [1'-carbonylmethylspiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide was After dissolving in ethyl acetate and cooling to 0 ° C., 4 mol / L hydrogen chloride-ethyl acetate solution (0.069 mL, 0.28 mmol) was added and stirred for 30 minutes, and then the solvent was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile: water = 40: 60) to give compound 158 (0.020 g, 53%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.90 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 3.98 (brd, J = 10.7 Hz, 1H), 3.88 (s, 3H), 3.86 (d, J = 9.9 Hz, 1H), 3.38 (t, J = 10.9 Hz, 2H), 3.20 (d, J = 9.9 Hz, 1H), 2.99 (d, J = 10.2 Hz, 1H), 2.42-1.73 (m, 9H), 1.58 (qt, J = 11.1, 3.4 Hz, 2H).

Cis-4-cyano-4- [1 '-(1-phenylmethoxycarbonylmethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid Amide (Compound 159)
Using compound 156 (0.084 g, 0.24 mmol) obtained in Example 155 and methyl-α-bromobenzylphenyl acetate, the reaction was carried out according to the method described in Example 156, and silica gel column chromatography (chloroform: methanol = Purification by 9: 1) gave Compound 159 (0.044 g, 42%, 3 steps from Compound 40) as a yellow oily liquid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.40-7.35 (m, 2H), 7.30-7.24 (m, 3H), 6.87 (d, J = 8.8 Hz, 0.5H), 6.86 (d, J = 8.8 Hz, 0.5H), 6.42 (d, J = 8.8 Hz, 0.5H), 6.41 (d, J = 8.8 Hz, 0.5H), 5.88 (brs, 2H), 3.80 (s, 1.5H), 3.79 (s, 1.5H), 3.61 (s, 1.5H), 3.60 (s, 1.5H), 3.18 (d, J = 11.4 Hz, 0.5H), 2.99 (d, J = 11.0 Hz, 0.5H), 2.93 (d, J = 11.4 Hz, 0.5H), 2.81 (d, J = 11.0 Hz, 0.5H), 2.79-2.58 (m, 2H), 2.40-2.23 (m, 3H), 2.12-1.88 (m, 9H ).

Cis-4-cyano-4- [1 '-(1-phenylcarboxymethyl) spiro (7-methoxy-1,3-benzodioxol-2,3'-pyrrolidin) -4-yl] cyclohexanecarboxylic acid amide (Compound 160)
Compound 159 (0.041 g, 0.09 mmol) obtained in Example 158 was treated according to the method described in Example 40, and then purified with a resin (aromatic synthetic adsorbent, SP-207). Compound 160 (0.033 g, 85%) was obtained as a white solid.
¹ H NMR (300 MHz, CD ₃ OD) δ (ppm) 7.57 (d, J = 6.6 Hz, 2H), 7.35-7.26 (m, 3H), 6.92 (d, J = 9.0 Hz, 0.5H), 6.89 (d, J = 11.6 Hz, 0.5H), 6.61 (d, J = 9.0 Hz, 1H), 3.95 (d, J = 4.4 Hz, 1H), 3.86 (s, 1.5H), 3.85 (s, 1.5H ), 3.29 (d, J = 11.4 Hz, 1H), 3.19-3.04 (m, 1H), 2.99 (d, J = 11.4 Hz, 1H), 2.80-2.66 (m, 1H), 2.45-2.43 (m, 3H), 2.28-2.19 (m, 2H), 2.13-1.86 (m, 6H).

Reference Example 1: 4-Cyano-4- (8-trifluoromethanesulfonyloxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid ethyl ester Argon atmosphere against dichloromethane (200 mL) Below, cis-4-cyano-4- (8-hydroxy-2,3-dihydrobenzo-1,4-dioxin-5-yl) cyclohexanecarboxylic acid prepared according to the method described in JP-A-12-57381 and the like Acid ethyl ester (12.6 g, 38.3 mmol) and triethylamine (8.0 mL, 58 mmol) were added and dissolved, and then cooled to -10 ° C. Trifluoromethanesulfonic anhydride (9.7 mL, 58 mmol) was added dropwise to the resulting solution and stirred at −10 ° C. for 1 hour. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with 0.5 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound (14.8 g, 84%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.94 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 4.41 (m, 4H), 4.17 (q, J = 7.1 Hz, 2H), 2.46-1.81 (m, 9H), 1.28 (t, J = 7.1 Hz, 3H).
Reference Example 2: 4 ', 5'-dihydrospiro (4-bromo-7-methoxy-1,3-benzodioxole-2,3'-thiophene)
Step 1:
3-Bromo-6-methoxycatechol (5.0 g, 22.8 mmol) prepared according to the method described in International Publication No. 01/81288 etc. was dissolved in methanol (120 mL) and ice-cooled. Acid dimethyl ester (3.57 g, 25.1 mmol) and sodium hydride (60% content; catalytic amount) were added, and the mixture was stirred at room temperature for 5 hours. Further, acetylenedicarboxylic acid dimethyl ester (1.46 g, 10.2 mmol) and sodium hydride (60%, catalytic amount) were added under ice-cooling, followed by stirring at room temperature for 3 hours. Water was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 → 2: 1) to give 4-bromo-7-methoxy-2-methoxycarbonylmethyl-1,3-benzo Dioxole-2-carboxylic acid methyl ester (8.24 g, quantitative) was obtained as an oil.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.94 (d, J = 9.1 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H ), 3.72 (s, 3H), 3.43 (d, J = 16.7 Hz 1H), 3.35 (d, J = 16.7 Hz 1H).
Step 2:
Under a nitrogen atmosphere, lithium aluminum hydride (1.16 g, 30.6 mmol) was added to THF (200 mL), cooled to 0 ° C, and then the compound obtained above (8.49 g, 23.5 mmol) Added below and stirred at room temperature for 4 hours. The reaction mixture was cooled to 0 ° C., sodium sulfate decahydrate (10.6 g, 32.9 mmol) was gradually added, and the mixture was stirred at room temperature for 1 hr. The obtained suspension was filtered through celite, the filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give 2- (4-bromo-2-hydroxymethyl-7-methoxy-1,3-benzodioxol-2-yl) ethanol (4.45 g, 62%). Obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.90 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 3.95-3.84 (m, 4H), 3.87 (s , 3H), 2.48 (t, J = 7.3 Hz 1H), 2.36 (t, J = 5.5 Hz, 2H), 2.06 (t, J = 5.5 Hz, 1H).
Step 3:
The compound obtained above (4.66 g, 15.3 mmol) was dissolved in dichloromethane (150 mL), and then triethylamine (4.26 mL, 30.5 mmol) and methanesulfonyl chloride (2.36 mL, 30.5 mmol) were added under ice-cooling. For 30 minutes. Further, triethylamine (2.13 mL, 15.3 mmol) and methanesulfonyl chloride (1.18 mL, 15.3 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with chloroform. The organic layer was washed with 2 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give methanesulfonic acid [2- (4-bromo-2-methanesulfonyloxymethyl- 7-Methoxy-1,3-benzodioxol-2-yl) ethyl] ester (9.06 g, quantitative) was obtained as an oily liquid.
Step 4:
After dissolving the compound obtained above (9.06 g, 15.3 mmol) in 1,4-dioxane (210 mL), add 1 mol / L sodium sulfide aqueous solution (61.2 mL, 61.2 mmol), and heat at 90 ° C. for 17 hours. Stir. Water was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 19: 1) and triturated with isopropyl alcohol to give the title compound (2.66 g, 57%) as a white solid. .
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.91 (d, J = 9.0 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H), 3.26 (s, 2H ), 3.04 (t, J = 6.8 Hz, 2H), 2.47 (t, J = 6.8 Hz, 2H).
Reference Example 3: 2 ', 3', 5 ', 6'-tetrahydrospiro (4-bromo-7-methoxy-1,3-benzodioxole-2,4'-thiopyran)
4,4-dimethoxy-2,3,5,6-tetrahydrothiopyran (3.85 g, prepared according to the method described in Tetrahedron, 2001, Vol. 57, p.217-225, etc. 23.8 mmol) was dissolved in toluene (20 mL) and 3-bromo-6-methoxycatechol (2.00 g, 9.13 mmol) and p-toluenesulfonic acid monohydrate (0.174 g, 0.915 mmol) were added. Heated to reflux. The reaction mixture was mixed with aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from acetone-diisopropyl ether to give the title compound (1.44 g, 49.9%) as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.87 (d, J = 9.0 Hz, 1H), 6.41 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 2.93-2.85 (m, 4H), 2.35-2.32 (m, 4H).
Reference Example 4: 4-Bromo-7-methoxy-1′-benzylspiro (1,3-benzodioxole-2,3′-pyrrolidine Step 2 of Reference Example 2 in dichloromethane (100 mL) under an argon atmosphere 2- (4-Bromo-2-hydroxymethyl-7-methoxy-1,3-benzodioxol-2-yl) ethanol (3.04 g, 9.96 mmol) and triethylamine (6.8 mL, 47 mmol) obtained in After cooling with ice, methanesulfonyl chloride (3.9 mL, 48 mmol) was added, and the mixture was stirred at room temperature for 1 hour.After adding water to the reaction solution, the mixture was extracted with chloroform, and the organic layer was washed with water and saturated brine. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in benzylamine (15 mL) and stirred for 15 minutes at 120 ° C. Ethyl acetate was added to the reaction solution to add saturated carbonate. The extract was washed with an aqueous sodium hydrogen solution and saturated brine, and dried over anhydrous sodium sulfate. Silica gel column chromatography (n- hexane: ethyl acetate = 4: 1) to afford the title compound (4.12 g, quantitative) as a yellow oily liquid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.35-7.22 (m, 5H), 6.86 (d, J = 9.0 Hz, 1H), 6.40 (d, J = 9.0 Hz, 1H), 3.86 (s , 3H), 3.67 (s, 2H), 3.04 (d, J = 11.0 Hz, 1H), 2.99 (d, J = 11.0 Hz, 1H), 2.83-2.77 (m, 2H), 2.46-2.37 (m, 2H).
Reference Example 5: Spiro (4-bromo-7-methoxy-1,3-benzodioxole-2,2'-bicyclo [2.2.1] heptane)
3-Bromo-6-methoxycatechol (17.2 g, 78.4 mmol) and norcamphor dimethyl acetal (31.8 g, 204 mmol) were suspended in toluene (340 mL), and p-toluenesulfonic acid monohydrate (1.49 g, 0.78 mmol) was added and refluxed for 4.6 hours. Ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1), and further purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1). The obtained title compound (22.2 g) was used in the next reaction (Example 45) without purification.
Reference Example 6: 4-Bromo-7-methoxy-1'-benzylspiro (1,3-benzodioxole-2,4'-piperidine)
Step 1:
3-Bromo-6-methoxycatechol (2.20 g, 10.0 mmol) obtained according to the method described in WO 01/81288 and the like was dissolved in acetone (700 mL) and ice-cooled. Potassium carbonate (6.92 g, 50.1 mmol) was added and stirred at room temperature for 2 hours. To the reaction solution, a solution of dimethylalene-1,3-dicarboxylate (1.57 g, 10.0 mmol) dissolved in acetone was added dropwise over 2 hours under ice cooling, followed by stirring at room temperature for 38 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 4-bromo-7-methoxy-1,3-benzodioxole-2,2-dicarboxylic acid Dimethyl ester (1.32 g, 35%) was obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.90 (d, J = 9.1 Hz, 1H), 6.44 (d, J = 9.1 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 6H ), 3.33 (s, 4H).
Step 2:
The compound obtained above (75.1 mg, 0.200 mmol) was dissolved in THF (2 mL), and the reaction solution was cooled to 0 ° C. Lithium borohydride (17.5 mg, 0.803 mmol) was added here, and it stirred at room temperature for 18.5 hours. After the reaction solution was cooled to 0 ° C., acetone was gradually added and stirred at room temperature for 15 minutes. The resulting suspension was filtered through celite, and the filtrate was concentrated under reduced pressure to give 2,2 ′-(4-bromo-7-methoxy-1,3-benzodioxole-2,2- A crude product of diyl) diethanol was obtained. This crude product was dissolved in dichloromethane (1 mL), triethylamine (62 μL, 0.45 mmol) was added, ice-cooled, methanesulfonyl chloride (23 μL, 0.30 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in acetonitrile (2 mL), benzylamine (72.6 mg, 0.678 mmol) was added, and the mixture was heated to reflux for 2.5 hours. After allowing to cool, ethyl acetate was added to the reaction solution, washed with a 1 mol / L aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give the title compound (45.4 mg, 48%) as a yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.34-7.26 (m, 5H), 6.86 (d, J = 9.1 Hz, 1H), 6.40 (d, J = 9.1 Hz, 1H), 3.87 (s , 3H), 3.59 (s, 2H), 2.68 (br t, J = 5.4 Hz, 4H), 2.10 (br t, J = 5.4 Hz, 4H).

Formulation Example 1: Tablet (Compound 1)
A tablet having the following composition is prepared by a conventional method. 40 g of Compound 1, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate, mixed, and tableted with a tableting machine (RT-15 model, manufactured by Kikusui Co., Ltd.) having a 8 mm diameter punch to contain tablets (containing 20 mg of active ingredient per tablet). To get).
Formulation Compound 1 20 mg
Lactose 143.4mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6mg
200 mg
Formulation Example 2: Tablet (Compound 2)
Using 40 g of compound 2, the title tablet (containing 20 mg of active ingredient per tablet) is obtained in the same manner as in Example 1.
Formulation Compound 2 20 mg
Lactose 143.4mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6mg
200 mg
Formulation Example 3: Injection (Compound 3)
An injection having the following composition is prepared by a conventional method. 1 g of Compound 3 and 5 g of D-mannitol are added to and mixed with distilled water for injection. Further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 6, and then the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formulation Compound 3 2 mg
D-mannitol 10 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

a

Claims (15)

Formula (I)

[Wherein m represents 0, 1 or 2; W represents —OR ⁵ (wherein R ⁵ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted; Lower alkynyl or aralkyl) or —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or Represents an unsubstituted lower alkynyl, or R ⁶ and R ⁷ together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group),
R ⁴ represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
R ² and R ³ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted polycycloalkyl, substituted or unsubstituted alicyclic heterocycle A group, a polycyclic heterocyclic group, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aralkyl. R ² and R ³ are present on the same carbon atom and together with the carbon atom are substituted or unsubstituted spirocycloalkanes, substituted or unsubstituted spiroalicyclic heterocycles, substituted or unsubstituted A spiropolycycloalkane, or a substituted or unsubstituted spiropolycyclic heterocycle,
R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, formyl, or —NR ⁸ R ⁹ (wherein R ⁸ and R ^{9 s} are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, formyl, or substituted or unsubstituted lower alkanoyl, or nitrogen in which R ⁸ and R ⁹ are adjacent to each other. Together with the atom to form a substituted or unsubstituted heterocyclic group)
Alternatively, one of R ² and R ³ represents a hydrogen atom and the other represents a polycyclic heterocyclic group, or R ² and R ³ are present on the same carbon, together with the carbon atom, substituted Or when forming an unsubstituted spiroalicyclic heterocycle, a substituted or unsubstituted spiropolycycloalkane or a substituted or unsubstituted spiropolycyclic heterocycle,
R ¹ represents hydroxy or substituted or unsubstituted lower alkoxy], or a pharmacologically acceptable salt thereof. R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, formyl, or —NR ⁸ R ⁹ (wherein R ⁸ and R ^9. The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ⁹ is as defined above. The oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein R ² and R ³ are hydrogen atoms. R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl, or the oxygen-containing heterocyclic compound or pharmacologically thereof according to any one of claims 1 to 3. Acceptable salt. The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is hydroxy or substituted or unsubstituted lower alkoxy. R ² and R ³ are on the same carbon and together with the carbon atom are substituted or unsubstituted spiroalicyclic heterocycles, substituted or unsubstituted spiropolycycloalkanes or substituted or unsubstituted spiro poly The oxygen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof forms a cyclic heterocyclic ring, and R ¹ is a substituted or unsubstituted lower alkoxy. R ² and R ³ are on the same carbon and together with the carbon atom form a substituted or unsubstituted spiroalicyclic heterocycle or substituted or unsubstituted spiropolycycloalkane, and R ¹ is substituted Or an oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 1, which is an unsubstituted lower alkoxy. Oxygen-containing heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7 R ⁴ is a hydrogen atom. W is ^(wherein, R ⁵ has the same meaning as defined above) -OR 5 Salts oxygen-containing heterocyclic compound or a pharmacologically acceptable according to claim 1 is. W is hydroxy, The oxygen-containing heterocyclic compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 8. W is -NR 7 ^R 8 ^(wherein, R ⁷ and R ⁸ have the same meanings as defined above) are oxygen-containing heterocyclic compound or a pharmacologically acceptable according to claim 1 which is Salt. m is 1, The oxygen-containing heterocyclic compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 11. m is 0, The oxygen-containing heterocyclic compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 11. The pharmaceutical containing the oxygen-containing heterocyclic compound in any one of Claims 1-13, or its pharmacologically acceptable salt. A phosphodiesterase (PDE) -IV inhibitor comprising the oxygen-containing heterocyclic compound according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof.