TW201300393A - Novel spiropiperidine derivative and pharmaceutical product containing same - Google Patents

Novel spiropiperidine derivative and pharmaceutical product containing same Download PDF

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TW201300393A
TW201300393A TW101117744A TW101117744A TW201300393A TW 201300393 A TW201300393 A TW 201300393A TW 101117744 A TW101117744 A TW 101117744A TW 101117744 A TW101117744 A TW 101117744A TW 201300393 A TW201300393 A TW 201300393A
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methyl
carboxylate
snail
piperidine
phenyl
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TW101117744A
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Toshiharu Morimoto
Tomoaki Koshizawa
Gen Watanabe
Tomoaki Fukuda
Tadaaki Ohgiya
Nao Yamasaki
Noriyuki Inoue
Takaaki Araki
Hitomi Tsukagoshi
Sumihiko Hagita
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Kowa Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Provided is a novel compound which has an effect of promoting insulin secretion from pancreatic ss cells and is useful as a prophylactic and/or therapeutic agent for diseases associated with high blood sugar, such as diabetes. A compound represented by general formula (1), a salt thereof, or a solvate of the compound or the salt. (In the formula, ring A represents a C6-C10 aryl group or a five- to ten-membered heterocyclic group; Z represents O, N-R9, S(O)m, CH2 or C=O; each of R1, R2, R3 and R4 is independently absent or represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a hydroxyl group, a nitro group, a tetrazolyl group or the like; each of R5, R6 and R7 independently represents a hydrogen atom, a halogen atom, a cyano group or a carboxyl group; R8 represents a C1-6 alkyl group, a C6-10 aryl group or the like; each of R13 and R14 represents a hydrogen atom or a halogen atom; and R15 represents a hydrogen atom, a hydroxyl group or an oxo group.)

Description

新穎之螺哌啶衍生物及含有其之醫藥 Novel spiropiperidine derivatives and medicines containing the same

本發明係關於一種具有促進來自胰臟β細胞之胰島素分泌的作用，而預防及/或治療因高血糖所引起之疾病、例如糖尿病的藥劑。 The present invention relates to an agent having an action of promoting insulin secretion from pancreatic β cells, and preventing and/or treating a disease caused by hyperglycemia, such as diabetes.

胰臟係來自內胚層的內分泌/外分泌腺體組織，由內分泌細胞/腺泡細胞/導管細胞所構成。屬於內分泌細胞之胰臟蘭格罕氏小島(胰臟蘭氏小島)係構成胰臟整體之1%，主要分類為4種細胞。亦即，分泌胰高血糖素之α細胞、分泌胰島素之β細胞、合成/分泌體抑素之δ細胞、合成/分泌胰臟多肽之F細胞。其中，由β細胞所分泌之胰島素具有使血糖降低的主要生理機能，為顯現血糖降低作用的唯一之荷爾蒙。胰島素係於胰臟β細胞中藉由感知血糖上昇而被分泌，釋出至門靜脈內。被釋出之胰島素係於肝臟中抑制糖新生或糖釋出，於末稍組織之脂肪/肌肉組織促進糖攝取，而發揮保持生體之血糖水準的作用。 The pancreas is derived from endocrine/exocrine glandular tissues of the endoderm and is composed of endocrine cells/acinar cells/catheter cells. The pancreas Langerhans island (the pancreatic islet) belonging to the endocrine cell constitutes 1% of the pancreas as a whole, and is mainly classified into four types of cells. That is, α cells secreting glucagon, β cells secreting insulin, δ cells synthesizing/secreting somatostatin, and F cells synthesizing/secreting pancreatic polypeptide. Among them, insulin secreted by β cells has the main physiological function of lowering blood sugar, and is the only hormone that exhibits a blood sugar lowering effect. Insulin is secreted in pancreatic beta cells by sensing elevated blood glucose and is released into the portal vein. The released insulin is in the liver to inhibit sugar granules or sugar release, and the fat/muscle tissue in the terminal tissue promotes sugar uptake, thereby exerting a blood sugar level that maintains the body.

糖尿病係因缺乏胰島素或其作用不足而引起的持續性高血糖狀態。糖尿病主要可分為：因自體免疫疾病等而胰臟胰島素分泌異常所產生的胰島素依存型糖尿病(IDDM)；與因胰島素作用不足(胰島素抗性)而導致持續性高胰島素狀態，以因其伴隨之胰衰竭所造成之胰島素分泌能力降低為原 因的胰島素非依存型糖尿病(NIDDM)二種。糖尿病所造成之持續性高血糖係引起血管障礙、於多臟器引發併發症。作為代表性之併發症，可舉例如糖尿病性腎病變、糖尿病性視網膜病變、糖尿病性神經病變等，而被視為生活品質(QOL)降低、醫療費增加、生存率降低等之問題。 Diabetes is a persistent hyperglycemia state caused by a lack of insulin or its insufficient effect. Diabetes can be mainly divided into: insulin-dependent diabetes mellitus (IDDM) caused by abnormal insulin secretion in the pancreas due to autoimmune diseases, and a persistent high insulin state due to insufficient insulin action (insulin resistance). Reduced insulin secretion caused by pancreatic failure Two types of insulin-independent diabetes mellitus (NIDDM). Persistent hyperglycemia caused by diabetes causes vascular disorders and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy, and are considered to be problems such as a decrease in quality of life (QOL), an increase in medical expenses, and a decrease in survival rate.

糖尿病之治療上，係進行運動療法、飲食療法、藥物療法。作為用於藥物療法之藥劑，例如有促進來自胰臟β細胞之胰島素分泌的藥劑、改善胰島素抗性的藥劑、抑制糖吸收的藥劑、促進糖利用的藥劑等。其中，胰島素分泌促進劑由於可期待使血中胰島素濃度上昇、使血糖降低的效果，故被期待能抑制高血糖、改善糖尿病，磺醯尿素製劑(SU藥)、速效型胰島素分泌促進劑、DPPIV抑制藥(參照非專利文獻1)、GLP-1類似物(參照非專利文獻2)等已實際使用於糖尿病治療現場。然而，於日本最被頻繁使用的SU藥，雖然刺激胰臟β細胞而促進內因性胰島素分泌(參照非專利文獻3)，但有發生低血糖之副作用的情形，尤其在高齡者、腎機能低落者或飲食不規則之情況的使用時需特別注意。又，其亦報告有體重增加等之副作用。再者，有由初期投予時未發現效果之一次無效、或於投予期間中臨床效果消失之二次無效發生的情形(參照非專利文獻4)，故期待開發出減輕此等副作用、或不損及胰島素分泌能力而對胰臟β細胞之負擔較少的胰島素分泌促進劑。 For the treatment of diabetes, exercise therapy, diet therapy, and drug therapy are performed. Examples of the agent for drug therapy include a drug that promotes insulin secretion from pancreatic β cells, a drug that improves insulin resistance, a drug that inhibits sugar absorption, and a drug that promotes sugar utilization. Among them, the insulin secretion promoter is expected to suppress the increase in blood insulin concentration and lower blood sugar, so it is expected to suppress hyperglycemia and improve diabetes, and the sulfonium urea preparation (SU medicine), the fast-acting insulin secretion promoter, and DPPIV. The inhibitory drug (see Non-Patent Document 1), the GLP-1 analog (see Non-Patent Document 2), and the like have been actually used in the diabetes treatment site. However, the most frequently used SU drug in Japan promotes endogenous insulin secretion while stimulating pancreatic β-cells (see Non-Patent Document 3), but there are cases of side effects of hypoglycemia, especially in elderly people and renal function. Special care should be taken when using or irregular eating conditions. In addition, it also reports side effects such as weight gain. In addition, there is a case where no effect is found at the time of initial administration, or a secondary ineffectiveness occurs in the clinical period during the administration period (see Non-Patent Document 4), and it is expected to develop such side effects, or An insulin secretion promoter which has less burden on insulin β-cells without impairing insulin secretion ability.

作為具有螺哌啶骨架之化合物，已報告有具有乙醯基-CoA羧化酶(ACC)抑制作用的化合物(專利文獻1~3)。然而，此等化合物的特徵均為於縮合環上之4位具有側氧基的環構造。又，已報告有具有硬脂醯基-CoA去飽和酶(SCD)抑制作用的化合物(專利文獻4)。然而，此等化合物的特徵均在於哌啶環氮原子上之取代基為雜芳基胺甲醯基。此外，報告有含氮螺環化合物(專利文獻5)。此等化合物已揭示作為等級III的抗心律不整劑。 As a compound having a spiropiperidine skeleton, a compound having an inhibitory action of acetyl-CoA carboxylase (ACC) has been reported (Patent Documents 1 to 3). However, these compounds are characterized by a ring structure having a pendant oxy group at the 4-position on the condensed ring. Further, a compound having a stearin-CoA desaturase (SCD) inhibitory action has been reported (Patent Document 4). However, such compounds are characterized in that the substituent on the piperidine ring nitrogen atom is a heteroarylaminecarbamyl group. Further, a nitrogen-containing spiro compound has been reported (Patent Document 5). These compounds have been disclosed as grade III antiarrhythmic agents.

(專利文獻1)國際專利WO2007/011809號說明書(專利文獻2)國際專利WO2007/011811號說明書(專利文獻3)國際專利WO2008/102749號說明書(專利文獻4)國際專利WO2010/112520號說明書(專利文獻5)日本專利特開平4-217960號說明書 (Patent Document 1) International Patent Publication No. WO2007/011809 (Patent Document 2) International Patent Publication No. WO2007/011811 (Patent Document 3) International Patent Publication No. WO2008/102749 (Patent Document 4) International Patent Publication No. WO2010/112520 (Patent Document 5) Japanese Patent Laid-Open No. 4-217960

(非專利文獻1)J Clin Endocrinol Metab, May 2004, 89(5):2078-2084(非專利文獻2)Regul Pept, 2004, 117(2):77-88(非專利文獻3)The Lancet, Aug 31, 1985, 2:474-475(非專利文獻4)The Lancet, Sep 12, 1998, 352:837-853 (Non-Patent Document 1) J Clin Endocrinol Metab, May 2004, 89(5): 2078-2084 (Non-Patent Document 2) Regul Pept, 2004, 117(2): 77-88 (Non-Patent Document 3) The Lancet, Aug 31, 1985, 2: 474-475 (Non-Patent Document 4) The Lancet, Sep 12, 1998, 352: 837-853

本發明之課題在於提供一種具有促進來自胰臟β細胞的胰島素分泌的作用，可用於作為因高血糖所引起之疾病、例 如糖尿病之預防治療藥的化合物。 An object of the present invention is to provide an action for promoting insulin secretion from pancreatic β cells, which can be used as a disease caused by hyperglycemia, and examples thereof. A compound such as a preventive and therapeutic drug for diabetes.

本發明者等人係於發現具有胰島素分泌促進活性之化合物的研究一環中，使用倉鼠胰臟β細胞株HIT-T15細胞，進行促進胰島素分泌之化合物的探索，結果發現，由一般式(1)所示之螺哌啶衍生物具有優越之促進來自胰臟β細胞之胰島素分泌的作用，可用於作為糖尿病預防治療藥，遂完成本發明。 The inventors of the present invention used a hamster pancreatic β-cell strain HIT-T15 cell to explore a compound which promotes insulin secretion, and found that the general formula (1) was found in a study of a compound having an insulin secretion-promoting activity. The spiropiperidine derivative shown has an excellent effect of promoting insulin secretion from pancreatic β cells, and can be used as a prophylactic and therapeutic agent for diabetes, and the present invention has been completed.

亦即，本發明係關於以下所示發明。 That is, the present invention relates to the invention shown below.

[1]一種化合物或其鹽或其等之溶媒合物，係由下述一般式(1)所示： [式中，A環表示C6-C10芳基或5-10員雜環基；Z表示O、N-R9、S(O)m、CH2或C=O(此處，R9表示氫原子、C1-6烷基、C1-7烷醯基或C1-6烷基磺醯基，m表示0~2之整數)；[化2]表示單鍵或雙鍵； R1、R2、R3及R4彼此獨立為不存在或氫原子、鹵素原子、C1-6烷基、羧基-C1-6烷基、C1-6烷氧基羰基-C1-6烷基、4-10員雜環-C1-6烷基(此處，4-10員雜環上亦可取代有C1-6烷基或C1-6烷基磺醯基)、C1-6烷氧基、C3-10環烷基-C1-6烷氧基、C1-6烷基磺醯基、C1-6烷基磺醯氧基、C1-6烷基磺醯胺基、羥基、氰基、硝基、四唑基、或下式(2)或式(3)所示之基： (式中，R10及R11彼此獨立表示氫原子、鹵素原子或C1-6烷基；R12表示C1-20烷基、C2-6烯基、鹵C1-6烷基、C2-7烷醯基、C6-10芳基、4-10員環雜環基(雜環上亦可取代有鹵素原子)、C3-10環烷基-C1-6烷基、胺基C1-6烷基、羥基-C1-6烷基、氰基-C1-6烷基、C1-6烷氧基-C1-6烷基、羧基-C1-6烷基、C1-6烷氧基羰基-C1-6烷基、胺甲醯基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C6-10芳基-C1-6烷基(此處，C6-10芳基上亦可取代有鹵素原子、C1-6烷基、鹵C1-6烷基、C1-6烷基磺醯基或羧基)或4-10員雜環-C1-6烷基(此處，雜環上亦可取代有C1-6烷基、鹵素原子、C1-6烷氧基或側氧基)；l表示1~3之整數，n表示0~2之整數)；R5、R6及R7彼此獨立表示氫原子、鹵素原子、氰基或羧基； R8表示C1-6烷基、C2-6烯基、C2-6炔基、鹵C1-6烷基、三烷基矽基-C1-6烷基、氰基C1-6烷基、C1-6烷氧基-C1-6烷基、C3-10環烷基(此處，環烷基上亦可取代有鹵素原子)、C3-10環烷基-C1-6烷基(此處，環烷基上亦可取代有C1-6烷基)、C6-10芳基(此處，C6-10芳基上亦可取代有鹵素原子、氰基、鹵C1-6烷氧基、胺基、二烷基胺基、C1-6烷基、鹵C1-6烷基、C1-6烷基硫基或C6-10芳基-C1-6烷基氧基)、C6-10芳基-C1-6烷基(此處，C6-10芳基上亦可取代有鹵素原子、C1-6烷基、鹵C1-6烷氧基或鹵C1-6烷基)、4-10員雜環-C1-6烷基(此處，雜環上亦可取代有C1-6烷基或C1-6烷氧基羰基)或4-10員雜環；R13或R14彼此獨立表示氫原子或鹵素原子；[化4]R15表示氫原子、羥基、或在環內之為單鍵時表示側氧基]。 [1] A compound or a salt thereof or a solvent thereof, which is represented by the following general formula (1): Wherein Ring A represents a C 6 -C 10 aryl group or a 5-10 membered heterocyclic group; Z represents O, NR 9 , S(O)m, CH 2 or C=O (here, R 9 represents hydrogen Atom, C 1-6 alkyl, C 1-7 alkanoyl or C 1-6 alkylsulfonyl, m represents an integer from 0 to 2; [Chemical 2] Represents a single bond or a double bond; R 1 , R 2 , R 3 and R 4 are independently of each other or a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a carboxy-C 1-6 alkyl group, a C 1-6 group alkoxycarbonyl-C 1-6 alkyl, 4-10 membered heterocyclic-C 1-6 alkyl (here, the 4-10 membered heterocyclic ring may also be substituted with C 1-6 alkyl or C 1- 6 alkylsulfonyl), C 1-6 alkoxy, C 3-10 cycloalkyl-C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl An oxy group, a C 1-6 alkylsulfonylamino group, a hydroxyl group, a cyano group, a nitro group, a tetrazolyl group, or a group represented by the following formula (2) or formula (3): (wherein R 10 and R 11 each independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group; and R 12 represents a C 1-20 alkyl group, a C 2-6 alkenyl group, a halogen C 1-6 alkyl group, a C 2-7 alkyl fluorenyl group, a C 6-10 aryl group, a 4-10 membered ring heterocyclic group (which may also be substituted with a halogen atom), a C 3-10 cycloalkyl-C 1-6 alkyl group, Amino C 1-6 alkyl, hydroxy-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, carboxy-C 1-6 alkane , C 1-6 alkoxycarbonyl-C 1-6 alkyl, amine mercapto-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 6- 10 aryl-C 1-6 alkyl (here, the C 6-10 aryl group may also be substituted with a halogen atom, a C 1-6 alkyl group, a halogen C 1-6 alkyl group, a C 1-6 alkyl sulfonate. Amidino or carboxy) or a 4-10 membered heterocyclic-C 1-6 alkyl group (here, the heterocyclic ring may also be substituted with a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group or a side oxygen group). Base); l represents an integer from 1 to 3, and n represents an integer from 0 to 2; R 5 , R 6 and R 7 independently of each other represent a hydrogen atom, a halogen atom, a cyano group or a carboxyl group; and R 8 represents a C 1-6 alkane; , C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, trialkyl decyl-C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-10 cycloalkyl (here, a cycloalkyl group may also be substituted with a halogen atom), C 3-10 cycloalkyl-C 1-6 alkyl (here, a cycloalkyl group may also be substituted with C) 1-6 alkyl), C 6-10 aryl (here, the C 6-10 aryl group may also be substituted with a halogen atom, a cyano group, a halogen C 1-6 alkoxy group, an amine group, a dialkylamine , C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylthio or C 6-10 aryl-C 1-6 alkyloxy), C 6-10 aryl - C 1-6 alkyl (here, the C 6-10 aryl group may also be substituted with a halogen atom, a C 1-6 alkyl group, a halogen C 1-6 alkoxy group or a halogen C 1-6 alkyl group), 4 a 10-membered heterocyclic-C 1-6 alkyl group (here, a heterocyclic ring may also be substituted with a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group) or a 4-10 membered heterocyclic ring; R 13 or R 14 independently of each other represents a hydrogen atom or a halogen atom; [Chem. 4] R 15 represents a hydrogen atom, a hydroxyl group, or a ring When it is a single bond, it represents a side oxy group].

[2]如上述[1]之化合物或其鹽或其等之溶媒合物，其中，A環為選自苯基、吡啶基、吲哚基、吡基、嗒基、嘧啶基、噻唑基及二唑基的基，Z為O。 [2] The compound of the above [1], or a salt thereof or a solvent thereof, wherein the ring A is selected from the group consisting of a phenyl group, a pyridyl group, a fluorenyl group, and a pyridyl group. Base Base, pyrimidinyl, thiazolyl and The base of the oxazolyl group, Z is O.

[3]如上述[1]或[2]之化合物或其鹽或其等之溶媒合物，其中，一般式(1)中，R1、R2、R3及R4中之一者為C1-6烷基磺醯基、4-10員雜環-C1-6烷基(此處，4-10員雜環上亦可具有上述取代基)或式(2)所示之基，其餘為不存在或氫原子、鹵素原子、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基-C1-6烷 氧基。 [3] The compound of the above [1] or [2] or a salt thereof or a solvent thereof, wherein, in the general formula (1), one of R 1 , R 2 , R 3 and R 4 is a C 1-6 alkylsulfonyl group, a 4-10 membered heterocyclic ring-C 1-6 alkyl group (here, the 4-10 membered heterocyclic ring may have the above substituent) or a group represented by the formula (2) the remainder is absent or a hydrogen atom, a halogen atom, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl -C 1-6 alkoxy.

[4]如上述[1]至[3]中任一項之化合物或其鹽或其等之溶媒合物，其中，式(2)所示之基為C1-6烷基-S(O)nCH2-、C6-10芳基-C1-6烷基-S(O)nCH2-或4-10員雜環-C1-6烷基-S(O)nCH2-(此處，芳基或雜環亦可具有上述取代基，n表示0~2之整數)。 [4] The compound of any one of the above [1] to [3] or a salt thereof or a solvent thereof, wherein the group represented by the formula (2) is a C 1-6 alkyl-S (O) n CH 2 -, C 6-10 aryl-C 1-6 alkyl-S(O) n CH 2 - or 4-10 membered heterocyclic-C 1-6 alkyl-S(O) n CH 2 - (here, the aryl or heterocyclic ring may have the above substituent, and n represents an integer of 0 to 2).

[5]如上述[1]至[4]中任一項之化合物或其鹽或其等之溶媒合物，其係選自下述之化合物群：第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-硝基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯胺)苯基)螺[唍-2,4’-哌啶]-1’-羧 酸酯、第三丁基6-(4-羥基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)氧基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基亞磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-甲基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-甲氧基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((甲基磺醯基)甲基)-3-丙氧基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-(環丙基甲氧基)-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((1-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((2-甲基磺醯基)丙烷-2-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(1H-四唑-1-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯基)甲基-N-哌啶基)螺[唍-2,4’-哌啶]-1’-羧酸酯、乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲氧基乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-雙(三氟甲基)苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、吡啶-4-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、吡啶-3-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、吡啶-2-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氯-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-1-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、氧雜環丁烷-3-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 四氫-2H-哌喃-4-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4,4-二氟環己基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((吡啶-4-基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苯基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((十二烷基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((十二烷基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((烯丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((2-甲氧基乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((環丙基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((環己基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡啶-3-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、環丙基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯、環丁基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1-甲基環丙基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(6-((甲基磺醯基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-((甲基磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-((甲基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基3-羥基-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)苯基)-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基4,4-二氘-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基4-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氰基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-[4-{(2-(異丙基磺醯基)甲基)苯基}]螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((2-氟乙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-(((氰基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((氰基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、 第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、異丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、異丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1-環丙基乙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(異丙基-d7)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(第三丁基-d9)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯、(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(R)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(R)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(R)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 新戊基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟異丙基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟異丙基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3-胺基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(S)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(R)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3-(3,3-二氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((甲基磺醯基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-((4-(1’-第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)丁酸、第三丁基6-(4-(((4-胺基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,3,4,4,4-五氟丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(乙基-d5)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(異丙基-d7)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 (第三丁基-d9)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1,1,1,3,3,3-六氟丙烷-2-基-2-d1)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1-(第三丁氧基羰基)哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1-甲基哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 新戊基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((苄基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((苄基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((4-氟苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((4-(三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((2-甲基苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((2-三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、第三丁基6-(4-(((4-(甲基磺醯基)苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-(甲基磺醯基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第二丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-甲基戊烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-甲基戊烷-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-甲基丁-3-烯-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基丁-3-炔-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-甲基戊-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、己-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氰基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,3,5-三甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1R,2S,4S)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1S,2R,4R)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(2-甲基氧雜環丁烷-3-基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 環己基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-1-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,3,4,4,4-五氟丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(甲基-d3)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 (乙基-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(異丙基-d7)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(第三丁基-d9)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1,1,1,3,3,3-六氟-2-丙烷-2-基-2-d1)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-苯基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-苯基丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基-1-苯基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基-4-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(三氟甲氧基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,6-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,3-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-6-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-氯-4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-雙(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(全氟苯基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、呋喃-2-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(三氟甲氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-(二甲基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-(二乙基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三戊基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(甲基硫基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,3-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-6-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 4-氯-2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-3-甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟-3-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟-5-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4,6-三氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(苄基氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(苯基-2,3,4,5,6-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-羧酸酯、新戊基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-((((6-(1’-(第三丁氧基羰基螺(唍-2,4’-哌啶)-6-基)吡啶-3-基)甲基)磺醯基)甲基)吡啶-1-氧化物、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、 1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((吡-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-(((噻唑-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((嘧啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)乙基)亞磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(2-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((1H-咪唑-1-基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(2-乙氧基-2-側氧基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(4-(1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苯基)醋酸、異丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯及異丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯。 [5] The compound of any one of the above [1] to [4] or a salt thereof or a solvent thereof, which is selected from the group consisting of the following compound: tert-butyl 6-(4-(A) Sulfosyl)phenyl) snail Terpene-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(3-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-nitrophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonamide)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-hydroxyphenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)oxy)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfinyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-methyl-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-methoxy-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)-3-propoxyphenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-(cyclopropylmethoxy)-4-((methylsulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1-methylsulfonyl)ethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((2-methylsulfonyl)propan-2-yl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(1H-tetrazol-1-yl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(methylsulfonyl)indol-1-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(5-(methylsulfonyl)indol-1-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonyl)methyl-N-piperidinyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methoxyethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, benzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3,5-bis(trifluoromethyl)benzyl 6-(4-((methylsulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-4-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-3-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-2-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trichloro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-1-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, oxetan-3-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tetrahydro-2H-piperidin-4-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4,4-difluorocyclohexyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3-fluoro-4-((methyl sulfonate) Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3-chloro-4-((methyl sulfonate) Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3,5-difluoro-4-(( Methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((pyridin-4-ylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((phenylthio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((phenylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazol-2-yl)sulfide) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazol-2-yl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((dodecylthio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((dodecylidene)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylidenethio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((propylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((allylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-methoxyethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((cyclopropylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((cyclohexylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-3-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-4-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, cyclopropylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Terpene-2,4'-piperidine]-1'-carboxylate, cyclobutylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-methylcyclopropyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclobutyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyridinium -2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(6-((methylsulfonyl)methyl)anthracene -3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)thiazol-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)thiazol-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-((methylsulfonyl)methyl)thiazol-5-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 3-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl)-3-oxooxy snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 4,4-diin-6-(4-((methylsulfonyl)methyl)phenyl)[ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 4-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-cyano-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)-3,5-di Fluorophenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-[4-{(2-(isopropylsulfonyl)methyl)phenyl}] snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((isopropylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((isopropylsulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-fluoroethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-(((cyanomethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((cyanomethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-(((3,3,3-trifluoropropyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((3,3,3-three) Fluoropropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((3,3,3-trifluoropropyl)) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-hydroxypropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, isopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, isobutyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4-piperidinyl-1'-carboxylate, 1-cyclopropylethyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((3-hydroxypropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-((3-hydroxypropyl)sulfonate Mercapto)methyl)pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (isopropyl-d7)6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(5-((3-(hydroxypropyl))sulfonyl)methyl)pyridine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl)[ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3-(hydroxypropyl))sulfonyl)methyl)pyrimidin-2-yl )[ 唍-2,4-piperidinyl-1'-carboxylate, (R)-tert-butyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (R)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (R)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2-methyl)) Propyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, (R)-1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, (S)-t-butyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (S)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (S)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2-methyl)) Propyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, (S)-1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-(((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridine -2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2,2-dimethylpropane) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy-2,2) -Dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) screw[ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoroisopropyl 6-(5-((3-(methoxypropyl))sulfonyl) Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((((methylamino))-3-yl)methyl)sulfonate Base) methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-(((3-methyloxetan-3-yl)methyl)sulfonyl) )methyl)pyrimidin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))))))))) -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))sulfonyl)methyl)pyridine-2- Snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoroisopropyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))sulfonyl) )methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl) Methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-aminopropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (S)-t-butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (R)-t-butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-(3,3-difluoropyrrolidin-1-yl)propyl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((methylsulfonyl)propyl)))))))))))) [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((4-methoxy-4-oxobutyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidinyl-1'-carboxylate, 4-((4-(1'-t-butoxycarbonyl)) snail [ Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)butyric acid, tert-butyl 6-(4-((4-amino-4-yloxybutyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1-ethoxy-2-methyl-1-oxopropane-2-) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3,3,4,4,4-pentafluorobutyl 6-(4-((benzylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((pyridin-4-ylmethyl)sulfonyl) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((benzylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((benzylsulfonyl)) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4 -((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (ethyl-d5)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (isopropyl-d7)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1)6-(4-(( Benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-(t-butoxycarbonyl)piperidin-4-yl)methyl 6-(4-((benzylsulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-methylpiperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylbenzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)benzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3,5-di Fluorophenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((benzylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((benzylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((4-)fluoro))))))))) 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((4-fluorobenzyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((4-(4-(4-(yl))))))))))) [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((4-(trifluoromethyl)benzyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((4-(trifluoromethyl)benzyl))sulfonyl)methyl)pyridine- 2-base) snail [ Indole-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-(((2-methylbenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((2-(trifluoromethyl))benzyl)sulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-((((((((((((((((((((((( 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, 3-((((((())))) Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, 2-((((()))) 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, tert-butyl 6-(4-((4-(methylsulfonyl))benzyl) Base) thio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((4-(methylsulfonyl)benzyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isobutyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, second butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, third pentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-methylpentan-2-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-methylpentan-3-yl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-methylbut-3-en-2-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methylbut-3-yn-2-yl-6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-methylpent-1-yn-3-yl-6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, hex-1-yn-3-yl-6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-cyanoethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, cyclohexyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)cyclohexyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,3,5-trimethylcyclohexyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, (1R, 2S, 4S)-2-isopropyl-4-methylcyclohexyl 6-(4-(((pyridine-2-) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1S, 2R, 4R)-2-isopropyl-4-methylcyclohexyl 6-(4-(((pyridine-2-) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (2-methyloxetan-3-yl)methyl 6-(4-(((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, cyclohexylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-1-ylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidinyl-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,3,4,4,4-pentafluorobutyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4 -(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (methyl-d3)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, (ethyl-d5)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, (isopropyl-d7)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) )screw[ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, (1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1)6-(4 -(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-phenylethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-phenylpropyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methyl-1-phenylpropan-2-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-phenylbutan-2-yl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-methyl-4-phenylbutan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-(trifluoromethoxy)benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-methylbenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(trifluoromethyl)benzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylbenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)benzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,3-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,5-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-6-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-4-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dimethylbenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-bis(trifluoromethyl)benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (perfluorophenyl)methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, furan-2-ylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-cyanophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidinyl-1'-carboxylate, 3-cyanophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-cyanophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 2-(trifluoromethoxy)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-(dimethylamino)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-(diethylamino)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylphenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-(tripentyl)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-(methylthio)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,3-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-difluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-difluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,5-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-6-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-4-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-2-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dimethylphenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dimethylphenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3-methylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoro-3-(trifluoromethyl)phenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoro-5-(trifluoromethyl)phenyl 6-(4-((pyridin-2-ylmethyl))sulfonate Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,4,6-trichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3,5-dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(benzyloxy)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, (phenyl-2,3,4,5,6-d5)6-(4-(((pyridin-2-ylmethyl))) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-carboxylate, neopentyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonate Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 2-((((6-(1'-)(t-butoxycarbonyl snail) Indole-2,4'-piperidine)-6-yl)pyridin-3-yl)methyl)sulfonyl)methyl)pyridine-1-oxide, tert-butyl 6-(5-((( Pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-(((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, isobutyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-(((5-fluoropyridin-2-yl))) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-(((5-fluoropyridin-2-yl))) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Pyrimidine-2-yl snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidine- 2-based snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)) Pyrimidine-2-yl snail 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-(((6-methylpyridin-2-yl)methyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-((thiazolyl-4-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((((3-isopropyl-1,2,4-) Diazol-5-yl)methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((pyrimidin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2- Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)sulfinyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)))))) Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)propyl)))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-(((2-(pyridin-2-yl)ethyl)))sulfonyl)methyl)phenyl )[ 唍-2,4'-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-(((2-pyridin-2-yl)ethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(2-methylsulfonyl)ethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1H-imidazol-1-yl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(2-ethoxy-2-oxoethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-(4-(1'-(t-butoxycarbonyl)) snail [ 唍-2,4'-piperidinyl]-6-yl)phenyl)acetic acid, isopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine-2 -base) snail 唍-2,4'-piperidine)-1'-carboxylate and isopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidinyl-1'-carboxylate.

[6]一種醫藥組成物，係含有上述[1]至[5]中任一項之化合物 或其鹽或其等之溶媒合物、及作為醫藥所容許的載體。 [6] A pharmaceutical composition comprising the compound according to any one of [1] to [5] above Or a salt thereof or a solvent thereof, and a carrier which is acceptable as a medicine.

[7]一種胰島素分泌促進劑，係以上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 [7] An insulin secretion-promoting agent, which comprises the compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof or the like as an active ingredient.

[8]一種血糖降低劑，係以上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 [8] A blood sugar lowering agent, which comprises the compound of any one of the above [1] to [5] or a salt thereof or a solvent mixture thereof as an active ingredient.

[9]一種糖尿病之預防及/或治療劑，係以上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 [9] A preventive and/or therapeutic agent for diabetes, which comprises the compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof or the like as an active ingredient.

[10]一種胰島素分泌促進方法，係投予上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物的有效量。 [10] A method for promoting the secretion of insulin, which is an effective amount of the compound of any one of the above [1] to [5], or a salt thereof or a solvent thereof.

[11]一種血糖降低方法，係投予上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物的有效量。 [11] A method for lowering blood sugar, which is an effective amount of a compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof.

[12]一種糖尿病之預防及/或治療方法，係投予上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物的有效量。 [12] A method for the prevention and/or treatment of diabetes, which is an effective amount of the compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof.

[13]如上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物，係用於促進胰島素分泌。 [13] The compound of any one of the above [1] to [5], or a salt thereof or a solvent thereof, for promoting insulin secretion.

[14]如上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物，係用於降低血糖。 [14] The compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof, for use in lowering blood sugar.

[15]如上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物，係用於糖尿病之預防及/或治療。 [15] The compound of any one of the above [1] to [5] or a salt thereof or a solvent thereof, for use in the prevention and/or treatment of diabetes.

[16]如上述[1]至[5]中任一項之化合物或其鹽或其等之溶媒合物之用途，係用於製造胰島素分泌促進劑、血糖降低劑或糖尿病之預防及/或治療劑。 [16] The use of the compound of any one of the above [1] to [5], or a salt thereof, or a solvent thereof, for the prevention of insulin secretion promoter, blood glucose lowering agent or diabetes and/or Therapeutic agent.

本發明之螺哌啶衍生物或其鹽或其等之溶媒合物，係具有強力地促進來自胰臟β細胞之胰島素分泌之作用的可經口投予的低分子性化合物，可用於作為包括人類之哺乳類之因高血糖所引起之疾病、例如糖尿病的預防及/或治療劑。 The spiropiperidine derivative of the present invention or a salt thereof or a solvent thereof, which is an orally administrable low molecular compound which strongly promotes the action of insulin secretion from pancreatic β cells, can be used as A disease caused by hyperglycemia in human mammals, such as a preventive and/or therapeutic agent for diabetes.

本說明書中，作為「鹵素原子」可舉例如氟原子、氯原子、溴原子或碘原子等。 In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

本說明書中，作為「氫原子」可舉例如氫原子(H)或氘原子(D)。 In the present specification, examples of the "hydrogen atom" include a hydrogen atom (H) or a halogen atom (D).

本說明書中，所謂「C1-20烷基」係指直鍵或分枝鏈之碳數1~20的烷基，可舉例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、正戊基、正辛基、正壬基、正癸基、正十二烷基、正十三烷基、正十四烷基、正十五烷基、正十六烷基、正十七烷基、正十八烷基、正十九烷基、廿烷基等。 In the present specification, the term "C 1-20 alkyl group" means an alkyl group having 1 to 20 carbon atoms in a straight bond or a branched chain, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a n-butyl group. Base, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-pentyl, n-octyl, n-decyl, n-decyl , n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, anthracene Alkyl and the like.

本說明書中，所謂「C1-6烷基」係指直鏈或分枝鏈之碳數1~6之烷基，可舉例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、1-甲基丙基、正戊基、2-甲基丁基、2,2-二甲基丙基、新戊基、正己基、1,3-二甲基丁基、3-甲基戊基等。 In the present specification, the term "C 1-6 alkyl group" means an alkyl group having 1 to 6 carbon atoms in a straight chain or a branched chain, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a n-butyl group. Base, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, neopentyl, n-hexyl, 1,3- Dimethyl butyl, 3-methylpentyl and the like.

本說明書中，所謂「鹵C1-6烷基」係指取代有1個~可取 代之最大數之相同或相異之鹵素原子的C1-6烷基，可舉例如單氟甲基、二氟甲基、三氟甲基、單氯甲基、二氯甲基、三氯甲基、單溴甲基、單碘甲基、2-氟乙基、2,2,2-三氟乙基、2,2,2-三氯乙基、1,1,1-三氟-2-甲基丙烷-2-基、1,1-二甲基-2,2,2-三氟乙基、1,1-二甲基-2,2,2-三氯乙基、3,3,3-三氟丙基等。 In the present specification, the term "halo C 1-6 alkyl" means substituted with one to replace it may be the same or different C 1-6 alkyl of a halogen atom of the maximum number includes, for example monofluoromethyl, Difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl, monoiodomethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl Base, 2,2,2-trichloroethyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1,1-dimethyl-2,2,2-trifluoroethyl 1,1-dimethyl-2,2,2-trichloroethyl, 3,3,3-trifluoropropyl, and the like.

本說明書中，作為「C3-10環烷基」可舉例如碳數3~10、較佳碳數3~8、更佳碳數3~6之單環式、多環式或縮合環式的環烷基。作為此種環烷基，可舉例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、金剛烷基等。 In the present specification, the "C 3-10 cycloalkyl group" may, for example, be a monocyclic, polycyclic or condensed ring having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Cycloalkyl. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and an adamantyl group.

本說明書中，作為「C2-6烯基」可舉例如乙烯基、丙-1-烯-1-基(丙烯基)、丙-2-烯-1-基(烯丙基)、異丙烯基、丁-1-烯-1-基、丁-2-烯-1-基(丁烯基)、丁-3-烯-1-基、2-甲基丙-2-烯-1-基、1-甲基丙-2-烯-1-基、戊-1-烯-1-基、戊-2-烯-1-基、戊-3-烯-1-基、戊-4-烯-1-基、3-甲基丁-2-烯-1-基、3-甲基丁-3-烯-1-基、己-1-烯-1-基、己-2-烯-1-基、己-3-烯-1-基、己-4-烯-1-基、己-5-烯-1-基、4-甲基戊-3-烯-1-基等。 In the present specification, examples of the "C 2-6 alkenyl group" include a vinyl group, a prop-1-en-1-yl group (propylene group), a prop-2-en-1-yl group (allyl group), and an isopropylene group. , but-1-en-1-yl, but-2-en-1-yl (butenyl), but-3-en-1-yl, 2-methylprop-2-en-1-yl , 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-ene -1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl, hex-2-ene-1 -yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl and the like.

本說明書中，作為「C2-6炔基」可舉例如乙炔基、丙炔基、3-甲基-1-戊炔-3-基、1-己炔-3-基等。 In the present specification, examples of the "C 2-6 alkynyl group" include an ethynyl group, a propynyl group, a 3-methyl-1-pentyn-3-yl group, and a 1-hexyn-3-yl group.

本說明書中，作為「C1-6烷氧基」可舉例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、正戊氧基、異戊氧基、新戊氧基、正己氧 基、異己氧基等。 In the present specification, examples of the "C 1-6 alkoxy group" include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a second butoxy group. And a third butoxy group, a n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, a n-hexyloxy group, an isohexyloxy group, and the like.

本說明書中，作為「鹵C1-6烷氧基」，係取代有1個~可取代之最大數之相同或相異之鹵素原子的C1-6烷氧基，可舉例如單氟甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基。 C of the same or different halogen atoms, the maximum number of the present specification, "halo C 1-6 alkoxy group" is substituted with a - line substitutable alkoxy of 1-6 includes, for example monofluorophosphate A Oxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy.

本說明書中，作為「C1-7烷醯基」可舉例如甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、三甲基乙醯基等。 In the present specification, examples of the "C 1-7 alkyl fluorenyl group" include a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentamidine group, an isoamyl group, a trimethyl acetyl group, and the like. .

本說明書中，作為「C1-6烷基磺醯基」可舉例如甲基磺醯基、乙基磺醯基、正丙基磺醯基、異丙基磺醯基、正丁基磺醯基、異丁基磺醯基、第二丁基磺醯基、第三丁基磺醯基、正戊基磺醯基、異戊基磺醯基、新戊基磺醯基、2-甲基丁基磺醯基、1-甲基丁基磺醯基、1-乙基丙基磺醯基、2,2-二甲基丙基磺醯基、正己基磺醯基、4-甲基戊基磺醯基、3-甲基戊基磺醯基、2-甲基戊基磺醯基、1-甲基戊基磺醯基、3,3-二甲基丁基磺醯基、2,2-二甲基丁基磺醯基、1,1-二甲基丁基磺醯基、1,2-二甲基丁基磺醯基、1,3-二甲基丁基磺醯基、2,3-二甲基丁基磺醯基、1-乙基丁基磺醯基、2-乙基丁基磺醯基等。 In the present specification, examples of the "C 1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonate. Base, isobutylsulfonyl, t-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 2-methyl Butylsulfonyl, 1-methylbutylsulfonyl, 1-ethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, n-hexylsulfonyl, 4-methylpentyl Sulfosyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2, 2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl and the like.

本說明書中，作為「C1-6烷基磺醯氧基」可舉例如甲基磺醯氧基、乙基磺醯氧基、正丙基磺醯氧基、異丙基磺醯氧基、正丁基磺醯氧基、異丁基磺醯氧基、第二丁基磺醯氧基、第三丁基磺醯氧基、正戊基磺醯氧基、異戊基磺醯氧基、新戊 基磺醯氧基、2-甲基丁基磺醯氧基、1-甲基丁基磺醯氧基、1-乙基丙基磺醯氧基、2,2-二甲基丙基磺醯氧基、正己基磺醯氧基、4-甲基戊基磺醯氧基、3-甲基戊基磺醯氧基、2-甲基戊基磺醯氧基、1-甲基戊基磺醯氧基、3,3-二甲基丁基磺醯氧基、2,2-二甲基丁基磺醯氧基、1,1-二甲基丁基磺醯氧基、1,2-二甲基丁基磺醯氧基、1,3-二甲基丁基磺醯氧基、2,3-二甲基丁基磺醯氧基、1-乙基丁基磺醯氧基、2-乙基丁基磺醯氧基等。 In the present specification, examples of the "C 1-6 alkylsulfonyloxy group" include a methylsulfonyloxy group, an ethylsulfonyloxy group, a n-propylsulfonyloxy group, and an isopropylsulfonyloxy group. N-butylsulfonyloxy, isobutylsulfonyloxy, t-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy, isopentylsulfonyloxy, Neopentylsulfonyloxy, 2-methylbutylsulfonyloxy, 1-methylbutylsulfonyloxy, 1-ethylpropylsulfonyloxy, 2,2-dimethylpropyl Sulfomethoxy, n-hexylsulfonyloxy, 4-methylpentylsulfonyloxy, 3-methylpentylsulfonyloxy, 2-methylpentylsulfonyloxy, 1-methylpentyl Sulfosulfonyloxy, 3,3-dimethylbutylsulfonyloxy, 2,2-dimethylbutylsulfonyloxy, 1,1-dimethylbutylsulfonyloxy, 1, 2-Dimethylbutylsulfonyloxy, 1,3-dimethylbutylsulfonyloxy, 2,3-dimethylbutylsulfonyloxy, 1-ethylbutylsulfonyloxy , 2-ethylbutylsulfonyloxy and the like.

本說明書中，作為「C1-6烷基磺醯基胺基」，可舉例如甲基磺醯基胺基、乙基磺醯基胺基、正丙基磺醯基胺基、異丙基磺醯基胺基、正丁基磺醯基胺基、異丁基磺醯基胺基、第二丁基磺醯基胺基、第三丁基磺醯基胺基、正戊基磺醯基胺基、異戊基磺醯基胺基、新戊基磺醯基胺基、2-甲基丁基磺醯基胺基、1-甲基丁基磺醯基胺基、1-乙基丙基磺醯基胺基、2,2-二甲基丙基磺醯基胺基、正己基磺醯基胺基、4-甲基戊基磺醯基胺基、3-甲基戊基磺醯基胺基、2-甲基戊基磺醯基胺基、1-甲基戊基磺醯基胺基、3,3-二甲基丁基磺醯基胺基、2,2-二甲基丁基磺醯基胺基、1,1-二甲基丁基磺醯基胺基、1,2-二甲基丁基磺醯基胺基、1,3-二甲基丁基磺醯基胺基、2,3-二甲基丁基磺醯基胺基、1-乙基丁基磺醯基胺基、2-乙基丁基磺醯基胺基等。 In the present specification, examples of the "C 1-6 alkylsulfonylamino group" include a methylsulfonylamino group, an ethylsulfonylamino group, a n-propylsulfonylamino group, and an isopropyl group. Sulfhydrylamino, n-butylsulfonylamino, isobutylsulfonylamino, t-butylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonyl Amino, isoamylsulfonylamino, neopentylsulfonylamino, 2-methylbutylsulfonylamino, 1-methylbutylsulfonylamino, 1-ethylpropane Sulfosylamino, 2,2-dimethylpropylsulfonylamino, n-hexylsulfonylamino, 4-methylpentylsulfonylamino, 3-methylpentylsulfonate Amino group, 2-methylpentylsulfonylamino group, 1-methylpentylsulfonylamino group, 3,3-dimethylbutylsulfonylamino group, 2,2-dimethyl Butylsulfonylamino, 1,1-dimethylbutylsulfonylamino, 1,2-dimethylbutylsulfonylamino, 1,3-dimethylbutylsulfonyl Amino, 2,3-dimethylbutylsulfonylamino, 1-ethylbutylsulfonylamino, 2-ethylbutylsulfonylamino and the like.

本說明書中，作為「C6-10芳基」可舉例如苯基、萘基、 薁基、二氫茚基等。 In the present specification, examples of the "C 6-10 aryl group" include a phenyl group, a naphthyl group, an anthracenyl group, and an indoline group.

本說明書中，「4-10員雜環基」係指含有1至4個選自氧原子、硫原子及氮原子之雜原子的4-10員的單環式、多環式或縮合環式的飽和或不飽和雜環基，可舉例如氧雜環丁基、吡咯啶基、哌啶基、哌基、啉基、呋喃基、噻吩基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、吡唑基、二唑基、噻二唑基、***基、四唑基、吡啶基、嘧啶基、吡基、嗒基、苯并呋喃基、二氫苯并呋喃基、異苯并呋喃基、苯并噻吩基、吲哚基、二氫吲哚基、異吲哚基、吲唑基、苯并咪唑基、苯并唑基、苯并異唑基、苯并噻唑基、苯并異噻唑基、苯并二唑基、苯并噻二唑基、苯并***基、喹啉基、異喹啉基、啉基、喹唑啉基、喹啉基、呔基、啶基、嘌呤基、喋啶基、呋喃并吡啶基、噻吩并吡啶基、吡咯并吡啶基、唑并吡啶基、噻唑并吡啶基、咪唑并吡啶基等。 In the present specification, the "4-10 membered heterocyclic group" means a monocyclic, polycyclic or condensed ring of 4 to 10 members having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. The saturated or unsaturated heterocyclic group may, for example, be oxetanyl, pyrrolidinyl, piperidinyl or piperidin base, Lolinyl, furyl, thienyl, pyrrolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, Diazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridyl Base Base, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothienyl, fluorenyl, indanyl, isodecyl, oxazolyl, benzimidazolyl, benzene and Azolyl, benzopyrene Azolyl, benzothiazolyl, benzisothiazolyl, benzo Diazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolyl, Olinyl, quinazolinyl, quin Olinyl group, hydrazine base, Pyridyl, fluorenyl, acridinyl, furopyridinyl, thienopyridyl, pyrrolopyridinyl, Zoxalopyridyl, thiazolopyridyl, imidazopyridyl and the like.

本說明書中，作為「C1-6烷氧基-C1-6烷基」，可舉例如甲氧基甲基、乙氧基甲基、正丙氧基甲基、異丙氧基甲基、甲氧基乙基、乙氧基乙基等。 In the present specification, examples of the "C 1-6 alkoxy-C 1-6 alkyl group" include a methoxymethyl group, an ethoxymethyl group, a n-propoxymethyl group, and an isopropoxymethyl group. , methoxyethyl, ethoxyethyl and the like.

本說明書中，作為「C3-10環烷基-C1-6烷基」，可舉例如環丙基甲基、1-甲基環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環己基甲基、環辛基甲基等。 In the present specification, examples of the "C 3-10 cycloalkyl-C 1-6 alkyl group" include a cyclopropylmethyl group, a 1-methylcyclopropylmethyl group, a cyclobutylmethyl group, and a cyclopentylmethyl group. , cyclohexylmethyl, cyclohexylmethyl, cyclooctylmethyl and the like.

本說明書中，作為「C3-10環烷基-C1-6烷氧基」，可舉例如 環丙基甲氧基、環丁基甲氧基、環戊基甲氧基、環己基甲氧基、環己基甲氧基、環辛基甲氧基等。 In the present specification, examples of the "C 3-10 cycloalkyl-C 1-6 alkoxy group" include a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, and a cyclohexylmethoxy group. , cyclohexylmethoxy, cyclooctylmethoxy, and the like.

本說明書中，作為「C6-10芳基-C1-6烷基」，可舉例如苄基、苯乙基、苯基丙基、萘基甲基等。 In the present specification, examples of the "C 6 - 10 aryl-C 1-6 alkyl group" include a benzyl group, a phenethyl group, a phenylpropyl group, and a naphthylmethyl group.

本說明書中，作為「4-10員雜環-C1-6烷基」，可舉例如氧雜環丁基甲基、吡啶基甲基、吡基甲基、咪唑基甲基、***基甲基、四唑基甲基等。 In the present specification, examples of the "4-10 member heterocyclic-C 1-6 alkyl group" include oxetanylmethyl group, pyridylmethyl group, and pyridyl. Methyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl, and the like.

本說明書中，羧基-C1-6烷基、C1-6烷氧基羰基-C1-6烷基、羥基-C1-6烷基、氰基-C1-6烷基、胺甲醯基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、三烷基矽基-C1-6烷基、二烷基胺基、C1-6烷基硫基等中之C1-6烷基或C1-6烷氧基部分，可舉例如與上述C1-6烷基或C1-6烷氧基相同之基。又，二烷基胺基及三烷基矽基中之烷基較佳亦為C1-6烷基。 In the present specification, carboxy-C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, hydroxy-C 1-6 alkyl, cyano-C 1-6 alkyl, amine A Mercapto-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, trialkylsulfonyl-C 1-6 alkyl, dialkylamino, C 1-6 The C 1-6 alkyl group or the C 1-6 alkoxy moiety in the alkylthio group or the like may, for example, be the same group as the above C 1-6 alkyl group or C 1-6 alkoxy group. Further, the alkyl group in the dialkylamino group and the trialkylfluorenyl group is preferably a C 1-6 alkyl group.

一般式(1)中，作為A環中之C6-10芳基，較佳為苯基、萘基，更佳為苯基。 In the general formula (1), as the C 6-10 aryl group in the ring A, a phenyl group or a naphthyl group is preferred, and a phenyl group is more preferred.

一般式(1)中，作為A環中之4-10員雜環基，較佳為氧雜環丁基、哌啶基、噻唑基、噻二唑基、***基、四唑基、吡啶基、嘧啶基、吡基、嗒基、二唑基、二氫吲哚基、二氫苯并呋喃基等。 In the general formula (1), as the 4-10 membered heterocyclic group in the ring A, an oxetanyl group, a piperidinyl group, a thiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group or a pyridine is preferred. Base, pyrimidinyl, pyridyl Base base, A oxazolyl group, a dihydroindenyl group, a dihydrobenzofuranyl group or the like.

一般式(1)中，作為R9中之C1-6烷基，較佳為C1-4烷基，更佳為甲基、乙基。 In the general formula (1), as the C 1-6 alkyl group in R 9 , a C 1-4 alkyl group is preferred, and a methyl group or an ethyl group is more preferred.

一般式(1)中，作為R9中之C1-7烷醯基，較佳為C2-5烷醯 基，更佳為乙醯基、丙醯基。 In the general formula (1), as the C 1-7 alkyl fluorenyl group in R 9 , a C 2-5 alkyl fluorenyl group is preferred, and an ethyl fluorenyl group or a propyl fluorenyl group is more preferred.

一般式(1)中，作為R9中之C1-6烷基磺醯基，較佳為C1-4烷基磺醯基，更佳為甲基磺醯基、乙基磺醯基。 In the general formula (1), as the C 1-6 alkylsulfonyl group in R 9 , a C 1-4 alkylsulfonyl group is preferred, and a methylsulfonyl group or an ethylsulfonyl group is more preferred.

一般式(1)中，作為m，較佳為0~2之整數，更佳為2。 In the general formula (1), m is preferably an integer of 0 to 2, more preferably 2.

一般式(1)中，作為R1、R2、R3、R4中之鹵素原子，較佳為氟原子、氯原子。 In the general formula (1), the halogen atom in R 1 , R 2 , R 3 or R 4 is preferably a fluorine atom or a chlorine atom.

一般式(1)中，作為R1、R2、R3、R4中之C1-6烷基，較佳為C1-4烷基，更佳為甲基、乙基。 In the general formula (1), the C 1-6 alkyl group in R 1 , R 2 , R 3 and R 4 is preferably a C 1-4 alkyl group, more preferably a methyl group or an ethyl group.

一般式(1)中，作為R1、R2、R3、R4中之4-10員雜環-C1-6烷基，較佳為5-10員雜環-C1-6烷基，更佳為5-6員雜環-C1-4烷基。此處，作為5員雜環基，較佳為吡咯基、咪唑基、***基、四唑基。又，作為C1-4烷基，較佳為甲基、乙基。作為6員雜環，可舉例如吡啶基、哌啶基、吡基、嗒基、嘧啶基。作為9員雜環，可舉例如吲哚基。此處，作為於4-10員雜環上取代之基，較佳為C1-4烷基或C1-4烷基磺醯基，更佳為甲基、乙基、甲基磺醯基、乙基磺醯基。作為4-10員雜環C1-6烷基的具體例，更佳為咪唑基甲基、1-甲基咪唑基甲基、1-甲基磺醯基咪唑基甲基、***基甲基、四唑基甲基。 In the general formula (1), as a 4-10 membered heterocyclic-C 1-6 alkyl group in R 1 , R 2 , R 3 and R 4 , preferably a 5-10 membered heterocyclic-C 1-6 alkane More preferably, it is a 5- to 6-membered heterocyclic-C 1-4 alkyl group. Here, as the 5-membered heterocyclic group, a pyrrolyl group, an imidazolyl group, a triazolyl group, or a tetrazolyl group is preferable. Further, as the C 1-4 alkyl group, a methyl group or an ethyl group is preferred. Examples of the 6-membered heterocyclic ring include a pyridyl group, a piperidinyl group, and a pyridyl group. Base Base, pyrimidinyl group. The 9-membered heterocyclic ring may, for example, be a fluorenyl group. Here, as the group substituted on the 4-10 membered heterocyclic ring, a C 1-4 alkyl group or a C 1-4 alkylsulfonyl group is preferred, and a methyl group, an ethyl group, or a methylsulfonyl group is more preferred. Ethyl sulfonyl. Specific examples of the 4-10 membered heterocyclic C 1-6 alkyl group are more preferably imidazolylmethyl, 1-methylimidazolylmethyl, 1-methylsulfonyl imidazolylmethyl, or triazolylmethyl. Base, tetrazolylmethyl.

一般式(1)中，作為R1、R2、R3、R4中之C1-6烷氧基，較佳為C1-4烷氧基，更佳為甲氧基、乙氧基、正丙氧基、異丙氧基。 In the general formula (1), as the C 1-6 alkoxy group in R 1 , R 2 , R 3 and R 4 , a C 1-4 alkoxy group is preferred, and a methoxy group or an ethoxy group is more preferred. , n-propoxy, isopropoxy.

一般式(1)中，作為R1、R2、R3、R4中之C3-10環烷基-C1-6烷氧基，較佳為C3-8環烷基-C1-6烷氧基，更佳為C3-6環烷基-C1-4烷氧基，再更佳為環丙基甲氧基、環丙基乙氧基、環戊基甲氧基、環己基甲氧基。 General formula (1), examples of R 1, R 2, R 3 , R in the 4 C 3-10 cycloalkyl, -C 1-6 alkoxy, C 3-8 cycloalkyl group is preferably a -C -6 alkoxy group, more preferably C 3-6 cycloalkyl-C 1-4 alkoxy group, still more preferably cyclopropyl methoxy group, cyclopropyl ethoxy group, cyclopentyl methoxy group, Cyclohexylmethoxy.

一般式(1)中，作為R1、R2、R3、R4中之C1-6烷基磺醯基，較佳為C1-4烷基磺醯基，更佳為甲基磺醯基、乙基磺醯基。 In the general formula (1), as the C 1-6 alkylsulfonyl group in R 1 , R 2 , R 3 and R 4 , a C 1-4 alkylsulfonyl group is preferred, and more preferably methylsulfonate. Mercapto, ethyl sulfonyl.

一般式(1)中，作為R1、R2、R3、R4中之C1-6烷基磺醯氧基，較佳為C1-4烷基磺醯氧基，更佳為甲基磺醯氧基、乙基磺醯氧基。 In the general formula (1), as the C 1-6 alkylsulfonyloxy group in R 1 , R 2 , R 3 and R 4 , a C 1-4 alkylsulfonyloxy group is preferred, and more preferably A Alkylsulfonyloxy, ethylsulfonyloxy.

一般式(1)中，作為R1、R2、R3、R4中之C1-6烷基磺醯基胺基，較佳為C1-4烷基磺醯基胺基，更佳為甲基磺醯基胺基、乙基磺醯基胺基。 In the general formula (1), as the C 1-6 alkylsulfonylamino group in R 1 , R 2 , R 3 and R 4 , a C 1-4 alkylsulfonylamino group is preferred, more preferably It is a methylsulfonylamino group or an ethylsulfonylamino group.

一般式(1)中，作為R1、R2、R3、R4中之羧基-C1-6烷基，可舉例如羧基甲基、羥基乙基等。又，作為C1-6烷氧基羰基C1-6烷基，可舉例如乙氧基羰基甲基、異丙氧基羰基甲基等。 In the general formula (1), examples of the carboxy-C 1-6 alkyl group in R 1 , R 2 , R 3 and R 4 include a carboxymethyl group and a hydroxyethyl group. Further, as the C 1-6 alkoxycarbonyl C 1-6 alkyl group includes, for example ethoxycarbonylmethyl, isopropoxycarbonyl group and the like.

式(2)中，作為R10、R11中之鹵素原子，較佳為氟原子、氯原子，更佳為氟原子。 In the formula (2), the halogen atom in R 10 and R 11 is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

式(2)中，作為R10、R11中之C1-6烷基，較佳為C1-4烷基，更佳為甲基。 In the formula (2), the C 1-6 alkyl group in R 10 and R 11 is preferably a C 1-4 alkyl group, more preferably a methyl group.

式(2)中，作為R12中之C1-20烷基，較佳為C1-12烷基，更佳為甲基、乙基、正丙基、異丙基、正丁基、正己基、正辛基、正癸基、正十二烷基。 In the formula (2), as the C 1-20 alkyl group in R 12 , a C 1-12 alkyl group is preferred, and more preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a hexyl group. Base, n-octyl, n-decyl, n-dodecyl.

式(2)中，作為R12中之C2-6烯基，較佳為C2-4烯基，更佳為烯丙基。 In the formula (2), as the C 2-6 alkenyl group in R 12 , a C 2-4 alkenyl group is preferred, and an allyl group is more preferred.

式(2)中，作為R12中之鹵C1-6烷基，較佳為鹵C1-4烷基，更佳為三氟甲基、2,2,2-三氟乙基、3,3,3-三氟丙基。 In the formula (2), the halogen C 1-6 alkyl group in R 12 is preferably a halogen C 1-4 alkyl group, more preferably a trifluoromethyl group, a 2,2,2-trifluoroethyl group, or 3 , 3,3-trifluoropropyl.

式(2)中，作為R12中之C2-7烷醯基，較佳為C2-5烷醯基，更佳為乙醯基、丙醯基。 In the formula (2), as the C 2-7 alkyl fluorenyl group in R 12 , a C 2-5 alkyl fluorenyl group is preferred, and an ethyl fluorenyl group or a propyl fluorenyl group is more preferred.

式(2)中，作為R12中之C6-10芳基，較佳為苯基、萘基，更佳為苯基。 In the formula (2), as the C 6-10 aryl group in R 12 , a phenyl group or a naphthyl group is preferred, and a phenyl group is more preferred.

式(2)中，作為R12中之4-10員雜環基，較佳為4-6員雜環基，較佳為氧雜環丁基、吡咯啶基、四氫哌喃基、四氫呋喃基、噻二唑基、吡啶基、氟吡啶基、二氟吡咯啶基。 In the formula (2), the 4- to 10-membered heterocyclic group in R 12 is preferably a 4- to 6-membered heterocyclic group, preferably an oxetanyl group, a pyrrolidinyl group, a tetrahydropyranyl group or a tetrahydrofuran. Base, thiadiazolyl, pyridyl, fluoropyridyl, difluoropyrrolidinyl.

式(2)中，作為R12中之C3-10環烷基-C1-6烷基，較佳為C3-6環烷基-C1-4烷基，更佳為環丙基甲基、環己基甲基。 In the formula (2), as C 3-10 cycloalkyl-C 1-6 alkyl group in R 12 , preferably C 3-6 cycloalkyl-C 1-4 alkyl group, more preferably cyclopropyl group Methyl, cyclohexylmethyl.

式(2)中，作為R12中之C1-6烷氧基-C1-6烷基，較佳為C1-4烷氧基-C1-4烷基，更佳為甲氧基乙基、乙氧基乙基。 Formula (2), as the 12 R C 1-6 alkoxy -C 1-6 alkyl group, preferably a C 1-4 alkoxy -C 1-4 alkyl group, more preferably a methoxy group Ethyl, ethoxyethyl.

式(2)中，作為羥基C1-6烷基，可舉例如羥基丙基、羥基丁基、羥基戊基等。又，作為氰基-C1-6烷基，可舉例如氰基甲基、氰基乙基等。作為胺基-C1-6烷基，可舉例如胺基乙基、胺基丙基。 In the formula (2), examples of the hydroxy C 1-6 alkyl group include a hydroxypropyl group, a hydroxybutyl group, and a hydroxypentyl group. Further, examples of the cyano-C 1-6 alkyl group include a cyanomethyl group and a cyanoethyl group. The amino-C 1-6 alkyl group may, for example, be an aminoethyl group or an aminopropyl group.

式(2)中，作為R12中之羧基-C1-6烷基，較佳為羧基-C1-4烷基，更佳為羧基甲基、羧基乙基、羧基丙基。 In the formula (2), the carboxy-C 1-6 alkyl group in R 12 is preferably a carboxy-C 1-4 alkyl group, more preferably a carboxymethyl group, a carboxyethyl group or a carboxypropyl group.

式(2)中，作為R12中之C6-10芳基-C1-6烷基，較佳為苯基 -C1-4烷基，更佳為苄基、2-羧基苄基、3-羧基苄基、4-羧基苄基、氟苄基、三氟苄基、甲基苄基、甲氧基苄基、二甲氧基苄基、甲基磺醯基苄基。 In the formula (2), as the C 6-10 aryl-C 1-6 alkyl group in R 12 , a phenyl-C 1-4 alkyl group is preferred, and a benzyl group or a 2-carboxybenzyl group is more preferred. 3-carboxybenzyl, 4-carboxybenzyl, fluorobenzyl, trifluorobenzyl, methylbenzyl, methoxybenzyl, dimethoxybenzyl, methylsulfonylbenzyl.

式(2)中，作為R12中之4-10員雜環-C1-6烷基，較佳為4-6員雜環-C1-4烷基，更佳為2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、2-吡基甲基、甲基氧雜環丁烷-甲基、四氫呋喃-甲基、四氫哌喃-甲基、嘧啶-甲基。 In the formula (2), as a 4-10 membered heterocyclic-C 1-6 alkyl group in R 12 , preferably a 4-6 membered heterocyclic-C 1-4 alkyl group, more preferably 2-pyridyl group Base, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyl Methyl, methyloxetane-methyl, tetrahydrofuran-methyl, tetrahydropyran-methyl, pyrimidine-methyl.

式(2)中，作為1，較佳為1或2，更佳為1。又，作為n，較佳為0~2之整數。 In the formula (2), as 1, preferably 1 or 2, more preferably 1. Further, as n, an integer of 0 to 2 is preferable.

一般式(1)中，作為R5、R6、R7中之鹵素原子，較佳為氟原子、氯原子。 In the general formula (1), the halogen atom in R 5 , R 6 and R 7 is preferably a fluorine atom or a chlorine atom.

一般式(1)中，作為R8中之C1-6烷基，較佳為C1-5烷基，更佳為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、新戊基。 In the general formula (1), as the C 1-6 alkyl group in R 8 , a C 1-5 alkyl group is preferred, and more preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or an n-butyl group. Isobutyl, tert-butyl, neopentyl.

一般式(1)中，作為R8中之C2-6烯基，可舉例如2-甲基-3-丁烯-2-基等。作為C2-6炔基，可舉例如2-甲基-3-丁炔-2-基、3-甲基-1-戊炔-3-基、1-己炔-3-基等。 In the general formula (1), examples of the C 2-6 alkenyl group in R 8 include a 2-methyl-3-buten-2-yl group. The C 2-6 alkynyl group may, for example, be 2-methyl-3-butyn-2-yl, 3-methyl-1-pentyn-3-yl or 1-hexyn-3-yl.

一般式(1)中，作為R8中之鹵C1-6烷基，較佳為鹵C1-4烷基，更佳為2-氟乙基、2,2,2-三氟乙基、2,2,2-三氯乙基、1,1,1-三氟-2-甲基丙烷-2-基、1,1-二甲基-2,2,2-三氟乙基、1,1-二甲基-2,2,2-三氯乙基。 In the general formula (1), the halogen C 1-6 alkyl group in R 8 is preferably a halogen C 1-4 alkyl group, more preferably a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group. , 2,2,2-trichloroethyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1,1-dimethyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

一般式(1)中，作為R8中之三烷基矽基-C1-6烷基，可舉例 如三甲基矽基甲基、三甲基矽基乙基等。作為氰基-C1-6烷基，可舉例如氰基甲基、氰基乙基等。 In the general formula (1), examples of the trialkylsulfonyl-C 1-6 alkyl group in R 8 include a trimethyldecylmethyl group and a trimethyldecylethyl group. The cyano-C 1-6 alkyl group may, for example, be a cyanomethyl group or a cyanoethyl group.

一般式(1)中，作為R8中之C1-6烷氧基-C1-6烷基，較佳為C1-4烷氧基-C1-4烷基，更佳為2-甲氧基乙基、2-乙氧基乙基。 General formula (1), as in the 8 C R 1-6 alkoxy -C 1-6 alkyl group, preferably a C 1-4 alkoxy -C 1-4 alkyl group, more preferably is 2 Methoxyethyl, 2-ethoxyethyl.

一般式(1)中，作為R8中之C3-10環烷基，較佳為C3-6環烷基、鹵C3-6環烷基，更佳為金剛烷基、環己基、4,4-二氟環己基、環丙基、1-甲基環丙基。 In the general formula (1), as the C 3-10 cycloalkyl group in R 8 , a C 3-6 cycloalkyl group or a halogen C 3-6 cycloalkyl group is preferred, and an adamantyl group or a cyclohexyl group is more preferred. 4,4-Difluorocyclohexyl, cyclopropyl, 1-methylcyclopropyl.

一般式(1)中，作為R8中之C3-10環烷基-C1-6烷基，較佳為C3-6環烷基-C1-6烷基，更佳為環丙基甲基、1-甲基環丙基甲基、環丁基甲基。 In the general formula (1), as C 3-10 cycloalkyl-C 1-6 alkyl in R 8 , preferably C 3-6 cycloalkyl-C 1-6 alkyl, more preferably cyclopropyl Methyl, 1-methylcyclopropylmethyl, cyclobutylmethyl.

一般式(1)中，作為R8中之C6-10芳基，較佳為苯基、鹵苯基、鹵C1-6烷氧基苯基、胺基苯基、二C1-6烷基胺基苯基、C1-6烷基苯基、二C1-6烷基苯基、C1-6烷基硫基苯基、苄基氧基苯基，更佳為苯基、氯苯基、氟苯基、二氯苯基、二氟苯基、氰基苯基、三氟甲氧基苯基、二甲基胺基苯基、二乙基胺基苯基、甲基苯基、異丙基苯基、第三丁基苯基、第三戊基苯基、甲基硫基苯基、二甲基苯基、氯(甲基)苯基、氟(三氟甲基)苯基、三氯苯基、氯(二甲基)苯基、苄基氧基苯基等。 In the general formula (1), as the C 6-10 aryl group in R 8 , a phenyl group, a halogenated phenyl group, a halogen C 1-6 alkoxyphenyl group, an aminophenyl group, a di C 1-6 group is preferred. An alkylaminophenyl group, a C 1-6 alkylphenyl group, a di C 1-6 alkylphenyl group, a C 1-6 alkylthiophenyl group, a benzyloxyphenyl group, more preferably a phenyl group, Chlorophenyl, fluorophenyl, dichlorophenyl, difluorophenyl, cyanophenyl, trifluoromethoxyphenyl, dimethylaminophenyl, diethylaminophenyl, methylbenzene Base, isopropylphenyl, tert-butylphenyl, tert-pentylphenyl, methylthiophenyl, dimethylphenyl, chloro(methyl)phenyl, fluoro(trifluoromethyl) Phenyl, trichlorophenyl, chloro(dimethyl)phenyl, benzyloxyphenyl, and the like.

一般式(1)中，作為R8中之C6-10芳基-C1-6烷基，較佳為苯基-C1-4烷基、鹵苯基-C1-4烷基、鹵C1-6烷基苯基-C1-4烷基、C1-6烷基苯基-C1-6烷基、鹵C1-6烷氧基苯基-C1-6烷基， 更佳為苄基、氯苄基、二氯苄基、氟苄基、二氟苄基、三氟甲基苄基、3,5-雙三氟甲基苄基、氟(氯)苄基、五氟苄基。 In the general formula (1), as a C 6-10 aryl-C 1-6 alkyl group in R 8 , a phenyl-C 1-4 alkyl group, a halophenyl-C 1-4 alkyl group, Halogen C 1-6 alkylphenyl-C 1-4 alkyl, C 1-6 alkylphenyl-C 1-6 alkyl, halo C 1-6 alkoxyphenyl-C 1-6 alkyl More preferably, it is benzyl, chlorobenzyl, dichlorobenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, 3,5-bistrifluoromethylbenzyl, fluoro(chloro)benzyl , pentafluorobenzyl.

一般式(1)中，作為R8中之4-10員雜環-C1-6烷基，較佳為4-6員雜環-C1-4烷基，更佳為氧雜環丁基甲基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基。 In the general formula (1), as a 4-10 membered heterocyclic-C 1-6 alkyl group in R 8 , preferably a 4-6 membered heterocyclic-C 1-4 alkyl group, more preferably an oxetanyl group Base, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl.

一般式(1)中，作為Z，較佳為O。 In the general formula (1), as Z, it is preferably O.

一般式(1)中，作為R1、R2、R3及R4之組合，較佳係此等中之一者為C1-6烷基磺醯基、4-10員雜環-C1-6烷基(此處，雜環亦可具有上述取代基)或式(2)所示之基，其餘為不存在或氫原子、鹵素原子、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基-C1-6烷氧基。作為式(2)所示之基，較佳為R12-S(O)n(CH2)1-，更佳為R12S(O)n-CH2-，再更佳為C1-6烷基-S(O)n-CH2-、C6-10芳基-C1-6烷基-S(O)n-CH2-或4-10員雜環-C1-6烷基-S(O)n-CH2-(此處，芳基或雜環亦可具有上述取代基)，特佳為C1-6烷基SO2-CH2-、C6-10芳基-C1-6烷基-SO2CH2-或4-10員雜環-C1-6烷基SO2-CH2-(此處，芳基或雜環亦可具有取代基)。 In the general formula (1), as a combination of R 1 , R 2 , R 3 and R 4 , one of these is preferably a C 1-6 alkylsulfonyl group and a 4-10 member heterocyclic ring-C. a 1-6 alkyl group (here, the heterocyclic ring may have the above substituent) or a group represented by the formula (2), and the remainder is absent or a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkoxy. The group represented by the formula (2) is preferably R 12 -S(O) n (CH 2 ) 1- , more preferably R 12 S(O) n -CH 2 -, still more preferably C 1- 6- alkyl-S(O) n -CH 2 -, C 6-10 aryl-C 1-6 alkyl-S(O) n -CH 2 - or 4-10 membered heterocyclic-C 1-6 alkane -S(O) n -CH 2 - (wherein the aryl or heterocyclic ring may have the above substituents), particularly preferably a C 1-6 alkyl SO 2 -CH 2 -, C 6-10 aryl group -C 1-6 alkyl-SO 2 CH 2 - or 4-10 membered heterocyclic ring - C 1-6 alkyl SO 2 -CH 2 - (wherein the aryl or heterocyclic ring may have a substituent).

一般式(1)中，作為R5、R6及R7之組合，更佳係此等中之二者為氫原子，其餘為氫原子、鹵素原子、氰基或羧基。 In the general formula (1), as a combination of R 5 , R 6 and R 7 , it is more preferred that two of these are hydrogen atoms, and the balance is a hydrogen atom, a halogen atom, a cyano group or a carboxyl group.

一般式(1)中，作為R8，更佳為C1-6烷基、鹵C1-6烷基、C1-6烷氧基-C1-6烷基、C3-8環烷基、C3-8環烷基-C1-6烷基。 In the general formula (1), as R 8 , more preferably C 1-6 alkyl, halogen C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkane Base, C 3-8 cycloalkyl-C 1-6 alkyl.

一般式(1)中，作為R13或R14之鹵素原子，較佳為氟原子。 In the general formula (1), as the halogen atom of R 13 or R 14 , a fluorine atom is preferred.

一般式(1)中，作為R8中之取代基所含的氫原子，在化學上容許的前提下，亦可被氘原子所取代。 In the general formula (1), the hydrogen atom contained in the substituent in R 8 may be substituted by a halogen atom on the premise of being chemically acceptable.

作為一般式(1)所示之螺哌啶衍生物的較佳化合物，可舉例如由下述所組成群選出之化合物：第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯(實施例1)、第三丁基6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例2)、第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例3)、第三丁基6-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例4)、第三丁基7-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例5)、第三丁基7-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例6)、第三丁基6-(4-硝基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例7)、第三丁基6-(4-(甲基磺醯胺)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例8)、第三丁基6-(4-羥基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例9)、 第三丁基6-(4-((甲基磺醯基)氧基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例10)、第三丁基6-(2-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例11)、第三丁基6-(2-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例12)、第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例13)、第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例14)、第三丁基6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例15A)、第三丁基6-(5-((甲基亞磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例15B)、第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例16)、第三丁基6-(3-甲基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例17)、第三丁基6-(3-甲氧基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例18)、第三丁基6-(4-((甲基磺醯基)甲基)-3-丙氧基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例19)、 第三丁基6-(3-(環丙基甲氧基)-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例20)、第三丁基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例21)、第三丁基6-(4-((1-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例22)、第三丁基6-(4-((2-甲基磺醯基)丙烷-2-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例23)、第三丁基6-(4-(1H-四唑-1-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例24)、第三丁基6-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例25)、第三丁基7-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例26)、第三丁基6-(4-(甲基磺醯基)甲基-N-哌啶基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例27)、乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例28)、2,2,2-三氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例29)、2,2,2-三氯乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例30)、 2-氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例31)、2-甲氧基乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例32)、異丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例33)、苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例34)、苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例35)、4-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例36)、3-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例37)、2-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例38)、4-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例39)、3-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例40)、2-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例41)、 3,5-雙(三氟甲基)苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例42)、吡啶-4-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例43)、吡啶-3-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例44)、吡啶-2-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例45)、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例46)、1,1,1-三氯-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例47)、新戊基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例48)、金剛烷-1-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例49)、金剛烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例50)、氧雜環丁烷-3-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例51)、四氫-2H-哌喃-4-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例52)、 4,4-二氟環己基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例53)、2,2,2-三氯乙基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例54)、苯基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例55)、1,1,1-三氟-2-甲基丙烷-2-基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例56)、新戊基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例57)、2,2,2-三氯乙基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例58)、苯基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例59)、1,1,1-三氟-2-甲基丙烷-2-基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例60)、新戊基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例61)、2,2,2-三氟乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例62)、2,2,2-三氯乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例63)、 苯基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例64)、1,1,1-三氟-2-甲基丙烷-2-基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例65)、新戊基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例66)、第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例67)、第三丁基6-(4-((吡啶-4-基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例68)、第三丁基6-(4-((苯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例69)、第三丁基6-(4-((苯基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例70)、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例71)、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例72)、第三丁基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例73)、第三丁基6-(4-((十二烷基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例74)、 第三丁基6-(4-((十二烷基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例75)、第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例76)、第三丁基6-(4-((丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例77)、第三丁基6-(4-((烯丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例78)、第三丁基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例79)、第三丁基6-(4-(((2-甲氧基乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例80)、第三丁基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例81)、第三丁基6-(4-(((環丙基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例82)、第三丁基6-(4-(((環己基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例83)、第三丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例84)、第三丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例85)、 第三丁基6-(4-(((吡啶-3-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例86)、第三丁基6-(4-(((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例87)、環丙基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯(實施例88)、環丁基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例89)、(1-甲基環丙基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例90)、1-甲基環丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例91)、1-甲基環丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例92)、(三甲基矽基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例93)、第三丁基6-(5-((甲基磺醯基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例94)、第三丁基6-(6-((甲基磺醯基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例95)、第三丁基6-(5-((甲基磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例96)、 第三丁基6-(4-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例97)、第三丁基6-(5-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例98)、第三丁基6-(2-((甲基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例99)、第三丁基6-(5-((甲基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例100)、第三丁基7-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例101)、第三丁基7-氟-6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例102)、第三丁基7-氟-6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例103)、第三丁基3-羥基-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例104)、第三丁基6-(4-((甲基磺醯基)甲基)苯基)-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例105)、第三丁基4,4-二氘-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例106)、第三丁基4-氟-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯(實施例107)、 第三丁基6-(3-氰基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例108)、2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例109)、第三丁基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例110)、2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例111)、新戊基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例112)、2,2,2-三氯乙基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例113)、新戊基6-[4-{(2-(異丙基磺醯基)甲基)苯基}]螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例114)、第三丁基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例115)、2,2,2-三氯乙基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例116)、第三丁基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例117)、2,2,2-三氯乙基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例118)、 新戊基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例119)、第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例120)、2,2,2-三氯乙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例121)、新戊基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例122)、1-甲基環丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例123)、1,1,1-三氟丙烷-2-基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例124)、第三丁基6-(4-(((2-氟乙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例125)、第三丁基6-(4-(((氰基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例126)、第三丁基6-(5-(((氰基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例127)、2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例128)、第三丁基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例129)、 2,2,2-三氯乙基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例130)、新戊基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例131)、第三丁基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例132)、2,2,2-三氯乙基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例133)、第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例134)、新戊基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例135)、1-甲基環丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例136)、1-環丙基乙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例137)、1,1,1-三氟丙烷-2-基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例138)、第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例139)、第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例140)、 異丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例141)、異丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例142)、新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例143)、1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例144)、1-環丙基乙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例145)、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例146)、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例147)、(異丙基-d7)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例148)、(第三丁基-d9)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例149)、第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例150)、新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯(實施例151)、 1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯(實施例152)、(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例153)、(R)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例154)、(R)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例155)、(R)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例156)、(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例157)、(S)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例158)、(S)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例159)、(S)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例160)、第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例161)、 新戊基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例162)、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例163)、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例164)、第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例165)、新戊基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例166)、1,1,1-三氟異丙基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例167)、第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例168)、第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例169)、第三丁基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例170)、新戊基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例171)、1,1,1-三氟異丙基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基) 吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例172)、第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例173)、第三丁基6-(4-(((3-胺基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例174)、(S)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例175)、(R)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例176)、第三丁基6-(4-(((3-(3,3-二氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例177)、第三丁基6-(4-(((甲基磺醯基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例178)、第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例179)、4-((4-(1’-第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)丁酸(實施例180)、第三丁基6-(4-(((4-胺基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例181)、第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例182)、乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧 酸酯(實施例183)、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例184)、異丙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例185)、2,2,2-三氟乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例186)、1-環丙基乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例187)、3,3,4,4,4-五氟丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例188)、1,1,1-三氟丙烷-2-基6-[4-{(吡啶-4-基甲基)磺醯基}甲基]苯基]螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例189)、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例190)、1,1,1,3,3,3-六氟丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例191)、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例192)、(乙基-d5)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例193)、(異丙基-d7)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌 啶]-1’-羧酸酯(實施例194)、(第三丁基-d9)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例195)、(1,1,1,3,3,3-六氟丙烷-2-基-2-d1)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例196)、(三甲基矽基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例197)、(1-(第三丁氧基羰基)哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例198)、(1-甲基哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例199)、4-異丙基苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例200)、4-(第三丁基)苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例201)、2-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例202)、4-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例203)、第三丁基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例204)、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍 -2,4’-哌啶]-1’-羧酸酯(實施例205)、新戊基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例206)、第三丁基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例207)、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例208)、第三丁基6-(5-((苄基磺醯基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯(實施例209)、第三丁基6-(5-((苄基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例210)、第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例211)、2,2,2-三氯乙基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例212)、新戊基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例213)、第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例214)、1,1,1-三氟丙烷-2-基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例215)、第三丁基6-(5-(((4-氟苄基)磺醯基)甲基)吡啶-2-基)螺[唍 -2,4-哌啶]-1’-羧酸酯(實施例216)、第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例217)、1,1,1-三氟丙烷-2-基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例218)、第三丁基6-(5-(((4-(三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例219)、第三丁基6-(5-(((2-甲基苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例220)、第三丁基6-(5-((((2-三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例221)、4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸(實施例222)、3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸(實施例223)、2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸(實施例224)、第三丁基6-(4-(((4-(甲基磺醯基)苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例225)、第三丁基6-(4-(((4-(甲基磺醯基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例226)、甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’- 哌啶]-1’-羧酸酯(實施例227)、乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例228)、異丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例229)、丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例230)、新戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例231)、異丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例232)、1-甲基環丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例233)、1-環丙基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例234)、第二丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例235)、第三戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例236)、4-甲基戊烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例237)、3-甲基戊烷-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基) 螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例238)、2-甲基丁-3-烯-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例239)、2-甲基丁-3-炔-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例240)、3-甲基戊-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例241)、己-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例242)、2-氰基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例243)、環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例244)、4-(第三丁基)環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例245)、3,3,5-三甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例246)、(1R,2S,4S)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例247)、(1S,2R,4R)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例 248)、(3-甲基氧雜環丁烷-3-基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例249)、環己基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例250)、金剛烷-1-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例251)、(三甲基矽基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例252)、2,2,2-三氯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例253)、2,2,2-三氟乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例254)、3,3,4,4,4-五氟丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例255)、1,1,1-三氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例256)、1,1,1-三氟-2-甲基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例257)、1,1,1,3,3,3-六氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例258)、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-(((吡啶-2-基甲 基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例259)、(甲基-d3)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例260)、(乙基-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例261)、(異丙基-d7)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例262)、(第三丁基-d9)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例263)、(1,1,1,3,3,3-六氟-2-丙烷-2-基-2-d1)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例264)、苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例265)、1-苯基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例266)、1-苯基丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例267)、苯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例268)、2-甲基-1-苯基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基) 苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例269)、2-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例270)、2-甲基-4-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例271)、2-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例272)、3-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例273)、4-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例274)、2-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例275)、3-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例276)、4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例277)、2-(三氟甲氧基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例278)、4-甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例279)、4-(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基) 螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例280)、4-異丙基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例281)、4-(第三丁基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例282)、2,6-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例283)、2,3-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例284)、2,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例285)、3,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例286)、3,5-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例287)、2,6-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例288)、2,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例289)、2,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例290)、3,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺 [唍-2,4’-哌啶]-1’-羧酸酯(實施例291)、3,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例292)、2-氯-6-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例293)、2-氯-4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例294)、2,4-二甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例295)、3,5-雙(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例296)、(全氟苯基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例297)、呋喃-2-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例298)、苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例299)、2-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例300)、4-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例301)、2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍 -2,4’-哌啶]-1’-羧酸酯(實施例302)、3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例303)、4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例304)、2-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例305)、3-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例306)、4-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例307)、2-(三氟甲氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例308)、3-(二甲基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例309)、3-(二乙基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例310)、4-異丙基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例311)、4-(第三丁基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例312)、4-(第三戊基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基) 螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例313)、4-(甲基硫基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例314)、2,6-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例315)、2,3-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例316)、2,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例317)、3,5-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例318)、3,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例319)、2,6-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例320)、3,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例321)、2,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例322)、2,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例323)、3,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺 [唍-2,4’-哌啶]-1’-羧酸酯(實施例324)、2-氯-6-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例325)、2-氯-4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例326)、4-氯-2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例327)、4-氯-3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例328)、2,4-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例329)、3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例330)、4-氯-3-甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例331)、2-氟-3-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例332)、2-氟-5-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例333)、2,4,6-三氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例334)、4-氯-3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯 基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例335)、4-(苄基氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例336)、(苯基-2,3,4,5,6-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例337)、第三丁基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例338)、2,2,2-三氯乙基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例339)、第三丁基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例340)、2,2,2-三氯乙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-羧酸酯(實施例341)、新戊基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例342)、1-甲基環丙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例343)、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例344)、2-((((6-(1’-(第三丁氧基羰基螺(唍-2,4’-哌啶)-6-基)吡啶-3-基)甲基)磺醯基)甲基)吡啶-1-氧化物(實施例345)、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺 [唍-2,4-哌啶]-1’-羧酸酯(實施例346)、新戊基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例347)、1-甲基環丙基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例348)、第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例349)、異丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例350)、新戊基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例351)、1-甲基環丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例352)、1-環丙基乙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例353)、1,1,1-三氟丙烷-2-基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例354)、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例355)、1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例356)、1,1,1-三氟丙烷-2-基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲 基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例357)、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯(實施例358)、新戊基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯(實施例359)、1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯(實施例360)、第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例361)、第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例362)、第三丁基6-(4-(((吡-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例363)、第三丁基6-(5-(((吡-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯(實施例364)、第三丁基6-(4-(((噻唑-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例365)、第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例366)、第三丁基6-(5-((((嘧啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例367)、第三丁基6-(4-(((1-(吡啶-2-基)乙基)亞磺醯基)甲基)苯基)螺 [唍-2,4’-哌啶]-1’-羧酸酯(實施例368)、第三丁基6-(4-(((1-(吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例369)、第三丁基6-(4-(((1-(吡啶-2-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例370)、第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例371)、新戊基6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯(實施例372)、1,1,1-三氟丙烷-2-基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例373)、第三丁基7-氟-6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例374)、第三丁基6-(4-(2-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例375)、第三丁基6-(4-((1H-咪唑-1-基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例376)、第三丁基6-(4-(2-乙氧基-2-側氧基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例377)、2-(4-(1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苯基)醋酸(實施例378)、異丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’- 哌啶]-1’-羧酸酯(實施例379)、異丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例380)及異丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(實施例381)。 A preferred compound of the spiropiperidine derivative represented by the general formula (1) is, for example, a compound selected from the group consisting of: tert-butyl 6-(4-(methylsulfonyl)phenyl )screw[ Terpene-2,4'-piperidine]-1'-carboxylate (Example 1), tert-butyl 6-(4-(methylsulfonyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 2), tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 3), tert-butyl 6-(3-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 4), tert-butyl 7-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 5), tert-butyl 7-(3-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 6), tert-butyl 6-(4-nitrophenyl) spiro[ Indole-2,4'-piperidine]-1'-carboxylate (Example 7), tert-butyl 6-(4-(methylsulfonamide)phenyl) spiro[ Indole-2,4'-piperidine]-1'-carboxylate (Example 8), tert-butyl 6-(4-hydroxyphenyl) spiro[ Indole-2,4'-piperidine]-1'-carboxylate (Example 9), tert-butyl 6-(4-((methylsulfonyl)oxy)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 10), tert-butyl 6-(2-fluoro-4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 11), tert-butyl 6-(2-chloro-4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 12), tert-butyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 13), tert-butyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 14), tert-butyl 6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 15A), tert-butyl 6-(5-((methylsulfinyl)methyl)pyridin-2-yl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 15B), tert-butyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 16), tert-butyl 6-(3-methyl-4-((methylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 17), tert-butyl 6-(3-methoxy-4-((methylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 18), tert-butyl 6-(4-((methylsulfonyl)methyl)-3-propoxybenzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 19), tert-butyl 6-(3-(cyclopropylmethoxy)-4-((methylsulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 20), tert-butyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 21), tert-butyl 6-(4-((1-methylsulfonyl)ethyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 22), tert-butyl 6-(4-((2-methylsulfonyl)propan-2-yl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 23), tert-butyl 6-(4-(1H-tetrazol-1-yl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 24), tert-butyl 6-(5-(methylsulfonyl)indol-1-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 25), tert-butyl 7-(5-(methylsulfonyl)indol-1-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 26), tert-butyl 6-(4-(methylsulfonyl)methyl-N-piperidinyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 27), ethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 28), 2,2,2-trifluoroethyl 6-(4-((methylsulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate (Example 29), 2,2,2-trichloroethyl 6-(4-((methylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 30), 2-fluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 31), 2-methoxyethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 32), isopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 33), benzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 34), phenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 35), 4-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 36), 3-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 37), 2-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 38), 4-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 39), 3-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 40), 2-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 41), 3,5-bis(trifluoromethyl)benzyl 6-(4-((methylsulfonyl)) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 42), pyridin-4-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 43), pyridin-3-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 44), pyridin-2-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 45), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((methyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 46), 1,1,1-trichloro-2-methylpropan-2-yl 6-(4-((methyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 47), neopentyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 48), adamantyl-1-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 49), adamantyl-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 50), oxetan-3-yl 6-(4-((methylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 51), tetrahydro-2H-piperidin-4-yl 6-(4-((methylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 52), 4,4-difluorocyclohexyl 6-(4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 53), 2,2,2-trichloroethyl 6-(3-fluoro-4-((methylsulfonyl)) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 54), phenyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 55), 1,1,1-trifluoro-2-methylpropan-2-yl-6-(3-fluoro-4- ((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 56), neopentyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 57), 2,2,2-trichloroethyl 6-(3-chloro-4-((methylsulfonyl)) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 58), phenyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 59), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3-chloro-4- ((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 60), neopentyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 61), 2,2,2-trifluoroethyl 6-(3,5-difluoro-4-((methylsulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 62), 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((methylsulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 63), phenyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 64), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3,5-difluoro -4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 65), neopentyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 66), tert-butyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 67), tert-butyl 6-(4-((pyridin-4-ylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 68), tert-butyl 6-(4-((phenylthio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 69), tert-butyl 6-(4-((phenylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 70), tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazole)- 2-yl)thio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 71), tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazole)- 2-yl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 72), tert-butyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 73), tert-butyl 6-(4-((dodecylthio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 74), tert-butyl 6-(4-((dodecylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 75), tert-butyl 6-(4-((ethylidenethio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 76), tert-butyl 6-(4-((propylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 77), tert-butyl 6-(4-((allylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 78), tert-butyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 79), tert-butyl 6-(4-(((2-methoxyethyl))sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 80), tert-butyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 81), tert-butyl 6-(4-(((cyclopropylmethyl))sulfonyl)methyl)phenyl) )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 82), tert-butyl 6-(4-((cyclohexylmethyl)sulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 83), tert-butyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 84), tert-butyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 85), tert-butyl 6-(4-((pyridin-3-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 86), tert-butyl 6-(4-((pyrid-4-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 87), cyclopropylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Terpene-2,4'-piperidine]-1'-carboxylate (Example 88), cyclobutylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 89), (1-methylcyclopropyl)methyl 6-(4-((methylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 90), 1-methylcyclobutyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 91), 1-methylcyclopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 92), (trimethyldecyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 93), tert-butyl 6-(5-((methylsulfonyl)methyl)pyridinium -2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 94), tert-butyl 6-(6-((methylsulfonyl)methyl)anthracene -3-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 95), tert-butyl 6-(5-((methylsulfonyl)methyl)pyrimidin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 96), tert-butyl 6-(4-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 97), tert-butyl 6-(5-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 98), tert-butyl 6-(2-((methylsulfonyl)methyl)thiazol-5-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 99), tert-butyl 6-(5-((methylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 100), tert-butyl 7-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 101), tert-butyl 7-fluoro-6-(3-fluoro-4-((methylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 102), tert-butyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridine-2 -base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 103), tert-butyl 3-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 104), tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl)-3- side Oxy snail Indole-2,4'-piperidine]-1'-carboxylate (Example 105), tert-butyl 4,4-dioxin-6-(4-((methylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 106), tert-butyl 4-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) [ Indole-2,4'-piperidine]-1'-carboxylate (Example 107), tert-butyl 6-(3-cyano-4-((methylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 108), 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 109), tert-butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluoro Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 110), 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)- 3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (Example 111), neopentyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorobenzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 112), 2,2,2-trichloroethyl 6-(4-((isopropylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 113), neopentyl 6-[4-{(2-(isopropylsulfonyl)methyl)phenyl}] screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 114), tert-butyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 115), 2,2,2-trichloroethyl 6-(3-fluoro-4-((isopropylsulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 116), tert-butyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 117), 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((isopropyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 118), neopentyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 119), tert-butyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 120), 2,2,2-trichloroethyl 6-(5-((isopropylsulfonyl)methyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 121), neopentyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 122), 1-methylcyclopropyl 6-(5-((isopropylsulfonyl)methyl)pyridine-2 -base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 123), 1,1,1-trifluoropropan-2-yl 6-(5-((isopropylsulfonyl)) Methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 124), tert-butyl 6-(4-(((2-fluoroethyl))sulfonyl)methyl)phenyl) )screw[ Indole-2,4-piperidinyl-1'-carboxylate (Example 125), tert-butyl 6-(4-(((cyanomethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 126), tert-butyl 6-(5-(((cyanomethyl)sulfonyl)methyl)pyrimidine-2 -base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 127), 2,2,2-trichloroethyl 6-(4-((3,3,3-trifluoropropane) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 128), tert-butyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 129), 2,2,2-trichloroethyl 6-(3-fluoro-4-((3,3,3) -trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 130), neopentyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonate Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 131), tert-butyl 6-(3,5-difluoro-4-((3,3,3-trifluoro) Propyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 132), 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((3, 3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 133), tert-butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl) Methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 134), neopentyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl) A Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 135), 1-methylcyclopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonate Mercapto)methyl)pyridin-2-yl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 136), 1-cyclopropylethyl 6-(5-((3,3,3-trifluoropropyl)sulfonate Mercapto)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 137), 1,1,1-trifluoropropan-2-yl 6-(5-((3,3,3-) Trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 138), tert-butyl 6-(4-(((3-hydroxypropyl))sulfonyl)methyl)phenyl) )screw[ Indole-2,4-piperidinyl-1'-carboxylate (Example 139), tert-butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridine-2 -base) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 140), isopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridine-2- Snail Indole-2,4-piperidinyl-1'-carboxylate (Example 141), isobutyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridine-2- Snail Indole-2,4-piperidinyl-1'-carboxylate (Example 142), neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridine-2- Snail Indole-2,4-piperidinyl-1'-carboxylate (Example 143), 1-methylcyclopropyl 6-(5-((3-(hydroxypropyl))sulfonyl)methyl) Pyridin-2-yl) snail Indole-2,4-piperidinyl-1'-carboxylate (Example 144), 1-cyclopropylethyl 6-(5-(((3-hydroxypropyl)sulfonyl)methyl)) Pyridin-2-yl) snail Indole-2,4-piperidinyl-1'-carboxylate (Example 145), 1,1,1-trifluoropropan-2-yl-6-(5-((3-hydroxypropyl)sulfonate Mercapto)methyl)pyridin-2-yl) snail Indole-2,4-piperidinyl-1'-carboxylate (Example 146), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3- Hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 147), (isopropyl-d7)6-(5-((3-hydroxypropyl)sulfonyl)methyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 148), (t-butyl-d9)6-(5-(((3-hydroxypropyl))sulfonyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 149), tert-butyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyrimidine- 2-base) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 150), neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2- base)[ Indole-2,4-piperidinyl-1'-carboxylate (Example 151), 1-methylcyclopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl) Pyrimidine-2-yl)[ Indole-2,4-piperidinyl-1'-carboxylate (Example 152), (R)-Tertibutyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonate Mercapto)methyl)pyridin-2-yl) snail Indole-2,4-piperidinyl-1'-carboxylate (Example 153), (R)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl) Methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 154), (R)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 155), (R)-1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-( ((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 156), (S)-Tertibutyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonate Mercapto)methyl)pyridin-2-yl) snail Indole-2,4-piperidinyl-1'-carboxylate (Example 157), (S)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl) Methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 158), (S)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 159), (S)-1,1,1-Trifluoro-2-methylpropan-2-yl 6-(5-( ((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 160), tert-butyl 6-(5-(((3-hydroxy-2,2-dimethylpropyl))sulfonate Methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 161), neopentyl 6-(5-(((3-hydroxy-2,2-dimethylpropyl))sulfonyl) )methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 162), 1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2,2) -Dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 163), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3- Hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 164), tert-butyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridine -2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 165), neopentyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridine- 2-base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 166), 1,1,1-trifluoroisopropyl 6-(5-((3-methoxypropyl)) Sulfhydryl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 167), tert-butyl 6-(4-((((methylthio))-3-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 168), tert-butyl 6-(5-(((3-methyloxetan-3-yl))) Sulfhydryl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 169), tert-butyl 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 170), neopentyl 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 171), 1,1,1-trifluoroisopropyl 6-(5-(((tetrahydrofuran-3-yl))) Sulfhydryl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 172), tert-butyl 6-(5-((((tetrahydro-2H-pyran-4-yl))methyl) Sulfhydryl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 173), tert-butyl 6-(4-((3-aminopropyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 174), (S)-Tertibutyl 6-(5-((3-(3-)-fluoropyrrolidine-1- Propyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 175), (R)-Tertibutyl 6-(5-((3-(3-)-fluoropyrrolidine-1- Propyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 176), tert-butyl 6-(4-((3-(3,3-difluoropyrrolidin-1-yl) )propyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 177), tert-butyl 6-(4-(((methylsulfonyl)propyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 178), tert-butyl 6-(4-((4-methoxy-4-oxobutyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 179), 4-((4-(1'-T-butoxycarbonyl)) spiro[ Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)butyric acid (Example 180), tert-butyl 6-(4-((4-amino-4-) side Oxybutyl)sulfonyl)methyl)phenyl) spiro[ Indole-2,4'-piperidine]-1'-carboxylate (Example 181), tert-butyl 6-(4-((1-(1-ethoxy-2-methyl-1-yloxy)) Propane-2-yl)sulfonyl)methyl)phenyl) spiro[ Indole-2,4'-piperidinyl-1'-carboxylate (Example 182), ethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 183), 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 184), isopropyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 185), 2,2,2-trifluoroethyl 6-(4-((benzylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 186), 1-cyclopropylethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 187), 3,3,4,4,4-pentafluorobutyl 6-(4-((benzylsulfonyl)) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 188), 1,1,1-trifluoropropan-2-yl 6-[4-{(pyridin-4-ylmethyl) Sulfhydryl}methyl]phenyl] snail Indole-2,4'-piperidine]-1'-carboxylate (Example 189), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((benzyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 190), 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((benzyl) Sulfosyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 191), 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane-2- 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 192), (ethyl-d5)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 193), (isopropyl-d7)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 194), (t-butyl-d9)6-(4-((benzylsulfonyl)methyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 195), (1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1)6- (4-((Benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 196), (trimethyldecyl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidinyl-1'-carboxylate (Example 197), (1-(T-butoxycarbonyl)piperidin-4-yl)methyl 6-(4-(( Benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 198), (1-methylpiperidin-4-yl)methyl 6-(4-((benzylsulfonyl)) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 199), 4-isopropylbenzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 200), 4-(t-butyl)benzyl 6-(4-((benzylsulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 201), 2-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 202), 4-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 203), tert-butyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 204), 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)- 3-fluorophenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 205), neopentyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 206), tert-butyl 6-(4-((benzylsulfonyl)methyl)-3,5-difluoro Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 207), 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)- 3,5-difluorophenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 208), tert-butyl 6-(5-((benzylsulfonyl)methyl)pyridin-2-yl) snail ( Indole-2,4'-piperidine)-1'-carboxylate (Example 209), tert-butyl 6-(5-((benzylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 210), tert-butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 211), 2,2,2-trichloroethyl 6-(2-((benzylsulfonyl)methyl)thiazole -5-base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 212), neopentyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 213), tert-butyl 6-(4-(((4-fluorobenzyl))sulfonyl)methyl)phenyl) )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 214), 1,1,1-trifluoropropan-2-yl 6-(4-((4-fluorobenzyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 215), tert-butyl 6-(5-((4-(4-fluorobenzyl))sulfonyl)methyl)pyridine- 2-base) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 216), tert-butyl 6-(4-((4-(trifluoromethyl)benzyl)sulfonyl) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 217), 1,1,1-trifluoropropan-2-yl 6-(4-((4-(trifluoro)) Benzyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 218), tert-butyl 6-(5-((4-(trifluoromethyl)benzyl)sulfonyl) Methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 219), tert-butyl 6-(5-(((2-methylbenzyl))sulfonyl)methyl)pyridine- 2-base) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 220), tert-butyl 6-(5-(((2-)trifluoromethyl)benzyl)sulfonyl) Methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 221), 4-((((()))) Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid (Example 222), 3-((((())) Carbonyl) snail Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid (Example 223), 2-((((())) Carbonyl) snail Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid (Example 224), tert-butyl 6-(4-((4-(methyl)) Sulfhydryl)benzyl)thio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 225), tert-butyl 6-(4-((4-(methylsulfonyl))benzyl)sulfonyl )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 226), methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidinyl-1'-carboxylate (Example 227), ethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 228), isopropyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 229), butyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 230), neopentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 231), isobutyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 232), 1-methylcyclopropyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 233), 1-cyclopropylethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 234), second butyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 235), third pentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 236), 4-methylpentan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 237), 3-methylpentan-3-yl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 238), 2-methylbut-3-en-2-yl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 239), 2-methylbut-3-yn-2-yl-6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 240), 3-methylpent-1-yn-3-yl-6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 241), hex-1-yn-3-yl-6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 242), 2-cyanoethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 243), cyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 244), 4-(t-butyl)cyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 245), 3,3,5-trimethylcyclohexyl 6-(4-(((pyridin-2-ylmethyl))) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 246), (1R, 2S, 4S)-2-isopropyl-4-methylcyclohexyl 6-(4-(( (pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 247), (1S, 2R, 4R)-2-isopropyl-4-methylcyclohexyl 6-(4-(( (pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 248), (3-methyloxetan-3-yl)methyl 6-(4-((pyridine) 2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 249), cyclohexylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 250), adamantyl-1-ylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 251), (trimethyldecyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 252), 2,2,2-trichloroethyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 253), 2,2,2-trifluoroethyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 254), 3,3,4,4,4-pentafluorobutyl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 255), 1,1,1-trifluoropropan-2-yl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate (Example 256), 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-(((pyridine) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 257), 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((( Pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 258), 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane-2- 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 259), (methyl-d3)6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 260), (ethyl-d5)6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 261), (isopropyl-d7)6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 262), (t-butyl-d9) 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 263), (1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 264), benzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidinyl-1'-carboxylate (Example 265), 1-phenylethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 266), 1-phenylpropyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 267), phenethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 268), 2-methyl-1-phenylpropan-2-yl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 269), 2-phenylbutan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 270), 2-methyl-4-phenylbutan-2-yl 6-(4-((pyridin-2-) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 271), 2-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 272), 3-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 273), 4-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 274), 2-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 275), 3-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 276), 4-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 277), 2-(trifluoromethoxy)benzyl 6-(4-((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 278), 4-methylbenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 279), 4-(trifluoromethyl)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 280), 4-isopropylbenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 281), 4-(t-butyl)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 282), 2,6-dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 283), 2,3-dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 284), 2,4-dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 285), 3,4-dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 286), 3,5-dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 287), 2,6-difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 288), 2,5-difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 289), 2,4-difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 290), 3,4-difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 291), 3,5-difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 292), 2-chloro-6-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 293), 2-chloro-4-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 294), 2,4-dimethylbenzyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 295), 3,5-bis(trifluoromethyl)benzyl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 296), (perfluorophenyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 297), furan-2-ylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 298), phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl )screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 299), 2-chlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 300), 4-chlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 301), 2-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 302), 3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 303), 4-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 304), 2-cyanophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 305), 3-cyanophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 306), 4-cyanophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate (Example 307), 2-(trifluoromethoxy)phenyl 6-(4-((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 308), 3-(dimethylamino)phenyl 6-(4-(((pyridin-2-ylmethyl))) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 309), 3-(diethylamino)phenyl 6-(4-((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 310), 4-isopropylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 311), 4-(t-butyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 312), 4-(tripentyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 313), 4-(methylthio)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 314), 2,6-dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 315), 2,3-dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 316), 2,4-dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 317), 3,5-dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 318), 3,4-dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 319), 2,6-difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 320), 3,5-difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 321), 2,5-difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 322), 2,4-difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 323), 3,4-difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 324), 2-chloro-6-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 325), 2-chloro-4-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 326), 4-chloro-2-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 327), 4-chloro-3-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 328), 2,4-dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonium) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 329), 3,5-dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 330), 4-chloro-3-methylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 331), 2-fluoro-3-(trifluoromethyl)phenyl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 332), 2-fluoro-5-(trifluoromethyl)phenyl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 333), 2,4,6-trichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonate Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 334), 4-chloro-3,5-dimethylphenyl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 335), 4-(benzyloxy)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Mercapto)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 336), (phenyl-2,3,4,5,6-d5)6-(4-(((pyridine) -ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 337), tert-butyl 6-(3-fluoro-4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 338), 2,2,2-trichloroethyl 6-(3-fluoro-4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 339), tert-butyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 340), 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((pyridine) 2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-carboxylate (Example 341), neopentyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 342), 1-methylcyclopropyl 6-(3,5-difluoro-4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 343), tert-butyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 344), 2-((((6-(1'-(T-butoxycarbonyl)) Indole-2,4'-piperidine)-6-yl)pyridin-3-yl)methyl)sulfonyl)methyl)pyridine-1-oxide (Example 345), tert-butyl 6-( 5-(((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 346), neopentyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidine- 2-base) snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 347), 1-methylcyclopropyl 6-(5-(((pyridin-2-ylmethyl)sulfonyl)) Pyrimidine-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 348), tert-butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonium) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 349), isobutyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 350), neopentyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 351), 1-methylcyclopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 352), 1-cyclopropylethyl 6-(4-(((5-fluoropyridin-2-yl)methyl) Sulfhydryl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 353), 1,1,1-trifluoropropan-2-yl 6-(4-(((5-fluoropyridine)- 2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 354), tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl))) Methyl)pyridin-2-yl) spiro[ Indole-2,4'-piperidine]-1'-carboxylate (Example 355), 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl) Sulfhydryl)methyl)pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 356), 1,1,1-trifluoropropan-2-yl 6-(5-(((5-fluoropyridine)- 2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 357), tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl))) Methyl)pyrimidin-2-yl snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 358), neopentyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)pyrimidin-2-yl snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 359), 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)) Sulfhydryl)methyl)pyrimidin-2-yl snail [ Indole-2,4-piperidinyl-1'-carboxylate (Example 360), tert-butyl 6-(4-(((6-methylpyridin-2-yl)methyl)sulfonium) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 361), tert-butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (Example 362), third butyl 6-(4-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 363), tert-butyl 6-(5-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Indole-2,4-piperidinyl-1'-carboxylate (Example 364), tert-butyl 6-(4-((thiazolyl-4-ylmethyl)sulfonyl)methyl)benzene Snail Indole-2,4'-piperidine]-1'-carboxylate (Example 365), tert-butyl 6-(4-((((3-isopropyl-1,2,4-) Diazol-5-yl)methyl)sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 366), tert-butyl 6-(5-(((pyrimidin-2-ylmethyl)sulfonyl)methyl) Pyrimidine-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 367), tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)) sulfinium) Base) methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 368), tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl))) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 369), tert-butyl 6-(4-(((1-(pyridin-2-yl))propyl)) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 370), tert-butyl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl) Methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 371), neopentyl 6-(4-(((2-(pyridin-2-yl)ethyl)sulfonyl)) Methyl)phenyl)[ Indole-2,4'-piperidine]-1'-carboxylate (Example 372), 1,1,1-trifluoropropan-2-yl 6-(4-(((2-pyridine-2-) Ethyl)ethylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 373), tert-butyl 7-fluoro-6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 374), tert-butyl 6-(4-(2-methylsulfonyl)ethyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 375), tert-butyl 6-(4-((1H-imidazol-1-yl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (Example 376), tert-butyl 6-(4-(2-ethoxy-2-o-oxyethyl)phenyl) screw[ Indole-2,4'-piperidine]-1'-carboxylate (Example 377), 2-(4-(1'-(T-butoxycarbonyl)) spiro[ Indole-2,4'-piperidinyl]-6-yl)phenyl)acetic acid (Example 378), isopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl )screw[ Indole-2,4'-piperidinyl-1'-carboxylate (Example 379), isopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl) Pyridin-2-yl) snail Indole-2,4'-piperidine]-1'-carboxylate (Example 380) and isopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) )methyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (Example 381).

在本發明之化合物存在幾何異構物或光學異構物的情況，其等之異構物亦涵括於本發明範圍內。此等異構物之分離係藉常法進行。 In the case where a geometric isomer or an optical isomer is present in the compound of the present invention, isomers thereof and the like are also included in the scope of the present invention. The separation of such isomers is carried out by conventional methods.

作為一般式(1)所示之化合物的鹽，若為醫藥上所容許之鹽則無特別限制。在將化合物作成酸性化合物而處理時，可舉例如鈉、鉀、鎂、鈣等之鹼金屬鹽或鹼土族金屬鹽；與三甲基胺、三乙基胺、吡啶、甲吡啶、N-甲基吡咯啶、N-甲基哌啶、N-甲基啉等之有機鹼的鹽等。在將化合物作成鹼性化合物而處理時，可舉例如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硝酸鹽、磷酸鹽般之礦酸的酸加成鹽；苯甲酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、醋酸鹽等之有機酸的酸加成鹽等。 The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. When the compound is treated as an acidic compound, for example, an alkali metal salt or an alkaline earth metal salt such as sodium, potassium, magnesium or calcium; and trimethylamine, triethylamine, pyridine, pyridyl, and N-methyl may be mentioned. Pyrrolidine, N-methylpiperidine, N-methyl a salt of an organic base such as a porphyrin or the like. When the compound is treated as a basic compound, for example, an acid addition salt of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a nitrate or a phosphate-like mineral acid; a benzoate; , methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, acetate, etc. Acid addition salts and the like.

作為一般式(1)所示之化合物或其鹽的溶媒合物，可舉例如水合物等，但並不限定此處。 The solvent of the compound represented by the general formula (1) or a salt thereof may, for example, be a hydrate or the like, but is not limited thereto.

尚且，於生體中被代謝而轉換為一般式(1)所示之化合物的化合物、亦即前驅物亦均涵括於本發明中。作為形成本發 明之化合物之前驅物的的基，可舉例如「Progress in Medicine」、Life Science Medica公司，1985年，5卷，2157-2161頁記載之基，或廣川書店1990年刊「醫藥品之開發」第7卷分子設計163-198頁記載的基。 Further, a compound which is metabolized in a living body and converted into a compound represented by the general formula (1), that is, a precursor is also included in the present invention. Forming the hair The basis of the precursor of the compound of the present invention is, for example, "Progress in Medicine", Life Science Medica, 1985, Vol. 5, pp. 2157-2161, or Hirokawa Shoten, 1990, "Development of Pharmaceuticals", No. 7 The basis of the volume molecular design described on pages 163-198.

上述一般式(1)所示之化合物或其鹽或其等之溶媒合物可藉各種公知方法進行製造，並無特別限制，例如可依照下述說明之反應步驟進行製造。又，在進行下述反應時，亦可對反應部位以外之官能基視需要先予以保護，再於適當階段予以脫保護。作為保護、脫保護條件，可參考一般使用之方法(例如Green’s Protective Group in Organic Synthesis Fourth Edition,John Wiley & Sons,Inc.,2006記載之方法)而進行。又，各步驟中，反應可依一般進行之方法(例如Comprehensive Organic Transformations Second Edition,John Wiley & Sons,Inc；1999記載之方法)實施，單離精製可係適當選擇結晶化、再結晶化、層析法等之通常方法，或予以組合進行。 The compound represented by the above formula (1) or a salt thereof or a solvent thereof can be produced by various known methods, and is not particularly limited. For example, it can be produced by a reaction step described below. Further, when the following reaction is carried out, functional groups other than the reaction site may be protected as needed, and then deprotected at an appropriate stage. As conditions for protection and deprotection, it can be carried out by referring to a method generally used (for example, a method described in Green's Protective Group in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc., 2006). Further, in each step, the reaction can be carried out according to a general method (for example, the method described in Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc., 1999), and the separation can be appropriately selected from crystallization, recrystallization, and layering. The usual methods such as analysis are performed or combined.

(一般式(1)所示之化合物的製造方法) (Method for producing a compound represented by the general formula (1))

本發明之一般式(1)所示的化合物，可藉由下述反應路徑圖1記載的方法進行製造。 The compound represented by the general formula (1) of the present invention can be produced by the method described in the following reaction scheme of Fig. 1.

[反應路徑圖1] [Reaction Path Figure 1]

[化5] (式中，A、Z、R1、R2、R3、R4、R5、R6、R7、R8、R13、R14及R15係與上述一般式(1)中者同義，X1表示鹵素原子，R16及R17表示氫原子或C1-6烷基，或R16與R17共同形成環之一部分。) [Chemical 5] (wherein A, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 and R 15 are the same as those in the above general formula (1) Synonymous, X 1 represents a halogen atom, R 16 and R 17 represent a hydrogen atom or a C 1-6 alkyl group, or R 16 and R 17 together form a part of a ring.

(A-1)A-1步驟係使化合物(2)於溶媒存在下或非存在下，於2級胺存在下與化合物(3)反應而製造化合物(4)的步驟。所使用之2級胺並無特別限制，可使用例如二乙基胺、啉、哌啶、吡咯啶等。較佳為哌啶。所使用之溶媒並無特別限定，例如異丙醇、乙醇、甲醇等之醇類；N,N-二甲基甲醯胺等之醯胺類；二乙基醚、二烷、四氫呋喃等之醚類；乙腈、丙腈等之腈類；二氯甲烷等之鹵化烴類等；此等可單獨使用或依任意比率混合使用。較佳為醇類，更佳為甲醇。反 應溫度為30~150℃、較佳50~100℃。反應時間為5分鐘~48小時，較佳為3小時~24小時。上述反應中所使用之化合物(2)或(3)可直接使用可取得物，或藉公知方法適當製造，但並不限定此處。 The step (A-1) A-1 is a step of producing a compound (4) by reacting the compound (2) with the compound (3) in the presence or absence of a solvent in the presence of a secondary amine. The second-grade amine to be used is not particularly limited, and for example, diethylamine can be used. Porphyrin, piperidine, pyrrolidine and the like. Peptidylene is preferred. The solvent to be used is not particularly limited, and examples thereof include alcohols such as isopropyl alcohol, ethanol, and methanol; guanamines such as N,N-dimethylformamide; and diethyl ether and An ether such as an alkane or a tetrahydrofuran; a nitrile such as acetonitrile or propionitrile; a halogenated hydrocarbon such as dichloromethane; and the like; these may be used singly or in any ratio. It is preferably an alcohol, more preferably methanol. The reaction temperature is 30 to 150 ° C, preferably 50 to 100 ° C. The reaction time is from 5 minutes to 48 hours, preferably from 3 hours to 24 hours. The compound (2) or (3) used in the above reaction may be used as it is, or may be suitably produced by a known method, but is not limited thereto.

(A-2)A-2步驟係使化合物(4)藉鈴木-宮浦偶合反應與化合物(5)反應而製造化合物(6)的步驟。所使用之金屬觸媒、鹼及反應條件，係若為通常鈴木-宮浦偶合反應中所使用的試藥及條件則無特別限定，可使用例如N.Miyaura,A.Suzuki,Chem.Rev.1995,95,2457-2483,(1995)等所記載的方法。作為所使用之金屬觸媒並無特別限制，例如為醋酸鈀(II)、二亞苯基丙酮鈀(0)、參(二亞苯基丙酮)二鈀(0)、雙(三第三丁基膦)鈀(0)、參(二亞苄基丙酮)(氯仿)二鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)、雙(三苯基膦)二氯化鈀(II)、肆(三苯基膦)鈀(0)等之鈀錯合物，較佳為[1,1’-雙(二苯基膦)二茂鐵]二氯鈀(II)、肆(三苯基膦)鈀(0)。作為鹼並無特別限制，例如氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、第三丁氧化鈉、第三丁氧化鉀等，較佳為碳酸鈉、碳酸銫。作為溶媒並無特別限制，可單獨或組合使用例如四氫呋喃、1,4-二烷、乙二醇二甲基醚等之醚類；甲苯等之芳香族烴類；N,N-二甲基甲醯胺、N-甲基吡咯啶酮等之醯胺類；二甲基亞碸、水等。較佳為四氫呋喃、乙二醇二甲基醚、N,N-二甲基甲醯胺、水及其等之混合溶媒。反應 溫度為0~200℃、較佳60~150℃。反應時間為1小時~48小時、較佳30分鐘~20小時。上述反應中所使用之化合物(5)，可直接使用可取得物，或藉公知方法適當製造，但並不限定此處 (A-2) The step A-2 is a step of producing a compound (6) by reacting the compound (4) with the compound (5) by a Suzuki-Miyaura coupling reaction. The metal catalyst, the base, and the reaction conditions to be used are not particularly limited as long as the reagents and conditions used in the usual Suzuki-Miyaura coupling reaction, and for example, N. Miyaura, A. Suzuki, Chem. Rev. 1995 can be used. , 95, 2457-2483, (1995) and the like. The metal catalyst to be used is not particularly limited, and examples thereof include palladium (II) acetate, palladium (0) diphenyleneacetate, diphenyl palladium (0), and bis (three third). Palladium (0), ginseng (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), A palladium complex of bis(triphenylphosphine)palladium(II) chloride, ruthenium (triphenylphosphine)palladium (0) or the like, preferably [1,1'-bis(diphenylphosphine) II Ferrocene] palladium (II) chloride, ruthenium (triphenylphosphine) palladium (0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium tributoxide, potassium third potassium hydride, and the like, preferably sodium carbonate. , cesium carbonate. The solvent is not particularly limited, and may be used alone or in combination, for example, tetrahydrofuran, 1,4-two. An ether such as an alkane or an ethylene glycol dimethyl ether; an aromatic hydrocarbon such as toluene; an amide such as N,N-dimethylformamide or N-methylpyrrolidone;碸, water, etc. Preferred are mixed solvents of tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, water, and the like. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is from 1 hour to 48 hours, preferably from 30 minutes to 20 hours. The compound (5) used in the above reaction may be used as it is, or may be suitably produced by a known method, but is not limited thereto.

(A-3)A-3步驟係將化合物(6)於溶媒存在下，與還原劑反應而製造化合物(7)的步驟。作為所使用之還原劑並無特別限制，可使用例如氫化硼鈉、氫化硼鉀、三乙醯氧基氫化硼鈉、氫化鋰鋁、氫化二異丁基鋁等。較佳為氫化硼鈉。作為所使用之溶媒並無特別限制，可為例如甲醇、乙醇、異丙醇等之醇類；二烷、四氫呋喃等之醚類；乙腈、丙腈等之腈類等，此等可單獨或組合使用。較佳為醇類，更佳為甲醇、乙醇。反應溫度為-20~100℃，較佳為0~60℃。反應時間為10分鐘~48小時，較佳為30分鐘~10小時。 The step (A-3) A-3 is a step of producing a compound (7) by reacting the compound (6) with a reducing agent in the presence of a solvent. The reducing agent to be used is not particularly limited, and for example, sodium borohydride, potassium borohydride, sodium triethoxy hydride hydride, lithium aluminum hydride, diisobutylaluminum hydride or the like can be used. Preferred is sodium borohydride. The solvent to be used is not particularly limited, and may be, for example, an alcohol such as methanol, ethanol or isopropanol; An ether such as an alkane or a tetrahydrofuran; a nitrile such as acetonitrile or propionitrile, or the like, which may be used singly or in combination. It is preferably an alcohol, more preferably methanol or ethanol. The reaction temperature is -20 to 100 ° C, preferably 0 to 60 ° C. The reaction time is from 10 minutes to 48 hours, preferably from 30 minutes to 10 hours.

(A-4)A-4步驟係將化合物(7)於溶媒存在下、鹼之存在下或非存在下，與脫水劑反應而製造化合物(1a)的步驟。作為所使用之脫水劑並無特別限制，可使用例如甲磺醯氯、對甲苯磺醯氯、胺甲酸甲基-N-(三乙基磺醯銨)等，較佳為胺甲酸甲基-N-(三乙基磺醯銨)。作為所使用之鹼並無特別限制，例如為三乙基胺、N,N,N-二異丙基乙基胺、1,8-二吖雙環[5.4.0]十一-7-烯(DBU)等。所使用之溶媒並無特別限制，可為例如N,N-二甲基甲醯胺等之醯胺類；二烷、四氫呋喃等之醚類；乙腈、丙腈等之腈類；甲苯等之芳香族烴類； 氯仿、二氯甲烷、1,2-二氯乙烷等之鹵化烴類等，此等可單獨或組合使用。較佳為醚類，更佳為四氫呋喃。反應溫度為0~150℃，較佳為30~110℃。反應時間為1~48小時，較佳為2~24小時。 (A-4) Step A-4 is a step of producing a compound (1a) by reacting the compound (7) in the presence of a solvent, in the presence or absence of a base, with a dehydrating agent. The dehydrating agent to be used is not particularly limited, and for example, methanesulfonium chloride, p-toluenesulfonyl chloride, methylamine N-(triethylsulfonium ammonium), or the like, preferably a methyl carbamate group, may be used. N-(triethylsulfonium ammonium). The base to be used is not particularly limited, and examples thereof include triethylamine, N,N,N-diisopropylethylamine, 1,8-difluorenebicyclo[5.4.0]undec-7-ene ( DBU) and so on. The solvent to be used is not particularly limited, and may be, for example, an amide such as N,N-dimethylformamide; An ether such as an alkane or a tetrahydrofuran; a nitrile such as acetonitrile or propionitrile; an aromatic hydrocarbon such as toluene; a halogenated hydrocarbon such as chloroform, dichloromethane or 1,2-dichloroethane; Or use in combination. It is preferably an ether, more preferably tetrahydrofuran. The reaction temperature is 0 to 150 ° C, preferably 30 to 110 ° C. The reaction time is from 1 to 48 hours, preferably from 2 to 24 hours.

(A-5)A-5步驟係將化合物(1a)於溶媒存在下、氫存在下或非存在下，於常壓或加壓下藉由使用了金屬觸媒之還原反應而製造化合物(1b)的步驟。作為所使用之金屬觸媒，為鈀碳、氫氧化鈀、林德拉觸媒、氧化鉑、參(三苯基膦)氯化銠(威爾金森觸媒)等，較佳為鈀碳。作為所使用之溶媒，可為甲醇、乙醇、異丙醇等之醇類；己烷等之烴類；醋酸乙酯等之酯類；四氫呋喃等之醚類等；較佳為醇類、醚類，更佳為甲醇、四氫呋喃。反應溫度為0~120℃，較佳為20~80℃。反應時間為1~48小時，較佳為2~24小時。 (A-5) Step A-5 is a method for producing a compound (1b) by a reduction reaction using a metal catalyst under normal pressure or under pressure in the presence of a solvent, in the presence or absence of hydrogen, or in the absence of hydrogen. )A step of. The metal catalyst to be used is palladium carbon, palladium hydroxide, lindra catalyst, platinum oxide, ruthenium (triphenylphosphine) ruthenium chloride (wilsonsen catalyst), etc., and palladium carbon is preferred. The solvent to be used may be an alcohol such as methanol, ethanol or isopropanol; a hydrocarbon such as hexane; an ester such as ethyl acetate; an ether such as tetrahydrofuran; or the like; preferably an alcohol or an ether. More preferably, it is methanol or tetrahydrofuran. The reaction temperature is 0 to 120 ° C, preferably 20 to 80 ° C. The reaction time is from 1 to 48 hours, preferably from 2 to 24 hours.

於R13、R14及R15具有氫原子以外之取代基的化合物，係使用本反應路徑圖之中間體，可藉由以例如Bioorg.Med.Chem.Lett.2010,746或WO2010/103381號說明書等記載之方法為參考而製造，但並不限定此處。 The compound having a substituent other than a hydrogen atom in R 13 , R 14 and R 15 is an intermediate of the reaction scheme, which can be used, for example, by Bioorg. Med. Chem. Lett. 2010, 746 or WO 2010/103381. The method described in the specification and the like is manufactured by reference, but is not limited thereto.

除了上述記載之方法以外，本發明之一般式(1)所示之化合物亦可藉由下述反應路徑圖2記載的方法進行製造。 In addition to the methods described above, the compound represented by the general formula (1) of the present invention can also be produced by the method described in the following reaction scheme.

[反應路徑圖2] [Reaction Path Figure 2]

[化6] (式中，A、X1、Z、R1、R2、R3、R4、R5、R6、R7、R8、R13、R14、R15、R16及R17係與上述同義，X2表示鹵素原子，R18及R19表示氫原子或C1-6烷基，或R18與R19共同形成環之一部分。) [Chemical 6] (wherein A, X 1 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 and R 17 are Synonymous with the above, X 2 represents a halogen atom, R 18 and R 19 represent a hydrogen atom or a C 1-6 alkyl group, or R 18 and R 19 together form a part of a ring.

(B-1)B-1步驟係使化合物(4)於溶媒存在下，與還原劑反應而製造化合物(8)的步驟。作為所使用之還原劑並無特別限制，可使用例如氫化硼鈉、氫化硼鉀、三乙醯氧基氫化硼鈉、氫化鋰鋁、氫化二異丁基鋁等。較佳為氫化硼鈉。作為所使用之溶媒並無特別限制，可為例如甲醇、乙醇、異丙醇等之醇類；二烷、四氫呋喃等之醚類；乙腈、丙腈等之腈類等，此等可單獨或組合使用。較佳為醇類，更佳為甲醇、乙醇。反應溫度為-20~100℃，較佳為0~60℃。反應時間為10分鐘~48小時，較佳為30分鐘~10小時。 (B-1) The step B-1 is a step of producing a compound (8) by reacting the compound (4) with a reducing agent in the presence of a solvent. The reducing agent to be used is not particularly limited, and for example, sodium borohydride, potassium borohydride, sodium triethoxy hydride hydride, lithium aluminum hydride, diisobutylaluminum hydride or the like can be used. Preferred is sodium borohydride. The solvent to be used is not particularly limited, and may be, for example, an alcohol such as methanol, ethanol or isopropanol; An ether such as an alkane or a tetrahydrofuran; a nitrile such as acetonitrile or propionitrile, or the like, which may be used singly or in combination. It is preferably an alcohol, more preferably methanol or ethanol. The reaction temperature is -20 to 100 ° C, preferably 0 to 60 ° C. The reaction time is from 10 minutes to 48 hours, preferably from 30 minutes to 10 hours.

(B-2)B-2步驟係將化合物(8)於溶媒存在下或非存在下，於酸存在下與還原劑反應而製造化合物(9)的步驟。作為所使用之還原劑並無特別限制，可使用例如氫化硼鈉、氫化硼鉀、三乙醯氧基氫化硼鈉、氫化鋰鋁、氫化二異丁基鋁、三乙基矽烷、苯基矽烷等，較佳為三乙基矽烷。作為所使用之酸並無特別限制，為醋酸、三氟醋酸、三氯醋酸、三氟硼烷‧二乙基醚、三甲基矽基三氟甲磺酸等，較佳為三氟醋酸。反應溫度為-20~120℃，較佳為50~100℃。反應時間為10分鐘~48小時，較佳為1~24小時。 (B-2) The step B-2 is a step of producing a compound (9) by reacting the compound (8) with a reducing agent in the presence or absence of a solvent in the presence of a solvent. The reducing agent to be used is not particularly limited, and for example, sodium borohydride, potassium borohydride, sodium triethoxy hydride hydride, lithium aluminum hydride, diisobutylaluminum hydride, triethyl decane, phenyl decane can be used. Etc., preferably triethyl decane. The acid to be used is not particularly limited, and is acetic acid, trifluoroacetic acid, trichloroacetic acid, trifluoroborane, diethyl ether or trimethyldecyltrifluoromethanesulfonic acid, and is preferably trifluoroacetic acid. The reaction temperature is -20 to 120 ° C, preferably 50 to 100 ° C. The reaction time is from 10 minutes to 48 hours, preferably from 1 to 24 hours.

(B-3)B-3步驟係使化合物(9)藉鈴木-宮浦偶合反應與化合物(5)反應而製造化合物(1b)的步驟。所使用之金屬觸媒、鹼及反應條件，係若為通常鈴木-宮浦偶合反應中所使用的試藥及條件則無特別限定，可使用例如N.Miyaura,A.Suzuki,Chem.Rev.1995,95,2457-2483,(1995)等所記載的方法。作為所使用之金屬觸媒並無特別限制，例如為醋酸鈀(II)、二亞苯基丙酮鈀(0)、參(二亞苯基丙酮)二鈀(0)、雙(三第三丁基膦)鈀(0)、參(二亞苄基丙酮)(氯仿)二鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)、雙(三苯基膦)二氯化鈀(II)、肆(三苯基膦)鈀(0)等之鈀錯體，較佳為[1,1’-雙(二苯基膦)二茂鐵]二氯鈀(II)、肆(三苯基膦)鈀(0)。作為鹼並無特別限制，例如氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、第三丁氧化鈉、第三丁氧化鉀等，較佳為碳酸 鈉、碳酸銫。作為溶媒並無特別限制，可單獨或組合使用例如四氫呋喃、1,4-二烷、乙二醇二甲基醚等之醚類；甲苯等之芳香族烴類；N,N-二甲基甲醯胺、N-甲基吡咯啶酮等之醯胺類；二甲基亞碸、水等。較佳為四氫呋喃、乙二醇二甲基醚、N,N-二甲基甲醯胺、水及其等之混合溶媒。反應溫度為0~200℃、較佳60~150℃。反應時間為1小時~48小時、較佳30分鐘~12小時。上述反應中所使用之化合物(5)，可直接使用可取得物，或藉公知方法適當製造，但並不限定此處。 (B-3) The step B-3 is a step of producing a compound (1b) by reacting the compound (9) with the compound (5) by a Suzuki-Miyaura coupling reaction. The metal catalyst, the base, and the reaction conditions to be used are not particularly limited as long as the reagents and conditions used in the usual Suzuki-Miyaura coupling reaction, and for example, N. Miyaura, A. Suzuki, Chem. Rev. 1995 can be used. , 95, 2457-2483, (1995) and the like. The metal catalyst to be used is not particularly limited, and examples thereof include palladium (II) acetate, palladium (0) diphenyleneacetate, diphenyl palladium (0), and bis (three third). Palladium (0), ginseng (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), Palladium complex of bis(triphenylphosphine)palladium(II) chloride, ruthenium (triphenylphosphine)palladium(0), etc., preferably [1,1'-bis(diphenylphosphino)dilen Iron] palladium (II) chloride, ruthenium (triphenylphosphine) palladium (0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium tributoxide, potassium third potassium hydride, and the like, preferably sodium carbonate. , cesium carbonate. The solvent is not particularly limited, and may be used alone or in combination, for example, tetrahydrofuran, 1,4-two. An ether such as an alkane or an ethylene glycol dimethyl ether; an aromatic hydrocarbon such as toluene; an amide such as N,N-dimethylformamide or N-methylpyrrolidone;碸, water, etc. Preferred are mixed solvents of tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, water, and the like. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is from 1 hour to 48 hours, preferably from 30 minutes to 12 hours. The compound (5) used in the above reaction can be used as it is, or can be suitably produced by a known method, but is not limited thereto.

(C-1)C-1步驟係由化合物(9)使用金屬觸媒製造硼烷化合物(10)的步驟。所使用之金屬觸媒並無特別限制，例如為醋酸鈀(II)、二亞苯基丙酮鈀(0)、參(二亞苯基丙酮)二鈀(0)、雙(三第三丁基膦)鈀(0)、參(二亞苄基丙酮)(氯仿)二鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)、雙(三苯基膦)二氯化鈀(II)、肆(三苯基膦)鈀(0)等之鈀錯合物，較佳為雙(三苯基膦)二氯鈀(II)。作為所使用之鹼並無特別限制，例如為碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、醋酸鉀、醋酸鈉等，較佳為醋酸鉀。作為所使用之溶媒並無特別限制，可單獨或組合使用例如四氫呋喃、1,4-二烷等之醚類；甲苯等之芳香族烴類；N,N-二甲基甲醯胺、N-甲基吡咯啶酮等之醯胺類；二甲基亞碸、水等。較佳為1,4-二烷與水的混合溶媒。反應溫度為0~200℃、較佳80~150℃。反應時間為1小時~48 小時、較佳2小時~24小時。 The step (C-1) C-1 is a step of producing a borane compound (10) from a compound (9) using a metal catalyst. The metal catalyst to be used is not particularly limited, and examples thereof include palladium (II) acetate, palladium (0) diphenyleneacetate, diphenyl palladium (0), and di(tris-tert-butyl). Phosphine) palladium (0), ginseng (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), double A palladium complex of (triphenylphosphine)palladium(II) chloride, ruthenium (triphenylphosphine)palladium (0) or the like is preferably bis(triphenylphosphine)dichloropalladium(II). The base to be used is not particularly limited, and examples thereof include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate, and the like, and potassium acetate is preferred. The solvent to be used is not particularly limited, and for example, tetrahydrofuran or 1,4-di can be used singly or in combination. An ether such as an alkane; an aromatic hydrocarbon such as toluene; an amide such as N,N-dimethylformamide or N-methylpyrrolidone; dimethylammonium or water. Preferably 1,4-two a mixed solvent of alkane and water. The reaction temperature is 0 to 200 ° C, preferably 80 to 150 ° C. The reaction time is from 1 hour to 48 hours, preferably from 2 hours to 24 hours.

(C-2)C-2步驟係使化合物(10)藉鈴木-宮浦偶合反應與化合物(11)反應而製造化合物(1b)的步驟。所使用之金屬觸媒、鹼及反應條件，係若為通常鈴木-宮浦偶合反應中所使用的試藥及條件則無特別限定，可使用例如N.Miyaura,A.Suzuki,Chem.Rev.1995,95,2457-2483,(1995)等所記載的方法。作為所使用之金屬觸媒並無特別限制，例如為醋酸鈀(II)、二亞苯基丙酮鈀(0)、參(二亞苯基丙酮)二鈀(0)、雙(三第三丁基膦)鈀(0)、參(二亞苄基丙酮)(氯仿)二鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)、雙(三苯基膦)二氯化鈀(II)、肆(三苯基膦)鈀(0)等之鈀錯合物，較佳為[1,1’-雙(二苯基膦)二茂鐵]二氯鈀(II)、肆(三苯基膦)鈀(0)。作為鹼並無特別限制，例如氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、第三丁氧化鈉、第三丁氧化鉀等，較佳為碳酸鈉、碳酸銫。作為溶媒並無特別限制，可單獨或組合使用例如四氫呋喃、1,4-二烷、乙二醇二甲基醚等之醚類；甲苯等之芳香族烴類；N,N-二甲基甲醯胺、N-甲基吡咯啶酮等之醯胺類；二甲基亞碸、水等。較佳為四氫呋喃、乙二醇二甲基醚、N,N-二甲基甲醯胺、水及其等之混合溶媒。反應溫度為0~200℃、較佳60~150℃。反應時間為1小時~48小時、較佳30分鐘~12小時。上述反應中所使用之化合物(11)，可直接使用可取得物，或藉公知方法適當製 造，但並不限定此處。 (C-2) The step C-2 is a step of producing a compound (1b) by reacting the compound (10) with the compound (11) by a Suzuki-Miyaura coupling reaction. The metal catalyst, the base, and the reaction conditions to be used are not particularly limited as long as the reagents and conditions used in the usual Suzuki-Miyaura coupling reaction, and for example, N. Miyaura, A. Suzuki, Chem. Rev. 1995 can be used. , 95, 2457-2483, (1995) and the like. The metal catalyst to be used is not particularly limited, and examples thereof include palladium (II) acetate, palladium (0) diphenyleneacetate, diphenyl palladium (0), and bis (three third). Palladium (0), ginseng (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), A palladium complex of bis(triphenylphosphine)palladium(II) chloride, ruthenium (triphenylphosphine)palladium (0) or the like, preferably [1,1'-bis(diphenylphosphine) II Ferrocene] palladium (II) chloride, ruthenium (triphenylphosphine) palladium (0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium tributoxide, potassium third potassium hydride, and the like, preferably sodium carbonate. , cesium carbonate. The solvent is not particularly limited, and may be used alone or in combination, for example, tetrahydrofuran, 1,4-two. An ether such as an alkane or an ethylene glycol dimethyl ether; an aromatic hydrocarbon such as toluene; an amide such as N,N-dimethylformamide or N-methylpyrrolidone;碸, water, etc. Preferred are mixed solvents of tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, water, and the like. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is from 1 hour to 48 hours, preferably from 30 minutes to 12 hours. The compound (11) used in the above reaction can be used as it is, or can be suitably produced by a known method, but is not limited thereto.

於R13、R14及R15具有氫原子以外之取代基的化合物，係使用本反應路徑圖之中間體，可藉由以例如Bioorg.Med.Chem.Lett.2010,746或WO2010/103381號說明書等記載之方法為參考而製造，但並不限定此處。 The compound having a substituent other than a hydrogen atom in R 13 , R 14 and R 15 is an intermediate of the reaction scheme, which can be used, for example, by Bioorg. Med. Chem. Lett. 2010, 746 or WO 2010/103381. The method described in the specification and the like is manufactured by reference, but is not limited thereto.

另外，上述反應所使用之一般式(1b)所示之化合物亦可藉由下述反應路徑圖3記載的方法進行製造。 Further, the compound represented by the general formula (1b) used in the above reaction can also be produced by the method described in the following reaction scheme of Fig. 3.

[反應路徑圖3] [Reaction Path Figure 3]

(式中，A、Z、R1、R2、R3、R4、R5、R6、R7、R8、R13、R14及R15係與上述同義，W表示脫離基。) (wherein A, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 and R 15 are the same as defined above, and W represents a leaving group. )

(D-1)D-1步驟係將化合物(1b’)於於酸存在下進行脫保護而製造化合物(12)的步驟。作為所使用之酸並無特別限制，為鹽酸、甲酸、三氟醋酸等，較佳為鹽酸。作為所使用之溶媒並無特別限制，可單獨或組合使用例如氯仿、二氯甲烷、 1,2-二氯乙烷等之鹵化烴類；甲醇、乙醇等之醇類；二乙基醚、四氫呋喃、1,4-二烷等之醚類；甲苯等之芳香族烴類等。較佳為醚類，更佳為1,4-二烷。反應溫度為0~120℃，較佳為0~50℃。反應時間為1小時~48小時，較佳為2小時~24小時。 The step (D-1) D-1 is a step of producing a compound (12) by subjecting the compound (1b') to deprotection in the presence of an acid. The acid to be used is not particularly limited, and is hydrochloric acid, formic acid, trifluoroacetic acid or the like, and hydrochloric acid is preferred. The solvent to be used is not particularly limited, and a halogenated hydrocarbon such as chloroform, dichloromethane or 1,2-dichloroethane; an alcohol such as methanol or ethanol; diethyl ether or tetrahydrofuran may be used singly or in combination. 1,4-two An ether such as an alkane; an aromatic hydrocarbon such as toluene or the like. Preferred as ethers, more preferably 1,4-two alkyl. The reaction temperature is 0 to 120 ° C, preferably 0 to 50 ° C. The reaction time is from 1 hour to 48 hours, preferably from 2 hours to 24 hours.

(D-2)D-2步驟係將化合物(12)於鹼之存在下，與化合物(13)反應而製造化合物(1b)的步驟。作為所使用之鹼並無特別限制，例如為氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫、三乙基胺、N,N,N-二異丙基乙基胺等，較佳為三乙基胺或N,N-二異丙基乙基胺。所使用之溶媒並無特別限制，可單獨或組合使用例如氯仿、二氯甲烷、1,2-二氯乙烷等之鹵化烴類；甲醇、乙醇等之醇類；二乙基醚、四氫呋喃、1,4-二烷等之醚類；甲苯等之芳香族烴類；N,N-二甲基甲醯胺、N-甲基吡咯啶酮等之醯胺類；二甲基亞碸等。較佳為二氯甲烷或N,N-二甲基甲醯胺。反應溫度為0℃~150℃，較佳為20℃~80℃。反應時間為10分鐘~48小時，較佳為1小時~15小時。上述反應中所使用之化合物(13)，可直接使用可取得物，或藉公知方法適當製造，但並不限定此處。 (D-2) The step D-2 is a step of producing a compound (1b) by reacting the compound (12) with a compound (13) in the presence of a base. The base to be used is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N,N-diisopropyl. The ethyl ethylamine or the like is preferably triethylamine or N,N-diisopropylethylamine. The solvent to be used is not particularly limited, and a halogenated hydrocarbon such as chloroform, dichloromethane or 1,2-dichloroethane; an alcohol such as methanol or ethanol; diethyl ether or tetrahydrofuran may be used singly or in combination. 1,4-two An ether such as an alkane; an aromatic hydrocarbon such as toluene; an amide such as N,N-dimethylformamide or N-methylpyrrolidone; dimethylammonium or the like. Preferred is dichloromethane or N,N-dimethylformamide. The reaction temperature is from 0 ° C to 150 ° C, preferably from 20 ° C to 80 ° C. The reaction time is from 10 minutes to 48 hours, preferably from 1 hour to 15 hours. The compound (13) used in the above reaction can be used as it is, or can be suitably produced by a known method, but is not limited thereto.

上述各反應所得之中間體及目標物，可藉由有機合成化學中常用之精製法，例如過濾、萃取、洗淨、乾燥、濃縮、再結晶、各種層析法等而視需要進行單離、精製。又，中間體 亦可不特別精製而供於下一反應。 The intermediates and targets obtained by the above respective reactions can be isolated as needed by a purification method commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like. refined. Again, intermediate It can also be used in the next reaction without special refining.

再者，各種之異構物可應用利用了異構物間之物理化學性質差別的常法予以單離。消旋混合物可藉由例如引導至與酒石酸等之一般之光學活性酸間的非鏡像異構物鹽而進行光學分割的方法，或藉由使用了光學活性管柱層析之方法等的一般性消旋分割法，而引導至光學性純粹之異構物。又，非鏡像異構物混合物可藉由例如分別結晶化或各種層析法等進行分割。又，光學活性之化合物亦可藉由使用適當之光學活性原料而製造。 Further, various isomers can be applied by a conventional method utilizing the difference in physicochemical properties between the isomers. The racemic mixture can be optically divided by, for example, a non-glyconomer salt which is guided to a general optically active acid such as tartaric acid, or a general method such as a method using optically active column chromatography. The racemic segmentation method leads to the optically pure isomer. Further, the mixture of the non-image isomers can be divided by, for example, crystallization separately or various kinds of chromatography. Further, optically active compounds can also be produced by using suitable optically active starting materials.

所得之化合物(1)可藉通常方法作成鹽。又，亦可作成反應溶媒、再結晶溶媒等之溶媒的溶媒合物或水合物。 The obtained compound (1) can be formed into a salt by a usual method. Further, a solvent or a hydrate of a solvent such as a reaction solvent or a recrystallization solvent may be used.

作為含有本發明之一般式(1)所示之化合物或其鹽或其等之溶媒合物作為有效成分的醫藥，可單獨使用該有效成分，但通常係調配作為醫藥所容許之載體、添加物等而使用。醫藥組成物之投予形態並無特別限定，可配合治療目的而適當選擇。可為例如經口劑、注射劑、栓劑、軟膏軟、吸入劑、點眼劑、點鼻劑、貼附劑等之任一種。適合此處等投予形態的醫藥組成物可藉公知之製劑方法進行製造。 The pharmaceutical composition containing the compound represented by the general formula (1) of the present invention or a salt thereof or a solvent thereof as an active ingredient can be used alone, but usually it is a carrier or an additive which is allowed as a medicine. Wait for use. The form of administration of the pharmaceutical composition is not particularly limited and may be appropriately selected in accordance with the purpose of treatment. For example, it may be any of an oral preparation, an injection, a suppository, an ointment, an inhalant, an eye drop, a nasal spray, a patch, and the like. The pharmaceutical composition suitable for the administration form such as this can be produced by a known preparation method.

在調製經口用固形製劑時，可於一般式(1)所示之化合物中加入賦形劑、視需要之結合劑、崩解劑、潤滑劑、著色劑、矯味劑、矯臭劑等後，藉常法製造錠劑、被覆錠劑、顆粒劑、散劑、膠囊劑等。添加劑可為該領域中一般使用者。例如， 作為賦形劑，可舉例如乳糖、白糖、氯化鈉、葡萄糖、澱粉、碳酸鈣、高嶺土、微結晶纖維素、矽酸等。作為結合劑，可舉例如乙醇、丙醇、單糖漿、葡萄糖液、澱粉液、明膠液、羧甲基纖維素、羥丙基纖維素、羥丙基澱粉、甲基纖維素、乙基纖維素、蟲膠、磷酸鈣、聚乙烯基吡咯啶酮等。作為崩解劑，可舉例如乾燥澱粉、褐藻酸鈉、寒天粉末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸單甘油酯、乳糖等。作為潤滑劑，可舉例如精製滑石、硬脂酸鹽、硼砂、聚乙二醇等。作為矯味劑，可舉例如白糖、橙皮、檸檬酸、酒石酸等。 When preparing a solid preparation for oral administration, an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, and the like may be added to the compound represented by the general formula (1). Tablets, coated tablets, granules, powders, capsules, and the like are produced by a conventional method. Additives can be a general user in the field. E.g, Examples of the excipient include lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and citric acid. The binding agent may, for example, be ethanol, propanol, monosaccharide syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose. , shellac, calcium phosphate, polyvinylpyrrolidone and the like. Examples of the disintegrator include dried starch, sodium alginate, cold weather powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. Examples of the lubricant include purified talc, stearate, borax, polyethylene glycol, and the like. Examples of the flavoring agent include white sugar, orange peel, citric acid, tartaric acid, and the like.

在調製經口用液體製劑時，可於一般式(1)所示之化合物中添加矯味劑、緩衝劑、安定化劑、矯臭劑等而藉常法製造內服液劑、糖漿劑、酏劑等。作為矯味劑可為上述所列舉者，作為緩衝劑可舉例如檸檬酸鈉等，作為安定化劑可舉例如黃蓍膠、***膠、明膠等。 When a liquid preparation for oral administration is prepared, a flavoring agent, a buffering agent, a stabilizer, a flavoring agent, etc. may be added to the compound represented by the general formula (1), and an internal liquid preparation, a syrup, an expectorant, etc. may be produced by a usual method. . The flavoring agent may be the above-mentioned ones, and examples of the buffering agent include sodium citrate and the like, and examples of the stabilizer include xanthan gum, gum arabic, and gelatin.

在調製注射劑時，可於一般式(1)所示之化合物中添加pH調節劑、緩衝劑、安定化劑、等張化劑、局部麻醉劑等，依常法製造皮下、肌肉及靜脈內注射劑。作為pH調製劑及緩衝劑，可舉例如檸檬酸鈉、醋酸鈉、磷酸鈉等。作為安定化劑可舉例如焦亞硫酸鈉、EDTA、硫乙醇酸、硫乳酸等。作為局部麻醉劑，可舉例如鹽酸普魯卡因、鹽酸利度卡因等。作為等張化劑，可舉例如氯化鈉、葡萄糖等。 When a preparation for injection is prepared, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic or the like may be added to the compound represented by the general formula (1), and a subcutaneous, intramuscular, and intravenous injection may be produced by a usual method. Examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidycaine hydrochloride. Examples of the isotonic agent include sodium chloride, glucose, and the like.

在調製栓劑時，可於一般式(1)所示之化合物中添加公知 之栓劑用載體，例如聚乙二醇、羊毛脂、可可脂、脂肪酸三甘油酯等，並視需要添加Tween(註冊商標)等之界面活性劑等後，依常法進行製造。 When a suppository is prepared, it can be added to the compound represented by the general formula (1). The carrier for a suppository, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and if necessary, a surfactant such as Tween (registered trademark) is added, and then it is produced by a usual method.

在調製軟膏劑的情況，係於一般式(1)所示之化合物中視需要調配一般使用之基劑、安定化劑、濕潤劑、保存劑等，依常法予以混合、製劑化。作為基劑，可舉例如流動石蠟、白色凡士林、白蜂蠟、十八烷基醇、石蠟等。作為保存劑，可舉例如對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等。 In the case of preparing an ointment, a base, a stabilizer, a wetting agent, a preservative, etc. which are generally used may be blended in a compound represented by the general formula (1) as needed, and mixed and formulated according to a usual method. Examples of the base include flowing paraffin, white petrolatum, white beeswax, stearyl alcohol, and paraffin wax. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and propyl p-hydroxybenzoate.

一般式(1)所示之化合物係除了上述之外，亦可藉常法作成吸入劑、點眼劑、點鼻劑。 In addition to the above, the compound represented by the general formula (1) can be used as an inhalant, an eye drop, or a nasal spray by a usual method.

如後述實施例般，一般式(1)所示之化合物係具有顯著地促進倉鼠胰臟β細胞株HIT-T15細胞之胰島素分泌的作用。因此，一般式(1)所示之化合物或其酸加成鹽或其等之溶媒合物，可用於作為血糖降低劑，或作為包括人類之哺乳類之因高血糖所引起的疾病、例如糖尿病的預防及/或治療劑。此處，作為糖尿病，更詳細可舉例如胰島素非依存型糖尿病(NIDDM)。 As shown in the examples below, the compound represented by the general formula (1) has an effect of significantly promoting insulin secretion from the hamster pancreatic β-cell line HIT-T15 cells. Therefore, the compound represented by the general formula (1) or an acid addition salt thereof or a solvent thereof or the like can be used as a blood sugar lowering agent, or as a disease caused by hyperglycemia including a human mammal, such as diabetes. Preventive and/or therapeutic agents. Here, as diabetes, for example, insulin-independent diabetes mellitus (NIDDM) can be mentioned in more detail.

本發明之一般式(1)所示之化合物係藉由經口投予或非經口投予而投予。本發明之醫藥的投予量，係視患者的體重、年齡、性別、症狀等而異，通常在成人的情況，較佳係將以一般式(1)所示之化合物計為一日0.01~1000mg、較佳 0.1~300mg分為1~3次進行投予。 The compound of the general formula (1) of the present invention is administered by oral administration or parenteral administration. The dosage of the medicine of the present invention varies depending on the body weight, age, sex, symptoms, and the like of the patient. Usually, in the case of an adult, it is preferred to count the compound represented by the general formula (1) as a daily 0.01~ 1000mg, preferably 0.1~300mg is divided into 1~3 times for administration.

(實施例) (Example)

接著，列舉實施例進一步說明本發明，但本發明並不限定此處等實施例。又，下述實施例中所使用之略語表示下述意義。 Next, the present invention will be further described by way of examples, but the present invention is not limited to the examples herein. Further, the abbreviations used in the following examples represent the following meanings.

s：單峰(singlet)d：雙峰(doublet)t：三峰(triplet)q：四峰(quartet)quint：五峰(quintet)hept：七峰(heptet)m：多峰(multiplet)br：寬峰(broad)brs：寬單峰(broad singlet)J：偶合常數(coupling constant)Hz：赫茲(Hertz)CDCl3：氘化氯仿d6-DMSO：氘化二甲基亞碸CD3OD：氘化甲醇1H-NMR：質子核磁共振IR：紅外線吸收光譜 s: singlet d: doublet t: triplet q: quartet quint: quintet hept: heptet m: multiplet br: wide Broad brs: broad singlet J: coupling constant Hz: Hertz CDCl 3 : deuterated chloroform d 6 -DMSO: deuterated dimethyl hydrazine CD 3 OD: 氘Methanol 1 H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectroscopy

實施例1第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’- 哌啶]-1’-羧酸酯之製造 Example 1 Ternyl 6-(4-(methylsulfonyl)phenyl) snail [ Manufacture of terpene-2,4'-piperidinyl-1'-carboxylate

步驟1：第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯之製造 Step 1: Third butyl 6-bromo-4-oneoxy snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將5’-溴-2’-羥基苯乙酮(6.45g，30mmol)及第三丁基4-側氧基-1-哌啶羧酸酯(5.98g，30mmol)溶解於甲醇(150mL)，加入哌啶(1.2mL，15mmol)，加熱迴流5小時。使反應液減壓濃縮，將所得殘渣溶解於醋酸乙酯。對有機層以水、飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=10：1→5：1)精製，得到淡黃色固體之標題化合物(10.9mg，92%)。 5'-Bromo-2'-hydroxyacetophenone (6.45 g, 30 mmol) and tert-butyl 4-oxo-l-piperidinecarboxylate (5.98 g, 30 mmol) were dissolved in methanol (150 mL). Piperidine (1.2 mL, 15 mmol) was added and heated to reflux for 5 h. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.46(9H,s),1.54-1.66(2H,m),1.96-2.05(2H,m),2.71(2H,s),3.12-3.28(2H,m),3.75-3.99(2H,m),6.90(1H,d,J=8.8Hz),7.57(1H,dd,J=8.8,2.7Hz),7.97(2H,d,J=2.7Hz). 1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.54-1.66 (2H, m), 1.96-2.05 (2H, m), 2.71 (2H, s), 3.12-3.28 (2H, m) , 3.75-3.99 (2H, m), 6.90 (1H, d, J = 8.8 Hz), 7.57 (1H, dd, J = 8.8, 2.7 Hz), 7.97 (2H, d, J = 2.7 Hz).

步驟2：第三丁基6-(4-(甲基磺醯基)苯基)-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(methylsulfonyl)phenyl)-4-yloxyspiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(154mg，0.42mmol)及(4-(甲基磺醯基)苯基)硼酸(100mg，0.50mmol)溶解於乙二醇二甲基醚(4mL)中，加入溶解了碳酸鈉(779mg，7.35mmol)之水溶液(4mL)，並加入肆三苯基膦鈀(0)(29mg，0.025mmol)，於90℃攪拌15小時。將反應液以醋酸乙酯稀釋，萃取有機層。對有機層以飽和食鹽水洗 淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到黃色非晶形之標題化合物(218mg，100%)。 The third butyl 6-bromo-4-yloxy snail [ Indole-2,4'-piperidine]-1'-carboxylate (154 mg, 0.42 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (100 mg, 0.50 mmol) were dissolved in ethylene glycol An aqueous solution (4 mL) in which sodium carbonate (779 mg, 7.35 mmol) was dissolved was added to methyl ether (4 mL), and triphenylphosphine palladium (0) (29 mg, 0.025 mmol) was added and stirred at 90 ° C for 15 hours. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.60-1.71(2H,m),2.02-2.11(2H,m),2.78(2H,s),3.09(3H,s),3.18-3.31(2H,m),3.88-4.00(2H,m),7.13(1H,d,J=8.5Hz),7.74-7.80(3H,m),8.01(2H,d,J=8.3Hz),8.14(1H,d,J=2.4Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.60-1.71 (2H, m), 2.02-2.11 (2H, m), 2.78 (2H, s), 3.09 (3H, s), 3.18 -3.31(2H,m),3.88-4.00(2H,m),7.13(1H,d,J=8.5Hz),7.74-7.80(3H,m),8.01(2H,d,J=8.3Hz), 8.14 (1H, d, J = 2.4Hz).

步驟3：第三丁基4-羥基-6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 4-hydroxy-6-(4-(methylsulfonyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-(甲基磺醯基)苯基)-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(177mg，0.38mmol)溶解於乙醇(5mL)，加入氫化硼鈉(15.6mg，0.41mmol)，於50℃攪拌1小時。將反應液減壓濃縮，將所得殘渣溶解於醋酸乙酯。對有機層以飽和氯化銨水溶液、飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(186mg，100%)。 The third butyl 6-(4-(methylsulfonyl)phenyl)-4-yloxy snail [ Indole-2,4'-piperidinyl-1'-carboxylate (177 mg, 0.38 mmol) was dissolved in ethanol (5 mL), and sodium borohydride (15.6 mg, 0.41 mmol) was added and stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.64-1.76(2H,m),1.78-1.88(1H,m),1.90-2.22(3H,m),2.16-2.25(1H,m),3.05-3.37(5H,m),3.76-4.01(2H,m),4.96(1H,q,J=7.1Hz),6.97(1H,d,J=8.5Hz),7.48(1H,dd,J=8.6,2.2Hz),7.71-7.76(3H,m),7.97(2H,d,J=8.3Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.64-1.76 (2H, m), 1.78-1.88 (1H, m), 1.90-2.22 (3H, m), 2.16-2.25 (1H, m), 3.05-3.37 (5H, m), 3.76-4.01 (2H, m), 4.96 (1H, q, J = 7.1 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.48 (1H, dd , J = 8.6, 2.2 Hz), 7.71 - 7.76 (3H, m), 7.97 (2H, d, J = 8.3 Hz).

步驟4：第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Tert-butyl 6-(4-(methylsulfonyl)phenyl) snail [ Manufacture of terpene-2,4'-piperidine]-1'-carboxylate

將第三丁基4-羥基-6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(76mg，0.16mmol)溶解於四氫呋喃(5mL)，加入胺甲酸甲基-N-(三乙基磺醯銨)(Burgess試藥)(114mg，0.48mmol)，加熱迴流5小時。於反應液中加入水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後’減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(30.4mg，42%)。 The third butyl 4-hydroxy-6-(4-(methylsulfonyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (76 mg, 0.16 mmol) was dissolved in tetrahydrofuran (5 mL), and methyl-N-(triethylsulfonium amide) was added to the drug (Burgess reagent) (114 mg, 0.48 mmol), heated under reflux for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例2第三丁基6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 2 Ternyl 6-(4-(methylsulfonyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯(56mg，0.12mmol)溶解於四氫呋喃(4mL)，加入鈀碳(8mg)，於氫環境下以60℃攪拌12小時。將反應液進行矽藻土過濾，將濾液減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(28.5mg，51%)。 The third butyl 6-(4-(methylsulfonyl)phenyl) snail [ The terpene-2,4'-piperidine]-1'-carboxylate (56 mg, 0.12 mmol) was dissolved in tetrahydrofuran (4 mL), palladium carbon (8 mg) was added, and the mixture was stirred at 60 ° C for 12 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例3第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 3 Ternyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-bromo snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯 (1.18g，3.0mmol)溶解於乙醇(20mL)，加入氫化硼鈉(125mg，3.3mmol)，於50℃攪拌1小時。將反應液減壓濃縮，所得殘渣溶解於醋酸乙酯。對有機層以飽和氯化鈉水溶液、飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，得到白色非晶形之第三丁基6-溴-4-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯的粗製物(1.30g)。 The third butyl 6-bromo-4-yloxy snail [ Indole-2,4'-piperidinyl-1'-carboxylate (1.18 g, 3.0 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (125 mg, 3.3 mmol) was added and stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and brine, dried over anhydrous sodium sulfate and evaporated Crude (1.30 g) of 唍-2,4'-piperidine]-1'-carboxylate.

將所得粗製物(1.30g)溶解於三氟醋酸(10mL)，加入三乙基矽烷(2.0mL，12.8mmol)，加熱迴流8小時。反應液冷卻後，減壓濃縮。於所得殘渣中加入二乙基醚，濾取析出之固體，予以乾燥，以白色固體得到6-溴螺[唍-2,4’-哌啶]三氟醋酸鹽的粗製物(0.91g)。將所得固體(200mg，0.52mmol)溶解於丙酮(5mL)，加入碳酸鉀(291mg，2.1mmol)、二碳酸二第三丁基酯(127mg，0.58mmol)，於室溫攪拌18小時。對反應液進行矽藻土過濾，將濾液減壓濃縮。將所得殘渣溶解於醋酸乙酯，對有機層以水、飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=2：1)精製，得到白色非晶形之標題化合物(190mg，94.1%)。 The obtained crude material (1.30 g) was dissolved in trifluoroacetic acid (10 mL), and triethyl hexane (2.0 mL, 12.8 mmol) was added, and the mixture was refluxed for 8 hours. The reaction solution was cooled and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give 6-bromo snail as a white solid. Crude (唍1,4'-piperidine]trifluoroacetate salt (0.91 g). The obtained solid (200 mg, 0.52 mmol) was dissolved in acetone (5 mL), and potassium carbonate (291 mg, 2.1 mmol). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.57(2H,m),1.73-1.81(4H,m),2.76(2H,t,J=6.8Hz),3.09-3.30(2H,m),3.73-4.01(2H,m),6.68-6.74(1H,m),7.15-7.21(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.57 (2H, m), 1.73-1.81 (4H, m), 2.76 (2H, t, J = 6.8 Hz), 3.09-3.30 (2H, m), 3.73-4.01 (2H, m), 6.68-6.74 (1H, m), 7.15-7.21 (2H, m).

步驟2：第三丁基6-(4-((甲基硫基)甲基)苯基)螺[唍-2,4’- 哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidinyl-1'-carboxylate

將第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(128mg，0.33mmol)及4,4,5,5-四甲基-2-(4-((甲基硫基)甲基)苯基)-1,3,2-二硼烷(106mg，0.40mmol)溶解於乙二醇二甲基醚(4mL)，加入溶解了碳酸鈉(625mg，5.9mmol)之水溶液(4mL)，加入肆三苯基膦鈀(0)(23mg，0.02mmol)，於90℃攪拌18小時。將反應液以醋酸乙酯稀釋，萃取有機層。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=3：1)精製，得到黃色油狀物之第三丁基6-(4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(95.6mg，65%)。 The third butyl 6-bromo snail [ 唍-2,4'-piperidine]-1'-carboxylate (128 mg, 0.33 mmol) and 4,4,5,5-tetramethyl-2-(4-((methylthio)methyl) )phenyl)-1,3,2-di Borane (106 mg, 0.40 mmol) was dissolved in ethylene glycol dimethyl ether (4 mL), and an aqueous solution (4 mL) of sodium carbonate (625 mg, 5.9 mmol) was added, and triphenylphosphine palladium (0) (23 mg) was added. , 0.02 mmol), stirred at 90 ° C for 18 hours. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 3:1) to give the title compound: butyl 6-(4-((methylthio)methyl)phenyl) screw[ Indole-2,4'-piperidinyl-1'-carboxylate (95.6 mg, 65%).

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.61(2H,m),1.78-1.87(4H,m),2.03(3H,s),2.84(2H,t,J=6.7Hz),3.16-3.34(2H,m),3.70(2H,s),3.76-3.99(2H,m),6.90(1H,d,J=8.3Hz),7.27-7.37(3H,m),7.48(2H,d,J=8.1Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.78-1.87 (4H, m), 2.03 (3H, s), 2.84 (2H, t, J = 6.7 Hz), 3.16-3.34 (2H, m), 3.70 (2H, s), 3.76-3.99 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.27-7.37 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

步驟3：第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(95.6mg，0.22mmol)溶解於二氯甲烷(3mL)，於0℃加入間氯過氧苯甲酸(65%，116mg，0.44mmol)，於室溫攪拌12小時。將反應液以飽和碳酸鈉水溶液稀釋，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥 後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：甲醇=20：1)精製，得到淡黃色非晶形之標題化合物(46.3mg，45%)。 The third butyl 6-(4-((methylthio)methyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (95.6 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL) and m-chloroperoxybenzoic acid (65%, 116 mg, 0.44) Methyl), stirred at room temperature for 12 hours. The reaction solution was diluted with a saturated aqueous solution of sodium carbonate and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut

實施例4第三丁基6-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 4 Ternyl 6-(3-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(3-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(3-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例3之步驟1所得的第三丁基6-溴-螺[唍-2,4’-哌啶]-1’-羧酸酯(50mg，0.13mmol)及4,4,5,5-四甲基-2-(3-((甲基硫基)甲基)苯基)-1,3,2-二硼烷(38mg，0.14mmol)的1,4-二烷(1.3mL)-水(1.3mL)混合溶液中，加入碳酸鈉(207mg，1.95mmol)及肆三苯基膦鈀(0)(15mg，0.013mmol)，於氬環境下，於95℃攪拌11小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=5：1)精製，得到白色非晶形之標題化合物(34.3mg，60%)。 The third butyl 6-bromo-spiro obtained in the first step of Example 3 [ 唍-2,4'-piperidine]-1'-carboxylate (50 mg, 0.13 mmol) and 4,4,5,5-tetramethyl-2-(3-((methylthio)methyl) )phenyl)-1,3,2-di Borane (38 mg, 0.14 mmol) of 1,4-two To a mixed solution of alkane (1.3 mL)-water (1.3 mL), sodium carbonate (207 mg, 1.95 mmol) and triphenylphosphine palladium (0) (15 mg, 0.013 mmol) were added and stirred at 95 ° C under argon. 11 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.48(9H,s),1.52-1.62(2H,m),1.78-1.88(4H,m),2.03(3H,s),2.85(2H,t,J=6.8Hz),3.16-3.34(2H,m),3.72(2H,s),3.76-4.00(2H,m),6.90(1H,d,J=8.8Hz),7.23(1H,dd,J=1.2,7.2Hz),7.30(1H,d,J=2.4Hz),7.32-7.37(2H,m),7.42(1H,d,J=7.2Hz),7.47(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.52-1.62 (2H, m), 1.78-1.88 (4H, m), 2.03 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.72 (2H, s), 3.76-4.00 (2H, m), 6.90 (1H, d, J = 8.8 Hz), 7.23 (1H, dd, J = 1.2) , 7.2 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.32 - 7.37 (2H, m), 7.42 (1H, d, J = 7.2 Hz), 7.47 (1H, s).

步驟2：第三丁基6-(3-((甲基磺醯基)甲基)苯基)螺[唍 -2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(3-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(3-((methylthio)methyl)phenyl) snail obtained in step 1 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例5第三丁基7-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 5 Ternyl 7-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基7-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 7-bromo-4-oneoxy snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代5’-溴-2’-羥基苯乙酮而使用4’-溴-2’-羥基苯乙酮，與實施例1之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 5'-bromo-2'-hydroxyacetophenone and using 4'-bromo-2'-hydroxyacetophenone, the reaction was carried out in the same manner as in Step 1 of Example 1 to give the title compound.

1H-NMR(CDCl3)δ：1.46(9H,s),1.57-1.66(2H,m),1.99(1H,s),2.02(1H,s),2.71(2H,s),3.20(2H,t,J=11.6Hz),3.78-3.96(2H,m),7.15(1H,dd,J=1.6,8.4Hz),7.21(1H,d,J=1.6Hz),7.72(1H,d,J=8.4Hz). 1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.57-1.66 (2H, m), 1.99 (1H, s), 2.02 (1H, s), 2.71 (2H, s), 3.20 (2H) , t, J = 11.6 Hz), 3.78-3.96 (2H, m), 7.15 (1H, dd, J = 1.6, 8.4 Hz), 7.21 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J=8.4Hz).

步驟2：第三丁基7-溴螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 7-bromo snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基7-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 7-bromo-4-oneoxy snail obtained in step 1 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 3 to give the title compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.58(2H,m),1.72-1.82(4H,m),2.72(2H,t,J=6.8Hz),3.10-3.28(2H,m),3.76-3.96(2H,m),6.91(1H,d,J=8.4Hz),6.96(1H,dd,J=8.4,2.0Hz), 7.01(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.58 (2H, m), 1.72-1.82 (4H, m), 2.72 (2H, t, J = 6.8 Hz), 3.10-3.28 (2H, m), 3.76-3.96 (2H, m), 6.91 (1H, d, J = 8.4 Hz), 6.96 (1H, dd, J = 8.4, 2.0 Hz), 7.01 (1H, d, J = 2.0) Hz).

步驟3：第三丁基7-(4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 7-(4-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基7-溴螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟2同樣地進行反應、處理，得到淡黃色油狀物之標題化合物。 Use the third butyl 7-bromo snail obtained in step 2 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 2 of Example 3 to give the title compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.54-1.60(2H,m),1.80-1.89(4H,m),2.03(3H,s),2.82(2H,t,J=6.8Hz),3.18-3.32(2H,m),3.71(2H,s),3.80-3.94(2H,m),7.08(1H,d,J=2.8Hz),7.09(1H,d,J=2.8Hz),7.11(1H,s),7.34(2H,d,J=8.0Hz),7.53(2H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.54-1.60 (2H, m), 1.80-1.89 (4H, m), 2.03 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 3.18-3.32 (2H, m), 3.71 (2H, s), 3.80-3.94 (2H, m), 7.08 (1H, d, J = 2.8 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.11 (1H, s), 7.34 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz).

步驟4：第三丁基7-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Ternyl 7-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟3所得之第三丁基7-(4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 7-(4-((methylthio)methyl)phenyl) snail obtained in step 3 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例6第三丁基7-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 6 Ternyl 7-(3-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基7-(3-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 7-(3-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4,4,5,5-四甲基-2-(4-((甲基硫基)甲基)苯基)-1,3,2-二硼烷而使用4,4,5,5-四甲基-2-(3-((甲基硫基)甲基)苯 基)-1,3,2-二硼烷，與實施例3之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 4,4,5,5-tetramethyl-2-(4-((methylthio)methyl)phenyl)-1,3,2-di Borane and 4,4,5,5-tetramethyl-2-(3-((methylthio)methyl)phenyl)-1,3,2-di The borane was reacted and treated in the same manner as in the step 2 of Example 3 to give the title compound as white crystals.

1H-NMR(CDCl3)δ：1.47(9H,s),1.53-1.60(2H,m),1.77-1.87(4H,m),2.02(3H,s),2.82(2H,t,J=6.4Hz),3.16-3.34(2H,m),3.73(2H,s),3.80-3.96(2H,m),7.06-7.15(3H,m),7.26-7.30(1H,m),7.36(1H,dd,J=7.2,8.0Hz),7.46(1H,d,J=8.0Hz),7.51(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.53-1.60 (2H, m), 1.77-1.87 (4H, m), 2.02 (3H, s), 2.82 (2H, t, J = 6.4 Hz), 3.16-3.34 (2H, m), 3.73 (2H, s), 3.80-3.96 (2H, m), 7.06-7.15 (3H, m), 7.26-7.30 (1H, m), 7.36 (1H) , dd, J = 7.2, 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.51 (1H, s).

步驟2：第三丁基7-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 7-(3-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基7-(3-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 7-(3-((methylthio)methyl)phenyl) snail obtained in step 1 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例7第三丁基6-(4-硝基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯 Example 7 Ternyl 6-(4-nitrophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，將第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.08mmol)溶解於四氫呋喃(0.4mL)與N,N-二甲基甲醯胺(0.4mL)之混合溶媒中，加入4-硝基苯基硼酸(20mg，0.12mmol)與碳酸銫(51mg，0.16mmol)及[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)(3mg，0.004mmol)，於90℃攪拌3小時，於反應液中加水，藉醋酸乙酯萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=3：1)精製， 得到黃色油狀物之標題化合物(20mg，61%)。 The third butyl 6-bromo snail under argon 唍-2,4'-Piperidine]-1'-carboxylate (30 mg, 0.08 mmol) was dissolved in a mixture of tetrahydrofuran (0.4 mL) and N,N-dimethylformamide (0.4 mL). 4-Nitrophenylboronic acid (20 mg, 0.12 mmol) and cesium carbonate (51 mg, 0.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3 mg) After stirring at 90 ° C for 3 hours, water was added to the reaction mixture, and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例8第三丁基6-(4-(甲基磺醯胺)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 8 Ternyl 6-(4-(methylsulfonamide)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-胺基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-aminophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-硝基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(16mg，0.004mmol)溶解於甲醇，加入鈀碳(1.6mg，10%w/w)，於氫環境下’於室溫攪拌4小時。將反應液進行矽藻土過濾後，減壓濃縮，得到粗製生成物之標題化合物(16mg)。 The third butyl 6-(4-nitrophenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (16 mg, 0.004 mmol) was dissolved in methanol, palladium on carbon (1.6 mg, 10% w/w) was added and stirred at room temperature under hydrogen atmosphere 4 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.

步驟2：第三丁基6-(4-(甲基磺醯胺)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(methylsulfonamide)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-胺基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的粗製生成物(16mg)溶解於二氯甲烷(2mL)，於0℃加入吡啶(10μL，0.12mmol)與甲磺醯氯(5μL，0.06mmol)，在室溫下攪拌整夜。於反應液中加入飽和碳酸氫鈉水溶液，以氯仿萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=2：1)精製，得到無色油狀物之標題化合物(14mg，74%)。 The third butyl 6-(4-aminophenyl) snail [ The crude product of hydrazine-2,4'-piperidinyl-1'-carboxylate (16 mg) was dissolved in dichloromethane (2 mL), and pyridine (10 μL, 0.12 mmol) and methanesulfonyl chloride were added at 0 °C. 5 μL, 0.06 mmol), stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例9第三丁基6-(4-羥基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 9 Ternyl 6-(4-hydroxyphenyl) spiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4-硝基苯基硼酸而使用4-羥基苯基硼酸，與實施例7同樣地進行反應、處理，得到白色非晶形之標題化合物(16mg，52%)。 The title compound (16 mg, 52%) was obtained as white white crystals.

實施例10第三丁基6-(4-((甲基磺醯基)氧基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 10 Ternyl 6-(4-((methylsulfonyl)oxy)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例9所得之第三丁基6-(4-羥基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(8mg，0.02mmol)溶解於二氯甲烷(1mL)，於0℃加入三乙基胺(8μL，0.06mmol)與甲磺醯氯(2μL，0.03mmol)，室溫下攪拌整夜。將反應液減壓濃縮，將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=2：1)精製，得到白色固體之標題化合物(9mg，82%)。 The third butyl 6-(4-hydroxyphenyl) spiro obtained in Example 9 [ Indole-2,4'-piperidine]-1'-carboxylate (8 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (8 μL, 0.06 mmol) and methanesulfonate were added at 0 °C. Chlorine (2 μL, 0.03 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj

實施例11第三丁基6-(2-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 11 Ternyl 6-(2-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4,4,5,5-四甲基-1,3,2-二硼烷-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4,4,5,5-tetramethyl-1,3,2-di Borane-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例3之步驟1所得的第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(2.5g，6.54mmol)之1,4-二烷(33mL)溶液中，加入雙(酯)二硼烷(2g，7.85mmol)、醋酸鉀(1.93g，19.62mmol)及雙(三苯基膦)二氯鈀(II)(0.23g，0.327mmol)，於氬環境下，在90℃攪拌12.5小時。濾除不溶物後，於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠 層析法(正己烷：醋酸乙酯=10：1~5：1)精製，得到白色固體之標題化合物(2.02g，72%)。 The third butyl 6-bromospiro obtained in the first step of Example 3 [ 1,4-2,4'-piperidine]-1'-carboxylate (2.5 g, 6.54 mmol) of 1,4-two In a solution of alkane (33 mL), add double ( Ethyl diborane (2 g, 7.85 mmol), potassium acetate (1.93 g, 19.62 mmol) and bis(triphenylphosphine)dichloropalladium(II) (0.23 g, 0.327 mmol) in argon at 90 Stir at °C for 12.5 hours. After the insoluble material was filtered off, water was added to the mixture and ethyl acetate was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.33(12H,s),1.46(9H,s),1.52-1.60(2H,m),1.75-1.84(4H,m),2.79(2H,t,J=6.8Hz),3.10-3.30(2H,m),3.74-3.98(2H,m),6.84(1H,d,J=8.0Hz),7.54-7.58(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.33 (12H, s), 1.46 (9H, s), 1.52-1.60 (2H, m), 1.75-1.84 (4H, m), 2.79 (2H, t, J = 6.8 Hz), 3.10-3.30 (2H, m), 3.74-3.98 (2H, m), 6.84 (1H, d, J = 8.0 Hz), 7.54 - 7.58 (2H, m).

步驟2：第三丁基6-(2-氟-4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(2-fluoro-4-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟1所得之第三丁基6-(4,4,5,5-四甲基-1,3,2-二硼烷-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(32.4mg，0.075mmol)及(4-溴-3-氟苄基)(甲基)硫烷(19.5mg，0.083mmol)之1,4-二烷(0.75mL)-水(0.75mL)混合溶液中，加入碳酸鈉(119.2mg，1.125mmol)及肆三苯基膦鈀(0)(8.7mg，0.0075mmol)，於氬環境下，在95℃攪拌11小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=5：1)精製，得到黃色油狀物之標題化合物(25.8mg，75%)。 The third butyl 6-(4,4,5,5-tetramethyl-1,3,2-di obtained in step 1 Borane-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (32.4 mg, 0.075 mmol) and (4-bromo-3-fluorobenzyl)(methyl)sulfane (19.5 mg, 0.083 mmol) 1,4-two To a mixed solution of alkane (0.75 mL)-water (0.75 mL), sodium carbonate (119.2 mg, 1.125 mmol) and palladium triphenylphosphine palladium (0) (8.7 mg, 0.0075 mmol) in argon at 95 Stir at °C for 11 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.60(2H,m),1.79-1.88(4H,m),2.04(3H,s),2.83(2H,t,J=6.8Hz),3.16-3.32(2H,m),3.68(2H,s),3.76-4.00(2H,m),6.90(1H,d,J=8.4Hz),7.00-7.20(2H,m),7.25-7.38(3H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.79-1.88 (4H, m), 2.04 (3H, s), 2.83 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.68 (2H, s), 3.76-4.00 (2H, m), 6.90 (1H, d, J = 8.4 Hz), 7.00-7.20 (2H, m), 7.25-7.38 (3H, m).

步驟3：第三丁基6-(2-氟-4-((甲基磺醯基)甲基)苯基)螺[ 唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(2-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(2-氟-4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(2-fluoro-4-((methylthio)methyl)phenyl) snail obtained in step 2 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例12第三丁基6-(2-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 12 Ternyl 6-(2-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(2-氯-4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(2-chloro-4-((methylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(4-溴-3-氯苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到黃色油狀物之標題化合物。 The reaction was carried out in the same manner as in Step 2 of Example 11 except that (4-bromo-3-fluorobenzyl)(methyl)sulfane was used instead of (4-bromo-3-chlorobenzyl)(methyl)sulfane. The title compound was obtained as a yellow oil.

1H-NMR(CDCl3)δ：1.48(9H,s),1.56-1.62(2H,m),1.78-1.88(4H,m),2.05(3H,s),2.82(2H,t,J=6.8Hz),3.16-3.34(2H,m),3.66(2H,s),3.80-4.00(2H,m),6.88(1H,d,J=8.4Hz),7.14(1H,d,J=2.0Hz),7.16-7.28(3H,m),7.40(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.56-1.62 (2H, m), 1.78-1.88 (4H, m), 2.05 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.66 (2H, s), 3.80-4.00 (2H, m), 6.88 (1H, d, J = 8.4 Hz), 7.14 (1H, d, J = 2.0) Hz), 7.16-7.28 (3H, m), 7.40 (1H, d, J = 2.0 Hz).

步驟2：第三丁基6-(2-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(2-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(2-氯-4-((甲基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(2-chloro-4-((methylthio)methyl)phenyl) snail obtained in step 1 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例13第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 13 Ternyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：4-溴-2-氟-1-((甲基磺醯基)甲基)苯的製造 Step 1: Preparation of 4-bromo-2-fluoro-1-((methylsulfonyl)methyl)benzene

於4-溴-2-氟苄基溴(1g，3.73mmol)之二甲基亞碸(5.4mL)溶液中加入甲亞磺酸鈉(1.33g，13.06mmol)，於120℃攪拌20分鐘。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。對所得殘渣上淋二乙基醚而洗淨，得到白色固體之標題化合物。 Sodium methanesulfinate (1.33 g, 13.06 mmol) was added to a solution of 4-bromo-2-fluorobenzyl bromide (1 g, 3.73 mmol Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was washed with diethyl ether and evaporated to give the title compound.

1H-NMR(CDCl3)δ：2.83(3H,s),4.27(2H,s),7.33-7.40(3H,m). 1 H-NMR (CDCl 3 ) δ: 2.83 (3H, s), 4.27 (2H, s), 7.33-7.40 (3H, m).

步驟2：第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用步驟1所得的4’-溴-2-氟-1-((甲基磺醯基)甲基)苯，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using 4'-bromo-2-fluoro-1-((methylsulfonyl)methyl)benzene obtained in Step 1 instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and carrying out The title compound was obtained as a white solid.

實施例14第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 14 Ternyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：2-氯-4-碘-1-((甲基磺醯基)甲基)苯的製造 Step 1: Manufacture of 2-chloro-4-iodo-1-((methylsulfonyl)methyl)benzene

於(2-氯-4-碘苯基)甲醇(0.54g，2.01mmol)之四氫呋喃(8.4mL)溶液中，在0℃加入三乙基胺(0.36mL，2.61mmol)及甲磺醯氯(0.17mL，2.21mmol)，於室溫下攪拌3小時後，以40℃攪拌1小時、60℃攪拌1小時。於反應液中加水，以氯仿萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。於殘渣中加入二甲基亞碸(2.9mL)、甲亞磺酸鈉(0.72g，7.04mmol)，以120℃攪拌30分鐘。於反應液中加水，以醋 酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。對所得殘渣上淋二乙基醚而洗淨，得到淡黃色固體之標題化合物(0.52g，79%)。 To a solution of (2-chloro-4-iodophenyl)methanol (0.54 g, 2.01 mmol) in tetrahydrofuran (8.4 mL), triethylamine (0.36 mL, 2.61 mmol) 0.17 mL, 2.21 mmol), stirred at room temperature for 3 hours, then stirred at 40 ° C for 1 hour and at 60 ° C for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. Dimethylhydrazine (2.9 mL) and sodium methanesulfinate (0.72 g, 7.04 mmol) were added to the residue, and stirred at 120 ° C for 30 minutes. Add water to the reaction solution to vinegar Extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was washed with EtOAc (EtOAc)EtOAc.

1H-NMR(CDCl3)δ：2.82(3H,s),4.41(2H,s),7.30(1H,d,J=8.4Hz),7.69(1H,dd,J=8.4,2.0Hz),7.83(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 2.82 (3H, s), 4.41 (2H, s), 7.30 (1H, d, J = 8.4 Hz), 7.69 (1H, dd, J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz).

步驟2：第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之2-氯-4-碘-1-((甲基磺醯基)甲基)苯以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using 2-chloro-4-iodo-1-((methylsulfonyl)methyl)benzene obtained in Step 1 to replace (4-bromo-3-fluorobenzyl)(methyl)sulfane, and examples The title compound was obtained as a white solid.

實施例15第三丁基6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(A)及第三丁基6-(5-((甲基亞磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(B)的製造 Example 15 Ternyl 6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (A) and tert-butyl 6-(5-((methylsulfinyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate (B)

步驟1：第三丁基6-(5-(羥基甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(hydroxymethyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用6-溴-3-吡啶甲醇，與實施例11之步驟2同樣地進行反應、處理，得到黃色油狀物之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane and using 6-bromo-3-pyridinemethanol, the reaction was carried out in the same manner as in the step 2 of Example 11 to give a yellow oil. Compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.60(2H,m),1.78-1.90(4H,m),2.17(1H,brs),2.87(2H,t,J=6.8Hz),3.12-3.34(2H,m),3.78-4.00(2H,m),4.74(2H,s),6.92(1H,d,J=8.4Hz), 7.65-7.80(4H,m),8.60(1H,d,J=1.2). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.78-1.90 (4H, m), 2.17 (1H, brs), 2.87 (2H, t, J = 6.8 Hz), 3.12-3.34 (2H, m), 3.78-4.00 (2H, m), 4.74 (2H, s), 6.92 (1H, d, J = 8.4 Hz), 7.65-7.80 (4H, m), 8.60 (1H, d, J = 1.2).

步驟2：第三丁基6-(5-(溴甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(bromomethyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在步驟1所得之第三丁基6-(5-羥基甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(25.3mg，0.062mmol)及三苯基膦(19.4mg，0.074mmol)的二氯甲烷(1.2mL)溶液中，於0℃加入四溴化碳(24.5mg，0.074mmol)之二氯甲烷(2.4mL)溶液，於室溫下攪拌4小時。於反應液中加水，以氯仿萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=2：1)精製，得到白色固體之標題化合物(7mg，24%)。 The third butyl 6-(5-hydroxymethyl)pyridin-2-yl) snail obtained in step 1 a solution of 唍-2,4'-piperidine]-1'-carboxylate (25.3 mg, 0.062 mmol) and triphenylphosphine (19.4 mg, 0.074 mmol) in dichloromethane (1.2 mL) at 0 ° C A solution of carbon tetrabromide (24.5 mg, 0.074 mmol) in dichloromethane (2.4 mL) was added and stirred at room temperature for 4 hr. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.61(2H,m),1.78-1.88(4H,m),2.87(2H,t,J=6.8Hz),3.16-3.32(2H,m),3.78-4.00(2H,m),4.52(2H,s),6.92(1H,d,J=8.8Hz),7.64(1H,d,J=8.4Hz),7.68-7.80(3H,m),8.63(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.78-1.88 (4H, m), 2.87 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.78-4.00 (2H, m), 4.52 (2H, s), 6.92 (1H, d, J = 8.8 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.68-7.80 ( 3H, m), 8.63 (1H, d, J = 2.0 Hz).

步驟3：第三丁基6-(5-((甲基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(5-((methylthio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在步驟2所得之第三丁基6-(5-溴甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(7mg，0.015mmol)的1,4-二烷(0.5mL)溶液中，加入甲基硫基鈉(1.2mg，0.0165mmol)，於95℃攪拌5.5小時。於反應液中加水，以醋酸乙酯萃取。對有機層以水及飽和食鹽水洗淨。藉無水硫酸鈉乾燥後，減壓濃縮。 得到無色油狀物之標題化合物(6.6mg，100%)。 The third butyl 6-(5-bromomethyl)pyridin-2-yl) snail obtained in step 2 1,4-2,4'-piperidine]-1'-carboxylate (7 mg, 0.015 mmol) of 1,4-di A solution of alkane (0.5 mL) was added with sodium methylsulfate (1.2 mg, 0.0165 mmol) and stirred at 95 ° C for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The title compound (6.6 mg, 100%) was obtained.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.62(2H,m),1.80-1.88(4H,m),2.03(3H,s),2.87(2H,t,J=6.8Hz),3.16-3.32(2H,m),3.68(2H,s),3.78-4.00(2H,m),6.92(1H,d,J=8.0Hz),7.63(1H,d,J=7.6Hz),7.66-7.72(2H,m),7.77(1H,d,J=2.0Hz),8.52(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.62 (2H, m), 1.80-1.88 (4H, m), 2.03 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.68 (2H, s), 3.78-4.00 (2H, m), 6.92 (1H, d, J = 8.0 Hz), 7.63 (1H, d, J = 7.6 Hz), 7.66-7.72 (2H, m), 7.77 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 2.0 Hz).

步驟4：第三丁基6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(A)及第三丁基6-(5-((甲基亞磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(B)的製造 Step 4: Tert-butyl 6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (A) and tert-butyl 6-(5-((methylsulfinyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate (B)

使用步驟3所得之第三丁基6-(5-((甲基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，使用矽膠分取薄層層析法(氯仿：甲醇=5：1)精製，得到白色固體之標題化合物(A)。。 Using the third butyl 6-(5-((methylthio)methyl)pyridin-2-yl) snail obtained in step 3 唍-2,4'-piperidine]-1'-carboxylate was reacted and treated in the same manner as in the third step of Example 3, and thin layer chromatography (chloroform:methanol = 5:1) was carried out using phthalocyanine. The title compound (A) was obtained as a white solid. .

進而得到無色油狀物之標題化合物(B)。 Further, the title compound (B) was obtained as a colorless oil.

實施例16第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 16 Ternyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：5-溴-2-((甲基磺醯基)甲基)吡啶的製造 Step 1: Preparation of 5-bromo-2-((methylsulfonyl)methyl)pyridine

在5-溴-2-吡啶甲醇(200mg，1.06mmol)的四氫呋喃(4.4mL)溶液中，於0℃加入三乙基胺(192μL，1.38mmol)及甲磺醯氯(91μL，1.17mmol)，於室溫下攪拌1小時。濾除不溶物後，減壓濃縮，得到紅褐色油狀物之甲磺酸(5-溴吡啶-2-基)甲酯(285mg，101%)。 Triethylamine (192 μL, 1.38 mmol) and methanesulfonium chloride (91 μL, 1.17 mmol) were added at 0 ° C in a solution of 5-bromo-2-pyridinemethanol (200 mg, 1.06 mmol) in THF. Stir at room temperature for 1 hour. The insoluble material was filtered, and then evaporated to dryness, mjjjjjjj

在所得之甲磺酸(5-溴吡啶-2-基)甲酯(285mg，1.07mmol)之二甲基亞碸(1.53mL)溶液中，加入甲亞磺酸鈉(382mg，3.75mmol)，於120℃攪拌15分鐘。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。對所得殘渣上淋二乙基醚而洗淨，得到褐色固體之標題化合物(180.4mg，67%)。 Sodium methanesulfinate (382 mg, 3.75 mmol) was added to a solution of (5-bromopyridin-2-yl)methyl methanesulfonate (285 mg, 1.07 mmol) in dimethyl hydrazide (1.53 mL). Stir at 120 ° C for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was washed with EtOAc (EtOAc)EtOAc.

1H-NMR(CDCl3)δ：2.92(3H,s),4.38(2H,s),7.40(1H,d,J=8.0Hz),7.90(1H,dd,J=2.4,8.0Hz),8.67(1H,d,J=2.4Hz). 1 H-NMR (CDCl 3 ) δ: 2.92 (3H, s), 4.38 (2H, s), 7.40 (1H, d, J = 8.0 Hz), 7.90 (1H, dd, J = 2.4, 8.0 Hz), 8.67 (1H, d, J = 2.4 Hz).

步驟2：第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之5-溴-2-((甲基磺醯基)甲基)吡啶，以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the 5-bromo-2-((methylsulfonyl)methyl)pyridine obtained in Step 1, to substitute (4-bromo-3-fluorobenzyl)(methyl)sulfane, and the procedure of Example 11 The reaction was carried out in the same manner.

實施例17第三丁基6-(3-甲基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 17 Ternyl 6-(3-methyl-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：4-溴-2-甲基-1-((甲基磺醯基)甲基)苯的製造 Step 1: Preparation of 4-bromo-2-methyl-1-((methylsulfonyl)methyl)benzene

取代5-溴-2-吡啶甲醇而使用(4-溴-2-甲基苯基)甲醇，與實施例16之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 5-bromo-2-pyridinemethanol to give the title compound as a white solid.

1H-NMR(CDCl3)δ：2.44(3H,s),2.84(3H,s),4.27(2H,s),7.21(1H,d,J=8.0Hz),7.38(1H,dd,J=2.0,8.4Hz),7.43(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.84 (3H, s), 4.27 (2H, s), 7.21. (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J =2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz).

步驟2：第三丁基6-(3-甲基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-methyl-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之4-溴2-甲基-1-((甲基磺醯基)甲基)苯以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using 4-bromo-2-methyl-1-((methylsulfonyl)methyl)benzene obtained in Step 1 to replace (4-bromo-3-fluorobenzyl)(methyl)sulfane, and examples The title compound was obtained as a white solid.

實施例18第三丁基6-(3-甲氧基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 18 Ternyl 6-(3-methoxy-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：4-溴-2-甲氧基-1-((甲基磺醯基)甲基)苯的製造 Step 1: Preparation of 4-bromo-2-methoxy-1-((methylsulfonyl)methyl)benzene

取代5-溴-2-吡啶甲醇而使用(4-溴-2-甲氧基苯基)甲醇，與實施例16之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 5-bromo-2-pyridinemethanol to (4-bromo-2-methoxyphenyl)methanol, the title compound was obtained as a white solid.

1H-NMR(CDCl3)δ：2.74(3H,s),3.89(3H,s),4.29(2H,s),7.09(1H,d,J=2.0Hz),7.17(1H,dd,J=2.0,8.4Hz),7.30(1H,d,J=8.4Hz). 1 H-NMR (CDCl 3 ) δ: 2.74 (3H, s), 3.89 (3H, s), 4.29 (2H, s), 7.09 (1H, d, J = 2.0 Hz), 7.17 (1H, dd, J =2.0, 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz).

步驟2：第三丁基6-(3-甲氧基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-methoxy-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之4-溴-2-甲氧基-1-((甲基磺醯基)甲基)苯以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 4-bromo-2-methoxy-1-((methylsulfonyl)methyl)benzene obtained in Step 1 is substituted for (4-bromo-3-fluorobenzyl)(methyl)sulfane, and The title compound was obtained as a white solid.

實施例19第三丁基6-(4-((甲基磺醯基)甲基)-3-丙氧基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 19 Ternyl 6-(4-((methylsulfonyl)methyl)-3-propoxyphenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：4-溴-1-((甲基磺醯基)甲基)-2-丙氧基苯的製造 Step 1: Preparation of 4-bromo-1-((methylsulfonyl)methyl)-2-propoxybenzene

於由市售化合物所衍生之4-溴-1-甲基-2-丙氧基苯(60.2mg，0.263mmol)的四氯化碳(2.6mL)溶液中，加入N-溴琥珀醯亞胺(46.8mg，0.263mmol)及偶氮雙異丁腈(0.1mg，0.53μmol)，於90℃攪拌5小時。於反應液中加水，以氯仿萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮，得到黃色油狀物之4-溴-1-(溴甲基)-2-丙氧基苯(81mg，100%)。 Addition of N-bromosuccinimide to a solution of 4-bromo-1-methyl-2-propoxybenzene (60.2 mg, 0.263 mmol) in carbon tetrachloride (2.6 mL) derived from a commercially available compound (46.8 mg, 0.263 mmol) and azobisisobutyronitrile (0.1 mg, 0.53 μmol) were stirred at 90 ° C for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate (MgSO4)

於所得之4-溴-1-(溴甲基)-2-丙氧基苯(81mg，0.263mmol)之二甲基亞碸(1mL)溶液中，加入甲亞磺酸鈉(94mg，0.921mmol)，於120℃攪拌20分鐘。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=3：1)精製，得到淡黃色固體之標題化合物(49.4mg，61%)。 To a solution of the obtained 4-bromo-1-(bromomethyl)-2-propoxybenzene (81 mg, 0.263 mmol) in dimethyl sulfonium (1 mL), sodium methanesulfinate (94 mg, 0.921 mmol) ), stirring at 120 ° C for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.07(3H,t,J=7.2Hz),1.80-1.90(2H,m),2.74(3H,s),3.98(2H,t,J=6.8Hz),4.30(2H,s),7.08(1H,d,J=2.0Hz),7.15(1H,dd,J=2.0,8.0Hz),7.30(1H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.07 (3H, t, J = 7.2 Hz), 1.80-1.90 (2H, m), 2.74 (3H, s), 3.98 (2H, t, J = 6.8 Hz), 4.30 (2H, s), 7.08 (1H, d, J = 2.0 Hz), 7.15 (1H, dd, J = 2.0, 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz).

步驟2：第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之4-溴-1-((甲基磺醯基)甲基-2-丙氧基苯以取代(4-溴-3-氟苯基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到淡黃色油狀物之標題化合物。 Using 4-bromo-1-((methylsulfonyl)methyl-2-propoxybenzene obtained in Step 1 to replace (4-bromo-3-fluorophenyl)(methyl)sulfane, and carrying out The title compound was obtained as a pale yellow oil.

實施例20第三丁基6-(3-(環丙基甲氧基)-4-((甲基磺醯基) 甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 20 Thirty butyl 6-(3-(cyclopropylmethoxy)-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：4-溴-2-(環丙基甲氧基)-1-((甲基磺醯基)甲基)苯的製造 Step 1: Preparation of 4-bromo-2-(cyclopropylmethoxy)-1-((methylsulfonyl)methyl)benzene

取代4-溴-1-甲基-2-丙氧基苯而使用4-溴-2-(環丙基甲氧基)-1-甲基苯，與實施例19之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 The reaction was carried out in the same manner as in Step 1 of Example 19, except that 4-bromo-1-methyl-2-propoxybenzene was used instead of 4-bromo-2-(cyclopropylmethoxy)-1-methylbenzene. The title compound was obtained as a white solid.

1H-NMR(CDCl3)δ：0.31-0.37(2H,m),0.65-0.72(2H,m),1.21-1.32(1H,m),2.78(3H,s),3.85(2H,d,J=6.8Hz),4.33(2H,s),7.03(1H,d,J=2.0Hz),7.15(1H,dd,J=2.0,8.4Hz),7.30(1H,d,J=8.4Hz). 1 H-NMR (CDCl 3 ) δ: 0.31-0.37 (2H, m), 0.65-0.72 (2H, m), 1.21-1.32 (1H, m), 2.78 (3H, s), 3.85 (2H, d, J = 6.8 Hz), 4.33 (2H, s), 7.03 (1H, d, J = 2.0 Hz), 7.15 (1H, dd, J = 2.0, 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz) .

步驟2：第三丁基6-(3-(環丙基甲氧基)-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3-(cyclopropylmethoxy)-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之4-溴-2-(環丙基甲氧基)-1-((甲基磺醯基)甲基)苯以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 4-bromo-2-(cyclopropylmethoxy)-1-((methylsulfonyl)methyl)benzene obtained in Step 1 was substituted for (4-bromo-3-fluorobenzyl) (methyl) The sulfane was reacted and treated in the same manner as in the step 2 of Example 11 to give the title compound as a white solid.

實施例21第三丁基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 21 Ternyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：5-溴-1,3-二氟-2-((甲基磺醯基)甲基)苯的製造 Step 1: Preparation of 5-bromo-1,3-difluoro-2-((methylsulfonyl)methyl)benzene

於4-溴-2,6-二氟苄基醇(1g，4.48mmol)的醋酸乙酯(9mL)溶液中，於0℃加入二異丙基乙基胺(0.78mL，4.48mmol)及亞硫醯氯(0.36mL，4.93mmol)，室溫下攪拌30分鐘。於反應液中加水及二異丙基乙基胺(0.78mL，4.48mmol)，以醋酸 乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，得到紅褐色油狀物之5-溴-2-(氯甲基)-1,3-二氟苯(1.1g，100%)。 To a solution of 4-bromo-2,6-difluorobenzyl alcohol (1 g, 4.48 mmol) in ethyl acetate (9 mL), diisopropylethylamine (0.78 mL, 4.48 mmol) Thiopurine chloride (0.36 mL, 4.93 mmol) was stirred at room temperature for 30 minutes. Water and diisopropylethylamine (0.78 mL, 4.48 mmol) were added to the reaction mixture to give acetic acid Ethyl acetate extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate , 100%).

於所得之5-溴-2-(氯甲基)-1,3-二氟苯(1.1g，4.48mmol)之二甲基亞碸(6.4mL)溶液中，加入甲亞磺酸鈉(1.6g，15.6mmol)，於120℃攪拌15分鐘。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。對所得殘渣上淋二乙基醚而洗淨’得到褐色固體之標題化合物(0.54g，42%)。 To a solution of the obtained 5-bromo-2-(chloromethyl)-1,3-difluorobenzene (1.1 g, 4.48 mmol) in dimethyl hydrazine (6.4 mL), sodium methanesulfinate (1.6) was added. g, 15.6 mmol), stirred at 120 ° C for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was washed with EtOAc (EtOAc m.

1H-NMR(CDCl3)δ：2.92(3H,s),4.35(2H,s),7.20-7.25(2H,m). 1 H-NMR (CDCl 3 ) δ: 2.92 (3H, s), 4.35 (2H, s), 7.20-7.25 (2H, m).

步驟2：第三丁基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之5-溴-1,3-二氟-2-((甲基磺醯基)甲基)苯以取代(4-溴-3-氟苄基)(甲基)硫烷，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 5-bromo-1,3-difluoro-2-((methylsulfonyl)methyl)benzene obtained in Step 1 to replace (4-bromo-3-fluorobenzyl)(methyl)sulfane, The reaction was carried out in the same manner as in the step 2 of Example 11 to give the title compound.

實施例22第三丁基6-(4-((1-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 22 Ternyl 6-(4-((1-methylsulfonyl)ethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-乙醯基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-ethylmercaptophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4,4,5,5-四甲基-2-(4-((甲基硫基)甲基)苯基)-1,3,2-二硼烷而使用4-乙醯基苯基硼酸，與實施例3之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 4,4,5,5-tetramethyl-2-(4-((methylthio)methyl)phenyl)-1,3,2-di The borane was added to the title compound as a white solid.

1H-NMR(CDCl3)δ：1.43-1.63(11H,m),1.78-1.88(4H,m),2.62(3H,s),2.86(2H,d,J=6.8Hz),3.15-3.40(2H,m),3.78-4.00(2H,m),6.93(1H,d,J=8.6Hz),7.35(2H,d,J=2.2Hz),7.40(1H,dd,J=8.4,2.2Hz),7.36(2H,d,J=8.3Hz),7.99(2H,d,J=8.5Hz). 1 H-NMR (CDCl 3 ) δ: 1.43-1.63 (11H, m), 1.78-1.88 (4H, m), 2.62 (3H, s), 2.86 (2H, d, J = 6.8 Hz), 3.15-3.40 (2H, m), 3.78-4.00 (2H, m), 6.93 (1H, d, J = 8.6 Hz), 7.35 (2H, d, J = 2.2 Hz), 7.40 (1H, dd, J = 8.4, 2.2 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.5 Hz).

步驟2：第三丁基6-(4-(1-羥基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(1-hydroxyethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟1所得之第三丁基6-(4-乙醯基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(35mg，0.08mmol)溶解於甲醇(0.4mL)與四氫呋喃(1mL)，於0℃加入氫化硼鈉(4mg，0.11mmol)，室溫下攪拌30分鐘。於反應液中在0℃加入1N稀鹽酸後，以飽和碳酸氫鈉水溶液予以中和，以氯仿萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(22mg，63%)。 The third butyl 6-(4-ethylmercaptophenyl) snail obtained in step 1 唍-2,4'-Piperidine]-1'-carboxylate (35 mg, 0.08 mmol) was dissolved in methanol (0.4 mL) and THF (1 mL). Stir at room temperature for 30 minutes. After adding 1 N of dilute hydrochloric acid to the reaction mixture at 0 ° C, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

1H-NMR(CDCl3)δ：1.44-1.63(14H,m),1.80-1.90(4H,m),2.84(2H,t,J=6.8Hz),3.31-3.35(2H,m),3.75-4.00(2H,m),4.88-4.98(1H,m),6.90(1H,d,J=8.5Hz),7.28(1H,d,J=2.0Hz),7.33(1H,dd,J=8.3,2.0Hz),7.41(2H,d,J=8.3Hz),7.51(2H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.44-1.63 (14H, m), 1.80-1.90 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.31-3.35 (2H, m), 3.75 -4.00 (2H, m), 4.88-4.98 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.33 (1H, dd, J = 8.3) , 2.0Hz), 7.41 (2H, d, J = 8.3Hz), 7.51 (2H, d, J = 8.0Hz).

步驟3：第三丁基6-(4-(1-甲基磺醯基)氧基]乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(4-(1-methylsulfonyl)oxy]ethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-(1-羥基乙基)苯基)螺[唍-2,4’-哌 啶]-1’-羧酸酯(22mg，0.05mmol)溶解於二氯甲烷(2.0mL)，於0℃加入三乙基胺(14μL，0.10mmol)與甲磺醯氯(5μL，0.07mmol)，室溫下攪拌4小時，於反應液中加入飽和氯化銨水溶液，以氯仿萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮，得到粗製生成物之標題化合物(33mg)。 The third butyl 6-(4-(1-hydroxyethyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (22 mg, 0.05 mmol) was dissolved in dichloromethane (2.0 mL), and triethylamine (14 μL, 0.10 mmol) and methane. The mixture was stirred for 4 hours at room temperature, and a saturated aqueous solution of ammonium chloride was added and the mixture was extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated.

步驟4：第三丁基6-(4-(1-甲基硫基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Tert-butyl 6-(4-(1-methylthio)ethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟3所得之第三丁基6-(4-(1-甲基磺醯基)氧基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的粗製生成物(22mg)溶解於N,N-二甲基甲醯胺(2.0mL)，加入甲基硫基鈉(5mg，0.08mmol)並於室溫攪拌整夜。反應結束後，將N,N-二甲基甲醯胺減壓餾除，於所得殘渣中加水，以醋酸乙酯萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=5：1)精製，得到白色固體之標題化合物(16mg，67%，2步驟)。 The third butyl 6-(4-(1-methylsulfonyl)oxy)ethyl)phenyl) snail obtained in the step 3 The crude product (22 mg) of 唍-2,4'-piperidine]-1'-carboxylate was dissolved in N,N-dimethylformamide (2.0 mL), and sodium methylthiosate (5 mg, 0.08 mmol) and stirred at room temperature overnight. After completion of the reaction, N,N-dimethylformamide was evaporated under reduced pressure. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.62(5H,m),1.80-1.87(4H,m),1.94(3H,s),2.84(2H,t,J=6.8Hz),3.14-3.34(2H,m),3.80-4.00(3H,m),6.89(1H,d,J=8.6Hz),7.28(1H,d,J=2.0Hz),7.31-7.37(3H,m),7.48(2H,d,J=8.3Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.62 (5H, m), 1.80-1.87 (4H, m), 1.94 (3H, s), 2.84 (2H, t, J = 6.8 Hz), 3.14-3.34 (2H, m), 3.80-4.00 (3H, m), 6.89 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.37 ( 3H, m), 7.48 (2H, d, J = 8.3 Hz).

步驟5：第三丁基6-(4-((1-(甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 5: Tert-butyl 6-(4-((1-(methylsulfonyl)ethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟4所得之第三丁基6-(4-(1-甲基硫基)乙基)苯基) 螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到無色油狀物之標題化合物。 Using the third butyl 6-(4-(1-methylthio)ethyl)phenyl) snail obtained in step 4 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例23第三丁基6-(4-((2-甲基磺醯基)丙烷-2-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯 Example 23 Ternyl 6-(4-((2-methylsulfonyl)propan-2-yl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate

將實施例3所得之第三丁基6-(4-(甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.06mmol)與碘甲烷(20μL，0.32mmol)，溶解於四氫呋喃(0.6mL)中，於0℃加入第三丁氧基鉀(18mg，0.16mmol)並於室溫攪拌整夜。於反應液中加入飽和氯化銨水溶液，以醋酸乙酯萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(22mg，69%)。 The third butyl 6-(4-(methylsulfonyl)methyl)phenyl) snail obtained in Example 3 唍-2,4'-Piperidine]-1'-carboxylate (30 mg, 0.06 mmol) and methyl iodide (20 μL, 0.32 mmol), dissolved in tetrahydrofuran (0.6 mL) Potassium (18 mg, 0.16 mmol) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例24第三丁基6-(4-(1H-四唑-1-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 24 Ternyl 6-(4-(1H-tetrazol-1-yl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用1-(4-溴苯基)-1H-四唑，與實施例11之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane and using 1-(4-bromophenyl)-1H-tetrazole, the reaction and treatment were carried out in the same manner as in Step 2 of Example 11 to obtain The title compound is a white solid.

實施例25第三丁基6-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 25 Ternyl 6-(5-(methylsulfonyl)indol-1-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例3之步驟1所得的第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(20mg，0.052mmol)及5-甲基磺醯基吲哚(15.5mg，0.078mmol)之甲苯(1mL)溶液中，加入第三丁氧基 鈉(7.5mg，0.078mmol)、雙(三-第三丁基膦)鈀(0)(2.7mg，0.0052mmol)，於氬環境下，於100℃攪拌6小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(25.4mg，98%)。 The third butyl 6-bromospiro obtained in the first step of Example 3 [ Add a solution of 唍-2,4'-piperidine]-1'-carboxylate (20 mg, 0.052 mmol) and 5-methylsulfonyl hydrazine (15.5 mg, 0.078 mmol) in toluene (1 mL) Sodium tributoxide (7.5 mg, 0.078 mmol), bis(tri-tert-butylphosphine)palladium(0) (2.7 mg, 0.0052 mmol) was stirred at 100 ° C for 6 hours under argon. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例26第三丁基7-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 26 Ternyl 7-(5-(methylsulfonyl)indol-1-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例5之步驟2所得之第三丁基7-溴螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例25同樣地進行反應、處理，得到淡黃色固體之標題化合物。 The third butyl 7-bromospiro obtained by the second step of Example 5 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in Example 25 to give the title compound.

實施例27第三丁基6-(4-(甲基磺醯基)甲基)哌啶-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 27 Ternyl 6-(4-(methylsulfonyl)methyl)piperidin-1-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例3之步驟1所得的第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(25.6mg，0.067mmol)及4-((甲基磺醯基)甲基)哌啶(21.4mg，0.1mmol)的甲苯(1.3mL)溶液中，加入第三丁氧基鈉(16mg，0.167mmol)、雙(三-第三丁基膦)鈀(0)(3.4mg，0.0067mmol)，於氬環境下，於100℃攪拌5小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到褐色非晶形之標題化合物(19.7mg，61%)。 The third butyl 6-bromospiro obtained in the first step of Example 3 [ 唍-2,4'-piperidine]-1'-carboxylate (25.6 mg, 0.067 mmol) and 4-((methylsulfonyl)methyl)piperidine (21.4 mg, 0.1 mmol) in toluene ( In a solution of 1.3 mL), sodium butoxide (16 mg, 0.167 mmol), bis(tris-tert-butylphosphine)palladium(0) (3.4 mg, 0.0067 mmol) was added in an argon atmosphere at 100 ° C. Stir for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例28乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 28 Ethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例3所得之第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(423mg，0.90mmol)溶解於甲醇(10mL)，加入4N鹽酸/1,4-二烷溶液(10mL)，於室溫下攪拌3小時。將反應溶液濃縮，得到6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(348mg)。將所得之粗製物(20.0mg，0.05mmol)溶解於二氯甲烷(1mL)中，加入三乙基胺(20.4μL，0.15mmol)、氯甲酸乙酯(5.6μL，0.06mmol)，於室溫攪拌12小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(22.4mg，100%)。 The third butyl 6-(4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 3 唍-2,4'-Piperidine]-1'-carboxylate (423 mg, 0.90 mmol) was dissolved in methanol (10 mL) and 4N hydrochloric acid / 1,4-di A solution of the alkane (10 mL) was stirred at room temperature for 3 hr. The reaction solution was concentrated to give 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Crude (唍2,4'-piperidine] hydrochloride salt (348 mg). The obtained crude material (20.0 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), triethylamine (20.4 μL, 0.15 mmol), ethyl chloroformate (5.6 μL, 0.06 mmol) at room temperature Stir for 12 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc)

實施例29 2,2,2-三氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 29 2,2,2-Trifluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(42.7μL，0.25mmol)、2,2,2-三氟乙基1H-咪唑-1-羧酸酯(28.5mg，0.15mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得 到白色非晶形之標題化合物(25.2mg，100%)。 6-(4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (42.7 μL, 0.25 mmol), 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate (28.5 mg, 0.15 mmol) was stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例30 2,2,2-三氯乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 30 2,2,2-Trichloroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸2,2,2-三氯乙酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 2,2,2-trichloroethyl chloroformate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例31 2-氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 31 2-Fluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸2-氟乙酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 2-fluoroethyl chloroformate was used, and the reaction mixture was treated in the same manner as in Example 28 to give the title compound.

實施例32 2-甲氧基乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 32 2-Methoxyethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸2-甲氧基乙酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 2-methoxyethyl chloroformate was used, and the reaction mixture was treated in the same manner as in Example 28 to give the title compound.

實施例33異丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 33 Isopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸異丙酯，與實施例28同樣地進行反應、處理，得到白色固體之標題化合物。 The ethyl chloroformate was used, and the title compound was obtained as a white solid.

實施例34苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 34 Benzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸苄酯，與實施例28同樣地進行反應、處理，得到白色固體之標題化合物。 The ethyl chloroformate was used, and the title compound was obtained as a white solid.

實施例35苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’- 哌啶]-1’-羧酸酯的製造 Example 35 Phenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidinyl-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸苯酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used instead of the phenyl chloroformate, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例36 4-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 36 4-Chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸4-氯苯酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 4-chlorophenyl chloroformate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例37 3-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 37 3-Chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用3-氯苯基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 3-chlorophenyl (4-nitrophenyl) carbonate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例38 2-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 38 2-Chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸2-氯苯酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 2-chlorophenyl chloroformate was used, and the reaction mixture was treated in the same manner as in Example 28 to give the title compound.

實施例39 4-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 39 4-Chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用4-氯苄基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was replaced with 4-chlorobenzyl (4-nitrophenyl) carbonate, and the title compound was obtained as white crystals.

實施例40 3-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍 -2,4’-哌啶]-1’-羧酸酯的製造 Example 40 3-Chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用3-氯苄基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 3-chlorobenzyl (4-nitrophenyl) carbonate was used, and the title compound was obtained as white crystals.

實施例41 2-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 41 2-Chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸2-氯苄酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 2-chlorobenzyl chloroformate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例42 3,5-雙(三氟甲基)苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 42 3,5-Bis(trifluoromethyl)benzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用3,5-雙(三氟甲基)苄基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 3,5-bis(trifluoromethyl)benzyl (4-nitrophenyl) carbonate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound.

實施例43吡啶-4-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 43 Pyridin-4-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用4-硝基苯基(吡啶-4-基甲基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m. m.

實施例44吡啶-3-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 44 pyridin-3-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用4-硝基苯基(吡啶-3-基甲基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色固體之 標題化合物。 The ethyl chloroformate was used, and 4-nitrophenyl (pyridin-3-ylmethyl) carbonate was used, and the reaction and the reaction were carried out in the same manner as in Example 28 to give a white solid. Title compound.

實施例45吡啶-2-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 45 Pyridin-2-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(42.7μL，0.25mmol)、吡啶-2-基甲基1H-咪唑-1-羧酸酯(19.9mg，0.15mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：丙酮=2：1)精製，得到白色非晶形之標題化合物(25.7mg，100%)。 6-(4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (42.7 μL, 0.25 mmol), pyridin-2-ylmethyl 1H-imidazole-1-carboxylate (19.9 mg, 0.15 mmol) was stirred at 80 ° C for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel chromatography (hexanes: hexanes: 2:1) to afford the title compound (25.7 mg, 100%).

實施例46 1,1,1-三氟-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 46 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)、1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯(28.5mg，0.15mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(42.7μL，0.25mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(25.2mg，100%)。 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Crude product of 2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylic acid The ester (28.5 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (42.7 μL, 0.25 mmol) was added and stirred at 80 ° C for 12 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例47 1,1,1-三氯-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 47 1,1,1-Trichloro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸1,1,1-三氯-2-甲基丙烷-2-基酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and 1,1,1-trichloro-2-methylpropan-2-yl chloroformate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound as white crystals.

實施例48新戊基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 48 Neopentyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用氯甲酸新戊酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was replaced with neopentyl chloroformate, and the reaction was carried out in the same manner as in Example 28 to give the title compound as white crystals.

實施例49金剛烷-1-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 49 adamantane-1-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用金剛烷-1-基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting ethyl chloroformate, adamantyl-1-yl(4-nitrophenyl)carbonate was used, and the reaction was carried out in the same manner as in Example 28 to give the title compound as white crystals.

實施例50金剛烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 50 adamantyl-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用金剛烷-2-基(4-硝基苯基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used, and adamantyl-2-yl (4-nitrophenyl) carbonate was used, and the reaction mixture was treated in the same manner as in Example 28 to give the title compound as white crystals.

實施例51氧雜環丁烷-3-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 51 Oxetane-3-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用4-硝基苯基(氧雜環丁烷-3-基)碳酸 酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting ethyl chloroformate, using 4-nitrophenyl (oxetan-3-yl) carbonate The ester was reacted and treated in the same manner as in Example 28 to give the title compound as white white.

實施例52四氫-2H-哌喃-4-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 52 tetrahydro-2H-piperidin-4-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯，使用4-硝基苯基(四氫-2H-哌喃-4-基)碳酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting ethyl chloroformate, 4-nitrophenyl (tetrahydro-2H-piperidin-4-yl) carbonate was used, and the reaction mixture was treated in the same manner as in Example 28 to give the title compound.

實施例53 4,4-二氯環己基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 53 4,4-Dichlorocyclohexyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(42.7μL，0.25mmol)、4,4-二氟環己基1H-咪唑-1-羧酸酯(33.8mg，0.15mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：甲醇=10：1)精製，得到白色非晶形之標題化合物(19.0mg，73%)。 6-(4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (42.7 μL, 0.25 mmol), 4,4-difluorocyclohexyl 1H-imidazol-1-carboxylate (33.8 mg, 0.15 mmol) was stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc)

實施例54 2,2,2-三氯乙基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 54 2,2,2-Trichloroethyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例13所得之第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(268mg，0.55mmol)溶解於甲醇(5mL)，加入4N鹽酸/1,4-二烷溶液(5mL)，於 室溫攪拌4小時。將反應溶液濃縮，得到6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(230mg)。將所得之粗製物(20.0mg，0.05mmol)溶解於二氯乙烷(1mL)，加入三乙基胺(19.5μL，0.14mmol)、氯甲酸2,2,2-三氯乙基酯(7.6μL，0.06mmol)，於室溫攪拌18小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(22.2mg，84%)。 The third butyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 13 唍-2,4'-Piperidine]-1'-carboxylate (268 mg, 0.55 mmol) was dissolved in methanol (5 mL) and 4N hydrochloric acid / 1,4-di A solution of the alkane (5 mL) was stirred at room temperature for 4 h. The reaction solution was concentrated to give 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Crude (2-3 mg of 唍-2,4'-piperidine] hydrochloride. The obtained crude material (20.0 mg, 0.05 mmol) was dissolved in dichloroethane (1 mL), triethylamine (19.5 μL, 0.14 mmol), and 2,2,2-trichloroethyl chloroformate (7.6). μL, 0.06 mmol), stirred at room temperature for 18 h. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例55苯基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 55 Phenyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸苯酯，與實施例54同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate, phenyl chloroformate was used, and the reaction was carried out in the same manner as in Example 54 to give the title compound.

實施例56 1,1,1-三氟-2-甲基丙烷-2-基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 56 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例54所得之6-[3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(32.7μL，0.19mmol)、1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯(15.7mg，0.08mmol)，於80℃攪拌4小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠 層析法(氯仿：甲醇=10：1)精製，得到白色非晶形之標題化合物(30.0mg，100%)。 6-[3-Fluoro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 54 The crude product of 唍-2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (32.7 μL, 0.19 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (15.7 mg, 0.08 mmol), stirred at 80 ° C for 4 h . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例57新戊基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 57 Neopentyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸新戊基酯，與實施例54同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate and using neopentyl chloroformate, the reaction was carried out in the same manner as in Example 54 to give the title compound as white crystals.

實施例58 2,2,2-三氯乙基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 58 2,2,2-Trichloroethyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例14所得之第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(347，0.69mmol)溶解於甲醇(7mL)，加入4N鹽酸/1,4-二烷溶液(7mL)，於室溫攪拌12小時。將反應溶液濃縮，得到6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(307mg)。將所得之粗製物(20.0mg，0.05mmol)溶解於二氯乙烷(1mL)，加入三乙基胺(18.7μL，0.14mmol)、氯甲酸2,2,2-三氯乙基酯(7.3μL，0.06mmol)，於室溫攪拌24小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(23.1mg，88%)。 The third butyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 14 唍-2,4'-Piperidine]-1'-carboxylate (347, 0.69 mmol) was dissolved in methanol (7 mL) and 4N hydrochloric acid / 1,4-di A solution of the alkane (7 mL) was stirred at room temperature for 12 h. The reaction solution was concentrated to give 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Crude (2-3 mg of 唍-2,4'-piperidine] hydrochloride. The obtained crude material (20.0 mg, 0.05 mmol) was dissolved in dichloroethane (1 mL), triethylamine (18.7 μL, 0.14 mmol), 2,2,2-trichloroethyl chloroformate (7.3) μL, 0.06 mmol), stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut

實施例59苯基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍 -2,4’-哌啶]-1’-羧酸酯的製造 Example 59 Phenyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸苯酯，與實施例58同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate, and using phenyl chloroformate, the reaction was carried out in the same manner as in Example 58 to give the title compound as white white.

實施例60 1,1,1-三氟-2-甲基丙烷-2-基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 60 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例58所得之6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(20.0mg，0.05mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(31.4μL，0.18mmol)、1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯(14.9mg，0.07mmol)，於80℃攪拌8小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：丙酮=2：1)精製，得到白色非晶形之標題化合物(12.3mg，49%)。 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 58 [ The crude product of 唍-2,4'-piperidine hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (31.4 μL, 0.18 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazol-1-carboxylate (14.9 mg, 0.07 mmol), stirred at 80 ° C for 8 hours . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例61新戊基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 61 Neopentyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸新戊酯，與實施例58同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate, and using neopentyl chloroformate, the reaction was carried out in the same manner as in Example 58 to give the title compound as white crystals.

實施例62 2,2,2-三氟乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 62 2,2,2-Trifluoroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例21所得之第三丁基6-(3,5-二氟-4-((甲基磺醯基) 甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(53.0mg，0.10mmol)溶解於甲醇(1.5mL)，加入4N鹽酸/1,4-二烷溶液(1mL)，於室溫攪拌4小時。將反應溶液濃縮，得到6-[3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(50.8mg)。將所得之粗製物(16.1mg，0.04mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(31.4μL，0.18mmol)、2,2,2-三氟乙基1H-咪唑-1-羧酸酯(21.0mg，0.11mmol)，於80℃攪拌18小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(4.1mg，21%)。 The third butyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 21 was obtained. 唍-2,4'-Piperidine]-1'-carboxylate (53.0 mg, 0.10 mmol) was dissolved in methanol (1.5 mL) and 4N hydrochloric acid / 1,4-di A solution of the alkane (1 mL) was stirred at room temperature for 4 h. The reaction solution was concentrated to give 6-[3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Crude (50.8 mg) of 唍-2,4'-piperidine hydrochloride. The obtained crude material (16.1 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (31.4 μL, 0.18 mmol), 2, 2,2-Trifluoroethyl 1H-imidazol-1-carboxylate (21.0 mg, 0.11 mmol) was stirred at 80 ° C for 18 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例63 2,2,2-三氯乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 63 2,2,2-Trichloroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例62所得之6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(14.3mg，0.03mmol)溶解於二氯甲烷(1mL)，加入三乙基胺(13.3μL，0.10mmol)、氯甲酸2,2,2-三氯乙基酯(5.2μL，0.04mmol)攪拌12小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：丙酮=2：1)精製，得到白色非晶形之標題化合物(5.5mg，29%)。 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 62 The crude product of 唍-2,4'-piperidine hydrochloride (14.3 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (13.3 μL, 0.10 mmol), chloroformic acid 2, 2 2-Trichloroethyl ester (5.2 μL, 0.04 mmol) was stirred for 12 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例64苯基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 64 Phenyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸苯酯，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate, and using phenyl chloroformate, the reaction was carried out in the same manner as in Example 63 to give the title compound.

實施例65 1,1,1-三氟-2-甲基丙烷-2-基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸製造 Example 65 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylic acid

將實施例62所得之6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(16.0mg，0.04mmol)溶解於N,N-二甲基甲醯胺(1mL)，加入N,N-二異丙基乙基胺(31.4μL，0.18mmol)、1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯(24.0mg，0.07mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：丙酮=2：1)精製，得到白色非晶形之標題化合物(19.0mg，94%)。 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail obtained in Example 62 The crude product of 唍-2,4'-piperidine hydrochloride (16.0 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethyl was added. Amine (31.4 μL, 0.18 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazol-1-carboxylate (24.0 mg, 0.07 mmol), stirred at 80 ° C for 12 hours . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (hexane: hexanes: 2:1).

實施例66新戊基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 66 Neopentyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯，使用氯甲酸新戊酯，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trichloroethyl chloroformate and using neopentyl chloroformate, the reaction was carried out in the same manner as in Example 63 to give the title compound as white crystals.

實施例67第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 67 Ternyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(羥基甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(hydroxymethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4,4,5,5-四甲基-2-(4-((甲基硫基)甲基)苯基)-1,3,2-二硼烷而使用(4-(羥基甲基)苯基)硼酸，與實施例3之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 4,4,5,5-tetramethyl-2-(4-((methylthio)methyl)phenyl)-1,3,2-di The (4-(hydroxymethyl)phenyl)boronic acid was used as a borane, and the title compound was obtained as a white solid.

1H-NMR(CDCl3)δ：1.47(9H,s),1.55(4H,dt,J=13.0,4.9Hz),1.79-1.87(4H,m),2.84(2H,t,J=6.8Hz),3.14-3.36(2H,m),3.75-4.02(2H,m),4.69-4.75(2H,br),6.90(1H,d,J=8.5Hz),7.29(1H,d,J=2.2Hz),7.34(1H,dd,J=8.3,2.2Hz),7.40(2H,d,J=8.0Hz),7.53(2H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.55 (4H, dt, J = 13.0, 4.9 Hz), 1.79-1.87 (4H, m), 2.84 (2H, t, J = 6.8 Hz ), 3.14 - 3.36 (2H, m), 3.75 - 4.02 (2H, m), 4.69 - 4.75 (2H, br), 6.90 (1H, d, J = 8.5 Hz), 7.29 (1H, d, J = 2.2 Hz), 7.34 (1H, dd, J = 8.3, 2.2 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz).

步驟2：第三丁基6-(4-(溴甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(bromomethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-(羥基甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(200mg，0.49mmol)溶解於二氯甲烷(5mL)，加入四溴化碳(162mg，0.73mmol)與三苯基膦(166mg，0.63mmol)，於室溫攪拌30分鐘。於反應液中加入飽和碳酸氫鈉水溶液，以氯仿萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=5：1→3：1→2：1)精製，得到白色固體之標題化合物(230mg，quant.)。 The third butyl 6-(4-(hydroxymethyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), and carbon tetrabromide (162 mg, 0.73 mmol) and triphenylphosphine (166 mg) , 0.63 mmol), stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.42-1.62(11H,m),1.78-1.88(4H,m),2.84(2H,t,J=6.8Hz),3.14-3.34(2H,m),3.75-4.02(2H,m), 4.54(2H,s),6.90(1H,d,J=8.3Hz),7.26-7.31(1H,br),7.33(1I,dd,J=8.4,2.2Hz),7.42(2H,d,J=8.0Hz),7.51(2H,d,J=8.3Hz). 1 H-NMR (CDCl 3 ) δ: 1.42-1.62 (11H, m), 1.78-1.88 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.14 - 3.34 (2H, m), 3.75 -4.02 (2H, m), 4.54 (2H, s), 6.90 (1H, d, J = 8.3 Hz), 7.26-7.31 (1H, br), 7.33 (1I, dd, J = 8.4, 2.2 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.3 Hz).

步驟3：第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-(溴甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(36mg，0.08mmol)溶解於四氫呋喃(1.5mL)，加入4-吡啶硫醇(10mg，0.09mmol)與N,N-二異丙基乙基胺(27μL，0.09mmol)，於室溫攪拌30分鐘。於反應液中添加飽和碳酸氫鈉水溶液，以氯仿萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分聚薄層層析法(正己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(17mg，45%)。 The third butyl 6-(4-(bromomethyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (36 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1.5 mL), and 4-pyridinethiol (10 mg, 0.09 mmol) was added with N,N-di Propylethylamine (27 μL, 0.09 mmol) was stirred at room temperature for 30 min. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例68第三丁基6-(4-((吡啶-4-基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 68 Ternyl 6-(4-((pyridin-4-ylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例67所得之第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail obtained in Example 67 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例69第三丁基6-(4-((苯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 69 Ternyl 6-(4-((phenylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4-吡啶硫醇，使用硫酚，與實施例67同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 4-pyridine thiol and thiophenol, the reaction was carried out in the same manner as in Example 67 to give the title compound.

實施例70第三丁基6-(4-((苯基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 70 Thirty butyl 6-(4-((phenylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例69所得之第三丁基6-(4-((苯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-((phenylthio)methyl)phenyl) snail obtained in Example 69 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例71第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 71 Third butyl 6-(4-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4-吡啶硫醇，使用5-甲基-1,3,4-噻二唑-2-硫酚，與實施例67同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 4-pyridyl mercaptan and 5-methyl-1,3,4-thiadiazole-2-thiol, the reaction was carried out in the same manner as in Example 67 to give the title compound.

實施例72第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 72 Ternyl 6-(4-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例71所得之第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-(((5-methyl-1,3,4-thiadiazol-2-yl))thio)methyl)phenyl) snail obtained in Example 71 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例73第三丁基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 73 Ternyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((ethylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4-吡啶硫醇，使用乙硫酚，與實施例67同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

1H-NMR(CDCl3)δ：1.27(3H,t,J=7.3Hz),1.42-1.61(11H,m),1.76-1.88(4H,m),2.47(2H,q,J=7.3Hz),2.84(2H,t,J=6.6Hz),3.15-3.33(2H,m),3.75(2H,s),3.80-4.01(2H,m),6.90(1H,d,J=8.3Hz),7.27-7.37(4H,m),7.47(2H,d,J=8.3Hz). 1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.42-1.61 (11H, m), 1.76-1.88 (4H, m), 2.47 (2H, q, J = 7.3 Hz) ), 2.84 (2H, t, J = 6.6 Hz), 3.15-3.33 (2H, m), 3.75 (2H, s), 3.80-4.01 (2H, m), 6.90 (1H, d, J = 8.3 Hz) , 7.27-7.37 (4H, m), 7.47 (2H, d, J = 8.3 Hz).

步驟2：第三丁基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((ethylthio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例74第三丁基6-(4-((十二烷基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 74 Ternyl 6-(4-((dodecylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代4-吡啶硫醇，使用十二烷硫酚，與實施例67同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

實施例75第三丁基6-(4-((十二烷基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 75 Ternyl 6-(4-((dodecylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例74所得之第三丁基6-(4-((十二烷基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-((dodecylthio)methyl)phenyl) snail obtained in Example 74 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例76第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 76 Ternyl 6-(4-((ethylidenethio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例67之步驟2所得的第三丁基6-(4-(溴甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(1.0g，2.12mmol)溶解於N,N- 二甲基甲醯胺(5mL)，加入硫醋酸S-鉀(484mg，4.23mmol)，於室溫攪拌2小時。於反應液中加水，以醋酸乙酯萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=5：1→3：1)精製，得到淡黃色固體之標題化合物(827mg，84%)。 The third butyl 6-(4-(bromomethyl)phenyl) snail obtained in the second step of Example 67 [ Indole-2,4'-piperidine]-1'-carboxylate (1.0 g, 2.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), sulphuric acid S-potassium (484 mg, 4.23) Methyl), stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例77第三丁基6-(4-((丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 77 Thirty butyl 6-(4-((propylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((propylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例76所得之第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.06mmol)溶解於甲醇(0.3mL)與四氫呋喃(0.3mL)，加入1-碘丙烷(8μL，0.08mmol)與4N氫氧化鈉水溶液(0.5mL)，於室溫攪拌2小時。於反應液中加水，以醋酸乙酯萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=3：1)精製，得到白色固體之標題化合物(21mg，70%)。 The third butyl 6-(4-((ethylidenethio)methyl)phenyl) snail obtained in Example 76 Indole-2,4'-piperidine]-1'-carboxylate (30 mg, 0.06 mmol) was dissolved in methanol (0.3 mL) and tetrahydrofuran (0.3 mL), and 1- iopropane (8 μL, 0.08 mmol) and 4N were added. Aqueous sodium hydroxide (0.5 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：0.97(3H,t,J=7.6Hz),1.47(9H,s),1.50-1.66(4H,m),1.78-1.88(4H,m),2.43(2H,t,J=7.6Hz),2.84(2H,t,J=6.8Hz),3.18-3.33(2H,m),3.73(2H,s),3.79-3.99(2H,m),6.90(1H,d,J=8.5Hz),7.28(1H,d,J=2.2Hz),7.34(3H,m),7.48(2H,d,J=8.1Hz). 1 H-NMR (CDCl 3 ) δ: 0.97 (3H, t, J = 7.6 Hz), 1.47 (9H, s), 1.50-1.66 (4H, m), 1.78-1.88 (4H, m), 2.43 (2H) , t, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.18-3.33 (2H, m), 3.73 (2H, s), 3.79-3.99 (2H, m), 6.90 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.34 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

步驟2：第三丁基6-(4-((丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(4-((propylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(4-((propylthio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例78第三丁基6-(4-((烯丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 78 Third butyl 6-(4-((allylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((烯丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((allylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷，使用1-碘丙-2-烯，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 Substituting 1-iodopropane and 1-iodoprop-2-ene, the reaction was carried out in the same manner as in Example 77 to give the title compound.

1H-NMR(CDCl3)δ：1.34-1.61(11H,m),1.76-1.86(4H,m),2.76-2.86(2H,m),3.07(2H,d,J=7.1Hz),3.22-3.34(2H,m),3.69(2H,s),3.75-4.01(2H,m),5.00-5.19(2H,m),5.68-5.86(1H,m),6.90(1H,d,J=8.5Hz),7.22-7.36(4H,m),7.47(1H,d,J=8.3Hz). 1 H-NMR (CDCl 3 ) δ: 1.34-1.61 (11H, m), 1.76-1.86 (4H, m), 2.76-2.86 (2H, m), 3.07 (2H, d, J = 7.1 Hz), 3.22 -3.34(2H,m), 3.69(2H,s),3.75-4.01(2H,m),5.00-5.19(2H,m),5.68-5.86(1H,m),6.90(1H,d,J= 8.5 Hz), 7.22-7.36 (4H, m), 7.47 (1H, d, J = 8.3 Hz).

步驟2：第三丁基6-(4-(烯丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(allylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-4-((烯丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of a third butyl 6-4-((allylthio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例79第三丁基6-(4-((3,3,3-三氟丙基)磺醯基)甲基)苯 基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 79 Thirty butyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((3,3,3-三氟丙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((3,3,3-trifluoropropyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用1-碘-3,3,3-三氟丙烷，與實施例77同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.63(2H,m),1.78-1.87(4H,m),2.24-2.38(2H,m),2.57-2.64(2H,m),2.85(2H,t,J=6.8Hz),3.18-3.26(2H,m),3.76(2H,s),3.80-3.96(2H,m),6.90(1H,d,J=8.3Hz),7.26-7.37(4H,m),7.50(1H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.63 (2H, m), 1.78-1.87 (4H, m), 2.24-2.38 (2H, m), 2.57-2.64 (2H, m), 2.85 (2H, t, J = 6.8 Hz), 3.18-3.26 (2H, m), 3.76 (2H, s), 3.80-3.96 (2H, m), 6.90 (1H, d, J = 8.3 Hz) ), 7.26-7.37 (4H, m), 7.50 (1H, d, J = 8.0Hz).

步驟2：第三丁基6-(4-((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((3,3,3-三氟丙基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((3,3,3-trifluoropropyl)thio)methyl]phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例80第三丁基6-(4-(((2-甲氧基乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 80 Ternyl 6-(4-(((2-methoxyethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((2-甲氧基乙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((2-methoxyethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用1-溴-2-甲氧基乙烷，與實施例77同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

1H-NMR(CDCl3)δ：1.40-1.62(11H,s),1.76-1.88(4H,m),2.64 (2H,t,J=6.6Hz),2.84(2H,t,J=6.8Hz),3.16-3.39(5H,m),3.53(2H,t,J=6.6Hz),3.70-4.00(4H,m),6.90(1H,d,J=8.6Hz),7.28(1H,d,J=2.0Hz),7.31-7.38(3H,m),7.48(2H,d,J=8.1Hz). 1 H-NMR (CDCl 3 ) δ: 1.40-1.62 (11H, s), 1.76-1.88 (4H, m), 2.64 (2H, t, J = 6.6 Hz), 2.84 (2H, t, J = 6.8 Hz ), 3.16-3.39 (5H, m), 3.53 (2H, t, J = 6.6 Hz), 3.70-4.00 (4H, m), 6.90 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.38 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

步驟2：第三丁基6-(4-((2-甲氧基乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((2-methoxyethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((2-甲氧基乙基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((2-methoxyethyl)thio)methyl]phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例81第三丁基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 81 Third butyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((異丙基硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((isopropylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用2-碘丙烷，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 The reaction mixture was treated in the same manner as in Example 77 to give the title compound.

1H-NMR(CDCl3)δ：1.27(6H,d,J=6.6Hz),1.47(9H,s),1.50-1.58(2H,m),1.77-1.87(4H,m),2.78-2.88(3H,m),3.15-3.31(2H,m),3.778(2H,s),3.80-4.00(2H,m),6.89(1H,d,J=8.5Hz),7.28(2H,d,J=2.2Hz),7.30-7.37(3H,m),7.47(2H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.27 (6H, d, J = 6.6 Hz), 1.47 (9H, s), 1.50-1.58 (2H, m), 1.77-1.87 (4H, m), 2.78-2.88 (3H, m), 3.15-3.31 (2H, m), 3.778 (2H, s), 3.80-4.00 (2H, m), 6.89 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J =2.2 Hz), 7.30-7.37 (3H, m), 7.47 (2H, d, J = 8.0 Hz).

步驟2：第三丁基6-(4-((異丙基磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((isopropylsulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((異丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((isopropylthio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例82第三丁基6-(4-(((環丙基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 82 Thirty butyl 6-(4-(((cyclopropylmethyl))sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((環丙基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((cyclopropylmethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用溴甲基環丙烷，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 The reaction product was treated in the same manner as in Example 77 to give the title compound.

1H-NMR(CDCl3)δ：0.12-0.21(2H,m),0.48-0.58(2H,m),0.92-1.02(1H,m),1.47(9H,s),1.50-1.61(2H,m),1.76-1.87(4H,m),2.40(2H,d,J=7.1Hz),2.84(2H,t,J=6.8Hz),3.14-3.36(2H,m),3.74-4.00(4H,m),6.90(1H,d,J=8.3Hz),7.28(1H,d,J=2.0Hz),7.31-7.38(3H,m),7.47(2H,d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 0.12-0.21 (2H, m), 0.48-0.58 (2H, m), 0.92-1.02 (1H, m), 1.47 (9H, s), 1.50-1.61 (2H, m), 1.76-1.87 (4H, m), 2.40 (2H, d, J = 7.1 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.14 - 3.36 (2H, m), 3.74 - 4.00 (4H , m), 6.90 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.38 (3H, m), 7.47 (2H, d, J = 8.0 Hz).

步驟2：第三丁基6-(4-((環丙基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((cyclopropylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((環丙基甲基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(4-((cyclopropylmethyl)thio)methyl]phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例83第三丁基6-(4-((環己基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 83 Tert-butyl 6-(4-((cyclohexylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((環己基甲基)硫基)甲基)苯基)螺[ 唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((cyclohexylmethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用溴甲基環己烷，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

1H-NMR(CDCl3)δ：0.84-0.98(2H,m),1.16-1.30(3H,m),1.36-1.73(15H,m),1.75-1.89(6H,m),2.34(2H,d,J=6.8Hz),2.84(2H,t,J=6.8Hz),3.13-3.35(2H,m),3.70(2H,s),3.78-4.01(2H,m),6.90(1H,d,J=8.3Hz),7.28(1H,d,J=1.9Hz),7.30-7.36(3H,m),7.47(2H,d,J=8.1Hz). 1 H-NMR (CDCl 3 ) δ: 0.84-0.98 (2H, m), 1.16-1.30 (3H, m), 1.36-1.73 (15H, m), 1.75-1.89 (6H, m), 2.34 (2H, d, J = 6.8 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.13 - 3.35 (2H, m), 3.70 (2H, s), 3.78-4.01 (2H, m), 6.90 (1H, d , J = 8.3 Hz), 7.28 (1H, d, J = 1.9 Hz), 7.30-7.36 (3H, m), 7.47 (2H, d, J = 8.1 Hz).

步驟2：第三丁基6-(4-((環己基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((cyclohexylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((環己基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(4-((cyclohexylmethyl)thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例84第三丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 84 Ternyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((苄基硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((benzylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用苄基溴，與實施例77同樣地進行反應、處理，得到無色油狀物之標題化合物。 The benzyl bromide was used instead of 1-iodopropane, and the title compound was obtained as a colorless oil.

1H-NMR(CDCl3)δ：1.42-1.60(1H,m),1.78-1.88(4H,m),2.85(2H,t,J=6.8Hz),3.16-3.34(2H,m),3.60-3.66(4H,m),3.75-4.00(2H,m),6.90(1H,d,J=8.3Hz),7.24-7.36(9H,m),7.48(2H, d,J=8.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.42-1.60 (1H, m), 1.78-1.88 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.60 -3.66 (4H, m), 3.75-4.00 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.24 - 7.36 (9H, m), 7.48 (2H, d, J = 8.0 Hz).

步驟2：第三丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((苄基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((benzylthio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例85第三丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 85 Ternyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((吡啶-2-基甲基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((pyridin-2-ylmethyl)thio)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用2-氯甲基吡啶鹽酸鹽，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 2-chloromethylpyridine hydrochloride was used instead of 1-iodopropane, and the title compound was obtained as a white solid.

1H-NMR(CDCl3)δ：1.42-1.60(2H,m),1.78-1.88(4H,m),2.84(2H,t,J=6.8Hz),3.24-3.32(2H,m),3.72(2H,s),3.78(2H,s),3.82-3.98(2H,m),6.90(2H,d,J=8.3Hz),7.16(1H,ddd,J=7.6,4.9,1.0Hz),7.27(1H,d,J=2.2Hz),7.29-7.36(4H,m),7.46(2H,d,J=8.3Hz),7.63(1H,dt,J=1.9,7.7Hz),8.55(1H,d,J=4.9Hz). 1 H-NMR (CDCl 3 ) δ: 1.42-1.60 (2H, m), 1.78-1.88 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.24-3.32 (2H, m), 3.72 (2H, s), 3.78 (2H, s), 3.82-3.98 (2H, m), 6.90 (2H, d, J = 8.3 Hz), 7.16 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.27 (1H, d, J = 2.2 Hz), 7.29-7.36 (4H, m), 7.46 (2H, d, J = 8.3 Hz), 7.63 (1H, dt, J = 1.9, 7.7 Hz), 8.55 (1H) , d, J = 4.9 Hz).

步驟2：第三丁基6-(4-((吡啶-2-基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-((吡啶-2-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(22mg，0.04mmol)溶解於異丙醇(0.5mL)與二氯甲烷(0.5mL)，於0℃加入鎢(VI)酸鈉二水合 物(1mg，0.004mmol)與37%過氧化氫水(16μL，0.17mmol)，於室溫攪拌整夜。於反應液中加入飽和碳酸氫鈉水溶液，以醋酸乙酯萃取3次。對有機層以飽和硫代硫酸鈉水溶液與飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=1：1)精製，得到無色油狀物之標題化合物(9mg，39%)。 The third butyl 6-(4-((pyridin-2-ylmethyl)thio)methyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (22 mg, 0.04 mmol) was dissolved in isopropanol (0.5 mL) and dichloromethane (0.5 mL). Sodium dihydrate (1 mg, 0.004 mmol) and 37% aqueous hydrogen peroxide (16 μL, 0.17 mmol) were stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied to ethyl acetate. The organic layer was washed with saturated aqueous sodium thiosulfate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例86第三丁基6-(4-(((吡啶-3-基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 86 Ternyl 6-(4-(((pyridin-3-ylmethyl))sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((吡啶-3-基甲基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((pyridin-3-ylmethyl)thio)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用3-溴甲基吡啶氫溴酸鹽，與實施例77同樣地進行反應、處理，得到白色固體之標題化合物。 The 3-bromomethylpyridine hydrobromide was used instead of 1-iodopropane, and the title compound was obtained as a white solid.

1H-NMR(CDCl3)δ：1.47(9H,s),1.55(2H,ddd,J=13.0,12.8,4.9Hz),1.81-1.86(4H,m),2.85(2H,t,J=6.8Hz),3.18-3.33(2H,m),3.60(2H,s),3.63(2H,s),3.77-3.95(2H,m),6.90(1H,d,J=8.3Hz),7.20-7.36(5H,m),7.48(2H,d,J=8.3Hz),7.61-7.67(1H,m),8.47-8.51(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.55 (2H, ddd, J = 13.0, 12.8, 4.9 Hz), 1.81-1.86 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.18-3.33 (2H, m), 3.60 (2H, s), 3.63 (2H, s), 3.77-3.95 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.20- 7.36 (5H, m), 7.48 (2H, d, J = 8.3 Hz), 7.61-7.67 (1H, m), 8.47-8.51 (2H, m).

步驟2：第三丁基6-(4-((吡啶-3-基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((pyridin-3-ylmethyl)sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-(4-((吡啶-3-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.06mmol)溶解於甲醇(2.0mL)與醋酸乙酯(0.5mL)，加入七鉬酸六銨四水合物 (1mg，0.004mmol)與37%過氧化氫水(0.2mL)，於室溫攪拌2日。於反應液中加水，以醋酸乙酯萃取3次。對有機層以飽和碳酸氫鈉水溶液與飽和硫代硫酸鈉水溶液洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=1：3)精製，得到白色固體之標題化合物(27mg，79%)。 The third butyl 6-(4-((pyridin-3-ylmethyl)thio)methyl)phenyl) snail [ 唍-2,4'-Piperidine]-1'-carboxylate (30 mg, 0.06 mmol) was dissolved in methanol (2.0 mL) and ethyl acetate (0.5 mL), and hexammonium heptamoate tetrahydrate (1 mg) , 0.004 mmol) and 37% hydrogen peroxide water (0.2 mL) were stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and saturated aqueous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut

實施例87第三丁基6-(4-((吡啶-4-基甲基)磺醯基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 87 Ternyl 6-(4-((pyridin-4-ylmethyl)sulfonyl)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((吡啶-4-基甲基)硫基)甲基]苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((pyridin-4-ylmethyl)thio)methyl]phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用4-溴甲基吡啶氫溴酸鹽，與實施例77同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oil (yield).

1H-NMR(CDCl3)δ：1.42-1.62(11H,m),1.78-1.89(4H,m),2.85(2H,t,J=6.8Hz),3.16-3.34(2H,m),3.57(2H,s),3.63(2H,s),3.80-4.00(2H,m),6.91(1H,d,J=8.6Hz),7.20-7.36(6H,m),7.48(2H,d,J=8.0Hz),8.54(2H,d,J=5.9Hz). 1 H-NMR (CDCl 3 ) δ: 1.42-1.62 (11H, m), 1.78-1.89 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.57 (2H, s), 3.63 (2H, s), 3.80-4.00 (2H, m), 6.91 (1H, d, J = 8.6 Hz), 7.20-7.36 (6H, m), 7.48 (2H, d, J = 8.0 Hz), 8.54 (2H, d, J = 5.9 Hz).

步驟2：第三丁基6-(4-((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((pyridin-4-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-((吡啶-4-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例86之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Use of tert-butyl 6-(4-((pyridin-4-ylmethyl)thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 86 to give the title compound.

實施例88環丙基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[ 唍烯-2,4’-哌啶]-1’-羧酸酯的製造 Example 88 cyclopropylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of terpene-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用環丙基甲基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate and using cyclopropylmethyl 1H-imidazole-1-carboxylate, reacting and treating in the same manner as in Example 29 to obtain white Amorphous title compound.

實施例89環丁基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 89 cyclobutylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用環丁基甲基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate and using cyclobutylmethyl 1H-imidazole-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 29 to give a white amorphous form. The title compound.

實施例90(1-甲基環丙基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 90 (1-Methylcyclopropyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用(1-甲基環丙基)甲基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate and using (1-methylcyclopropyl)methyl 1H-imidazol-1-carboxylate was carried out in the same manner as in Example 29 Reaction and treatment gave the title compound as a white amorphous material.

實施例91 1-甲基環丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 91 1-Methylcyclobutyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用1-甲基環丁基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 29 except that the 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate was replaced with 1-methylcyclobutyl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例92 1-甲基環丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 92 1-Methylcyclopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用1-甲基環丙 基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate and using 1-methylcyclopropane The 1H-imidazole-1-carboxylate was reacted and treated in the same manner as in Example 29 to give the title compound as white crystals.

實施例93(三甲基矽基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 93 (Trimethylmethyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用(三甲基矽基)甲基1H-咪唑-1-羧酸酯，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 29 except that 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate was used and (trimethylsulfonyl)methyl 1H-imidazol-1-carboxylate was used. Treatment gave the title compound as a white amorphous material.

實施例94第三丁基6-(5-((甲基磺醯基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 94 Ternyl 6-(5-((methylsulfonyl)methyl)pyridinium -2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(羥基甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(hydroxymethyl)pyrrole -2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(5-氯吡-2-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到黃色油狀物之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane for use (5-chloropyridyl) The reaction was carried out in the same manner as in the step 2 of Example 11 to give the title compound.

1H-NMR(CDCl3)δ：1.48(9H,s),1.58-1.63(2H,m),1.79-1.90(4H,m),2.89(2H,t,J=6.6Hz),3.16-3.35(2H,m),3.79-4.04(2H,m),4.85(2H,s),6.96(1H,d,J=8.3Hz),7.73-7.80(2H,m),8.60(1H,s),8.90(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.58-1.63 (2H, m), 1.79-1.90 (4H, m), 2.89 (2H, t, J = 6.6 Hz), 3.16-3.35 (2H, m), 3.79-4.04 (2H, m), 4.85 (2H, s), 6.96 (1H, d, J = 8.3 Hz), 7.73-7.80 (2H, m), 8.60 (1H, s), 8.90 (1H, s).

步驟2：第三丁基6-(5-((甲基磺醯基)氧基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((methylsulfonyl)oxy)methyl)pyridinium -2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，在第三丁基6-(5-(羥基甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(29mg，0.07mmol)、三乙基胺 (30μL，0.21mmol)的無水二氯甲烷溶液(1.4mL)中，於0℃緩慢滴下甲磺醯氯(10μL，0.11mmol)，直接於其溫度下攪拌20分鐘。加水使反應停止，以醋酸乙酯萃取。以無水硫酸鈉乾燥後，減壓濃縮，得到黃色非晶形之標題化合物(65mg，粗產物)。 In the argon environment, in the third butyl 6-(5-(hydroxymethyl)pyridinium -2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (29 mg, 0.07 mmol), triethylamine (30 μL, 0.21 mmol) in anhydrous dichloromethane (1.4 mL), slowly at 0 ° C Methylsulfonium chloride (10 μL, 0.11 mmol) was added dropwise and stirred at the same temperature for 20 minutes. Water was added to stop the reaction and extracted with ethyl acetate. The title compound (65 mg, crude)

步驟3：第三丁基6-(5-((甲基磺醯基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(5-((methylsulfonyl)methyl)pyridinium -2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，在第三丁基6-(5-(((甲基磺醯基)氧基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(35mg，粗產物)的無水二甲基亞碸溶液(1.4mL)中，加入甲亞硫酸鈉(28mg，0.28mmol)，於120℃攪拌1小時。加水使反應停止，以二乙基醚萃取。以無水硫酸鈉乾燥後，減壓濃縮，將所得殘渣使用矽膠分取薄層層析法(氯仿：甲醇=100：1)精製，得到白色非晶形之標題化合物(22mg，65%二步驟)。 In the argon atmosphere, in the third butyl 6-(5-(((methylsulfonyl)oxy)methyl)pyridyl) -2-yl) snail [ To a solution of hydrazine-2,4'-piperidinyl-1'-carboxylate (35 mg, crude) in anhydrous dimethyl hydrazide (1.4 mL), sodium sulphite (28 mg, 0.28 mmol), at 120 ° C Stir for 1 hour. Water was added to stop the reaction and it was extracted with diethyl ether. After drying over anhydrous sodium sulfate, the residue was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

實施例95第三丁基6-(6-((甲基磺醯基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 95 Ternyl 6-(6-((methylsulfonyl)methyl)anthracene -3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(6-(羥基甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(6-(hydroxymethyl)anthracene -3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(6-氯嗒-3-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use (6-chloropurine instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane -3-yl)methanol was reacted and treated in the same manner as in the step 2 of Example 11 to give the title compound as white crystals.

1H-NMR(CDCl3)δ：1.47(9H,s),1.55-1.59(2H,m),1.84-1.86 (4H,m),2.89(2H,t,J=6.8Hz),3.17-3.32(2H,m),3.48-3.61(1H,m),3.80-4.01(2H,m),4.98(2H,s),6.97(1H,d,J=8.3Hz),7.50(1H,d,J=8.8Hz),7.74-7.82(2H,m),7.89(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.55-1.59 (2H, m), 1.84-1.86 (4H, m), 2.89 (2H, t, J = 6.8 Hz), 3.17-3.32 (2H, m), 3.48-3.61 (1H, m), 3.80-4.01 (2H, m), 4.98 (2H, s), 6.97 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.74 - 7.82 (2H, m), 7.89 (1H, s).

步驟2：第三丁基6-(6-(((甲基磺醯基)氧基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(6-(((methylsulfonyl)oxy)methyl)) -3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(6-(羥基甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Use the third butyl 6-(6-(hydroxymethyl) hydrazine obtained in step 1. -3-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 94 to give the title compound.

步驟3：第三丁基6-(6-((甲基磺醯基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(6-((methylsulfonyl)methyl)anthracene -3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(6-(((甲基磺醯基)氧基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(6-(((methylsulfonyl))oxy)methyl) hydrazine obtained in step 2 -3-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound.

實施例96第三丁基6-(5-((甲基磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 96 Ternyl 6-(5-((methylsulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(羥基甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(hydroxymethyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(2-氯嘧啶-5-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (2-bromo-3-fluorobenzyl)(methyl)sulfane and using (2-chloropyrimidin-5-yl)methanol, the reaction was carried out in the same manner as in the step 2 of Example 11 to obtain a white amorphous form. The title compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.55(2H,td,J=12.8,4.6Hz), 1.79-1.88(4H,m),2.88(2H,t,J=6.6Hz),3.16-3.32(2H,m),3.77-4.02(2H,m),4.74(2H,s),6.93(1H,d,J=8.3Hz),8.15-8.21(2H,m),8.74(2H,s). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.55 (2H, td, J = 12.8, 4.6 Hz), 1.79-1.88 (4H, m), 2.88 (2H, t, J = 6.6 Hz ), 3.16-3.32 (2H, m), 3.77-4.02 (2H, m), 4.74 (2H, s), 6.93 (1H, d, J = 8.3 Hz), 8.15-8.21 (2H, m), 8.74 ( 2H, s).

步驟2：第三丁基6-(5-(((甲基磺醯基)氧基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((methylsulfonyl)oxy)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-(羥基甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(5-(hydroxymethyl)pyrimidin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 94 to give the title compound.

步驟3：第三丁基6-(5-((甲基磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(5-((methylsulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(5-(((甲基磺醯基)氧基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(5-(((methylsulfonyl)oxy)methyl)pyrimidin-2-yl) snail obtained in step 2 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound.

實施例97第三丁基6-(4-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 97, Third butyl 6-(4-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(羥基甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(hydroxymethyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(4-溴噻唑-2-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane and using (4-bromothiazol-2-yl)methanol, the reaction was carried out in the same manner as in the step 2 of Example 11 to give a white amorphous form. The title compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.52-1.59(2H,m),1.78-1.87 (4H,m),2.36-2.38(1H,br m),2.84(2H,t,J=6.8Hz),3.14-3.36(2H,m),3.80-4.04(2H,m),4.80(2H,s),6.88(1H,d,J=8.3Hz),7.09(1H,s),7.63-7.71(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.52-1.59 (2H, m), 1.78-1.87 (4H, m), 2.36-2.38 (1H, br m), 2.84 (2H, t , J=6.8Hz), 3.14-3.36(2H,m), 3.80-4.04(2H,m), 4.80(2H,s),6.88(1H,d,J=8.3Hz),7.09(1H,s) , 7.63-7.71 (2H, m).

步驟2：第三丁基6-(4-(((甲基磺醯基)氧基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((methylsulfonyl)oxy)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(羥基甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(4-(hydroxymethyl)thiazol-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 94 to give the title compound.

步驟3：第三丁基6-(4-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(4-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(4-(((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(4-(((methylsulfonyl)methyl)thiazol-2-yl) snail obtained in step 2 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound.

實施例98第三丁基6-(5-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 98 Ternyl 6-(5-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(羥基甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(hydroxymethyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(2-溴噻唑-5-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (2-bromo-3-fluorobenzyl)(methyl)sulfane and using (2-bromothiazol-5-yl)methanol, the reaction was carried out in the same manner as in the step 2 of Example 11 to give a white amorphous form. The title compound.

1H-NMR(CDCl3)δ：1.42-1.62(11H,m),1.75-1.89(4H,m),2.84(2H,t,J=6.8Hz),3.16-3.24(2H,m),3.77-4.02(2H,m),4.87 (2H,s),6.88(1H,d,J=8.6Hz),7.58-7.71(3H,m). 1 H-NMR (CDCl 3 ) δ: 1.42-1.62 (11H, m), 1.75-1.89 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.16-3.24 (2H, m), 3.77 -4.02 (2H, m), 4.87 (2H, s), 6.88 (1H, d, J = 8.6 Hz), 7.58-7.71 (3H, m).

步驟2：第三丁基6-(5-(((甲基磺醯基)氧基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(5-(((methylsulfonyl)oxy)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-(羥基甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(5-(hydroxymethyl)thiazol-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 94 to give the title compound.

步驟3：第三丁基6-(5-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(5-((methylsulfonyl)methyl)thiazol-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(5-(((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(5-(((methylsulfonyl)methyl)thiazol-2-yl) snail obtained in step 2 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound.

實施例99第三丁基6-(2-((甲基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 99 Ternyl 6-(2-((methylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(2-(羥基甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(2-(hydroxymethyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用(5-溴噻唑-2-基)甲醇，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (5-bromo-3-fluorobenzyl)(methyl)sulfane and using (5-bromothiazol-2-yl)methanol, the reaction was carried out in the same manner as in the step 2 of Example 11 to give a white amorphous form. The title compound.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.60(2H,m),1.78-1.87(4H,m),2.81(2H,t,J=6.6Hz),3.15-3.32(2H,m),3.80-3.98(2H,m),4.93(2H,s),6.86(1H,d,J=8.3Hz),7.21-7.31(2H,m),7.75(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.78-1.87 (4H, m), 2.81 (2H, t, J = 6.6 Hz), 3.15-3.32 (2H, m), 3.80-3.98 (2H, m), 4.93 (2H, s), 6.86 (1H, d, J = 8.3 Hz), 7.21 - 7.31 (2H, m), 7.75 (1H, s).

步驟2：第三丁基6-(2-(((甲基磺醯基)氧基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(2-(((methylsulfonyl)oxy)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(2-(羥基甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(2-(hydroxymethyl)thiazol-5-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 94 to give the title compound.

步驟3：第三丁基6-(2-((甲基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(2-((methylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(2-(((甲基磺醯基)氧基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到黃色非晶形之標題化合物。 The third butyl 6-(2-(((methylsulfonyl)oxy)methyl)thiazol-5-yl) snail obtained in step 2 was used [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound.

實施例100第三丁基6-(5-((甲基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 100 Ternyl 6-(5-((methylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-氰基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-cyano snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，在實施例3所得之第三丁基6-氰基螺[唍-2,4’-哌啶]-1’-羧酸酯(300mg，0.78mmol)與氰化鋅(184mg，1.57mmol)的N-甲基吡咯啶酮溶液(4ml)中，加入肆三苯基膦鈀(0)(91mg，0.078mmol)，於140℃攪拌2小時。將反應液以醋酸乙酯稀釋，萃取有機層。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=3：1)精製，得到白色固體之標 題化合物(141mg，55%)。 The third butyl 6-cyanospiro obtained in Example 3 under an argon atmosphere [ Indole-2,4'-piperidine]-1'-carboxylate (300 mg, 0.78 mmol) and zinc cyanide (184 mg, 1.57 mmol) in N-methylpyrrolidone (4 ml) Phenylphosphine palladium (0) (91 mg, 0.078 mmol) was stirred at 140 ° C for 2 h. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.47(9H,s),1.52-1.64(2H,m),1.74-1.86(4H,m),2.80(2H,t,J=6.9Hz),3.11-3.37(2H,m),3.79-4.00(2H,br),6.88(1H,d,J=9.2Hz),7.37-7.41(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.52-1.64 (2H, m), 1.74-1.86 (4H, m), 2.80 (2H, t, J = 6.9 Hz), 3.11-3.37 (2H, m), 3.79-4.00 (2H, br), 6.88 (1H, d, J = 9.2 Hz), 7.37-7.41 (2H, m).

步驟2：第三丁基6-(N’-羥基脒基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(N'-hydroxyindenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在步驟1所得之第三丁基6-氰基螺[唍-2,4’-哌啶]-1’-羧酸酯(165mg，0.50mmol)的乙醇(6ml)溶液中’加入鹽酸羥基胺(105mg，1.51mmol)與碳酸氫鈉(127mg，151mmol)，於75℃攪拌4小時。餾除乙醇後，於殘渣中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，得到粗製生成物(155mg)。 The third butyl 6-cyano snail obtained in step 1 [ Add a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (165 mg, 0.50 mmol) in ethanol (6 ml) - hydroxyamine hydrochloride (105 mg, 1.51 mmol) and sodium bicarbonate (127 mg, 151 mmol) Stir at 75 ° C for 4 hours. After distilling off the ethanol, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated.

步驟3：第三丁基6-(5-(乙醯氧基甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(5-(ethyloxymethyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於冰冷下，在步驟2所得之第三丁基6-(N’-羥基脒基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.08mmol)的二氯甲烷(0.8ml)溶液中，加入吡啶(20μL，0.25mmol)與乙醯氧基醋酸氯(11mg，0.08mmol)，於室溫攪拌2小時後，餾除溶媒。於所得殘渣中加入甲苯(0.5mL)，加熱迴流12小時。餾除甲苯後，將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(8.8mg，24%)。 The third butyl 6-(N'-hydroxyindenyl) snail obtained in step 2 under ice cooling [ To a solution of 唍-2,4'-piperidine]-1'-carboxylate (30 mg, 0.08 mmol) in dichloromethane (0.8 ml), pyridine (20 μL, 0.25 mmol) and acetoxyacetic acid chloride ( 11 mg, 0.08 mmol), after stirring at room temperature for 2 hours, the solvent was distilled off. Toluene (0.5 mL) was added to the residue, and the mixture was refluxed for 12 hr. After distilling off the toluene, the obtained residue was purified eluted eluted elut elut elut elut elut elut

1H-NMR(CDCl3)δ：1.43-1.64(11H,m),1.76-1.88(4H,m),2.82- 2.88(2H,m),2.22(3H,s),2.85(2H,t,J=6.6Hz),3.14-3.32(2H,m),3.86-4.00(2H,m),5.33(2H,s),6.92(1H,d,J=9.0Hz),7.78-7.84(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.43-1.64 (11H, m), 1.76-1.88 (4H, m), 2.82- 2.88 (2H, m), 2.22 (3H, s), 2.85 (2H, t, J=6.6 Hz), 3.14-3.32 (2H, m), 3.86-4.00 (2H, m), 5.33 (2H, s), 6.92 (1H, d, J = 9.0 Hz), 7.78-7.84 (2H, m ).

步驟4：第三丁基(6-(5-(羥基甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Third butyl (6-(5-(hydroxymethyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在步驟3所得之第三丁基6-(5-(乙醯氧基甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(34mg，0.08mmol)的甲醇(1.5mL)溶液中，加入碳酸鉀(106mg，0.77mmol)，於室溫下攪拌30分鐘。餾除溶媒後，對所得殘渣加水並以氯仿萃取。對有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓濃縮，得到白色非晶形之標題化合物(25mg，81%)。 The third butyl 6-(5-(ethyloxymethyl)-1,2,4- obtained in step 3 Diazol-3-yl) snail [ To a solution of hydrazine-2,4'-piperidinyl-1'-carboxylate (34 mg, 0.08 mmol) in MeOH (1 mL) After distilling off the solvent, water was added to the residue and extracted with chloroform. The organic layer was washed with EtOAc (EtOAc m.

1H-NMR(CDCl3)δ：1.47(9H,s),1.51-1.62(2H,m),1.76-1.86(4H,m),2.80-2.86(2H,m),3.17-3.32(2H,m),3.80-3.94(2H,m),4.93(2H,s),6.91(1H,d,J=9.6Hz),7.78-7.84(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.51-1.62 (2H, m), 1.76-1.86 (4H, m), 2.80-2.86 (2H, m), 3.17-3.32 (2H, m), 3.80-3.94 (2H, m), 4.93 (2H, s), 6.91 (1H, d, J = 9.6 Hz), 7.78-7.84 (2H, m).

步驟5：第三丁基6-(5-(((甲基磺醯基)氧基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 5: Tert-butyl 6-(5-(((methylsulfonyl)oxy)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於冰冷下，在步驟4所得之第三丁基6-(5-(羥基甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(25mg，0.06mmol)的二氯甲烷(2.0mL)溶液中，加入三乙基胺(26μL，0.19mmol)與甲磺醯氯(7μL，0.09mmol)，於室溫下攪拌1小時。於反應液中加水並以氯仿萃取。對有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓濃縮，得到粗 製生成物(30mg)。 The third butyl 6-(5-(hydroxymethyl)-1,2,4- obtained in step 4 under ice cooling Diazol-3-yl) snail [ To a solution of 唍-2,4'-piperidine]-1'-carboxylate (25 mg, 0.06 mmol) in dichloromethane (2.0 mL), triethylamine (26 μL, 0.19 mmol) and methanesulfonyl chloride (7 μL, 0.09 mmol), stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

步驟6：第三丁基6-(5-((甲基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 6: Tert-butyl 6-(5-((methylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟5所得之第三丁基6-(5-(((甲基磺醯基)氧基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(5-(((methylsulfonyl))oxy)methyl)-1,2,4- obtained in step 5 Diazol-3-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 94 to give the title compound as white crystals.

實施例101第三丁基7-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 101 Thirty butyl 7-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基7-氟-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 7-fluoro-4-sided oxo snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用市售之4’-氟-2’-羥基苯乙酮，與實施例1之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The reaction product was treated in the same manner as in the step 1 of Example 1 to give the title compound.

步驟2：第三丁基7-氟螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 7-fluorospiro [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基7-氟-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 Using the third butyl 7-fluoro-4-sideoxy snail obtained in step 1 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 3 to give the title compound.

步驟3：第三丁基6-溴-7-氟螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-bromo-7-fluorospiro [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在步驟2所得之第三丁基7-氟螺[唍-2,4’-哌啶]-1’-羧酸酯(1.7g，5.29mmol)的N,N-二甲基甲醯胺(14mL)溶液中，加入N-溴琥珀醯亞胺(1.1g，6.35mmol)，於50℃攪拌30分鐘。 於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=10：1)精製，得到無色油狀物之標題化合物(1.79g，84%)。 The third butyl 7-fluorospiro obtained in step 2 [ To a solution of 唍-2,4'-piperidine]-1'-carboxylate (1.7 g, 5.29 mmol) in N,N-dimethylformamide (14 mL), N-bromosuccinimide ( 1.1 g, 6.35 mmol), stirred at 50 ° C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.42-1.58(11H,m),1.74-1.84(4H,m),2.73(2H,t,J=6.8Hz),3.08-3.24(2H,m),3.76-3.98(2H,m),6.63(1H,d,J=10.0Hz),7.21(1H,dJ=7.6). 1 H-NMR (CDCl 3 ) δ: 1.42-1.58 (11H, m), 1.74-1.84 (4H, m), 2.73 (2H, t, J = 6.8 Hz), 3.08-3.24 (2H, m), 3.76 -3.98 (2H, m), 6.63 (1H, d, J = 10.0 Hz), 7.21 (1H, dJ = 7.6).

步驟4：第三丁基7-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Tert-butyl 7-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟3所得之第三丁基6-溴-7-氟螺[唍-2,4’-哌啶]-1’-羧酸酯(46mg，0.11mmol)及4,4,5,5-四甲基-2-(4-((甲基磺醯基)甲基)苯基)-1,3,2-二硼烷(41mg，0.14mmol)，溶解於乙二醇二甲基醚(2mL)，加入溶解了碳酸鈉(122mg，1.15mmol)的水溶液(1mL)，並加入肆三苯基膦鈀(0)(13mg，0.011mmol)，於90℃攪拌12小時。以醋酸乙酯稀釋反應液，萃取有機層。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(42mg，75%)。 The third butyl 6-bromo-7-fluorospiro obtained in step 3 [ 唍-2,4'-piperidine]-1'-carboxylate (46 mg, 0.11 mmol) and 4,4,5,5-tetramethyl-2-(4-((methylsulfonyl)) Base) phenyl)-1,3,2-di Borane (41 mg, 0.14 mmol), dissolved in ethylene glycol dimethyl ether (2 mL), an aqueous solution (1 mL) in which sodium carbonate (122 mg, 1.15 mmol) was dissolved, and added triphenylphosphine palladium (0) (13 mg, 0.011 mmol), stirred at 90 ° C for 12 hours. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例102第三丁基7-氟-6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 102 Thirty butyl 7-fluoro-6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例101之步驟3所得之第三丁基6-溴-7-氟螺[唍 -2,4’-哌啶]-1’-羧酸酯(22mg，0.055mmol)及2-(3-氟-4-((甲基磺醯基)甲基)苯基-4,4,5,5-四甲基-1,3,2-二硼烷(21mg，0.066mmol)溶解於乙二醇二甲基醚(2mL)，加入溶解了碳酸鈉(58mg，0.55mmol)的水溶液(1mL)，並加入肆三苯基膦鈀(0)(6mg，0.005mmol)，於90℃攪拌12小時。以醋酸乙酯稀釋反應液，萃取有機層。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到淡黃色固體之標題化合物(21mg，75%)。 The third butyl 6-bromo-7-fluorospiro obtained in the third step of Example 101 [ 唍-2,4'-piperidine]-1'-carboxylate (22 mg, 0.055 mmol) and 2-(3-fluoro-4-((methylsulfonyl)methyl)phenyl-4,4 ,5,5-tetramethyl-1,3,2-di Borane (21 mg, 0.066 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL), and an aqueous solution (1 mL) in which sodium carbonate (58 mg, 0.55 mmol) was dissolved was added, and triphenylphosphine palladium (0) was added ( 6 mg, 0.005 mmol), stirred at 90 ° C for 12 hours. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

實施例103第三丁基7-氟-6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 103 Ternyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基7-氟-6-(4,4,5,5-四甲基-1,3,2-二硼烷-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-di Borane-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

在實施例101之步驟3所得的第三丁基6-溴-7-氟螺[唍-2,4’-哌啶]-1’-羧酸酯(235mg，0.59mmol)之1,4-二烷(4mL)溶液中，加入雙(酯)二硼烷(179mg，0.70mmol)、醋酸鉀(173mg，1.76mmol)及雙(三苯基膦)二氯鈀(II)(41mg，0.059mmol)，於氬環境下，在90℃攪拌12.5小時。濾除不溶物後，於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=10：1)精製，得到白色固體之標題化合物(67mg，25%)。 The third butyl 6-bromo-7-fluorospiro obtained in the step 3 of Example 101 [ 1,4-2,4'-piperidine]-1'-carboxylate (235 mg, 0.59 mmol) of 1,4-two In a solution of alkane (4 mL), add double ( Ethyl diborane (179 mg, 0.70 mmol), potassium acetate (173 mg, 1.76 mmol) and bis(triphenylphosphine)dichloropalladium(II) (41 mg, 0.059 mmol), stirred at 90 ° C under argon. 12.5 hours. After the insoluble material was filtered off, water was added to the mixture and ethyl acetate was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.32(12H,s),1.40-1.58(11H,m),1.72-1.84(4H,m),2.74(2H,t,6.4Hz),3.10-3.26(2H,m),3.76-3.96(2H,m),6.52(1H,d,J=10.4Hz),7.44(1H,d,J=6.8Hz). 1 H-NMR (CDCl 3 ) δ: 1.32 (12H, s), 1.40-1.58 (11H, m), 1.72-1.84 (4H, m), 2.74 (2H, t, 6.4 Hz), 3.10-3.26 (2H , m), 3.76-3.96 (2H, m), 6.52 (1H, d, J = 10.4 Hz), 7.44 (1H, d, J = 6.8 Hz).

步驟2：第三丁基7-氟-6-(5-(羥基甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 7-fluoro-6-(5-(hydroxymethyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基7-氟-6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例15之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 15 to give the title compound as white white.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.61(2H,m),1.75-1.85(4H,m),2.82(2H,t,J=6.8Hz),3.14-3.28(2H,m),3.78-3.98(2H,m),4.75(2H,s),6.65(1H,d,J=12.8Hz),7.55(1H,d,J=l0.0Hz),7.63-7.72(2H,m),8.64(1H,s). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.75-1.85 (4H, m), 2.82 (2H, t, J = 6.8 Hz), 3.14 - 3.28 (2H,m), 3.78-3.98(2H,m),4.75(2H,s),6.65(1H,d,J=12.8Hz),7.55(1H,d,J=l0.0Hz),7.63-7.72 (2H,m), 8.64 (1H, s).

步驟3：第三丁基7-氟-6-(5-(((甲基磺醯基)氧基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 7-fluoro-6-(5-((methylsulfonyl)oxy)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基7-氟-6-(5-(羥基甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟2同樣地進行反應、處理，得到粗製生成物。 Using the third butyl 7-fluoro-6-(5-(hydroxymethyl)pyridin-2-yl) snail obtained in step 2 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 2 of Example 94 to give a crude product.

步驟4：第三丁基7-氟-6-(5-(((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Tert-butyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟3所得之第三丁基7-氟-6-(5-(((甲基磺醯基)氧基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例94之步驟3同樣地進行反應、處理，得到白色非晶形物。 Using the third butyl 7-fluoro-6-(5-((methylsulfonyl)oxy)methyl)pyridin-2-yl) snail obtained in step 3 Indole-2,4'-piperidine]-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 94 to give a white amorphous material.

實施例104第三丁基3-羥基-6-[4-{(甲基磺醯基)甲基}苯基]螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 104 Third butyl 3-hydroxy-6-[4-{(methylsulfonyl)methyl}phenyl] snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-溴-4-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-bromo-4-hydroxyspiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將實施例1之步驟1所得的第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(200mg，0.505mmol)溶解於甲醇(5mL)，於冰冷下，加入氫化硼鈉(24.8mg，0.656mmol)，於室溫下攪拌1.5小時。於冰冷下，在反應液中加入1當量鹽酸，以氯仿萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(己烷：醋酸乙酯=1：1)精製，得到無色非晶形之標題化合物(201mg，100%)。 The third butyl 6-bromo-4-indolyl snail obtained in the first step of Example 1 [ Indole-2,4'-piperidinyl-1'-carboxylate (200 mg, 0.505 mmol) was dissolved in MeOH (5 mL). Stir for 1.5 hours. Under ice cooling, 1N hydrochloric acid was added to the reaction mixture, and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

1H-NMR(CDCl3)δ：1.46(9H,s),1.51-1.69(2H,m),1.75-1.94(5H,m),2.12(1H,dd,J=6.1,13.6Hz),2.15(1H,brs),3.05-3.30(2H,m),3.75-3.90(2H,m),4.83(1H,q,J=6.9Hz),6.73(1H,d,J=8.8Hz),7.29(1H,d,J=2.4Hz),7.57(1H,d,J=2.4Hz). 1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.51-1.69 (2H, m), 1.75-1.94 (5H, m), 2.12 (1H, dd, J = 6.1, 13.6 Hz), 2.15 (1H, brs), 3.05-3.30 (2H, m), 3.75-3.90 (2H, m), 4.83 (1H, q, J = 6.9 Hz), 6.73 (1H, d, J = 8.8 Hz), 7.29 ( 1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 2.4 Hz).

步驟2：第三丁基6-溴-4-氯螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-bromo-4-chlorospiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-4-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯(200mg，0.505mmol)溶解於二氯甲烷(5mL)，於冰冷下加入甲磺醯氯(86.3mg，0.753mmol)與三乙基胺(76.2mg，0.753mmol)，於室溫攪拌4小時。於反應液中加水，以氯仿萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮，得到 淡黃色非晶形之標題化合物。 The third butyl 6-bromo-4-hydroxyspiro[ Indole-2,4'-piperidine]-1'-carboxylate (200 mg, 0.505 mmol) was dissolved in dichloromethane (5 mL). methanesulfonium chloride (86.3 mg, 0.753 mmol) and triethyl The amine (76.2 mg, 0.753 mmol) was stirred at room temperature for 4 h. Water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was dried with anhydrous sodium sulfate and evaporated

步驟3：第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-bromo snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-4-氯螺[唍-2,4’-哌啶]-1’-羧酸酯(239mg，0.505ml)溶解於N-甲基吡咯啶酮(2mL)，加入DBU(84.1mg，0.552mmol)，以100℃攪拌2小時。於反應液中加飽和氯化銨水溶液，以醋酸乙酯萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=3：1)精製，得到無色油狀物之標題化合物(191mg，100%)。 The third butyl 6-bromo-4-chlorospiro[ 唍-2,4'-Piperidine]-1'-carboxylate (239 mg, 0.505 ml) was dissolved in N-methylpyrrolidone (2 mL), and DBU (84.1 mg, 0.552 mmol) was added and stirred at 100 ° C 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.65(2H,m),1.90-2.00(2H,m),3.20-3.35(2H,m),3.80-3.90(2H,m),5.59(1H,d,J=9.8Hz),6.33(1H,d,J=9.8Hz),6.71(1H,d,J=8.5Hz),7.11(1H,d,J=2.4Hz),7.20(1H,dd,J=2.4,8.8Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.65 (2H, m), 1.90-2.00 (2H, m), 3.20-3.35 (2H, m), 3.80-3.90 (2H, m), 5.59 (1H, d, J = 9.8 Hz), 6.33 (1H, d, J = 9.8 Hz), 6.71 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 2.4 Hz) , 7.20 (1H, dd, J = 2.4, 8.8 Hz).

步驟4：第三丁基1a,7b-二氫螺(氧吮[2,3-c]唍烯-2,4’-哌啶)-1’-羧酸酯的製造 Step 4: Tert-butyl 1a,7b-dihydrospiro (oxo[2,3-c] Manufacture of terpene-2,4'-piperidine)-1'-carboxylate

將第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯(70.0mg，0.184mmol)溶解於二氯甲烷(2mL)，於冰冷下，加入間氯過氧苯甲酸(47.6mg，0.276mmol)與碳酸氫鈉(30.9mg，0.368mmol)，於室溫下攪拌4小時。於反應液中加水，以氯仿萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(己烷：醋酸乙酯=3：1)精製，得到無色油狀物之標題化合物(44.5mg，61%)。 The third butyl 6-bromo snail [ Indole-2,4'-piperidinyl-1'-carboxylate (70.0 mg, 0.184 mmol) was dissolved in dichloromethane (2 mL). m. m. And sodium hydrogencarbonate (30.9 mg, 0.368 mmol), stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:

1H-NMR(CDCl3)δ：1.48(9H,s),1.54-1.66(2H,m),1.81(1H,dt,J=4.9,13.0Hz),2.06(1H,dd,J=1.7,10.2Hz),2.95-3.10(1H,m),3.20-3.35(1H,m),3.43(1H,d,J=4.4Hz),3.84(1H,d,J=4.4Hz),3.90-4.10(2H,m),6.75(1H,d,J=8.6Hz),7.36(1H,dd,J=2.4,8.6Hz),7.47(1H,d,J=2.4Hz). 1 H-NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.54-1.66 (2H, m), 1.81 (1H, dt, J = 4.9, 13.0 Hz), 2.06 (1H, dd, J = 1.7, 10.2 Hz), 2.95-3.10 (1H, m), 3.20-3.35 (1H, m), 3.43 (1H, d, J = 4.4 Hz), 3.84 (1H, d, J = 4.4 Hz), 3.90-4.10 ( 2H, m), 6.75 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 2.4, 8.6 Hz), 7.47 (1H, d, J = 2.4 Hz).

步驟5：第三丁基6-溴-3-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 5: Tert-butyl 6-bromo-3-hydroxyspiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基1a,7b-二氫螺(氧吮[2,3-c]唍烯-2,4’-哌啶)-1’-羧酸酯(44.0mg，0.111mmol)溶解於四氫呋喃(1mL)，於冰冷下，加入氫化鋁鋰(4.06mg，0.122mmol)，於0℃攪拌1小時。於反應液中加水，在室溫下攪拌30分鐘後，矽藻土過濾，將濾液藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=3：1)精製，得到無色油狀物之標題化合物(39.5mg，89%)。 The third butyl 1a,7b-dihydrospiro (oxo[2,3-c] The terpene-2,4'-piperidinyl-1'-carboxylate (44.0 mg, 0.111 mmol) was dissolved in tetrahydrofuran (1 mL). Stir at °C for 1 hour. After adding water to the reaction mixture and stirring at room temperature for 30 minutes, the celite was filtered, and the filtrate was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

1H-NMR(CDCl3)δ：1.46(9H,s),1.54-1.65(3H,m),1.95-2.30(1H,m),1.97(1H,dd,J=2.4,13.9Hz),2.77(1H,d,J=4.9,17.3Hz),3.03(1H,dd,J=4.9,17.3),2.95-3.20(2H,m),3.74-3.75(1H,m),3.80-4.05(2H,m),6.77(1H,d,J=8.5Hz),7.20-7.24(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.54-1.65 (3H, m), 1.95-2.30 (1H, m), 1.97 (1H, dd, J = 2.4, 13.9 Hz), 2.77 (1H, d, J=4.9, 17.3 Hz), 3.03 (1H, dd, J=4.9, 17.3), 2.95-3.20 (2H, m), 3.74-3.75 (1H, m), 3.80-4.05 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.20-7.24 (2H, m).

步驟6：第三丁基3-羥基-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 6: Tert-butyl 3-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代第三丁基6-溴螺[唍-2,4’-哌啶]-1’-羧酸酯而使用第 三丁基6-溴-3-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯，並取代4,4,5,5-四甲基-2-(4-((甲基硫基)甲基)苯基)-1,3,2-二硼酸酯而使用4,4，5,5-四甲基-2-[4-{(甲基磺醯基)甲基}苯基]-1,3,2-二硼烷，與實施例3之步驟2同樣地進行反應、處理，得到白色非晶形固體之標題化合物(14.0mg，33%)。 Substituting the third butyl 6-bromo snail [ 唍-2,4'-piperidine]-1'-carboxylate using a third butyl 6-bromo-3-hydroxyspiro[ 唍-2,4'-piperidine]-1'-carboxylate and substituted 4,4,5,5-tetramethyl-2-(4-((methylthio)methyl)phenyl) -1,3,2-two Boric acid ester using 4,4,5,5-tetramethyl-2-[4-{(methylsulfonyl)methyl}phenyl]-1,3,2-di The borane was reacted and treated in the same manner as in the step 2 of Example 3 to give the title compound (14.0 mg, 33%).

實施例105第三丁基6-[4-{(甲基磺醯基)甲基}苯基]-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 105 Ternyl 6-[4-{(methylsulfonyl)methyl}phenyl]-3-yloxy snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-溴-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-bromo-3-indolyl snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-3-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯(20.0mg，0.050mmol)溶解於二氯甲烷(0.5mL)，於冰冷下，加入戴斯馬汀氧化劑(31.9mg，0.075mmol)，於室溫下攪拌1小時。於反應液中加水，以醋酸乙酯萃取3次。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=3：1)精製，得到無色油狀物之標題化合物(18.4mg，93%)。 The third butyl 6-bromo-3-hydroxyspiro[ Indole-2,4'-piperidine]-1'-carboxylate (20.0 mg, 0.050 mmol) was dissolved in dichloromethane (0.5 mL). EtOAc (3. ), stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut

1H-NMR(CDCl3)δ：1.47(9H,s),1.62-1.69(2H,m),1.84-1.90(2H,m),3.10-3.30(2H,m),3.58(2H,s),3.90-4.10(2H,m),6.94(1H,d,J=8.5Hz),7.25-7.26(1H,m),7.35(1H,dd,J=1.9,8.5Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.62-1.69 (2H, m), 1.84-1.90 (2H, m), 3.10-3.30 (2H, m), 3.58 (2H, s) , 3.90-4.10 (2H, m), 6.94 (1H, d, J = 8.5 Hz), 7.25-7.26 (1H, m), 7.35 (1H, dd, J = 1.9, 8.5 Hz).

步驟2：第三丁基6-(4-((甲基磺醯基)甲基)苯基)-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl)-3-yloxy snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-溴-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例104之步驟6同樣地進行反應、處理，得到白色淡黃色非晶形之標題化合物(6.50mg，29%)。 Use of a third butyl 6-bromo-3-indolyl snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 6 of Example 104 to give the title compound (6.50 mg, 29%).

實施例106第三丁基4,4-二氘-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 106 Ternylbutyl 4,4-diin-6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-溴-4-氘-4-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-bromo-4-indol-4-hydroxyspiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(100mg，0.27mmol)的甲醇溶液(1.4mL)中，在室溫下緩慢加入氘化硼鈉(11mg，0.27mmol)。攪拌1小時後，加水並以氯仿萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮，得到淡黃色油狀物之粗製生成物(108mg)。 In the third butyl 6-bromo-4-oneoxy snail [ To a solution of hydrazine-2,4'-piperidinyl-1'-carboxylate (100 mg, 0.27 mmol) in methanol (1.4 mL), sodium borohydride (11 mg, 0.27 mmol) was slowly added at room temperature. After stirring for 1 hour, water was added and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and evaporated.

步驟2：第三丁基6-溴-4-氯-4-氘螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-bromo-4-chloro-4-purine snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，在第三丁基6-溴-4-氘-4-羥基螺[唍-2,4’-哌啶]-1’-羧酸酯(d1)(108mg，粗產物)、三乙基胺(75μL，0.54mmol)的無水二氯甲烷溶液(1mL)中，於0℃緩慢加入甲磺醯氯(46mg，0.41mmol)。於室溫下攪拌5小時後，加水並以氯仿萃取。藉無水硫酸鈉乾燥後，減壓濃縮，得到淡黃色油狀物之標題化合物。 In the argon environment, in the third butyl 6-bromo-4-indole-4-hydroxy spiro[ 唍-2,4'-piperidine]-1'-carboxylate (d1) (108 mg, crude product), triethylamine (75 μL, 0.54 mmol) in anhydrous dichloromethane (1 mL) Methanesulfonium chloride (46 mg, 0.41 mmol) was slowly added at °C. After stirring at room temperature for 5 hours, water was added and extracted with chloroform. After drying over anhydrous sodium sulfate,

步驟3：第三丁基6-溴-4,4-二氘螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-bromo-4,4-diindole [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-溴-4-氯-4-氘螺[唍-2,4’-哌啶]-1’-羧酸酯(d1)(86mg，0.21mmol)、氯化鎳6水合物(73mg，0.31mmol)之甲醇(1mL)溶液中，加入氘化硼鈉(39mg，0.93mmol)，於室溫下攪拌1小時。予以濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=10：1)精製，得到白色固體之標題化合物(22mg，28%)。 In the third butyl 6-bromo-4-chloro-4-indole [ Add a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (d1) (86 mg, 0.21 mmol), nickel chloride hexahydrate (73 mg, 0.31 mmol) in methanol (1 mL) Sodium borohydride (39 mg, 0.93 mmol) was stirred at room temperature for 1 hour. The residue was purified by EtOAc EtOAcjjjjjjj

步驟4：第三丁基4,4-二氘-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: Tert-butyl 4,4-diin-6-(4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將第三丁基6-溴-4,4-二氘螺[唍-2,4’-哌啶]-1’-羧酸酯(20mg，0.052mmol)及4,4,5,5-四甲基-2-(4-((甲基磺醯基)甲基)苯基)-1,3,2-二硼烷(23mg，0.078mmol)溶解於1,4-二烷(0.8mL)，加入溶解了碳酸鈉(28mg，0.26mmol)的水溶液(0.2mL)，並加入肆三苯基膦鈀(0)(6mg，0.005mmol)，於90℃攪拌18小時。以醋酸乙酯稀釋反應液，萃取有機層。將有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：醋酸乙酯=6：1)精製，得到白色非晶形之標題化合物(11mg，44%)。 The third butyl 6-bromo-4,4-diindole [ 唍-2,4'-piperidine]-1'-carboxylate (20 mg, 0.052 mmol) and 4,4,5,5-tetramethyl-2-(4-((methylsulfonyl)) Base) phenyl)-1,3,2-di Borane (23mg, 0.078mmol) was dissolved in 1,4-two Alkane (0.8 mL) was added, and aqueous solution (0.2 mL) of sodium carbonate (28 mg, 0.26 mmol) was added, and triphenylphosphine palladium (0) (6 mg, 0.005 mmol) was added and stirred at 90 ° C for 18 hours. The reaction solution was diluted with ethyl acetate and the organic layer was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例107第三丁基4-氟-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 107 Third butyl 4-fluoro-6-(4-((methylsulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((甲基磺醯基)甲基)苯基)-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((methylsulfonyl)methyl)phenyl)-4-yloxy snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代第三丁基6-溴-4,4-二氘螺[唍-2,4’-哌啶]-1’-羧酸酯 而使用第三丁基6-溴-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例106之步驟4同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting tert-butyl 6-bromo-4,4-diindole [ 唍-2,4'-piperidinyl-1'-carboxylate using a third butyl 6-bromo-4-yloxy snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 4 of Example 106 to give the title compound as white crystals.

步驟2：第三丁基4-羥基-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 4-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-(4-((甲基磺醯基)甲基)苯基)-4-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯(121mg，0.25mmol)的甲醇溶液(2.5mL)中，加入氫化硼鈉(10mg，0.25mmol)，於室溫下攪拌1小時。將反應液濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=1：2)精製，得到白色非晶形之標題化合物(121mg，quant)。 In the third butyl 6-(4-((methylsulfonyl)methyl)phenyl)-4-yloxy snail [ To a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (121 mg, 0.25 mmol) in MeOH (2.5 mL), sodium hydride (10 mg, 0.25 mmol). . The reaction mixture was concentrated, and the residue was purified eluting eluting eluting eluting eluting

步驟3：第三丁基4-氟-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 4-fluoro-6-(4-((methylsulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，將第三丁基4-羥基-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.061mmol)的二氯甲烷溶液中，加入Dexo fluor(40μL)，於室溫下攪拌10分鐘。將反應液濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=1：2)精製，得到白色非晶形之標題化合物(22mg，73%)。 Third butyl 4-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl) in an argon atmosphere To a solution of hydrazone-2,4'-piperidinyl-1'-carboxylate (30 mg, 0.061 mmol) in dichloromethane was added EtOAc (40 mL). The reaction mixture was concentrated, and the residue was purified eluted eluted elut elut elut eluting

實施例108第三丁基6-(3-氰基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 108 Ternyl 6-(3-cyano-4-((methylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用5-溴-2-((甲基磺醯 基)甲基)苄腈，與實施例11之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 5-bromo-2-((methylsulfonate) The methyl)benzonitrile was reacted and treated in the same manner as in the step 2 of Example 11 to give the title compound.

實施例109 2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 109 2,2,2-Trichloroethyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：S-4-(螺[唍-2,4’-哌啶]-基)苄基乙硫羥酸酯鹽酸鹽 Step 1: S-4-(Snail [ 唍-2,4'-piperidinyl]-yl)benzyl ethane thiol ester hydrochloride

將實施例76所得之第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(49mg，0.10mmol)溶解於二氯甲烷(0.5mL)，加入4N鹽酸/醋酸乙酯溶液(0.5mL)，於室溫下攪拌4小時。將反應溶液濃縮，得到S-4-(螺[唍-2,4’-哌啶]基)苄基乙硫羥酸酯鹽酸鹽的粗製物。 The third butyl 6-(4-((ethylidenethio)methyl)phenyl) snail obtained in Example 76 唍-2,4'-Piperidine]-1'-carboxylate (49 mg, 0.10 mmol) was dissolved in dichloromethane (0.5 mL), then 4N hydrochloric acid / ethyl acetate (0.5 mL) Stir for 4 hours. The reaction solution was concentrated to obtain S-4-(spiral [ Crude product of indole-2,4'-piperidinyl)benzyl ethane thiol ester hydrochloride.

步驟2：2,2,2-三氯乙基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(4-((ethylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之S-4-(螺[唍-2,4’-哌啶]-基)苄基乙硫羥酸酯鹽酸鹽，與實施例30同樣地進行反應、處理，得到白色固體之標題化合物。 Use the S-4-(snail [[[ Indole-2,4'-piperidinyl]-yl)ethyl thioacetate hydrochloride was reacted and treated in the same manner as in Example 30 to give the title compound.

步驟3：2,2,2-三氯乙基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: 2,2,2-trichloroethyl 6-(4-((ethylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟2所得之2,2,2-三氯乙基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.06mmol)溶解於甲醇(0.3mL)與四氫呋喃(0.3mL)，加入1-碘甲烷(10μL，0.13mmol)與6N氫氧化鈉水溶液(0.05mL)，於室溫下攪拌2小時。於反應液中加水，以醋酸乙酯萃取3次。對有機層以 飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=3：1)精製，得到白色非晶形之標題化合物(22mg，74%)。 2,2,2-trichloroethyl 6-(4-((ethylthio)methyl)phenyl) snail obtained in step 2 Indole-2,4'-piperidine]-1'-carboxylate (30 mg, 0.06 mmol) was dissolved in methanol (0.3 mL) and tetrahydrofuran (0.3 mL). Aqueous sodium hydroxide (0.05 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

步驟4：2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 4: 2,2,2-Trichloroethyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於2,2,2-三氯乙基6-(4-((乙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(21mg，0.040mmol)的二氯甲烷溶液(1mL)中，於0℃緩慢加入間氯過氧苯甲酸(30mg，0.122mmol)，攪拌一晚。加入硫代硫酸鈉水溶液使反應停止，以氯仿萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=1：1)精製，得到白色非晶形之標題化合物(14mg，61%)。 On 2,2,2-trichloroethyl 6-(4-((ethylthio)methyl)phenyl) snail [ To a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (21 mg, 0.040 mmol) in dichloromethane (1 mL), m. m. Stir for one night. The reaction was quenched by the addition of aqueous sodium thiosulfate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例110第三丁基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 110 Thirty butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用5-溴-2-((乙基磺醯基)甲基)-1,3-二氟苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 5-bromo-2-((ethylsulfonyl)methyl)-1,3-difluorobenzene was used instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and Example 11 In the same manner as in the step 2, the title compound was obtained as a white amorphous material.

實施例111 2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 111 2,2,2-Trichloroethyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(4-((Ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例110所得之第三丁基6-(4-((乙基磺醯基)甲 基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail obtained in Example 110 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine] hydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound as white crystals.

實施例112新戊基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 112 neopentyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸新戊酯，與實施例111之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in the step 2 of Example 111, except that the 2,2,2-trichloroethyl chloroformate was used, and the title compound was obtained as white crystals.

實施例113 2,2,2-三氯乙基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 113 2,2,2-Trichloroethyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：2,2,2-三氯乙基6-(4-((異丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: 2,2,2-Trichloroethyl 6-(4-((isopropylthio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代碘乙烷而使用2-碘丙烷，與實施例109之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in the step 3 of Example 109, the title compound was obtained.

步驟2：2,2,2-三氯乙基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之2,2,2-三氯乙基6-(4-((異丙基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟4同樣地進行反應、處理，得到黃色非晶形之標題化合物。 2,2,2-trichloroethyl 6-(4-((isopropylthio)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 4 of Example 109 to give the title compound as a yellow amorphous material.

實施例114新戊基6-[4-{(2-(異丙基磺醯基)甲基)苯基}]螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 114 neopentyl 6-[4-{(2-(isopropylsulfonyl)methyl)phenyl}] spiro[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-[4-{(2-(異丙基磺醯基)甲基)苯基}螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-[4-{(2-(Isopropylsulfonyl)methyl)phenyl} snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例81所得之第三丁基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽粗製物的標題化合物。 The third butyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail obtained in Example 81 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give the title compound.

步驟2：新戊基6-(4-(2-(異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(4-(2-(isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-(2-(異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(10.0mg，0.02mmol)溶解於二氯乙烷(0.5mL)，加入三乙基胺(16.0μL，0.11mmol)、氯甲酸新戊酯(5.1μL，0.03mmol)，於室溫下攪拌24小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：丙酮=100：1)精製，得到白色固體之標題化合物(13.5mg，quant.)。 6-(4-(2-(isopropylsulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine] hydrochloride (10.0 mg, 0.02 mmol) was dissolved in dichloroethane (0.5 mL), triethylamine (16.0 μL, 0.11 mmol), chloroformic acid Amyl ester (5.1 μL, 0.03 mmol) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc)

實施例115第三丁基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 115 tert-butyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用4-溴-2-氟-1-((異丙基磺醯基)甲基)苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 4-bromo-2-fluoro-1-((isopropylsulfonyl)methyl)benzene, and the procedure of Example 11 The reaction was carried out in the same manner, and the title compound was obtained as white crystals.

實施例116 2,2,2-三氯乙基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 116 2,2,2-Trichloroethyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(3-Fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例115所得之第三丁基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail obtained in Example 115 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽，與實施例54同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 54 to give the title compound as white crystals.

實施例117第三丁基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 117 tert-butyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用5-溴-1,3-二氟-2-((異丙基磺醯基)甲基)苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 5-bromo-1,3-difluoro-2-((isopropylsulfonyl)methyl)benzene was used instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and examples Step 2 of Step 11 was carried out in the same manner and the title compound was obtained.

實施例118 2,2,2-三氯乙基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 118 2,2,2-Trichloroethyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(3,5-Difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例117所得之第三丁基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail obtained in Example 117 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine] hydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound as white crystals.

實施例119新戊基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 119 neopentyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸新戊酯，與實施例118之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

實施例120第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 120 Ternyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((乙醯基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((ethylidenethio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例15之步驟1所得的第三丁基6-(5-((羥基甲基) 吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(0.28g，0.69mmol)及三乙基胺(0.13mL，0.90mmol)的四氫呋喃(2.9mL)溶液中，加入甲磺醯氯(48.3μL，0.76mmol)，於室溫下攪拌1小時。濾除析出之鹽，減壓餾除溶媒。將殘渣溶解於二甲基甲醯胺(3.5mL)，加入硫基醋酸S-鉀(0.12g，1.04mmol)，於室溫下攪拌1小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，使用矽膠層析法精製，得到淡黃色固體之標題化合物(0.2g，62%)。 The third butyl 6-(5-((hydroxymethyl)pyridin-2-yl) snail obtained in the first step of Example 15 To a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (0.28 g, 0.69 mmol) and triethylamine (0.13 mL, 0.90 mmol) in tetrahydrofuran (2.9 mL) (48.3 μL, 0.76 mmol), stirred at room temperature for 1 hour. The precipitated salt was filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in dimethylformamide (3.5 mL), and then succinic acid ethyl acetate (0.12 g, 1.04 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc.

1H-NMR(CDCl3)δ：1.47(9H,s),1.54-1.60(2H,m),1.78-1.88(4H,m),2.37(3H,s),2.86(2H,t,J=6.8Hz),3.16-3.32(2H,m),3.78-4.00(2H,m),4.12(2H,s),6.91(1H,d,J=8.8Hz),7.56-7.78(4H,m),8.55(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.54-1.60 (2H, m), 1.78-1.88 (4H, m), 2.37 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.78-4.00 (2H, m), 4.12 (2H, s), 6.91 (1H, d, J = 8.8 Hz), 7.56-7.78 (4H, m), 8.55 (1H, d, J = 2.0 Hz).

步驟2：第三丁基6-(5-((異丙基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((isopropylthio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-(5-((乙醯基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(35mg，0.08mmol)的甲醇(1mL)及四氫呋喃(1mL)溶液中，加入2-碘丙烷(11.2μL，0.11mmol)及1N氫氧化鈉水溶液(0.25mL)，於室溫下攪拌13.5小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，使用矽膠層析法精製，得到白色固體之標題化合物(15.8mg，45%)。 In the third butyl 6-(5-((ethylidenethio)methyl)pyridin-2-yl) snail [ Add 2-iodopropane (11.2 μL, 0.11 mmol) and 1 N to a solution of 唍-2,4'-piperidine]-1'-carboxylate (35 mg, 0.08 mmol) in methanol (1 mL) and THF (1 mL) Aqueous sodium hydroxide (0.25 mL) was stirred at room temperature for 13.5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate

1H-NMR(CDCl3)δ：1.27(6H,d,J=6.4Hz),1.47(9H,s),1.50-1.60(2H,m),1.80-1.88(4H,m),2.74-2.90(3H,m),3.18-3.34(2H,m),3.75(2H,s),3.80-4.00(2H,m),6.92(1H,d,J=8.0Hz),7.62(2H,d,J=8.0Hz),7.66-7.74(2H,m),7.77(1H,d,J=2.4Hz),8.54(1H,d,J=2.0Hz). 1 H-NMR (CDCl 3 ) δ: 1.27 (6H, d, J = 6.4 Hz), 1.47 (9H, s), 1.50-1.60 (2H, m), 1.80-1.88 (4H, m), 2.74-2.90 (3H, m), 3.18-3.34 (2H, m), 3.75 (2H, s), 3.80-4.00 (2H, m), 6.92 (1H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 7.66-7.74 (2H, m), 7.77 (1H, d, J = 2.4 Hz), 8.54 (1H, d, J = 2.0 Hz).

步驟3：第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-(5-((異丙基硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(15.8mg，0.034mmol)的甲醇(0.5mL)及醋酸乙酯(0.5mL)溶液中，加入七鉬酸六銨‧四水合物(8.4mg，0.007mmol)及30%過氧化氫水(68μL)，於室溫下攪拌48小時。於反應液中加水，以氯仿/甲醇(5/1)萃取。對有機層藉無水硫酸鈉乾燥後，減壓濃縮，使用矽膠層析法精製，得到白色固體之標題化合物(15.5mg，91%)。 In the third butyl 6-(5-((isopropylthio)methyl)pyridin-2-yl) snail [ Add hexammonium heptamoate ‧ tetrahydrate to a solution of 唍-2,4'-piperidine]-1'-carboxylate (15.8 mg, 0.034 mmol) in methanol (0.5 mL) and ethyl acetate (0.5 mL) (8.4 mg, 0.007 mmol) and 30% aqueous hydrogen peroxide (68 μL) were stirred at room temperature for 48 hr. Water was added to the reaction mixture, followed by extraction with chloroform / methanol (5 / 1). The organic layer was dried over anhydrous sodium

實施例121 2,2,2-三氯乙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造. Example 121 2,2,2-Trichloroethyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate.

步驟1：6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-((Isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例120所得之第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail obtained in Example 120 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：2,2,2-三氯乙基6-(5-((異丙基磺醯基)甲基)吡啶-2- 基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽之粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽之粗製體，與實施例63同樣地進行反應、處理，得到白色固體之標題化合物。 Using 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine]dihydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of bis-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound.

實施例122新戊基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 122 Neopentyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸新戊酯，與實施例121之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in the step 2 of Example 121, except that the 2,2,2-trichloroethyl chloroformate was used, and the title compound was obtained as white crystals.

實施例123 1-甲基環丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 123 1-Methylcyclopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，加入6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]鹽酸鹽(4mg，0.002mmol)、1-甲基環丙基1H-咪唑-1-羧酸酯(2mg，0.012mmol)、N,N-二異丙基乙胺(30μL)、N,N-二甲基甲醯胺(0.5mL)，於80℃攪拌一晚。加水並以氯仿萃取，藉無水硫酸鈉乾燥後，減壓濃縮，將所得殘渣使用矽膠分取薄層層析法(氯仿：甲醇=50：1)精製，得到白色非晶形之標題化合物(1mg，23%)。 Add 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail under argon atmosphere [ 唍-2,4'-piperidine] hydrochloride (4 mg, 0.002 mmol), 1-methylcyclopropyl 1H-imidazol-1-carboxylate (2 mg, 0.012 mmol), N,N-diisopropyl Ethylethylamine (30 μL), N,N-dimethylformamide (0.5 mL) was stirred at 80 ° C overnight. After adding water and extracting with chloroform, and drying over anhydrous sodium sulfate, EtOAc (EtOAc m. twenty three%).

實施例124 1,1,1-三氟丙烷-2-基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 124 1,1,1-Trifluoropropan-2-yl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-甲基環丙基1H-咪唑-1-羧酸酯而使用1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例123同樣地進行反應、處理，得到淡褐色非晶形之標題化合物。 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazol-1-carboxylate was used instead of 1-methylcyclopropyl 1H-imidazole-1-carboxylate, and examples The title compound was obtained as a pale brown amorphous material.

實施例125第三丁基6-(4-(((2-氟乙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 125 Ternyl 6-(4-(((2-fluoroethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(4-(((2-氟乙基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((2-fluoroethyl))thio)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代1-碘丙烷而使用甲磺酸2-氟乙基酯，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 2-fluoroethyl methanesulfonate was used instead of 1-iodopropane, and the reaction was carried out in the same manner as in the step 1 of Example 77 to give the title compound as white crystals.

步驟2：第三丁基6-(4-(((2-氟乙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Ternyl butyl 6-(4-(((2-fluoroethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(4-(((2-氟乙基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using a third butyl 6-(4-(((2-fluoroethyl))thio)methyl)phenyl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white crystals.

實施例126第三丁基6-(4-(((氰基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 126 tert-butyl 6-(4-(((cyanomethyl)))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((氰基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((cyanomethyl))thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用溴乙腈，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in the step 1 of Example 77.

步驟2：第三丁基6-(4-(((氰基甲基)磺醯基)甲基)苯基)螺[ 唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((cyanomethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-(((氰基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(4-(((cyanomethyl))thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例127第三丁基6-(5-(((氰基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 127 tert-butyl 6-(5-(((cyanomethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：新戊基6-(5-((乙醯基硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Neopentyl 6-(5-((ethylidenethio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例96之步驟1所得之第三丁基6-(5-((羥基甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例120之步驟1同樣地進行反應、處理，得到褐色固體之標題化合物。 The third butyl 6-(5-((hydroxymethyl)pyrimidin-2-yl) snail obtained in the first step of Example 96 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 1 of Example 120 to give the title compound.

步驟2：第三丁基6-(5-(((氰基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((cyanomethyl)thio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-(5-((乙醯基硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(30mg，0.06mmol)的甲醇(0.15mL)及四氫呋喃(0.15mL)溶液中，加入2-溴乙腈(15mg，0.13mmol)及1N氫氧化鈉水溶液(0.05mL)，於室溫下攪拌13.5小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，使用矽膠層析法精製，得到無色油狀物之標題化合物(20mg，67%)。 In the third butyl 6-(5-((ethylidenethio)methyl)pyrimidin-2-yl) snail [ Add 2-bromoacetonitrile (15 mg, 0.13 mmol) to a solution of hydrazine-2,4'-piperidinyl-1'-carboxylate (30 mg, 0.06 mmol) in methanol (0.15 mL) and THF (0.15 mL) A 1N aqueous sodium hydroxide solution (0.05 mL) was stirred at room temperature for 13.5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with EtOAc EtOAc m.

步驟3：第三丁基6-(5-(((氰基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(5-(((cyanomethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(5-(((氰基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到黃色非晶形之標題化合物。 Using the third butyl 6-(5-(((cyanomethyl))thio)methyl)pyrimidin-2-yl) snail obtained in step 2 [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as a yellow crystal.

實施例128 2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 128 2,2,2-Trichloroethyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: 2,2,2-Trichloroethyl 6-(4-((3,3,3-trifluoropropyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代碘乙烷而使用1-碘-3,3,3-三氟丙烷，與實施例109之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in the step 3 of Example 109, the title compound was obtained as white crystals.

步驟2：2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟4同樣地進行反應、處理，得到白色非晶形之標題化合物。 2,2,2-trichloroethyl 6-(4-((3,3,3-trifluoropropyl)thio)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 4 of Example 109 to give the title compound as white white.

實施例129第三丁基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 129 tert-butyl 6-(3-fluoro-4-(((3,3,3-trifluoropropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用4-溴-2-氟-1-(((3,3,3-三氟丙基)磺醯基)甲基)苯，與實施例11之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 4-bromo-2-fluoro-1-((3,3,3-trifluoropropyl)sulfonyl)methyl The benzene was reacted and treated in the same manner as in the step 2 of Example 11 to give the title compound.

1H-NMR(CDCl3)δ：1.48(9H,s),1.51-1.62(2H,m),1.79-1.88 (4H,m),2.56-2.70(2H,m),2.85(2H,t,J=6.8Hz),3.10-3.16(2H,m),3.18-3.31(2H,m),3.80-3.99(2H,m),4.37(2H,s),6.93(1H,d,J=8.7Hz),7.29-7.36(3H,m),7.41(1H,dd,J=1.8,8.2Hz),7.50(1H,d,J=8.2Hz). 1 H-NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.62 (2H, m), 1.79-1.88 (4H, m), 2.56-2.70 (2H, m), 2.85 (2H, t, J=6.8Hz), 3.10-3.16(2H,m), 3.18-3.31(2H,m), 3.80-3.99(2H,m),4.37(2H,s),6.93(1H,d,J=8.7Hz ), 7.29-7.36 (3H, m), 7.41 (1H, dd, J = 1.8, 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz).

實施例130 2,2,2-三氯乙基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 130 2,2,2-Trichloroethyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(3-Fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例129所得之第三丁基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(3-fluoro-4-(((3,3,3-trifluoropropyl))sulfonyl)methyl)phenyl) snail obtained in Example 129 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3-fluoro-4-(((3,3,3-trifluoropropyl))sulfonyl)methyl)phenyl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine] hydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound as white crystals.

實施例131新戊基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 131 Neopentyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例130之步驟1所得之6-(3-氟-4-(((3,3,3-三氟丙 基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物，與實施例114之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(3-Fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail obtained in Step 1 of Example 130. The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in the step 2 of Example 114 to give the title compound as white crystals.

實施例132第三丁基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 132 Ternyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用5-溴-1,3-二氟-2-(((3,3,3-三氟丙基)磺醯基)甲基)苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 5-bromo-1,3-difluoro-2-((3,3,3-trifluoropropyl)sulfonyl Methyl)benzene was reacted and treated in the same manner as in Step 2 of Example 11 to give the title compound as white crystals.

實施例133 2,2,2-三氯乙基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 133 2,2,2-Trichloroethyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(3,5-Difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例132所得之第三丁基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail obtained in Example 132 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶] 鹽酸鹽的粗製物，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine] hydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound as white crystals.

實施例134第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 134 Third butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(((3,3,3-三氟丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((3,3,3-trifluoropropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用1-碘-3,3,3-三氟丙烷，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2-iodopropane and 1-iodo-3,3,3-trifluoropropane, the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

1H-NMR(CDCl3)δ：1.47(9H,s),1.54-1.64(2H,m),1.80-1.88(4H,m),2.28-2.42(2H,m),2.58-2.66(2H,m),2.87(3H,t,J=6.8Hz),3.16-3.32(2H,m),3.75(2H,s),3.80-3.98(2H,m),6.92(1H,d,J=8.8Hz),7.62-7.72(3H,m),7.78(1H,d,J=2.0Hz),8.54(1H,d,J=1.2Hz). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.54-1.64 (2H, m), 1.80-1.88 (4H, m), 2.28-2.42 (2H, m), 2.58-2.66 (2H, m), 2.87 (3H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.75 (2H, s), 3.80-3.98 (2H, m), 6.92 (1H, d, J = 8.8 Hz) ), 7.62 - 7.72 (3H, m), 7.78 (1H, d, J = 2.0 Hz), 8.54 (1H, d, J = 1.2 Hz).

步驟2：第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine 2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-(((3,3,3-三氟丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到淡褐色固體之標題化合物。 Using the third butyl 6-(5-((3,3,3-trifluoropropyl)thio)methyl)pyridin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 2 of Example 85 to give the title compound.

實施例135新戊基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 135 neopentyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-((3,3,3-Trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例134所得之第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 134 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：新戊基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的粗製物以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物，與實施例114之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine]dihydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted in the same manner as in Step 2 of Example 114 to give the title compound.

實施例136 1-甲基環丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 136 1-Methylcyclopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例135之步驟1所得之6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的粗製物，與實施例123同樣地進行反應、處理，得到淡黃色油狀物之標題化合物。 Using 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 of Example 135 [ The crude product of bis-2,4'-piperidine dihydrochloride was reacted and treated in the same manner as Example 123 to give the title compound.

實施例137 1-環丙基乙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 137 1-Cyclopropylethyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-甲基環丙基1H-咪唑-1-羧酸酯而使用1-環丙基乙 基1H-咪唑-1-羧酸酯，與實施例136同樣地進行反應、處理，得到褐色油狀物之標題化合物。 Substituting 1-methylcyclopropyl 1H-imidazole-1-carboxylate for 1-cyclopropylethyl The 1H-imidazole-1-carboxylate was reacted and treated in the same manner as Example 136.

實施例138 1,1,1-三氟丙烷-2-基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 138 1,1,1-Trifluoropropan-2-yl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-甲基環丙基1H-咪唑-1-羧酸酯而使用1,1,1-三氟丙烷-2-基1H-咪唑-1-羧酸酯，與實施例136同樣地進行反應、處理，得到淡黃色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 136 except that 1-methylcyclopropyl 1H-imidazole-1-carboxylate was used instead of 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate. The title compound was obtained as a pale yellow amorphous material.

實施例139第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 139 Thirty butyl 6-(4-(((3-hydroxypropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(4-(((3-羥基丙基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((3-hydroxypropyl))thio)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代1-碘丙烷而使用3-溴-1-丙醇，與實施例77之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

步驟2：第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((3-hydroxypropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((羥基丙基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(4-(((hydroxypropyl))thio)methyl)phenyl) snail obtained in step 1 The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例140第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 140 Ternyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((3-羥基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((3-hydroxypropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用3-溴-1-丙醇，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 3-bromo-1-propanol was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((3,3,3-三氟丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-((3,3,3-trifluoropropyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例141異丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 141 isopropyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinium dihydrochloride

使用實施例140所得之第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 140 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude product of the dihydrochloride salt.

步驟2：異丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Isopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

將步驟1所得之6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的粗製物(10.0mg，0.02mmol)溶解於二氯乙烷(0.5mL)與N,N-二甲基甲醯胺(0.5mL)，加入N,N-二異丙基乙基胺(20μL，0.11mmol)、氯甲酸異丙酯(3.0mg，0.024mmol)，於室溫下攪拌12小時。對反應液減 壓濃縮，將所得殘渣使用矽膠層析法(氯仿：甲醇=9：1)精製，得到白色固體之標題化合物(7mg，63%)。 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 The crude product of 唍-2,4-piperidinium dihydrochloride (10.0 mg, 0.02 mmol) was dissolved in dichloroethane (0.5 mL) and N,N-dimethylformamide (0.5 mL). N,N-Diisopropylethylamine (20 μL, 0.11 mmol), isopropyl chloroformate (3.0 mg, 0.024 mmol) was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj

實施例142異丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 142 Isobutyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

將實施例141之步驟1所得的6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的粗製物(10.0mg，0.02mmol)溶解於N,N-二甲基甲醯胺(0.5mL)，加入N,N-二異丙基乙基胺(20.0μL，0.11mmol)、異丁基1H-1咪唑-1-羧酸酯(9.0mg，0.04mmol)，於80℃下攪拌12小時。將反應液減壓濃縮，將所得殘渣使用矽膠層析法(氯仿：甲醇=9：1)精製，得到白色非晶形之標題化合物(5.0mg，45%)。 The 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in the first step of Example 141 [ The crude product of 唍-2,4-piperidinium dihydrochloride (10.0 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), and N,N-diisopropyl The amine (20.0 μL, 0.11 mmol), isobutyl 1H-1 imidazole-1-carboxylate (9.0 mg, 0.04 mmol) was stirred at 80 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj

實施例143新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 143 neopentyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代氯甲酸異丙酯而使用氯甲酸新戊酯，與實施例141之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The pentyl chloroformate was used, and neopentyl chloroformate was used, and the reaction was carried out in the same manner as in the step 2 of Example 141 to give the title compound as white crystals.

實施例144 1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 144 1-Methylcyclopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1-甲基環丙基1H-咪唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate and using 1-methylcyclopropyl 1H-imidazole-1-carboxylate, the reaction was carried out in the same manner as in Example 142 to give the title compound .

實施例145 1-環丙基乙基6-(5-(((3-羥基丙基)磺醯基)甲基) 吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 145 1-Cyclopropylethyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1-環丙基乙基1H-咪唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate and using 1-cyclopropylethyl 1H-imidazole-1-carboxylate, the reaction was carried out in the same manner as in Example 142 to give the title compound .

實施例146 1,1,1-三氟丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 146 1,1,1-Trifluoropropan-2-yl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1,1,1-三氟丙烷-2-基1H-咪唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 1,1,1-trifluoropropan-2-yl 1H-imidazol-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and the reaction and treatment were carried out in the same manner as in Example 142. White amorphous title compound.

實施例147 1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 147 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazol-1-carboxylate was used in the same manner as in Example 142 except that the isobutyl 1H-imidazole-1-carboxylate was replaced. Reaction and treatment gave the title compound as a white amorphous material.

實施例148(異丙基-d7)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 148 (isopropyl-d7) 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(異丙基-d7)1H-咪唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate, (isopropyl-d7)1H-imidazole-1-carboxylate, and reacting and treating in the same manner as in Example 142 to give the title compound .

實施例149(第三丁基-d9)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 149 (Third butyl-d9) 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(第三丁基-d9)1H-咪 唑-1-羧酸酯，與實施例142同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate for use (t-butyl-d9) 1H-imi The azole-1-carboxylate was reacted and treated in the same manner as in Example 142 to give the title compound as white white.

實施例150第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 150 Ternyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((3-羥基丙基)硫基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((3-hydroxypropyl)thio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-溴乙腈而使用3-溴-1-丙醇，與實施例127之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2-bromoacetonitrile to 3-bromo-1-propanol, the reaction was carried out in the same manner as in the step 2 of Example 127.

步驟2：第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((3-羥基丙基)硫基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((3-hydroxypropyl))thio)methyl)pyrimidin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例151新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 151 neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl)[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]鹽酸鹽的製造 Step 1: 6-(5-(((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidine] hydrochloride

使用實施例150所得之第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail obtained in Example 150 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt.

步驟2：新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-(((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]鹽酸鹽的粗製物以取代6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的粗製物，與實施例143同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail obtained in step 1 The crude product of 唍-2,4-piperidine] hydrochloride is substituted for 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ The crude product of hydrazine-2,4-piperidinium dihydrochloride was reacted and treated in the same manner as in Example 143 to give the title compound as white crystals.

實施例152 1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 152 1-Methylcyclopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl)[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用實施例151之步驟1所得之6-(5-(((3-羥基丙基)磺醯基)甲基)啶啶-2-基)螺[唍-2,4-哌啶]鹽酸鹽，與實施例144同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(5-(((3-hydroxypropyl))sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 of Example 151 The indole-2,4-piperidinyl hydrochloride salt was reacted and treated in the same manner as in Example 144 to give the title compound as white crystals.

實施例153(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 153(R)-Tertibutyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: (R)-Tertiary Butyl 6-(5-(((3-hydroxy-2-methylpropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用(R)-3-溴-2-甲基丙烷-1-醇，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 (R)-3-bromo-2-methylpropan-1-ol was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: (R)-Tertibutyl 6-(5-((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (R)-t-butyl 6-(5-((3-hydroxy-2-methylpropyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例154(R)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 154(R)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：(R)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽的製造 Step 1: (R)-2-methyl-3-(((6-(spiro[ Manufacture of 唍-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)-1-propanol dihydrochloride

使用實施例153之步驟2所得之(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The (R)-t-butyl 6-(5-((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in the second step of Example 153. [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude product of the dihydrochloride salt.

步驟2：(R)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: (R)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之(R)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽的粗製物以取代6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的粗製物，與實施例143同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use (R)-2-methyl-3-((6-(spiro[ a crude product of 唍-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)-1-propanol dihydrochloride to replace 6-(5-((( 3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ The crude product of hydrazine-2,4-piperidinium dihydrochloride was reacted and treated in the same manner as in Example 143 to give the title compound as white crystals.

實施例155(R)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 155(R)-1,1,1-Trifluoropropan-2-yl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridine-2- Snail Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(R)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽，與實施例146同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (R)-2-methyl-3-(((6-(spiro[ Indole-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)-1-propanol dihydrochloride was reacted and treated in the same manner as in Example 146. White amorphous title compound.

實施例156(R)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基 -2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 156(R)-1,1,1-Trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl) Pyridin-2-yl) snail Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代1,1,1-三氟丙烷-2-基1H-咪唑-1-羧酸酯而使用1,1,1-三氟丙烷-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例155同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate and using 1,1,1-trifluoropropane-2-methylpropan-2-yl 1H-imidazol-1- The carboxylic acid ester was reacted and treated in the same manner as in Example 155 to give the title compound as white crystals.

實施例157(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 157(S)-Third butyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: (S)-Tertiary Butyl 6-(5-(((3-hydroxy-2-methylpropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用(S)-3-溴-2-甲基丙-1-醇，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 (S)-3-bromo-2-methylpropan-1-ol was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: (S)-Tertiary Butyl 6-(5-((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (S)-t-butyl 6-(5-(((3-hydroxy-2-methylpropyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例158(S)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 158(S)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(S)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽，與實施例154同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (S)-2-methyl-3-(((6-(spiro[ Indole-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)-1-propanol dihydrochloride was reacted and treated in the same manner as in Example 154. White amorphous title compound.

實施例159(S)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 159(S)-1,1,1-Trifluoropropan-2-yl-6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)pyridine-2- Snail Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(S)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽，與實施例155同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (S)-2-methyl-3-(((6-(spiro[ Indole-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)-1-propanol dihydrochloride was reacted and treated in the same manner as in Example 155. White amorphous title compound.

實施例160(S)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 160(S)-1,1,1-Trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl) Pyridin-2-yl) snail Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用(S)-2-甲基-3-(((6-(螺[唍-2,4’-哌啶]-6-基)吡啶-3-基)甲基)磺醯基)丙-1-醇二鹽酸鹽，與實施例156同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using (S)-2-methyl-3-(((6-(spiro[ Indole-2,4'-piperidinyl]-6-yl)pyridin-3-yl)methyl)sulfonyl)propan-1-ol dihydrochloride was reacted and treated in the same manner as in Example 156. White amorphous title compound.

實施例161第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 161, tert-butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用3-溴-2,2-二甲基-丙-1-醇，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 3-bromo-2,2-dimethyl-propan-1-ol was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)硫基)甲基) 吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例162新戊基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 162 Neopentyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯二鹽酸鹽的製造 Step 1: 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate dihydrochloride

使用實施例161所得之第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 161 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude product of the dihydrochloride salt.

步驟2：新戊基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯二鹽酸鹽的粗製物以取代6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的粗製物，與實施例154同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 a crude product of 唍-2,4-piperidinyl-1'-carboxylate dihydrochloride to replace 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridine-2- Snail The crude product of hydrazine-2,4-piperidinium dihydrochloride was reacted and treated in the same manner as in Example 154 to give the title compound as white white.

實施例163 1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 163 1,1,1-Trifluoropropan-2-yl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl )screw[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯二鹽酸鹽，與實施例155同 樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate dihydrochloride was reacted and treated in the same manner as in Example 155 to give the title compound as white crystals.

實施例164 1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 164 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl) Pyridin-2-yl) snail Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯二鹽酸鹽，與實施例156同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4-piperidinyl-1'-carboxylate dihydrochloride was reacted and treated in the same manner as in Example 156 to give the title compound as white crystals.

實施例165第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 165, Third butyl 6-(5-(((3-methoxypropyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((3-甲氧基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((3-methoxypropyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用1-溴-3-甲氧基丙烷，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2-bromo-3-propane and 1-bromo-3-methoxypropane, the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((3-甲氧基丙基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((3-methoxypropyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例166新戊基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 166 neopentyl 6-(5-(((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[ 唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例165所得之第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 165 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt.

步驟2：新戊基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例143同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl dihydrochloride salt was reacted and treated in the same manner as in Example 143 to give the title compound as white crystals.

實施例167 1,1,1-三氟異丙基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 167 1,1,1-Trifluoroisopropyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例166之步驟1所得之6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例146同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 of Example 166 [ The indole-2,4'-piperidinedihydrochloride salt was reacted and treated in the same manner as in Example 146 to give the title compound as white crystals.

實施例168第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 168, tert-butyl 6-(4-(((3-methyloxetan-3-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((3-methyloxetan-3-yl)methyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

將實施例67之步驟2所得之第三丁基6-(4-溴甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(12mg，0.025mmol)溶解於甲醇 (0.3mL)與四氫呋喃(0.3mL)，加入S-((3-甲基氧雜環丁烷-3-基)乙硫羥酸(6mg，0.037mmol)與4N氫氧化鈉水溶液(0.5mL)，於室溫下攪拌2小時。於反應液中加水，以氯仿萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(正己烷：醋酸乙酯=2：1)精製，得到白色非晶形之標題化合物(14mg，quant.)。 The third butyl 6-(4-bromomethyl)phenyl) snail obtained in the second step of Example 67 [ 唍-2,4'-Piperidine]-1'-carboxylate (12 mg, 0.025 mmol) was dissolved in methanol (0.3 mL) and tetrahydrofuran (0.3 mL). Alkyl-3-yl)ethylthio acid (6 mg, 0.037 mmol) and 4N aqueous sodium hydroxide (0.5 mL) were stirred at room temperature for 2 hr. Water was added to the reaction mixture and extracted with chloroform three times. The extract was washed with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate and evaporated. Compound (14 mg, quant.).

步驟2：第三丁基6-(4-((((3-甲基氧環雜丁烷-3-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Ternyl butyl 6-(4-(((3-(3-(oxy)))))))))))))) Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(4-((((methylthio)))))))))))))) The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white crystals.

實施例169第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 169 tert-butyl 6-(5-(((3-methyloxetan-3-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((3-methyloxetan-3-yl)methyl)thio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用甲磺酸氧雜環丁烷-3-基甲酯，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction product was treated in the same manner as in the step 2 of Example 120, except that 2-iodopropane was used instead of 2-iodopropane.

步驟2：第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)磺 醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((3-methyloxetan-3-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((3-methyloxetan-3-yl)methyl)thio)methyl)pyrimidin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例170第三丁基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 170 Ternyl 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((((四氫呋喃-3-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((((tetrahydrofuran-3-yl)methyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用甲磺酸(四氫呋喃-3-基)甲酯，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl iodide (tetrahydrofuran-3-yl)methyl ester was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120.

步驟2：第三丁基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((((tetrahydrofuran-3-yl)methyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-((((四氫呋喃-3-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-((((tetrahydrofuran-3-yl)methyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例171新戊基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 171 neopentyl 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例170所得之第三丁基6-(5-((((四氫呋喃-3-基) 甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((((tetrahydrofuran-3-yl)methyl))sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 170 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：新戊基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-(((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例143同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-(((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 The indole-2,4'-piperidinyl dihydrochloride salt was reacted and treated in the same manner as in Example 143 to give the title compound as white crystals.

實施例172 1,1,1-三氟異丙基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 172 1,1,1-Trifluoroisopropyl 6-(5-((((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例171之步驟1所得之6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例146之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-(((tetrahydrofuran-3-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 of Example 171 [ The indole-2,4'-piperidinyl dihydrochloride salt was reacted and treated in the same manner as in the step 1 of Example 146 to give the title compound as white crystals.

實施例173第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 173, tert-butyl 6-(5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用甲磺酸(四氫-2H-哌喃-4-基)甲酯，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methanesulfonic acid (tetrahydro-2H-pyran-4-yl)methyl ester was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120.

步驟2：第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((tetrahydro-2H-piperidin-4-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯二鹽酸鹽，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate dihydrochloride was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例174第三丁基6-(4-(((3-胺基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 174 Third butyl 6-(4-((3-aminopropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((3-溴丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((3-bromopropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例139所得之第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(28mg，0.05mmol)、四溴化碳(20mg，0.06mmol)、三苯基膦(20mg，0.08mmol)中，加入二氯甲烷(1mL)，室溫下攪拌整夜。將反應液濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(17mg，59%)。 The third butyl 6-(4-(((3-hydroxypropyl)))sulfonyl)methyl)phenyl) sulphate obtained in Example 139 Indole-2,4'-piperidine]-1'-carboxylate (28 mg, 0.05 mmol), carbon tetrabromide (20 mg, 0.06 mmol), triphenylphosphine (20 mg, 0.08 mmol) Methane (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, EtOAcjjjjjjjjjj

步驟2：第三丁基6-(4-(((3-疊氮基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(4-((3-azidopropyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，於第三丁基6-(4-(((3-溴丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(15mg，0.03mmol)、疊氮化鈉(7mg，0.10mmol)中，加入無水N,N-二甲基甲醯胺 (0.5mL)，攪拌整夜。於反應液中加水，以醋酸乙酯萃取。藉無水硫酸鈉乾燥後，減壓濃縮，得到淡黃色油狀物之標題化合物(14mg，粗產物)。 In the argon atmosphere, in the third butyl 6-(4-(((3-bromopropyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (15 mg, 0.03 mmol), sodium azide (7 mg, 0.10 mmol), anhydrous N,N-dimethylformamide (0.5) mL), stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The title compound (14 mg, crude)

步驟3：第三丁基6-(4-(((3-胺基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Third butyl 6-(4-((3-aminopropyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於第三丁基6-(4-(((3-疊氮基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(14mg，粗產物)、三苯基膦(13mg，0.03mmol)中’加入四氫呋喃(1mL)、水(0.3mL)，室溫下攪拌一夜。將反應液濃縮，將所得殘渣使用矽膠分取薄層層析法(氯仿：甲醇=20：1)精製，得到無色結晶之標題化合物(11mg，81%)。 In the third butyl 6-(4-((3-azidopropyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate (14 mg, crude product), triphenylphosphine (13 mg, 0.03 mmol), THF (1 mL), water (0.3 mL), room temperature Stir under night. The reaction mixture was concentrated, and the residue was purified eluted eluted elut elut elut elut elut elut elut elut

實施例175(S)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 175(S)-Tertiary Butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例174之步驟1所得之第三丁基6-(4-(((3-溴丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(16mg，0.028mmol)的二氯甲烷溶液(2.5mL)中，加入三乙基胺(12μL，0.083mmol)與(S)-(+)-3-氟吡咯啶鹽酸鹽(5mg，0.041mmol)，於室溫下攪拌一夜。將反應液濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=2：1)精製，得到淡黃色固體之標題化合物(6mg，35%)。 The third butyl 6-(4-(((3-(bromopropyl)))sulfonyl)methyl)phenyl) snail obtained in the first step of Example 174 To a solution of 唍-2,4'-piperidine]-1'-carboxylate (16 mg, 0.028 mmol) in dichloromethane (2.5 mL), triethylamine (12 μL, 0.083 mmol) and (S)- (+)-3-Fluoropyridinium hydrochloride (5 mg, 0.041 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was crystalljjjjjjjjjjjjjjjj

實施例176(R)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 176(R)-Third-butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(S)-(+)-3-氟吡咯啶鹽酸鹽而使用(R)-(-)-3-氟吡咯啶鹽酸鹽，與實施例175同樣地進行反應、處理，得到淡黃色固體之標題化合物。 (R)-(-)-3-fluoropyrrolidine hydrochloride was used instead of (S)-(+)-3-fluoropyrrolidine hydrochloride, and the reaction and the treatment were carried out in the same manner as in Example 175 to give a pale yellow color. The title compound of the solid.

實施例177第三丁基6-(4-(((3-(3,3-二氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 177 tert-butyl 6-(4-((3-(3,3-difluoropyrrolidin-1-yl)propyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(S)-(+)-3-氟吡咯啶鹽酸鹽而使用3,3-二氟吡咯啶鹽酸鹽，與實施例175同樣地進行反應、處理，得到淡黃色固體之標題化合物。 The (S)-(+)-3-fluoropyrrolidine hydrochloride was used, and 3,3-difluoropyrrolidine hydrochloride was used, and the title compound was obtained as a pale yellow solid.

實施例178第三丁基6-(4-(((甲基磺醯基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 178 Third butyl 6-(4-(((methylsulfonyl)propyl)))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例174之步驟1所得之第三丁基6-(4-(((3-溴丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(10mg，0.017mmol)之=甲基亞碸溶液(1mL)中，加入甲亞磺酸鈉(5mg，0.052mmol)，於l20℃攪拌25分鐘。於反應液中加水，以醋酸乙酯萃取。將有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=1：3)精製，得到白色固體之標題化合物(3mg，33%)。 The third butyl 6-(4-(((3-(bromopropyl)))sulfonyl)methyl)phenyl) snail obtained in the first step of Example 174 To a solution of 唍-2,4'-piperidine]-1'-carboxylate (10 mg, 0.017 mmol) = methyl hydrazine solution (1 mL), sodium methanesulfinate (5 mg, 0.052 mmol) was added at l20 Stir at °C for 25 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel chromatography eluting elut elut elut elut elut

實施例179第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 179 Thirty butyl 6-(4-(((4-methoxy-4-yloxybutyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((4-methoxy-4-oxobutyl)butyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用4-溴丁酸甲酯，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-((4-methoxy-4-oxobutyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯二鹽酸鹽，與實施例85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-(((4-methoxy-4-yloxy)butyl))))))))) The indole-2,4'-piperidinyl-1'-carboxylate dihydrochloride was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例180 4-(((4-(1’-第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)丁酸的製造 Example 180 4-(((4-(1'-T-Butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)butyric acid

將實施例179所得之第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(17mg，0.03mmol)溶解於甲醇(1.0mL)與四氫呋喃(2.0mL)，加入4N氫氧化鈉水溶液(0.1ml)，室溫下攪拌20分鐘。對反應液以二乙基醚洗淨後，加入1N鹽酸直到成為pH4，以氯仿萃取3次。將有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，得到白色固體之標題化合物(13mg，quant.)。 The third butyl 6-(4-((4-methoxy-4-oxobutyl)sulfonyl)methyl)phenyl) snail obtained in Example 179. 唍-2,4'-Piperidine]-1'-carboxylate (17 mg, 0.03 mmol) was dissolved in methanol (1.0 mL) and tetrahydrofuran (2.0 mL). Stir under 20 minutes. After the reaction solution was washed with diethyl ether, 1N hydrochloric acid was added until pH 4 and extracted with chloroform three times. The organic layer was washed with EtOAc EtOAc EtOAc.

實施例181第三丁基6-(4-(((4-胺基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 181 tert-butyl 6-(4-(((4-amino-4-yloxybutyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例180所得之4-(((4-(1’-第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)丁酸(6mg，0.011mmol)之二氯 甲烷溶液(1.5mL)中，加入WSCD‧HCl(3mg，0.013mmol)、氨水溶液(0.1mL)與N,N-二甲基-4-胺基吡啶(觸媒量)，攪拌2小時。於反應液中加水，以氯仿萃取3次。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠分取薄層層析法(氯仿：甲醇=10：1)精製，得到白色固體之標題化合物(1mg，18%)。 4-(((4-(1'-)-t-butoxycarbonyl) snail obtained in Example 180 [ 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)butyric acid (6 mg, 0.011 mmol) in dichloromethane (1.5 mL), WSCD HCl (3 mg, 0.013 mmol) Aqueous ammonia solution (0.1 mL) and N,N-dimethyl-4-aminopyridine (catalyst amount) were stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

實施例182第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 182 tert-butyl 6-(4-(((1-ethoxy-2-methyl-1-yloxypropan-2-yl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((1-ethoxy-2-methyl-1-yloxypropan-2-yl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用2-溴-2-甲基丙酸，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: tert-butyl 6-(4-((1-ethoxy-2-methyl-1-yloxypropan-2-yl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到無色油狀物之標題化合物。 The third butyl 6-(4-(((1-ethoxy-2-methyl-1-yloxypropan-2-yl))thio)methyl)phenyl) snail obtained in Step 1 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound.

實施例183乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 183 ethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例84所得之第三丁基6-(4-((苄基磺醯基)甲基) 苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例28同樣地進行反應、處理，得到白色非晶形之標題化合物。 The third butyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail obtained in Example 84 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Example 28 to give the title compound as white crystals.

實施例184 2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 184 2,2,2-Trichloroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯而使用氯甲酸2,2,2-三氯乙酯，與實施例183同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m. m.

實施例185異丙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 185 isopropyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯而使用氯甲酸異丙酯，與實施例183同樣地進行反應、處理，得到白色固體之標題化合物。 The ethyl chloroformate was used instead of ethyl chloroformate, and the title compound was obtained as a white solid.

實施例186 2,2,2-三氟乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 186 2,2,2-Trifluoroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽，與實施例29同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 29 to give the title compound as white crystals.

實施例187 1-環丙基乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 187 1-Cyclopropylethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用1-環丙基乙基1H-咪唑-1-羧酸酯，與實施例186同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 186 except that 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate was used instead of 1-cyclopropylethyl 1H-imidazol-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例188 3,3,4,4,4-五氟丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 188 3,3,4,4,4-pentafluorobutyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，於3,3,4,4,4-五氟丁醇(7.4mg，0.045mmol)、三光氣(4.5mg，0.0l5mmol)的無水二氯甲烷溶液(0.2mL)中，在0℃滴下N,N-二異丙基乙基胺(16μL，0.090mmol)，攪拌30分鐘。於0℃加入6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶](10.0mg，0.021mmol)，再攪拌30分鐘。加水使反應停止，以氯仿萃取。藉無水硫酸鈉乾燥後，減壓濃縮，將所得殘渣使用矽膠分取薄層層析法(氯仿：醋酸乙酯=4：1)精製’得到白色非晶形之標題化合物(4.3mg，33%)。 In an argon atmosphere, in a solution of 3,3,4,4,4-pentafluorobutanol (7.4 mg, 0.045 mmol), triphosgene (4.5 mg, 0.015 mmol) in anhydrous dichloromethane (0.2 mL) N,N-Diisopropylethylamine (16 μL, 0.090 mmol) was added dropwise at 0 ° C and stirred for 30 min. Add 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail at 0 °C Indole-2,4'-piperidine] (10.0 mg, 0.021 mmol) was stirred for additional 30 min. Water was added to stop the reaction and extracted with chloroform. After drying over anhydrous sodium sulfate, the title compound was obtained (yield: EtOAc, EtOAc) .

實施例189 1,1,1-三氟丙烷-2-基6-[4-((吡啶-4-基甲基)磺醯基)甲基]苯基]螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 189 1,1,1-Trifluoropropan-2-yl 6-[4-((pyridin-4-ylmethyl)sulfonyl)methyl]phenyl] snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用1,1,1-三氟丙-2-醇，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 188, the title compound was obtained as a white crystals, m.p.

實施例190 1,1,1-三氟-2-甲基丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 190 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例186同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate and using 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate, The reaction and the reaction were carried out in the same manner as in Example 186 to give the title compound as white crystals.

實施例191 1,1,1,3,3,3-六氟丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 191 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用1,1,3,3,3-五氟丙-2-醇，與 實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 Instead of 3,3,4,4,4-pentafluorobutanol, 1,1,3,3,3-pentafluoropropan-2-ol is used, Example 188 was reacted and treated in the same manner to give the title compound as white crystals.

實施例192 1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 192 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4-((benzylsulfonyl)methyl)phenyl) screw[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用1,1,1,3,3,3-六氟-2-(三氟甲基)丙-2-醇，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol was used instead of 3,3,4,4,4-pentafluorobutanol, and Example 188 The reaction was carried out in the same manner to give the title compound as white white crystals.

實施例193(乙基-d5)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 193 (ethyl-d5) 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用(乙基-d5)1H-咪唑-1-羧酸酯，與實施例186同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate and using (ethyl-d5)1H-imidazol-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 186. White amorphous title compound.

實施例194(異丙基-d7)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 194 (isopropyl-d7) 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用(異丙基-d7)1H-咪唑-1-羧酸酯，與實施例186同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 186 except that 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate was used instead of (isopropyl-d7)1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例195(第三丁基-d9)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 195 (Third butyl-d9) 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2,2,2-三氟乙基1H-咪唑-1-羧酸酯而使用(第三丁基-d7)1H-咪唑-1-羧酸酯，與實施例186同樣地進行反應、處 理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 186 except that 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate was used instead of (t-butyl-d7)1H-imidazol-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例196(1,1,1,3,3,3-六氟丙烷-2-基-2-d1)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 196 (1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用1,1,1,3,3,3-六氟-2-丙醇-d1，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 188 except that 1,1,1,3,3,3-hexafluoro-2-propanol-d1 was used instead of 3,3,4,4,4-pentafluorobutanol. The title compound was obtained as a white amorphous material.

實施例197(三甲基矽基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 197 (trimethylsulfonyl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用(三甲基矽基)甲醇，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 188, the title compound was obtained as white crystals.

實施例198(1-(第三丁氧基羰基)哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 198 (1-(Tertibutoxycarbonyl)piperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用第三丁基4-(羥基甲基)哌啶-1-羧酸酯，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 The third butyl 4-(hydroxymethyl)piperidine-1-carboxylate was replaced with 3,3,4,4,4-pentafluorobutanol, and reacted and treated in the same manner as in Example 188 to obtain white. Amorphous title compound.

實施例199(1-甲基哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 199 (1-methylpiperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：哌啶-4-基甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Piperidin-4-ylmethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於(1-第三丁氧基羰基)哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的之二氯甲烷溶液 (1mL)中，加入4N-鹽酸-醋酸乙酯(1mL)，室溫下攪拌一夜。加入醋酸乙酯，過濾沉澱物，得到哌啶-4-基甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯鹽酸鹽的粗製物。 (1-tert-butoxycarbonyl)piperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ To a solution of hydrazine-2,4'-piperidinyl-1'-carboxylate (1 mL) was added 4N-hydrochloride-ethyl acetate (1 mL). Ethyl acetate was added and the precipitate was filtered to give piperidin-4-ylmethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Crude product of indole-2,4'-piperidinyl-1'-carboxylate hydrochloride.

步驟2：(1-甲基哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: (1-Methylpiperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，於哌啶-4-基甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯鹽酸鹽(24mg，0.039mmol)、三聚甲醛(12mg，0.39mmol)中，加入1,2-二氯乙烷(0.5mL)與甲醇(0.5mL)，於室溫攪拌10分鐘後，加入三乙醯氧基硼化鈉(82mg，0.39mmol)，攪拌一夜。將反應液濃縮，並將所得殘渣使用矽膠分取薄層層析法(氯仿：氨甲醇=30：1)精製，得到淡黃色非晶形之標題化合物(16mg，66%)。 In the argon atmosphere, piperidin-4-ylmethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate hydrochloride (24 mg, 0.039 mmol), trioxane (12 mg, 0.39 mmol), 1,2-dichloroethane (0.5 mL) After stirring with methanol (0.5 mL) at room temperature for 10 min, sodium triethyl sulfoxide (82 mg, 0.39 mmol) was added and stirred overnight. The reaction mixture was concentrated, and the residue was purified eluted eluted elut elut elut elut elut elut elut

實施例200 4-異丙基苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 200 4-isopropylbenzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4，4，4-五氟丁醇而使用4-異丙基苄基醇，與實施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the same procedure as in Example 188, using 3- propyl benzyl alcohol.

實施例201 4-(第三丁基)苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 201 4-(Tertiary Butyl)benzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代3,3,4,4,4-五氟丁醇而使用4-(第三丁基)苄基醇，與實 施例188同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 3,3,4,4,4-pentafluorobutanol and using 4-(t-butyl)benzyl alcohol, In the same manner as in Example 188, the title compound was obtained as white crystals.

實施例202 2-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 202 2-Chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯而使用氯甲酸2-氯苯酯，與實施例183同樣地進行反應、處理，得到白色固體之標題化合物。 The ethyl chloroformate was used instead of 2-chlorophenyl chloroformate, and the title compound was obtained as a white solid.

實施例203 4-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 203 4-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸乙酯而使用氯甲酸4-氯苯酯，與實施例183同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used instead of ethyl chloroformate, and the title compound was obtained as white white crystals.

實施例204第三丁基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 204 Ternyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用1-((苄基磺醯基)甲基)-4-溴-2-氟苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 1-((benzylsulfonyl)methyl)-4-bromo-2-fluorobenzene, and step 2 of Example 11 The reaction was carried out in the same manner to give the title compound as white white crystals.

實施例205 2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 205 2,2,2-Trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-((苄基磺醯基)甲基)-3-氯苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯鹽酸鹽的製造 Step 1: 6-(4-((Benzylsulfonyl)methyl)-3-chlorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate hydrochloride

使用實施例204所得之第三丁基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail obtained in Example 204 was used. The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於步驟1所得之6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯鹽酸鹽(16mg，0.028mmol)的二氯甲烷(1.0mL)溶液中，加入三乙基胺(20μL，0.14mmol)、氯甲酸2,2,2-三氯乙酯(5.0μL，0.034mmol)，於室溫攪拌12小時。將反應液濃縮，並將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：3)精製’得到白色非晶形之標題化合物(9mg，50%)。 6-(4-((Benzylsulfonyl)methyl)-3-fluorophenyl) snail obtained in step 1 To a solution of 唍-2,4'-piperidine]-1'-carboxylate hydrochloride (16 mg, 0.028 mmol) in dichloromethane (1.0 mL), triethylamine (20 μL, 0.14 mmol) 2,2,2-Trichloroethyl formate (5.0 μL, 0.034 mmol) was stirred at room temperature for 12 h. The reaction mixture was concentrated, and EtOAc mjjjjjjjjj

實施例206新戊基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 206 neopentyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸新戊酯，與實施例205同樣地進行反應、處理，得到淡黃色油狀物之標題化合物。 The title compound was obtained as a pale yellow oil, m.p.

實施例207第三丁基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 207 tert-butyl 6-(4-((benzylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用2-{(苄基磺醯基)甲基}-5-溴-1,3-二氟苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 2-{(benzylsulfonyl)methyl}-5-bromo-1,3-difluorobenzene was used instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and Example 11 In the same manner as in the step 2, the title compound was obtained as a white amorphous material.

實施例208 2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 208 2,2,2-Trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’- 哌啶]鹽酸鹽，與實施例205同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-((benzylsulfonyl)methyl)-3,5-difluorophenyl) snail [ Indole-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 205 to give the title compound as white crystals.

實施例209第三丁基6-(5-((苄基磺醯基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯的製造 Example 209 tert-butyl 6-(5-((benzylsulfonyl)methyl)pyridin-2-yl) snail ( Manufacture of 唍-2,4'-piperidine)-1'-carboxylate

步驟1：第三丁基6-(5-((苄基硫基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((benzylthio)methyl)pyridin-2-yl) snail ( Manufacture of 唍-2,4'-piperidine)-1'-carboxylate

取代2-碘丙烷而使用溴化苄基，與實施例120之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The benzyl bromide was used instead of 2-iodopropane, and the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound.

步驟2：第三丁基6-(5-((苄基磺醯基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((benzylsulfonyl)methyl)pyridin-2-yl) snail ( Manufacture of 唍-2,4'-piperidine)-1'-carboxylate

使用步驟1所得之第三丁基6-(5-((苄基硫基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯，與實施例86之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(5-((benzylthio)methyl)pyridin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 2 of Example 86 to give the title compound.

實施例210第三丁基6-(5-((苄基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 210 Ternyl 6-(5-((benzylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((苄基硫基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((benzylthio)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於實施例100之步驟2所得的第三丁基6-(N’-羥基甲脒基)螺[唍-2,4’-哌啶]-1’-羧酸酯鹽酸鹽(30mg，0.083mmol)的四氬呋喃(2.0mL)溶液中，加入2-(苄基硫基)醋酸(17mg，0.091mmol)、N,N-二異丙基乙基胺(29μL，0.17mmol)、WSCD‧HCl(19mg，0.1mmol)與1-羥基苯并***(13mg， 0.1mmol)，於室溫下攪拌24小時後，餾除溶媒。於所得殘渣中加入甲苯(0.5mL)，加熱迴流6小時。餾除甲苯後，將殘渣使用矽膠層析法(正己烷：醋酸乙酯=3：1)精製，得到無色油狀物之標題化合物(21mg，50%)。 The third butyl 6-(N'-hydroxymethyl fluorenyl) snail obtained in the second step of Example 100 [ To a solution of 唍-2,4'-piperidine]-1'-carboxylate hydrochloride (30 mg, 0.083 mmol) in tetrabromofuran (2.0 mL), 2-(benzylthio)acetic acid (17 mg, 0.091 mmol), N,N-diisopropylethylamine (29 μL, 0.17 mmol), WSCD HCl (19 mg, 0.1 mmol) and 1-hydroxybenzotriazole (13 mg, 0.1 mmol) at room temperature After stirring for 24 hours, the solvent was distilled off. Toluene (0.5 mL) was added to the residue, and the mixture was refluxed for 6 hr. After the toluene was distilled off, the residue was purified eluted eluted elut elut elut elut elut elut elut

步驟2：第三丁基6-(5-((苄基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((benzylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-((苄基硫基)甲基)-1,2,4-二唑-3-基))螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(5-((benzylthio)methyl)-1,2,4- obtained in step 1 Diazol-3-yl)) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例211第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 211 tert-butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(2-((乙醯基硫基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(2-((ethylidenethio)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，於實施例99之步驟2所得的第三丁基6-(2-(((甲基磺醯基)氧基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯(135mg，0.27mmol)的無水N,N-二甲基甲醯胺溶液(1mL)中，加入硫醋酸鉀(90mg，0.79mmol)，於室溫攪拌1小時。加水使反應停止，以醋酸乙酯萃取。藉無水硫酸鈉乾燥後，減壓濃縮，將所得殘渣使用矽膠分取薄層層析法(己烷：醋酸乙酯=2：1)精製，得到褐色非晶形之標題化合物(69mg，44%)。 The third butyl 6-(2-(((methylsulfonyl)oxy)methyl)thiazol-5-yl) snail obtained in Step 2 of Example 99 under argon atmosphere [ Potassium thioacetate (90 mg, 0.79 mmol) was added to a solution of hydrazine-2,4'-piperidine]-1'-carboxylate (135 mg, 0.27 mmol) in anhydrous N,N-dimethylformamide (1 mL). ), stirred at room temperature for 1 hour. Water was added to stop the reaction and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the title compound (mjjjjjjjj .

步驟2：第三丁基6-(2-((苄基硫基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(2-((benzylthio)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(2-((乙醯基硫基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例209之步驟1同樣地進行反應、處理，得到黃色油狀物之標題化合物。 Using the third butyl 6-(2-((ethylidenethio)methyl)thiazol-5-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 1 of Example 209.

步驟3：第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 3: Tert-butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟2所得之第三丁基6-(2-((苄基硫基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(2-((benzylthio)methyl)thiazol-5-yl) snail obtained in step 2 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例212 2,2,2-三氯乙基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造步驟1：6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Example 212 2,2,2-Trichloroethyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Process for the preparation of 唍-2,4'-piperidine]-1'-carboxylate 1:6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用實施例Dt所得之第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail obtained using Example Dt The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]鹽酸鹽之粗製物，與實施例205同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail obtained in step 1 The crude product of hydrazine-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 205 to give the title compound as white crystals.

實施例213新戊基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 213 neopentyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸新戊酯，與實施例212同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 212, and the title compound was obtained as white white crystals.

實施例214第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 214 Thirty butyl 6-(4-(((4-)fluoro))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((4-氟苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((4-fluorobenzyl))thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用1-(溴甲基)-4-氟苯，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in the step 1 of Example 77, 1-(bromomethyl)-4-fluorobenzene was used, and the title compound was obtained as white crystals.

步驟2：第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((4-(4-(4-(4-(yl)))))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-(((4-氟苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using a third butyl 6-(4-(((4-fluorobenzyl))thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例215 1,1,1-三氟丙烷-2-基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 215 1,1,1-Trifluoropropan-2-yl 6-(4-(((4-fluorobenzyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(4-(((4-(4-(4-(4-(yl))))))) Manufacture of 唍-2,4'-piperidine] hydrochloride

使用第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[ 唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 Use of tert-butyl 6-(4-(((4-(4-(4-(4-(yl)))))))))))) The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：1,1,1-三氟丙烷-2-基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 1,1,1-Trifluoropropan-2-yl 6-(4-(((4-fluorobenzyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽，與實施例189同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-(((4-fluorobenzyl))sulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 189 to give the title compound as white crystals.

實施例216第三丁基6-(5-(((4-氟苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 216, tert-butyl 6-(5-(((4-fluorobenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((4-氟苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((4-fluorobenzyl))thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用1-(溴甲基)-4-氟苯，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in the step 2 of Example 120, 1-(bromomethyl)-4-fluorobenzene was used instead of 2-iodopropane, and the title compound was obtained as white crystals.

步驟2：第三丁基6-(5-(((4-氟苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((4-fluorobenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((4-氟苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((4-fluorobenzyl))thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例217第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 217 tert-butyl 6-(4-(((4-(trifluoromethyl)benzyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((4-((三氟甲基)苄基)硫基)甲基)苯基) 螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((4-((trifluoromethyl)benzyl))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用1-(溴甲基)-4-(三氟甲基)苄，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained in the same manner as in the step 1 of Example 77, using 1-(bromomethyl)-4-(trifluoromethyl)benzyl.

步驟2：第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((4-(trifluoromethyl)benzyl)))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(4-(((4-(三氟甲基)苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例3之步驟3同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(4-(((4-(trifluoromethyl)benzyl))))))))) The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 3 of Example 3 to give the title compound as white white.

實施例218 1,1,1-三氟丙烷-2-基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 218 1,1,1-Trifluoropropan-2-yl 6-(4-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的製造 Step 1: 6-(4-((4-(Trifluoromethyl)benzyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] hydrochloride

使用第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 Use of tert-butyl 6-(4-(((4-(trifluoromethyl))benzyl)sulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude salt of the hydrochloride salt.

步驟2：1,1,1-三氟丙烷-2-基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 1,1,1-Trifluoropropan-2-yl 6-(4-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽，與實施例189同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-(((4-(trifluoromethyl)benzyl))sulfonyl)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 189 to give the title compound as white crystals.

實施例219第三丁基6-(5-(((4-(三氟甲基)苄基)磺醯基)甲 基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 219 tert-butyl 6-(5-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((4-(三氟甲基)苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((4-(trifluoromethyl)benzyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用1-(溴甲基)-4-(三氟甲基)苯，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the title compound (1) (2-(bromomethyl)-4-(trifluoromethyl)benzene.

步驟2：第三丁基6-(5-(((4-(三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用第三丁基6-(5-(((4-(三氟甲基)苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-((4-(trifluoromethyl)benzyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例220第三丁基6-(5-(((2-甲基苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 220 Ternyl 6-(5-(((2-methylbenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(((2-甲基苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((2-methylbenzyl))thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用1-(溴甲基)-2-甲基苯，與實施例120之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(5-(((2-甲基苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((2-methylbenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-(((2-甲基苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地 進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((2-methylbenzyl))thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例221第三丁基6-(5-((((2-三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 221 tert-butyl 6-(5-(((2-)trifluoromethyl)benzyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((((2-三氟甲基)苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((2-)trifluoromethyl)benzyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用1-(溴甲基)-2-(三氟甲基)苯，與實施例120之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oil. m. m.

步驟2：第三丁基6-(5-((((2-三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((2-trifluoromethyl)benzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-((((2-三氟甲基)苄基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use of tert-butyl 6-(5-(((2-)trifluoromethyl)benzyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例222 4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Example 222 4-(((()-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

步驟1：4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸的製造 Step 1: 4-((((4'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)thio)methyl)benzoic acid

取代1-碘丙烷而使用4-(溴甲基)苯甲酸甲酯，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 1-iodopropane and using methyl 4-(bromomethyl)benzoate, the reaction was carried out in the same manner as in the step 1 of Example 77 to give the title compound as white crystals.

步驟2：4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Step 2: 4-((((3'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

使用4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use 4-((((3'-(T-butoxycarbonyl)) snail [ 唍-2,4'-Piperidine]-6-yl)benzyl)thio)methyl)benzoic acid was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例223 3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Example 223 3-((((4'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

步驟1：3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸的製造 Step 1: 3-((((3'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)thio)methyl)benzoic acid

取代1-碘丙烷而使用3-(溴甲基)苯甲酸甲酯，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl 3-(bromomethyl)benzoate was used instead of 1-iodopropane, and the reaction was carried out in the same manner as in the step 1 of Example 77 to give the title compound.

步驟2：3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Step 2: 3-((((3'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

使用3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 3-((((((((((((((((((( 唍-2,4'-Piperidine]-6-yl)benzyl)thio)methyl)benzoic acid was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例224 2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Example 224 2-(((()-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

步驟1：2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸的製造 Step 1: 2-((((3'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)thio)methyl)benzoic acid

取代1-碘丙烷而使用2-(溴甲基)苯甲酸甲酯，與實施例77之步驟1同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 1-iodopropane and using methyl 2-(bromomethyl)benzoate, the reaction was carried out in the same manner as in the step 1 of Example 77 to give the title compound as white crystals.

步驟2：2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸的製造 Step 2: 2-((((3'-(T-butoxycarbonyl)) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid

使用2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)硫基)甲基)苯甲酸，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 2-((((3'-(T-butoxycarbonyl)) snail [ 唍-2,4'-Piperidine]-6-yl)benzyl)thio)methyl)benzoic acid was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例225第三丁基6-(4-(((4-(甲基磺醯基)苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 225, Ternyl 6-(4-(((4-(methylsulfonyl)benzyl))))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代碘化丙基而使用1-(溴甲基)-4-(甲基磺醯基)苯，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oil, m. m.

實施例226第三丁基6-(4-(((4-(甲基磺醯基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 226 Ternyl 6-(4-(((4-(methylsulfonyl)))))))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例225所得之第三丁基6-(4-(((4-(甲基磺醯基)苄基)硫基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The third butyl 6-(4-(((4-(methylsulfonyl))benzyl)))))))))) The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例227甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 227 methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例85所得之第三丁基6-(4-((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例 109之步驟1同樣地進行反應、處理，得到二鹽酸鹽的粗製物。 The third butyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail obtained in Example 85 was used. The indole-2,4'-piperidine]-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟1所得之6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽(10.0mg，0.022mmol)溶解於二氯乙烷(0.2mL)中，加入N,N-二異丙基乙基胺(20μL，0.11mmol)、氯甲酸甲酯(3mg，0.033mmol)，於室溫攪拌12小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：醋酸乙酯=4：1)精製，得到白色非晶形之標題化合物(9.0mg，83%)。 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail obtained in step 1 唍-2,4'-piperidine]dihydrochloride (10.0 mg, 0.022 mmol) was dissolved in dichloroethane (0.2 mL), and N,N-diisopropylethylamine (20 μL, 0.11 mmol) Methyl chloroformate (3 mg, 0.033 mmol) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

實施例228乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 228 ethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸乙酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The ethyl chloroformate was used instead of methyl chloroformate, and the reaction mixture was treated in the same manner as in Example 227.

實施例229異丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 229 isopropyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸異丙酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of the methyl chloroformate, and the reaction was carried out in the same manner as in Example 227.

實施例230丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 230 Butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

於氬環境下，於丁-1-醇(4.0mg，0.066mmol)、三光氣(7.0mg，0.022mmol)之二氯甲烷溶液(0.2mL)中，在0℃滴下N,N-二異丙基乙基胺(40μL，0.22mmol)，攪拌30分鐘。於0℃加入6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶](10.0mg，0.022mmol)，再攪拌30分鐘。加水使反應停止，以氯仿萃取。藉無水硫酸鈉乾燥後，減壓濃縮，並將所得殘渣使用矽膠分取薄層層析法(氯仿：醋酸乙酯=4：1)精製’得到白色非晶形之標題化合物(10.1mg，80%)。 N,N-diisopropyl was added at 0 ° C in a solution of butan-1-ol (4.0 mg, 0.066 mmol) and triphosgene (7.0 mg, 0.022 mmol) in dichloromethane (0.2 mL) under argon. Ethylethylamine (40 μL, 0.22 mmol) was stirred for 30 minutes. Add 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail at 0 °C Indole-2,4'-piperidine] (10.0 mg, 0.022 mmol) was stirred for additional 30 min. Water was added to stop the reaction and extracted with chloroform. After drying over anhydrous sodium sulfate, the title compound was obtained (yield: EtOAc (EtOAc) ).

實施例231新戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 231 neopentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸新戊酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of methyl chloroformate, and the reaction was carried out in the same manner as in Example 227.

實施例232異丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 232 isobutyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽的粗製物(10.0mg，0.022mmol)溶解於N,N-二甲基甲醯胺(0.2mL)中，加入N,N-二異丙基乙基胺(20.0μL，0.11mmol)、異丁基1H-咪唑-1-羧酸酯(4.0mg，0.022mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：醋酸乙酯=4：1)精製，得到白色非晶形之標題化合物(10.0mg，84%)。 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine hydrochloride (10.0 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (0.2 mL), and N,N-diisopropyl was added. Ethylamine (20.0 μL, 0.11 mmol), isobutyl 1H-imidazole-1-carboxylate (4.0 mg, 0.022 mmol) was stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc (EtOAc:EtOAc:EtOAc

實施例233 1-甲基環丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 233 1-Methylcyclopropyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1-甲基環丙基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate and using 1-methylcyclopropyl 1H-imidazol-1-carboxylate, the reaction was carried out in the same manner as in Example 232 to give the title compound as white amorphous. .

實施例234 1-環丙基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 234 1-Cyclopropylethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用1-環丙基乙醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230.

實施例235第二丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 235 Second butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用第二丁基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound of the white amorphous form was obtained by the reaction of the same procedure as in Example 232, using the butyl 1H-imidazole-l-carboxylate.

實施例236第三戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 236 Third pentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用第二戊基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the same procedure as in Example 232.

實施例237 4-甲基戊烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 237 4-methylpentan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用4-甲基戊烷-2-基 1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate using 4-methylpentan-2-yl 1H-Imidazole-1-carboxylate was reacted and treated in the same manner as in Example 232 to give the title compound as white crystals.

實施例238 3-甲基戊烷-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 238 3-methylpentan-3-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用3-甲基戊烷-3-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 3-methylpentan-3-yl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and the reaction and treatment were carried out in the same manner as in Example 232 to give white amorphous. The title compound.

實施例239 2-甲基丁-3-烯-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 239 2-Methylbut-3-en-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-甲基丁-3-烯-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was replaced with 2-methylbut-3-en-2-yl 1H-imidazole-1-carboxylate. White amorphous title compound.

實施例240 2-甲基丁-3-炔-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 240 2-Methylbut-3-yn-2-yl-6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-甲基丁-3-炔-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was replaced with 2-methylbut-3-yn-2-yl-1H-imidazole-1-carboxylate. White amorphous title compound.

實施例241 3-甲基戊-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 241 3-methylpent-1-yn-3-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用3-甲基戊-1-炔-3-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 3-methylpent-1-yn-3-yl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and reaction and treatment were carried out in the same manner as in Example 232. White amorphous title compound.

實施例242己-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 242 hex-1-yn-3-yl-6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用己-1-炔-3-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituted isobutyl 1H-imidazole-1-carboxylate and hex-1-yn-3-yl 1H-imidazol-1-carboxylate was used, and reacted and treated in the same manner as in Example 232 to give a white amorphous material. Title compound.

實施例243 2-氰基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 243 2-cyanoethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氰基乙醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-cyanoethanol, and the title compound was obtained as white crystals.

實施例244環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 244 cyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用環己基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous material, which was obtained by the reaction of the titled compound (1H-imidazole-l-carboxylate).

實施例245 4-(第三丁基)環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 245 4-(Third butyl)cyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用4-(第三丁基)環己基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(t-butyl)cyclohexyl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and the reaction and treatment were carried out in the same manner as in Example 232 to give white amorphous. The title compound.

實施例246 3,3,5-三甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 246 3,3,5-Trimethylcyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用3,3,5-三甲基環己基 1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate to use 3,3,5-trimethylcyclohexyl 1H-Imidazole-1-carboxylate was reacted and treated in the same manner as in Example 232 to give the title compound as white crystals.

實施例247(1R,2S,4S)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 247 (1R, 2S, 4S)-2-isopropyl-4-methylcyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(1R,2S,4S)-2-異丙基-4-甲基環己基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 (1R, 2S, 4S)-2-isopropyl-4-methylcyclohexyl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and was the same as in Example 232. The reaction was carried out and treated to give the title compound as white crystals.

實施例248(1S,2R,4R)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 248 (1S, 2R, 4R)-2-isopropyl-4-methylcyclohexyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(1S,2R,4R)-2-異丙基-4-甲基環己基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 (1S, 2R, 4R)-2-isopropyl-4-methylcyclohexyl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and was the same as in Example 232. The reaction was carried out and treated to give the title compound as white crystals.

實施例249(3-甲基氧雜環丁烷-3-基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 249 (3-methyloxetan-3-yl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(3-甲基氧雜環丁烷-3-基)甲基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 232 except that the (3-methyloxetan-3-yl)methyl 1H-imidazol-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例250環己基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 250 cyclohexylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用環己基甲基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound. The title compound was obtained as white crystals.

實施例251金剛烷-1-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 251 adamantyl-1-ylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用金剛烷-1-基甲基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The adamantyl-1-ylmethyl 1H-imidazol-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and the reaction was carried out in the same manner as in Example 232 to give a white amorphous title. Compound.

實施例252(三甲基矽基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 252 (trimethylsulfonyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用(三甲基矽基)甲醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, and the title compound was obtained as white crystals.

實施例253 2,2,2-三氯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 253 2,2,2-Trichloroethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸2,2,2-三氯乙酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of 2,2,2-trichloroethyl chloroformate, and the reaction was carried out in the same manner as in Example 227 to give the title compound as white crystals.

實施例254 2,2,2-三氟乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 254 2,2,2-Trifluoroethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2,2,2-三氟乙基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate and using 2,2,2-trifluoroethyl 1H-imidazol-1-carboxylate, reacted and treated in the same manner as in Example 232 to obtain a white amorphous form. The title compound.

實施例255 3,3,4,4,4-五氟丁基6-(4-(((吡啶-2-基甲基)磺醯 基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 255 3,3,4,4,4-pentafluorobutyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,3,4,4,4-五氟丁醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例256 1,1,1-三氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 256 1,1,1-Trifluoropropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用1,1,1-三氟丙-2-醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous material by the reaction of the same procedure as in Example 230.

實施例257 1,1,1-三氟-2-甲基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 257 1,1,1-Trifluoro-2-methylpropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1,1,1-三氟-2-甲基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazol-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and the same procedure as in Example 232 was carried out. Reaction and treatment gave the title compound as a white amorphous material.

實施例258 1,1,1,3,3,3-六氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 258 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用1,1,1,3,3,3-六氟-2-丙醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例259 1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 259 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-醇，與實施例230同樣地進行反應、處理，得到白色非晶形 之標題化合物。 The reaction was carried out in the same manner as in Example 230 except that 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol was used instead of butan-1-ol to obtain white. Amorphous The title compound.

實施例260(甲基-d3)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 260 (methyl-d3)6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(甲基-d3)1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The (meth-d3)1H-imidazole-1-carboxylate was replaced with the isobutyl 1H-imidazole-1-carboxylate, and the reaction was carried out in the same manner as in Example 232.

實施例261(乙基-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 261 (ethyl-d5) 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(乙基-d5)1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The (ethyl-d5)1H-imidazol-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and the reaction was carried out in the same manner as in Example 232.

實施例262(異丙基-d7)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 262 (isopropyl-d7) 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(異丙基-d7)1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting isobutyl 1H-imidazole-1-carboxylate and using (isopropyl-d7)1H-imidazol-1-carboxylate, the reaction was carried out in the same manner as in Example 232 to give the title compound as white crystals. .

實施例263(第三丁基-d9)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 263 (Third butyl-d9) 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用(第三丁基-d9)1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The (t-butyl-d9)1H-imidazole-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and the reaction was carried out in the same manner as in Example 232 to give a white amorphous title. Compound.

實施例264(1,1,1,3,3,3-六氟-2-丙烷-2-基-2-d1)6-(4-(((吡 啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 264 (1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1)6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用1,1,1,3,3,3-六氟-2-丙醇-d1，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例265苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 265 benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸苄酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of methyl chloroformate, and the reaction was carried out in the same manner as in Example 227.

實施例266 1-苯基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 266 1-Phenylethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1-苯基乙基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 232, the title compound was obtained as a white crystals, m.p.

實施例267 1-苯基丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 267 1-phenylpropyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用1-苯基丙基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The isophenyl 1H-imidazole-1-carboxylate was replaced with 1-phenylpropyl 1H-imidazole-1-carboxylate, and the title compound was obtained as white crystals.

實施例268苯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 268 phenethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用苯乙基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非 晶形之標題化合物。 Instead of the isobutyl 1H-imidazole-1-carboxylate, phenethyl 1H-imidazole-1-carboxylate was used, and the reaction and treatment were carried out in the same manner as in Example 232 to give a white non. The title compound of the crystalline form.

實施例269 2-甲基-1-苯基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 269 2-Methyl-1-phenylpropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-甲基-1-苯基丙烷-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was replaced with 2-methyl-1-phenylpropan-2-yl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例270 2-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 270 2-Phenylbutan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-苯基丁烷-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 232, 2-phenylbutan-2-yl 1H-imidazole-1-carboxylate was used instead of the isobutyl 1H-imidazole-1-carboxylate, and a white amorphous form was obtained. The title compound.

實施例271 2-甲基-4-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 271 2-Methyl-4-phenylbutan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-甲基-4-苯基丁烷-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction and treatment were carried out in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was used instead of 2-methyl-4-phenylbutan-2-yl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous material.

實施例272 2-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 272 2-Chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-chlorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例273 3-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 273 3-Chlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 3-chlorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例274 4-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 274 4-Chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氯苄基甲醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-chlorobenzylmethanol.

實施例275 2-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 275 2-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-fluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例276 3-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 276 3-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 3-fluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例277 4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 277 4-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-fluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例278 2-(三氟甲氧基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 278 2-(Trifluoromethoxy)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-(三氟甲氧基)苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the title compound (2-(trifluoromethoxy) benzyl alcohol).

實施例279 4-甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 279 4-Methylbenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-甲基苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-methylbenzyl alcohol, and the title compound was obtained as white crystals.

實施例280 4-(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 280 4-(Trifluoromethyl)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-(三氟甲基)苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(Trifluoromethyl)benzyl alcohol was used instead of butan-1-ol, and the reaction was carried out in the same manner as in Example 230 to give the title compound as white crystals.

實施例281 4-異丙基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 281 4-isopropylbenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-異丙基苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-isopropylbenzyl alcohol, and the title compound was obtained as white crystals.

實施例282 4-(第三丁基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 282 4-(Tertiary butyl)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-(第三丁基)苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(tert-butyl)benzyl alcohol was used instead of butan-1-ol, and the reaction was carried out in the same manner as in Example 230 to give the title compound as white crystals.

實施例283 2,6-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 283 2,6-Dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,6-二氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例284 2,3-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 284 2,3-Dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,3-二氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例285 2,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 285 2,4-Dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例286 3,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 286 3,4-Dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,4-二氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using the 3,4-dichlorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例287 3,5-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 287 3,5-Dichlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-二氯苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, and the title compound was obtained as white crystals.

實施例288 2,6-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 288 2,6-Difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,6-二氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using the 2,6-difluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例289 2,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 289 2,5-Difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,5-二氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using the 2,5-difluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例290 2,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 290 2,4-Difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例291 3,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 291 3,4-Difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,4-二氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例292 3,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 292 3,5-Difluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-二氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using the 3,5-difluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例293 2-氯-6-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 293 2-Chloro-6-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氯-6-氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-chloro-6-fluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例294 2-氯-4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 294 2-Chloro-4-fluorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氯-4-氟苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-chloro-4-fluorobenzyl alcohol, and the title compound was obtained as white crystals.

實施例295 2,4-二甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 295 2,4-Dimethylbenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二甲基苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例296 3,5-雙(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 296 3,5-Bis(trifluoromethyl)benzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-雙(三氟甲基)苄基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, and the title compound was obtained as white white crystals.

實施例297(全氟苯基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 297 (perfluorophenyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用(全氟苯基)甲基醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230.

實施例298呋喃-2-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 298 furan-2-ylmethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用呋喃-2-基甲醇，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the title compound.

實施例299苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 299 Phenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸苯酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The phenyl chloroformate was used instead of the methyl chloroformate, and the reaction was carried out in the same manner as in Example 227.

實施例300 2-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 300 2-Chlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸2-氯苯酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of the methyl chloroformate, and the reaction mixture was treated in the same manner as in Example 227.

實施例301 4-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 301 4-chlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸甲酯而使用氯甲酸4-氯苯酯，與實施例227同樣地進行反應、處理，得到白色非晶形之標題化合物。 The methyl chloroformate was used instead of methyl chloroformate, and the reaction was carried out in the same manner as in Example 227.

實施例302 2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 302 2-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例303 3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 303 3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, and the title compound was obtained as white crystals.

實施例304 4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 304 4-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-fluorophenol, and the title compound was obtained as white crystals.

實施例305 2-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 305 2-cyanophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氰基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例306 3-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 306 3-cyanophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-氰基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例307 4-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 307 4-cyanophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氰基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, and the title compound was obtained as white crystals.

實施例308 2-(三氟甲氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 308 2-(Trifluoromethoxy)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-(三氟甲氧基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-(trifluoromethoxy)phenol, and the title compound was obtained as white crystals.

實施例309 3-(二甲基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 309 3-(Dimethylamino)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-(二甲基胺基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例310 3-(二乙基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 310 3-(Diethylamino)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3-(二乙基胺基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, the title compound was obtained as white crystals.

實施例311 4-異丙基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 311 4-isopropylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用2-甲基-4-苯基丁烷-2-基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、 處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was replaced with 2-methyl-4-phenylbutan-2-yl 1H-imidazole-1-carboxylate. Treatment gave the title compound as a white amorphous material.

實施例312 4-(第三丁基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 312 4-(Third butyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用4-(第三丁基)苯基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(tert-butyl)phenyl 1H-imidazol-1-carboxylate was used instead of isobutyl 1H-imidazole-1-carboxylate, and the reaction and treatment were carried out in the same manner as in Example 232 to obtain a white amorphous form. The title compound.

實施例313 4-(第三戊基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 313 4-(Thrylpentyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代異丁基1H-咪唑-1-羧酸酯而使用4-(第三戊基)苯基1H-咪唑-1-羧酸酯，與實施例232同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 4-(tripentyl)phenyl 1H-imidazol-1-carboxylate was used in the same manner as in Example 232 except that the isobutyl 1H-imidazole-1-carboxylate was replaced, and a white amorphous form was obtained. The title compound.

實施例314 4-(甲基硫基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 314 4-(Methylthio)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-(甲基硫基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(methylthio)phenol was used instead of butan-1-ol, and the reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例315 2,6-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 315 2,6-Dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,6-二氯苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例316 2,3-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 316 2,3-Dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,3-二氯苯酚，與實施例230同樣地 進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, 2,3-dichlorophenol was used instead of butan-1-ol. The reaction was carried out and the title compound was obtained as white crystals.

實施例317 2,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 317 2,4-Dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二氯苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例318 3,5-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 318 3,5-Dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-二氯苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例319 3,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 319 3,4-Dichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,4-二氯苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例320 2,6-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 320 2,6-Difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,6-二氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例321 3,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 321 3,5-Difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-二氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例322 2,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲 基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 322 2,5-Difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,5-二氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例323 2,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 323 2,4-Difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例324 3,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 324 3,4-Difluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,4-二氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例325 2-氯-6-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 325 2-Chloro-6-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氯-6-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-chloro-6-fluorophenol, and the title compound was obtained as white crystals.

實施例326 2-氯-4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 326 2-Chloro-4-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氯-4-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 2-chloro-4-fluorophenol, and the title compound was obtained as white crystals.

實施例327 4-氯-2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 327 4-Chloro-2-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氯-2-氟苯酚，與實施例230同樣地 進行反應、處理，得到白色非晶形之標題化合物。 In the same manner as in Example 230, 4-chloro-2-fluorophenol was used instead of butan-1-ol. The reaction was carried out and the title compound was obtained as white crystals.

實施例328 4-氯-3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 328 4-Chloro-3-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氯-3-氟苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-chloro-3-fluorophenol, and the title compound was obtained as white crystals.

實施例329 2,4-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 329 2,4-Dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4-二甲基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例330 3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 330 3,5-Dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用3,5-二甲基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例331 4-氯-3-甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 331 4-Chloro-3-methylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氯-3-甲基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-chloro-3-methylphenol, and the title compound was obtained as white crystals.

實施例332 2-氟-3-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 332 2-Fluoro-3-(trifluoromethyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氟-3-(三氟甲基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous material, which was obtained by the reaction of the titled compound (yield: 2-fluoro-3-(trifluoromethyl) phenol.

實施例333 2-氟-5-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基) 磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 333 2-Fluoro-5-(trifluoromethyl)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2-氟-5-(三氟甲基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained by the reaction of the same procedure as in Example 230, using 2-fluoro-5-(trifluoromethyl)phenol.

實施例334 2,4,6-三氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 334 2,4,6-Trichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用2,4,6-三氯苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 to give the title compound.

實施例335 4-氯-3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 335 4-Chloro-3,5-dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-氯-3,5-二甲基苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230, using 4-chloro-3,5-dimethylphenol, and the title compound was obtained as white crystals.

實施例336 4-(苄基氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 336 4-(Benzyloxy)phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用4-(苄基氧基)苯酚，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 4-(Benzyloxy)phenol was used instead of butan-1-ol, and the reaction was carried out in the same manner as in Example 230 to give the title compound as white crystals.

實施例337(苯基-2,3,4,5,6-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 337 (phenyl-2,3,4,5,6-d5) 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代丁-1-醇而使用(苯酚-2,3,4,5,6-d5)，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction was carried out in the same manner as in Example 230 (yield: phenol-2,3,4,5,6-d5).

實施例338第三丁基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 338 tert-butyl 6-(3-fluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用2-(((4-溴-2-氟苄基) 磺醯基)甲基)吡啶，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane with 2-(((4-bromo-2-fluorobenzyl)) Sulfhydryl)methyl)pyridine was reacted and treated in the same manner as in Step 2 of Example 11 to give the title compound as white crystals.

實施例339 2,2,2-三氯乙基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 339 2,2,2-Trichloroethyl 6-(3-fluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(3-Fluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例338所得之第三丁基6-(3-氟-4-((((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(3-fluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail obtained in Example 338 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-Trichloroethyl 6-(3-fluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽之粗製物，以取代6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]鹽酸鹽之粗製物，與實施例63同樣地進行反應、處理，得到白色固體之標題化合物。 Using 6-(3-fluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail obtained in step 1 a crude product of 唍-2,4'-piperidine]dihydrochloride to replace 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ The crude product of bis-2,4'-piperidine hydrochloride was reacted and treated in the same manner as in Example 63 to give the title compound.

實施例340第三丁基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 340 Tert-butyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用2-(((4-溴-2,6-二氟苄基)磺醯基)甲基)吡啶，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 2-(((4-bromo-2,6-difluorobenzyl)sulfonyl)methyl)pyridine was used instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and examples Step 2 of Step 11 was carried out in the same manner and the title compound was obtained.

實施例341 2,2,2-三氯乙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-羧酸酯的製造 Example 341 2,2,2-Trichloroethyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-carboxylate

步驟1：6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(3,5-Difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例340所得之第三丁基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail obtained in Example 340 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：2,2,2-三氯乙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例63同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidinedihydrochloride salt was reacted and treated in the same manner as in Example 63 to give the title compound as white crystals.

實施例342新戊基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 342 neopentyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例231同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidinyl dihydrochloride was reacted and treated in the same manner as in Example 231 to give the title compound as white crystals.

實施例343 1-甲基環丙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 343 1-Methylcyclopropyl 6-(3,5-difluoro-4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例233同樣地進行反 應、處理，得到白色非晶形之標題化合物。 Using 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ The indole-2,4'-piperidinyl dihydrochloride salt was reacted and treated in the same manner as in Example 233 to give the title compound as white crystals.

實施例344第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 344 Third butyl 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(((吡啶-2-基甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((pyridin-2-ylmethyl))thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用2-溴甲基吡啶溴酸鹽，與實施例120之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

1H-NMR(CDCl3)δ：1.47(9H,s),1.50-1.60(2H,m),1.80-1.88(4H,m),2.87(2H,t,J=6.8Hz),3.16-3.24(2H,m),3.70(2H,s),3.78(2H,s),3.80-4.00(2H,m),6.92(1H,d,J=8.8Hz),7.15-7.17(1H,m),7.31(1H,d,J=7.6Hz),7.56-7.78(5H,m),8.52-8.58(2H,m). 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.80-1.88 (4H, m), 2.87 (2H, t, J = 6.8 Hz), 3.16-3.24 (2H, m), 3.70 (2H, s), 3.78 (2H, s), 3.80-4.00 (2H, m), 6.92 (1H, d, J = 8.8 Hz), 7.15-7.17 (1H, m), 7.31 (1H, d, J = 7.6 Hz), 7.56-7.78 (5H, m), 8.52 - 8.58 (2H, m).

步驟2：第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用第三丁基6-(5-(((吡啶-2-基甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例120之步驟3同樣地進行反應、處理，得到淡黃色固體之標題化合物。 Use of tert-butyl 6-(5-(((pyridin-2-ylmethyl))thio)methyl)pyridin-2-yl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted in the same manner as in the step 3 of Example 120 to give the title compound.

實施例345 2-((((6-(1’-(第三丁氧基羰基螺(唍-2,4’-哌啶)-6-基)吡啶-3-基)甲基)磺醯基)甲基)吡啶-1-氧化物的製造 Example 345 2-(((6-(1'-(T-butoxycarbonyl snail) Manufacture of 唍-2,4'-piperidinyl-6-yl)pyridin-3-yl)methyl)sulfonyl)methyl)pyridine-1-oxide

與實施例344同樣地進行反應、處理，得到淡黃色固體之 標題化合物。 The reaction and the treatment were carried out in the same manner as in Example 344 to give a pale yellow solid. Title compound.

實施例346第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 346, tert-butyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((吡啶-2-基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((pyridin-2-ylmethyl))thio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-溴乙腈而使用2-溴甲基吡啶溴酸鹽，與實施例127之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 2-bromomethylpyridine bromo acid salt was used instead of 2-bromoacetonitrile, and the reaction was carried out in the same manner as in the step 2 of Example 127.

步驟2：第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: tert-butyl 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之第三丁基6-(5-(((吡啶-2-基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(5-(((pyridin-2-ylmethyl))thio)methyl)pyrimidin-2-yl) snail obtained in step 1 The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例347新戊基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 347 neopentyl 6-(5-(((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-(((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinium dihydrochloride

使用實施例346所得之第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail obtained in Example 346 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to obtain a crude product of the dihydrochloride salt.

步驟2：新戊基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽，與實施例114同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail obtained in step 1 The indole-2,4-piperidinyl dihydrochloride was reacted and treated in the same manner as in Example 114 to give the title compound as white crystals.

實施例348 1-甲基環丙基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 348 1-Methylcyclopropyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例347之步驟1所得的6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]二鹽酸鹽，與實施例233同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-(((pyridin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail obtained in Step 1 of Example 347 [ The indole-2,4-piperidinyl dihydrochloride was reacted and treated in the same manner as in Example 233 to give the title compound as white crystals.

實施例349第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 349 Thirty butyl 6-(4-(((5-fluoropyridin-2-yl)methyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((((5-氟吡啶-2-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用甲磺酸(5-氟吡啶-2-基)甲酯，與實施例77之步驟1同樣地進行反應、處理，得到淡黃色固體之標題化合物。 The title compound was obtained as a pale yellow solid (yield: m.p.

步驟2：第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例 85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(4-(((5-fluoropyridin-2-yl)methyl))sulfonyl)methyl)phenyl) snail obtained in Step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例350異丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 350 Isobutyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例349所得之第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail obtained in Example 349 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：異丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Isobutyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將步驟1所得之6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的粗製物(150mg，0.28mmol)溶解於二氯乙烷(3mL)中，加入三乙基胺(0.19mL，1.39mmol)、氯甲酸異丁酯(55.0μL，0.42mmol)，於室溫攪拌12小時。於反應液中加水，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=1：1)精製，得到白色固體之標題化合物(115mg，44%)。 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail obtained in step 1 The crude product of 唍-2,4'-piperidine]dihydrochloride (150 mg, 0.28 mmol) was dissolved in dichloroethane (3 mL), triethylamine (0.19 mL, 1.39 mmol), chloroformic acid Butyl ester (55.0 μL, 0.42 mmol) was stirred at room temperature for 12 h. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc

實施例351新戊基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 351 neopentyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸異丁酯而使用氯甲酸新戊酯，與實施例350同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

實施例352 1-甲基環丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 352 1-Methylcyclopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]二鹽酸鹽的粗製物(205.0mg，0.46mmol)溶解於N,N-二甲基甲醯胺(5mL)中，加入N,N-二異丙基乙基胺(0.39mL，2.32mmol)、1-甲基環丙基1H-咪唑-1-羧酸酯(92.0mg，0.56mmol)，於80℃攪拌12小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(正己烷：醋酸乙酯=2：1)精製，得到白色非晶形之標題化合物(130mg，50%)。 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ The crude product of 唍-2,4'-piperidine]dihydrochloride (205.0 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropyl was added. Ethylamine (0.39 mL, 2.32 mmol), 1-methylcyclopropyl 1H-imidazol-1-carboxylate (92.0 mg, 0.56 mmol) was stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例353 1-環丙基乙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 353 1-Cyclopropylethyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-甲基環丙基1H-咪唑-1-羧酸酯而使用1-環丙基乙基1H-咪唑-1-羧酸酯，與實施例352同樣地進行反應、處理，得到淡黃色固體之標題化合物。 Substituting 1-methylcyclopropyl 1H-imidazole-1-carboxylate and using 1-cyclopropylethyl 1H-imidazole-1-carboxylate, the reaction was carried out in the same manner as in Example 352 to give a pale yellow color. The title compound of the solid.

實施例354 1,1,1-三氟丙烷-2-基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 354 1,1,1-Trifluoropropan-2-yl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-甲基環丙基1H-咪唑-1-羧酸酯而使用1,1,1-三氟丙烷-2-基1H-咪唑-1-羧酸酯，與實施例352同樣地進行反應、 處理，得到白色固體之標題化合物。 The reaction was carried out in the same manner as in Example 352 except that 1-methylcyclopropyl 1H-imidazole-1-carboxylate was used instead of 1,1,1-trifluoropropan-2-yl 1H-imidazol-1-carboxylate. , Treatment gave the title compound as a white solid.

實施例355第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 355 tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-((((5-氟吡啶-2-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-碘丙烷而使用甲磺酸(5-氟吡啶-2-基)甲酯，與實施例120之步驟2同樣地進行反應、處理，得到淡褐色非晶形之標題化合物。 Substituting 2-iodopropane and using (5-fluoropyridin-2-yl)methyl methanesulfonate, the reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as a pale brown crystal.

步驟2：第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-((((5-氟吡啶-2-基)甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)thio)methyl)pyridin-2-yl) snail obtained in Step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例356 1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 356 1-Methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例355所得之第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽之粗製物。 The third butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Example 355 was used. The hydrazone-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: 1-Methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例352同樣地進行反應、處理，得到黃色固體之標題化合物。 Using 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 The indole-2,4'-piperidinyl dihydrochloride salt was reacted and treated in the same manner as Example 352 to give the title compound.

實施例357 1,1,1-三氟丙烷-2-基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 357 1,1,1-Trifluoropropan-2-yl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) screw[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例356之步驟1所得之6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]二鹽酸鹽，與實施例354同樣地進行反應、處理，得到白色固體之標題化合物。 Using 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyridin-2-yl) snail obtained in Step 1 of Example 356 [ The indole-2,4'-piperidine dihydrochloride was reacted and treated in the same manner as in Example 354 to give the title compound.

實施例358第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 358 tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-溴乙腈而使用甲磺酸(5-氟吡啶-2-基)甲酯，與實施例127之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Substituting 2-bromoacetonitrile and using (5-fluoropyridin-2-yl)methyl methanesulfonate, the reaction was carried out in the same manner as in Step 2 of Example 127 to give the title compound as white crystals.

實施例359新戊基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 359 neopentyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]鹽酸鹽的製造 Step 1: 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail [ Manufacture of 唍-2,4-piperidine] hydrochloride

使用實施例358所得之第三丁基6-(5-((((5-氟吡啶-2-基) 甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到鹽酸鹽之粗製物。 The third butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail obtained in Example 358 was used. The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt.

步驟2：新戊基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]鹽酸鹽，與實施例231同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail obtained in step 1 The indole-2,4-piperidinyl hydrochloride salt was reacted and treated in the same manner as in Example 231 to give the title compound as white crystals.

實施例360 1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 360 1-Methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-ylspiro[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用實施例359之步驟1所得之6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]鹽酸鹽的粗製物，與實施例233同樣地進行反應、處理，得到白色非晶形之標題化合物。 The 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidin-2-yl snail obtained from the step 1 of Example 359. The crude product of hydrazine-2,4-piperidine hydrochloride was reacted and treated in the same manner as in Example 233 to give the title compound as white white.

實施例361第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 361 tert-butyl 6-(4-(((6-methylpyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((6-methylpyridin-2-yl)methyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用2-(溴甲基)-6-甲基吡啶，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)磺醯基)甲 基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((6-methylpyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(4-(((6-methylpyridin-2-yl)methyl)thio)methyl)phenyl) phenyl) obtained in Step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例362第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 362 tert-butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代S-((3-甲基氧雜環丁烷-3-基)乙硫羥酸酯而使用S-((6-甲氧基吡啶-2-基)甲基)乙硫羥酸酯，與實施例168之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 S-((6-methoxypyridin-2-yl)methyl)ethyl thiol ester is used instead of S-((3-methyloxetan-3-yl)ethyl thiol ester, The title compound was obtained as a colorless oil.

步驟2：第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Using the third butyl 6-(4-(((6-methoxypyridin-2-yl)methyl))thio)methyl)phenyl) snail obtained in Step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例363第三丁基6-(4-(((吡-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 363 tert-butyl 6-(4-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((吡-2-基甲基)硫基)甲基)苯基)螺 [唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((pyridyl) -2-ylmethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用2-(溴甲基)吡，與實施例77之步驟1同樣地進行反應、處理，得到淡黃色非晶形之標題化合物。 2-(Bromomethyl)pyridyl instead of 1-iodopropane The reaction and the reaction were carried out in the same manner as in the step 1 of Example 77 to give the title compound.

步驟2：第三丁基6-(4-(((吡-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(4-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((吡-2-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use the third butyl 6-(4-(((pyridyl)) obtained in step 1. -2-ylmethyl)thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例364第三丁基6-(5-(((吡-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Example 364, tert-butyl 6-(5-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

步驟1：第三丁基6-(5-(((吡-2-基甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-(((pyridyl) -2-ylmethyl)thio)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

取代2-碘丙烷而使用2-(溴甲基)吡，與實施例120之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 2-(Bromomethyl)pyridyl instead of 2-iodopropane The reaction was carried out in the same manner as in the step 2 of Example 120 to give the title compound as white crystals.

步驟2：第三丁基6-(5-(((吡-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(5-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)pyridin-2-yl) spiro[ Manufacture of 唍-2,4-piperidinyl-1'-carboxylate

使用步驟1所得之第三丁基6-(5-(((吡-2-基甲基)硫基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Use the third butyl 6-(5-(((pyridyl) obtained in step 1 -2-ylmethyl)thio)methyl)pyridin-2-yl) snail [ The indole-2,4-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例365第三丁基6-(4-(((噻唑-4-基甲基)磺醯基)甲基) 苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 365 Thirty butyl 6-(4-(((thiazol-4-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((噻唑-4-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((thiazolyl-4-ylmethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用4-(氯甲基)噻唑鹽酸鹽，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(4-(((噻唑-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((thiazol-4-ylmethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((噻唑-4-基甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Using the third butyl 6-(4-(((thiazolyl-4-ylmethyl))thio)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例366第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 366 Thirty butyl 6-(4-((((3-isopropyl)-1,2,4-) Diazol-5-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-((((3-isopropyl-1,2,4-)) Diazol-5-yl)methyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用5-(氯甲基)-3-異丙基-唑，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 Instead of 1-iodopropane, 5-(chloromethyl)-3-isopropyl- The azole was reacted and treated in the same manner as in the step 1 of Example 77 to give the title compound.

步驟2：第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Third butyl 6-(4-((((3-isopropyl-1,2,4-)) Diazol-5-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-((((3-異丙基-1,2,4-二 唑-5-基)甲基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Using the third butyl 6-(4-((((3-isopropyl-1,2,4-))) Diazol-5-yl)methyl)thio)methyl)phenyl) snail [ The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例367第三丁基6-(5-((((嘧啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 367 tert-butyl 6-(5-(((pyrimidin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(5-(((嘧啶-2-基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(5-((pyrimidin-2-ylmethyl)thio)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代2-溴乙腈而使用甲磺酸嘧啶-2-基甲酯，與實施例127之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 The title compound was obtained as a white amorphous compound, which was obtained from the title compound.

步驟2：第三丁基6-(5-((((嘧啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(5-(((pyrimidin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(5-((((嘧啶-2-基甲基)硫基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(5-(((pyrimidin-2-ylmethyl))thio)methyl)pyrimidin-2-yl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例368第三丁基6-(4-(((1-(吡啶-2-基)乙基)亞磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 368 T-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)sulfinyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((1-(吡啶-2-基基)乙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((1-(pyridin-2-yl)))))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用甲磺酸1-(吡啶-2-基)乙酯，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之 標題化合物。 The 1-(pyridin-2-yl)ethyl methanesulfonate was used instead of 1-iodopropane, and the reaction was carried out in the same manner as in the step 1 of Example 77 to give a colorless oil. Title compound.

步驟2：第三丁基6-(4-(((1-(吡啶-2-基)乙基)亞磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)sulfinyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((1-(吡啶-2-基)乙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(4-(((1-(pyridin-2-yl)ethyl)))))))))) The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white crystals.

實施例369第三丁基6-(4-(((1-(吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 369 tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

與實施例368同樣地進行反應、處理，得到白色非晶形之標題化合物。 The reaction and the treatment were carried out in the same manner as in Example 368 to give the title compound as white white.

實施例370第三丁基6-(4-(((1-(吡啶-2-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 370 Thirty butyl 6-(4-(((1-(pyridin-2-yl)propyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((1-(吡啶-2-基)丙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((1-(pyridin-2-yl)propyl))))))))) Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代1-碘丙烷而使用甲磺酸1-(吡啶-2-基)丙酯，與實施例77之步驟1同樣地進行反應、處理，得到無色油狀物之標題化合物。 The title compound was obtained as a colorless oily product.

步驟2：第三丁基6-(4-(((1-(吡啶-2-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((1-(pyridin-2-yl)propyl))sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((1-(吡啶-2-基)丙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85 之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using the third butyl 6-(4-(((1-(pyridin-2-yl))propyl))))))))) The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound as white white.

實施例371第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 371, Third butyl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：第三丁基6-(4-(((2-吡啶-2-基)乙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 1: Third butyl 6-(4-(((2-pyridin-2-yl)ethyl)thio)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代S-((3-甲基雜氧環丁烷-3-基)乙硫羥酸酯而使用S-(2-(吡啶-2-基)乙基)乙硫羥酸酯，與實施例168之步驟1同樣地進行反應、處理，得到白色固體之標題化合物。 S-(2-(pyridin-2-yl)ethyl)ethyl thiol ester was used instead of S-((3-methylheooxycyclobutane-3-yl)ethyl thiol ester, and examples The title compound was obtained as a white solid.

步驟2：第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Tert-butyl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之第三丁基6-(4-(((2-吡啶-2-基)乙基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例85之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 Using the third butyl 6-(4-(((2-pyridin-2-yl)ethyl)) thio)methyl)phenyl) snail obtained in step 1 The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in the step 2 of Example 85 to give the title compound.

實施例372新戊基6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 372 neopentyl 6-(4-(((2-(pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

步驟1：6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]二鹽酸鹽的製造 Step 1: 6-(4-(((2-(pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine] dihydrochloride

使用實施例371之步驟2所得的第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯，與實施例109之步驟1同樣地進行反應、處理，得到二鹽酸鹽的粗製物。 The third butyl 6-(4-(((2-pyridin-2-yl)ethyl))sulfonyl)methyl)phenyl) snail obtained in the second step of Example 371 was used. The indole-2,4'-piperidine]-1'-carboxylate was reacted and treated in the same manner as in the step 1 of Example 109 to give a crude salt of the dihydrochloride salt.

步驟2：新戊基6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯的製造 Step 2: Neopentyl 6-(4-(((2-(pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl)[ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用步驟1所得之6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]二鹽酸鹽，與實施例231同樣地進行反應、處理，得到白色非晶形之標題化合物。 Using 6-(4-(((2-(pyridin-2-yl)ethyl)))sulfonyl)methyl)phenyl)[ The indole-2,4'-piperidinyl dihydrochloride was reacted and treated in the same manner as in Example 231 to give the title compound as white crystals.

實施例373 1,1,1-三氟丙烷-2-基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 373 1,1,1-Trifluoropropan-2-yl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例372之步驟1所得之6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]二鹽酸鹽，與實施例230同樣地進行反應、處理，得到白色非晶形之標題化合物。 6-(4-(((2-(pyridin-2-yl)ethyl)))sulfonyl)methyl)phenyl)[ The indole-2,4'-piperidinedihydrochloride salt was reacted and treated in the same manner as in Example 230 to give the title compound as white crystals.

實施例374第三丁基7-氟-6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 374 tert-butyl 7-fluoro-6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

使用實施例101之步驟3所得的第三丁基6-溴-7-氟螺(唍-2,4’-哌啶)-1’-羧酸酯，與實施例85同樣地進行反應、處理，得到白色非晶形之標題化合物。 The third butyl 6-bromo-7-fluorospiro obtained using the step 3 of Example 101 ( The indole-2,4'-piperidinyl-1'-carboxylate was reacted and treated in the same manner as in Example 85 to give the title compound as white white.

實施例375第三丁基6-(4-(2-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 375 tert-butyl 6-(4-(2-methylsulfonyl)ethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用1-溴-4-(2-(甲基磺醯基)乙基)苯，與實施例11之步驟2同樣地進行反應、處理，得到白色非晶形之標題化合物。 1-bromo-4-(2-(methylsulfonyl)ethyl)benzene was used instead of (4-bromo-3-fluorobenzyl)(methyl)sulfane, and the same procedure as in Step 2 of Example 11 was carried out. The reaction was carried out and the title compound was obtained as white crystals.

實施例376第三丁基6-(4-((1H-咪唑-1-基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 376 tert-butyl 6-(4-((1H-imidazol-1-yl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

將咪唑(3.0mg，0.048mmol)溶解於四氫呋喃(0.3mL)中，於冰冷下，加入60%氫化鈉(3.0mg，0.064mmol)，攪拌15分鐘後，加入第三丁基6-(4-(溴甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(15.0mg，0.032mmol)，於室溫下攪拌1小時。於反應液中加水，以醋酸乙酯萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮。將所得殘渣使用矽膠層析法(氯仿：甲醇=10：1)精製，得到白色非晶形之標題化合物(11.0mg，79%)。 The imidazole (3.0 mg, 0.048 mmol) was dissolved in tetrahydrofuran (0.3 mL), and then, under ice cooling, 60% sodium hydride (3.0 mg, 0.064 mmol) was added, and after stirring for 15 minutes, tributyl 6-(4- (bromomethyl)phenyl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate (15.0 mg, 0.032 mmol) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc)

實施例377第三丁基6-(4-(2-乙氧基-2-側氧基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 377 tert-butyl 6-(4-(2-ethoxy-2-oxoethoxyethyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代(4-溴-3-氟苄基)(甲基)硫烷而使用乙基2-(4-溴苯基)醋酸，與實施例11之步驟2同樣地進行反應、處理，得到無色油狀物之標題化合物。 Substituting (4-bromo-3-fluorobenzyl)(methyl)sulfane and using ethyl 2-(4-bromophenyl)acetic acid, the reaction was carried out in the same manner as in the step 2 of Example 11 to give a colorless oil. The title compound.

實施例378 2-(4-(1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苯基)醋酸的製造 Example 378 2-(4-(1'-(T-butoxycarbonyl) snail [ Manufacture of 唍-2,4'-piperidinyl]-6-yl)phenyl)acetic acid

將實施例377所得之第三丁基6-(4-(2-乙氧基-2-側氧基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯(10mg，0.021mmol)溶解於甲醇(0.1mL)與四氫呋喃(0.1mL)，並加入4N氫氧化鈉水溶液(0.1mL)，攪拌3O分鐘。於反應液中添加稀鹽酸予以中和後，以氯仿萃取。對有機層以飽和食鹽水洗淨，藉無水硫酸鈉乾燥後，減壓濃縮，得到白色固體之標題化合物(5mg，56%)。 The third butyl 6-(4-(2-ethoxy-2-oxoethyl)phenyl) snail obtained in Example 377 唍-2,4'-Piperidine]-1'-carboxylate (10 mg, 0.021 mmol) was dissolved in methanol (0.1 mL) and tetrahydrofuran (0.1 mL). 3O minutes. After adding neutral hydrochloric acid to the reaction solution for neutralization, it was extracted with chloroform. The organic layer was washed with EtOAcq.

實施例379異丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 379 isopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸2,2,2-三氯乙酯而使用氯甲酸異丙酯，與實施例121之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

實施例380異丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺(唍-2,4’-哌啶)-1’-羧酸酯的製造 Example 380 isopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridin-2-yl) snail ( Manufacture of 唍-2,4'-piperidine)-1'-carboxylate

取代氯甲酸新戊酯而使用氯甲酸異丙酯，與實施例135之步驟2同樣地進行反應、處理，得到白色固體之標題化合物。 The chloroformic acid chloroformate was used instead of the isopropyl chloroformate, and the reaction was carried out in the same manner as in the step 2 of Example 135.

實施例381異丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯的製造 Example 381 isopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)phenyl) snail [ Manufacture of 唍-2,4'-piperidine]-1'-carboxylate

取代氯甲酸異丁酯而使用氯甲酸異丙酯，與實施例350同樣地進行反應、處理，得到白色固體之標題化合物。 The title compound was obtained as a white solid, m.p.

將上述實施例所得之化合物示於表1~表77。 The compounds obtained in the above examples are shown in Tables 1 to 77.

試驗例1胰島素分泌促進作用 Test Example 1 Insulin secretion promoting effect

將倉鼠胰臟β細胞株HIT-T15細胞使用含有盤尼西林(100單位/mL)、鏈鰴素(100μg/mL)及10%胎牛血清的Ham’s F-12K培養基進行繼代培養。播種於24孔培養盤，以37℃培養48小時後，以含0.1%白蛋白之KRBH緩衝液洗淨。接著，藉同一緩衝液於37℃靜置1小時，於其中依最終濃度成為2mM的方式添加葡萄糖，再將依各濃度(由0.0001μM依公比10至10μM為止)之1000倍之濃度溶解於二甲基亞 碸的本發明化合物，依於緩衝液中含有0.1體積%之條件予以添加。添加本發明化合物後，於1小時、37℃靜置後，依胰島素套組(SCETI Medical股份有限公司)測定上清液中所含的胰島素濃度。於標準溶液中使用倉鼠-胰島素標準溶液(Shibayaki股份有限公司)。作為對照組係使用僅添加了二甲基亞碸者。將結果作成各被檢化合物之50%效果濃度(EC50值，50% effect concentration)並示於表19。又，EC50值係使用統計分析系統、SAS前臨床封裝Ver5.0(SAS institute Japan Co.，東京)所算出。 Hamster pancreatic β-cell line HIT-T15 cells were subcultured using Ham's F-12K medium containing penicillin (100 units/mL), streptomycin (100 μg/mL), and 10% fetal bovine serum. The cells were seeded in a 24-well culture dish, and cultured at 37 ° C for 48 hours, and then washed with KRBH buffer containing 0.1% albumin. Then, the mixture was allowed to stand at 37 ° C for 1 hour in the same buffer, and glucose was added thereto in such a manner that the final concentration became 2 mM, and then dissolved at a concentration of 1000 times each concentration (from 0.0001 μM to 10 μM). The compound of the present invention of dimethylhydrazine is added in an amount of 0.1% by volume based on the buffer. After the addition of the compound of the present invention, the insulin concentration in the supernatant was measured in an insulin-based kit (SCETI Medical Co., Ltd.) after standing at 1 hour and 37 °C. A hamster-insulin standard solution (Shibayaki Co., Ltd.) was used in the standard solution. As the control group, only those in which dimethyl hydrazine was added were used. The results were made each 50% of the effect concentration (value 50 EC, 50% effect concentration) of the subject compound and shown in Table 19. Further, the EC 50 value was calculated using a statistical analysis system and a SAS pre-clinical package Ver5.0 (SAS institute Japan Co., Tokyo).

由以上可知，本發明化合物具有強力之胰島素分泌促進效果。 From the above, it is understood that the compound of the present invention has a potent insulin secretion promoting effect.

(產業上之可利用性) (industrial availability)

本發明之一般式(1)所示之螺哌啶衍生物或其鹽或其等之溶媒合物，係具有優越的胰島素分泌促進作用，可用於糖尿病之預防及/或治療，故具有產業上之可利用性。 The spiropiperidine derivative represented by the general formula (1) of the present invention or a salt thereof or a solvent thereof has a superior insulin secretion promoting action and can be used for the prevention and/or treatment of diabetes, so that it has an industrial property. Availability.

Claims (9)

一種化合物或其鹽或其等之溶媒合物，係由下述一般式(1)所示： [式中，A環表示C6-C10芳基或5-10員雜環基；Z表示O、N-R9、S(O)m、CH2或C=O(此處，R9表示氫原子、C1-6烷基、C1-7烷醯基或C1-6烷基磺醯基，m表示0~2之整數)；[化2]表示單鍵或雙鍵；R1、R2、R3及R4彼此獨立為不存在或氫原子、鹵素原子、C1-6烷基、羧基-C1-6烷基、C1-6烷氧基羰基-C1-6烷基、4-10員雜環-C1-6烷基(此處，4-10員雜環上亦可取代有C1-6烷基或C1-6烷基磺醯基)、C1-6烷氧基、C3-10環烷基-C1-6烷氧基、C1-6烷基磺醯基、C1-6烷基磺醯氧基、C1-6烷基磺醯胺基、羥基、氰基、硝基、四唑基、或下式(2)或式(3)所示之基：[化3] (式中，R10及R11彼此獨立表示氫原子、鹵素原子或C1-6烷基；R12表示C1-20烷基、C2-6烯基、鹵C1-6烷基、C2-7烷醯基、C6-10芳基、4-10員雜環基(雜環上亦可取代有鹵素原子)、C3-10環烷基-C1-6烷基、胺基C1-6烷基、羥基-C1-6烷基、氰基-C1-6烷基、C1-6烷氧基-C1-6烷基、羧基-C1-6烷基、C1-6烷氧基羰基-C1-6烷基、胺甲醯基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C6-10芳基-C1-6烷基(此處，C6-10芳基上亦可取代有鹵素原子、C1-6烷基、鹵C1-6烷基、C1-6烷基磺醯基或羧基)或4-10員雜環-C1-6烷基(此處，雜環上亦可取代有C1-6烷基、鹵素原子、C1-6烷氧基或側氧基)；1表示1~3之整數，n表示0~2之整數)；R5、R6及R7彼此獨立表示氫原子、鹵素原子、氰基或羧基；R8表示C1-6烷基、C2-6烯基、C2-6炔基、鹵C1-6烷基、三烷基矽基-C1-6烷基、氰基C1-6烷基、C1-6烷氧基-C1-6烷基、C3-10環烷基(此處，環烷基上亦可取代有鹵素原子)、C3-10環烷基-C1-6烷基(此處，環烷基上亦可取代有C1-6烷基)、C6-10芳基(此處，C6-10芳基上亦可取代有鹵素原子、氰基、鹵C1-6烷氧基、胺基、二烷基胺基、C1-6烷基、鹵C1-6烷基、C1-6烷基硫基或C6-10芳基-C1-6烷基氧基)、C6-10芳基-C1-6烷 基(此處，C6-10芳基上亦可取代有鹵素原子、C1-6烷基、鹵C1-6烷氧基或鹵C1-6烷基)、4-10員雜環-C1-6烷基(此處，雜環上亦可取代有C1-6烷基或C1-6烷氧基羰基)或4-10員雜環；R13或R14彼此獨立表示氫原子或鹵素原子；[化4]R15表示氫原子、羥基、或在環內之為單鍵時表示側氧基]。 A compound or a salt thereof or a solvent thereof, which is represented by the following general formula (1): Wherein Ring A represents a C 6 -C 10 aryl group or a 5-10 membered heterocyclic group; Z represents O, NR 9 , S(O)m, CH 2 or C=O (here, R 9 represents hydrogen Atom, C 1-6 alkyl, C 1-7 alkanoyl or C 1-6 alkylsulfonyl, m represents an integer from 0 to 2; [Chemical 2] Represents a single bond or a double bond; R 1 , R 2 , R 3 and R 4 are independently of each other or a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a carboxy-C 1-6 alkyl group, or a C 1-6 group alkoxycarbonyl-C 1-6 alkyl, 4-10 membered heterocyclic-C 1-6 alkyl (here, the 4-10 membered heterocyclic ring may also be substituted with C 1-6 alkyl or C 1- 6 alkylsulfonyl), C 1-6 alkoxy, C 3-10 cycloalkyl-C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl An oxy group, a C 1-6 alkylsulfonylamino group, a hydroxyl group, a cyano group, a nitro group, a tetrazolyl group, or a group represented by the following formula (2) or formula (3): [Chemical 3] (wherein R 10 and R 11 each independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group; and R 12 represents a C 1-20 alkyl group, a C 2-6 alkenyl group, a halogen C 1-6 alkyl group, C 2-7 alkyl fluorenyl, C 6-10 aryl, 4-10 membered heterocyclic group (halogen may also be substituted with a halogen atom), C 3-10 cycloalkyl-C 1-6 alkyl, amine Group C 1-6 alkyl, hydroxy-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, carboxy-C 1-6 alkyl , C 1-6 alkoxycarbonyl-C 1-6 alkyl, amine mercapto-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 6-10 Aryl-C 1-6 alkyl (here, the C 6-10 aryl group may also be substituted with a halogen atom, a C 1-6 alkyl group, a halogen C 1-6 alkyl group, a C 1-6 alkyl sulfonium group) Or a carboxyl group or a 4-10 membered heterocyclic-C 1-6 alkyl group (here, the heterocyclic ring may also be substituted with a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group or a pendant oxy group). 1 represents an integer from 1 to 3, and n represents an integer from 0 to 2; R 5 , R 6 and R 7 independently of each other represent a hydrogen atom, a halogen atom, a cyano group or a carboxyl group; and R 8 represents a C 1-6 alkyl group; , C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, trialkyl fluorenyl-C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkane oxy-C 1-6 alkyl, C 3- 10 cycloalkyl (here, a cycloalkyl group may also be substituted with a halogen atom), C 3-10 cycloalkyl-C 1-6 alkyl (here, a cycloalkyl group may also be substituted with C 1-6 Alkyl), C 6-10 aryl (here, a C 6-10 aryl group may also be substituted with a halogen atom, a cyano group, a halogen C 1-6 alkoxy group, an amine group, a dialkylamino group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylthio or C 6-10 aryl-C 1-6 alkyloxy), C 6-10 aryl-C 1- 6 alkyl (here, C 6-10 aryl may also be substituted with a halogen atom, a C 1-6 alkyl group, a halogen C 1-6 alkoxy group or a halogen C 1-6 alkyl group), 4-10 members Heterocyclic-C 1-6 alkyl (here, the heterocyclic ring may also be substituted with a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group) or a 4-10 membered heterocyclic ring; R 13 or R 14 are each other Independently represents a hydrogen atom or a halogen atom; [Chemical 4] R 15 represents a hydrogen atom, a hydroxyl group, or When it is a single bond, it represents a side oxy group]. 如申請專利範圍第1項之化合物或其鹽或其等之溶媒合物，其中，A環為選自苯基、吡啶基、吲哚基、吡基、嗒基、嘧啶基、噻唑基及二唑基的基，Z為O。 The solvent of the compound of claim 1 or a salt thereof or a solvent thereof, wherein the ring A is selected from the group consisting of a phenyl group, a pyridyl group, a fluorenyl group, and a pyridyl group. Base Base, pyrimidinyl, thiazolyl and The base of the oxazolyl group, Z is O. 如申請專利範圍第1項之化合物或其鹽或其等之溶媒合物，其中，一般式(1)中，R1、R2、R3及R4中之一者為C1-6烷基磺醯基、4-10員雜環-C1-6烷基(此處，雜環亦可具有上述取代基)或式(2)所示之基，其餘為不存在或氫原子、鹵素原子、氰基、C1-6烷基、C1-6烷氧基、C3-8環烷基-C1-6烷氧基。 The solvent of the compound of claim 1 or a salt thereof or a solvent thereof, wherein, in the general formula (1), one of R 1 , R 2 , R 3 and R 4 is a C 1-6 alkane a sulfonyl group, a 4-10 membered heterocyclic-C 1-6 alkyl group (wherein the heterocyclic ring may have the above substituent) or a group represented by the formula (2), and the remainder is absent or a hydrogen atom or a halogen Atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkoxy. 如申請專利範圍第1項之化合物或其鹽或其等之溶媒合物，其中，式(2)所示之基為C1-6烷基-S(O)nCH2-、C6-10芳基-C1-6烷基-S(O)nCH2-或4-10員雜環-C1-6烷基-S(O)nCH2-(此處，芳基或雜環亦可具有上述取代基，n表示0~2之整數)。 The solvent of the compound of claim 1 or a salt thereof or a solvent thereof, wherein the group represented by the formula (2) is a C 1-6 alkyl-S(O) n CH 2 -, C 6- 10 aryl group -C 1-6 alkyl -S (O) n CH 2 -, or 4-10 membered heterocyclyl -C 1-6 alkyl -S (O) n CH 2 - ( herein, aryl or heteroaryl The ring may have the above substituents, and n represents an integer of 0 to 2). 如申請專利範圍第1項之化合物或其鹽或其等之溶媒合物，其係選自下述之化合物群： 第三丁基6-(4-(甲基磺醯基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(3-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-硝基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯胺)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-羥基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)氧基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基亞磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(6-((甲基磺醯基)甲基)吡啶-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-甲基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-甲氧基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)-3-丙氧基苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-(環丙基甲氧基)-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((1-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((2-甲基磺醯基)丙烷-2-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(1H-四唑-1-基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-(5-(甲基磺醯基)吲哚-1-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(甲基磺醯基)甲基-N-哌啶基)螺[唍-2,4’-哌啶]-1’-羧酸酯、乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲氧基乙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-雙(三氟甲基)苄基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、吡啶-4-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、吡啶-3-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 吡啶-2-基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氯-2-甲基丙烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-1-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-2-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、氧雜環丁烷-3-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、四氫-2H-哌喃-4-基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4,4-二氟環己基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 1,1,1-三氟-2-甲基丙烷-2-基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氯-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3,5-二氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((吡啶-4-基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((吡啶-4-基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苯基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((5-甲基-1,3,4-噻二唑-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((十二烷基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((十二烷基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙醯基硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-((烯丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((2-甲氧基乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((環丙基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((環己基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡啶-3-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、環丙基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍烯-2,4’-哌啶]-1’-羧酸酯、 環丁基甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1-甲基環丙基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丁基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)吡-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(6-((甲基磺醯基)甲基)嗒-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((甲基磺醯基)甲基)噻唑-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-((甲基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-((甲基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(3-氟-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(5-((甲基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基3-羥基-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((甲基磺醯基)甲基)苯基)-3-側氧基螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基4,4-二氘-6-(4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基4-氟-6-(4-((甲基磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氰基-4-((甲基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((乙基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-(2-(異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3,5-二氟-4-((異丙基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 新戊基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((2-氟乙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-(((氰基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((氰基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(3-氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氯乙基6-(3,5-二氟-4-(((3,3,3-三氟丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3-羥基丙基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、異丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、異丁基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1-環丙基乙基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(異丙基-d7)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(第三丁基-d9)6-(5-(((3-羥基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((3-羥基丙基)磺醯基)甲基)嘧啶-2-基)[唍-2,4-哌啶]-1’-羧酸酯、(R)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(R)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 (R)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(R)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-第三丁基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-新戊基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、(S)-1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2-甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(5-(((3-羥基-2,2-二甲基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、 新戊基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟異丙基6-(5-(((3-甲氧基丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-((((3-甲基氧雜環丁烷-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟異丙基6-(5-((((四氫呋喃-3-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((四氫-2H-哌喃-4-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((3-胺基丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(S)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(R)-第三丁基6-(5-(((3-(3-氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-(((3-(3,3-二氟吡咯啶-1-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((甲基磺醯基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-甲氧基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(((4-(1’-第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)丁酸、第三丁基6-(4-(((4-胺基-4-側氧基丁基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-乙氧基-2-甲基-1-側氧基丙烷-2-基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氟乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 3,3,4,4,4-五氟丁基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((吡啶-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(乙基-d5)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(異丙基-d7)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(第三丁基-d9)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1,1,1,3,3,3-六氟丙烷-2-基-2-d1)6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1-(第三丁氧基羰基)哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 (1-甲基哌啶-4-基)甲基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苄基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-((苄基磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((苄基磺醯基)甲基)-3-氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-((苄基磺醯基)甲基)-3,5-二氟苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((苄基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-((苄基磺醯基)甲基)-1,2,4-二唑-3-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(2-((苄基磺醯基)甲基)噻唑-5-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((4-氟苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((4-氟苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((4-(三氟甲基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((4-(三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(5-(((2-甲基苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-((((2-三氟甲基)苄基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、3-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、2-((((4-1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苄基)磺醯基)甲基)苯甲酸、第三丁基6-(4-((((4-(甲基磺醯基)苄基)硫基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((4-(甲基磺醯基)苄基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 異丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-環丙基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第二丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三戊基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-甲基戊烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-甲基戊烷-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基丁-3-烯-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基丁-3-炔-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-甲基戊-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、己-1-炔-3-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2-氰基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,3,5-三甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1R,2S,4S)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1S,2R,4R)-2-異丙基-4-甲基環己基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(3-甲基氧雜環丁烷-3-基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、環己基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、金剛烷-1-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(三甲基矽基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,2,2-三氟乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,3,4,4,4-五氟丁基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟-2-甲基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1,3,3,3-六氟-2-(三氟甲基)丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(甲基-d3)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(乙基-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(異丙基-d7)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(第三丁基-d9)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(1,1,1,3,3,3-六氟-2-丙烷-2-基-2-d1)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-苯基乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-苯基丙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯乙基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基-1-苯基丙烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-甲基-4-苯基丁烷-2-基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 3-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(三氟甲氧基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,3-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 3,5-二氯苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-6-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-4-氟苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二甲基苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-雙(三氟甲基)苄基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(全氟苯基)甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 呋喃-2-基甲基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氰基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(三氟甲氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 3-(二甲基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3-(二乙基胺基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-異丙基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三丁基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(第三戊基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(甲基硫基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,6-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,3-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 2,6-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,5-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,4-二氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-6-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氯-4-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-2-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-3-氟苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 4-氯-3-甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟-3-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-氟-5-(三氟甲基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,4,6-三氯苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-氯-3,5-二甲基苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、4-(苄基氧基)苯基6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、(苯基-2,3,4,5,6-d5)6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3-氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2,2,2-三氯乙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-羧酸酯、 新戊基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(3,5-二氟-4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-((((6-(1’-(第三丁氧基羰基螺(唍-2,4’-哌啶)-6-基)吡啶-3-基)甲基)磺醯基)甲基)吡啶-1-氧化物、第三丁基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-(((吡啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丁基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 1-環丙基乙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、新戊基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、1-甲基環丙基6-(5-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)嘧啶-2-基螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-((((6-甲基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((6-甲氧基吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((吡-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(5-(((吡-2-基甲基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4-哌啶]-1’-羧酸酯、第三丁基6-(4-(((噻唑-4-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((((3-異丙基-1,2,4-二唑-5-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(5-((((嘧啶-2-基甲基)磺醯基)甲基)嘧啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)乙基)亞磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((1-(吡啶-2-基)丙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、新戊基6-(4-(((2-(吡啶-2-基)乙基)磺醯基)甲基)苯基)[唍-2,4’-哌啶]-1’-羧酸酯、1,1,1-三氟丙烷-2-基6-(4-(((2-吡啶-2-基)乙基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基7-氟-6-(4-(((吡啶-2-基甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、 第三丁基6-(4-(2-甲基磺醯基)乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-((1H-咪唑-1-基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、第三丁基6-(4-(2-乙氧基-2-側氧基乙基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯、2-(4-(1’-(第三丁氧基羰基)螺[唍-2,4’-哌啶]-6-基)苯基)醋酸、異丙基6-(5-((異丙基磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、異丙基6-(5-(((3,3,3-三氟丙基)磺醯基)甲基)吡啶-2-基)螺[唍-2,4’-哌啶]-1’-羧酸酯、及異丙基6-(4-((((5-氟吡啶-2-基)甲基)磺醯基)甲基)苯基)螺[唍-2,4’-哌啶]-1’-羧酸酯。 A compound according to claim 1 or a salt thereof or a solvent thereof, which is selected from the group consisting of: a third butyl 6-(4-(methylsulfonyl)phenyl) snail [ Terpene-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(3-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-nitrophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonamide)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-hydroxyphenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)oxy)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfinyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(6-((methylsulfonyl)methyl)pyridin-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-methyl-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-methoxy-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)-3-propoxyphenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-(cyclopropylmethoxy)-4-((methylsulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1-methylsulfonyl)ethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((2-methylsulfonyl)propan-2-yl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(1H-tetrazol-1-yl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(methylsulfonyl)indol-1-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-(5-(methylsulfonyl)indol-1-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(methylsulfonyl)methyl-N-piperidinyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoroethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methoxyethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, benzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorobenzyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3,5-bis(trifluoromethyl)benzyl 6-(4-((methylsulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-4-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-3-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, pyridin-2-ylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trichloro-2-methylpropan-2-yl 6-(4-((methylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-1-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-2-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, oxetan-3-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tetrahydro-2H-piperidin-4-yl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4,4-difluorocyclohexyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3-fluoro-4-((methyl sulfonate) Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3-chloro-4-((methyl sulfonate) Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-chloro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(3,5-difluoro-4-(( Methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3,5-difluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((pyridin-4-ylthio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((pyridin-4-ylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((phenylthio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((phenylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazol-2-yl)sulfide) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((5-methyl-1,3,4-thiadiazol-2-yl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((dodecylthio)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((dodecylidene)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylidenethio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((propylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((allylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-methoxyethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((cyclopropylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((cyclohexylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-3-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridin-4-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, cyclopropylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ Terpene-2,4'-piperidine]-1'-carboxylate, cyclobutylmethyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-methylcyclopropyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclobutyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyridinium -2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(6-((methylsulfonyl)methyl)anthracene -3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)thiazol-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)thiazol-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-((methylsulfonyl)methyl)thiazol-5-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((methylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(3-fluoro-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(5-((methylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 3-hydroxy-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((methylsulfonyl)methyl)phenyl)-3-oxooxy snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 4,4-diin-6-(4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 4-fluoro-6-(4-((methylsulfonyl)methyl)phenyl)[ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-cyano-4-((methylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((ethylsulfonyl)methyl)-3,5-di Fluorophenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((ethylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-(2-(isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((isopropylsulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((isopropylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3,5-difluoro-4-((isopropylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((isopropylsulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-fluoroethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-(((cyanomethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((cyanomethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((3,3,3-trifluoropropyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-(((3,3,3-trifluoropropyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(3-fluoro-4-((3,3,3-trifluoropropyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-((3,3,3-trifluoropropyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-((3,3,3-three) Fluoropropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((3,3,3-trifluoropropyl)) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-hydroxypropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, isopropyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, isobutyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3-(hydroxypropyl))sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4-piperidinyl-1'-carboxylate, 1-cyclopropylethyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-((3-hydroxypropyl)sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-((3-hydroxypropyl)sulfonate Mercapto)methyl)pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (isopropyl-d7)6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(5-((3-(hydroxypropyl))sulfonyl)methyl)pyridine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-hydroxypropyl)sulfonyl)methyl)pyrimidin-2-yl)[ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((3-(hydroxypropyl))sulfonyl)methyl)pyrimidin-2-yl )[ 唍-2,4-piperidinyl-1'-carboxylate, (R)-tert-butyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (R)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (R)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2-methyl)) Propyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, (R)-1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, (S)-t-butyl 6-(5-(((3-hydroxy-2-methylpropyl))sulfonyl)methyl Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (S)-neopentyl 6-(5-(((3-hydroxy-2-methylpropyl)sulfonyl)methyl)) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, (S)-1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2-methyl)) Propyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, (S)-1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy) -2-methylpropyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl) Pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-hydroxy-2,2-dimethylpropyl)sulfonyl)methyl)pyridine -2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-(((3-hydroxy-2,2-dimethylpropane) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(5-(((3-hydroxy-2,2) -Dimethylpropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) screw[ 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-((3-methoxypropyl)sulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoroisopropyl 6-(5-((3-(methoxypropyl))sulfonyl) Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((((methylamino))-3-yl)methyl)sulfonate Base) methyl)phenyl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-(((3-methyloxetan-3-yl)methyl)sulfonyl) )methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))))))))) -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))sulfonyl)methyl)pyridine-2- Snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoroisopropyl 6-(5-((((tetrahydrofuran-3-yl)methyl)))sulfonyl) )methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)) Methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-aminopropyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (S)-t-butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (R)-t-butyl 6-(5-((3-(3-fluoropyrrolidin-1-yl)propyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((3-(3,3-difluoropyrrolidin-1-yl)propyl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((methylsulfonyl)propyl)))))))))))) [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((4-methoxy-4-oxobutyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidinyl-1'-carboxylate, 4-((4-(1'-t-butoxycarbonyl)) snail [ Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)butyric acid, tert-butyl 6-(4-((4-amino-4-yloxybutyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1-ethoxy-2-methyl-1-oxopropane-2-) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3,3,4,4,4-pentafluorobutyl 6-(4-((benzylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-(((pyridin-4-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-((benzylsulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-((benzylsulfonyl)) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4 -((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (ethyl-d5)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (isopropyl-d7)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1)6-(4-(( Benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-(t-butoxycarbonyl)piperidin-4-yl)methyl 6-(4-((benzylsulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1-methylpiperidin-4-yl)methyl 6-(4-((benzylsulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylbenzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)benzyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((benzylsulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((benzylsulfonyl)methyl)-3-fluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((benzylsulfonyl)methyl)-3,5-difluorophenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-((benzylsulfonyl)methyl)-3,5-di Fluorophenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((benzylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((benzylsulfonyl)methyl)-1,2,4- Diazol-3-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(2-((benzylsulfonyl)methyl)thiazol-5-yl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((4-)fluoro))))))))) 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((4-fluorobenzyl)sulfonyl) A Phenyl) snail Indole-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((4-(4-(4-(yl))))))))))) [ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-((4-(trifluoromethyl)benzyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((4-(trifluoromethyl)benzyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((4-(trifluoromethyl)benzyl))sulfonyl)methyl)pyridine- 2-base) snail [ Indole-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(5-(((2-methylbenzyl))sulfonyl)methyl)pyridin-2-yl) snail [ Indole-2,4'-piperidinyl-1'-carboxylate, tert-butyl 6-(5-(((2-)trifluoromethyl)benzyl)sulfonyl)methyl)pyridine- 2-base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-((((((((((((((((((((((( 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, 3-((((((())))) Indole-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, 2-((((()))) 唍-2,4'-piperidinyl]-6-yl)benzyl)sulfonyl)methyl)benzoic acid, tert-butyl 6-(4-((((4-(methylsulfonyl)))) Benzyl)thio)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((4-(methylsulfonyl)benzyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, ethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ Indole-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isobutyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, second butyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, third pentyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-methylpentan-2-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-methylpentan-3-yl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-methylbut-3-en-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methylbut-3-yn-2-yl-6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-methylpent-1-yn-3-yl-6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, hex-1-yn-3-yl-6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-cyanoethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, cyclohexyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)cyclohexyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,3,5-trimethylcyclohexyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, (1R, 2S, 4S)-2-isopropyl-4-methylcyclohexyl 6-(4-(((pyridine-2-) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (1S, 2R, 4R)-2-isopropyl-4-methylcyclohexyl 6-(4-(((pyridine-2-) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (3-methyloxetan-3-yl)methyl 6-(4-(((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, cyclohexylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, adamantyl-1-ylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, (trimethylmethyl)methyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trifluoroethyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,3,4,4,4-pentafluorobutyl 6-(4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoro-2-methylpropan-2-yl 6-(4-(((pyridin-2-yl)) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoropropan-2-yl 6-(4-(((pyridin-2-yl)) Methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl 6-(4 -(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (methyl-d3)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, (ethyl-d5)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, (isopropyl-d7)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) )screw[ 唍-2,4'-piperidine]-1'-carboxylate, (t-butyl-d9)6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, (1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1)6-(4 -(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-phenylethyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-phenylpropyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-methyl-1-phenylpropan-2-yl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-phenylbutan-2-yl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-methyl-4-phenylbutan-2-yl 6-(4-((pyridin-2-ylmethyl)sulfonate Mercapto)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorobenzyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-(trifluoromethoxy)benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-methylbenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(trifluoromethyl)benzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylbenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)benzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,3-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dichlorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,5-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-difluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-6-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-4-fluorobenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dimethylbenzyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-bis(trifluoromethyl)benzyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, (perfluorophenyl)methyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, furan-2-ylmethyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, phenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-chlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-chlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-fluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-cyanophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidinyl-1'-carboxylate, 3-cyanophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-cyanophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl) screw[ 唍-2,4'-piperidine]-1'-carboxylate, 2-(trifluoromethoxy)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-(dimethylamino)phenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3-(diethylamino)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-isopropylphenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 4-(t-butyl)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-(tripentyl)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-(methylthio)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,3-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dichlorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,6-difluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-difluorophenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,5-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 3,4-difluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-6-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-chloro-4-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-2-fluorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3-fluorophenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,4-dimethylphenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 3,5-dimethylphenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3-methylphenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoro-3-(trifluoromethyl)phenyl 6-(4-(((pyridin-2-ylmethyl))sulfonyl) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-fluoro-5-(trifluoromethyl)phenyl 6-(4-((pyridin-2-ylmethyl))sulfonate Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2,4,6-trichlorophenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl)methyl Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 4-chloro-3,5-dimethylphenyl 6-(4-((pyridin-2-ylmethyl)sulfonyl) )methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 4-(benzyloxy)phenyl 6-(4-(((pyridin-2-ylmethyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, (phenyl-2,3,4,5,6-d5)6-(4-(((pyridin-2-ylmethyl))) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3-fluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3-fluoro-4-((pyridin-2-ylmethyl)sulfonate) Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, 2,2,2-trichloroethyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-carboxylate, neopentyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(3,5-difluoro-4-(((pyridin-2-ylmethyl))sulfonate Base) methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyridin-2-yl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, 2-((((6-(1'-)(t-butoxycarbonyl snail) Indole-2,4'-piperidine)-6-yl)pyridin-3-yl)methyl)sulfonyl)methyl)pyridine-1-oxide, tert-butyl 6-(5-((( Pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-(((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidin-2-yl) snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-((pyridin-2-ylmethyl)sulfonyl)methyl)pyrimidine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, isobutyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1-cyclopropylethyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-(((5-fluoropyridin-2-yl))) Sulfhydryl)methyl)phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl) Methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(5-(((5-fluoropyridin-2-yl))) Sulfhydryl)methyl)pyridin-2-yl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Pyrimidine-2-yl snail 唍-2,4-piperidinyl-1'-carboxylate, neopentyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl)pyrimidine- 2-based snail [ 唍-2,4-piperidinyl-1'-carboxylate, 1-methylcyclopropyl 6-(5-(((5-fluoropyridin-2-yl)methyl)sulfonyl)) Pyrimidine-2-yl snail 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-(((6-methylpyridin-2-yl)methyl)sulfonyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((6-methoxypyridin-2-yl)methyl)sulfonyl)) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((pyridyl) -2-ylmethyl)sulfonyl)methyl)pyridin-2-yl) spiro[ 唍-2,4-piperidinyl-1'-carboxylate, tert-butyl 6-(4-((thiazolyl-4-ylmethyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((((3-isopropyl-1,2,4-) Diazol-5-yl)methyl)sulfonyl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(5-(((pyrimidin-2-ylmethyl))sulfonyl)methyl)pyrimidin-2- Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)sulfinyl)methyl) Phenyl) snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)ethyl)))))) Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((1-(pyridin-2-yl)propyl)))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(((2-pyridin-2-yl)ethyl)sulfonyl)methyl)phenyl )screw[ 唍-2,4'-piperidine]-1'-carboxylate, neopentyl 6-(4-(((2-(pyridin-2-yl)ethyl)))sulfonyl)methyl)phenyl )[ 唍-2,4'-piperidinyl-1'-carboxylate, 1,1,1-trifluoropropan-2-yl 6-(4-(((2-pyridin-2-yl)ethyl)) Sulfhydryl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 7-fluoro-6-(4-(((pyridin-2-ylmethyl))sulfonyl)methyl)benzene Snail 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(2-methylsulfonyl)ethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-((1H-imidazol-1-yl)methyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, tert-butyl 6-(4-(2-ethoxy-2-oxoethyl)phenyl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, 2-(4-(1'-(t-butoxycarbonyl)) snail [ 唍-2,4'-piperidinyl]-6-yl)phenyl)acetic acid, isopropyl 6-(5-((isopropylsulfonyl)methyl)pyridin-2-yl) snail [ 唍-2,4'-piperidine]-1'-carboxylate, isopropyl 6-(5-((3,3,3-trifluoropropyl)sulfonyl)methyl)pyridine-2 -base) snail [ 唍-2,4'-piperidine]-1'-carboxylate, and isopropyl 6-(4-(((5-fluoropyridin-2-yl)methyl)sulfonyl)methyl) Phenyl) snail Indole-2,4'-piperidinyl-1'-carboxylate. 一種醫藥組成物，係含有申請專利範圍第1至5項中任一項之化合物或其鹽或其等之溶媒合物、及作為醫藥所容許的載體。 A pharmaceutical composition comprising a compound of any one of claims 1 to 5, a salt thereof, or a solvent thereof, and a carrier acceptable for use as a medicine. 一種胰島素分泌促進劑，係以申請專利範圍第1至5項中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 An insulin secretion-promoting agent is used as an active ingredient of the compound of any one of Claims 1 to 5, or a salt thereof, or a solvent thereof. 一種血糖降低劑，係以申請專利範圍第1至5項中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 A blood sugar lowering agent, which is a compound of any one of the above claims 1 to 5, or a salt thereof or a solvent thereof, as an active ingredient. 一種糖尿病之預防及/或治療劑，係以申請專利範圍第1 至5項中任一項之化合物或其鹽或其等之溶媒合物作為有效成分。 A preventive and/or therapeutic agent for diabetes, which is patented first The compound of any one of the above 5 or a salt thereof or a solvent thereof or the like is used as an active ingredient.
TW101117744A 2011-05-20 2012-05-18 Novel spiropiperidine derivative and pharmaceutical product containing same TW201300393A (en)

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