TW202045494A - Pyridine compound substituted by heteroaryl - Google Patents

Pyridine compound substituted by heteroaryl Download PDF

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TW202045494A
TW202045494A TW109103944A TW109103944A TW202045494A TW 202045494 A TW202045494 A TW 202045494A TW 109103944 A TW109103944 A TW 109103944A TW 109103944 A TW109103944 A TW 109103944A TW 202045494 A TW202045494 A TW 202045494A
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川村円
舟山浩介
鈴木一瑛
田中宏明
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日商大正製藥股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention provides a compound represented by formula (I'), which has an inhibitory effect on an enzyme that produces 20-HETE, or a pharmaceutically acceptable salt of the compound. (In formula (I'), ring D represents one of the groups represented by formula (I'-1) to formula (I'-3); each of R1, R2, R3 and R4 independently represents a hydrogen atom, a fluorine atom, a methyl group or the like; X represents -O-, -S- or -CH2-; and R5 represents one of the structures represented by formulae (II).).

Description

經雜芳基取代的吡啶化合物Pyridine compounds substituted by heteroaryl

本發明係關於產生20-羥基二十碳四烯酸(20-Hydroxyeicosatetraenoic acid，以下亦記載為「20-HETE」。)之酵素的阻礙物質。更詳細係關於產生20-HETE的酵素的阻礙物質之經雜芳基取代的吡啶化合物。The present invention relates to an inhibitor of an enzyme that produces 20-Hydroxyeicosatetraenoic acid (20-Hydroxyeicosatetraenoic acid, also referred to as "20-HETE" below). In more detail, it is a pyridine compound substituted with a heteroaryl group, which is an inhibitor of the enzyme producing 20-HETE.

作為從花生四烯酸產生的生理活性物質，除了由環氧化酶產生的前列腺素類及由脂氧合酶產生的白三烯類，在近年，漸漸瞭解由屬於細胞色素P450之酵素從花生四烯酸產生的20-HETE在活體內具有各種功能。到目前為止明白20-HETE在腦血管或腎臓等之主要臓器中，調節血管緊張性或引起細胞增殖，暗示在活體內具有重要生理作用同時與各種腦血管疾病、腎疾病、循環器官疾病等之病態有高度相關(非專利文獻1~3)。進一步，在近年，清楚明白多囊腎的病態形成與20-HETE有關。多囊腎被分類為體染色體顯性多囊腎及體染色體隱性多囊腎，為在腎臓形成大量囊腫而損害腎機能之遺傳性囊腫性腎疾病。暗示對於多囊腎發病的病態動物，20-HETE阻礙藥抑制細胞內增殖信號且發揮腎囊腫改善效果(非專利文獻4)。又，體染色體顯性多囊腎患者中，認為腎容積增大及腎機能降低與血漿中20-HETE濃度上昇有相關性，暗示多囊腎的病態進行與20-HETE有關連(非專利文獻5)。 產生20-HETE的酵素的阻礙物質方面，報告有羥基甲脒衍生物(專利文獻1)或具有苯基唑骨架之化合物的雜環衍生物(專利文獻2)或苯基唑化合物(專利文獻3)等。在專利文獻2雖有吡唑基等之經雜芳基取代的吡啶化合物的揭示，但限定於吡啶之3位取代。又，在專利文獻4雖有吡啶的2位經三唑基等之雜芳基取代的吡啶化合物的揭示，但吡啶5位之取代基被限定，且無羧基等顯示酸性之基的揭示。 [先前技術文獻] [專利文獻] [專利文獻1] WO01/032164 [專利文獻2] WO03/022821 [專利文獻3] WO2004/092163 [專利文獻4] WO2017/141927 [非專利文獻] [非專利文獻1] Journal of Vascular Research，第32卷，79頁，1995年 [非專利文獻2] The American Journal of Physiology，第277卷，R607頁，1999年 [非專利文獻3] Physiological Reviews，第82卷，131頁，2002年 [非專利文獻4] American Journal of Physiology Renal Physiology，第296卷，F575頁，2009年 [非專利文獻5] Journal of Lipid Research、第55卷、1139頁、2014年As physiologically active substances produced from arachidonic acid, in addition to prostaglandins produced by cyclooxygenase and leukotrienes produced by lipoxygenase, in recent years, it has gradually been understood that the enzymes belonging to cytochrome P450 are 20-HETE produced by enoic acid has various functions in vivo. So far, it is understood that 20-HETE regulates vascular tone or causes cell proliferation in the main organs such as cerebrovascular or kidney, implying that it has an important physiological role in the living body and is also associated with various cerebrovascular diseases, kidney diseases, and circulatory organ diseases. Illness is highly correlated (Non-Patent Documents 1~3). Furthermore, in recent years, it has become clear that the pathogenesis of polycystic kidney disease is related to 20-HETE. Polycystic kidneys are classified into autosomal dominant polycystic kidneys and autosomal recessive polycystic kidneys, which are hereditary cystic kidney diseases that form a large number of cysts in the kidney and impair kidney function. It is suggested that, for diseased animals with polycystic kidney disease, a 20-HETE inhibitor suppresses intracellular proliferation signals and exerts a renal cyst improvement effect (Non-Patent Document 4). In addition, in patients with autosomal dominant polycystic kidney disease, it is believed that the increase in renal volume and decrease in renal function are related to the increase in the concentration of 20-HETE in plasma, suggesting that the progression of polycystic kidney disease is related to 20-HETE (Non-Patent Document 5). Regarding inhibitors of enzymes that produce 20-HETE, hydroxyformamidine derivatives (Patent Document 1) or heterocyclic derivatives of compounds having a phenylazole skeleton (Patent Document 2) or phenylazole compounds (Patent Document 3) have been reported. )Wait. Although Patent Document 2 discloses a pyrazole compound substituted with a heteroaryl group such as a pyrazolyl group, it is limited to the 3-position substitution of pyridine. In addition, although Patent Document 4 discloses a pyridine compound in which the 2-position of pyridine is substituted with a heteroaryl group such as a triazolyl group, the substituent at the 5-position of pyridine is limited, and there is no disclosure of an acidic group such as a carboxyl group. [Prior Technical Literature] [Patent Literature] [Patent Document 1] WO01/032164 [Patent Document 2] WO03/022821 [Patent Document 3] WO2004/092163 [Patent Document 4] WO2017/141927 [Non-Patent Literature] [Non-Patent Document 1] Journal of Vascular Research, Volume 32, Page 79, 1995 [Non-Patent Document 2] The American Journal of Physiology, Volume 277, page R607, 1999 [Non-Patent Document 3] Physiological Reviews, Vol. 82, p. 131, 2002 [Non-Patent Document 4] American Journal of Physiology Renal Physiology, Volume 296, Page F575, 2009 [Non-Patent Document 5] Journal of Lipid Research, Volume 55, Page 1139, 2014

[發明所欲解決之課題] 本發明之目的係提供阻礙產生20-HETE的酵素之新穎化合物。 [用以解決課題之手段] 本發明者們為了達成上述課題，努力檢討之結果，發現下述式[I’]所表示之化合物(以下，亦記載為化合物[I’]。)具有阻礙產生20-HETE的酵素之作用。 以下將本發明詳細說明。 即，本發明之態樣如下。 (1)本發明之一個態樣為提供 下述式[I’]所表示之化合物或其製藥學上所容許之鹽

Figure 02_image001
{上述式[I’]中， 環D為式[I’-1]~式[I’-3]所表示之基之任一
Figure 02_image003
； R1 為氫原子、氟原子、氯原子、或甲基； R2 、R3 、及R4 獨立地為氫原子、氟原子、或甲基； X為式-O-、式-S-、或式-CH2 -； R5 為下述式群[II]所表示之構造之任一
Figure 02_image005
； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III]所表示之構造之任一
Figure 02_image007
， 在此， 式[III-4]表示之構造可被1~2個羥基取代， 又，環C為 (i)C3-6 環烷烴、 (ii)含有氧原子的4到6員之飽和的雜環、或 (iii)含有硫原子的4到6員之飽和的雜環(該含有硫原子的4到6員之飽和的雜環的硫原子可被1~2個側氧基取代。)； Y為式-CH2 -、式-CHMe-、式-CMe2 -、或式-O-； W1 為C2-10 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基或羧基甲基； 環A為下述式群[IV]所表示之構造之任一
Figure 02_image009
， 在此， 前述式[IV-1]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-5]所表示之構造可被1個甲基取代； W2 為C4-8 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； 環B為 (a)苯基、 (b)吡啶基、或 (c)苯並二氫吡喃基； W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-6 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子、氟原子、氯原子、或甲基； (b)環B為吡啶基時， R53 係選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基、 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-4 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基； 此時，R61 及R62 獨立地為氫原子或甲基。}。 (2)本發明之其他態樣方面，提供(1)記載之化合物或其製藥學上所容許之鹽， 前述式[I’]中， 環D為前述式[I’-1]所表示之基， 前述式[I’]為下述式[I]：
Figure 02_image011
。 (3)本發明之其他態樣方面，係提供(1)記載之化合物或其製藥學上所容許之鹽， 前述式[I’]中， X為式-O-。 (4)本發明之其他態樣方面，係提供(2)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中， X為式-O-。 (5)本發明之其他態樣方面，係提供(4)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； R1 為氫原子； R2 為氫原子、 R3 為氫原子、 R4 為氫原子； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’]所表示之構造之任一
Figure 02_image013
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基或羧基甲基； 環A為下述式群[IV’]所表示之構造之任一
Figure 02_image015
， 在此， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-5]所表示之構造可被1個甲基取代； W2 為C4-6 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (iii)被羧基取代的C3-6 環烷基、及 (iv)被羧基取代的單C1-6 烷基胺基羰基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (b)環B為吡啶基時， R53 係選自 (iii)被羧基取代的C3-6 環烷基及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基； 此時，R61 及R62 獨立地為氫原子或甲基。 (6)本發明之其他態樣方面，係提供(5)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 02_image017
， 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image019
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 (7)本發明之其他態樣方面，係提供(6)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造；且 R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 02_image021
， 在此， 式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基。 (8)本發明之其他態樣方面，係提供(6)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image023
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基。 (9)本發明之其他態樣方面，係提供(6)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 (10)本發明之其他態樣方面，係提供(5)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image025
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image027
， 在此， 前述式[IV-6]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 同是氫原子。 (11)本發明之其他態樣方面，係提供(10)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造；且 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image029
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基。 (12)本發明之其他態樣方面，係提供(10)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (B) R5 為前述式[II-2]所表示之構造；且 R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image031
， 在此， 前述式[IV-6]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基。 (13)本發明之其他態樣方面，係提供(10)記載之化合物或其製藥學上所容許之鹽， 前述式[I]中； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 同是氫原子。 (14)本發明之其他態樣方面，係提供(3)記載之化合物或其製藥學上所容許之鹽， 前述式[I’]中， 環D為前述式[I’-2]所表示之基。 (15)本發明之其他態樣方面，係提供請求項3記載之化合物或其製藥學上所容許之鹽， 前述式[I’]中， 環D為前述式[I’-3]所表示之基。 (16)本發明之其他態樣方面，係提供(1)~(4)之任一記載之以下所示之化合物或其製藥學上所容許之鹽：
Figure 02_image033
Figure 02_image035
。 (17)本發明之其他態樣方面，係提供(1)~(4)之任一記載之以下所示之化合物或其製藥學上所容許之鹽：
Figure 02_image037
。 (18)本發明之其他態樣方面，係提供(1)~(3)、(14)之任一記載之以下所示之化合物或其製藥學上所容許之鹽：
Figure 02_image039
。 (19)本發明之其他態樣方面，係提供(1)~(3)、(15)之任一記載之以下所示之化合物或其製藥學上所容許之鹽：
Figure 02_image041
。 (20)本發明之其他態樣方面，係提供含有以(1)~(19)之任一記載之化合物或其製藥學上所容許之鹽作為有效成分之醫藥。 (21)本發明之其他態樣方面，係提供含有以(1)~(19)之任一記載之化合物或其製藥學上所容許之鹽作為有效成分之20-HETE產生酵素阻礙劑。 (22)本發明之其他態樣方面，係提供含有以(1)~(19)之任一記載之化合物或其製藥學上所容許之鹽為有效成分之多囊腎的預防或改善劑。 [發明之效果] 本發明化合物(以下亦記載為「本發明化合物」。)具有阻礙產生20-HETE的酵素之作用。[Problem to be solved by the invention] The object of the present invention is to provide a novel compound that inhibits the enzyme producing 20-HETE. [Means to Solve the Problem] The inventors of the present inventors worked hard to achieve the above-mentioned problem and found that the compound represented by the following formula [I'] (hereinafter, also referred to as compound [I'].) inhibits production The function of 20-HETE's enzyme. The present invention will be described in detail below. That is, the aspect of the present invention is as follows. (1) One aspect of the present invention is to provide a compound represented by the following formula [I'] or a pharmaceutically acceptable salt thereof
Figure 02_image001
{In the above formula [I'], ring D is any one of the groups represented by the formula [I'-1]~the formula [I'-3]
Figure 02_image003
; R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group; R 2 , R 3 , and R 4 are independently a hydrogen atom, a fluorine atom, or a methyl group; X is a formula -O-, a formula -S- , Or formula -CH 2 -; R 5 is any one of the structures represented by the following formula group [II]
Figure 02_image005
; (A) When R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III]
Figure 02_image007
Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups, and ring C is (i) C 3-6 cycloalkane, (ii) saturated with 4 to 6 members containing oxygen atoms Or (iii) a 4- to 6-membered saturated heterocyclic ring containing a sulfur atom (the sulfur atom of the 4- to 6-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 pendant oxy groups. ); Y is the formula -CH 2 -, the formula -CHMe-, the formula -CMe 2 -, or the formula -O-; W 1 is a C 2-10 alkanediyl group; (B) R 5 is the aforementioned formula [II-2 ] When the structure is represented; R 52 is a carboxyl group or a carboxymethyl group; Ring A is any one of the structures represented by the following formula group [IV]
Figure 02_image009
Here, the structure represented by the aforementioned formula [IV-1] may be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, and the aforementioned formula [IV-2] The structure may be substituted by one group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group. The structure represented by the aforementioned formula [IV-5] may be substituted by one methyl group; W 2 is C 4 -8 Alkane diyl; (C) When R 5 is the structure represented by the aforementioned formula [II-3]; Ring B is (a) phenyl, (b) pyridyl, or (c) chroman W 3 is a C 1-3 alkanediyl group; here, (a) when ring B is a phenyl group, R 53 is selected from (i) a carboxy group, (ii) a C 1-4 alkyl group substituted by a carboxy group ( iii) C 3-6 cycloalkyl substituted by carboxy, (iv) mono C 1-6 alkylaminocarbonyl substituted by carboxy, and (v) C 1-4 alkoxy substituted by carboxy Group; In this case, R 61 and R 62 are independently a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group; (b) When ring B is a pyridyl group, R 53 is selected from (i) a carboxyl group, (ii) a Carboxy substituted C 1-4 alkyl, (iii) C 3-6 cycloalkyl substituted by carboxy, (iv) mono C 1-4 alkylaminocarbonyl substituted by carboxy, and (v) substituted by carboxy C 1-4 alkoxy group constituted; At this time, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (c) when B is a ring-chromanyl, R 53 is carboxy or Carboxymethyl; In this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. }. (2) In another aspect of the present invention, the compound described in (1) or a pharmaceutically acceptable salt thereof is provided. In the aforementioned formula [I'], ring D is represented by the aforementioned formula [I'-1] The aforementioned formula [I'] is the following formula [I]:
Figure 02_image011
. (3) In another aspect of the present invention, the compound described in (1) or a pharmaceutically acceptable salt thereof is provided. In the aforementioned formula [I'], X is the formula -O-. (4) In another aspect of the present invention, the compound described in (2) or a pharmaceutically acceptable salt thereof is provided. In the aforementioned formula [I], X is the formula -O-. (5) Another aspect of the present invention provides the compound described in (4) or a pharmaceutically acceptable salt thereof, in the aforementioned formula [I]; R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 Is a hydrogen atom and R 4 is a hydrogen atom; (A) when R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any of the structures represented by the following formula group [III'] One
Figure 02_image013
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group; (B) R When 5 is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group or a carboxymethyl group; Ring A is any of the structures represented by the following formula group [IV']
Figure 02_image015
Here, the structure represented by the aforementioned formula [IV-2] can be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, and the aforementioned formula [IV-5] The structure can be substituted by 1 methyl group; W 2 is a C 4-6 alkane diyl group; (C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is a C 1-3 alkane diyl group; Here, (a) when ring B is a phenyl group, R 53 is selected from (i) a carboxy group, (iii) a C 3-6 cycloalkyl group substituted with a carboxy group, and (iv) a mono C 1- substituted with a carboxy group. 6 Alkylaminocarbonyl groups; in this case, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (b) when ring B is a pyridyl group, R 53 is selected from (iii) substituted with a carboxyl group A group consisting of a C 3-6 cycloalkyl group and (v) a C 1-4 alkoxy group substituted with a carboxyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (c) ring B is In the case of the chroman group, R 53 is a carboxyl group or a carboxymethyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. (6) In other aspects of the present invention, the compound described in (5) or a pharmaceutically acceptable salt thereof is provided, in the aforementioned formula [I]; (A) R 5 is the aforementioned formula [II-1] When the structure is represented; R 51 is a carboxyl group; L is any of the structures represented by the following formula group [III”]
Figure 02_image017
Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is C 7 alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 02_image019
, Here, the structure represented by the aforementioned formula [IV-6] can be substituted by a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 is a C 4 alkanediyl group; ( C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is C 1-2 alkanediyl; here, (c) when ring B is chromanyl, the benzo The dihydropyranyl group is a pyran-7-yl group; R 53 is a carboxyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. (7) In other aspects of the present invention, the compound described in (6) or a pharmaceutically acceptable salt thereof is provided, in the aforementioned formula [I]; (A) R 5 is the aforementioned formula [II-1] The structure represented; and R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III”]
Figure 02_image021
Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group. (8) Another aspect of the present invention provides the compound described in (6) or a pharmaceutically acceptable salt thereof, in the aforementioned formula [I]; (B) R 5 is the aforementioned formula [II-2] When the structure is shown; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 02_image023
Here, the structure represented by the aforementioned formula [IV-6] may be substituted by one group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 is a C 4 alkanediyl group. (9) In another aspect of the present invention, the compound described in (6) or a pharmaceutically acceptable salt thereof is provided, in the aforementioned formula [I]; (C) R 5 is the aforementioned formula [II-3] Represents the structure; and W 3 is a C 1-2 alkanediyl group; here, (c) when ring B is a chromanyl group, the chromanyl group is a pyran-7-yl group; R 53 is a carboxyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. (10) In other aspects of the present invention, the compound described in (5) or a pharmaceutically acceptable salt thereof is provided, in the aforementioned formula [I]; (A) R 5 is the aforementioned formula [II-1] When the structure is shown; R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image025
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group; (B) R When 5 is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 02_image027
, Here, the structure represented by the aforementioned formula [IV-6] can be substituted by one methyl group; W 2 is a C 4 alkanediyl group; (C) R 5 is the structure represented by the aforementioned formula [II-3]; And W 3 is a C 1-2 alkanediyl group; here, (c) when ring B is a chroman group, the chroman group is a pyran-6-yl group or a pyran-7 group -Group; R 53 is a carboxyl group; in this case, R 61 and R 62 are both hydrogen atoms. (11) Another aspect of the present invention provides the compound described in (10) or a pharmaceutically acceptable salt thereof, in the aforementioned formula [I]; (A) R 5 is the aforementioned formula [II-1] The structure represented; and R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image029
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group. (12) Another aspect of the present invention provides the compound described in (10) or a pharmaceutically acceptable salt thereof, in the aforementioned formula [I]; (B) R 5 is the aforementioned formula [II-2] The structure represented; and R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 02_image031
Here, the structure represented by the aforementioned formula [IV-6] may be substituted by one methyl group; W 2 is a C 4 alkanediyl group. (13) Another aspect of the present invention provides the compound described in (10) or a pharmaceutically acceptable salt thereof, in the aforementioned formula [I]; (C) R 5 is the aforementioned formula [II-3] Represents the structure; and W 3 is a C 1-2 alkanediyl group; here, (c) when ring B is a chromanyl group, the chromanyl group is a pyran-6-yl group or Pyran-7-yl; R 53 is a carboxyl group; in this case, R 61 and R 62 are both hydrogen atoms. (14) Another aspect of the present invention provides the compound described in (3) or a pharmaceutically acceptable salt thereof. In the aforementioned formula [I'], ring D is represented by the aforementioned formula [I'-2] The base. (15) In another aspect of the present invention, the compound described in claim 3 or a pharmaceutically acceptable salt thereof is provided. In the aforementioned formula [I'], ring D is represented by the aforementioned formula [I'-3] The base. (16) In other aspects of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof as described in any one of (1) to (4):
Figure 02_image033
Figure 02_image035
. (17) In other aspects of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof as described in any one of (1) to (4):
Figure 02_image037
. (18) In other aspects of the present invention, there are provided the following compounds described in any of (1) to (3), (14) or their pharmaceutically acceptable salts:
Figure 02_image039
. (19) In other aspects of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof as described in any one of (1) to (3), (15):
Figure 02_image041
. (20) In another aspect of the present invention, there is provided a medicine containing the compound described in any one of (1) to (19) or its pharmaceutically acceptable salt as an active ingredient. (21) In another aspect of the present invention, there is provided a 20-HETE enzyme production inhibitor containing the compound described in any of (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient. (22) Another aspect of the present invention provides a preventive or ameliorating agent for polycystic kidney disease containing the compound described in any one of (1) to (19) or a pharmaceutically acceptable salt thereof as an active ingredient. [Effects of the invention] The compound of the present invention (hereinafter also referred to as "the compound of the present invention") has an effect of inhibiting the enzyme producing 20-HETE.

[實施發明之最佳形態] 本發明提供具有阻礙20-HETE產生酵素之作用的上述式[I’]所表示之化合物或其製藥學上所容許之鹽。 以下對本發明化合物再詳細說明，但本發明不限於例示者。 「鹵素原子」係指氟原子、氯原子、溴原子、碘原子。 「C1-4 烷基」係指具有1~4個碳原子的直鏈狀或分枝狀的烷基。例如甲基、乙基、n-丙基、異丙基、n-丁基、異丁基、sec-丁基、tert-丁基。 「C1-6 烷基」係指具有1~6個碳原子的直鏈狀或分枝狀的烷基。例如甲基、乙基、n-丙基、異丙基、n-丁基、異丁基、sec-丁基、tert-丁基、n-戊基、異戊基、n-己基等。 「C3-6 環烷烴」係指具有3~6個碳原子的烴的環。例如環丙烷、環丁烷、環戊烷、環己烷。 「C3-6 環烷基」係指具有3~6個碳原子的環狀的烷基。例如環丙基、環丁基、環戊基、環己基。 「飽和的雜環」係指由氧原子、硫原子及氮原子所構成的群選出的相同或相異的1個以上之原子與1~7個碳原子所構成的3~8員的單環式飽和雜環基。例如氧雜環丁烷、四氫呋喃、四氫吡喃、氧雜環己烷、吖丁啶、吡咯烷、哌啶、吖庚環、硫呾、四氫硫代苯基、四氫硫代吡喃、哌嗪、吡唑烷、嗎啉、哌嗪、硫代嗎啉、1,3-奧沙濟南、異噻唑烷等。 「含有氧原子的4到6員之飽和的雜環」係指由1個氧原子與3~5個碳原子所構成的4~6員的單環式飽和雜環。例如氧雜環丁烷、四氫呋喃、四氫吡喃等。 「含有硫原子的4到6員之飽和的雜環」係指由1個硫原子與3~5個碳原子所構成的4~6員的單環式飽和雜環。例如硫呾、四氫噻吩、四氫硫代吡喃等。 「C1-4 烷氧基」係指具有1~4個碳原子的直鏈狀或分枝狀的烷氧基。例如甲氧基、乙氧基、n-丙氧基、異丙氧基、n-丁氧基、異丁氧基、sec-丁氧基、tert-丁氧基。 「單C1-4 烷基胺基」係指具有1個前述「C1-4 烷基」作為取代基之胺基。例如甲基胺基、乙基胺基、n-丙基胺基、異丙基胺基、n-丁基胺基、異丁基胺基、sec-丁基胺基、tert-丁基胺基。 「單C1-6 烷基胺基」係指具有1個前述「C1-6 烷基」作為取代基之胺基。例如甲基胺基、乙基胺基、n-丙基胺基、異丙基胺基、n-丁基胺基、異丁基胺基、sec-丁基胺基、tert-丁基胺基、n-戊基胺基、異戊基胺基、n-己基胺基等。 「單C1-4 烷基胺基羰基」係指前述「單C1-4 烷基胺基」與羰基鍵結的基。可舉例如甲基胺基羰基、乙基胺基羰基、n-丙基胺基羰基、異丙基胺基羰基、n-丁基胺基羰基、異丁基胺基羰基、sec-丁基胺基羰基、tert-丁基胺基羰基。 「單C1-6 烷基胺基羰基」係指前述「單C1-6 烷基胺基」與羰基鍵結的基。可舉例如甲基胺基羰基、乙基胺基羰基、n-丙基胺基羰基、異丙基胺基羰基、n-丁基胺基羰基、異丁基胺基羰基、sec-丁基胺基羰基、tert-丁基胺基羰基、n-戊基胺基羰基、異戊基胺基羰基、n-己基胺基羰基等。 「側氧基」係指氧原子透過雙鍵進行取代的取代基(=O)。因此，側氧基取代於碳原子之情況，與該碳原子一起形成羰基，1個側氧基於1個硫原子取代之情況，與該硫原子一起形成亞磺醯基，2個側氧基於1個硫原子取代之情況，與該硫原子一起形成磺醯基。 在本發明中側氧基取代於飽和的雜環之情況的有側氧基取代的飽和的雜環的具體的例方面，例如2-側氧基吡咯烷基、2-側氧基哌啶基、2-側氧基哌嗪基、3-側氧基哌嗪基、1,1-二氧化物四氫硫代苯基、1-氧化物四氫-2H-噻喃基、1,1-二氧化物四氫-2H-噻喃基、1,1-二氧化物異噻唑烷基、2-側氧基-1,3-噁唑啶基、2-側氧基-1,3-噁嗪烷基、6-側氧基-1,6-二氫吡啶、6-側氧基-1,1-二氫噠嗪基、1-側氧基-1,2,3,4-四氫異喹啉基-7-基、1,1-二氧化硫雜環丁烷基等。 「C1-2 烷烴二基」係指從具有1~2個碳原子的烷基除去1個氫原子而成的2價烴基。例如甲烷二基、乙烷-1,1-二基、乙烷-1,2-二基。 「C1-3 烷烴二基」係指從具有1~3個碳原子的烷基除去1個氫原子而成的2價烴基。例如甲烷二基、乙烷-1,1-二基、乙烷-1,2-二基、丙烷-1,1-二基、丙烷-1,2-二基、丙烷-1,3-二基、丙烷-2,2-二基。 「C4-6 烷烴二基」係指從具有4~6個碳原子的烷基除去1個氫原子而成的2價烴基。例如丁烷-1,4-二基、戊烷-1,5-二基、己烷-1,6-二基、3,3-二甲基-丙烷-1,3-二基等。 「C4-8 烷烴二基」係指從具有4~8個碳原子的烷基除去1個氫原子而成的2價烴基。例如丁烷-1,4-二基、戊烷-1,5-二基、己烷-1,6-二基、庚烷-1,7-二基、辛烷-1,8-二基、3,3-二甲基-丙烷-1,3-二基等。 「C2-10 烷烴二基」係指從具有2~10個碳原子的烷基除去1個氫原子而成的2價烴基。例如乙烷-1,1-二基、丙烷-1,3-二基、丁烷-1,4-二基、戊烷-1,5-二基、己烷-1,6-二基、庚烷-1,7-二基、辛烷-1,8-二基、壬烷-1,9-二基、癸烷-1,10-二基、3,3-二甲基-丙烷-1,3-二基、8,8-二甲基-辛烷-1,8-二基等。 「苄基系保護基」係指苄基的苯基部分或亞甲基部分可被取代的苄基，且保護官能基之基。例如苄基或4-甲氧基苄基、二苯甲基等。 又，被苄基系保護基保護之官能基方面，例如羥基、羧基等。 又，保護羥基之情況，有將該基稱為「苄基醚系保護基」之情形。同樣地，保護羧基之情況，有將該基稱為「苄基酯系保護基」之情形。 「縮醛系保護基」係指與羥基一起形成縮醛構造，保護官能基之基。例如甲氧基甲基、四氫吡喃基。 又，被縮醛系保護基保護之官能基方面，例如羥基等。 「矽烷基醚系保護基」係指被由烷基及芳基所選出的3個基取代的矽烷基，且為保護官能基之基。例如三甲基矽烷基、三異丙基矽烷基、tert-丁基二甲基矽烷基等。 又，以矽烷基系保護基保護的官能基方面，例如羥基等。 本發明化合物的一較佳態樣如下。 前述式[I’]所表示之化合物或其製藥學上所容許之鹽中； 較佳環D為式[I’-1]或式[I’-2]所表示之基； 在此， 一個更較佳環D為式[I’-1]所表示之基、 其他更較佳環D為式[I’-2]所表示之基。 較佳R1 為氫原子； 較佳R2 為氫原子、 較佳R3 為氫原子、 較佳R4 為氫原子； 較佳X為式-O-。 在此，較佳R5 如下。 (1)一較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’]所表示之構造之任一

Figure 02_image043
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基或羧基甲基； 環A為下述式群[IV’]所表示之構造之任一
Figure 02_image045
， 在此， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-5]所表示之構造可被1個甲基取代； W2 為C4-6 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (iii)被羧基取代的C3-6 環烷基、及 (iv)被羧基取代的單C1-6 烷基胺基羰基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (b)環B為吡啶基時， R53 係選自 (iii)被羧基取代的C3-6 環烷基及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基； 此時，R61 及R62 獨立地為氫原子或甲基。 (2)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’]所表示之構造之任一
Figure 02_image047
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-2]、式[IV-4]、式[IV-5]所表示之構造之任一
Figure 02_image049
， 在此， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4-6 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (iii)被羧基取代的C3-6 環烷基、及 (iv)被羧基取代的單C1-6 烷基胺基羰基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (b)環B為吡啶基時， R53 係選自 (v)被羧基取代的C1-4 烷氧基； 此時，R61 及R62 同是氫原子； (c)環B為苯並二氫吡喃基時， R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 (3)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image051
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-2]所表示之構造
Figure 02_image053
， 在此， 前述式[IV-2]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， R53 為羧基； 此時，R61 及R62 同是氫原子。 (4)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-3]~式[III-4]、式[III-6]~式[III-9]所表示之構造之任一
Figure 02_image055
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]、式[IV-4]所表示之構造之任一
Figure 02_image057
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4-6 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時； 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-3]~式[III-4]、式[III-6]~式[III-9]所表示之構造之任一
Figure 02_image059
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基、或下述式[IV-4]所表示之構造之雙環[1.1.1]戊烷-1-基的3位上取代之羧基； 環A為下述式[IV-6]、式[IV-4]所表示之構造之任一
Figure 02_image061
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為丁烷-1,4-二基或己烷-1,6-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 為氫原子或該吡喃-7-基的2位上取代的甲基， R62 為氫原子。 (5)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-4]、式[III-8]所表示之構造之任一
Figure 02_image063
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]、式[IV-7]所表示之構造之任一
Figure 02_image065
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-4]、式[III-8]所表示之構造之任一
Figure 02_image067
； 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基或下述式[IV-7]所表示之構造之吡啶-3-基的6位上取代之羧基； 環A為下述式[IV-6]、式[IV-7]所表示之構造之任一
Figure 02_image069
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代； W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 為氫原子或該吡喃-7-基的2位上取代的甲基， R62 為氫原子。 (6)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 02_image071
， 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image073
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 02_image075
， 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image077
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代， W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 為氫原子或該吡喃-7-基的2位上取代的甲基， R62 為氫原子。 此時，再較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下之任一時：
Figure 02_image079
； (B) R5 為前述式[II-2]所表示之構造時， 式[II-2]所表示之構造為以下之任一時：
Figure 02_image081
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image083
。 (7)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image085
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image087
， 在此， 前述式[IV-6]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 同是氫原子。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image089
； 在此， 式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image091
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被1個甲基取代； W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； 該苯並二氫吡喃基為吡喃-6-基時， R53 為該吡喃-6-基的3位上取代之羧基； 此時，R61 及R62 同是氫原子； 該苯並二氫吡喃基為吡喃-7-基時， R53 為該吡喃-7-基的2位或3位上取代之羧基； 此時，R61 及R62 同是氫原子。 此時，再較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下之任一時：
Figure 02_image093
； (B) R5 為前述式[II-2]所表示之構造時， 式[II-2]所表示之構造為以下之任一時：
Figure 02_image095
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image097
。 (8)其他的較佳R5 為以下的態樣。 為符合上述(6)的態樣或(7)的態樣之態樣，且 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image099
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image101
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image103
； 在此， 式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image105
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代； W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； 該苯並二氫吡喃基為吡喃-6-基時， R53 為該吡喃-6-基的3位上取代之羧基； 此時，R61 及R62 同是氫原子； 該苯並二氫吡喃基為吡喃-7-基時， R53 為該吡喃-7-基的2位或3位上取代之羧基； 此時，R61 為氫原子或該吡喃-7-基的2位上取代的甲基， R62 為氫原子。 此時，再較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下之任一時：
Figure 02_image107
； (B) R5 為前述式[II-2]所表示之構造時， 式[II-2]所表示之構造為以下之任一時：
Figure 02_image109
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image111
。 (9)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-4]、式[III-6]~式[III-9]所表示之構造之任一
Figure 02_image113
， Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image115
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的5位被1個甲氧基取代， W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 及R62 同是氫原子。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下之任一時：
Figure 02_image117
； (B) R5 為前述式[II-2]所表示之構造時， 式[II-2]所表示之構造為以下時：
Figure 02_image119
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image121
。 (10)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-8]所表示之構造
Figure 02_image123
， Y為式-O-； W1 為庚烷-1,7-二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image125
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被1個甲基取代、或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代， W2 為丁烷-1,4-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 及R62 同是氫原子。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下時：
Figure 02_image127
； (B) R5 為前述式[II-2]所表示之構造時， 式[II-2]所表示之構造為以下之任一時：
Figure 02_image129
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image131
。 (11)其他的較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image133
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 及R62 同是氫原子。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下之任一時：
Figure 02_image135
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image137
。 (12)其他的較佳R5 為以下的態樣。 為同時符合上述(9)~(11)的態樣之態樣，且 (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式[III-8]所表示之構造
Figure 02_image139
； Y為式-O-； W1 為庚烷-1,7-二基； (C) R5 為前述式[II-3]所表示之構造時； W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為該吡喃-7-基的2位上取代之羧基； 此時，R61 及R62 同是氫原子。 此時，更較佳R5 為以下的態樣。 (A) R5 為前述式[II-1]所表示之構造時， 式[II-1]所表示之構造為以下時：
Figure 02_image141
； (C) R5 為前述式[II-3]所表示之構造時， 式[II-3]所表示之構造為以下之任一時：
Figure 02_image143
。 本發明化合物的其他的較佳態樣為下述式[I-A]所表示之化合物或其製藥學上所容許之鹽。
Figure 02_image145
在此，R51 、L、Y、及W1 的較佳態樣同前述。 上述式[I-A]所表示之化合物中，更佳態樣如下。 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image147
， 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基之情況。 此時，再佳態樣如下。 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image149
， 在此， 式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為庚烷-1,7-二基之情況。 此時，一個特佳態樣如下。 式[I-A]所表示之化合物為以下之任一之情況：
Figure 02_image151
。 此時，其他特佳態樣如下。 式[I-A]所表示之化合物為以下之情況：
Figure 02_image153
。 此時，其他特佳態樣如下。 式[I-A]所表示之化合物為以下之情況：
Figure 02_image155
。 此時，其他特佳態樣如下。 式[I-A]所表示之化合物為以下之情況：
Figure 02_image157
。 此時，其他特佳態樣如下。 式[I-A]所表示之化合物為以下之情況：
Figure 02_image159
。 此時，其他特佳態樣如下。 式[I-A]所表示之化合物為以下之情況：
Figure 02_image161
。 本發明化合物的其他的較佳態樣為下述式[I-B]所表示之化合物或其製藥學上所容許之鹽。
Figure 02_image163
。 在此，R52 、環A及W2 的較佳態樣同前述。 上述式[I-B]所表示之化合物中，更佳態樣如下。 R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image165
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基之情況。 此時，再佳態樣如下。 R52 為下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image167
， 在此， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代； W2 為丁烷-1,4-二基之情況。 此時，一個特佳態樣如下。 式[I-B]所表示之化合物為以下之任一之情況：
Figure 02_image169
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image171
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image173
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image175
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image177
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image179
。 又，上述式[I-B]所表示之化合物中，其他更佳態樣如下。 R52 為羧基； 環A為下述式[IV-4]或式[IV-6]所表示之構造
Figure 02_image181
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4―6 烷烴二基之情況。 此時，一個再佳態樣如下。 R52 為下述式[IV-4]所表示之構造的3位上取代之羧基； 環A為下述式[IV-4]所表示之構造
Figure 02_image183
； W2 為己烷-1,6-二基之情況。 此時，特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image185
。 又，其他再佳態樣如下。 R52 為下述式[IV-6]所表示之構造之吡啶-2-基的4位上取代之羧基、下述式[IV-6]所表示之構造之吡啶-2-基的5位上取代之羧基、或下述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基； 環A為下述式[IV-6]所表示之構造
Figure 02_image187
， 在此， R52 為前述式[IV-6]所表示之構造之吡啶-2-基的6位上取代之羧基時， 前述式[IV-6]所表示之構造之吡啶-2-基的3位可被由氟原子及甲基所成群組中選出的1個基取代，或 前述式[IV-6]所表示之構造之吡啶-2-基的5位可被由甲基及甲氧基所成群組中選出的1個基取代； W2 為丁烷-1,4-二基之情況。 此時，一個特佳態樣如下。 式[I-B]所表示之化合物為以下之任一之情況：
Figure 02_image189
。
Figure 02_image191
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image193
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image195
此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image197
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image199
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image201
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image203
。 此時，其他特佳態樣如下。 式[I-B]所表示之化合物為以下之情況：
Figure 02_image205
。 本發明化合物的其他的較佳態樣為下述式[I-C]所表示之化合物或其製藥學上所容許之鹽。
Figure 02_image207
在此，R53 、R61 、R62 、環B、及W3 的較佳態樣同前述。 上述式[I-C]所表示之化合物中，更佳態樣如下。 R53 為羧基； W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； 此時，R61 及R62 獨立地為氫原子或甲基之情況。 此時，再佳態樣如下。 W3 為甲烷二基或乙烷-1,2-二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； 該苯並二氫吡喃基為吡喃-6-基時， R53 為該吡喃-6-基的3位上取代之羧基； 此時，R61 及R62 同是氫原子； 該苯並二氫吡喃基為吡喃-7-基時， R53 為該吡喃-7-基的2位或3位上取代之羧基； 此時，R61 為氫原子或該吡喃-7-基的2位上取代的甲基， R62 為氫原子， 此時，一個特佳態樣如下。 式[I-C]所表示之化合物為以下之任一之情況：
Figure 02_image209
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image211
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image213
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image215
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image217
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image219
。 此時，其他特佳態樣如下。 式[I-C]所表示之化合物為以下之情況：
Figure 02_image221
。 本發明化合物的其他的較佳態樣為下述式[I-E]所表示之化合物或其製藥學上所容許之鹽。
Figure 02_image223
在此，R51 、L、Y、及W1 的較佳態樣同前述。 上述式[I-E]所表示之化合物中，更佳態樣如下。 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image225
， 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基之情況。 此時，再佳態樣如下。 R51 為羧基； L為下述式[III-4]所表示之構造
Figure 02_image227
； Y為式-O-； W1 為庚烷-1,7-二基之情況。 此時，特佳態樣如下。 式[I-E]所表示之化合物為以下之情況：
Figure 02_image229
。 本發明化合物的其他的較佳態樣為下述式[I-F]所表示之化合物或其製藥學上所容許之鹽。
Figure 02_image231
在此，R51 、L、Y、及W1 的較佳態樣同前述。 上述式[I-F]所表示之化合物中，更佳態樣如下。 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 02_image233
， 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基之情況。 此時，再佳態樣如下。 R51 為羧基； L為下述式[III-4]所表示之構造
Figure 02_image235
； Y為式-O-； W1 為庚烷-1,7-二基之情況。 此時，特佳態樣如下。 式[I-F]所表示之化合物為以下之情況：
Figure 02_image237
。 本發明化合物為具有以經三唑基或嘧啶-5-基、咪唑基的雜芳基取代的吡啶作為基本骨架之化合物，亦可為其製藥學上所容許之鹽。 製藥學的所容許之鹽方面，例如鹽酸鹽、氫溴酸鹽、碘化氫酸鹽、磷酸鹽、硫酸鹽、硝酸鹽般無機酸鹽、甲磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、p-甲苯磺酸鹽、三氟甲磺酸鹽般磺酸鹽、草酸鹽、酒石酸鹽、檸檬酸鹽、馬來酸鹽、琥珀酸鹽、乙酸鹽、三氟乙酸鹽、安息香酸鹽、杏仁酸鹽、抗壞血酸鹽、乳酸鹽、葡萄糖酸鹽、蘋果酸鹽般有機酸鹽等之酸加成鹽、甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天門冬胺酸鹽般胺基酸鹽、或鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽般無機鹽或者銨鹽、三乙基胺鹽、二異丙基胺鹽、環己基胺鹽般與有機鹼之鹽。又，鹽包含含水鹽。 本發明化合物有具有不對稱中心之情形，該場合存在種種之光學異構物。因此，本發明化合物可存在有(R)及(S)的各自光學活性體、及消旋體或(RS)混合物。又，具有2個以上不對稱中心的化合物之情況，亦進一步存在因各自的光學異構性所致之非鏡像異構物。本發明化合物亦包含以任意的比例含有此等全部的型態之混合物。例如，非鏡像異構物可以該業者習知的方法、例如分段結晶法等來分離，又，光學活性體，可藉由該目的習知的有機化學的手法得到。又，本發明化合物中有存在Cis體、trans體等之幾何異構物之情形。進一步，本發明化合物具有互變異構性且存在種種之互變異構物。本發明化合物亦包含彼等之異構物、及以任意的比例含有彼等之異構物的混合物。 進一步，本發明化合物或其鹽形成水合物或溶劑合物時，彼等亦包含於本發明化合物或其鹽之範圍內。 20-HETE產生酵素係指催化花生四烯酸的ω位氫氧化，以花生四烯酸為基質產生20-HETE的細胞色素P450 4A11、4F2。 而如前述，20-HETE在活體內有各種功能，且與多囊腎的病態形成或各種腦血管疾病、腎疾病、循環器官疾病等之病態有關。 因此，藉由阻礙產生20-HETE的酵素，可預防或改善多囊腎、與多囊腎有關的疾病、與多囊腎有關的症狀。又，可預防或改善高血壓、腦血管疾病、缺血性心臟疾病、慢性腎功能衰竭、動脈硬化、脂肪肝、癌。 本發明化合物具有阻礙產生20-HETE的酵素之作用。因此，本發明化合物可用作為20-HETE產生酵素阻礙劑、或多囊腎的預防或改善劑的有效成分。 又，本發明化合物亦可用作為高血壓、腦血管疾病、缺血性心臟疾病、慢性腎功能衰竭、動脈硬化、脂肪肝、癌的預防或改善劑的有效成分。 在此，「多囊腎」包含因基因變異而兩側腎臓大量囊腫逐漸產生及增大的「體染色體顯性多囊腎」與「體染色體隱性多囊腎」。「與多囊腎有關的疾病」可舉例如慢性腎功能衰竭、高血壓、血管疾病、肝臓及胰臟的囊腫、泌尿道感染症、肝膽道系感染症、泌尿道結石等。又，「與多囊腎有關的症狀」方面，包含疼痛、血尿、腹脹。 又，評估本發明化合物的阻礙產生20-HETE的酵素之作用，可藉由例如後述本說明書試驗例記載之方法等習知手法進行。 關於本發明之醫藥，所含有的本發明化合物之阻礙產生20-HETE的酵素之化合物或其製藥學上所容許之鹽，可單獨或與藥學上或者藥劑學上容許的添加劑一起投與。 添加劑方面，可使用常用的賦形劑或稀釋劑、以及因應必要一般所使用的結合劑、崩散劑、潤滑劑、被覆劑、糖衣劑、pH調整劑、溶解劑或水性或者非水性溶劑。具體上如水、乳糖、葡萄糖、果糖、蔗糖、山梨醣醇、甘露醇、聚乙二醇、丙二醇、澱粉、玉米澱粉、膠、明膠、海藻酸鹽、矽酸鈣、磷酸鈣、纖維素、水糖漿、甲基纖維素、聚乙烯基吡咯烷酮、烷基對羥基苯甲酸酯、滑石、硬脂酸、硬脂酸鎂、寒天、果膠、阿拉伯膠、甘油、芝麻油、橄欖油、大豆油可可脂、乙二醇、低黏度羥基丙基纖維素(HPC-L)、微結晶纖維素、羧基甲基纖維素(CMC)、羧基甲基纖維素鈉(CMC-Na)等或其他常用者。 本發明之醫藥可為固體組成物、液體組成物及其他組成物之任一形態，因應必要選擇最佳者。 本發明之醫藥，可在本發明化合物添加前述添加劑，且藉由常用之製劑技術調製成錠劑、丸劑、膠囊劑、顆粒劑、粉劑、散劑、液劑、乳劑、懸濁劑、注射劑等。 又，本發明之醫藥，可以本發明化合物與α、β或者γ-環糊精或甲基化環糊精等形成包接化合物後製劑化。 本發明之醫藥，關於可與本發明化合物併用的化合物，可作成單一之製劑(摻合劑)、或分別製劑化而得到的2種以上之製劑(併用劑)。 將此等之化合物分別製劑化作成2種以上之製劑時，可將個別製劑同時或間隔一定時間間隔投與。該場合，何者先投與都無妨。該2種以上之製劑可1日各自以不同次數進行投與。又，該2種以上之製劑亦可以不同路徑進行投與。 將此等之化合物分別製劑化作成2種之製劑時，亦有同時或以極短的間隔投與之情形，例如以在市售醫藥品的附件或販售手冊等之文書以記載有各自併用為佳。 又，將此等之有效成分分別製劑化作成由2種之製劑所構成的套組的形態亦為佳。 將本發明化合物用作為20-HETE產生酵素阻礙劑等時，可將本發明化合物直接經口投與。又，亦可作為含有本發明化合物作為有效成分之劑進行經口投與。 將本發明化合物用作為多囊腎的預防或改善劑等時，可將本發明化合物直接經口投與。又，亦可作為含有本發明化合物作為有效成分之劑進行經口投與。 本發明化合物的投與量因投與對象、投與路徑、對象疾病、症狀等而異，但例如經口投與成人患者時，通常1次量為0.1mg~1000mg、較佳為1mg~200mg，該量以1日1次~3次、或2日~3日1次投與為佳。 本發明化合物之製劑之製造例如以下所示。 製劑例1 製造含以下成分的顆粒劑。 成分：式[I’]所表示之化合物或其製藥學上所容許之鹽、乳糖、玉米澱粉、HPC-L。 將式[I’]所表示之化合物或其製藥學上所容許之鹽與乳糖過篩。使玉米澱粉過篩。將此等以混合機進行混合。於混合末添加HPC-L水溶液，進行捏合、造粒(擠出造粒)後，進行乾燥。使得到的乾燥顆粒以振動篩子進行過篩，得到顆粒劑。 製劑例2 製造含以下成分的膠囊充填用散劑。 成分：式[I’]所表示之化合物或其製藥學上所容許之鹽、乳糖、玉米澱粉、硬脂酸鎂。 將式[I’]所表示之化合物或其製藥學上所容許之鹽與乳糖過篩。使玉米澱粉過篩。使此等與硬脂酸鎂以混合機混合，得到散劑。得到的散劑可充填於膠囊。 製劑例3 製造含以下成分的膠囊充填用顆粒劑。 成分：式[I’]所表示之化合物或其製藥學上所容許之鹽、乳糖、玉米澱粉、HPC-L。 將式[I’]所表示之化合物或其製藥學上所容許之鹽與乳糖過篩。使玉米澱粉過篩。將此等以混合機進行混合。於混合末添加HPC-L水溶液，進行捏合、造粒後，進行乾燥。使得到的乾燥顆粒以振動篩子進行過篩，進行整粒，得到顆粒。得到的顆粒可充填於膠囊。 製劑例4 製造含以下成分的錠劑。 成分：式[I’]所表示之化合物或其製藥學上所容許之鹽、乳糖、微結晶纖維素、硬脂酸鎂、CMC-Na。 將式[I’]所表示之化合物或其製藥學上所容許之鹽與乳糖與微結晶纖維素、CMC-Na過篩，進行混合。於混合末添加硬脂酸鎂，得到製劑用混合末。將本混合末直接打錠得到錠劑。 以下，將本發明化合物[I’]之製造方法詳細說明，但製造方法僅為例示而非特別限定。又，在反應使用的溶劑，為不阻礙各反應之溶劑即可，不特別限定為下述之記載。 本發明化合物[I’]可藉由本身習知方法、例如以下所示之製造法1~8、或依據此等之方法來製造。 又，本發明化合物[I’]之製造中，各製造法中各步驟的順序可適當改變。 又，以下的各製造方法中，原料化合物可用作為鹽，鹽方面，例如前述「製藥學的所容許之鹽」。 化合物[I’]中，X為式-O-、環D為前述式[I’-1]所表示之基的化合物可藉由以下所示之製造法1~3、或根據此等的方法來製造。 化合物[I’]中，X為式-O-、環D為前述式[I’-1]所表示之基的化合物之製造中間體的化合物[1-e]，可藉由例如下述製造法1或根據其之方法來製造。 製造法1：
Figure 02_image239
[路徑中， R1 、R2 、R3 、及R4 同前述定義， XA 為氯原子或溴原子。 又，Pro1 為羥基的保護基， 例如(i)苄基、4-甲氧基苄基等(與羥基一起形成苄基醚構造之保護基。在本說明書亦有稱「苄基醚系保護基」之情形。)； (ii)甲氧基甲基、四氫吡喃基等(與羥基一起形成縮醛構造之保護基。在本說明書亦有稱「縮醛系保護基」之情形。)； (iii)三甲基矽烷基、三異丙基矽烷基、tert-丁基二甲基矽烷基等(與羥基一起形成矽烷基醚構造之保護基。在本說明書亦有稱「矽烷基醚系保護基」之情形。)。] [步驟1-1] 本步驟為藉由將化合物[1-a]的羥基以保護基Pro1 保護，製造化合物[1-b]之方法。 本反應可依據文獻(Protective Groups in Organic Synthesis，第4版，2007年，G.M.Wuts、T.W.Greene編)記載之方法或根據其之方法進行。 [步驟1-2] 本步驟為藉由使化合物[1-b]與化合物[1-c]反應，製造化合物[1-d]之方法。 本反應為所謂Ullmann型的耦合反應，可在銅鹽、配位基、及鹼的存在下，在不阻礙反應的溶劑中進行。 本反應中所使用的銅鹽方面，例如碘化銅(I)、溴化銅(I)、氯化銅(I)、氧化銅(I)、三氟甲磺酸銅(I)-苯錯合物等。使用的銅鹽的量，相對化合物[1-b]1當量，為0.1~2當量、較佳為0.1~0.5當量。 本反應中所使用的配位基方面，例如2-異丁醯基環己酮、L-脯胺酸、反式-N,N’-二甲基環己烷-1,2-二胺等。使用的配位基的量，相對化合物[1-b]1當量，為0.1~2當量、較佳為0.1~0.5當量。 本反應中所使用的鹼方面，例如碳酸鉀、磷酸鉀、碳酸銫、N,N-二異丙基乙基胺、三乙基胺等。使用的鹼的量，相對化合物[1-b]1當量，為1~5當量、較佳為1~2當量。 本反應中所使用的溶劑，可舉例如二甲基亞碸、N,N-二甲基甲醯胺、N-甲基吡咯烷酮、1,4-二噁烷、乙腈、甲苯等，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在迴流溫度下進行1~24小時。 [步驟1-3] 本步驟為藉由使化合物[1-d]的羥基的保護基Pro1 脫保護，製造化合物[1-e]之方法。 (i)Pro1 為苄基、4-甲氧基苄基等之苄基醚系保護基時，本反應可在金屬觸媒及氫源存在下、在不阻礙反應的溶劑中進行。 本反應使用的金屬觸媒方面，例如鈀碳、氫氧化鈀碳等。使用的金屬觸媒的量，相對化合物[1-d]1當量，為0.001~1當量、較佳為0.01~0.5當量。 本反應使用的氫壓為常壓~10氣壓、較佳為常壓~4氣壓。 本反應使用的溶劑方面，例如甲醇、乙醇、水、四氫呋喃、乙酸乙酯等，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 (ii)Pro1 為甲氧基甲基、四氫吡喃基等之縮醛系保護基時，本反應可在酸存在下、在不阻礙反應的溶劑中進行。 本反應使用的酸方面，例如鹽酸、三氟乙酸等。使用的酸的量，相對化合物[1-d]1當量，為1~5當量、較佳為1~3當量。 本反應使用的溶劑方面，例如甲醇、乙醇、水、二氯甲烷、氯仿等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 (iii)Pro1 為三甲基矽烷基、三異丙基矽烷基、tert-丁基二甲基矽烷基等之矽烷基醚系保護基時，本反應可在酸存在下、在不阻礙反應的溶劑中進行。 本反應使用的酸方面，例如鹽酸、乙酸、三氟乙酸等。使用的酸的量，相對化合物[1-d]1當量，為1~5當量、較佳為1~3當量。 本反應使用的溶劑方面，例如四氫呋喃、甲醇、乙醇、水等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 又，本反應可在氟化物離子存在下、在不阻礙反應的溶劑中進行。 本反應使用的氟化物離子源方面，例如氟化鉀、四丁基銨氟化物等。使用的氟化物離子源的量，相對化合物[1-d]1當量，為1~5當量、較佳為1~3當量。 本反應使用的溶劑方面，例如四氫呋喃、N,N-二甲基甲醯胺、甲醇、乙醇等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 如此得到的化合物[1-e]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在上述製造法1，用作為原料化合物的化合物[1-a]、[1-c]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]，且X為式-O-、環D為前述式[I’-1]所表示之基的化合物中，R5 所表示之構造各自對應前述式[II-1]、式[II-2]、及式[II-3]所表示之構造的化合物[2-c]、[2-f]、及[2-i]，例如可藉由下述製造法2或根據其之方法來製造。 製造法2：
Figure 02_image241
[路徑中， R1 、R2 、R3 、R4 、R61 、R62 、L、Y、W1 、W2 、W3 、環A、及環B同前述定義， LG1 為羥基或離去基， 在此，LG1 所表示之「離去基」為例如氯原子、溴原子等之鹵素原子；甲磺醯基氧基等之C1-4 烷基磺醯基氧基；或p-甲苯磺醯基氧基等之芳基磺醯基氧基， Pro3 為甲基、乙基、2-丙基等之1~2級烷基；苄基、4-甲氧基苄基等之苄基系保護基；或tert-丁基， L1 為單鍵或甲烷二基， R53 ’為從R53 除去羧基而成的2價基， 具體上 羧基與R53 ’所構成的下述式[V]所表示之基為由R53 所選出的以下的基：
Figure 02_image243
(a)環B為苯基時， R53 為選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-6 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； (b)環B為吡啶基時， R53 為選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-4 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基。] [步驟2-1] 本步驟為藉由使化合物[1-e]與化合物[2-a]進行反應，製造化合物[2-b]之方法。 (i)化合物[2-a]的LG1 為羥基時，本反應可使用習知方法、所謂光延反應(Synthesis，1頁，1981年)進行。 本反應中所使用的化合物[2-a]的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的偶氮化合物方面，例如偶氮二羧酸雙(2-甲氧基乙基)酯、偶氮二羧酸二異丙酯、1,1’-偶氮雙(N,N-二甲基甲醯胺)等。使用的偶氮化合物的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的膦化合物方面，例如三苯基膦、三丁基膦等。使用的膦化合物的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的溶劑方面，例如四氫呋喃、1,4-二噁烷、二乙基醚、氯仿、二氯甲烷、甲苯、N,N-二甲基甲醯胺、二甲基亞碸等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 又，本反應亦可使用Tetrahedron Letters，第36卷，2531頁，1995年、或Tetrahedron Letters，第37卷，2463頁，1996年記載之方法進行。 本反應使用的試藥方面，例如氰基亞甲基三甲基磷烷或氰基亞甲基三丁基磷烷等。使用的試藥的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的溶劑可舉例與前述光延反應相同者。 本反應，通常可在室溫~迴流溫度進行1~24小時。 (ii)化合物[2-a]的LG1 為離去基時，本反應可在鹼的存在下進行。 本反應中所使用的化合物[2-a]的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的鹼方面，例如三乙基胺、N,N-二異丙基乙基胺、1,8-二氮雜雙環[4,3,0]十一碳-7-烯等之胺、氫化鈉等之鹼金屬氫化物、氫氧化鉀等之鹼金屬氫氧化物、碳酸銫、碳酸鉀、碳酸鈉等之鹼金屬碳酸鹽、tert-丁氧基鉀等之烷氧基鹼金屬等。使用的鹼的量，相對化合物[1-e]1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的溶劑方面，例如四氫呋喃、二甲基亞碸、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯烷酮等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 又，化合物[2-a]的LG1 為羥基時，本反應亦可將羥基變更為離去基後進行。 羥基變更為離去基，可使用慣用的方法進行。例如在不阻礙反應的溶劑中，(a)鹵化試藥、或(b)鹼的存在下，與磺酸酯化試藥反應，可製造LG1 為離去基的化合物[2-a]。 本反應使用的(a)鹵化試藥方面，例如亞硫醯氯、氯化磷醯、N-氯琥珀醯亞胺、溴、N-溴琥珀醯亞胺等。使用的鹵化試藥的量，相對於該具有羥基的化合物1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的溶劑方面，可舉例如氯仿、二氯甲烷等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 又，本反應使用的(b)磺酸酯化試藥方面，例如甲烷磺醯氯、三氟甲烷磺醯氯、p-甲苯磺醯氯等。使用的磺酸酯化試藥的量，相對於該具有羥基的化合物1當量，為1~5當量、較佳為1~3當量。 本反應使用的鹼方面，可舉例如三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶等。使用的鹼的量，相對使用的磺酸酯化試藥1當量，為1~5當量、較佳為1~3當量。 本反應中所使用的溶劑方面，可舉例如氯仿、二氯甲烷等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 [步驟2-2] 本步驟為藉由使化合物[2-b]的保護基Pro3 脫保護，製造化合物[2-c]之方法。 在此，製造化合物[2-c]時，存在一些製造條件。在以下分別記載。 (i)化合物[2-b]的Pro3 為甲基、乙基、2-丙基等之1~2級烷基時，本反應可在鹼性條件下進行。 本反應中所使用的鹼方面，例如氫氧化鈉或氫氧化鉀等之鹼金屬氫氧化物。使用的鹼的量，相對化合物[2-b]1當量，為1~100當量、較佳為1~10當量。 本反應中所使用的溶劑方面，例如甲醇、乙醇、2-丙醇、丙酮、四氫呋喃、1,4-二噁烷、水等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應通常在0℃~迴流溫度進行1~24小時。 (ii)化合物[2-b]的Pro3 為苄基、4-甲氧基苄基等之苄基醚系保護基時，本反應可在金屬觸媒及氫源存在下、在不阻礙反應的溶劑中進行。 本反應使用的金屬觸媒方面，例如鈀碳、氫氧化鈀碳等。使用的金屬觸媒的量，相對化合物[2-b]1當量，為0.001~1當量、較佳為0.01~0.5當量。 本反應使用的氫壓為常壓~10氣壓、較佳為常壓~4氣壓。 本反應使用的溶劑方面，例如甲醇、乙醇、水、四氫呋喃、乙酸乙酯等，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 (iii)化合物[2-b]的Pro3 為tert-丁基時，本反應可在較溫和的酸性條件下進行。 本反應中所使用的酸方面，例如鹽酸或甲酸、三氟乙酸等。使用的酸的量，相對化合物[2-b]1當量，為1當量~溶劑量、較佳為1~10當量。 本反應中所使用的溶劑方面，例如甲醇、乙醇、四氫呋喃、水、乙酸乙酯、1,4-二噁烷等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應通常可在0℃~室溫，進行1~24小時。 如此得到的化合物[2-c]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟2-3] 本步驟為藉由使化合物[1-e]與化合物[2-d]進行反應，製造化合物[2-e]之方法。 本反應可藉由本製造法之步驟2-1記載之方法或根據其之方法進行。 [步驟2-4] 本步驟為藉由使化合物[2-e]的保護基Pro3 脫保護，製造化合物[2-f]之方法。 本反應可藉由本製造法之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[2-f]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟2-5] 本步驟為藉由使化合物[1-e]與化合物[2-g]進行反應，製造化合物[2-h]之方法。 本反應可藉由本製造法之步驟2-1記載之方法或根據其之方法進行。 [步驟2-6] 本步驟為藉由使化合物[2-h]的保護基Pro3 脫保護，製造化合物[2-i]之方法。 本反應可藉由本製造法之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[2-i]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[1-e]、[2-a]、[2-d]、及[2-g]可藉由前述之製造法1或者根據其之方法、或本身習知方法製造、或以購入市售品之方式取得。 又，化合物[2-b]亦可藉由例如下述製造法3或根據其之方法來製造。 製造法3：
Figure 02_image245
[路徑中， R1 、R2 、R3 、R4 、XA 、Pro3 、W1 、Y、L、及LG1 同前述定義。] [步驟3-1] 本步驟為藉由使化合物[1-a]與化合物[2-a]進行反應，製造化合物[3-a]之方法。 本反應可藉由製造法3之步驟2-1記載之方法或根據其之方法進行。 [步驟3-2] 本步驟為藉由使化合物[3-a]與化合物[1-c]進行反應，製造化合物[2-b]之方法。 本反應可藉由製造法1之步驟1-2記載之方法或根據其之方法進行。 如此得到的化合物[2-b]可藉由製造法2之步驟2-2記載之方法或根據此等的方法，轉化為化合物[2-c]。 又，在上述製造法3，用作為原料化合物的化合物[1-a]、[2-a]、及[1-c]可藉由本身習知方法製造、或由市售品之購入取得。 又，本製造法之步驟3-1中，取代化合物[2-a]而與化合物[2-d]或化合物[2-g]反應，接著，如上述步驟3-2般與化合物[1-c]反應，使保護基Pro3 脫保護，藉由此可各自製造化合物[2-f]或化合物[2-i]。 化合物[I’]中，X為式-O-、環D為前述式[I’-2]所表示之基的化合物可藉由以下所示之製造法4~6、或根據此等的方法來製造。 化合物[I’]中，X為式-O-、環D為前述式[I’-2]所表示之基的化合物之製造中間體的化合物[4-c]亦可藉由例如下述製造法4或根據其之方法來製造。 製造法4：
Figure 02_image247
[路徑中， R1 、R2 、R3 、R4 、XA 、及Pro1 同前述定義， G為亞硼酸基或亞硼酸酯基。] [步驟4-1] 本步驟為藉由使化合物[1-b]與化合物[4-a]進行反應，製造化合物[4-b]之方法。 本反應可藉由所謂鈴木-宮浦耦合反應、鈀觸媒及鹼的存在下、文獻(Tetrahedron Letters，第20卷，3437頁，1979年；Chemical reviews，第95卷，2457頁，1995年)記載之方法或根據其之方法來進行。 本反應中所使用的化合物[4-a]的量，相對化合物[1-b]1當量，為1~5當量、較佳為1~3當量。 鈀觸媒方面，例如肆(三苯基膦)鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物、雙(三苯基膦)鈀(II)二氯化物等。使用的鈀觸媒的量，相對化合物[1-b]1當量，通常為0.001~0.5當量、較佳為0.001~0.3當量。 鹼方面，例如碳酸鉀、碳酸銫、碳酸鈉等之鹼金屬碳酸鹽或其水溶液、氟化鉀、氟化銫、三乙基胺等。使用的鹼的量，相對化合物[1-b]1當量，通常為1~5當量、較佳為1~3當量。 反應溶劑方面，例如N,N-二甲基甲醯胺、二甲基亞碸、甲苯、1,4-二噁烷、四氫呋喃、1,2-二甲氧基乙烷、乙醇、水等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 此等之反應，通常可在室溫~迴流溫度進行1~24小時，又亦可在微波照射下進行。 [步驟4-2] 本步驟為藉由使化合物[4-b]的保護基Pro1 脫保護，製造化合物[4-c]之方法。 本反應可藉由製造法1之步驟1-3記載之方法或根據其之方法進行。 如此得到的化合物[4-c]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在上述製造法4，用作為原料化合物的化合物[1-b]及[4-a]可藉由本身習知方法製造、或由市售品之購入取得。 而，本發明化合物[I’]且X為式-O-、環D為前述式[I’-2]所表示之基的化合物中，R5 所表示之構造各自對應前述式[II-1]、式[II-2]、及式[II-3]所表示之構造的化合物[5-b]、[5-d]、及[5-f]，可藉由例如使化合物[4-c]各自與前述的化合物[2-a]、化合物[2-d]、化合物[2-g]作用，以下述製造法5或根據其之方法來製造。 製造法5：
Figure 02_image249
[路徑中， R1 、R2 、R3 、R4 、R61 、R62 、L、Y、W1 、W2 、W3 、環A、環B、LG1 、L1 、Pro3 、及R53’ 同前述定義。] [步驟5-1] 本步驟為藉由使化合物[4-c]與化合物[2-a]進行反應，製造化合物[5-a]之方法。 本反應可藉由製造法2之步驟2-1記載之方法或根據其之方法進行。 [步驟5-2] 本步驟為藉由使化合物[5-a]的保護基Pro3 脫保護，製造化合物[5-b]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[5-b]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟5-3] 本步驟為藉由使化合物[4-c]與化合物[2-d]進行反應，製造化合物[5-c]之方法。 本反應可藉由製造法2之步驟2-3記載之方法或根據其之方法進行。 [步驟5-4] 本步驟為藉由使化合物[5-c]的保護基Pro3 脫保護，製造化合物[5-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[5-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟5-5] 本步驟為藉由使化合物[4-c]與化合物[2-g]進行反應，製造化合物[5-e]之方法。 本反應可藉由製造法2之步驟2-5記載之方法或根據其之方法進行。 [步驟5-6] 本步驟為藉由使化合物[5-e]的保護基Pro3 脫保護，製造化合物[5-f]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[5-f]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[4-c]、[2-a]、[2-d]、及[2-g]可藉由前述之製造法4或者根據其之方法、或本身習知方法來製造、或以購入市售品之方式取得。 又，化合物[5-a]亦可藉由例如下述製造法6或根據其之方法來製造。 製造法6：
Figure 02_image251
[路徑中， R1 、R2 、R3 、R4 、XA 、Pro3 、W1 、Y、L、LG1 、及G同前述定義。] [步驟6-1] 本步驟為藉由使化合物[1-a]與化合物[2-a]進行反應，製造化合物[3-a]之方法。 本反應可藉由製造法3之步驟2-1記載之方法或根據其之方法進行。 [步驟6-2] 本步驟為藉由使化合物[3-a]與化合物[4-a]進行反應，製造化合物[5-a]之方法。 本反應可藉由製造法4的步驟4-1記載之方法或根據其之方法進行。 如此得到的化合物[5-a]可藉由製造法5之步驟5-2記載之方法或根據此等的方法，轉化為化合物[5-b]。 又，在上述製造法6，用作為原料化合物的化合物[3-a]及[4-a]可藉由前述之製造法3或者根據其之方法、或本身習知方法來製造、或以購入市售品之方式取得。 又，本製造法之步驟6-1中，取代化合物[2-a]而與化合物[2-d]或化合物[2-g]反應，接著，如上述步驟6-2般，與化合物[4-a]反應，使保護基Pro3 脫保護，藉由此可各自製造化合物[5-d]或化合物[5-f]。 化合物[I’]中，X為式-O-、環D為前述式[I’-3]所表示之基的化合物可藉由以下所示之製造法7~8、或根據此等的方法來製造。 化合物[I’]且X為式-O-、環D為前述式[I’-3]所表示之基的化合物中，R5 所表示之構造對應前述式[II-1]所表示之構造的化合物[7-g]亦可藉由例如下述製造法7或根據其之方法來製造。 製造法7：
Figure 02_image253
[路徑中， R1’ 、R1” 、R2 、R3 、R4 、XB 、Pro3 、W1 、Y、L、及LG1 同前述定義， R1’ 為氫原子或甲基， R1” 為氫原子或甲基， XB 為氯原子、溴原子、或碘原子。] [步驟7-1] 本步驟為藉由使化合物[7-a]與化合物[2-a]進行反應，製造化合物[7-b]之方法。 本反應可藉由製造法2之步驟2-1記載之方法或根據其之方法進行。 [步驟7-2] 本步驟為藉由使化合物[7-b]與鹵化試藥作用，製造化合物[7-c]之方法。 鹵化試藥方面，例如N-溴琥珀醯亞胺、N-氯琥珀醯亞胺、溴、氫溴酸、三甲基苯基銨三溴化物等。 本反應中所使用的鹵化試藥的量，相對化合物[7-b]1當量，為1~2當量、較佳為1~1.1當量。 反應溶劑方面，例如氯仿、二氯甲烷、水、甲醇、四氫呋喃、乙酸等之不阻礙反應的溶劑。 此等之反應可在0度~迴流溫度進行1分鐘~15小時，又亦可在微波照射下進行。 [步驟7-3] 本步驟為藉由使化合物[7-c]、[7-d]、或[7-e]進行反應，製造化合物[7-f]之方法。 本反應中所使用的化合物[7-d]或[7-e]的量，相對化合物[7-c]1當量，為1~50當量、較佳為1~20當量。 反應溶劑方面，例如N,N-二甲基甲醯胺、乙腈、四氫呋喃、乙醇、水等之不阻礙反應的溶劑。又，化合物[7-d]亦可用作為溶劑。 此等之反應可在室溫~210度進行5分鐘~20小時，又亦可在微波照射下進行。 [步驟7-4] 本步驟為藉由使化合物[7-f]的保護基Pro3 脫保護，製造化合物[7-g]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[7-g]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在上述製造法7用作為原料化合物的化合物[2-a]、[7-a]、[7-d]、及[7-e]可藉由本身習知方法製造、或由市售品之購入取得。 又，例如以下所示之製造法8般，在本製造法之步驟7-1中，取代化合物[2-a]而與化合物[2-d]或[2-g]反應，接著，如上述步驟7-2、7-3般，與鹵化試藥、化合物[7-d]或[7-e]反應，使保護基Pro3 脫保護，藉由此可各自製造化合物[8-d]或[8-h]。 製造法8：
Figure 02_image255
[路徑中， R1’ 、R1” 、R2 、R3 、R4 、XB 、R61 、R62 、W2 、W3 、環A、環B、LG1 、L1 、Pro3 、及R53’ 同前述定義。] [步驟8-1] 本步驟為藉由使化合物[7-a]與化合物[2-d]進行反應，製造化合物[8-a]之方法。 本反應可藉由製造法2之步驟2-3記載之方法或根據其之方法進行。 [步驟8-2] 本步驟為藉由使化合物[8-a]與鹵化試藥反應，製造化合物[8-b]之方法。 本反應可藉由製造法7之步驟7-2記載之方法或根據其之方法進行。 [步驟8-3] 本步驟為藉由使化合物[8-b]與化合物[7-d]或化合物[7-e]進行反應，製造化合物[8-c]之方法。 本反應可藉由製造法7之步驟7-3記載之方法或根據其之方法進行。 [步驟8-4] 本步驟為藉由使化合物[8-c]的保護基Pro3 脫保護，製造化合物[8-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[8-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟8-5] 本步驟為藉由使化合物[7-a]與化合物[2-g]進行反應，製造化合物[8-e]之方法。 本反應可藉由製造法2之步驟2-5記載之方法或根據其之方法進行。 [步驟8-6] 本步驟為藉由使化合物[8-e]與鹵化試藥反應，製造化合物[8-f]之方法。 本反應可藉由製造法7之步驟7-2記載之方法或根據其之方法進行。 [步驟8-7] 本步驟為藉由使化合物[8-f]與化合物[7-d]或化合物[7-e]進行反應，製造化合物[8-g]之方法。 本反應可藉由製造法7之步驟7-3記載之方法或根據其之方法進行。 [步驟8-8] 本步驟為藉由使化合物[8-g]的保護基Pro3 脫保護，製造化合物[8-h]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[8-h]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在上述製造法8用作為原料化合物的化合物[7-a]、[2-d]、[2-g]、[7-d]、及化合物[7-e]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]中，X為式-S-之化合物可藉由以下所示之製造法9~12、或根據此等的方法來製造。 化合物[I’]且X為式-S-之化合物中，環D為前述式[I’-1]所表示之基的化合物[9-c]、[9-e]、及[9-g]可藉由例如下述製造法9或根據其之方法來製造。 製造法9：
Figure 02_image257
[路徑中， R1 、R2 、R3 、R4 、R61 、R62 、L、Y、W1 、W2 、W3 、環A、環B、LG1 、L1 、Pro3 、及R53’ 同前述定義。] [步驟9-1] 本步驟為藉由使化合物[9-a]與化合物[2-a]進行反應，製造化合物[9-b]之方法。 本反應可藉由製造法2之步驟2-1記載之方法或根據其之方法進行。 [步驟9-2] 本步驟為藉由使化合物[9-b]的保護基Pro3 脫保護，製造化合物[9-c]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[9-c]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟9-3] 本步驟為藉由使化合物[9-a]與化合物[2-d]進行反應，製造化合物[9-d]之方法。 本反應可藉由製造法2之步驟2-3記載之方法或根據其之方法進行。 [步驟9-4] 本步驟為藉由使化合物[9-d]的保護基Pro3 脫保護，製造化合物[9-e]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[9-e]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟9-5] 本步驟為藉由使化合物[9-a]與化合物[2-g]進行反應，製造化合物[9-f]之方法。 本反應可藉由製造法2之步驟2-5記載之方法或根據其之方法進行。 [步驟9-6] 本步驟為藉由使化合物[9-f]的保護基Pro3 脫保護，製造化合物[9-g]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[9-g]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[9-a]、[2-a]、[2-d]、及[2-g]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]且X為式-S-之化合物中，環D為前述式[I’-2]或[I’-3]所表示之基的化合物之製造中間體[10-c]及[10-d]可藉由例如下述製造法10或根據其之方法來製造。 製造法10：
Figure 02_image259
[路徑中， R1 、R1’ 、R1” 、R2 、R3 、R4 、及G同前述定義， Pro4 為甲基、乙基等之C1-6 烷基或苄基。] [步驟10-1] 本步驟為藉由使化合物[10-a]與[4-a]進行反應，製造化合物[10-b]之方法。 本反應可藉由製造法4的步驟4-1記載之方法或根據其之方法進行。 [步驟10-2] 本步驟為藉由使化合物[10-b]的保護基Pro4 脫保護，製造化合物[10-c]之方法。 本反應可在鹼金屬醇化物存在下、在不阻礙反應的溶劑中進行。 本反應使用的鹼金屬醇化物方面，例如叔丁醇鉀、叔丁醇鈉等。使用的鹼金屬醇化物的量，相對化合物[10-b]1當量，為1~20當量、較佳為1~10當量。 本反應使用的溶劑方面，例如N,N-二甲基甲醯胺、N-甲基-2-吡咯烷酮、1,3-二甲基-2-咪唑啉酮、N,N’-二甲基丙烯尿素等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 本反應以在惰性氣體環境下進行為佳。 如此得到的化合物[10-c]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 如此得到的化合物[10-c]可藉由後述之製造法11記載之方法或根據此等的方法轉化為化合物[11-b]、[11-d]、或[11-f]。 [步驟10-3] 本步驟為藉由使化合物[10-a]與化合物[10-d]進行反應，製造化合物[10-e]之方法。 本反應可藉由製造法4的步驟4-1記載之方法或根據其之方法進行。 [步驟10-4] 本步驟為藉由使化合物[10-e]的保護基Pro4 脫保護，製造化合物[10-f]之方法。 本反應可藉由製造法10的步驟10-2記載之方法或根據其之方法進行。 如此得到的化合物[10-f]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 如此得到的化合物[10-f]可藉由後述之製造法12記載之方法或根據此等的方法，各自與化合物[2-a]、[2-d]、或[2-g]反應，轉化為化合物[12-b]、[12-d]、或[12-f]。 又，在本製造法用作為原料化合物的化合物[10-a]、[4-a]、及[10-d]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]且X為式-S-之化合物中，環D為前述式[I’-2]所表示之基的化合物[11-b]、[11-d]、及[11-f]可藉由例如下述製造法11或根據其之方法來製造。 化合物[I’]且X為式-S-之化合物中，環D為前述式[I’-2]所表示之基的化合物[11-b]、[11-d]、及[11-f]可藉由例如下述製造法11或根據其之方法來製造。 製造法11：
Figure 02_image261
[路徑中， R1 、R2 、R3 、R4 、R61 、R62 、L、Y、W1 、W2 、W3 、環A、環B、LG1 、L1 、Pro3 、及R53’ 同前述定義。] [步驟11-1] 本步驟為藉由使化合物[10-c]與化合物[2-a]進行反應，製造化合物[11-a]之方法。 本反應可藉由製造法2之步驟2-1記載之方法或根據其之方法進行。 [步驟11-2] 本步驟為藉由使化合物[11-a]的保護基Pro3 脫保護，製造化合物[11-b]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[11-b]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟11-3] 本步驟為藉由使化合物[10-c]與化合物[2-d]進行反應，製造化合物[11-c]之方法。 本反應可藉由製造法2之步驟2-3記載之方法或根據其之方法進行。 [步驟11-4] 本步驟為藉由使化合物[11-c]的保護基Pro3 脫保護，製造化合物[11-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[11-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟11-5] 本步驟為藉由使化合物[10-c]與化合物[2-g]進行反應，製造化合物[11-e]之方法。 本反應可藉由製造法2之步驟2-5記載之方法或根據其之方法進行。 [步驟11-6] 本步驟為藉由使化合物[11-e]的保護基Pro3 脫保護，製造化合物[11-f]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[11-f]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[2-a]、[2-d]、及[2-g]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]且X為式-S-之化合物中，環D為前述式[I’-3]所表示之基的化合物[12-b]、[12-d]、及[12-f]可藉由例如下述製造法12或根據其之方法來製造。 製造法12：
Figure 02_image263
[路徑中， R1’ 、R1” 、R2 、R3 、R4 、R61 、R62 、L、Y、W1 、W2 、W3 、環A、環B、LG1 、L1 、Pro3 、及R53’ 同前述定義。] [步驟12-1] 本步驟為藉由使化合物[10-f]與化合物[2-a]進行反應，製造化合物[12-a]之方法。 本反應可藉由本製造法之步驟2-1記載之方法或根據其之方法進行。 [步驟12-2] 本步驟為藉由使化合物[12-a]的保護基Pro3 脫保護，製造化合物[12-b]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[12-b]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟12-3] 本步驟為藉由使化合物[10-f]與化合物[2-d]進行反應，製造化合物[12-c]之方法。 本反應可藉由製造法2之步驟2-3記載之方法或根據其之方法進行。 [步驟12-4] 本步驟為藉由使化合物[12-c]的保護基Pro3 脫保護，製造化合物[12-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[12-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 [步驟12-5] 本步驟為藉由使化合物[10-f]與化合物[2-g]進行反應，製造化合物[12-e]之方法。 本反應可藉由製造法2之步驟2-5記載之方法或根據其之方法進行。 [步驟12-6] 本步驟為藉由使化合物[12-e]的保護基Pro3 脫保護，製造化合物[12-f]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[12-f]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[2-a]、[2-d]、及[2-g]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]中，X為式-CH2 -之化合物可藉由以下所示之製造法13~15、或根據此等的方法來製造。 化合物[I’]且X為式-CH2 -之化合物中，R5 所表示之構造對應前述式[II-1]所表示之構造之化合物[13-e]可藉由例如下述製造法13或根據其之方法來製造。 製造法13：
Figure 02_image265
[路徑中， R1 、R2 、R3 、R4 、L、Y、環D、及Pro3 同前述定義， XC 為溴原子或碘原子， W4 為單鍵或C1-8 烷烴二基， Z為乙烯-1、2-二基或乙炔-1、2-二基。] [步驟13-1] 本步驟為藉由使化合物[13-a]與化合物[13-b]進行反應，製造化合物[13-c]之方法。本反應可藉由所謂薗頭反應(“Handbook of Organopalladium Chemistry for Organic Synthesis”, Chapter III.2.8., pp493-535)或者所謂Heck反應(Angewandte Chemie International Edition in English，第33卷，2379頁、1995年)進行。 Z為乙炔-1,2-二基時，本反應可藉由所謂薗頭反應(“Handbook of Organopalladium Chemistry for Organic Synthesis”, Chapter III.2.8., pp493-535)，在鈀觸媒、銅(I)鹽、及鹼存在下之文獻記載之方法或根據其之方法進行。 本反應使用的化合物[13-a]的量，相對化合物[13-b]1當量，通常為1~5當量、較佳為1~2當量。 本反應使用的鈀觸媒方面，例如肆(三苯基膦)鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷錯合物、雙(三苯基膦)鈀(II)二氯化物等。使用的鈀觸媒的量，相對化合物[13-b]1當量，通常為0.001~0.5當量、較佳為0.005~0.3當量。 本反應使用的銅(I)鹽方面，例如碘化銅(I)等。使用的銅鹽(I)的量，相對化合物[13-b]1當量，通常為0.01~1當量、較佳為0.02~0.3當量。 本反應使用的鹼方面，例如三乙基胺或N,N-二異丙基乙基胺等之胺。使用的鹼的量，相對化合物[13-b]1當量，通常為2當量~溶劑量、較佳為2~5當量。 本反應使用的反應溶劑方面，可舉例如N,N-二甲基甲醯胺、二乙基醚、1,4-二噁烷、四氫呋喃、1,2-二甲氧基乙烷等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 此等之反應，通常可在室溫~迴流溫度進行1~24小時，又亦可在微波照射下進行。 Z為乙烯-1,2-二基時，本反應可藉由所謂Heck反應、在鈀觸媒及鹼的存在下、文獻(Angewandte Chemie International Edition in English，第33卷，2379頁、1995年)記載之方法或根據其之方法進行。 本反應使用的化合物[13-a]的量，相對化合物[13-b]1當量，通常為1~5當量、較佳為1~1.5當量。 本反應使用的鈀觸媒方面，可舉例如肆(三苯基膦)鈀(0)、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物、雙(三苯基膦)鈀(II)二氯化物等。本反應使用的鈀觸媒的量，相對化合物[13-b]1當量，通常為0.01~0.2當量、較佳為0.01~0.1當量。 本反應使用的鹼方面，可使用三乙基胺、N-乙基-N,N-二異丙基胺、碳酸鉀、碳酸鈣、碳酸銫、叔丁醇鉀、乙酸鉀等。本反應使用的鹼的量，相對化合物[13-b]1當量，通常為1~5當量、較佳為1~3當量。 本反應使用的溶劑方面，可舉例如乙腈、甲苯、四氫呋喃、N,N-二甲基甲醯胺等之不阻礙反應的溶劑，此等之溶劑可以適宜的比例混合使用。 此等之反應，通常可在室溫~迴流溫度進行1~24小時，又亦可在微波照射下進行。 [步驟13-2] 本步驟為藉由使化合物[13-c]的乙烯基或乙炔基進行催化氫化，製造化合物[13-d]之方法。本反應可在金屬觸媒及氫源存在下、在不阻礙反應的溶劑中進行。 本反應使用的金屬觸媒方面，例如鈀碳、氫氧化鈀碳、鈀碳-伸乙二胺複合體、參(三苯基膦)銠(I)氯化物等。使用的金屬觸媒的量，相對化合物[13-c]1當量，為0.001~1當量、較佳為0.01~0.5當量。 本反應使用的溶劑方面，例如甲醇、乙醇、水、四氫呋喃、乙酸乙酯等，此等之溶劑可以適宜的比例混合使用。 本反應，通常可在室溫~迴流溫度進行1~24小時。 [步驟13-3] 本步驟為藉由使化合物[13-d]的保護基Pro3 脫保護，製造化合物[13-e]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[13-e]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[13-a]及[13-b]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]且X為式-CH2 -之化合物中，R5 所表示之構造對應前述式[II-2]所表示之構造的化合物[14-d]可藉由例如下述製造法14或根據其之方法來製造。 製造法14：
Figure 02_image267
[路徑中， R1 、R2 、R3 、R4 、環A、環D、L1 、Pro3 、XC 、及Z同前述定義， W5 為C2-6 烷烴二基。] [步驟14-1] 本步驟為藉由使化合物[13-a]與化合物[14-a]進行反應，製造化合物[14-b]之方法。 本反應可藉由製造法13之步驟13-1記載之方法或根據其之方法進行。 [步驟14-2] 本步驟為藉由使化合物[14-b]的乙烯基或乙炔基進行催化氫化，製造化合物[14-c]之方法。 本反應可藉由製造法13之步驟13-2記載之方法或根據其之方法進行。 [步驟14-3] 本步驟為藉由使化合物[14-c]的保護基Pro3 脫保護，製造化合物[14-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[14-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[13-a]、[14-a]可藉由本身習知方法製造、或由市售品之購入取得。 化合物[I’]且X為式-CH2 -之化合物中，R5 所表示之構造對應前述式[II-3]所表示之構造的化合物[15-d]可藉由例如下述製造法15或根據其之方法來製造。 製造法15：
Figure 02_image269
[路徑中， R1 、R2 、R3 、R4 、R61 、R62 、環B、環D、Pro3 、R53’ 、XC 、及Z同前述定義， W6 為單鍵或C1 烷烴二基。] [步驟15-1] 本步驟為藉由使化合物[13-a]與化合物[15-a]進行反應，製造化合物[15-b]之方法。 本反應可藉由製造法13之步驟13-1記載之方法或根據其之方法進行。 [步驟15-2] 本步驟為藉由使化合物[15-b]的乙烯基或乙炔基進行催化氫化，製造化合物[15-c]之方法。 本反應可藉由製造法13之步驟13-2記載之方法或根據其之方法進行。 [步驟15-3] 本步驟為藉由使化合物[15-c]的保護基Pro3 脫保護，製造化合物[15-d]之方法。 本反應可藉由製造法2之步驟2-2記載之方法或根據其之方法進行。 如此得到的化合物[15-d]可藉由習知分離精製手段，例如濃縮、減壓濃縮、再沈澱、溶劑萃取、結晶化、層析法等進行分離精製。 又，在本製造法用作為原料化合物的化合物[13-a]、及[15-a]可藉由本身習知方法製造、或由市售品之購入取得。 以下的參考例及實施例中，二氧化矽膠體滲透層析法使用填充管柱(Grace公司製Reveleris(註冊商標)Flash Cartridges Silica、或Biotage公司製Biotage(註冊商標)SNAP Cartridge HP-Sphere)。NH二氧化矽膠體滲透層析法，使用填充管柱(Grace公司製Reveleris(註冊商標)Flash Cartridges Amino、或Biotage公司製Biotage(註冊商標)SNAP Cartridge KP-NH)。製備型薄層層析法，使用默克公司製PLC板20×20cm二氧化矽膠體60F254 ，2mm。溶出溶劑的比在未特別限制下，為容量比。相分離裝置使用Biotage公司製ISOLUTE(註冊商標)Phase Separator。 本說明書中使用的縮寫為下述意義。 s：單峰(singlet) d：二重峰(doublet) t：三重峰(triplet) q：四重峰(quartet) quin：五重峰(quintet) sxt：六重峰(sextet) spt：七重峰(septet) dd：雙二重峰(double doublet) dt：雙三重峰(double triplet) td：三二重峰(triple doublet) tt：三三重峰(triple triplet) qd：四二重峰(quarter doublet) m：多重峰(multiplet) br：寬峰(broad) J：耦合常數(coupling constant) Hz：赫茲(Hertz) CHLOROFORM-d：重氯仿 DMSO-d6 ：重二甲基亞碸 MeOH-d4 ：重甲醇 ACETONE-d6 ：重丙酮 D2 O：重水 THP：四氫吡喃基 TMS：三甲基矽烷基 Rf：阻滯因子(retardation factor)1 H-NMR(質子核磁共振頻譜)使用四甲基矽烷作為內部標準，以下述傅立葉變換型NMR進行測定，全δ值以ppm表示。 200MHz：Gemini2000(Agilent Technologies) 300MHz：Inova300(Agilent Technologies) 400MHz：AVANCE III HD400(Bruker) 500MHz：JNM-ECA500(JEOL) 600MHz：JNM-ECA600(JEOL) 解析使用ACD/Spectrus Processor 2017.1.3 ACD/Labs 2017.1.3 Release(File Version S70S41， Build 97027， 27 Sep 2017)(商品名)等。羥基或胺基、醯胺、吡唑等之質子為非常平緩的波峰亦有不記載之情形。 又，化合物的解析中，亦存在有與水或溶劑的波峰重疊而無法鑑定之質子的情況。 MS(質譜圖)為用以下的裝置測定。 PlatformLC(Waters) LCMS-2010EV(Shimadzu) LCMS-IT-TOF(Shimadzu) Agilent6130(Agilent) Agilent6150(Agilent) 離子化法方面，使用ESI(Electrospray Ionization、電噴霧電離化)法、EI(Electron Ionization、電子離子化法)、或ESI及APCI(Atmospheric Pressure Chemical Ionization、大氣壓化學離子化)法之雙重電離法。數據記載實測值(found)。通常觀測到分子離子波峰，但為具有tert-丁氧基羰基(-Boc)的化合物時，亦有觀測到碎片離子之tert-丁氧基羰基或者tert-丁基脫離的波峰之情形。又，為具有四氫吡喃基(THP)的化合物時，亦有觀測到作為碎片離子之四氫吡喃基脫離的波峰之情形。又，為具有羥基(-OH)的化合物時，亦有觀測到作為碎片波峰之H2 O或OH自由基脫離的波峰之情形。鹽之情況，通常觀測到自由形式的分子離子波峰或者碎片離子波峰。 實施例、參考例之LC-MS用以下的條件測定。 HPLC：Agilent 1290 Infinity MS：Agilent 6130 或 6150 [HPLC條件] 管柱：Acquity UPLC CSH C18、1.7μm、2.1x×50mm(WATERS) 溶劑：A液；含0.1%甲酸之水、B液；含0.1%甲酸之乙腈 (方法A) 梯度：0.00分鐘(A液/B液=80/20)、1.20分鐘(A液/B液=1/99)、1.40分鐘(A液/B液=1/99)、1.41分鐘(A液/B液=80/20)、1.50分鐘(A液/B液=80/20) (方法B) 梯度：0.00分鐘(A液/B液=95/5)、0.80分鐘(A液/B液=60/40)、1.08分鐘(A液/B液=1/99)、1.38分鐘(A液/B液=1/99)、1.41分鐘(A液/B液=95/5)、1.50分鐘(A液/B液=80/20) (方法C) 梯度：0.00分鐘(A液/B液=70/30)、0.80分鐘(A液/B液=1/99)、1.40分鐘(A液/B液=1/99)、1.42分鐘(A液/B液=70/30)、1.50分鐘(A液/B液=70/30) 注入量：0.5μL、流速：0.8mL/min 檢出法：UV210nm、254nm 連接蒸發光散射偵測器(ELSD)時 Agilent 385-ELSD MS條件 離子化法：ESI 或 ESI/APCI多模式 實施例、參考例之製備型HPLC的精製用以下的條件進行。 機器：Gilson 公司高產率精製系統 管柱：Triart C18、5μm、30×50mm(YMC)、或X-Bridge Prep C18 5um OBD、30x50(Waters) 溶劑：A液；含0.1%甲酸之水、B液；含0.1%甲酸之乙腈、或A液；含0.1%三氟乙酸之水、B液；含0.1%三氟乙酸之乙腈 (方法A) 梯度：0.00分鐘(A液/B液=90/10)、2.00分鐘(A液/B液=90/10)、11.0分鐘(A液/B液=20/80)、12.0分鐘(A液/B液=5/95)、13.52分鐘(A液/B液=5/95)、15.0分鐘(A液/B液=90/10) (方法B) 梯度：0.00分鐘(A液/B液=95/5)、3.00分鐘(A液/B液=95/5)、8.53分鐘(A液/B液=80/20)、10.0分鐘(A液/B液=80/20)、11.0分鐘(A液/B液=50/50)、12.02分鐘(A液/B液=5/95)、13.5分鐘(A液/B液=5/95)、13.65分鐘(A液/B液=95/5)、15.0分鐘(A液/B液=95/5) (方法C) 梯度：0.00分鐘(A液/B液=80/20)、2.00分鐘(A液/B液=80/20)、10.0分鐘(A液/B液=5/95)、11.5分鐘(A液/B液=1/99)、13.5分鐘(A液/B液=1/99)、13.55分鐘(A液/B液=80/20)、15.0分鐘(A液/B液=5/95)、15.0分鐘(A液/B液=95/5) 流速：40mL/min 檢出法：UV210nm、UV254nm 連接ELSD時 SofTA MODEL 300S ELSD 實施例、參考例之製備型LC-MS的精製用以下的條件進行。 HPLC：Agilent 1260 Infinity [HPLC條件] 管柱：X-SELECT CSH C18、5μm、OBD、30x50(Waters) 溶劑：A液；含0.1%甲酸之水、B液；含0.1%甲酸之乙腈、或A液；含0.1%三氟乙酸之水、B液；含0.1%三氟乙酸之乙腈 (方法A) 梯度：0.00分鐘(A液/B液=90/10)、0.50分鐘(A液/B液=90/10)、7.50分鐘(A液/B液=20/80)、7.95分鐘(A液/B液=20/80)、8.00分鐘(A液/B液=5/95)、9.00分鐘(A液/B液=5/95)、9.05分鐘(A液/B液=90/10)、10.0分鐘(A液/B液=90/10) (方法B) 梯度：0.00分鐘(A液/B液=95/5)、0.50分鐘(A液/B液=95/5)、7.50分鐘(A液/B液=50/50)、7.95分鐘(A液/B液=50/50)、8.00分鐘(A液/B液=5/95)、9.00分鐘(A液/B液=5/95)、9.05分鐘(A液/B液=95/5)、10.00分鐘(A液/B液=95/5) (方法C) 梯度：0.00分鐘(A液/B液=80/20)、0.50分鐘(A液/B液=80/20)、7.00分鐘(A液/B液=5/95)、7.45分鐘(A液/B液=5/95)、7.50分鐘(A液/B液=1/99)、9.00分鐘(A液/B液=1/99)、9.20分鐘(A液/B液=80/20)、10.0分鐘(A液/B液=80/20) 流速：50mL/min 檢出法：UV210nm、UV254nm MS：Agilent 6130 連接ELSD時 Agilent 385 ELSD MS條件 離子化法：ESI或ESI/APCI多模式 實施例、參考例之手性HPLC製備用以下的機器實施。 HPLC：Gilson 公司高產率精製系統或Waters公司製備型LC系統 檢出法：UV210nm、254nm 微波反應裝置使用Biotage公司Initiator、或Anton-Paar公司MONOWAVE300。 化合物的熔點使用股份公司Rigaku製熱重量示差熱分析裝置Thermo Plus Evo TG8120，以示差熱･熱重量測定(TG-DTA)法測定。 化合物名以Openeye公司製、PipelinePilot9.5之組成分、Molecular to Chemical Name(version 1)命名。 在本說明書，「室溫」係指20~30℃。 關於參考例及實施例的化合物中之不對稱碳，在本說明書所示之立體構造為絕對配置。關於不對稱碳，有絕對配置符號的化合物為光學活性體。 本發明用以下的參考例、實施例、試驗例及製劑例更詳細說明，但此等不限制本發明，又，可在不脫離本發明之範圍的範圍變化。 參考例1-1 6-(1,2,4-三唑-1-基)吡啶-3-醇
Figure 02_image271
(1)在市售的2-溴-5-羥基吡啶(31.6g)的丙酮(400mL)溶液中，在冰冷卻下，加入碳酸鉀(37.7g)及苄基溴化物(22.6mL)，在室溫進行2小時攪拌。將溶劑在減壓下餾去後，於殘渣加入水，以乙酸乙酯進行萃取。以相分離裝置將有機層分離，減壓下將溶劑餾去。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~4：1)進行精製，得到2-溴-5-(苄基氧基)吡啶(43.8g)之無色粉末。 (2)在上述(1)所得到的化合物(23.1g)、1,2,4-三唑(9.07g)、反式-N,N’-二甲基環己烷-1,2-二胺(22.1mL)、氫氧化鉀(10.3g)、乙腈(185mL)、及水(15.8mL)的混合物中，氮環境下加入碘化銅(3.34g)，在95℃進行10小時攪拌。使混合物冷卻至室溫，在減壓下進行濃縮。於殘渣中加入氯仿及水後進行攪拌，濾出不溶物。將有機層分離並使水層以氯仿進行萃取。將合併的有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(氯仿：甲醇=97：3)進行精製。使得到的粗生成物在n-己烷：乙醇=2：1混合液中，室溫下進行2日攪拌。濾出析出的固體，以n-己烷：乙醇=4：1混合液進行洗淨。使濾取物通氣乾燥，得到5-苯基甲氧基-2-(1,2,4-三唑-1-基)吡啶(18.9g)之淡黃色固體。 (3)在上述(2)所得到的化合物(18.9g)的甲醇(249mL)懸濁液中，加入5%鈀碳(1.89g)，氫環境下、在室溫進行20小時攪拌。使反應系進行氮取代，在50℃進行30分鐘攪拌。冷卻至室溫後，濾出觸媒，並以四氫呋喃進行洗淨。使濾液在減壓下濃縮，於得到的殘渣中加入n-己烷：乙醇=3：2混合液，在室溫進行一晩攪拌。濾出析出的固體，並以n-己烷：乙醇=3：2混合液洗淨，並在減壓下進行乾燥，得到標題化合物(11.6g)之淡灰色固體。1 H NMR(400 MHz, DMSO-d6 )δ ppm 7.39-7.49(m, 1H)7.71(d, J=8.4Hz, 1H)8.05(s, 1 H)8.22(s, 1H)9.19(s, 1H)10.34(br s, 1H). MS ESI posi:163[M+H]+ . MS ESI nega:161[M-H]- . 參考例1-2 2-(1,2,4-三唑-1-基)嘧啶-5-醇
Figure 02_image273
(1)使用市售的2-氯嘧啶-5-醇(3g)，依據參考例1-1-(1)記載之方法進行反應，得到2-氯-5-苯基甲氧基嘧啶(5g)之淡黃色固體。 (2)在上述(1)所得到的化合物(500mg)的N,N-二甲基甲醯胺(4.53mL)溶液中，加入1,2,4-三唑(235mg)及碳酸鉀(940mg)，在室溫進行1小時及在90℃進行1小時攪拌。使混合物冷卻至室溫後，加入水後以乙酸乙酯進行2次萃取。將合併的有機層通過相分離裝置，在減壓下進行濃縮。於得到的殘渣加入二乙基醚(15mL)，在室溫進行10分鐘攪拌。濾出析出的固體，並以二乙基醚進行洗淨，在減壓下進行乾燥，得到5-苯基甲氧基-2-(1,2,4-三唑-1-基)嘧啶(430mg)之無色固體。 (3)使用上述(2)所得到的化合物(820mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(430mg)之無色固體。1 H NMR(400MHz, DMSO-d6 )δ ppm 8.24(s, 1H)8.42(s, 2H) 9.26(s, 1H). MS ESI posi：164[M+H]+ . MS ESI nega：162[M-H]- . 參考例1-3 6-(1,2,4-三唑-1-基)噠嗪-3-醇
Figure 02_image275
(1)在苄基醇(1.60mL)的四氫呋喃(44.7mL)溶液中，在冰冷卻下加入氫化鈉(60%礦油分散物、387mg)，進行1小時攪拌。在混合物緩緩加入3,6-二氯噠嗪(2g)。在室溫進行18小時及在60℃進行4小時攪拌。使混合物冷卻至室溫後，加入水及飽和氯化銨水溶液，以乙酸乙酯進行萃取。使有機層通過相分離裝置，進行減壓濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到3-氯-6-苯基甲氧基噠嗪(400mg)之無色固體。 (2)在微波反應用試驗管內，於上述(1)所得到的化合物(50mg)的N,N-二甲基甲醯胺(906μL)溶液中，加入1,2,4-三唑(235mg)及碳酸銫(221mg)。將容器內的氣體取代為氮且密封後，使混合物在微波照射下於140℃進行1小時攪拌。使混合物冷卻至室溫，加入水後以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=22：3~僅乙酸乙酯)進行精製，得到3-苯基甲氧基-6-(1,2,4-三唑-1-基)噠嗪(13mg)之無色固體。 (3)使用上述(2)所得到的化合物(13mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(7mg)之無色固體。 MS ESI posi：164[M+H]+ . 參考例2-1 2-(7-羥基庚氧基)乙酸乙基酯
Figure 02_image277
(1)在庚烷-1,7-二醇(25g)的甲苯(378mL)懸濁液中，在冰冷卻下加入三乙基胺(52.7mL)、N,N-二甲基胺基吡啶(1.85g)、及氯化p-甲苯磺酸(37.9g)後，在室溫進行一晩攪拌。在該混合物，在冰冷卻下加入飽和氯化銨水溶液，以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥後進行過濾。使濾液在減壓下濃縮，使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=3：2~1：3)進行精製，得到4-甲基苯磺酸7-羥基庚酯(31.4g)之無色油狀物質。 (2)在上述(1)所得到的化合物(31.4g)的氯仿(110mL)溶液中，加入p-甲苯磺酸一水合物(2.1g)。在冰冷卻下於該混合物中加入3,4-二氫-2H-吡喃(25mL)。離開冰浴後進行1小時攪拌。再度使反應系以冰冷卻，於混合物中加入飽和碳酸氫鈉水溶液，以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=87：13~13：7)進行精製，得到4-甲基苯磺酸7-(噁烷-2-基氧基)庚酯(35.8g)之淡黃色油狀物質。 (3)在2-羥基乙酸乙酯(152μL)的N,N-二甲基甲醯胺(1.2mL)溶液，在冰冷卻下加入氫化鈉(60%礦油分散物、24mg)，在同溫度進行30分鐘攪拌。於該混合物中加入上述(2)所得到的化合物(200mg)的N,N-二甲基甲醯胺(1.0mL)溶液，在室溫進行整夜攪拌後，在70℃進行5小時攪拌。冷卻至室溫後，於混合物中加入飽和氯化銨水溶液，以乙酸乙酯進行萃取。將有機層依序以水及飽和食鹽水進行洗淨，通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：1)進行精製，得到2-[7-(噁烷-2-基氧基)庚氧基]乙酸乙酯(46mg)之無色油狀物質。 (4)在上述(3)所得到的化合物(120mg)的甲醇(3mL)及水(1mL)溶液，在冰冷卻下加入三氟乙酸(0.5mL)，在室溫進行2.5小時攪拌。在混合物中加入飽和碳酸氫鈉水溶液，並以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=23：2~1：2)進行精製，得到標題化合物(65mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.25-1.31(m, 3H)1.32-1.45(m, 6H)1.56-1.69(m, 4H)3.52(t, J=6.6Hz, 2H) 3.59-3.68(m, 2H)4.06(s, 2H)4.22(q, J=7.1Hz, 2H). 參考例2-2 2-(7-羥基庚氧基)丁烷酸乙酯
Figure 02_image279
(1)在參考例2-1-(3)所得到的化合物(200mg)的四氫呋喃(2.2mL)溶液，在-78℃冷卻下加入六甲基二矽氮烷鋰(1.3 mol/L四氫呋喃溶液、0.61mL)，並在同溫度進行30分鐘攪拌後，滴下碘乙烷(63.5μL)。滴下完畢後，邊使混合物慢慢升溫至室溫，邊進行15小時攪拌。於該混合物中加入飽和氯化銨水溶液，並以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=49：1~4：1)進行精製，得到含2-[7-(噁烷-2-基氧基)庚氧基]丁烷酸乙酯之混合物(100mg)。 (2)使用上述(1)所得到的混合物(100mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(55mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 0.97(t, J=7.5Hz, 3H)1.29(t, J=7.2Hz, 3H)1.32-1.42(m, 6H)1.57-1.68(m, 4H) 1.68-1.81(m, 2H)3.26-3.37(m, 1H)3.50-3.70(m, 3H)3.73(dd, J=7.3, 5.4Hz, 1H)4.18-4.28(m, 2H). MS ESI posi：247[M+H]+ . 以下的參考例2-3~2-5使用參考例2-1-(2)所得到的化合物及對應之市售的醇，並依據參考例2-1-(3)及(4)記載之方法進行合成。化合物的構造、NMR數據、MS數據如表1-1所示。
Figure 02_image281
參考例3-1 3-(8-羥基辛基)-1,1-二側氧基硫呾-3-甲腈
Figure 02_image283
(1)在2-(8-溴辛氧基)噁烷(2.0g)的N,N-二甲基甲醯胺(27mL)溶液中，加入氰基乙酸甲酯(1.22mL)及碳酸鉀(2.83g)，在75℃進行3小時攪拌。在反應液中加入飽和氯化銨水溶液，以二乙基醚進行萃取。將有機層依序以水及飽和食鹽水進行洗淨，以無水硫酸鎂進行乾燥。過濾乾燥劑後，使濾液在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~7：3)進行精製，得到2-氰-10-(噁烷-2-基氧基)癸烷酸甲酯(1.40g)之無色油狀物質。 (2)在上述(1)所得到的化合物(1.40g)的乙腈(15mL)溶液中，加入37%甲醛(1.52mL)及三乙基胺(63μL)，在65℃進行5小時攪拌。使反應液在減壓下進行濃縮，在得到的殘渣中加入水，並以乙酸乙酯進行萃取。使有機層以飽和食鹽水進行洗淨後，以無水硫酸鎂進行乾燥。過濾乾燥劑，使濾液在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=7：3~9：11)進行精製，得到2-氰-2-(羥基甲基)-10-(噁烷-2-基氧基)癸烷酸甲酯(1.5g)之無色油狀物質。 (3)在上述(2)所得到的化合物(1.5g)的四氫呋喃(22mL)溶液中，在冰冷卻下加入硼氫化鋰(160mg)，在室溫進行整夜攪拌。使混合物以冰冷卻，加入水及飽和氯化銨水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(氯仿：甲醇=99：1~91：9)進行精製，得到2,2-雙(羥基甲基)-10-(噁烷-2-基氧基)癸烷腈(1.09g)之無色油狀物質。 (4)在上述(3)所得到的化合物(546mg)的乙酸乙酯(8.7mL)溶液中，在冰冷卻下加入N,N-二異丙基乙基胺(1.2mL)及甲烷磺醯氯(410μL)，在室溫進行整夜攪拌。在冰冷卻下加入飽和碳酸氫鈉水溶液後使反應停止，以乙酸乙酯進行萃取。使有機層以飽和食鹽水進行洗淨後，通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=7：3~3：7)進行精製，得到甲磺酸[2-氰-2-(甲基磺醯基氧基甲基)-10-(噁烷-2-基氧基)癸基]酯(750mg)之無色油狀物質。 (5)在上述(4)所得到的化合物(750mg)的N,N-二甲基甲醯胺(16mL)溶液中，加入硫化鈉九水合物(1.92g)及碘化四丁基銨(118mg)，氮環境下在50℃進行整夜攪拌。在反應液中加入水，以乙酸乙酯進行萃取後，將有機層依序以水及飽和食鹽水進行洗淨，通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~4：1)進行精製，得到3-[8-(噁烷-2-基氧基)辛基]硫呾-3-甲腈(36mg)之無色油狀物質。 (6)在上述(5)所得到的化合物(36mg)的氯仿(1.2mL)溶液中，在冰冷卻下加入m-氯過氧苯甲酸(66mg)，在室溫進行2.5小時攪拌。使混合物以冰冷卻，加入飽和碳酸氫鈉水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=3：1=1：1)進行精製，得到3-[8-(噁烷-2-基氧基)辛基]-1,1-二側氧基硫呾-3-甲腈(28mg)之無色油狀物質。 (7)使用上述(6)所得到的化合物(28mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(16mg)之無色固體。1 H NMR(600MHz, CHLOROFORM-d)δ ppm 1.18-1.61(m, 13H) 2.00-2.06(m, 2H)3.62-3.69(m, 2H)4.09-4.15(m, 2H) 4.57-4.63 (m, 2H). MS ESI/APCI Multi posi:282[M+Na]+ . MS ESI/APCI Multi nega:294[M+Cl]- . 參考例4-1 10-羥基-2,2-雙(甲氧基甲基)癸烷腈
Figure 02_image285
(1)在參考例3-1-(3)所得到的化合物(500mg)的四氫呋喃(8mL)溶液中，在冰冷卻下加入氫化鈉(60%礦油分散物、191mg)，在同溫度進行30分鐘攪拌。在該混合物中，滴下碘甲烷(400μL)的四氫呋喃(8mL)溶液，在室溫進行2.5小時及在60℃進行3小時攪拌。使反應混合物以冰冷卻，加入飽和氯化銨水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~7：3)進行精製，得到2,2-雙(甲氧基甲基)-10-(噁烷-2-基氧基)癸烷腈(403mg)之無色油狀物質。 (2)使用上述(1)所得到的化合物(150mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(108mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.34-1.65(m, 14H) 3.40(s, 6H)3.48(s, 4H)3.64(t, J=6.6Hz, 2H). MS ESI/APCI Multi posi：258[M+H]+ . 參考例5-1 3-(7-羥基庚氧基)氧雜環丁烷-3-羧酸甲酯
Figure 02_image287
(1)使用庚烷-1,7-二醇(10.0g)，依據參考例2-1-(2)記載之方法進行反應，得到7-(噁烷-2-基氧基)庚烷-1-醇(8g)之無色油狀物質。 (2)在上述(1)所得到的化合物(7.0g)的氯仿(50mL)溶液中，邊使反應容器以水浴冷卻邊加入乙酸銠(II)(71.5mg)。使混合物進行5分鐘攪拌後，花5分鐘滴下重氮基丙二酸二甲酯(5.1g)的氯仿(20mL)溶液。滴下完畢後，使混合物在室溫進行2日攪拌，加入飽和碳酸氫鈉水溶液後搖動，使用相分離裝置將有機層分離。使有機層在減壓下進行濃縮，使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到2-[7-(噁烷-2-基氧基)庚氧基]丙烷二酸二甲酯(11.5g)之無色油狀物質。 (3)使用上述(2)所得到的化合物(10g)，依據參考例3-1-(2)記載之方法進行反應，得到2-(羥基甲基)-2-[7-(噁烷-2-基氧基)庚氧基]丙烷二酸二甲酯(5.6g)之無色油狀物質。 (4)在上述(3)所得到的化合物(5.6g)的N,N-二甲基甲醯胺(17mL)溶液中，在冰冷卻下緩緩加入咪唑(2.0g)及tert-丁基二苯基氯矽烷(6.1g)後，在室溫進行18小時攪拌。於混合物中加入飽和氯化銨水溶液，以二乙基醚進行萃取。使有機層以飽和氯化銨水溶液進行洗淨，通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到2-[[tert-丁基(二苯基)矽烷基]氧基甲基]-2-[7-(噁烷-2-基氧基)庚氧基]丙烷二酸二甲酯(10g)之無色油狀物質。 (5)使用上述(4)所得到的化合物(5.0g)，依據參考例3-1-(3)記載之方法進行反應，得到2-[[tert-丁基(二苯基)矽烷基]氧基甲基]-2-[7-(噁烷-2-基氧基)庚氧基]丙烷-1,3-二醇(3.5g)之無色油狀物質。 (6)在上述(5)所得到的化合物(1.0g)的四氫呋喃(7.2mL)溶液中，在冰冷卻下緩緩加入N-丁基鋰(1.6mol/L己烷溶液、1.2mL)，在同溫度進行20分鐘攪拌。在該混合物中，加入氯化p-甲苯磺酸(380mg)的四氫呋喃(2mL)溶液，進行1小時攪拌。進一步加入n-丁基鋰(1.6mol/L己烷溶液、1.2 mL)，在冰冷卻下進行40分鐘，在室溫進行10分鐘、在70℃進行8小時，接著室溫下進行2日攪拌。於該混合物中加入飽和氯化銨水溶液，以二乙基醚進行萃取。使有機層以飽和氯化銨水溶液進行洗淨，通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到tert-丁基-[[3-[7-(噁烷-2-基氧基)庚氧基]氧雜環丁烷-3-基]甲氧基]-二苯基矽烷(630mg)之無色油狀物質。 (7)在上述(6)所得到的化合物(630mg)的四氫呋喃(3.9mL)溶液中，在冰冷卻下加入四丁基銨氟化物(1.0mol/L四氫呋喃溶液、1.3mL)，在室溫進行1小時攪拌。於混合物中加入飽和碳酸氫鈉水溶液，並以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=23：2~僅乙酸乙酯)進行精製，得到[3-[7-(噁烷-2-基氧基)庚氧基]氧雜環丁烷-3-基]甲醇(360mg)之無色油狀物質。 (8)在上述(7)所得到的化合物(360mg)的乙腈(4.0mL)及磷酸緩衝液(pH7.0、4mL)溶液中，在冰冷卻下加入2-羥基-2-氮雜金剛烷(18mg)、亞氯酸鈉(410mg)、及安替佛民(1mL)，在室溫進行1.5小時攪拌。在混合物中加入飽和硫代硫酸鈉水溶液，在室溫進行1小時攪拌，以乙酸乙酯進行萃取。使有機層在減壓下進行濃縮，得到含3-[7-(噁烷-2-基氧基)庚氧基]氧雜環丁烷-3-羧酸之混合物(315mg)。 (9)使用上述(8)所得到的化合物(310mg)，依據參考例2-1-(4)記載之方法進行反應，得到含3-(7-羥基庚氧基)氧雜環丁烷-3-羧酸之混合物。 (10)在上述(9)所得到的混合物的甲苯(4.9mL)及甲醇(0.49mL)溶液中，在冰冷卻下加入(三甲基矽烷基)重氮甲烷(230μL)，在室溫進行1小時攪拌。在混合物中加入甲醇(2.5mL)、水(1mL)、及三氟乙酸(1mL)，在同溫度進行2小時攪拌。於該混合物中加入飽和碳酸氫鈉水溶液，以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=22：3~僅乙酸乙酯)進行精製，得到標題化合物(130mg)之無色固體。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29-1.75(m, 10H)3.37(t, J=6.5Hz, 2H)3.65(t, J=6.5Hz, 2H)3.85(s, 3H) 4.69(d, J=6.9Hz, 2H)4.86(d, J=6.9Hz, 2H). 參考例6-1 3-(8-羥基辛基)氧雜環丁烷-3-羧酸甲酯
Figure 02_image289
(1)氮環境下、在以乾冰-丙酮浴冷卻的氧雜環丁烷-3-羧酸甲酯(500mg)及2-(8-溴辛氧基)噁烷(1.26g)的四氫呋喃(17mL)溶液中，滴下六甲基二矽氮烷鉀(0.5mоl/L甲苯溶液、10mL)。滴下完畢後，除去乾冰-丙酮浴，邊昇溫到室溫邊進行4小時攪拌。在混合物中加入飽和氯化銨水溶液後，使反應停止，以二乙基醚進行萃取。使得到的有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到含3-[8-(噁烷-2-基氧基)辛基]氧雜環丁烷-3-羧酸甲酯之混合物(100mg)。 (2)使用上述(1)所得到的混合物(100mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(65mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.10-1.40(m, 12H)1.94-2.02(m, 2H)3.64(t, J=6.6Hz, 2H)3.76(s, 3H)4.43 (d, J=6.1Hz, 2H)4.89(d, J=6.1Hz, 2H). MS ESI posi:245[M+H]+ . 參考例7-1 7-(羥基甲基)-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯
Figure 02_image291
(1)在市售的7-羥基-4-側氧基-1-苯并哌喃-2-羧酸乙酯(3.27g)的乙酸(30mL)溶液中，加入鈀碳(981mg)，氫環境下(50psi)，在30℃進行12小時攪拌。使反應溶液進行矽藻土(註冊商標)過濾後，將濾液濃縮。於得到的殘渣中加入乙酸乙酯，以飽和碳酸氫鈉水溶液及飽和食鹽水依序進行洗淨。使有機層以相分離裝置進行分離，在減壓下進行濃縮。於得到的殘渣中加入二乙基醚及n-己烷，過濾析出的固體，得到7-羥基-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯(2.91g)之無色粉末。 (2)在上述(1)所得到的化合物(1.00g)的氯仿(15mL)溶液中，加入吡啶(730μL)，在冰冷卻下滴下三氟甲磺酸酐(910μL)。昇溫至室溫，進行1小時攪拌。在反應液中，在冰冷卻下加入1mol/L鹽酸(20mL)及水(5mL)後進行攪拌。以分液漏斗將有機層分離，以飽和碳酸氫鈉水溶液進行洗淨。通過相分離裝置後在減壓下進行濃縮，使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~1：1)進行精製，得到7-(三氟甲基磺醯基氧基)-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯(1.61g)之無色油狀物質。 (3)在上述(2)所得到的化合物(400mg)的1,4-二噁烷(3mL)及水(0.6mL)溶液中，加入乙烯基三氟硼酸鉀(272mg)、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(92mg)、及碳酸鉀(468mg)，氮環境下在100℃進行2小時攪拌。使混合物冷卻至室溫後，過濾不溶物，將濾液濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：2)進行精製，得到7-乙烯基-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯(212mg)之無色油狀物質。 (4)將上述(3)所得到的化合物(212mg)及N-甲基嗎啉-N-氧化物(267mg)溶於tert-丁基醇(4.6mL)、四氫呋喃(4.6mL)、及水(0.91mL)，加入4%四氧化鋨水溶液(118μL)後在室溫進行2小時攪拌後，在60℃進行20分鐘攪拌。反應溶液中，加入飽和硫代硫酸鈉水溶液，並以乙酸乙酯進行萃取。通過相分離裝置後在減壓下進行濃縮，得到含7-(1,2-二羥基乙基)-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯之混合物(271mg)。 (5)在上述(4)得到的化合物(271mg)的四氫呋喃(5.0mL)及水(5.0mL)溶液中，加入過碘酸鈉(239mg)後，在室溫進行30分鐘攪拌。於混合物中加入水，以乙酸乙酯進行萃取。使有機層通過相分離裝置，減壓下進行濃縮，得到含7-甲醯基-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯之混合物(217 mg)。 (6)在上述(5)得到的混合物的乙醇(4.6mL)溶液中，在冰冷卻下加入氫硼化鈉(46mg)後，在同溫進行30分鐘攪拌。加入飽和氯化銨水溶液及水，並以乙酸乙酯進行萃取。使有機層以相分離裝置進行分離，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~1：1)進行精製，得到標題化合物(170mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)2.13-2.33(m, 2H)2.68-2.88(m, 2H)4.25(q, J=7.1 Hz, 2H) 4.62(d, J=6.0 Hz, 2H)4.69-4.76(m, 1H)6.88(d, J=7.7Hz, 1H)6.94(s, 1H)7.02(d, J=7.7 Hz, 1H). MS ESI posi：259[M+Na]+ . 參考例7-2 7-(羥基甲基)-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯(光學活性體)
Figure 02_image293
(1)使用具備手性管柱的製備型HPLC，將參考例7-1(540 mg)的光學異構物分離(分離條件如下。管柱：CHIRALPAK IB、5μm、20x250mm。溶劑：A液；乙醇、B液；n-己烷。溶出條件：A液/B液=10/90。流速：10mL/min、溫度：40℃)。得到參考例7-2(236mg)之無色油狀物質作為滯留時間18.8分鐘之成分。 參考例7-3 7-(溴甲基)-2-甲基-3,4-二氫色烯-2-羧酸乙酯
Figure 02_image295
(1)使用參考例7-1所得到的化合物(1.00g)，依據參考例2-1-(2)記載之方法進行反應，得到7-(噁烷-2-基氧基甲基)-3,4-二氫-2H-色烯-2-羧酸乙酯(1.19g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(403mg)及碘甲烷(313μL)，依據參考例2-2-(1)記載之方法進行反應，得到2-甲基-7-(噁烷-2-基氧基甲基)-3,4-二氫-2H-色烯-2-羧酸乙酯(266mg)之無色油狀物質。 (3)使用上述(2)所得到的化合物(275mg)，依據參考例2-1-(4)記載之方法進行反應，得到7-(羥基甲基)-2-甲基-3,4-二氫色烯-2-羧酸乙酯(184mg)之無色油狀物質。 (4)在上述(3)所得到的化合物(74mg)的氯仿(2mL)溶液中，在冰冷卻下加入三苯基膦(155mg)及四溴化碳(75μL)，在室溫進行2小時攪拌。於混合物中加入飽和碳酸氫鈉水溶液，以氯仿進行3次萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~13：7)進行精製，得到標題化合物(144mg)之無色油狀物質。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.20(t, J=7.1Hz, 3H)1.62 (s, 3H)1.89(ddd, J=13.5, 10.8, 6.7Hz, 1H)2.40(dt, J=13.5, 4.6Hz, 1H)2.61-2.77(m, 2H)4.12-4.21(m, 2H)4.43(s, 2H)6.88 (d, J=7.7 Hz, 1H)6.94-7.01(m, 2H). MS ESI posi:335, 337[M+Na]+ . 參考例8-1 7-(羥基甲基)-3,4-二氫-2H-色烯-3-羧酸乙酯
Figure 02_image297
(1)氮環境下，在7-溴-3,4-二氫-2H-苯並呋喃-4-酮(950mg)的四氫呋喃(13.9mL)溶液中，在-78℃加入六甲基二矽氮烷鋰(1mol/L四氫呋喃溶液、4.60mL)，在同溫度進行30分鐘攪拌。於其中加入氰基甲酸乙酯(455μL)，在冰冷卻下進行2小時攪拌。再冷卻至-78℃，加入六甲基二矽氮烷鋰(1mol/L四氫呋喃溶液、4.60mL)，在冰冷卻下進行2小時攪拌。加入飽和氯化銨水溶液後，使反應停止，以氯仿進行萃取。使有機層以相分離裝置進行分離，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=4：1~2：3)進行精製，得到7-溴-4-側氧基-2,3-二氫色烯-3-羧酸乙酯(630mg)之無色固體。 (2)使用上述(1)所得到的化合物(630mg)，依據參考例7-1-(6)記載之方法進行反應，得到7-溴-4-羥基-3,4-二氫-2H-色烯-3-羧酸乙酯(330mg)之無色固體。 (3)氮環境下，使上述(2)所得到的化合物(330mg)的氯仿(11mL)溶液以冰冷卻，於其中加入二苯基雙[1-苯基-1-(三氟甲基)-2,2,2-三氟乙氧基]硫(IV)(1.11g)，在室溫進行5小時半攪拌。使混合物在減壓下進行濃縮，使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=4：1~2：3)進行精製，得到7-溴-2H-色烯-3-羧酸乙酯(293mg)之無色固體。 (4)在微波反應試驗管，使上述(3)所得到的化合物(293mg)、N-甲醯基糖精(328mg)、碳酸鈉(165mg)、三乙基矽烷(215μL)、1,4-雙(二苯基膦基)丁烷(66.2mg)、及乙酸鈀(II)(23.2mg)在N,N-二甲基甲醯胺(2.59mL)中混合，將容器內的大氣取代為氮，進行密封。將混合物在微波照射下於110℃進行2小時半攪拌。冷卻至室溫後，使混合物注入飽和氯化銨水溶液中，以乙酸乙酯：甲苯=1：1混合溶劑進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：2)進行精製，得到7-甲醯基-2H-色烯-3-羧酸乙酯(50mg)之黃色固體。 (5)使用上述(4)所得到的化合物(50mg)及作為觸媒的鈀碳-伸乙二胺複合體(25mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(28mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)2.94-3.12(m, 3H)4.08-4.15(m, 1H)4.20(q, J=7.1Hz, 2H)4.38-4.49(m, 1H)4.61(s, 2H)6.80-6.92(m, 2H)7.05-7.11(m, 1H). MS ESI posi:259[M+Na]+ , 219[M-OH]+ . 參考例9-1 6-(羥基甲基)-3,4-二氫-2H-1-苯并哌喃-3-羧酸乙酯
Figure 02_image299
(1)在市售的6-溴-3,4-二氫-2H-1-苯并哌喃-3-羧酸(500 mg)中，加入2mol/L氯化氫-乙醇溶液(9.7mL)，在75℃進行18小時攪拌。使反應液在減壓下進行濃縮，得到6-溴-3,4-二氫-2H-1-苯并哌喃-3-羧酸乙酯(510mg)。 (2)在微波反應容器內，將上述(1)所得到的化合物(510 mg)、肆(三苯基膦)鈀(0)(207mg)、氰化鋅(322mg)、及N,N-二甲基甲醯胺(3.6mL)混合，將容器內的大氣取代為氮，進行密封。使混合物在微波照射下在150℃進行30分鐘攪拌。冷卻至室溫後，在混合物中加入水及乙酸乙酯，濾出不溶物。將濾液以乙酸乙酯進行萃取。將有機層依序以水及飽和食鹽水進行洗淨，通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以NH二氧化矽膠體滲透層析法(僅n-己烷~n-己烷：乙酸乙酯=4：1)進行精製，得到6-氰-3,4-二氫-2H-1-苯并哌喃-3-羧酸乙酯(147mg)之無色固體。 (3)在上述(2)所得到的化合物(147mg)的吡啶(1.6mL)及乙酸(1.6mL)溶液中，加入磷酸二氫鈉(458mg)及雷氏鎳(水懸濁液、3mL)，在100℃進行1.5小時攪拌。濾出觸媒，並以乙醇進行洗淨。使濾液在減壓下進行濃縮。使得到的殘渣以乙酸乙酯稀釋，依序以1mol/L鹽酸、飽和碳酸氫鈉水溶液、及飽和食鹽水進行洗淨。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(僅n-己烷~n-己烷：乙酸乙酯=3：2)進行精製，得到6-甲醯基-3,4-二氫-2H-1-苯并哌喃-3-羧酸乙酯(86mg)之無色油狀物質。 (4)使用上述(3)所得到的化合物(82mg)，依據參考例7-1-(6)記載之方法進行合成，得到標題化合物(81mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.2Hz, 3H)2.94-3.15(m, 3H)4.07-4.25(m, 3H)4.39-4.48(m, 1H)4.58 (s, 2H)6.76-6.87(m, 1H)7.03-7.16(m, 2H). MS ESI posi:219[M-OH]+ . 參考例10-1 7-(2-羥基乙基)-3,4-二氫-2H-色烯-2-羧酸乙酯
Figure 02_image301
(1)在參考例7-1所得到的化合物(1.00g)氯仿(20mL)溶液中，在冰冷卻下加入戴斯-馬丁氧化劑(2.2g)，在室溫進行1小時攪拌。於經冰冷卻的混合物中加入飽和硫代硫酸鈉水溶液及飽和碳酸氫鈉水溶液，在室溫進行10分鐘攪拌後，以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(僅n-己烷~n-己烷：乙酸乙酯=7：3)進行精製，得到7-甲醯基-3,4-二氫-2H-色烯-2-羧酸乙酯(962mg)之無色油狀物質。 (2)氬環境下，在(甲氧基甲基)三苯基鏻氯化物(1.01g)的甲苯(6.5mL)溶液中，加入tert-丁氧基鉀(330mg)，在室溫進行1小時攪拌。在該反應溶液中，在冰冷卻下加入上述(1)所得到的化合物(459mg)的甲苯(4.0mL)溶液，在室溫進行1小時攪拌。再度使反應系以冰冷卻，加入飽和氯化銨水溶液，使反應停止，以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(僅n-己烷~n-己烷：乙酸乙酯=9：1)進行精製，得到7-[(E)-2-甲氧基乙烯基]-3,4-二氫-2H-色烯-2-羧酸乙酯(230mg)之無色油狀物質。 (3)在上述(2)所得到的化合物(230mg)的乙腈(8.0mL)溶液中，加入水(1.0mL)及濃鹽酸(220μL)，在室溫進行4小時攪拌。在混合物中加入飽和碳酸氫鈉水溶液，使有機溶劑在減壓下餾去。使剩下的水層以氯仿進行萃取。藉由使有機層以相分離裝置進行分離，並在減壓下進行濃縮，得到含7-(2-氧代乙基)-3,4-二氫-2H-色烯-2-羧酸乙酯之混合物(241mg)。 (4)使用上述(3)所得到的混合物(241mg)，依據參考例7-1-(6)記載之方法進行反應，得到標題化合物(131mg)之無色固體。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.30(t, J=7.1Hz, 3H)2.10-2.33(m, 2H)2.66-2.90(m, 4H)3.71-3.98(m, 2H)4.20-4.40(m, 2H)4.66-4.74(m, 1H)6.74(d, J=7.8Hz, 1H)6.82(s, 1H) 6.98(d, J=7.8 Hz, 1H). MS ESI posi：251[M+H]+ , 273[M+Na]+ . 參考例11-1 6-(2-羥基乙基)-3,4-二氫-2H-色烯-2-羧酸乙酯
Figure 02_image303
(1)使用6-溴-3,4-二氫-2H-1-苯并哌喃-2-羧酸(490mg)，依據參考例9-1-(1)記載之方法進行反應，得到6-溴-3,4-二氫-2H-1-苯并哌喃-2-羧酸乙酯(528mg)之黃色油狀物質。 (2)使用上述(1)所得到的化合物(513mg)，依據參考例7-1-(3)記載之方法進行反應，得到6-乙烯基-3,4-二氫-2H-色烯-2-羧酸乙酯(343mg)之無色油狀物質。 (3)使用上述(2)所得到的化合物(343mg)，依據參考例7-1-(4)記載之方法進行反應，得到6-(1,2-二羥基乙基)-3,4-二氫-2H-色烯-2-羧酸乙酯(370mg)之無色油狀物質。 (4)使用上述(3)所得到的化合物(370mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(91mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.23-1.33(m, 4H)2.12-2.33(m, 2H)2.66-2.91(m, 4H)3.75-3.90(m, 2H)4.20-4.33(m, 1H)4.64-4.74(m, 1H)6.84-6.92(m, 2H)6.98(d, J=8.1 Hz, 1H). MS ESI posi:251[M+H]+ , 273[M+Na]+ . 參考例12-1 7-(2-羥基乙基)-3,4-二氫-2H-色烯-3-羧酸乙酯
Figure 02_image305
(1)使用7-溴-3,4-二氫-2H-苯並呋喃-4-酮(2.5g)，依據參考例7-1-(3)記載之方法進行反應，得到7-乙烯基-2,3-二氫色烯-4-酮(1.64g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(1.64g)，依據參考例7-1-(4)記載之方法進行反應，得到7-(1,2-二羥基乙基)-2,3-二氫色烯-4-酮(2.18g)之無色固體。 (3)在上述(2)所得到的化合物(2.18g)的丙酮(20.9mL)溶液中，在冰冷卻下加入2,2-二甲氧基丙烷(20.9mL)及吡啶鎓p-甲苯磺酸(263mg)，在室溫進行攪拌。在混合物中加入飽和碳酸氫鈉水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=97：3~4：1)進行精製，得到7-(2,2-二甲基-1,3-二氧戊環-4-基)-2,3-二氫色烯-4-酮(1.83g)之無色油狀物質。 (4)使用上述(3)所得到的化合物(1.83g)，依據參考例8-1-(1)記載之方法進行反應，得到7-(2,2-二甲基-1,3-二氧戊環-4-基)-4-側氧基-2,3-二氫色烯-3-羧酸乙酯(1.55g)之無色油狀物質。 (5)使用上述(4)所得到的化合物(1.55g)，依據參考例7-1-(6)記載之方法進行反應，得到7-(2,2-二甲基-1,3-二氧戊環-4-基)-4-羥基-3,4-二氫-2H-色烯-3-羧酸乙酯(1.05g)之無色油狀物質。 (6)使用上述(5)所得到的化合物(120mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(92mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)1.37(t, J=5.9Hz, 1H)2.79(t, J=6.5Hz, 2H)2.95-3.09(m, 3H) 3.84(td, J=6.5, 5.9Hz, 2H)4.05-4.15(m, 1H)4.20(q, J=7.1Hz, 2H)4.38-4.48(m, 1H)6.68-6.78(m, 2H)7.03(d, J=7.7Hz, 1H). MS ESI posi:251[M+H]+ , 233[M-OH]+ . 以下的參考例12-2為使用對應市售的溴-3,4-二氫-2H-苯並呋喃酮，依據參考例12-1記載之方法進行合成。化合物的構造、NMR數據、MS數據如表2-1所示。
Figure 02_image307
參考例13-1 2-[6-(2-羥基乙基)-3,4-二氫-2H-色烯-4-基]乙酸乙酯
Figure 02_image309
(1)氮環境下，在以乾冰-甲醇浴冷卻的二異丙基胺(521mL)的四氫呋喃(7.43mL)溶液中，加入n-丁基鋰(1.60mol/L n-己烷溶液、2.41mL)，在冰冷卻下進行30分鐘攪拌。使反應系以乾冰-甲醇浴再度冷卻，加入(三甲基矽烷基)乙酸乙酯(680μL)，在同溫度進行1小時攪拌。於其中加入參考例12-2合成時得到的合成中間體(6-(2,2-二甲基-1,3-二氧戊環-4-基)-2,3-二氫色烯-4-酮；由市售的6-溴-3,4-二氫-2H-苯並呋喃-4-酮以3步驟得到的化合物、300mg)的四氫呋喃(7.34mL)溶液，邊緩緩昇溫至室溫邊進行整夜攪拌。在混合物中加入飽和氯化銨水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~4：1)進行精製，得到(2E)-2-[6-(2,2-二甲基-1,3-二氧戊環-4-基)-2,3-二氫色烯-4-叉]乙酸乙酯(220mg)之淡黃色油狀物質。 (2)使用上述(1)所得到的化合物(220mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(138mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.28(t, J=7.2Hz, 3H)1.37(t, J=5.9Hz, 1H)1.79-1.90(m, 1H)2.09-2.23(m, 1H)2.53 (dd, J=15.5, 9.9Hz, 1H)2.73-2.83(m, 3H)3.30-3.40(m, 1H) 3.81(q, J=6.2 Hz, 2H)4.13-4.24(m, 4H)6.76(d, J=8.6Hz, 1H) 6.92-7.02(m, 2H). MS ESI posi:247[M-OH]+ . 265[M+H]+ , 287[M+Na]+ . 以下的參考例13-2為使用參考例12-1-(3)所得到的化合物，依據參考例13-1記載之方法進行合成。化合物的構造、NMR數據、MS數據如表3-1所示。
Figure 02_image311
參考例14-1 1-(6-羥基己基)-3-雙環[1.1.1]戊烷羧酸甲酯
Figure 02_image313
(1)在1-苯基-5-四唑基硫醇(1g)的N,N-二甲基甲醯胺(11mL)溶液中，在室溫加入碳酸鉀(1.6g)及苄基5-溴戊基醚(1.28mL)，在同溫進行一晩攪拌。加入水後以乙酸乙酯進行萃取，將有機層依序以水及飽和食鹽水進行洗淨，以無水硫酸鎂進行乾燥。過濾乾燥劑，使濾液在減壓下進行濃縮。使殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=17：3~3：2)進行精製，得到1-苯基-5-(5-苯基甲氧基戊基硫代)四唑酯(1.80g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(1.8g)及碳酸氫鈉，依據參考例3-1-(6)記載之方法進行合成，得到1-苯基-5-(5-苯基甲氧基戊基磺醯基)四唑酯(1.11g)之無色油狀物質。 (3)氮環境下、在以乾冰-丙酮浴冷卻的乙二醯氯(1.1mL)的氯仿(9.1mL)溶液中，滴下二甲基亞碸(1.4mL)的氯仿(11 mL)溶液，在同溫度進行5分鐘攪拌。於其中滴下1-(羥基甲基)-3-雙環[1.1.1]戊烷羧酸甲酯(1g)的氯仿(8.5mL)溶液，在同溫度進行15分鐘攪拌後，滴下三乙基胺(5.4mL)，在室溫進行4小時攪拌。使混合物以氯仿稀釋，依序以飽和氯化銨水溶液及飽和食鹽水洗淨，使有機層通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~1：1)進行精製，得到1-甲醯基-3-雙環[1.1.1]戊烷羧酸甲酯(692mg)之褐色油狀物質。 (4)氮環境下，在上述(2)所得到的化合物(590mg)的四氫呋喃(3.4mL)溶液中，在-60℃以下的溫度滴下鈉雙(三甲基矽烷基)醯胺(1.14mol/L四氫呋喃溶液、1.34mL)，在同溫進行30分鐘攪拌。接著滴下上述(3)所得到的化合物(196mg)的四氫呋喃(2.0mL)溶液，在室溫進行一晩攪拌。在反應液中在冰冷卻下加入飽和氯化銨水溶液，並以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥，過濾乾燥劑。使濾液在減壓下濃縮，殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~3：1)進行精製，得到1-[(E)-6-苯基甲氧基六-1-烯基]-3-雙環[1.1.1]戊烷羧酸甲酯(198mg)之無色油狀物質。 (5)使用上述(4)所得到的化合物(196mg)，依據參考例1-1-(3)記載之方法進行合成，得到標題化合物(140mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.10-1.67(m, 10H)1.89(s, 6H)3.56-3.73(m, 5H). MS ESI/APCI Multi posi:249[M+Na]+ . 參考例15-1 3-(3-羥基丙基)安息香酸甲酯
Figure 02_image315
(1)使丙-2-炔-1-醇(200mg)、3-溴安息香酸甲酯(500mg)、雙(三苯基膦)鈀(II)二氯化物(200mg)、及三乙基胺(4mL)溶於四氫呋喃(6mL)，氮環境下加入碘化銅(20mg)後，在室溫進行7小時攪拌。使混合物以二乙基醚(30mL)稀釋，濾出不溶物。使濾液在減壓下濃縮，得到含3-(3-羥基丙-1-炔基)安息香酸甲酯之混合物。 (2)使用上述(1)所得到的混合物，依據參考例1-1-(3)記載之方法進行反應，得到含標題化合物之混合物(140mg)。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.86-1.98(m, 2H)2.77(t, J=7.6 Hz, 2H)3.64-3.73(m, 2H)3.92(s, 3H)7.33-7.40(m, 2H)7.83-7.93(m, 2H). 以下的參考例15-2~15-15為使用市售的芳基溴及炔烴，依據參考例15-1記載之方法進行合成。化合物的構造、NMR數據、MS數據如表4-1~表4-2所示。
Figure 02_image317
Figure 02_image319
參考例15-17 6-(4-羥基丁基)-5-甲氧基吡啶-2-羧酸甲酯
Figure 02_image321
(1)使用市售的6-溴-5-苯基甲氧基吡啶-2-羧酸甲酯(400mg)及3-丁炔-1-醇(131mg)，依據參考例15-1-(1)記載之方法進行反應，得到6-(4-羥基丁-1-炔基)-5-苯基甲氧基吡啶-2-羧酸甲酯(190mg)之暗黃色油狀物質。 (2)使用上述(1)所得到的化合物(190mg)，依據參考例1-1-(3)記載之方法進行反應，得到5-羥基-6-(4-羥基丁基)吡啶-2-羧酸甲酯(100mg)之暗黃色油狀物質。 (3)在上述(2)所得到的化合物(100mg)的丙酮(4.4mL)溶液中，加入碳酸鉀(120mg)及碘甲烷(30μL)，在60℃進行4.5小時，在室溫進行2日攪拌。使混合物在減壓下進行濃縮，以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=22：3~僅乙酸乙酯)進行精製，得到標題化合物(40mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.61-1.71(m, 3H) 1.81-1.91(m, 2H)2.93(t, J=7.4 Hz, 2H)3.61-3.69(m, 2H) 3.90(s, 3H)3.96(s, 3H)7.15(d, J=8.6Hz, 1H)8.01(d, J=8.6Hz, 1H). MS ESI posi:240[M+H]+ . 參考例15-18 3-氟-6-(4-羥基丁基)吡啶-2-羧酸甲酯
Figure 02_image323
(1)使用6-氯-3-氟吡啶-2-羧酸(300mg)，依據參考例5-1-(10)記載之方法進行反應，得到6-氯-3-氟吡啶-2-羧酸甲酯(285mg)之無色固體。 (2)使用上述(1)所得到的化合物(140mg)及3-丁炔-1-醇(77.6mg)，依據參考例15-1-(1)記載之方法進行反應，得到3-氟-6-(4-羥基丁-1-炔基)吡啶-2-羧酸甲酯(175mg)之暗黃色油狀物質。 (3)使用上述(2)所得到的化合物(175mg)，依據參考例1-1-(3)記載之方法進行反應，得到標題化合物(110mg)之淡黃色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.63-1.72(m, 2H)1.82-1.94(m, 2H)2.96-3.01(m, 2H)3.64-3.71(m, 2H)3.99(s, 3H)7.44(t, J=8.6Hz, 1H)8.00-8.06(m, 1H). MS ESI posi:228[M+H]+ . 以下的參考例15-19為使用市售的芳基溴及炔烴，依據參考例15-18記載之方法進行合成。化合物的構造、NMR數據、MS數據如表4-3所示。
Figure 02_image325
參考例15-20 2-[3-(4-羥基丁基)-2-側氧基吡啶-1-基]乙酸丙烷-2-基酯
Figure 02_image327
(1)在3-溴-2-羥基吡啶(3.0g)的N,N-二甲基甲醯胺(17mL)溶液中，加入碳酸鉀(2.6g)及溴乙酸異丙酯(2.5mL)後，在室溫進行1小時攪拌。加入飽和氯化銨水溶液(10mL)後，使反應停止，以甲苯：乙酸乙酯=1：1混合液進行萃取。使得到的有機層通過相分離裝置後，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：7)進行精製，得到2-(3-溴-2-側氧基吡啶-1-基)乙酸丙烷-2-基酯(3.44g)之無色固體。 (2)使用上述(1)所得到的化合物(0.70g)，依據參考例15-1-(1)記載之方法進行反應，得到2-[3-(4-羥基丁-1-炔基)-2-側氧基吡啶-1-基]乙酸丙烷-2-基酯(0.50g)之黃色油狀物質。 (3)使用上述(2)所得到的化合物(500mg)，依據參考例1-1-(3)記載之方法進行反應，得到含標題化合物之混合物(336mg)。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.27(d, J=6.4Hz, 6H)1.59-1.72(m, 4H)2.57(t, J=7.0Hz, 2H)3.63-3.76(m, 2H) 4.60(s, 2H)5.01-5.15(m, 1H)6.15(t, J=6.7Hz, 1H)7.11(d, J=6. 8Hz, 1H)7.22(d, J=6.6Hz, 1H). MS ESI posi:268[M+H]+ , 290[M+Na]+ . 參考例16-1 2-[2-氟-3-(羥基甲基)苯基]環丙烷-1-羧酸乙酯
Figure 02_image329
(1)氮環境下，在以冰冷卻的3-溴-2-氟安息香酸(15.9g)的四氫呋喃(50mL)溶液中，加入硼烷-四氫呋喃錯合物(0.9mol/L四氫呋喃溶液、94mL)，在室溫進行4小時攪拌。在冰冷卻下、於混合物中加入飽和氯化銨水溶液，並以乙酸乙酯進行萃取。使合併的有機層依序以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，通過相分離裝置後在減壓下進行濃縮。使得到的粗生成物以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~1：1)進行精製，得到含(3-溴-2-氟苯基)甲醇之混合物(15.3g)。 (2)在上述(1)所得到的化合物(10.1g)的N,N-二甲基甲醯胺(32.8mL)溶液中，加入三乙基胺(13.7mL)、三(鄰甲苯基)膦(1.50g)、乙酸鈀(II)(553mg)、及丙烯酸乙酯(5.35mL)。將容器密封，進行3次減壓與氮導入後，使混合物在80℃進行3小時攪拌。冷卻至室溫後，於混合物中加入飽和氯化銨水溶液，濾出不溶物後，使濾液以二乙基醚進行萃取。使得到的有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~1：1)進行精製，得到3-氟-6-(4-羥基丁-1-炔基)吡啶-2-羧酸甲酯(11.5g)之黃色油狀物質。 (3)使用上述(2)所得到的化合物(11.5g)，依據參考例2-1-(2)記載之方法進行反應，得到(E)-3-[2-氟-3-(噁烷-2-基氧基甲基)苯基]丙-2-烯酸乙酯(12.8g)之無色油狀物質。 (4)氮環境下，在以冰冷卻的氫化鈉(60%礦油分散物、508mg)的二甲基亞碸(16.9mL)懸濁液中，加入三甲基碘化亞碸(2.79g)，在室溫進行30分鐘攪拌。使混合物再以冰冷卻，在混合物中加入上述(3)所得到的化合物(2.61g)的二甲基亞碸(16.9mL)溶液後，在室溫進行整夜攪拌。在混合物中加入飽和氯化銨水溶液，以二乙基醚進行萃取。使得到的有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~4：1)進行精製，得到2-[2-氟-3-(噁烷-2-基氧基甲基)苯基]環丙烷-1-羧酸乙酯(588mg)之無色油狀物質。 (5)使用上述(4)所得到的化合物(588mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(360mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)1.32-1.38(m, 1H)1.60(dt, J=9.3, 4.8Hz, 1H)1.75(t, J=6.2 Hz, 1H)1.88-1.95(m, 1H)2.62-2.72(m, 1H)4.19(q, J=7.1Hz, 2H)4.76(d, J=6.2Hz, 2H)6.91(t, J=7.6Hz, 1H)7.06(t, J=7.6 Hz, 1H)7.25-7.31(m, 1H). MS ESI posi:221[M+H]+ , 239[M+Na]+ . 參考例16-2 2-[4-(2-羥基乙基)苯基]環丙烷-1-羧酸乙酯
Figure 02_image331
使用2-(4-溴苯基)乙醇(3.0g)，依據參考例16-1-(2)~(5)記載之方法進行反應，得到標題化合物(688mg)之無色固體。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.23-1.31(m, 4H) 1.32-1.38(m, 1H)1.56-1.62(m, 1H)1.84-1.92(m, 1H)2.45-2.55 (m, 1H)2.84(t, J=6.5 Hz, 2H)3.80-3.89(m, 2H)4.17(q, J=7.1 Hz, 2H)7.05(d, J=7.9Hz, 2H)7.15(d, J=7.9Hz, 2H). MS ESI posi:235[M+H]+ . 參考例16-3 2-[5-(2-羥基乙基)吡啶-2-基]環丙烷-1-羧酸乙酯
Figure 02_image333
(1)使用2-(6-氯吡啶-3-基)乙醇(1.8g)，依據參考例2-1-(2)記載之方法進行反應，得到2-氯-5-[2-(噁烷-2-基氧基)乙基]吡啶(1.95g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(510mg)，依據參考例7-1-(3)記載之方法進行反應，得到2-乙烯基-5-[2-(噁烷-2-基氧基)乙基]吡啶(490mg)之無色油狀物質。 (3)在上述(2)所得到的化合物(250mg)的甲苯(3.6mL)溶液中，加入重氮基乙酸乙酯(0.17mL)，微波照射下在120℃進行30分鐘、在130℃進行45分鐘攪拌。使混合物冷卻至室溫，進行減壓濃縮。使得到的殘渣以二氧化矽膠體層析法(n-己烷：乙酸乙酯=19：1~3：2)進行精製，得到2-[5-[2-(噁烷-2-基氧基)乙基]吡啶-2-基]環丙烷-1-羧酸乙酯(230mg)之無色油狀物質。 (4)使用上述(3)所得到的化合物(230mg)，依據參考例2-1-(4)記載之方法進行反應，得到標題化合物(100mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.27(t, J=7.1Hz, 3H)1.42(t, J=5.2Hz, 1H)1.54-1.65(m, 2H)2.17-2.28(m, 1H) 2.50-2.64(m, 1H)2.82(t, J=6.5Hz, 2H)3.77-3.92(m, 2H)4.16(q, J=7.1Hz, 2H)7.18(d, J=7.9Hz, 1H)7.45(d, J=7.9Hz, 1H)8.32(s, 1 H). MS ESI posi:236[M+H]+ . 參考例17-1 3-[5-(溴甲基)吡啶-2-基]氧基-2,2-二甲基丙烷酸甲酯
Figure 02_image335
(1)使3-羥基-2,2-二甲基丙烷酸甲酯(1.40mL)、5-甲基吡啶-2-醇(1.0g)、及三苯基膦(3.61g)在甲苯(46mL)中進行混合，將反應容器內的大氣取代為氮。在以冰冷卻的混合物中加入偶氮二羧酸雙(2-甲氧基乙基)酯(3.22g)，在同溫度進行2.5小時，在室溫進行2小時，及在70℃進行3小時攪拌。使混合物冷卻至室溫後，使混合物在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=19：1~4：1)進行精製，得到2,2-二甲基-3-(5-甲基吡啶-2-基)氧基丙烷酸甲酯(1.08g)之無色油狀物質。 (2)在上述(1)所得到的化合物(1.08g)的四氯化碳(12mL)溶液中，加入N-溴琥珀醯亞胺(947mg)及2,2’-偶氮雙(異丁腈)(80mg)，在加熱迴流下進行3.5小時攪拌。冷卻至室溫後，過濾反應液，使濾液在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：1)進行精製，得到含標題化合物之混合物(1.36g)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.30(s, 6H) 3.69 (s, 3H)4.33(s, 2H)4.45(s, 2H)6.70-6.76(m, 1H)7.58-7.66 (m, 1H)8.10-8.16(m, 1H). MS ESI/APCI Multi posi:302[M+H]+ , 324[M+Na]+ . 參考例17-2 3-[4-(羥基甲基)吡啶-2-基]氧基-2,2-二甲基丙烷酸甲酯
Figure 02_image337
(1)使用4-溴吡啶-2-醇(2.0g)，依據參考例17-1-(1)記載之方法進行反應，得到3-(4-溴吡啶-2-基)氧基-2,2-二甲基丙烷酸甲酯(2.2g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(500mg)及烯丙基亞硼酸頻哪醇酯(440mg)，依據參考例7-1-(3)記載之方法進行反應，得到含2,2-二甲基-3-[4-[丙-1-烯基]吡啶-2-基]氧基丙烷酸甲酯之混合物(403mg)。 (3)在上述(2)所得到的混合物(403mg)的tert-丁醇(3.2mL)、四氫呋喃(3.2mL)、及水(0.81mL)溶液中，加入過碘酸鈉(1.4g)及四氧化鋨(4%水溶液、0.42mL)，在室溫進行1小時攪拌。使混合物以冰冷卻，於其中緩緩加入氫硼化鈉(0.31g)的水(0.81mL)溶液，在同溫度進行1.5小時攪拌。在混合物中加入飽和氯化銨水溶液，並以氯仿進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~2：3)進行精製，得到標題化合物(140mg)之無色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.31(s, 6H) 3.69(s, 3H)4.32(s, 2H)4.68(s, 2H)6.76(s, 1H)6.85(d, J=5.2 Hz, 1H)8.10(d, J=5.2Hz, 1H). MS ESI posi:240[M+H]+ . 參考例18-1 3-[3-氟-4-(羥基甲基)吡啶-2-基]氧基-2,2-二甲基丙烷酸甲酯
Figure 02_image339
(1)將2,3-二氟-4-碘吡啶(1.0g)及氰化銅(450mg)的丙腈(4.1mL)懸濁液在微波照射下在160℃進行3.5小時攪拌。冷卻至室溫後，懸濁液以氯仿稀釋，並進行矽藻土(註冊商標)過濾，使濾液在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=17：3~13：7)進行精製，得到2,3-二氟吡啶-4-甲腈(374mg)之無色油狀物質。 (2)將3-羥基-2,2-二甲基丙烷酸甲酯(375μL)及氫化鈉(60%礦油分散物、118mg)在四氫呋喃(8mL)中進行混合。在冰冷卻下於該混合物中滴下上述(1)所得到的化合物(374mg)的四氫呋喃(5mL)溶液。滴下完畢後，在室溫進行3.5小時攪拌。再使混合物以冰冷卻，於其中加入飽和氯化銨水溶液，並以氯仿進行萃取。使有機層通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=4：1~3：2)進行精製，得到3-(4-氰-3-氟吡啶-2-基)氧基-2,2-二甲基丙烷酸甲酯(365mg)之無色油狀物質。 (3)使上述(2)所得到的化合物(361mg)及磷酸二氫鈉(1.03g)在吡啶(3.6mL)/乙酸(3.6mL)中進行混合。在該懸濁液加入雷氏鎳(水懸濁液、7.2mL，使懸濁液均勻後用移液器量取)，在100℃進行2.5小時攪拌。使反應液進行矽藻土(註冊商標)過濾，使濾液在減壓下進行濃縮。使得到的殘渣以乙酸乙酯稀釋後，依序以稀鹽酸、飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，通過相分離裝置後在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=13：7~7：13)進行精製，得到標題化合物(92mg)之淡黃色油狀物質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.33(s, 6H) 2.84(t, J=6.7Hz, 1H)3.74(s, 3H)4.14(s, 2H)4.67(d, J=6.7Hz, 2H)7.20(d, J=4.5Hz, 1H)7.87(d, J=4.5Hz, 1H). MS ESI posi:258[M+H]+ . 參考例19-1 2-甲基-2-[7-[2-(1,2,4-三唑-1-基)嘧啶-5-基]氧基庚氧基]丙烷酸
Figure 02_image341
使用參考例1-2所得到的化合物(52mg)及參考例2-3所得到的化合物(80mg)，依據後示之實施例1-1記載之方法進行反應，得到標題化合物(95mg)之無色固體。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.29(s, 6H)1.31-1.55(m, 8H)1.72-1.82(m, 2H)3.27-3.31(m, 2H)4.20(t, J=6.5Hz, 2H) 8.27(s, 1H)8.68(s, 2 )9.32(s, 1H). MS ESI posi:364[M+H]+ . MS ESI nega:362[M-H]- . 參考例20-1 2-甲基-2-[7-[6-(1,2,4-三唑-1-基)噠嗪-3-基]氧基庚氧基]丙烷酸
Figure 02_image343
(1)使用參考例1-3所得到的化合物(7mg)及參考例2-3所得到的化合物(23.6mg)，依據後示之實施例4-1-(1)記載之方法進行反應，得到2-甲基-2-[7-[6-(1,2,4-三唑-1-基)噠嗪-3-基]氧基庚氧基]丙烷酸tert-丁基(15mg)之淡黃色油狀物質。 (2)使用上述(1)所得到的化合物(15mg)，依據後示之實施例1-1-(2)記載之方法進行反應，得到標題化合物(1.5mg)之無色非晶質。1 H NMR(400MHz, METHANOL-d4 )δ ppm 1.32-1.45(m, 12H) 1.51-1.61(m, 2H)1.82-1.92(m, 2H)3.40(t, J=6.5Hz, 2H) 4.20 (t, J=7.3Hz, 2H)7.21(d, J=9.8Hz, 1H)8.06(d, J=9.8Hz, 1H) 8.21(s, 1H)9.15(s, 1 H). MS ESI posi:364[M+H]+ , 386[M+Na]+ . MS ESI nega:362[M-H]- . 參考例21-1 2-[5-[3-(羥基甲基)苯基]-2-側氧基-1-吡啶]乙酸丙烷-2-基酯
Figure 02_image345
(1)在5-溴-1H-吡啶-2-酮(1.50g)的N,N-二甲基甲醯胺(8.6mL)溶液中，加入碳酸鉀(1.3g)及溴乙酸異丙酯(1.2 mL)後，在室溫進行1小時攪拌。加入飽和氯化銨水溶液(10mL)後使反應停止，以乙酸乙酯進行萃取。使得到的有機層通過相分離裝置後，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=7：3~3：7)進行精製，得到2-(5-溴-2-側氧基-1-吡啶)乙酸丙烷-2-基(1.2g)之無色固體。 (2)在上述(1)得到的化合物(100mg)及市售的[3-(羥基甲基)苯基]亞硼酸(58mg)的二甲氧基乙烷：水(4：1、4.5mL)溶液中，氮環境下加入碳酸鉀(100mg)及肆(三苯基膦)鈀(0)(42mg)後，微波照射下在120℃進行30分鐘攪拌。使反應混合物進行矽藻土(註冊商標)過濾，於濾液加入飽和氯化銨水溶液(5mL)後，以乙酸乙酯進行萃取。使得到的有機層通過相分離裝置後，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=7：3~1：9)進行精製，得到標題化合物(73mg)之茶色非晶質。1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(d, J=6.3 Hz, 6H)1.86(t, J=5.7Hz, 1H)4.68(s, 2H)4.75(d, J=5.7Hz, 2H) 5.11(spt, J=6.3Hz, 1H)6.67(d, J=9.4Hz, 1H)7.29-7.50(m, 5H) 7.62-7.74(m, 1H). MS ESI posi:302[M+H]+ . 參考例22-1 5-溴-2,2-二甲基-1-環戊酮
Figure 02_image347
在2,2-二甲基-1-環戊酮(500mg)的四氫呋喃(45mL)溶液中，在冰冷卻下，加入三甲基苯基銨三溴化物(1.84g)，在室溫進行5小時攪拌。在反應液中加入水，以二乙基醚進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鎂進行乾燥。過濾乾燥劑後，使濾液在減壓下濃縮，使殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=49：1~17：3)進行精製，得到標題化合物(592mg)之無色油狀物質。 MS EI posi：190[M]+ . 實施例1-1 2-甲基-2-[7-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基庚氧基]丙烷酸
Figure 02_image349
(1)氮環境下，在參考例1-1所得到的化合物(100mg)的甲苯(3.1mL)懸濁液中，加入參考例2-3所得到的化合物(203mg)及氰基亞甲基三丁基磷烷(320μL)，在100℃進行1小時攪拌。使反應液在減壓下進行濃縮，使得到的殘渣以NH二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=4：1~3：2)進行精製，得到2-甲基-2-[7-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基庚氧基]丙烷酸tert-丁酯(338mg)之淡褐色油狀物質。 (2)使上述(1)所得到的化合物(338mg)溶於4mol/L氯化氫-1,4-二噁烷(2.5mL)，在75℃進行3小時攪拌。使反應液在減壓下進行濃縮，使得到的殘渣以製備型HPLC進行精製。將含有目的物的餾分濃縮，將得到的固體以二乙基醚進行懸濁攪拌後過濾，得到標題化合物(137mg)之無色固體。又，得到標題化合物可藉由乙酸乙酯進行再結晶。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.29(s, 6H)1.30-1.53(m, 8H)1.70-1.79(m, 2H)3.29-3.31(m, 2H)4.11(t, J=6.5Hz, 2H)7.67 (dd, J=8.9, 2.9Hz, 1H)7.80(d, J=8.9Hz, 1H)8.23(d, J=2.9Hz, 1H)8.25(s, 1H)9.24(s, 1H). MS ESI posi:363[M+H]+ . MS ESI nega:361[M-H]- . 熔點：121.2℃(TG-DTA) 以下的實施例1-2為使用參考例1-1所得到的化合物及參考例2-4所得到的化合物，依據實施例1-1記載之方法進行合成。此等之化合物的構造、NMR數據、MS數據如表5-1所示。
Figure 02_image351
實施例2-1 2,2-雙(羥基甲基)-10-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基癸烷酸
Figure 02_image353
(1)使用參考例4-1所得到的化合物(87mg)，依據實施例1-1-(1)記載之方法進行反應，得到含2,2-雙(甲氧基甲基)-10-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基癸烷腈之混合物(134mg)。 (2)在上述(1)所得到的混合物(134mg)中，加入濃鹽酸(620μL)，微波照射下、在130℃進行3小時及在140℃進行1小時攪拌。使混合物以製備型HPLC精製，得到標題化合物(18mg)之無色固體。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.14-1.47(m, 14H)1.69-1.79(m, 2H)3.43-3.48(m, 2H)3.49-3.54(m, 2H)4.10(t, J=6.3 Hz, 2H)7.64-7.69(m, 1H)7.79(d, J=8.8Hz, 1H)8.21-8.24(m, 1H)8.24(s, 1H)9.24(s, 1H). MS ESI posi:393[M+H]+ . MS ESI nega:391[M-H]- . 實施例3-1 3-[8-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基辛基]氧雜環丁烷-3-羧酸
Figure 02_image355
(1)使用參考例6-1所得到的化合物(45mg)，依據參考例1-1-(1)記載之方法進行反應，得到含3-[8-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基辛基]氧雜環丁烷-3-羧酸甲酯之混合物(140mg)。 (2)將上述(1)所得到的混合物(140mg)懸濁於甲醇(1.8 mL)，加入1mol/L氫氧化鈉水溶液(387μL)，在室溫進行一晩攪拌。使混合物以製備型HPLC進行精製。使含目的物之餾分濃縮，將得到的固體以二乙基醚進行懸濁攪拌後過濾，得到標題化合物(42mg)之無色固體。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.13-1.47(m, 10H)1.70-1.79(m, 2H)1.85-1.93(m, 2H)4.10(t, J=6.4Hz, 2H)4.32(d, J= 5.9Hz, 2H)4.68(d, J=5.9Hz, 2H)7.67(dd, J=8.9, 2.7Hz, 1H)7.80 (d, J=8.9Hz, 1H)8.23(d, J=2.7Hz, 1H)8.25(s, 1H)9.24(s, 1H). MS ESI posi:375[M+H]+ . MS ESI nega:373[M-H]- . 以下的實施例3-2~3-38為使用參考例2-1~2-2、2-5、3-1、5-1、7-1~7-2、8-1、9-1、10-1、11-1、12-1~12-2、13-1~13-2、14-1、15-1~15-11、15-16~15-20、16-1~16-3、17-2、或18-1所得到的化合物，依據實施例3-1記載之方法進行合成。此等之化合物的構造、NMR數據、MS數據如表6-1~表6-5所示。
Figure 02_image357
Figure 02_image359
Figure 02_image361
Figure 02_image363
Figure 02_image365
實施例4-1 4-甲氧基-6-[4-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基丁基]吡啶-2-羧酸
Figure 02_image367
(1)氮環境下，使參考例15-12所得到的化合物(40mg)及三苯基膦(66mg)的甲苯(840μL)溶液以冰冷卻，於其中加入偶氮二羧酸雙(2-甲氧基乙基)酯(59mg)及參考例1-1所得到的化合物(29.8mg)。使混合物在室溫進行15小時攪拌後，減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(n-己烷：乙酸=22：3~僅乙酸乙酯)進行精製，得到含4-甲氧基-6-[4-[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基丁基]吡啶-2-羧酸甲酯之混合物(80mg)。 (2)使用上述(1)所得到的混合物(80mg)，依據實施例3-1-(2)記載之方法進行反應，得到標題化合物(3mg)之無色固體。1 H NMR(400 MHz, DMSO-d6 )δ ppm 1.74-1.92(m, 4H)2.82(t, J=7.5Hz, 2H)3.88(s, 3H)4.16(t, J=5.7Hz, 2H)7.05-7.11(m, 1H)7.34-7.40(m, 1H)7.65-7.71(m, 1H)7.79(d, J=9.0Hz, 1H)8.20-8.27(m, 2H)9.24(s, 1H). MS ESI posi:370[M+H]+ . MS ESI nega:368[M-H]- . 以下的實施例4-2~4-4為使用參考例15-13~15-15所得到的化合物，依據實施例4-1記載之方法進行合成。此等之化合物的構造、NMR數據、MS數據如表7-1所示。
Figure 02_image369
實施例5-1 2-甲基-7-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]-3,4-二氫色烯-2-羧酸
Figure 02_image371
(1)在參考例7-3所得到的化合物(73mg)的丙酮(3mL)溶液中，加入參考例1-1所得到的化合物(37.8mg)、N,N-二甲基甲醯胺(1mL)、及碳酸鉀(83.8mg)，在室溫進行16小時攪拌。過濾不溶物，使濾液在減壓下進行濃縮。使得到的殘渣以NH二氧化矽膠體滲透層析法(n-己烷：乙酸乙酯=9：1~3：2)進行精製，得到2-甲基-7-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]-3,4-二氫色烯-2-羧酸乙酯(86mg)之無色非晶質。 (2)使用上述(1)所得到的化合物(84mg)，依據實施例3-1-(2)記載之方法進行反應，得到標題化合物(68mg)之無色固體。1 H NMR(400 MHz, DMSO-d6 )δ ppm 1.59(s, 3H)1.82-1.94(m, 1H)2.39(dt, J=13.6, 4.6Hz, 1H)2.71-2.79(m, 2H)5.15(s, 2H) 6.90-6.97(m, 2H)7.06(d, J=7.6Hz, 1H)7.63(dd, J=8.9, 2.5Hz, 1H)7.84(d, J=8.9 Hz, 1H)8.13(s, 1H)8.22(d, J=2.5Hz, 1H) 9.19(s, 1H). MS ESI posi:367[M+H]+ . MS ESI nega:365[M-H]- . 以下的實施例5-2為使用參考例17-1所得到的化合物，依據實施例5-1記載之方法進行合成。此等之化合物的構造、NMR數據、MS數據如表8-1所示。
Figure 02_image373
實施例6-1 2,2-二甲基-4-[[3-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]苯甲醯基]胺基]丁烷酸
Figure 02_image375
(1)使用市售的3-(溴甲基)安息香酸甲酯(210mg)，依據實施例5-1-(1)記載之方法進行反應，得到3-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]安息香酸甲酯(257mg)之無色固體。 (2)使用上述(1)所得到的化合物(257mg)，依據實施例3-1-(2)記載之方法進行反應，得到3-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]安息香酸(207mg)之無色固體。 (3)在4-胺基-2,2-二甲基丁烷酸甲酯鹽酸鹽(77mg)的N,N-二甲基甲醯胺(1mL)溶液中，加入三乙基胺(150μL)、上述(2)所得到的化合物(63mg)、N-羥基苯並三唑一水合物(33mg)、及1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(61mg)，在室溫進行20小時攪拌。在混合物中加入水，並以乙酸乙酯進行萃取。使有機層通過相分離裝置，在減壓下進行濃縮。使得到的殘渣以二氧化矽膠體滲透層析法(僅n-己烷~n-己烷：乙酸乙酯=3：7)進行精製，得到2,2-二甲基-4-[[3-[[6-(1,2,4-三唑-1-基)吡啶-3-基]氧基甲基]苯甲醯基]胺基]丁烷酸甲酯(65mg)之無色油狀物質。 (4)使用上述(3)所得到的化合物(63mg)，依據實施例3-1-(2)記載之方法進行反應，得到標題化合物(19mg)之無色固體。1 H NMR(400 MHz, DMSO-d6 )δ ppm 1.14(s, 6H)1.71-1.79(m, 2H)3.22-3.28(m, 2H)5.31(s, 2H)7.46-7.53(m, 1H)7.63(d, J= 7.7Hz, 1H)7.74-7.86(m, 3H)7.96(s, 1H)8.25(s, 1H)8.31-8.35 (m, 1H)8.53-8.64(m, 1H)9.25(s, 1H). MS ESI posi:410[M+H]+ . MS ESI nega:408[M-H]- . 實施例7-1 2-甲基-2-[7-(6-嘧啶-5-基吡啶-3-基)氧基庚氧基]丙烷酸
Figure 02_image377
(1)使用2-溴-4-羥基吡啶(760mg)及參考例2-3所得到的化合物(1.0g)，依據實施例1-1-(1)記載之方法進行反應，得到2-[7-(6-溴吡啶-3-基)氧基庚氧基]-2-甲基丙烷酸tert-丁酯(1.4g)之無色油狀物質。 (2)使用上述(1)所得到的化合物(200mg)，依據參考例21-1-(2)記載之方法進行反應，得到2-甲基-2-[7-(6-嘧啶-5-基吡啶-3-基)氧基庚氧基]丙烷酸tert-丁酯(67mg)之無色油狀物質。 (3)使用上述(2)所得到的化合物(67mg)，依據實施例1-1-(2)記載之方法進行反應，得到標題化合物(16mg)之無色固體。1 H NMR(400 MHz, DMSO-d6 )δ ppm 1.28(s, 6 H)1.30-1.54(m, 8H)1.70-1.81(m, 2H)3.28-3.34(m, 2H)4.12(t, J=6.5Hz, 2H) 7.56(dd, J=8.7, 2.8Hz, 1H)8.09(d, J=8.7Hz, 1H)8.44(d, J=2.8Hz, 1H)9.18(s, 1H)9.38(s, 2H). MS ESI posi:374[M+H]+ . MS ESI nega:372[M-H]- . 實施例8-1 2-[7-[6-(1H-咪唑-5-基)吡啶-3-基]氧基庚氧基]-2-甲基丙烷酸
Figure 02_image379
(1)使用1-(5-羥基吡啶-2-基)乙酮(110mg)及參考例2-3所得到的化合物(260mg)，依據實施例1-1-(1)記載之方法進行反應，得到2-[7-(6-乙醯基吡啶-3-基)氧基庚氧基]-2-甲基丙烷酸tert-丁酯(280mg)之無色油狀物質。 (2)使用上述(1)所得到的化合物(270mg)，依據參考例22-1記載之方法進行反應，得到2-[7-[6-(2-溴乙醯基)吡啶-3-基]氧基庚氧基]-2-甲基丙烷酸tert-丁酯(175mg)之無色油狀物質。 (3)使上述(2)所得到的化合物(175mg)的甲醯胺(370μL)懸濁液在170℃進行2小時攪拌。使反應液冷卻至室溫後，以製備型HPLC進行精製。將餾分濃縮殘渣以乙基醚固化，得到標題化合物(20mg)之無色固體。1 H NMR(400MHz, DMSO-d6 )δ ppm 1.29(s, 6H)1.30-1.53(m, 8H)1.67-1.77(m, 2H)3.35-3.42(m, 2H)4.04(t, J=6.4 Hz, 2H) 7.33-7.44(m, 1H)7.46-7.55(m, 1H)7.67(s, 1H)7.71-7.82(m, 1H) 8.16-8.24(m, 1H). MS ESI posi:362[M+H]+ . MS ESI nega:360[M-H]- . 將本發明化合物的20-HETE產生酵素的阻礙作用用以下的試驗例1記載之方法測定。 試驗例1 (1)本發明之各化合物的20-HETE產生酵素(CYP4F2及CYP4A11)的阻礙試驗 在CYP4F2阻礙試驗，於表現人CYP4F2的大腸菌膜部分(100μg/mL protein)中，加入含各化合物的反應液[最終濃度 50mM KPO4 (pH7.4)、2.5μM 螢光素衍生物、及1mM NADPH]後，在CYP4A11阻礙試驗，於表現人CYP4A11的大腸菌膜部分(100μg/mL protein)，加入含各化合物的反應液[最終濃度 100mM Tris-HCl(pH7.5)、60μM 螢光素衍生物、1.3mM NADP+ 、3.3mM Glucose 6-Phosphate、3.3mM MgCl2 、及0.4U/mL Glucose 6-Phosphate dehydrogenase]後，在室溫進行60分鐘靜置，進行酵素反應。反應後添加螢光素檢出試藥，使用平板讀數器測定發光值。使用該值，將20-HETE產生酵素阻礙率(%)依據下述式算出，算出各化合物的50%阻礙濃度(IC50 值)。 20-HETE產生酵素阻礙率(%)=[1-(A-B)/(C-B)]*100 A：化合物添加時的發光值 B：化合物及酵素未添加時的發光值 C：化合物未添加時的發光值 (2)結果 本發明之各化合物對CYP4F2及CYP4A11的阻礙活性如以下表9-1~表9-2所示。
Figure 02_image381
Figure 02_image383
又，本發明化合物的阻礙產生20-HETE的酵素之作用亦可用以下的試驗例2記載之方法測定。 試驗例2 (1)本發明之各化合物的使用人腎微粒體的20-HETE產生酵素的阻礙試驗 於人腎微粒體(250μg/mL protein)，加入含各化合物的反應液[最終濃度 100mM KPO4 (pH7.4)、20μM Arachidonic acid、4mM NADPH]後，在37℃靜置45分鐘，進行20-HETE產生反應。加入甲酸使反應停止後，添加9倍量的乙腈，以離心(1000rpm、4℃、10分鐘)進行除蛋白。之後，使用液體層析法-串聯型質量分析裝置(LC-MS/MS)，測定20-HETE的波峰面積值，使用該值，將20-HETE產生酵素阻礙率(%)依據下述式算出，算出各化合物的50%阻礙濃度(IC50 值)。 20-HETE產生酵素阻礙率(%)=[1-(A-B)/(C-B)]*100 A：化合物添加時的20-HETE的波峰面積值/內部標準物質的波峰面積值 B：化合物及NADPH未添加時的 20-HETE的波峰面積值/內部標準物質的波峰面積值 C：化合物未添加時的20-HETE的波峰面積值/內部標準物質的波峰面積值 (2)結果 本發明之各化合物對20-HETE產生酵素的阻礙活性如以下表10-1所示。
Figure 02_image385
試驗例3 本發明之各化合物的、CYP選擇性試驗 (1)本發明之各化合物的CYP4F22選擇性試驗 於表現人CYP4F22的細胞膜部分(30μg/mL protein)，加入含各化合物的反應液[最終濃度 100mM KPO4 (pH7.4)、14μM 螢光素衍生物、及1mM NADPH]後，在室溫進行50分鐘靜置，進行酵素反應。反應後添加螢光素檢出試藥，使用平板讀數器測定發光值。使用該值，將CYP4F22的酵素反應阻礙率(%)依據下述式算出，算出各化合物的50%阻礙濃度(IC50 值)。 CYP4F22酵素阻礙率(%)=[1-(A-B)/(C-B)]*100 A：化合物添加時的發光值 B：化合物及酵素未添加時的發光值 C：化合物未添加時的發光值 (2)結果 本發明之各化合物對CYP4F22的阻礙活性如以下表11-1所示。
Figure 02_image387
(3)本發明之各化合物的CYP4V2選擇性試驗 於表現人CYP4V2的細胞膜部分(38μg/mL protein)，加入含各化合物的反應液[最終濃度 100mM KPO4 (pH7.4)、7μM 螢光素衍生物、及1mM NADPH]後，在室溫進行40分鐘靜置，進行酵素反應。反應後添加螢光素檢出試藥，使用平板讀數器測定發光值。使用該值，將CYP4V2的酵素反應阻礙率(%)依據下述式算出，算出各化合物的50%阻礙濃度(IC50 值)。 CYP4V2酵素阻礙率(%)=[1-(A-B)/(C-B)]*100 A：化合物添加時的發光值 B：化合物及酵素未添加時的發光值 C：化合物未添加時的發光值 (4)結果 本發明之各化合物對CYP4V2的阻礙活性如以下表11-2所示。
Figure 02_image389
又，亦可用同樣的方法算出各化合物的90%阻礙濃度(IC90 值)。因情況有以90%阻礙濃度為指標較佳之情形。 試驗例4 (1)本發明之各化合物的體內安定性的評估試驗 依據以下的方法，可算出血漿中半衰期。 將各化合物溶於10%HP-β-CD水溶液中(0.5mg/mL)，靜脈內投與至大鼠(Sprague-Dawley(SD)、雄、7週齡、絕食、投與量：0.5mg/kg)。在各採血時間由尾靜脈採血，藉由離心分離，採取血漿。血漿中之各化合物的定量分析使用LC-MS/MS實施。血漿中半衰期(t1/2eff )可使用Phoenix WinNonlin(Certara)，藉由非模室數據分析由算出的清除率(CL)及分布容積(Vdss )依據下述式算出。 t1/2eff =LN(2)/(CL/Vdss ) 而本發明之各化合物亦存在有對CYP4F2及CYP4A11之選擇性高於與20-HETE產生酵素(CYP4F2及CYP4A11)為同家族的CYP4F22、CYP4V2者。 此等之化合物期待作為具有強藥效且副作用風險小的醫藥品。 又，本發明之各化合物的有效性可使用小鼠或大鼠等之模型動物確認。例如可藉由確認腎臓中之20-HETE產生量的抑制或多囊腎的改善而達成。 [產業上之利用性] 本發明化合物具有優異的阻礙產生20-HETE的酵素之作用，藉由本發明，期待可提供有效預防或治療源自多囊腎的疾病等之醫藥品，減輕患者之負擔，且促進醫藥品產業。[Best Mode for Carrying Out the Invention] The present invention provides a compound represented by the above formula [I'] or a pharmaceutically acceptable salt thereof, which has the effect of inhibiting the production of 20-HETE enzyme. The compound of the present invention will be described in detail below, but the present invention is not limited to the exemplified ones. "Halogen atom" means fluorine atom, chlorine atom, bromine atom, and iodine atom. "C 1-4 "Alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. "C 1-6 "Alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like. "C 3-6 "Cycloalkane" refers to a hydrocarbon ring having 3 to 6 carbon atoms. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane. "C 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. "Saturated heterocyclic ring" refers to a 3- to 8-membered monocyclic ring consisting of one or more identical or different atoms and 1 to 7 carbon atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms Formula saturated heterocyclic group. For example, oxetane, tetrahydrofuran, tetrahydropyran, oxane, azetidine, pyrrolidine, piperidine, azepine ring, sulfur, tetrahydrothiophenyl, tetrahydrothiopyran , Piperazine, pyrazolidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinan, isothiazolidine, etc. "A 4- to 6-membered saturated heterocyclic ring containing an oxygen atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic ring composed of 1 oxygen atom and 3 to 5 carbon atoms. For example, oxetane, tetrahydrofuran, tetrahydropyran and the like. "A 4- to 6-membered saturated heterocyclic ring containing a sulfur atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic ring composed of 1 sulfur atom and 3 to 5 carbon atoms. For example, sulfur, tetrahydrothiophene, tetrahydrothiopyran, etc. "C 1-4 "Alkoxy" refers to a linear or branched alkoxy group having 1 to 4 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. "Single C 1-4 "Alkylamino group" means having one of the aforementioned "C 1-4 "Alkyl" is an amine group as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino . "Single C 1-6 "Alkylamino group" means having one of the aforementioned "C 1-6 "Alkyl" is an amine group as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino , N-pentylamino, isopentylamino, n-hexylamino, etc. "Single C 1-4 "Alkylaminocarbonyl" refers to the aforementioned "single C 1-4 "Alkylamino group" is a group bonded to a carbonyl group. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylamine Carbonyl, tert-butylaminocarbonyl. "Single C 1-6 "Alkylaminocarbonyl" refers to the aforementioned "single C 1-6 "Alkylamino group" is a group bonded to a carbonyl group. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylamine Carbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, n-hexylaminocarbonyl, etc. "Pendant oxy group" refers to a substituent (=0) in which an oxygen atom is substituted through a double bond. Therefore, when the pendant oxy group is substituted with a carbon atom, it forms a carbonyl group together with the carbon atom. When one pendant oxy group is substituted with one sulfur atom, it forms a sulfinyl group together with the sulfur atom, and the two pendant oxy groups form a When one sulfur atom is substituted, it forms a sulfonyl group together with the sulfur atom. In the present invention, when the pendant oxy group is substituted with a saturated heterocyclic ring, specific examples of a saturated heterocyclic ring substituted with a pendant oxy group include 2-side oxypyrrolidinyl and 2-side oxypiperidinyl. , 2-oxopiperazinyl, 3-oxopiperazinyl, 1,1-dioxide tetrahydrothiophenyl, 1-oxide tetrahydro-2H-thiopyranyl, 1,1- Dioxide tetrahydro-2H-thiopyranyl, 1,1-dioxide isothiazolidinyl, 2-oxo-1,3-oxazolidinyl, 2-oxo-1,3-oxa Azinyl group, 6-side oxy-1,6-dihydropyridine, 6-side oxy-1,1-dihydropyridazinyl, 1-side oxy-1,2,3,4-tetrahydro Isoquinolinyl-7-yl, 1,1-thioetanyl dioxide, etc. "C 1-2 "Alkanediyl" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 1 to 2 carbon atoms. For example, methane-diyl, ethane-1,1-diyl, ethane-1,2-diyl. "C 1-3 "Alkanediyl" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms. For example, methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl Base, propane-2,2-diyl. "C 4-6 "Alkanediyl" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 4 to 6 carbon atoms. For example, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, 3,3-dimethyl-propane-1,3-diyl and the like. "C 4-8 "Alkanediyl" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 4 to 8 carbon atoms. For example, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl , 3,3-Dimethyl-propane-1,3-diyl, etc. "C 2-10 "Alkanediyl" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 2 to 10 carbon atoms. For example, ethane-1,1-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, Heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, 3,3-dimethyl-propane- 1,3-diyl, 8,8-dimethyl-octane-1,8-diyl, etc. The "benzyl-based protecting group" refers to a benzyl group in which the phenyl moiety or the methylene moiety of the benzyl group may be substituted, and a group protecting the functional group. For example, benzyl or 4-methoxybenzyl, benzhydryl and the like. In addition, functional groups protected by benzyl-based protecting groups include, for example, hydroxyl groups and carboxyl groups. In addition, when protecting a hydroxyl group, the group may be referred to as a "benzyl ether protecting group". Similarly, when protecting a carboxyl group, the group may be referred to as a "benzyl ester-based protecting group". "Acetal protecting group" refers to a group that forms an acetal structure together with a hydroxyl group to protect a functional group. For example, methoxymethyl, tetrahydropyranyl. In addition, the functional group protected by the acetal protecting group includes, for example, a hydroxyl group. The "silyl ether-based protecting group" refers to a silyl group substituted with three groups selected from an alkyl group and an aryl group, and is a group that protects the functional group. For example, trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and the like. In addition, functional groups protected with silyl-based protecting groups include, for example, hydroxyl groups. A preferred aspect of the compound of the present invention is as follows. In the compound represented by the aforementioned formula [I'] or a pharmaceutically acceptable salt thereof; preferably ring D is a group represented by the formula [I'-1] or formula [I'-2]; here, a More preferably, ring D is a group represented by formula [I'-1], and other more preferably ring D is a group represented by formula [I'-2]. Better R 1 Is a hydrogen atom; preferably R 2 Is a hydrogen atom, preferably R 3 Is a hydrogen atom, preferably R 4 Is a hydrogen atom; preferably X is the formula -O-. Here, better R 5 as follows. (1) A better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III']
Figure 02_image043
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 It is a carboxyl group or a carboxymethyl group; ring A is any one of the structures represented by the following formula group [IV']
Figure 02_image045
Here, the structure represented by the aforementioned formula [IV-2] can be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, and the aforementioned formula [IV-5] The structure can be substituted by 1 methyl group; W 2 Is C 4-6 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-3 Alkane diyl; here, (a) when ring B is phenyl, R 53 Is selected from (i) carboxyl, (iii) C substituted by carboxyl 3-6 Cycloalkyl, and (iv) single C substituted by carboxy 1-6 Alkylaminocarbonyl group; in this case, R 61 And R 62 Independently a hydrogen atom or a fluorine atom; (b) when ring B is pyridyl, R 53 Is selected from (iii) C substituted by carboxyl 3-6 Cycloalkyl and (v) C substituted by carboxyl 1-4 Group composed of alkoxy; at this time, R 61 And R 62 Independently hydrogen atom or fluorine atom; (c) when ring B is chromanyl group, R 53 Is carboxy or carboxymethyl; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. (2) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III']
Figure 02_image047
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; Ring A is any of the structures represented by the following formula [IV-2], formula [IV-4], and formula [IV-5]
Figure 02_image049
, Here, the structure represented by the aforementioned formula [IV-2] may be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group; W 2 Is C 4-6 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-3 Alkane diyl; here, (a) when ring B is phenyl, R 53 Is selected from (i) carboxyl, (iii) C substituted by carboxyl 3-6 Cycloalkyl, and (iv) single C substituted by carboxy 1-6 Alkylaminocarbonyl group; in this case, R 61 And R 62 Independently a hydrogen atom or a fluorine atom; (b) when ring B is pyridyl, R 53 Is selected from (v) C substituted by carboxyl 1-4 Alkoxy; at this time, R 61 And R 62 Both are hydrogen atoms; (c) When ring B is chromanyl, R 53 Is a carboxyl group; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. (3) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image051
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-2]
Figure 02_image053
, Here, the structure represented by the aforementioned formula [IV-2] can be substituted by 1 methyl group; W 2 Is C 4 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, R 53 Is a carboxyl group; in this case, R 61 And R 62 Both are hydrogen atoms. (4) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula [III-3] ~ formula [III-4], formula [III-6] ~ formula [III-9]
Figure 02_image055
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; Ring A is any of the structures represented by the following formula [IV-6] and formula [IV-4]
Figure 02_image057
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4-6 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is a chroman group; the chroman group is a pyran-7-yl group; R 53 Is a carboxyl group; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula [III-3] ~ formula [III-4], formula [III-6] ~ formula [III-9]
Figure 02_image059
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 The carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6], or the bicyclo[1.1.1]pentane- having the structure represented by the following formula [IV-4] The carboxyl group substituted at the 3-position of the 1-group; Ring A is any one of the structures represented by the following formula [IV-6] and formula [IV-4]
Figure 02_image061
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted with one group selected from the group consisting of a fluorine atom and a methyl group, or the aforementioned formula [IV- 6] The 5-position of the pyridin-2-yl group of the structure represented by the structure may be substituted by a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is butane-1,4-diyl or hexane-1,6-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 Is a hydrogen atom or a methyl group substituted at the 2-position of the pyran-7-yl group, R 62 Is a hydrogen atom. (5) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula [III-4] and formula [III-8]
Figure 02_image063
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; ring A is any one of the structures represented by the following formula [IV-6] and formula [IV-7]
Figure 02_image065
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-7-yl; R 53 Is a carboxyl group; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula [III-4] and formula [III-8]
Figure 02_image067
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 The carboxyl group substituted at the 6 position of the pyridin-2-yl group represented by the following formula [IV-6] or the pyridin-3-yl group substituted at the 6 position of the structure represented by the following formula [IV-7] The carboxyl group; Ring A is any one of the structures represented by the following formula [IV-6] and formula [IV-7]
Figure 02_image069
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted with one group selected from the group consisting of a fluorine atom and a methyl group, or the aforementioned formula [IV- 6] The 5-position of the pyridin-2-yl group of the structure shown can be substituted by a group selected from a methyl group and a methoxy group; W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 Is a hydrogen atom or a methyl group substituted at the 2-position of the pyran-7-yl group, R 62 Is a hydrogen atom. (6) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III”]
Figure 02_image071
, Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-6]
Figure 02_image073
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-7-yl; R 53 Is a carboxyl group; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III”]
Figure 02_image075
, Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image077
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted with one group selected from the group consisting of a fluorine atom and a methyl group, or the aforementioned formula [IV- 6] The 5-position of the pyridin-2-yl group of the structure represented by can be substituted by a group selected from the group consisting of methyl and methoxy, W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 Is a hydrogen atom or a methyl group substituted at the 2-position of the pyran-7-yl group, R 62 Is a hydrogen atom. In this case, R 5 For the following aspect. (A) R 5 In the case of the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is any of the following:
Figure 02_image079
; (B) R 5 When it is the structure represented by the aforementioned formula [II-2], the structure represented by the formula [II-2] is any of the following:
Figure 02_image081
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image083
. (7) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image085
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-6]
Figure 02_image087
, Here, the structure represented by the aforementioned formula [IV-6] can be substituted by 1 methyl group; W 2 Is C 4 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyran-7-yl; R 53 Is a carboxyl group; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image089
; Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image091
, Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted by a methyl group; W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyranyl Pyran-7-yl; when the chroman group is pyran-6-yl, R 53 Is the carboxyl group substituted at the 3-position of the pyran-6-yl group; in this case, R 61 And R 62 Both are hydrogen atoms; when the chroman group is a pyran-7-yl group, R 53 Is the carboxyl group substituted at the 2-position or 3-position of the pyran-7-yl; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 In the case of the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is any of the following:
Figure 02_image093
; (B) R 5 When it is the structure represented by the aforementioned formula [II-2], the structure represented by the formula [II-2] is any of the following:
Figure 02_image095
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image097
. (8) Other better R 5 For the following aspect. Is the aspect that meets the aspect of (6) or the aspect of (7) above, and (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image099
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 Alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-6]
Figure 02_image101
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4 Alkane diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyran-7-yl; R 53 Is a carboxyl group; in this case, R 61 And R 62 It is independently a hydrogen atom or a methyl group. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image103
; Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image105
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted with one group selected from the group consisting of a fluorine atom and a methyl group, or the aforementioned formula [IV- 6] The 5-position of the pyridin-2-yl group of the structure shown can be substituted by a group selected from a methyl group and a methoxy group; W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 Is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyranyl Pyran-7-yl; when the chroman group is pyran-6-yl, R 53 Is the carboxyl group substituted at the 3-position of the pyran-6-yl group; in this case, R 61 And R 62 Both are hydrogen atoms; when the chroman group is a pyran-7-yl group, R 53 Is the carboxyl group substituted at the 2-position or 3-position of the pyran-7-yl; in this case, R 61 Is a hydrogen atom or a methyl group substituted at the 2-position of the pyran-7-yl group, R 62 Is a hydrogen atom. In this case, R 5 For the following aspect. (A) R 5 In the case of the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is any of the following:
Figure 02_image107
; (B) R 5 When it is the structure represented by the aforementioned formula [II-2], the structure represented by the formula [II-2] is any of the following:
Figure 02_image109
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image111
. (9) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula [III-4], formula [III-6] ~ formula [III-9]
Figure 02_image113
, Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image115
, Here, the 5-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] is substituted by a methoxy group, W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 In the case of the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is any of the following:
Figure 02_image117
; (B) R 5 In the case of the structure represented by the aforementioned formula [II-2], the structure represented by the formula [II-2] is as follows:
Figure 02_image119
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image121
. (10) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is the structure represented by the following formula [III-8]
Figure 02_image123
, Y is the formula -O-; W 1 Is heptane-1,7-diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image125
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted by one methyl group, or the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] The 5-position of may be substituted by a group selected from the group consisting of methyl and methoxy, W 2 Is butane-1,4-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is as follows:
Figure 02_image127
; (B) R 5 When it is the structure represented by the aforementioned formula [II-2], the structure represented by the formula [II-2] is any of the following:
Figure 02_image129
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image131
. (11) Other better R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image133
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is heptane-1,7-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 In the case of the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is any of the following:
Figure 02_image135
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image137
. (12) Other better R 5 For the following aspect. Is a pattern that also meets the patterns of (9) to (11) above, and (A) R 5 When the structure represented by the aforementioned formula [II-1]; R 51 Is a carboxyl group; L is the structure represented by the following formula [III-8]
Figure 02_image139
; Y is the formula -O-; W 1 Is heptane-1,7-diyl; (C) R 5 When it is the structure represented by the aforementioned formula [II-3]; W 3 R is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-7-yl; R 53 Is the carboxyl group substituted at the 2-position of the pyran-7-yl group; in this case, R 61 And R 62 Both are hydrogen atoms. In this case, R 5 For the following aspect. (A) R 5 When the structure represented by the aforementioned formula [II-1], the structure represented by the formula [II-1] is as follows:
Figure 02_image141
; (C) R 5 When it is the structure represented by the foregoing formula [II-3], the structure represented by the formula [II-3] is any of the following:
Figure 02_image143
. Another preferred aspect of the compound of the present invention is a compound represented by the following formula [IA] or a pharmaceutically acceptable salt thereof.
Figure 02_image145
Here, R 51 , L, Y, and W 1 The preferred aspect is the same as described above. Among the compounds represented by the above formula [IA], more preferable aspects are as follows. R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image147
, Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 In the case of alkanediyl. At this time, the best aspect is as follows. R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image149
, Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 In the case of heptane-1,7-diyl. At this time, a particularly good aspect is as follows. The compound represented by formula [IA] is any of the following:
Figure 02_image151
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IA] is as follows:
Figure 02_image153
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IA] is as follows:
Figure 02_image155
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IA] is as follows:
Figure 02_image157
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IA] is as follows:
Figure 02_image159
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IA] is as follows:
Figure 02_image161
. Another preferred aspect of the compound of the present invention is a compound represented by the following formula [IB] or a pharmaceutically acceptable salt thereof.
Figure 02_image163
. Here, R 52 , Ring A and W 2 The preferred aspect is the same as described above. Among the compounds represented by the above formula [IB], more preferable aspects are as follows. R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-6]
Figure 02_image165
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4 In the case of alkanediyl. At this time, the best aspect is as follows. R 52 Is the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; ring A is the structure represented by the following formula [IV-6]
Figure 02_image167
Here, the 3-position of the pyridin-2-yl group of the structure represented by the aforementioned formula [IV-6] may be substituted with one group selected from the group consisting of a fluorine atom and a methyl group, or the aforementioned formula [IV- 6] The 5-position of the pyridin-2-yl group of the structure shown can be substituted by a group selected from a methyl group and a methoxy group; W 2 In the case of butane-1,4-diyl. At this time, a particularly good aspect is as follows. The compound represented by formula [IB] is one of the following:
Figure 02_image169
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image171
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image173
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image175
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image177
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image179
. In addition, among the compounds represented by the above formula [IB], other preferable aspects are as follows. R 52 Is a carboxyl group; ring A is the structure represented by the following formula [IV-4] or formula [IV-6]
Figure 02_image181
, Here, the structure represented by the aforementioned formula [IV-6] may be substituted with a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 Is C 4-6 In the case of alkanediyl. At this time, an even better aspect is as follows. R 52 A carboxyl group substituted at the 3-position of the structure represented by the following formula [IV-4]; Ring A is the structure represented by the following formula [IV-4]
Figure 02_image183
; W 2 In the case of hexane-1,6-diyl. At this time, the particularly preferred aspect is as follows. The compound represented by formula [IB] is as follows:
Figure 02_image185
. Also, the other best aspects are as follows. R 52 The carboxyl group substituted at the 4-position of the pyridin-2-yl group represented by the following formula [IV-6], and the 5-position substituted pyridin-2-yl group of the structure represented by the following formula [IV-6] The carboxyl group or the carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the following formula [IV-6]; Ring A is the structure represented by the following formula [IV-6]
Figure 02_image187
, Here, R 52 When it is a carboxyl group substituted at the 6-position of the pyridin-2-yl group represented by the aforementioned formula [IV-6], the 3-position of the pyridin-2-yl group represented by the aforementioned formula [IV-6] can be replaced by The 5-position of the pyridin-2-yl group represented by the fluorine atom and the methyl group may be substituted by a methyl group and a methoxy group. One group selected from the group is substituted; W 2 In the case of butane-1,4-diyl. At this time, a particularly good aspect is as follows. The compound represented by formula [IB] is one of the following:
Figure 02_image189
.
Figure 02_image191
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image193
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image195
At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image197
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image199
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image201
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image203
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IB] is as follows:
Figure 02_image205
. Another preferred aspect of the compound of the present invention is a compound represented by the following formula [IC] or a pharmaceutically acceptable salt thereof.
Figure 02_image207
Here, R 53 , R 61 , R 62 , Ring B, and W 3 The preferred aspect is the same as described above. Among the compounds represented by the above formula [IC], more preferable aspects are as follows. R 53 Is a carboxyl group; W 3 Is C 1-2 Alkane diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyran-7-yl; in this case, R 61 And R 62 In the case of independently being a hydrogen atom or a methyl group. At this time, the best aspect is as follows. W 3 Is methanediyl or ethane-1,2-diyl; here, (c) when ring B is chromanyl, the chromanyl is pyran-6-yl or pyranyl Pyran-7-yl; when the chroman group is pyran-6-yl, R 53 Is the carboxyl group substituted at the 3-position of the pyran-6-yl group; in this case, R 61 And R 62 Both are hydrogen atoms; when the chroman group is a pyran-7-yl group, R 53 Is the carboxyl group substituted at the 2-position or 3-position of the pyran-7-yl; in this case, R 61 Is a hydrogen atom or a methyl group substituted at the 2-position of the pyran-7-yl group, R 62 It is a hydrogen atom, at this time, a particularly preferable aspect is as follows. The compound represented by the formula [IC] is one of the following:
Figure 02_image209
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image211
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image213
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image215
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image217
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image219
. At this time, other particularly preferred aspects are as follows. The compound represented by formula [IC] is as follows:
Figure 02_image221
. Another preferred aspect of the compound of the present invention is a compound represented by the following formula [IE] or a pharmaceutically acceptable salt thereof.
Figure 02_image223
Here, R 51 , L, Y, and W 1 The preferred aspect is the same as described above. Among the compounds represented by the above formula [IE], more preferable aspects are as follows. R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image225
, Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 In the case of alkanediyl. At this time, the best aspect is as follows. R 51 Is a carboxyl group; L is the structure represented by the following formula [III-4]
Figure 02_image227
; Y is the formula -O-; W 1 In the case of heptane-1,7-diyl. At this time, the particularly preferred aspect is as follows. The compound represented by formula [IE] is as follows:
Figure 02_image229
. Another preferred aspect of the compound of the present invention is a compound represented by the following formula [IF] or a pharmaceutically acceptable salt thereof.
Figure 02_image231
Here, R 51 , L, Y, and W 1 The preferred aspect is the same as described above. Among the compounds represented by the above formula [IF], more preferable aspects are as follows. R 51 Is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 02_image233
, Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -Or-O-; W 1 Is C 7 In the case of alkanediyl. At this time, the best aspect is as follows. R 51 Is a carboxyl group; L is the structure represented by the following formula [III-4]
Figure 02_image235
; Y is the formula -O-; W 1 In the case of heptane-1,7-diyl. At this time, the particularly preferred aspect is as follows. The compound represented by the formula [IF] is as follows:
Figure 02_image237
. The compound of the present invention is a compound having a pyridine substituted with a triazolyl group, a pyrimidin-5-yl group, or an imidazolyl heteroaryl group as a basic skeleton, and may also be a pharmaceutically acceptable salt thereof. Pharmaceutical allowable salts, such as hydrochloride, hydrobromide, hydrogen iodide, phosphate, sulfate, nitrate and other inorganic acid salts, methanesulfonate, ethanesulfonate, benzene Sulfonate, p-toluenesulfonate, trifluoromethanesulfonate, oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, Acid addition salts such as benzoate, mandelic acid, ascorbate, lactate, gluconate, malate and other organic acid salts, glycinate, lysine, arginine, ornithine Salt, glutamate, aspartate like amino acid salt, or lithium, sodium, potassium, calcium, magnesium salt like inorganic salt or ammonium salt, triethylamine salt, diisopropyl Amine salt, cyclohexylamine salt and organic base salt. In addition, salt includes hydrated salt. The compound of the present invention may have an asymmetric center, in which case there are various optical isomers. Therefore, the compound of the present invention may have respective optically active forms of (R) and (S), and racemates or (RS) mixtures. In addition, in the case of a compound having two or more asymmetric centers, there are further diastereomers due to the respective optical isomers. The compound of the present invention also includes a mixture containing all of these forms in any ratio. For example, diastereomers can be separated by a method known to the industry, for example, a segmented crystallization method, and the optically active substance can be obtained by a method of organic chemistry known for the purpose. In addition, there may be geometric isomers such as Cis form and trans form in the compounds of the present invention. Furthermore, the compound of the present invention has tautomerism and various tautomers exist. The compounds of the present invention also include their isomers and mixtures containing their isomers in any ratio. Furthermore, when the compound of the present invention or its salt forms a hydrate or solvate, they are also included in the scope of the compound of the present invention or its salt. 20-HETE-producing enzyme refers to catalyzing the ω-position of arachidonic acid to produce 20-HETE cytochrome P450 4A11, 4F2 using arachidonic acid as a substrate. As mentioned above, 20-HETE has various functions in the living body, and it is related to the pathogenesis of polycystic kidney disease or various cerebrovascular diseases, kidney diseases, circulatory organ diseases, etc. Therefore, by blocking the enzyme that produces 20-HETE, polycystic kidney disease, polycystic kidney-related diseases, and polycystic kidney-related symptoms can be prevented or improved. In addition, it can prevent or improve hypertension, cerebrovascular disease, ischemic heart disease, chronic renal failure, arteriosclerosis, fatty liver, and cancer. The compound of the present invention has the effect of hindering the enzyme producing 20-HETE. Therefore, the compound of the present invention can be used as an active ingredient of a 20-HETE production enzyme inhibitor, or an agent for preventing or improving polycystic kidney disease. In addition, the compound of the present invention can also be used as an active ingredient of a preventive or ameliorating agent for hypertension, cerebrovascular disease, ischemic heart disease, chronic renal failure, arteriosclerosis, fatty liver, and cancer. Here, "polycystic kidney" includes "autosomal dominant polycystic kidney" and "autosomal recessive polycystic kidney" in which a large number of cysts on both sides of the kidney are gradually produced and enlarged due to genetic mutation. Examples of "diseases related to polycystic kidney disease" include chronic renal failure, hypertension, vascular disease, liver and pancreas cysts, urinary tract infections, hepatobiliary tract infections, and urinary tract stones. In addition, "symptoms related to polycystic kidney disease" include pain, hematuria, and abdominal distension. In addition, evaluation of the effect of the compound of the present invention on the enzyme that inhibits the production of 20-HETE can be performed by conventional methods such as the method described in the test examples of this specification described later. Regarding the medicine of the present invention, the compound of the present compound contained in the enzyme that inhibits the production of 20-HETE, or a pharmaceutically acceptable salt thereof, can be administered alone or together with a pharmaceutically or pharmaceutically acceptable additive. As for additives, commonly used excipients or diluents, as well as binders, disintegrating agents, lubricants, coatings, sugar coating agents, pH adjusters, dissolving agents, or aqueous or non-aqueous solvents, can be used as necessary. Specifically, such as water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, glue, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water Syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl parabens, talc, stearic acid, magnesium stearate, cold weather, pectin, acacia, glycerin, sesame oil, olive oil, soybean oil, cocoa Fat, ethylene glycol, low-viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), etc. or other commonly used ones. The medicine of the present invention can be in any form of solid composition, liquid composition, and other composition, and the best one is selected according to necessity. The medicine of the present invention can be added to the compound of the present invention with the aforementioned additives, and can be prepared into tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, injections, etc. by common preparation techniques. In addition, the medicine of the present invention can be formulated as an inclusion compound formed by the compound of the present invention and α, β, or γ-cyclodextrin or methylated cyclodextrin. The medicine of the present invention can be used in combination with the compound of the present invention as a single preparation (admixture) or two or more preparations (combined agents) prepared separately. When these compounds are separately formulated into two or more preparations, the individual preparations can be administered at the same time or at regular intervals. On this occasion, it doesn't matter which one vote first. The two or more preparations can be administered at different times each day. In addition, the two or more preparations can also be administered in different routes. When these compounds are separately formulated into two kinds of preparations, they may also be administered at the same time or at very short intervals. For example, they may be used in documents such as appendices of commercially available drugs or sales manuals to indicate that they are used together. Better. In addition, it is also preferable that these active ingredients are separately formulated into a form of a set consisting of two kinds of preparations. When the compound of the present invention is used as a 20-HETE-producing enzyme inhibitor, etc., the compound of the present invention can be directly administered orally. Furthermore, it can also be administered orally as an agent containing the compound of the present invention as an active ingredient. When the compound of the present invention is used as a preventive or ameliorating agent for polycystic kidney disease, the compound of the present invention can be directly orally administered. Furthermore, it can also be administered orally as an agent containing the compound of the present invention as an active ingredient. The dosage of the compound of the present invention varies depending on the subject of administration, route of administration, subject disease, symptom, etc., but for example, when administered orally to an adult patient, the dose is usually 0.1 mg to 1000 mg, preferably 1 mg to 200 mg. , The amount is preferably 1 to 3 times a day, or once every 2 to 3 days. Examples of the preparation of the compound of the present invention are shown below. Formulation Example 1 Granules containing the following ingredients were produced. Ingredients: the compound represented by the formula [I'] or its pharmaceutically acceptable salt, lactose, corn starch, HPC-L. The compound represented by formula [I'] or its pharmaceutically acceptable salt and lactose are sieved. Sift the cornstarch. These are mixed with a mixer. The HPC-L aqueous solution is added at the end of mixing, kneaded and granulated (extrusion granulation), and then dried. The obtained dry granules are sieved with a vibrating screen to obtain granules. Formulation Example 2 A powder for capsule filling containing the following ingredients was produced. Ingredients: The compound represented by the formula [I'] or its pharmaceutically acceptable salt, lactose, corn starch, and magnesium stearate. The compound represented by formula [I'] or its pharmaceutically acceptable salt and lactose are sieved. Sift the cornstarch. These are mixed with magnesium stearate in a mixer to obtain a powder. The obtained powder can be filled in capsules. Formulation Example 3 A granule for capsule filling containing the following ingredients was produced. Ingredients: The compound represented by the formula [I'] or its pharmaceutically acceptable salt, lactose, corn starch, HPC-L. The compound represented by formula [I'] or its pharmaceutically acceptable salt and lactose are sieved. Sift the cornstarch. These are mixed with a mixer. The HPC-L aqueous solution is added at the end of mixing, kneaded and granulated, and then dried. The obtained dry granules are sieved with a vibrating sieve to be sized to obtain granules. The resulting granules can be filled in capsules. Formulation Example 4 A tablet containing the following ingredients was produced. Ingredients: The compound represented by formula [I'] or its pharmaceutically acceptable salt, lactose, microcrystalline cellulose, magnesium stearate, CMC-Na. The compound represented by the formula [I'] or its pharmaceutically acceptable salt, lactose, microcrystalline cellulose, and CMC-Na are sieved and mixed. Magnesium stearate is added to the mixing end to obtain the mixing end for preparations. The mixture is directly beaten into tablets to obtain tablets. Hereinafter, the production method of the compound [I'] of the present invention will be described in detail, but the production method is only an example and not particularly limited. In addition, the solvent used in the reaction may be a solvent that does not hinder each reaction, and is not particularly limited to the following description. The compound [I'] of the present invention can be produced by a method known per se, for example, the production methods 1 to 8 shown below, or a method based on these. In addition, in the production of the compound [I'] of the present invention, the order of the steps in each production method can be appropriately changed. In addition, in each of the following production methods, the raw material compound can be used as a salt. For the salt, for example, the aforementioned "pharmaceutical acceptable salt". In compound [I'], the compound in which X is the formula -O- and ring D is the group represented by the aforementioned formula [I'-1] can be prepared by the following production methods 1 to 3, or according to these methods To make. In compound [I'], compound [1-e], which is an intermediate for the production of a compound in which X is the formula -O- and ring D is the group represented by the aforementioned formula [I'-1], can be produced, for example, as follows Method 1 or manufacture according to its method. Manufacturing method 1:
Figure 02_image239
[In the path, R 1 , R 2 , R 3 , And R 4 Same as the previous definition, X A It is a chlorine atom or a bromine atom. Again, Pro 1 It is a protecting group for hydroxyl, such as (i) benzyl, 4-methoxybenzyl, etc. (together with hydroxyl to form a protecting group of benzyl ether structure. In this specification, it is also called "benzyl ether protecting group".); (ii) Methoxymethyl, tetrahydropyranyl, etc. (a protective group that forms an acetal structure together with a hydroxyl group. In this specification, it is also referred to as an "acetal-based protective group".); (iii) ) Trimethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, etc. (together with hydroxyl to form a protecting group of silyl ether structure. Also referred to as "silyl ether protecting group" in this specification "The situation.). ] [Step 1-1] In this step, the hydroxyl group of compound [1-a] is protected by Pro 1 Protection, method of producing compound [1-b]. This reaction can be carried out according to the method described in the literature (Protective Groups in Organic Synthesis, 4th edition, 2007, edited by GMWuts, TW Greene) or according to the method. [Step 1-2] This step is a method for producing compound [1-d] by reacting compound [1-b] with compound [1-c]. This reaction is a so-called Ullmann-type coupling reaction, which can be carried out in a solvent that does not hinder the reaction in the presence of a copper salt, ligand, and base. The copper salts used in this reaction, such as copper (I) iodide, copper (I) bromide, copper chloride (I), copper oxide (I), copper (I) trifluoromethanesulfonate Compound etc. The amount of copper salt used is 0.1 to 2 equivalents, preferably 0.1 to 0.5 equivalents relative to 1 equivalent of compound [1-b]. As for the ligand used in this reaction, for example, 2-isobutyrylcyclohexanone, L-proline, trans-N,N'-dimethylcyclohexane-1,2-diamine and the like. The amount of ligand used is 0.1 to 2 equivalents, preferably 0.1 to 0.5 equivalents, relative to 1 equivalent of compound [1-b]. The base used in this reaction includes, for example, potassium carbonate, potassium phosphate, cesium carbonate, N,N-diisopropylethylamine, and triethylamine. The amount of the base used is 1 to 5 equivalents, preferably 1 to 2 equivalents relative to 1 equivalent of compound [1-b]. The solvent used in this reaction includes, for example, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, acetonitrile, toluene, etc. Solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at reflux temperature for 1 to 24 hours. [Step 1-3] In this step, the protective group Pro of the hydroxyl group of compound [1-d] 1 Deprotection, the method of manufacturing compound [1-e]. (i)Pro 1 In the case of benzyl ether-based protecting groups such as benzyl and 4-methoxybenzyl, this reaction can be carried out in the presence of a metal catalyst and a hydrogen source in a solvent that does not hinder the reaction. The metal catalyst used in this reaction, for example, palladium on carbon, palladium hydroxide on carbon, etc. The amount of the metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent relative to 1 equivalent of compound [1-d]. The hydrogen pressure used in this reaction is normal pressure to 10 atmospheres, preferably normal pressure to 4 atmospheres. As for the solvent used in this reaction, for example, methanol, ethanol, water, tetrahydrofuran, ethyl acetate, etc., these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. (ii) Pro 1 When it is an acetal protecting group such as methoxymethyl and tetrahydropyranyl, this reaction can be carried out in the presence of an acid in a solvent that does not hinder the reaction. The acid used in this reaction includes, for example, hydrochloric acid, trifluoroacetic acid, etc. The amount of acid used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-d]. As for the solvent used in this reaction, for example, methanol, ethanol, water, dichloromethane, chloroform and other solvents that do not hinder the reaction, these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. (iii) Pro 1 When it is a silyl ether protecting group such as trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, etc., this reaction can be carried out in the presence of an acid in a solvent that does not hinder the reaction. The acid used in this reaction includes, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, etc. The amount of acid used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-d]. Regarding the solvent used in this reaction, for example, tetrahydrofuran, methanol, ethanol, water and other solvents that do not hinder the reaction, and these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. In addition, this reaction can be carried out in the presence of fluoride ion in a solvent that does not inhibit the reaction. The fluoride ion source used in this reaction includes potassium fluoride and tetrabutylammonium fluoride. The amount of the fluoride ion source used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-d]. As for the solvent used in this reaction, for example, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol and other solvents that do not hinder the reaction, and these solvents can be mixed and used in a suitable ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. The compound [1-e] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. In addition, in the above-mentioned production method 1, the compounds [1-a] and [1-c] used as the raw material compounds can be produced by a known method or purchased from a commercially available product. In the compound [I'], X is the formula -O- and ring D is the group represented by the aforementioned formula [I'-1], R 5 The structures represented respectively correspond to the compounds [2-c], [2-f], and [2- of the structures represented by the aforementioned formula [II-1], formula [II-2], and formula [II-3] i], for example, it can be manufactured by the following manufacturing method 2 or a method according to it. Manufacturing method 2:
Figure 02_image241
[In the path, R 1 , R 2 , R 3 , R 4 , R 61 , R 62 , L, Y, W 1 , W 2 , W 3 , Ring A, and ring B have the same definition as above, LG 1 Is a hydroxyl group or a leaving group, where LG 1 The "leaving group" represented is a halogen atom such as a chlorine atom, a bromine atom, etc.; the C of the methanesulfonyloxy group, etc. 1-4 Alkylsulfonyloxy; or p-toluenesulfonyloxy and other arylsulfonyloxy groups, Pro 3 1~2 level alkyl such as methyl, ethyl, 2-propyl; benzyl protecting group such as benzyl and 4-methoxybenzyl; or tert-butyl, L 1 Single bond or methane diyl group, R 53 'For slave R 53 The divalent group formed by removing the carboxyl group, specifically the carboxyl group and R 53 The base represented by the following formula [V] is composed of R 53 The following bases were selected:
Figure 02_image243
(a) When ring B is phenyl, R 53 Is selected from (i) carboxyl, (ii) C substituted by carboxyl 1-4 Alkyl (iii) C substituted by carboxyl 3-6 Cycloalkyl, (iv) single C substituted by carboxy 1-6 Alkylaminocarbonyl, and (v) C substituted by carboxy 1-4 Group formed by alkoxy; (b) When ring B is pyridyl, R 53 Is selected from (i) carboxyl, (ii) C substituted by carboxyl 1-4 Alkyl (iii) C substituted by carboxyl 3-6 Cycloalkyl, (iv) single C substituted by carboxy 1-4 Alkylaminocarbonyl, and (v) C substituted by carboxy 1-4 Group composed of alkoxy; (c) When ring B is chromanyl, R 53 It is carboxy or carboxymethyl. ] [Step 2-1] This step is a method for producing compound [2-b] by reacting compound [1-e] with compound [2-a]. (i) LG of compound [2-a] 1 When it is a hydroxyl group, this reaction can be carried out using a conventional method, the so-called Mitsunobu reaction (Synthesis, page 1, 1981). The amount of the compound [2-a] used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the compound [1-e]. The azo compound used in this reaction, for example bis(2-methoxyethyl) azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-azobis(N, N-dimethylformamide) and so on. The amount of the azo compound used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-e]. The phosphine compound used in this reaction includes, for example, triphenylphosphine and tributylphosphine. The amount of the phosphine compound used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-e]. The solvent used in this reaction, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, chloroform, dichloromethane, toluene, N,N-dimethylformamide, dimethyl sulfide, etc. It is a solvent that does not hinder the reaction, and these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. In addition, this reaction can also be carried out using the method described in Tetrahedron Letters, Vol. 36, page 2531, 1995, or Tetrahedron Letters, Vol. 37, page 2463, 1996. The reagent used in this reaction, for example, cyanomethylene trimethylphosphorane or cyanomethylene tributylphosphorane. The amount of reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-e]. The solvent used in this reaction may be the same as the aforementioned Mitsunobu reaction. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. (ii) LG of compound [2-a] 1 When it is a leaving group, this reaction can be carried out in the presence of a base. The amount of the compound [2-a] used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the compound [1-e]. The base used in this reaction, for example, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[4,3,0]undec-7-ene, etc. Alkali metal hydrides such as amines, sodium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, etc., and alkoxy bases such as potassium tert-butoxide Metal etc. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-e]. The solvents used in this reaction, such as tetrahydrofuran, dimethyl sulfide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc. do not hinder the reaction The solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. Also, the LG of compound [2-a] 1 In the case of a hydroxyl group, this reaction may be carried out after changing the hydroxyl group to a leaving group. Changing the hydroxyl group to a leaving group can be carried out using a usual method. For example, in a solvent that does not hinder the reaction, (a) halogenated reagent, or (b) alkali, react with sulfonic acid ester reagent to produce LG 1 Compounds that are leaving groups [2-a]. (A) Halogenated reagents used in this reaction, such as sulfite chloride, phosphonium chloride, N-chlorosuccinimide, bromine, N-bromosuccinimide, etc. The amount of the halogenated reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the compound having a hydroxyl group. The solvent used in this reaction includes, for example, solvents that do not inhibit the reaction such as chloroform and dichloromethane, and these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. In addition, the (b) sulfonic acid esterification reagent used in this reaction includes, for example, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and p-toluenesulfonyl chloride. The amount of the sulfonated reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound having a hydroxyl group. The base used in this reaction includes, for example, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the sulfonation reagent used. The solvent used in this reaction includes, for example, solvents that do not inhibit the reaction such as chloroform and dichloromethane, and these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. [Step 2-2] In this step, the protecting group Pro of compound [2-b] 3 Deprotection, a method for producing compound [2-c]. Here, when producing compound [2-c], there are some production conditions. They are described separately below. (i) Pro of compound [2-b] 3 When it is a 1- to 2-stage alkyl group such as methyl, ethyl, 2-propyl, etc., this reaction can be carried out under basic conditions. The alkali used in this reaction includes alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. The amount of the base used is 1 to 100 equivalents, preferably 1 to 10 equivalents relative to 1 equivalent of compound [2-b]. The solvent used in this reaction, for example, methanol, ethanol, 2-propanol, acetone, tetrahydrofuran, 1,4-dioxane, water and other solvents that do not hinder the reaction, these solvents can be mixed and used in an appropriate ratio . This reaction is usually carried out at 0°C to reflux temperature for 1 to 24 hours. (ii) Pro of compound [2-b] 3 In the case of benzyl ether-based protecting groups such as benzyl and 4-methoxybenzyl, this reaction can be carried out in the presence of a metal catalyst and a hydrogen source in a solvent that does not hinder the reaction. The metal catalyst used in this reaction, for example, palladium on carbon, palladium hydroxide on carbon, etc. The amount of the metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent relative to 1 equivalent of compound [2-b]. The hydrogen pressure used in this reaction is normal pressure to 10 atmospheres, preferably normal pressure to 4 atmospheres. As for the solvent used in this reaction, for example, methanol, ethanol, water, tetrahydrofuran, ethyl acetate, etc., these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. (iii) Pro of compound [2-b] 3 In the case of tert-butyl, this reaction can be carried out under milder acidic conditions. The acid used in this reaction includes, for example, hydrochloric acid, formic acid, and trifluoroacetic acid. The amount of acid used is 1 equivalent to solvent amount, preferably 1 to 10 equivalents relative to 1 equivalent of compound [2-b]. As for the solvent used in this reaction, for example, methanol, ethanol, tetrahydrofuran, water, ethyl acetate, 1,4-dioxane and other solvents that do not hinder the reaction, these solvents can be mixed and used in a suitable ratio. This reaction can usually be carried out at 0°C to room temperature for 1 to 24 hours. The compound [2-c] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. [Step 2-3] This step is a method for producing compound [2-e] by reacting compound [1-e] with compound [2-d]. This reaction can be carried out by the method described in step 2-1 of this production method or a method based thereon. [Step 2-4] This step is to make the protecting group Pro of compound [2-e] 3 Deprotection, a method for producing compound [2-f]. This reaction can be carried out by the method described in step 2-2 of this production method or a method based on it. The compound [2-f] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. [Step 2-5] This step is a method for producing compound [2-h] by reacting compound [1-e] with compound [2-g]. This reaction can be carried out by the method described in step 2-1 of this production method or a method based thereon. [Step 2-6] In this step, the protecting group Pro of compound [2-h] 3 Deprotection, the method of producing compound [2-i]. This reaction can be carried out by the method described in step 2-2 of this production method or a method based on it. The compound [2-i] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. In addition, the compounds [1-e], [2-a], [2-d], and [2-g] used as the raw material compounds in this production method can be used in the aforementioned production method 1 or according to the method thereof, Or it can be manufactured by its own known method, or obtained by purchasing commercially available products. In addition, the compound [2-b] can also be produced by the following production method 3 or a method based thereon, for example. Manufacturing method 3:
Figure 02_image245
[In the path, R 1 , R 2 , R 3 , R 4 , X A , Pro 3 , W 1 , Y, L, and LG 1 Same as the previous definition. ] [Step 3-1] This step is a method for producing compound [3-a] by reacting compound [1-a] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 3 or a method based thereon. [Step 3-2] This step is a method for producing compound [2-b] by reacting compound [3-a] with compound [1-c]. This reaction can be carried out by the method described in Step 1-2 of Production Method 1, or a method based thereon. The compound [2-b] thus obtained can be converted into the compound [2-c] by the method described in Step 2-2 of Production Method 2 or according to these methods. In addition, in the above-mentioned production method 3, the compounds [1-a], [2-a], and [1-c] used as the raw material compounds can be produced by a known method or obtained from the purchase of commercially available products. Furthermore, in step 3-1 of this production method, the compound [2-a] is substituted to react with the compound [2-d] or the compound [2-g], and then the compound [1- c] Reaction to make the protecting group Pro 3 Deprotection can be used to produce compound [2-f] or compound [2-i]. In the compound [I'], the compound in which X is the formula -O- and the ring D is the group represented by the aforementioned formula [I'-2] can be produced by the following production methods 4 to 6, or according to these methods To make. In compound [I'], compound [4-c] in which X is the formula -O- and ring D is the compound represented by the aforementioned formula [I'-2] can also be manufactured by, for example, the following Method 4 or manufacture according to its method. Manufacturing method 4:
Figure 02_image247
[In the path, R 1 , R 2 , R 3 , R 4 , X A , And Pro 1 As defined above, G is a boronic acid group or a boronic acid ester group. ] [Step 4-1] This step is a method for producing compound [4-b] by reacting compound [1-b] with compound [4-a]. This reaction can be described by the so-called Suzuki-Miyaura coupling reaction, in the presence of a palladium catalyst and alkali, in the literature (Tetrahedron Letters, Volume 20, Page 3437, 1979; Chemical reviews, Volume 95, Page 2457, 1995) The method or according to its method. The amount of the compound [4-a] used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of the compound [1-b]. Palladium catalysts, such as four (triphenylphosphine) palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, Bis(triphenylphosphine)palladium(II) dichloride and the like. The amount of palladium catalyst used is usually 0.001 to 0.5 equivalents, preferably 0.001 to 0.3 equivalents relative to 1 equivalent of compound [1-b]. In terms of bases, for example, alkali metal carbonates such as potassium carbonate, cesium carbonate, and sodium carbonate or their aqueous solutions, potassium fluoride, cesium fluoride, triethylamine and the like. The amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [1-b]. In terms of reaction solvents, for example, N,N-dimethylformamide, dimethyl sulfide, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethanol, water, etc. Solvents that do not hinder the reaction, and these solvents can be mixed and used in an appropriate ratio. These reactions can usually be carried out at room temperature to reflux temperature for 1 to 24 hours, and can also be carried out under microwave irradiation. [Step 4-2] In this step, the protecting group Pro of compound [4-b] 1 Deprotection, a method for producing compound [4-c]. This reaction can be carried out by the method described in Steps 1-3 of Production Method 1, or a method based thereon. The compound [4-c] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. In addition, in the above-mentioned production method 4, the compounds [1-b] and [4-a] used as the raw material compounds can be produced by a known method or obtained from the purchase of commercially available products. And, in the compound of the present invention [I'] and X is the formula -O-, ring D is the group represented by the aforementioned formula [I'-2], R 5 The structures represented respectively correspond to the compounds [5-b], [5-d], and [5-b], [5-d], and [5-b] of the structures represented by the aforementioned formula [II-1], formula [II-2], and formula [II-3] f], for example, by reacting each of compound [4-c] with the aforementioned compound [2-a], compound [2-d], and compound [2-g], the following production method 5 or a method according to it can be used To make. Manufacturing method 5:
Figure 02_image249
[In the path, R 1 , R 2 , R 3 , R 4 , R 61 , R 62 , L, Y, W 1 , W 2 , W 3 , Ring A, ring B, LG 1 , L 1 , Pro 3 , And R 53' Same as the previous definition. ] [Step 5-1] This step is a method for producing compound [5-a] by reacting compound [4-c] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 2 or a method based thereon. [Step 5-2] In this step, the protecting group Pro of compound [5-a] 3 Deprotection, a method for producing compound [5-b]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [5-b] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. [Step 5-3] This step is a method for producing compound [5-c] by reacting compound [4-c] with compound [2-d]. This reaction can be carried out by the method described in Step 2-3 of Production Method 2 or a method based thereon. [Step 5-4] In this step, the protecting group Pro of compound [5-c] 3 Deprotection, a method for producing compound [5-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [5-d] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 5-5] This step is a method for producing compound [5-e] by reacting compound [4-c] with compound [2-g]. This reaction can be carried out by the method described in Step 2-5 of Production Method 2 or a method according to it. [Step 5-6] In this step, the protecting group Pro of compound [5-e] 3 Deprotection, a method for producing compound [5-f]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [5-f] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. In addition, the compounds [4-c], [2-a], [2-d], and [2-g] used as the raw material compounds in this production method can be used in the aforementioned production method 4 or according to its method, Or they can be manufactured by their own known methods, or they can be obtained by purchasing commercially available products. In addition, the compound [5-a] can also be produced by the following production method 6 or a method based thereon, for example. Manufacturing method 6:
Figure 02_image251
[In the path, R 1 , R 2 , R 3 , R 4 , X A , Pro 3 , W 1 , Y, L, LG 1 , And G are the same as defined above. ] [Step 6-1] This step is a method for producing compound [3-a] by reacting compound [1-a] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 3 or a method based thereon. [Step 6-2] This step is a method for producing compound [5-a] by reacting compound [3-a] with compound [4-a]. This reaction can be carried out by the method described in Step 4-1 of Production Method 4 or a method based thereon. The compound [5-a] thus obtained can be converted into the compound [5-b] by the method described in step 5-2 of Production Method 5 or according to these methods. In addition, in the above-mentioned production method 6, the compounds [3-a] and [4-a] used as the raw material compounds can be produced by the aforementioned production method 3 or according to the method thereof, or a method known in the art, or purchased Obtained by means of commercially available products. Furthermore, in step 6-1 of this production method, compound [2-a] is substituted to react with compound [2-d] or compound [2-g], and then, as in step 6-2 above, with compound [4 -a] Reaction to make the protecting group Pro 3 By deprotection, compound [5-d] or compound [5-f] can be produced by this. In the compound [I'], the compound in which X is the formula -O- and the ring D is the group represented by the aforementioned formula [I'-3] can be prepared by the following production methods 7 to 8, or according to these methods To make. In the compound [I'] and X is the formula -O-, ring D is the group represented by the aforementioned formula [I'-3], R 5 The compound [7-g] whose structure shown corresponds to the structure shown by the aforementioned formula [II-1] can also be produced by, for example, the following production method 7 or a method based thereon. Manufacturing method 7:
Figure 02_image253
[In the path, R 1' , R 1" , R 2 , R 3 , R 4 , X B , Pro 3 , W 1 , Y, L, and LG 1 Same as the previous definition, R 1' Is a hydrogen atom or a methyl group, R 1" Is a hydrogen atom or a methyl group, X B It is a chlorine atom, a bromine atom, or an iodine atom. ] [Step 7-1] This step is a method of producing compound [7-b] by reacting compound [7-a] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 2 or a method based thereon. [Step 7-2] This step is a method for producing compound [7-c] by reacting compound [7-b] with a halogenated reagent. Halogenated reagents, such as N-bromosuccinimide, N-chlorosuccinimide, bromine, hydrobromic acid, trimethylphenylammonium tribromide, etc. The amount of halogenated reagent used in this reaction is 1 to 2 equivalents, preferably 1 to 1.1 equivalents, relative to 1 equivalent of compound [7-b]. As for the reaction solvent, for example, chloroform, dichloromethane, water, methanol, tetrahydrofuran, acetic acid and other solvents that do not hinder the reaction. These reactions can be carried out at 0 degrees to reflux temperature for 1 minute to 15 hours, or under microwave irradiation. [Step 7-3] This step is a method for producing compound [7-f] by reacting compound [7-c], [7-d], or [7-e]. The amount of compound [7-d] or [7-e] used in this reaction is 1 to 50 equivalents, preferably 1 to 20 equivalents relative to 1 equivalent of compound [7-c]. Regarding the reaction solvent, for example, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, ethanol, water and other solvents that do not hinder the reaction. In addition, compound [7-d] can also be used as a solvent. These reactions can be carried out at room temperature to 210 degrees for 5 minutes to 20 hours, or under microwave irradiation. [Step 7-4] In this step, the protecting group Pro of compound [7-f] 3 Deprotection, a method for producing compound [7-g]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [7-g] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. In addition, the compounds [2-a], [7-a], [7-d], and [7-e] used as the starting compounds in the above-mentioned production method 7 can be produced by their own known methods or commercially available. Purchase of products. Also, for example, as in the production method 8 shown below, in step 7-1 of this production method, the compound [2-a] is substituted to react with the compound [2-d] or [2-g], and then, as described above Like steps 7-2 and 7-3, react with halogenated reagent, compound [7-d] or [7-e] to make the protective group Pro 3 Deprotection can be used to produce compound [8-d] or [8-h]. Manufacturing method 8:
Figure 02_image255
[In the path, R 1' , R 1" , R 2 , R 3 , R 4 , X B , R 61 , R 62 , W 2 , W 3 , Ring A, ring B, LG 1 , L 1 , Pro 3 , And R 53' Same as the previous definition. ] [Step 8-1] This step is a method for producing compound [8-a] by reacting compound [7-a] with compound [2-d]. This reaction can be carried out by the method described in Step 2-3 of Production Method 2 or a method based thereon. [Step 8-2] This step is a method for producing compound [8-b] by reacting compound [8-a] with a halogenated reagent. This reaction can be carried out by the method described in Step 7-2 of Production Method 7 or a method based thereon. [Step 8-3] This step is a method for producing compound [8-c] by reacting compound [8-b] with compound [7-d] or compound [7-e]. This reaction can be carried out by the method described in Step 7-3 of Production Method 7 or a method based thereon. [Step 8-4] In this step, the protecting group Pro of compound [8-c] 3 Deprotection, the method of manufacturing compound [8-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [8-d] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 8-5] This step is a method for producing compound [8-e] by reacting compound [7-a] with compound [2-g]. This reaction can be carried out by the method described in Step 2-5 of Production Method 2 or a method according to it. [Step 8-6] This step is a method for producing compound [8-f] by reacting compound [8-e] with a halogenated reagent. This reaction can be carried out by the method described in Step 7-2 of Production Method 7 or a method based thereon. [Step 8-7] This step is a method for producing compound [8-g] by reacting compound [8-f] with compound [7-d] or compound [7-e]. This reaction can be carried out by the method described in Step 7-3 of Production Method 7 or a method based thereon. [Step 8-8] In this step, the protecting group Pro of compound [8-g] 3 Deprotection, the method of manufacturing compound [8-h]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [8-h] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. In addition, the compounds [7-a], [2-d], [2-g], [7-d], and compound [7-e] used as the starting compounds in the above-mentioned production method 8 can be known by themselves Method of manufacturing, or obtained from the purchase of commercially available products. In the compound [I'], the compound in which X is the formula -S- can be produced by the following production methods 9 to 12, or according to these methods. In the compound [I'] and X is the compound of formula -S-, ring D is the group represented by the aforementioned formula [I'-1], compounds [9-c], [9-e], and [9-g ] It can be manufactured by, for example, the following manufacturing method 9 or a method based thereon. Manufacturing method 9:
Figure 02_image257
[In the path, R 1 , R 2 , R 3 , R 4 , R 61 , R 62 , L, Y, W 1 , W 2 , W 3 , Ring A, ring B, LG 1 , L 1 , Pro 3 , And R 53' Same as the previous definition. ] [Step 9-1] This step is a method for producing compound [9-b] by reacting compound [9-a] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 2 or a method based thereon. [Step 9-2] In this step, the protecting group Pro of compound [9-b] 3 Deprotection, the method of producing compound [9-c]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [9-c] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. [Step 9-3] This step is a method for producing compound [9-d] by reacting compound [9-a] with compound [2-d]. This reaction can be carried out by the method described in Step 2-3 of Production Method 2 or a method based thereon. [Step 9-4] In this step, the protecting group Pro of compound [9-d] 3 Deprotection, the method of manufacturing compound [9-e]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [9-e] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 9-5] This step is a method for producing compound [9-f] by reacting compound [9-a] with compound [2-g]. This reaction can be carried out by the method described in Step 2-5 of Production Method 2 or a method according to it. [Step 9-6] In this step, the protecting group Pro of compound [9-f] 3 Deprotection, a method for producing compound [9-g]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [9-g] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like. In addition, the compounds [9-a], [2-a], [2-d], and [2-g] used as raw material compounds in this production method can be produced by their own known methods or can be produced from commercially available products. The purchase is obtained. In the compound of compound [I'] and X is of formula -S-, ring D is the compound of the aforementioned formula [I'-2] or [I'-3], the production intermediate [10-c] and [10-d] It can be manufactured by, for example, the following manufacturing method 10 or a method based thereon. Manufacturing method 10:
Figure 02_image259
[In the path, R 1 , R 1' , R 1" , R 2 , R 3 , R 4 , And G are the same as the aforementioned definition, Pro 4 C for methyl, ethyl, etc. 1-6 Alkyl or benzyl. ] [Step 10-1] This step is a method for producing compound [10-b] by reacting compound [10-a] with [4-a]. This reaction can be carried out by the method described in Step 4-1 of Production Method 4 or a method based thereon. [Step 10-2] In this step, the protecting group Pro of compound [10-b] 4 Deprotection, the method of manufacturing compound [10-c]. This reaction can be carried out in the presence of an alkali metal alcoholate in a solvent that does not hinder the reaction. The alkali metal alcoholate used in this reaction includes potassium tert-butoxide and sodium tert-butoxide. The amount of the alkali metal alkoxide used is 1-20 equivalents, preferably 1-10 equivalents relative to 1 equivalent of compound [10-b]. The solvent used in this reaction, for example, N,N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolinone, N,N'-dimethyl Solvents that do not hinder the reaction, such as propylene urea, can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. This reaction is preferably carried out under an inert gas environment. The compound [10-c] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. The compound [10-c] thus obtained can be converted into the compound [11-b], [11-d], or [11-f] by the method described in Production Method 11 described below or according to these methods. [Step 10-3] This step is a method for producing compound [10-e] by reacting compound [10-a] with compound [10-d]. This reaction can be carried out by the method described in Step 4-1 of Production Method 4 or a method based thereon. [Step 10-4] In this step, the protecting group Pro of compound [10-e] 4 Deprotection, a method for producing compound [10-f]. This reaction can be carried out by the method described in Step 10-2 of Production Method 10 or a method based thereon. The compound [10-f] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. The compound [10-f] thus obtained can be each reacted with the compound [2-a], [2-d], or [2-g] by the method described in the production method 12 described later or according to these methods, Converted into compound [12-b], [12-d], or [12-f]. In addition, the compounds [10-a], [4-a], and [10-d] used as the raw material compounds in this production method can be produced by their own known methods or purchased from commercially available products. In the compound [I'] and X is the compound of formula -S-, the compound [11-b], [11-d], and [11-f in which ring D is the group represented by the aforementioned formula [I'-2] ] It can be manufactured by, for example, the following manufacturing method 11 or a method based thereon. In the compound [I'] and X is the compound of formula -S-, the compound [11-b], [11-d], and [11-f in which ring D is the group represented by the aforementioned formula [I'-2] ] It can be manufactured by, for example, the following manufacturing method 11 or a method based thereon. Manufacturing method 11:
Figure 02_image261
[In the path, R 1 , R 2 , R 3 , R 4 , R 61 , R 62 , L, Y, W 1 , W 2 , W 3 , Ring A, ring B, LG 1 , L 1 , Pro 3 , And R 53' Same as the previous definition. ] [Step 11-1] This step is a method for producing compound [11-a] by reacting compound [10-c] with compound [2-a]. This reaction can be carried out by the method described in Step 2-1 of Production Method 2 or a method based thereon. [Step 11-2] In this step, the protecting group Pro of compound [11-a] 3 Deprotection, the method of manufacturing compound [11-b]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [11-b] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 11-3] This step is a method for producing compound [11-c] by reacting compound [10-c] with compound [2-d]. This reaction can be carried out by the method described in Step 2-3 of Production Method 2 or a method based thereon. [Step 11-4] In this step, the protecting group Pro of compound [11-c] 3 Deprotection, the method of producing compound [11-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [11-d] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 11-5] This step is a method for producing compound [11-e] by reacting compound [10-c] with compound [2-g]. This reaction can be carried out by the method described in Step 2-5 of Production Method 2 or a method according to it. [Step 11-6] In this step, the protecting group Pro of compound [11-e] 3 Deprotection, a method for producing compound [11-f]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [11-f] thus obtained can be separated and purified by conventional separation and purification means, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. In addition, the compounds [2-a], [2-d], and [2-g] used as the raw material compounds in this production method can be produced by a known method or purchased from a commercially available product. In compound [I'] and X is the compound of formula -S-, ring D is the group represented by the aforementioned formula [I'-3], compounds [12-b], [12-d], and [12-f ] It can be manufactured by, for example, the following manufacturing method 12 or a method based thereon. Manufacturing method 12:
Figure 02_image263
[In the path, R 1' , R 1" , R 2 , R 3 , R 4 , R 61 , R 62 , L, Y, W 1 , W 2 , W 3 , Ring A, ring B, LG 1 , L 1 , Pro 3 , And R 53' Same as the previous definition. ] [Step 12-1] This step is a method for producing compound [12-a] by reacting compound [10-f] with compound [2-a]. This reaction can be carried out by the method described in step 2-1 of this production method or a method based thereon. [Step 12-2] In this step, the protecting group Pro of compound [12-a] 3 Deprotection, the method of manufacturing compound [12-b]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [12-b] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 12-3] This step is a method for producing compound [12-c] by reacting compound [10-f] with compound [2-d]. This reaction can be carried out by the method described in Step 2-3 of Production Method 2 or a method based thereon. [Step 12-4] In this step, the protecting group Pro of compound [12-c] 3 Deprotection, the method of manufacturing compound [12-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [12-d] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, reduced pressure concentration, reprecipitation, solvent extraction, crystallization, chromatography, etc. [Step 12-5] This step is a method for producing compound [12-e] by reacting compound [10-f] with compound [2-g]. This reaction can be carried out by the method described in Step 2-5 of Production Method 2 or a method according to it. [Step 12-6] In this step, the protecting group Pro of compound [12-e] 3 Deprotection, the method of manufacturing compound [12-f]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [12-f] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc. In addition, the compounds [2-a], [2-d], and [2-g] used as the raw material compounds in this production method can be produced by a known method or purchased from a commercially available product. In compound [I'], X is the formula -CH 2 -The compound can be produced by the following production methods 13 to 15, or according to these methods. Compound [I'] and X is of formula -CH 2 -Of the compound, R 5 The compound [13-e] in which the structure represented corresponds to the structure represented by the aforementioned formula [II-1] can be produced by, for example, the following production method 13 or a method based thereon. Manufacturing method 13:
Figure 02_image265
[In the path, R 1 , R 2 , R 3 , R 4 , L, Y, Ring D, and Pro 3 Same as the previous definition, X C Is bromine atom or iodine atom, W 4 Single bond or C 1-8 Alkane diyl, Z is ethylene-1, 2-diyl or acetylene-1, 2-diyl. ] [Step 13-1] This step is a method for producing compound [13-c] by reacting compound [13-a] with compound [13-b]. This reaction can be performed by the so-called "Handbook of Organopalladium Chemistry for Organic Synthesis", Chapter III.2.8., pp493-535) or the so-called Heck reaction (Angewandte Chemie International Edition in English, Vol. 33, p. 2379, 1995 Year). When Z is acetylene-1,2-diyl, this reaction can be carried out by the so-called "Handbook of Organopalladium Chemistry for Organic Synthesis"("Handbook of Organopalladium Chemistry for Organic Synthesis", Chapter III.2.8., pp493-535) in palladium catalyst, copper ( I) The method described in the literature in the presence of salt and alkali or according to the method. The amount of compound [13-a] used in this reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents relative to 1 equivalent of compound [13-b]. The palladium catalyst used in this reaction, such as tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane Complexes, bis(triphenylphosphine)palladium(II) dichloride, etc. The amount of palladium catalyst used is usually 0.001 to 0.5 equivalents, preferably 0.005 to 0.3 equivalents relative to 1 equivalent of compound [13-b]. The copper (I) salt used in this reaction includes, for example, copper (I) iodide. The amount of copper salt (I) used is usually 0.01 to 1 equivalent, preferably 0.02 to 0.3 equivalent relative to 1 equivalent of compound [13-b]. The base used in this reaction includes amines such as triethylamine or N,N-diisopropylethylamine. The amount of base used is usually 2 equivalents to solvent amount, preferably 2 to 5 equivalents relative to 1 equivalent of compound [13-b]. The reaction solvent used in this reaction includes, for example, N,N-dimethylformamide, diethyl ether, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc. The solvents that hinder the reaction can be mixed and used in an appropriate ratio. These reactions can usually be carried out at room temperature to reflux temperature for 1 to 24 hours, and can also be carried out under microwave irradiation. When Z is ethylene-1,2-diyl, this reaction can be carried out by the so-called Heck reaction, in the presence of a palladium catalyst and alkali, in the literature (Angewandte Chemie International Edition in English, Volume 33, Page 2379, 1995) The recorded method or the method according to it. The amount of compound [13-a] used in this reaction is usually 1 to 5 equivalents, preferably 1 to 1.5 equivalents relative to 1 equivalent of compound [13-b]. The palladium catalyst used in this reaction includes, for example, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Methyl chloride adduct, bis(triphenylphosphine)palladium(II) dichloride, etc. The amount of the palladium catalyst used in this reaction is usually 0.01 to 0.2 equivalents, preferably 0.01 to 0.1 equivalents relative to 1 equivalent of compound [13-b]. As for the base used in this reaction, triethylamine, N-ethyl-N,N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium tert-butoxide, potassium acetate, etc. can be used. The amount of the base used in this reaction is usually 1 to 5 equivalents, preferably 1 to 3 equivalents relative to 1 equivalent of compound [13-b]. The solvent used in this reaction includes, for example, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylformamide, and other solvents that do not hinder the reaction, and these solvents can be mixed and used in an appropriate ratio. These reactions can usually be carried out at room temperature to reflux temperature for 1 to 24 hours, and can also be carried out under microwave irradiation. [Step 13-2] This step is a method of producing compound [13-d] by catalytically hydrogenating the vinyl group or ethynyl group of compound [13-c]. This reaction can be carried out in the presence of a metal catalyst and a hydrogen source in a solvent that does not hinder the reaction. The metal catalysts used in this reaction include palladium on carbon, palladium hydroxide on carbon, palladium on carbon-ethylenediamine complex, ginseng (triphenylphosphine) rhodium (I) chloride, and the like. The amount of the metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent relative to 1 equivalent of compound [13-c]. As for the solvent used in this reaction, for example, methanol, ethanol, water, tetrahydrofuran, ethyl acetate, etc., these solvents can be mixed and used in an appropriate ratio. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. [Step 13-3] In this step, the protecting group Pro of compound [13-d] 3 Deprotection, the method of manufacturing compound [13-e]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [13-e] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography. In addition, the compounds [13-a] and [13-b] used as the raw material compounds in this production method can be produced by their own known methods or purchased from commercially available products. Compound [I'] and X is of formula -CH 2 -Of the compound, R 5 The compound [14-d] whose structure corresponds to the structure of the aforementioned formula [II-2] can be produced by, for example, the following production method 14 or a method based thereon. Manufacturing method 14:
Figure 02_image267
[In the path, R 1 , R 2 , R 3 , R 4 , Ring A, ring D, L 1 , Pro 3 , X C , And Z are the same as the aforementioned definitions, W 5 Is C 2-6 Alkane diyl. ] [Step 14-1] This step is a method for producing compound [14-b] by reacting compound [13-a] with compound [14-a]. This reaction can be carried out by the method described in Step 13-1 of Production Method 13 or a method based thereon. [Step 14-2] This step is a method for producing compound [14-c] by catalytically hydrogenating the vinyl group or ethynyl group of compound [14-b]. This reaction can be carried out by the method described in Step 13-2 of Production Method 13 or a method according to the method. [Step 14-3] In this step, the protecting group Pro of compound [14-c] 3 Deprotection, the method of manufacturing compound [14-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [14-d] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography. In addition, the compounds [13-a] and [14-a] used as the raw material compounds in this production method can be produced by their own known methods or obtained from the purchase of commercially available products. Compound [I'] and X is of formula -CH 2 -Of the compound, R 5 The compound [15-d] whose structure corresponds to the structure represented by the aforementioned formula [II-3] can be produced by, for example, the following production method 15 or a method based thereon. Manufacturing method 15:
Figure 02_image269
[In the path, R 1 , R 2 , R 3 , R 4 , R 61 , R 62 , Ring B, ring D, Pro 3 , R 53' , X C , And Z are the same as the aforementioned definitions, W 6 Single bond or C 1 Alkane diyl. ] [Step 15-1] This step is a method for producing compound [15-b] by reacting compound [13-a] with compound [15-a]. This reaction can be carried out by the method described in Step 13-1 of Production Method 13 or a method based thereon. [Step 15-2] This step is a method for producing compound [15-c] by catalytically hydrogenating the vinyl group or ethynyl group of compound [15-b]. This reaction can be carried out by the method described in Step 13-2 of Production Method 13 or a method according to the method. [Step 15-3] In this step, the protecting group Pro of compound [15-c] 3 Deprotection, the method of manufacturing compound [15-d]. This reaction can be carried out by the method described in Step 2-2 of Production Method 2 or a method based thereon. The compound [15-d] thus obtained can be separated and purified by conventional separation and purification methods, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography. In addition, the compounds [13-a] and [15-a] used as the raw material compounds in this production method can be produced by their own known methods or obtained from the purchase of commercially available products. In the following reference examples and examples, the silica gel permeation chromatography method uses a packed column (Reveleris (registered trademark) Flash Cartridges Silica manufactured by Grace Corporation, or Biotage (registered trademark) SNAP Cartridge HP-Sphere manufactured by Biotage Corporation). The NH silica colloidal permeation chromatography method uses a packed column (Reveleris (registered trademark) Flash Cartridges Amino manufactured by Grace Corporation, or Biotage (registered trademark) SNAP Cartridge KP-NH manufactured by Biotage Corporation). Preparative thin-layer chromatography, using PLC plate 20×20cm silica gel 60F made by Merck 254 , 2mm. The ratio of the eluted solvent is the volume ratio without particular limitation. ISOLUTE (registered trademark) Phase Separator manufactured by Biotage Corporation was used as the phase separation device. The abbreviations used in this manual have the following meanings. s: singlet (singlet) d: doublet (doublet) t: triplet (triplet) q: quartet (quartet) quin: quintet (quintet) sxt: sextet (sextet) spt: septet (septet) dd: double doublet (double doublet) dt: double triplet (double triplet) td: triple doublet (triple doublet) tt: triple triplet (triple triplet) qd: quadruple doublet (quarter doublet) m: multiplet (multiplet) br: broad peak (broad) J: coupling constant (coupling constant) Hz: Hertz (Hertz) CHLOROFORM-d: heavy chloroform DMSO-d 6 ：Heavy dimethyl sulfide MeOH-d 4 ：Heavy methanol ACETONE-d 6 ：Heavy Acetone D 2 O: heavy water THP: tetrahydropyranyl TMS: trimethylsilyl Rf: retardation factor 1 H-NMR (Proton Nuclear Magnetic Resonance Spectrum) uses tetramethylsilane as an internal standard and is measured by the following Fourier transform NMR, and the total δ value is expressed in ppm. 200MHz: Gemini2000 (Agilent Technologies) 300MHz: Inova300 (Agilent Technologies) 400MHz: AVANCE III HD400 (Bruker) 500MHz: JNM-ECA500 (JEOL) 600MHz: JNM-ECA600 (JEOL) Analysis using ACD/Spectrus Processor 2017.1.3 ACD/Labs 2017.1.3 Release (File Version S70S41, Build 97027, 27 Sep 2017) (trade name) etc. The protons of hydroxyl groups or amino groups, amides, pyrazoles, etc. have very gentle peaks, and there are cases where it is not recorded. In addition, in the analysis of the compound, there may be protons that overlap with the peaks of water or solvent and cannot be identified. MS (mass spectrum) was measured with the following equipment. PlatformLC (Waters) LCMS-2010EV (Shimadzu) LCMS-IT-TOF (Shimadzu) Agilent 6130 (Agilent) Agilent 6150 (Agilent) ionization method, using ESI (Electrospray Ionization, electrospray ionization) method, EI (Electron Ionization, electron Ionization method), or ESI and APCI (Atmospheric Pressure Chemical Ionization, atmospheric pressure chemical ionization) method of double ionization. The data records the measured value (found). Normally, molecular ion peaks are observed, but in the case of compounds with tert-butoxycarbonyl (-Boc), there are also cases where fragment ions of tert-butoxycarbonyl or tert-butyl are detached. In addition, in the case of a compound having a tetrahydropyranyl group (THP), a peak where the tetrahydropyranyl group as a fragment ion is separated may be observed. In addition, in the case of a compound having a hydroxyl group (-OH), H as a fragment wave peak is also observed 2 The situation of the peak of O or OH radical detachment. In the case of salt, free-form molecular ion peaks or fragment ion peaks are usually observed. The LC-MS of the Examples and Reference Examples was measured under the following conditions. HPLC: Agilent 1290 Infinity MS: Agilent 6130 or 6150 [HPLC conditions] Column: Acquity UPLC CSH C18, 1.7μm, 2.1x×50mm (WATERS) Solvent: A solution; water containing 0.1% formic acid, solution B; containing 0.1 Acetonitrile with% formic acid (Method A) Gradient: 0.00 minutes (A liquid/B liquid=80/20), 1.20 minutes (A liquid/B liquid=1/99), 1.40 minutes (A liquid/B liquid=1/99 ), 1.41 minutes (A liquid/B liquid=80/20), 1.50 minutes (A liquid/B liquid=80/20) (Method B) Gradient: 0.00 minutes (A liquid/B liquid=95/5), 0.80 Minutes (A liquid/B liquid=60/40), 1.08 minutes (A liquid/B liquid=1/99), 1.38 minutes (A liquid/B liquid=1/99), 1.41 minutes (A liquid/B liquid= 95/5), 1.50 minutes (A liquid/B liquid=80/20) (Method C) Gradient: 0.00 minutes (A liquid/B liquid=70/30), 0.80 minutes (A liquid/B liquid=1/99 ), 1.40 minutes (A liquid/B liquid=1/99), 1.42 minutes (A liquid/B liquid=70/30), 1.50 minutes (A liquid/B liquid=70/30) Injection volume: 0.5μL, flow rate ：0.8mL/min Detection method: UV210nm, 254nm when connected to the evaporative light scattering detector (ELSD) Agilent 385-ELSD MS conditional ionization method: ESI or ESI/APCI multi-mode example, reference example of preparative HPLC The purification is performed under the following conditions. Machine: Gilson High-yield Refining System Column: Triart C18, 5μm, 30×50mm (YMC), or X-Bridge Prep C18 5um OBD, 30x50 (Waters) Solvent: A solution; 0.1% formic acid-containing water, B solution ；Acetonitrile containing 0.1% formic acid, or liquid A; water containing 0.1% trifluoroacetic acid, liquid B; acetonitrile containing 0.1% trifluoroacetic acid (Method A) Gradient: 0.00 minutes (liquid A/liquid B=90/10 ), 2.00 minutes (A liquid/B liquid=90/10), 11.0 minutes (A liquid/B liquid=20/80), 12.0 minutes (A liquid/B liquid=5/95), 13.52 minutes (A liquid/ B solution=5/95), 15.0 minutes (A solution/B solution=90/10) (Method B) Gradient: 0.00 minutes (A solution/B solution=95/5), 3.00 minutes (A solution/B solution= 95/5), 8.53 minutes (A liquid/B liquid=80/20), 10.0 minutes (A liquid/B liquid=80/20), 11.0 minutes (A liquid/B liquid=50/50), 12.02 minutes ( A liquid/B liquid=5/95), 13.5 minutes (A liquid/B liquid=5/95), 13.65 minutes (A liquid/B liquid=95/5), 15.0 minutes (A liquid/B liquid=95/ 5) (Method C) Gradient: 0.00 minutes (A liquid/B liquid=80/20), 2.00 minutes (A liquid/B liquid=80/20), 10.0 minutes (A liquid/B liquid=5/95), 11.5 minutes (A liquid/B liquid=1/99), 13.5 minutes (A liquid/B liquid=1/99), 13.55 minutes (A liquid/B liquid=80/20), 15.0 minutes (A liquid/B liquid =5/95), 15.0 minutes (A liquid/B liquid=95/5) Flow rate: 40mL/min Detection method: UV210nm, UV254nm When connected to ELSD SofTA MODEL 300S ELSD Example, Reference Example of the preparative LC-MS The purification is performed under the following conditions. HPLC: Agilent 1260 Infinity [HPLC conditions] Column: X-SELECT CSH C18, 5μm, OBD, 30x50 (Waters) Solvent: A solution; water containing 0.1% formic acid, solution B; acetonitrile containing 0.1% formic acid, or A Liquid; water containing 0.1% trifluoroacetic acid, liquid B; acetonitrile containing 0.1% trifluoroacetic acid (method A) Gradient: 0.00 minutes (liquid A/liquid B=90/10), 0.50 minutes (liquid A/liquid B) =90/10), 7.50 minutes (A liquid/B liquid=20/80), 7.95 minutes (A liquid/B liquid=20/80), 8.00 minutes (A liquid/B liquid=5/95), 9.00 minutes (A liquid/B liquid=5/95), 9.05 minutes (A liquid/B liquid=90/10), 10.0 minutes (A liquid/B liquid=90/10) (Method B) Gradient: 0.00 minutes (A liquid /B liquid=95/5), 0.50 minutes (A liquid/B liquid=95/5), 7.50 minutes (A liquid/B liquid=50/50), 7.95 minutes (A liquid/B liquid=50/50) , 8.00 minutes (A liquid/B liquid=5/95), 9.00 minutes (A liquid/B liquid=5/95), 9.05 minutes (A liquid/B liquid=95/5), 10.00 minutes (A liquid/B Solution=95/5) (Method C) Gradient: 0.00 minutes (A solution/B solution=80/20), 0.50 minutes (A solution/B solution=80/20), 7.00 minutes (A solution/B solution=5 /95), 7.45 minutes (A liquid/B liquid=5/95), 7.50 minutes (A liquid/B liquid=1/99), 9.00 minutes (A liquid/B liquid=1/99), 9.20 minutes (A Solution/B solution=80/20), 10.0 minutes (A solution/B solution=80/20) Flow rate: 50mL/min Detection method: UV210nm, UV254nm MS: Agilent 6130 when connected to ELSD Agilent 385 ELSD MS conditional ionization method ：ESI or ESI/APCI multi-mode example, the chiral HPLC preparation of the reference example was implemented with the following equipment. HPLC: High-yield purification system from Gilson Company or Preparative LC system from Waters Company Detection method: UV210nm, 254nm Microwave reaction device using Biotage Company Initiator, or Anton-Paar Company MONOWAVE300. The melting point of the compound was measured by the differential calorimetry and thermogravimetry (TG-DTA) method using the Thermo Plus Evo TG8120 thermal gravimetric analysis device manufactured by Rigaku Corporation. The compound name is named after the composition of PipelinePilot9.5, Molecular to Chemical Name (version 1) manufactured by Openeye. In this manual, "room temperature" refers to 20~30°C. Regarding the asymmetric carbon in the compounds of the reference examples and the examples, the three-dimensional structure shown in this specification is an absolute arrangement. Regarding asymmetric carbon, compounds with absolute configuration symbols are optically active. The present invention is explained in more detail with the following reference examples, examples, test examples, and formulation examples, but these do not limit the present invention, and can be changed without departing from the scope of the present invention. Reference Example 1-1 6-(1,2,4-triazol-1-yl)pyridin-3-ol
Figure 02_image271
(1) To a commercially available 2-bromo-5-hydroxypyridine (31.6g) in acetone (400mL) solution, under ice cooling, potassium carbonate (37.7g) and benzyl bromide (22.6mL) were added, Stir at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~4:1) to obtain 2-bromo-5-(benzyloxy)pyridine (43.8 g) The colorless powder. (2) The compound (23.1g) obtained in (1) above, 1,2,4-triazole (9.07g), trans-N,N'-dimethylcyclohexane-1,2-di To a mixture of amine (22.1 mL), potassium hydroxide (10.3 g), acetonitrile (185 mL), and water (15.8 mL), copper iodide (3.34 g) was added under a nitrogen atmosphere, and the mixture was stirred at 95°C for 10 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Add chloroform and water to the residue and stir to filter out insoluble materials. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was passed through a phase separation device and concentrated under reduced pressure. The resulting residue was purified by silica gel permeation chromatography (chloroform: methanol = 97: 3). The obtained crude product was stirred at room temperature for 2 days in a mixture of n-hexane:ethanol=2:1. The precipitated solid was filtered, and washed with a mixture of n-hexane:ethanol=4:1. The filtrate was ventilated and dried to obtain 5-phenylmethoxy-2-(1,2,4-triazol-1-yl)pyridine (18.9 g) as a pale yellow solid. (3) To a methanol (249 mL) suspension of the compound (18.9 g) obtained in (2) above, 5% palladium on carbon (1.89 g) was added, and stirring was performed at room temperature under a hydrogen atmosphere for 20 hours. The reaction system was substituted with nitrogen and stirred at 50°C for 30 minutes. After cooling to room temperature, the catalyst was filtered out and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and a mixture of n-hexane:ethanol=3:2 was added to the obtained residue, and the mixture was stirred overnight at room temperature. The precipitated solid was filtered, washed with a mixture of n-hexane:ethanol=3:2, and dried under reduced pressure to obtain the title compound (11.6 g) as a pale gray solid. 1 H NMR(400 MHz, DMSO-d 6 )δ ppm 7.39-7.49(m, 1H)7.71(d, J=8.4Hz, 1H)8.05(s, 1 H)8.22(s, 1H)9.19(s, 1H)10.34(br s, 1H). MS ESI posi:163[M+H] + . MS ESI nega:161[MH] - . Reference Example 1-2 2-(1,2,4-Triazol-1-yl)pyrimidin-5-ol
Figure 02_image273
(1) Using commercially available 2-chloropyrimidin-5-ol (3g), the reaction was carried out according to the method described in Reference Example 1-1-(1) to obtain 2-chloro-5-phenylmethoxypyrimidine (5g ) The light yellow solid. (2) To the N,N-dimethylformamide (4.53mL) solution of the compound (500mg) obtained in (1) above, add 1,2,4-triazole (235mg) and potassium carbonate (940mg) ), stirring at room temperature for 1 hour and at 90°C for 1 hour. After the mixture was cooled to room temperature, water was added and extraction was performed twice with ethyl acetate. The combined organic layer was passed through a phase separation device and concentrated under reduced pressure. Diethyl ether (15 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was filtered, washed with diethyl ether, and dried under reduced pressure to obtain 5-phenylmethoxy-2-(1,2,4-triazol-1-yl)pyrimidine ( 430mg) colorless solid. (3) Using the compound (820 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (430 mg) as a colorless solid. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 8.24(s, 1H)8.42(s, 2H) 9.26(s, 1H). MS ESI posi: 164[M+H] + . MS ESI nega: 162[MH] - . Reference Example 1-3 6-(1,2,4-triazol-1-yl)pyridazin-3-ol
Figure 02_image275
(1) To a solution of benzyl alcohol (1.60 mL) in tetrahydrofuran (44.7 mL), sodium hydride (60% mineral oil dispersion, 387 mg) was added under ice cooling, and the mixture was stirred for 1 hour. Slowly add 3,6-dichloropyridazine (2g) to the mixture. It was stirred at room temperature for 18 hours and at 60°C for 4 hours. After the mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~3:2) to obtain 3-chloro-6-phenylmethoxypyridazine (400mg ) Is a colorless solid. (2) In the microwave reaction test tube, add the compound (50 mg) obtained in the above (1) N,N-dimethylformamide (906 μL) solution, and add 1,2,4-triazole ( 235mg) and cesium carbonate (221mg). After replacing the gas in the container with nitrogen and sealing, the mixture was stirred under microwave irradiation at 140°C for 1 hour. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 22: 3 ~ ethyl acetate only) to obtain 3-phenylmethoxy-6-(1,2 ,4-Triazol-1-yl)pyridazine (13 mg) as a colorless solid. (3) Using the compound (13 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (7 mg) as a colorless solid. MS ESI posi: 164[M+H] + . Reference Example 2-1 2-(7-Hydroxyheptyloxy) Ethyl Acetate
Figure 02_image277
(1) To a suspension of heptane-1,7-diol (25g) in toluene (378mL), add triethylamine (52.7mL) and N,N-dimethylaminopyridine under ice cooling (1.85g) and chlorinated p-toluenesulfonic acid (37.9g), then stirred overnight at room temperature. To this mixture, saturated aqueous ammonium chloride solution was added under ice cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=3:2~1:3) to obtain 4-methylbenzenesulfonic acid 7-Hydroxyheptyl ester (31.4g) is a colorless oily substance. (2) To a chloroform (110 mL) solution of the compound (31.4 g) obtained in (1) above, p-toluenesulfonic acid monohydrate (2.1 g) was added. 3,4-Dihydro-2H-pyran (25 mL) was added to the mixture under ice cooling. Stir for 1 hour after leaving the ice bath. The reaction system was cooled with ice again, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=87:13~13:7) to obtain 4-methylbenzenesulfonic acid 7-(oxane-2- (Oxy)heptyl ester (35.8g) is a pale yellow oily substance. (3) Add sodium hydride (60% mineral oil dispersion, 24mg) in a solution of 2-hydroxyethyl acetate (152μL) in N,N-dimethylformamide (1.2mL) under ice-cooling. The temperature is stirred for 30 minutes. A N,N-dimethylformamide (1.0 mL) solution of the compound (200 mg) obtained in (2) above was added to this mixture, and after stirring at room temperature overnight, stirring was performed at 70°C for 5 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in this order, passed through a phase separator, and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:1) to obtain 2-[7-(oxan-2-yloxy) Heptyloxy] ethyl acetate (46 mg) as a colorless oily substance. (4) To a methanol (3 mL) and water (1 mL) solution of the compound (120 mg) obtained in (3) above, trifluoroacetic acid (0.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium bicarbonate solution was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 23: 2 to 1: 2) to obtain the title compound (65 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.25-1.31(m, 3H)1.32-1.45(m, 6H)1.56-1.69(m, 4H)3.52(t, J=6.6Hz, 2H) 3.59-3.68( m, 2H)4.06(s, 2H)4.22(q, J=7.1Hz, 2H). Reference example 2-2 Ethyl 2-(7-hydroxyheptyloxy)butanoate
Figure 02_image279
(1) In the tetrahydrofuran (2.2 mL) solution of the compound (200 mg) obtained in Reference Example 2-1-(3), add lithium hexamethyldisilazane (1.3 mol/L tetrahydrofuran solution) under cooling at -78°C , 0.61mL), and after stirring at the same temperature for 30 minutes, iodoethane (63.5μL) was dropped. After the dripping was completed, the mixture was slowly heated to room temperature and stirred for 15 hours. A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=49:1~4:1) to obtain 2-[7-(oxan-2-yloxy ) A mixture of ethyl heptyloxy]butanoate (100 mg). (2) Using the mixture (100 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (55 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 0.97(t, J=7.5Hz, 3H)1.29(t, J=7.2Hz, 3H)1.32-1.42(m, 6H)1.57-1.68(m, 4H) 1.68 -1.81(m, 2H)3.26-3.37(m, 1H)3.50-3.70(m, 3H)3.73(dd, J=7.3, 5.4Hz, 1H)4.18-4.28(m, 2H). MS ESI posi: 247 [M+H] + . The following Reference Examples 2-3 to 2-5 use the compounds obtained in Reference Example 2-1-1 (2) and the corresponding commercially available alcohols, and are described in accordance with Reference Examples 2-1-1 (3) and (4) The method for synthesis. The structure, NMR data, and MS data of the compound are shown in Table 1-1.
Figure 02_image281
Reference Example 3-1 3-(8-Hydroxyoctyl)-1,1-dioxothio-3-carbonitrile
Figure 02_image283
(1) To the N,N-dimethylformamide (27mL) solution of 2-(8-bromooctyloxy)oxane (2.0g), add methyl cyanoacetate (1.22mL) and potassium carbonate (2.83g), stirred at 75°C for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extraction was performed with diethyl ether. The organic layer was washed sequentially with water and saturated brine, and dried with anhydrous magnesium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~7:3) to obtain 2-cyano-10-(oxan-2-yloxy ) The colorless oily substance of methyl decanoate (1.40g). (2) To an acetonitrile (15 mL) solution of the compound (1.40 g) obtained in (1) above, 37% formaldehyde (1.52 mL) and triethylamine (63 μL) were added, and the mixture was stirred at 65°C for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried with anhydrous magnesium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=7:3-9:11) to obtain 2-cyano-2-(hydroxymethyl)-10-( A colorless oily substance of methyl oxan-2-yloxy)decanoate (1.5g). (3) To a tetrahydrofuran (22 mL) solution of the compound (1.5 g) obtained in (2) above, lithium borohydride (160 mg) was added under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was ice-cooled, water and saturated ammonium chloride aqueous solution were added, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (chloroform:methanol=99:1~91:9) to obtain 2,2-bis(hydroxymethyl)-10-(oxan-2-yl) A colorless oily substance of oxy)decane nitrile (1.09 g). (4) To the ethyl acetate (8.7 mL) solution of the compound (546 mg) obtained in the above (3), N,N-diisopropylethylamine (1.2 mL) and methanesulfonate were added under ice cooling Chlorine (410 μL), stir overnight at room temperature. Under ice cooling, saturated sodium bicarbonate aqueous solution was added to stop the reaction, and extraction was performed with ethyl acetate. After the organic layer was washed with saturated brine, it was passed through a phase separator and then concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=7:3~3:7) to obtain methanesulfonic acid [2-cyano-2-(methylsulfonic acid) A colorless oily substance of oxymethyl)-10-(oxan-2-yloxy)decyl]ester (750mg). (5) To the N,N-dimethylformamide (16 mL) solution of the compound (750 mg) obtained in (4) above, add sodium sulfide nonahydrate (1.92 g) and tetrabutylammonium iodide ( 118 mg), stirred overnight at 50°C under nitrogen. Water was added to the reaction solution, and after extraction with ethyl acetate, the organic layer was washed sequentially with water and saturated brine, passed through a phase separator, and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~4:1) to obtain 3-[8-(oxan-2-yloxy) A colorless oily substance of octyl]sulfan-3-carbonitrile (36 mg). (6) To a chloroform (1.2 mL) solution of the compound (36 mg) obtained in (5) above, m-chloroperoxybenzoic acid (66 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The mixture was ice-cooled, a saturated aqueous sodium hydrogen carbonate solution was added, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=3:1=1:1) to obtain 3-[8-(oxan-2-yloxy) Octyl]-1,1-dioxothio-3-carbonitrile (28mg) is a colorless oily substance. (7) Using the compound (28 mg) obtained in (6) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (16 mg) as a colorless solid. 1 H NMR(600MHz, CHLOROFORM-d) δ ppm 1.18-1.61(m, 13H) 2.00-2.06(m, 2H)3.62-3.69(m, 2H)4.09-4.15(m, 2H) 4.57-4.63 (m, 2H) ). MS ESI/APCI Multi posi:282[M+Na] + . MS ESI/APCI Multi nega:294[M+Cl] - . Reference Example 4-1 10-hydroxy-2,2-bis(methoxymethyl)decane nitrile
Figure 02_image285
(1) To a tetrahydrofuran (8 mL) solution of the compound (500 mg) obtained in Reference Example 3-1-(3), sodium hydride (60% mineral oil dispersion, 191 mg) was added under ice-cooling, and proceeded at the same temperature Stir for 30 minutes. In this mixture, a tetrahydrofuran (8 mL) solution of methyl iodide (400 μL) was dropped, and the mixture was stirred at room temperature for 2.5 hours and at 60° C. for 3 hours. The reaction mixture was ice-cooled, a saturated aqueous ammonium chloride solution was added, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~7:3) to obtain 2,2-bis(methoxymethyl)-10- (Oxan-2-yloxy)decanenitrile (403mg) is a colorless oily substance. (2) Using the compound (150 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (108 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.34-1.65(m, 14H) 3.40(s, 6H)3.48(s, 4H)3.64(t, J=6.6Hz, 2H). MS ESI/APCI Multi posi: 258[M+H] + . Reference Example 5-1 3-(7-Hydroxyheptyloxy)oxetane-3-carboxylic acid methyl ester
Figure 02_image287
(1) Using heptane-1,7-diol (10.0g), the reaction was carried out according to the method described in Reference Example 2-1-(2) to obtain 7-(oxan-2-yloxy)heptane- 1-alcohol (8g) is a colorless oily substance. (2) To the chloroform (50 mL) solution of the compound (7.0 g) obtained in (1) above, rhodium (II) acetate (71.5 mg) was added while cooling the reaction vessel in a water bath. After the mixture was stirred for 5 minutes, a chloroform (20 mL) solution of dimethyl diazomalonate (5.1 g) was dropped over 5 minutes. After the dropping was completed, the mixture was stirred at room temperature for 2 days, a saturated aqueous sodium bicarbonate solution was added and then shaken, and the organic layer was separated using a phase separator. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 19:1~3:2) to obtain 2-[7- (Oxan-2-yloxy)heptyloxy]propanedioic acid dimethyl ester (11.5g) is a colorless oily substance. (3) Using the compound (10 g) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 3-1-(2) to obtain 2-(hydroxymethyl)-2-[7-(oxane- 2-yloxy)heptyloxy]propanedioic acid dimethyl (5.6g) is a colorless oily substance. (4) To the N,N-dimethylformamide (17 mL) solution of the compound (5.6 g) obtained in (3) above, slowly add imidazole (2.0 g) and tert-butyl under ice cooling After diphenylchlorosilane (6.1 g), stirring was performed at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with diethyl ether. The organic layer was washed with a saturated aqueous ammonium chloride solution, passed through a phase separator, and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~3:2) to obtain 2-[[tert-butyl(diphenyl)silyl group) ]Oxymethyl]-2-[7-(oxan-2-yloxy)heptyloxy]propanedioic acid dimethyl ester (10g) is a colorless oily substance. (5) Using the compound (5.0 g) obtained in (4) above, the reaction was carried out according to the method described in Reference Example 3-1-(3) to obtain 2-[[tert-butyl(diphenyl)silyl group] Oxymethyl]-2-[7-(oxan-2-yloxy)heptyloxy]propane-1,3-diol (3.5g) is a colorless oily substance. (6) To the tetrahydrofuran (7.2 mL) solution of the compound (1.0 g) obtained in (5) above, slowly add N-butyllithium (1.6 mol/L hexane solution, 1.2 mL) under ice cooling, Stir at the same temperature for 20 minutes. To this mixture, a solution of chlorinated p-toluenesulfonic acid (380 mg) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 1 hour. Furthermore, n-butyllithium (1.6 mol/L hexane solution, 1.2 mL) was added, 40 minutes under ice cooling, 10 minutes at room temperature, 8 hours at 70°C, followed by stirring at room temperature for 2 days . A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with diethyl ether. The organic layer was washed with a saturated aqueous ammonium chloride solution, passed through a phase separator, and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~3:2) to obtain tert-butyl-[[3-[7-(oxane -2-yloxy)heptyloxy]oxetan-3-yl]methoxy]-diphenylsilane (630mg) is a colorless oily substance. (7) To the tetrahydrofuran (3.9 mL) solution of the compound (630 mg) obtained in (6) above, tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 1.3 mL) was added under ice cooling, and the mixture was heated at room temperature. Stir for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The resulting residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 23: 2~ ethyl acetate only) to obtain [3-[7-(oxan-2-yloxy Yl)heptyloxy]oxetan-3-yl]methanol (360mg) as a colorless oily substance. (8) To a solution of the compound (360 mg) obtained in (7) above in acetonitrile (4.0 mL) and phosphate buffer (pH 7.0, 4 mL), add 2-hydroxy-2-azaadamantane under ice cooling (18 mg), sodium chlorite (410 mg), and antifomin (1 mL) were stirred at room temperature for 1.5 hours. A saturated aqueous sodium thiosulfate solution was added to the mixture, stirred at room temperature for 1 hour, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a mixture (315 mg) containing 3-[7-(oxan-2-yloxy)heptyloxy]oxetane-3-carboxylic acid. (9) Using the compound (310 mg) obtained in (8) above, the reaction was carried out according to the method described in Reference Example 2-1-1 (4) to obtain 3-(7-hydroxyheptyloxy)oxetane-containing A mixture of 3-carboxylic acids. (10) To the toluene (4.9 mL) and methanol (0.49 mL) solution of the mixture obtained in (9) above, add (trimethylsilyl) diazomethane (230 μL) under ice cooling, and proceed at room temperature Stir for 1 hour. Methanol (2.5 mL), water (1 mL), and trifluoroacetic acid (1 mL) were added to the mixture, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 22: 3 ~ ethyl acetate only) to obtain a colorless solid of the title compound (130 mg). 1 H NMR(400MHz, CHLOROFORM-d) δ ppm 1.29-1.75(m, 10H) 3.37(t, J=6.5Hz, 2H) 3.65(t, J=6.5Hz, 2H) 3.85(s, 3H) 4.69(d , J=6.9Hz, 2H) 4.86(d, J=6.9Hz, 2H). Reference example 6-1 3-(8-hydroxyoctyl)oxetane-3-carboxylic acid methyl ester
Figure 02_image289
(1) Tetrahydrofuran (methyl oxetane-3-carboxylate (500mg) and 2-(8-bromooctyloxy)oxane (1.26g)) cooled in a dry ice-acetone bath under a nitrogen environment 17mL) Potassium hexamethyldisilazane (0.5mоl/L toluene solution, 10mL) was dropped into the solution. After the dropping was completed, the dry ice-acetone bath was removed, and stirring was performed for 4 hours while raising the temperature to room temperature. After adding saturated ammonium chloride aqueous solution to the mixture, the reaction was stopped, and extraction was performed with diethyl ether. The obtained organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~3:2) to obtain 3-[8-(oxan-2-yloxy ) A mixture of octyl]oxetane-3-carboxylic acid methyl ester (100 mg). (2) Using the mixture (100 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (65 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.10-1.40(m, 12H)1.94-2.02(m, 2H)3.64(t, J=6.6Hz, 2H)3.76(s, 3H)4.43 (d, J= 6.1Hz, 2H)4.89(d, J=6.1Hz, 2H). MS ESI posi:245[M+H] + . Reference Example 7-1 Ethyl 7-(hydroxymethyl)-3,4-dihydro-2H-1-benzopiperan-2-carboxylate
Figure 02_image291
(1) To a commercially available ethyl 7-hydroxy-4-oxo-1-benzopiperan-2-carboxylate (3.27g) in acetic acid (30mL), add palladium on carbon (981mg), hydrogen Under ambient (50 psi), stirring was performed at 30°C for 12 hours. After subjecting the reaction solution to Celite (registered trademark) filtration, the filtrate was concentrated. Ethyl acetate was added to the obtained residue, and washed with saturated sodium bicarbonate aqueous solution and saturated brine in this order. The organic layer was separated by a phase separator, and concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue, and the precipitated solid was filtered to obtain ethyl 7-hydroxy-3,4-dihydro-2H-1-benzopiperan-2-carboxylate (2.91 g) The colorless powder. (2) Pyridine (730 μL) was added to a chloroform (15 mL) solution of the compound (1.00 g) obtained in (1) above, and trifluoromethanesulfonic anhydride (910 μL) was dropped under ice cooling. The temperature was raised to room temperature, and stirring was performed for 1 hour. To the reaction solution, 1 mol/L hydrochloric acid (20 mL) and water (5 mL) were added under ice cooling, and then stirred. The organic layer was separated with a separatory funnel, and washed with a saturated sodium bicarbonate aqueous solution. After passing through a phase separation device, it is concentrated under reduced pressure, and the obtained residue is purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~1:1) to obtain 7-( Trifluoromethylsulfonyloxy)-3,4-dihydro-2H-1-benzopiperan-2-carboxylic acid ethyl ester (1.61g) is a colorless oily substance. (3) To the 1,4-dioxane (3 mL) and water (0.6 mL) solution of the compound (400 mg) obtained in (2) above, potassium vinyl trifluoroborate (272 mg), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (92mg) and potassium carbonate (468mg) were stirred at 100°C for 2 hours in a nitrogen environment. After the mixture was cooled to room temperature, the insoluble matter was filtered, and the filtrate was concentrated. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:2) to obtain 7-vinyl-3,4-dihydro-2H-1 -A colorless oily substance of ethyl benzopiperan-2-carboxylate (212 mg). (4) The compound (212 mg) and N-methylmorpholine-N-oxide (267 mg) obtained in (3) above were dissolved in tert-butyl alcohol (4.6 mL), tetrahydrofuran (4.6 mL), and water (0.91 mL), added 4% osmium tetroxide aqueous solution (118 μL) and stirred at room temperature for 2 hours, and then stirred at 60° C. for 20 minutes. To the reaction solution, a saturated aqueous sodium thiosulfate solution was added, and extraction was performed with ethyl acetate. After passing through a phase separation device, it is concentrated under reduced pressure to obtain a compound containing 7-(1,2-dihydroxyethyl)-3,4-dihydro-2H-1-benzopiperan-2-carboxylic acid ethyl ester Mixture (271 mg). (5) To a tetrahydrofuran (5.0 mL) and water (5.0 mL) solution of the compound (271 mg) obtained in (4) above, sodium periodate (239 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device, and concentrated under reduced pressure to obtain a mixture containing ethyl 7-methanyl-3,4-dihydro-2H-1-benzopiperan-2-carboxylate (217 mg) . (6) To an ethanol (4.6 mL) solution of the mixture obtained in (5) above, sodium borohydride (46 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution and water were added, and extraction was performed with ethyl acetate. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 9:1 to 1:1) to obtain the title compound (170 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)2.13-2.33(m, 2H)2.68-2.88(m, 2H)4.25(q, J=7.1 Hz, 2H) 4.62 (d, J=6.0 Hz, 2H)4.69-4.76(m, 1H)6.88(d, J=7.7Hz, 1H)6.94(s, 1H)7.02(d, J=7.7 Hz, 1H). MS ESI posi ：259[M+Na] + . Reference Example 7-2 Ethyl 7-(hydroxymethyl)-3,4-dihydro-2H-1-benzopiperan-2-carboxylate (optically active substance)
Figure 02_image293
(1) Use a preparative HPLC with a chiral column to separate the optical isomers of Reference Example 7-1 (540 mg) (the separation conditions are as follows. Column: CHIRALPAK IB, 5μm, 20x250mm. Solvent: Liquid A; Ethanol, B liquid; n-hexane. Dissolution conditions: A liquid/B liquid = 10/90. Flow rate: 10 mL/min, temperature: 40°C). The colorless oily substance of Reference Example 7-2 (236 mg) was obtained as a component with a residence time of 18.8 minutes. Reference Example 7-3 Ethyl 7-(bromomethyl)-2-methyl-3,4-dihydrochromene-2-carboxylate
Figure 02_image295
(1) Using the compound (1.00 g) obtained in Reference Example 7-1, the reaction was carried out according to the method described in Reference Example 2-1-1 (2) to obtain 7-(oxan-2-yloxymethyl)- 3,4-Dihydro-2H-chromene-2-carboxylic acid ethyl ester (1.19g) is a colorless oily substance. (2) Using the compound (403 mg) obtained in (1) above and methyl iodide (313 μL), the reaction was carried out according to the method described in Reference Example 2-2-(1) to obtain 2-methyl-7-(oxane- 2-yloxymethyl)-3,4-dihydro-2H-chromene-2-carboxylic acid ethyl ester (266 mg) as a colorless oily substance. (3) Using the compound (275 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain 7-(hydroxymethyl)-2-methyl-3,4- A colorless oily substance of ethyl dihydrochromene-2-carboxylate (184 mg). (4) To a chloroform (2 mL) solution of the compound (74 mg) obtained in (3) above, triphenylphosphine (155 mg) and carbon tetrabromide (75 μL) were added under ice cooling, and the reaction was carried out at room temperature for 2 hours Stir. A saturated aqueous sodium bicarbonate solution was added to the mixture, and extraction was performed 3 times with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The obtained residue was purified by silica colloidal permeation chromatography (n-hexane: ethyl acetate = 19:1 to 13:7) to obtain the title compound (144 mg) as a colorless oily substance. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.20(t, J=7.1Hz, 3H)1.62 (s, 3H)1.89(ddd, J=13.5, 10.8, 6.7Hz, 1H)2.40(dt, J=13.5, 4.6Hz, 1H)2.61- 2.77(m, 2H)4.12-4.21(m, 2H)4.43(s, 2H)6.88 (d, J=7.7 Hz, 1H)6.94-7.01(m, 2H). MS ESI posi:335, 337[M+ Na] + . Reference Example 8-1 7-(Hydroxymethyl)-3,4-dihydro-2H-chromene-3-carboxylic acid ethyl ester
Figure 02_image297
(1) In a nitrogen environment, add hexamethyldisilicate to a solution of 7-bromo-3,4-dihydro-2H-benzofuran-4-one (950mg) in tetrahydrofuran (13.9mL) at -78℃ Lithium azepine (1 mol/L tetrahydrofuran solution, 4.60 mL) was stirred at the same temperature for 30 minutes. Ethyl cyanoformate (455 μL) was added thereto, and the mixture was stirred for 2 hours under ice cooling. After cooling to -78°C, lithium hexamethyldisilazane (1 mol/L tetrahydrofuran solution, 4.60 mL) was added, and stirring was performed for 2 hours under ice cooling. After adding saturated ammonium chloride aqueous solution, the reaction was stopped, and extraction was performed with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=4:1~2:3) to obtain 7-bromo-4-oxo-2,3-di A colorless solid of ethyl hydrochromene-3-carboxylate (630 mg). (2) Using the compound (630 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 7-1-(6) to obtain 7-bromo-4-hydroxy-3,4-dihydro-2H- Ethyl chromene-3-carboxylate (330 mg) as a colorless solid. (3) Under a nitrogen atmosphere, a chloroform (11 mL) solution of the compound (330 mg) obtained in (2) above was cooled with ice, and diphenylbis[1-phenyl-1-(trifluoromethyl) was added thereto -2,2,2-Trifluoroethoxy]sulfur (IV) (1.11 g), stirred at room temperature for 5 hours and a half. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=4:1~2:3) to obtain 7-bromo-2H- A colorless solid of ethyl chromene-3-carboxylate (293 mg). (4) In a microwave reaction test tube, the compound (293 mg) obtained in (3) above, N-methanyl saccharin (328 mg), sodium carbonate (165 mg), triethyl silane (215 μL), 1,4- Bis(diphenylphosphino)butane (66.2mg) and palladium(II) acetate (23.2mg) were mixed in N,N-dimethylformamide (2.59mL), and the atmosphere in the container was replaced with Nitrogen, seal it. The mixture was stirred at 110°C for 2 hours and a half under microwave irradiation. After cooling to room temperature, the mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with a mixed solvent of ethyl acetate: toluene=1:1. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:2) to obtain 7-methanyl-2H-chromene-3-carboxylic acid Ethyl ester (50 mg) as a yellow solid. (5) Using the compound (50 mg) obtained in the above (4) and the palladium carbon-ethylenediamine complex (25 mg) as a catalyst, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain A colorless oily substance of the title compound (28 mg). 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)2.94-3.12(m, 3H)4.08-4.15(m, 1H)4.20(q, J=7.1Hz, 2H) 4.38 -4.49(m, 1H)4.61(s, 2H)6.80-6.92(m, 2H)7.05-7.11(m, 1H). MS ESI posi:259[M+Na] + , 219[M-OH] + . Reference Example 9-1 6-(hydroxymethyl)-3,4-dihydro-2H-1-benzopiperan-3-carboxylic acid ethyl ester
Figure 02_image299
(1) Add 2mol/L hydrogen chloride-ethanol solution (9.7mL) to commercially available 6-bromo-3,4-dihydro-2H-1-benzopiperan-3-carboxylic acid (500 mg), Stirring was performed at 75°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain ethyl 6-bromo-3,4-dihydro-2H-1-benzopiperan-3-carboxylate (510 mg). (2) In a microwave reaction vessel, the compound (510 mg) obtained in (1) above, tetrakis (triphenylphosphine) palladium (0) (207 mg), zinc cyanide (322 mg), and N,N- Dimethylformamide (3.6 mL) was mixed, the atmosphere in the container was replaced with nitrogen, and the container was sealed. The mixture was stirred at 150°C for 30 minutes under microwave irradiation. After cooling to room temperature, water and ethyl acetate were added to the mixture, and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, passed through a phase separator, and concentrated under reduced pressure. The residue obtained was purified by NH silica gel permeation chromatography (only n-hexane~n-hexane: ethyl acetate=4:1) to obtain 6-cyano-3,4-dihydro-2H Ethyl-1-benzopiperan-3-carboxylate (147 mg) as a colorless solid. (3) To the pyridine (1.6 mL) and acetic acid (1.6 mL) solution of the compound (147 mg) obtained in (2) above, sodium dihydrogen phosphate (458 mg) and Raleigh nickel (aqueous suspension, 3 mL) were added , Stir at 100°C for 1.5 hours. The catalyst is filtered out and washed with ethanol. The filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine in this order. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (only n-hexane~n-hexane: ethyl acetate=3:2) to obtain 6-methanyl-3,4-dihydro- A colorless oily substance of ethyl 2H-1-benzopiperan-3-carboxylate (86 mg). (4) Using the compound (82 mg) obtained in (3) above, it was synthesized according to the method described in Reference Example 7-1-(6) to obtain the title compound (81 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.2Hz, 3H)2.94-3.15(m, 3H)4.07-4.25(m, 3H)4.39-4.48(m, 1H)4.58 (s, 2H)6.76-6.87(m, 1H)7.03-7.16(m, 2H). MS ESI posi:219[M-OH] + . Reference example 10-1 7-(2-hydroxyethyl)-3,4-dihydro-2H-chromene-2-carboxylic acid ethyl ester
Figure 02_image301
(1) To the chloroform (20 mL) solution of the compound (1.00 g) obtained in Reference Example 7-1, Dess-Martin oxidizer (2.2 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated sodium thiosulfate aqueous solution and a saturated sodium bicarbonate aqueous solution were added to the ice-cooled mixture, stirred at room temperature for 10 minutes, and then extracted with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (only n-hexane~n-hexane: ethyl acetate=7:3) to obtain 7-methanyl-3,4-dihydro- A colorless oily substance of ethyl 2H-chromene-2-carboxylate (962 mg). (2) In an argon environment, add tert-butoxy potassium (330 mg) to a solution of (methoxymethyl)triphenylphosphonium chloride (1.01g) in toluene (6.5mL), and perform 1 Stir for hours. To this reaction solution, a toluene (4.0 mL) solution of the compound (459 mg) obtained in (1) above was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction system was cooled with ice again, saturated aqueous ammonium chloride solution was added to stop the reaction, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane~n-hexane: ethyl acetate=9:1) to obtain 7-[(E)-2-methoxyethylene Yl]-3,4-dihydro-2H-chromene-2-carboxylic acid ethyl ester (230 mg) as a colorless oily substance. (3) To an acetonitrile (8.0 mL) solution of the compound (230 mg) obtained in (2) above, water (1.0 mL) and concentrated hydrochloric acid (220 μL) were added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the organic solvent was distilled off under reduced pressure. The remaining aqueous layer was extracted with chloroform. The organic layer was separated by a phase separation device and concentrated under reduced pressure to obtain ethyl 7-(2-oxoethyl)-3,4-dihydro-2H-chromene-2-carboxylic acid A mixture of esters (241 mg). (4) Using the mixture (241 mg) obtained in the above (3), the reaction was carried out according to the method described in Reference Example 7-1-(6) to obtain the title compound (131 mg) as a colorless solid. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.30(t, J=7.1Hz, 3H)2.10-2.33(m, 2H)2.66-2.90(m, 4H)3.71-3.98(m, 2H)4.20-4.40( m, 2H)4.66-4.74(m, 1H)6.74(d, J=7.8Hz, 1H)6.82(s, 1H) 6.98(d, J=7.8 Hz, 1H). MS ESI posi: 251[M+H ] + , 273[M+Na] + Reference example 11-1 6-(2-hydroxyethyl)-3,4-dihydro-2H-chromene-2-carboxylic acid ethyl ester
Figure 02_image303
(1) Using 6-bromo-3,4-dihydro-2H-1-benzopiperan-2-carboxylic acid (490 mg), the reaction was carried out according to the method described in Reference Example 9-1-(1) to obtain 6 -Bromo-3,4-dihydro-2H-1-benzopiperan-2-carboxylic acid ethyl ester (528mg) as a yellow oily substance. (2) Using the compound (513 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 7-1-(3) to obtain 6-vinyl-3,4-dihydro-2H-chromene- Colorless oily substance of ethyl 2-carboxylate (343 mg). (3) Using the compound (343 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 7-1-(4) to obtain 6-(1,2-dihydroxyethyl)-3,4- A colorless oily substance of ethyl dihydro-2H-chromene-2-carboxylate (370 mg). (4) Using the compound (370 mg) obtained in (3) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (91 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d) δ ppm 1.23-1.33(m, 4H)2.12-2.33(m, 2H)2.66-2.91(m, 4H)3.75-3.90(m, 2H)4.20-4.33(m, 1H )4.64-4.74(m, 1H)6.84-6.92(m, 2H)6.98(d, J=8.1 Hz, 1H). MS ESI posi:251[M+H] + , 273[M+Na] + . Reference Example 12-1 7-(2-hydroxyethyl)-3,4-dihydro-2H-chromene-3-carboxylic acid ethyl ester
Figure 02_image305
(1) Use 7-bromo-3,4-dihydro-2H-benzofuran-4-one (2.5g) to react according to the method described in Reference Example 7-1-(3) to obtain 7-vinyl group -2,3-Dihydrochromen-4-one (1.64g) is a colorless oily substance. (2) Using the compound (1.64 g) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 7-1-1 (4) to obtain 7-(1,2-dihydroxyethyl)-2,3 -Dihydrochromen-4-one (2.18g) as a colorless solid. (3) In an acetone (20.9 mL) solution of the compound (2.18 g) obtained in (2) above, 2,2-dimethoxypropane (20.9 mL) and pyridinium p-toluenesulfonate were added under ice cooling Acid (263 mg), stirred at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The resulting residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=97:3~4:1) to obtain 7-(2,2-dimethyl-1,3- Dioxolane-4-yl)-2,3-dihydrochromen-4-one (1.83g) is a colorless oily substance. (4) Using the compound (1.83 g) obtained in (3) above, the reaction was carried out according to the method described in Reference Example 8-1-(1) to obtain 7-(2,2-dimethyl-1,3-di Oxolane-4-yl)-4-oxo-2,3-dihydrochromene-3-carboxylic acid ethyl ester (1.55g) is a colorless oily substance. (5) Using the compound (1.55 g) obtained in (4) above, the reaction was carried out according to the method described in Reference Example 7-1-1 (6) to obtain 7-(2,2-dimethyl-1,3-di Oxolane-4-yl)-4-hydroxy-3,4-dihydro-2H-chromene-3-carboxylic acid ethyl ester (1.05g) is a colorless oily substance. (6) Using the compound (120 mg) obtained in (5) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (92 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)1.37(t, J=5.9Hz, 1H)2.79(t, J=6.5Hz, 2H)2.95-3.09(m, 3H) 3.84(td, J=6.5, 5.9Hz, 2H)4.05-4.15(m, 1H)4.20(q, J=7.1Hz, 2H)4.38-4.48(m, 1H)6.68-6.78(m, 2H) 7.03(d, J=7.7Hz, 1H). MS ESI posi:251[M+H] + , 233[M-OH] + . The following Reference Example 12-2 uses the corresponding commercially available bromo-3,4-dihydro-2H-benzofuranone to synthesize according to the method described in Reference Example 12-1. The structure, NMR data, and MS data of the compound are shown in Table 2-1.
Figure 02_image307
Reference Example 13-1 2-[6-(2-hydroxyethyl)-3,4-dihydro-2H-chromen-4-yl]ethyl acetate
Figure 02_image309
(1) Under a nitrogen environment, add n-butyllithium (1.60mol/L n-hexane solution, 2.41 mol/L n-hexane solution, 2.41 mL) to a diisopropylamine (521 mL) solution in tetrahydrofuran (7.43 mL) cooled in a dry ice-methanol bath mL), stirring under ice cooling for 30 minutes. The reaction system was cooled again in a dry ice-methanol bath, ethyl (trimethylsilyl)acetate (680 μL) was added, and the mixture was stirred at the same temperature for 1 hour. The synthetic intermediate (6-(2,2-dimethyl-1,3-dioxolane-4-yl)-2,3-dihydrochromene- 4-ketone; a compound obtained in 3 steps from commercially available 6-bromo-3,4-dihydro-2H-benzofuran-4-one, 300mg) in tetrahydrofuran (7.34mL) solution, slowly heating to Stir overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~4:1) to obtain (2E)-2-[6-(2,2-di Methyl-1,3-dioxolane-4-yl)-2,3-dihydrochrome-4-ylidene] ethyl acetate (220 mg) is a pale yellow oily substance. (2) Using the compound (220 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (138 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.28(t, J=7.2Hz, 3H)1.37(t, J=5.9Hz, 1H)1.79-1.90(m, 1H)2.09-2.23(m, 1H)2.53 (dd, J=15.5, 9.9Hz, 1H)2.73-2.83(m, 3H)3.30-3.40(m, 1H) 3.81(q, J=6.2 Hz, 2H)4.13-4.24(m, 4H)6.76(d , J=8.6Hz, 1H) 6.92-7.02(m, 2H). MS ESI posi:247[M-OH] + . 265[M+H] + , 287[M+Na] + The following Reference Example 13-2 is a compound obtained by using Reference Example 12-1-(3), and was synthesized according to the method described in Reference Example 13-1. The structure, NMR data, and MS data of the compound are shown in Table 3-1.
Figure 02_image311
Reference Example 14-1 Methyl 1-(6-hydroxyhexyl)-3-bicyclo[1.1.1]pentanecarboxylate
Figure 02_image313
(1) To a solution of 1-phenyl-5-tetrazolyl mercaptan (1g) in N,N-dimethylformamide (11mL), add potassium carbonate (1.6g) and benzyl 5 at room temperature -Bromopentyl ether (1.28 mL), stirring at the same temperature overnight. After adding water, extraction was performed with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, and dried with anhydrous magnesium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=17:3~3:2) to obtain 1-phenyl-5-(5-phenylmethoxypentyl) A colorless oily substance of thio)tetrazolium ester (1.80g). (2) Using the compound (1.8g) obtained in (1) above and sodium bicarbonate, it was synthesized according to the method described in Reference Example 3-1-(6) to obtain 1-phenyl-5-(5-phenyl) A colorless oily substance of methoxypentylsulfonyl tetrazolium ester (1.11 g). (3) In a chloroform (9.1 mL) solution of ethanedichloride (1.1 mL) cooled in a dry ice-acetone bath under a nitrogen environment, drop a solution of dimethyl sulfoxide (1.4 mL) in chloroform (11 mL), Stir at the same temperature for 5 minutes. A chloroform (8.5 mL) solution of methyl 1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanecarboxylate (1 g) was dropped into it, and after stirring at the same temperature for 15 minutes, triethylamine was dropped. (5.4 mL), stirred at room temperature for 4 hours. The mixture was diluted with chloroform, washed with saturated ammonium chloride aqueous solution and saturated brine in this order, and the organic layer was passed through a phase separator and then concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~1:1) to obtain 1-methanyl-3-bicyclo[1.1.1]penta A brown oily substance of methyl alkanoate (692 mg). (4) In a tetrahydrofuran (3.4 mL) solution of the compound (590 mg) obtained in the above (2) under a nitrogen environment, drop sodium bis(trimethylsilyl)amide (1.14 mol) at a temperature below -60°C /L tetrahydrofuran solution, 1.34 mL), and stir at the same temperature for 30 minutes. Next, a tetrahydrofuran (2.0 mL) solution of the compound (196 mg) obtained in (3) above was dropped, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice cooling, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~3:1) to obtain 1-[(E)-6-benzene A colorless oily substance of methyl methoxyhexa-1-enyl]-3-bicyclo[1.1.1]pentanecarboxylate (198mg). (5) Using the compound (196 mg) obtained in (4) above, it was synthesized according to the method described in Reference Example 1-1-(3) to obtain the title compound (140 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.10-1.67(m, 10H)1.89(s, 6H)3.56-3.73(m, 5H). MS ESI/APCI Multi posi:249[M+Na] + . Reference Example 15-1 Methyl 3-(3-hydroxypropyl)benzoate
Figure 02_image315
(1) Make prop-2-yn-1-ol (200mg), methyl 3-bromobenzoate (500mg), bis(triphenylphosphine)palladium(II) dichloride (200mg), and triethyl The amine (4 mL) was dissolved in tetrahydrofuran (6 mL), copper iodide (20 mg) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 7 hours. The mixture was diluted with diethyl ether (30 mL), and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain a mixture containing methyl 3-(3-hydroxyprop-1-ynyl)benzoate. (2) Using the mixture obtained in (1) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain a mixture (140 mg) containing the title compound. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.86-1.98(m, 2H)2.77(t, J=7.6 Hz, 2H)3.64-3.73(m, 2H)3.92(s, 3H)7.33-7.40(m, 2H)7.83-7.93(m, 2H). The following Reference Examples 15-2 to 15-15 used commercially available aryl bromides and alkynes, and were synthesized according to the method described in Reference Example 15-1. The structure, NMR data, and MS data of the compound are shown in Table 4-1 to Table 4-2.
Figure 02_image317
Figure 02_image319
Reference Example 15-17 Methyl 6-(4-hydroxybutyl)-5-methoxypyridine-2-carboxylate
Figure 02_image321
(1) Using commercially available methyl 6-bromo-5-phenylmethoxypyridine-2-carboxylate (400 mg) and 3-butyn-1-ol (131 mg), according to Reference Example 15-1-( 1) The reaction was carried out according to the method described in the description to obtain 6-(4-hydroxybut-1-ynyl)-5-phenylmethoxypyridine-2-carboxylic acid methyl ester (190 mg) as a dark yellow oily substance. (2) Using the compound (190 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain 5-hydroxy-6-(4-hydroxybutyl)pyridine-2- Dark yellow oily substance of methyl carboxylate (100 mg). (3) To the acetone (4.4 mL) solution of the compound (100 mg) obtained in (2) above, potassium carbonate (120 mg) and methyl iodide (30 μL) were added, and the reaction was carried out at 60°C for 4.5 hours and at room temperature for 2 days Stir. The mixture was concentrated under reduced pressure, and purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 22: 3 ~ ethyl acetate only) to obtain the title compound (40 mg) as a colorless oil substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.61-1.71(m, 3H) 1.81-1.91(m, 2H)2.93(t, J=7.4 Hz, 2H)3.61-3.69(m, 2H) 3.90(s, 3H)3.96(s, 3H)7.15(d, J=8.6Hz, 1H)8.01(d, J=8.6Hz, 1H). MS ESI posi:240[M+H] + . Reference Example 15-18 3-fluoro-6-(4-hydroxybutyl)pyridine-2-carboxylic acid methyl ester
Figure 02_image323
(1) Using 6-chloro-3-fluoropyridine-2-carboxylic acid (300 mg), the reaction was carried out according to the method described in Reference Example 5-1-(10) to obtain 6-chloro-3-fluoropyridine-2-carboxylic acid Colorless solid of methyl ester (285 mg). (2) Using the compound (140 mg) obtained in (1) above and 3-butyn-1-ol (77.6 mg), the reaction was carried out according to the method described in Reference Example 15-1-(1) to obtain 3-fluoro- Dark yellow oily substance of methyl 6-(4-hydroxybut-1-ynyl)pyridine-2-carboxylate (175 mg). (3) Using the compound (175 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain the title compound (110 mg) as a pale yellow oily substance. 1 H NMR(400MHz, CHLOROFORM-d) δ ppm 1.63-1.72(m, 2H)1.82-1.94(m, 2H)2.96-3.01(m, 2H)3.64-3.71(m, 2H)3.99(s, 3H)7.44 (t, J=8.6Hz, 1H)8.00-8.06(m, 1H). MS ESI posi:228[M+H] + . The following Reference Examples 15-19 used commercially available aryl bromides and alkynes, and were synthesized according to the method described in Reference Examples 15-18. The structure, NMR data, and MS data of the compound are shown in Table 4-3.
Figure 02_image325
Reference Example 15-20 2-[3-(4-hydroxybutyl)-2-oxopyridin-1-yl] propan-2-yl acetate
Figure 02_image327
(1) Add potassium carbonate (2.6g) and isopropyl bromoacetate (2.5mL) to a solution of 3-bromo-2-hydroxypyridine (3.0g) in N,N-dimethylformamide (17mL) Then, stirring was performed at room temperature for 1 hour. After adding saturated ammonium chloride aqueous solution (10 mL), the reaction was stopped, and extraction was carried out with a mixed solution of toluene: ethyl acetate=1:1. After passing the obtained organic layer through a phase separation device, it was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:7) to obtain 2-(3-bromo-2-oxopyridine-1) -Yl) propan-2-yl acetate (3.44 g) as a colorless solid. (2) Using the compound (0.70 g) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 15-1-(1) to obtain 2-[3-(4-hydroxybut-1-ynyl) 2-Pyridin-1-yl]acetate propan-2-yl ester (0.50 g) is a yellow oily substance. (3) Using the compound (500 mg) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 1-1-(3) to obtain a mixture (336 mg) containing the title compound. 1 H NMR(400MHz, CHLOROFORM-d) δ ppm 1.27(d, J=6.4Hz, 6H)1.59-1.72(m, 4H)2.57(t, J=7.0Hz, 2H)3.63-3.76(m, 2H) 4.60 (s, 2H)5.01-5.15(m, 1H)6.15(t, J=6.7Hz, 1H)7.11(d, J=6.8Hz, 1H)7.22(d, J=6.6Hz, 1H). MS ESI posi:268[M+H] + , 290[M+Na] + . Reference Example 16-1 2-[2-Fluoro-3-(hydroxymethyl)phenyl]cyclopropane-1-carboxylic acid ethyl ester
Figure 02_image329
(1) Under a nitrogen environment, add a borane-tetrahydrofuran complex (0.9mol/L tetrahydrofuran solution, 94mL) to an ice-cooled 3-bromo-2-fluorobenzoic acid (15.9g) solution in tetrahydrofuran (50mL) ), stirring at room temperature for 4 hours. Under ice cooling, a saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, passed through a phase separator, and concentrated under reduced pressure. The crude product obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~1:1) to obtain methanol containing (3-bromo-2-fluorophenyl) The mixture (15.3g). (2) To the N,N-dimethylformamide (32.8 mL) solution of the compound (10.1 g) obtained in (1) above, add triethylamine (13.7 mL) and tris(o-tolyl) Phosphine (1.50 g), palladium(II) acetate (553 mg), and ethyl acrylate (5.35 mL). The container was sealed, and after pressure reduction and nitrogen introduction were performed three times, the mixture was stirred at 80°C for 3 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the mixture, and the insoluble matter was filtered out, and the filtrate was extracted with diethyl ether. The obtained organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~1:1) to obtain 3-fluoro-6-(4-hydroxybut-1-yne) Yl)pyridine-2-carboxylic acid methyl ester (11.5g) as a yellow oily substance. (3) Using the compound (11.5g) obtained in (2) above, the reaction was carried out according to the method described in Reference Example 2-1-1(2) to obtain (E)-3-[2-fluoro-3-(oxane) 2-yloxymethyl)phenyl]prop-2-enoic acid ethyl ester (12.8g) is a colorless oily substance. (4) In a nitrogen atmosphere, add trimethyl sulfinium iodide (2.79 g) to a dimethyl sulfoxide (16.9 mL) suspension of sodium hydride (60% mineral oil dispersion, 508 mg) cooled with ice ), stirring at room temperature for 30 minutes. The mixture was cooled with ice again, and a dimethyl sulfoxide (16.9 mL) solution of the compound (2.61 g) obtained in (3) above was added to the mixture, followed by stirring at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with diethyl ether. The obtained organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 19:1~4:1) to obtain 2-[2-fluoro-3-(oxane-2- A colorless oily substance of ethyloxymethyl)phenyl]cyclopropane-1-carboxylate (588mg). (5) Using the compound (588 mg) obtained in (4) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (360 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(t, J=7.1Hz, 3H)1.32-1.38(m, 1H)1.60(dt, J=9.3, 4.8Hz, 1H)1.75(t, J=6.2 Hz, 1H)1.88-1.95(m, 1H)2.62-2.72(m, 1H)4.19(q, J=7.1Hz, 2H)4.76(d, J=6.2Hz, 2H)6.91(t, J=7.6Hz , 1H)7.06(t, J=7.6 Hz, 1H)7.25-7.31(m, 1H). MS ESI posi:221[M+H] + , 239[M+Na] + . Reference Example 16-2 2-[4-(2-hydroxyethyl)phenyl]cyclopropane-1-carboxylic acid ethyl ester
Figure 02_image331
Using 2-(4-bromophenyl)ethanol (3.0 g), the reaction was carried out according to the method described in Reference Example 16-1-(2) to (5) to obtain the title compound (688 mg) as a colorless solid. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.23-1.31(m, 4H) 1.32-1.38(m, 1H)1.56-1.62(m, 1H)1.84-1.92(m, 1H)2.45-2.55 (m, 1H) )2.84(t, J=6.5 Hz, 2H)3.80-3.89(m, 2H)4.17(q, J=7.1 Hz, 2H)7.05(d, J=7.9Hz, 2H)7.15(d, J=7.9Hz , 2H). MS ESI posi:235[M+H] + . Reference Example 16-3 2-[5-(2-hydroxyethyl)pyridin-2-yl]cyclopropane-1-carboxylic acid ethyl ester
Figure 02_image333
(1) Using 2-(6-chloropyridin-3-yl)ethanol (1.8g), the reaction was carried out according to the method described in Reference Example 2-1-(2) to obtain 2-chloro-5-[2-(oxa Alk-2-yloxy)ethyl]pyridine (1.95g) is a colorless oily substance. (2) Using the compound (510 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 7-1-(3) to obtain 2-vinyl-5-[2-(oxan-2-yl A colorless oily substance of oxy)ethyl]pyridine (490mg). (3) To a toluene (3.6 mL) solution of the compound (250 mg) obtained in (2) above, add ethyl diazoacetate (0.17 mL), and carry out microwave irradiation at 120°C for 30 minutes and at 130°C. Stir for 45 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate=19:1~3:2) to obtain 2-[5-[2-(oxan-2-yloxy) Yl)ethyl]pyridin-2-yl]cyclopropane-1-carboxylic acid ethyl ester (230 mg) as a colorless oily substance. (4) Using the compound (230 mg) obtained in (3) above, the reaction was carried out according to the method described in Reference Example 2-1-(4) to obtain the title compound (100 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.27(t, J=7.1Hz, 3H)1.42(t, J=5.2Hz, 1H)1.54-1.65(m, 2H)2.17-2.28(m, 1H) 2.50 -2.64(m, 1H)2.82(t, J=6.5Hz, 2H)3.77-3.92(m, 2H)4.16(q, J=7.1Hz, 2H)7.18(d, J=7.9Hz, 1H)7.45( d, J=7.9Hz, 1H)8.32(s, 1 H). MS ESI posi:236[M+H] + . Reference Example 17-1 3-[5-(Bromomethyl)pyridin-2-yl]oxy-2,2-dimethylpropane acid methyl ester
Figure 02_image335
(1) Make 3-hydroxy-2,2-dimethylpropane acid methyl ester (1.40mL), 5-methylpyridine-2-ol (1.0g), and triphenylphosphine (3.61g) in toluene ( 46 mL) was mixed, and the atmosphere in the reaction vessel was replaced with nitrogen. Add bis(2-methoxyethyl) azodicarboxylate (3.22g) to the ice-cooled mixture, and proceed at the same temperature for 2.5 hours, at room temperature for 2 hours, and at 70°C for 3 hours Stir. After the mixture was cooled to room temperature, the mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=19:1~4:1) to obtain 2,2-dimethyl-3-(5-methyl A colorless oily substance of methyl pyridin-2-yl)oxypropanoate (1.08 g). (2) To the carbon tetrachloride (12mL) solution of the compound (1.08g) obtained in (1) above, add N-bromosuccinimidyl (947mg) and 2,2'-azobis(isobutyl Nitrile) (80 mg), and stirring was performed under heating and reflux for 3.5 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:1) to obtain a colorless oily substance containing a mixture (1.36 g) of the title compound. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.30(s, 6H) 3.69 (s, 3H)4.33(s, 2H)4.45(s, 2H)6.70-6.76(m, 1H)7.58-7.66 (m, 1H )8.10-8.16(m, 1H). MS ESI/APCI Multi posi:302[M+H] + , 324[M+Na] + . Reference Example 17-2 3-[4-(hydroxymethyl)pyridin-2-yl]oxy-2,2-dimethylpropane acid methyl ester
Figure 02_image337
(1) Using 4-bromopyridin-2-ol (2.0g), the reaction was carried out according to the method described in Reference Example 17-1-(1) to obtain 3-(4-bromopyridin-2-yl)oxy-2 , A colorless oily substance of methyl 2-dimethylpropaneate (2.2g). (2) Using the compound (500 mg) obtained in the above (1) and allyl boronic acid pinacol ester (440 mg), the reaction was carried out according to the method described in Reference Example 7-1-1 (3) to obtain 2,2 -A mixture of methyl dimethyl-3-[4-[prop-1-enyl]pyridin-2-yl]oxypropanoate (403 mg). (3) To the tert-butanol (3.2mL), tetrahydrofuran (3.2mL), and water (0.81mL) solution of the mixture (403mg) obtained in (2) above, add sodium periodate (1.4g) and Osmium tetroxide (4% aqueous solution, 0.42 mL) was stirred at room temperature for 1 hour. The mixture was ice-cooled, a solution of sodium borohydride (0.31 g) in water (0.81 mL) was slowly added thereto, and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the mixture, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 9:1 to 2:3) to obtain the title compound (140 mg) as a colorless oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.31(s, 6H) 3.69(s, 3H)4.32(s, 2H)4.68(s, 2H)6.76(s, 1H)6.85(d, J=5.2 Hz, 1H)8.10(d, J=5.2Hz, 1H). MS ESI posi:240[M+H] + . Reference Example 18-1 3-[3-Fluoro-4-(hydroxymethyl)pyridin-2-yl]oxy-2,2-dimethylpropane acid methyl ester
Figure 02_image339
(1) A propionitrile (4.1 mL) suspension of 2,3-difluoro-4-iodopyridine (1.0 g) and copper cyanide (450 mg) was stirred at 160° C. for 3.5 hours under microwave irradiation. After cooling to room temperature, the suspension was diluted with chloroform, filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=17:3~13:7) to obtain 2,3-difluoropyridine-4-carbonitrile (374mg) The colorless oily substance. (2) Methyl 3-hydroxy-2,2-dimethylpropaneate (375 μL) and sodium hydride (60% mineral oil dispersion, 118 mg) were mixed in tetrahydrofuran (8 mL). A tetrahydrofuran (5 mL) solution of the compound (374 mg) obtained in (1) above was dropped into the mixture under ice cooling. After completion of the dropping, stirring was performed at room temperature for 3.5 hours. The mixture was cooled with ice, a saturated aqueous ammonium chloride solution was added thereto, and extraction was performed with chloroform. The organic layer was passed through a phase separation device and then concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=4:1~3:2) to obtain 3-(4-cyano-3-fluoropyridin-2-yl ) A colorless oily substance of methyl oxy-2,2-dimethylpropaneate (365mg). (3) The compound (361 mg) obtained in (2) above and sodium dihydrogen phosphate (1.03 g) were mixed in pyridine (3.6 mL)/acetic acid (3.6 mL). To this suspension was added Raleigh's nickel (aqueous suspension, 7.2 mL, the suspension was uniformized and then measured with a pipette), and the mixture was stirred at 100°C for 2.5 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine in this order, passed through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica colloidal permeation chromatography (n-hexane: ethyl acetate = 13: 7-7: 13) to obtain the title compound (92 mg) as a pale yellow oily substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.33(s, 6H) 2.84(t, J=6.7Hz, 1H)3.74(s, 3H)4.14(s, 2H)4.67(d, J=6.7Hz, 2H )7.20(d, J=4.5Hz, 1H)7.87(d, J=4.5Hz, 1H). MS ESI posi:258[M+H] + . Reference Example 19-1 2-Methyl-2-[7-[2-(1,2,4-triazol-1-yl)pyrimidin-5-yl]oxyheptyloxy]propane acid
Figure 02_image341
Using the compound (52 mg) obtained in Reference Example 1-2 and the compound (80 mg) obtained in Reference Example 2-3, the reaction was carried out according to the method described in Example 1-1 below to obtain the title compound (95 mg) as a colorless solid. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.29(s, 6H)1.31-1.55(m, 8H)1.72-1.82(m, 2H)3.27-3.31(m, 2H)4.20(t, J=6.5Hz, 2H) 8.27(s, 1H) 8.68(s, 2 )9.32(s, 1H). MS ESI posi:364[M+H] + . MS ESI nega:362[MH] - . Reference Example 20-1 2-Methyl-2-[7-[6-(1,2,4-triazol-1-yl)pyridazin-3-yl]oxyheptyloxy]propane acid
Figure 02_image343
(1) Using the compound (7 mg) obtained in Reference Example 1-3 and the compound (23.6 mg) obtained in Reference Example 2-3, the reaction was carried out according to the method described in Example 4-1-1 (1) shown later, Obtain 2-methyl-2-[7-[6-(1,2,4-triazol-1-yl)pyridazin-3-yl]oxyheptyloxy]propane acid tert-butyl (15mg) The light yellow oily substance. (2) Using the compound (15 mg) obtained in (1) above, the reaction was carried out according to the method described in Example 1-1-1 (2) shown below to obtain the title compound (1.5 mg) as a colorless amorphous substance. 1 H NMR(400MHz, METHANOL-d 4 )δ ppm 1.32-1.45(m, 12H) 1.51-1.61(m, 2H)1.82-1.92(m, 2H)3.40(t, J=6.5Hz, 2H) 4.20 (t, J=7.3Hz, 2H)7.21 (d, J=9.8Hz, 1H)8.06(d, J=9.8Hz, 1H) 8.21(s, 1H)9.15(s, 1 H). MS ESI posi:364[M+H] + , 386[M+Na] + . MS ESI nega:362[MH] - . Reference Example 21-1 2-[5-[3-(hydroxymethyl)phenyl]-2-oxo-1-pyridine]acetate propan-2-yl ester
Figure 02_image345
(1) To 5-bromo-1H-pyridin-2-one (1.50g) in N,N-dimethylformamide (8.6mL) solution, add potassium carbonate (1.3g) and isopropyl bromoacetate (1.2 mL), stir at room temperature for 1 hour. After adding saturated ammonium chloride aqueous solution (10 mL), the reaction was stopped, and extraction was performed with ethyl acetate. After passing the obtained organic layer through a phase separation device, it was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: ethyl acetate=7:3~3:7) to obtain 2-(5-bromo-2-oxo-1- Pyridine) propan-2-yl acetate (1.2 g) as a colorless solid. (2) The compound (100 mg) obtained in (1) above and the commercially available [3-(hydroxymethyl)phenyl]boronic acid (58 mg) in dimethoxyethane: water (4:1, 4.5 mL In the solution, potassium carbonate (100 mg) and tetrakis (triphenylphosphine) palladium (0) (42 mg) were added under a nitrogen environment, and then stirred at 120°C for 30 minutes under microwave irradiation. The reaction mixture was filtered through Celite (registered trademark), and after adding saturated ammonium chloride aqueous solution (5 mL) to the filtrate, extraction was performed with ethyl acetate. After passing the obtained organic layer through a phase separation device, it was concentrated under reduced pressure. The obtained residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 7: 3 to 1: 9) to obtain the title compound (73 mg) as a brown amorphous substance. 1 H NMR(400MHz, CHLOROFORM-d)δ ppm 1.29(d, J=6.3 Hz, 6H) 1.86(t, J=5.7Hz, 1H) 4.68(s, 2H) 4.75(d, J=5.7Hz, 2H) 5.11(spt, J=6.3Hz, 1H)6.67(d, J=9.4Hz, 1H)7.29-7.50(m, 5H) 7.62-7.74(m, 1H). MS ESI posi:302[M+H] + . Reference Example 22-1 5-Bromo-2,2-dimethyl-1-cyclopentanone
Figure 02_image347
In a solution of 2,2-dimethyl-1-cyclopentanone (500mg) in tetrahydrofuran (45mL), under ice cooling, trimethylphenylammonium tribromide (1.84g) was added, and the process was carried out at room temperature. Stir for hours. Water was added to the reaction liquid, and extraction was performed with diethyl ether. The organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel permeation chromatography (n-hexane: ethyl acetate = 49:1-17:3) to obtain the title compound (592 mg ) Is a colorless oily substance. MS EI posi: 190[M] + . Example 1-1 2-Methyl-2-[7-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxyheptyloxy]propane acid
Figure 02_image349
(1) In a toluene (3.1 mL) suspension of the compound (100 mg) obtained in Reference Example 1-1 under a nitrogen environment, the compound (203 mg) obtained in Reference Example 2-3 and the cyanomethylene group were added Tributylphosphorane (320 μL) was stirred at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel permeation chromatography (n-hexane: ethyl acetate=4:1~3:2) to obtain 2-methyl -2-[7-[6-(1,2,4-Triazol-1-yl)pyridin-3-yl]oxyheptyloxy]propanoic acid tert-butyl ester (338mg) light brown oily substance . (2) The compound (338 mg) obtained in (1) above was dissolved in 4 mol/L hydrogen chloride-1,4-dioxane (2.5 mL), and stirred at 75°C for 3 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC. The fraction containing the target product was concentrated, and the obtained solid was suspended in diethyl ether and stirred, and then filtered to obtain the title compound (137 mg) as a colorless solid. In addition, the title compound obtained can be recrystallized from ethyl acetate. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.29(s, 6H)1.30-1.53(m, 8H)1.70-1.79(m, 2H)3.29-3.31(m, 2H)4.11(t, J=6.5Hz, 2H)7.67 (dd, J= 8.9, 2.9Hz, 1H)7.80(d, J=8.9Hz, 1H)8.23(d, J=2.9Hz, 1H)8.25(s, 1H)9.24(s, 1H). MS ESI posi:363(M+ H] + . MS ESI nega:361[MH] - Melting point: 121.2°C (TG-DTA) The following Example 1-2 uses the compound obtained in Reference Example 1-1 and the compound obtained in Reference Example 2-4, and was synthesized according to the method described in Example 1-1 . The structure, NMR data, and MS data of these compounds are shown in Table 5-1.
Figure 02_image351
Example 2-1 2,2-bis(hydroxymethyl)-10-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxydecanoic acid
Figure 02_image353
(1) Using the compound (87 mg) obtained in Reference Example 4-1, the reaction was carried out according to the method described in Example 1-1-1 (1) to obtain 2,2-bis(methoxymethyl)-10- A mixture of [6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxydecane nitrile (134 mg). (2) To the mixture (134 mg) obtained in the above (1), concentrated hydrochloric acid (620 μL) was added, and the mixture was stirred at 130°C for 3 hours and 140°C for 1 hour under microwave irradiation. The mixture was purified by preparative HPLC to obtain the title compound (18 mg) as a colorless solid. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.14-1.47(m, 14H)1.69-1.79(m, 2H)3.43-3.48(m, 2H)3.49-3.54(m, 2H)4.10(t, J=6.3 Hz, 2H)7.64-7.69( m, 1H)7.79(d, J=8.8Hz, 1H)8.21-8.24(m, 1H)8.24(s, 1H)9.24(s, 1H). MS ESI posi:393[M+H] + . MS ESI nega:391[MH] - . Example 3-1 3-[8-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxyoctyl]oxetane-3-carboxylic acid
Figure 02_image355
(1) Using the compound (45 mg) obtained in Reference Example 6-1, the reaction was carried out according to the method described in Reference Example 1-1-1(1) to obtain 3-[8-[6-(1,2,4- Mixture of methyl triazol-1-yl)pyridin-3-yl]oxyoctyl]oxetane-3-carboxylate (140 mg). (2) The mixture (140 mg) obtained in (1) above was suspended in methanol (1.8 mL), a 1 mol/L sodium hydroxide aqueous solution (387 μL) was added, and the mixture was stirred overnight at room temperature. The mixture was refined by preparative HPLC. The fraction containing the target product was concentrated, and the obtained solid was suspended in diethyl ether and stirred, and then filtered to obtain the title compound (42 mg) as a colorless solid. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.13-1.47(m, 10H)1.70-1.79(m, 2H)1.85-1.93(m, 2H)4.10(t, J=6.4Hz, 2H)4.32(d, J= 5.9Hz, 2H)4.68 (d, J=5.9Hz, 2H)7.67(dd, J=8.9, 2.7Hz, 1H)7.80 (d, J=8.9Hz, 1H)8.23(d, J=2.7Hz, 1H)8.25(s, 1H )9.24(s, 1H). MS ESI posi:375[M+H] + . MS ESI nega:373[MH] - The following examples 3-2~3-38 are reference examples 2-1~2-2, 2-5, 3-1, 5-1, 7-1~7-2, 8-1, 9- 1, 10-1, 11-1, 12-1~12-2, 13-1~13-2, 14-1, 15-1~15-11, 15-16~15-20, 16-1~ The compound obtained at 16-3, 17-2, or 18-1 was synthesized according to the method described in Example 3-1. The structure, NMR data, and MS data of these compounds are shown in Table 6-1~Table 6-5.
Figure 02_image357
Figure 02_image359
Figure 02_image361
Figure 02_image363
Figure 02_image365
Example 4-1 4-Methoxy-6-[4-[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxybutyl]pyridine-2-carboxylic acid
Figure 02_image367
(1) In a nitrogen environment, a toluene (840 μL) solution of the compound (40 mg) and triphenylphosphine (66 mg) obtained in Reference Example 15-12 was cooled with ice, and azodicarboxylic acid bis(2- Methoxyethyl) ester (59 mg) and the compound (29.8 mg) obtained in Reference Example 1-1. After the mixture was stirred at room temperature for 15 hours, it was concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (n-hexane: acetic acid = 22: 3 ~ ethyl acetate only) to obtain 4-methoxy-6-[4-[6-( A mixture of methyl 1,2,4-triazol-1-yl)pyridin-3-yl]oxybutyl]pyridine-2-carboxylate (80 mg). (2) Using the mixture (80 mg) obtained in (1) above, the reaction was carried out according to the method described in Example 3-1-1 (2) to obtain the title compound (3 mg) as a colorless solid. 1 H NMR(400 MHz, DMSO-d 6 )δ ppm 1.74-1.92(m, 4H)2.82(t, J=7.5Hz, 2H)3.88(s, 3H)4.16(t, J=5.7Hz, 2H)7.05-7.11(m, 1H)7.34-7.40 (m, 1H)7.65-7.71(m, 1H)7.79(d, J=9.0Hz, 1H)8.20-8.27(m, 2H)9.24(s, 1H). MS ESI posi:370[M+H] + . MS ESI nega:368[MH] - The following Examples 4-2 to 4-4 are compounds obtained using Reference Examples 15-13 to 15-15, and were synthesized according to the method described in Example 4-1. The structure, NMR data, and MS data of these compounds are shown in Table 7-1.
Figure 02_image369
Example 5-1 2-Methyl-7-[[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxymethyl]-3,4-dihydrochromene -2-carboxylic acid
Figure 02_image371
(1) To a solution of the compound (73 mg) obtained in Reference Example 7-3 in acetone (3 mL), the compound (37.8 mg) obtained in Reference Example 1-1, N,N-dimethylformamide ( 1 mL), and potassium carbonate (83.8 mg) were stirred at room temperature for 16 hours. The insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel permeation chromatography (n-hexane: ethyl acetate=9:1~3:2) to obtain 2-methyl-7-[[6-(1, 2,4-Triazol-1-yl)pyridin-3-yl]oxymethyl]-3,4-dihydrochromene-2-carboxylic acid ethyl ester (86mg) is a colorless amorphous substance. (2) Using the compound (84 mg) obtained in (1) above, the reaction was carried out according to the method described in Example 3-1-1 (2) to obtain the title compound (68 mg) as a colorless solid. 1 H NMR(400 MHz, DMSO-d 6 )δ ppm 1.59(s, 3H)1.82-1.94(m, 1H)2.39(dt, J=13.6, 4.6Hz, 1H)2.71-2.79(m, 2H)5.15(s, 2H) 6.90-6.97(m, 2H)7.06(d, J=7.6Hz, 1H)7.63(dd, J=8.9, 2.5Hz, 1H)7.84(d, J=8.9 Hz, 1H)8.13(s, 1H)8.22(d, J=2.5 Hz, 1H) 9.19(s, 1H). MS ESI posi:367[M+H] + . MS ESI nega:365[MH] - The following Example 5-2 is a compound obtained using Reference Example 17-1, and was synthesized according to the method described in Example 5-1. The structure, NMR data, and MS data of these compounds are shown in Table 8-1.
Figure 02_image373
Example 6-1 2,2-Dimethyl-4-[[3-[[6-(1,2,4-triazol-1-yl)pyridin-3-yl]oxymethyl]benzyl Amino]butanoic acid
Figure 02_image375
(1) Using commercially available methyl 3-(bromomethyl)benzoate (210 mg), the reaction was carried out according to the method described in Example 5-1-1 (1) to obtain 3-[[6-(1,2, 4-triazol-1-yl)pyridin-3-yl]oxymethyl]benzoic acid methyl ester (257 mg) as a colorless solid. (2) Using the compound (257 mg) obtained in (1) above, the reaction was carried out according to the method described in Example 3-1-1 (2) to obtain 3-[[6-(1,2,4-triazole-1 -Yl)pyridin-3-yl]oxymethyl]benzoic acid (207 mg) as a colorless solid. (3) To 4-amino-2,2-dimethylbutanoic acid methyl ester hydrochloride (77mg) in N,N-dimethylformamide (1mL) solution, add triethylamine ( 150μL), the compound obtained in (2) above (63mg), N-hydroxybenzotriazole monohydrate (33mg), and 1-(3-dimethylaminopropyl)-3-ethylcarba Imine hydrochloride (61 mg) was stirred at room temperature for 20 hours. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was passed through a phase separation device and concentrated under reduced pressure. The residue obtained was purified by silica gel permeation chromatography (only n-hexane~n-hexane: ethyl acetate=3:7) to obtain 2,2-dimethyl-4-[[3 -[[6-(1,2,4-Triazol-1-yl)pyridin-3-yl]oxymethyl]benzyl]amino]butanoic acid methyl ester (65mg) as a colorless oil substance. (4) Using the compound (63 mg) obtained in (3) above, the reaction was carried out according to the method described in Example 3-1-1 (2) to obtain the title compound (19 mg) as a colorless solid. 1 H NMR(400 MHz, DMSO-d 6 )δ ppm 1.14(s, 6H)1.71-1.79(m, 2H)3.22-3.28(m, 2H)5.31(s, 2H)7.46-7.53(m, 1H)7.63(d, J= 7.7Hz, 1H) 7.74-7.86(m, 3H)7.96(s, 1H)8.25(s, 1H)8.31-8.35 (m, 1H)8.53-8.64(m, 1H)9.25(s, 1H). MS ESI posi:410[M +H] + . MS ESI nega:408[MH] - . Example 7-1 2-Methyl-2-[7-(6-pyrimidin-5-ylpyridin-3-yl)oxyheptyloxy]propane acid
Figure 02_image377
(1) Using 2-bromo-4-hydroxypyridine (760 mg) and the compound (1.0 g) obtained in Reference Example 2-3, the reaction was carried out according to the method described in Example 1-1-1 (1) to obtain 2-[ 7-(6-Bromopyridin-3-yl)oxyheptyloxy]-2-methylpropane acid tert-butyl ester (1.4g) is a colorless oily substance. (2) Using the compound (200 mg) obtained in (1) above, the reaction was carried out according to the method described in Reference Example 21-1-(2) to obtain 2-methyl-2-[7-(6-pyrimidine-5- Pyridin-3-yl)oxyheptyloxy]propanoic acid tert-butyl ester (67mg) is a colorless oily substance. (3) Using the compound (67 mg) obtained in (2) above, the reaction was carried out according to the method described in Example 1-1-1 (2) to obtain the title compound (16 mg) as a colorless solid. 1 H NMR(400 MHz, DMSO-d 6 )δ ppm 1.28(s, 6 H)1.30-1.54(m, 8H)1.70-1.81(m, 2H)3.28-3.34(m, 2H)4.12(t, J=6.5Hz, 2H) 7.56(dd, J =8.7, 2.8Hz, 1H)8.09(d, J=8.7Hz, 1H)8.44(d, J=2.8Hz, 1H)9.18(s, 1H)9.38(s, 2H). MS ESI posi:374(M +H] + . MS ESI nega:372[MH] - . Example 8-1 2-[7-[6-(1H-imidazol-5-yl)pyridin-3-yl]oxyheptyloxy]-2-methylpropane acid
Figure 02_image379
(1) Using 1-(5-hydroxypyridin-2-yl)ethanone (110 mg) and the compound (260 mg) obtained in Reference Example 2-3, the reaction was carried out according to the method described in Example 1-1-1 (1) , A colorless oily substance of 2-[7-(6-acetylpyridin-3-yl)oxyheptyloxy]-2-methylpropane acid tert-butyl ester (280 mg) was obtained. (2) Using the compound (270 mg) obtained in the above (1), the reaction was carried out according to the method described in Reference Example 22-1 to obtain 2-[7-[6-(2-bromoacetinyl)pyridin-3-yl ]Oxyheptyloxy]-2-methylpropanoic acid tert-butyl ester (175mg) is a colorless oily substance. (3) A suspension of formamide (370 µL) of the compound (175 mg) obtained in (2) above was stirred at 170°C for 2 hours. After cooling the reaction liquid to room temperature, it was purified by preparative HPLC. The concentrated fraction was solidified with ethyl ether to obtain the title compound (20 mg) as a colorless solid. 1 H NMR(400MHz, DMSO-d 6 )δ ppm 1.29(s, 6H)1.30-1.53(m, 8H)1.67-1.77(m, 2H)3.35-3.42(m, 2H)4.04(t, J=6.4 Hz, 2H) 7.33-7.44(m, 1H)7.46-7.55(m, 1H)7.67(s, 1H)7.71-7.82(m, 1H) 8.16-8.24(m, 1H). MS ESI posi:362[M+H] + . MS ESI nega:360[MH] - The inhibitory effect of the 20-HETE producing enzyme of the compound of the present invention was measured by the method described in Test Example 1 below. Test Example 1 (1) Inhibition test of 20-HETE-producing enzymes (CYP4F2 and CYP4A11) of each compound of the present invention In the CYP4F2 inhibition test, the coliform membrane portion (100μg/mL protein) expressing human CYP4F2 was added containing each compound Reaction solution [final concentration 50mM KPO 4 (pH7.4), 2.5μM luciferin derivative, and 1mM NADPH], after the CYP4A11 inhibition test, the coliform membrane portion (100μg/mL protein) expressing human CYP4A11 was added to the reaction solution containing each compound [final concentration 100mM Tris-HCl (pH7.5), 60μM luciferin derivative, 1.3mM NADP + , 3.3mM Glucose 6-Phosphate, 3.3mM MgCl 2 , And 0.4U/mL Glucose 6-Phosphate dehydrogenase], then let it stand at room temperature for 60 minutes to perform enzyme reaction. After the reaction, the luciferin detection reagent is added, and the luminescence value is measured using a plate reader. Using this value, the 20-HETE-producing enzyme inhibition rate (%) is calculated according to the following formula, and the 50% inhibition concentration (IC 50 value). 20-HETE production enzyme inhibition rate (%)=[1-(AB)/(CB)]*100 A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: When compound is not added Luminescence value (2) results The inhibitory activity of each compound of the present invention on CYP4F2 and CYP4A11 is shown in the following Table 9-1 to Table 9-2.
Figure 02_image381
Figure 02_image383
In addition, the effect of the compound of the present invention on the enzyme that inhibits the production of 20-HETE can also be measured by the method described in Test Example 2 below. Test Example 2 (1) Inhibition test of 20-HETE-producing enzyme using human kidney microsomes of each compound of the present invention In human kidney microsomes (250μg/mL protein), a reaction solution containing each compound was added [final concentration 100mM KPO 4 (pH7.4), 20μM Arachidonic acid, 4mM NADPH], and then let it stand at 37°C for 45 minutes to perform a 20-HETE generation reaction. After the reaction was stopped by adding formic acid, 9 times the amount of acetonitrile was added, and the protein was removed by centrifugation (1000 rpm, 4°C, 10 minutes). After that, liquid chromatography-tandem mass spectrometer (LC-MS/MS) was used to measure the peak area value of 20-HETE, and using this value, the 20-HETE-producing enzyme inhibition rate (%) was calculated according to the following formula , Calculate the 50% inhibitory concentration (IC 50 value). 20-HETE production enzyme inhibition rate (%)=[1-(AB)/(CB)]*100 A: 20-HETE peak area value when compound is added / peak area value of internal standard substance B: compound and NADPH The peak area value of 20-HETE when not added/the peak area value of the internal standard material C: The peak area value of 20-HETE when the compound is not added/the peak area value of the internal standard material (2) Results Each compound of the present invention The inhibitory activity of 20-HETE producing enzyme is shown in Table 10-1 below.
Figure 02_image385
Test Example 3 CYP selectivity test for each compound of the present invention (1) CYP4F22 selectivity test for each compound of the present invention was performed on the cell membrane portion (30 μg/mL protein) expressing human CYP4F22, and the reaction solution containing each compound was added [Final Concentration 100mM KPO 4 (pH 7.4), 14 μM luciferin derivative, and 1 mM NADPH], then let it stand at room temperature for 50 minutes to perform an enzyme reaction. After the reaction, the luciferin detection reagent is added, and the luminescence value is measured using a plate reader. Using this value, the enzyme reaction inhibition rate (%) of CYP4F22 was calculated according to the following formula, and the 50% inhibition concentration (IC 50 value). CYP4F22 Enzyme inhibition rate (%)=[1-(AB)/(CB)]*100 A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: Luminescence value when compound is not added ( 2) Results The inhibitory activity of each compound of the present invention on CYP4F22 is shown in Table 11-1 below.
Figure 02_image387
(3) The CYP4V2 selectivity test of each compound of the present invention was performed on the cell membrane part (38μg/mL protein) expressing human CYP4V2, and the reaction solution containing each compound was added [final concentration 100mM KPO 4 (pH 7.4), 7 μM luciferin derivative, and 1 mM NADPH], then let it stand at room temperature for 40 minutes to perform an enzyme reaction. After the reaction, the luciferin detection reagent is added, and the luminescence value is measured using a plate reader. Using this value, the enzyme reaction inhibition rate (%) of CYP4V2 was calculated according to the following formula, and the 50% inhibition concentration (IC 50 value). CYP4V2 Enzyme inhibition rate (%)=[1-(AB)/(CB)]*100 A: Luminescence value when compound is added B: Luminescence value when compound and enzyme are not added C: Luminescence value when compound is not added ( 4) Results The inhibitory activity of each compound of the present invention on CYP4V2 is shown in Table 11-2 below.
Figure 02_image389
In addition, the same method can also be used to calculate the 90% inhibition concentration (IC 90 value). Due to circumstances, it may be better to use 90% barrier concentration as the index. Test Example 4 (1) Evaluation test of the in vivo stability of each compound of the present invention According to the following method, the plasma half-life can be calculated. Each compound was dissolved in a 10% HP-β-CD aqueous solution (0.5mg/mL) and administered intravenously to rats (Sprague-Dawley (SD), male, 7 weeks old, fasted, dosage: 0.5 mg /kg). Blood was collected from the tail vein at each blood collection time, and plasma was collected by centrifugation. The quantitative analysis of each compound in the plasma was performed using LC-MS/MS. Half-life in plasma (t 1/2eff )Phoenix WinNonlin (Certara) can be used, and the clearance rate (CL) and volume of distribution (Vd ss ) Is calculated according to the following formula. t 1/2eff =LN(2)/(CL/Vd ss ) And each compound of the present invention also has a higher selectivity for CYP4F2 and CYP4A11 than 20-HETE producing enzymes (CYP4F2 and CYP4A11) which are CYP4F22 and CYP4V2 of the same family. These compounds are expected to be medicines with strong efficacy and low side effects risk. In addition, the effectiveness of each compound of the present invention can be confirmed using model animals such as mice or rats. For example, it can be achieved by confirming the suppression of 20-HETE production in the kidney or the improvement of polycystic kidney disease. [Industrial Applicability] The compound of the present invention has an excellent effect of inhibiting the production of 20-HETE enzymes. Through the present invention, it is expected to provide effective prevention or treatment of polycystic kidney-derived diseases, etc., and reduce the burden on patients , And promote the pharmaceutical industry.

Figure 109103944-A0101-11-0002-8
Figure 109103944-A0101-11-0002-8

Claims (22)

一種下述式[I’] 所表示之化合物或其製藥學上所容許之鹽，
Figure 03_image001
{上述式[I’]中， 環D為式[I’-1]~式[I’-3]所表示之基之任一
Figure 03_image003
； R1 為氫原子、氟原子、氯原子、或甲基； R2 、R3 、及R4 獨立地為氫原子、氟原子、或甲基； X為式-O-、式-S-、或式-CH2 -； R5 為下述式群[II]所表示之構造之任一
Figure 03_image005
； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III]所表示之構造之任一
Figure 03_image007
， 在此， 式[III-4]表示之構造可被1~2個羥基取代， 又，環C為 (i)C3-6 環烷烴、 (ii)含有氧原子的4到6員之飽和的雜環、或 (iii)含有硫原子的4到6員之飽和的雜環(該含有硫原子的4到6員之飽和的雜環的硫原子可被1~2個側氧基取代)； Y為式-CH2 -、式-CHMe-、式-CMe2 -、或式-O-； W1 為C2-10 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基或羧基甲基； 環A為下述式群[IV]所表示之構造之任一
Figure 03_image009
， 在此， 前述式[IV-1]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-5]所表示之構造可被1個甲基取代； W2 為C4-8 烷烴二基； (C) R5 為前述式[II-3]所表示之構造時； 環B為 (a)苯基、 (b)吡啶基、或 (c)苯並二氫吡喃基； W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基、 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-6 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子、氟原子、氯原子、或甲基； (b)環B為吡啶基時， R53 係選自 (i)羧基、 (ii)被羧基取代的C1-4 烷基 (iii)被羧基取代的C3-6 環烷基、 (iv)被羧基取代的單C1-4 烷基胺基羰基、及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基； 此時，R61 及R62 獨立地為氫原子或甲基}。A compound represented by the following formula [I'] or a pharmaceutically acceptable salt thereof,
Figure 03_image001
{In the above formula [I'], ring D is any one of the groups represented by the formula [I'-1]~the formula [I'-3]
Figure 03_image003
; R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group; R 2 , R 3 , and R 4 are independently a hydrogen atom, a fluorine atom, or a methyl group; X is a formula -O-, a formula -S- , Or formula -CH 2 -; R 5 is any one of the structures represented by the following formula group [II]
Figure 03_image005
; (A) When R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III]
Figure 03_image007
Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups, and ring C is (i) C 3-6 cycloalkane, (ii) saturated with 4 to 6 members containing oxygen atoms Or (iii) a 4- to 6-membered saturated heterocyclic ring containing a sulfur atom (the sulfur atom of the 4- to 6-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 pendant oxy groups) ; Y is formula -CH 2 -, formula -CHMe-, formula -CMe 2 -, or formula -O-; W 1 is C 2-10 alkanediyl; (B) R 5 is the aforementioned formula [II-2] When the structure is represented; R 52 is a carboxyl group or a carboxymethyl group; Ring A is any of the structures represented by the following formula group [IV]
Figure 03_image009
Here, the structure represented by the aforementioned formula [IV-1] may be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, and the aforementioned formula [IV-2] The structure may be substituted by one group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group. The structure represented by the aforementioned formula [IV-5] may be substituted by one methyl group; W 2 is C 4 -8 Alkane diyl; (C) When R 5 is the structure represented by the aforementioned formula [II-3]; Ring B is (a) phenyl, (b) pyridyl, or (c) chroman W 3 is a C 1-3 alkanediyl group; here, (a) when ring B is a phenyl group, R 53 is selected from (i) a carboxy group, (ii) a C 1-4 alkyl group substituted by a carboxy group, (iii) C 3-6 cycloalkyl substituted with carboxy, (iv) mono C 1-6 alkylaminocarbonyl substituted with carboxy, and (v) C 1-4 alkoxy substituted with carboxy In this case, R 61 and R 62 are independently a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group; (b) When ring B is a pyridyl group, R 53 is selected from (i) a carboxyl group, (ii) C 1-4 alkyl substituted with carboxy (iii) C 3-6 cycloalkyl substituted with carboxy, (iv) mono C 1-4 alkylaminocarbonyl substituted with carboxy, and (v) substituted with carboxy C 1-4 alkoxy group constituted; At this time, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (c) when B is a ring-chromanyl, R 53 is carboxy or Carboxymethyl; In this case, R 61 and R 62 are independently a hydrogen atom or a methyl group}. 如請求項1記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I’]中， 環D為前述式[I’-1]所表示之基， 前述式[I’]為下述式[I]：
Figure 03_image011
。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I'], ring D is the group represented by the aforementioned formula [I'-1], and the aforementioned formula [I'] is The following formula [I]:
Figure 03_image011
. 如請求項1記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I’]中， X為式-O-。Such as the compound described in claim 1 or its pharmaceutically acceptable salt, in which: In the aforementioned formula [I’], X is the formula -O-. 如請求項2記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中， X為式-O-。Such as the compound described in claim 2 or its pharmaceutically acceptable salt, in which, In the aforementioned formula [I], X is the formula -O-. 如請求項4記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； R1 為氫原子； R2 為氫原子、 R3 為氫原子、 R4 為氫原子； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’]所表示之構造之任一
Figure 03_image013
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R53 為羧基或羧基甲基； 環A為下述式群[IV’]所表示之構造之任一
Figure 03_image015
， 在此， 前述式[IV-2]所表示之構造可被由鹵素原子、甲基、及甲氧基所成群組中選出的1個基取代， 前述式[IV-5]所表示之構造可被1個甲基取代； W2 為C4-6 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-3 烷烴二基； 在此， (a)環B為苯基時， R53 係選自 (i)羧基、 (iii)被羧基取代的C3-6 環烷基、及 (iv)被羧基取代的單C1-6 烷基胺基羰基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (b)環B為吡啶基時， R53 係選自 (iii)被羧基取代的C3-6 環烷基及 (v)被羧基取代的C1-4 烷氧基 所構成的群； 此時，R61 及R62 獨立地為氫原子或氟原子； (c)環B為苯並二氫吡喃基時， R53 為羧基或羧基甲基； 此時，R61 及R62 獨立地為氫原子或甲基。The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 is a hydrogen atom, and R 4 is a hydrogen atom; (A) When R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III']
Figure 03_image013
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group; (B) R When 5 is the structure represented by the aforementioned formula [II-2]; R 53 is a carboxyl group or a carboxymethyl group; Ring A is any of the structures represented by the following formula group [IV']
Figure 03_image015
Here, the structure represented by the aforementioned formula [IV-2] can be substituted by a group selected from the group consisting of a halogen atom, a methyl group, and a methoxy group, and the aforementioned formula [IV-5] The structure can be substituted by 1 methyl group; W 2 is a C 4-6 alkane diyl group; (C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is a C 1-3 alkane diyl group; Here, (a) when ring B is a phenyl group, R 53 is selected from (i) a carboxy group, (iii) a C 3-6 cycloalkyl group substituted with a carboxy group, and (iv) a mono C 1- substituted with a carboxy group. 6 Alkylaminocarbonyl groups; in this case, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (b) when ring B is a pyridyl group, R 53 is selected from (iii) substituted with a carboxyl group A group consisting of a C 3-6 cycloalkyl group and (v) a C 1-4 alkoxy group substituted with a carboxyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a fluorine atom; (c) ring B is In the case of the chroman group, R 53 is a carboxyl group or a carboxymethyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. 如請求項5記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 03_image017
， 在此， 前述式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 03_image019
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。The compound described in claim 5 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (A) when R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any of the structures represented by the following formula group [III”]
Figure 03_image017
Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is C 7 alkane diyl; (B) R 5 When it is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 03_image019
, Here, the structure represented by the aforementioned formula [IV-6] can be substituted by a group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 is a C 4 alkanediyl group; ( C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is C 1-2 alkanediyl; here, (c) when ring B is chromanyl, the benzo The dihydropyranyl group is a pyran-7-yl group; R 53 is a carboxyl group; in this case, R 61 and R 62 are independently a hydrogen atom or a methyl group. 如請求項6記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造；且 R51 為羧基； L為下述式群[III”]所表示之構造之任一
Figure 03_image021
， 在此， 式[III-4]表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基。The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (A) R 5 is the structure represented by the aforementioned formula [II-1]; and R 51 is a carboxyl group; L is any of the structures represented by the following formula group [III”]
Figure 03_image021
Here, the structure represented by the formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group. 如請求項6記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 03_image023
， 在此， 前述式[IV-6]所表示之構造可被由氟原子、甲基、及甲氧基所成群組中選出的1個基取代； W2 為C4 烷烴二基。The compound described in claim 6 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (B) when R 5 is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 03_image023
Here, the structure represented by the aforementioned formula [IV-6] may be substituted by one group selected from the group consisting of a fluorine atom, a methyl group, and a methoxy group; W 2 is a C 4 alkanediyl group. 如請求項6記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-7-基； R53 為羧基； 此時，R61 及R62 獨立地為氫原子或甲基。The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is C 1 -2 alkanediyl; here, (c) when ring B is a chromanyl group, the chromanyl group is a pyran-7-yl group; R 53 is a carboxyl group; in this case, R 61 And R 62 is independently a hydrogen atom or a methyl group. 如請求項5記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造時； R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 03_image025
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基； (B) R5 為前述式[II-2]所表示之構造時； R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 03_image027
， 在此， 前述式[IV-6]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 同是氫原子。The compound described in claim 5 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (A) when R 5 is the structure represented by the aforementioned formula [II-1]; R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 03_image025
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group; (B) R When 5 is the structure represented by the aforementioned formula [II-2]; R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 03_image027
, Here, the structure represented by the aforementioned formula [IV-6] can be substituted by one methyl group; W 2 is a C 4 alkanediyl group; (C) R 5 is the structure represented by the aforementioned formula [II-3]; And W 3 is a C 1-2 alkanediyl group; here, (c) when ring B is a chroman group, the chroman group is a pyran-6-yl group or a pyran-7 group -Group; R 53 is a carboxyl group; in this case, R 61 and R 62 are both hydrogen atoms. 如請求項10記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (A) R5 為前述式[II-1]所表示之構造；且 R51 為羧基； L為下述式群[III’”]所表示之構造之任一
Figure 03_image029
； 在此， 前述式[III-4]所表示之構造可被1~2個羥基取代； Y為式-CH2 -或式-O-； W1 為C7 烷烴二基。The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (A) R 5 is the structure represented by the aforementioned formula [II-1]; and R 51 is a carboxyl group; L is any one of the structures represented by the following formula group [III'”]
Figure 03_image029
; Here, the structure represented by the aforementioned formula [III-4] can be substituted by 1 to 2 hydroxyl groups; Y is the formula -CH 2 -or the formula -O-; W 1 is a C 7 alkanediyl group. 如請求項10記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (B) R5 為前述式[II-2]所表示之構造；且 R52 為羧基； 環A為下述式[IV-6]所表示之構造
Figure 03_image031
， 在此， 前述式[IV-6]所表示之構造可被1個甲基取代； W2 為C4 烷烴二基。The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (B) R 5 is the structure represented by the aforementioned formula [II-2]; and R 52 is a carboxyl group; Ring A is the structure represented by the following formula [IV-6]
Figure 03_image031
Here, the structure represented by the aforementioned formula [IV-6] may be substituted by one methyl group; W 2 is a C 4 alkanediyl group. 如請求項10記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I]中； (C) R5 為前述式[II-3]所表示之構造；且 W3 為C1-2 烷烴二基； 在此， (c)環B為苯並二氫吡喃基時， 該苯並二氫吡喃基為吡喃-6-基或吡喃-7-基； R53 為羧基； 此時，R61 及R62 同是氫原子。The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein, in the aforementioned formula [I]; (C) R 5 is the structure represented by the aforementioned formula [II-3]; and W 3 is C 1 -2 alkanediyl; here, (c) when ring B is chromanyl, the chromanyl group is pyran-6-yl or pyran-7-yl; R 53 is Carboxy; In this case, R 61 and R 62 are both hydrogen atoms. 如請求項3記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I’]中， 環D為前述式[I’-2]所表示之基。Such as the compound described in claim 3 or a pharmaceutically acceptable salt thereof, in which: In the aforementioned formula [I’], Ring D is a group represented by the aforementioned formula [I'-2]. 如請求項3記載之化合物或其製藥學上所容許之鹽，其中， 前述式[I’]中， 環D為前述式[I’-3]所表示之基。Such as the compound described in claim 3 or a pharmaceutically acceptable salt thereof, in which: In the aforementioned formula [I’], Ring D is a group represented by the aforementioned formula [I'-3]. 如請求項1~4中任1項記載之化合物或其製藥學上所容許之鹽，其如以下所示
Figure 03_image033
Figure 03_image035
Figure 03_image037
。The compound described in any one of claims 1 to 4 or its pharmaceutically acceptable salt is as follows
Figure 03_image033
Figure 03_image035
Figure 03_image037
. 如請求項1~4中任1項記載之化合物或其製藥學上所容許之鹽，其如以下所示
Figure 03_image039
。The compound described in any one of claims 1 to 4 or its pharmaceutically acceptable salt is as follows
Figure 03_image039
. 如請求項1~3、14中任1項記載之化合物或其製藥學上所容許之鹽，其如以下所示
Figure 03_image041
。The compound described in any one of claims 1 to 3 and 14 or a pharmaceutically acceptable salt thereof is as follows
Figure 03_image041
. 如請求項1~3、15中任1項記載之化合物或其製藥學上所容許之鹽，其如以下所示
Figure 03_image043
。The compound described in any one of claims 1 to 3, 15 or a pharmaceutically acceptable salt thereof is as follows
Figure 03_image043
. 一種醫藥，其係含有請求項1~19中任1項記載之化合物或其製藥學上所容許之鹽作為有效成分。A medicine containing the compound described in any one of Claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. 一種20-HETE產生酵素阻礙劑，其係含有請求項1~19中任1項記載之化合物或其製藥學上所容許之鹽作為有效成分。A 20-HETE production enzyme inhibitor, which contains the compound described in any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. 一種多囊腎的預防或改善劑，其係含有請求項1~19中任1項記載之化合物或其製藥學上所容許之鹽作為有效成分。A preventive or ameliorating agent for polycystic kidney disease, which contains the compound described in any one of Claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient.
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