TW201400472A - 5-hydroxyprimidine-4-carboxamide derivatives - Google Patents

5-hydroxyprimidine-4-carboxamide derivatives Download PDF

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TW201400472A
TW201400472A TW102111317A TW102111317A TW201400472A TW 201400472 A TW201400472 A TW 201400472A TW 102111317 A TW102111317 A TW 102111317A TW 102111317 A TW102111317 A TW 102111317A TW 201400472 A TW201400472 A TW 201400472A
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piperidin
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Naoki Tanaka
Takashi Ishiyama
Riki Goto
Takeshi Fukuda
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Daiichi Sankyo Co Ltd
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Abstract

Provided is a compound which is able to enhance production of an erythropoietin. Provided is a compound represented by formula (1) [in the formula (1), R1: formula(1A) [in the formula(1A), R4, R5: H, halogen, alkyl; R6: H, halogen, alkyl, etc.; R7: substitutable alkanoyl alkyl, substitutable [(alkoxycarbonyl) amino]alkyl, substitutable [(alkyl carbamoyl)oxy] alkyl, etc.; substituent groups α : oxo, hydroxy, amino, etc.; ring Q1: monocyclic heterocycle; ring Q2: monocyclic hydrocarbon ring group, monocyclic heterocycle; ring Q3: monocyclic hydrocarbon ring group, monocyclic heterocycle; X: single bond, methylene, ethylene; R2: alkyl, methylsulfanyl; R3: H, methyl].

Description

5-羥基嘧啶-4-甲醯胺衍生物 5-hydroxypyrimidine-4-carboxamide derivative

本發明係關於一種具有增強紅血球生成素產生活性之低分子化合物。 The present invention relates to a low molecular compound having an activity of enhancing erythropoietin production.

紅血球生成素(以下稱為EPO)係在紅血球造血中不可或缺之糖蛋白荷爾蒙，通常由腎臓所分泌，藉由作用於骨髓之紅血球系幹細胞以促進紅血球之產生。就伴隨內因性EPO生產低下而來的疾病(例如慢性腎功能不全)等而言，由於紅血球產生之低下而呈現貧血症狀，故有施行藉由基因重組人類EPO之補充療法。然而，基因重組人類EPO為人所詬病之缺點為生物製劑的高額醫療、因注射劑而便利性不佳、有抗原性等。 Erythropoietin (hereinafter referred to as EPO) is a glycoprotein hormone indispensable in hematopoietic hematopoiesis, usually secreted by the renal pelvis, which promotes the production of red blood cells by acting on the red blood cell stem cells of the bone marrow. In the case of a disease caused by low production of endogenous EPO (for example, chronic renal insufficiency), anemia is caused by a decrease in red blood cell production, and supplemental therapy by genetically recombined human EPO is performed. However, the shortcomings of genetically recombinant human EPO are human diseases, such as high medical treatment of biological agents, poor convenience due to injections, and antigenicity.

另一方面，作為低分子之EPO衍生劑，已知的有吡啶衍生物、啉衍生物、喹啉衍生物及異喹啉衍生物(參照專利文獻1~6、8)、6-羥基-2,4-二側氧四氫嘧啶衍生物(參照專利文獻7)、4-羥基嘧啶-5-甲醯胺衍生物(參照專利文獻9)、5-羥基嘧啶-4-甲醯胺衍生物(參照專利文獻10~14)等之化合物。 On the other hand, as a low molecular EPO derivatizing agent, a pyridine derivative is known, a porphyrin derivative, a quinoline derivative, and an isoquinoline derivative (see Patent Documents 1 to 6, 8), and a 6-hydroxy-2,4-di- oxytetrahydropyrimidine derivative (see Patent Document 7), 4- A compound such as a hydroxypyrimidine-5-formamide derivative (see Patent Document 9) or a 5-hydroxypyrimidine-4-carboxamide derivative (see Patent Documents 10 to 14).

先前技術文獻 Prior technical literature 專利文獻 Patent literature

專利文獻1 國際公開第2003/049686號小冊子 Patent Document 1 International Publication No. 2003/049686

專利文獻2 國際公開第2003/053997號小冊子 Patent Document 2 International Publication No. 2003/053997

專利文獻3 國際公開第2004/108681號小冊子 Patent Document 3 International Publication No. 2004/108681

專利文獻4 國際公開第2006/133391號小冊子 Patent Document 4 International Publication No. 2006/133391

專利文獻5 國際公開第2007/038571號小冊子 Patent Document 5 International Publication No. 2007/038571

專利文獻6 國際公開第2007/136990號小冊子 Patent Document 6 International Publication No. 2007/136990

專利文獻7 國際公開第2007/150011號小冊子 Patent Document 7 International Publication No. 2007/150011

專利文獻8 國際公開第2008/002576號小冊子 Patent Document 8 International Publication No. 2008/002576

專利文獻9 國際公開第2009/117269號小冊子 Patent Document 9 International Publication No. 2009/117269

專利文獻10 國際公開第2009/131127號小冊子 Patent Document 10 International Publication No. 2009/131127

專利文獻11 國際公開第2009/131129號小冊子 Patent Document 11 International Publication No. 2009/131129

專利文獻12 國際公開第2011/049126號小冊子 Patent Document 12 International Publication No. 2011/049126

專利文獻13 國際公開第2011/049127號小冊子 Patent Document 13 International Publication No. 2011/049127

專利文獻14 國際公開第2011/132633號小冊子 Patent Document 14 International Publication No. 2011/132633

本發明者們進行以提供一種具有優異的增強EPO產生的活性、且可有效治療起因於EPO低下之疾病的低分子之新穎化合物，且進一步提供含有這些化合物的醫藥為目的的研究。 The present inventors conducted studies aimed at providing a novel compound having an excellent activity for enhancing the production of EPO, and being effective for treating a low molecular compound which is caused by a disease caused by EPO, and further providing a medicine containing these compounds.

本發明者們為了解決上述之課題，發現具有5-羥基嘧啶-4-甲醯胺結構之新穎化合物具有優異的增強EPO產生的活性，可有效治療起因於EPO低下之疾病，進而完成本發明。 In order to solve the above problems, the present inventors have found that a novel compound having a 5-hydroxypyrimidine-4-carboxamide structure has an excellent activity for enhancing EPO production, and can effectively treat a disease caused by EPO deficiency, thereby completing the present invention.

根據本發明，可提供以下述之通式(1)表示之新穎的5-羥基嘧啶-4-甲醯胺化合物或其藥理上容許鹽(以下稱為本發明之化合物)。 According to the present invention, a novel 5-hydroxypyrimidine-4-carboxamide compound represented by the following formula (1) or a pharmacologically acceptable salt thereof (hereinafter referred to as a compound of the present invention) can be provided.

即本發明為：[1]一種以通式(1)表示之化合物或其藥理上容許鹽， That is, the present invention is: [1] a compound represented by the formula (1) or a pharmacologically acceptable salt thereof,

[通式(1)中，R1表示以下述之通式(1A)表示之基；R2表示C1~C3烷基或甲基硫烷基(methylsulfanyl)；R3表示氫原子或甲基]； [In the formula (1), R 1 represents a group represented by the following formula (1A); R 2 represents a C 1 -C 3 alkyl group or a methylsulfanyl group; and R 3 represents a hydrogen atom or a group; base];

[通式(1A)中，R4及R5各自獨立地表示氫原子、鹵原子或C1~C6烷基； R6表示氫原子、鹵原子、C1~C6烷基、胺甲醯基、C1~C6烷基胺甲醯基、或(C1~C6烷基)(C1~C6烷基)胺甲醯基；R7表示可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C2~C6烯基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯基氧基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷氧基羰基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷硫基羰基胺基C1~C6烷基、或可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷磺醯基胺基C1~C6烷基；取代基群組α表示包含側氧基、羥基、胺基、羧基、胺甲醯基、C1~C6烷氧基、鹵化C1~C6烷氧基、C2~C7烷醯胺基、羥基亞胺基、及C1~C6烷氧基亞胺基之群組；環Q1表示單環之雜環基(該雜環基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)；環Q2表示單環之烴環基(該烴環基含有5至7員之芳香族烴環及非芳香族烴環)、或單環之雜環基(該雜環基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)； 環Q3表示單環之烴環基(該烴環基含有5至7員之芳香族烴環及非芳香族烴環)、或單環之雜環基(該雜環基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)；X表示單鍵、亞甲基、或伸乙基]。 [In the formula (1A), R 4 and R 5 each independently represent a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; and R 6 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an amine group A; An indenyl group, a C 1 -C 6 alkylamine carbenyl group, or a (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amine carbenyl group; R 7 represents one or two a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group selected from the substituents of the independent substituent group α, which may have one or two substituents selected from the independent substituent group α C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, C 1 -C 6 alkylamine methyl fluorenyloxy group which may have 1 or 2 substituents selected from the independent substituent group α C 1 ~ C 6 alkyl group which may have one or two substituents independently selected from the group of α substituent group C 1 ~ C 6 alkyl amine acyl group C 1 ~ C 6 alkyl group, a C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group which may have 1 or 2 substituents selected from the independent substituent group α, may have 1 or 2 selected from a C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group of a substituent of the independent substituent group α, or may have one or two substituents selected from the group of independent substituents α Base C 1 ~ C 6 alkylsulfonylamino group C 1 ~C 6 alkyl; the substituent group α represents a side oxy group, a hydroxyl group, an amine group, a carboxyl group, an amine carbenyl group, a C 1 -C 6 alkoxy group, a halogenated C 1 a group of a ~C 6 alkoxy group, a C 2 -C 7 alkanoguanamine group, a hydroxyimino group, and a C 1 -C 6 alkoxyimino group; the ring Q 1 represents a monocyclic heterocyclic group (this The heterocyclic group contains 5 to 7 members of an aromatic heterocyclic ring and a non-aromatic heterocyclic ring, and contains 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom); the ring Q 2 represents a single a hydrocarbon ring group of a ring (the hydrocarbon ring group contains 5 to 7 members of an aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic heterocyclic group (the heterocyclic group contains 5 to 7 members of an aromatic heterocyclic ring) And a non-aromatic heterocyclic ring, and containing 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom); the ring Q 3 represents a monocyclic hydrocarbon ring group (the hydrocarbon ring group contains 5 to a 7-membered aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring) or a monocyclic heterocyclic group (the heterocyclic group contains 5 to 7 members of an aromatic heterocyclic ring and a non-aromatic heterocyclic ring, and contains 1 or 2 An atom selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom; X represents a single , Methylene, or ethyl extension].

[2]如[1]之化合物或其藥理上容許鹽，其中環Q1為哌啶基，環Q2為苯基或吡啶基，環Q3為苯基或吡啶基；[3]如[1]或[2]之化合物或其藥理上容許鹽，其中R2為甲基，R3為氫原子；[4]如[1]至[3]之任一項之化合物或其藥理上容許鹽，其中R1為以下述之通式(1B)表示之基； Compound [2] [1] or a pharmacologically acceptable salt thereof of, wherein the ring Q 1 is piperidinyl, ring Q 2 is phenyl or pyridyl, the ring Q 3 is phenyl or pyridyl; [3] to [ Or a pharmacologically acceptable salt thereof, wherein R 2 is a methyl group, and R 3 is a hydrogen atom; [4] a compound according to any one of [1] to [3] or a pharmacologically acceptable compound thereof a salt, wherein R 1 is a group represented by the following formula (1B);

[通式(1B)中，R7表示C2~C7烷醯基C1~C6烷基、C2~C7烷醯基C2~C6烯基、C1~C6烷基胺甲醯基氧基C1~C6烷基、C1~C6烷基胺甲醯基胺基C1~C6烷基、C1~C6烷氧基羰基胺基C1~C6烷基、C1~C6烷硫基羰基胺基C1~C6烷基、或C1~C6烷磺醯基胺基C1~C6烷基；X表示單鍵或亞甲基； Y及Z各自獨立地表示氮原子或以式=CH-表示之基。] [In the formula (1B), R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkyl group; Aminomethyl methoxy-C 1 -C 6 alkyl, C 1 -C 6 alkylamine-methylaminomethyl C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino C 1 ~C a 6- alkyl, C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group, or a C 1 -C 6 alkanesulfonylamino group C 1 -C 6 alkyl group; X represents a single bond or a methylene group Y and Z each independently represent a nitrogen atom or a group represented by the formula =CH-. ]

[5]如[1]至[4]任一項之化合物或其藥理上容許鹽，其中R1為以下述之通式(1B-1)、通式(1B-2)、通式(1B-3)或通式(1B-4)之任一者表示之基； [5] The compound of any one of [1] to [4] or a pharmacologically acceptable salt thereof, wherein R 1 is the following formula (1B-1), formula (1B-2), formula (1B) a group represented by any one of -3) or (1B-4);

[通式(1B-1)、通式(1B-2)、通式(1B-3)或通式(1B-4)中，R7表示C2~C7烷醯基C1~C6烷基、C2~C7烷醯基C2~C6烯基、C1~C6烷基胺甲醯基氧基C1~C6烷基、C1~C6烷基胺甲醯基胺基C1~C6烷基、C1~C6烷氧基羰基胺基C1~C6烷基、C1~C6烷硫基羰基胺基C1~C6烷基、或C1~C6烷磺醯基胺基C1~C6烷基。] [In the formula (1B-1), the formula (1B-2), the formula (1B-3) or the formula (1B-4), R 7 represents a C 2 -C 7 alkanoyl group C 1 to C 6 Alkyl, C 2 ~C 7 alkanoyl C 2 ~C 6 alkenyl, C 1 ~C 6 alkylamine methyl methoxycarbonyl C 1 ~C 6 alkyl, C 1 ~C 6 alkylamine formazan Alkyl C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl, C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl, or C 1 ~ C 6 alkanesulfonylamino group C 1 ~ C 6 alkyl. ]

[6]如[1]至[5]任一項之化合物或其藥理上容許鹽，其中R7為2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側 氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、({[(乙硫基)羰基]胺基}甲基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)氧基]甲基或[(甲磺醯基)胺基]甲基；[7]如[1]至[6]任一項之化合物或其藥理上容許鹽，其中R7為2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基或[(乙基胺甲醯基)氧基]甲基；[8]如[1]中之化合物或其藥理上容許鹽，其係選自如下：{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸、({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、 ({[2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙基胺甲醯基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸、[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、 [({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(3-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、[({5-羥基-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{5-[3-(2-側氧丁基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-2-({1-[5-(4-{[(甲氧基羰基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[5-(4-{[(乙基胺甲醯基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[5-(4-{[(乙基胺甲醯基)氧基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸；[9]一種醫藥組成物，其係含有如上述[1]至[8]任一項之化合物或其藥理上容許鹽作為有效成分；[10]如上述[9]之醫藥組成物，其係用以預防及/或治療貧血； [11]如上述[10]之醫藥組成物，其中貧血為腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血；[12]如上述[10]之醫藥組成物，其中貧血為伴隨慢性腎臟病之貧血；[13]如上述[9]之醫藥組成物，其係用以產生紅血球生成素；[14]一種如上述[1]至[8]任一項之化合物或其藥理上容許鹽之用途，其係用以製造醫藥；[15]如上述[14]之用途，其中醫藥係用以預防及/或治療貧血之醫藥；[16]如上述[15]之用途，其中貧血為腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血；[17]如上述[15]之用途，其中貧血為伴隨慢性腎臟病之貧血；[18]一種產生紅血球生成素之方法，其係對哺乳動物或鳥類投予如上述[1]至[8]任一項之化合物或其藥理上容許鹽之藥理的有效量而成；[19]一種用以預防及/或治療疾病之方法，其係對哺乳動物投予如上述[1]至[8]任一項之化合物或其藥理上容許鹽之藥理的有效量而成；[20]如上述[19]之方法，其中疾病為貧血； [21]如上述[19]之方法，其中疾病為腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血；[22]如上述[19]之方法，其中疾病為伴隨慢性腎臟病之貧血；[23]如[19]至[22]任一項之方法，其中哺乳動物為人類；[24]如上述[1]至[8]任一項之化合物或其藥理上容許鹽，其係在用以治療或預防疾病之方法中使用；[25]如上述[24]之化合物或其藥理上容許鹽，其中疾病為貧血；[26]如上述[24]之化合物或其藥理上容許鹽，其中疾病為腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血；或[27]如上述[24]之化合物或其藥理上容許鹽，其中疾病為伴隨慢性腎臟病之貧血。 [6] The compound according to any one of [1] to [5] wherein R 7 is 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 2- Side oxypentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxy) Carbonyl)amino]methyl, ({[(ethylthio)carbonyl)amino}methyl, [(ethylaminecarbamimidino)amino]methyl, [(ethylamine)methyl)oxy A compound or a pharmacologically acceptable salt thereof, wherein R 7 is a 2-sided oxypropyl group, or a pharmacologically acceptable salt thereof, wherein R 7 is a 2-oxopropyl propyl group; , 2-sided oxybutyl, 3-oxobutyl, 2-oxopentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(B Oxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amino]methyl or [(ethylaminemethylindenyl)oxy]methyl; [8] as in [1] Or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: {[(2-{[1-(4'-{[(ethoxycarbonyl))amino]methyl}biphenyl-4-yl)piperidine- 4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, ({[2-({1-[4'-({[(ethylthio)))) Carbonyl]amino}methyl)biphenyl-4-yl] Acridine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{[( Tributoxycarbonyl)amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino )acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4-(6-{[(methylsulfonyl)amino)methyl}pyridin-3-yl)phenyl] Piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{[(ethylamine)methyl)) ]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2- ({1-[4-(6-{[(ethoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6- Methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{[(ethylamine)methyl)oxy)methyl}pyridine-3- Phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, {[(5-hydroxy-6-methyl-2) -{[1-(4-{6-[(1E)-3-oxooxybut-1-en-1-yl]pyridin-3-yl}phenyl)piperidin-4-yl]methyl}pyrimidine 4-yl)carbonyl]amino}acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4-[6-(3-o-oxybutyl)pyridin-3-yl]] Phenyl "piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4-[4-(2) -Phenoxybutyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-6-methyl-2-() {1-[4'-(2-Siloxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5- Hydroxy-6-methyl-2-({1-[4'-(2-oxobutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl} Amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidin-4-yl}) ()pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[3'-(2-trioxypropyl)biphenyl-4- (piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4-[4-( 2-sided oxypropyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-) [(1-{4'-[(1E)-3-Sideoxybut-1-en-1-yl]biphenyl-4-yl}piperidin-4-yl)methyl]pyrimidin-4-yl} Carbonyl)amino]acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4'-(3-oxobutyl)biphenyl-4-yl]piperidin-4-yl) }methyl)pyrimidin-4-yl]carbonyl}amino)ethyl Acid, [({5-hydroxy-6-methyl-2-[(1-{5-[4-(2-oxopropyl)phenyl]pyridin-2-yl}piperidin-4-yl)) Methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-[(1-{5-[3-(2-oxobutyl))phenyl) Pyridin-2-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-2-({1-[5-(4-{ [(Methoxycarbonyl)amino]methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[5-(4-{[(ethylaminomethyl)amino)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl) -5-Hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[5-(4-{[(ethylamine)methyl)oxy)] Methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid; [9] a pharmaceutical composition And the pharmacologically acceptable salt of the compound according to any one of the above [1] to [8], wherein the pharmaceutical composition is used for the prevention and/or prevention. Treatment of anemia; [11] The pharmaceutical composition of the above [10], wherein anemia is renal anemia, anemia in premature infants, and poor with chronic diseases Anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia, or anemia associated with septic heart failure; [12] The pharmaceutical composition of the above [10], wherein anemia is anemia associated with chronic kidney disease; [13] The pharmaceutical composition according to the above [9], which is for use in the production of erythropoietin; [14] the use of a compound according to any one of the above [1] to [8] or a pharmacologically acceptable salt thereof, For the manufacture of medicines; [15] The use of the above [14], wherein the medicine is used for the prevention and/or treatment of anemia; [16] the use of the above [15], wherein the anemia is renal anemia, premature infant Anemia, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia, or anemia associated with septic heart failure; [17] as described in [15] above, wherein anemia is accompanied by chronic kidneys An anemia of the disease; [18] A method for producing erythropoietin, which is effective for administering a compound of any one of the above [1] to [8] or a pharmacologically acceptable salt thereof to a mammal or a bird. Cheng [19] a method for preventing and/or treating diseases, The method of administering the compound of any one of the above [1] to [8] or a pharmacologically acceptable salt thereof to the mammal; [20] The method according to [19] above, wherein the disease is anemia [21] The method according to the above [19], wherein the disease is renal anemia, anemia of premature infants, anemia accompanied by chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia or concomitant septic heart [22] The method of the above [19], wherein the disease is anemia associated with chronic kidney disease; [23] the method according to any one of [19] to [22] wherein the mammal is a human; The compound of any one of the above [1] to [8], or a pharmacologically acceptable salt thereof, for use in a method for treating or preventing a disease; [25] a compound according to the above [24] or a pharmacologically Permissible salt, wherein the disease is anemia; [26] A compound according to the above [24] or a pharmacologically acceptable salt thereof, wherein the disease is renal anemia, anemia of premature infants, anemia accompanied by chronic diseases, anemia accompanied by cancer chemotherapy, cancer Anemia, inflammation-related anemia, or anemia associated with septic heart failure; or [27] The compound of the above [24] or a pharmacologically acceptable salt thereof, wherein the disease is anemia accompanied by chronic kidney disease.

以上述通式(1)表示之本發明之化合物，具有5-羥基嘧啶-4-甲醯胺骨架，該嘧啶環之2位之取代基具有3個之環狀基，該環狀基具有特定之取代基。本發明之化合物或其藥理上容許鹽具有優異的增強EPO產生的活性。 The compound of the present invention represented by the above formula (1) has a 5-hydroxypyrimidine-4-carboxamide skeleton, and the substituent at the 2-position of the pyrimidine ring has three cyclic groups, and the cyclic group has a specific Substituent. The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent activity for enhancing EPO production.

以下，就關於本發明之化合物之取代基加以說明。 Hereinafter, the substituents of the compound of the present invention will be described.

在R4、R5、及R6之定義中，所謂的「鹵原子」係為氟原子、氯原子、溴原子或碘原子，較佳為氟原子。 In the definition of R 4 , R 5 and R 6 , the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom.

在R2之定義中，所謂的「C1~C3烷基」表示碳數1至3個之直鏈或支鏈之烷基。可列舉例如甲基、乙基、丙基、異丙基。 In the definition of R 2 , the so-called "C 1 -C 3 alkyl group" means a straight or branched alkyl group having 1 to 3 carbon atoms. For example, a methyl group, an ethyl group, a propyl group, and an isopropyl group are mentioned.

在R4、R5、及R6之定義中，所謂的「C1~C6烷基」表示碳數1至6個之直鏈或支鏈之烷基。可列舉例如甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基等。C1~C6烷基較佳為C1~C4烷基，更佳為C1~C3烷基。 In the definition of R 4 , R 5 , and R 6 , the so-called "C 1 -C 6 alkyl group" means a straight or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl and the like. C 1 ~ C 6 alkyl group is preferably C 1 ~ C 4 alkyl, more preferably C 1 ~ C 3 alkyl group.

在取代基群組α之定義中，所謂的「C1~C6烷氧基」表示上述「C1~C6烷基」為鍵結於氧原子之基。可列舉例如甲氧基、乙氧基、正丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基等。C1~C6烷氧基較佳為C1~C4烷氧基，更佳為C1~C2烷氧基。 In the definition of the substituent group α, the "C 1 -C 6 alkoxy group" means that the above "C 1 -C 6 alkyl group" is a group bonded to an oxygen atom. For example, a methoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group, a second butoxy group, a third butoxy group, a n-pentyloxy group, etc. are mentioned. The C 1 -C 6 alkoxy group is preferably a C 1 -C 4 alkoxy group, more preferably a C 1 -C 2 alkoxy group.

在取代基群組α之定義中，所謂的「鹵化C1~C6烷氧基」表示上述「C1~C6烷氧基」之1個或2個氫原子被上述「鹵原子」取代之基。可列舉例如氟甲氧基、氯甲氧基、1-氟乙氧基、1-氯乙氧基、2-氟乙氧基、1,2-二氟丙氧基等。鹵化C1~C6烷氧基較佳為鹵化C1~C4烷氧基，更佳為鹵化C1~C3烷氧基。 In the definition of the substituent group α, the "halogenated C 1 -C 6 alkoxy group" means that one or two hydrogen atoms of the above "C 1 -C 6 alkoxy group" are substituted by the above "halogen atom". The basis. For example, a fluoromethoxy group, a chloromethoxy group, a 1-fluoroethoxy group, a 1-chloroethoxy group, a 2-fluoroethoxy group, a 1,2-difluoropropoxy group, etc. are mentioned. The halogenated C 1 -C 6 alkoxy group is preferably a halogenated C 1 -C 4 alkoxy group, more preferably a halogenated C 1 -C 3 alkoxy group.

在取代基群組α之定義中，所謂的「C1~C6烷氧基亞胺基」表示上述「C1~C6烷氧基」鍵結於亞胺基之基。可列舉例如甲氧基亞胺基、乙氧基亞胺基、正丙氧基亞胺基、異丙氧基亞胺基、正丁氧基亞胺基、異丁氧基亞胺基、第二丁氧基亞胺基、第三丁氧基亞胺基、正戊氧基亞胺基、異戊氧基亞胺基、2-甲基丁氧基亞胺基等。C1~C6烷氧基亞胺基較佳為C1~C4烷氧基亞胺基，更佳為C1~C3烷氧基亞胺基。 In the definition of the substituent group α, the "C 1 -C 6 alkoxyimino group" means a group in which the above "C 1 -C 6 alkoxy group" is bonded to an imine group. For example, a methoxyimino group, an ethoxyimino group, a n-propoxy imine group, an isopropoxyimine group, a n-butoxy imine group, an isobutoxy imine group, and a Dibutoxyimino, third butoxyimino, n-pentyloxyimido, isopentyloxyimido, 2-methylbutoxyimino, and the like. The C 1 -C 6 alkoxyimino group is preferably a C 1 -C 4 alkoxyimino group, more preferably a C 1 -C 3 alkoxyimino group.

在R7之定義中，所謂的「C1~C6烷氧基羰基胺基C1~C6烷基」表示上述「C1~C6烷基」與氮原子鍵結之「胺基C1~C6烷基」(例如胺甲基、胺乙基、胺異丙基等)的氮原子，與上述「C1~C6烷氧基」與羰基之碳原子鍵結之基之C1~C6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基、正丁氧基羰基、第二丁氧基羰基、第三丁氧基羰基等)之羰基的碳原子鍵結之基。可列舉例如[(甲氧基羰基)胺基]甲基、[(甲氧基羰基)胺基]乙基、[(乙氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]乙基、[(正丙氧基羰基)胺基]甲基、[(正丙氧基羰基)胺基]乙基、[(異丙氧基羰基)胺基]甲基、[(異丙氧基羰基)胺基]乙基、[(正丁氧基羰基)胺基]甲基、[(正丁氧基羰基)胺基]乙基、[(第二丁氧基羰基)胺基]甲基、[(第二丁氧基羰基)胺基]乙基、[(第三丁氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]乙基等。C1~C6烷氧基羰基胺基C1~C6烷基較佳為C1~C4烷氧基羰基胺基C1~C4烷基，更佳為C1~C3烷氧基羰基胺基C1~C3烷基。 In the definition of R 7 , the so-called "C 1 -C 6 alkoxycarbonylamino group C 1 -C 6 alkyl group" means the above-mentioned "C 1 -C 6 alkyl group" bonded to the nitrogen atom "amine group C" a nitrogen atom of a 1 - C 6 alkyl group (e.g., an amine methyl group, an amine ethyl group, an amine isopropyl group, etc.), and a C bond to the carbon atom of the above "C 1 -C 6 alkoxy group" and a carbonyl group 1 to C 6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second butoxycarbonyl, tert-butoxy) A carbon atom-bonded group of a carbonyl group such as a carbonyl group. For example, [(methoxycarbonyl)amino]methyl, [(methoxycarbonyl)amino]ethyl, [(ethoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amine Ethyl, [(n-propoxycarbonyl)amino]methyl, [(n-propoxycarbonyl)amino]ethyl, [(isopropoxycarbonyl)amino]methyl, [(different Propyloxycarbonyl)amino]ethyl, [(n-butoxycarbonyl)amino]methyl, [(n-butoxycarbonyl)amino]ethyl, [(second butoxycarbonyl)amino ]methyl, [(second butoxycarbonyl)amino]ethyl, [(t-butoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amino]ethyl, and the like. The C 1 -C 6 alkoxycarbonylamino group C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkoxycarbonylamino group C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkoxy group. Alkylcarbonylamino C 1 -C 3 alkyl.

在R7之定義中，所謂的「C1~C6烷硫基羰基胺基C1~C6烷基」表示上述「胺基C1~C6烷基」之氮原子與上述「C1~C6烷基」與硫基羰基的硫原子鍵結之基的C1~C6烷硫基羰基(例如(甲硫基)羰基、(乙硫基)羰基、(正丙硫基)羰基、(異丙硫基)羰基、(正丁硫基)羰基、(第二丁硫基)羰基、(第三丁硫基)羰基等)之羰基的碳原子鍵結之基。可列舉例如{[(甲硫基)羰基]胺基}甲基、{[(甲硫基)羰基]胺基}乙基、{[(乙硫基)羰基]胺基}甲基、{[(乙硫基)羰基]胺基}乙基、{[(正丙硫基)羰基]胺基}甲基、{[(正丙硫基)羰基]胺基}乙基、{[(異丙硫基)羰基]胺基}甲基、{[(異丙硫基)羰基]胺基}乙基、{[(正丁硫基)羰基]胺基}甲基、{[(正丁硫基)羰基]胺基}乙基、{[(第二丁硫基)羰基]胺基}甲基、{[(第二丁硫基)羰基]胺基}乙基、{[(第三丁硫基)羰基]胺基}甲基、{[(第三丁硫基)羰基]胺基}乙基等。C1~C6烷硫基羰基胺基C1~C6烷基較佳為C1~C4烷硫基羰基胺基C1~C4烷基，更佳為C1~C3烷硫基羰基胺基C1~C3烷基。 In the definition of R 7 , the phrase "C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl" means the nitrogen atom of the above "amino C 1 -C 6 alkyl group" and the above "C 1 ~ C 6 alkyl group bonded to a sulfur atom of the C "and the carbonyl group of 1 ~ C 6 alkylthio-carbonyl group (e.g., (methylthio) carbonyl, (ethylthio) carbonyl, (n-propylthio) carbonyl a carbon atom-bonded group of a carbonyl group of (isopropylthio)carbonyl, (n-butylthio)carbonyl, (second butylthio)carbonyl, (tributylthio)carbonyl, and the like. For example, {[(methylthio)carbonyl]amino}methyl, {[(methylthio)carbonyl]amino}ethyl, {[(ethylthio)carbonyl]amino}methyl, {[ (ethylthio)carbonyl]amino}ethyl, {[(n-propylthio)carbonyl]amino}methyl, {[(n-propylthio)carbonyl]amino}ethyl, {[(isopropyl Thio)carbonyl]amino}methyl, {[(isopropylthio)carbonyl]amino}ethyl, {[(n-butylthio)carbonyl]amino}methyl, {[(n-butylthio) )carbonyl]amino}ethyl, {[(second butylthio)carbonyl]amino}methyl, {[(second butylthio)carbonyl]amino}ethyl, {[(third butyl sulphur) Alkyl]carbonyl]amino}methyl, {[(t-butylthio)carbonyl]amino}ethyl, and the like. The C 1 -C 6 alkylthiocarbonylamino group C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylthiocarbonylamino group C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl sulfide. Alkylcarbonylamino C 1 -C 3 alkyl.

在R7之定義中，所謂的「C1~C6烷磺醯基胺基C1~C6烷基」表示上述「胺基C1~C6烷基」之氮原子，與上述「C1~C6烷基」與磺醯基之硫原子鍵結之基之C1~C6烷基磺醯基(例如甲磺醯基、乙磺醯基、正丙磺醯基、異丙基磺醯基、正丁磺醯基、第二丁磺醯基、第三丁磺醯基等)的硫黃原子鍵結之基。可列舉例如[(甲磺醯基)胺基]甲基、[(甲磺醯基)胺基]乙基、[(乙磺醯基)胺基]甲基、[(乙磺醯基)胺基]乙基、[(正丙磺醯基)胺基]甲基、 [(正丙磺醯基)胺基]乙基、[(異丙磺醯基)胺基]甲基、[(異丙基磺醯基)胺基]乙基、[(正丁磺醯基)胺基]甲基、[(正丁磺醯基)胺基]乙基、[(第二丁磺醯基)胺基]甲基、[(第二丁磺醯基)胺基]乙基、[(第三丁磺醯基)胺基]甲基、[(第三丁磺醯基)胺基]乙基等。C1~C6烷磺醯基胺基C1~C6烷基較佳為C1~C4烷磺醯基胺基C1~C4烷基，更佳為C1~C3烷磺醯基胺基C1~C3烷基。 In the definition of R 7 , the "C 1 -C 6 alkanesulfonylamino group C 1 -C 6 alkyl group" means the nitrogen atom of the above "amino group C 1 -C 6 alkyl group", and the above "C" the bonding of sulfur-yl 1 ~ C 6 alkyl group "and the atoms of the acyl sulfo C 1 ~ C 6 alkylsulfonyl group (e.g., methanesulfonamide acyl, acyl ethanesulfonyl, n-propanesulfonamide acyl, isopropyl A group of a sulfur atom-bonded group of a sulfonyl group, a n-butylsulfonyl group, a second butyl sulfonyl group, a third butyl sulfonyl group, or the like. For example, [(methylsulfonyl)amino]methyl, [(methylsulfonyl)amino]ethyl, [(ethanesulfonyl)amino]methyl, [(ethanesulfonyl)amine Ethyl, [(n-propionyl)amino]methyl, [(n-propionyl)amino]ethyl, [(isopropylsulfonyl)amino]methyl, [(iso Propylsulfonyl)amino]ethyl, [(n-butylsulfonyl)amino]methyl, [(n-butylsulfonyl)amino]ethyl, [(second sulfonyl) amine Methyl, [(2-butylsulfonyl)amino]ethyl, [(t-butylsulfonyl)amino]methyl, [(t-butylsulfonyl)amino]ethyl, etc. . The C 1 -C 6 alkanesulfonylamino group C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkanesulfonylamino group C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkane sulfonate. Mercaptoamine C 1 ~ C 3 alkyl.

在R6之定義中，所謂的「C1~C6烷基胺甲醯基」表示胺甲醯基之1個氫原子被上述「C1~C6烷基」取代之基。可列舉例如甲基胺甲醯基、乙基胺甲醯基、正丙基胺甲醯基等。C1~C6烷基胺甲醯基，較佳為C1~C4烷基胺甲醯基，更佳為C1~C3烷基胺甲醯基。 In the definition of R 6 , the "C 1 -C 6 alkylaminecarbamyl group" means a group in which one hydrogen atom of the amine carbenyl group is substituted by the above "C 1 -C 6 alkyl group". For example, a methylamine methyl fluorenyl group, an ethylamine methyl fluorenyl group, a n-propyl carbyl fluorenyl group, etc. are mentioned. The C 1 -C 6 alkylaminecarbamyl group is preferably a C 1 -C 4 alkylaminecarbamyl group, more preferably a C 1 -C 3 alkylaminecarbamyl group.

在R6之定義中，所謂的「(C1~C6烷基)(C1~C6烷基)胺甲醯基」表示胺甲醯基之2個氫原子分別被上述「C1~C6烷基」取代之基。可列舉例如二甲基胺甲醯基、甲基乙基胺甲醯基、甲基丙基胺甲醯基、二乙基胺甲醯基等。(C1~C6烷基)(C1~C6烷基)胺甲醯基較佳為(C1~C4烷基)(C1~C4烷基)胺甲醯基，更佳為(C1~C2烷基)(C1~C2烷基)胺甲醯基。 In the definition of R 6 , the so-called "(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amine mercapto" means that the two hydrogen atoms of the amine carbenyl group are respectively "C 1 ~ a C 6 alkyl group substituted group. For example, a dimethylaminoformyl group, a methylethylamine-methyl group, a methylpropylamine-methyl group, a diethylamine-methyl group, etc. are mentioned. (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amine mercapto group is preferably (C 1 -C 4 alkyl)(C 1 -C 4 alkyl)amine mercapto group, more preferably It is (C 1 -C 2 alkyl)(C 1 -C 2 alkyl)amine carbenyl.

在R7之定義中，所謂的「C1~C6烷基胺甲醯氧基C1~C6烷基」表示上述「C1~C6烷基」之1個氫原子被C1~C6烷基胺甲醯氧基(例如(甲基胺甲醯基)氧基、(乙基胺甲醯基)氧基、(正丙基胺甲醯基)氧基等)取代之基，該C1~C6烷基胺甲醯氧基係氧原子鍵結於上述「C1~C6烷基胺甲醯基」之羰基而成之基。可列舉例如[(甲基胺 甲醯基)氧基]甲基、[(乙基胺甲醯基)氧基]甲基、[(正丙基胺甲醯基)氧基]甲基、[(甲基胺甲醯基)氧基]乙基、[(乙基胺甲醯基)氧基]乙基等。C1~C6烷基胺甲醯基氧基C1~C6烷基較佳為C1~C4烷基胺甲醯基氧基C1~C4烷基，更佳為C1~C2烷基胺甲醯基氧基C1~C2烷基。 In the definition of R 7 , the phrase "C 1 -C 6 alkylamine methyl methoxy C 1 -C 6 alkyl" means that one hydrogen atom of the above "C 1 -C 6 alkyl group" is C 1 ~ a C 6 alkylamine methyl methoxy group (e.g., (methylaminomethyl methoxy) oxy group, (ethyl carbamoyl) oxy group, (n-propyl carbamoyl) oxy), etc., The C 1 -C 6 alkylamine methyl methoxy group oxygen atom is bonded to the carbonyl group of the above-mentioned "C 1 -C 6 alkylamine formazan group". For example, [(methylamine-mercapto)oxy]methyl, [(ethylaminemethylindenyl)oxy]methyl, [(n-propylaminomethylcarbonyl)oxy]methyl, [ (Methylamine-mercapto)oxy]ethyl, [(ethylamine-methylindenyl)oxy]ethyl and the like. The C 1 -C 6 alkylamine carbaryloxy C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylamine carbaryloxy C 1 -C 4 alkyl group, more preferably C 1 ~ C 2 alkylamine isonyloxy C 1 -C 2 alkyl.

在R7之定義中，所謂的「C1~C6烷基胺甲醯基胺基C1~C6烷基」表示上述「C1~C6烷基」之1個氫原子被C1~C6烷基胺甲醯基胺基(例如(甲基胺甲醯基)胺基、(乙基胺甲醯基)胺基、(正丙基胺甲醯基)胺基等)取代之基，該C1~C6烷基胺甲醯基胺基係胺基鍵結於上述「C1~C6烷基胺甲醯基」之羰基而成之基。可列舉例如[(甲基胺甲醯基)胺基]甲基、[(甲基胺甲醯基)胺基]乙基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)胺基]乙基、[(正丙基胺甲醯基)胺基]甲基、[(正丙基胺甲醯基)胺基]乙基等。C1~C6烷基胺甲醯基胺基C1~C6烷基較佳為C1~C4烷基胺甲醯基胺基C1~C4烷基，更佳為C1~C2烷基胺甲醯基胺基C1~C2烷基。 In the definition of R 7 , the phrase "C 1 -C 6 alkylamine-methylaminomethyl C 1 -C 6 alkyl" means that one hydrogen atom of the above "C 1 -C 6 alkyl group" is C 1 ~C 6 alkylamine-mercaptoamino group (for example, (methylamine-methyl) amino group, (ethylamine-methyl) amino group, (n-propylaminomethyl) amino group, etc.) A group in which the C 1 -C 6 alkylamine-methylamino group-based amine group is bonded to the carbonyl group of the above-mentioned "C 1 -C 6 alkylamine-methyl fluorenyl group". For example, [(methylamine-mercapto)amino]methyl, [(methylamine-methyl)amino]ethyl, [(ethylamine-methyl)amino]methyl, [( Ethylamine, mercapto)amino]ethyl, [(n-propylaminomethylmethyl)amino]methyl, [(n-propylaminomethyl)amino]ethyl, and the like. The C 1 -C 6 alkylamine carbarylamino group C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylamine carbarylamino group C 1 -C 4 alkyl group, more preferably C 1 ~ C 2 alkylamine isonylamino C 1 ~ C 2 alkyl.

在取代基群組α之定義中，所謂的「C2~C7烷醯基胺基」表示碳數2至7個之直鏈或支鏈烷醯基之C2~C7烷醯基(例如乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、三甲基乙醯基、纈草醯基、異纈草醯基、己醯基、庚醯基等)鍵結於胺基之基。可列舉例如乙醯基胺基、丙醯基胺基、丁醯基胺基、異丁醯基胺基、戊醯基胺基等。C2~C7烷醯基胺基較佳為C2~C5烷醯基胺基，更佳為C2~C4烷醯基胺基。 In the substituent definitions of the group α, the so-called "C 2 ~ C 7 alkyl acyl group" represents a carbon number of 2-7 straight chain or branched chain alkanoyl group of C 2 ~ C 7 alkanoyl group ( For example, an ethyl group, a propyl group, a butyl group, a butyl group, an isobutyl group, a pentamidine group, a trimethyl acetyl group, a valeryl group, an isoamyl group, a hexyl group, a heptyl group, etc., are bonded to an amine group. The basis. For example, an ethyl fluorenylamino group, a propyl fluorenyl group, a butyl fluorenyl group, an isobutyl decyl amine group, a pentamyl amine group, etc. are mentioned. The C 2 -C 7 alkanoylamino group is preferably a C 2 -C 5 alkanoylamino group, more preferably a C 2 -C 4 alkanoylamino group.

在R7之定義中，所謂的「C2~C7烷醯基C1~C6烷基」表示上述「C1~C6烷基」之1個氫原子被上述「C2~C7烷醯基」取代之基。可列舉例如2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧戊基、4-側氧戊基等。C2~C7烷醯基C1~C6烷基較佳為C2~C5烷醯基C1~C4烷基，更佳為C2~C3烷醯基C1~C2烷基。 In the definition of R 7 , the "C 2 -C 7 alkanoyl C 1 -C 6 alkyl group" means that one hydrogen atom of the above "C 1 -C 6 alkyl group" is represented by the above "C 2 ~ C 7". Alkyl group substituted. Examples thereof include a 2-sided oxypropyl group, a 2-sided oxybutyl group, a 3-sided oxybutyl group, a 2-oxo-pentyl group, a 3-oxo-pentyl group, and a 4-oxo-pentyl group. The C 2 -C 7 alkanoyl C 1 -C 6 alkyl group is preferably a C 2 -C 5 alkanoyl C 1 -C 4 alkyl group, more preferably a C 2 -C 3 alkanoyl group C 1 -C 2 alkyl.

在R7之定義中，所謂的「C2~C7烷醯基C2~C6烯基」表示碳數2至6個之直鏈或支鏈的烯基之C2~C6烯基(例如乙烯基、1-丙烯基、2-丙烯基、異丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-戊烯基、4-戊烯基、1-甲基-4-戊烯基、5-己烯基等)之1個氫原子被上述「C2~C7烷醯基」取代之基。可列舉例如3-側氧基-1-丁烯基、3-側氧基-1-戊烯基、4-側氧基-1-戊烯基、4-側氧基-2-戊烯基等。C2~C7烷醯基C2~C6烯基較佳為C2~C4烷醯基C2~C4烯基。 In the definition of R 7 , the so-called "C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group" means a C 2 -C 6 alkenyl group of a straight or branched alkenyl group having 2 to 6 carbon atoms. (e.g., vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl One of 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 5-hexenyl, etc. A hydrogen atom is substituted by the above-mentioned "C 2 -C 7 alkano group". For example, a 3-oxo-1-butenyl group, a 3-sided oxy-1-pentenyl group, a 4-sided oxy-1-pentenyl group, and a 4-sided oxy-2-pentenyl group are mentioned. Wait. The C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group is preferably a C 2 -C 4 alkanoyl C 2 -C 4 alkenyl group.

在環Q2及環Q3之定義中，所謂的「單環之烴環基」表示飽和、部分不飽和或不飽和之5至7員之單環之烴基。可列舉例如：如苯基之單環芳香族烴環基；如環戊基、環己基、環庚基、環戊烯基、環己烯基、環庚醯基之單環非芳香族烴環基。在本發明中，較佳為6員之芳香族烴環基或非芳香族烴環基，更佳為6員之芳香族烴環基。 In the definition of ring Q 2 and ring Q 3 , the so-called "monocyclic hydrocarbon ring group" means a saturated, partially unsaturated or unsaturated 5- to 7-membered monocyclic hydrocarbon group. For example, a monocyclic aromatic hydrocarbon ring group such as a phenyl group; a monocyclic non-aromatic hydrocarbon ring such as a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexenyl group or a cycloheptanyl group; base. In the present invention, a 6-membered aromatic hydrocarbon ring group or a non-aromatic hydrocarbon ring group is preferred, and a 6-membered aromatic hydrocarbon ring group is more preferred.

在環Q1、環Q2及環Q3之定義中，所謂的「單環之雜環基」表示含有1或2個選自包含氮原子、 硫原子及氧原子之群組中的原子之飽和、部分不飽和或不飽和之5至7員的單環之雜環基。可列舉例如：如四氫呋喃基、四氫哌喃基、二氧戊環基(dioxolanyl)、二烷基(dioxanyl)、二氧庚環基(dioxepanyl)、吡咯啶基、哌啶基、氮雜環庚烷基(azepanyl)、二氫吡咯基、二氫吡啶基、四氫吡啶基、哌基、啉基、二氫唑基、二氫噻唑基之單環非芳香族雜環基；如吡咯基、吡啶基、噻吩基、呋喃基、嘧啶基、哌喃基、嗒基、吡基、吡唑基、咪唑基、噻唑基、異噻唑基、唑基、異唑基之單環芳香族雜環基等。作為在本發明中之「單環之雜環基」，較佳為含有1個或2個氮原子之6員芳香族雜環基或非芳香族雜環基，更佳為含有1個氮原子之6員芳香族雜環基或非芳香族雜環基。在環Q1中，單環之雜環基進一步更佳為含有1個氮原子之6員非芳香族雜環基。 In the definition of the ring Q 1 , the ring Q 2 and the ring Q 3 , the so-called "monocyclic heterocyclic group" means an atom having 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. A monocyclic heterocyclic group of 5 to 7 members which is saturated, partially unsaturated or unsaturated. For example, there may be mentioned, for example, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, and Dioxanyl, dioxepanyl, pyrrolidinyl, piperidinyl, azepanyl, dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, piperidine base, Olinyl, dihydrogen Monocyclic non-aromatic heterocyclic group of azolyl or dihydrothiazolyl; such as pyrrolyl, pyridyl, thienyl, furyl, pyrimidinyl, piperidyl, anthracene Base Base, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, Azolyl, different A monocyclic aromatic heterocyclic group such as an azole group. The "monocyclic heterocyclic group" in the invention is preferably a 6-membered aromatic heterocyclic group or a non-aromatic heterocyclic group having one or two nitrogen atoms, more preferably one nitrogen atom. A 6-membered aromatic heterocyclic group or a non-aromatic heterocyclic group. In the ring Q 1 , the monocyclic heterocyclic group is more preferably a 6-membered non-aromatic heterocyclic group containing one nitrogen atom.

就本發明之化合物中之R1於以下加以說明。 R 1 in the compounds of the present invention is described below.

在本發明之化合物中，R1表示以以下之通式(1A)表示之基。 In the compound of the present invention, R 1 represents a group represented by the following formula (1A).

在上述通式(1A)中，R4及R5各自獨立地表示氫原子、鹵原子或C1~C6烷基，R6表示氫原子、鹵原子、C1~C6烷基、胺甲醯基、C1~C6烷基胺甲醯基、或(C1~C6烷基)(C1~C6烷基)胺甲醯基。 In the above formula (1A), R 4 and R 5 each independently represent a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group, and R 6 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an amine. A mercapto group, a C 1 -C 6 alkylamine carbenyl group, or a (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amine carbenyl group.

在本發明中，較佳為R4表示氫原子。 In the present invention, R 4 preferably represents a hydrogen atom.

在本發明中，R5較佳為表示氫原子、鹵原子或甲基，更佳為表示氫原子。 In the present invention, R 5 preferably represents a hydrogen atom, a halogen atom or a methyl group, and more preferably represents a hydrogen atom.

在本發明中，R6較佳為表示氫原子、鹵原子或甲基，更佳為表示氫原子、氯原子或甲基，進一步更佳為表示氫原子。 In the present invention, R 6 preferably represents a hydrogen atom, a halogen atom or a methyl group, more preferably represents a hydrogen atom, a chlorine atom or a methyl group, and still more preferably represents a hydrogen atom.

在本發明中，R7表示可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C2~C6烯基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯氧基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷氧基羰基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷硫基羰基胺基C1~C6烷基、或可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷磺醯基胺基C1~C6烷基；取代基群組α表示包含側氧基、羥基、胺基、羧基、胺甲醯基、C1~C6烷氧基、鹵化C1~C6烷氧基、C2~C7烷醯胺基、羥基亞胺基及C1~C6烷氧基亞胺基之群組。 In the present invention, R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group which may have 1 or 2 substituents selected from the independent substituent group α, and may have 1 or Two C 2 -C 7 alkanoyl C 2 -C 6 alkenyl groups selected from the substituents of the independent substituent group α may have one or two selected from the group of independent substituents α a C 1 -C 6 alkylamine methyl methoxy C 1 -C 6 alkyl group of a substituent, a C 1 -C 6 alkane which may have 1 or 2 substituents selected from the independent substituent group α ylamine acyl group C 1 ~ C 6 alkyl group which may have one or two substituents independently selected from the group of substituent α C 1 ~ C 6 alkoxycarbonyl group C 1 ~ a C 6 alkyl group, which may have 1 or 2 C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl groups selected from the substituents of the independent substituent group α, or may have 1 or 2 substituents independently selected from the group of substituent α C 1 ~ C 6 alkyl sulfonic acyl group C 1 ~ C 6 alkyl; substituent group α represents a group comprising oxo, hydroxyl, amine group, a carboxyl group, a carbamoyl acyl, C 1 ~ C 6 alkoxy, halogenated C 1 ~ C 6 alkoxy group, C 2 ~ C 7 alkanoyl group, hydroxyimino and C 1 ~ C 6 alkyl The imino group.

在本發明中取代基群組α較佳為包含羥基、C1~C6烷氧基、鹵化C1~C6烷氧基及C2~C7烷醯胺基之群組，更佳為包含羥基及C1~C2烷氧基之群組。 In the present invention, the substituent group α is preferably a group comprising a hydroxyl group, a C 1 -C 6 alkoxy group, a halogenated C 1 -C 6 alkoxy group, and a C 2 -C 7 alkanoguanamine group, more preferably A group comprising a hydroxyl group and a C 1 -C 2 alkoxy group.

在本發明中，較佳為R7表示C2~C7烷醯基C1~C6烷基、C2~C7烷醯基C2~C6烯基、C1~C6烷基胺甲醯基氧基C1~C6烷基、C1~C6烷基胺甲醯基胺基C1~C6烷基、C1~C6烷氧基羰基胺基C1~C6烷基、C1~C6烷硫基羰基胺基C1~C6烷基、或C1~C6烷磺醯基胺基C1~C6烷基，更佳為表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、({[(乙硫基)羰基]胺基}甲基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)氧基]甲基、或[(甲磺醯基)胺基]甲基，進一步更佳為表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、或[(乙基胺甲醯基)氧基]甲基。 In the present invention, R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkyl group. Aminomethyl methoxy-C 1 -C 6 alkyl, C 1 -C 6 alkylamine-methylaminomethyl C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino C 1 ~C a 6- alkyl group, a C 1 -C 6 alkylthiocarbonylamino group C 1 -C 6 alkyl group, or a C 1 -C 6 alkanesulfonylamino group C 1 -C 6 alkyl group, more preferably a 2-sided side Oxypropyl, 2-oxobutyl, 3-oxobutyl, 2-oxopentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amino]methyl, ({[(ethylthio)carbonyl)amino}methyl, [(ethylamine A) Mercapto)amino]methyl, [(ethylaminemethylindenyl)oxy]methyl, or [(methylsulfonyl)amino]methyl, further more preferably 2-sided oxypropyl, 2-sided oxybutyl, 3-oxobutyl, 2-oxopentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxy Alkylcarbonyl)amino]methyl, [(t-butoxycarbonyl)amino]methyl, or [(ethylaminemethylindenyl)oxy]methyl.

在本發明中，X較佳為表示單鍵或亞甲基，更佳為表示單鍵。 In the present invention, X preferably represents a single bond or a methylene group, and more preferably represents a single bond.

在本發明中，R1較佳為以以下之通式(1B)表示之基。 In the present invention, R 1 is preferably a group represented by the following formula (1B).

在上述通式(1B)中，Y及Z各自獨立地表示碳原子(具有1個之氫原子)或氮原子，X表示單鍵或亞甲基，R7表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、({[(乙硫基)羰基]胺基}甲基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)氧基]甲基、或[(甲磺醯基)胺基]甲基。上述R7較佳為表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、或[(乙基胺甲醯基)氧基]甲基。 In the above formula (1B), Y and Z each independently represent a carbon atom (having one hydrogen atom) or a nitrogen atom, X represents a single bond or a methylene group, and R 7 represents a 2-sided oxypropyl group, 2 - side oxybutyl, 3-oxobutyl, 2-oxopentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxy) Carbonyl)amino]methyl, [(t-butoxycarbonyl)amino]methyl, ({[(ethylthio)carbonyl)amino}methyl, [(ethylaminecarbamimidyl)amino) a methyl group, [(ethylamine-mercapto)oxy]methyl, or [(methylsulfonyl)amino]methyl. The above R 7 preferably represents a 2-sided oxypropyl group, a 2-side Oxybutyl, 3-oxobutyl, 2-oxopentyl, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl) Amino]methyl, [(t-butoxycarbonyl)amino]methyl, or [(ethylaminemethylindenyl)oxy]methyl.

在本發明之化合物中，R1更佳為以以下之通式(1B-1)至通式(1B-4)表示之基。 In the compound of the present invention, R 1 is more preferably a group represented by the following formula (1B-1) to formula (1B-4).

在上述通式(1B-1)至通式(1B-4)中，R7表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、({[(乙硫基)羰基]胺基}甲基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)氧基]甲基或[(甲磺醯基)胺基]甲基。上述R7較佳為表示2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、或[(乙基胺甲醯基)氧基]甲基。 In the above formula (1B-1) to formula (1B-4), R 7 represents a 2-sided oxypropyl group, a 2-sided oxybutyl group, a 3-oxobutyl group, a 2-oxo-pentyl group, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amino] Methyl, ({[(ethylthio)carbonyl)amino}methyl, [(ethylaminecarbamimidino)amino]methyl, [(ethylaminecarbamido)oxy]methyl or [ (Methanesulfonyl)amino]methyl. The above R 7 preferably represents 2-sided oxypropyl, 2-sided oxybutyl, 3-oxobutyl, 2-oxopentyl, 3-side Oxy-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amino]methyl, Or [(ethylamine-mercapto)oxy]methyl.

在本發明之化合物中，R2表示C1~C3烷基或甲基硫烷基，較佳為表示甲基或甲基硫烷基，更佳為甲基。 In the compound of the present invention, R 2 represents a C 1 -C 3 alkyl group or a methylsulfanyl group, preferably a methyl group or a methylsulfanyl group, more preferably a methyl group.

在本發明之化合物中，R3表示氫原子或甲基，較佳為氫原子。 In the compound of the present invention, R 3 represents a hydrogen atom or a methyl group, preferably a hydrogen atom.

作為本發明之化合物，較佳為選自下述之化合物或其藥理上容許鹽之一者：{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸、({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙基胺甲醯基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸、 [({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(3-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、[({5-羥基-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{5-[3-(2-側氧丁基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-2-({1-[5-(4-{[(甲氧基羰基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸、 ({[2-({1-[5-(4-{[(乙基胺甲醯基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[5-(4-{[(乙基胺甲醯基)氧基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸。 The compound of the present invention is preferably one selected from the group consisting of the following compounds or a pharmacologically acceptable salt thereof: {[(2-{[1-(4'-{[(ethoxycarbonyl))amino]-) }}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, ({[2-({1- [4'-({[(ethylthio)carbonyl)amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidine-4- (carbonyl)amino)acetic acid, ({[2-({1-[4-(6-{[(t-butoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidyl Acridine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[ 4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid , ({[2-({1-[4-(6-{[(ethylaminomethyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl -5-Hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{[(ethoxycarbonyl)))] }}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({ 1-[4-(6-{[(ethylamine-methyl)methoxy)methyl}pyridinium -3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, {[(5-hydroxy-6-) Base-2-{[1-(4-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-3-yl}phenyl)piperidin-4-yl]- Pyrimidine-4-yl)carbonyl]amino}acetic acid, [({5-Hydroxy-6-methyl-2-[(1-{4-[6-(3-oxobutyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4-[4-(2-)oxybutyl)benzyl]benzene ({}5-hydroxy-6-methyl-2-({1-[4'-(2-) Side oxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-() {1-[4'-(2-Sideoxybutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5- Hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl} Amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[3'-(2-oxopropyl)biphenyl-4-yl]piperidin-4-yl}) ()pyrimidin-4-yl]carbonyl}amino)acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4-[4-(2-oxopropyl)benzyl)] Phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4'-[( 1E)-3-oxobut-1-en-1-yl]biphenyl-4-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[ 5-hydroxy-6-methyl-2-({1-[4'- (3-oxobutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, [({5-hydroxy-6-methyl-) 2-[(1-{5-[4-(2-Siloxypropyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino] Acetic acid, [({5-hydroxy-6-methyl-2-[(1-{5-[3-(2-oxobutyl)phenyl]pyridin-2-yl}piperidin-4-yl) Methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-2-({1-[5-(4-{[(methoxycarbonyl)amino]methyl}benzene) Pyridin-2-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[5-(4-{[(ethylaminomethyl)amino)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl) -5-Hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[5-(4-{[(ethylamine)methyl)oxy)] Methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid.

在本發明之化合物中，按取代基之種類可存在幾何異構物或互變異構物。又，本發明之化合物具有不對稱碳原子時，則可存在光學異構物。本發明包含此等異構物之分離物(例如鏡相異構物或非鏡像異構物)或混合物(例如外消旋物或非鏡像異構物混合物)。還有標幟體化合物，即本發明化合物之1個以上之原子以任意比例被對應之放射性同位素或非放射性同位素取代而成之化合物也包含在本發明內。 In the compounds of the present invention, geometric isomers or tautomers may be present depending on the type of substituent. Further, when the compound of the present invention has an asymmetric carbon atom, an optical isomer may exist. The invention encompasses isolates of such isomers (e.g., mirror isomers or non-image isomers) or mixtures (e.g., racemates or mixtures of non-image areomers). Further, a standard compound, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a corresponding radioisotope or non-radioactive isotope in an arbitrary ratio is also included in the present invention.

本發明之化合物具有胺基等之鹼性基時，可依據期望而形成藥理上容許酸加成鹽。作為此酸加成鹽，可列舉例如：氫氟酸鹽、鹽酸鹽、溴化氫溴酸鹽、氫碘酸鹽等之鹵化氫酸鹽；硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等之無機酸鹽；甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽等之低級烷鏈磺酸鹽；苯磺酸鹽、p-甲苯磺酸鹽等之芳基磺酸鹽；乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽等之有機酸鹽；或鳥胺酸鹽、麩胺酸鹽、天門冬胺酸鹽等之胺基酸鹽，較佳為鹵化氫酸鹽及有機酸鹽。 When the compound of the present invention has a basic group such as an amine group, a pharmacologically acceptable acid addition salt can be formed as desired. Examples of the acid addition salt include a hydrohalide salt such as a hydrofluoride salt, a hydrochloride salt, a hydrobromide bromide or a hydroiodide; a nitrate, a perchlorate, a sulfate, and a phosphoric acid; a mineral acid salt such as a salt; a lower alkyl chain sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; an arylsulfonic acid such as a besylate or a p-toluenesulfonate; Salt; organic acid salt of acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; or alanine, bran Amino acid salts of amine salts, aspartate, and the like, preferably hydrogen halides and organic acid salts.

本發明之化合物含有羧基等之酸性基時，通常可能形成藥理上容許鹼加成鹽。作為如此種鹼加成鹽，可列舉例如鈉鹽、鉀鹽、鋰鹽等之鹼金屬鹽；鈣鹽、鎂鹽等之鹼土金屬鹽；銨鹽等之無機鹽；或二苄基胺鹽、啉鹽、苯基甘胺酸烷基酯鹽、伸乙基二胺鹽、N-甲基還原葡糖胺鹽、二乙胺鹽、三乙胺鹽、環己胺鹽、二環己胺鹽、N,N’-二苄基伸乙基二胺鹽、二乙醇胺鹽、N-苄基-N-(2-苯基乙氧基)胺鹽、哌鹽、四甲基銨鹽、參(羥甲基)胺基甲烷鹽等之有機胺鹽等。 When the compound of the present invention contains an acidic group such as a carboxyl group, it is usually possible to form a pharmacologically acceptable base addition salt. Examples of such a base addition salt include an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; or a dibenzylamine salt. Alkaloid salt, alkyl phenylglycine salt, ethyl diamine salt, N-methyl reduced glucosamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt , N,N'-dibenzylethylidene diamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine An organic amine salt such as a salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt.

本發明之化合物也有作為無溶劑合物或溶劑合物存在。作為溶劑合物，若為藥理上可容許者則無特別限定，具體而言，較佳為水合物、乙醇合物等。此外，以通式(1)表示之化合物中有氮原子存在時，也可以成為N-氧化物，此等溶劑合物及N-氧化物亦包含在本發明之範圍內。 The compounds of the invention also exist as unsolvates or solvates. The solvate is not particularly limited as long as it is pharmacologically acceptable, and specifically, a hydrate or an ethanolate is preferable. Further, when a compound represented by the formula (1) has a nitrogen atom, it may be an N-oxide. These solvates and N-oxides are also included in the scope of the present invention.

在本發明之化合物中，按取代基之種類及組合，可存在順式異構物、反式異構物等之幾何異構物、互變異構物或d體、l體等光學異構物等之各種異構物，本發明之化合物無特別限定時，也包含彼等全部的異構物及任一比例之此等異構物之混合物。 In the compound of the present invention, geometric isomers, tautomers, or optical isomers such as d-forms and l-forms may be present depending on the kind and combination of the substituents. When the compound of the present invention is not particularly limited, the various isomers of the present invention include all of the isomers and a mixture of such isomers in any ratio.

此外，本發明之化合物可含有1個以上構成此種化合物之原子的非天然比例的同位素。作為同位素，可列舉例如氘(2H；D)、氚(3H；T)、碘-125(125I)或碳-14(14C)等。此外，本發明之化合物可以例如氚(3H)、碘-125(125I)、或碳-14(14C)等之放射性同位素放射標幟。 放射性標幟化合物作為治療或預防劑、研究試藥(例如分析試藥)及診斷劑(例如生物體內影像診斷劑)有用的。含有全部比例之放射性或非放射性之同位素的本發明之化合物係包含在本發明之範圍內。 Further, the compound of the present invention may contain one or more unnatural proportion isotopes constituting the atoms of such a compound. Examples of the isotope include hydrazine ( 2 H; D), hydrazine ( 3 H; T), iodine-125 ( 125 I) or carbon-14 ( 14 C). Furthermore, the compounds of the present invention may for example tritium (3 H), iodine -125 (125 I), or carbon -14 (14 C), etc. flag radioisotope radiation. The radioactive label compound is useful as a therapeutic or prophylactic agent, a research reagent (for example, an analytical reagent), and a diagnostic reagent (for example, an in vivo imaging diagnostic reagent). Compounds of the invention containing all proportions of radioactive or non-radioactive isotopes are included within the scope of the invention.

本發明之化合物也可因應其基本骨架或取代基之種類，而適用各種習知之合成法來製造。此時，視官能基之種類，該官能基可在原料至中間體之階段以適當的保護基來保護、或預先取代成容易轉換成該官能基之基。作為此種官能基，有例如胺基、羥基、羧基等，作為彼等之保護基，有例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999中所記載之保護基等，可因應反應條件而適當地選擇使用。根據此種方法，導入該保護基進行反應後，因應需要，藉由去除保護基、或轉變成期望之基，而可以得到期望之化合物。所得到的本發明之化合物，藉由元素分析、NMR、質量分析(mass spectroscopy)、IR分析等之標準分析技術予以鑑定，可分析其組成或純度。 The compounds of the present invention can also be produced by various conventional synthetic methods depending on the type of the basic skeleton or substituent. At this time, depending on the kind of the functional group, the functional group may be protected with a suitable protecting group at the stage of the raw material to the intermediate, or may be preliminarily substituted into a group which is easily converted into the functional group. Examples of such a functional group include an amine group, a hydroxyl group, a carboxyl group and the like, and as such a protective group, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc. The protecting group or the like described in New York, 1999 can be appropriately selected and used depending on the reaction conditions. According to such a method, after the reaction group is introduced and reacted, the desired compound can be obtained by removing the protective group or converting into a desired group as needed. The obtained compound of the present invention is identified by standard analytical techniques such as elemental analysis, NMR, mass spectroscopy, and IR analysis, and its composition or purity can be analyzed.

本發明之化合物製造所用到的原料或試藥，可由供應商購入或根據文獻之方法加以合成。 The starting materials or reagents used in the manufacture of the compounds of the present invention can be purchased from suppliers or synthesized according to the literature.

在本發明中，貧血包含腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血(congestive heart failure)，其中慢性疾病之貧血包含伴隨慢性腎臟病之貧血，慢性腎臓疾病包含慢性腎功能不 全。此外，被投予本發明之化合物的患者，可為接受或未接受透析之患者。 In the present invention, anemia includes renal anemia, anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia, or congestive heart failure accompanied by septic heart failure Anemia of chronic diseases including anemia associated with chronic kidney disease, chronic renal pelvic disease including chronic renal function all. Further, the patient to whom the compound of the present invention is administered may be a patient who has received or not received dialysis.

本發明之化合物或其藥理上容許鹽在使用Hep3B細胞之分析系統中顯示優異的增強EPO產生的活性，且安全性優異。即藉由對哺乳動物(人類、牛、馬或豬等)或鳥類(雞等)投予含有本發明之化合物或其藥理上容許鹽的醫藥組成物，可增強EPO產生。因此，含有本發明之化合物或其藥理上容許鹽之醫藥組成物，可適用於起因於EPO低下之疾病、缺血性腦疾病等之EPO低下的疾病或病狀之預防及/或治療、或對預定手術的患者的自身儲血等。就起因於EPO低下之疾病而言，可列舉例如貧血、特別是腎性貧血(透析期、保存期)、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血。 The compound of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent activity for enhancing EPO production in an analysis system using Hep3B cells, and is excellent in safety. That is, EPO production can be enhanced by administering a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof to a mammal (human, cow, horse or pig, etc.) or a bird (chicken, etc.). Therefore, the pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof can be suitably used for the prevention and/or treatment of a disease or condition caused by an EPO with a low EPO, an ischemic brain disease, or the like, or Self-storage of a patient scheduled for surgery, etc. Examples of diseases caused by low EPO include, for example, anemia, particularly renal anemia (dialysis period, shelf life), anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, inflammation Associated anemia or anemia associated with septic heart failure.

[用以實施發明之態樣] [Used to implement the aspect of the invention]

以下例示本發明之化合物之代表性的製造方法。此外，本發明之製造方法不限於以下所示實例。 Representative methods for the production of the compounds of the present invention are exemplified below. Further, the manufacturing method of the present invention is not limited to the examples shown below.

具有本發明之通式(1)的化合物可藉由以下所述方法得到。 The compound of the formula (1) of the present invention can be obtained by the method described below.

(第1步驟) (Step 1)

第1步驟是由後述之具有通式(2)的化合物製造具有通式(1)的化合物之步驟。 The first step is a step of producing a compound of the formula (1) from a compound of the formula (2) described later.

在上述中，R1至R3表示與前述意義相同，R8表示經取代或未經取代之芳香基或雜芳香基，R1a及R1b表示前述之R1或成為彼等之前驅物之基，R2a表示前述之R2或成為其前驅物之基，R7a及R7b表示前述之R7或成為其前驅物之基，Pro1至Pro4表示選自習知之保護基(例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等)各個官能基之保護基。Pro1至Pro4只要在反應中安定地存在，又不阻礙反應的話，則無別限定，較佳為Pro1表示苄基、Pro2表示第三丁基、Pro3表示甲基、乙基、第三丁基或苄基、Pro4表示第三丁氧基羰基。在1-1c步驟、1-1d步驟、或1-1e步驟中的X1只要與氧結合一起形成脫離基之取代基，則無特別限定，較佳為三氟甲烷磺醯基。 In the above, R 1 to R 3 represent the same meaning as defined above, R 8 represents a substituted or unsubstituted aryl or heteroaryl group, and R 1a and R 1b represent the aforementioned R 1 or become their precursors. a group, R 2a represents a group of R 2 or a precursor thereof, R 7a and R 7b represent a group of the above R 7 or a precursor thereof, and Pro 1 to Pro 4 represent a group selected from a conventional protecting group (for example, Protective Groups). In Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, etc.) protecting groups for individual functional groups. Pro 1 to Pro 4 are not particularly limited as long as they are present in the reaction without any hindrance, and Pro 1 represents a benzyl group, Pro 2 represents a third butyl group, and Pro 3 represents a methyl group or an ethyl group. The third butyl or benzyl group, Pro 4 represents a third butoxycarbonyl group. X 1 in the step 1-1c, the step 1-1d, or the step 1-1e is not particularly limited as long as it forms a substituent of a leaving group in combination with oxygen, and is preferably a trifluoromethanesulfonyl group.

以下就各步驟加以詳述。 The steps are detailed below.

(1-1步驟) (1-1 step)

1-1步驟為由後述之具有通式(2)的化合物製造具有通式(3)的化合物之步驟。作為所需的之反應，可列舉1-1a步驟：保護基Pro2之脫保護反應；1-1b步驟：與具有通式H2NCH(R3)CO2Pro3之胺基酸或胺基酸鹽之縮合反應；1-1c步驟：於6位羥基導入脫離基(-OX1)之反應；1-1d步驟：將脫離基(-OX1)轉變成取代基R2a之反應。 The step 1-1 is a step of producing a compound of the formula (3) from a compound of the formula (2) described later. As a desired reaction, there may be mentioned a step 1-1a: a deprotection reaction of a protecting group Pro 2 ; a step 1-1b: an amino acid or an amine group having a formula H 2 NCH(R 3 )CO 2 Pro 3 Condensation reaction of acid salt; 1-1c step: reaction of introducing a leaving group (-OX 1 ) at the 6-position hydroxyl group; 1-1d step: converting the leaving group (-OX 1 ) into a substituent R 2a .

此外，因應需要可加入1-1e步驟：將R1a轉變成R1b之反應。 Further, a step 1-1e may be added as needed: a reaction for converting R 1a to R 1b .

也可依照1-1a至1-1e步驟任一順序進行。 It can also be carried out in any order according to the steps 1-1a to 1-1e.

(1-1a步驟) (Step 1-1a)

本步驟為進行將保護基Pro2脫保護之步驟。因應使用的Pro2，可從例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等所記載之習知方法中適當地選出，本步驟依其來進行。在此，雖然記載關於選擇第三丁基作為較適當之Pro2，在惰性之溶劑中使用鹼，將Pro2轉變成氫原子之方法(1-1a1步驟)、或在惰性之溶劑中使用酸，將Pro2轉變成氫原子之方法(1-1a2步驟)，但本步驟並非限定於彼等者。 This step is a step of deprotecting the protecting group Pro 2 . Pro 2 may be suitably used from a conventional method such as that described in Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, and the like. Selected, this step is carried out according to it. Here, although a method of selecting a third butyl group as a more appropriate Pro 2 , using a base in an inert solvent, converting Pro 2 into a hydrogen atom (step 1-1a1), or using an acid in an inert solvent is described. A method of converting Pro 2 into a hydrogen atom (step 1-1a2), but this step is not limited to those of them.

(1-1a1步驟) (Step 1-1a1)

本步驟為在惰性之溶劑中，使用適當的鹼將Pro2轉變成氫原子之步驟。 This step is a step of converting Pro 2 to a hydrogen atom using an appropriate base in an inert solvent.

作為所使用之溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙酸乙酯、乙酸丙酯之酯類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. Halogen-based hydrocarbons; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; an ester such as ethyl acetate or propyl acetate; a nitrile such as acetonitrile; An amine, an amine of N,N-dimethylformamide; a sulfinoid such as dimethylsulfinium; a mixed solvent of any ratio of a plurality of organic solvents; or a mixture of such ratios with water Solvents, etc.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，可列舉例如：如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉、氫氧化鉀之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；或磷酸三鉀之磷酸鹼金屬鹽類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and examples thereof include, for example, triethylamine, N,N-diisopropylethylamine, and N-methyl group. An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; or alkali metal phosphates of tripotassium phosphate.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至150℃，較佳為10℃至90℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 10 ° C to 90 ° C.

反應時間隨原料化合物、試藥等而不同，通常為1分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 1 minute to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，目的化合物藉由餾除有機溶劑、加入酸，可得到固體。另一方面，即使加入酸但無法得到固體時，以如乙酸乙酯之有機溶劑萃取有機物，將有機層以一般所使用的程序乾燥後，藉由在減壓下濃縮而可得到目的化合物。 After completion of the reaction, the objective compound is obtained by distilling off an organic solvent and adding an acid. On the other hand, even if a solid is not obtained by adding an acid, the organic substance is extracted with an organic solvent such as ethyl acetate, and the organic layer is dried under a procedure generally used, and then the objective compound is obtained by concentration under reduced pressure.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1a2步驟) (Step 1-1a2)

本步驟為在惰性之溶劑中，使用適當的酸將Pro2轉變成氫原子之步驟。 This step is a step of converting Pro 2 to a hydrogen atom using an appropriate acid in an inert solvent.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；可列舉例如：如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, a halogenated hydrocarbon of methyl chloride or chloroform; an ester such as ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol or ethanol; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; For example, a sulfoximine of dimethylsulfinone; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio of such water and the like.

所使用的酸，只要在一般反應下可作為酸使用，則無特別限定，可列舉例如：如鹽酸、硫酸等之無 機酸；如三氟化氟化硼、三氯化硼、三溴硼、碘化三甲基矽烷之路易斯酸；或如三氟乙酸之有機酸等。 The acid to be used is not particularly limited as long as it can be used as an acid under a general reaction, and examples thereof include, for example, hydrochloric acid, sulfuric acid, and the like. An acid; a Lewis acid such as boron trifluoride fluoride, boron trichloride, boron tribromide or trimethyl decane iodide; or an organic acid such as trifluoroacetic acid.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為-78℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably -78 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，目的化合物藉由餾除有機溶劑、加入鹼，可得到固體。另一方面，即使加入鹼但無法得到固體時，以如乙酸乙酯之有機溶劑萃取有機物，將有機層以一般所使用的程序乾燥後，藉由在減壓下濃縮而可得到目的化合物。 After completion of the reaction, the objective compound can be obtained by distilling off an organic solvent and adding a base. On the other hand, when a solid is not obtained by adding a base, the organic substance is extracted with an organic solvent such as ethyl acetate, and the organic layer is dried under a procedure generally used, and then the objective compound is obtained by concentration under reduced pressure.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1b步驟) (Step 1-1b)

本步驟為將以1-1a步驟所得到的羧酸與具有通式H2NCH(R3)CO2Pro3之胺基酸或胺基酸鹽縮合之步驟，在惰性之溶劑中、鹼之存在下或不存在下，使用縮合劑來進行。 This step is a step of condensing the carboxylic acid obtained in the step 1-1a with an amino acid or an amine acid salt having the general formula H 2 NCH(R 3 )CO 2 Pro 3 in an inert solvent, a base The use of a condensing agent is carried out in the presence or absence.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；可列舉例如：如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基 乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, a halogenated hydrocarbon of methyl chloride or chloroform; an ester such as ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide a guanamine; for example, a sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳為可列舉例如：如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；或如磷酸三鉀之磷酸鹼金屬鹽類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and examples thereof include, for example, triethylamine, N,N-diisopropylethylamine, and N-methyl group. An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxide such as sodium hydroxide; alkaline earth metal hydroxide such as calcium hydroxide; or alkali metal phosphate such as tripotassium phosphate.

作為所使用的縮合劑，只要可作為形成醯胺鍵的縮合劑而被使用者(例如第四版實驗科學講座(22.有機合成IV酸‧胺基酸‧胜肽)、楠本正一等、日本化學會、丸善股份有限公司、1990；泉屋信夫等、胜肽合成之基礎與實驗、丸善、1985等)則無特別限定，較佳為可列舉例如O-苯并***-N,N,N’,N’-四甲基脲六氟磷酸鹽(HBTU)、2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲四氟硼酸鹽(TBTU)、1-(3-二甲基胺丙基)-3-乙基碳二醯亞胺鹽酸鹽(EDCI)、4-(2-{[(環己基亞胺基)亞甲基]胺基}乙基-4-甲基啉-4-鎓對甲苯磺酸鹽(CMC)、二環己碳二醯亞胺(DCC)、1,1’-羰基雙(1H-咪唑)(CDI)、(1H-苯并***-1-基氧基)(三吡咯啶-1-基)鏻六氟磷酸鹽(PyBOP)、溴(三吡咯啶-1-基)鏻六氟磷酸鹽(PyBrOP)、氯化4-(4,6-二甲氧 基-1,3,5-三-2-基)-4-甲基啉鎓(DMT-MM)或2-氯-4,6-二甲氧基-1,3,5-三(DMT)等。也可進一步加入1-羥基苯并***(HOBT)或N,N-二甲基胺吡啶等作為添加劑。 As the condensing agent to be used, it can be used as a condensing agent for forming a guanamine bond (for example, the fourth edition of the experimental science lecture (22. Organic synthesis IV acid ‧ amino acid ‧ peptide), Nanben Zhengyi, etc. The Japanese Chemical Society, Maruzen Co., Ltd., 1990; Izumi Yukio, etc., the basis and experiment of peptide synthesis, Maruzen, 1985, etc.) are not particularly limited, and preferably, for example, O-benzotriazole-N,N, N', N'-tetramethylurea hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate ( TBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 4-(2-{[(cyclohexylimido)methylene] Amino}ethyl-4-methyl Porphyrin-4-indole p-toluenesulfonate (CMC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyl bis(1H-imidazole) (CDI), (1H-benzotriazole- 1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), chlorinated 4-(4, 6-dimethoxy-1,3,5-three -2-yl)-4-methyl Porphyrin (DMT-MM) or 2-chloro-4,6-dimethoxy-1,3,5-three (DMT) and so on. Further, 1-hydroxybenzotriazole (HOBT) or N,N-dimethylamine pyridine or the like may be further added as an additive.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至150℃，較佳為0℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至24小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 24 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1C步驟) (1-1C step)

本步驟為將6位羥基轉變成脫離基(-OX1)之步驟，在惰性之溶劑中、鹼之存在下或不存在下，藉由與氯化物或酸酐反應來進行。 This step is a step of converting the 6-hydroxy group into a leaving group (-OX 1 ) by reacting with a chloride or an acid anhydride in an inert solvent, in the presence or absence of a base.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類； 如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；或複數有機溶劑之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An ether of 1,2,2-dimethoxyethane; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; such as dimethyl sulfin a sulfinamide; or a mixed solvent of any ratio of a plurality of organic solvents.

所使用的氯化物或酸酐，只要具有如-OX1基成為習知之脫離基之X1的氯化物或酸酐，則無特別限定，較佳為可列舉例如：如三氟甲烷磺酸酐之經取代或未經取代之烷基磺酸酐或芳香基磺酸酐；如甲烷磺醯基氯化物、p-甲苯磺醯基氯化物之經取代或未經取代之烷基磺醯基氯化物或芳香基磺醯基氯化物；或經取代或未經取代之烷基磷酸氯化物或芳香基磷酸氯化物。 Chloride or acid anhydride to be used, as long as it has a group -OX be of conventional leaving group of X 1 is chloride or acid anhydride is not particularly limited, but preferably include, for example: as trifluoromethanesulfonic acid anhydride of a substituted Or unsubstituted alkyl sulfonic anhydride or aryl sulfonic anhydride; substituted or unsubstituted alkyl sulfonyl chloride or aryl sulfonate such as methanesulfonyl chloride or p-toluenesulfonyl chloride Mercapto chloride; or substituted or unsubstituted alkyl phosphate chloride or aryl phosphate chloride.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；或如磷酸三鉀之磷酸鹼金屬鹽類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxide such as sodium hydroxide; alkaline earth metal hydroxide such as calcium hydroxide; or alkali metal phosphate such as tripotassium phosphate.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為-80℃至40℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably -80 ° C to 40 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1d步驟) (1-1d step)

本步驟為將脫離基(-OX1)轉變成取代基R2a之步驟。R2a為烷基或烯基時，在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，藉由與烷基硼化合物或烯基硼化合物反應來進行(1-1d1步驟)。此外，R2a為甲基硫烷基時，在惰性之溶劑中、鹼之存在下或不存在下，藉由與甲烷硫醇或甲烷硫醇之金屬鹽反應來進行(1-1d2步驟)。 This step is a step of converting the leaving group (-OX 1 ) to the substituent R 2a . When R 2a is an alkyl or alkenyl group, in the presence of an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the absence of a metal catalyst, by an alkyl boron compound or alkene The boron compound is reacted to carry out (step 1-1d1). Further, when R 2a is a methylsulfanyl group, it is carried out by reacting with a metal salt of methanethiol or methanethiol in an inert solvent in the presence or absence of a base (1-1d2 step).

(1-1d1步驟) (step 1-1d1)

本步驟為將脫離基(-OX1)轉變成烷基或烯基之步驟，在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，藉由與烷基硼化合物或烯基硼化合物反應來進行。此反應條件可從例如Zou,G.,Reddy,Y.K.,Falck,J.R.,Tetrahedron Lett.,2001,42,7213；Molander,G.A.,Yun,C.-S.,Tetrahedron,2002,58,1465；Tsuji,J.,Palladium Reagents and Catalysts,John Wiley & Sons,Inc.,England,2004；Metal-Catalyzed Cross-Coupling Reactions,de Meijere,A.,Diederich,F.,Wiley-VCH,Weinheim,2004等所記載之習知方法中適當地選擇，本步驟依其來進行。 雖然本步驟之反應條件較佳為如下所述者，但並非限定於彼等者。 This step is a step of converting a leaving group (-OX 1 ) into an alkyl group or an alkenyl group, in the presence of an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the presence or absence of a metal catalyst. The reaction is carried out by reacting with an alkyl boron compound or an alkenyl boron compound. Such reaction conditions can be obtained, for example, from Zou, G., Reddy, YK, Falck, JR, Tetrahedron Lett., 2001, 42, 7213; Molander, GA, Yun, C.-S., Tetrahedron, 2002, 58, 1465; Tsuji , J., Palladium Reagents and Catalysts, John Wiley & Sons, Inc., England, 2004; Metal-Catalyzed Cross-Coupling Reactions, de Meijere, A., Diederich, F., Wiley-VCH, Weinheim, 2004, etc. The appropriate selection is made in the conventional method, and this step is performed in accordance with this. Although the reaction conditions in this step are preferably as described below, they are not limited to those of them.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide a guanamine; for example, a sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；如磷酸三鉀之磷酸鹼金屬鹽類；或如第三丁醇鈉、第三丁醇鉀之金屬烷氧化物類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxide such as sodium hydroxide; alkaline earth metal hydroxide such as calcium hydroxide; alkali metal phosphate such as tripotassium phosphate; or third butanol Sodium, metal alkoxides of potassium butoxide, and the like.

作為所使用的添加劑，只要是在習知之方法中使用者，並無特別限定，較佳可列舉例如：如氧化銀、氧化鋁之金屬氧化物；如三苯基膦、三-第三丁基膦、三環己膦、三(o-甲苯甲醯基)膦、二苯基膦基二茂鐵、2-二環己膦基-2’,6’-二甲氧基-1,1’-聯苯(S-PHOS)、2-二環 己膦基-2’,4’,6’-三異丙基-1,1’-聯苯(X-PHOS)、2,2’-雙(二苯基膦基)-1,1’-聯萘(BINAP)之膦類；如三苯基氧化物之膦氧化物類；如氯化鋰、氟化鉀、氟化銫之金屬鹽；或如溴化四丁基銨之銨鹽等。此等亦可使用任意比例組合。 The additive to be used is not particularly limited as long as it is a user in a conventional method, and examples thereof include metal oxides such as silver oxide and aluminum oxide; for example, triphenylphosphine and tri-tert-butyl group. Phosphine, tricyclohexylphosphine, tris(o-tolylmethyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1' -biphenyl (S-PHOS), 2-bicyclic Hexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-bis(diphenylphosphino)-1,1'- a phosphine of binaphthyl (BINAP); a phosphine oxide such as a triphenyl oxide; a metal salt such as lithium chloride, potassium fluoride or cesium fluoride; or an ammonium salt such as tetrabutylammonium bromide. These can also be combined in any ratio.

所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如肆(三苯基膦)鈀、雙(三-第三丁基膦)鈀、2乙酸鈀、2氯化鈀二苯基膦基二茂鐵錯合物、2氯化鈀苯并腈錯合物、2氯化鈀乙腈錯合物、雙(二亞苄基丙酮)鈀、參(二亞苄基丙酮)二鈀、雙[1,2-雙(二苯基膦基)乙烷]鈀、3-氯吡啶[1,3-雙(2,6-二異丙苯基)咪唑-2-亞基]鈀、鈀-活性碳之鈀觸媒。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, ruthenium (triphenylphosphine) palladium or bis(tri-tert-butylphosphine) palladium or 2 is used. Palladium acetate, palladium chloride diphenylphosphinoferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, ginseng (dibenzylideneacetone) dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl) Imidazole-2-ylidene] palladium, palladium-activated carbon palladium catalyst.

所使用的烷基硼化合物或烯基硼化合物，只要可使用作為習知之反應試藥者，則無特別限定，R2a為烷基時，可列舉例如甲基硼酸、甲基硼酸酯、三氟(甲基)硼(trifluoro(methyl)boranuide)金屬鹽、乙基硼酸、乙基硼酸酯或乙基三氟硼(ethyltrifluoroboranuide)金屬鹽等，R2a為烯基時，可列舉例如乙烯硼酸、4,4,5,5-四甲基-2-乙烯-1,3,2-二氧硼戊環、乙烯硼酸酯、乙烯三氟硼(vinyltrifluoroboranuide)金屬鹽、烯丙基硼酸、烯丙基硼酸酯或烯丙基(三氟)硼(allyltrifluoroboranuide)金屬鹽等。 The alkyl boron compound or the alkenyl boron compound to be used is not particularly limited as long as it can be used as a conventional reaction reagent. When R 2a is an alkyl group, for example, methylboronic acid, methyl borate, and the like are mentioned. a metal salt of a trifluoro(methyl)boranuide, an ethylboronic acid, an ethyl borate or an ethyltrifluoroboranuide metal salt, and when R 2a is an alkenyl group, for example, ethylene boric acid , 4,4,5,5-tetramethyl-2-ethene-1,3,2-dioxaborolan, ethylene borate, vinyltrifluoroboranuide metal salt, allyl boric acid, alkene A propyl borate or an allyltrifluoroboranuide metal salt or the like.

所使用的烷基硼酸酯之酯部分、三氟(烷基)硼金屬鹽之金屬、烯基硼酸酯之酯部分、及三氟(烯基)硼金屬鹽之金屬，只要作為習知之化合物而廣為人知者、或以習知之方法為標準所合成者，則無特別限定。 The ester portion of the alkyl borate ester, the metal of the trifluoro(alkyl)boron metal salt, the ester portion of the alkenyl borate ester, and the metal of the trifluoro(alkenyl) boron metal salt, as long as it is conventional The compound is widely known or synthesized by a conventional method, and is not particularly limited.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至200℃，較佳為0℃至150℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至12小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

此外，R2a為烯基時，可藉由進行依與後述之1-2a1步驟相同之反應條件之加氫反應，將該烯基轉變成對應之烷基。 Further, when R 2a is an alkenyl group, the alkenyl group can be converted into a corresponding alkyl group by a hydrogenation reaction under the same reaction conditions as in the step 1-2a1 described later.

(1-1d2步驟) (step 1-1d2)

本步驟為將脫離基(-OX1)轉變成甲基硫烷基之步驟，在惰性之溶劑中、鹼之存在下或不存在下，藉由與甲烷硫醇或甲烷硫醇之金屬鹽反應來進行。 This step is a step of converting a leaving group (-OX 1 ) to a methylsulfanyl group by reacting with a metal salt of methanethiol or methanethiol in an inert solvent, in the presence or absence of a base, or in the absence of a base. Come on.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類； 如甲醇、乙醇之醇類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; an alcohol such as methanol or ethanol; For example, a sulfoximine of dimethylsulfinone; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio of such water and the like.

在所使用的甲烷硫醇之金屬鹽中之金屬雖無特別限定，不過較佳可列舉如鈉之鹼金屬或如鎂之鹼土金屬等。 The metal in the metal salt of methanethiol to be used is not particularly limited, and preferably an alkali metal such as sodium or an alkaline earth metal such as magnesium.

所使用的鹼，只要在一般反應下可作為鹼使用者，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；如磷酸三鉀之磷酸鹼金屬鹽類；或如第三丁醇鈉、第三丁醇鉀之金屬烷氧化物類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate of sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; for example, calcium hydrogencarbonate Alkaline earth metal hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal phosphates such as tripotassium phosphate; or sodium tert-butoxide , metal alkoxides of potassium butoxide, and the like.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至150℃，較佳為0℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至12小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1e步驟) (1-1e step)

本步驟為將R1a轉變成R1b之步驟，依環Q1之雜環之種類而有不同的合成法。R1a具有環Q1，而環Q1為含有氮原子之雜環，關於在該氮原子上具有保護基Pro4之情況，於敘述如下。 This step is a step of converting R 1a to R 1b , and has a different synthesis method depending on the kind of the hetero ring of ring Q 1 . R 1a has a ring Q 1 and ring Q 1 is a hetero ring containing a nitrogen atom, and the case where the protective group Pro 4 is present on the nitrogen atom is described below.

作為(1-1e步驟)所需之反應可列舉：1-1e1步驟：保護基Pro4之脫保護反應；1-1e2步驟：取代基R8之導入反應。 The reaction required as the (1-1e step) can be exemplified by a step 1-1e1: a deprotection reaction of the protective group Pro 4 ; and a step 1-1e2: an introduction reaction of the substituent R 8 .

此外，因應需要可加入：1-1e3步驟：將環Q3上之取代基R7a轉變成R7b之反應。 Further, a step of 1-1e3: a reaction of converting the substituent R 7a on the ring Q 3 to R 7b may be added as needed.

上述1-1e1步驟及1-1e2步驟之反應式表示R1a為於第1位具有保護基Pro4之哌啶-4-基時，以下1-1e1步驟之說明雖然表示Pro4為第三丁氧基羰基的情形，但1-1e步驟並非限定於彼等者。 The reaction formulas of the above steps 1-1e1 and 1-1e2 indicate that R 1a is a piperidin-4-yl group having a protecting group Pro 4 at the first position, and the description of the following step 1-1e1 indicates that Pro 4 is a third group. In the case of an oxycarbonyl group, the steps 1-1e are not limited to those of them.

(1-1e1步驟) (Step 1-1e1)

本步驟為製造具有通式(5)或(8)的化合物之步驟。因應作為保護基使用的Pro4，而可從例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等所記載之習知方法中適當地選擇，本步驟依其來進行。Pro4為第三丁氧基羰基時，本步驟為藉由將在惰性之溶劑中，適當的試藥加至具有通式(4)或(7)的化合物來進行。 This step is a step of producing a compound having the formula (5) or (8). Pro 4 can be used as a protective group, and can be obtained, for example, from Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, and the like. The method is appropriately selected, and this step is carried out according to it. When Pro 4 is a third butoxycarbonyl group, this step is carried out by adding a suitable reagent to a compound having the formula (4) or (7) in an inert solvent.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如乙酸乙酯、乙酸丙酯之酯類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；或複數之有機溶劑之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. Halogen hydrocarbons; diethyl ether, tetrahydrofuran, 1,4-two An ether of 1,2,2-dimethoxyethane; an ester such as ethyl acetate or propyl acetate; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide Amidoxime; such as sulfinium sulfoximine; or a mixed solvent of any ratio of a plurality of organic solvents.

所使用的試藥，只要在一般反應下可使用作為將第三丁氧基羰基脫保護之試藥者，則無特別限定，較佳可列舉如鹽酸、硫酸之無機酸；如乙酸、三氟乙酸之有機酸；如碘化三甲基矽烷、三氟化硼之路易斯酸；如氯化乙醯之氯化物；或如氫氧化鈉之鹼金屬氫氧化物類等。 The reagent to be used is not particularly limited as long as it can be used as a reagent for deprotecting the third butoxycarbonyl group under a general reaction, and preferably an inorganic acid such as hydrochloric acid or sulfuric acid; for example, acetic acid or trifluorocarbon An organic acid of acetic acid; such as a Lewis acid of trimethyl decane iodide or boron trifluoride; a chloride such as acethanide chloride; or an alkali metal hydroxide such as sodium hydroxide.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至100℃，較佳為10℃至50℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 10 ° C to 50 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，餾除溶劑，藉由於所得到的殘留物中加入正己烷等而得到固體物質。將此過濾後，經由乾燥，而得到具有通式(5)或(8)的化合物之鹽。另一方面，即使加入正己烷等也無法得到固體物質時，如以乙酸乙酯之有機溶劑萃取有機物後，可將有機層以一般所使用的程序乾燥後濃縮，或藉由直接在減壓下濃縮而得到目的化合物。 After completion of the reaction, the solvent is distilled off, and a solid substance is obtained by adding n-hexane or the like to the obtained residue. After filtering this, it is dried to obtain a salt of the compound of the formula (5) or (8). On the other hand, when a solid substance cannot be obtained even if n-hexane or the like is added, the organic layer can be dried by a procedure generally used after the organic substance is extracted with an organic solvent of ethyl acetate, or directly under reduced pressure. Concentration gave the desired compound.

(1-1e2步驟) (step 1-1e2)

本步驟為可依據(i)1-1e2-1步驟；(ii)1-1e2-2及1-1e2-3步驟之組合；或(iii)1-1e2-2、1-1e2-4及1-1e2-5步驟之組合來進行。 This step is a combination of steps (i) 1-1e2-1; (ii) steps 1-1e2-2 and 1-1e2-3; or (iii) 1-1e2-2, 1-1e2-4 and 1 A combination of -1e2-5 steps is performed.

(1-1e2-1步驟) (Step 1-1e2-1)

本步驟為製造具有通式(6)或(9)的化合物之步驟，在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，藉由使含有環Q2及環Q3之經取代或未經取代之芳香基鹵化物或雜芳基鹵化物或芳香基假鹵化物或雜芳基假鹵化物與具有通式(5)或(8)的化合物反應來進行。此反應條件可從例如Tsuji,J.Palladium Reagents and Catalysts,John Wiley & Sons,Inc.,England,2004；Jiang,L.,Buchwald,S.L.,Palladium-Catalyzed Aromatic Carbon-Nitorogen Bond Formation；Metal-Catalyzed Cross-Coupling Reactions,de Meijere,A.,Diederich,F.,Wiley-VCH,Weinheim,2004,Chapter 13等所記載之習知方法中適當地選擇，本步驟依其來進行。雖然本步驟之反應條件較佳為如下所述者，但並非限定於彼等者。 This step is a step of producing a compound having the formula (6) or (9) in the presence of an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the absence of a metal catalyst, By having a substituted or unsubstituted aryl halide or heteroaryl halide or an aromatic pseudohalide or a heteroaryl pseudohalide containing ring Q 2 and ring Q 3 having the formula (5) or The compound of (8) is reacted to carry out. Such reaction conditions can be obtained, for example, from Tsuji, J. Palladium Reagents and Catalysts, John Wiley & Sons, Inc., England, 2004; Jiang, L., Buchwald, SL, Palladium-Catalyzed Aromatic Carbon-Nitorogen Bond Formation; Metal-Catalyzed Cross. -Coupling Reactions, de Meijere, A., Diederich, F., Wiley-VCH, Weinheim, 2004, Chapter 13 and the like are appropriately selected from the conventional methods, and this step is carried out according to this. Although the reaction conditions in this step are preferably as described below, they are not limited to those of them.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二乙 醚、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide a guanamine; for example, a sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；如乙酸鈉、乙酸鉀之鹼金屬乙酸鹽類；如磷酸三鉀之磷酸鹼金屬鹽類；如第三丁醇鈉、第三丁醇鉀之金屬烷氧化物類；如鋰二異丙基醯胺、鈉六甲基二矽胺之有機金屬醯胺類；或如第三丁基鋰之有機金屬化合物；如氫化鉀之金屬氫化物類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate of sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; for example, calcium hydrogencarbonate Alkaline earth metal hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal acetates such as sodium acetate or potassium acetate; An alkali metal phosphate; for example, a metal alkoxide of sodium t-butoxide or potassium t-butoxide; an organometallic guanamine such as lithium diisopropyl decylamine or sodium hexamethyldiamine; or An organometallic compound of a third butyllithium; a metal hydride such as potassium hydride.

所使用的添加劑，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如：如氧化銀、氧化鋁之金屬氧化物；如三苯基膦、三-第三丁基膦、三環己膦、三(o-甲苯甲醯基)膦、二苯基膦基二茂鐵、2-二環己膦基-2’,6’-二甲氧基-1,1’-聯苯(S-PHOS)、2-二環己膦基-2’,4’,6’-三異丙基-1,1’-聯苯(X-PHOS)、2,2’-雙(二苯基膦基)-1,1’-聯萘(BINAP)之膦類；如三苯基膦氧化物之膦氧化物類；如氯化鋰、氟化鉀、氟化銫之金 屬鹽；或如溴四丁基銨之銨鹽等。此等亦可使用任意比例組合。 The additive to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, a metal oxide such as silver oxide or aluminum oxide; such as triphenylphosphine or tri-t-butyl group; Phosphine, tricyclohexylphosphine, tris(o-tolylmethyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1' -biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-double a phosphine of (diphenylphosphino)-1,1'-binaphthyl (BINAP); a phosphine oxide such as triphenylphosphine oxide; a gold such as lithium chloride, potassium fluoride or cesium fluoride Is a salt; or an ammonium salt such as tetrabutylammonium bromide. These can also be combined in any ratio.

作為所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如肆(三苯基膦)鈀、雙(三-第三丁基膦)鈀、2乙酸鈀、2氯化鈀二苯基膦基二茂鐵錯合物、2氯化鈀苯并腈錯合物、2氯化鈀乙腈錯合物、雙(二亞苄基丙酮)鈀、參(二亞苄基丙酮)二鈀、雙[1,2-雙(二苯基膦基)乙烷]鈀、3-氯吡啶[1,3-雙(2,6-二異丙苯基)咪唑-2-亞基]鈀、鈀-活性碳之鈀觸媒等。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, ruthenium (triphenylphosphine)palladium or bis(tris-tert-butylphosphine)palladium, 2 palladium acetate, palladium diphenylphosphinoferrocene complex, 2 palladium palladium benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, Preference (dibenzylideneacetone) dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl) Imidazole-2-ylidene]palladium, palladium-activated carbon palladium catalyst, and the like.

所謂的假鹵化物表示具有假鹵素基的化合物，假鹵素基表示：在使用過渡金屬觸媒的耦合反應中，已知可對與鹵原子相同的低原子價過渡金屬觸媒進行氧化加成者之基。假鹵素基只要是已知可產生上述氧化加成反應者之基，則無特別限定，可列舉例如三氟甲烷磺醯基氧基、甲烷磺醯基氧基、p-甲苯磺醯基氧基之磺醯基氧基；如乙醯基氧基之醯氧基；二重氮基；或磷酸基(phosphonyloxy)等。 The so-called pseudohalide means a compound having a pseudohalogen group, and the pseudohalogen group means that, in a coupling reaction using a transition metal catalyst, it is known that an oxide addition agent which is the same low-valent transition metal catalyst as a halogen atom is known. The basis. The pseudohalogen group is not particularly limited as long as it is known to generate the above-mentioned oxidative addition reaction, and examples thereof include a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. a sulfonyloxy group; such as an oxiranyloxy group; a diazo group; or a phosphonyloxy group.

所使用的經取代或未經取代之芳香基鹵化物或雜芳基鹵化物或芳香基假鹵化物或雜芳基假鹵化物只要為習知之化合物、或以習知之方法為標準所合成者，則無特別限定。 The substituted or unsubstituted aryl halide or heteroaryl halide or the aryl pseudohalide or heteroaryl pseudohalide used may be synthesized as a conventional compound or by a conventional method. There is no particular limitation.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至200℃，較佳為0℃至150℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至12小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1e2-2步驟) (step 1-1e2-2)

本步驟為在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，含有環Q2且不含環Q3，使經取代或未經取代之芳香基鹵化物或雜芳基鹵化物或芳香基假鹵化物或雜芳基假鹵化物與具有通式(5)或(8)的化合物進行反應之步驟。 This step comprises ring Q 2 and no ring Q 3 in the presence of an inert solvent, in the absence or presence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, such that substituted or not The step of reacting a substituted aryl halide or heteroaryl halide or an aromatic pseudohalide or a heteroaryl pseudohalide with a compound of the formula (5) or (8).

本步驟可依據以1-1e2-1步驟為標準的方法進行。 This step can be carried out according to the method using the step 1-1e2-1 as a standard.

(1-1e2-3步驟) (1-1e2-3 step)

本步驟為在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，將於1-1e2-2步驟所得到之於環Q2具有如鹵原子或-OX1基之脫離基的化合物，藉由與經取代或未經取代之芳香基硼酸或雜芳香基硼酸反應，製造具有通式(6)或(9)的化合物 之步驟。此反應條件可從例如Miyaura,N.，Yamada,K.,Suzuki,A.,Tetrahedron Lett.,1979,36,3437；Miyaura,N.,Suzuki,A.,Chem.Rev.,1995,95,2457等所記載之習知方法中適當地選擇，本步驟依其來進行。本步驟之反應條件較佳為如下所述者，但並非限定於彼等者。 This step is carried out in the presence of an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, and the ring Q 2 obtained in the step 1-1e2-2 has A compound having a compound of the formula (6) or (9) is produced by reacting a halogen atom or a leaving group of a -OX 1 group with a substituted or unsubstituted aromatic boronic acid or a heteroaromatic boronic acid. Such reaction conditions can be obtained, for example, from Miyaura, N., Yamada, K., Suzuki, A., Tetrahedron Lett., 1979, 36, 3437; Miyaura, N., Suzuki, A., Chem. Rev., 1995, 95. The conventional method described in 2457 or the like is appropriately selected, and this step is carried out in accordance with this. The reaction conditions in this step are preferably as described below, but are not limited to those of them.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；如複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide Amidoxime; such as sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；如乙酸鈉、乙酸鉀之鹼金屬乙酸鹽類；如磷酸三鉀之磷酸鹼金屬鹽類；如第三丁醇鈉、第三丁醇鉀之金屬烷氧化物類；如鋰二異丙基醯胺、鈉六甲基二矽胺之有機金屬醯胺類；如第三丁基鋰之有機金屬化合物；或如氫化鉀之金屬氫化物類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate of sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; for example, calcium hydrogencarbonate Alkaline earth metal hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal acetates such as sodium acetate or potassium acetate; An alkali metal phosphate; for example, a metal alkoxide of sodium butoxide or potassium t-butoxide; an organometallic amide such as lithium diisopropyl decylamine or sodium hexamethyldiamine; An organometallic compound of tributyllithium; or a metal hydride such as potassium hydride.

所使用的添加劑，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如：如氧化銀、氧化鋁之金屬氧化物；如三苯基膦、三-第三丁基膦、三環己膦、三(o-甲苯甲醯基)膦、二苯基膦基二茂鐵、2-二環己膦基-2’,6’-二甲氧基-1,1’-聯苯(S-PHOS)、2-二環己膦基-2’,4’,6’-三異丙基-1,1’-聯苯(X-PHOS)、2,2’-雙(二苯基膦基)-1,1’-聯萘(BINAP)之膦類；如三苯基膦氧化物之膦氧化物類；如氯化鋰、氟化鉀、氟化銫之金屬鹽；或如溴四丁基銨之銨鹽等。此等亦可使用任意比例組合。 The additive to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, a metal oxide such as silver oxide or aluminum oxide; such as triphenylphosphine or tri-t-butyl group; Phosphine, tricyclohexylphosphine, tris(o-tolylmethyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1' -biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-double a phosphine of (diphenylphosphino)-1,1'-binaphthyl (BINAP); a phosphine oxide such as triphenylphosphine oxide; a metal salt such as lithium chloride, potassium fluoride or cesium fluoride Or an ammonium salt such as tetrabutylammonium bromide. These can also be combined in any ratio.

所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如肆(三苯基膦)鈀、雙(三-第三丁基膦)鈀、2乙酸鈀、2氯化鈀二苯基膦基二茂鐵錯合物、2氯化鈀苯并腈錯合物、2氯化鈀乙腈錯合物、雙(二亞苄基丙酮)鈀、參(二亞苄基丙酮)二鈀、雙[1,2-雙(二苯基膦基)乙烷]鈀、3-氯吡啶[1,3-雙(2,6-二異丙苯基)咪唑-2-亞基]鈀、鈀-活性碳之鈀觸媒等。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, ruthenium (triphenylphosphine) palladium or bis(tri-tert-butylphosphine) palladium or 2 is used. Palladium acetate, palladium chloride diphenylphosphinoferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, ginseng (dibenzylideneacetone) dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl) Imidazole-2-ylidene]palladium, palladium-activated carbon palladium catalyst, and the like.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至200℃，較佳為0℃至150℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至12小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1e2-4步驟) (Step 1-1e2-4)

本步驟為在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，將於1-1e2-2步驟所得到之於環Q2具有如鹵原子或-OX1基之脫離基之化合物，藉由與硼試藥反應，轉變成對應的硼化合物之步驟。此反應條件可從例如Ishiyama,T.,Murata,M.,Miyaura,N.,J.Org.Chem.,1995,60,7508；Ishiyama,T.,Takagi,J.,Ishida,K.,Miyaura,N.,Anastasi,N.R.,Hartwig,J.F.,J.Am.Chem.Soc.,2002,124,390；Ishiyama,T.,Takagi,J.,Hartwig,J.F.,Miyaura,N.,Angew.Chem.Int.Ed.,2002,41,3056等所記載之習知方法中適當地選擇，本步驟依其來進行。本步驟之反應條件較佳為如下所述者，但並非限定於彼等者。 This step is carried out in the presence of an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, and the ring Q 2 obtained in the step 1-1e2-2 has A compound such as a halogen atom or a -OX 1 group-releasing group is converted into a corresponding boron compound by reacting with a boron reagent. The reaction conditions can be, for example, from Ishiyama, T., Murata, M., Miyaura, N., J. Org. Chem., 1995, 60, 7508; Ishiyama, T., Takagi, J., Ishida, K., Miyaura. , N., Anastasi, NR, Hartwig, JF, J. Am. Chem. Soc., 2002, 124 , 390; Ishiyama, T., Takagi, J., Hartwig, JF, Miyaura, N., Angew. The conventional method described in Int. Ed ., 2002, 41 , 3056, etc. is appropriately selected, and this step is carried out in accordance with this. The reaction conditions in this step are preferably as described below, but are not limited to those of them.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之 亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide a guanamine; for example, a sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

作為所使用的硼試藥，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二-1,3,2-二氧硼戊環等。 The boron reagent to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, 4, 4, 4', 4', 5, 5, 5', 5'-eight Methyl-2,2'-di-1,3,2-dioxaborolan and the like.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；如乙酸鈉、乙酸鉀之鹼金屬乙酸鹽類；如磷酸三鉀之磷酸鹼金屬鹽類；如第三丁醇鈉、第三丁醇鉀之金屬烷氧化物類等；如鋰二異丙基醯胺、鈉六甲基二矽胺之有機金屬醯胺類；或如第三丁基鋰之有機金屬化合物；如氫化鉀之金屬氫化物類等。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxide such as sodium hydroxide; alkaline earth metal hydroxide such as calcium hydroxide; alkali metal acetate such as sodium acetate or potassium; An alkali metal phosphate; for example, a sodium alkoxide, a metal alkoxide of potassium butoxide; an organometallic guanamine such as lithium diisopropyl decylamine or sodium hexamethyl decylamine; Or an organometallic compound such as a tert-butyllithium; a metal hydride such as potassium hydride or the like.

所使用的添加劑，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如：如氧化銀、氧化鋁之金屬氧化物；如三苯基膦、三-第三丁基膦、三環己膦、三(o-甲苯甲醯基)膦、二苯基膦基二茂鐵、2-二環己膦基-2’,6’-二甲氧基-1,1’-聯苯(S-PHOS)、2-二環己膦基-2’,4’,6’-三異丙基-1,1’-聯苯(X-PHOS)、2,2’-雙(二苯基膦基)-1,1’-聯萘(BINAP)之膦類；如三苯基膦 氧化物之膦氧化物類；如氯化鋰、氟化鉀、氟化銫之金屬鹽；或如溴四丁基銨之銨鹽等。此等亦可使用任意比例組合。 The additive to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, a metal oxide such as silver oxide or aluminum oxide; such as triphenylphosphine or tri-t-butyl group; Phosphine, tricyclohexylphosphine, tris(o-tolylmethyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1' -biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-double a phosphine of (diphenylphosphino)-1,1'-binaphthyl (BINAP); such as triphenylphosphine a phosphine oxide of an oxide; a metal salt such as lithium chloride, potassium fluoride or cesium fluoride; or an ammonium salt such as tetrabutylammonium bromide. These can also be combined in any ratio.

所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如肆(三苯基膦)鈀、雙(三-第三丁基膦)鈀、2乙酸鈀、2氯化鈀二苯基膦基二茂鐵錯合物、2氯化鈀苯并腈錯合物、2氯化鈀乙腈錯合物、雙(二亞苄基丙酮)鈀、參(二亞苄基丙酮)二鈀、雙[1,2-雙(二苯基膦基)乙烷]鈀、3-氯吡啶[1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基]鈀、鈀-活性碳之鈀觸媒等。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and preferably, for example, ruthenium (triphenylphosphine) palladium or bis(tri-tert-butylphosphine) palladium or 2 is used. Palladium acetate, palladium chloride diphenylphosphinoferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, ginseng (dibenzylideneacetone) dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl) Imidazole-2-ylidene]palladium, palladium-activated carbon palladium catalyst, and the like.

反應溫度隨原料化合物、試藥等而不同，通常為-10℃至200℃，較佳為0℃至150℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至48小時，較佳為10分鐘至12小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1e2-5步驟) (step 1-1e2-5)

本步驟為在惰性之溶劑中、鹼之存在下或不存在下、添加劑之存在下或不存在下、金屬觸媒之存在下，將於 1-1e2-4步驟所得到的硼化合物，藉由與含有環Q3之經取代或未經取代之芳香基鹵化物雜芳基鹵化物或芳香基假鹵化物或雜芳基假鹵化物進行反應，以製造具有通式(6)或(9)的化合物之步驟。本步驟可依據以1-1e2-3步驟為標準的方法進行。 This step is a boron compound obtained in the step 1-1e2-4 in the presence of an inert solvent, in the absence or presence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, Reacting with a substituted or unsubstituted aryl halide heteroaryl halide or an aromatic pseudohalide or a heteroaryl pseudohalide containing a ring Q 3 to produce a formula (6) or (9) The steps of the compound. This step can be carried out according to the method using the step 1-1e2-3 as a standard.

(1-1e3步驟) (step 1-1e3)

本步驟為將環Q3上之取代基R7a轉變成R7b之步驟，依據R7b之取代基之種類而有不同的合成法。R7b為烷基胺甲醯基氧基烷基、烷基胺甲醯基胺基烷基、烷氧基羰基胺基烷基、烷硫基羰基胺基烷基或烷磺醯基胺基烷基時藉由1-1e3-1步驟進行，此外，R7b為烷醯基烷基或烷醯基烯基時藉由1-1e3-2步驟來進行。 This step is a step of converting the substituent R 7a on the ring Q 3 to R 7b , and has a different synthesis depending on the kind of the substituent of R 7b . R 7b is alkylamine-mercaptooxyalkyl, alkylamine-methylaminoalkyl, alkoxycarbonylaminoalkyl, alkylthiocarbonylaminoalkyl or alkanesulfonylaminoalkane The base time is carried out by the step 1-1e3-1, and further, when R 7b is an alkylalkylalkyl group or an alkylnonenyl group, it is carried out by the step 1-1e3-2.

(1-1e3-1步驟)。 (Step 1-1e3-1).

本步驟為由作為R7a之羥基烷基或具有胺基烷基的化合物導入作為R7b的(a)烷基胺甲醯基氧基烷基、或具有(b)烷基胺甲醯基胺基烷基、烷氧基羰基胺基烷基、烷硫基羰基胺基烷基、或烷磺醯基胺基烷基的化合物之步驟。R7b為(a)時，使用具有羥基烷基的化合物作為R7a，此外，R7b為(b)時，使用具有胺基烷基的化合物作為R7a，在惰性之溶劑中、鹼之存在下或不存在下，藉由與適當的反應化劑反應來進行。 This step is carried out by introducing a compound of the hydroxyalkyl group of R 7a or a compound having an aminoalkyl group as (a) an alkylamine-mercaptooxyalkyl group as R 7b or (b) an alkylamine-methyl decylamine. The step of a compound of an alkyl group, an alkoxycarbonylaminoalkyl group, an alkylthiocarbonylaminoalkyl group, or an alkanesulfonylaminoalkyl group. When R 7b is (a), a compound having a hydroxyalkyl group is used as R 7a , and when R 7b is (b), a compound having an aminoalkyl group is used as R 7a in the presence of an inert solvent and a base. It is carried out by reacting with a suitable reactant in the presence or absence.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉 如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；或複數有機溶劑之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An ether of 1,2,2-dimethoxyethane; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; such as dimethylsulfin a sulfinamide; or a mixed solvent of any ratio of a plurality of organic solvents.

所使用的反應化劑隨R7b之取代基的種類而有不同，只要可以作為對應R7b之反應化劑使用，則無特別限定。較佳為R7b為烷基胺甲醯基氧基烷基及烷基胺甲醯基胺基烷基時可列舉異氰酸烷酯、為烷氧基羰基胺基烷基時可列舉如烷氧基羰基氯化物、為烷硫基羰基胺基烷基時可列舉(烷硫基)羰基氯化物、為烷磺醯基胺基烷基時可列舉烷基磺醯基氯化物。 The reaction agent used with the kind of the substituents R 7b being different, as long as the reaction of the corresponding R 7b agent used is not particularly limited. When R 7b is an alkylamine-methylcarbonyloxyalkyl group or an alkylamine-methylaminoalkyl group, an alkyl isocyanate may be mentioned, and when it is an alkoxycarbonylaminoalkyl group, for example, an alkane may be mentioned. Examples of the oxycarbonyl chloride and the alkylthiocarbonylaminoalkyl group include an (alkylthio)carbonyl chloride, and the alkylsulfonylaminoalkyl group is an alkylsulfonyl chloride.

所使用的鹼，只要在一般反應下可作為鹼使用，則無特別限定，較佳可列舉如三乙胺、N,N-二異丙基乙胺、N-甲基啉、二甲吡啶、吡啶之有機鹼類；如碳酸鈉、碳酸鉀之鹼金屬碳酸鹽類；如碳酸鈣之鹼土金屬碳酸鹽類；如碳酸氫鉀之鹼金屬碳酸氫鹽類；如碳酸氫鈣之鹼土金屬碳酸氫鹽類；如氫氧化鈉之鹼金屬氫氧化物類；如氫氧化鈣之鹼土金屬氫氧化物類；或如磷酸三鉀之磷酸鹼金屬鹽類。 The base to be used is not particularly limited as long as it can be used as a base under a general reaction, and preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methyl group An organic base of porphyrin, dimethylpyridine or pyridine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as calcium carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Calcium alkaline earth metal hydrogencarbonate; alkali metal hydroxide such as sodium hydroxide; alkaline earth metal hydroxide such as calcium hydroxide; or alkali metal phosphate such as tripotassium phosphate.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為0℃至50℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-1e3-2步驟) (step 1-1e3-2)

本步驟為由作為R7a之具有羥基烷基的化合物，導入具有作為R7b之烷醯基烷基、或烷醯基烯基的化合物之步驟，藉由對二級醇化合物使用適當的氧化劑來進行。所使用的氧化劑雖無特別限定，不過可從例如第四版實驗科學講座(21.有機合成III醛‧酮‧醌)、丸山和博等、日本化學會、丸善股份有限公司、1990等所記載之習知方法中適當地選擇，本步驟依其來進行。作為代表的氧化反應例可列舉例如使用鉻酸酐、氧化鉻(VI)-吡啶錯合物(Collins試藥)、氯鉻酸吡啶鎓(PCC)、二鉻酸吡啶鎓(PDC)、氧化鉻(VI)-硫酸-丙酮(Jones試藥)等之鉻酸之氧化反應、使用活性化二氧化錳之氧化反應、使用組合二環己碳二醯亞胺(DCC)、醋酸酐、五氧化磷、三氧化硫-吡啶錯合物、或草醯氯等與二甲亞碸(DMSO)之氧化反應、使用超原子化碘化合物(Dess-Martin試藥)之氧化反應等。 This step is a step of introducing a compound having an alkylalkylalkyl group or an alkylnonenyl group as R 7b from a compound having a hydroxyalkyl group as R 7a by using a suitable oxidizing agent for the secondary alcohol compound. get on. The oxidizing agent to be used is not particularly limited, but can be described, for example, from the fourth edition of the experimental science lecture (21. Organic synthesis III aldehyde ketone ketone 醌), Maruyama Ka, etc., Japanese Chemical Society, Maruzen Co., Ltd., 1990, etc. This step is appropriately selected in the conventional method, and this step is performed in accordance therewith. Examples of the oxidation reaction include, for example, chromic anhydride, chromium (VI)-pyridine complex (Collins reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and chromium oxide (for example). VI)-oxidation reaction of chromic acid such as sulfuric acid-acetone (Jones reagent), oxidation reaction using activated manganese dioxide, use of dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, Oxidation reaction of sulfur trioxide-pyridine complex or oxalic acid chloride with dimethyl hydrazine (DMSO), oxidation reaction using a super atomized iodine compound (Dess-Martin reagent), and the like.

此外，在1-1e3步驟中R7a具有保護基時，進一步含有施行其脫保護之步驟，因應所使用的保護基，而可從例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等所記載之習知方法中適當地選擇，本步驟依其來進行。在此，雖然記載關於選擇甲氧基甲基或第三丁基(二甲基)矽烷基或三異丙基矽烷基作為較佳的保護基，在惰性之溶劑中使用酸進行甲氧基甲基之脫保護的方法(1-1e3-3步驟)，在惰性之溶劑中使用酸進行第三丁基(二甲基)矽烷基或三異丙基矽烷基之脫保護的方法(1-1e3-4步驟)、或在惰性之溶劑中使用氟化物進行第三丁基(二甲基)矽烷基或三異丙基矽烷基之脫保護的方法(1-1e3-5步驟)，但本步驟並非限定於彼等者。 Further, in step 1-1e3 R 7a having a protecting group, further comprising the step of deprotection purposes which, in response to the protecting group used, but can be from e.g. Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, The conventional method described in Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, etc. is appropriately selected, and this step is carried out in accordance therewith. Here, although it is described that methoxymethyl or tert-butyl(dimethyl)decylalkyl or triisopropyldecylalkyl is selected as a preferred protecting group, an acid is used for the methoxy group in an inert solvent. Method for deprotecting a base (step 1-1e3-3), a method for deprotecting a tributyl(dimethyl)decylalkyl group or a triisopropyldecylalkyl group using an acid in an inert solvent (1-1e3) -4 step), or a method of deprotecting a tributyl(dimethyl)decylalkyl group or a triisopropyldecylalkyl group using a fluoride in an inert solvent (step 1-1e3-5), but this step Not limited to them.

(1-1e3-3步驟) (step 1-1e3-3)

本步驟為施行甲氧基甲基之脫保護的步驟，可依據以1-1a2步驟為標準的方法進行。 This step is a step of performing deprotection of the methoxymethyl group, which can be carried out according to the method of the step 1-1a2.

(1-1e3-4步驟) (step 1-1e3-4)

本步驟為施行第三丁基(二甲基)矽烷基或三異丙基矽烷基之脫保護的步驟，可依據以1-1a2步驟為標準的方法進行。 This step is a step of performing deprotection of a tributyl(dimethyl)decylalkyl group or a triisopropyldecylalkyl group, which can be carried out according to the method of the step 1-1a2.

(1-1e3-5步驟) (Step 1-1e3-5)

本步驟為施行脫保護第三丁基(二甲基)矽烷基或三異丙基矽烷基之步驟，在惰性之溶劑中使用氟化物來進行。 This step is carried out by subjecting a step of deprotecting a tributyl(dimethyl)decylalkyl group or a triisopropyldecylalkyl group to a fluoride in an inert solvent.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇、第三丁醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or a third butanol; a nitrile such as acetonitrile; such as formamide, N,N-dimethylformamide a guanamine; for example, a sulfinium sulfoximine; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water.

作為所使用的氟化物，只要可在脫保護矽烷基中使用，則無特別限定，較佳可列舉如氟化四銨、氟化氫-吡啶、二氟三甲基矽酸參(二甲胺基)鋶鹽等。 The fluoride to be used is not particularly limited as long as it can be used in the deprotected alkylene group, and examples thereof include tetraammonium fluoride, hydrogen fluoride-pyridine, and difluorotrimethyldecanoate (dimethylamino).鋶 salt and so on.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為-20℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably -20 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-2步驟) (1-2 steps)

1-2步驟為從具有通式(3)的化合物中製造具有通式(1)的化合物之步驟。作為所需之反應，可列舉：1-2a步驟：保護基Pro1之脫保護反應；1-2b步驟：保護基Pro3之脫保護反應。 The step 1-2 is a step of producing a compound having the formula (1) from the compound of the formula (3). As the desired reaction, there may be mentioned a step 1-2a: a deprotection reaction of the protective group Pro 1 , and a step 1-2b: a deprotection reaction of the protective group Pro 3 .

此外，因應需要可加入1-2c步驟：將R1b轉變成R1之反應；1-2d步驟：將R2a轉變成R2之反應。 Further, a step 1-2c may be added as needed: a reaction for converting R 1b to R 1 ; a step 1-2d: a reaction for converting R 2a to R 2 .

也可依照1-2a至1-2d步驟任一順序進行。 It can also be carried out in any order from 1-2a to 1-2d.

(1-2a步驟) (1-2a step)

本步驟為施行將保護基Pro1脫保護之步驟。因應使用的Pro1，而可從例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等所記載之習之方法中適當地選擇，本步驟依其來進行。在此雖記載，較佳為選擇作為Pro1之苄基，在氫氣環境下、惰性之溶劑中、添加劑之存在下或不存在下，使用觸媒將Pro1轉變成氫原子之方法(1-2a1步驟)，在能成為氫來源的有機化合物存在下、氮氣或氬氣環境下、惰性之溶劑中、添加劑之存在下或不存在下，使用觸媒將Pro1轉變成氫原子之方法(1-2a2步驟)、或在惰性之溶劑中，只要記載使用適當的酸將Pro1轉變成氫原子之方法(1-2a3步驟)，本步驟並非限定於彼等者。 This step is a step of deprotecting the protecting group Pro 1 . Suitable according to the method described in, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, etc., depending on the Pro 1 used. Ground selection, this step is carried out according to it. Here, it is preferred to select a benzyl group as Pro 1 , and to convert Pro 1 into a hydrogen atom using a catalyst under a hydrogen atmosphere, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive. Step 2a1), a method for converting Pro 1 into a hydrogen atom using a catalyst in the presence of an organic compound capable of being a hydrogen source, in a nitrogen or argon atmosphere, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive (1) -2a2 step), or in an inert solvent, as long as a method of converting Pro 1 into a hydrogen atom using an appropriate acid (step 1-2a3) is described, this step is not limited to those.

(1-2a1步驟) (Step 1-2a1)

本步驟為在氫氣環境下、惰性之溶劑中、添加劑之存在下或不存在下，使用觸媒將Pro1轉變成氫原子之步驟。 This step is a step of converting Pro 1 into a hydrogen atom using a catalyst under a hydrogen atmosphere, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷之醚類；如甲醇、乙醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2-dimethoxyethane; an alcohol such as methanol or ethanol; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; For example, a sulfoximine of dimethylsulfinone; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio of such water and the like.

所使用的添加劑，只要是在習知之方法中所使用者，並無特別限定，可列舉例如鹽酸。 The additive to be used is not particularly limited as long as it is used in a conventional method, and examples thereof include hydrochloric acid.

作為所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如鈀-活性碳、參(三苯基膦)氯化銠、氫氧化鈀等。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and examples thereof include palladium-activated carbon, ruthenium (triphenylphosphine) ruthenium chloride, and palladium hydroxide.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為0℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為1分鐘至24小時，較佳為5分鐘至10小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 1 minute to 24 hours, preferably from 5 minutes to 10 hours.

反應結束後，本反應之目的化合物可藉由例如濾除不溶解物，並在減壓下濃縮濾液而得到。所得到的化合 物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 After completion of the reaction, the objective compound of the present reaction can be obtained, for example, by filtering off insolubles and concentrating the filtrate under reduced pressure. The resulting combination The substance may be further refined by a general method such as recrystallization, re-deeping, and rubber column chromatography if necessary.

R2a為烯基時，在本步驟中將轉變成對應之烷基。 When R 2a is an alkenyl group, it will be converted into the corresponding alkyl group in this step.

(1-2a2步驟) (Step 1-2a2)

本步驟為在能成為氫來源的有機化合物存在下、氮氣或氬氣環境下、惰性之溶劑中、添加劑之存在下或不存在下，使用觸媒將Pro1轉變成氫原子之步驟。 This step is a step of converting Pro 1 into a hydrogen atom using a catalyst in the presence or absence of an organic compound capable of becoming a hydrogen source, in a nitrogen or argon atmosphere, in an inert solvent, in the presence or absence of an additive.

作為所使用的溶劑，只要不阻礙反應，且某種程度溶解起始物質時，則無特別限定，較佳為可列舉如苯、甲苯、二甲苯之芳香族烴類；如二氯甲烷、氯仿之鹵素系烴類；如乙酸乙酯、乙酸丙酯之酯類；如二***、四氫呋喃、1,4-二烷、1,2二甲氧基乙烷之醚類；如甲醇、乙醇之醇類；如乙腈之腈類；如甲醯胺、N,N-二甲基甲醯胺之醯胺類；如二甲基亞磺醯之亞磺醯類；複數有機溶劑之任意比率的混合溶劑；或此等與水之任意比率的混合溶劑等。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as an ester of ethyl acetate or propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-two An alkane, an ether of 1,2 dimethoxyethane; an alcohol such as methanol or ethanol; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; a sulfinium sulfoxime; a mixed solvent of any ratio of a plurality of organic solvents; or a mixed solvent of any ratio with water or the like.

作為所使用的有機化合物，只要是在習知之方法中所使用者，並無特別限定，可列舉例如甲酸。 The organic compound to be used is not particularly limited as long as it is used in a conventional method, and for example, formic acid can be mentioned.

所使用的添加劑，只要是在習知之方法中所使用者，並無特別限定，可列舉例如鹽酸。 The additive to be used is not particularly limited as long as it is used in a conventional method, and examples thereof include hydrochloric acid.

作為所使用的金屬觸媒，只要是在習知之方法中所使用者，並無特別限定，較佳可列舉例如鈀-活性碳、參(三苯基膦)氯化銠、氫氧化鈀等。 The metal catalyst to be used is not particularly limited as long as it is used in a conventional method, and examples thereof include palladium-activated carbon, ruthenium (triphenylphosphine) ruthenium chloride, and palladium hydroxide.

反應溫度隨原料化合物、試藥等而不同，通常為-100℃至150℃，較佳為-78℃至100℃。 The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 150 ° C, preferably -78 ° C to 100 ° C.

反應時間隨原料化合物、試藥等而不同，通常為5分鐘至24小時，較佳為10分鐘至6小時。 The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

反應結束後，以例如濃縮反應混合物，加入如乙酸乙酯之有機溶劑，以水清洗後，分離含有目的化合物之有機層，以無水硫酸鈉等乾燥後，將溶劑餾除而得到本反應之目的化合物。 After completion of the reaction, for example, the reaction mixture is concentrated, and an organic solvent such as ethyl acetate is added thereto, followed by washing with water, and then the organic layer containing the objective compound is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the purpose of the reaction. Compound.

所得到的化合物，必要的話可以藉由一般方法，例如再結晶、再沈殿、矽膠管柱層析法等更進一步予以精製。 The obtained compound can be further purified by a usual method such as recrystallization, re-isolation, gel column chromatography or the like, if necessary.

(1-2a3步驟) (1-2a3 step)

本步驟為在惰性之溶劑中使用適當的酸將Pro1轉變成氫原子之步驟。本步驟可依據以1-1a2步驟為標準之方法進行。 This step is a step of converting Pro 1 into a hydrogen atom using an appropriate acid in an inert solvent. This step can be carried out according to the method of the step 1-1a2.

(1-2b步驟) (1-2b step)

本步驟為施行將保護基Pro3脫保護之步驟。本步驟可依據以1-1a步驟為標準之方法進行。Pro3為苄基時，本步驟可依據以1-2a1步驟為標準之方法進行。 This step is a step of deprotecting the protecting group Pro 3 . This step can be carried out according to the method of the step 1-1a. When Pro 3 is a benzyl group, this step can be carried out according to the method of the step 1-2a1.

(1-2c步驟) (1-2c step)

本步驟為將R1b轉變成R1之步驟。本步驟可依據以1-1e2步驟為標準之方法進行。此外，因應需要包含將環 Q3上之取代基R7b轉變成R7之步驟，可依據以1-1e3步驟為標準之方法進行。 This step is a step of converting R 1b to R 1 . This step can be carried out according to the method using the step 1-1e2 as a standard. Further, the step of converting the substituent R 7b on the ring Q 3 to R 7 may be carried out according to the method of the step 1-1e3.

(1-2d步驟) (1-2d step)

本步驟為將R2a轉變成R2之步驟，R2a為烯基時，依據以1-2a1步驟為標準之方法可將該烯基轉變成對應之烷基。 This step is a step of converting R 2a to R 2 . When R 2a is an alkenyl group, the alkenyl group can be converted to the corresponding alkyl group according to the method of the 1-2a1 step.

(第2步驟) (Step 2)

第2步驟為製造在第1步驟所使用之化合物(2)之步驟。 The second step is a step of producing the compound (2) used in the first step.

在上述中，R1a表示與前述意義相同，Pro5表示選自習知之保護基(例如Protective Groups in Organic Synthesis,3rd ed.,Greene,T.W.,Wuts,P.G.M.,John Wiley & Sons,Inc.,New York,1999等)各個官能基之保護基。Pro5只要在反應中安定地存在，又不阻礙反應的話，則無特別限定，較佳為甲基。 In the above, R 1a is the same as defined above, and Pro 5 is selected from a conventional protecting group (for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New). York, 1999, etc.) protecting groups for each functional group. Pro 5 is not particularly limited as long as it is stably present in the reaction and does not inhibit the reaction, and is preferably a methyl group.

具有通式(2)的化合物係可使用習知之方法[例如(i)將以習知之方法為標準合成而成之取代乙烷亞胺醯胺(10)與2-烷基氧基-3-側氧琥珀酸二酯(11)在鹼存在下縮合之方法：Dreher,S.D.,Ikemoto,N.,Gresham,V.,Liu,J.,Dormer,P.G.,Balsells,J.,Mathre,D.,Novak.T.,Armstrong III,J.D.,Tetrahedron Lett.,2004,45,6023；或(ii)將N-羥基取代乙烷亞胺醯胺類(12)與乙炔二甲酸二酯(13)縮合之方法：Culbertson,T.P.,J.Heterocycl.Chem.,1979,16,1423]或以習知之方法為標準來合成。 The compound having the formula (2) can be obtained by a conventional method [for example, (i) a substituted ethaneimine decylamine (10) and a 2-alkyloxy-3- which are synthesized by a conventional method. Method for condensing a side oxysuccinic acid diester (11) in the presence of a base: Dreher, SD, Ikemoto, N., Gresham, V., Liu, J., Dormer, PG, Balsells, J., Mathre, D., Novak.T., Armstrong III, JD, Tetrahedron Lett., 2004, 45, 6023; or (ii) condensation of N-hydroxy substituted ethaneimine oxime (12) with acetylenedicarboxylic acid diester (13) Method: Culbertson, TP, J. Heterocycl. Chem., 1979, 16, 1423] or synthesized by standard methods.

藉由上述之各步驟所得到的反應生成物係被單離、精製而作為無溶劑合物、其鹽或水合物等之各種溶劑合物。鹽可藉由一般方法製造。單離或精製則適合使用萃取、濃縮、餾除、結晶化、過濾、再結晶、各種層析法等之一般方法來進行。 The reaction product obtained by each of the above steps is isolated and purified to obtain various solvates such as an unsolvate, a salt thereof or a hydrate. Salt can be produced by a general method. The separation or purification is suitably carried out by a general method such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography methods.

各種異構物係利用異構物間之物理化學的性質差異，可藉由一般方法單離。例如光學異構物可藉由一般的光學離析(例如分化結晶化或層析法等)予以分離。此外，光學異構物可藉由適當的光學活性原料化合物予以製造。 The various isomers utilize the difference in physicochemical properties between the isomers and can be separated by a general method. For example, optical isomers can be separated by general optical resolution (for example, differentiation crystallization or chromatography, etc.). Furthermore, optical isomers can be made by suitable optically active starting compounds.

含有本發明之化合物作為有效成分之製劑，係使用一般製劑所用之載體、賦形劑等之添加劑所調製。本發明之化合物的投予係可以錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等形態之經口投予、或注射劑(例如靜脈注射、肌肉注射等)、栓劑、經皮劑、經鼻劑、吸入劑等形態之非經口投予。本發明之化合物之投予量及投予 次數係考量到症狀、投予對象之年齡或性別等，而因應個別情況而適宜地決定。經口投予時，投予量通常為成人每次0.001mg/kg至100mg/kg，靜脈投予時，投予量通常為成人每次0.0001mg/kg至10mg/kg。投予次數通常從1天1次至6次或1天1次至7天1次。對接受透析之患者之投予，也可在該患者接受各項透析之前後(較佳為透析之前)投予1次。 The preparation containing the compound of the present invention as an active ingredient is prepared by using an additive such as a carrier or an excipient used in a general preparation. The administration of the compound of the present invention may be orally administered in the form of a tablet, a pill, a capsule, a granule, a powder or a liquid, or an injection (for example, intravenous injection, intramuscular injection, etc.), a suppository, a transdermal agent, or the like. Intranasal administration, inhalation, and the like are administered orally. Dosage and administration of the compound of the present invention The number of times is determined by the symptoms, the age or sex of the subject, and is appropriately determined depending on individual circumstances. In the case of oral administration, the administration amount is usually from 0.001 mg/kg to 100 mg/kg per adult, and when administered intravenously, the administration amount is usually from 0.0001 mg/kg to 10 mg/kg per adult. The number of administrations is usually from 1 day to 6 times or once every day to 7 days. Administration of a patient undergoing dialysis may also be administered once before the patient receives various dialysis, preferably prior to dialysis.

根據本發明之用以經口投予之固體製劑，可為錠劑、散劑、顆粒劑等。此種製劑係藉由一個或其以上之活性物質與惰性賦形劑、潤滑劑、崩解劑或溶解輔助劑等混合，而依照一般方法所製造。賦形劑可為例如乳糖、甘露糖醇、葡萄糖。潤滑劑可為例如硬脂酸鎂。崩解劑可為例如羧甲基澱粉鈉。錠劑或丸劑視需要也可以糖衣或胃溶性或腸溶性被覆劑加以被膜。 The solid preparation for oral administration according to the present invention may be a tablet, a powder, a granule or the like. Such a preparation is prepared according to a general method by mixing one or more active substances with an inert excipient, a lubricant, a disintegrating agent or a dissolution aid. The excipient can be, for example, lactose, mannitol, glucose. The lubricant can be, for example, magnesium stearate. The disintegrant can be, for example, sodium carboxymethyl starch. The tablets or pills may also be coated with a sugar-coated or gastric-soluble or enteric coating agent as needed.

用以經口投予之液體製劑可為藥劑上容許的乳劑、液劑、懸浮劑、糖漿劑或酏劑等。此種製劑含有一般所使用的惰性溶劑(例如精製水、乙醇)，也可進一步含有可溶化劑、濕潤劑、懸浮化劑、甘味劑、矯味劑、芳香劑、或防腐劑。 The liquid preparation for oral administration may be a pharmaceutically acceptable emulsion, liquid, suspension, syrup or elixir. Such a preparation contains an inert solvent (for example, purified water or ethanol) which is generally used, and may further contain a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, or a preservative.

用以非經口投予之注射劑可為無菌之水性或非水性液劑、懸浮劑或乳劑。注射劑用之水性溶劑可為例如蒸餾水或生理食鹽水。注射劑用之非水性溶劑可為例如丙二醇、聚乙二醇、橄欖油之植物油，如乙醇之醇類或聚山梨醇酯80(藥典名)。此種製劑也可進一步含有等張劑、防腐劑、濕潤劑、乳化劑、分散劑、安定劑或 溶解輔助劑。此等之製劑可藉由例如細菌截留過濾器過濾，再藉由配合殺菌劑或放射線照射使其無菌化。此外，也可在使用之前將無菌之固體組成物於無菌之水或注射用溶劑溶解或懸浮所得到的組成物作為此等之製劑使用。 The injection for parenteral administration may be a sterile aqueous or nonaqueous liquid, suspension or emulsion. The aqueous solvent for injection can be, for example, distilled water or physiological saline. The nonaqueous solvent for injection may be, for example, propylene glycol, polyethylene glycol, vegetable oil of olive oil, such as alcohol of ethanol or polysorbate 80 (Pharmacopoeia). The preparation may further comprise an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer or Dissolving adjuvant. These preparations can be sterilized by, for example, a bacterial retention filter, and then sterilized by a bactericide or radiation. Further, the composition obtained by dissolving or suspending the sterile solid composition in sterile water or an injection solvent may be used as such a preparation before use.

〔實施例〕 [Examples]

以下記載實施例、試驗例，並進一步詳細地說明本發明，但本發明之範圍並非受限於此等者。 The present invention will be described in more detail below with reference to examples and test examples, but the scope of the invention is not limited thereto.

(實施例1) (Example 1)

{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸鹽酸鹽 {[(2-{[1-(4'-{](ethoxycarbonyl)amino)methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6 -methylpyrimidin-4-yl)carbonyl]amino}acetic acid hydrochloride

(1)4-(氰基亞甲基)哌啶-1-甲酸第三丁酯 (1) tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate

將氰基甲基膦酸二乙酯(16mL,100mmol)溶解於四氫呋喃(360mL)中，在氮氣環境下，於-70℃加入鋰六甲基二矽胺之四氫呋喃溶液(1M,100mL,100mmol)及4-側氧基哌啶-1-甲酸第三丁酯(18g,91mmol)之四氫呋喃溶液(36mL)後，於相同溫度攪拌40分鐘。於反應液中加入飽和氯化銨水溶液後，以乙酸乙酯萃取，萃取液以飽和氯化銨水溶液洗淨。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到白色固體的標的化合物(22g)(產率定量的)。 Diethyl cyanomethylphosphonate (16 mL, 100 mmol) was dissolved in tetrahydrofuran (360 mL), and a solution of lithium hexamethyldiamine in tetrahydrofuran (1 M, 100 mL, 100 mmol) was added at -70 ° C under nitrogen atmosphere. After a solution of 4-butyloxypiperidine-l-carboxylic acid tert-butyl ester (18 g, 91 mmol) in tetrahydrofuran (36 mL), the mixture was stirred at the same temperature for 40 min. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22g) .

1H-NMR(500MHz,CDCl3)δ：5.19(1H,s),3.56-3.46(4H,m),2.56(2H,t,J=5Hz),2.33(2H,t,J=5Hz),1.48(9H,s). 1 H-NMR (500MHz, CDCl 3 ) δ: 5.19 (1H, s), 3.56-3.46 (4H, m), 2.56 (2H, t, J = 5 Hz), 2.33 (2H, t, J = 5 Hz), 1.48 (9H, s).

(2)4-(氰基甲基)哌啶-1-甲酸第三丁酯 (2) tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate

將4-(氰基亞甲基)哌啶-1-二甲酸第三丁酯(20g,91mmol)溶解於乙酸乙酯(400mL)中，加入10%鈀-活性碳(3.0g)，在氫氣環境下，於室溫攪拌3.5小時。以Celite(矽藻土)過濾反應液，在減壓下濃縮濾液。藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到白色固體的標的化合物(23g)(產率定量的)。 3-(cyanomethylene)piperidine-1-dicarboxylic acid tert-butyl ester (20 g, 91 mmol) was dissolved in ethyl acetate (400 mL), and 10% palladium-activated carbon (3.0 g) was added to hydrogen Under the environment, stir at room temperature for 3.5 hours. The reaction solution was filtered through Celite (EtOAc) and evaporated. The title compound (23 g) was obtained as a white solid (yield quantitatively).

1H-NMR(500MHz,CDCl3)δ：4.24-4.0.7(2H,m),2.78-2.64(2H,m),2.32(2H,d,J=6Hz),1.89-1.75(3H,m),1.46(9H,s),1.32-1.21(2H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 4.24-4.0.7 (2H, m), 2.78-2.64 (2H, m), 2.32 (2H, d, J = 6 Hz), 1.89-1.75 (3H, m ), 1.46 (9H, s), 1.32-1.21 (2H, m).

(3)4-(2-胺基-2-亞胺乙基)哌啶-1-甲酸第三丁酯乙酸鹽 (3) 4-(2-Amino-2-imineethyl)piperidine-1-carboxylic acid tert-butyl acetate acetate

將4-(氰基甲基)哌啶-1-甲酸第三丁酯(23g)溶解於乙醇(200mL)中，加入羥基胺水溶液(50%,17mL,170mmol)後，加熱回流3.5小時。冷卻反應液後，藉由在減壓下濃縮，而得到無色無定形固體的4-[2-胺基-2-(羥基亞胺基)乙基]哌啶-1-甲酸第三丁酯。 4-(cyanomethyl)piperidine-1-carboxylic acid tert-butyl ester (23 g) was dissolved in ethanol (200 mL), and aqueous hydroxyamine (50%, 17 mL, 170 mmol) was added, and the mixture was refluxed for 3.5 hr. After cooling the reaction mixture, it was concentrated under reduced pressure to give 4-[2-amino-2-(hydroxyimino)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a colorless amorphous solid.

將其溶解於1,4-二烷(100mL)中，於室溫加入乙酸酐(17mL,180mmol)及三乙胺(15mL,180mmol)後，於相同溫度攪拌2小時。將反應液以乙酸乙酯稀釋後，依序以水、稀鹽酸及水洗淨，以無水硫酸鈉乾燥有機層。在減壓下餾除溶劑，藉由將所得到的固體以己烷洗淨，而得到白色固體的4-[2-(乙醯氧基亞胺基)-2-胺乙基]哌啶-1-甲酸第三丁酯。 Dissolve it in 1,4-two After adding acetic anhydride (17 mL, 180 mmol) and triethylamine (15 mL, 180 mmol) at room temperature, the mixture was stirred at the same temperature for 2 hours. After the reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was washed with hexane to give 4-[2-(ethyloxyimino)-2-amineethyl]piperidine as a white solid. 1-butylic acid tert-butyl ester.

將其溶解於乙醇(200mL)及二氯甲烷(40mL)中，加入10%鈀-活性碳(3.6g)，在氫氣環境下，於室溫 攪拌5小時。以Celite過濾反應液後，藉由在減壓下濃縮濾液，而得到白色固體的標的化合物(24g,79mmol)(產率85%)。 Dissolve it in ethanol (200 mL) and dichloromethane (40 mL), add 10% palladium-activated carbon (3.6 g), under hydrogen atmosphere at room temperature Stir for 5 hours. After the reaction mixture was filtered with EtOAc EtOAcjjjjjjj

1H-NMR(500MHz,DMSO-d6)δ：3.99-3.86(2H,m),2.81-2.58(2H,m),2.23(2H,d,J=8Hz),1.85(1H,m),1.64(3H,s),1.64-1.56(2H,m),1.40(9H,s),0.99-1.08(2H,m). 1 H-NMR (500MHz, DMSO -d 6) δ: 3.99-3.86 (2H, m), 2.81-2.58 (2H, m), 2.23 (2H, d, J = 8Hz), 1.85 (1H, m), 1.64(3H,s), 1.64-1.56(2H,m), 1.40(9H,s),0.99-1.08(2H,m).

(4)5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-羥基嘧啶-4-甲酸第三丁酯 (4) 5-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

將二異丙基胺(30mL,210mmol)溶解於四氫呋喃(100mL)中，在3℃滴入正丁基鋰之己烷溶液(2.77M,77mL,210mmol)後，藉由在-78℃攪拌30分鐘，調製鋰二異丙基醯胺(LDA)之四氫呋喃溶液。 Diisopropylamine (30 mL, 210 mmol) was dissolved in tetrahydrofuran (100 mL), and a solution of n-butyllithium in hexane (2.77 M, 77 mL, 210 mmol) was added dropwise at 3 ° C, and stirred at -78 ° C. In a minute, a solution of lithium diisopropyl decylamine (LDA) in tetrahydrofuran was prepared.

將草酸第三丁甲酯(34g,210mmol)及(苄氧基)乙酸甲酯(35g,190mmol)溶解於四氫呋喃(250mL)中，在氮氣環境下，於-78℃滴入調製的LDA之四氫呋喃溶液後，於相同溫度攪拌3小時。將反應液徐徐地升溫至-40℃後，加入鹽酸(2M,210mL)，以乙酸乙酯萃取。 將萃取液以水及飽和氯化鈉水溶液洗淨，以無水硫酸鎂乾燥有機層後，藉由在減壓下餾除溶劑，而得到黃色油狀物質的2-(苄氧基)-3-側氧琥珀酸4-第三丁1-甲酯(62g)。 Dimethyl oxalate (34 g, 210 mmol) and methyl (benzyloxy)acetate (35 g, 190 mmol) were dissolved in tetrahydrofuran (250 mL), and the tetrahydrofuran of the prepared LDA was added dropwise at -78 ° C under nitrogen atmosphere. After the solution, it was stirred at the same temperature for 3 hours. After the reaction mixture was slowly warmed to -40 ° C, hydrochloric acid (2M, 210 mL) The extract was washed with water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(benzyloxy)-3- 4-oxet-1-methyl oxosuccinate (62 g).

將其一部分(36g,120mmol)及4-(2-胺基-2-亞胺乙基)哌啶-1-二甲酸第三丁基乙酸鹽(24g,79mmol)溶解於甲醇(240mL)中，於3℃加入甲醇鈉之甲醇溶液(28%,48mL,240mmol)後，於室溫攪拌14.5小時。於反應液中加入鹽酸(1M,130mL)後，藉由過濾所析出的固體，而得到白色固體的標的化合物(26g,52mmol)(產率66%)。 A portion (36 g, 120 mmol) and 4-(2-amino-2-iminoethyl)piperidine-1-dicarboxylic acid tert-butyl acetate (24 g, 79 mmol) were dissolved in methanol (240 mL). After adding a methanol solution of sodium methoxide (28%, 48 mL, 240 mmol) at 3 ° C, the mixture was stirred at room temperature for 14.5 hours. After a hydrochloric acid (1 M, 130 mL) was added to the mixture, the solid crystals were filtered to give the title compound (26 g, 52 mmol) (yield: 66%).

1H-NMR(500MHz,CDCl3)δ：7.47-7.44(2H,m),7.40-7.31(3H,m),5.23(2H,s),4.21-3.91(2H,m),2.74-2.58(2H,m),2.62(2H,d,J=7Hz),2.06(1H,m),1.69-1.60(2H,m),1.53(9H,s),1.43(9H,s),1.28-1.16(2H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 7.47-7.44 (2H, m), 7.40-7.31 (3H, m), 5.23 (2H, s), 4.21-3.91 (2H, m), 2.74-2.58 ( 2H, m), 2.62 (2H, d, J = 7 Hz), 2.06 (1H, m), 1.69-1.60 (2H, m), 1.53 (9H, s), 1.43 (9H, s), 1.28-1.16 ( 2H, m).

(5)5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-{[(三氟甲基)磺醯基]氧基}嘧啶-4-甲酸第三丁酯 (5) 5-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-{[(trifluoromethyl)sulfonyl] Oxygen}pyrimidine-4-carboxylic acid tert-butyl ester

將5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-羥基嘧啶-4-甲酸第三丁酯(5.0g,10mmol)溶解於二氯甲烷(100mL)中，於-78℃加入三氟甲烷磺酸酐(2.1mL,12mmol)及三乙胺(2.1mL,15mmol)後，於相同溫度攪拌30分鐘。在減壓下濃縮反應液後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到黃色油狀物質的標的化合物(6.0g,9.5mmol)(產率95%)。 5-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (5.0 g, 10 mmol) was dissolved in dichloromethane (100 mL), and trifluoromethanesulfonic anhydride (2.1 mL, 12 mmol) and triethylamine (2.1 mL, 15 mmol) were added at -78 ° C, and then stirred at the same temperature for 30 min. After concentrating the reaction mixture under reduced pressure, the title compound (jjjjjjj (Yield 95%).

1H-NMR(500MHz,CDCl3)δ：7.44-7.36(5H,m),5.14(2H,s),4.21-3.95(2H,m),2.88(2H,d,J=7Hz),2.80-2.62(2H,m),2.07(1H,m),1.67-1.60(2H,m),1.57(9H,s),1.46(9H,s),1.27-1.17(2H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 7.44 - 7.36 (5H, m), 5.14 (2H, s), 4.21-3.95 (2H, m), 2.88 (2H, d, J = 7 Hz), 2.80- 2.62(2H,m), 2.07(1H,m),1.67-1.60(2H,m), 1.57(9H,s), 1.46(9H,s),1.27-1.17(2H,m).

(6)5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯 (6) 5-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

將5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-{[(三氟甲基)磺醯基]氧基}嘧啶-4-甲酸第三丁酯(6.0g,9.5mmol)溶解於四氫呋喃(90mL)中，於室溫加入甲基硼酸(1.8g,30mmol)、氧化銀(6.7g,29mmol)、 碳酸鉀(4.0g,29mmol)及[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷錯合物(0.78g,0.96mmol)後，在氮氣環境下，加熱回流3小時。將反應液冷卻至室溫後，濾除不溶解物。在減壓下濃縮濾液後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到黃色油狀物質的標的化合物(4.4g,8.8mmol)(產率93%)。 5-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-{[(trifluoromethyl)sulfonyl]oxy The pyrimidine-4-carboxylic acid tert-butyl ester (6.0 g, 9.5 mmol) was dissolved in tetrahydrofuran (90 mL), and methylboronic acid (1.8 g, 30 mmol), silver oxide (6.7 g, 29 mmol), Potassium carbonate (4.0 g, 29 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.78 g, 0.96 mmol) in a nitrogen atmosphere Heated to reflux for 3 hours. After the reaction solution was cooled to room temperature, the insoluble matter was filtered off. After concentrating the filtrate under reduced pressure, the title compound (yield: hexane, ethyl acetate) Yield 93%).

1H-NMR(500MHz,CDCl3)δ：7.44-7.34(5H,m),5.00(2H,s),4.17-3.98(2H,m),2.85(2H,d,J=7Hz),2.77-2.64(2H,m),2.44(3H,s),2.09(1H,m),1.66-1.59(2H,m),1.59(9H,s),1.45(9H,s),1.30-1.19(2H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 7.44 - 7.34 (5H, m), 5.00 (2H, s), 4.17-3.98 (2H, m), 2.85 (2H, d, J = 7 Hz), 2.77- 2.64 (2H, m), 2.44 (3H, s), 2.09 (1H, m), 1.66-1.59 (2H, m), 1.59 (9H, s), 1.45 (9H, s), 1.30-1.19 (2H, m).

(7)5-(苄氧基)-6-甲基-2-(哌啶-4-基甲基)嘧啶-4-甲酸第三丁酯鹽酸鹽 (7) 5-(Benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylic acid tert-butyl ester hydrochloride

將5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯(4.4g,8.8mmol)溶解於乙酸乙酯(44mL)中，加入氯化氫乙酸乙酯溶液(4M,68mL,270mmol)後，於室溫攪拌3小時。藉由於反應 液加入己烷(100mL)及乙酸乙酯(100mL)而析出固體。過濾取得所得到的固體，藉由在減壓下乾燥，而得到白色固體的標的化合物(3.7g,8.5mmol)(產率95%)。 3-(Benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester (4.4 g The mixture was dissolved in ethyl acetate (44 mL). By reaction A solid was precipitated by adding hexane (100 mL) and ethyl acetate (100 mL). The obtained solid was obtained by filtration,yield to dryness to dryness to give the title compound (3.7 g, 8.5 mmol) (yield 95%).

1H-NMR(500MHz,DMSO-d6)δ：7.47-7.34(5H,m),4.99(2H,s),3.26-3.18(2H,m),2.90-2.78(2H,m),2.78(2H,d,J=7Hz),2.46(3H,s),2.12(1H,m),1.78-1.70(2H,m),1.51(9H,s),1.51-1.39(2H,m). 1 H-NMR (500MHz, DMSO -d 6) δ: 7.47-7.34 (5H, m), 4.99 (2H, s), 3.26-3.18 (2H, m), 2.90-2.78 (2H, m), 2.78 ( 2H, d, J = 7 Hz), 2.46 (3H, s), 2.12 (1H, m), 1.78-1.70 (2H, m), 1.51 (9H, s), 1.51-1.39 (2H, m).

(8)5-(苄氧基)-2-({1-[4’-({[第三丁基(二甲基)矽烷基]氧基}甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯 (8) 5-(Benzyloxy)-2-({1-[4'-({[t-butyl(dimethyl)decyl)oxy}methyl)biphenyl-4-yl]piperidin Tributyl butyl 4-methyl}methyl)-6-methylpyrimidine-4-carboxylate

於甲苯(50mL)中懸浮5-(苄氧基)-6-甲基-2-(哌啶-4-基甲基)嘧啶-4-甲酸第三丁酯鹽酸鹽(1.0g,2.3mmol)、[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷(0.92g,2.4mmol)、第三丁醇鈉(0.67g,7.0mmol)、2-二環己膦基-2,,4’,6’-三異丙基聯苯(X-PHOS)(0.11g,0.23mmol)及參(二亞苄基丙酮)二鈀(0.11g,0.12mmol)，在氮氣環境下，加熱回流3小時。將反應液冷卻至室溫，以Celite過濾後，在減壓下濃縮濾液。藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到 黃色油狀物質的標的化合物(0.98g,1.4mmol)(產率61%)。 Suspension of 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylic acid tert-butyl ester hydrochloride (1.0 g, 2.3 mmol) in toluene (50 mL) , [(4'-bromobiphenyl-4-yl)methoxy] (t-butyl) dimethyl decane (0.92 g, 2.4 mmol), sodium butoxide (0.67 g, 7.0 mmol), 2-dicyclohexylphosphino-2,,4',6'-triisopropylbiphenyl (X-PHOS) (0.11 g, 0.23 mmol) and gins(dibenzylideneacetone) dipalladium (0.11 g, 0.12 mmol), heated under reflux for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered over Celite, and evaporated. By purifying the obtained residue by gel column chromatography (hexane/ethyl acetate) The title compound (0.98 g, 1.4 mmol) of yellow oily material (yield: 61%).

1H-NMR(500MHz,CDCl3)δ：7.52(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.45-7.32(7H,m),6.99(2H,d,J=8Hz),5.01(2H,s),4.76(2H,s),3.73(2H,d,J=12Hz),2.91(2H,d,J=7Hz),2.75(2H,t,J=12Hz),2.46(3H,s),2.17-2.06(1H,m),1.80(2H,d,J=12Hz),1.59(9H,s),1.54(2H,q,J=12Hz),0.95(9H,s),0.11(6H,s). 1 H-NMR (500MHz, CDCl 3 ) δ: 7.52 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz), 7.45-7.32 (7H, m), 6.99 (2H, d, J =8 Hz), 5.01 (2H, s), 4.76 (2H, s), 3.73 (2H, d, J = 12 Hz), 2.91 (2H, d, J = 7 Hz), 2.75 (2H, t, J = 12 Hz) , 2.46 (3H, s), 2.17-2.06 (1H, m), 1.80 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.54 (2H, q, J = 12 Hz), 0.95 (9H, s), 0.11 (6H, s).

(9)5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯 (9) 5-(Benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine- 4-butylic acid tert-butyl ester

將5-(苄氧基)-2-({1-[4’-({[第三丁基(二甲基)矽烷基]氧基}甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯(0.98g,1.4mmol)溶解於1,4-二烷(10mL)中，加入氯化氫二烷溶液(4M,1.0mL,4.0mmol)後，於室溫攪拌1.5小時。於反應液加入飽和碳酸氫鈉溶液使之中和，以乙酸乙酯萃取後，藉由在減壓下濃縮有機層，而得到黃色油狀物質的標的化合物(0.81g,1.4mmol)(產率99%)。 5-(Benzyloxy)-2-({1-[4'-({[t-butyl(dimethyl)decyl)oxy}methyl)biphenyl-4-yl]piperidine- Tetrabutyl 4-methyl}methyl)-6-methylpyrimidine-4-carboxylate (0.98 g, 1.4 mmol) was dissolved in 1,4-di In the alkane (10mL), add hydrogen chloride After the alkane solution (4M, 1.0 mL, 4.0 mmol), The reaction mixture was added to aq. EtOAc (EtOAc m. 99%).

1H-NMR(500MHz,CDCl3)δ：7.56(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.45-7.34(7H,m),7.00(2H,d,J=8Hz),5.01(2H,s),4.72(2H,s),3.73(2H,d,J=12Hz),2.91(2H,d,J=7Hz),2.76(2H,t,J=12Hz),2.46(3H,s),2.17-2.06(1H,m),1.80(2H,d,J=12Hz),1.59(9H,s),1.54(2H,q,J=12Hz). 1 H-NMR (500 MHz, CDCl 3 ) δ: 7.56 (2H, d, J = 8 Hz), 7.50 (2H, d, J = 8 Hz), 7.45-7.34 (7H, m), 7.00 (2H, d, J) =8 Hz), 5.01 (2H, s), 4.72 (2H, s), 3.73 (2H, d, J = 12 Hz), 2.91 (2H, d, J = 7 Hz), 2.76 (2H, t, J = 12 Hz) , 2.46 (3H, s), 2.17-2.06 (1H, m), 1.80 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.54 (2H, q, J = 12 Hz).

(10)({[5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (10) ({[5-(Benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-) Ethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

將5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯(0.81g,1.4mmol)溶解於四氫呋喃(10mL)及甲醇(10mL)的混合溶劑中，加入氫氧化鈉水溶液(5M,10mL,50mmol)後，於50℃攪拌15分鐘。將反應液冷卻至室溫，加入鹽酸(5M,10mL,50mmol)後，以乙酸乙酯萃取。藉由在減壓下濃縮有機層，而得到黃色固體的5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸。 5-(Benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4- The toluene formic acid (0.81 g, 1.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and aqueous sodium hydroxide (5M, 10 mL, 50 mmol) was added, and the mixture was stirred at 50 ° C for 15 minutes. The reaction solution was cooled to room temperature, then hydrochloric acid (5M, 10 mL, The 5-(benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4- was obtained as a yellow solid. }}methyl)-6-methylpyrimidine-4-carboxylic acid.

將其溶解於四氫呋喃(10mL)及甲醇(10mL)的混合溶劑中，加入甘胺酸乙酯鹽酸鹽(0.30g,2.1mmol)、 4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基氟硼化氯(0.51g,1.8mmol)及N-甲基啉(0.39mL,3.5mmol)後，於室溫攪拌14小時。在減壓下濃縮反應液，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)，而得到黃色固體的標的化合物(0.32g,0.53mmol)(產率38%)。 This was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and ethyl glycinate (0.30 g, 2.1 mmol), 4-(4,6-dimethoxy-1,3) , 5-three -2-yl)-4-methylfluoroboron chloride (0.51 g, 1.8 mmol) and N-methyl The morpholine (0.39 mL, 3.5 mmol) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj 38%).

1H-NMR(500MHz,CDCl3)δ：8.36(1H,t,J=6Hz),7.56(2H,d,J=8Hz),7.52-7.47(4H,m),7.43-7.34(5H,m),7.00(2H,d,J=8Hz),5.12(2H,s),4.73(2H,d,J=6Hz),4.30-4.19(4H,m),3.75(2H,d,J=12Hz),2.90(2H,d,J=7Hz),2.78(2H,t,J=12Hz),2.47(3H,s),2.17-2.07(1H,m),1.79(2H,d,J=12Hz),1.59-1.48(2H,m),1.32(3H,t,J=7Hz). 1 H-NMR (500MHz, CDCl 3 ) δ: 8.36 (1H, t, J = 6 Hz), 7.56 (2H, d, J = 8 Hz), 7.52-7.47 (4H, m), 7.43-7.34 (5H, m ), 7.00 (2H, d, J = 8 Hz), 5.12 (2H, s), 4.73 (2H, d, J = 6 Hz), 4.30-4.19 (4H, m), 3.75 (2H, d, J = 12 Hz) , 2.90 (2H, d, J = 7 Hz), 2.78 (2H, t, J = 12 Hz), 2.47 (3H, s), 2.17-2.07 (1H, m), 1.79 (2H, d, J = 12 Hz), 1.59-1.48 (2H, m), 1.32 (3H, t, J = 7Hz).

(11)({[2-({1-[4’-(疊氮甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (11)({[2-({1-[4'-(azidomethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-(benzyloxy)-6-) Methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

將({[5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.91g,1.5mmol)及四溴化碳(0.75g,2.3mmol)溶解於二氯甲烷(22mL)中，加入1,3-雙(二苯基膦基)丙烷(0.46g,1.1mmol)後，於室溫攪拌2小時。於反應液中加入疊氮化鈉 (0.29g,4.5mmol)後，進一步於室溫攪拌一晚。於反應液中加入飽和氯化鈉水溶液，以乙酸乙酯萃取，將萃取液以無水硫酸鈉乾燥。在減壓下將溶劑餾除後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到淡黃色固體的標的化合物(0.40g,0.64mmol)(產率42%)。 ({[5-(Benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine) Ethyl -4-yl]carbonyl}amino)acetate (0.91 g, 1.5 mmol) and carbon tetrabromide (0.75 g, 2.3 mmol) were dissolved in dichloromethane (22 mL). Phenylphosphino)propane (0.46 g, 1.1 mmol) was stirred at room temperature for 2 h. Adding sodium azide to the reaction solution After (0.29 g, 4.5 mmol), it was further stirred at room temperature overnight. A saturated aqueous solution of sodium chloride was added to the mixture, and ethyl acetate was evaporated. The title compound (0.40 g, 0.64 mmol) was obtained as a pale yellow solid. ) (yield 42%).

1H-NMR(400MHz,CDCl3)δ：8.36(1H,t,J=5Hz),7.57(2H,d,J=8Hz),7.53-7.47(4H,m),7.42-7.33(5H,m),7.00(2H,d,J=8Hz),5.12(2H,s),4.36(2H,s),4.27(2H,q,J=7Hz),4.25(2H,d,J=5Hz),3.76(2H,d,J=12Hz),2.90(2H,d,J=7Hz),2.79(2H,t,J=12Hz),2.47(3H,s),2.19-2.06(1H,m),1.79(2H,d,J=12Hz),1.59-1.51(2H,m),1.32(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3) δ: 8.36 (1H, t, J = 5Hz), 7.57 (2H, d, J = 8Hz), 7.53-7.47 (4H, m), 7.42-7.33 (5H, m ), 7.00 (2H, d, J = 8 Hz), 5.12 (2H, s), 4.36 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 5 Hz), 3.76 (2H, d, J = 12 Hz), 2.90 (2H, d, J = 7 Hz), 2.79 (2H, t, J = 12 Hz), 2.47 (3H, s), 2.19 - 2.06 (1H, m), 1.79 ( 2H,d,J=12Hz), 1.59-1.51(2H,m), 1.32(3H,t,J=7Hz).

(12)({[2-({1-[4’-(胺甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (12)({[2-({1-[4'-(Aminomethyl)biphenyl-4-yl)piperidin-4-yl}methyl)-5-(benzyloxy)-6-A Ethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

將({[2-({1-[4’-(疊氮甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.34g,0.53mmol)溶解於乙酸乙酯(15mL)中，加入三苯基膦(0.28g,1.1mmol)，於室溫攪拌7小時。於反應 液中加入水(0.096mL,5.3mmol)後，進一步於室溫攪拌25小時。在減壓下將反應液濃縮後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/甲醇)精製，而得到淡黃色固體的標的化合物(0.30g,0.49mmol)(產率92%)。 ({[2-({1-[4'-(azidomethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-(benzyloxy)-6-methyl Ethyl pyrimidin-4-yl]carbonyl}amino)acetate (0.34 g, 0.53 mmol) was dissolved in ethyl acetate (15 mL), triphenylphosphane (0.28 g, 1.1 mmol) . Reaction After adding water (0.096 mL, 5.3 mmol) to the solution, the mixture was further stirred at room temperature for 25 hr. After concentrating the reaction mixture under reduced pressure, the title compound (0.30 g, m. Yield 92%).

1H-NMR(400MHz,CDCl3)δ：8.37(1H,t,J=5Hz),7.56-7.46(6H,m),7.41-7.32(5H,m),7.00(2H,d,J=9Hz),5.12(2H,s),4.27(2H,q,J=7Hz),4.25(2H,d,J=5Hz),3.89(2H,s),3.74(2H,d,J=12Hz),2.90(2H,d,J=7Hz),2.78(2H,t,J=12Hz),2.47(3H,s),2.18-2.03(1H,m),1.78(2H,d,J=12Hz),1.65-1.43(2H,m),1.32(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.37 (1H, t, J = 5 Hz), 7.56-7.46 (6H, m), 7.41-7.32 (5H, m), 7.00 (2H, d, J = 9 Hz ), 5.12 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 5 Hz), 3.89 (2H, s), 3.74 (2H, d, J = 12 Hz), 2.90 (2H, d, J = 7 Hz), 2.78 (2H, t, J = 12 Hz), 2.47 (3H, s), 2.18-2.03 (1H, m), 1.78 (2H, d, J = 12 Hz), 1.65- 1.43(2H,m), 1.32 (3H, t, J=7Hz).

(13)({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (13) ({[5-(Benzyloxy)-2-{[1-(4'-{[(ethoxycarbonyl)amino)methyl}biphenyl-4-yl)piperidin-4- Ethyl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

將({[2-({1-[4’-(胺甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.11g,0.17mmol)溶解於二氯甲烷(5mL)中，加入氯甲酸乙酯(0.025mL,0.26mmol)及三乙胺(0.036mL,0.26 mmol)後，於室溫攪拌1小時。於反應液加入飽和氯化鈉水溶液，以二氯甲烷萃取，將萃取液以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到白色固體的標的化合物(0.040g,0.059mmol)(產率33%)。 ({[2-({1-[4'-(Aminomethyl)biphenyl-4-yl)piperidin-4-yl}methyl)-5-(benzyloxy)-6-methylpyrimidine Ethyl -4-yl]carbonyl}amino)acetate (0.11 g, 0.17 mmol) was dissolved in dichloromethane (5 mL), ethyl chloroacetate (0.025 mL, 0.26 mmol) and triethylamine (0.036 mL, 0.26 After mmol), it was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium chloride was added to the mixture and the mixture was extracted with dichloromethane. The solvent was evaporated under reduced pressure. EtOAc (mjjjjjj Yield 33%).

1H-NMR(400MHz,CDCl3)δ：8.36(1H,t,J=5Hz),7.55-7.45(6H,m),7.42-7.29(5H,m),7.00(2H,d,J=9Hz),5.12(2H,s),4.96(1H,brs),4.39(2H,d,J=6Hz),4.27(2H,q,J=7Hz),4.25(2H,d,J=5Hz),4.16(2H,q,J=7Hz),3.75(2H,d,J=12Hz),2.90(2H,d,J=7Hz),2.78(2H,t,J=12Hz),2.47(3H,s),2.19-2.05(1H,m),1.79(2H,d,J=12Hz),1.60-1.47(2H,m),1.32(3H,t,J=7Hz),1.26(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 8.36 (1H, t, J = 5 Hz), 7.55-7.45 (6H, m), 7.42-7.29 (5H, m), 7.00 (2H, d, J = 9 Hz) ), 5.12 (2H, s), 4.96 (1H, brs), 4.39 (2H, d, J = 6 Hz), 4.27 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 5 Hz), 4.16 (2H,q,J=7Hz), 3.75(2H,d,J=12Hz), 2.90(2H,d,J=7Hz), 2.78(2H,t,J=12Hz), 2.47(3H,s), 2.19-2.05(1H,m), 1.79(2H,d,J=12Hz),1.60-1.47(2H,m), 1.32(3H,t,J=7Hz), 1.26(3H,t,J=7Hz) .

(14){[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯 (14) {[(2-{[1-(4'-{[(ethoxycarbonyl)amino)methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5- Ethyl hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate

將({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基} 胺基)乙酸乙酯(0.039g,0.057mmol)溶解於乙醇(3mL)及二氯甲烷(2mL)的混合溶劑中，加入10%鈀-活性碳(0.020g)後，在氫氣環境下，於室溫攪拌30分鐘。以Celite過濾反應液，藉由在減壓下濃縮濾液而析出固體。過濾所得到的固體，藉由在減壓下乾燥，而得到淡黃色固體的標的化合物(0.033g,0.056mmol)(產率98%)。 ({[5-(Benzyloxy)-2-{[1-(4'-{[(ethoxycarbonyl)amino)methyl}biphenyl-4-yl)piperidin-4-yl] Methyl}-6-methylpyrimidin-4-yl]carbonyl} Ethyl ethyl acetate (0.039 g, 0.057 mmol) was dissolved in a mixed solvent of ethanol (3 mL) and dichloromethane (2 mL), and then 10% palladium-activated carbon (0.020 g) was added to the hydrogen atmosphere. Stir at room temperature for 30 minutes. The reaction solution was filtered through Celite, and the solid was precipitated by concentrating the filtrate under reduced pressure. The obtained solid was filtered, and dried (jjjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=5Hz),7.52(2H,d,J=8Hz),7.48(2H,d,J=8Hz),7.32(2H,d,J=8Hz),6.99(2H,d,J=8Hz),4.98(1H,brs),4.39(2H,d,J=6Hz),4.28(2H,q,J=7Hz),4.23(2H,d,J=5Hz),4.16(2H,q,J=7Hz),3.73(2H,d,J=12Hz),2.83(2H,d,J=7Hz),2.76(2H,t,J=12Hz),2.54(3H,s),2.13-1.99(1H,m),1.78(2H,d,J=12Hz),1.57-1.45(2H,m),1.33(3H,t,J=7Hz),1.26(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3) δ: 11.37 (1H, s), 8.50 (1H, t, J = 5Hz), 7.52 (2H, d, J = 8Hz), 7.48 (2H, d, J = 8Hz ), 7.32 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 4.98 (1H, brs), 4.39 (2H, d, J = 6 Hz), 4.28 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 5 Hz), 4.16 (2H, q, J = 7 Hz), 3.73 (2H, d, J = 12 Hz), 2.83 (2H, d, J = 7 Hz), 2.76 (2H) ,t,J=12Hz),2.54(3H,s),2.13-1.99(1H,m),1.78(2H,d,J=12Hz),1.57-1.45(2H,m),1.33(3H,t, J = 7 Hz), 1.26 (3H, t, J = 7 Hz).

(15){[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸鹽酸鹽 (15){[(2-{[1-(4'-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5- Hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid hydrochloride

將{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯(0.033g,0.056mmol)溶解於甲醇(1mL)及四氫呋喃(1mL)的混合溶劑中，加入氫氧化鈉水溶液(1M,0.56mL)後，於室溫攪拌30分鐘。在減壓下濃縮反應液，藉由於所得到的殘留物加入鹽酸(1M,0.56mL)而析出固體。過濾所得到的固體，藉由在減壓下乾燥，而得到 淡褐色固體的標的化合物(0.026g,0.043mmol)(產率77%)。 {[(2-{[1-(4'-{[(ethoxycarbonyl)amino)methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy- 6-Methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate (0.033 g, 0.056 mmol) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), and aqueous sodium hydroxide (1M, 0.56) After mL), it was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the solid was evaporated to ethylamine (1M, 0.56mL). The resulting solid was filtered and dried by drying under reduced pressure. The title compound (0.026 g, 0.043 mmol) (yield: 77%)

MS m/z：562(M+H)+； MS m / z: 562 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.83(1H,brs),11.96(1H,brs),9.50(1H,t,J=6Hz),7.93(2H,brs),7.82(2H,d,J=8Hz),7.72(1H,t,J=6Hz),7.66(2H,d,J=8Hz),7.35(2H,d,J=8Hz),4.22(2H,d,J=6Hz),4.02(2H,d,J=6Hz),4.01(2H,q,J=7Hz),3.57(4H,brs),2.86(2H,d,J=7Hz),2.46(3H,s),2.43-2.31(1H,m),2.11-1.78(4H,m),1.17(3H,t,J=7Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.83 (1H, brs), 11.96 (1H, brs), 9.50 (1H, t, J = 6Hz), 7.93 (2H, brs), 7.82 (2H, d, J = 8 Hz), 7.72 (1H, t, J = 6 Hz), 7.66 (2H, d, J = 8 Hz), 7.35 (2H, d, J = 8 Hz), 4.22 (2H, d, J = 6 Hz) , 4.02 (2H, d, J = 6 Hz), 4.01 (2H, q, J = 7 Hz), 3.57 (4H, brs), 2.86 (2H, d, J = 7 Hz), 2.46 (3H, s), 2.43- 2.31 (1H, m), 2.11-1.78 (4H, m), 1.17 (3H, t, J = 7Hz).

(實施例2) (Example 2)

({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸鹽酸鹽 ({[2-({1-[4'-({[(ethylthio)carbonyl)]amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-hydroxyl -6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrochloride

(1)({[5-(苄氧基)-2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (1) ({[5-(Benzyloxy)-2-({1-[4'-({[(ethylthio)carbonyl)amino}methyl)biphenyl-4-yl]piperidine- Ethyl 4-methyl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

將以實施例1-(12)所得到的({[2-({1-[4’-(胺基甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.29g,0.48mmol)溶解於二氯甲烷(12mL)中，加入(乙硫基)羰基氯(0.075mL,0.72mmol)及三乙胺(0.10mL,0.72mmol)後，於室溫攪拌30分鐘。於反應液加入飽和氯化鈉水溶液，以二氯甲烷萃取後，將萃取液以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到淡黃色固體的標的化合物(0.20g,0.29mmol)(產率59%)。 ({[2-({1-[4'-(Aminomethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5) obtained in Example 1-(12) Ethyl (-benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.29 g, 0.48 mmol) was dissolved in dichloromethane (12 mL). (0.075 mL, 0.72 mmol) and triethylamine (0.10 mL, 0.72 mmol) were stirred at room temperature for 30 min. After adding a saturated aqueous solution of sodium chloride to the reaction mixture and extracting with dichloromethane, the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAc m. m. (Yield 59%).

1H-NMR(400MHz,CDCl3)δ：8.36(1H,t,J=5Hz),7.53(2H,d,J=8Hz),7.51-7.45(4H,m),7.42-7.34(3H,m),7.31(2H,d,J=8Hz),7.00(2H,d,J=9Hz),5.59(1H,brs),5.12(2H,s),4.50(2H,d,J=5Hz),4.27(2H,q,J=7Hz),4.25(2H,d,J=5Hz),3.75(2H,d,J=12Hz),2.96(2H,q,J=7Hz),2.90(2H,d,J=7Hz),2.77(2H,t,J=12Hz),2.47(3H,s),2.18-2.05(1H,m),1.79(2H,d,J=12Hz),1.63-1.47(2H,m),1.32(3H,t,J=7Hz),1.31(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 8.36 (1H, t, J = 5 Hz), 7.53 (2H, d, J = 8 Hz), 7.51-7.45 (4H, m), 7.42-7.34 (3H, m ), 7.31 (2H, d, J = 8 Hz), 7.00 (2H, d, J = 9 Hz), 5.59 (1H, brs), 5.12 (2H, s), 4.50 (2H, d, J = 5 Hz), 4.27 (2H,q,J=7Hz), 4.25(2H,d,J=5Hz), 3.75(2H,d,J=12Hz), 2.96(2H,q,J=7Hz), 2.90(2H,d,J =7 Hz), 2.77 (2H, t, J = 12 Hz), 2.47 (3H, s), 2.18-2.05 (1H, m), 1.79 (2H, d, J = 12 Hz), 1.63-1.47 (2H, m) , 1.32 (3H, t, J = 7Hz), 1.31 (3H, t, J = 7Hz).

(2)({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[2-({1-[4'-({[(ethylthio)carbonyl)]amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)- 5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

將({[5-(苄氧基)-2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.13g,0.19mmol)溶解於二氯甲烷(6mL)中，在氮氣環境下，加入三氟乙酸(3mL)後，於室溫攪拌18小時。在減壓下濃縮反應液後，以二氯甲烷稀釋，並依序以飽和碳酸氫鈉水溶液及飽和氯化鈉水溶液洗淨。將有機層以無水硫酸鈉乾燥後，在減壓下餾除溶劑，藉由將所得到的殘留物以矽膠管柱式層析法(二氯甲烷/乙酸乙酯)精製，而得到淡黃色固體的標的化合物(0.11g,0.19mmol)(產率98%)。 ({[5-(Benzyloxy)-2-({1-[4'-({[(ethylthio)carbonyl)amino}methyl)biphenyl-4-yl]piperidin-4- Ethyl ethyl methacrylate-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.13 g, 0.19 mmol) was dissolved in dichloromethane (6 mL). After (3 mL), it was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, evaporated, m. The title compound (0.11 g, 0.19 mmol) (yield 98%).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=6Hz),7.53(2H,d,J=8Hz),7.48(2H,d,J=9Hz),7.31(2H,d,J=8Hz),6.99(2H,d,J=9Hz),5.60(1H,brs),4.50(2H,d,J=5Hz),4.28(2H,q,J=7Hz),4.23(2H,d,J=6Hz),3.74(2H,d,J=13Hz),2.96(2H,q,J=7Hz), 2.83(2H,d,J=7Hz),2.77(2H,t,J=13Hz),2.54(3H,s),2.13-2.01(1H,m),1.78(2H,d,J=13Hz),1.58-1.45(2H,m),1.33(3H,t,J=7Hz),1.32(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.50 (1H, t, J = 6 Hz), 7.53 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 9 Hz) ), 7.31 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 9 Hz), 5.60 (1H, brs), 4.50 (2H, d, J = 5 Hz), 4.28 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 3.74 (2H, d, J = 13 Hz), 2.96 (2H, q, J = 7 Hz), 2.83 (2H, d, J = 7 Hz), 2.77 (2H) , t, J = 13 Hz), 2.54 (3H, s), 2.13 - 2.01 (1H, m), 1.78 (2H, d, J = 13 Hz), 1.58-1.45 (2H, m), 1.33 (3H, t, J=7Hz), 1.32 (3H, t, J=7Hz).

(3)({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸鹽酸鹽 (3)({[2-({1-[4'-({[(ethylthio)carbonyl)]amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)- 5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrochloride

將({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.023g,0.038mmol)溶解於1,4-二烷(2mL)中，於室溫加入鹽酸(1M,1mL)後，於80℃攪拌1小時。在減壓下濃縮乾燥反應液後，將所得到的殘留物溶解於水(2mL)及1,4-二烷(1mL)的混合溶劑中，藉由將此加以冷凍乾燥，而得到淡褐色固體的標的化合物(0.023g,0.037mmol)(產率98%)。 ({[2-({1-[4'-({[(ethylthio)carbonyl)]amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5- Ethyl hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.023 g, 0.038 mmol) was dissolved in 1,4-di Hydrochloric acid (1 M, 1 mL) was added to aq. (2 mL), and stirred at 80 ° C for one hour. After concentrating and drying the reaction mixture under reduced pressure, the obtained residue was dissolved in water (2 mL) and 1,4- The title compound (0.023 g, 0.037 mmol) (yield 98%) was obtained as a pale brown solid.

MS m/z：578(M+H)+； MS m / z: 578 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.87(1H,brs),11.95(1H,brs),9.46(1H,t,J=6Hz),8.69(1H,t,J=6Hz),7.75(4H,brs),7.64(2H,d,J=8Hz),7.32(2H,d,J=8Hz),4.37(2H,brs),4.33(2H,d,J=6Hz),4.02(2H,d,J=6Hz),3.63(2H,brs),2.85(2H,d,J=6Hz),2.80(2H,q,J=7Hz),2.46(3H,s),2.37-2.21(1H,m),1.91-1.77(4H,m),1.19(3H,t,J=7Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.87 (1H, brs), 11.95 (1H, brs), 9.46 (1H, t, J = 6Hz), 8.69 (1H, t, J = 6Hz), 7.75(4H,brs), 7.64(2H,d,J=8Hz), 7.32(2H,d,J=8Hz), 4.37(2H,brs),4.33(2H,d,J=6Hz),4.02(2H , d, J = 6 Hz), 3.63 (2H, brs), 2.85 (2H, d, J = 6 Hz), 2.80 (2H, q, J = 7 Hz), 2.46 (3H, s), 2.37 - 2.21 (1H, m), 1.91-1.77 (4H, m), 1.19 (3H, t, J = 7 Hz).

(實施例3) (Example 3)

({[2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[4-(6-{[(T-Butoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲基}胺基甲酸第三丁酯 (1) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl}aminocarboxylic acid third Butyl ester

將[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯(0.66g,2.3mmol)溶解於1,4-二烷(13mL)中，於室溫加入雙二硼烷(0.77g,3.0mmol)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷錯合物(0.13g,0.15mmol)及乙酸鉀(0.68g,6.9mmol)後，於85℃攪拌19小時。將反應液冷卻至室溫後，加入二氯甲烷及水予以分液，以二氯甲烷萃取水層。依序以飽和碳酸氫鈉水溶液及飽和氯化鈉水 溶液洗淨合併的有機層後，以無水硫酸鈉乾燥。藉由在減壓下餾除溶劑，而得到油狀物質的標的化合物(1.13g)(產率定量的)。 Dissolving [(5-bromopyridin-2-yl)methyl]carbamic acid tert-butyl ester (0.66 g, 2.3 mmol) in 1,4-di In alkane (13 mL), add double at room temperature Diborane (0.77 g, 3.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride methylene chloride complex (0.13 g, 0.15 mmol) and potassium acetate ( After stirring at 85 ° C for 19 hours, 0.68 g, 6.9 mmol. After cooling the reaction mixture to room temperature, dichloromethane and water were added to separate the layers, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The title compound (1.13 g) of an oily substance (yield quantitative) was obtained by distilling solvent under reduced pressure.

1H-NMR(400MHz,CDCl3)δ：8.85(1H,brs),8.02(1H,dd,J=8Hz,2Hz),7.25(1H,d,J=8Hz),5.57(1H,brs),4.73-4.70(2H,m),1.46(9H,s),1.35(12H,s). 1 H-NMR (400MHz, CDCl 3) δ: 8.85 (1H, brs), 8.02 (1H, dd, J = 8Hz, 2Hz), 7.25 (1H, d, J = 8Hz), 5.57 (1H, brs), 4.73-4.70(2H,m), 1.46(9H,s), 1.35(12H,s).

(2)5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯 (2) 5-(Benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

以實施例1-(8)為標準，使用1,4-二溴苯代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到橙色油狀物質的標的化合物(產率18%)。 Using Example 1-(8) as a standard, 1,4-dibromobenzene was used instead of [(4'-bromobiphenyl-4-yl)methoxy](t-butyl)dimethylsilane. The title compound of the orange oily substance (yield 18%).

1H-NMR(500MHz,CDCl3)δ：7.46-7.35(5H,m),7.31(2H,d,J=8Hz),6.80(2H,d,J=8Hz),5.01(2H,s),3.62(2H,d,J=12Hz),2.89(2H,d,J=7Hz),2.69(2H,t,J=12Hz),2.46(3H,s),2.15-2.03(1H,m),1.77(2H,d,J=12Hz),1.59(9H,s),1.51(2H,q,J=12Hz). 1 H-NMR (500 MHz, CDCl 3 ) δ: 7.46-7.35 (5H, m), 7.31 (2H, d, J = 8 Hz), 6.80 (2H, d, J = 8 Hz), 5.01 (2H, s), 3.62 (2H, d, J = 12 Hz), 2.89 (2H, d, J = 7 Hz), 2.69 (2H, t, J = 12 Hz), 2.46 (3H, s), 2.15-2.03 (1H, m), 1.77 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.51 (2H, q, J = 12 Hz).

(3)({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (3) ({[5-(Benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl} Amino ethyl acetate

以實施例1-(10)為標準，使用5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯，而得到油狀物質的標的化合物(產率94%)。 Using 1-(benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine as the standard, using 1-(10) as the standard Tertiary 4-carboxylic acid tert-butyl ester instead of 5-(benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6 -Methylpyrimidine-4-carboxylic acid tert-butyl ester, the title compound was obtained as an oily substance (yield: 94%).

1H-NMR(400MHz,CDCl3)δ：8.34(1H,t,J=6Hz),7.53-7.47(2H,m),7.43-7.31(5H,m),6.79(2H,d,J=8Hz),5.11(2H,s),4.26(2H,q,J=7Hz),4.24(2H,d,J=6Hz),3.63(2H,brs),2.88(2H,d,J=7Hz),2.71(2H,dt,J=12Hz,4Hz),2.46(3H,s),2.15-2.03(1H,m),1.75(2H,brs),1.56-1.42(2H,m),1.31(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.34 (1H, t, J = 6 Hz), 7.53-7.47 (2H, m), 7.43-7.31 (5H, m), 6.79 (2H, d, J = 8 Hz ), 5.11 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz), 3.63 (2H, brs), 2.88 (2H, d, J = 7 Hz), 2.71 (2H, dt, J=12 Hz, 4 Hz), 2.46 (3H, s), 2.15-2.03 (1H, m), 1.75 (2H, brs), 1.56-1.42 (2H, m), 1.31 (3H, t, J=7Hz).

(4)({[5-(苄氧基)-2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (4) ({[5-(Benzyloxy)-2-({1-[4-(6-{[(t-butoxycarbonyl)amino]methyl}pyridin-3-yl)phenyl) Ethyl piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)

將({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.61g,1.0mmol)及{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲基}胺基甲酸第三丁酯(0.76g,2.3mmol)溶解於甲苯(24mL)、乙醇(3mL)及水(6mL)的混合溶劑中，於室溫加入肆(三苯基膦)鈀(0.12g,0.11mmol)及碳酸鈉(0.33g,3.1mmol)後，加熱回流18小時。將反應液冷卻至室溫後，加入乙酸乙酯及飽和氯化銨水溶液予以分液。將水層以乙酸乙酯萃取，以無水硫酸鈉乾燥合併的有機層。於減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/甲醇)精製，而得到褐色無定形固體的標的化合物(0.24g,0.33mmol)(產率32%)。 ({[5-(Benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino) Ethyl acetate (0.61 g, 1.0 mmol) and {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl ]Methyl}aminobutyl carbamic acid tert-butyl ester (0.76 g, 2.3 mmol) was dissolved in a mixed solvent of toluene (24 mL), ethanol (3 mL) and water (6 mL), and hydrazine (triphenylphosphine) was added at room temperature. Palladium (0.12 g, 0.11 mmol) and sodium carbonate (0.33 g, 3.1 mmol) were heated and refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate and a saturated aqueous solution of ammonium chloride were added to separate. The aqueous layer was extracted with EtOAc. After the solvent was evaporated under reduced pressure, the title compound was obtained (jjjjjjjjj Yield 32%).

1H-NMR(400MHz,CDCl3)δ：8.72(1H,d,J=4Hz),8.35(1H,t,J=6Hz),7.80(1H,dd,J=8Hz,4Hz),7.50-7.25(8H,m),7.01(2H,d,J=8Hz),5.52(1H,brs),5.12(2H,s),4.46(2H,d,J=6Hz),4.26(2H,q,J=7Hz),4.24(2H,d,J=6Hz),3.76(2H,brs),2.89(2H,d,J=7Hz),2.84-2.75(2H,m),2.46(3H,s),2.20-2.08(1H,m),1.79(2H,brs),1.60-1.48(2H,m),1.47(9H,s),1.32(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.72 (1H, d, J = 4 Hz), 8.35 (1H, t, J = 6 Hz), 7.80 (1H, dd, J = 8 Hz, 4 Hz), 7.50-7.25 (8H,m),7.01(2H,d,J=8Hz),5.52(1H,brs),5.12(2H,s), 4.46(2H,d,J=6Hz), 4.26(2H,q,J= 7 Hz), 4.24 (2H, d, J = 6 Hz), 3.76 (2H, brs), 2.89 (2H, d, J = 7 Hz), 2.84 - 2.75 (2H, m), 2.46 (3H, s), 2.20- 2.08(1H,m), 1.79(2H,brs),1.60-1.48(2H,m), 1.47(9H,s), 1.32(3H,t,J=7Hz).

(5)({[2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 (5)({[2-({1-[4-(6-{[(T-Butoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl} Methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例1-(14)、1-(15)為標準，使用({[5-(苄氧基)-2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3- 基)苯基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯代替({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到固體的標的化合物(產率61%)。 Using the formula 1-(14), 1-(15) as the standard, ({[5-(benzyloxy)-2-({1-[4-(6-{[(T-butoxycarbonyl))) Amino]methyl}pyridine-3- Ethyl phenyl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ({[5-(benzyloxy)-2-{[ 1-(4'-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl} Amino)acetate to give the title compound as a solid (yield: 61%).

MS m/z：589(M-H)-； MS m / z: 589 (MH) - ;

1H-NMR(400MHz,DMSO-d6)δ：12.89(1H,brs),11.92(1H,brs),9.41(1H,t,J=6Hz),8.71(1H,d,J=3Hz),7.96(1H,dd,J=8Hz,3Hz),7.55(2H,d,J=8Hz),7.45(1H,t,J=6Hz),7.27(1H,d,J=8Hz),7.02(2H,d,J=8Hz),4.22(2H,d,J=6Hz),4.00(2H,d,J=6Hz),3.76(2H,brs),2.82-2.66(4H,m),2.44(3H,s),2.18-2.05(1H,m),1.78-1.62(2H,m),1.45-1.25(2H,m),1.41(9H,s). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.89 (1H, brs), 11.92 (1H, brs), 9.41 (1H, t, J = 6Hz), 8.71 (1H, d, J = 3Hz), 7.96 (1H, dd, J = 8 Hz, 3 Hz), 7.55 (2H, d, J = 8 Hz), 7.45 (1H, t, J = 6 Hz), 7.27 (1H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz), 4.22 (2H, d, J = 6 Hz), 4.00 (2H, d, J = 6 Hz), 3.76 (2H, brs), 2.82-2.66 (4H, m), 2.44 (3H, s ), 2.18-2.05 (1H, m), 1.78-1.62 (2H, m), 1.45-1.25 (2H, m), 1.41 (9H, s).

(實施例4) (Example 4)

({[5-羥基-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 ({[5-Hydroxy-6-methyl-2-({1-[4-(6-{[(methylsulfonyl)amino)methyl}pyridin-3-yl)phenyl]piperidine- 4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1)[({2-[(1-{4-[6-(胺甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽 (1) [({2-[(1-{4-[6-(Aminomethyl)pyridin-3-yl)phenyl}piperidin-4-yl)methyl]-5-(benzyloxy) -6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride

將以實施例3-(4)所得到的({[5-(苄氧基)-2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.11g,0.15mmol)溶解於二氯甲烷(2.5mL)中，加入氯化氫二烷溶液(4M,2.5mL,10mmol)後，於室溫攪拌1小時。藉由在減壓下濃縮反應液，而得到標的化合物(0.13g)(產率定量的)。 ({[5-(Benzyloxy)-2-({1-[4-(6-{[(T-butoxycarbonyl)amino)methyl) obtained in Example 3-(4) Ethylpyridin-3-yl)phenyl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.11 g, 0.15 mmol) dissolved in dichloro In methane (2.5mL), add hydrogen chloride After an alkane solution (4M, 2.5 mL, 10 mmol), The title compound (0.13 g) (quantitative yield) was obtained by concentrating the reaction mixture under reduced pressure.

1H-NMR(400MHz,DMSO-d6)δ：9.17(1H,t,J=6Hz),8.96(1H,brs),8.46(3H,brs),8.23(1H,d,J=6Hz),7.90(2H,brs),7.62(1H,d,J=6Hz),7.53-7.35(4H,m),5.05(2H,s),4.29-4.21(2H,m),4.13(2H,q,J=7Hz),4.06(2H,d,J=6Hz),3.68-3.57(4H,m),2.86(2H,d,J=7Hz),2.42(3H,s),2.36-2.30(1H,m),1.85(4H,brs),1.20(3H,t,J=7Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 9.17 (1H, t, J = 6Hz), 8.96 (1H, brs), 8.46 (3H, brs), 8.23 (1H, d, J = 6Hz), 7.90 (2H, brs), 7.62 (1H, d, J = 6 Hz), 7.53 - 7.35 (4H, m), 5.05 (2H, s), 4.29 - 4.21 (2H, m), 4.13 (2H, q, J =7 Hz), 4.06 (2H, d, J = 6 Hz), 3.68-3.57 (4H, m), 2.86 (2H, d, J = 7 Hz), 2.42 (3H, s), 2.36-2.30 (1H, m) , 1.85 (4H, brs), 1.20 (3H, t, J = 7Hz).

(2)({[5-(苄氧基)-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[5-(Benzyloxy)-6-methyl-2-({1-[4-(6-{[(methylsulfonyl)amino)methyl}pyridin-3-yl) Ethyl phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)ethyl acetate

於二氯甲烷(5mL)懸浮[({2-[(1-{4-[6-(胺甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽(0.13g)，加入甲烷磺醯基氯(0.45mL,5.8mmol)及三乙胺(0.13mL,0.96mmol)後，於室溫攪拌2小時。於反應液中加入水及二氯甲烷予以分液後，以二氯甲烷萃取水層。以飽和氯化鈉水溶液洗淨合併的有機層後，以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠薄層層析法(二氯甲烷/甲醇)精製，而得到固體的標的化合物(0.090g,0.13mmol)(產率85%)。 Suspension of [({2-[(1-{4-[6-(Aminomethyl)pyridin-3-yl)phenyl)piperidin-4-yl)methyl]-5- in dichloromethane (5 mL) (Benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride (0.13 g), methanesulfonyl chloride (0.45 mL, 5.8 mmol) and triethylamine ( After stirring at room temperature for 2 hours, 0.13 mL, 0.96 mmol. After water and dichloromethane were added to the reaction mixture for separation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (dichloromethane/methanol) to give the title compound (0.090 g, 0.13 mmol) %).

1H-NMR(400MHz,CDCl3)δ：8.74(1H,t,J=2Hz),8.35(1H,t,J=5Hz),7.83(1H,dd,J=8,2Hz),7.55-7.46(4H,m),7.43-7.34(3H,m),7.31(1H,d,J=8Hz),7.02(2H,d,J=8Hz),5.56(1H,brs),5.12(2H,s),4.46(2H,d,J=5Hz),4.30-4.20(4H,m),3.77(2H,brs),2.94-2.87(2H,m),2.93(3H,s),2.86-2.76(2H,m),2.47(3H,s),2.20-2.08(1H,m),1.78(2H,brs),1.59-1.45(2H,m),1.32(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.74 (1H, t, J = 2 Hz), 8.35 (1H, t, J = 5 Hz), 7.83 (1H, dd, J = 8, 2 Hz), 7.55-7.46 (4H,m), 7.43-7.34(3H,m), 7.31(1H,d,J=8Hz),7.02(2H,d,J=8Hz),5.56(1H,brs),5.12(2H,s) , 4.46 (2H, d, J = 5 Hz), 4.30-4.20 (4H, m), 3.77 (2H, brs), 2.94-2.87 (2H, m), 2.93 (3H, s), 2.86-2.76 (2H, m), 2.47 (3H, s), 2.20-2.08 (1H, m), 1.78 (2H, brs), 1.59-1.45 (2H, m), 1.32 (3H, t, J = 7 Hz).

(3)({[5-羥基-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 (3) ({[5-Hydroxy-6-methyl-2-({1-[4-(6-{[(methylsulfonyl)amino)methyl}pyridin-3-yl)phenyl] Piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例1-(14)、1-(15)為標準，使用({[5-(苄氧基)-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙.酯代替({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到固體的標的化合物(產率73%)。 Using the formulas 1-(14) and 1-(15) as the standard, ({[5-(benzyloxy)-6-methyl-2-({1-[4-(6-{[( Sulfhydryl)amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl ester instead of ({[5- (Benzyloxy)-2-{[1-(4'-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-6- Ethyl acetate of methylpyrimidin-4-yl]carbonyl}amino) gave the title compound as a solid (yield: 73%).

MS m/z：567(M-H)-； MS m/z: 567 (MH) - ;

1H-NMR(400MHz,DMSO-d6)δ：12.88(1H,brs),11.90(1H,s),9.40(1H,t,J=6Hz),8.76(1H,d,J=2Hz),8.01(1H,dd,J=8Hz,2Hz),7.66(1H,t,J=6Hz),7.57(2H,d,J=8Hz),7.47(1H,d,J=8Hz),7.03(2H,d,J=8Hz),4.27(2H,d,J=6Hz),4.00(2H,d,J=6Hz),3.77(2H,brs),2.94(3H,s),2.81-2.65(4H,m),2.44(3H,s),2.23-2.05(1H,m),1.68(2H,brs),1.43-1.23(2H,m). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.88 (1H, brs), 11.90 (1H, s), 9.40 (1H, t, J = 6 Hz), 8.76 (1H, d, J = 2 Hz), 8.01 (1H, dd, J = 8 Hz, 2 Hz), 7.66 (1H, t, J = 6 Hz), 7.57 (2H, d, J = 8 Hz), 7.47 (1H, d, J = 8 Hz), 7.03 (2H, d, J = 8 Hz), 4.27 (2H, d, J = 6 Hz), 4.00 (2H, d, J = 6 Hz), 3.77 (2H, brs), 2.94 (3H, s), 2.81-2.65 (4H, m ), 2.44 (3H, s), 2.23 - 2.05 (1H, m), 1.68 (2H, brs), 1.43-1.23 (2H, m).

(實施例5) (Example 5)

({[2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[4-(6-{[(ethylaminomethyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1)({[5-(苄氧基)-2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (1) ({[5-(Benzyloxy)-2-({1-[4-(6-{[(ethylaminomethylamino)amino]methyl}pyridin-3-yl)phenyl) Ethyl piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)

於四氫呋喃(3mL)懸浮以實施例4-(1)所得到的[({2-[(1-{4-[6-(胺甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽(0.079g)，於室溫加入異氰酸乙酯(0.046mL,0.58mmol)及三乙胺(0.064mL,0.46mmol)後，於室溫攪拌5小時。於反應液加入水及二氯甲烷予以分液後，以二氯甲烷萃取水層。以飽和氯化鈉水溶液洗淨合併的有機層後，以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠薄層層析法(二氯甲烷/甲醇)精製，而得到固體的標的化合物(0.054g,0.079mmol)(產率82%)。 [({2-[(1-{4-[6-(Aminomethyl)pyridin-3-yl]phenyl}piperidin-4) obtained in Example 4-(1) was suspended in tetrahydrofuran (3 mL) -yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride (0.079 g), ethyl isocyanate was added at room temperature (0.046 mL, 0.58 mmol) and triethylamine (0.064 mL, 0.46 mmol). After water and dichloromethane were added to the reaction mixture for separation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (dichloromethane/methanol) to give the title compound (0.054 g, %).

1H-NMR(400MHz,CDCl3)δ：8.70(1H,d,J=2Hz),8.35(1H,t,J=5Hz),7.80(1H,dd,J=8Hz,2Hz),7.54-7.45(3H,m),7.42-7.25(5H,m),7.01(2H,d,J=8Hz),5.39(1H,brs),5.12(2H,s),4.60(1H,brs),4.50(2H,d,J=5Hz),4.29-4.21(4H,m),3.77(2H,brs),3.29-3.17(2H,m),2.89(2H,d,J=7Hz),2.85-2.74(2H,m),2.46(3H,s),2.18-2.07(1H,m),1.78(2H,brs),1.60-1.47(2H,m),1.32(3H,t,J=7Hz),1.15(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.70 (1H, d, J = 2 Hz), 8.35 (1H, t, J = 5 Hz), 7.80 (1H, dd, J = 8 Hz, 2 Hz), 7.54 - 7.45 (3H,m), 7.42-7.25(5H,m),7.01(2H,d,J=8Hz), 5.39(1H,brs),5.12(2H,s),4.60(1H,brs),4.50(2H , d, J = 5 Hz), 4.29 - 4.21 (4H, m), 3.77 (2H, brs), 3.29 - 3.17 (2H, m), 2.89 (2H, d, J = 7 Hz), 2.85 - 2.74 (2H, m), 2.46 (3H, s), 2.18-2.07 (1H, m), 1.78 (2H, brs), 1.60-1.47 (2H, m), 1.32 (3H, t, J = 7 Hz), 1.15 (3H, t, J = 7Hz).

(2)({[2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 (2) ({[2-({1-[4-(6-{[(ethylaminomethyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl} Methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例1-(14)、1-(15)為標準，使用({[5-(苄氧基)-2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯代替({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到固體的標的化合物(產率27%)。 Using the formula 1-(14), 1-(15) as the standard, ({[5-(benzyloxy)-2-({1-[4-(6-{[(ethylamine)) Amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ({[5 -(benzyloxy)-2-{[1-(4'-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-6 -Methylpyrimidin-4-yl]carbonyl}amino)acetate to give the title compound as a solid (yield: 27%).

MS m/z：560(M-H)-； MS m/z: 560 (MH) - ;

1H-NMR(400MHz,DMSO-d6)δ：9.06(1H,brs),8.71(1H,d,J=2Hz),7.94(1H,dd,J=8Hz,2Hz),7.54(2H,d,J=8Hz),7.28(1H,d,J=8Hz),7.02(2H,d,J=8Hz),6.45(1H,t,J=6Hz),6.09(1H,t,J=6Hz),4.29(2H,d,J=6Hz),3.75(2H,brs),3.60(2H,brs),3.07-3.00(2H,m),2.79-2.65(2H,m),2.76(2H,d,J=8Hz),2.42(3H,s), 2.12-1.98(1H,m),1.69(2H,brs),1.42-1.27(2H,m),1.00(3H,t,J=6Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 9.06 (1H, brs), 8.71 (1H, d, J = 2Hz), 7.94 (1H, dd, J = 8Hz, 2Hz), 7.54 (2H, d , J = 8 Hz), 7.28 (1H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz), 6.45 (1H, t, J = 6 Hz), 6.09 (1H, t, J = 6 Hz), 4.29(2H,d,J=6Hz), 3.75(2H,brs), 3.60(2H,brs),3.07-3.00(2H,m),2.79-2.65(2H,m),2.76(2H,d,J =8 Hz), 2.42 (3H, s), 2.12-1.98 (1H, m), 1.69 (2H, brs), 1.42-1.27 (2H, m), 1.00 (3H, t, J = 6 Hz).

(實施例6) (Example 6)

({[2-({1-[4-(6-{[(乙氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[4-(6-{[(ethoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5 -hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例1-(13)~1-(15)為標準，使用以實施例4-(1)所得到的[({2-[(1-{4-[6-(胺甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽代替({[2-({1-[4’-(胺甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到固體的標的化合物(產率45%)。 Using [1-{2-[(1-{4-[6-(aminomethyl)pyridine) obtained in Example 4-(1) using the examples 1-(13)~1-(15) as a standard -3-yl]phenyl}piperidin-4-yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride instead {[2-({1-[4'-(Aminomethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-(benzyloxy)-6-methylpyrimidine-4 Ethyl-carbonyl]carbonyl}amino)acetate gave the title compound as a solid (yield 45%).

MS m/z：563(M+H)+； MS m / z: 563 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.91(1H,brs),11.93(1H,brs),9.40(1H,t,J=6Hz),8.72(1H,d,J=2Hz),7.96(1H,dd,J=8Hz,2Hz),7.71(1H,t,J=6Hz),7.55(2H,d,J=8Hz),7.29(1H,d,J=8Hz),7.02(2H,d,J=8Hz),4.27(2H,d,J=6Hz),4.07-3.97(4H,m),3.76(2H, brs),2.77(2H,d,J=8Hz),2.77-2.66(2H,m),2.44(3H,s),2.18-2.05(1H,m),1.68(2H,brs),1.42-1.29(2H,m),1.18(3H,t,J=7Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.91 (1H, brs), 11.93 (1H, brs), 9.40 (1H, t, J = 6 Hz), 8.72 (1H, d, J = 2 Hz), 7.96 (1H, dd, J = 8 Hz, 2 Hz), 7.71 (1H, t, J = 6 Hz), 7.55 (2H, d, J = 8 Hz), 7.29 (1H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz), 4.27 (2H, d, J = 6 Hz), 4.07-3.97 (4H, m), 3.76 (2H, brs), 2.77 (2H, d, J = 8 Hz), 2.77-2.66 (2H , m), 2.44 (3H, s), 2.18-2.05 (1H, m), 1.68 (2H, brs), 1.42-1.29 (2H, m), 1.18 (3H, t, J = 7 Hz).

(實施例7) (Example 7)

({[2-({1-[4-(6-{[(乙基胺甲醯基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[4-(6-{[(ethylamine)methyl)oxy)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1)乙基胺基甲酸(5-溴吡啶-2-基)甲酯 (1) ethylaminocarbamic acid (5-bromopyridin-2-yl)methyl ester

將(5-溴吡啶-2-基)甲醇(1.0g,5.4mmol)溶解於四氫呋喃(15mL)中，於室溫加入異氰酸乙酯(1.3mL,16mmol)及三乙胺(0.76mL,5.5mmol)後，於45℃攪拌8小時，進一步於室溫攪拌3日。於反應液加入二氯甲烷及水予以分液後，以二氯甲烷萃取水層。以飽和氯化鈉水溶液 洗淨合併的有機層後，以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到固體的標的化合物(1.2g,4.4mmol)(產率81%)。 (5-Bromopyridin-2-yl)methanol (1.0 g, 5.4 mmol) was dissolved in tetrahydrofuran (15 mL), ethyl acetate (1.3 mL, 16 mmol) and triethylamine (0.76 mL, After 5.5 mmol), the mixture was stirred at 45 ° C for 8 hours and further stirred at room temperature for 3 days. After separating the reaction solution with dichloromethane and water, the aqueous layer was extracted with dichloromethane. Saturated aqueous sodium chloride solution The combined organic layers were washed and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.2 g, 4.4 mmol) 81%).

1H-NMR(400MHz,CDCl3)δ：8.64(1H,d,J=2Hz),7.81(1H,dd,J=8Hz,2Hz),7.26(1H,d,J=8Hz),5.16(2H,s),4.82(1H,brs),3.30-3.21(2H,m),1.16(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.64 (1H, d, J = 2 Hz), 7.81 (1H, dd, J = 8 Hz, 2 Hz), 7.26 (1H, d, J = 8 Hz), 5.16 (2H) , s), 4.82 (1H, brs), 3.30-3.21 (2H, m), 1.16 (3H, t, J = 7 Hz).

(2)乙基胺基甲酸[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲酯 (2) ethylaminocarbamic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl ester

以實施例3-(1)為標準，使用乙基胺基甲酸(5-溴吡啶-2-基)甲酯代替[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯，而得到油狀物質的標的化合物(產率定量的)。 Using 3-(5-bromopyridin-2-yl)methyl ethyl carbazate instead of [(5-bromopyridin-2-yl)methyl]carbamic acid tert-butyl as the standard of Example 3-(1) The ester is obtained to give the title compound (quantitative yield) of the oily substance.

1H-NMR(400MHz,CDCl3)δ：8.91(1H,d,J=2Hz),8.06(1H,dd,J=8Hz,2Hz),7.33(1H,d,J=8Hz),5.22(2H,s),4.85(1H,brs),3.31-3.22(2H,m),1.35(12H,s),1.15(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.91 (1H, d, J = 2 Hz), 8.06 (1H, dd, J = 8 Hz, 2 Hz), 7.33 (1H, d, J = 8 Hz), 5.22 (2H) , s), 4.85 (1H, brs), 3.31-3.22 (2H, m), 1.35 (12H, s), 1.15 (3H, t, J = 7 Hz).

(3)({[2-({1-[4-(6-{[(乙基胺甲醯基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 (3)({[2-({1-[4-(6-{[(ethylamine)methyl)oxy)methyl}pyridin-3-yl)phenyl]piperidin-4-yl} Methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例3-(4)、1-(10)、2-(2)、1-(15)為標準，使用以實施例3-(2)所得到的5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，及使用乙基胺基甲酸[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲酯代替{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲基}胺基甲酸第三丁酯，而得到固體的化合物(產率35%)。 5-(Benzyloxy)-2 obtained in Example 3-(2) was used as the standard in Examples 3-(4), 1-(10), 2-(2), 1-(15). -{[1-(4-Bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester instead of ({[5-(benzyloxy)-2-) {[1-(4-Bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate, and using ethylaminocarbamic acid [5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl ester instead of {[5-(4,4,5, 3-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl}aminocarboxylic acid tert-butyl ester to give a solid compound (yield 35%) .

MS m/z：563(M+H)+； MS m / z: 563 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.93(1H,brs),11.95(1H,brs),9.40(1H,t,J=6Hz),8.78(1H,d,J=2Hz),8.01(1H,dd,J=8Hz,2Hz),7.57(2H,d,J=8Hz),7.40-7.34(2H,m),7.03(2H,d,J=8Hz),5.07(2H,s),3.98(2H,d,J=6Hz),3.78(2H,brs),3.09-3.00(2H,m),2.78(2H,d,J=7Hz),2.78-2.67(2H,m),2.44(3H,s),2.18-2.04(1H,m),1.68(2H,brs),1.42-1.30(2H,m),1.03(3H,t,J=7Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.93 (1H, brs), 11.95 (1H, brs), 9.40 (1H, t, J = 6 Hz), 8.78 (1H, d, J = 2 Hz), 8.01 (1H, dd, J = 8 Hz, 2 Hz), 7.57 (2H, d, J = 8 Hz), 7.40-7.34 (2H, m), 7.03 (2H, d, J = 8 Hz), 5.07 (2H, s) , 3.98 (2H, d, J = 6 Hz), 3.78 (2H, brs), 3.09-3.00 (2H, m), 2.78 (2H, d, J = 7 Hz), 2.78-2.67 (2H, m), 2.44 ( 3H, s), 2.18-2.04 (1H, m), 1.68 (2H, brs), 1.42-1.30 (2H, m), 1.03 (3H, t, J = 7 Hz).

(實施例8) (Example 8)

{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸 {[(5-Hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxoxybut-1-en-1-yl]pyridin-3-yl}benzene (piperidin-4-yl)methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid

(1)5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-{[(三異丙基矽烷基)氧基]甲基}吡啶 (1) 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[(triisopropyldecyl)oxy] Methyl}pyridine

以實施例3-(1)為標準，使用5-溴-2-{[(三異丙基矽烷基)氧基]甲基}吡啶代替[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯，而得到油狀物質的標的化合物(產率定量的)。 Using 5-bromo-2-{[(triisopropyldecyl)oxy]methyl}pyridine in place of [(5-bromopyridin-2-yl)methyl] using Example 3-(1) as a standard The third butyl carbamate was obtained to give the title compound (quantitative yield) of the oily substance.

1H-NMR(400MHz,CDCl3)δ：8.83(1H,d,J=2Hz),8.09(1H,dd,J=8Hz,2Hz),7.58(1H,d,J=2Hz),4.95(2H,s),1.35(12H,s),1.25-1.17(3H,m),1.09(18H,d,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.83 (1H, d, J = 2 Hz), 8.09 (1H, dd, J = 8 Hz, 2 Hz), 7.58 (1H, d, J = 2 Hz), 4.95 (2H) , s), 1.35 (12H, s), 1.25-1.17 (3H, m), 1.09 (18H, d, J = 7Hz).

(2)({[5-羥基-6-甲基-2-({1-[4-(6-{[(三異丙基矽烷基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[5-hydroxy-6-methyl-2-({1-[4-(6-{[(triisopropyldecyl)oxy)methyl}pyridin-3-yl)benzene) Ethyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)ethyl acetate

以實施例3-(4)、1-(10)、1-(14)為標準，使用以實施例3-(2)所得到的5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，及使用5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-{[(三異丙基矽烷基)氧基]甲基}吡啶代替{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲基}胺基甲酸第三丁酯，而得到油狀物質的標的化合物(產率26%)。 5-(Benzyloxy)-2-{[1-() obtained in Example 3-(2) was used as the standard in Examples 3-(4), 1-(10), 1-(14). Tert-butyl 4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate ({[5-(benzyloxy)-2-{[1-(4) -Bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate, and 5-(4,4,5,5-tetramethyl) Base-1,3,2-dioxaborolan-2-yl)-2-{[(triisopropyldecyl)oxy]methyl}pyridine instead of {[5-(4,4,5, Tributyl butyl 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl}carbamate, to give the title compound as an oily substance 26%).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.68(1H,d,J=2Hz),8.49(1H,t,J=5Hz),7.86(1H,dd,J=8Hz,2Hz),7.60(1H,d,J=8Hz),7.48(2H,d,J=8Hz),7.01(2H,d,J=8Hz),4.96(2H,s),4.28(2H,q,J=7Hz),4.22(2H,d,J=5Hz),3.75(2H,brs),2.83(2H,d,J=7Hz),2.83-2.78(2H,m),2.54(3H,s),2.14-2.05(1H,m),1.78(2H,brs),1.58-1.45(2H,m),1.32(3H,t,J=7Hz),1.25-1.16(3H,m),1.11(18H,d,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.68 (1H, d, J = 2 Hz), 8.49 (1H, t, J = 5 Hz), 7.86 (1H, dd, J = 8 Hz) , 2 Hz), 7.60 (1H, d, J = 8 Hz), 7.48 (2H, d, J = 8 Hz), 7.01 (2H, d, J = 8 Hz), 4.96 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 3.75 (2H, brs), 2.83 (2H, d, J = 7 Hz), 2.83 - 2.78 (2H, m), 2.54 (3H, s), 2.14-2.05(1H,m), 1.78(2H,brs),1.58-1.45(2H,m), 1.32(3H,t,J=7Hz),1.25-1.16(3H,m),1.11(18H,d , J=7Hz).

(3)[({5-羥基-2-[(1-{4-[6-(羥甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯 (3) [({5-Hydroxy-2-[(1-{4-[6-(hydroxymethyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-6-A Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

將({[5-羥基-6-甲基-2-({1-[4-(6-{[(三異丙基矽烷基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯(0.26g,0.39mmol)溶解於吡啶(12mL)中，於0℃加入氫化氟-吡啶(4.0mL)後，於室溫攪拌18小時。以二氯甲烷稀釋反應液後，加入飽和碳酸氫鈉水溶液予以分液。以二氯甲烷萃取水層，以飽和氯化鈉水溶液洗淨合併的有機層後，以無水硫酸鈉乾燥。在減壓下餾除溶劑，將所得到的殘留物溶解於二氯甲烷中，藉由將加入己烷所析出的固體過濾，而得到固體的標的化合物(0.18g,0.35mmol)(產率92%)。 ({[5-Hydroxy-6-methyl-2-({1-[4-(6-{[(triisopropyldecyl)oxy)methyl}pyridin-3-yl)phenyl] Ethyl piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.26 g, 0.39 mmol) was dissolved in pyridine (12 mL). After that, it was stirred at room temperature for 18 hours. After diluting the reaction mixture with dichloromethane, a saturated aqueous solution of sodium hydrogencarbonate was added to separate. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj %).

1H-NMR(500MHz,DMSO-d6)δ：11.82(1H,s),9.50(1H,t,J=5Hz),8.71(1H,d,J=2Hz),7.98(1H,dd,J=8Hz,2Hz),7.55(2H,d,J=8Hz),7.47(1H,d,J=8Hz),7.02(2H,d,J=8Hz),5.40(1H,t,J=5Hz),4.56(2H,d,J=5Hz),4.14(2H,q,J=7Hz),4.07(2H,d,J=5Hz),3.76(2H,brs),2.78(2H,d,J=7Hz),2.77-2.68(2H,m),2.44(3H,s),2.17-2.05(1H,m),1.67(2H,brs),1.41-1.30(2H,m),1.21(3H,t,J=7Hz). 1 H-NMR (500MHz, DMSO -d 6) δ: 11.82 (1H, s), 9.50 (1H, t, J = 5Hz), 8.71 (1H, d, J = 2Hz), 7.98 (1H, dd, J =8 Hz, 2 Hz), 7.55 (2H, d, J = 8 Hz), 7.47 (1H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz), 5.40 (1H, t, J = 5 Hz), 4.56 (2H, d, J = 5 Hz), 4.14 (2H, q, J = 7 Hz), 4.07 (2H, d, J = 5 Hz), 3.76 (2H, brs), 2.78 (2H, d, J = 7 Hz) , 2.77-2.68(2H,m), 2.44(3H,s), 2.17-2.05(1H,m),1.67(2H,brs),1.41-1.30(2H,m),1.21(3H,t,J= 7Hz).

(4)({[2-({1-[4-(6-甲醯基吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (4)({[2-({1-[4-(6-Methylpyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidine) -4-yl]carbonyl}amino)ethyl acetate

將[({5-羥基-2-[(1-{4-[6-(羥甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯(0.10g,0.19mmol)溶解於二氯甲烷(5mL)中，於室溫加入二氧化錳(0.34g,3.9mmol)後，攪拌1.5小時。於反應液加入二氧化錳(0.34g,3.9mmol)後，進一步攪拌1小時。以Celite過濾反應液，藉由在減壓下濃縮乾燥固化濾液，而得到固體的標的化合物(0.067g,0.13mmol)(產率68%)。 [({5-Hydroxy-2-[(1-{4-[6-(hydroxymethyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidine] Ethyl acetate -4-yl}carbonyl)amino]] (0.10 g, 0.19 mmol) was dissolved in dichloromethane (5 mL). After adding manganese dioxide (0.34 g, 3.9 mmol) to the reaction liquid, it was further stirred for 1 hour. The reaction solution was filtered through Celite, and then evaporated and evaporated to dryness.

1H-NMR(400MHz,CDCl3)δ：11.38(1H,s),10.09(1H,s),8.99(1H,brs),8.49(1H,t,J=5Hz),8.05-7.99(2H,m),7.57(2H,d,J=8Hz),7.03(2H,d,J=8Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=5Hz),3.82(2H,brs),2.89-2.78(4H,m),2.54(3H,s),2.18-2.04(1H,m),1.78(2H,brs),1.57-1.43(2H,m),1.33(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3) δ: 11.38 (1H, s), 10.09 (1H, s), 8.99 (1H, brs), 8.49 (1H, t, J = 5Hz), 8.05-7.99 (2H, m), 7.57 (2H, d, J = 8 Hz), 7.03 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 3.82 (2H) , brs), 2.89-2.78 (4H, m), 2.54 (3H, s), 2.18-2.04 (1H, m), 1.78 (2H, brs), 1.57-1.43 (2H, m), 1.33 (3H, t , J=7Hz).

(5){[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸乙酯 (5) {[(5-Hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxoxybut-1-en-1-yl]pyridine-3- Ethyl phenyl)piperidin-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}ethyl acetate

將(2-側氧丙基)膦酸二甲基(0.039mL,0.29mmol)溶解於乙腈(1mL)中，加入氯化鋰(0.015g,0.34mmol)及N,N-二異丙基乙胺(0.059mL,0.34mmol)後，於室溫攪拌15分鐘。於反應液加入({[2-({1-[4-(6-甲醯基吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.044g,0.085mmol)之四氫呋喃(1.5mL)溶液後，進一步於室溫攪拌30分鐘。於反應液中加入二氯甲烷及水予以分液後，以二氯甲烷萃取水層。以飽和氯化鈉水溶液洗淨合併的有機層後，以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠薄層層析法(二氯甲烷/甲醇)精製，而得到固體的標的化合物(0.041g,0.073mmol)(產率86%)。 (2-Phenyloxypropyl)phosphonic acid dimethyl (0.039 mL, 0.29 mmol) was dissolved in acetonitrile (1 mL), and lithium chloride (0.015 g, 0.34 mmol) and N,N-diisopropyl The amine (0.059 mL, 0.34 mmol) was stirred at room temperature for 15 min. Add ({[2-({1-[4-(6-methylpyridin-3-yl)phenyl)piperidin-4-yl}methyl)-5-hydroxy-6-methyl to the reaction solution After a solution of ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.044 g, 0.085 mmol) in tetrahydrofurane (1.5 mL), After separating dichloromethane and water into the reaction mixture, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (dichloromethane/methanol) to give the title compound (0.041 g, 0.073 %).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.87(1H,d,J=2Hz),8.49(1H,t,J=5Hz),7.86(1H,dd,J=8Hz,2Hz),7.56(1H,d,J=16Hz),7.53(2H,d,J=8Hz),7.51(1H,d,J=8Hz),7.13(1H,d,J=16Hz),7.01(2H,d,J=8Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=5Hz),3.78(2H,brs),2.85-2.76(2H,m),2.83(2H,d,J=7Hz),2.54(3H,s),2.42(3H,s),2.15-2.04(1H,m),1.78(2H,brs),1.58-1.45(2H,m),1.33(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.87 (1H, d, J = 2 Hz), 8.49 (1H, t, J = 5 Hz), 7.86 (1H, dd, J = 8 Hz) , 2Hz), 7.56 (1H, d, J = 16Hz), 7.53 (2H, d, J = 8Hz), 7.51 (1H, d, J = 8Hz), 7.13 (1H, d, J = 16Hz), 7.01 ( 2H,d,J=8Hz), 4.28(2H,q,J=7Hz), 4.22(2H,d,J=5Hz),3.78(2H,brs),2.85-2.76(2H,m),2.83(2H , d, J = 7 Hz), 2.54 (3H, s), 2.42 (3H, s), 2.15-2.04 (1H, m), 1.78 (2H, brs), 1.58-1.45 (2H, m), 1.33 (3H ,t,J=7Hz).

(6){[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸 (6) {[(5-Hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxo-but-1-en-1-yl]pyridine-3- Phenyl)phenyl)piperidin-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid

以實施例1-(15)為標準，使用{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸乙酯代替{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯，而得到固體的標的化合物(產率87%)。 Using the formula 1-(15) as the standard, {[(5-hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxoxybut-1-ene) was used. -1-yl]pyridin-3-yl}phenyl)piperidin-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}ethyl acetate instead of {[(2-{[1-(4) '-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl] Amino}ethyl acetate gave the title compound as a solid (yield: 87%).

MS m/z：528(M-H)-； MS m/z: 528 (MH) - ;

1H-NMR(400MHz,DMSO-d6)δ：12.88(1H,brs),11.91(1H,s),9.41(1H,t,J=5Hz),8.94(1H,d,J=2Hz),8.09(1H,dd,J=8Hz,2Hz),7.75(1H,d,J=8Hz),7.66(2H,d,J=8Hz),7.64(1H,d,J=16Hz),7.07(1H,d,J=16Hz),7.04(2H,d,J=8Hz),4.00(2H,d,J=5Hz),3.82(2H,brs),2.82-2.70(4H,m),2.44(3H,s),2.37(3H,s),2.20-2.07(1H,m),1.68(2H,brs),1.42-1.29(2H,m). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.88 (1H, brs), 11.91 (1H, s), 9.41 (1H, t, J = 5Hz), 8.94 (1H, d, J = 2Hz), 8.09 (1H, dd, J = 8 Hz, 2 Hz), 7.75 (1H, d, J = 8 Hz), 7.66 (2H, d, J = 8 Hz), 7.64 (1H, d, J = 16 Hz), 7.07 (1H, d, J = 16 Hz), 7.04 (2H, d, J = 8 Hz), 4.00 (2H, d, J = 5 Hz), 3.82 (2H, brs), 2.82-2.70 (4H, m), 2.44 (3H, s ), 2.37 (3H, s), 2.20-2.07 (1H, m), 1.68 (2H, brs), 1.42-1.29 (2H, m).

(實施例9) (Example 9)

[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{4-[6-(3-oxobutyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

(1)[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯 (1) [({5-Hydroxy-6-methyl-2-[(1-{4-[6-(3-oxobutyl)pyridin-3-yl]phenyl}piperidin-4-yl) Ethylmethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

將以實施例8-(5)所得到的{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸乙酯(0.037g,0.067mmol)溶解於乙酸乙酯(1mL)、甲醇(1mL)及四氫呋喃(2mL)的混合溶劑中，加入10%鈀-活性碳(0.029g)後，在氫氣環境下，於室溫攪拌1小時。以Celite過濾反應液，在減壓下濃縮濾液後，藉由將所得到的殘留物以矽膠薄層層析法(二氯甲烷/甲醇)精製，而得到固體的標的化合物(0.028g,0.050mmol)(產率75%)。 {[(5-Hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxoxybut-1-ene) obtained in Example 8-(5) Ethyl acetate (0.037 g, 0.067 mmol) in ethyl acetate (0.037 g, 0.067 mmol) was dissolved in ethyl acetate. 10% palladium-activated carbon (0.029 g) was added to a mixed solvent of (1 mL), methanol (1 mL) and tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. ) (yield 75%).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.69(1H,d,J=2Hz),8.49(1H,t,J=5Hz),7.72(1H,dd,J=8Hz,2Hz),7.45(2H,d,J=8Hz),7.20(1H,d,J=8Hz),7.00(2H,d,J=8Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=5Hz),3.74(2H,brs),3.08(2H,t,J=6Hz),2.97(2H,t,J=6Hz),2.83(2H,d,J=7Hz),2.83-2.72(2H,m),2.54(3H,s),2.19(3H,s),2.14-2.00(1H,m),1.78(2H,brs),1.60-1.43(2H,m),1.33(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.69 (1H, d, J = 2 Hz), 8.49 (1H, t, J = 5 Hz), 7.72 (1H, dd, J = 8 Hz) , 2Hz), 7.45 (2H, d, J = 8Hz), 7.20 (1H, d, J = 8Hz), 7.00 (2H, d, J = 8Hz), 4.28 (2H, q, J = 7Hz), 4.22 ( 2H,d,J=5Hz), 3.74(2H,brs),3.08(2H,t,J=6Hz), 2.97(2H,t,J=6Hz),2.83(2H,d,J=7Hz),2.83 -2.72(2H,m),2.54(3H,s),2.19(3H,s),2.14-2.00(1H,m),1.78(2H,brs),1.60-1.43(2H,m),1.33(3H ,t,J=7Hz).

(2)[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 (2) [({5-Hydroxy-6-methyl-2-[(1-{4-[6-(3-oxobutyl)pyridin-3-yl]phenyl}piperidin-4-yl) Methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

以實施例1-(15)為標準，使用[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯代替{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯，而得到固體的標的化合物(產率51%)。 Using [1-{5-hydroxy-6-methyl-2-[(1-{4-[6-(3-o-oxybutyl)pyridin-3-yl] as the standard of Example 1-(15) Ethyl phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate in place of {[(2-{[1-(4'-{[(ethoxycarbonyl))amine) Ethyl]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate to give a solid The title compound (yield 51%).

MS m/z：530(M-H)-； MS m/z: 530 (MH) - ;

1H-NMR(400MHz,DMSO-d6)δ：12.89(1H,brs),11.91(1H,s),9.41(1H,t,J=5Hz),8.68(1H,d,J=2Hz),7.88(1H,dd,J=8Hz,2Hz),7.53(2H,d,J=8Hz),7.28(1H,d,J=8Hz),7.01(2H,d,J=8Hz),4.00(2H,d,J=5Hz),3.75(2H,brs),2.98-2.86(4H,m),2.77(2H,d,J=7Hz),2.77-2.65(2H,m),2.44(3H,s),2.15-2.05(1H,m),2.13(3H,s),1.67(2H,brs),1.42-1.29(2H,m). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.89 (1H, brs), 11.91 (1H, s), 9.41 (1H, t, J = 5Hz), 8.68 (1H, d, J = 2Hz), 7.88 (1H, dd, J = 8 Hz, 2 Hz), 7.53 (2H, d, J = 8 Hz), 7.28 (1H, d, J = 8 Hz), 7.01 (2H, d, J = 8 Hz), 4.00 (2H, d, J = 5 Hz), 3.75 (2H, brs), 2.98-2.86 (4H, m), 2.77 (2H, d, J = 7 Hz), 2.77-2.65 (2H, m), 2.44 (3H, s), 2.15-2.05 (1H, m), 2.13 (3H, s), 1.67 (2H, brs), 1.42-1.29 (2H, m).

(實施例10) (Embodiment 10)

[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-oxobutyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidine- 4-yl}carbonyl)amino]acetic acid

(1)1-[4-(4-溴苄基)苯基]丁烷-2-醇 (1) 1-[4-(4-Bromobenzyl)phenyl]butan-2-ol

將氯化正丁基鎂之四氫呋喃溶液(2M,1.0mL,2.0mmol)稀釋於四氫呋喃(2mL)，在氮氣環境下，於0℃加入正丁基鋰之己烷溶液(2.6M,1.5mL,4.0mmol)後，藉由於相同溫度攪拌20分鐘，調製成三正丁基鎂鋰之四氫呋喃溶液。 A solution of n-butylmagnesium chloride in tetrahydrofuran (2M, 1.0 mL, 2.0 mmol) was diluted in tetrahydrofuran (2 mL), and a hexane solution of n-butyllithium (2.6 M, 1.5 mL, was added at 0 ° C under nitrogen atmosphere. After 4.0 mmol), a tetrahydrofuran solution of tri-n-butylmagnesium lithium was prepared by stirring at the same temperature for 20 minutes.

將4,4’-二溴二苯基甲烷(1.6g,4.9mmol)溶解於四氫呋喃(10mL)中，在氮氣環境下，於0℃加入三正丁基鎂鋰之四氫呋喃溶液後，於相同溫度攪拌1小時。於反應液加入2-乙氧基矽烷(0.47mL,5.4mmol)後，於室溫下升溫，進一步攪拌15小時。於反應液加入飽和氯化銨水溶液後，以乙酸乙酯萃取。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到白色固體的標的化合物(0.39g,1.2mmol)(產率25%)。 4,4'-dibromodiphenylmethane (1.6 g, 4.9 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of tri-n-butylmagnesium hydride in tetrahydrofuran was added at 0 ° C under nitrogen atmosphere at the same temperature. Stir for 1 hour. After adding 2-ethoxy decane (0.47 mL, 5.4 mmol) to the reaction mixture, the mixture was warmed at room temperature and stirred for further 15 hours. After a saturated aqueous solution of ammonium chloride was added to the reaction mixture, ethyl acetate was evaporated. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjj Rate 25%).

1H-NMR(500MHz,CDCl3)δ：7.40(2H,d,J=8Hz),7.15(2H,d,J=8Hz),7.11(2H,d,J=8Hz),7.06(2H,d,J=8Hz),3.90(2H,s),3.76-3.68(1H,m),2.81(1H,dd,J=14Hz,4Hz),2.62(1H,dd,J=14Hz,8Hz),1.61-1.47(2H,m),1.47(1H,d,J=4Hz),0.99(3H,t,J=8Hz). 1 H-NMR (500MHz, CDCl 3 ) δ: 7.40 (2H, d, J = 8 Hz), 7.15 (2H, d, J = 8 Hz), 7.11 (2H, d, J = 8 Hz), 7.06 (2H, d , J = 8 Hz), 3.90 (2H, s), 3.76-3.68 (1H, m), 2.81 (1H, dd, J = 14 Hz, 4 Hz), 2.62 (1H, dd, J = 14 Hz, 8 Hz), 1.61 1.47(2H,m), 1.47(1H,d,J=4Hz), 0.99(3H,t,J=8Hz).

(2){1-[4-(4-溴苄基)苄基]丙氧基}(第三丁基)二甲基矽烷 (2) {1-[4-(4-Bromobenzyl)benzyl]propoxy}(t-butyl)dimethyl decane

將1-[4-(4-溴苄基)苯基]丁烷-2-醇(0.39g,1.2mmol)及咪唑(0.16g,2.4mmol)溶解於N,N-二甲基甲醯胺(10mL)中，在氮氣環境下，加入第三丁基二甲基氯矽烷(0.36g,2.4mmol)後，於室溫攪拌1小時。於反應液加入水，以乙酸乙酯萃取。在減壓下濃縮有機層後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到無色油狀物質的標的化合物(0.49g,1.1mmol)(產率94%)。 1-[4-(4-Bromobenzyl)phenyl]butan-2-ol (0.39 g, 1.2 mmol) and imidazole (0.16 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), after adding butyl dimethyl chloro decane (0.36 g, 2.4 mmol) under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The title compound (0.49 g, 1.1 mmol) was obtained as a colorless oily material. (Yield 94%).

1H-NMR(400MHz,CDCl3)δ：7.40-7.36(2H,m),7.11-7.02(6H,m),3.89(2H,s),3.77-3.70(1H,m),2.70(1H,dd,J=13Hz,6Hz),2.65(1H,dd,J=13Hz,7Hz),1.51-1.36(2H,m),0.90(3H,t,J=7Hz),0.84(9H,s),-0.06(3H,s),-0.21(3H,s). 1 H-NMR (400MHz, CDCl 3) δ: 7.40-7.36 (2H, m), 7.11-7.02 (6H, m), 3.89 (2H, s), 3.77-3.70 (1H, m), 2.70 (1H, Dd, J = 13 Hz, 6 Hz), 2.65 (1H, dd, J = 13 Hz, 7 Hz), 1.51-1.36 (2H, m), 0.90 (3H, t, J = 7 Hz), 0.84 (9H, s), - 0.06 (3H, s), -0.21 (3H, s).

(3)[({5-羥基-2-[(1-{4-[4-(2-羥丁基)苄基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯 (3) [({5-Hydroxy-2-[(1-{4-[4-(2-hydroxybutyl)benzyl]phenyl}piperidin-4-yl)methyl]-6-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

以實施例1-(8)~1-(10)、1-(14)為標準，使用{1-[4-(4-溴苄基)苄基]丙氧基}(第三丁基)二甲基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到黃色油狀物質的標的化合物(產率47%)。 Using 1-1-(8)~1-(10), 1-(14) as the standard, using {1-[4-(4-bromobenzyl)benzyl]propoxy}(t-butyl) Dimethyl decane was substituted for [(4'-bromobiphenyl-4-yl)methoxy](t-butyl)dimethyl decane to give the title compound (yield: 47%).

1H-NMR(500MHz,CDCl3)δ：11.36(1H,s),8.49(1H,t,J=6Hz),7.14-7.10(4H,m),7.06(2H,d,J=8Hz),6.87(2H,d,J=8Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=6Hz),3.87(2H,s),3.75-3.68(1H,m),3.64-3.58(2H,m),2.82(2H,d,J=7Hz),2.80(1H,dd,J=13Hz,4Hz),2.70-2.63(2H,m),2.60(1H,dd,J=13Hz,9Hz),2.53(3H,s),2.06-1.96(1H,m),1.78-1.71(2H,m),1.57-1.44(4H,m),1.48(1H,d,J=4Hz),1.32(3H,t,J=7Hz),0.99(3H,t,J=7Hz). 1 H-NMR (500MHz, CDCl 3) δ: 11.36 (1H, s), 8.49 (1H, t, J = 6Hz), 7.14-7.10 (4H, m), 7.06 (2H, d, J = 8Hz), 6.87(2H,d,J=8Hz), 4.28(2H,q,J=7Hz), 4.22(2H,d,J=6Hz),3.87(2H,s),3.75-3.68(1H,m),3.64 -3.58 (2H, m), 2.82 (2H, d, J = 7 Hz), 2.80 (1H, dd, J = 13 Hz, 4 Hz), 2.70-2.63 (2H, m), 2.60 (1H, dd, J = 13 Hz) , 9Hz), 2.53 (3H, s), 2.06-1.96 (1H, m), 1.78-1.71 (2H, m), 1.57-1.44 (4H, m), 1.48 (1H, d, J = 4Hz), 1.32 (3H, t, J = 7 Hz), 0.99 (3H, t, J = 7 Hz).

(4)[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯 (4) [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-oxobutyl)benzyl]phenyl}piperidin-4-yl)methyl) Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

將氧化鉻(0.040g,0.40mmol)及正過碘酸(9.1g,40mmol)溶解於乙腈(91ml)及水(0.70ml)的混合溶劑中，在氮氣環境下，藉由於室溫攪拌2小時，調製成氧化鉻-正過碘酸之乙腈溶液。 Chromium oxide (0.040 g, 0.40 mmol) and n-periodic acid (9.1 g, 40 mmol) were dissolved in a mixed solvent of acetonitrile (91 ml) and water (0.70 ml), and stirred for 2 hours at room temperature under a nitrogen atmosphere. Prepared into a chromic oxide-periodic acid acetonitrile solution.

將[({5-羥基-2-[(1-{4-[4-(2-羥丁基)苄基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯(0.20g,0.35mmol)溶解於乙腈(5mL)中，在氮氣環境下，於0℃加入氧化鉻-正過碘酸之乙腈溶液(5mL)後，於相同溫度攪拌1.75小時。於反應液加入磷酸氫二鈉水溶液，以乙酸乙酯萃取，依序以亞硫酸氫鈉水溶液、飽和氯化鈉水溶液洗淨。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到黃色油狀物質的標的化合物(0.10g,0.17mmol)(產率50%)。 [({5-Hydroxy-2-[(1-{4-[4-(2-hydroxybutyl)benzyl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidine- Ethyl 4-ethyl}carbonyl)amino]acetate (0.20 g, 0.35 mmol) was dissolved in acetonitrile (5 mL), and then EtOAc <RTI ID=0.0> , stirred at the same temperature for 1.75 hours. An aqueous solution of disodium hydrogen phosphate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then washed with aqueous sodium hydrogen sulfate and saturated aqueous sodium chloride. The solvent was evaporated under reduced pressure. EtOAc m. ) (yield 50%).

1H-NMR(500MHz,CDCl3)δ：11.35(1H,s),8.49(1H,t,J=6Hz),7.13(2H,d,J=8Hz),7.10(2H,d,J=8Hz),7.05(2H,d,J=8Hz),6.86(2H,d,J=8Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=6Hz),3.87(2H,s),3.63(2H,s),3.65-3.58(2H,m),2.82(2H,d,J=7Hz),2.70-2.63(2H,m),2.53(3H,s),2.46(2H,q,J=7Hz),2.06-1.96(1H,m),1.78-1.71(2H,m),1.56-1.43(2H,m),1.32(3H,t,J=7Hz),1.01(3H,t,J=7Hz). 1 H-NMR (500MHz, CDCl 3 ) δ: 11.35 (1H, s), 8.49 (1H, t, J = 6 Hz), 7.13 (2H, d, J = 8 Hz), 7.10 (2H, d, J = 8 Hz) ), 7.05 (2H, d, J = 8 Hz), 6.86 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 3.87 (2H, s), 3.63 (2H, s), 3.65-3.58 (2H, m), 2.82 (2H, d, J = 7 Hz), 2.70-2.63 (2H, m), 2.53 (3H, s), 2.46 (2H, q, J=7 Hz), 2.06-1.96 (1H, m), 1.78-1.71 (2H, m), 1.56-1.43 (2H, m), 1.32 (3H, t, J = 7 Hz), 1.01 (3H, t , J=7Hz).

(5)[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 (5) [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-oxobutyl)benzyl]phenyl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

以實施例1-(15)之方法為標準，使用[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯代替{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯，而得到黃色固體的標的化合物(產率16%)。 Using the method of Example 1-(15) as a standard, [({5-hydroxy-6-methyl-2-[(1-{4-[4-(2-)-oxybutyl)benzyl]benzene was used. Ethyl acetate of hydrazino-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]]{{(2-{[1-(4'-{[(ethoxycarbonyl))amino) Methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate to give a yellow solid The title compound (yield 16%).

MS m/z：545(M+H)+； MS m/z: 545 (M+H) + ;

1H-NMR(500MHz,DMSO-d6)δ：11.92(1H,brs),9.38(1H,t,J=6Hz),7.12(2H,d,J=8Hz),7.07(2H,d,J=8Hz),7.03(2H,d,J=8Hz),6.83(2H,d,J=8Hz),3.99(2H,d,J=6Hz),3.78(2H,s),3.67(2H,s),3.61-3.55(2H,m),2.76(2H,d,J=7Hz),2.62-2.55(2H,m),2.48(2H,q,J=7Hz),2.43(3H,s),2.09-1.98(1H,m),1.69-1.61(2H,m),1.39-1.28(2H,m),0.89(3H,t,J=7Hz). 1 H-NMR (500 MHz, DMSO-d 6 ) δ: 11.92 (1H, brs), 9.38 (1H, t, J = 6 Hz), 7.12 (2H, d, J = 8 Hz), 7.07 (2H, d, J) =8 Hz), 7.03 (2H, d, J = 8 Hz), 6.83 (2H, d, J = 8 Hz), 3.99 (2H, d, J = 6 Hz), 3.78 (2H, s), 3.67 (2H, s) , 3.61-3.55 (2H, m), 2.76 (2H, d, J = 7 Hz), 2.62-2.55 (2H, m), 2.48 (2H, q, J = 7 Hz), 2.43 (3H, s), 2.09- 1.98(1H,m), 1.69-1.61(2H,m), 1.39-1.28(2H,m),0.89(3H,t,J=7Hz).

(實施例11) (Example 11)

({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 ({[5-Hydroxy-6-methyl-2-({1-[4'-(2-flavopropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -carbonyl]carbonyl}amino)acetic acid

(1)({[5-羥基-2-({1-[4’-(2-羥基丙基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (1) ({[5-Hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine -4-yl]carbonyl}amino)ethyl acetate

以實施例1-(8)~1-(10)、1-(14)之方法為標準，使用[2-(4’-溴聯苯-4-基)-1-甲基乙氧基](第三丁基)二甲基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到白色固體的標的化合物(產率35%)。 Using the methods of Examples 1-(8)~1-(10), 1-(14) as the standard, [2-(4'-bromobiphenyl-4-yl)-1-methylethoxy] (T-butyl) dimethyl decane in place of [(4'-bromobiphenyl-4-yl)methoxy](t-butyl)dimethyl decane to give the title compound as a white solid (yield 35 %).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=6Hz),7.51(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.25(2H,d,J=8Hz),6.99(2H,d,J=8Hz),4.29(2H,q,J=7Hz),4.23(2H,d,J=6Hz),4.10-4.01(1H,m),3.73(2H,d,J=13Hz),2.84(2H,d,J=7Hz),2.83-2.67(4H,m),2.54(3H,s),2.12-2.01(1H,m),1.78(2H,d,J=13Hz),1.58-1.46(2H,m),1.55(1H,d,J=4Hz),1.33(3H,t,J=7Hz),1.28(3H,d,J=6Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.50 (1H, t, J = 6 Hz), 7.51 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz) ), 7.25 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 4.29 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.10-4.01 ( 1H,m),3.73(2H,d,J=13Hz), 2.84(2H,d,J=7Hz),2.83-2.67(4H,m),2.54(3H,s),2.12-2.01(1H,m ), 1.78 (2H, d, J = 13 Hz), 1.58-1.46 (2H, m), 1.55 (1H, d, J = 4 Hz), 1.33 (3H, t, J = 7 Hz), 1.28 (3H, d, J=6Hz).

(2)({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[5-hydroxy-6-methyl-2-({1-[4'-(2-o-oxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl) Pyrimidine-4-yl]carbonyl}amino)ethyl acetate

將草醯氯(0.046g,0.37mmol)溶解於二氯甲烷(5mL)中，於-78℃滴入二甲基亞磺醯(0.057g,0.73mmol)後，於相同溫度攪拌10分鐘。於反應液滴入({[5-羥基-2-({1-[4’-(2-羥基丙基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.10g,0.018mmol)之二氯甲烷溶液(3mL)，於相同溫度攪拌40分鐘後，滴入三乙胺(0.20mL,1.5mmol)，放上30分鐘升溫至室溫。於反應液加入水，以二氯甲烷萃取後，以無水硫酸鈉乾燥萃取液。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到白色固體的標的化合物(0.048g,0.087mmol)(產率48%)。 The chloroform (0.046 g, 0.37 mmol) was dissolved in dichloromethane (5 mL), and dimethylsulfinium (0.057 g, 0.73 mmol) was added dropwise at -78 ° C, and then stirred at the same temperature for 10 minutes. Into the reaction droplets ({[5-hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-A A solution of ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.10 g, 0.018 mmol) in dichloromethane (3 mL). After stirring 40 mins at the same temperature, triethylamine (0.20 mL, 1.5 mmol) ), put it on for 30 minutes and warm to room temperature. After adding water to the reaction mixture and extracting with dichloromethane, the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjj Rate 48%).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=6Hz),7.52(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.23(2H,d,J=8Hz),6.99(2H,d,J=8Hz),4.29(2H,q,J=7Hz),4.23(2H,d,J=6Hz),3.73(2H,d,J=13Hz),3.72(2H,s),2.83(2H,d,J=7Hz),2.76(2H,t,J=6Hz),2.55(3H,s),2.19(3H,s),2.12-2.01(1H,m),1.78(2H,d,J=13Hz),1.58-1.46(2H,m),1.33(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.50 (1H, t, J = 6 Hz), 7.52 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz) ), 7.23 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 4.29 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 3.73 (2H, d, J = 13 Hz), 3.72 (2H, s), 2.83 (2H, d, J = 7 Hz), 2.76 (2H, t, J = 6 Hz), 2.55 (3H, s), 2.19 (3H, s), 2.12-2.01(1H,m), 1.78(2H,d,J=13Hz), 1.58-1.46(2H,m), 1.33(3H,t,J=7Hz).

(3)({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 (3) ({[5-hydroxy-6-methyl-2-({1-[4'-(2-Siloxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl) Pyrimidin-4-yl]carbonyl}amino)acetic acid

將({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯(0.027g,0.050mmol)溶解於甲醇(1mL)、四氫呋喃(1mL)及水(1mL)的混合溶劑中，加入氫氧化鋰一水合物(0.010g,0.25mmol)後，於室溫攪拌15分鐘。在減壓下濃縮反應液後，藉由於殘留物加入鹽酸(1M)析出固體。過濾所得到的固體，藉由在減壓下乾燥，而得到淡黃白色固體的標的化合物(0.023g,0.045mmol)(產率90%)。 ({[5-Hydroxy-6-methyl-2-({1-[4'-(2-Siloxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine- Ethyl 4-ethyl]carbonyl}amino)acetate (0.027 g, 0.050 mmol) was dissolved in a mixed solvent of methanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL). After 0.25 mmol), it was stirred at room temperature for 15 minutes. After concentrating the reaction mixture under reduced pressure, a solid was precipitated from hydrochloric acid (1M). The obtained solid was filtered, and dried (jjjjjjjjjjj

MS m/z：517(M+H)+ MS m/z: 517 (M+H) +

1H-NMR(500MHz,DMSO-d6)δ：12.88(1H,brs),11.91(1H,brs),9.39(1H,t,J=6Hz),7.53(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.21(2H,d,J=8Hz),6.99(2H,d,J=8Hz),4.01(2H,d,J=6Hz),3.77(2H,s),3.77-3.71(2H,m),2.78(2H,d,J=7Hz),2.74-2.67(2H,m),2.44(3H,s),2.14(3H,s),2.15-2.05(1H,m),1.72-1.65(2H,m),1.42-1.31(2H,m). 1 H-NMR (500MHz, DMSO -d 6) δ: 12.88 (1H, brs), 11.91 (1H, brs), 9.39 (1H, t, J = 6Hz), 7.53 (2H, d, J = 8Hz), 7.50 (2H, d, J = 8 Hz), 7.21 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 4.01 (2H, d, J = 6 Hz), 3.77 (2H, s) , 3.77-3.71 (2H, m), 2.78 (2H, d, J = 7 Hz), 2.74 - 2.67 (2H, m), 2.44 (3H, s), 2.14 (3H, s), 2.15-2.05 (1H, m), 1.72-1.65 (2H, m), 1.42-1.31 (2H, m).

(實施例12) (Embodiment 12)

({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 ({[5-Hydroxy-6-methyl-2-({1-[4'-(2-oxobutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -carbonyl]carbonyl}amino)acetic acid

以實施例1-(8)~1-(10)、1-(14)、11-(2)、11-(3)之方法為標準，使用{(1S)-1-[(4’-溴聯苯-4-基)甲基]丙氧基}(第三丁基)二甲基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到淡褐色固體的標的化合物(產率5.7%)。 Using the methods of Examples 1-(8)~1-(10), 1-(14), 11-(2), and 11-(3) as the standard, use {(1S)-1-[(4'- Bromobiphenyl-4-yl)methyl]propoxy}(t-butyl)dimethyl decane instead of [(4'-bromobiphenyl-4-yl)methoxy](t-butyl) Methyl decane gave the title compound as a light brown solid (yield: 5.7%).

MS m/z：531(M+H)+ MS m/z: 531 (M+H) +

1H-NMR(400MHz,CDCl3)δ：8.60(1H,brs),7.55-7.49(4H,m),7.34-7.24(4H,m),4.28(2H,d,J=6Hz),3.72(2H,s),3.71-3.68(2H,m),3.00-2.92(2H,m),2.89(2H,d,J=7Hz),2.51(2H,q,J=7Hz),2.53(3H,s),2.17-2.07(1H,brs),2.00-1.66(4H,m),1.05(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.60 (1H, brs), 7.55-7.49 (4H, m), 7.34-7.24 (4H, m), 4.28 (2H, d, J = 6 Hz), 3.72 ( 2H, s), 3.71-3.68 (2H, m), 3.00-2.92 (2H, m), 2.89 (2H, d, J = 7 Hz), 2.51 (2H, q, J = 7 Hz), 2.53 (3H, s ), 2.17-2.07 (1H, brs), 2.00-1.66 (4H, m), 1.05 (3H, t, J = 7Hz).

(實施例13) (Example 13)

({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 ({[5-Hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -carbonyl]carbonyl}amino)acetic acid

(1)({[5-羥基-2-({1-[4’-(2-羥戊基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (1) ({[5-Hydroxy-2-({1-[4'-(2-hydroxypentyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine -4-yl]carbonyl}amino)ethyl acetate

以實施例1-(8)~1-(10)、1-(14)之方法為標準，使用{1-[(4’-溴聯苯-4-基)甲基]丁氧基}(第三丁基)二甲基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到白色固體的標的化合物(產率30%)。 Using the method of Examples 1-(8)~1-(10), 1-(14) as the standard, {1-[(4'-bromobiphenyl-4-yl)methyl]butoxy} ( The third butyl)dimethyl decane was substituted for [(4'-bromobiphenyl-4-yl)methoxy](t-butyl)dimethyl decane to give the title compound as a white solid (yield 30%) ).

1H-NMR(400MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=6Hz),7.51(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.25(2H,d,J=8Hz),6.99(2H,d,J=8Hz),4.29(2H,q,J=7Hz),4.23(2H,d,J=6Hz),3.96(1H,d,J=6Hz),3.88-3.83(1H,m),3.74-3.71(2H,m),2.84(2H,d,J=7Hz),2.75(2H,t,J=13Hz),2.66(1H,dd,J=13Hz,9Hz),2.54(3H,s),2.12-2.02(1H,m),1.80-1.76(2H,m),1.54-1.51(6H,m),1.49-1.39(1H,m),1.33(3H,t,J=7Hz),0.95(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.50 (1H, t, J = 6 Hz), 7.51 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz) ), 7.25 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 4.29 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 3.96 (1H, d, J = 6 Hz), 3.88-3.83 (1H, m), 3.74 - 3.71 (2H, m), 2.84 (2H, d, J = 7 Hz), 2.75 (2H, t, J = 13 Hz), 2.66 (1H) ,dd,J=13Hz,9Hz),2.54(3H,s),2.12-2.02(1H,m),1.80-1.76(2H,m),1.54-1.51(6H,m),1.49-1.39(1H, m), 1.33 (3H, t, J = 7 Hz), 0.95 (3H, t, J = 7 Hz).

(2)({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[5-hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidin-4-yl}methyl) Pyrimidine-4-yl]carbonyl}amino)ethyl acetate

將({[5-羥基-2-({1-[4’-(2-羥戊基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯(0.41g,0.71mmol)溶解於二氯甲烷(15mL)中，於室溫加入Dess-Martin試藥(0.45g,1.1mmol)後，於相同溫度攪拌2小時。於反應液加入飽和碳酸氫鈉水溶液，以二氯甲烷萃取，將萃取液以飽和氯化鈉水溶液洗淨，並以無水硫酸鈉乾燥有機層。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到黃色固體的標的化合物(0.061g,0.11mmol)(產率15%)。 ({[5-Hydroxy-2-({1-[4'-(2-hydroxypentyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4 Ethyl-carbonyl]amino)acetic acid ethyl ester (0.41 g, 0.71 mmol) was dissolved in dichloromethane (15 mL), and the mixture was stirred at room temperature (0.45 g, 1.1 mmol) and stirred at the same temperature. 2 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with dichloromethane. The solvent was evaporated under reduced pressure. EtOAc m. Rate 15%).

1H-NMR(500MHz,CDCl3)δ：11.37(1H,s),8.50(1H,t,J=5Hz),7.52(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.23(2H,d,J=8Hz),7.00(2H,d,J=8Hz),4.29(2H,q,J=7Hz),4.23(2H,d,J=5Hz),3.73(2H,d,J=12Hz),3.70(2H,s),2.84(2H,d,J=7Hz),2.76(2H,t,J=12Hz),2.55(3H,s),2.46(2H,t,J=7Hz),2.10-2.04(1H,m),1.78(2H,d,J=12Hz),1.64-1.56(2H,m),1.58-1.48(2H,m),1.33(3H,t,J=7Hz),0.89(3H,t,J=7Hz). 1 H-NMR (500MHz, CDCl 3 ) δ: 11.37 (1H, s), 8.50 (1H, t, J = 5 Hz), 7.52 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz) ), 7.23 (2H, d, J = 8 Hz), 7.00 (2H, d, J = 8 Hz), 4.29 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 5 Hz), 3.73 (2H, d, J = 12 Hz), 3.70 (2H, s), 2.84 (2H, d, J = 7 Hz), 2.76 (2H, t, J = 12 Hz), 2.55 (3H, s), 2.46 (2H, t, J =7 Hz), 2.10-2.04 (1H, m), 1.78 (2H, d, J = 12 Hz), 1.64-1.56 (2H, m), 1.58-1.48 (2H, m), 1.33 (3H, t, J = 7Hz), 0.89 (3H, t, J = 7Hz).

(3)({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 (3) ({[5-hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidin-4-yl}methyl) Pyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例11-(3)之方法為標準，使用({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯代替({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到黃色固體的標的化合物(產率83%)。 Using the method of Example 11-(3) as a standard, ({[5-hydroxy-6-methyl-2-({1-[4'-(2-oxo-oxypentyl)biphenyl-4-yl) was used. [piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetate instead of ({[5-hydroxy-6-methyl-2-({1-[4'-(2) -Phenoxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetate to give the title compound as a yellow solid (yield 83%) ).

MS m/z：545(M+H)+ MS m/z: 545 (M+H) +

1H-NMR(500MHz,CDCl3)δ：11.47(1H,brs),8.58(1H,t,J=5Hz),7.54(2H,d,J=7Hz),7.50(2H,d,J=7Hz),7.27-7.24(4H,m),4.27(2H,d,J=5Hz),3.73-3.71(2H,m),3.71(2H,s),2.94-2.91(2H,m),2.88(2H,d,J=7Hz),2.54(3H,s),2.47(2H,t,J=7Hz),2.14-2.07(1H,m),1.88-1.80(4H,m),1.61(2H,q,J=7Hz),0.89(3H,t,J=7Hz). 1 H-NMR (500MHz, CDCl 3 ) δ: 11.47 (1H, brs), 8.58 (1H, t, J = 5 Hz), 7.54 (2H, d, J = 7 Hz), 7.50 (2H, d, J = 7 Hz) ), 7.27-7.24(4H,m), 4.27(2H,d,J=5Hz),3.73-3.71(2H,m),3.71(2H,s),2.94-2.91(2H,m),2.88(2H , d, J = 7 Hz), 2.54 (3H, s), 2.47 (2H, t, J = 7 Hz), 2.14 - 2.07 (1H, m), 1.88-1.80 (4H, m), 1.61 (2H, q, J = 7 Hz), 0.89 (3H, t, J = 7 Hz).

(實施例14) (Example 14)

({[5-羥基-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸鹽酸鹽 ({[5-Hydroxy-6-methyl-2-({1-[3'-(2-flavopropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -yl]carbonyl}amino)acetic acid hydrochloride

(1)1-[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]丙酮 (1) 1-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetone

以實施例3-(1)之方法為標準，使用1-(3-溴苯基)丙酮代替[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯，而得到白色固體的標的化合物(產率99%)。 Using the method of Example 3-(1) as a standard, 1-(3-bromophenyl)acetone was used instead of [(5-bromopyridin-2-yl)methyl]carbamic acid tert-butyl ester to give white The title compound of the solid (yield 99%).

1H-NMR(400MHz,CDCl3)δ：7.72(1H,d,J=7Hz),7.64(1H,s),7.41-7.27(2H,m),3.70(2H,s),2.15(3H,s),1.34(12H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.72 (1H, d, J = 7 Hz), 7.64 (1H, s), 7.41-7.27 (2H, m), 3.70 (2H, s), 2.15 (3H, s), 1.34 (12H, s).

(2)5-(苄氧基)-2-{[1-(4-{[第三丁基(二苯基)矽烷基]氧基}苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯 (2) 5-(Benzyloxy)-2-{[1-(4-{[t-butyl(diphenyl)decyl]oxy}phenyl)piperidin-4-yl]methyl} -6-methylpyrimidine-4-carboxylic acid tert-butyl ester

以實施例1-(8)之方法為標準，使用(4-溴苯氧基)(第三丁基)二苯基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三 丁基)二甲基矽烷，而得到橙色油狀物質的標的化合物(產率74%)。 Using the method of Example 1-(8) as a standard, (4-bromophenoxy)(t-butyl)diphenylnonane was used instead of [(4'-bromobiphenyl-4-yl)methoxy] (third Butyl) dimethyl decane gave the title compound (yield 74%) as an orange oil.

1H-NMR(400MHz,CDCl3)δ：7.71-7.70(4H,m),7.42-7.33(11H,m),6.70-6.65(4H,m),4.99(2H,s),3.43(2H,d,J=12Hz),2.87(2H,d,J=7Hz),2.55(2H,t,J=12Hz),2.44(3H,s),2.03-1.98(1H,m),1.73(2H,d,J=12Hz),1.58(9H,s),1.48(2H,q,J=12Hz),1.08(9H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.71-7.70 (4H, m), 7.42-7.33 (11H, m), 6.70-6.65 (4H, m), 4.99 (2H, s), 3.43 (2H, d, J = 12 Hz), 2.87 (2H, d, J = 7 Hz), 2.55 (2H, t, J = 12 Hz), 2.44 (3H, s), 2.03-1.98 (1H, m), 1.73 (2H, d , J = 12 Hz), 1.58 (9H, s), 1.48 (2H, q, J = 12 Hz), 1.08 (9H, s).

(3)5-(苄氧基)-2-{[1-(4-羥苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯 (3) 5-(Benzyloxy)-2-{[1-(4-hydroxyphenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

將5-(苄氧基)-2-{[1-(4-{[第三丁基(二苯基)矽烷基]氧基}苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯(2.8g,3.8mmol)溶解於四氫呋喃(60mL)，氟化四丁基銨之四氫呋喃溶液(1.0M、8.0mL，加入8.0mmol)後，於室溫攪拌30分鐘。將反應液以乙酸乙酯稀釋，並以飽和氯化鈉水溶液洗淨後，以無水硫酸鈉乾燥有機層。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到白色固體的標的化合物(1.8g,3.7mmol)(產率97%)。 5-(Benzyloxy)-2-{[1-(4-{[t-butyl(diphenyl)decyl]oxy}phenyl)piperidin-4-yl]methyl}-6 -Methylpyrimidine-4-carboxylic acid tert-butyl ester (2.8 g, 3.8 mmol) was dissolved in tetrahydrofuran (60 mL), tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 8.0 mL, 8.0 mmol) Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous The solvent was evaporated under reduced pressure, and the residue obtained was purified eluted eluted eluted eluted eluted eluted The rate is 97%).

1H-NMR(400MHz,CDCl3)δ：7.44-7.36(5H,m),6.84(2H,d,J=9Hz),6.73(2H,d,J=9Hz),5.05(1H,brs),5.01(2H,s),3.44(2H,d,J=12Hz),2.89(2H,d,J=7Hz),2.57(2H,t,J=12Hz),2.46(3H,s),2.06-1.90(1H,m),1.75(2H,d,J=12Hz),1.59-1.51(2H,m),1.55(9H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.44 - 7.36 (5H, m), 6.84 (2H, d, J = 9 Hz), 6.73 (2H, d, J = 9 Hz), 5.05 (1H, brs), 5.01 (2H, s), 3.44 (2H, d, J = 12 Hz), 2.89 (2H, d, J = 7 Hz), 2.57 (2H, t, J = 12 Hz), 2.46 (3H, s), 2.06-1.90 (1H, m), 1.75 (2H, d, J = 12 Hz), 1.59-1.51 (2H, m), 1.55 (9H, s).

(4)5-(苄氧基)-6-甲基-2-{[1-(4-{[(三氟甲基)磺醯基]氧基}苯基)哌啶-4-基]甲基}嘧啶-4-甲酸第三丁酯 (4) 5-(Benzyloxy)-6-methyl-2-{[1-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)piperidin-4-yl] Methyl}pyrimidine-4-carboxylic acid tert-butyl ester

以實施例1-(5)之方法為標準，使用5-(苄氧基)-2-{[1-(4-羥苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替5-(苄氧基)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-6-羥基嘧啶-4-甲酸第三丁酯，而得到橙色油狀物質的標的化合物(產率88%)。 Using the method of Example 1-(5) as a standard, 5-(benzyloxy)-2-{[1-(4-hydroxyphenyl)piperidin-4-yl]methyl}-6-methyl was used. Pyridyl-4-carboxylic acid tert-butyl ester instead of 5-(benzyloxy)-2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-6-hydroxypyrimidine-4- The title compound was obtained as an orange oily substance (yield 88%).

1H-NMR(400MHz,CDCl3)δ：7.41-7.38(5H,m),7.12-7.09(2H,m),6.91-6.88(2H,m),5.01(2H,s),3.66(2H,d,J=12Hz),2.89(2H,d,J=7Hz),2.75(2H,t,J=12Hz),2.46(3H,s),2.16-2.05(1H,m),1.79(2H,d,J=12Hz),1.59(9H,s),1.52-1.49(2H,m). 1 H-NMR (400MHz, CDCl 3) δ: 7.41-7.38 (5H, m), 7.12-7.09 (2H, m), 6.91-6.88 (2H, m), 5.01 (2H, s), 3.66 (2H, d, J = 12 Hz), 2.89 (2H, d, J = 7 Hz), 2.75 (2H, t, J = 12 Hz), 2.46 (3H, s), 2.16 - 2.05 (1H, m), 1.79 (2H, d , J = 12 Hz), 1.59 (9H, s), 1.52-1.49 (2H, m).

(5)5-(苄氧基)-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-甲酸第三丁酯 (5) 5-(Benzyloxy)-6-methyl-2-({1-[3'-(2-oxopropyl)biphenyl-4-yl]piperidin-4-yl}methyl Pyrimidine-4-carboxylic acid tert-butyl ester

將5-(苄氧基)-6-甲基-2-{[1-(4-{[(三氟甲基)磺醯基]氧基}苯基)哌啶-4-基]甲基}嘧啶-4-甲酸第三丁酯(0.60g,0.97mmol)及1-[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]丙酮(0.38g,1.5mmol)溶解於甲苯(4mL)、乙醇(2mL)及水(1mL)的混合容液中，於室溫加入肆(三苯基膦)鈀(0.12g,0.097mmol)及碳酸鈉(0.42g,4.0mmol)後，於80℃攪拌2小時。將反應液冷卻至室溫，以乙酸乙酯稀釋後，依序以水及飽和氯化鈉水溶液洗淨，以無水硫酸鈉乾燥有機層。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到橙色油狀物質的標的化合物(0.26g,0.43mmol)(產率45%)。 5-(Benzyloxy)-6-methyl-2-{[1-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)piperidin-4-yl]methyl Pyrimidine-4-carboxylic acid tert-butyl ester (0.60 g, 0.97 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenyl]acetone (0.38g, 1.5mmol) was dissolved in a mixed solution of toluene (4mL), ethanol (2mL) and water (1mL), and hydrazine (triphenylphosphine) palladium (0.12g) was added at room temperature. After 0.099 mmol) and sodium carbonate (0.42 g, 4.0 mmol), the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAc EtOAcjjjjjj (Yield 45%).

1H-NMR(400MHz,CDCl3)δ：7.50-7.35(10H,m),7.12(1H,d,J=7Hz),6.99(2H,dd,J=9Hz,2Hz),5.01(2H,s),3.84-3.68(4H,m),2.89(2H,d,J=7Hz),2.76(2H,t,J=12Hz),2.46(3H,s),2.17(3H,s), 2.16-2.05(1H,m),1.80(2H,d,J=12Hz),1.59(9H,s),1.57-1.45(2H,m) 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.50-7.35 (10H, m), 7.12 (1H, d, J = 7 Hz), 6.99 (2H, dd, J = 9 Hz, 2 Hz), 5.01 (2H, s ), 3.84-3.68 (4H, m), 2.89 (2H, d, J = 7 Hz), 2.76 (2H, t, J = 12 Hz), 2.46 (3H, s), 2.17 (3H, s), 2.16-2.05 (1H,m), 1.80 (2H,d,J=12Hz), 1.59(9H,s),1.57-1.45(2H,m)

(6)({[5-羥基-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸鹽酸鹽 (6) ({[5-hydroxy-6-methyl-2-({1-[3'-(2-Siloxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl) Pyrimidin-4-yl]carbonyl}amino)acetic acid hydrochloride

以實施例1-(10)、2-(2)、1-(15)之方法為標準，使用5-(苄氧基)-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-甲酸第三丁酯代替5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯，而得到白色固體的標的化合物(產率12%)。 Using the methods of Examples 1-(10), 2-(2), 1-(15) as standard, 5-(benzyloxy)-6-methyl-2-({1-[3'-( 2-tertoxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4-carboxylic acid tert-butyl ester instead of 5-(benzyloxy)-2-({1-[4 '-(Hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester gave the title compound as a white solid (yield 12 %).

MS m/z：517(M+H)+； MS m/z: 517 (M+H) + ;

1H-NMR(400MHz,pyridine-d5)δ：10.43(1H,t,J=6Hz),7.73-7.63(4H,m),7.44(1H,t,J=8Hz),7.28-7.21(1H,m),7.10(2H,d,J=8Hz),4.67(2H,d,J=6Hz),3.85(2H,s),3.73(2H,d,J=12Hz),2.78(2H,d,J=7Hz),2.65(2H,t,J=12Hz),2.56(3H,s),2.15(3H,s),2.12-2.01(1H,m),1.66(2H,d,J=12Hz),1.44-1.31(2H,m). 1 H-NMR (400 MHz, pyridine-d 5 ) δ: 10.43 (1H, t, J = 6 Hz), 7.73-7.63 (4H, m), 7.44 (1H, t, J = 8 Hz), 7.28-7.21 (1H , m), 7.10 (2H, d, J = 8 Hz), 4.67 (2H, d, J = 6 Hz), 3.85 (2H, s), 3.73 (2H, d, J = 12 Hz), 2.78 (2H, d, J=7 Hz), 2.65 (2H, t, J=12 Hz), 2.56 (3H, s), 2.15 (3H, s), 2.12-2.01 (1H, m), 1.66 (2H, d, J = 12 Hz), 1.44-1.31 (2H, m).

(實施例15) (Example 15)

[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-)-oxypropyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidine- 4-yl}carbonyl)amino]acetic acid

(1)第三丁基(二甲基){1-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]乙氧基}矽烷 (1) Tert-butyl (dimethyl) {1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenyl]ethoxy}decane

以實施例3-(1)之方法為標準，使用[2-(4-溴苯基)-1-甲基乙氧基](第三丁基)二甲基矽烷代替[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯，而得到白色固體的標的化合物(產率56%)。 Using the method of Example 3-(1) as a standard, [2-(4-bromophenyl)-1-methylethoxy](t-butyl)dimethyl decane was used instead of [(5-bromopyridine). The tert-butyl 2-methyl)methyl]carbamate gave the title compound as a white solid (yield: 56%).

1H-NMR(400MHz,CDCl3)δ：7.71(2H,d,J=8Hz),7.18(2H,d,J=8Hz),3.99-3.98(1H,m),2.76(1H,dd,J=13Hz,6Hz),2.67(1H,dd,J=13Hz,6Hz),1.35(12H,s),1.13(3H,d,J=6Hz),0.84(9H,s),-0.05(3H,s),-0.15(3H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.71 (2H, d, J = 8 Hz), 7.18 (2H, d, J = 8 Hz), 3.99 - 3.98 (1H, m), 2.76 (1H, dd, J =13 Hz, 6 Hz), 2.67 (1H, dd, J = 13 Hz, 6 Hz), 1.35 (12H, s), 1.13 (3H, d, J = 6 Hz), 0.84 (9H, s), -0.05 (3H, s ), -0.15 (3H, s).

(2){2-[4-(4-溴苄基)苯基]-1-甲基乙氧基}(第三丁基)二甲基矽烷 (2) {2-[4-(4-Bromobenzyl)phenyl]-1-methylethoxy}(t-butyl)dimethyl decane

以實施例3-(4)之方法為標準，使用1-溴-4-(溴甲基)苯代替({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，及使用第三丁基(二甲基){1-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]乙氧基}矽烷代替{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]甲基}胺基甲酸第三丁酯，而得到無色油狀物質的標的化合物(產率56%。 Using the method of Example 3-(4) as a standard, 1-bromo-4-(bromomethyl)benzene was used instead ({[5-(benzyloxy)-2-{[1-(4-bromophenyl) Ethyl piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate, and using tert-butyl(dimethyl){1-methyl-2- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethoxy}decane instead of {[5-(4,4, 3,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl}aminocarboxylic acid tert-butyl ester to give the title compound as a colorless oily substance (Yield 56%.

1H-NMR(400MHz,CDCl3)δ：7.39-7.37(2H,m),7.10-7.02(6H,m),3.96-3.89(1H,m),3.89(2H,s),2.72-2.55(2H,m),1.14(3H,d,J=6Hz),0.83(9H,s),-0.08(3H,s),-0.19(3H,s). 1 H-NMR (400MHz, CDCl 3 ) δ: 7.39-7.37 (2H, m), 7.10-7.02 (6H, m), 3.96-3.89 (1H, m), 3.89 (2H, s), 2.72-2.55 ( 2H, m), 1.14 (3H, d, J = 6 Hz), 0.83 (9H, s), -0.08 (3H, s), -0.19 (3H, s).

(3)[({5-羥基-2-[(1-{4-[4-(2-羥基丙基)苄基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯 (3) [({5-Hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidin-4-yl)methyl]-6-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

以實施例1-(8)~1-(10)、1-(14)之方法為標準，使用{2-[4-(4-溴苄基)苯基]-1-甲基乙氧基}(第三丁基)二甲基矽烷代替[(4’-溴聯苯-4-基)甲氧基](第三丁基)二甲基矽烷，而得到淡黃色油狀物質的標的化合物(產率27%)。 Using the method of Examples 1-(8)~1-(10), 1-(14) as standard, {2-[4-(4-bromobenzyl)phenyl]-1-methylethoxy } (T-butyl) dimethyl decane in place of [(4'-bromobiphenyl-4-yl)methoxy](t-butyl)dimethyl decane to give the title compound as a pale yellow oily material (Yield 27%).

1H-NMR(400MHz,CDCl3)δ：11.35(1H,s),8.49(1H,t,J=6Hz),7.14-7.05(6H,m),6.86(2H,d,J=9Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=6Hz),4.00-3.96(1H,m),3.87(2H,s),3.61(2H,d,J=12Hz),2.82(2H,d,J=7Hz),2.78-2.61(4H,m),2.53(3H,s),2.05-1.99(1H,m),1.75(2H,d,J=12Hz),1.57-1.47(3H,m),1.32(3H,t,J=7Hz),1.24(3H,d,J=6Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 11.35 (1H, s), 8.49 (1H, t, J = 6 Hz), 7.14 - 7.05 (6H, m), 6.86 (2H, d, J = 9 Hz), 4.28(2H,q,J=7Hz), 4.22(2H,d,J=6Hz), 4.00-3.96(1H,m),3.87(2H,s),3.61(2H,d,J=12Hz),2.82 (2H, d, J = 7 Hz), 2.78-2.61 (4H, m), 2.53 (3H, s), 2.05-1.99 (1H, m), 1.75 (2H, d, J = 12 Hz), 1.57-1.47 ( 3H,m), 1.32 (3H, t, J=7Hz), 1.24 (3H, d, J=6Hz).

(4)[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯 (4) [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-oxopropyl)benzyl]phenyl}piperidin-4-yl)methyl) Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

將[({5-羥基-2-[(1-{4-[4-(2-羥基丙基)苄基]苯基}哌啶-4-基)甲基]-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯(0.50g,0.89mmol)溶解於二氯甲烷(15mL)中，在冰冷下加入二甲基亞磺醯(0.63mL,8.9mmol)、N,N-二異丙基乙胺(0.62mL,3.6mmol)及三氧化硫-吡啶錯合物(0.63g,4.0mmol)後，於相同溫度攪拌10分鐘。於反應液加入水，以乙酸乙酯萃取後，萃取液以飽和氯化鈉水溶液洗淨，將有機層以無水硫酸鈉乾燥。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到淡黃色油狀物質的標的化合物(0.38g,0.67mmol)(產率76%)。 [({5-Hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidine- Ethyl 4-ethyl}carbonyl)amino]acetate (0.50 g, 0.89 mmol) was dissolved in dichloromethane (15 mL) and dimethyl sulfoxime (0.63 mL, 8.9 mmol), N, N After diisopropylethylamine (0.62 mL, 3.6 mmol) and sulfur trioxide-pyridine complex (0.63 g, 4.0 mmol), the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the solvent was evaporated under reduced pressure, the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted Mmmol) (yield 76%).

1H-NMR(400MHz,CDCl3)δ：11.35(1H,s),8.48(1H,t,J=6Hz),7.12-7.07(4H,m),7.05(2H,d,J=9Hz),6.86(2H,d,J=9Hz),4.28(2H,q,J=7Hz),4.22(2H,d,J=6Hz),3.88(2H,s),3.64(2H,s),3.61(2H,d,J=12Hz),2.82(2H,d,J=7Hz),2.67(2H,t,J=12Hz),2.53(3H,s),2.13(3H,s),2.07-1.95(1H,m),1.75(2H,d,J=12Hz),1.52-1.49(2H,m),1.32(3H,t,J=7Hz). 1 H-NMR (400MHz, CDCl 3) δ: 11.35 (1H, s), 8.48 (1H, t, J = 6Hz), 7.12-7.07 (4H, m), 7.05 (2H, d, J = 9Hz), 6.86(2H,d,J=9Hz), 4.28(2H,q,J=7Hz), 4.22(2H,d,J=6Hz),3.88(2H,s),3.64(2H,s),3.61(2H , d, J = 12 Hz), 2.82 (2H, d, J = 7 Hz), 2.67 (2H, t, J = 12 Hz), 2.53 (3H, s), 2.13 (3H, s), 2.07-1.95 (1H, m), 1.75 (2H, d, J = 12 Hz), 1.52-1.49 (2H, m), 1.32 (3H, t, J = 7 Hz).

(5)[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 (5) [({5-Hydroxy-6-methyl-2-[(1-{4-[4-(2-oxopropyl)benzyl]phenyl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

以實施例1-(15)之方法為標準，使用[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯代替{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸乙酯，而得到淡褐色固體的標的化合物(產率51%)。 Using the method of Example 1-(15) as a standard, [({5-hydroxy-6-methyl-2-[(1-{4-[4-(2-)-oxypropyl)benzyl]benzene Ethyl acetate of hydrazino-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]]{{(2-{[1-(4'-{[(ethoxycarbonyl))amino) Methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate to give a pale brown solid The target compound (yield 51%).

MS m/z：531(M+H)+； MS m / z: 531 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.92(1H,brs),11.92(1H,brs),9.39(1H,t,J=6Hz),7.13(2H,d,J=8Hz),7.07(2H,d,J=8Hz),7.03(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.98(2H,d,J=6Hz),3.78(2H,s),3.69(2H,s),3.59(2H,d,J=12Hz),2.76(2H,d,J=7Hz),2.59(2H,t,J=12Hz),2.43(3H,s),2.13-1.96(1H,m),2.10(3H,s),1.65(2H,d,J=12Hz),1.40-1.27(2H,m). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.92 (1H, brs), 11.92 (1H, brs), 9.39 (1H, t, J = 6Hz), 7.13 (2H, d, J = 8Hz), 7.07(2H,d,J=8Hz),7.03(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.98(2H,d,J=6Hz),3.78(2H,s) , 3.69 (2H, s), 3.59 (2H, d, J = 12 Hz), 2.76 (2H, d, J = 7 Hz), 2.59 (2H, t, J = 12 Hz), 2.43 (3H, s), 2.13 1.96 (1H, m), 2.10 (3H, s), 1.65 (2H, d, J = 12 Hz), 1.40-1.27 (2H, m).

(實施例16) (Embodiment 16)

[({5-羥基-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{4'-[(1E)-3-oxoxybut-1-en-1-yl]biphenyl-4-yl}piperidine 4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1)({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸第三丁酯 (1) ({[5-(Benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl} Amino)acetic acid tert-butyl ester

以實施例1-(10)之方法為標準，使用以實施例3-(2)所得到的5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯，及使用甘胺酸第三丁酯鹽酸鹽代替甘胺酸乙酯鹽酸鹽，而得到橙色油狀物質的標的化合物(產率定量的)。 Using the method of Example 1-(10) as a standard, 5-(benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4 obtained in Example 3-(2) was used. -yl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester in place of 5-(benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl) ???]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester, and using glycine acid tert-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride The standard compound of orange oily substance (quantitative yield).

1H-NMR(500MHz,CDCl3)δ：8.29(1H,t,J=5Hz),7.50-7.46(2H,m),7.41-7.34(3H,m),7.32(2H,d,J=9Hz),6.80(2H,d,J=9Hz),5.11(2H,s),4.15(2H,d,J=5Hz),3.65-3.60(2H,m),2.88(2H,d,J=7Hz),2.78(2H,dt,J=12Hz,2Hz),2.46(3H,s),2.14-2.04(1H,m),1.79-1.73(2H,m),1.58-1.45(2H,m),1.51(9H,s). 1 H-NMR (500MHz, CDCl 3 ) δ: 8.29 (1H, t, J = 5 Hz), 7.50-7.46 (2H, m), 7.41-7.34 (3H, m), 7.32 (2H, d, J = 9 Hz) ), 6.80 (2H, d, J = 9 Hz), 5.11 (2H, s), 4.15 (2H, d, J = 5 Hz), 3.65-3.60 (2H, m), 2.88 (2H, d, J = 7 Hz) , 2.78 (2H, dt, J = 12 Hz, 2 Hz), 2.46 (3H, s), 2.14 - 2.04 (1H, m), 1.79-1.73 (2H, m), 1.58-1.45 (2H, m), 1.51 ( 9H, s).

(2)({[5-(苄氧基)-6-甲基-2-({1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸第三丁酯 (2)({[5-(Benzyloxy)-6-methyl-2-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Tert-butyl ester of pentocyclo-2-yl)phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetate

將({[5-(苄氧基)-2-{[1-(4-溴苯基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸第三丁酯(1.6g,2.7mmol)溶解於1,4-二烷(90mL)中，於室溫加入雙二硼烷(0.82g,3.2mmol)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷錯合物(0.22g,0.27mmol)及乙酸鉀(0.79g,8.1mmol)後，在氮氣環境下，加熱回流3.5小時。將反應液冷卻至室溫後，以Celite過濾不溶解物，藉由在減壓下濃縮濾液，而得到黑色油狀物質的標的化合物(1.8g)(產率定量的)。 ({[5-(Benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino) ) tert-butyl acetate (1.6 g, 2.7 mmol) dissolved in 1,4-two In alkane (90 mL), add double at room temperature Diborane (0.82 g, 3.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.22 g, 0.27 mmol) and potassium acetate ( After 0.79 g, 8.1 mmol), the mixture was heated under reflux for 3.5 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g) (yield quantitatively).

MS m/z：657(M+H)+. MS m/z: 657 (M+H) + .

(3)[({5-(苄氧基)-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸第三丁酯 (3) [({5-(Benzyloxy)-6-methyl-2-[(1-{4'-[(1E)-3-oxo-but-1-en-1-yl]biphenyl) -4-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid tert-butyl ester

將({[5-(苄氧基)-6-甲基-2-({1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸第三丁酯(1.8g)及(3E)-4-(4-溴苯基)丁氧基-3-烯-2-酮(0.77g,3.2mmol)溶解於甲苯(40mL)、乙醇(24mL)及水(24mL)的混合溶劑中，於室溫加入肆(三苯基膦)鈀(0.62g,0.54mmol)及碳酸鈉(1.4g,13mmol)後，加熱回流1.5小時。將反應液冷卻至室溫，於室溫放置一晚後，使用乙酸乙酯及水以Celite過濾。以乙酸乙酯萃取濾液，將萃取液以飽和氯化鈉水溶液洗淨後，以無水硫酸鎂乾燥有機層。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(二氯甲烷/乙酸乙酯)精製，而得到黃色固體的標的化合物(0.50g,0.74mmol)(產率27%)。 ({[5-(Benzyloxy)-6-methyl-2-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) 3-butyl)phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid tert-butyl ester (1.8 g) and (3E)-4-(4-bromobenzene Butyloxy-3-en-2-one (0.77 g, 3.2 mmol) was dissolved in a mixed solvent of toluene (40 mL), ethanol (24 mL) and water (24 mL). Palladium (0.62 g, 0.54 mmol) and sodium carbonate (1.4 g, 13 mmol) were evaporated and evaporated. The reaction solution was cooled to room temperature and then stood at room temperature for one night, then filtered over Celite with ethyl acetate and water. The filtrate was extracted with ethyl acetate, and the mixture was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. EtOAcjjjjjjj Yield 27%).

1H-NMR(400MHz,CDCl3)δ：8.30(1H,t,J=5Hz),7.63-7.46(9H,m),7.42-7.34(3H,m),7.01(2H,d,J=9 Hz),6.74(1H,d,J=16Hz),5.12(2H,s),4.16(2H,d,J=5Hz),3.81-3.74(2H,m),2.90(2H,d,J=7Hz),2.81(2H,dt,J=12Hz,2Hz),2.47(3H,s),2.40(3H,s),2.20-2.07(1H,m),1.83-1.75(2H,m),1.59-1.47(2H,m),1.51(9H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.30 (1H, t, J = 5 Hz), 7.63-7.46 (9H, m), 7.42-7.34 (3H, m), 7.01 (2H, d, J=9) Hz), 6.74 (1H, d, J = 16 Hz), 5.12 (2H, s), 4.16 (2H, d, J = 5 Hz), 3.81-3.74 (2H, m), 2.90 (2H, d, J = 7 Hz) ), 2.81 (2H, dt, J = 12 Hz, 2 Hz), 2.47 (3H, s), 2.40 (3H, s), 2.20-2.07 (1H, m), 1.83-1.75 (2H, m), 1.59-1.47 (2H,m), 1.51 (9H, s).

(4)[({5-羥基-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 (4) [({5-Hydroxy-6-methyl-2-[(1-{4'-[(1E)-3-oxyxan-1-en-1-yl]biphenyl-4-yl) }piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

將[({5-(苄氧基)-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸第三丁酯(0.20g,0.30mmol)溶解於二氯甲烷(8mL)中，在氮氣環境下，加入三氟乙酸(4mL)後，於室溫攪拌62小時。在減壓下濃縮反應液，並於殘留物加入水及過剩之氫氧化鈉水溶液(1M)後，再加入鹽酸(1M)以析出固體。過濾所得到的固體，藉由在減壓下乾燥，而得到淡橙色固體的標的化合物(0.020g,0.038mmol)(產率13%)。 [({5-(Benzyloxy)-6-methyl-2-[(1-{4'-[(1E)-3- sideoxybut-1-en-1-yl]biphenyl-4 -3 -piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid tert-butyl ester (0.20 g, 0.30 mmol) dissolved in dichloromethane (8 mL) under nitrogen After adding trifluoroacetic acid (4 mL), it was stirred at room temperature for 62 hours. The reaction mixture was concentrated under reduced pressure, and water and aqueous sodium hydroxide (1M) was added to the residue, and then hydrochloric acid (1M) was added to precipitate a solid. The obtained solid was filtered, and dried (jjjjjjjjjjjj

MS m/z：529(M+H)+ MS m/z: 529 (M+H) +

1H-NMR(500MHz,DMSO-d6)δ：12.91(1H,brs),11.95(1H,brs),9.37(1H,t,J=6Hz),7.74(2H,d,J=9Hz),7.68(2H,d,J=9Hz),7.64(1H,d,J=16Hz),7.60(2H,d,J=9Hz),7.01(2H,d,J=9Hz),6.81(1H,d,J=16Hz),3.98(2H,d,J=6Hz),3.81-3.75(2H,m),2.78(2H,d,J=7Hz),2.74(2H,dt,J=12Hz,2Hz),2.44(3H,s),2.34(3H,s),2.16-2.06(1H,m),1.72-1.65(2H,m),1.41-1.30(2H,m). 1 H-NMR (500MHz, DMSO -d 6) δ: 12.91 (1H, brs), 11.95 (1H, brs), 9.37 (1H, t, J = 6Hz), 7.74 (2H, d, J = 9Hz), 7.68 (2H, d, J = 9 Hz), 7.64 (1H, d, J = 16 Hz), 7.60 (2H, d, J = 9 Hz), 7.01 (2H, d, J = 9 Hz), 6.81 (1H, d, J = 16 Hz), 3.98 (2H, d, J = 6 Hz), 3.81-3.75 (2H, m), 2.78 (2H, d, J = 7 Hz), 2.74 (2H, dt, J = 12 Hz, 2 Hz), 2.44 (3H, s), 2.34 (3H, s), 2.16-2.06 (1H, m), 1.72-1.65 (2H, m), 1.41-1.30 (2H, m).

(實施例17) (Example 17)

({[5-羥基-6-甲基-2-({1-[4’-(3-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸 ({[5-Hydroxy-6-methyl-2-({1-[4'-(3-oxobutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -carbonyl]carbonyl}amino)acetic acid

以實施例9-(1)、16-(4)之方法為標準，使用以實施例16-(3)所得到的[({5-(苄氧基)-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸第三丁酯代替{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸乙酯，而得到淡黃白色固體的標記化合物標的化合物(產率51%)。 Using the method of Example 9-(1), 16-(4) as a standard, [({5-(benzyloxy)-6-methyl-2-[] obtained by Example 16-(3) was used. (1-{4'-[(1E)-3-Sideoxybut-1-en-1-yl]biphenyl-4-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl Amino]acetic acid tert-butyl ester replaces {[(5-hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3- oxetane-1-ene-1) -Pyryl-3-pyridin-3-yl}phenyl)piperidin-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}ethyl acetate to give the title compound as a pale yellow solid. The rate is 51%).

MS m/z：531(M+H)+ MS m/z: 531 (M+H) +

1H-NMR(500MHz,DMSO-d6)δ：12.89(1H,brs),11.91(1H,brs),9.41(1H,t,J=6Hz),7.49(2H,d,J=9Hz),7.48(2H,d,J=9Hz),7.23(2H,d,J=9Hz),6.98(2H,d,J=9Hz),4.01(2H,d,J=6Hz),3.76-3.70(2H,m),2.80-2.76(6H,m),2.70(2H,dt,J=12Hz,2Hz),2.44(3H,s),2.10(3H,s),2.14-2.04(1H,m),1.71-1.64(2H,m),1.42-1.31(2H,m). 1 H-NMR (500MHz, DMSO -d 6) δ: 12.89 (1H, brs), 11.91 (1H, brs), 9.41 (1H, t, J = 6Hz), 7.49 (2H, d, J = 9Hz), 7.48 (2H, d, J = 9 Hz), 7.23 (2H, d, J = 9 Hz), 6.98 (2H, d, J = 9 Hz), 4.01 (2H, d, J = 6 Hz), 3.76-3.70 (2H, m), 2.80-2.76 (6H, m), 2.70 (2H, dt, J = 12 Hz, 2 Hz), 2.44 (3H, s), 2.10 (3H, s), 2.14 - 2.04 (1H, m), 1.71 1.64(2H,m), 1.42-1.31(2H,m).

(實施例18) (Embodiment 18)

[({5-羥基-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{5-[4-(2-oxopropyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

(1)5-(苄氧基)-2-{[1-(5-溴吡啶-2-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯 (1) 5-(Benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylic acid tertidine ester

將以實施例1-(7)所得到的5-(苄氧基)-6-甲基-2-(哌啶-4-基甲基)嘧啶-4-甲酸第三丁酯鹽酸鹽(6.5g,15mmol)、2,5-二溴吡啶(5.3g,7.5mmol)及碳酸鉀(6.2g,45mmol)懸浮於N,N-二甲基甲醯胺(150mL)，於100℃攪拌22小時。在減壓下濃縮反應液，加入乙酸乙酯後，以水洗淨有機層。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到無色油狀物質的標的化合物(2.3g,4.1mmol)(產率27%)。 5-(Benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylic acid tert-butyl ester hydrochloride obtained in Example 1-(7) ( 6.5 g, 15 mmol), 2,5-dibromopyridine (5.3 g, 7.5 mmol) and potassium carbonate (6.2 g, 45 mmol) were suspended in N,N-dimethylformamide (150 mL) and stirred at 100 ° C 22 hour. The reaction liquid was concentrated under reduced pressure, and ethyl acetate was added, and the organic layer was washed with water. After the solvent was evaporated under reduced pressure, the title compound was purified (jjjjjjjjj (Yield 27%).

1H-NMR(500MHz,CDCl3)δ：8.16(1H,s),7.49(1H,d,J=9Hz),7.45-7.33(5H,m),6.55(1H,d,J=9Hz),5.01(2H,s),4.21(2H,d,J=12Hz),2.87(2H,t,J=7Hz),2.83(2H,t,J=12Hz),2.45(3H,s),2.24-2.14(1H,m),1.75(2H,d,J=12Hz),1.59(9H,s),1.37(2H,dq,J=12Hz,3Hz). 1 H-NMR (500MHz, CDCl 3) δ: 8.16 (1H, s), 7.49 (1H, d, J = 9Hz), 7.45-7.33 (5H, m), 6.55 (1H, d, J = 9Hz), 5.01(2H,s), 4.21(2H,d,J=12Hz), 2.87(2H,t,J=7Hz),2.83(2H,t,J=12Hz),2.45(3H,s),2.24-2.14 (1H, m), 1.75 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.37 (2H, dq, J = 12 Hz, 3 Hz).

(2)({[5-(苄氧基)-2-{[1-(5-溴吡啶-2-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯 (2) ({[5-(Benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl) Carbonyl}amino)ethyl acetate

以實施例1-(10)為標準，使用5-(苄氧基)-2-{[1-(5-溴吡啶-2-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-甲酸第三丁酯代替5-(苄氧基)-2-({1-[4’-(羥甲基)聯苯-4-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-甲酸第三丁酯，而得到黃色油狀物質的標的化合物(產率95%)。 5-(Benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-A was used as the standard in Example 1-(10) Tert-butyl pyrimidine-4-carboxylic acid instead of 5-(benzyloxy)-2-({1-[4'-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl -6-methylpyrimidine-4-carboxylic acid tert-butyl ester gave the title compound as a yellow oily material (yield 95%).

1H-NMR(400MHz,CDCl3)δ：8.29(1H,t,J=5Hz),7.52-7.46(2H,m),7.42-7.30(4H,m),6.82-6.77(2H,m),5.11(2H,s),4.14(2H,d,J=5Hz),4.12(2H,q,J=7Hz),3.66-3.59(2H,m),2.88(2H,d,J=7Hz),2.71(2H,t,J=8Hz),2.46(3H,s),2.15-2.04(1H,m),1.76(2H,d,J=12Hz),1.48(2H,dq,J=12Hz,3Hz),1.32(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.29 (1H, t, J = 5 Hz), 7.52-7.46 (2H, m), 7.42-7.30 (4H, m), 6.82-6.77 (2H, m), 5.11 (2H, s), 4.14 (2H, d, J = 5 Hz), 4.12 (2H, q, J = 7 Hz), 3.66-3.59 (2H, m), 2.88 (2H, d, J = 7 Hz), 2.71 (2H, t, J = 8 Hz), 2.46 (3H, s), 2.15-2.04 (1H, m), 1.76 (2H, d, J = 12 Hz), 1.48 (2H, dq, J = 12 Hz, 3 Hz), 1.32 (3H, t, J = 7Hz).

(3)({[5-(苄氧基)-6-甲基-2-({1-[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸乙酯 (3) ({[5-(Benzyloxy)-6-methyl-2-({1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Ethyl pentocyclo-2-yl)pyridin-2-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)

以實施例3-(1)為標準，使用({[5-(苄氧基)-2-{[1-(5-溴吡啶-2-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯代替[(5-溴吡啶-2-基)甲基]胺基甲酸第三丁酯，而得到黑色油狀物質的標的化合物(產率定量的)。 Using the compound of Example 3-(1), ({[5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-) Ethyl acetate of 6-methylpyrimidin-4-yl]carbonyl}amino) in place of [(5-bromopyridin-2-yl)methyl]carbamic acid tert-butyl ester to give the title compound as a black oily substance (Quantitative yield).

MS m/z：630(M+H)+. MS m/z: 630 (M+H) + .

(4)[({5-(苄氧基)-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯 (4) [({5-(Benzyloxy)-6-methyl-2-[(1-{5-[4-(2-oxopropyl)phenyl]pyridin-2-yl}piperidine) Ethyl 4-methyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate

將({[5-(苄氧基)-6-甲基-2-({1-[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2-基]哌啶-4-基}甲基)嘧 啶-4-基]羰基}胺基)乙酸乙酯及1-(4-溴苯基)丙酮(0.26g,1.2mmol)溶解於甲苯(12mL)、乙醇(10mL)及水(10mL)的混合溶劑中，於室溫加入肆(三苯基膦)鈀(0.23g,0.20mmol)及碳酸鈉(0.53g,5.0mmol)後，加熱回流1.5小時。將反應液冷卻至室溫後，加入水以乙酸乙酯萃取。在減壓下餾除溶劑後，藉由將所得到的殘留物以矽膠管柱層析法(己烷/乙酸乙酯)精製，而得到淡黃色油狀物質的標的化合物(0.24g,0.37mmol)(產率37%)。 ({[5-(Benzyloxy)-6-methyl-2-({1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl)pyridin-2-yl]piperidin-4-yl}methyl)pyrimidine Ethyl acetate of pyridine-4-yl]carbonyl}amino) and 1-(4-bromophenyl)acetone (0.26 g, 1.2 mmol) were dissolved in a mixture of toluene (12 mL), ethanol (10 mL) and water (10 mL) To a solvent, hydrazine (triphenylphosphine)palladium (0.23 g, 0.20 mmol) and sodium carbonate (0.53 g, 5.0 mmol) were added at room temperature, and the mixture was heated under reflux for 1.5 hours. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. ) (yield 37%).

1H-NMR(400MHz,CDCl3)δ：8.42(1H,d,J=2Hz),8.36(1H,t,J=5Hz),7.68(1H,dd,J=8Hz,2Hz),7.53-7.46(6H,m),7.42-7.34(3H,m),6.73(1H,d,J=8Hz),5.13(2H,s),4.33(2H,d,J=12Hz),4.26(2H,d,J=5Hz),4.12(2H,q,J=7Hz),3.73(2H,s),2.90(2H,d,J=7Hz),2.88(2H,t,J=8Hz),2.46(3H,s),2.20(3H,s),2.15-2.04(1H,m),1.77(2H,d,J=12Hz),1.44(2H,dq,J=12Hz,3Hz),1.33(3H,t,J=7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 8.42 (1H, d, J = 2 Hz), 8.36 (1H, t, J = 5 Hz), 7.68 (1H, dd, J = 8 Hz, 2 Hz), 7.53-7.46 (6H,m), 7.42-7.34(3H,m), 6.73(1H,d,J=8Hz), 5.13(2H,s), 4.33(2H,d,J=12Hz), 4.26(2H,d, J=5Hz), 4.12(2H,q,J=7Hz), 3.73(2H,s), 2.90(2H,d,J=7Hz),2.88(2H,t,J=8Hz),2.46(3H,s ), 2.20 (3H, s), 2.15-2.04 (1H, m), 1.77 (2H, d, J = 12 Hz), 1.44 (2H, dq, J = 12 Hz, 3 Hz), 1.33 (3H, t, J = 7Hz).

(5)[({5-羥基-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 (5) [({5-Hydroxy-6-methyl-2-[(1-{5-[4-(2-oxopropyl)phenyl]pyridin-2-yl}piperidin-4-yl) Methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

以實施例1-(14)、11-(3)為標準，使用[({5-(苄氧基)-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸乙酯代替({[5-(苄氧基)-2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，而得到標的化合物(產率74%)。 Using the examples 1-(14), 11-(3) as the standard, [({5-(benzyloxy)-6-methyl-2-[(1-{5-[4-(2-) Oxypropyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate instead of ({[5-(benzyloxy)-2) -{[1-(4'-{[(ethoxycarbonyl)amino]methyl}biphenyl-4-yl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl [carbonyl]amino)acetate to give the title compound (yield: 74%).

MS m/z：518(M+H)+； MS m / z: 518 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：9.22(1H,t,J=5Hz),8.42(1H,d,J=2Hz),7.81(1H,dd,J=6Hz,2Hz),7.55(2H,d,J=8Hz),7.23(2H,d,J=8Hz),6.89(1H,d,J=6Hz),4.32(2H,d,J=12Hz),3.80(2H,d,J=5Hz),3.73(2H,s),2.83(2H,t,J=8Hz),2.75(2H,d,J=7Hz),2.43(3H,s),2.23-2.08(1H,m),2.15(3H,s),1.67(2H,d,J=12Hz),1.24(2H,dq,J=12Hz,3Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 9.22 (1H, t, J = 5 Hz), 8.42 (1H, d, J = 2 Hz), 7.81 (1H, dd, J = 6 Hz, 2 Hz), 7.55 (2H,d,J=8Hz), 7.23(2H,d,J=8Hz), 6.89(1H,d,J=6Hz), 4.32(2H,d,J=12Hz),3.80(2H,d,J =5 Hz), 3.73 (2H, s), 2.83 (2H, t, J = 8 Hz), 2.75 (2H, d, J = 7 Hz), 2.43 (3H, s), 2.23 - 2.08 (1H, m), 2.15 (3H, s), 1.67 (2H, d, J = 12 Hz), 1.24 (2H, dq, J = 12 Hz, 3 Hz).

(實施例19) (Embodiment 19)

[({5-羥基-6-甲基-2-[(1-{5-[3-(2-側氧丁基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸 [({5-Hydroxy-6-methyl-2-[(1-{5-[3-(2-oxobutyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

以實施例18-(4)、1-(14)、11-(3)為標準，使用1-(3-碘苯基)丁烷-2-酮代替1-(4-溴苯基)丙酮，而得到白色固體的標的化合物(產率2.3%)。 Using 1-(3-iodophenyl)butan-2-one instead of 1-(4-bromophenyl)acetone using the examples 18-(4), 1-(14), 11-(3) The title compound was obtained as a white solid (yield: 2.3%).

MS m/z：532(M+H)+； MS m/z: 532 (M+H) + ;

1H-NMR(400MHz,DMSO-d6)δ：9.17(1H,t,J=5Hz),8.41(1H,d,J=2Hz),7.80(1H,dd,J=8Hz,2Hz),7.47(1H,d,J=8Hz),7.42(1H,s),7.35(1H,t,J=8Hz),7.10(1H,d,J=8Hz),6.90(1H,d,J=8Hz),4.32(2H,d,J =12Hz),3.80(2H,s),3.78(2H,d,J=5Hz),2.83(2H,t,J=8Hz),2.75(2H,d,J=7Hz),2.54(2H,q,J=7Hz),2.49(3H,s),2.23-2.08(1H,m),1.67(2H,d,J=12Hz),1.24(2H,dq,J=12Hz,3Hz),0.92(3H,t,J=7Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 9.17 (1H, t, J = 5Hz), 8.41 (1H, d, J = 2Hz), 7.80 (1H, dd, J = 8Hz, 2Hz), 7.47 (1H, d, J = 8 Hz), 7.42 (1H, s), 7.35 (1H, t, J = 8 Hz), 7.10 (1H, d, J = 8 Hz), 6.90 (1H, d, J = 8 Hz), 4.32 (2H, d, J = 12 Hz), 3.80 (2H, s), 3.78 (2H, d, J = 5 Hz), 2.83 (2H, t, J = 8 Hz), 2.75 (2H, d, J = 7 Hz) , 2.54 (2H, q, J = 7 Hz), 2.49 (3H, s), 2.23 - 2.08 (1H, m), 1.67 (2H, d, J = 12 Hz), 1.24 (2H, dq, J = 12 Hz, 3 Hz ), 0.92 (3H, t, J = 7Hz).

(實施例20) (Embodiment 20)

({[5-羥基-2-({1-[5-(4-{[(甲氧基羰基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[5-hydroxy-2-({1-[5-(4-{[(methoxycarbonyl)amino)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}A -6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1)[({2-[(1-{5-[4-(胺甲基)苯基]吡啶-2-基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽 (1) [({2-[(1-{5-[4-(Aminomethyl)phenyl)pyridin-2-yl}piperidin-4-yl)methyl]-5-(benzyloxy)) -6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride

以實施例18-(4)、4-(1)為標準，使用(4-溴苄基)亞胺二碳酸-第三丁酯代替1-(4-溴苯基)丙酮，而得到白色固體的標的化合物(產率43%)。 Using (4-bromobenzyl)imine dicarbonate-t-butyl ester instead of 1-(4-bromophenyl)acetate as a standard, using the procedure of Example 18-(4), 4-(1) The target compound (yield 43%).

1H-NMR(400MHz,DMSO-d6)δ：9.15(1H,t,J=5Hz),8.49(2H,brs),8.34(1H,d,J=2Hz),8.23(1H,s),7.78(2H,d,J=8Hz),7.61(2H,d,J=8Hz),7.57-7.44(3H,m),7.42-7.35(3H,m),5.05(2H,s),4.39(2H,d,J=12Hz),4.13(2H,q,J=7Hz),4.06(2H,d,J=5Hz),4.05(2H,brs),3.23(2H,t,J=8Hz),2.81(2H,d,J=7Hz),2.41(3H,s),2.37-2.23(1H,m),1.77(2H,d,J=12Hz),1.36(2H,dq,J=12Hz,3Hz),1.20(3H,t,J=7Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 9.15 (1H, t, J = 5 Hz), 8.49 (2H, brs), 8.34 (1H, d, J = 2 Hz), 8.23 (1H, s), 7.78(2H,d,J=8Hz), 7.61(2H,d,J=8Hz), 7.57-7.44(3H,m),7.42-7.35(3H,m),5.05(2H,s),4.39(2H , d, J = 12 Hz), 4.13 (2H, q, J = 7 Hz), 4.06 (2H, d, J = 5 Hz), 4.05 (2H, brs), 3.23 (2H, t, J = 8 Hz), 2.81 ( 2H,d,J=7Hz), 2.41(3H,s), 2.37-2.23(1H,m), 1.77(2H,d,J=12Hz), 1.36(2H,dq,J=12Hz,3Hz),1.20 (3H, t, J = 7Hz).

(2)({[5-羥基-2-({1-[5-(4-{[(甲氧基羰基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸 (2) ({[5-hydroxy-2-({1-[5-(4-{[(methoxycarbonyl)amino)methyl}phenyl)pyridin-2-yl]piperidin-4- Methyl)methyl--6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例1-(13)~1-(15)為標準，使用[({2-[(1-{5-[4-(胺甲基)苯基]吡啶-2-基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽代替({[2-({1-[4’-(胺甲基)聯苯-4-基]哌啶-4-基}甲基)-5-(苄氧基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸乙酯，及使用氯甲酸甲酯代替氯甲酸乙酯，而得到淡黃色固體的標的化合物(產率13%)。 Using the formula 1-(13)~1-(15) as the standard, [({2-[(1-{5-[4-(aminomethyl)phenyl)pyridin-2-yl}piperidine-) 4-yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride instead of ({[2-({1-[4') -(Aminomethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate And using methyl chloroformate instead of ethyl chloroformate to give the title compound as a pale yellow solid (yield 13%).

MS m/z：549(M+H)+； MS m / z: 549 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：9.10(1H,t,J=5Hz),8.40(1H,d,J=2Hz),7.79(1H,dd,J=8Hz,2Hz),7.71(1H,t,J=6Hz),7.55(2H,d,J=8Hz),7.29(2H,d,J=8Hz),6.89(1H,d,J=8Hz),4.32(2H,d,J=12Hz),4.19(2H,d,J=6Hz),3.70(2H,d,J=5Hz),3.55(3H,s), 2.83(2H,t,J=8Hz),2.73(2H,d,J=7Hz),2.42(3H,s),2.20-2.07(1H,m),1.67(2H,d,J=12Hz),1.24(2H,dq,J=12Hz,3Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 9.10 (1H, t, J = 5 Hz), 8.40 (1H, d, J = 2 Hz), 7.79 (1H, dd, J = 8 Hz, 2 Hz), 7.71 (1H, t, J = 6 Hz), 7.55 (2H, d, J = 8 Hz), 7.29 (2H, d, J = 8 Hz), 6.89 (1H, d, J = 8 Hz), 4.32 (2H, d, J) =12 Hz), 4.19 (2H, d, J = 6 Hz), 3.70 (2H, d, J = 5 Hz), 3.55 (3H, s), 2.83 (2H, t, J = 8 Hz), 2.73 (2H, d, J=7 Hz), 2.42 (3H, s), 2.20-2.07 (1H, m), 1.67 (2H, d, J = 12 Hz), 1.24 (2H, dq, J = 12 Hz, 3 Hz).

(實施例21) (Example 21)

({[2-({1-[5-(4-{[(乙基胺甲醯基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[5-(4-{[(ethylaminomethyl)amino)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例5-(1)、1-(14)、1-(15)為標準，使用以實施例20-(1)所得到的[({2-[(1-{5-[4-(胺甲基)苯基]吡啶-2-基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽代替[({2-[(1-{4-[6-(胺甲基)吡啶-3-基]苯基}哌啶-4-基)甲基]-5-(苄氧基)-6-甲基嘧啶-4-基}羰基)胺基]乙酸乙酯鹽酸鹽，而得到淡黃色固體的標的化合物(產率9.8%)。 Using the results of Examples 5-(1), 1-(14), 1-(15), [({2-[(1-{5-[4-] obtained in Example 20-(1)) (Aminomethyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid B Ester hydrochloride instead of [({2-[(1-{4-[6-(aminomethyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]-5-(benzyloxy) Ethyl acetate-6-methylpyrimidin-4-yl}carbonyl)amino]acetate hydrochloride gave the title compound (yield 9.8%) as a pale yellow solid.

MS m/z：562(M+H)+； MS m / z: 562 (M + H) + ;

1H-NMR(500MHz,DMSO-d6)δ：9.32(1H,t,J=5Hz),8.40(1H,d,J=2Hz),7.79(1H,dd,J=8Hz,2Hz),7.54(2H,d,J=8Hz),7.28(2H,d,J=8Hz),6.89(1H,d,J =8Hz),6.32(1H,t,J=6Hz),5.91(1H,t,J=5Hz),4.32(2H,d,J=12Hz),4.21(2H,d,J=5Hz),3.94(2H,d,J=5Hz),3.03(2H,dq,J=7Hz,5Hz),2.83(2H,t,J=8Hz),2.75(2H,d,J=7Hz),2.44(3H,s),2.24-2.12(1H,m),1.66(2H,d,J=12Hz),1.24(2H,dq,J=12Hz,3Hz),1.00(3H,t,J=7Hz). 1 H-NMR (500 MHz, DMSO-d 6 ) δ: 9.32 (1H, t, J = 5 Hz), 8.40 (1H, d, J = 2 Hz), 7.79 (1H, dd, J = 8 Hz, 2 Hz), 7.54 (2H,d,J=8Hz), 7.28(2H,d,J=8Hz), 6.89(1H,d,J=8Hz),6.32(1H,t,J=6Hz),5.91(1H,t,J =5 Hz), 4.32 (2H, d, J = 12 Hz), 4.21 (2H, d, J = 5 Hz), 3.94 (2H, d, J = 5 Hz), 3.03 (2H, dq, J = 7 Hz, 5 Hz), 2.83 (2H, t, J = 8 Hz), 2.75 (2H, d, J = 7 Hz), 2.44 (3H, s), 2.24 - 2.12 (1H, m), 1.66 (2H, d, J = 12 Hz), 1.24 (2H, dq, J=12Hz, 3Hz), 1.00(3H, t, J=7Hz).

(實施例22) (Example 22)

({[2-({1-[5-(4-{[(乙基胺甲醯基)氧基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[5-(4-{[(ethylamine)methyl)oxy)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

以實施例18-(4)、7-(1)、2-(2)、11-(3)為標準，使用(4-碘苯基)甲醇代替1-(4-溴苯基)丙酮，而得到白色固體的標的化合物(產率12%)。 Using (4-iodophenyl)methanol instead of 1-(4-bromophenyl)acetone, using the procedures of Examples 18-(4), 7-(1), 2-(2), and 11-(3), The title compound was obtained as a white solid (yield 12%).

MS m/z：563(M+H)+； MS m / z: 563 (M + H) + ;

1H-NMR(400MHz,DMSO-d6)δ：9.25(1H,t,J=5Hz),8.43(1H,d,J=2Hz),7.82(1H,dd,J=8Hz,2Hz),7.60(2H,d,J=8Hz),7.38(2H,d,J=8Hz),7.25(1H,t,J=6Hz),6.90(1H,d,J=8Hz),5.01(2H,s),4.32(2H,d,J =12Hz),3.83(2H,d,J=5Hz),3.02(2H,dq,J=7Hz,6Hz),2.83(2H,t,J=8Hz),2.75(2H,d,J=7Hz),2.43(3H,s),2.24-2.11(1H,m),1.66(2H,d,J=12Hz),1.24(2H,dq,J=12Hz,3Hz),1.01(3H,t,J=7Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 9.25 (1H, t, J = 5 Hz), 8.43 (1H, d, J = 2 Hz), 7.82 (1H, dd, J = 8 Hz, 2 Hz), 7.60 (2H,d,J=8Hz), 7.38(2H,d,J=8Hz), 7.25(1H,t,J=6Hz), 6.90(1H,d,J=8Hz),5.01(2H,s), 4.32 (2H, d, J = 12 Hz), 3.83 (2H, d, J = 5 Hz), 3.02 (2H, dq, J = 7 Hz, 6 Hz), 2.83 (2H, t, J = 8 Hz), 2.75 (2H, d, J = 7 Hz), 2.43 (3H, s), 2.24 - 2.11 (1H, m), 1.66 (2H, d, J = 12 Hz), 1.24 (2H, dq, J = 12 Hz, 3 Hz), 1.01 (3H) ,t,J=7Hz).

(實施例23) (Example 23)

4’-[4-({4-[(羧甲基)胺甲醯基]-5-羥基-6-甲基嘧啶-2-基}甲基)哌啶-1-基]聯苯-4-甲酸 4'-[4-({4-[(carboxymethyl)aminemethanyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidin-1-yl]biphenyl-4 -formic acid

以實施例16-(3)、16-(4)為標準，使用4-碘安息香酸第三丁酯代替(3E)-4-(4-溴苯基)丁氧基-3-烯-2-酮，而得到黃茶色固體的標的化合物(產率19%)。 Using the 16-(3), 16-(4) standard as an example, the (3E)-4-(4-bromophenyl)butoxy-3-ene-2 was replaced with 4-butyl benzoic acid tert-butyl ester. - Ketone to give the title compound as a yellow brown solid (yield 19%).

MS m/z：505(M+H)+； MS m/z: 505 (M+H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.88(1H,brs),11.92(1H,brs),9.42(1H,t,J=6Hz),7.95(2H,d,J=9Hz),7.73(2H,d,J=9Hz),7.61(2H,d,J=9Hz),7.03(2H,d,J=9Hz),4.01(2H,d,J=6Hz),3.83-3.76(2H,m),2.78(2H,d,J=7Hz),2.78-2.69(2H,m),2.44(3H,s),2.19-2.05(1H,m),1.73-1.63(2H,m),1.42-1.29(2H,m). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.88 (1H, brs), 11.92 (1H, brs), 9.42 (1H, t, J = 6Hz), 7.95 (2H, d, J = 9Hz), 7.73 (2H, d, J = 9 Hz), 7.61 (2H, d, J = 9 Hz), 7.03 (2H, d, J = 9 Hz), 4.01 (2H, d, J = 6 Hz), 3.83 - 3.76 (2H, m), 2.78 (2H, d, J = 7 Hz), 2.78-2.69 (2H, m), 2.44 (3H, s), 2.19-2.05 (1H, m), 1.73-1.63 (2H, m), 1.42 1.29 (2H, m).

(實施例24) (Example 24)

({[2-({1-[4’-(羧甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸 ({[2-({1-[4'-(carboxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl] Carbonyl}amino)acetic acid

以實施例16-(3)、16-(4)為標準，使用(4-碘苯基)乙酸第三丁基代替(3E)-4-(4-溴苯基)丁氧基-3-烯-2-酮，而得到白色固體的標的化合物(產率27%)。 Using (4-iodophenyl)acetic acid tert-butyl instead of (3E)-4-(4-bromophenyl)butoxy-3- as the standard of Examples 16-(3), 16-(4) The alken-2-one gave the title compound as a white solid (yield: 27%).

MS m/z：519(M+H)+； MS m/z: 519 (M+H) + ;

1H-NMR(400MHz,DMSO-d6)δ：12.55(1H,brs),11.94(1H,brs),9.40(1H,t,J=5Hz),7.53(2H,d,J=9Hz),7.50(2H,d,J=9Hz),7.28(2H,d,J=8Hz),6.99(2H,d,J=8Hz),3.99(2H,d,J=5Hz),3.74(2H,m),3.57(2H,s),2.78(2H,d,J=7Hz),2.70(2H,t,J=12Hz),2.44(3H,s),2.16-2.02(1H,m),1.68(2H,d,J=12Hz),1.38(2H,dq,J=12Hz,3Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 12.55 (1H, brs), 11.94 (1H, brs), 9.40 (1H, t, J = 5Hz), 7.53 (2H, d, J = 9Hz), 7.50 (2H, d, J = 9 Hz), 7.28 (2H, d, J = 8 Hz), 6.99 (2H, d, J = 8 Hz), 3.99 (2H, d, J = 5 Hz), 3.74 (2H, m) , 3.57 (2H, s), 2.78 (2H, d, J = 7 Hz), 2.70 (2H, t, J = 12 Hz), 2.44 (3H, s), 2.16-2.02 (1H, m), 1.68 (2H, d, J = 12 Hz), 1.38 (2H, dq, J = 12 Hz, 3 Hz).

(製劑例) (Formulation example)

製劑例1(注射劑) Formulation Example 1 (injection)

將1.5重量%之實施例化合物於10容量%之丙二醇中攪拌，接著，以注射用水調整至一定容量後，滅菌作為注射劑。 1.5% by weight of the compound of the example was stirred in 10% by volume of propylene glycol, and then adjusted to a certain volume with water for injection, and sterilized as an injection.

製劑例2(硬膠囊劑) Formulation Example 2 (hard capsule)

混合100mg之粉末狀之實施例化合物、128.7mg之乳糖、70mg之纖維素及1.3mg之硬脂酸鎂，通過60網眼之篩網後，將所得到的粉末裝入250mg之3號明膠膠囊，作為膠囊劑。 100 mg of the powdered example compound, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed and passed through a 60 mesh screen, and the obtained powder was placed in a 250 mg No. 3 gelatin capsule. As a capsule.

製劑例3(錠劑) Formulation Example 3 (tablet)

混合100mg之粉末狀之實施例化合物、124mg之乳糖、25mg之纖維素及1mg之硬脂酸鎂，藉由打錠機打錠，製成1錠250mg之錠劑。此錠劑因應需要可施加糖衣。 100 mg of the powdered Example compound, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate were mixed and tableted by a tableting machine to prepare a tablet of 250 mg of a tablet. This tablet can be coated with sugar as needed.

(試驗例) (test example)

本發明之化合物之藥理活性係藉由以下之試驗確認。 The pharmacological activity of the compounds of the present invention is confirmed by the following tests.

使用源自人類肝癌之Hep3B細胞株(ATCC,Manassas,VA)，評估被驗化合物之體外(in vitro)紅血球生成素(EPO)誘導活性。將Hep3B細胞在10%FBS(胎牛血清)存在下、DMEM(Dulbecco's modified Eagle's medium)中，於37℃培養一晚(24-孔培養板、1.0 x 105細胞/孔)。替換成含有溶解於0.5% DMSO(二甲亞碸)之被驗化合物(調製成濃度1.56μM)或溶劑對照(對照組：0.5% DMSO)之新鮮DMEM(+10% FBS)後，於37℃下培養 32~33小時。回收培養上清後，使用人類EPO酵素結合免疫吸附分析法套組(human EPO ELISA kits)(StemCell Technologies)，定量培養上清中之EPO濃度。 The in vitro erythropoietin (EPO)-inducing activity of the test compound was evaluated using a Hep3B cell line derived from human liver cancer (ATCC, Manassas, VA). Hep3B cells were cultured in DMEM (Dulbecco's modified Eagle's medium) in the presence of 10% FBS (fetal calf serum) overnight at 37 ° C (24-well culture plates, 1.0 x 10 5 cells/well). Replaced with fresh DMEM (+10% FBS) containing the test compound dissolved in 0.5% DMSO (dimethyl hydrazine) (prepared to a concentration of 1.56 μM) or solvent control (control group: 0.5% DMSO) at 37 ° C Incubate for 32~33 hours. After recovering the culture supernatant, the EPO concentration in the culture supernatant was quantified using human EPO ELISA kits (StemCell Technologies).

使用各實施例化合物作為被驗化合物時之EPO濃度係以對照組中EPO濃度之倍數表示。結果顯示於表1。使用各實施例化合物時之EPO濃度相較於與溶劑對照組(Control)之EPO濃度，顯著地增高。即，本發明之化合物表示優異的增強EPO產生活性，作為醫藥(尤其是用以預防或治療貧血之醫藥)是有用的。 The EPO concentration when each of the example compounds was used as the test compound was expressed as a multiple of the EPO concentration in the control group. The results are shown in Table 1. The EPO concentration at the time of using the compounds of the examples was significantly higher than that of the solvent control group (Control). That is, the compound of the present invention is excellent in enhancing EPO production activity, and is useful as a medicine (especially a medicine for preventing or treating anemia).

[產業上之利用可能性] [Industry use possibility]

本發明之化合物或其藥理上容許鹽具有優異的增強EPO產生活性，對於起因於EPO低下之疾病等是有用的。具體而言，本發明之化合物或其藥理上容許鹽作為用以預防及/或治療貧血，較佳為腎性貧血、早產兒貧血、伴隨慢性疾病之貧血、伴隨癌化學療法之貧血、癌性貧血、炎症關聯性之貧血或伴隨鬱血性心衰竭之貧血，更佳為伴隨慢性腎臟病之貧血之醫藥是有用的，亦可作為用以預防及/或治療缺血性腦疾病等之醫藥而使用。 The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent activity for enhancing EPO production, and is useful for diseases caused by EPO deficiency and the like. Specifically, the compound of the present invention or a pharmacologically acceptable salt thereof is used for preventing and/or treating anemia, preferably renal anemia, anemia of premature infants, anemia accompanied by chronic diseases, anemia associated with cancer chemotherapy, cancerousness Anemia, inflammation-related anemia, or anemia associated with septic heart failure, more preferably an anemia drug associated with chronic kidney disease, or as a medicine for preventing and/or treating ischemic brain diseases. use.

Claims (18)

一種以通式(1)表示之化合物或其藥理上容許鹽， [通式(1)中，R1係以下述之通式(1A)表示之基；R2表示C1~C3烷基或甲基硫烷基(methylsulfanyl)；R3表示氫原子或甲基]； [通式(1A)中，R4及R5係各自獨立地表示氫原子、鹵原子、或C1~C6烷基； R6表示氫原子、鹵原子、C1~C6烷基、胺甲醯基、C1~C6烷基胺甲醯基、或(C1~C6烷基)(C1~C6烷基)胺甲醯基；R7表示可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C2~C7烷醯基C2~C6烯基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯基氧基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷基胺甲醯基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷氧基羰基胺基C1~C6烷基、可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷硫基羰基胺基C1~C6烷基、或可具有1個或2個之選自獨立的取代基群組α之取代基的C1~C6烷磺醯基胺基C1~C6烷基；取代基群組α表示選自包含側氧基、羥基、胺基、羧基、胺甲醯基、C1~C6烷氧基、鹵化C1~C6烷氧基、C2~C7烷醯基胺基、羥基亞胺基、及C1~C6烷氧基亞胺基之群組；環Q1表示單環之雜環基(該雜環基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)；環Q2表示單環之烴環基(該烴環基包含5至7員之芳香族烴環及非芳香族烴環)、或單環之雜環基(該雜環 基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)；環Q3表示單環之烴環基(該烴環基包含5至7員之芳香族烴環及非芳香族烴環)、或單環之雜環基(該雜環基包含5至7員之芳香族雜環及非芳香族雜環，且含有1或2個選自包含氮原子、硫原子及氧原子之群組中的原子)；X表示單鍵、亞甲基、或伸乙基]。 a compound represented by the formula (1) or a pharmacologically acceptable salt thereof, [In the formula (1), R 1 is a group represented by the following formula (1A); R 2 represents a C 1 -C 3 alkyl group or a methylsulfanyl group; and R 3 represents a hydrogen atom or a group; base]; [In the formula (1A), R 4 and R 5 each independently represent a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group; and R 6 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, An amine methyl sulfhydryl group, a C 1 -C 6 alkylamine carbhydryl group, or a (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amine carbaryl group; R 7 represents 1 or 2 a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group selected from the substituents of the independent substituent group α, which may have one or two substituents selected from the group of independent substituents α a C 2 -C 7 alkyl fluorenyl C 2 -C 6 alkenyl group having 1 or 2 C 1 -C 6 alkylamine fluorenyl groups selected from the substituents of the independent substituent group α An oxy C 1 -C 6 alkyl group, a C 1 -C 6 alkylamine-methyl fluorenyl C 1 -C 6 alkane which may have 1 or 2 substituents selected from the independent substituent group α a C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group which may have 1 or 2 substituents selected from the independent substituent group α, may have 1 or 2 a C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group selected from the substituents of the independent substituent group α, or may have one or two selected from the group of independent substituents α Substituted C 1 to C 6 alkanesulfonylamino group C 1 to C 6 alkyl; the substituent group α represents a group selected from the group consisting of a pendant oxy group, a hydroxyl group, an amine group, a carboxyl group, an amine carbenyl group, and a C 1 -C 6 alkoxy group. a group of a halogenated C 1 -C 6 alkoxy group, a C 2 -C 7 alkylalkylamino group, a hydroxyimino group, and a C 1 -C 6 alkoxyimino group; the ring Q 1 represents a single ring a heterocyclic group containing 5 to 7 members of an aromatic heterocyclic ring and a non-aromatic heterocyclic ring, and having 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom) The ring Q 2 represents a monocyclic hydrocarbon ring group (the hydrocarbon ring group contains 5 to 7 members of an aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic heterocyclic group (the heterocyclic group contains 5 to 7) Aromatic heterocyclic ring and non-aromatic heterocyclic ring, and containing 1 or 2 atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms; ring Q 3 represents a monocyclic hydrocarbon ring group (this The hydrocarbon ring group contains 5 to 7 members of an aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic heterocyclic group (the heterocyclic group contains 5 to 7 membered aromatic heterocyclic rings and non-aromatic heterocyclic rings, And containing 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom) X represents a single bond, methylene, or ethyl extension]. 如請求項1之化合物或其藥理上容許鹽，其中環Q1為哌啶基，環Q2為苯基或吡啶基，環Q3為苯基或吡啶基。 A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein ring Q 1 is piperidinyl, ring Q 2 is phenyl or pyridyl, and ring Q 3 is phenyl or pyridyl. 如請求項1或2之化合物或其藥理上容許鹽，其中R2為甲基，R3為氫原子。 A compound according to claim 1 or 2, wherein R 2 is a methyl group and R 3 is a hydrogen atom, or a pharmacologically acceptable salt thereof. 如請求項1至3中之任一項之化合物或其藥理上容許鹽，其中R1為以下述之通式(1B)表示之基， [通式(1B)中，R7表示C2~C7烷醯基C1~C6烷基、C2~C7烷醯基C2~C6烯基、C1~C6烷基胺甲醯基氧基C1~C6烷基、C1~C6烷基胺甲醯基胺基C1~C6烷基、C1~C6烷氧基羰基胺基C1~C6烷基、C1~C6烷硫基羰基胺基C1~C6烷基、或C1~C6烷磺醯基胺基C1~C6烷基；X表示單鍵、或亞甲基；Y及Z各自獨立地表示氮原子或以式=CH-表示之基]。 The compound of any one of claims 1 to 3, wherein R 1 is a group represented by the following formula (1B), or a pharmacologically acceptable salt thereof; [In the formula (1B), R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkyl group; Aminomethyl methoxy-C 1 -C 6 alkyl, C 1 -C 6 alkylamine-methylaminomethyl C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino C 1 ~C a 6- alkyl group, a C 1 -C 6 alkylthiocarbonylamino group C 1 -C 6 alkyl group, or a C 1 -C 6 alkanesulfonylamino group C 1 -C 6 alkyl group; X represents a single bond, or a sub Methyl; Y and Z each independently represent a nitrogen atom or a group represented by the formula =CH-]. 如請求項1至4中之任一項之化合物或其藥理上容許鹽，其中R1為以下述通式(1B-1)、通式(1B-2)、通式(1B-3)、或通式(1B-4)之任一者表示之基， [通式(1B-1)、通式(1B-2)、通式(1B-3)、或通式(1B-4)中， R7表示C2~C7烷醯基C1~C6烷基、C2~C7烷醯基C2~C6烯基、C1~C6烷基胺甲醯基氧基C1~C6烷基、C1~C6烷基胺甲醯基胺基C1~C6烷基、C1~C6烷氧基羰基胺基C1~C6烷基、C1~C6烷硫基羰基胺基C1~C6烷基、或C1~C6烷磺醯基胺基C1~C6烷基]。 The compound of any one of claims 1 to 4, wherein R 1 is a compound of the following formula (1B-1), formula (1B-2), formula (1B-3), or a pharmacologically acceptable salt thereof, Or a base represented by any one of the formulae (1B-4), [In the formula (1B-1), the formula (1B-2), the formula (1B-3), or the formula (1B-4), R 7 represents a C 2 -C 7 alkanoyl group C 1 ~C 6 alkyl, C 2 ~ C 7 alkyl fluorenyl C 2 ~ C 6 alkenyl, C 1 ~ C 6 alkyl amine methyl fluorenyl C 1 ~ C 6 alkyl, C 1 ~ C 6 alkyl amine a mercaptoamine group C 1 -C 6 alkyl group, a C 1 -C 6 alkoxycarbonylamino group C 1 -C 6 alkyl group, a C 1 -C 6 alkylthiocarbonylamino group C 1 -C 6 alkyl group, Or C 1 ~ C 6 alkanesulfonylamino group C 1 ~ C 6 alkyl]. 如請求項1至5中之任一項之化合物或其藥理上容許鹽，其中R7為2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、({[(乙硫基)羰基]胺基}甲基、[(乙基胺甲醯基)胺基]甲基、[(乙基胺甲醯基)氧基]甲基、或[(甲磺醯基)胺基]甲基。 The compound of any one of claims 1 to 5, wherein R 7 is 2-sided oxypropyl, 2-sided oxybutyl, 3-oxobutyl butyl, 2-oxo pentane, or a pharmacologically acceptable salt thereof 3-, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amine Methyl, ({[(ethylthio)carbonyl)amino}methyl, [(ethylaminecarbamimidino)amino]methyl, [(ethylaminecarbamido)oxy]methyl Or [(methylsulfonyl)amino]methyl. 如請求項1至6中之任一項之化合物或其藥理上容許鹽，其中R7為2-側氧丙基、2-側氧丁基、3-側氧丁基、2-側氧戊基、3-側氧基-1-丁烯基、[(甲氧基羰基)胺基]甲基、[(乙氧基羰基)胺基]甲基、[(第三丁氧基羰基)胺基]甲基、或[(乙基胺甲醯基)氧基]甲基。 The compound of any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, wherein R 7 is 2-sided oxypropyl, 2-sided oxybutyl, 3-oxobutyl, 2-oxo-pentane 3-, 3-oxo-1-butenyl, [(methoxycarbonyl)amino]methyl, [(ethoxycarbonyl)amino]methyl, [(t-butoxycarbonyl)amine Methyl, or [(ethylamine-mercapto)oxy]methyl. 如請求項1中之化合物或其藥理上容許鹽，其係選自如下：{[(2-{[1-(4’-{[(乙氧基羰基)胺基]甲基}聯苯-4-基)哌啶-4-基]甲基}-5-羥基-6-甲基嘧啶-4-基)羰基]胺基}乙酸、({[2-({1-[4’-({[(乙硫基)羰基]胺基}甲基)聯苯-4-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、 ({[2-({1-[4-(6-{[(第三丁氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4-(6-{[(甲磺醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙基胺甲醯基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙氧基羰基)胺基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[4-(6-{[(乙基胺甲醯基)氧基]甲基}吡啶-3-基)苯基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、{[(5-羥基-6-甲基-2-{[1-(4-{6-[(1E)-3-側氧丁-1-烯-1-基]吡啶-3-基}苯基)哌啶-4-基]甲基}嘧啶-4-基)羰基]胺基}乙酸、[({5-羥基-6-甲基-2-[(1-{4-[6-(3-側氧丁基)吡啶-3-基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丁基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、 ({[5-羥基-6-甲基-2-({1-[4’-(2-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[4’-(2-側氧戊基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、({[5-羥基-6-甲基-2-({1-[3’-(2-側氧丙基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、[({5-羥基-6-甲基-2-[(1-{4-[4-(2-側氧丙基)苄基]苯基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{4’-[(1E)-3-側氧丁-1-烯-1-基]聯苯-4-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-6-甲基-2-({1-[4’-(3-側氧丁基)聯苯-4-基]哌啶-4-基}甲基)嘧啶-4-基]羰基}胺基)乙酸、[({5-羥基-6-甲基-2-[(1-{5-[4-(2-側氧丙基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、[({5-羥基-6-甲基-2-[(1-{5-[3-(2-側氧丁基)苯基]吡啶-2-基}哌啶-4-基)甲基]嘧啶-4-基}羰基)胺基]乙酸、({[5-羥基-2-({1-[5-(4-{[(甲氧基羰基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-6-甲基嘧啶-4-基]羰基}胺基)乙酸、({[2-({1-[5-(4-{[(乙基胺甲醯基)胺基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸、 ({[2-({1-[5-(4-{[(乙基胺甲醯基)氧基]甲基}苯基)吡啶-2-基]哌啶-4-基}甲基)-5-羥基-6-甲基嘧啶-4-基]羰基}胺基)乙酸。 A compound according to claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: {[(2-{[1-(4'-{[(ethoxycarbonyl))amino]methyl}biphenyl- 4-yl)piperidin-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, ({[2-({1-[4'-( {[(Ethylthio)carbonyl]amino}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amine Acetate, acetic acid, ({[2-({1-[4-(6-{[(T-Butoxycarbonyl)amino)methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl) -5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4-(6-{[( Sulfhydryl)amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1 -[4-(6-{[(ethylamine-methyl)amino]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6- Pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{[(ethoxycarbonyl)amino)methyl}pyridin-3-yl)benzene (piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4-(6-{ [(Ethylaminomethylmethyl)oxy]methyl}pyridin-3-yl)phenyl]piperidin-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl }amino)acetic acid, {[(5-hydroxy-6-methyl-2-{[1-(4-{6-[(1E)-3-oxobut-1-en-1-yl]pyridine) -3-yl}phenyl)piperidin-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, [({5-hydroxy-6-methyl-2-[(1-{) 4-[6-(3-Phenoxybutyl)pyridin-3-yl]phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5- Hydroxy-6-A Benzyl-2-[(1-{4-[4-(2-oxobutyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid , ({[5-hydroxy-6-methyl-2-({1-[4'-(2-Siloxypropyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine- 4-yl]carbonyl}amino)acetic acid, ({[5-Hydroxy-6-methyl-2-({1-[4'-(2-oxobutyl)biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidine-4 -yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4'-(2-oxo-pentyl)biphenyl-4-yl]piperidine- 4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[5-hydroxy-6-methyl-2-({1-[3'-(2-trioxypropyl)) Biphenyl-4-yl]piperidin-4-yl}methyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, [({5-hydroxy-6-methyl-2-[(1-{4) -[4-(2-Siloxypropyl)benzyl]phenyl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-) Methyl-2-[(1-{4'-[(1E)-3-oxooxybut-1-en-1-yl]biphenyl-4-yl}piperidin-4-yl)methyl]pyrimidine 4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-6-methyl-2-({1-[4'-(3-oxobutyl)biphenyl-4-yl]piperidin [(5-hydroxy-5-methyl-2-[(1-{5-[4-(2-) Oxypropyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-methyl-2-) [(1-{5-[3-(2-Phenoxybutyl)phenyl]pyridin-2-yl}piperidin-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-2-({1-[5-(4-{[( Methoxycarbonyl)amino]methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({ [2-({1-[5-(4-{[(ethylaminecarbamimidyl)amino]methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl)-5 -hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[5-(4-{[(ethylamine)methyl)oxy)methyl}phenyl)pyridin-2-yl]piperidin-4-yl}methyl) -5-Hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid. 一種醫藥組成物，其係含有如請求項1至8中之任一項之化合物或其藥理上容許鹽作為有效成分。 A pharmaceutical composition containing the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. 如請求項9之醫藥組成物，其係用以預防及/或治療貧血。 The pharmaceutical composition of claim 9 for use in the prevention and/or treatment of anemia. 如請求項9之醫藥組成物，其係用以產生紅血球生成素。 A pharmaceutical composition according to claim 9 which is for producing erythropoietin. 一種如請求項1至8中之任一項之化合物或其藥理上容許鹽之用途，其係用以製造醫藥。 A use of a compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof for the manufacture of a medicament. 如請求項12之用途，其中醫藥係用以預防及/或治療貧血之醫藥。 The use of claim 12, wherein the medicine is a medicine for preventing and/or treating anemia. 一種產生紅血球生成素的方法，其係對人類投予如請求項1至8中之任一項之化合物或其藥理上容許鹽之藥理的有效量而成。 A method of producing erythropoietin which is administered to a human in an amount effective to administer a compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof. 一種用以預防及/或治療疾病之方法，其係對人類投予如請求項1至8中之任一項之化合物或其藥理上容許鹽之藥理的有效量而成。 A method for preventing and/or treating a disease, which comprises administering to a human an effective amount of a compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof. 如請求項15之方法，其中疾病為貧血。 The method of claim 15, wherein the disease is anemia. 如請求項1至8中之任一項之化合物或其藥理上容許鹽，其係在用以治療或預防疾病之方法中使用。 A compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof, for use in a method for treating or preventing a disease. 如請求項17之化合物或其藥理上容許鹽，其中疾病為貧血。 The compound of claim 17, or a pharmacologically acceptable salt thereof, wherein the disease is anemia.
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