TW201625588A - Cyclic amine derivative - Google Patents

Cyclic amine derivative Download PDF

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TW201625588A
TW201625588A TW104136115A TW104136115A TW201625588A TW 201625588 A TW201625588 A TW 201625588A TW 104136115 A TW104136115 A TW 104136115A TW 104136115 A TW104136115 A TW 104136115A TW 201625588 A TW201625588 A TW 201625588A
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methyl
phenyl
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dihydro
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TW104136115A
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永持雅敏
五反田建德
野口哲司
後藤泰治
佐佐木潤子
鳥羽田宗史
吉野利治
磯部崇
文卡塔拉曼 拉馬達斯
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第一三共股份有限公司
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Abstract

The present invention pertains to a compound having an exceptional effect for inhibiting retinoic-acid-receptor-related orphan receptors [gamma]t, or a pharmacologically acceptable salt thereof. A compound represented by general formula (I) (in the formula, R1 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a phenyl group; R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or the like; R3 represents a hydrogen atom, a C2-C7 carboxyalkyl group, or a hydroxyl group; R4 represents a halogen atom or a C1-C6 alkyl group; R5 represents a hydrogen atom or a C1-C6 alkyl group; R6 represents a hydrogen atom, a halogen atom, or a C1-C6 alkyl group; Q1 represents a nitrogen atom or a group represented by the formula =CH-; Q2 represents a nitrogen atom or a group represented by the formula =CH-; a group represented by the formula -U-T- represents a group represented by the formula -CH2-CH2-, or the like; Y represents a methylene group or an oxygen atom; V represents a nitrogen atom or a group represented by the formula =C(R7)-; R7 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or the like; E represents a piperidine-1-yl group, piperidine-4-yl group, or 1,2,3,6-tetrahydropyridine-4-yl group optionally substituted independently by from one to four groups selected from substituent group A, or the like; substituent group A includes C1-C6 alkyl groups, C1-C6 alkyl halide groups, groups represented by the formula -L-R8, and the like; L represents a carbonyl group, an oxalyl group, or the like; R8 represents a C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a mono-C1-C6 alkylamino group, or the like), or a pharmacologically acceptable salt thereof.

Description

環狀胺衍生物 Cyclic amine derivative

本發明係關於具有優異視網酸受體關連孤兒受體γt(retinoic acid receptor-related orphan receptors)(本說明書中有縮寫為RORγt的情形)之抑制作用，且有用於作為乾癬等之治療藥的化合物或其藥學上可容許的鹽。 The present invention relates to an inhibitory effect of retinoic acid receptor-related orphan receptors (in the present specification, abbreviated as RORγt), and is useful as a therapeutic drug for cognac or the like. a compound or a pharmaceutically acceptable salt thereof.

雖然許多自體免疫疾病被認為原因不明，但一直以來已知於許多疾病中與T細胞異常有深切關連。尤其，高量產生IFN-γ之輔助型T細胞(Th1細胞)其關聯性自很久以前已被報告，但Th1細胞之異常中亦有無法完全說明疾病發病機制的問題點，而於與Th1細胞有關的定論存有疑問。於2006年，IL-17高產生之輔助型T細胞(Th17細胞)的存在被報告，而提倡自體免疫疾病與Th17細胞之異常有深切關連。從此以後，與Th17細胞有關的研究被大力地進行，有些自體免疫疾病其關連性已變得明瞭，Th17細胞之重要性變得為受到注目。Th17細胞由初始T細胞(Naive T cells)分化的過程、及Th17細胞產生IL-17的過程中，核內受體之RORγt發揮機能。RORγt剔除小鼠之初始T細胞中，向Th17細胞之分化被抑制、IL-17產生被抑制，而獲得為多發性硬化症之病態模型的實驗自體免疫 腦脊髓炎(Experimental Autoimmune Encephalomyelitis)之發病被抑制的結果(非專利文獻1)。又於其他病態模型，亦有RORγt於向Th17細胞之分化、IL-17之產生及病態發症上扮演重要角色的報告(非專利文獻2-3)。由此等之知識見解，而考慮抑制RORγt之轉錄活性的物質，即RORγt抑制劑成為自體免疫疾病等之治療藥的可能性。 Although many autoimmune diseases are thought to be unexplained, they have long been known to be deeply involved in T cell abnormalities in many diseases. In particular, the association of high-volume IFN-γ-producing helper T cells (Th1 cells) has been reported for a long time, but there are also problems in the abnormalities of Th1 cells that cannot fully explain the pathogenesis of the disease, but with Th1 cells. There are doubts about the conclusions. In 2006, the presence of IL-17-producing helper T cells (Th17 cells) was reported, and the promotion of autoimmune diseases was deeply related to the abnormalities of Th17 cells. Since then, studies related to Th17 cells have been vigorously carried out, and the relevance of some autoimmune diseases has become clear, and the importance of Th17 cells has become noticeable. During the process of differentiation of Th17 cells from naive T cells and the production of IL-17 by Th17 cells, RORγt of nuclear receptors functions. In the initial T cells of RORγt knockout mice, differentiation to Th17 cells was inhibited, IL-17 production was inhibited, and experimental autoimmune was obtained as a pathological model of multiple sclerosis. The result of the inhibition of the onset of the cerebral myelitis (Experimental Autoimmune Encephalomyelitis) (Non-Patent Document 1). In other pathological models, there is also a report that RORγt plays an important role in the differentiation into Th17 cells, the production of IL-17, and pathological symptoms (Non-Patent Document 2-3). From such knowledge, it is considered that a substance that inhibits the transcriptional activity of RORγt, that is, a RORγt inhibitor, may be a therapeutic drug such as an autoimmune disease.

由於自體免疫疾病之原因迄今不明，因而於其治療法中使用抑制全體免疫的免疫抑制劑。然而於此治療法，對自體免疫疾病的原因本身的效果並未被期待，因其不過是對症治療法，而不認為有充足的治療效果，或未達到緩解而再復發為多的。因此，為了產生充分治療效果而達到緩解，適合自體免疫疾病原因的治療法為必要的。最近，已確認IL-17產生為亢進的Th17細胞之異常為一些自體免疫疾病之原因。然而，於現時點，因可治療Th17細胞之異常的方法並不存在，可改善Th17細胞之異常的新治療法已被認為是必要的。 Since the cause of the autoimmune disease has not been known so far, an immunosuppressive agent that suppresses overall immunity is used in the treatment method. However, in this treatment, the effect of the cause of the autoimmune disease itself is not expected, because it is merely a symptomatic treatment method, and it is not considered that there is sufficient therapeutic effect, or it does not relapse and then relapses. Therefore, in order to achieve a sufficient therapeutic effect and to achieve remission, a treatment suitable for the cause of autoimmune diseases is necessary. Recently, it has been confirmed that the abnormality of IL-17 production of Th17 cells is a cause of some autoimmune diseases. However, at present, a new method for improving the abnormality of Th17 cells has been considered as a method for treating abnormalities of Th17 cells, which is considered to be necessary.

[先前技術文獻] [Previous Technical Literature] [專利文獻1] [Patent Document 1]

[非專利文獻1]Cell, 126, 1121-1133(2006) [Non-Patent Document 1] Cell, 126, 1121-1133 (2006)

[非專利文獻2]The Journal of Clinical Investigation, 122, 2252-2256(2012) [Non-Patent Document 2] The Journal of Clinical Investigation, 122, 2252-2256 (2012)

[非專利文獻3]Arthritis and Rheumatology, 66, 579-588(2014) [Non-Patent Document 3] Arthritis and Rheumatology, 66, 579-588 (2014)

本發明者們針對具有RORγt抑制作用的化合物專心進行研究的結果，發現具有特定之化學構造的環狀胺衍生物具有選擇性地且優異的Th17細胞之分化抑制作用及IL-17產生抑制作用，對於自體免疫疾病等之RORγt有關的疾病之預防及治療為有用的。本發明者們發現此環狀胺衍生物有用於作為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病(克隆氏病(Crohn's disease)或潰瘍性大腸炎等)、修格連氏症候群(Sjogren's syndrome)、全身性紅斑狼瘡(systemic lupus erythematosus)、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(graft-versus-host disease，GvHD)、斑禿(alopecia areata)、白斑、川崎氏病、貝塞氏症(Behcet’s disease)、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病(Hashimoto’s disease)、硬皮症(scleroderma)、巨細胞性動脈炎、接觸性皮膚炎、視神經炎等之自體免疫疾病或IL-17之產生與病態發病有關的大腸癌之治療及/或預防用之醫藥之有效成分。本發明係基於上述之知識見解而完成。 As a result of intensive studies on a compound having a RORγt inhibitory effect, the present inventors have found that a cyclic amine derivative having a specific chemical structure has selective and excellent differentiation inhibitory action of Th17 cells and inhibition of IL-17 production. It is useful for the prevention and treatment of diseases related to RORγt such as autoimmune diseases. The present inventors have found that this cyclic amine derivative is useful as cognac, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease) or Ulcerative colitis, etc., Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft resistance Graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. Autoimmune diseases or the production of IL-17 for the treatment and/or prevention of colorectal cancer associated with pathological onset The active ingredient of the medicine. The present invention has been completed based on the above knowledge.

本發明為以下各者。 The present invention is as follows.

(1)一種通式(I)所表示的化合物或其藥學上可容許的鹽， (1) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

[式中，R1表示C1-C6烷基、C3-C6環烷基或苯基，R2表示氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基，R3表示氫原子、C2-C7羧基烷基或羥基，R4表示鹵素原子或C1-C6烷基，R5表示氫原子或C1-C6烷基，R6表示氫原子、鹵素原子或C1-C6烷基，Q1表示氮原子或式=CH-所表示的基，Q2表示氮原子或式=CH-所表示的基，式-U-T-所表示的基表示式-CH2-CH2-所表示的基或式-CH=CH-所表示的基，Y表示亞甲基或氧原子，V表示氮原子或式=C(R7)-所表示的基，R7表示氫原子、鹵素原子、C1-C6烷基、C3-C6環烷基、C2-C6烯基、C1-C6烷氧基、C1-C6鹵化烷氧基、(C1-C6烷氧基)-(C1-C6烷基)基、(C1-C6烷氧基)-(C1-C6烷氧基)基、C2-C7烷基羰基、四氫呋喃基或氧唉基氧基(oxetyloxy)，E表示可獨立經1至4個選自取代基群組A的基取代 的哌啶-1-基、哌啶-3-基、哌啶-4-基、1,2,3,6-四氫吡啶-4-基、哌-1-基、啉-4-基、吡咯啶-1-基或吡咯啶-3-基，取代基群組A表示由C1-C6烷基、C1-C6鹵化烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、羧基甲基、羥基、單-C2-C7烷基羰基胺基、側氧基、環氧丙烷-3-基、(1,4-二烷-2-基)甲基、與E之亞甲基部位以第2位鍵結而構築螺環接結構的1,3-二氧戊環及式-L-R8所表示的基所構成的群組，L表示羰基、草醯基(oxalyl)或磺醯基，R8表示C1-C6烷基、C1-C6羥基烷基、C1-C6二羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、二(C1-C6烷氧基)-(C1-C6烷基)基、(C1-C6烷氧基)-(C1-C6羥基烷基)基、C3-C6羥基環烷基、C1-C6氰基烷基、C1-C6烷氧基、羥基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、(C2-C7烷羰氧基)-(C1-C6烷基)基、(單-C3-C6環烷基胺基)-(C1-C6烷基)基、(C2-C7羥基烷羰氧基)-(C1-C6烷基)基、(單-C1-C6羥基烷基胺基)-(C1-C6烷基)基、四羥基環己基、四氫呋喃-2-基、四氫呋喃-3-基、環氧丙烷-2-基、環氧丙烷-3-基、1,4-二烷-2-基、四氫吖唉(azetidine)-1-基、啉-4-基、(啉-4-基)甲基、可獨立經1或2個C1-C6烷基取代的吡咯-2-基、可獨立經1或2個C1-C6烷基取代的啉-2-基、可獨立經1或2個C1-C6烷基取代的咪唑-5-基或可獨立經1至5個選自鹵素原子、C1-C6烷基、羥基、C1-C6羥基烷基、C2-C7烷基羰基及側 氧基的基取代的吡咯啶-2-基]。 Wherein R 1 represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a phenyl group, and R 2 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkane Oxy group, R 3 represents a hydrogen atom, a C 2 -C 7 carboxyalkyl group or a hydroxyl group, R 4 represents a halogen atom or a C 1 -C 6 alkyl group, and R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group, R 6 Represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group, Q 1 represents a nitrogen atom or a group represented by the formula =CH-, and Q 2 represents a nitrogen atom or a group represented by the formula =CH-, and the formula -UT- The base represented by the formula -CH 2 -CH 2 - represents a group or a group represented by the formula -CH=CH-, Y represents a methylene group or an oxygen atom, and V represents a nitrogen atom or a formula = C(R 7 )- The group represented, R 7 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 6 alkoxy group, C 1 -C 6 halogenated alkoxy, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy group a C 2 -C 7 alkylcarbonyl group, a tetrahydrofuranyl group or an oxetyloxy group, and E represents a piperidin-1-yl group which may be independently substituted with 1 to 4 groups selected from the substituent group A. , piperidin-3-yl, piperidin-4-yl, 1,2,3,6-tetra Pyridin-4-yl, piperazine, -1-base, Polin-4-yl, pyrrolidin-1-yl or pyrrolidin-3-yl, the substituent group A represents a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 hydroxyl group Alkyl, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, carboxymethyl group, hydroxyl group, mono-C 2 -C 7 alkylcarbonylamino group, pendant oxy group, epoxy Propane-3-yl, (1,4-di a group consisting of a 1,3-dioxolane having a spiro-ring structure and a group represented by the formula -LR 8 bonded to the methylene moiety of E at the 2nd position Group, L represents carbonyl, oxalyl or sulfonyl, R 8 represents C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 dihydroxyalkyl, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, di(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy) ()C 1 -C 6 hydroxyalkyl) group, C 3 -C 6 hydroxycycloalkyl group, C 1 -C 6 cyanoalkyl group, C 1 -C 6 alkoxy group, hydroxyl group, amine group, single -C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di-(C 1 -C 6 alkyl)amino group, (C 2 -C 7 alkylcarbonyloxy)- (C 1 -C 6 alkyl) group, (mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group, (C 2 -C 7 hydroxyalkylcarbonyloxy)- (C 1 -C 6 alkyl) group, (mono-C 1 -C 6 hydroxyalkylamino)-(C 1 -C 6 alkyl) group, tetrahydroxycyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, propylene oxide-2-yl, propylene oxide-3-yl, 1,4-di Alkan-2-yl, azetidine-1-yl, Porphyrin-4-yl, ( Phenyl-4-yl)methyl, pyrrol-2-yl which may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups, may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups a pyridin-2-yl group, an imidazole-5-yl group which may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups or may be independently selected from 1 to 5 selected from a halogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, C 1 -C 6 hydroxyalkyl, C 2 -C 7 alkylcarbonyl and pendant oxy-pyrrolidin-2-yl].

於本發明，可適當地列舉以下。 In the present invention, the following are exemplified as appropriate.

(2)如(1)之化合物或其藥學上可容許的鹽，其中R1為C1-C6烷基。 (2) A compound according to (1), wherein R 1 is a C 1 -C 6 alkyl group, or a pharmaceutically acceptable salt thereof.

(3)如(1)之化合物或其藥學上可容許的鹽，其中R1為甲基或乙基。 (3) (1) The compound or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or ethyl.

(4)如選自(1)至(3)中任一項之化合物或其藥學上可容許的鹽，其中R2為氫原子。 (4) A compound according to any one of (1) to (3), wherein R 2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(5)如選自(1)至(4)中任一項之化合物或其藥學上可容許的鹽，其中R3為氫原子。 (5) A compound according to any one of (1) to (4), wherein R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(6)如選自(1)至(5)中任一項之化合物或其藥學上可容許的鹽，其中R4為C1-C6烷基。 (6) A compound according to any one of (1) to (5), wherein R 4 is a C 1 -C 6 alkyl group, or a pharmaceutically acceptable salt thereof.

(7)如選自(1)至(5)中任一項之化合物或其藥學上可容許的鹽，其中R4為甲基。 (7) A compound according to any one of (1) to (5), wherein R 4 is a methyl group, or a pharmaceutically acceptable salt thereof.

(8)如選自(1)至(7)中任一項之化合物或其藥學上可容許的鹽，其中R5為氫原子或C1-C6烷基。 (8) A compound according to any one of (1) to (7), wherein R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, or a pharmaceutically acceptable salt thereof.

(9)如選自(1)至(7)中任一項之化合物或其藥學上可容許的鹽，其中R5為氫原子或甲基。 (9) A compound according to any one of (1) to (7), wherein R 5 is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

(10)如選自(1)至(9)中任一項之化合物或其藥學上可容許的鹽，其中R6為氫原子。 (10) A compound according to any one of (1) to (9), wherein R 6 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(11)如選自(1)至(10)中任一項之化合物或其藥學上可容許的鹽，其中Q1為式=CH-所表示的基。 (11) A compound of any one of (1) to (10) or a pharmaceutically acceptable salt thereof, wherein Q 1 is a group represented by the formula: CH-.

(12)如選自(1)至(11)中任一項之化合物或其藥學上可容許的鹽，其中Q2為式=CH-所表示的基。 (12) A compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof, wherein Q 2 is a group represented by the formula: CH-.

(13)如選自(1)至(12)中任一項之化合物或其藥學上 可容許的鹽，其中式-U-T-所表示的基為式-CH2-CH2-所表示的基。 (13) A compound of any one of (1) to (12) or a pharmaceutically acceptable salt thereof, wherein the group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 - .

(14)如選自(1)至(13)中任一項之化合物或其藥學上可容許的鹽，其中Y為氧原子。 (14) A compound according to any one of (1) to (13), or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.

(15)如選自(1)至(14)中任一項之化合物或其藥學上可容許的鹽，其中V為式=C(R7)-所表示的基。 (15) A compound according to any one of (1) to (14), or a pharmaceutically acceptable salt thereof, wherein V is a group represented by the formula: C(R 7 )-.

(16)如選自(1)至(15)中任一項之化合物或其藥學上可容許的鹽，其中R7為氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基。 (16) A compound according to any one of (1) to (15), wherein R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C, or a pharmaceutically acceptable salt thereof 6 alkoxy.

(17)如選自(1)至(15)中任一項之化合物或其藥學上可容許的鹽，其中R7為氫原子或甲基。 (17) A compound according to any one of (1) to (15), wherein R 7 is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

(18)如選自(1)至(14)中任一項之化合物或其藥學上可容許的鹽，其中V為氮原子。 (18) A compound according to any one of (1) to (14), or a pharmaceutically acceptable salt thereof, wherein V is a nitrogen atom.

(19)如選自(1)至(18)中任一項之化合物或其藥學上可容許的鹽，其中E為經1個式-L-R8所表示的基取代的哌啶-4-基、1,2,3,6-四氫吡啶-4-基或哌-1-基。 (19) is selected from (1) to the salt (18) a compound according to any one of the allowable, or a pharmaceutically, wherein E is a group of formula -LR 8 with 1 substituent represented by a piperidin-4-yl 1,2,3,6-tetrahydropyridin-4-yl or piperidine -1- base.

(20)如選自(1)至(18)中任一項之化合物或其藥學上可容許的鹽，其中E為經式-L-R8所表示的基於1位被取代的哌啶-4-基或1,2,3,6-四氫吡啶-4-基。 (20) A compound according to any one of (1) to (18), or a pharmaceutically acceptable salt thereof, wherein E is a 1-based substituted piperidine-4- represented by the formula -LR 8 Or 1,2,3,6-tetrahydropyridin-4-yl.

(21)如選自(1)至(18)中任一項之化合物或其藥學上可容許的鹽，其中取代基群組A為式-L-R8所表示的基。 (21) A compound according to any one of (1) to (18), wherein the substituent group A is a group represented by the formula -LR 8 or a pharmaceutically acceptable salt thereof.

(22)如選自(1)至(21)中任一項之化合物或其藥學上可容許的鹽，其中L為羰基或草醯基。 (22) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (21), wherein L is a carbonyl group or a sulfhydryl group.

(23)如選自(1)至(22)中任一項之化合物或其藥學上可容許的鹽，其中R8為C1-C6烷基、C1-C6羥基烷基、(C1-C6 烷氧基)-(C1-C6烷基)基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、啉-2-基、或獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基。 (23) selected from (1) to (22) of a compound or a pharmaceutically acceptable salt thereof, wherein R 8 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, ( C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, amine group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, two -(C 1 -C 6 alkyl)amino group, A phenyl-2-yl group, or a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group.

(24)如選自(1)至(22)中任一項之化合物或其藥學上可容許的鹽，其中R8為甲基、1-羥基乙基、甲氧基甲基、甲基胺基、乙基胺基、2,2-二氟乙基胺基、啉-2-基或4,4-二氟-1-甲基吡咯啶-2-基。 (24) A compound, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (22), wherein R 8 is methyl, 1-hydroxyethyl, methoxymethyl, methylamine Base, ethylamino group, 2,2-difluoroethylamino group, Orido-2-yl or 4,4-difluoro-1-methylpyrrolidin-2-yl.

(25)如(1)之化合物或其藥學上可容許的鹽，其中R1為C1-C6烷基，R2為氫原子，R3為氫原子，R4為C1-C6烷基，R5為氫原子或C1-C6烷基，R6為氫原子，Q1為氮原子或式=CH-所表示的基，Q2為氮原子或式=CH-所表示的基，式-U-T-所表示的基為式-CH2-CH2-所表示的基或式-CH=CH-所表示的基，Y為氧原子，V為式=C(R7)-所表示的基，R7為氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基，E為經1個式-L-R8所表示的基取代的哌啶-4-基、1,2,3,6-四氫吡啶-4-基或哌-1-基，L為羰基或草醯基，R8為C1-C6烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、啉-2-基、或獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基。 (25) A compound of (1), wherein R 1 is C 1 -C 6 alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, and R 4 is C 1 -C 6 , or a pharmaceutically acceptable salt thereof. An alkyl group, R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, R 6 is a hydrogen atom, Q 1 is a nitrogen atom or a group represented by the formula =CH-, Q 2 is a nitrogen atom or represented by the formula =CH- The group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 - or a group represented by the formula -CH=CH-, Y is an oxygen atom, and V is a formula = C(R 7 ) a group represented by R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, and E is a group-substituted piperidine represented by the formula -LR 8 - 4-yl, 1,2,3,6-tetrahydropyridin-4-yl or piperidine -1-yl, L is carbonyl or oxalyl, R 8 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, (C 1 -C 6 alkoxy)-(C 1 -C 6 Alkyl) group, amine group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di-(C 1 -C 6 alkyl)amino group, A phenyl-2-yl group, or a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group.

(26)如(1)之化合物或其藥學上可容許的鹽，其中R1為甲基或乙基，R2為氫原子，R3為氫原子，R4為甲基，R5為氫原子或甲基，R6為氫原子，Q1為式=CH-所表示的基，Q2為式=CH-所表示的基，式-U-T-所表示的基為 式-CH2-CH2-所表示的基，Y為氧原子，V為式=C(R7)-所表示的基，R7為氫原子或甲基，E為經式-L-R8所表示的基於1位取代的哌啶-4-基或1,2,3,6-四氫吡啶-4-基，L為羰基或草醯基，R8為甲基、1-羥基乙基、甲氧基甲基、甲基胺基、乙基胺基、2,2-二氟乙基胺基、啉-2-基或4,4-二氟-1-甲基吡咯啶-2-基。 (26) A compound of (1), wherein R 1 is a methyl group or an ethyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a methyl group, and R 5 is hydrogen, or a pharmaceutically acceptable salt thereof. An atom or a methyl group, R 6 is a hydrogen atom, Q 1 is a group represented by the formula =CH-, Q 2 is a group represented by the formula =CH-, and a group represented by the formula -UT- is a formula -CH 2 -CH 2 - a group represented, Y is an oxygen atom, V is a group represented by the formula = C(R 7 )-, R 7 is a hydrogen atom or a methyl group, and E is a 1-position substitution represented by the formula -LR 8 Piperidin-4-yl or 1,2,3,6-tetrahydropyridin-4-yl, L is carbonyl or oxalyl, R 8 is methyl, 1-hydroxyethyl, methoxymethyl, Methylamino, ethylamino, 2,2-difluoroethylamino, Orido-2-yl or 4,4-difluoro-1-methylpyrrolidin-2-yl.

(27)如(1)之化合物或其藥學上可容許的鹽，其中R1為C1-C6烷基，R2為氫原子，R3為氫原子，R4為C1-C6烷基，R5為氫原子或C1-C6烷基，R6為氫原子，Q1為氮原子或式=CH-所表示的基，Q2為氮原子或式=CH-所表示的基，式-U-T-所表示的基為式-CH2-CH2-所表示的基或式-CH=CH-所表示的基，Y為氧原子，V為氮原子，E為經1個式-L-R8所表示的基取代的哌啶-4-基、1,2,3,6-四氫吡啶-4-基或哌-1-基，L為羰基或草醯基，R8為C1-C6烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、啉-2-基或獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基。 (27) A compound of (1), wherein R 1 is C 1 -C 6 alkyl, R 2 is a hydrogen atom, R 3 is a hydrogen atom, and R 4 is C 1 -C 6 , or a pharmaceutically acceptable salt thereof. An alkyl group, R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, R 6 is a hydrogen atom, Q 1 is a nitrogen atom or a group represented by the formula =CH-, Q 2 is a nitrogen atom or represented by the formula =CH- The group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 - or a group represented by the formula -CH=CH-, Y is an oxygen atom, V is a nitrogen atom, and E is 1 a group-substituted piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl or piperidyl represented by the formula -LR 8 -1-yl, L is carbonyl or oxalyl, R 8 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, (C 1 -C 6 alkoxy)-(C 1 -C 6 Alkyl) group, amine group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di-(C 1 -C 6 alkyl)amino group, A phenyl-2-yl group or a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group.

(28)如(1)之化合物或其藥學上可容許的鹽，其中R1為甲基或乙基，R2為氫原子，R3為氫原子，R4為甲基，R5為氫原子或甲基，R6為氫原子，Q1為式=CH-所表示的基，Q2為式=CH-所表示的基，式-U-T-所表示的基為式-CH2-CH2-所表示的基，Y為氧原子，V為氮原子，E為經式-L-R8所表示的基於1位取代的哌啶-4-基或1,2,3,6-四氫吡啶-4-基，L為羰基或草醯基，R8為甲基、1-羥基 乙基、甲氧基甲基、甲基胺基、乙基胺基、2,2-二氟乙基胺基、啉-2-基或4,4-二氟-1-甲基吡咯啶-2-基。 (28) A compound of (1), wherein R 1 is a methyl group or an ethyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a methyl group, and R 5 is hydrogen, or a pharmaceutically acceptable salt thereof. An atom or a methyl group, R 6 is a hydrogen atom, Q 1 is a group represented by the formula =CH-, Q 2 is a group represented by the formula =CH-, and a group represented by the formula -UT- is a formula -CH 2 -CH 2 - a group represented, Y is an oxygen atom, V is a nitrogen atom, and E is a piperidin-4-yl group or a 1,2,3,6-tetrahydropyridine based on a 1-position represented by the formula -LR 8 4-yl, L is carbonyl or oxalyl, R 8 is methyl, 1-hydroxyethyl, methoxymethyl, methylamino, ethylamino, 2,2-difluoroethylamine base, Orido-2-yl or 4,4-difluoro-1-methylpyrrolidin-2-yl.

(29)一種化合物或其藥學上可容許的鹽，其係：1-[5-(4-{1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯、2-甲氧基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮、1-{5-[4-(1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、N-(2,2-二氟乙基)-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺、2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-N-甲基-2-側氧基乙醯胺、(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯 基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮、N-乙基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或、1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮。 (29) A compound or a pharmaceutically acceptable salt thereof, which is 1-[5-(4-{1-[(2S)-1,4-di) Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Phenyl)phenyl]ethanone, 1-{5-[4-(1-epiphenylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone, 4-{2-methyl-4-[(4-methyl-1-{[2-(A 3-sulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester, 2-methoxy 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]phenyl}piperidin-1-yl)ethanone, 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-methylpyrrolidine) -2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonate) Mercapto)phenyl]ethanone, N-(2,2-difluoroethyl)-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide, 2-( 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy (phenyl)piperidin-1-yl)-N-methyl-2-oxoethoxyacetamide, (2S)-2-hydroxy-1-[4-{2-methyl- 4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]benzene }},6-dihydropyridine-1(2H)-yl]propan-1-one, N-ethyl-2-[4-{2-methyl-4-[(4-methyl-1) -{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine -1(2H)-yl]-2-oxoethoxyacetamide, N-methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-( Methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)- 2-yloxyacetamide, 1-{5-[4-(4-ethenyl) -1-yl)-3-methylphenoxy]4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethylketone, 1-{5-[(1'-ethylindolyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone, 1-{5-[4-(1- Acetylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl] Ethyl Ketone, 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-( Ethylsulfonyl)phenyl]ethanone, 1-{5-[4-(1-ethinylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro- 1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone, or 1-{5-[4-(1-ethenyl-1, 2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[3-(Methylsulfonyl)pyridin-2-yl]ethanone.

(30)如(29)記載的化合物或其藥學上可容許的鹽中之化合物。 (30) A compound of the compound according to (29) or a pharmaceutically acceptable salt thereof.

(31)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基 -2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 (31) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl -2,3-Dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof.

(32)(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮、或其藥學上可容許的鹽。 (32) (2S)-2-hydroxy-1-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl) }-2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]propan-1-one, or a pharmaceutical thereof Tolerable salt.

(33)N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、或其藥學上可容許的鹽。 (33) N-Methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide, or a pharmaceutical thereof Permissible salt.

(34)1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 (34) 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2 -[2-(Methylsulfonyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof.

(35)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 (35) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-( Ethylsulfonyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof.

(36)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或其藥學上可容許的鹽。 (36) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-inden-1-yl} -2-[3-(methylsulfonyl)pyridin-2-yl]ethanone, or a pharmaceutically acceptable salt thereof.

(37)1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或其藥學上可容許的鹽。 (37) 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl Base-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone, or a pharmaceutically acceptable salt thereof.

(38)一種醫藥組成物，其含有作為有效成分之選自如(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽。 (38) A pharmaceutical composition comprising the compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof as an active ingredient.

(39)如(38)記載之醫藥組成物，其中醫藥組成物係具有視網酸受體關聯孤兒受體γt抑制作用。 (39) The pharmaceutical composition according to (38), wherein the pharmaceutical composition has a retinoid acid receptor-associated orphan receptor γt inhibitory action.

(40)如(38)記載之醫藥組成物，其中醫藥組成物係用以治療及/或預防藉由視網酸受體關聯孤兒受體γt抑制作用而被治療及/或預防的疾病。 (40) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for treating and/or preventing a disease which is treated and/or prevented by the retinoid acid receptor-associated orphan receptor γt inhibitory action.

(41)如(38)記載之醫藥組成物，其中醫藥組成物係用以治療及/或預防藉由Th17細胞分化之抑制及/或IL-17產生之抑制而可進行症狀之治療、改善、減輕及/或預防的疾病。 (41) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is used for treating and/or preventing the treatment of symptoms, improvement, and inhibition of inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. A disease that is alleviated and/or prevented.

(42)如(38)記載之醫藥組成物，其中醫藥組成物係用以治療及/或預防乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌。 (42) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory Enteropathy, Shering's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease , Behcet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(43)如(38)記載之醫藥組成物，其中醫藥組成物係用以治療及/或預防乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群或慢性阻塞性肺病。 (43) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory Enteropathy, Shering's syndrome or chronic obstructive pulmonary disease.

(44)如(38)記載之醫藥組成物，其中醫藥組成物係用以治療及/或預防乾癬或乾癬性關節炎。 (44) The pharmaceutical composition according to (38), wherein the pharmaceutical composition is for treating and/or preventing dryness or dryness arthritis.

(45)如(42)或(43)記載之醫藥組成物，其中炎症性腸病係克隆氏病或潰瘍性大腸炎。 (45) The pharmaceutical composition according to (42) or (43), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(46)一種視網酸受體關聯孤兒受體γt抑制劑，其含有選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽作為有效成分。 (46) A retinoid acid receptor-associated orphan receptor γt inhibitor comprising the compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof as an active ingredient.

(47)一種選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽之用途，其係用以製造醫藥組成物。 (47) Use of a compound according to any one of (1) to (37), or a pharmaceutically acceptable salt thereof, for producing a pharmaceutical composition.

(48)如(47)記載之用途，其中醫藥組成物係用以抑制視網酸受體關聯孤兒受體γt的組成物。 (48) The use according to (47), wherein the pharmaceutical composition is for inhibiting a composition of a reticulum receptor associated orphan receptor γt.

(49)如(47)記載之用途，其中醫藥組成物係用以治療及/或預防乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌之組成物。 (49) The use according to (47), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease , Sjogren's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, shellfish A composition of Seychelles, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(50)如(47)記載之用途，其中醫藥組成物係用以治療及/或預防乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群或慢性阻塞性肺病之組成物。 (50) The use according to (47), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease , the composition of Shering's syndrome or chronic obstructive pulmonary disease.

(51)如(47)記載之用途，其中醫藥組成物係用以治療及/或預防乾癬或乾癬性關節炎之組成物。 (51) The use of (47), wherein the pharmaceutical composition is for treating and/or preventing a composition of dry or dry arthritis.

(52)如(49)或(50)記載之用途，其中炎症性腸病為克隆氏病或潰瘍性大腸炎。 (52) The use according to (49) or (50), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(53)一種選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽，其係用於藉由視網酸受體關聯孤兒 受體γt抑制作用而被治療及/或預防的疾病之治療及/或預防的方法中的用途。 (53) A compound according to any one of (1) to (37), or a pharmaceutically acceptable salt thereof, for use in orphans associated with a reticulum receptor Use in a method of treating and/or preventing a disease which is treated and/or prevented by a receptor γt inhibitory action.

(54)一種選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽，其係用於乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌之治療及/或預防之方法中的用途。 (54) A compound according to any one of (1) to (37), or a pharmaceutically acceptable salt thereof, which is used for dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, Rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD) , alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer Use in methods of treatment and/or prevention.

(55)一種選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽，其係用於乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群或慢性阻塞性肺病之治療及/或預防之方法中的用途。 (55) A compound according to any one of (1) to (37), or a pharmaceutically acceptable salt thereof, which is used for dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, Use in methods of treatment and/or prevention of rheumatoid arthritis, inflammatory bowel disease, repair syndrome or chronic obstructive pulmonary disease.

(56)一種選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽，其係用於乾癬或乾癬性關節炎之治療及/或預防之方法中的用途。 (56) A compound according to any one of (1) to (37), or a pharmaceutically acceptable salt thereof, for use in a method of treatment and/or prevention of dryness or dryness arthritis .

(57)如(54)或(55)記載之化合物或其藥學上可容許的鹽，其中炎症性腸病為克隆氏病或潰瘍性大腸炎。 (57) The compound according to (54) or (55), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis, or a pharmaceutically acceptable salt thereof.

(58)一種視網酸受體關聯孤兒受體γt抑制方法，其係將藥理上有效量之選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽投予至溫血動物。 (58) A method for inhibiting a reticulum receptor-associated orphan receptor γt, which comprises administering a pharmacologically effective amount of the compound according to any one of (1) to (37) or a pharmaceutically acceptable salt thereof. To warm-blooded animals.

(59)一種疾病之治療及/或預防方法，其係將藥理上 有效量之選自(1)至(37)中任一項記載的化合物或其藥學上可容許的鹽投予至溫血動物。 (59) A method of treating and/or preventing a disease, which is pharmacologically An effective amount of the compound of any one of (1) to (37) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal.

(60)如(59)記載之方法，其中疾病為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌。 (60) The method according to (59), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sedative syndrome, systemic Lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, myocardium Disease, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(61)如(59)記載之方法，其中疾病為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群或慢性阻塞性肺病。 (61) The method according to (59), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, sedative syndrome or chronic obstruction Sexual lung disease.

(62)如(59)記載之方法，其中疾病為乾癬或乾癬性關節炎。 (62) The method according to (59), wherein the disease is dry or dry arthritis.

(63)如(60)或(61)記載之方法，其中炎症性腸病為克隆氏病或潰瘍性大腸炎。 (63) The method according to (60) or (61), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(62)如選自(58)至(63)中任一項記載之方法，其中溫血動物為人類。 (62) The method according to any one of (58) to (63) wherein the warm-blooded animal is a human.

於本發明，「鹵素原子」為氟原子、氯原子、溴原子或碘原子。適合為氟原子或氯原子，更適合為氟原子。 In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Suitable as a fluorine atom or a chlorine atom, more suitable as a fluorine atom.

於本發明，「C1-C6烷基」為碳數1至6個之直鏈或分枝鏈烷基。例如，甲基、乙基、丙基、異丙基、丁基、異丁基、s-丁基、t-丁基、戊基、異戊基、2- 甲基丁基、新戊基、1-乙基丙基、己基、異己基、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、1,1-二甲基丁基或1,2-二甲基丁基。適合為碳數1至3個之直鏈或分枝鏈烷基(C1-C3烷基)，更適合為甲基或乙基(C1-C2烷基)，進一步更適合為甲基。 In the present invention, the "C 1 -C 6 alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-Dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl. Suitable as a linear or branched alkyl group (C 1 -C 3 alkyl) having 1 to 3 carbon atoms, more preferably methyl or ethyl (C 1 -C 2 alkyl), further more suitable for A base.

於本發明，「C3-C6環烷基」為環丙基、環丁基、環戊基或環己基。適合為環丙基。 In the present invention, the "C 3 -C 6 cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Suitable as a cyclopropyl group.

於本發明，「C1-C6鹵化烷基」為相同或相異的1至5個之前述「鹵素原子」與前述「C1-C6烷基」結合的基。例如，三氟甲基、三氯甲基、二氟甲基、氟甲基、2,2,2-三氟乙基、3,3,3-三氟丙基、3,3-二氟丙基、2,2,2-三氯乙基、2-溴乙基或2-氟乙基。適合為相同或相異的1至5個之「鹵素原子」與「C1-C3烷基」結合的基(C1-C3鹵化烷基)，更適合為3,3,3-三氟丙基或3,3-二氟丙基。 In the present invention, the "C 1 -C 6 halogenated alkyl group" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "C 1 -C 6 alkyl group". For example, trifluoromethyl, trichloromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropane Base, 2,2,2-trichloroethyl, 2-bromoethyl or 2-fluoroethyl. Suitable for the same or different 1 to 5 "halogen atom" and "C 1 -C 3 alkyl" group (C 1 -C 3 halogenated alkyl), more suitable for 3,3,3-three Fluoropropyl or 3,3-difluoropropyl.

於本發明，「C2-C6烯基」為前述「C1-C6烷基」之中具有1個之雙鍵的碳數2至6個之基。例如，乙烯基、1-丙烯基、2-丙烯基、異丙烯基、1-甲基-2-丙烯基、1-甲基-1-丙烯基、1-丁烯基或5-己烯基，適合為碳數2至4個之烯基(C2-C4烯基)，更適合為異丙烯基。 In the present invention, the "C 2 -C 6 alkenyl group" is a group having 2 to 6 carbon atoms having one double bond among the above-mentioned "C 1 -C 6 alkyl groups". For example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-butenyl or 5-hexenyl Suitable as an alkenyl group (C 2 -C 4 alkenyl group) having 2 to 4 carbon atoms, more preferably isopropenyl group.

於本發明，「C1-C6烷氧基」為前述「C1-C6烷基」與氧原子結合的基，為碳數1至6個之直鏈或分枝鏈烷氧基。例如，甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、s-丁氧基、t-丁氧基、戊氧基、2-甲基丁氧基、3-乙基丙氧基、新戊氧基、己氧基或2,3- 二甲基丁氧基。適合為碳數1至4個之直鏈或分枝鏈烷氧基(C1-C4烷氧基)，更適合為甲氧基、乙氧基或t-丁氧基，進一步更適合為甲氧基。 In the present invention, the "C 1 -C 6 alkoxy group" is a group in which the above-mentioned "C 1 -C 6 alkyl group" is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, 2-methylbutoxy Base, 3-ethylpropoxy, neopentyloxy, hexyloxy or 2,3-dimethylbutoxy. Suitable as a linear or branched alkoxy group (C 1 -C 4 alkoxy) having 1 to 4 carbon atoms, more preferably a methoxy group, an ethoxy group or a t-butoxy group, furthermore preferably Methoxy.

於本發明，「C1-C6鹵化烷氧基」為相同或相異的1至5個之前述「鹵素原子」與前述「C1-C6烷氧基」結合的基。例如，三氟甲氧基、三氯甲氧基、二氟甲氧基、氟甲氧基、2,2,2-三氟乙氧基、2-溴乙氧基、2-氯乙氧基、五氟乙氧基或4-氟丁氧基，適合為相同或相異的1至5個之前述「鹵素原子」與前述「C1-C4烷氧基」結合的基(C1-C4鹵化烷氧基)，更適合為相同或相異的1至5個之前述「鹵素原子」與前述「C1-C2烷氧基」結合的基(C1-C2鹵化烷氧基)，進一步更適合為二氟甲氧基。 In the present invention, the "C 1 -C 6 halogenated alkoxy group" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "C 1 -C 6 alkoxy group". For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy , pentafluoroethoxy or 4-fluorobutoxy, suitable for the same or different 1 to 5 of the above-mentioned "halogen atom" and the above-mentioned "C 1 -C 4 alkoxy" group (C 1 - C 4 -halogenated alkoxy), more preferably 1 to 5 of the same or different "halogen atom" in combination with the aforementioned "C 1 -C 2 alkoxy group" (C 1 -C 2 halogenated alkoxylate) Further, it is more suitable as difluoromethoxy.

於本發明，「(C1-C6烷氧基)-(C1-C6烷基)基」係1個之前述「C1-C6烷氧基」與前述「C1-C6烷基」結合的基。例如，甲氧基甲基、乙氧基甲基、丙氧基甲基、異丙氧基甲基、丁氧基甲基、t-丁氧基甲基、2-甲氧基乙基、2-乙氧基乙基、2-丁氧基乙基、1-丁氧基乙基、1-異丁氧基乙基或3-異丙氧基丙基，適合為1個之前述「C1-C4烷氧基」與前述「C1-C3烷基」結合的基((C1-C4烷氧基)-(C1-C3烷基)基)，更適合為1個之前述「C1-C2烷氧基」與前述「C1-C2烷基」結合的基((C1-C2烷氧基)-(C1-C2烷基)基)，進一步更適合為甲氧基甲基或2-甲氧基乙基。 In the present invention, "(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group" is one of the aforementioned "C 1 -C 6 alkoxy groups" and the above "C 1 -C 6 Alkyl" bonded group. For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethyl, 2 - ethoxyethyl, 2-butoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl or 3-isopropoxypropyl, suitably one of the aforementioned "C 1 -C 4 alkoxy" group ((C 1 -C 4 alkoxy)-(C 1 -C 3 alkyl) group) bonded to the above-mentioned "C 1 -C 3 alkyl group", more preferably 1 a group ((C 1 -C 2 alkoxy)-(C 1 -C 2 alkyl) group) in which the above-mentioned "C 1 -C 2 alkoxy group" is bonded to the above-mentioned "C 1 -C 2 alkyl group", Further more suitable is methoxymethyl or 2-methoxyethyl.

於本發明，「(C1-C6烷氧基)-(C1-C6烷氧基)基」係1個之前述「C1-C6烷氧基」與前述「C1-C6烷氧基」結合的基。例如，甲氧基甲氧基、乙氧基甲氧基、丙 氧基甲氧基、異丙氧基甲氧基、丁氧基甲氧基、t-丁氧基甲氧基、2-甲氧基乙氧基、2-乙氧基乙氧基、2-丁氧基乙氧基或3-異丙氧基丙氧基，適合為1個之前述「C1-C4烷氧基」與前述「C1-C4烷氧基」結合的基((C1-C4烷氧基)-(C1-C4烷氧基)基)，更適合為1個之前述「C1-C2烷氧基」與前述「C1-C2烷氧基」結合的基((C1-C2烷氧基)-(C1-C2烷氧基)基)，進一步更適合為甲氧基甲氧基。 In the present invention, "(C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group" is one of the aforementioned "C 1 -C 6 alkoxy groups" and the aforementioned "C 1 -C" 6 alkoxy" bonded group. For example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, t-butoxymethoxy, 2-methyl An oxyethoxy group, a 2-ethoxyethoxy group, a 2-butoxyethoxy group or a 3-isopropoxypropoxy group, suitably one of the aforementioned "C 1 -C 4 alkoxy groups" The group ((C 1 -C 4 alkoxy)-(C 1 -C 4 alkoxy) group) bonded to the above-mentioned "C 1 -C 4 alkoxy group" is more preferably one of the aforementioned "C 1 -C 2 alkoxy" group bonded to the above "C 1 -C 2 alkoxy group" ((C 1 -C 2 alkoxy)-(C 1 -C 2 alkoxy) group), further suitable It is a methoxymethoxy group.

於本發明，「C2-C7羧基烷基」係1個之羧基與前述「C1-C6烷基」結合的基。例如，羧基甲基、2-羧基乙基、1-羧基乙基或3-羧基丙基。適合為1個之羧基與「C1-C2烷基」結合的基，更適合為羧基甲基。 In the present invention, "C 2 -C 7 carboxyalkyl" is a group in which one of the carboxyl groups is bonded to the above-mentioned "C 1 -C 6 alkyl group". For example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl or 3-carboxypropyl. A group in which one carboxyl group is bonded to "C 1 -C 2 alkyl group" is more preferably a carboxymethyl group.

於本發明，「C1-C6羥基烷基」係1個之羥基與前述「C1-C6烷基」結合的基。例如，2-羥基乙基、1-羥基乙基、(R)-1-羥基乙基、(S)-1-羥基乙基或3-羥基丙基。適合為1個之羥基與「C1-C2烷基」結合的基(C1-C2羥基烷基)，更適合為(R)-1-羥基乙基。 In the present invention, "C 1 -C 6 hydroxyalkyl" is a group in which one of the hydroxyl groups is bonded to the above-mentioned "C 1 -C 6 alkyl group". For example, 2-hydroxyethyl, 1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-hydroxyethyl or 3-hydroxypropyl. Suitably a hydroxyl group and the "C 1 -C 2 alkyl group" bonded group (C 1 -C 2 hydroxyalkyl), more suitably (R) -1- hydroxyethyl.

於本發明，「C1-C6二羥基烷基」係2個之羥基與前述「C1-C6烷基」結合的基。例如，1,2-二羥基乙基、1,2-二羥基丙基、1,3-二羥基丙基或2,3-二羥基丙基。適合為1,2-二羥基乙基。 In the present invention, "C 1 -C 6 dihydroxyalkyl" is a group in which two hydroxyl groups are bonded to the above-mentioned "C 1 -C 6 alkyl group". For example, 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl or 2,3-dihydroxypropyl. Suitable as 1,2-dihydroxyethyl.

於本發明，「二(C1-C6烷氧基)-(C1-C6烷基)基」係2個之前述「C1-C6烷氧基」與前述「C1-C6烷基」結合的基。適合為1,1-二乙氧基甲基。 In the present invention, "di(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group" is the above two "C 1 -C 6 alkoxy groups" and the above "C 1 -C" a 6 alkyl group bonded group. Suitable as 1,1-diethoxymethyl.

於本發明，「(C1-C6烷氧基)-(C1-C6羥基烷基)基」係1個之前述「C1-C6烷氧基」與前述「C1-C6羥基 烷基」結合的基。適合為1-羥基-2-甲氧基乙基。 In the present invention, "(C 1 -C 6 alkoxy)-(C 1 -C 6 hydroxyalkyl) group" is one of the aforementioned "C 1 -C 6 alkoxy groups" and the aforementioned "C 1 -C" a 6 -hydroxyalkyl group bonded group. Suitable as 1-hydroxy-2-methoxyethyl.

於本發明，「C3-C6羥基環烷基」係1個之羥基與前述「C3-C6環烷基」結合的基。適合為1-羥基環丙基。 In the present invention, the "C 3 -C 6 hydroxycycloalkyl group" is a group in which one of the hydroxyl groups is bonded to the above-mentioned "C 3 -C 6 cycloalkyl group". Suitable as 1-hydroxycyclopropyl.

於本發明，「C1-C6氰基烷基」係1個之氰基與前述「C1-C6烷基」結合的基。例如，氰基甲基、2-氰基乙基、1-氰基乙基或3-氰基丙基。適合為1個之氰基與「C1-C2烷基」結合的基，更適合為氰基甲基。 In the present invention, "C 1 -C 6 cyanoalkyl" is a group in which one cyano group is bonded to the above-mentioned "C 1 -C 6 alkyl group". For example, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl. It is preferably a group in which one cyano group is bonded to "C 1 -C 2 alkyl group", and is more suitably a cyanomethyl group.

於本發明，「單-C1-C6烷基胺基」係有1個之前述「C1-C6烷基」結合的胺基。例如，甲基胺基、乙基胺基、丙基胺基、異丙基胺基或丁基胺基。適合為有1個之「C1-C4烷基」結合的胺基(單-C1-C4烷基胺基)，更適合為甲基胺基或乙基胺基(單-C1-C2烷基胺基)。 In the present invention, the "mono-C 1 -C 6 alkylamino group" is an amine group in which one of the above-mentioned "C 1 -C 6 alkyl groups" is bonded. For example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group or a butylamino group. It is suitable for an amine group having a "C 1 -C 4 alkyl group" (mono-C 1 -C 4 alkylamino group), more preferably a methylamino group or an ethylamino group (mono-C 1 -C 2 alkylamino group).

於本發明，「單-C1-C6鹵化烷基胺基」係有1個之前述「C1-C6鹵化烷基」與胺基結合的基。例如，2,2,2-三氟乙基胺基、3,3,3-三氟丙基胺基、2,2-二氟乙基胺基、3,3-二氟丙基胺基、2,2,2-三氯乙基胺基、2-溴乙基胺基或2-氟乙基胺基。適合為有1個之「C1-C3鹵化烷基」結合的胺基(單-C1-C3鹵化烷基胺基)，更適合為2,2,2-三氟乙基胺基、2,2-二氟乙基胺基或2-氟乙基胺基，進一步更適合為2,2-二氟乙基胺基。 In the present invention, the "mono-C 1 -C 6 halogenated alkylamino group" has one group in which the above-mentioned "C 1 -C 6 halogenated alkyl group" is bonded to an amine group. For example, 2,2,2-trifluoroethylamino, 3,3,3-trifluoropropylamino, 2,2-difluoroethylamino, 3,3-difluoropropylamino, 2,2,2-trichloroethylamino, 2-bromoethylamino or 2-fluoroethylamino. It is suitable for an amine group (mono-C 1 -C 3 halogenated alkylamino group) having one "C 1 -C 3 halogenated alkyl group", more preferably 2,2,2-trifluoroethylamino group Further, 2,2-difluoroethylamino or 2-fluoroethylamino is further more suitable as 2,2-difluoroethylamino.

於本發明，「二-(C1-C6烷基)胺基」係有相同或相異的2個之前述「C1-C6烷基」結合的胺基。例如，二甲基胺基、二乙基胺基、二丙基胺基、N-乙基-N-甲基胺基、N-甲基-N-丙基胺基或N-丁基-N-甲基胺基。 適合為有相同或相異的2個之「C1-C4烷基」結合的胺基(二-(C1-C4烷基)胺基)，更適合為二甲基胺基、二乙基胺基或N-乙基-N-甲基胺基(二-(C1-C2烷基)胺基)，進一步更適合為二甲基胺基。 In the present invention, the "di-(C 1 -C 6 alkyl)amino group" has the same or different two "C 1 -C 6 alkyl"-bonded amine groups. For example, dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N - Methylamino group. Suitable as an amine group (di-(C 1 -C 4 alkyl)amino group) having the same or different "C 1 -C 4 alkyl group", more suitable for dimethylamino group, two Ethylamino or N-ethyl-N-methylamino (di-(C 1 -C 2 alkyl)amino) is further more preferably a dimethylamino group.

於本發明，「(C2-C7烷羰氧基)-(C1-C6烷基)基」係1個之前述「C2-C7烷羰氧基」與前述「C1-C6烷基」結合的基。適合為乙醯氧基甲基。 In the present invention, "(C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group" is one of the above-mentioned "C 2 -C 7 alkylcarbonyloxy group" and the above "C 1 - C 6 alkyl" bonded group. Suitable as ethoxymethyl.

於本發明，「(單-C3-C6環烷基胺基)-(C1-C6烷基)基」係1個之前述「單-C3-C6環烷基胺基」與前述「C1-C6烷基」結合的基。適合為單-環丙基胺基甲基。 In the present invention, "(mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group" is one of the above-mentioned "mono-C 3 -C 6 cycloalkylamino group". a group bonded to the aforementioned "C 1 -C 6 alkyl group". Suitable as mono-cyclopropylaminomethyl.

於本發明，「(C2-C7羥基烷羰氧基)-(C1-C6烷基)基」係1個之前述「C2-C7羥基烷羰氧基」與前述「C1-C6烷基」結合的基。適合為1-羥基乙基羰基氧基乙基-1-基。 In the present invention, "(C 2 -C 7 hydroxyalkylcarbonyloxy)-(C 1 -C 6 alkyl) group" is one of the above-mentioned "C 2 -C 7 hydroxyalkylcarbonyloxy group" and the aforementioned "C" a 1 -C 6 alkyl" bonded group. Suitably 1-hydroxyethylcarbonyloxyethyl-1-yl.

於本發明，「(單-C1-C6羥基烷基胺基)-(C1-C6烷基)基」係1個之前述「單-C1-C6羥基烷基胺基」與前述「C1-C6烷基」結合的基。適合為單-2-羥基乙基胺基甲基。 In the present invention, "(mono-C 1 -C 6 hydroxyalkylamino)-(C 1 -C 6 alkyl) group" is one of the above-mentioned "mono-C 1 -C 6 hydroxyalkylamine groups" a group bonded to the aforementioned "C 1 -C 6 alkyl group". Suitable as mono-2-hydroxyethylaminomethyl.

於本發明，「C2-C7烷基羰基」係1個之前述「C1-C6烷基」與羰基結合的基。例如，乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、三甲基乙醯基或纈草醯基。適合為1個之「C1-C4烷基」與羰基結合的基(C2-C5烷基羰基)，更適合為乙醯基或丙醯基(C2-C3烷基羰基)，進一步更適合為乙醯基。 In the present invention, the "C 2 -C 7 alkylcarbonyl group" is a group in which one of the above-mentioned "C 1 -C 6 alkyl groups" is bonded to a carbonyl group. For example, ethyl, propyl, butyl, isobutyl, pentylene, trimethylethyl or valeryl. Suitable as a group in which a "C 1 -C 4 alkyl group" is bonded to a carbonyl group (C 2 -C 5 alkylcarbonyl group), more preferably an ethyl hydrazino group or a propyl fluorenyl group (C 2 -C 3 alkylcarbonyl group) Further suitable for ethyl ketone.

於本發明，「單-C2-C7烷基羰基胺基」係1個之前述「C2-C7烷基羰基」與胺基結合的基。例如，甲 基羰基胺基、乙基羰基胺基、丙基羰基胺基、或t-丁基羰基胺基。適合為1個之「C2-C3烷基羰基」與胺基結合的基(C2-C3烷基羰基胺基)，更適合為甲基羰基胺基。 In the present invention, the "mono-C 2 -C 7 alkylcarbonylamino group" is a group in which one of the above-mentioned "C 2 -C 7 alkylcarbonyl groups" is bonded to an amine group. For example, a methylcarbonylamino group, an ethylcarbonylamino group, a propylcarbonylamino group, or a t-butylcarbonylamino group. Suitably of a "C 2 -C 3 alkylcarbonyl" group (C 2 -C 3 alkylcarbonyl group) with an amine in combination, more suitably methyl carbonyl group.

於本發明，「四氫呋喃基」係適合為3-四氫呋喃基。 In the present invention, "tetrahydrofuranyl" is suitably 3-tetrahydrofuranyl.

於本發明，「氧唉基氧基」係適合為3-氧唉基氧基。 In the present invention, "oxycarbonyloxy group" is suitably a 3-oxomethoxy group.

於本發明，「四羥基環己基」係適合為1,3,4,5-四羥基環己基。 In the present invention, "tetrahydroxycyclohexyl" is suitably 1,3,4,5-tetrahydroxycyclohexyl.

於本發明，「可獨立經1至4個選自取代基群組A的基取代的哌啶-1-基」係哌啶-1-基或獨立經1至4個選自取代基群組A的基取代的哌啶-1-基。適合為哌啶-1-基或4位經1個式-L-R8所表示的基取代的哌啶-1-基。 In the present invention, "piperidin-1-yl which may be independently substituted with 1 to 4 groups selected from the substituent group A" is piperidin-1-yl or independently from 1 to 4 selected from the group of substituents A radically substituted piperidin-1-yl group of A. It is suitably a piperidin-1-yl group which is a piperidin-1-yl group or a 4-position represented by the formula represented by the formula -LR 8 .

於本發明，「可獨立經1至4個選自取代基群組A的基取代的哌啶-3-基」係哌啶-3-基或獨立經1至4個選自取代基群組A的基取代的哌啶-3-基。適合為1位經1個式-L-R8所表示的基取代的哌啶-3-基。 In the present invention, "piperidin-3-yl substituted with 1 to 4 substituents selected from substituent group A" is a piperidin-3-yl group or independently of 1 to 4 selected from the group of substituents. A radically substituted piperidin-3-yl group of A. Suitable is a piperidin-3-yl group substituted by one group represented by the formula -LR 8 .

於本發明，「可獨立經1至4個選自取代基群組A的基取代的哌啶-4-基」係哌啶-4-基或獨立經1至4個選自取代基群組A的基取代的哌啶-4-基。適合為1位經1個式-L-R8所表示的基取代的哌啶-4-基，更適合為1-乙醯基哌啶-4-基、1-[(1S)-1-羥基乙基羰基]哌啶-4-基、1-甲氧基甲基羰基哌啶-4-基、1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基、1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基、1-(甲基胺基草醯基)哌啶-4-基或1-(2,2-二 氟乙基胺基草醯基)哌啶-4-基。 In the present invention, "piperidin-4-yl substituted with 1 to 4 groups selected from substituent group A" is piperidin-4-yl or independently from 1 to 4 selected from the group of substituents. A radically substituted piperidin-4-yl group of A. Suitable for a 1-piperidin-4-yl group substituted by one group represented by the formula -LR 8 , more preferably 1-ethylhydrazinopiperidin-4-yl, 1-[(1S)-1-hydroxyethyl Carbocarbonyl]piperidin-4-yl, 1-methoxymethylcarbonylpiperidin-4-yl, 1-[(2S)-1,4-di Alkyl-2-ylcarbonyl]piperidin-4-yl, 1-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl, 1 - (Methylaminopyristyl)piperidin-4-yl or 1-(2,2-difluoroethylaminoglycosyl)piperidin-4-yl.

於本發明，「可獨立經1至4個選自取代基群組A的基取代的1,2,3,6-四氫吡啶-4-基」係1,2,3,6-四氫吡啶-4-基或獨立經1至4個選自取代基群組A的基取代的1,2,3,6-四氫吡啶-4-基。適合為1位經1個式-L-R8所表示的基取代的1,2,3,6-四氫吡啶-4-基，更適合為1-乙醯基-1,2,3,6-四氫吡啶-4-基、1-[(1S)-1-羥基乙基羰基]-1,2,3,6-四氫吡啶-4-基、1-甲基胺基草醯基-1,2,3,6-四氫吡啶-4-基或1-乙基胺基草醯基-1,2,3,6-四氫吡啶-4-基。 In the present invention, "1,2,3,6-tetrahydropyridin-4-yl which may be independently substituted with 1 to 4 groups selected from the substituent group A" is 1,2,3,6-tetrahydrogen. Pyridin-4-yl or 1,2,3,6-tetrahydropyridin-4-yl optionally substituted with 1 to 4 groups selected from the group of substituents A. It is suitable for the 1,2,3,6-tetrahydropyridin-4-yl group substituted by one group represented by the formula -LR 8 , and more preferably 1-ethylindenyl-1,2,3,6- Tetrahydropyridin-4-yl, 1-[(1S)-1-hydroxyethylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl, 1-methylaminoglycolyl-1 , 2,3,6-tetrahydropyridin-4-yl or 1-ethylaminoglycolyl-1,2,3,6-tetrahydropyridin-4-yl.

於本發明，「可獨立經1至4個選自取代基群組A的基取代的哌-1-基」係哌-1-基或獨立經1至4個選自取代基群組A的基取代的哌-1-基。適合為4位經1個式-L-R8所表示的基取代的哌-1-基，更適合為4-乙醯基哌-1-基。 In the present invention, "a pipe which can be substituted independently with 1 to 4 groups selected from the substituent group A -1-yl" -1-yl or independently substituted via 1 to 4 groups selected from substituent group A -1- base. Suitable for 4-position substituted by a group represented by the formula -LR 8 -1-yl, more suitable for 4-ethylhydrazine -1- base.

於本發明，「可獨立經1至4個選自取代基群組A的基取代的啉-4-基」係啉-4-基或獨立經1至4個選自取代基群組A的基取代的啉-4-基。適合為啉-4-基、或2位或3位經1個式-L-R8所表示的基取代的啉-4-基。 In the present invention, "may be independently substituted with 1 to 4 groups selected from the group of substituents A Phenyl-4-yl Orolin-4-yl or independently substituted with from 1 to 4 groups selected from substituent group A Andolin-4-yl. Suitable for a phenyl-4-yl group, or a 2- or 3-position substituted with one group represented by the formula -LR 8 Andolin-4-yl.

於本發明，「可獨立經1至4個選自取代基群組A的基取代的吡咯啶-1-基」係吡咯啶-1-基或獨立經1至4個選自取代基群組A的基取代的吡咯啶-1-基。適合為3位經1個式-L-R8所表示的基取代的吡咯啶-1-基。 In the present invention, "pyrrolidin-1-yl" which may be independently substituted with 1 to 4 groups selected from the substituent group A is pyrrolidin-1-yl or independently from 1 to 4 selected from the group of substituents A radically substituted pyrrolidin-1-yl group of A. It is suitably a pyrrolidin-1-yl group substituted at the 3-position by one group represented by the formula -LR 8 .

於本發明，「可獨立經1至4個選自取代基群組A的基取代的吡咯啶-3-基」係吡咯啶-3-基或獨立經1 至4個選自取代基群組A的基取代的吡咯啶-3-基。適合為1位經1個式-L-R8所表示的基取代的吡咯啶-3-基。 In the present invention, "pyrrolidin-3-yl" pyrrolidin-3-yl which may be independently substituted with 1 to 4 groups selected from the substituent group A or independently from 1 to 4 selected from the group of substituents A radically substituted pyrrolidin-3-yl group of A. It is suitably a pyrrolidin-3-yl group substituted by one group represented by one formula -LR 8 .

於本發明，「可獨立經1或2個C1-C6烷基取代的吡咯-2-基」係吡咯-2-基或獨立經1或2個C1-C6烷基取代的吡咯-2-基。適合為1-甲基-吡咯-2-基。 In the present invention, "can be independently substituted with 1 or 2 C 1 -C 6 alkyl substituted pyrrol-2-yl" line-2-yl or independently substituted with 1 or 2 C 1 -C 6 alkyl-substituted pyrrole -2-yl. Suitable as 1-methyl-pyrrol-2-yl.

於本發明，「可獨立經1或2個C1-C6烷基取代的啉-2-基」係啉-2-基或獨立經1或2個C1-C6烷基取代的啉-2-基。適合為啉-2-基、4-甲基-啉-2-基或4-乙基-啉-2-基。 In the present invention, "may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups. Phenyl-2-yl Phenyl-2-yl or independently substituted by 1 or 2 C 1 -C 6 alkyl Porphyrin-2-yl. Suitable for Porphyrin-2-yl, 4-methyl- Orido-2-yl or 4-ethyl- Porphyrin-2-yl.

於本發明，「可獨立經1或2個C1-C6烷基取代的咪唑-5-基」係咪唑-5-基或獨立經1或2個C1-C6烷基取代的咪唑-5-基。適合為咪唑-5-基或1-甲基-咪唑-5-基。 In the present invention, "imidazol-5-yl which may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups" is an imidazole-5-yl group or an imidazole substituted independently with 1 or 2 C 1 -C 6 alkyl groups. -5-based. Suitable as imidazole-5-yl or 1-methyl-imidazole-5-yl.

於本發明，「可獨立經1至5個選自鹵素原子、C1-C6烷基、羥基、C1-C6羥基烷基、C2-C7烷基羰基及側氧基的基取代的吡咯啶-2-基」係吡咯啶-2-基或獨立經1至5個選自鹵素原子、C1-C6烷基、羥基、C1-C6羥基烷基、C2-C7烷基羰基及側氧基的基取代的吡咯啶-2-基。適合為獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基，更適合為4,4-二氟-1-甲基吡咯啶-2-基。 In the present invention, "1 to 5 groups independently selected from a halogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, a C 1 -C 6 hydroxyalkyl group, a C 2 -C 7 alkylcarbonyl group and a pendant oxy group may be independently used. Substituted pyrrolidin-2-yl"pyrrolidin-2-yl or independently from 1 to 5 selected from a halogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, a C 1 -C 6 hydroxyalkyl group, a C 2 - A C 7 alkylcarbonyl group and a pendant alkyl substituted pyrrolidin-2-yl group. Suitable as a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group, more preferably 4,4-difluoro-1-methylpyrrolidine-2- base.

於本發明，適合的R1為C1-C6烷基，更適合的R1為甲基或乙基。 In the present invention, a suitable R 1 is a C 1 -C 6 alkyl group, and a more suitable R 1 is a methyl group or an ethyl group.

於本發明，適合的R2為氫原子。 In the present invention, a suitable R 2 is a hydrogen atom.

於本發明，適合的R3為氫原子。 In the present invention, a suitable R 3 is a hydrogen atom.

於本發明，適合的R4為C1-C6烷基，更適合的R4為甲基。 In the present invention, a suitable R 4 is a C 1 -C 6 alkyl group, and a more suitable R 4 is a methyl group.

於本發明，適合的R5為氫原子或C1-C6烷基，更適合的R5為氫原子或甲基，進一步更適合的R5為氫原子。 In the present invention, a suitable R 5 is a hydrogen atom or a C 1 -C 6 alkyl group, and more preferably R 5 is a hydrogen atom or a methyl group, and further more suitably R 5 is a hydrogen atom.

於本發明，適合的R6為氫原子。 In the present invention, a suitable R 6 is a hydrogen atom.

於本發明，適合的Q1為式=CH-所表示的基。 In the present invention, a suitable Q 1 is a group represented by the formula =CH-.

於本發明，適合的Q2為式=CH-所表示的基。 In the present invention, a suitable Q2 is a group represented by the formula =CH-.

於本發明，適合的式-U-T-所表示的基為式-CH2-CH2-所表示的基。 In the present invention, a suitable group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 -.

於本發明，適合的Y為氧原子。 In the present invention, a suitable Y is an oxygen atom.

於本發明，適合的R7為氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基，更適合的R7為氫原子或甲基。 In the present invention, a suitable R 7 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group, and more preferably R7 is a hydrogen atom or a methyl group.

於本發明，適合的V為氮原子、式=CH-所表示的基或式=C(CH3)-所表示的基。 In the present invention, a suitable V is a nitrogen atom, a group represented by the formula =CH- or a group represented by the formula =C(CH 3 )-.

於本發明，適合的L為羰基或草醯基。 In the present invention, a suitable L is a carbonyl group or a sulfhydryl group.

於本發明，適合的R8為C1-C6烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、啉-2-基或獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基，更適合的R8為甲基、1-羥基乙基、甲氧基甲基、甲基胺基、乙基胺基、2,2-二氟乙基胺基、啉-2-基或4,4-二氟-1-甲基吡咯啶-2-基。 In the present invention, a suitable R 8 is a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, an amine group. , a mono-C 1 -C 6 alkylamino group, a mono-C 1 -C 6 halogenated alkylamino group, a di-(C 1 -C 6 alkyl)amino group, a phenyl-2-yl group or a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group, more preferably R 8 is a methyl group, a 1-hydroxyethyl group, Methoxymethyl, methylamino, ethylamino, 2,2-difluoroethylamino, Orido-2-yl or 4,4-difluoro-1-methylpyrrolidin-2-yl.

於本發明，適合的取代基群組A為式-L-R8所表示的基，更適合的取代基群組A為乙醯基、(1S)-1-羥基乙基羰基、甲氧基甲基羰基、(2S)-1,4-二烷-2-基羰基、[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基、甲基胺 基草醯基、乙基胺基草醯基或2,2-二氟乙基胺基草醯基。 In the present invention, a suitable substituent group A is a group represented by the formula -LR 8 , and a more suitable substituent group A is an ethyl hydrazino group, a (1S)-1-hydroxyethylcarbonyl group, a methoxymethyl group. Carbonyl, (2S)-1,4-di Alk-2-ylcarbonyl, [(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl, methylaminoglycine, ethylaminoglycine or 2, 2-Difluoroethylaminoglyoxime.

於本發明，適合的E為經1個式-L-R8所表示的基取代的哌啶-4-基、1,2,3,6-四氫吡啶-4-基或哌-1-基，更適合的E為1-乙醯基哌啶-4-基、1-[(1S)-1-羥基乙基羰基]哌啶-4-基、1-甲氧基甲基羰基哌啶-4-基、1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基、1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基、1-(甲基胺基草醯基)哌啶-4-基、1-(2,2-二氟乙基胺基草醯基)哌啶-4-基、1-乙醯基-1,2,3,6-四氫吡啶-4-基、1-[(1S)-1-羥基乙基羰基]-1,2,3,6-四氫吡啶-4-基、1-甲基胺基草醯基-1,2,3,6-四氫吡啶-4-基、1-乙基胺基草醯基-1,2,3,6-四氫吡啶-4-基或4-乙醯基哌-1-基。 In the present invention, a suitable E is a group-substituted piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl or piperidyl represented by the formula -LR 8 -1-yl, more suitable E is 1-ethenylpiperidin-4-yl, 1-[(1S)-1-hydroxyethylcarbonyl]piperidin-4-yl, 1-methoxymethyl Carbonylpiperidin-4-yl, 1-[(2S)-1,4-di Alkyl-2-ylcarbonyl]piperidin-4-yl, 1-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl, 1 -(Methylaminopyristyl)piperidin-4-yl, 1-(2,2-difluoroethylaminooxalyl)piperidin-4-yl, 1-ethylindenyl-1,2 ,3,6-tetrahydropyridin-4-yl, 1-[(1S)-1-hydroxyethylcarbonyl]-1,2,3,6-tetrahydropyridin-4-yl, 1-methylamino Phytosyl-1,2,3,6-tetrahydropyridin-4-yl, 1-ethylaminoglycolyl-1,2,3,6-tetrahydropyridin-4-yl or 4-ethyl hydrazine Kipi -1- base.

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽具有全部的異構物(酮-烯醇異構物、非鏡像異構物、光學異構物、轉動異構物等)。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has all of the isomers (keto-enol isomer, non-image isomer, optical isomer, and rotational isomer) Wait).

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽因於其分子內存有不對稱碳原子，故具有各種之異構物。關於本發明之化合物，此等之異構物及此等之異構物之混合物全部以單一式，即以通式(I)表示。因此，本發明為亦包含此等之異構物及此等之異構物的任意比率之混合物全部者。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers due to the presence of an asymmetric carbon atom in its molecule. With respect to the compounds of the present invention, such isomers and mixtures of such isomers are all represented in a single formula, i.e., in formula (I). Accordingly, the present invention is intended to include a mixture of such isomers and any ratios of such isomers.

如上述的立體異構物可藉由使用光學活性的原料化合物、或使用不對稱合成或不對稱誘導之手法來合成與本發明有關的化合物、或者依其冀望將合成的與本發明有關的化合物藉由使用通常之光學離析法或分離 法進行單離而可加以獲得。 The stereoisomers as described above may be synthesized by using an optically active starting compound or by asymmetric synthesis or asymmetric induction to synthesize a compound related to the present invention or a compound related to the present invention which is expected to be synthesized. By using the usual optical separation method or separation The law can be obtained by arbitrarily separating.

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽於構成此種化合物的原子之1個以上亦可含有原子同位素之非天然比率。就原子同位素而言，例如，可列舉氘(2H)、氚(3H)、碘-125(125I)或碳-14(14C)等。又，前述化合物係例如，可經氚(3H)、碘-125(125I)或碳-14(14C)等之放射性同位素被放射性標識。被放射性標識的化合物有用於作為治療或預防劑、研究試藥，例如，分析試藥、及診斷劑，例如，活體內影像診斷劑。本發明之化合物之全部的同位素變異種不論是否為放射性，皆被包含於本發明之範圍。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an atomic isotope ratio of one or more of the atoms constituting the compound. Examples of the atomic isotope include ruthenium ( 2 H), ruthenium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). In addition, the compound is for example, may be tritium (3 H), iodine -125 (125 I) or carbon -14 (14 C) and other radioactive isotopes are radioactive identified. The radiolabeled compound is useful as a therapeutic or prophylactic agent, a research reagent, for example, an analytical reagent, and a diagnostic agent, for example, an in vivo imaging diagnostic agent. All isotopic variations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

「其藥學上可容許的鹽」係指不具有顯著毒性，且可使用作為醫藥的鹽。本發明之通式(I)所表示的化合物於具有鹼性基的情形，藉由使其與酸反應可作成鹽，又於具有酸性基的情形，藉由使其與鹼反應可作成鹽。 The "pharmaceutically acceptable salt" means a salt which is not highly toxic and can be used as a medicine. When the compound represented by the formula (I) of the present invention has a basic group, it can be used as a salt by reacting it with an acid, and in the case of having an acidic group, it can be formed into a salt by reacting it with a base.

就基於鹼性基的鹽而言，可列舉例如，如氟化氫酸鹽、鹽酸鹽、溴化氫酸鹽、碘化氫酸鹽之類的鹵化氫酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等之無機酸鹽；如甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽之類的C1-C6烷基磺酸鹽、如苯磺酸鹽、p-甲苯磺酸鹽之類的芳基磺酸鹽、乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、琥珀酸鹽、檸檬酸鹽、抗壞血酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽等之有機酸鹽；及如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之類 的胺基酸鹽。 Examples of the basic group-based salt include, for example, hydrogen halides such as hydrogen fluoride salts, hydrochloride salts, hydrogen bromide salts, and hydrogen iodides, nitrates, perchlorates, and the like. a mineral acid salt of a sulfate, a phosphate or the like; a C 1 -C 6 alkyl sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate, such as a benzenesulfonate, p Aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, butylene An organic acid salt of an acid salt or the like; and an amino acid salt such as a glycinate, an amidate, a arginine, an alanate, a glutamate or an aspartate.

另一方面，就基於酸性基的鹽而言，可列舉例如，如鈉鹽、鉀鹽、鋰鹽之類的鹼金屬鹽、如鈣鹽、鎂鹽之類的鹼土類金屬鹽、鋁鹽、鐵鹽等之金屬鹽；如銨鹽之類的無機鹽、如t-丁基胺鹽、二異丙基胺鹽、t-辛基胺鹽、二苄基胺鹽、啉鹽、葡糖胺(glucosamine)鹽、苯基甘胺酸烷基酯鹽、乙二胺鹽、N-甲基葡萄糖胺(N-methylglucamine)鹽、胍鹽、二乙基胺鹽、三乙基胺鹽、二環己基胺鹽、N,N’-二苄基伸乙基二胺鹽、氯普魯卡因鹽(chloroprocaine)、普魯卡因鹽、二乙醇胺鹽、N-苄基苯乙基胺鹽、哌鹽、四甲基銨鹽、參(羥甲基)胺基甲烷鹽之類的有機鹽等之胺鹽；及如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之類的胺基酸鹽。 On the other hand, the acid group-based salt may, for example, be 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, or an aluminum salt. a metal salt such as an iron salt; an inorganic salt such as an ammonium salt, such as t-butylamine salt, diisopropylamine salt, t-octylamine salt, dibenzylamine salt, A porphyrin salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, an N-methylglucamine salt, a phosphonium salt, a diethylamine salt, a triethyl sulphate Base amine salt, dicyclohexylamine salt, N,N'-dibenzylethylidene diamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl phenyl Base amine salt An amine salt such as an organic salt such as a salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt; and such as a glycinate, an amide salt, a arginine salt, an alanine salt, Amino acid salt such as glutamate or aspartate.

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽係放置於大氣中、或藉由作再結晶，而有吸收水分、有吸附水吸附，成為水合物的情形，此種水合物亦包含於本發明之鹽。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is placed in the atmosphere or is recrystallized to absorb water and adsorb water to form a hydrate. A hydrate is also included in the salt of the present invention.

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽有吸收其他某些溶媒，而成為溶媒合物的情形，此種溶媒合物亦被包含於本發明之鹽。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be a solvent if it absorbs some other solvent, and such a solvent is also included in the salt of the present invention.

本發明之通式(I)所表示的化合物或其藥學上可容許的鹽具有選擇性且優異的Th17細胞之分化抑制作用及IL-17產生抑制作用，有用於與自體免疫疾病等之 RORγt有關的疾病或與IL-17產生有關的病態發病的癌之治療及/或預防。就具體的疾病而言，為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病(克隆氏病或潰瘍性大腸炎等)、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌。就較佳的疾病而言，為乾癬、乾癬性關節炎、僵直性脊椎炎、修格連氏症候群或慢性阻塞性肺病(COPD)，尤其為乾癬或乾癬性關節炎。又，本發明之通式(I)所表示的化合物或其藥學上可容許的鹽被期待有於已存的治療法中為不可能之可選擇性地預防及治療Th17細胞之異常的效果。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has selective and excellent Th17 cell differentiation inhibitory action and IL-17 production inhibitory action, and is useful for autoimmune diseases and the like. Treatment and/or prevention of RORγt-related diseases or pathological cancers associated with IL-17 production. For specific diseases, dryness, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease or ulcerative colitis, etc.), Xiagelian Syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, Spherical nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. In the case of a preferred disease, dryness, dryness arthritis, ankylosing spondylitis, Sjogren's syndrome or chronic obstructive pulmonary disease (COPD), especially dry or dry arthritis. Further, the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is expected to have an effect of selectively preventing and treating abnormalities of Th17 cells which are impossible in the existing therapeutic method.

於本發明，「預防」係意指在藉由遺傳的背景或慢性炎症等，而被診斷為本發明作為對象的疾病之發病風險高的情形，抑制或延遲此疾病之發病。已知於自體免疫疾病的情形，為藉由單核苷酸多型性(SNPs)或基因變異等，而可診斷發病風險的疾病。又，已知於大腸癌的情形，因大腸炎為慢性地持續，而大腸癌之風險顯著提高。本發明之通式(I)所表示的化合物或其藥學上可容許的鹽因具有選擇性地且優異的Th17細胞之分化抑制作用及IL-17產生抑制作用，被期待藉由對被診斷為此種疾病之發病風險高的患者進行預防性投予，而抑制或延遲發病的效果。 In the present invention, the term "prevention" refers to a situation in which the risk of developing a disease which is diagnosed as a subject by a genetic background or chronic inflammation is high, and the onset of the disease is suppressed or delayed. It is known that in the case of an autoimmune disease, it is a disease which can diagnose a risk of onset by single nucleotide polymorphism (SNPs) or gene mutation. Further, it is known that in the case of colorectal cancer, colitis is chronically sustained, and the risk of colorectal cancer is remarkably improved. The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is expected to be diagnosed by the pair because it has selective and excellent differentiation inhibitory action of Th17 cells and IL-17 production inhibitory action. Patients with a high risk of developing such diseases are administered prophylactically to inhibit or delay the onset of the disease.

[實施發明之形態] [Formation of the Invention]

本發明之通式(I)所表示的化合物可按照以下記載的A法至K法來製造。 The compound represented by the formula (I) of the present invention can be produced by the methods A to K described below.

於下述A法至K法之各步驟之反應所使用的溶媒只要不抑制反應，且可某程度溶解起始原料者即可，並未特別限定，例如，可選自下述溶媒群組。溶媒群組包含戊烷、己烷、辛烷、石油醚、石油英(ligroin)、環己烷之類的烴類；甲醯胺、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基-2-吡咯啶酮(N-methyl-2-pyrrolidone)、N-甲基-2-吡咯烷酮(N-methyl-2-pyrrolidinone)、六甲基磷酸三醯胺之類的醯胺類；二乙基醚、二異丙基醚、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷、二乙二醇二甲基醚、環戊基甲基醚之類的醚類；甲醇、乙醇、n-丙醇、i-丙醇、n-丁醇、2-丁醇、2-甲基-1-丙醇、t-丁醇、異戊醇、二乙二醇、甘油、辛醇、環己醇、甲基賽璐蘇之類的醇類；二甲基亞碸之類的亞碸類；環丁碸之類的碸類；乙腈、丙腈、丁腈、異丁腈之類的腈類；甲酸乙酯、乙酸乙酯、乙酸丙酯、乙酸丁酯、碳酸二乙酯之類的酯類；丙酮、甲基乙基酮、4-甲基-2-戊酮、甲基異丁基酮、異佛爾酮(isophorone)、環己酮之類的酮類；硝基乙烷、硝基苯之類的硝基化合物類；二氯甲烷、1,2-二氯乙烷、氯苯、二氯苯、氯仿、四氯化碳之類的鹵化烴 類；苯、甲苯、二甲苯之類的芳香族烴類；乙酸、甲酸、丙酸、丁醯基酸、三氟乙酸之類的羧酸類；N-甲基啉、三乙基胺、三丙基胺、三丁基胺、二異丙基乙基胺、二環己基胺、N-甲基哌啶、吡啶、2,6-二甲基吡啶、4-吡咯啶基吡啶、甲基吡啶、4-(N,N-二甲基胺基)吡啶、2,6-二(t-丁基)-4-甲基吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)、1,8-二氮雜雙環[5.4.0]十一-7-烯(DBU)、哌啶之類的胺類；水；及此等之混合溶媒。 The solvent to be used in the reaction of each of the following steps A to K is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, it may be selected from the following solvent groups. The solvent group comprises hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N,N-dimethylformamide, N,N- Dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone, hexamethyl phosphate Indoleamines such as guanamine; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-two An ether such as an alkane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether or cyclopentyl methyl ether; methanol, ethanol, n-propanol, i-propanol, n- Alcohols such as butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, methyl cedar Anthraquinones such as dimethyl hydrazine; hydrazines such as cyclobutyl hydrazine; nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; ethyl formate, ethyl acetate, and acetonitrile Esters such as ester, butyl acetate, diethyl carbonate; acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone, ring Ketones such as ketone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride Halogenated hydrocarbons such as aromatic hydrocarbons such as benzene, toluene, and xylene; carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid, and trifluoroacetic acid; N-methyl Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4- Pyrrolidinylpyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-di Methylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), an amine such as piperidine; water; and a mixed solvent thereof.

於下述A法至K法之各步驟之反應所使用的鹼係例如，碳酸鈉、碳酸鉀、碳酸鋰、碳酸銫之類的鹼金屬碳酸鹽類；碳酸氫鈉、碳酸氫鉀、碳酸氫鋰之類的鹼金屬碳酸氫鹽類；乙酸鈉、乙酸鉀、乙酸鋰、乙酸銫之類的鹼金屬乙酸鹽類；氫化鋰、氫化鈉、氫化鉀之類的鹼金屬氫化物類；氫氧化鈉、氫氧化鉀、氫氧化鋇、氫氧化鋰之類的鹼金屬氫氧化物類；磷酸鈉、磷酸鉀之類的鹼金屬磷酸鹽類；L-脯胺酸鈉、L-脯胺酸鉀之類的鹼金屬鹽類；氟化鈉、氟化鉀之類的鹼金屬氟化物類等之無機鹼類；甲醇鈉、乙醇鈉、三級丁醇鈉、三級丁醇鉀之類的鹼金屬烷氧化物類；三甲基矽烷醇鈉(sodium trimethyl siloxide)、三甲基矽烷醇鉀、三甲基矽烷醇鋰之類的鹼金屬三烷基矽烷醇類；N-甲基啉、三乙基胺、三丙基胺、三丁基胺、二異丙基乙基胺、二環己基胺、N-甲基哌啶、吡啶、2,6-二甲基吡啶、柯林鹼(collidine) 、4-吡咯啶基吡啶、甲基吡啶、4-(N,N-二甲基胺基)吡啶、2,6-二(t-丁基)-4-甲基吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN)、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)、1,8-二氮雜雙環[5.4.0]十一-7-烯(DBU)之類的有機鹼類；二異丙基醯胺鋰、六甲基二矽氮烷鋰(lithium hexamethyldisilazane)、六甲基二矽氮烷鈉之類的鹼金屬醯胺類；或脯胺酸之類的胺基酸。 The base used in the reaction of each of the following steps A to K is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate; sodium hydrogencarbonate, potassium hydrogencarbonate or hydrogencarbonate. Alkali metal hydrogencarbonates such as lithium; alkali metal acetates such as sodium acetate, potassium acetate, lithium acetate, cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; sodium L-guanidinate, potassium L-proline An alkali metal salt such as an alkali metal such as sodium fluoride or potassium fluoride; a base such as sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; Metal alkoxides; alkali trimethyl siloxides, potassium trimethyl decoxide, lithium trimethyl stanols, alkali metal trialkyl stanols; N-methyl Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, Colin Collidine, 4-pyrrolidinylpyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quin Porphyrin, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); lithium diisopropyl guanamine, hexa An alkali metal amide such as lithium hexamethyldisilazane or sodium hexamethyldisodium sulphate; or an amino acid such as lysine.

於下述A法至K法之各步驟之反應所使用的縮合劑係例如，偶氮二甲酸二乙酯-三苯基膦之類的偶氮二甲酸二低級烷基酯-三苯基膦類；1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺、1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽、N,N’-二環己基碳化二亞胺之類的碳化二亞胺衍生物；2-氯-1-甲基吡啶鎓碘化物之類的2-鹵-1-低級烷基吡啶鎓鹵化物類；疊氮磷酸二苯酯(diphenylphosphoryl azide)之類的疊氮磷酸二芳基酯類；二乙基氯化磷醯之類的氯化磷醯類；N,N’-碳二咪唑之類的咪唑衍生物；O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯、(1H-苯并三唑-1-基氧基)三吡咯烷鏻六氟磷酸酯之類的苯并三唑衍生物；或氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓之類的氯化啉鎓衍生物。 The condensing agent used in the reaction of each of the following steps A to K is, for example, diazoalkyl azodicarboxylate-triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride a carbodiimide derivative such as N,N'-dicyclohexylcarbodiimide; a halogenated 2-halo-1-lower alkylpyridinium such as 2-chloro-1-methylpyridinium iodide Species; diarylphosphoryl azide such as diphenylphosphoryl azide; phosphonium chloride such as diethylphosphonium chloride; N,N'-carbodiimidazole Imidazole derivatives of the class; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, (1H-benzotriazole- a benzotriazole derivative such as 1-yloxy)tripyrrolidinium hexafluorophosphate; or 4-(4,6-dimethoxy-1,3,5-trichloride) -2-yl)-4-methyl Chlorination A guanidine derivative.

於下述A法至K法之各步驟之反應，反應溫度係依溶媒、起始原料、試藥等而異，反應時間係依溶媒、起始原料、試藥、反應溫度等而異。 The reaction temperature varies depending on the solvent, the starting material, the reagent, and the like in the respective steps of the following A to K methods, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like.

於下述A法至K法之各步驟之反應，反應結束後，各目的化合物係按照通常方法，自反應混合物採取。例如，將反應混合物適當中和，又，於不溶物存在的情形藉由過濾去除後，添加乙酸乙酯之類與水不混和的有機溶媒，將含目的化合物的有機層分離，以水等洗淨後，以無水硫酸鎂、無水硫酸鈉等乾燥，過濾後，藉由餾除溶劑而獲得。獲得的目的化合物若必要的話，可適當組合通常方法，例如再結晶、再沉澱、層析(例如，使用矽膠、氧化鋁、鎂-矽膠系之Florisil、SO3H-silica(富士SILYSIA製)之類的載體的吸附管柱層析法；使用Sephadex LH-20(Pharmacia公司製)、Amberlite XAD-11(Rohm and Haas公司製)、Diaion HP-20(三菱化學公司製)之類的載體的分配管柱層析等之合成吸附劑的方法；使用離子交換層析的方法；利用矽膠或烷基化矽膠的順相‧逆相管柱層析法(適合為高速液體層析)，以適當溶離劑加以溶析)等之通常於有機化合物之分離純化上慣用的方法加以適宜組合，而可分離、純化。於溶媒中不溶的目的化合物可藉由將獲得的固體之粗生成物以溶媒洗淨而加以純化。又，各步驟之目的化合物亦可不純化而直接使用於下一反應。 After the reaction of each step of the following methods A to K, after completion of the reaction, each compound of interest is taken from the reaction mixture according to a usual method. For example, the reaction mixture is appropriately neutralized, and after being removed by filtration in the presence of insoluble matter, an organic solvent which is not mixed with water such as ethyl acetate is added, and the organic layer containing the objective compound is separated and washed with water or the like. After drying, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, and after filtration, it is obtained by distilling off a solvent. The obtained target compound may be appropriately combined with a usual method such as recrystallization, reprecipitation, and chromatography (for example, using silica gel, alumina, magnesium-ruthenium-based Florisil, SO3H-silica (Fuji SILYSIA), etc.) Adsorption column chromatography of the carrier; distribution column of a carrier such as Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas Co., Ltd.), Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) a method of synthesizing an adsorbent by chromatography or the like; a method using ion exchange chromatography; a cis phase ‧ reverse phase column chromatography using tannin or alkylated tantalum (suitable for high speed liquid chromatography), and a suitable dissolving agent The methods conventionally used for the separation and purification of organic compounds, such as elution and the like, are appropriately combined and can be isolated and purified. The objective compound which is insoluble in the solvent can be purified by washing the obtained crude product as a solvent. Further, the objective compound of each step can be directly used in the next reaction without purification.

於下述A法至K法之各步驟之反應，R1、R2、R3、R4、R5、R6、R7、E、Q1、Q2及V表示與前述者相同之意義。R3a係表示除了R3之基所含的羥基或羧基為可經保護的羥基或羧基之外，與R3之基之定義中的基為同樣的基。Ea係表示除了E之基所含的胺基、羥基及/或羧 基為可經保護的胺基、羥基及/或羧基之外，與E之基之定義中的基為同樣的基，再者，表示包含成為E之基所含的取代基之先驅物的基的E。R8表示C1-C6烷基或苄基。X1、X2、X3、X4及X5表示鹵素原子或三氟甲烷磺醯基。V係式=C(R7)-所表示的基，R6及R7不同時為氫原子，且X1為溴原子或碘原子的情形，X2適合為氯原子或溴原子。X3適合為溴原子或碘原子，更適合為碘原子。X4適合為溴原子、碘原子或三氟甲烷磺醯基。Tf表示三氟甲烷磺醯基。 In the reaction of each of the following steps A to K, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E, Q 1 , Q 2 and V represent the same as the above. significance. R 3a represents the same group as the group in the definition of the group of R 3 except that the hydroxyl group or the carboxyl group contained in the group of R 3 is a protected hydroxyl group or a carboxyl group. E a is a group which is the same as the group in the definition of the group of E, except that the amine group, the hydroxyl group and/or the carboxyl group contained in the group of E are a protected amine group, a hydroxyl group and/or a carboxyl group. It is the E which contains the base of the precursor which becomes the substituent of the base of E. R 8 represents a C 1 -C 6 alkyl group or a benzyl group. X 1 , X 2 , X 3 , X 4 and X 5 represent a halogen atom or a trifluoromethanesulfonyl group. V is a group represented by C(R 7 )-, and when R 6 and R 7 are not simultaneously a hydrogen atom, and X 1 is a bromine atom or an iodine atom, X 2 is preferably a chlorine atom or a bromine atom. X 3 is suitably a bromine atom or an iodine atom, and is more suitably an iodine atom. X 4 is suitably a bromine atom, an iodine atom or a trifluoromethanesulfonyl group. Tf represents a trifluoromethanesulfonyl group.

A法係製造通式(I)所表示的化合物之中，式-U-T-所表示的基為式-CH2-CH2-所表示的基的通式(Ia)所表示的化合物的方法。 A method of producing a compound represented by the formula (Ia) wherein the group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 - among the compounds represented by the formula (I).

(A法) (A method)

A-I步驟 A-I step

本步驟係於溶媒中，藉由使通式(II)所表示的化合物與酸反應，而製造通式(III)所表示的化合物之鹽的步驟。 This step is a step of producing a salt of the compound represented by the formula (III) by reacting a compound represented by the formula (II) with an acid in a solvent.

於本步驟所使用的溶媒係適合為鹵化烴類，更適合 為二氯甲烷。 The solvent used in this step is suitable for halogenated hydrocarbons, and is more suitable. It is dichloromethane.

於本步驟所使用的酸係適合為乙酸類或質子酸類，更適合為三氟乙酸或鹽酸之1,4-二烷溶液。通式(III)所表示的化合物之鹽係表示使用鹽酸類的情形。 The acid used in this step is suitable for acetic acid or protic acid, more suitable for trifluoroacetic acid or hydrochloric acid 1,4-two Alkane solution. The salt of the compound represented by the formula (III) means a case where hydrochloric acid is used.

本步驟中的反應溫度通常為-10℃至50℃，適合為0℃至30℃。 The reaction temperature in this step is usually -10 ° C to 50 ° C, suitably 0 ° C to 30 ° C.

本步驟中的反應時間通常為1分鐘至24小時，適合為10分鐘至6小時。 The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 10 minutes to 6 hours.

A-II步驟 A-II step

本步驟係於溶媒中，縮合劑及鹼之存在下，藉由使通式(III)所表示的化合物之鹽，與通式(IV)所表示的化合物或其鹽反應，而製造通式(V)所表示的化合物的步驟 This step is carried out by reacting a salt of the compound represented by the formula (III) with a compound represented by the formula (IV) or a salt thereof in the presence of a condensing agent and a base in the presence of a condensing agent and a base to produce a formula ( Step of the compound represented by V)

於本步驟所使用的通式(IV)所表示的化合物之鹽係例如鹼金屬鹽、有機鹼鹽或銨鹽，適合為鈉鹽。 The salt of the compound represented by the formula (IV) used in this step is, for example, an alkali metal salt, an organic base salt or an ammonium salt, and is preferably a sodium salt.

於本步驟所使用的溶媒係適合為醯胺類、醚類、腈類或鹵化烴類，更適合為N,N-二甲基甲醯胺。 The solvent used in this step is suitably a guanamine, an ether, a nitrile or a halogenated hydrocarbon, and more preferably N,N-dimethylformamide.

於本步驟所使用的縮合劑係適合為1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽、N,N’-二環己基碳化二亞胺或4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基氯化啉鎓。 The condensing agent used in this step is suitably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide or 4-(4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl chlorination Porphyrin.

於本步驟所使用的鹼係適合為有機鹼類，更適合為N-甲基啉、三乙基胺或二異丙基乙基胺。 The base used in this step is suitable as an organic base, and is more suitable as an N-methyl group. Porphyrin, triethylamine or diisopropylethylamine.

本步驟中的反應溫度通常為0℃至60℃，適合為10℃至30℃。 The reaction temperature in this step is usually from 0 ° C to 60 ° C, suitably from 10 ° C to 30 ° C.

本步驟中的反應時間通常為5分鐘至48小時，適合為 1小時至24小時。 The reaction time in this step is usually 5 minutes to 48 hours, which is suitable for 1 hour to 24 hours.

A-III步驟 Step A-III

本步驟係於溶媒中、鈀觸媒及鹼之存在下，使通式(V)所表示的化合物與通式(VI)所表示的化合物反應後，依所冀望，藉由去除R3a及/或Ea中的胺基、羥基及/或羧基之保護基及/或藉由使用周知之有機化學的手法變換Ea之基所含的基，而製造通式(Ia)所表示的化合物的步驟。 This step is carried out by reacting a compound represented by the formula (V) with a compound represented by the formula (VI) in the presence of a solvent, a palladium catalyst and a base, and removing R 3a and/or as desired. Or a protecting group of an amine group, a hydroxyl group and/or a carboxyl group in E a and/or a compound represented by the formula (Ia) by converting a group contained in the group of E a by a well-known organic chemistry method step.

於本步驟所使用的溶媒係適合為醚類或芳香族烴類，更適合為1,2-二甲氧基乙烷或甲苯。 The solvent used in this step is suitably an ether or an aromatic hydrocarbon, more preferably 1,2-dimethoxyethane or toluene.

於本步驟所使用的鈀觸媒係適合為肆(三苯基膦)鈀(0)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(II)二氯甲烷錯合物或XPhos-Pd-G2(II)。 The palladium catalyst used in this step is suitably palladium (triphenylphosphine) palladium (0), [1,1 ' -bis(diphenylphosphino)ferrocene]palladium(II) dichloride. Methane complex or XPhos-Pd-G2 (II).

於本步驟所使用的鹼係適合為鹼金屬碳酸鹽類或鹼金屬磷酸鹽類，更適合為碳酸鈉、碳酸鈉水溶液、磷酸鉀或磷酸鉀水溶液。 The base used in this step is preferably an alkali metal carbonate or an alkali metal phosphate, and more preferably sodium carbonate, sodium carbonate aqueous solution, potassium phosphate or potassium phosphate aqueous solution.

本步驟中的反應溫度通常為室溫至200℃，適合為50℃至120℃。 The reaction temperature in this step is usually from room temperature to 200 ° C, suitably from 50 ° C to 120 ° C.

本步驟中的反應時間通常為5分鐘至24小時，適合為20分鐘至15小時。 The reaction time in this step is usually from 5 minutes to 24 hours, and is suitably from 20 minutes to 15 hours.

本步驟可於微波照射下進行。 This step can be carried out under microwave irradiation.

B法係製造於通式(I)所表示的化合物之中，式-U-T-所表示的基為式-CH2-CH2-所表示的基的通式(Ia)所表示的化合物的方法。 The method of the B method is a method of producing a compound represented by the formula (Ia) in which the group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 - .

(B法) (Method B)

B-I步驟 B-I step

本步驟係於溶媒中，鈀觸媒及鹼之存在下，藉由使通式(V)所表示的化合物與化合物(VII)反應，而製造通式(VIII)所表示的化合物的步驟。 This step is a step of producing a compound represented by the formula (VIII) by reacting a compound represented by the formula (V) with a compound (VII) in the presence of a palladium catalyst and a base in a solvent.

本步驟係可依據J.Org.Chem.1995,60，7508記載的方法來實施。 This step can be carried out in accordance with the method described in J. Org. Chem. 1995, 60, 7508.

B-II步驟 B-II step

本步驟係於溶媒中，鈀觸媒及鹼之存在下，藉由使通式(VIII)所表示的化合物與通式(IX)所表示的化合物反應，與A法之A-III步驟同樣地進行後，依所冀望，藉由去除R3a及/或Ea中的胺基、羥基及/或羧基之保護基及/或使用之周知之有機化學的手法變換Ea之基所含的基，而製造通式(Ia)所表示的化合物的步驟。 This step is carried out in the presence of a palladium catalyst and a base, and the compound represented by the formula (VIII) is reacted with a compound represented by the formula (IX) in the same manner as in the A-III step of the method A. After proceeding, the base contained in the group of E a is converted by removing the protecting group of the amine group, the hydroxyl group and/or the carboxyl group in R 3a and/or E a and/or the well-known organic chemistry using the desired method. And the step of producing the compound represented by the formula (Ia).

C法係製造於通式(I)所表示的化合物之中，式-U-T-所表示的基為式-CH2-CH2-所表示的基的通式(Ia)所表示的化合物的方法。 Process C is a method of producing a compound represented by the formula (Ia) wherein the group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 -, which is a compound represented by the formula (I) .

(C法) (Method C)

C-I步驟 C-I step

本步驟係於溶媒中，鈀觸媒及鹼之存在下，藉由使通式(II)所表示的化合物與通式(VI)所表示的化合物反應，與A法之A-III步驟同樣地進行，而製造通式(X)所表示的化合物的步驟。 This step is carried out in the presence of a palladium catalyst and a base, and the compound represented by the formula (II) is reacted with a compound represented by the formula (VI) in the same manner as in the A-III step of the method A. The step of producing the compound represented by the formula (X) is carried out.

C-II步驟 C-II step

本步驟係於溶媒中，藉由使通式(X)所表示的化合物與酸反應，與A法之A-I步驟同樣地進行，而製造通式(XI)所表示的化合物之鹽的步驟。通式(XI)所表示的化合物之鹽表示使用鹽酸類作為酸的情形。 This step is a step in which a compound represented by the formula (X) is reacted with an acid in the same manner as in the A-I step of the A method to produce a salt of the compound represented by the formula (XI). The salt of the compound represented by the formula (XI) represents a case where hydrochloric acid is used as the acid.

C-III步驟 C-III step

本步驟係於溶媒中，鹼之存在下，藉由使通式(XI)所表示的化合物之鹽與通式(IV)所表示的化合物或其鹽反應，藉由與A法之A-II步驟同樣地進行，而製造通式(Ia)所表示的化合物的步驟。 This step is carried out in a solvent, by reacting a salt of the compound represented by the formula (XI) with a compound represented by the formula (IV) or a salt thereof in the presence of a base, by A-II with the A method. The procedure is carried out in the same manner to produce a compound represented by the formula (Ia).

C-I步驟至C-III步驟之間，依所冀望，將R3a 及/或Ea中的胺基、羥基及/或羧基之保護基去除及/或將Ea之基所含的基以周知之有機化學的手法來變換。 Between the CI step and the C-III step, the protecting group of the amine group, the hydroxyl group and/or the carboxyl group in R 3a and/or E a is removed and/or the group contained in the group of E a is known as desired. The method of organic chemistry is to change.

D法係製造通式(I)所表示的化合物之中，式-U-T-所表示的基為式-CH=CH-所表示的基的通式(Ib)所表示的化合物的方法。 The method of the compound represented by the formula (I), wherein the group represented by the formula -U-T- is a compound represented by the formula (Ib) represented by the formula -CH=CH-.

(D法) (D method)

D-I步驟 D-I step

本步驟係於溶媒中，藉由使通式(Ia)所表示的化合物與氧化劑反應，而製造通式(Ib)所表示的化合物的步驟。 This step is a step of producing a compound represented by the formula (Ib) by reacting a compound represented by the formula (Ia) with an oxidizing agent in a solvent.

於本步驟所使用的通式(Ia)所表示的化合物可使用A法至C法來製造。 The compound represented by the formula (Ia) used in this step can be produced by the method A to method C.

於本步驟所使用的溶媒係適合為鹵化烴類，更適合為二氯甲烷或氯仿。 The solvent used in this step is suitably a halogenated hydrocarbon, more preferably dichloromethane or chloroform.

於本步驟所使用的氧化劑係適合為2,3-二氯-5,6-二氰基-p-苯醌。 The oxidizing agent used in this step is suitably 2,3-dichloro-5,6-dicyano-p-benzoquinone.

本步驟中的反應溫度係室溫至加熱回流溫度，加熱回流溫度係依溶媒而異。通常，5℃至150℃，適合為10℃至70℃。 The reaction temperature in this step is room temperature to heating under reflux temperature, and the heating reflux temperature varies depending on the solvent. Usually, it is 5 ° C to 150 ° C, suitably 10 ° C to 70 ° C.

本步驟中的反應時間通常為30分鐘至72小時，適合為1小時至24小時。 The reaction time in this step is usually from 30 minutes to 72 hours, and is suitably from 1 hour to 24 hours.

E法係製造於A法之A-I步驟及C法之C-I步驟 所使用的通式(II)所表示的化合物之中，Y為亞甲基的通式(XVI)所表示的化合物的方法。 The E method is manufactured in the A-I step of the A method and the C-I step of the C method. Among the compounds represented by the formula (II), a method in which Y is a methylene group represented by the formula (XVI).

(E法) (E law)

E-I步驟 E-I step

本步驟係於溶媒中，鹼之存在下，藉由使通式(XII)所表示的化合物與三氟甲烷磺醯基化劑反應，而製造通式(XIII)所表示的化合物的步驟。 This step is a step of producing a compound represented by the formula (XIII) by reacting a compound represented by the formula (XII) with a trifluoromethanesulfonyl amide in the presence of a base in a solvent.

於本步驟所使用的溶媒係適合為鹵化烴類，更適合為二氯甲烷。 The solvent used in this step is suitably a halogenated hydrocarbon, more preferably dichloromethane.

於本步驟所使用的鹼係適合為有機鹼類，更適合為吡啶。 The base used in this step is preferably an organic base, and more preferably pyridine.

於本步驟所使用的三氟甲烷磺醯基化劑係適合為三氟甲烷磺醯基化合物，更適合為三氟甲烷磺酸酐。 The trifluoromethanesulfonylation agent used in this step is suitably a trifluoromethanesulfonyl compound, more preferably trifluoromethanesulfonic anhydride.

本步驟中的反應溫度通常為-20℃至50℃，適合為0℃至20℃。 The reaction temperature in this step is usually from -20 ° C to 50 ° C, suitably from 0 ° C to 20 ° C.

本步驟中的反應時間通常為1分鐘至24小時，適合為10分鐘至6小時。 The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 10 minutes to 6 hours.

E-II步驟 E-II step

本步驟係於溶媒中、鈀觸媒及鹼之存在下，藉由使通式(XIII)所表示的化合物與化合物(VII)反應，與B法之B-I步驟同樣地進行，而製造通式(XIV)所表示的化合物的步驟。 This step is carried out in the same manner as the BI step of the B method by reacting the compound represented by the formula (XIII) with the compound (VII) in the presence of a solvent, a palladium catalyst and a base to produce a general formula ( The step of the compound represented by XIV).

於本步驟所使用的溶媒係適合為醯胺類、醚類、亞碸類或此等之混合溶媒，更適合為二甲氧基乙烷與二甲基亞碸之混合溶媒。 The solvent used in this step is preferably a guanamine, an ether, an anthracene or a mixed solvent thereof, and is more preferably a mixed solvent of dimethoxyethane and dimethylarylene.

E-III步驟 E-III step

本步驟係於溶媒中，鈀觸媒及鹼之存在下，藉由使通式(XIV)所表示的化合物與通式(XV)所表示的化合物反應，與A法之A-III步驟同樣地進行，而製造通式(XVI)所表示的化合物的步驟。 This step is carried out in the presence of a palladium catalyst and a base, and the compound represented by the formula (XIV) is reacted with a compound represented by the formula (XV) in the same manner as in the A-III step of the method A. The step of producing a compound represented by the formula (XVI) is carried out.

F法係製造於A法之A-I步驟及C法之C-I步驟所使用的通式(II)所表示的化合物之中，Y為氧原子的通式(XVIII)所表示的化合物的方法。 The F method is a method of producing a compound represented by the formula (XVIII) wherein Y is an oxygen atom among the compounds represented by the formula (II) used in the A-I step of the A method and the C-I step of the C method.

(F法) (F method)

F-I步驟 F-I step

本步驟係於溶媒中，銅觸媒、助觸媒及鹼之存在下，藉由使通式(XII)所表示的化合物與通式(XVII)所表示的化合物反應，而製造通式(XVIII)所表示的化合物的步驟。 This step is carried out by reacting a compound represented by the formula (XII) with a compound represented by the formula (XVII) in the presence of a copper catalyst, a cocatalyst and a base in a solvent to produce a formula (XVIII). The step of the compound represented.

於本步驟所使用的溶媒係適合為醯胺類或醚類，更適合為N,N-二甲基甲醯胺或1,4-二烷。 The solvent used in this step is suitable for guanamine or ether, and more suitable for N,N-dimethylformamide or 1,4-two. alkyl.

於本步驟所使用的銅觸媒係適合為碘化銅(I)。 The copper catalyst used in this step is suitably copper (I) iodide.

於本步驟所使用的助觸媒係適合為N,N-二甲基甘胺酸。 The cocatalyst used in this step is suitably N,N-dimethylglycine.

於本步驟所使用的鹼係適合為鹼金屬碳酸鹽類，更適合為碳酸銫。 The base used in this step is suitably an alkali metal carbonate, and more preferably cesium carbonate.

本步驟中的反應溫度通常為50℃至150℃，適合為80℃至110℃。 The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 80 ° C to 110 ° C.

本步驟中的反應時間通常為3小時至72小時，適合為12小時至48小時。 The reaction time in this step is usually from 3 hours to 72 hours, and is suitably from 12 hours to 48 hours.

又，本步驟係於溶媒中，鹼之存在下，藉由使通式(XII)所表示的化合物與通式(XVII)所表示的化合物反應，而製造通式(XVIII)所表示的化合物的步驟。 Further, this step is carried out by reacting a compound represented by the formula (XII) with a compound represented by the formula (XVII) in the presence of a base to produce a compound represented by the formula (XVIII). step.

於本步驟所使用的溶媒係適合為醯胺類或醚類，更適合為N,N-二甲基甲醯胺或1,4-二烷。 The solvent used in this step is suitable for guanamine or ether, and more suitable for N,N-dimethylformamide or 1,4-two. alkyl.

於本步驟所使用的鹼係適合為鹼金屬碳酸鹽類，更適合為碳酸銫。 The base used in this step is suitably an alkali metal carbonate, and more preferably cesium carbonate.

本步驟中的反應溫度通常為50℃至200℃，適合為80℃至160℃。 The reaction temperature in this step is usually from 50 ° C to 200 ° C, suitably from 80 ° C to 160 ° C.

本步驟中的反應時間通常為3小時至72小時，適合為12小時至48小時。 The reaction time in this step is usually from 3 hours to 72 hours, and is suitably from 12 hours to 48 hours.

本步驟可於微波照射下進行。此時之反應時間通常為10分鐘至3小時，適合為15分鐘至90分鐘。 This step can be carried out under microwave irradiation. The reaction time at this time is usually from 10 minutes to 3 hours, and is suitably from 15 minutes to 90 minutes.

G法係製造於C法之C-II步驟所使用的通式 (X)所表示的化合物之中，Y為氧原子的通式(XXI)所表示的化合物的方法。 The G method is a general formula used in the C-II step of the C method. Among the compounds represented by the formula (X), the method of the compound represented by the formula (XXI) wherein Y is an oxygen atom.

(G法) (G law)

G-I步驟 G-I step

本步驟係於溶媒中，鈀觸媒及鹼之存在下，藉由使通式(VI)所表示的化合物與通式(XIX)所表示的化合物反應，與A法之A-III步驟同樣地進行，而製造通式(XX)所表示的化合物的步驟。 This step is carried out in the presence of a palladium catalyst and a base, and the compound represented by the formula (VI) is reacted with a compound represented by the formula (XIX) in the same manner as in the A-III step of the method A. The step of producing the compound represented by the formula (XX) is carried out.

G-II步驟 G-II step

本步驟係於溶媒中，銅觸媒、助觸媒及鹼之存在下，藉由使通式(XX)所表示的化合物與通式(XII)所表示的化合物反應，與F法之F-I步驟同樣地進行，而製造通式(XXI)所表示的化合物的步驟。 This step is carried out in a solvent, in the presence of a copper catalyst, a cocatalyst and a base, by reacting a compound represented by the formula (XX) with a compound represented by the formula (XII), and an FI step of the F method. The procedure of the compound represented by the formula (XXI) is carried out in the same manner.

又，本步驟係於溶媒中，鹼之存在下，藉由使通式(XX)所表示的化合物與通式(XII)所表示的化合物反應，與F法之F-I步驟同樣地進行，而製造通式(XXI)所表示的化合物的步驟。 In addition, this step is carried out in the same manner as in the case of a base, and a compound represented by the formula (XX) is reacted with a compound represented by the formula (XII) in the same manner as in the FI step of the F method. The step of the compound represented by the formula (XXI).

H法係製造A法之A-II步驟及C法之C-III步驟所使用的通式(IV)所表示的化合物或其鹽的方法。惟，Q1為氮原子的情形，Q2為式=CH-所表示的基。 The H method is a method for producing the compound represented by the formula (IV) or a salt thereof used in the A-II step of the method A and the step C-III of the method C. However, when Q 1 is a nitrogen atom, Q 2 is a group represented by the formula =CH-.

(H法) (H method)

H-I步驟 H-I step

本步驟係於溶媒中，銅觸媒與鹼之存在下，藉由使通式(XXII)所表示的化合物與通式(XXIII)所表示的化合物反應，製造通式(XXIV)所表示的化合物的步驟。 This step is carried out by reacting a compound represented by the formula (XXII) with a compound represented by the formula (XXIII) in the presence of a copper catalyst and a base to produce a compound represented by the formula (XXIV). A step of.

於本步驟所使用的溶媒係適合為醯胺類或亞碸類，更適合為N,N-二甲基甲醯胺或二甲基亞碸。 The solvent used in this step is suitably a guanamine or an anthracene, more preferably N,N-dimethylformamide or dimethylammonium.

於本步驟所使用的銅觸媒係適合為碘化銅(I)。 The copper catalyst used in this step is suitably copper (I) iodide.

於本步驟所使用的鹼係適合為L-脯胺酸之鹼金屬鹽類，更適合為L-脯胺酸鈉。 The base used in this step is suitably an alkali metal salt of L-valine, and more preferably L-sodium citrate.

本步驟中的反應溫度通常為50℃至150℃，適合為70℃至110℃。 The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 70 ° C to 110 ° C.

本步驟中的反應時間通常為10分鐘至48小時，適合為30分鐘至12小時。 The reaction time in this step is usually from 10 minutes to 48 hours, and is suitably from 30 minutes to 12 hours.

H-II步驟 H-II step

本步驟係於溶媒中，藉由使通式(XXIV)所表示的化合物與鹼反應，而製造通式(IV)所表示的化合物的步驟。 This step is a step of producing a compound represented by the formula (IV) by reacting a compound represented by the formula (XXIV) with a base in a solvent.

於本步驟所使用的溶媒係適合為醚類、醇類或此等之混合溶媒，更適合為四氫呋喃與甲醇之混合溶媒或四氫呋喃與乙醇之混合溶媒。 The solvent used in this step is preferably an ether, an alcohol or a mixed solvent thereof, and is more preferably a mixed solvent of tetrahydrofuran and methanol or a mixed solvent of tetrahydrofuran and ethanol.

於本步驟所使用的鹼係適合為鹼金屬氫氧化物，更適合為氫氧化鈉或氫氧化鋰水溶液。 The base used in this step is suitably an alkali metal hydroxide, and more preferably an aqueous solution of sodium hydroxide or lithium hydroxide.

本步驟中的反應溫度通常為0℃至80℃，適合為15℃至45℃。 The reaction temperature in this step is usually from 0 ° C to 80 ° C, suitably from 15 ° C to 45 ° C.

本步驟中的反應時間通常為5分鐘至48小時，適合為10分鐘至24小時。 The reaction time in this step is usually from 5 minutes to 48 hours, and is suitably from 10 minutes to 24 hours.

通式(IV)所表示的化合物之鹽係反應結束後，自鹼性之反應混合物採取。採取的鹽係依反應所使用的鹼而異。 After the salt reaction of the compound represented by the formula (IV) is completed, it is taken from the basic reaction mixture. The salt to be used varies depending on the base used in the reaction.

I法係製造A法之A-II步驟及C法之C-III步驟所使用的通式(IV)所表示的化合物或其鹽之中，Q1為式=CH-所表示的基，Q2為氮原子，且R3a為氫原子的通式(XXIX)所表示的化合物或其鹽的方法。 In the method of the method A, the A-II step of the method A and the compound represented by the formula (IV) used in the step C-III of the method C or a salt thereof, Q 1 is a group represented by the formula: CH-, Q A method in which 2 is a nitrogen atom and R 3a is a hydrogen atom of a compound represented by the formula (XXIX) or a salt thereof.

(I法) (I law)

I-I步驟 I-I step

本步驟係於溶媒中，鹼之存在下，藉由使通式(XXV)所表示的化合物與通式(XXVI)所表示的化合物反應，而製造通式(XXVII)所表示的化合物的步驟。 This step is a step of producing a compound represented by the formula (XXVII) by reacting a compound represented by the formula (XXV) with a compound represented by the formula (XXVI) in the presence of a base in a solvent.

於本步驟所使用的溶媒係適合為醯胺類或亞碸類，更適合為二甲基亞碸。 The solvent used in this step is suitably an guanamine or an anthracene, and is more suitably a dimethyl hydrazine.

於本步驟所使用的鹼係適合為無機鹼類，更適合為鹼金屬碳酸鹽類，進一步更適合為碳酸銫。 The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and still more preferably cesium carbonate.

本步驟中的反應溫度通常為30℃至200℃，適合為 80℃至120℃。 The reaction temperature in this step is usually from 30 ° C to 200 ° C, suitable for 80 ° C to 120 ° C.

本步驟中的反應時間通常為1小時至24小時，適合為5小時至10小時。 The reaction time in this step is usually from 1 hour to 24 hours, and is suitably from 5 hours to 10 hours.

I-II步驟 I-II step

本步驟係於溶媒中，銅觸媒與鹼之存在下，藉由使通式(XXVII)所表示的化合物與通式(XXIII)所表示的化合物反應，與H法之H-I步驟同樣地，製造通式(XXVIII)所表示的化合物的步驟。 This step is carried out in the presence of a copper catalyst and a base by reacting a compound represented by the formula (XXVII) with a compound represented by the formula (XXIII) in the same manner as in the HI step of the H method. The step of the compound represented by the formula (XXVIII).

I-III步驟 Step I-III

本步驟係於溶媒中，藉由使通式(XXVIII)所表示的化合物與鹼反應，與H法之H-II步驟同樣地進行，而製造通式(XXIX)所表示的化合物或其鹽的步驟。 This step is carried out in the same manner as in the H-II step of the H method by reacting the compound represented by the formula (XXVIII) with a base to produce a compound represented by the formula (XXIX) or a salt thereof. step.

通式(XXIX)所表示的化合物之鹽係反應結束後自鹼性之反應混合物採取。採取的鹽係依反應所使用的鹼而異。 The salt of the compound represented by the formula (XXIX) is taken from the basic reaction mixture after completion of the reaction. The salt to be used varies depending on the base used in the reaction.

又，R8為苄基的情形，本步驟係於溶媒中，鈀觸媒之存在下，藉由使通式(XXVIII)所表示的化合物於氫氣環境下反應，而製造通式(XXIX)所表示的化合物的步驟。 Further, when R 8 is a benzyl group, this step is carried out in a solvent, and in the presence of a palladium catalyst, a compound represented by the formula (XXVIII) is reacted in a hydrogen atmosphere to produce a compound of the formula (XXIX). The step of expressing the compound.

於本步驟所使用的溶媒係適合為醚類、醇類、酯類或此等之混合溶媒，更適合為四氫呋喃、甲醇、乙醇、乙酸乙基或此等之混合溶媒。 The solvent used in this step is preferably an ether, an alcohol, an ester or a mixed solvent thereof, and is more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent thereof.

於本步驟所使用的鈀觸媒係適合為鈀-碳。 The palladium catalyst used in this step is suitably palladium-carbon.

本步驟中的反應溫度通常為0℃至80℃，適合為室溫至50℃。 The reaction temperature in this step is usually from 0 ° C to 80 ° C, and is suitably from room temperature to 50 ° C.

本步驟中的反應時間通常為10分鐘至60小時，適合 為1小時至24小時。 The reaction time in this step is usually 10 minutes to 60 hours, suitable It is 1 hour to 24 hours.

又，2處所之R8中的一者為三級丁基的情形，本步驟係於溶媒中，使通式(XXVIII)所表示的化合物與酸反應後，於溶媒中，藉由與鹼反應，與H法之H-II步驟同樣地進行，而製造通式(XXIX)所表示的化合物或其鹽的步驟。 Further, in the case where one of R 8 of the two sites is a tertiary butyl group, this step is carried out in a solvent, and the compound represented by the formula (XXVIII) is reacted with an acid, and then reacted with a base in a solvent. The step of producing the compound represented by the formula (XXIX) or a salt thereof is carried out in the same manner as the H-II step of the H method.

於本步驟所使用的溶媒係適合為鹵化烴類，更適合為二氯甲烷。 The solvent used in this step is suitably a halogenated hydrocarbon, more preferably dichloromethane.

於本步驟所使用的酸係適合為三氟乙酸。 The acid used in this step is suitably trifluoroacetic acid.

本步驟中的反應溫度通常為-10℃至100℃，適合為0℃至30℃。 The reaction temperature in this step is usually -10 ° C to 100 ° C, and is suitably 0 ° C to 30 ° C.

本步驟中的反應時間通常為1分鐘至24小時，適合為1小時至8小時。 The reaction time in this step is usually from 1 minute to 24 hours, and is suitably from 1 hour to 8 hours.

J法係製造I法之I-III步驟所使用的通式(XXVIII)所表示的化合物的方法。 The J method is a method for producing a compound represented by the formula (XXVIII) used in the step I-III of the method I.

(J法) (J law)

J-I步驟 J-I step

本步驟係於溶媒中，鹼、銅觸媒及助觸媒之存在下，藉由使通式(XXX)所表示的化合物與通式(XXVI)所表示的化合物反應，而製造通式(XXVIII)所表示的化合物的步驟。 This step is carried out by reacting a compound represented by the formula (XXX) with a compound represented by the formula (XXVI) in the presence of a base, a copper catalyst and a cocatalyst in a solvent to produce a formula (XXVIII). The step of the compound represented.

於本步驟所使用的溶媒係適合為醯胺類、醚類或亞碸類，更適合為1,4-二烷。 The solvent used in this step is suitable for guanamines, ethers or guanidines, and more suitable for 1,4-two. alkyl.

於本步驟所使用的鹼係適合為無機鹼類，更適合為鹼金屬碳酸鹽類，進一步更適合為碳酸銫。 The base used in this step is preferably an inorganic base, more preferably an alkali metal carbonate, and still more preferably cesium carbonate.

於本步驟所使用的銅觸媒係適合為碘化銅(I)或氯化銅(I)。 The copper catalyst used in this step is suitably copper (I) iodide or copper (I) chloride.

於本步驟所使用的助觸媒係適合為吡啶甲酸。 The cocatalyst used in this step is suitably picolinic acid.

本步驟中的反應溫度通常為30℃至200℃，適合為80℃至120℃。 The reaction temperature in this step is usually from 30 ° C to 200 ° C, suitably from 80 ° C to 120 ° C.

本步驟中的反應時間通常為1小時至24小時，適合為5小時至12小時。 The reaction time in this step is usually from 1 hour to 24 hours, and is suitably from 5 hours to 12 hours.

K法係製造A法之A-II步驟及C法之C-III步驟所使用的通式(IV)所表示的化合物之中，Q1為式=CH-所表示的基，Q2為式=CH-所表示的基的通式(XXXII)所表示的化合物的方法。 Among the compounds represented by the general formula (IV) used in the A-II step of the A method and the C-III step of the C method, Q 1 is a group represented by the formula =CH-, and Q 2 is a formula. =CH- The method of the compound represented by the formula (XXXII) represented by the group.

(K法) (K method)

K-I步驟 K-I step

本步驟係於溶媒中，銅觸媒與鹼之存在下，藉由使通式(XXXI)所表示的化合物與通式(XXIII)所表示的化合物反應，而製造通式(XXXII)所表示的化合物的步驟。 This step is carried out by reacting a compound represented by the formula (XXXI) with a compound represented by the formula (XXIII) in the presence of a copper catalyst and a base to produce a compound represented by the formula (XXXII). The step of the compound.

於本步驟所使用的溶媒係適合為醯胺類或亞碸類， 更適合為N,N-二甲基甲醯胺或二甲基亞碸。 The solvent used in this step is suitable for guanamine or anthraquinone. More suitable is N,N-dimethylformamide or dimethylammonium.

於本步驟所使用的銅觸媒係適合為碘化銅(I)。 The copper catalyst used in this step is suitably copper (I) iodide.

於本步驟所使用的鹼係適合為鹼金屬氫氧化物，更適合為氫氧化鈉或氫氧化鈉水溶液。 The base used in this step is suitably an alkali metal hydroxide, more preferably an aqueous solution of sodium hydroxide or sodium hydroxide.

本步驟中的反應溫度通常為50℃至150℃，適合為70℃至110℃。 The reaction temperature in this step is usually from 50 ° C to 150 ° C, suitably from 70 ° C to 110 ° C.

本步驟中的反應時間通常為10分鐘至48小時，適合為30分鐘至12小時。 The reaction time in this step is usually from 10 minutes to 48 hours, and is suitably from 30 minutes to 12 hours.

通式(II)、(IV)、(VI)、(IX)、(XII)、(XV)、(XVII)、(XIX)、(XXII)、(XXIII)、(XXV)、(XXVI)、(XXX)及(XXXI)所表示的化合物係周知化合物，或者可以周知化合物作為起始原料而按照周知方法或類似其之方法而容易地製造。 General formulae (II), (IV), (VI), (IX), (XII), (XV), (XVII), (XIX), (XXII), (XXIII), (XXV), (XXVI), The compound represented by (XXX) and (XXXI) is a known compound, or can be easily produced by a known method or a similar method using a known compound as a starting material.

於上述，R3a及Ea之定義中的「可經保護的胺基、羥基及/或羧基」之保護基係指藉由加氫分解、水解、電解、光分解之類的化學的方法而可斷裂的保護基，表示有機合成化學中一般可使用的保護基(例如，T.W.參照Greene等人，Protective Groups in Organic Synthesis,3rd Edition,John Wiley & Sons,Inc.(1999年))。 In the above, the protective group of "protectable amine group, hydroxyl group and/or carboxyl group" in the definition of R 3a and E a means a chemical method by hydrodecomposition, hydrolysis, electrolysis, photolysis or the like. A cleavable protecting group represents a protecting group which is generally used in organic synthetic chemistry (for example, TW, see Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

於上述，可經保護的羥基之「保護基」係只要於有機合成化學領域中可使用的羥基保護基即可，並未特別限定，例如，甲醯基、前述「C2-C7烷基羰基」、2,2,2-三氯乙基羰基之類的C2-C7鹵化烷基羰基、甲氧基乙醯基之類的烷氧基烷基羰基、丙烯醯基、丙炔醯基、甲基丙烯醯基、巴豆醯基、異巴豆醯基、(E)-2-甲基-2- 丁烯醯基之類的不飽和烷基羰基等之「烷基羰基」；苄醯基、α-萘甲醯基、β-萘甲醯基之類的芳基羰基、2-溴苄醯基、4-氯苄醯基之類的鹵化芳基羰基、2,4,6-三甲基苄醯基、4-甲苯甲醯基(4-toluoyl)之類的C1-C6烷基化芳基羰基、4-大茴香醯基之類的C1-C6烷氧基化芳基羰基、4-硝基苄醯基、2-硝基苄醯基之類的硝基化芳基羰基、2-(甲氧基羰基)苄醯基之類的C2-C7烷氧基羰基化芳基羰基、4-苯基苄醯基之類的芳基化芳基羰基等之「芳基羰基」；甲氧基羰基、乙氧基羰基之類的C2-C7烷氧基羰基、2,2,2-三氯乙氧基羰基、2-三甲基矽基乙氧基羰基之類的鹵素或經三-(C1-C6烷基)矽基取代的C2-C7烷氧基羰基等之「烷氧基羰基」；四氫哌喃-2-基、3-溴四氫哌喃-2-基、4-甲氧基四氫哌喃-4-基、四氫硫哌喃-2-基、4-甲氧基四氫硫哌喃-4-基之類的「四氫哌喃基或四氫硫哌喃基」；四氫呋喃-2-基、四氫硫呋喃-2-基之類的「四氫呋喃基或四氫硫呋喃基」；三甲基矽基(trimethylsilyl)、三乙基矽基、異丙基二甲基矽基、t-丁基二甲基矽基、甲基二異丙基矽基、甲基二-t-丁基矽基、三異丙基矽基之類的三-(C1-C6烷基)矽基、二苯基甲基矽基、二苯基丁基矽基、二苯基異丙基矽基、苯基二異丙基矽基之類的(C1-C6烷基)二芳基矽基或二-(C1-C6烷基)芳基矽基等之「矽基(silyl)」；甲氧基甲基、1,1-二甲基-1-甲氧基甲基、乙氧基甲基、丙氧基甲基、異丙氧基甲基、丁氧基甲基、t-丁氧基甲基之類的(C1-C6烷氧基)甲基、2-甲氧基乙氧基甲基之類的(C1-C6烷氧基)-(C1-C6烷氧基)甲基、2,2,2-三 氯乙氧基甲基、雙(2-氯乙氧基)甲基之類的(C1-C6鹵化烷氧基)甲基等之「烷氧基甲基」；1-乙氧基乙基、1-(異丙氧基)乙基之類的(C1-C6烷氧基)乙基、2,2,2-三氯乙基之類的鹵化乙基等之「取代乙基」；苄基、α-萘基甲基、β-萘基甲基、二苯基甲基、三苯基甲基、α-萘基二苯基甲基、9-蒽基甲基之類的經1至3個芳基取代的C1-C6烷基，4-甲基苄基、2,4,6-三甲基苄基、3,4,5-三甲基苄基、4-甲氧基苄基、4-甲氧基苯基二苯基甲基、2-硝基苄基、4-硝基苄基、4-氯苄基、4-溴苄基、4-氰基苄基之類的經1至3個芳基取代的C1-C6烷基等之「芳烷基」，該芳基的芳環係經C1-C6烷基、C1-C6烷氧基、硝基、鹵素、氰基取代；乙烯氧基羰基、烯丙氧基羰基之類的「烯氧基羰基」；苄氧基羰基、4-甲氧基苄氧基羰基、3,4-二甲氧基苄氧基羰基、2-硝基苄氧基羰基、4-硝基苄氧基羰基之類的可經1或2個之C1-C6烷氧基或硝基取代芳環的「芳烷氧基羰基」，適合為烷基羰基、矽基或芳烷基。 In the above, the "protecting group" of the protected hydroxyl group is not particularly limited as long as it is a hydroxy protecting group which can be used in the field of organic synthetic chemistry, for example, a thiol group, the aforementioned "C 2 -C 7 alkyl group". a C 2 -C 7 halogenated alkylcarbonyl group such as a carbonyl group, a 2,2,2-trichloroethylcarbonyl group, an alkoxyalkylcarbonyl group such as a methoxyethenyl group, an acryl group or a propynylene group; "Alkylcarbonyl" of an unsaturated alkylcarbonyl group such as a methacryloyl fluorenyl group, a crotonyl group, an crotonyl group or an (E)-2-methyl-2-butenyl group; a halogenated arylcarbonyl group such as an arylcarbonyl group such as a group, an α-naphthylmethyl group or a β-naphthylmethyl group, a 2-bromobenzyl group or a 4-chlorobenzyl group, 2,4,6-three C 1 -C 6 alkoxylation of methyl benzyl hydrazino, C 1 -C 6 alkylated arylcarbonyl such as 4-toluoyl, 4-anisyl fluorenyl a C 2 -C 7 alkoxy group such as an arylcarbonyl group, a 4-nitrobenzyl fluorenyl group, a nitroated arylcarbonyl group such as a 2-nitrobenzyl fluorenyl group or a 2-(methoxycarbonyl)benzyl fluorenyl group An arylcarbonyl group such as an arylcarbonyl group or an arylated arylcarbonyl group such as a 4-phenylbenzylidene group; A halogen such as a C 2 -C 7 alkoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group or a 2-trimethyldecylethoxycarbonyl group such as a carbonyl group or an ethoxycarbonyl group "Alkoxycarbonyl" of a tri-(C 1 -C 6 alkyl)indenyl-substituted C 2 -C 7 alkoxycarbonyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran- Tetrahydropyran, 2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl "tetrahydrofuranyl or tetrahydrothiofuranyl" such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; trimethylsilyl, triethyl Mercapto, isopropyl dimethyl fluorenyl, t-butyl dimethyl fluorenyl, methyl diisopropyl decyl, methyl di-t-butyl fluorenyl, triisopropyl decyl Tri-(C 1 -C 6 alkyl)indenyl, diphenylmethylindenyl, diphenylbutylindenyl, diphenylisopropylindenyl, phenyldiisopropyldecyl or the like a "C 1 -C 6 alkyl"diarylsulfonyl group or a "silk" of a bis-(C 1 -C 6 alkyl)aryl fluorenyl group; methoxymethyl, 1,1 - dimethyl-1-methoxymethyl, ethoxylated , Propoxymethyl, isopropoxymethyl, butoxymethyl, T-butoxymethyl and the like (C 1 -C 6 alkoxy) methyl, 2-methoxy-ethoxy (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy)methyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethyl) "Alkoxymethyl" such as (C 1 -C 6 halogenated alkoxy)methyl such as oxy)methyl; 1-ethoxyethyl, 1-(isopropoxy)ethyl "Substituted ethyl" such as a halogenated ethyl group such as (C 1 -C 6 alkoxy)ethyl or 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β C 1 -C substituted with 1 to 3 aryl groups such as naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenylmethyl 6 alkyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl Substituted with 1 to 3 aryl groups such as diphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl An "aralkyl group" such as a C 1 -C 6 alkyl group, the aromatic ring of the aryl group is a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a halogen group, a cyano group "Alkenyloxycarbonyl" such as ethyleneoxycarbonyl or allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, An "aralkyloxycarbonyl group" which may have an aromatic ring substituted by 1 or 2 C 1 -C 6 alkoxy groups or a nitro group, such as 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, Suitable as an alkylcarbonyl group, a fluorenyl group or an aralkyl group.

於上述，可經保護的羧基之「保護基」係只要於有機合成化學領域使用的羧基保護基即可，並未特別限定，例如，前述「C1-C6烷基」；乙烯基、烯丙基之類的C2-C6烯基；乙炔基、1-丙炔基(1-propynyl)、2-丙炔基、1-甲基-2-丙炔基、1-丁炔基之類的C2-C6炔基；前述「C1-C6鹵化烷基」；前述「C1-C6羥基烷基」；乙醯基甲基之類的(C2-C7烷基羰基)-(C1-C6烷基)基；前述「芳烷基」；或前述「矽基」，適合為C1-C6烷基或芳烷基。 In the above, the "protecting group" of the protected carboxyl group is not particularly limited as long as it is a carboxyl group protecting group used in the field of organic synthetic chemistry, for example, the above-mentioned "C 1 -C 6 alkyl group"; vinyl group, alkene C 2 -C 6 alkenyl such as propyl; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl a C 2 -C 6 alkynyl group; the aforementioned "C 1 -C 6 halogenated alkyl group"; the aforementioned "C 1 -C 6 hydroxyalkyl group"; an ethyl chloromethyl group (C 2 -C 7 alkyl group) Carbonyl)-(C 1 -C 6 alkyl) group; the aforementioned "aralkyl group"; or the aforementioned "mercapto group", suitably a C 1 -C 6 alkyl group or an aralkyl group.

於上述，可經保護的胺基之「保護基」只要 為有機合成化學領域中使用的胺基之保護基即可，並未特別限定，例如，表示與前述「羥基之保護基」中的「烷基羰基」；「芳基羰基」；「烷氧基羰基」；「矽基」；「芳烷基」；「烯基氧基羰基」；或「芳烷基氧基羰基」同樣的基或者N,N-二甲基胺基亞甲基、亞苄基、4-甲氧基亞苄基、4-硝基亞苄基、亞柳基(salicylidene)、5-氯亞柳基、二苯基亞甲基、(5-氯-2-羥基苯基)苯基亞甲基之類的「形成希夫鹼(Schiff base)之經取代的亞甲基」，適合為烷基羰基、芳基羰基或烷氧基羰基，更適合為烷氧基羰基。 In the above, the "protecting group" of the protected amine group is as long as The protecting group for the amine group used in the field of organic synthetic chemistry is not particularly limited, and for example, it means "alkylcarbonyl group" in the "protecting group for a hydroxyl group"; "arylcarbonyl group"; "alkoxy group" "carbonyl"; "mercapto"; "aralkyl"; "alkenyloxycarbonyl"; or "aralkyloxycarbonyl" the same group or N,N-dimethylaminomethylene, benzidine , 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorolinalylene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) The "substituted methylene group forming a Schiff base" such as a phenylmethylene group is preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group.

保護‧脫保護為必要的步驟係依據已知方法(例如，「Protective Groups in Organic Synthesis」(Theodora W.Greene、Peter G.M.Wuts著、1999年、Wiley-Interscience Publication發行)等記載之方法)來進行。 The steps necessary for protection and deprotection are carried out according to known methods (for example, "Protective Groups in Organic Synthesis" (the method described by Theodora W. Greene, Peter GMWuts, 1999, Wiley-Interscience Publication). .

本發明之化合物或其藥學上可容許的鹽可以各種形態投予。就其投予形態而言，可列舉例如，利用錠劑、膠囊劑、顆粒劑、乳劑、丸劑、散劑、糖漿劑(液劑)等的經口投予；或利用注射劑(靜脈內、肌肉內、皮下或腹腔內投予)、點滴劑、栓劑(直腸投予)、外用劑(經皮投予)等的非經口投予。此等之各種製劑按照通常方法，於主藥可使用賦形劑、結合劑、崩解劑、潤滑劑、矯味矯臭劑、溶解輔助劑、懸浮劑、包衣劑、溶媒、基劑等之醫藥之製劑技術領域中通常可使用的輔助劑而加以製劑化。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration using a tablet, a capsule, a granule, an emulsion, a pill, a powder, a syrup (liquid), or the like; or an injection (intravenous or intramuscular) Oral administration by subcutaneous or intraperitoneal administration, drip, suppository (rectal administration), external preparation (transdermal administration), and the like. Each of these preparations may be an excipient, a binding agent, a disintegrating agent, a lubricant, a flavoring agent, a dissolution aid, a suspending agent, a coating agent, a solvent, a base, etc., according to a usual method. Formulations are usually formulated with adjuvants that are commonly used in the art of formulation.

作為錠劑使用的情形，作為載體，可使用例如，乳糖、白糖、氯化鈉、葡萄糖、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素、矽酸等之賦形劑；水、乙醇、丙醇、單糖漿(simple syrup)、葡萄糖液、澱粉液、明膠溶液、羧甲基纖維素、蟲膠(shellac)、甲基纖維素、磷酸鉀、聚乙烯吡咯啶酮等之結合劑；乾燥澱粉、藻酸鈉、瓊脂粉末、昆布糖(laminaran)粉末、碳酸氫鈉、碳酸鈣、聚氧乙烯山梨醇酐脂肪酸酯、月桂基硫酸鈉、硬脂酸單甘油酯、澱粉、乳糖等之崩解劑；白糖、硬脂(stearin)、可可脂、氫化油等之崩解抑制劑；第4級銨鹽類、月桂基硫酸鈉等之吸收促進劑；甘油、澱粉等之保濕劑；澱粉、乳糖、高嶺土、膨潤土、膠體狀矽酸等之吸附劑；精製滑石、硬脂酸鹽、硼酸粉末、聚乙二醇等之潤滑劑等。又，因應需要可作成施予通常之包衣的錠劑，例如糖衣錠、明膠被包錠(gelatin-coated tablets)、腸溶被錠(enteric-coated tablets)、膜衣錠或雙層錠、多層錠。 In the case of use as a tablet, as the carrier, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid or the like; water, ethanol, and c can be used; Alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; dry starch , sodium alginate, agar powder, laminar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. a dissolving agent; a disintegrating inhibitor of sugar, stearin, cocoa butter, hydrogenated oil; a fourth-stage ammonium salt, an absorption enhancer such as sodium lauryl sulfate; a moisturizing agent such as glycerin or starch; An adsorbent for lactose, kaolin, bentonite, colloidal citric acid, etc.; a lubricant such as refined talc, stearate, boric acid powder, polyethylene glycol, and the like. Further, if necessary, a tablet which can be applied to a usual coating such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layer ingot, or a plurality of layers can be prepared. ingot.

作為丸劑使用的情形，作為載體，可使用例如，葡萄糖、乳糖、可可脂、澱粉、硬化植物油、高嶺土、滑石等之賦形劑；阿拉伯膠粉末、黃蓍膠(tragacanth)粉末、明膠、乙醇等之結合劑；昆布糖、瓊脂等之崩解劑等。 In the case of use as a pill, as the carrier, for example, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; gum arabic powder, tragacanth powder, gelatin, ethanol, etc. may be used. a binding agent; a disintegrant such as laminaria, agar, or the like.

作為栓劑使用的情形，可廣泛使用此領域中周知者作為載體，可列舉例如，聚乙二醇、可可脂、高級醇、高級醇之酯類、明膠、半合成甘油酯等。 As a suppository, a well-known person in the art can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

作為注射劑使用的情形，可作為液劑、乳劑或懸浮劑使用。此等之液劑、乳劑或懸浮劑係經殺菌，且與血液等張者為較佳。此等液劑、乳劑或懸浮劑之製造所使用的溶媒係只要可使用作為醫療用之稀釋劑者即可，並未特別限定，可列舉例如，水、乙醇、丙二醇、乙氧基化異硬脂醇(ethoxylated isostearyl alcohol)、聚氧化異硬脂醇(polyoxylated isostearyl alcohol)、聚氧乙烯山梨醇酐脂肪酸酯類等。又，於此情形，調製等張性之溶液時可於製劑中含充分量之食鹽、葡萄糖或甘油，或可含通常之溶解輔助劑、緩衝劑、緩和劑(soothing agent)等。 As the injection, it can be used as a liquid, emulsion or suspension. Such liquids, emulsions or suspensions are sterilized and are preferably the same as blood. The solvent used for the production of the liquid preparation, the emulsion or the suspension is not particularly limited as long as it can be used as a diluent for medical use, and examples thereof include water, ethanol, propylene glycol, and ethoxylated iso-hard. Ethylenelated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, in this case, a solution of the isotonicity may be formulated to contain a sufficient amount of salt, glucose or glycerin in the preparation, or may contain a usual dissolution aid, a buffer, a soothing agent or the like.

作為外用劑使用的情形，可作為外用固形劑、外用液劑(擦劑(liniment)、洗劑(lotion))、噴霧劑、軟膏劑、乳霜劑、凝膠劑或貼附劑使用。此等之外用劑可使用通常醫藥品所使用的溶媒、基劑、添加劑、賦形劑等而依據通常方法來製造。 When it is used as an external preparation, it can be used as an external solid preparation, a external liquid preparation (liniment, lotion), a spray, an ointment, a cream, a gel, or a patch. These external preparations can be produced according to a usual method using a solvent, a base, an additive, an excipient, or the like which is usually used in pharmaceuticals.

又，於上述之製劑，因應需要亦可包含著色劑、保存劑、香料、風味劑、甘味劑等，亦可進一步包含其他醫藥品。 Further, the above-mentioned preparation may contain a coloring agent, a preservative, a flavor, a flavor, a sweetener, etc., as needed, and may further contain other pharmaceuticals.

上述製劑所含的有效成分化合物之量並未特別限定，而可廣範圍地被適當選擇，但通常為總組成物中含有0.5至70重量%，較佳為1至30重量%。 The amount of the active ingredient compound contained in the above-mentioned preparation is not particularly limited, and can be appropriately selected from a wide range, but is usually from 0.5 to 70% by weight, preferably from 1 to 30% by weight, based on the total composition.

其使用量係依患者(溫血動物，尤其人類)之症狀、年齡等而異，但期望於經口投予的情形，以每1次下限為0.001mg/kg體重(較佳為0.01mg/kg體重)，上限 為500mg/kg體重(較佳為50mg/kg體重)的方式；於靜脈內投予的情形，以每1次，下限為0.005mg/kg體重(較佳為0.05mg/kg體重)，上限為50mg/kg體重(較佳為5mg/kg體重)的方式，因應症狀而每1日投予1次至數次。 The amount to be used varies depending on the symptoms, age, and the like of the patient (warm-blooded animal, especially human), but it is desirable that in the case of oral administration, the lower limit per one time is 0.001 mg/kg body weight (preferably 0.01 mg/ Kg weight), upper limit The method is 500 mg/kg body weight (preferably 50 mg/kg body weight); in the case of intravenous administration, the lower limit is 0.005 mg/kg body weight (preferably 0.05 mg/kg body weight) per one time, and the upper limit is The method of 50 mg/kg body weight (preferably 5 mg/kg body weight) is administered once or several times per day depending on the symptoms.

[實施例] [Examples]

以下，列舉實施例及試驗例而進一步詳細地說明本發明，但本發明之範圍並未限定於此等例。 Hereinafter, the present invention will be described in more detail by way of examples and test examples, but the scope of the invention is not limited thereto.

實施例中，管柱層析中的溶析係於利用TLC(Thin Layer Chromatography，薄層層析)的觀察下進行。於TLC觀察，就TLC板而言採用Merck公司製之矽膠60F254，就展開溶媒而言採用在管柱層析中作為溶析溶媒使用的溶媒，就檢測法而言採用UV檢測器。管柱用矽膠使用Merck公司製之矽膠SK-85(230~400網目)、山善公司製之矽膠(Hi-FlashTM管柱、INJECT COLUMNTM)、Biotage公司製之矽膠(SNAP、SNAP Ultra)或者富士SILYSIA化學公司製之矽膠(FL100B、Chromatorex-SO3H)。通常之管柱層析之外，適當使用山善公司之自動層析裝置(YFLC-5405-FC-GRII、W-Prep 2XY)、及Biotage公司之自動層析裝置(Isolera、SP-1)。又，實施例所使用的縮寫具有如下的意義。 In the examples, the elution in column chromatography was carried out under the observation by TLC (Thin Layer Chromatography). As for the TLC plate, a silicone resin 60F 254 manufactured by Merck Co., Ltd. was used for the TLC plate, and a solvent used as a solvent for elution in column chromatography was used for developing the solvent, and a UV detector was used for the detection method. For the column, the silicone resin SK-85 (230-400 mesh) made by Merck, the silicone rubber (Hi-Flash TM column, INJECT COLUMN TM ) made by Shanshan Co., Ltd., the silicone (SNAP, SNAP Ultra) made by Biotage, or Silicone (FL100B, Chromatorex-SO3H) manufactured by Fuji SILYSIA Chemical Co., Ltd. In addition to the usual column chromatography, an automatic chromatography device (YFLC-5405-FC-GRII, W-Prep 2XY) from Yamanatsu Co., Ltd., and an automatic chromatography device (Isolera, SP-1) from Biotage Co., Ltd. are used as appropriate. Further, the abbreviations used in the examples have the following meanings.

mg：毫克、g：克、mL：毫升、MHz：兆赫、Hz：赫 Mg: mg, g: gram, mL: ml, MHz: megahertz, Hz: Hz

於以下之實施例，核磁共振(以下，1H-NMR)光譜使用四甲基矽烷作為標準物質，將化學位移值記載為δ值(ppm)。測定溶媒使用CDCl3：氘化氯仿、MeOH-d4：氘化甲醇或DMSO-d6：氘化二甲基亞碸。分裂樣式係 將單峰表示為s，二重峰表現為d，三重峰表示為t，四重峰表示為q，五重峰表示為quint，六重峰表示為sext，七重峰表示為hept，多重峰表示為m，寬峰(broad)表示為br。 In the following examples, the nuclear magnetic resonance (hereinafter, 1 H-NMR) spectrum used tetramethyl decane as a standard material, and the chemical shift value was described as a δ value (ppm). The solvent was measured using CDCl 3 : deuterated chloroform, MeOH-d 4 : deuterated methanol or DMSO-d 6 : deuterated dimethyl hydrazine. The splitting pattern expresses a single peak as s, a doublet as d, a triplet as t, a quartet as q, a quartet as quint, a quartet as a sext, and a quartet as a hept. The multiple peak is denoted as m, and the broad peak is denoted as br.

質量分析(以下，MS)係以APCI(大氣壓力化學離子化法，Atmospheric Pressure Chemical Ionization)法、FAB(快速原子撞擊，Fast Atom Bombardment)法、EI(電子離子化，Electron Ionization)法、或ESI(電子噴霧離子化，Electron Spray Ionization)法來進行。又，一部分測定係使用自動地分別使用ESI及APCI作為離子化法的測定機種。 Mass analysis (hereinafter, MS) is performed by APCI (Atmospheric Pressure Chemical Ionization) method, FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method. Further, in some measurement systems, ESI and APCI were used as measurement means for ionization.

(實施例1) (Example 1)

(實施例1-1)：於實施例(1c)合成 (Example 1-1): Synthesis in Example (1c)

4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy Phenyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester

(實施例1-2)：於實施例(1d)合成 (Example 1-2): Synthesis in Example (1d)

4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1(2H)-甲酸三級丁酯 4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy Phenyl]phenyl}piperidine-1(2H)-carboxylic acid tert-butyl butyl ester

(實施例1-3)：於實施例(1e)合成 (Examples 1-3): Synthesis in Example (1e)

1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2-(A Sulfosyl)phenyl]ethanone hydrochloride

(實施例1-4)：於實施例(1f)合成 (Examples 1-4): Synthesis in Example (1f)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

(實施例1-5)：於實施例(1g)單離 (Examples 1-5): Isolation in Example (1g)

1-[5-(4-{1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2S)-1,4-two Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

(實施例1-6)：於實施例(1g)單離 (Examples 1-6): Isolation in Example (1g)

1-[5-(4-{1-[(2R)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2R)-1,4-two Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

(1a)5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (1a) 5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於公知(WO2007/129745)之5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(10g)及1-溴-4-碘苯(13.6g)之二烷(150mL)溶液中添加碘化銅(I)(1.53g)、N,N-二甲基甘胺酸(1.66g)、碳酸銫(26.1g)，並於100℃攪拌24小時。於反應液中添加飽和氯化銨水溶液(60mL)、飽和碳酸氫鈉水溶液(30mL)，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以己烷洗淨後，藉由濾取、乾燥，獲得呈白色固體之標題化合物(12.8g)。 5-Hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester (10 g) and 1-bromo-4-iodobenzene (13.6) (WO2007/129745) g) bis To the solution of the alkane (150 mL), copper (I) iodide (1.53 g), N,N-dimethylglycine (1.66 g), and cesium carbonate (26.1 g) were added, and the mixture was stirred at 100 ° C for 24 hours. Saturated aqueous ammonium chloride solution (60 mL) and a saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the mixture. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was washed with EtOAc (mjjjjjjd

1H-NMR(400MHz,CDCl3)δ：1.55(9H,s),2.04(3H,s),2.95-3.09(2H,m),3.93-4.07(2H,br m),6.68-6.81(3H,m),7.30-7.39(2H,m),7.62-7.75(1H,br m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.55 (9H, s), 2.04 (3H, s), 2.95-3.09 (2H, m), 3.93-4.07 (2H, br m), 6.68-6.81 (3H , m), 7.30-7.39 (2H, m), 7.62-7.75 (1H, br m).

(1b)1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (1b) 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonyl) Phenyl]ethanone

於實施例(1a)所獲得的化合物(12.8g)之二氯甲烷(10mL)溶液中添加4N鹽酸二烷溶液(20mL)，並於室溫攪拌5小時。減壓下濃縮反應液，藉由減壓乾燥，獲得呈灰色固體之粗製之5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(11g)。 4N hydrochloric acid was added to a solution of the compound (12.8 g) obtained in Example (1a) in dichloromethane (10 mL) Alkane solution (20 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and evaporated to dryness crystals crystals crystals (11g).

於獲得的化合物(11g)之N,N-二甲基甲醯胺(30mL) 溶液中添加三乙基胺(8.9mL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(13.3g)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(8.27g)，再於室溫攪拌12小時。減壓下濃縮反應液後，添加水(100mL)，濾取析出的固體。以己烷將獲得的固體洗淨，獲得呈淡褐色固體之標題化合物(15.2g)。 Triethylamine (8.9 mL) was added to a solution of the obtained compound (11 g) in N,N-dimethylcarbamide (30 mL), and stirred at room temperature for 5 min. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (13.3 g) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (8.27 g) were stirred at room temperature for 12 hours. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with EtOAc (EtOAc m.

1H-NMR(400MHz,DMSO-d6)δ：2.03(3H,s),3.13-3.22(5H,m),4.28(2H,t,J=8.5Hz),4.33(2H,s),6.77-6.85(3H,m),7.44-7.51(3H,m),7.52-7.62(1H,m),7.65-7.74(1H,m),7.87(1H,d,J=8.5Hz),7.97(1H,d,J=8.5Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 2.03 (3H, s), 3.13-3.22 (5H, m), 4.28 (2H, t, J = 8.5Hz), 4.33 (2H, s), 6.77 -6.85(3H,m),7.44-7.51(3H,m),7.52-7.62(1H,m), 7.65-7.74(1H,m),7.87(1H,d,J=8.5Hz),7.97(1H , d, J = 8.5Hz).

MS(APCI)m/z：500(M+H)+。 MS (APCI) m/z: 500 (M+H) + .

(1c)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (1c) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyl oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl acrylate

於實施例(1b)所獲得的化合物(500mg)、1-三級丁氧基羰基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫-2H-吡啶(463mg)之1,2-二甲氧基乙烷(10mL)溶液中添加碳酸鈉(317mg)之水溶液(3mL)，並於室溫攪拌5分鐘。添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(81.6mg)，以微波反應裝置，使於130℃反應30分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析( 乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(219.4mg)。 Compound (500 mg) obtained in Example (1b), 1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A solution of sodium carbonate (317 mg) (3 mL) was added to a solution of 2-yl)-3,6-dihydro-2H-pyridine (463 mg) in 1,2-dimethoxyethane (10 mL). Stir for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (81.6 mg) was added, and the mixture was reacted at 130 ° C for 30 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was chromatographed on a silica gel column ( The title compound (219.4 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.49(9H,s),2.12(3H,s),2.45-2.54(2H,m),3.12(3H,s),3.21(2H,t,J=8.5Hz),3.56-3.69(2H,m),4.08(2H,d,J=15.3Hz),4.29(2H,t,J=8.5Hz),4.36(2H,s),5.96(1H,br s),6.79(1H,d,J=8.5Hz),6.83(2H,d,J=8.5Hz),7.24-7.33(2H,m),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.60-7.64(1H,m),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.49 (9H, s), 2.12 (3H, s), 2.45-2.54 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.56-3.69 (2H, m), 4.08 (2H, d, J = 15.3 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.96 (1H, br s ), 6.79 (1H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.24 - 7.33 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.60-7.64 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：603(M+H)+。 MS (APCI) m/z: 603 (M+H) + .

(1d)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1(2H)-甲酸三級丁酯 (1d) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyl oxy]phenyl}piperidine-1(2H)-carboxylic acid tert-butyl butyl ester

將實施例(1c)所獲得的化合物(219mg)溶解於四氫呋喃(4mL)及乙酸乙酯(4mL)，添加7.5%鈀碳(77.5mg)，氫氣環境下，於室溫攪拌4小時。濾除反應液中之不溶物，藉由減壓下餾除溶媒，獲得呈白色固體之標題化合物(205mg)。 The compound (219 mg) obtained in Example (1c) was dissolved in tetrahydrofuran (4 mL) and ethyl acetate (4 mL), and 7.5% palladium carbon (77.5 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The title compound (205 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.54-1.64(2H,m),1.74-1.85(2H,m),2.13(3H,s),2.53-2.64(1H,m),2.73-2.86(2H,m),3.12(3H,s),3.21(2H,t,J=8.2Hz),4.13-4.33(4H,m),4.36(2H,s),6.71-6.85(3H,m),7.10(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.48-7.55(1H,m),7.57-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.54-1.64 (2H, m), 1.74-1.85 (2H, m), 2.13 (3H, s), 2.53-2.64 (1H, m), 2.73-2.86 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.2 Hz), 4.13-4.33 (4H, m), 4.36 (2H, s), 6.71-6.85 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.48-7.55 (1H, m), 7.57-7.66 (1H, m), 7.97 ( 1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：549(M+H)+。 MS (APCI) m/z: 549 (M+H) + .

(1e)1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (1e) 1-{4-Methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2 -(methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(1d)所獲得的化合物(205mg)之二氯甲烷(1.5mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌3小時。減壓下濃縮反應液，將殘渣以乙酸乙酯洗淨後濾取，藉由乾燥而獲得呈白色固體之標題化合物(197mg)。 4N hydrochloric acid was added to a solution of the compound (205 mg) obtained in Example (1d) in dichloromethane (1.5 mL) Alkane solution (2 mL) was stirred at room temperature for 3 h. The residue was evaporated to dryness crystals crystals crystals crystals

1H-NMR(400MHz,CDCl3)δ：1.48-1.71(2H,m),1.97-2.22(6H,m),2.66-2.79(1H,m),2.92-3.04(2H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.57-3.66(2H,m),4.29(2H,t,J=8.2Hz),4.37(2H,s),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.14(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.48-1.71 (2H, m), 1.97-2.22 (6H, m), 2.66-2.79 (1H, m), 2.92-3.04 (2H, m), 3.12 ( 3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.66 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 6.76 (1H, d , J=8.5Hz), 6.82(2H,d,J=8.5Hz), 7.14(2H,d,J=8.5Hz), 7.36(1H,d,J=7.9Hz),7.52(1H,t,J =7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：505(M+H)+。 MS (APCI) m/z: 505 (M+H) + .

(1f)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (1f)1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

於實施例(1e)所獲得的化合物(21.2mg)之N,N-二甲基甲醯胺(2mL)溶液中添加三乙基胺(11.7μL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(17.4mg)及1,4-二烷-2-甲酸(6.7mg)，並於室溫攪拌12小時。於反應液中添加水並以乙酸乙 酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(19.0mg)。 Triethylamine (11.7 μL) was added to a solution of the compound (21.2 mg), m. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (17.4mg) and 1,4-two Alkyl-2-carboxylic acid (6.7 mg) was stirred at room temperature for 12 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.57-1.72(2H,m),1.84-1.93(2H,m),2.14(3H,s),2.59-2.78(2H,m),3.03-3.11(1H,m),3.12(3H,s),3.15-3.27(2H,m),3.68-3.90(5H,m),3.91-3.98(1H,m),4.05-4.16(1H,m),4.25-4.34(3H,m),4.36(2H,s),4.63-4.76(1H,m),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.07-7.13(2H,m),7.35-7.39(1H,m),7.47-7.56(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 ( 1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25- 4.34(3H,m), 4.36(2H,s),4.63-4.76(1H,m), 6.76(1H,d,J=8.5Hz), 6.81(2H,d,J=8.5Hz),7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 8.5Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(1g) (1g)

(1g-1)1-[5-(4-{1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮及(1g-2)1-[5-(4-{1-[(2R)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (1g-1)1-[5-(4-{1-[(2S)-1,4-two Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Mercapto)phenyl]ethanone and (1g-2)1-[5-(4-{1-[(2R)-1,4-di Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

使用CHIRALPAK IA(甲醇/乙腈)將實施例(1f)所獲得的化合物(14.5g)作光學離析，各自獲得呈白色固體之光學異構物2種，前波峰(1g-1、6.2g、98%ee)、後波峰 (1g-2、6.5g、98%ee)。 The compound obtained in Example (1f) (14.5 g) was optically isolated using CHIRALPAK IA (methanol / acetonitrile) to obtain two kinds of optical isomers as a white solid, and the anterior peaks (1 g-1, 6.2 g, 98) %ee), post-peak (1g-2, 6.5g, 98% ee).

(1g-1) (1g-1)

1H-NMR(400MHz,CDCl3)δ：1.57-1.72(2H,m),1.84-1.93(2H,m),2.14(3H,s),2.59-2.78(2H,m),3.03-3.11(1H,m),3.12(3H,s),3.15-3.27(2H,m),3.68-3.90(5H,m),3.91-3.98(1H,m),4.05-4.16(1H,m),4.25-4.34(3H,m),4.36(2H,s),4.63-4.76(1H,m),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.07-7.13(2H,m),7.35-7.39(1H,m),7.47-7.56(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 ( 1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25- 4.34(3H,m), 4.36(2H,s),4.63-4.76(1H,m), 6.76(1H,d,J=8.5Hz), 6.81(2H,d,J=8.5Hz),7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 8.5Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(1g-2) (1g-2)

1H-NMR(400MHz,CDCl3)δ：1.57-1.72(2H,m),1.84-1.93(2H,m),2.14(3H,s),2.59-2.78(2H,m),3.03-3.11(1H,m),3.12(3H,s),3.15-3.27(2H,m),3.68-3.90(5H,m),3.91-3.98(1H,m),4.05-4.16(1H,m),4.25-4.34(3H,m),4.36(2H,s),4.63-4.76(1H,m),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.07-7.13(2H,m),7.35-7.39(1H,m),7.47-7.56(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.72 (2H, m), 1.84-1.93 (2H, m), 2.14 (3H, s), 2.59-2.78 (2H, m), 3.03-3.11 ( 1H, m), 3.12 (3H, s), 3.15-3.27 (2H, m), 3.68-3.90 (5H, m), 3.91-3.98 (1H, m), 4.05-4.16 (1H, m), 4.25- 4.34(3H,m), 4.36(2H,s),4.63-4.76(1H,m), 6.76(1H,d,J=8.5Hz), 6.81(2H,d,J=8.5Hz),7.07-7.13 (2H, m), 7.35-7.39 (1H, m), 7.47-7.56 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 8.5Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(實施例2)：於實施例(2e)合成 (Example 2): Synthesis in Example (2e)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苯氧基 }-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethyl sulfonate Mercapto)phenyl]ketone

(2a)1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮 (2a) 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(ethylsulfonyl) Phenyl]ethanone

於實施例(1a)所獲得的化合物(12.8g)之二氯甲烷(10mL)溶液中添加4N鹽酸二烷溶液(20mL)，並於室溫攪拌5小時。減壓下濃縮反應液，藉由減壓乾燥，獲得呈灰色固體之粗製之5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(11g)。 4N hydrochloric acid was added to a solution of the compound (12.8 g) obtained in Example (1a) in dichloromethane (10 mL) Alkane solution (20 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and evaporated to dryness crystals crystals crystals (11g).

於獲得的化合物(710mg)之N,N-二甲基甲醯胺(10mL)溶液中添加三乙基胺(580μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(874mg)及實施例所獲得的[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(571mg)，並於室溫攪拌12小時。減壓下濃縮反應液，添加水(100mL)並濾取析出的固體、乾燥。獲得的固體以乙酸乙酯/己烷(1/5)之混合溶媒洗淨，獲得呈淡橙色固體之標題化合物(1.17g)。 Triethylamine (580 μL) was added to a solution of the obtained compound (710 mg) in N,N-dimethylformamide (10 mL) and stirred at room temperature for 5 min. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl The ruthenium hydride (874 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (571 mg) obtained from the mixture were stirred at room temperature for 12 hours. The reaction liquid was concentrated under reduced pressure, and water (100 mL) was added, and the precipitated solid was filtered and dried. The obtained solid was washed with ethyl acetate / hexane (1/5).

1H-NMR(400MHz,CDCl3)δ：1.27(3H,t,J=7.3Hz),2.08(3H,s),3.15-3.26(4H,m),4.22-4.30(2H,m),4.37(2H,s),6.70-6.80(3H,m),7.34-7.43(3H,m),7.51(1H,t,J=7.9Hz),7.63(1H,t,J=7.9Hz),7.96-8.07(2H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.08 (3H, s), 3.15-3.26 (4H, m), 4.22-4.30 (2H, m), 4.37 (2H, s), 6.70-6.80 (3H, m), 7.34-7.43 (3H, m), 7.51 (1H, t, J = 7.9 Hz), 7.63 (1H, t, J = 7.9 Hz), 7.96- 8.07 (2H, m).

MS(APCI)m/z：514(M+H)+。 MS (APCI) m/z: 514 (M+H) + .

(2b)4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (2b) 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester

於實施例(2a)所獲得的化合物(500mg)、1-三級丁氧基羰基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫-2H-吡啶(360mg)之1,2-二甲氧基乙烷(12mL)溶液中添加碳酸鈉(309mg)水溶液(3mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(79.4mg)，以微波反應裝置，使於130℃反應30分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(461mg)。 Compound (500 mg) obtained in Example (2a), 1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A solution of sodium carbonate (309 mg) (3 mL) was added to a solution of 2-yl)-3,6-dihydro-2H-pyridine (360 mg) in 1,2-dimethoxyethane (12 mL). 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (79.4 mg) was added and reacted at 130 ° C for 30 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.49(9H,s),2.12(3H,s),2.43-2.54(2H,br m),3.16-3.28(4H,m),3.58-3.68(2H,m),4.02-4.09(2H,br m),4.27(2H,t,J=8.5Hz),4.37(2H,s),5.95(1H,br s),6.75-6.87(3H,m),7.25-7.31(2H,m),7.39(1H,d,J=7.9Hz),7.48-7.53(1H,m),7.58-7.66(1H,m),7.98(1H,d,J=9.2Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.26 (3H, t, J = 7.3Hz), 1.49 (9H, s), 2.12 (3H, s), 2.43-2.54 (2H, br m), 3.16- 3.28(4H,m), 3.58-3.68(2H,m), 4.02-4.09(2H,br m), 4.27(2H,t,J=8.5Hz), 4.37(2H,s),5.95(1H,br s), 6.75-6.87 (3H, m), 7.25-7.31 (2H, m), 7.39 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.58-7.66 (1H, m) , 7.98 (1H, d, J = 9.2 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：617(M+H)+。 MS (APCI) m/z: 617 (M+H) + .

(2c)4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1- 甲酸三級丁酯 (2c) 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}piperidine-1- Butyl formate

將實施例(2b)所獲得的化合物(461mg)溶解於四氫呋喃(10mL)及乙酸乙酯(10mL)，添加7.5%鈀碳(92.4mg)，氫氣環境下，於室溫攪拌10小時。於反應液中添加乙酸乙酯，濾除不溶物後，藉由減壓下將濾液餾除溶媒，獲得呈白色固體之標題化合物(448mg)。 The compound (461 mg) obtained in Example (2b) was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (10 mL), and 7.5% palladium carbon (92.4 mg) was added, and the mixture was stirred at room temperature for 10 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the title compound (448 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.48(9H,s),1.51-1.66(2H,m),1.73-1.84(2H,m),2.13(3H,s),2.55-2.66(1H,m),2.70-2.87(2H,br m),3.13-3.26(4H,m),4.16-4.28(4H,m),4.37(2H,s),6.77(1H,d,J=9.2Hz),6.81(2H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.39(1H,d,J=7.9Hz),7.45-7.53(1H,m),7.60-7.64(1H,m),7.96(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.48 (9H, s), 1.51-1.66 (2H, m), 1.73-1.84 (2H, m), 2.13 (3H, s), 2.55-2.66 (1H, m), 2.70-2.87 (2H, br m), 3.13 - 3.26 (4H, m), 4.16-4.28 (4H, m), 4.37 (2H, s), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.45- 7.53 (1H, m), 7.60-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m / z: 619 (M + H) +.

(2d)2-[2-(乙基磺醯基)苯基]-1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}乙酮鹽酸鹽 (2d) 2-[2-(ethylsulfonyl)phenyl]-1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-di Hydrogen-1H-indol-1-yl}ethanone hydrochloride

於實施例(2c)所獲得的化合物(448mg)之二氯甲烷(1.5mL)溶液中添加4N鹽酸二烷溶液(3mL)，於室溫攪拌2小時。減壓下濃縮反應液，將殘渣以乙酸乙酯洗淨後，濾取、藉由乾燥而獲得呈白色固體之標題化合物(386mg)。 4N hydrochloric acid was added to a solution of the compound (448 mg) obtained in Example (2c) in dichloromethane (1.5 mL) A solution of the alkane (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced vacuo.

MS(APCI)m/z：519(M+H)+。 MS (APCI) m/z: 519 (M+H) + .

(2e)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶 -4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮 (2e)1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethyl sulfonate Mercapto)phenyl]ketone

於實施例(2d)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(100μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(149mg)及1,4-二烷-2-甲酸(57.1mg)，於室溫攪拌16小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(136mg)。 Triethylamine (100 μL) was added to a solution of the compound (m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (149mg) and 1,4-two Alkyl-2-carboxylic acid (57.1 mg) was stirred at room temperature for 16 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.59-1.77(2H,m),1.83-1.97(2H,m),2.12(3H,s),2.57-2.81(2H,m),2.99-3.15(1H,m),3.16-3.27(4H,m),3.67-3.90(5H,m),3.90-3.98(1H,m),4.07-4.16(1H,m),4.24-4.34(3H,m),4.37(2H,s),4.65-4.79(1H,m),6.77(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.06-7.14(2H,m),7.33-7.44(1H,m),7.51(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.59-1.77 (2H, m), 1.83-1.97 (2H, m), 2.12 (3H, s), 2.57 -2.81 (2H, m), 2.99-3.15 (1H, m), 3.16-3.27 (4H, m), 3.67-3.90 (5H, m), 3.90-3.98 (1H, m), 4.07-4.16 (1H, m), 4.24 - 4.34 (3H, m), 4.37 (2H, s), 4.65-4.79 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz) ), 7.06-7.14 (2H, m), 7.33-7.44 (1H, m), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：633(M+H)+。 MS (APCI) m/z: 633 (M+H) + .

(實施例3) (Example 3)

(實施例3-1)：於實施例(3c)合成 (Example 3-1): Synthesis in Example (3c)

1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基 )-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methylphenoxy}-4-methyl-2,3-dihydro-1H-indole -1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例3-2)：於實施例(3d)合成 (Example 3-2): Synthesis in Example (3d)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-methylphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2 -(methylsulfonyl)phenyl]ethanone

(3a)5-(4-溴-3-甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (3a) 5-(4-Bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於1-溴-4-碘-2-甲基苯(12.5g)及5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(7.00g)之1,4-二烷(250mL)溶液中添加碘化銅(I)(107mg)、N,N-二甲基甘胺酸(116mg)及碳酸銫(18.3g)，並於100℃攪拌5小時30分鐘。冷卻至室溫後靜置一晚，再次於100℃攪拌9小時，將反應液以矽藻土過濾。將獲得的濾液於減壓下濃縮，殘渣以矽膠管柱層析(二氯甲烷/己烷)純化，獲得呈無色固體之標題化合物(5.26g)。 1-bromo-4-iodo-2-methylbenzene (12.5 g) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (7.00 g) 1,4-two Copper (I) iodide (107 mg), N,N-dimethylglycine (116 mg) and cesium carbonate (18.3 g) were added to a solution of alkane (250 mL), and stirred at 100 ° C for 5 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and again stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure.

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),2.04(3H,s),2.32(3H,s),3.03(2H,t,J=8.8Hz),3.97-4.10(2H,m),6.55(1H,dd,J=8.8,2.7Hz),6.69-6.83(2H,m),7.20-7.74(2H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.04 (3H, s), 2.32 (3H, s), 3.03 (2H, t, J = 8.8 Hz), 3.97-4.10 (2H m), 6.55 (1H, dd, J = 8.8, 2.7 Hz), 6.69-6.83 (2H, m), 7.20-7.74 (2H, m).

(3b)1-[5-(4-溴-3-甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (3b) 1-[5-(4-Bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-( Methylsulfonyl)phenyl]ketone

於實施例(3a)所獲得的化合物(5.25g)之二氯甲烷(50mL)溶液中添加4N鹽酸二烷溶液(50mL)，並於室溫攪拌3小時。將反應液濃縮，獲得粗製之5-(4-溴-3-甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(4.54g)。 4N hydrochloric acid was added to a solution of the compound (5.25 g) obtained in Example (3a) in dichloromethane (50 mL) Alkane solution (50 mL) was stirred at room temperature for 3 h. The reaction solution was concentrated to give crude 5-(4-bromo-3-methylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (4.54 g).

於獲得的化合物(4.54g)之N,N-二甲基甲醯胺(100mL)溶液中添加N-甲基啉(2.07mL)，並於室溫攪拌10分鐘。其次，於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(4.51g)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(2.82g)，於室溫攪拌14小時30分鐘。減壓下濃縮反應液，殘渣以矽膠管柱層析(二氯甲烷/己烷→乙酸乙酯/二氯甲烷)純化，獲得呈無色固體之標題化合物(7.14g)。 Add N-methyl to a solution of the obtained compound (4.54 g) in N,N-dimethylformamide (100 mL) The morpholine (2.07 mL) was stirred at room temperature for 10 min. Next, adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borane (4.51 g) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (2.82 g) were stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：2.10(3H,s),2.33(3H,s),3.12(3H,s),3.22(2H,t,J=8.5Hz),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.59-6.55(1H,m),6.74-6.80(2H,m),7.34-7.42(2H,m),7.50-7.55(1H,m),7.60-7.65(1H,m),7.99(1H,d,J=8.5Hz),8.06-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.10 (3H, s), 2.33 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t , J = 8.5 Hz), 4.36 (2H, s), 6.59 - 6.55 (1H, m), 6.74 - 6.80 (2H, m), 7.34 - 7.42 (2H, m), 7.50 - 7.55 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.06-8.10 (1H, m).

MS(APCI)m/z：514(M+H)+。 MS (APCI) m/z: 514 (M+H) + .

(3c)1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (3c)1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methylphenoxy}-4-methyl-2,3-dihydro-1H-indole -1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(3b)所獲得的化合物(100mg)、實施例(103b)所獲得的化合物(75.4mg)之1,2-二甲氧基乙烷(3 mL)溶液中添加碳酸鈉(61.8mg)之水溶液(1mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(15.9mg)，以微波反應裝置，使於130℃反應30分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(98.9mg)。 The compound obtained in Example (3b) (100 mg), the compound obtained in Example (103b) (75.4 mg), 1,2-dimethoxyethane (3) An aqueous solution (1 mL) of sodium carbonate (61.8 mg) was added to the solution and stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride methylene chloride complex (15.9 mg) was added and reacted at 130 ° C for 30 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.22(3H,s),2.30-2.40(1H,br m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.59-4.06(10H,m),4.22-4.37(6H,m),5.53(0.5H,s),5.57(0.5H,s),6.60-6.72(1H,m),6.63-6.70(2H,m),6.96(1H,d,J=8.5Hz),7.36(1H,d,J=6.7Hz),7.49-7.55(1H,m),7.58-7.66(1H,m),7.98(1H,d,J=8.5Hz),8.08(1H,d,J=6.7Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22 (3H, s), 2.30-2.40 (1H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.59-4.06 (10H, m), 4.22-4.37 (6H, m), 5.53 (0.5H, s), 5.57 (0.5H, s), 6.60-6.72 (1H, m), 6.63 6.70 (2H, m), 6.96 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 6.7 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 6.7 Hz).

MS(APCI)m/z：631(M+H)+。 MS (APCI) m/z: 631 (M+H) + .

(3d)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (3d) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-methylphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2 -(methylsulfonyl)phenyl]ethanone

將實施例(3c)所獲得的化合物(98.9mg)溶解於四氫呋喃(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(19.8mg)，並氫氣環境下，於室溫攪拌4小時。於反應液中添加乙酸乙酯，濾除不溶物後，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(64.0mg)。 The compound obtained in Example (3c) (98.9 mg) was dissolved in tetrahydrofuran (2 mL) and ethyl acetate (2 mL), and then 7.5% palladium carbon (19.8 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.58-1.72(2H,m),1.75-1.87(2H,m),2.13(3H,s),2.30(3H,s),2.56-2.76(1H,m),2.82-2.97(1H,m),3.04-3.28(6H,m),3.63-3.91(5H,m),3.91-3.99(1H,m),4.09-4.18(1H,m),4.26-4.38(5H,m),4.67-4.82(1H,m),6.64-6.72(2H,m),6.73-6.79(1H,m),6.99-7.08(1H,m),7.34-7.40(1H,m),7.48-7.55(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=7.9Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.58-1.72 (2H, m), 1.75-1.87 (2H, m), 2.13 (3H, s), 2.30 (3H, s), 2.56-2.76 (1H, m), 2.82-2.97 (1H, m), 3.04-3.28 (6H, m), 3.63-3.91 (5H, m), 3.91-3.99 (1H, m), 4.09-4.18 (1H, m), 4.26- 4.38(5H,m),4.67-4.82(1H,m),6.64-6.72(2H,m),6.73-6.79(1H,m),6.99-7.08(1H,m),7.34-7.40(1H,m ), 7.48-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：633(M+H)+。 MS (APCI) m/z: 633 (M+H) + .

(實施例4) (Example 4)

(實施例4-1)：於實施例(4a)合成 (Example 4-1): Synthesis in Example (4a)

1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenoxy]-4-methyl-2,3- Dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例4-2)：於實施例(4b)合成 (Example 4-2): Synthesis in Example (4b)

1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-2,3-dihydro-1H-indole-1- }[2-(methylsulfonyl)phenyl]ethanone

(4a)1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基} -2-[2-(甲基磺醯基)苯基]乙酮 (4a) 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenoxy]-4-methyl-2 ,3-dihydro-1H-indol-1-yl} -2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(3b)所獲得的化合物(200mg)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(146mg)之1,2-二甲氧基乙烷(6mL)溶液中添加碳酸鈉(123mg)之水溶液(2mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(31.8mg)，以微波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(222mg)。 Compound (200 mg) obtained in Example (3b), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 Add a solution of sodium carbonate (123 mg) (2 mL) to a solution of 6-dihydropyridine-1(2H)-yl]ethanone (146 mg) in 1,2-dimethoxyethane (6 mL). Stir for 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (31.8 mg) was added and reacted at 130 ° C for 15 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.16(3H,d,J=4.9Hz),2.22(3H,s),2.31-2.43(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.59-3.67(1H,m),3.75-3.82(1H,m),4.07-4.10(1H,br m),4.18-4.21(1H,br m),4.29(2H,t,J=8.5Hz),4.37(2H,s),5.53(0.5H,s),5.59(0.5H,s),6.61-6.66(1H,m),6.70(1H,s),6.79(1H,d,J=8.5Hz),6.96(1H,d,J=7.9Hz),7.36(1H,d,J=7.9Hz),7.50-7.55(1H,m),7.59-7.65(1H,m),7.98(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.16 (3H, d, J = 4.9 Hz), 2.22 (3H, s), 2.31-2.43 (2H, m), 3.12 (3H) , s), 3.22 (2H, t, J = 8.5 Hz), 3.59-3.67 (1H, m), 3.75-3.82 (1H, m), 4.07-4.10 (1H, br m), 4.18-4.21 (1H, Br m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 5.53 (0.5H, s), 5.59 (0.5H, s), 6.61-6.66 (1H, m), 6.70 ( 1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：559(M+H)+。 MS (APCI) m/z: 559 (M+H) + .

(4b)1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (4b) 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-2,3-dihydro-1H-indole -1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(4a)所獲得的化合物(222mg)溶解於甲醇(3mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(44.4mg)，氫氣環境下，於60℃攪拌4小時。於反應液中添加乙酸乙酯，濾除不溶物後，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(46.9mg)。 The compound (222 mg) obtained in Example (4a) was dissolved in methanol (3 mL) and ethyl acetate (2 mL), and 7.5% palladium carbon (44.4 mg) was added, and the mixture was stirred at 60 ° C for 4 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAcjjjjjjli

1H-NMR(400MHz,CDCl3)δ：1.48-1.65(2H,m),1.72-1.86(2H,m),2.13(3H,s),2.22(1H,s),2.22(3H,s),2.56-2.67(1H,m),2.81-2.95(1H,m),3.12(3H,s),3.17-3.25(3H,m),3.60-3.66(0.5H,m),3.74-3.83(0.5H,m),3.88-3.98(1H,m),4.04-4.11(0.4H,br m),4.18-4.22(0.6H,br m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.75-4.86(0.6H,m),5.50-5.61(0.4H,m),6.61-6.71(2H,m),6.77(1H,t,J=8.9Hz),7.03(1H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.48-1.65 (2H, m), 1.72-1.86 (2H, m), 2.13 (3H, s), 2.22 (1H, s), 2.22 (3H, s) , 2.56-2.67 (1H, m), 2.81-2.95 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.60-3.66 (0.5H, m), 3.74-3.83 (0.5 H, m), 3.88-3.98 (1H, m), 4.04-4.11 (0.4H, br m), 4.18-4.22 (0.6H, br m), 4.29 (2H, t, J = 8.2 Hz), 4.36 ( 2H, s), 4.75-4.86 (0.6H, m), 5.50-5.61 (0.4H, m), 6.61-6.71 (2H, m), 6.77 (1H, t, J = 8.9 Hz), 7.03 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：561(M+H)+。 MS (APCI) m/z: 561 (M+H) + .

(實施例5) (Example 5)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2- [2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(21.2mg)之二氯甲烷 (8mL)溶液中添加三乙基胺(95μL)，並於室溫攪拌5分鐘。添加乙酸酐(35.2μL)，並於室溫攪拌2小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(11.6mg)。 Methylene chloride of the compound obtained in Example (1e) (21.2 mg) Triethylamine (95 μL) was added to the solution (8 mL), and stirred at room temperature for 5 min. Acetic anhydride (35.2 μL) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.53-1.65(2H,m),1.80-1.93(2H,m),2.13(6H,s),2.55-2.74(2H,m),3.12(3H,s),3.14-3.25(3H,m),3.89-3.96(1H,m),4.29(2H,t,J=8.5Hz),4.38(2H,s),4.74-4.82(1H,m),6.77(1H,d,J=7.9Hz),6.80-6.84(2H,m),7.07-7.11(2H,m),7.36(1H,d,J=7.9Hz),7.49-7.55(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.65 (2H, m), 1.80-1.93 (2H, m), 2.13 (6H, s), 2.55-2.74 (2H, m), 3.12 (3H, s), 3.14 - 3.25 (3H, m), 3.89 - 3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.38 (2H, s), 4.74 - 4.82 (1H, m), 6.77 (1H, d, J = 7.9 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：547(M+H)+。 MS (APCI) m/z: 547 (M+H) + .

(實施例6)：於實施例(6c)合成 (Example 6): Synthesis in Example (6c)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2- [2-(ethylsulfonyl)phenyl]ethanone

(6a)5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (6a) 5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-吲哚-1-carboxylic acid tertiary butyl ester

於實施例(1a)所獲得的化合物(200mg)與1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫 吡啶-1(2H)-基]乙酮(149mg)之1,2-二甲氧基乙烷(6mL)溶液中添加碳酸鈉(157mg)之水溶液(2mL)，並於室溫攪拌5分鐘。添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(40.4mg)，以微波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡褐色固體之標題化合物(149mg)。 The compound (200 mg) obtained in Example (1a) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 ,6-dihydrogen To a solution of pyridine-1(2H)-yl]ethanone (149 mg) in EtOAc (EtOAc) (EtOAc) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (40.4 mg) was added, and the mixture was reacted at 130 ° C for 15 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),2.06(3H,s),2.15(3H,d,J=11.5Hz),2.48-2.61(2H,m),3.03(2H,t,J=8.8Hz),3.57-3.69(1H,m),3.99-4.07(2H,br m),4.10-4.15(2H,m),4.18-4.27(1H,m),5.93(0.5H,s),5.99(0.5H,s),6.74-6.86(3H,m),7.24-7.30(1H,m),7.32-7.39(1H,m),7.61-7.77(1H,br m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.06 (3H, s), 2.15 (3H, d, J = 11.5 Hz), 2.48-2.61 (2H, m), 3.03 (2H) , t, J = 8.8 Hz), 3.57-3.69 (1H, m), 3.99-4.07 (2H, br m), 4.10-4.15 (2H, m), 4.18-4.27 (1H, m), 5.93 (0.5H , s), 5.99 (0.5H, s), 6.74-6.86 (3H, m), 7.24-7.30 (1H, m), 7.32-7.39 (1H, m), 7.61-7.77 (1H, br m).

MS(APCI)m/z：449(M+H)+。 MS (APCI) m/z: 449 (M+H) + .

(6b)5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (6b) 5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

將實施例(6a)所獲得的化合物(307mg)溶解於甲醇(5mL)及乙酸乙酯(5mL)，添加7.5%鈀碳(62.0mg)，氫氣環境下，於室溫攪拌10小時。於反應液中添加乙酸乙酯，濾除不溶物，藉由減壓下將濾液餾除溶媒，獲得呈白色固體之標題化合物(207mg)。 The compound (307 mg) obtained in Example (6a) was dissolved in methanol (5 mL) and ethyl acetate (5mL), and then, 7.5% palladium carbon (62.0 mg) was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the title compound (207 mg) was evaporated.

1H-NMR(400MHz,CDCl3)δ：1.56(11H,br m),1.81-1.93(2H,m),2.07(3H,s),2.13(3H,s), 2.53-2.76(2H,m),3.03(2H,t,J=8.9Hz),3.10-3.21(1H,m),3.86-3.96(1H,m),3.97-4.09(2H,br m),4.74-4.82(1H,m),6.74-6.85(3H,m),7.08(2H,d,J=8.5Hz),7.59-7.75(1H,br m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56 (11H, br m), 1.81-1.93 (2H, m), 2.07 (3H, s), 2.13 (3H, s), 2.53-2.76 (2H, m ), 3.03 (2H, t, J = 8.9 Hz), 3.10-3.21 (1H, m), 3.86-3.96 (1H, m), 3.97-4.09 (2H, br m), 4.74-4.82 (1H, m) , 6.74 - 6.85 (3H, m), 7.08 (2H, d, J = 8.5 Hz), 7.59 - 7.75 (1H, br m).

MS(APCI)m/z：451(M+H)+。 MS (APCI) m/z: 451 (M+H) + .

(6c)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (6c) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-inden-1-yl} -2-[2-(ethylsulfonyl)phenyl]ethanone

於實施例(6b)所獲得的化合物(207mg)之二氯甲烷(1mL)溶液中添加三氟乙酸(3mL)，並於室溫攪拌18小時。將反應液減壓濃縮後，添加飽和碳酸氫鈉水溶液(15mL)，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥，藉由減壓下濃縮，獲得呈茶色固體之粗製之1-(4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮(122mg)。 Trifluoroacetic acid (3 mL) was added to aq. The reaction mixture was concentrated under reduced vacuo. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone (122 mg).

於獲得的化合物(122mg)之N,N-二甲基甲醯胺(3mL)溶液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(145mg)及[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(95.7mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(174mg)。 To the solution of the obtained compound (122 mg) in N,N-dimethylformamide (3 mL), 4-(4,6-dimethoxy-1,3,5- -2-yl)-4-methyl Borax (145 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (95.7 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.51-1.67(2H,m),1.83-1.93(2H,m),2.13(6H,s),2.56-2.75(2H,m),3.10-3.24(5H,m),3.87-3.96(1H,m), 4.27(2H,t,J=8.5Hz),4.37(2H,s),4.74-4.81(1H,m),6.77(1H,d,J=7.3Hz),6.80-6.84(2H,m),7.07-7.11(2H,m),7.39(1H,d,J=7.3Hz),7.47-7.53(1H,m),7.60-7.65(1H,m),7.97(1H,d,J=7.9Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.26 (3H, t, J = 7.3Hz), 1.51-1.67 (2H, m), 1.83-1.93 (2H, m), 2.13 (6H, s), 2.56 -2.75(2H,m),3.10-3.24(5H,m),3.87-3.96(1H,m), 4.27(2H,t,J=8.5Hz), 4.37(2H,s),4.74-4.81(1H , m), 6.77 (1H, d, J = 7.3 Hz), 6.80-6.84 (2H, m), 7.07-7.11 (2H, m), 7.39 (1H, d, J = 7.3 Hz), 7.47-7.53 ( 1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：561(M+H)+。 MS (APCI) m/z: 561 (M+H) + .

(實施例7)：於實施例(7d)合成 (Example 7): Synthesis in Example (7d)

1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indole-1 -yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(7a)5-(4-溴-3-甲氧基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (7a) 5-(4-Bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於1-溴-4-碘-2-甲氧基苯(1.51g)及5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(600mg)之1,4-二烷(8mL)溶液中添加碘化銅(I)(22.9mg)、N,N-二甲基甘胺酸(24.8mg)及碳酸銫(1.57g)，並於100℃攪拌6小時。冷卻至室溫後靜置一晚，再度於100℃攪拌9小時，將反應液以矽藻土過濾。將獲得的濾液於減壓下濃縮，殘渣以矽膠管柱層析(二氯甲烷/己烷)純化，獲得呈無色固體之標題化合物(529mg)。 1-Bromo-4-iodo-2-methoxybenzene (1.51g) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (600mg 1,4-two Copper (I) iodide (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added to the solution of the alkane (8 mL), and stirred at 100 ° C for 6 hours. After cooling to room temperature, it was allowed to stand overnight, and then stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure.

1H-NMR(400MHz,CDCl3)δ：1.55(9H,s),2.05(3H,s),3.03(2H,t,J=8.8Hz),3.83(3H,s),3.97-4.09(2H,m), 6.24(1H,dd,J=8.5,2.4Hz),6.54(1H,br s),6.75-6.84(1H,m),7.20-7.74(2H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.55 (9H, s), 2.05 (3H, s), 3.03 (2H, t, J = 8.8Hz), 3.83 (3H, s), 3.97-4.09 (2H , m), 6.24 (1H, dd, J = 8.5, 2.4 Hz), 6.54 (1H, br s), 6.75-6.84 (1H, m), 7.20-7.74 (2H, m).

(7b)5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (7b) 5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenoxy]-4-methyl-2,3 -Dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester

於實施例(7a)所獲得的化合物(200mg)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(173mg)之1,2-二甲氧基乙烷(6mL)溶液中添加碳酸鈉(61.8mg)之水溶液(2mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(37.6mg)，以微波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈茶色油狀物之標題化合物(214mg)。 Compound (200 mg) obtained in Example (7a), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 An aqueous solution (2 mL) of sodium carbonate (61.8 mg) was added to a solution of 6-dihydropyridine-1(2H)-yl]ethanone (173 mg) in 1,2-dimethoxyethane (6 mL). Stir at room temperature for 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (37.6 mg) was added and reacted at 130 ° C for 15 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),1.48-1.62(2H,m),2.08(3H,s),2.14(3H,d,J=7.3Hz),2.46-2.57(2H,br m),2.99-3.08(2H,m),3.56-3.63(1H,m),3.75(3H,s),3.99-4.07(2H,m),4.17-4.21(1H,br m),5.71(0.5H,s),5.75(0.5H,s),6.28(1H,d,J=8.5Hz),6.51(1H,br s),6.76-6.86(1H,br m),6.98(1H,d,J=8.5Hz),7.59-7.78(1H,br m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56 (9H, s), 1.48-1.62 (2H, m), 2.08 (3H, s), 2.14 (3H, d, J = 7.3 Hz), 2.46-2.57 (2H, br m), 2.99-3.08 (2H, m), 3.56-3.63 (1H, m), 3.75 (3H, s), 3.99-4.07 (2H, m), 4.17-4.21 (1H, br m) , 5.71 (0.5H, s), 5.75 (0.5H, s), 6.28 (1H, d, J = 8.5 Hz), 6.51 (1H, br s), 6.76-6.86 (1H, br m), 6.98 (1H , d, J = 8.5 Hz), 7.59-7.78 (1H, br m).

(7c)5-[4-(1-乙醯基哌啶-4-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (7c) 5-[4-(1-Ethylpiperidin-4-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indole-1 -Tributyl carboxylic acid ester

將實施例(7b)所獲得的化合物(214mg)溶解於甲醇 (3mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(43.0mg)，氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯，濾除不溶物後，藉由減壓下將濾液濃縮，獲得呈白色固體之標題化合物(195mg)。 The compound obtained in Example (7b) (214 mg) was dissolved in methanol (3 mL) and ethyl acetate (2 mL) were added 7.5% palladium carbon (43.0 mg), and stirred at room temperature for 18 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the title compound (195 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.50-1.63(11H,m),1.77-1.94(2H,m),2.08(3H,s),2.12(3H,s),2.53-2.70(1H,m),2.98-3.23(4H,m),3.77(3H,s),3.85-3.93(1H,m),3.97-4.08(2H,br m),4.73-4.81(1H,m),6.25-6.32(1H,m),6.52(1H,br s),6.75-6.85(1H,br m),6.90-6.97(1H,m),7.59-7.74(1H,br m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.63 (11H, m), 1.77-1.94 (2H, m), 2.08 (3H, s), 2.12 (3H, s), 2.53-2.70 (1H, m), 2.98-3.23 (4H, m), 3.77 (3H, s), 3.85-3.93 (1H, m), 3.97-4.08 (2H, br m), 4.73-4.81 (1H, m), 6.25-6.32 (1H, m), 6.52 (1H, br s), 6.75-6.85 (1H, br m), 6.90-6.97 (1H, m), 7.59-7.74 (1H, br m).

MS(APCI)m/z：461(M+H)+。 MS (APCI) m/z: 461 (M+H) + .

(7d)1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (7d) 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(7c)所獲得的化合物(195mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(3mL)，並於室溫攪拌18小時。減壓下濃縮反應液，藉由減壓乾燥，獲得呈白色固體之粗製之1-(4-{2-甲氧基-4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮鹽酸鹽(212mg)。 4N hydrochloric acid was added to a solution of the compound (195 mg) obtained in Example (7c) in dichloromethane (1 mL) Alkane solution (3 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and evaporated to dryness crystals crystalssssssssssssss Indole-5-yl)oxy]phenyl}piperidin-1-yl)ethanone hydrochloride (212 mg).

於獲得的化合物(212mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(140μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(211mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(131mg)，於室溫攪拌48小時。於反應液中 添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(174mg)。 Triethylamine (140 μL) was added to a solution of the obtained compound (212 mg) in N,N-dimethylcarbamide (3 mL) and stirred at room temperature for 5 min. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (211 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (131 mg) were stirred at room temperature for 48 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.47-1.60(2H,m),1.75-1.92(2H,m),2.12(3H,s),2.14(3H,s),2.57-2.68(1H,m),3.03-3.26(7H,m),3.78(3H,s),3.85-3.93(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.71-4.80(1H,m),6.32(1H,dd,J=8.5,2.4Hz),6.52(1H,d,J=2.4Hz),6.78(1H,d,J=8.5Hz),6.96(1H,d,J=8.5Hz),7.36(1H,d,J=8.5Hz),7.50-7.55(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.60 (2H, m), 1.75-1.92 (2H, m), 2.12 (3H, s), 2.14 (3H, s), 2.57-2.68 (1H, m), 3.03-3.26 (7H, m), 3.78 (3H, s), 3.85-3.93 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71-4.80 (1H, m), 6.32 (1H, dd, J = 8.5, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.50 - 7.55 (1H, m), 7.59 - 7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 ( 1H, d, J = 8.5Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例8)：於實施例(8c)合成 (Example 8): Synthesis in Example (8c)

(2S)-2-羥基-1-(4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2S)-2-hydroxy-1-(4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(8a)4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (8a) 4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

將實施例(95a)所獲得的化合物(2g)溶解於二氯甲 烷(10mL)及甲醇(10mL)，添加10%鈀碳(400mg)並於氫氣環境下，於室溫攪拌10小時。於反應液中添加二氯甲烷，濾除不溶物後，藉由減壓下將濾液濃縮而獲得呈白色固體之標題化合物(1.08g)。 The compound (2 g) obtained in Example (95a) was dissolved in dichloromethane. Alkane (10 mL) and methanol (10 mL) were added 10% palladium carbon (400 mg) and stirred at room temperature for 10 hr under hydrogen atmosphere. Methylene chloride was added to the reaction mixture, and the title compound (1.08 g) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.51-1.65(2H,m),1.67-1.77(2H,m),2.13(3H,s),2.29(3H,s),2.70-2.88(3H,br m),3.12(3H,s),3.21(2H,t,J=8.5Hz),4.18-4.32(4H,m),4.36(2H,s),6.63-6.71(2H,m),6.76(1H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.96(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.77 (2H, m), 2.13 (3H, s), 2.29 (3H, s) , 2.70-2.88 (3H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.18-4.32 (4H, m), 4.36 (2H, s), 6.63-6.71 ( 2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.05 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6) Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(8b)1-{4-甲基-5-[3-甲基-4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (8b) 1-{4-methyl-5-[3-methyl-4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl} -2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(8a)所獲得的化合物(1.08g)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌3小時。將混合液於減壓下濃縮，獲得的固體以乙酸乙酯洗淨後濾取，使乾燥而獲得呈白色固體之標題化合物(1.12g)。 4N hydrochloric acid was added to a solution of the compound (1.08 g) obtained in Example (8a) in dichloromethane (2 mL) Alkane solution (2 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure.

MS(APCI)m/z：519(M+H)+。 MS (APCI) m/z: 519 (M+H) + .

(8c)(2S)-2-羥基-1-(4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (8c)(2S)-2-hydroxy-1-(4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl) }-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(8b)所獲得的化合物(200mg)之N,N-二甲 基甲醯胺(5mL)溶液中添加三乙基胺(109μL)，並於室溫攪拌5分鐘。其次添加L-乳酸(37.1μL)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(82.9mg)、1-羥基苯并三唑一水和物(55.2mg)，並於室溫攪拌18小時。於混合液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(178mg)。 N,N-dimethyl hydride of the compound (200 mg) obtained in Example (8b) Triethylamine (109 μL) was added to a solution of carbamide (5 mL) and stirred at room temperature for 5 min. Next, L-lactic acid (37.1 μL), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (82.9 mg), 1-hydroxybenzotriazole-water and (55.2 mg) and stirred at room temperature for 18 h. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.36(3H,dd,J=15.9,6.1Hz),1.48-1.67(2H,m),1.79-1.92(2H,m),2.13(3H,s),2.30(3H,s),2.69-2.83(1H,m),2.86-2.97(1H,m),3.12(3H,s),3.13-3.25(3H,m),3.77-3.88(1H,m),3.94(1H,br s),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.44-4.60(1H,m),4.64-4.87(1H,m),6.63-6.71(2H,m),6.76(1H,d,J=8.5Hz),6.99-7.06(1H,m),7.36(1H,d,J=8.5Hz),7.48-7.55(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.36 (3H, dd, J = 15.9,6.1Hz), 1.48-1.67 (2H, m), 1.79-1.92 (2H, m), 2.13 (3H, s) , 2.30 (3H, s), 2.69-2.83 (1H, m), 2.86-2.97 (1H, m), 3.12 (3H, s), 3.13 - 3.25 (3H, m), 3.77-3.88 (1H, m) , 3.94 (1H, br s), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44 - 4.60 (1H, m), 4.64 - 4.87 (1H, m), 6.63 - 6.71 ( 2H, m), 6.76 (1H, d, J = 8.5 Hz), 6.99-7.06 (1H, m), 7.36 (1H, d, J = 8.5 Hz), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例9)：於實施例(9d)合成 (Example 9): Synthesis in Example (9d)

(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2-羥基丙烷-1-酮 (2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole哚-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2-hydroxypropan-1-one

(9a)4-{2-甲基-4-[(4-甲基-1-{[2-(乙基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (9a) 4-{2-Methyl-4-[(4-methyl-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester

於藉由與實施例(1b)同樣的手法合成的1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮(2g)、1-三級丁氧基羰基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫-2H-吡啶(1.4g)之1,2-二甲氧基乙烷(36mL)溶液中添加碳酸鈉(1.2g)之水溶液(12mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(123mg)，並以微波反應裝置，使於130℃反應15分鐘。再實施相同反應3次，冷卻至室溫後，合併全部的反應液，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(1.67g)。 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-inden-1-yl]- synthesized by the same method as in Example (1b) 2-[2-(ethylsulfonyl)phenyl]ethanone (2g), 1-tertiary butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2 Add sodium carbonate (1.2 g) to a solution of 1-dioxolan-2-yl)-3,6-dihydro-2H-pyridine (1.4 g) in 1,2-dimethoxyethane (36 mL) Aqueous solution (12 mL) was stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride methylene chloride complex (123 mg) was added and reacted at 130 ° C for 15 minutes in a microwave reactor. . The same reaction was carried out three times, and after cooling to room temperature, all the reaction liquids were combined, and water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.50(9H,s),2.13(3H,s),2.22(3H,s),2.27-2.38(2H,br m),3.21(4H,q,J=7.3Hz),3.55-3.65(2H,m),3.99-4.05(2H,br m),4.27(2H,t,J=8.2Hz),4.37(2H,s),5.53(1H,br s),6.63(1H,d,J=8.2Hz),6.69(1H,s),6.79(1H,d,J=8.5Hz),6.98(1H,t,J=7.9Hz),7.39(1H,d,J=6.7Hz),7.47-7.53(1H,m),7.59-7.64(1H,m),7.98(1H,d,J=8.5Hz),8.03(1H,d,J=6.7Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.26 (3H, t, J = 7.3Hz), 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.27-2.38 (2H , br m), 3.21 (4H, q, J = 7.3 Hz), 3.55-3.65 (2H, m), 3.99-4.05 (2H, br m), 4.27 (2H, t, J = 8.2 Hz), 4.37 ( 2H, s), 5.53 (1H, br s), 6.63 (1H, d, J = 8.2 Hz), 6.69 (1H, s), 6.79 (1H, d, J = 8.5 Hz), 6.98 (1H, t, J = 7.9 Hz), 7.39 (1H, d, J = 6.7 Hz), 7.47 - 7.53 (1H, m), 7.59 - 7.64 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.03 ( 1H, d, J = 6.7 Hz).

(9b)4-{2-甲基-4-[(4-甲基-1-{[2-(乙基磺醯基)苯 基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (9b) 4-{2-methyl-4-[(4-methyl-1-{[2-(ethylsulfonyl)benzene) Tert-butyl ketone}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

將實施例(9a)所獲得的化合物(1.1g)溶解於二氯甲烷(10mL)及甲醇(10mL)，添加10%鈀碳(220mg)並於氫氣環境下，於室溫攪拌10小時。於反應液中添加二氯甲烷並濾除不溶物後，藉由減壓下將濾液濃縮而獲得呈白色固體之標題化合物(1.27g)。 The compound (1.1 g) obtained in Example (9a) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and 10% palladium carbon (220 mg) was added and stirred at room temperature for 10 hours under hydrogen atmosphere. The title compound (1.27 g) was obtained as a white solid.

MS(APCI)m/z：633(M+H)+。 MS (APCI) m/z: 633 (M+H) + .

(9c)1-{4-甲基-5-[3-甲基-4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮鹽酸鹽 (9c) 1-{4-methyl-5-[3-methyl-4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl} -2-[2-(ethylsulfonyl)phenyl]ethanone hydrochloride

於實施例(9b)所獲得的化合物(1.27g)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌7小時。減壓下濃縮反應液，將殘渣以乙酸乙酯洗淨後濾取，藉由乾燥而獲得呈白色固體之標題化合物(1.15g)。 4N hydrochloric acid was added to a solution of the compound (1.27 g) obtained in Example (9b) in dichloromethane (2 mL) Alkane solution (2 mL) was stirred at room temperature for 7 h. The residue was evaporated to dryness crystals crystals crystals crystals

MS(APCI)m/z：533(M+H)+。 MS (APCI) m/z: 533 (M+H) + .

(9d)(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2-羥基丙烷-1-酮 (9d)(2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2-hydroxypropan-1-one

於實施例(9c)所獲得的化合物(150mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(110μL)，並於室溫攪拌5分鐘。其次添加L-乳酸(27.1μL)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(60.6mg)、1-羥基苯并三唑一水合物(40.4mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水 洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(109mg)。 Triethylamine (110 μL) was added to a solution of the compound (m. Next, L-lactic acid (27.1 μL), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (60.6 mg), 1-hydroxybenzotriazole monohydrate were added. (40.4 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. Organic layer with water and saturated brine After washing, it was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.36(3H,dd,J=15.9,6.7Hz),1.46-1.66(2H,m),1.78-1.92(2H,m),2.12(3H,s),2.30(3H,s),2.70-2.79(1H,m),2.84-3.00(1H,m),3.10-3.26(5H,m),3.78-3.88(1H,m),3.94(1H,d,J=7.3Hz),4.27(2H,t,J=7.9Hz),4.37(2H,s),4.45-4.58(1H,m),4.71-4.83(1H,m),6.63-6.71(2H,m),6.76(1H,d,J=9.2Hz),6.99-7.05(1H,m),7.39(1H,d,J=9.2Hz),7.47-7.53(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.36 (3H, dd, J = 15.9, 6.7 Hz), 1.46-1.66 (2H, m), 1.78-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.79 (1H, m), 2.84-3.00 (1H, m), 3.10-3.26 (5H, m), 3.78-3.88 (1H, m), 3.94 (1H, d, J = 7.3 Hz), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.45-4.58 (1H, m), 4.71-4.83 ( 1H,m),6.63-6.71(2H,m),6.76(1H,d,J=9.2Hz),6.99-7.05(1H,m),7.39(1H,d,J=9.2Hz),7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：605.2(M+H)+。 MS (APCI) m/z: 605.2 (M+H) + .

(實施例10) (Embodiment 10)

(2S)-2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2S)-2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(230μL)，並於室溫攪拌5分鐘。其次添加L-乳酸(57.1μL)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(159mg)、1-羥基苯并三 唑一水合物(84.9mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(152mg)。 Triethylamine (230 μL) was added to a solution of the compound (m. Next, L-lactic acid (57.1 μL), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (159 mg), 1-hydroxybenzotriene were added. The azole monohydrate (84.9 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.35(3H,dd,J=13.1,6.4Hz),1.57-1.73(2H,m),1.86-2.00(2H,m),2.13(3H,s),2.63-2.82(2H,m),3.02-3.15(4H,m),3.15-3.25(2H,m),3.71-3.87(1H,m),3.88-3.96(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.44-4.56(1H,m),4.67-4.82(1H,m),6.77(1H,d,J=8.5Hz),6.79-6.86(2H,m),7.06-7.15(2H,m),7.36(1H,d,J=7.9Hz),7.49-7.55(1H,m),7.59-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.35 (3H, dd, J = 13.1,6.4Hz), 1.57-1.73 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s) , 2.63-2.82 (2H, m), 3.02-3.15 (4H, m), 3.15-3.25 (2H, m), 3.71-3.87 (1H, m), 3.88-3.96 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44 - 4.56 (1H, m), 4.67 - 4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.86 (2H , m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J =8.5Hz), 8.07 (1H, d, J = 8.5Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例11) (Example 11)

(實施例11-1)：於實施例(11a)合成 (Example 11-1): Synthesis in Example (11a)

乙酸(2R)-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 Acetic acid (2R)-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

(實施例11-2)：於實施例(11b)合成 (Example 11-2): Synthesis in Example (11b)

(2R)-2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基) 苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2R)-2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(11a)乙酸(2R)-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 (11a) Acetic acid (2R)-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

於實施例(1e)所獲得的化合物(31.6mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(16μL)，並於室溫攪拌5分鐘。其次添加(S)-(-)-2-乙醯氧基丙酸(9.3mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(24.2mg)，並於室溫攪拌18小時。於反應物中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(31.7mg)。 Triethylamine (16 μL) was added to a solution of the compound (31.6 mg. Next, add (S)-(-)-2-ethyloxypropionic acid (9.3 mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (24.2 mg) was stirred at room temperature for 18 hours. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.42-1.49(3H,m),1.51-1.63(2H,m),1.83-1.98(2H,br m),2.13(3H,s),2.14(3H,s),2.63-2.79(2H,m),3.08-3.26(6H,m),3.88-3.99(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.70-4.79(1H,br m),5.40-5.50(1H,m),6.77(1H,d,J=9.2Hz),6.79-6.88(2H,m),7.05-7.15(2H,m),7.36(1H,d,J=7.3Hz),7.50-7.54(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 (3H) , s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3) Hz).

(11b)(2R)-2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (11b)(2R)-2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3 -dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(1a)所獲得的化合物(31.7mg)之四氫呋喃(2mL)與水(500μL)之混合溶液中添加1N氫氧化鈉水溶液(76.9μL)，並於室溫攪拌15小時。於減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(10.0mg)。 A 1N aqueous solution of sodium hydroxide (76.9 μL) was added to a mixed solution of the compound (31.7 mg) of THF (m. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.35(3H,dd,J=13.4,6.7Hz),1.56-1.70(2H,m),1.82-1.98(2H,m),2.12(3H,s),2.68-2.82(2H,m),3.09-3.27(6H,m),3.74-3.87(1H,m),3.98-4.06(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.45-4.53(1H,m),4.69-4.84(1H,m),6.67-6.85(3H,m),7.04-7.12(2H,m),7.34-7.39(1H,m),7.49-7.54(1H,m),7.57-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.70 (2H, m), 1.82-1.98 (2H, m), 2.12 (3H, s) , 2.68-2.82 (2H, m), 3.09-3.27 (6H, m), 3.74-3.87 (1H, m), 3.98-4.06 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.53 (1H, m), 4.69-4.84 (1H, m), 6.67-6.85 (3H, m), 7.04-7.12 (2H, m), 7.34-7.39 (1H, m) , 7.49-7.54 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例12) (Embodiment 12)

1-[5-(4-{1-[(1-羥基環丙基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(1-Hydroxycyclopropyl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indole -1-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲 基甲醯胺(5mL)溶液中添加三乙基胺(230μL)，並於室溫攪拌5分鐘。其次添加1-羥基-1-環丙烷甲酸(67.9mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(159mg)、1-羥基苯并三唑一水合物(84.9mg)，並於室溫攪拌5小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(233mg)。 N,N-dimethyl ester of the compound (300 mg) obtained in Example (1e) Triethylamine (230 μL) was added to a solution of carbamide (5 mL) and stirred at room temperature for 5 min. Next, 1-hydroxy-1-cyclopropanecarboxylic acid (67.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (159 mg), 1-hydroxybenzoate were added. Triazole monohydrate (84.9 mg) was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：0.94-1.03(2H,m),1.10-1.19(2H,m),1.60-1.69(2H,m),1.87-1.95(2H,m),2.13(3H,s),2.68-2.77(1H,m),2.84(1H,s),2.90-3.01(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.60-4.71(2H,m),6.75-6.78(1H,m),6.80-6.84(2H,m),7.08-7.13(2H,m),7.35-7.38(1H,m),7.49-7.55(1H,m),7.59-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 0.94-1.03 (2H, m), 1.10-1.19 (2H, m), 1.60-1.69 (2H, m), 1.87-1.95 (2H, m), 2.13 ( 3H, s), 2.68-2.77 (1H, m), 2.84 (1H, s), 2.90-3.01 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.60-4.71 (2H, m), 6.75-6.78 (1H, m), 6.80-6.84 (2H, m), 7.08-7.13 (2H , m), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J =8.5Hz).

MS(APCI)m/z：589(M+H)+。 MS (APCI) m/z: 589 (M+H) + .

(實施例13)：於實施例(13b)合成 (Example 13): Synthesis in Example (13b)

(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3 -dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(13a)1-{5-[4-(1-{[(4S)-2,2-二甲基-1,3-二氧戊環 -4-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (13a) 1-{5-[4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan) 4-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。添加按照文獻記載之方法(Bioorganic and Medicinal Chemistry Letters，2004，14，3231)合成的(4S)-2,2-二甲基-1,3-二氧戊環-4-甲酸(100mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯乙烷)純化，獲得呈白色固體之標題化合物(377mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. (4S)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid (100 mg) synthesized according to the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231), chlorine 4-(4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.40-1.45(6H,m),1.51-1.72(2H,m),1.84-1.95(2H,m),2.13(3H,s),2.62-2.79(2H,m),3.01-3.25(6H,m),4.10-4.19(1H,m),4.22-4.32(3H,m),4.36(2H,s),4.41-4.51(1H,m),4.67-4.76(2H,m),7.97(1H,d,J=9.2Hz),6.80-6.86(2H,m),7.06-7.11(2H,m),7.36(1H,d,J=6.7Hz),7.49-7.55(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40-1.45 (6H, m), 1.51-1.72 (2H, m), 1.84-1.95 (2H, m), 2.13 (3H, s), 2.62-2.79 ( 2H, m), 3.01-3.25 (6H, m), 4.10-4.19 (1H, m), 4.22-4.32 (3H, m), 4.36 (2H, s), 4.41-4.51 (1H, m), 4.67- 4.76 (2H, m), 7.97 (1H, d, J = 9.2 Hz), 6.80-6.86 (2H, m), 7.06-7.11 (2H, m), 7.36 (1H, d, J = 6.7 Hz), 7.49 - 7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).

(13b)(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (13b)(2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-) 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(13a)所獲得的化合物(200mg)之二氯甲烷 (1mL)與水(500μL)之混合溶液中添加4N鹽酸二烷溶液(2mL)，於室溫攪拌6小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，藉由減壓下濃縮，獲得呈白色固體之標題化合物(163mg)。 4N hydrochloric acid was added to a mixed solution of the compound (200 mg) obtained in Example (13a) in dichloromethane (1 mL) and water (500 μL) A solution of the alkane (2 mL) was stirred at room temperature for 6 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.52-1.69(1H,m),1.89-1.99(2H,m),2.12(3H,s),2.33-2.40(1H,m),2.70-2.82(2H,m),3.12(3H,s),3.15-3.24(3H,m),3.57-3.66(1H,m),3.74-3.80(1H,m),3.85-3.95(1H,m),3.98-4.02(1H,m),4.29(3H,t,J=8.5Hz),4.36(2H,s),4.45-4.55(1H,m),4.67-4.80(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.05-7.13(2H,m),7.33-7.38(1H,m),7.48-7.56(1H,m),7.58-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.69 (1H, m), 1.89-1.99 (2H, m), 2.12 (3H, s), 2.33-2.40 (1H, m), 2.70-2.82 ( 2H,m), 3.12(3H,s), 3.15-3.24(3H,m),3.57-3.66(1H,m),3.74-3.80(1H,m),3.85-3.95(1H,m),3.98- 4.02 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.45-4.55 (1H, m), 4.67-4.80 (1H, m), 6.77 (1H, d, J=8.5 Hz), 6.82 (2H, d, J=8.5 Hz), 7.05-7.13 (2H, m), 7.33-7.38 (1H, m), 7.48-7.56 (1H, m), 7.58-7.66 (1H , m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：593(M+H)+。 MS (APCI) m/z: 593 (M+H) + .

(實施例14)：於實施例(14b)合成 (Example 14): Synthesis in Example (14b)

(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2,3-二羥基丙烷-1-酮 (2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole哚-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2,3-dihydroxypropan-1-one

(14a)1-{5-[4-(1-{[(4S)-2,2-二甲基-1,3-二氧戊環-4-基]羰基}哌啶-4-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (14a) 1-{5-[4-(1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]carbonyl}piperidin-4-yl) -3-methylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

於實施例(9c)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(97μL)，並於室溫攪拌5分鐘。其次添加(4S)-2,2-二甲基-1,3-二氧戊環-4-甲酸(62.0mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(145mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(160mg)。 Triethylamine (97 μL) was added to a solution of the compound (m. Next, (4S)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid (62.0 mg) and 4-(4,6-dimethoxy-1,3,5 chloride were added. -three -2-yl)-4-methyl The guanidine (145 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.43(6H,d,J=9.8Hz),1.52-1.72(2H,m),1.76-1.89(2H,m),2.12(3H,s),2.30(3H,s),2.64-2.78(1H,m),2.86-2.98(1H,m),3.03-3.14(1H,m),3.16-3.28(4H,m),4.12-4.19(1H,m),4.23-4.31(3H,m),4.37(2H,s),4.41-4.47(1H,m),4.69-4.80(2H,m),6.62-6.72(2H,m),6.77(1H,d,J=8.5Hz),6.98-7.06(1H,m),7.39(1H,d,J=7.9Hz),7.46-7.55(1H,m),7.58-7.67(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.43 (6H, d, J = 9.8 Hz), 1.52-1.72 (2H, m), 1.76-1.89 (2H , m), 2.12 (3H, s), 2.30 (3H, s), 2.64-2.78 (1H, m), 2.86-2.98 (1H, m), 3.03-3.14 (1H, m), 3.16-3.28 (4H , m), 4.12-4.19 (1H, m), 4.23-4.31 (3H, m), 4.37 (2H, s), 4.41-4.47 (1H, m), 4.69-4.80 (2H, m), 6.62-6.72 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.06 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.46-7.55 (1H, m), 7.58- 7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

(14b)(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2,3-二羥基丙烷-1-酮 (14b)(2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2,3-dihydroxypropan-1-one

於實施例(14a)所獲得的化合物(160mg)之二氯甲烷(1mL)與水(500μL)之混合溶液中添加4N鹽酸二烷溶液(2mL)，於室溫攪拌18小時。於反應液中添加水，並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無 水硫酸鈉乾燥後，藉由減壓下濃縮，獲得呈白色固體之標題化合物(127mg)。 4N hydrochloric acid was added to a mixed solution of the compound (160 mg) obtained in Example (14a) in dichloromethane (1 mL) and water (500 μL) A solution of the alkane (2 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.56-1.67(2H,m),1.79-1.91(2H,m),2.12(3H,s),2.29(3H,d,J=9.8Hz),2.35-2.43(1H,m),2.73-2.82(1H,m),2.87-2.98(1H,m),3.13-3.26(5H,m),3.60-3.67(1H,m),3.75-3.82(1H,m),3.88-3.97(1H,m),4.00-4.04(1H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.47-4.56(1H,m),4.70-4.80(1H,m),6.64-6.70(2H,m),6.77(1H,d,J=8.5Hz),6.98-7.04(1H,m),7.40(1H,d,J=7.3Hz),7.47-7.54(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.26 (3H, t, J = 7.3Hz), 1.56-1.67 (2H, m), 1.79-1.91 (2H, m), 2.12 (3H, s), 2.29 (3H,d,J=9.8Hz), 2.35-2.43(1H,m),2.73-2.82(1H,m),2.87-2.98(1H,m),3.13-3.26(5H,m),3.60-3.67 (1H, m), 3.75-3.82 (1H, m), 3.88-3.97 (1H, m), 4.00-4.04 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s ), 4.47-4.56 (1H, m), 4.70-4.80 (1H, m), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 6.98-7.04 (1H, m), 7.40 (1H, d, J = 7.3 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5Hz).

MS(APCI)m/z：621(M+H)+。 MS (APCI) m/z: 621 (M+H) + .

(實施例15) (Example 15)

1-(4-甲基-5-{4-[1-(甲基磺醯基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(4-Methyl-5-{4-[1-(methylsulfonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl )-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(100mg)之二氯甲烷(5mL)溶液中添加甲磺醯氯(17.3μL)、三乙基胺(51μL)，並於室溫攪拌18小時。減壓下將反應液濃縮，並餾除溶媒。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(106mg)。 Methanesulfonium chloride (17.3 μL) and triethylamine (51 μL) were added to a solution of the compound (m. The reaction solution was concentrated under reduced pressure, and the solvent was evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.75-1.87(2H,m), 1.90-1.98(2H,m),2.13(3H,s),2.47-2.62(1H,m),2.70-2.80(2H,m),2.82(3H,s),3.12(3H,s),3.16-3.25(2H,m),3.87-3.98(2H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.77(1H,d,J=7.9Hz),6.83(2H,d,J=8.5Hz),7.11(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.49-7.55(1H,m),7.58-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.75-1.87 (2H, m), 1.90-1.98 (2H, m), 2.13 (3H, s), 2.47-2.62 (1H, m), 2.70-2.80 ( 2H,m), 2.82 (3H, s), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.87-3.98 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 7.9 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.11 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：583(M+H)+。 MS (APCI) m/z: 583 (M+H) + .

(實施例16) (Embodiment 16)

1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1,2-二酮 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Ethyl]phenyl]piperidin-1-yl)propane-1,2-dione

於實施例(1e)所獲得的化合物(143mg)之二氯甲烷(4mL)溶液中添加2-側氧基丙酸(0.027mL)-1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(101mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(36.0mg)、N,N-二異丙基乙基胺(0.138mL)並於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(131mg)。 To a solution of the compound (143 mg) obtained in m. m. m. Propyl)carboxylimine hydrochloride (101 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (36.0 mg), N,N-diisopropyl Ethylamine (0.138 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(500MHz,CDCl3)δ：1.60-1.73(2H,m),1.85-1.98(2H,m),2.12(3H,s),2.45(3H,s),2.70-2.81(2H,m),3.09-3.24(6H,m),3.85-3.93(1H,m), 4.25-4.32(2H,m),4.36(2H,s),4.62-4.67(1H,m),6.75-6.85(3H,m),7.08-7.13(2H,m),7.35-7.38(1H,m),7.50-7.55(1H,m),7.60-7.64(1H,m),7.96-7.99(1H,m),8.06-8.10(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 1.60-1.73 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.45 (3H, s), 2.70-2.81 (2H, m), 3.09-3.24 (6H, m), 3.85-3.93 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.62-4.67 (1H, m), 6.75-6.85 ( 3H,m),7.08-7.13(2H,m),7.35-7.38(1H,m), 7.50-7.55(1H,m), 7.60-7.64(1H,m),7.96-7.99(1H,m), 8.06-8.10 (1H, m).

MS(APCI)m/z：575(M+H)+。 MS (APCI) m/z: 575 (M+H) + .

(實施例17)：於實施例(17b)合成 (Example 17): Synthesis in Example (17b)

3-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 3-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(17a)1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-3-(丙-2-烯-1-基氧基)丙烷-1-酮 (17a) 1-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole) -5-yl)oxy]phenyl}piperidin-1-yl)-3-(prop-2-en-1-yloxy)propan-1-one

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。添加3-烯丙氧基丙酸(81.7μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(213mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. Add 3-allyloxypropionic acid (81.7 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.48-1.66(2H,m), 1.81-1.94(2H,m),2.13(3H,s),2.57-2.76(4H,m),3.04-3.25(6H,m),3.79(2H,t,J=7.0Hz),3.96-4.05(3H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.73-4.84(1H,m),5.18(1H,d,J=10.4Hz),5.28(1H,d,J=17.1Hz),5.85-5.99(1H,m),6.77(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.66 (2H, m), 1.81-1.94 (2H, m), 2.13 (3H, s), 2.57-2.76 (4H, m), 3.04-3.25 ( 6H,m), 3.79 (2H, t, J=7.0Hz), 3.96-4.05(3H,m), 4.29(2H,t,J=8.5Hz), 4.36(2H,s),4.73-4.84(1H , m), 5.18 (1H, d, J = 10.4 Hz), 5.28 (1H, d, J = 17.1 Hz), 5.85-5.99 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H) , t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(17b)3-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (17b) 3-Hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(17a)所獲得的化合物(213mg)之四氫呋喃(5mL)溶液中添加1,3-二甲基巴比妥酸(1,3-dimethyl-barbituric acid)(107mg)、肆(三苯基膦)鈀(0)(20.0mg)，氮氣環境下，於90℃攪拌7小時。減壓下將反應液濃縮，藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)及胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(147mg)。 1,3-dimethyl-barbituric acid (107 mg), hydrazine (triphenylbenzene) was added to a solution of the compound (213 mg) obtained in Example (17a) in tetrahydrofuran (5 mL). Palladium (0) (20.0 mg) was stirred at 90 ° C for 7 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and purified, m. m. m. The title compound (147 mg) was obtained as white crystal.

1H-NMR(400MHz,CDCl3)δ：1.51-1.64(2H,m),1.85-1.95(2H,m),2.13(3H,s),2.54-2.75(4H,m),3.06-3.15(4H,m),3.21(2H,t,J=8.5Hz),3.48-3.56(1H,m),3.85-3.95(3H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.75-4.82(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=8.5Hz),7.49-7.54(1H,m),7.59-7.64(1H,m),7.97(1H,d,J= 8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.64 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.54-2.75 (4H, m), 3.06-3.15 ( 4H,m), 3.21 (2H, t, J=8.5Hz), 3.48-3.56(1H,m), 3.85-3.95(3H,m), 4.29(2H,t,J=8.5Hz), 4.36(2H , s), 4.75-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H,d,J=8.5Hz), 7.49-7.54(1H,m), 7.59-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5 Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例18) (Embodiment 18)

2,2-二乙氧基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 2,2-diethoxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。其次添加二乙氧基乙酸(98.6mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(353mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. Secondly added diethoxyacetic acid (98.6mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.20-1.29(6H,m),1.53-1.66(2H,m),1.81-1.93(2H,m),2.13(3H,s),2.62-2.78(2H,m),2.95-3.08(1H,m),3.12(3H,s),3.14-3.24(2H,m),3.55-3.67(2H,m),3.68-3.80(2H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.48-4.58(1H,m),4.63-4.73(1H,m),4.99(1H,s),6.74-6.86(3H,m),7.05-7.14(2H,m),7.36(1H,d,J=7.3Hz),7.48-7.55(1H, m),7.58-7.67(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.20-1.29 (6H, m), 1.53-1.66 (2H, m), 1.81-1.93 (2H, m), 2.13 (3H, s), 2.62-2.78 ( 2H, m), 2.95-3.08 (1H, m), 3.12 (3H, s), 3.14-3.24 (2H, m), 3.55-3.67 (2H, m), 3.68-3.80 (2H, m), 4.28 ( 2H,t,J=8.2Hz), 4.36(2H,s), 4.48-4.58(1H,m),4.63-4.73(1H,m),4.99(1H,s),6.74-6.86(3H,m) , 7.05-7.14(2H,m), 7.36(1H,d,J=7.3Hz), 7.48-7.55(1H, m), 7.58-7.67(1H,m),7.97(1H,d,J=8.5Hz ), 8.07 (1H, d, J = 8.5Hz).

MS(APCI)m/z：635(M+H)+。 MS (APCI) m/z: 635 (M+H) + .

(實施例19) (Embodiment 19)

(2S)-2-羥基丙酸(2S)-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 (2S)-2-hydroxypropionic acid (2S)-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

於實施例(1e)所獲得的化合物(150mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(77μL)，並於室溫攪拌5分鐘。其次添加L-乳酸(35.7μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(115mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯乙烷)純化，獲得呈白色固體之標題化合物(26.6mg)。 Triethylamine (77 μL) was added to a solution of the compound (l. Next added L-lactic acid (35.7 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (115 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.47-1.60(8H,m),1.83-1.95(2H,m),2.13(3H,s),2.64-2.78(2H,m),3.09-3.14(4H,m),3.16-3.26(3H,m),3.84-3.96(1H,m),4.29(2H,t,J=8.5Hz),4.35-4.38(3H,m),4.66-4.78(1H,m),5.45-5.55(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.06-7.14(2H,m),7.33-7.38(1H,m),7.49-7.57(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5 Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.60 (8H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.64-2.78 (2H, m), 3.09-3.14 ( 4H,m), 3.16-3.26(3H,m),3.84-3.96(1H,m), 4.29(2H,t,J=8.5Hz), 4.35-4.38(3H,m),4.66-4.78(1H, m), 5.45-5.55 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.33 - 7.38 (1H , m), 7.49-7.57 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：649(M+H)+。 MS (APCI) m/z: 649 (M+H) + .

(實施例20) (Embodiment 20)

2-甲氧基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 2-methoxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H) -吲哚-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

於實施例(1e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(4mL)溶液中添加三乙基胺(205μL)，並於室溫攪拌5分鐘。其次添加甲氧基乙酸(34.2μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(153mg)，並於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(125mg)。 Triethylamine (205 μL) was added to a solution of the compound (m. Next added methoxyacetic acid (34.2 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (153 mg) and stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.53-1.66(2H,m),1.84-1.94(2H,m),2.13(3H,s),2.60-2.79(2H,m),3.03-3.14(4H,m),3.16-3.26(2H,m),3.46(3H,s),3.93-4.03(1H,m),4.06-4.21(2H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.69-4.77(1H,m),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.58-7.64(1H, m),7.97(1H,d,J=7.9Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.66 (2H, m), 1.84-1.94 (2H, m), 2.13 (3H, s), 2.60-2.79 (2H, m), 3.03-3.14 ( 4H,m), 3.16-3.26(2H,m), 3.46(3H,s),3.93-4.03(1H,m),4.06-4.21(2H,m), 4.28(2H,t,J=8.2Hz) , 4.36 (2H, s), 4.69-4.77 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.07 (1H, d , J = 7.9Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例21) (Example 21)

3-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-3-側氧基丙腈 3-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Oxy]phenyl]piperidin-1-yl)-3-oxopropiononitrile

於2-氰基乙酸(100mg)之二氯甲烷(3mL)溶液中添加草醯氯(151μL)、N,N-二甲基甲醯胺(9.05μL)，並於室溫攪拌1小時。減壓下將反應液濃縮，獲得為茶色油狀物之粗製的2-氰基乙醯氯(121mg)。 To a solution of 2-cyanoacetic acid (100 mg) in dichloromethane (3 mL), EtOAc (EtOAc m. The reaction mixture was concentrated to dryness crystals crystals crystals crystals

於實施例(1e)所獲得的化合物(61.9mg)之二氯甲烷(3mL)溶液中依序添加上述2-氰基乙醯氯(121mg)、三乙基胺(240μL)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈淡黃色固體之標題化合物(40.6mg)。 The above 2-cyanoacetonitrile chloride (121 mg) and triethylamine (240 μL) were sequentially added to a solution of the compound (61.9 mg) obtained from m. Stir for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.53-1.72(1H,m),1.86-2.01(2H,m),2.12(3H,s),2.66-2.80(2H,m),3.12(3H,s),3.18-3.36(3H,m),3.52(2H,d,J=3.1Hz),3.78-3.86(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.68-4.78(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J= 8.5Hz),7.10(3H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.48-7.57(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.53-1.72 (1H, m), 1.86-2.01 (2H, m), 2.12 (3H, s), 2.66-2.80 (2H, m), 3.12 (3H, s), 3.18-3.36 (3H, m), 3.52 (2H, d, J = 3.1 Hz), 3.78-3.86 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s ), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (3H, d, J = 8.5 Hz), 7.36 (1H) , d, J = 7.9 Hz), 7.48-7.57 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz) .

MS(APCI)m/z：572(M+H)+。 MS (APCI) m/z: 572 (M+H) + .

(實施例22) (Example 22)

(實施例22-1)：於實施例(22a)合成 (Example 22-1): Synthesis in Example (22a)

1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-氟苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-fluorophenoxy}-4-methyl-2,3-dihydro-1H-indole- 1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例22-2)：於實施例(22b)合成 (Example 22-2): Synthesis in Example (22b)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-氟苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-fluorophenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2- (methylsulfonyl)phenyl]ethanone

(22a)1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-氟苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (22a) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-fluorophenoxy}-4-methyl-2,3-dihydro-1H-indole- 1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於1-[5-(4-溴-3-氟苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮(65.5mg)、實施例(103b)所獲得的化合物(61.3mg)之1,2-二甲氧基乙烷(3 mL)溶液中添加碳酸鈉(40.2mg)之水溶液(1mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(10.3mg)，以微波反應裝置，使於130℃反應40分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(34.1mg)。 1-[5-(4-Bromo-3-fluorophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Benzyl)phenyl]ethanone (65.5 mg), the compound obtained in Example (103b) (61.3 mg) of 1,2-dimethoxyethane (3) An aqueous solution (1 mL) of sodium carbonate (40.2 mg) was added to the solution and stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride methylene chloride complex (10.3 mg) was added, and the mixture was reacted at 130 ° C for 40 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.10(3H,s),2.43-2.68(2H,br m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.64-3.89(7H,m),3.93-4.00(1H,m),4.20-4.39(1H,m),4.21-4.37(6H,m),5.89(1H,br s),6.54(1H,d,J=11.0Hz),6.63(1H,d,J=11.0Hz),6.82(1H,d,J=8.5Hz),7.13(1H,t,J=8.5Hz),7.37(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),8.01(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 2.10 (3H, s), 2.43 - 2.68 (2H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.64 3.89 (7H, m), 3.93-4.00 (1H, m), 4.20-4.39 (1H, m), 4.21-4.37 (6H, m), 5.89 (1H, br s), 6.54 (1H, d, J = 11.0 Hz), 6.63 (1H, d, J = 11.0 Hz), 6.82 (1H, d, J = 8.5 Hz), 7.13 (1H, t, J = 8.5 Hz), 7.37 (1H, d, J = 7.9 Hz) ), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

(22b)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-氟苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (22b)1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-fluorophenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2- (methylsulfonyl)phenyl]ethanone

將實施例(22a)所獲得的化合物(34.1mg)溶解於四氫呋喃(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(7.0mg)並於氫氣環境下，於室溫攪拌15小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(28.3mg)。 The compound (34.1 mg) obtained in Example (22a) was dissolved in tetrahydrofuran (2 mL) and ethyl acetate (2 mL), and then 7.5% palladium carbon (7.0 mg) was added and stirred at room temperature for 15 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.57-1.75(2H,m),1.81-1.96(2H,m),2.10(3H,s),2.24-2.35(1H,m),2.58-2.72(1H,m),2.98-3.14(4H,m),3.17-3.25(2H,m),3.68-3.90(5H,m),3.91-3.97(1H,m),4.02-4.16(1H,m),4.27-4.38(5H,m),4.67-4.77(1H,m),6.50-6.57(1H,m),6.60-6.64(1H,m),6.78-6.82(1H,m),7.01-7.10(1H,m),7.36(1H,d,J=7.9Hz),7.49-7.56(1H,m),7.60-7.65(1H,m),8.00(1H,d,J=8.5Hz),8.06-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.75 (2H, m), 1.81-1.96 (2H, m), 2.10 (3H, s), 2.24-2.35 (1H, m), 2.58-2.72 ( 1H, m), 2.98-3.14 (4H, m), 3.17-3.25 (2H, m), 3.68-3.90 (5H, m), 3.91-3.97 (1H, m), 4.02-4.16 (1H, m), 4.27-4.38 (5H, m), 4.67-4.77 (1H, m), 6.50-6.57 (1H, m), 6.60-6.64 (1H, m), 6.78-6.82 (1H, m), 7.01-7.10 (1H , m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.56 (1H, m), 7.60-7.65 (1H, m), 8.00 (1H, d, J = 8.5 Hz), 8.06-8.10 ( 1H, m).

MS(APCI)m/z：637(M+H)+。 MS (APCI) m/z: 637 (M+H) + .

(實施例23) (Example 23)

(實施例23-1)：於實施例(23b)合成 (Example 23-1): Synthesis in Example (23b)

1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-甲氧基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methoxyphenoxy}-4-methyl-2,3-dihydro-1H-indole哚-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例23-2)：於實施例(23c)合成 (Example 23-2): Synthesis in Example (23c)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-甲氧基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-methoxyphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[ 2-(methylsulfonyl)phenyl]ethanone

(23a)1-[5-(4-溴-3-甲氧基苯氧基)-4-甲基-2,3-二氫 -1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (23a) 1-[5-(4-Bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro -1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(7a)所獲得的化合物(400mg)之二氯甲烷(4mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌2小時30分鐘。將反應液濃縮，獲得粗製之5-(4-溴-3-甲氧基苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(336mg)。 4N hydrochloric acid was added to a solution of the compound (400 mg) obtained in Example (7a) in dichloromethane (4 mL) Alkane solution (4 mL) was stirred at room temperature for 2 h 30 min. The reaction solution was concentrated to give crude 5-(4-bromo-3-methoxyphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (336 mg).

於獲得的化合物(336mg)之N,N-二甲基甲醯胺(10mL)溶液中添加N-甲基啉(0.202mL)，並於室溫攪拌15分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(382mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(256mg)，並於室溫攪拌16小時30分鐘。減壓下濃縮反應液，殘渣以矽膠管柱層析(二氯甲烷/己烷→乙酸乙酯/二氯甲烷)純化，獲得呈無色固體之標題化合物(534mg)。 Add N-methyl to a solution of the obtained compound (336 mg) in N,N-dimethylformamide (10 mL) The morpholine (0.202 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borane (382 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (256 mg) were stirred at room temperature for 16 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：2.11(3H,s),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.84(3H,s),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.25-6.29(1H,m),6.54-6.56(1H,m),6.80(1H,d,J=8.5Hz),7.34-7.39(2H,m),7.50-7.55(1H,m),7.60-7.65(1H,m),7.99(1H,d,J=9.1Hz),8.06-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5Hz), 3.84 (3H, s), 4.29 (2H, t , J = 8.5 Hz), 4.36 (2H, s), 6.25-6.29 (1H, m), 6.54 - 6.56 (1H, m), 6.80 (1H, d, J = 8.5 Hz), 7.34 - 7.39 (2H, m), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 7.99 (1H, d, J = 9.1 Hz), 8.06-8.09 (1H, m).

MS(APCI)m/z：530(M+H)+。 MS (APCI) m/z: 530 (M+H) + .

(23b)1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-3-甲氧基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (23b) 1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-methoxyphenoxy}-4-methyl-2,3-dihydro-1H-indole哚-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(23a)所獲得的化合物(70.0mg)及實施例 (103b)所獲得的化合物(64.0mg)之1,2-二甲氧基乙烷(3mL)溶液中添加碳酸鈉(40.2mg)之水溶液(1mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(10.8mg)，以微波反應裝置，使於130℃反應1小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(40.6mg)。 Compound (70.0 mg) obtained in Example (23a) and examples (103b) A solution (1 mL) of sodium carbonate (40.2 mg) was added. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (10.8 mg) was added and reacted at 130 ° C for 1 hour in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.46-2.62(2H,br m),3.13(3H,s),3.18-3.26(2H,m),3.59-3.91(10H,m),3.92-3.99(1H,m),4.07-4.22(1H,m),4.24-4.40(6H,m),5.69-5.78(1H,m),6.26-6.34(1H,m),6.52(1H,br s),6.81(1H,d,J=9.2Hz),7.00(1H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.60-7.64(1H,m),7.99(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.46-2.62 (2H, br m), 3.13 (3H, s), 3.18-3.26 (2H, m), 3.59-3.91 (10H , m), 3.92-3.99 (1H, m), 4.07-4.22 (1H, m), 4.24-4.40 (6H, m), 5.69-5.78 (1H, m), 6.26-6.34 (1H, m), 6.52 (1H, br s), 6.81 (1H, d, J = 9.2 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(23c)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-3-甲氧基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (23c)1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-3-methoxyphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[ 2-(methylsulfonyl)phenyl]ethanone

將實施例(23b)所獲得的化合物(35.2mg)溶解於四氫呋喃(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(7.0mg)並於氫氣環境下，於室溫攪拌15小時。於反應液中添加乙酸乙酯，濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得 呈白色固體之標題化合物(31.3mg)。 The compound (35.2 mg) obtained in Example (23b) was dissolved in THF (2 mL) and ethyl acetate (2 mL). Ethyl acetate was added to the reaction mixture, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane). The title compound (31.3 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.54-1.66(2H,m),1.78-1.97(2H,m),2.14(3H,s),2.23-2.34(1H,m),2.58-2.75(1H,m),3.05-3.15(4H,m),3.18-3.25(2H,m),3.64-3.98(9H,m),4.03-4.15(1H,m),4.24-4.39(5H,m),4.63-4.76(1H,m),6.28-6.33(1H,m),6.48-6.53(1H,m),6.75-6.82(1H,m),6.91-7.03(1H,m),7.33-7.40(1H,m),7.47-7.55(1H,m),7.59-7.67(1H,m),7.93-7.99(1H,m),8.05-8.11(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.66 (2H, m), 1.78-1.97 (2H, m), 2.14 (3H, s), 2.23 - 2.34 (1H, m), 2.58-2. 1H,m), 3.05-3.15(4H,m), 3.18-3.25(2H,m),3.64-3.98(9H,m),4.03-4.15(1H,m),4.24-4.39(5H,m), 4.63-4.76 (1H, m), 6.28-6.33 (1H, m), 6.48-6.53 (1H, m), 6.75-6.82 (1H, m), 6.91-7.03 (1H, m), 7.33-7.40 (1H , m), 7.47-7.55 (1H, m), 7.59-7.67 (1H, m), 7.93-7.99 (1H, m), 8.05-8.11 (1H, m).

MS(APCI)m/z：649(M+H)+。 MS (APCI) m/z: 649 (M+H) + .

(實施例24) (Example 24)

(實施例24-1)：於實施例(24c)合成 (Example 24-1): Synthesis in Example (24c)

1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2,5-dimethylphenoxy}-4-methyl-2,3-dihydro-1H -吲哚-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例24-2)：於實施例(24d)合成 (Example 24-2): Synthesis in Example (24d)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-2,5-dimethylphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2 -[2-(methylsulfonyl)phenyl]ethanone

(24a)5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (24a) 5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於1-溴-2,5-二甲基-4-碘苯(1.50g)及5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(600mg)之1,4-二烷(9mL)溶液中添加碘化銅(I)(22.9mg)、N,N-二甲基甘胺酸(24.8mg)及碳酸銫(1.57g)，並於100℃攪拌4小時30分鐘。冷卻至室溫後靜置一晚，再度於100℃攪拌9小時，將反應液以矽藻土過濾。將獲得的濾液於減壓下濃縮，殘渣以矽膠管柱層析(二氯甲烷/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(587mg)。 1-bromo-2,5-dimethyl-4-iodobenzene (1.50 g) and 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (600mg) of 1,4-two Copper (I) iodide (22.9 mg), N,N-dimethylglycine (24.8 mg) and cesium carbonate (1.57 g) were added to the alkane (9 mL) solution, and stirred at 100 ° C for 4 hours and 30 minutes. After cooling to room temperature, it was allowed to stand overnight, and then stirred at 100 ° C for 9 hours, and the reaction liquid was filtered through celite. The obtained filtrate was concentrated under reduced pressure.

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),2.07(3H,s),2.20-2.27(6H,m),3.03(2H,t,J=8.8Hz),3.99-4.08(2H,m),6.40-6.48(1H,m),6.58-6.71(1H,m),7.19-7.70(2H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56 (9H, s), 2.07 (3H, s), 2.20-2.27 (6H, m), 3.03 (2H, t, J = 8.8 Hz), 3.99-4.08 (2H, m), 6.40-6.48 (1H, m), 6.58-6.71 (1H, m), 7.19-7.70 (2H, m).

(24b)1-[5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (24b) 1-[5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[ 2-(methylsulfonyl)phenyl]ethanone

於實施例(24a)所獲得的化合物(300mg)之二氯甲烷(4mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌1小時。將反應液濃縮，獲得粗製之5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(312mg)。 4N hydrochloric acid was added to a solution of the compound (300 mg) obtained in Example (24a) in dichloromethane (4 mL) A solution of the alkane (4 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 5-(4-bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride (312 mg).

於獲得的化合物(312mg)之N,N-二甲基甲醯胺(4mL)溶液中添加N-甲基啉(0.153mL)，並於室溫攪拌15分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(288mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(193mg)，並於室溫攪拌18 小時30分鐘。減壓下濃縮反應液，殘渣以矽膠管柱層析(二氯甲烷/己烷→乙酸乙酯/二氯甲烷)純化，獲得呈無色固體之標題化合物(383mg)。 Add N-methyl to a solution of the obtained compound (312 mg) in N,N-dimethylformamide (4 mL) The morpholine (0.153 mL) was stirred at room temperature for 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (288 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (193 mg) were stirred at room temperature for 18 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.21-2.30(6H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),4.28(2H,t,J=8.5Hz),4.36(2H,s),6.49(1H,s),6.61(1H,d,J=8.5Hz),7.34-7.38(2H,m),7.49-7.55(1H,m),7.59-7.64(1H,m),7.94(1H,d,J=8.5Hz),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.21-2.30 (6H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 4.28 (2H) , t, J = 8.5 Hz), 4.36 (2H, s), 6.49 (1H, s), 6.61 (1H, d, J = 8.5 Hz), 7.34 - 7.38 (2H, m), 7.49 - 7.55 (1H, m), 7.59-7.64 (1H, m), 7.94 (1H, d, J = 8.5 Hz), 8.05-8.10 (1H, m).

MS(APCI)m/z：528(M+H)+。 MS (APCI) m/z: 528 (M+H) + .

(24c)1-(5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (24c)1-(5-{4-[1-(1,4-di) Alkan-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2,5-dimethylphenoxy}-4-methyl-2,3-dihydro-1H -吲哚-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(24b)所獲得的化合物(70.0mg)、實施例(103b)所獲得的化合物(64.2mg)之1,2-二甲氧基乙烷(3mL)溶液中添加碳酸鈉(42.1mg)之水溶液(1mL)，並於室溫攪拌5分鐘。添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(10.8mg)，以微波反應裝置，使於130℃反應1小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(31.1mg)。 Sodium carbonate (42.1 mg) was added to a solution of the compound obtained in Example (24b) (70.0 mg) and the compound obtained in Example (103b) (64.2 mg) in 1,2-dimethoxyethane (3 mL) The aqueous solution (1 mL) was stirred at room temperature for 5 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (10.8 mg) was added, and the mixture was reacted at 130 ° C for 1 hour in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.15(6H,d,J=11.6Hz),2.24(3H,s),2.31-2.52(2H,m),3.12(3H,s),3.23(2H, t,J=8.5Hz),3.60-3.92(7H,m),3.94-4.02(1H,m),4.06-4.18(1H,m),4.19-4.38(6H,m),5.50-5.60(1H,m),6.45(1H,s),6.62(1H,d,J=8.5Hz),6.92(1H,s),7.36(1H,d,J=7.9Hz),7.53(1H,d,J=7.9Hz),7.61(1H,d,J=7.9Hz),7.94(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (6H, d, J = 11.6 Hz), 2.24 (3H, s), 2.31-2.52 (2H, m), 3.12 (3H, s), 3.23 (2H) , t, J = 8.5 Hz), 3.60-3.92 (7H, m), 3.94-4.02 (1H, m), 4.06-4.18 (1H, m), 4.19-4.38 (6H, m), 5.50-5.60 (1H , m), 6.45 (1H, s), 6.62 (1H, d, J = 8.5 Hz), 6.92 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(24d)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (24d) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]-2,5-dimethylphenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2 -[2-(methylsulfonyl)phenyl]ethanone

將實施例(24c)所獲得的化合物(31.1mg)溶解於四氫呋喃(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(7.0mg)並於氫氣環境下，於室溫攪拌15小時。於反應液中添加乙酸乙酯，並濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(19.3mg)。 The compound (31.1 mg) obtained in Example (24c) was dissolved in THF (2 mL) and ethyl acetate (2 mL), and then 7.5% palladium carbon (7.0 mg) was added and stirred at room temperature for 15 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.62-1.73(2H,m),1.76-1.88(2H,m),2.16(3H,s),2.22(6H,s),2.59-2.72(1H,m),2.81-2.94(1H,m),3.09(3H,s),3.18-3.26(2H,m),3.66-4.01(7H,m),4.10-4.18(1H,m),4.25-4.40(5H,m),4.68-4.78(1H,m),6.46(1H,s),6.57(1H,d,J=8.5Hz),6.94-7.02(1H,m),7.33-7.39(1H,m),7.47-7.56(1H,m),7.61-7.62(1H,m),7.92(1H,d,J=8.5Hz),8.08(1H,d,J=8.5Hz). 1H-NMR (400MHz, CDCl 3 ) δ: 1.62-1.73 (2H, m), 1.76-1.88 (2H, m), 2.16 (3H, s), 2.22 (6H, s), 2.59-2.72 (1H, m ), 2.81-2.94 (1H, m), 3.09 (3H, s), 3.18-3.26 (2H, m), 3.66-4.01 (7H, m), 4.10-4.18 (1H, m), 4.25-4.40 (5H , m), 4.68-4.78 (1H, m), 6.46 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.94-7.02 (1H, m), 7.33-7.39 (1H, m), 7.47-7.56 (1H, m), 7.61-7.62 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：647(M+H)+。 MS (APCI) m/z: 647 (M+H) + .

(實施例25) (Embodiment 25)

2-[2-(甲基磺醯基)苯基]-1-(4-甲基-5-{4-[1-(四氫呋喃-3-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)乙酮 2-[2-(Methylsulfonyl)phenyl]-1-(4-methyl-5-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenoxy }-2,3-dihydro-1H-indol-1-yl)ethanone

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31μL)，並於室溫攪拌5分鐘。其次四氫-3-呋喃酸(12.7μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(46.0mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(57.0mg)。 Triethylamine (31 μL) was added to a solution of the compound (10.0 mg), m. Next tetrahydro-3-furanoic acid (12.7 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (46.0 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.48-1.62(2H,m),1.85-1.99(2H,m),2.05-2.17(4H,m),2.18-2.36(1H,m),2.57-2.77(2H,m),3.06-3.32(7H,m),3.83-3.95(3H,m),3.99-4.07(2H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.72-4.85(1H,m),6.76(1H,d,J=9.2Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.33-7.39(1H,m),7.50-7.54(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.05-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 1.48-1.62 (2H, m), 1.85-1.99 (2H, m), 2.05-2.17 (4H, m), 2.18-2.36 (1H, m), 2.57- 2.77 (2H, m), 3.06-3.32 (7H, m), 3.83-3.95 (3H, m), 3.99-4.07 (2H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.72-4.85 (1H, m), 6.76 (1H, d, J = 9.2 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.33 7.39 (1H, m), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).

MS(APCI)m/z：603(M+H)+。 MS (APCI) m/z: 603 (M+H) + .

(實施例26) (Example 26)

2-[2-(甲基磺醯基)苯基]-1-(4-甲基-5-{4-[1-(四氫呋喃-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)乙酮 2-[2-(Methylsulfonyl)phenyl]-1-(4-methyl-5-{4-[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]phenoxy }-2,3-dihydro-1H-indol-1-yl)ethanone

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31μL)，並於室溫攪拌5分鐘。其次添加四氫呋喃-2-甲酸(12.8μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(46.0mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(53.4mg)。 Triethylamine (31 μL) was added to a solution of the compound (10.0 mg), m. Next, add tetrahydrofuran-2-carboxylic acid (12.8 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (46.0 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.59-1.75(2H,m),1.82-1.94(2H,m),1.99-2.17(5H,m),2.23-2.35(1H,m),2.59-2.76(2H,m),3.02-3.15(4H,m),3.16-3.26(3H,m),3.82-3.92(1H,m),3.93-4.03(1H,m),4.14-4.21(1H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.61-4.70(1H,m),4.70-4.78(1H,m),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=7.9Hz),7.10(2H,d,J=7.9Hz),7.31-7.40(1H,m),7.48-7.55(1H,m),7.59-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.59-1.75 (2H, m), 1.82-1.94 (2H, m), 1.99-2.17 (5H, m), 2.23-2.35 (1H, m), 2.59- 2.76(2H,m), 3.02-3.15(4H,m), 3.16-3.26(3H,m),3.82-3.92(1H,m),3.93-4.03(1H,m),4.14-4.21(1H,m ), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.61-4.70 (1H, m), 4.70-4.78 (1H, m), 6.76 (1H, d, J = 8.5 Hz) , 6.81 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.31-7.40 (1H, m), 7.48-7.55 (1H, m), 7.59-7.64 (1H, m ), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：603(M+H)+。 MS (APCI) m/z: 603 (M+H) + .

(實施例27) (Example 27)

1-(4-甲基-5-{4-[1-(氧呾-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(4-Methyl-5-{4-[1-(oxaindole-2-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indole-1 -yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(60mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31μL)，並於室溫攪拌5分鐘。其次添加氧呾-2-甲酸(13.6mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(46.0mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(44.0mg)。 Triethylamine (31 μL) was added to a solution of the compound (m. Next, add oxindole-2-carboxylic acid (13.6 mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (46.0 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.47-1.71(2H,m),1.80-1.93(2H,m),2.12(3H,s),2.63-2.88(3H,m),2.99-3.25(7H,m),3.74-3.88(1H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.54-4.62(1H,m),4.64-4.77(2H,m),5.38(1H,q,J=8.1Hz),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.04-7.12(2H,m),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.3Hz),7.58-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.71 (2H, m), 1.80-1.93 (2H, m), 2.12 (3H, s), 2.63-2.88 (3H, m), 2.99-3.25 ( 7H,m),3.74-3.88(1H,m), 4.28(2H,t,J=8.2Hz), 4.36(2H,s),4.54-4.62(1H,m),4.64-4.77(2H,m) , 5.38 (1H, q, J = 8.1 Hz), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.04-7.12 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.3 Hz), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5) Hz).

MS(APCI)m/z：589(M+H)+。 MS (APCI) m/z: 589 (M+H) + .

(實施例28) (Embodiment 28)

1-(4-甲基-5-{4-[1-(氧呾-3-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(4-Methyl-5-{4-[1-(oxaindole-3-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indole-1 -yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31μL)，並於室溫攪拌5分鐘。其次氧呾-3-甲酸(13.6mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(46.0mg)，並於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(19.9mg)。 Triethylamine (31 μL) was added to a solution of the compound (10.0 mg), m. Next, oxon-3-carboxylic acid (13.6 mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (46.0 mg) and stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.49-1.65(2H,m),1.84-1.93(2H,m),2.12(3H,s),2.60-2.76(2H,m),3.03-3.14(4H,m),3.21(2H,t,J=8.5Hz),3.34-3.45(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.76-4.86(3H,m),4.92-5.01(2H,m),6.73-6.86(4H,m),7.08(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.49-7.57(1H,m),7.57-7.67(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.65 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.60-2.76 (2H, m), 3.03-3.14 ( 4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.34 - 3.45 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.86 (3H , m), 4.92-5.01 (2H, m), 6.73-6.86 (4H, m), 7.08 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.57 ( 1H, m), 7.57-7.67 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：589(M+H)+。 MS (APCI) m/z: 589 (M+H) + .

(實施例29)：於實施例(29b)合成 (Example 29): Synthesis in Example (29b)

3-羥基-2-甲基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯 基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 3-hydroxy-2-methyl-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonate) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(29a)3-(苄氧基)-2-甲基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (29a) 3-(Benzyloxy)-2-methyl-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethenyl) }-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31μL)，並於室溫攪拌5分鐘。其次添加3-苄氧基-2-甲基丙酸(25.8mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(46.0mg)，於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(62.6mg)。 Triethylamine (31 μL) was added to a solution of the compound (10.0 mg), m. Next, 3-benzyloxy-2-methylpropionic acid (25.8 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (46.0 mg) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.15(3H,dd,J=13.1,7.0Hz),1.56-1.67(2H,m),1.76-1.95(2H,m),2.13(3H,s),2.55-2.77(2H,m),3.03-3.15(5H,m),3.21(2H,t,J=8.5Hz),3.42-3.56(1H,m),3.69-3.80(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.43-4.61(2H,m),4.76-4.88(1H,m),6.70-6.84(3H,m),6.92-7.02(1H,m),7.09(1H,d,J=8.5Hz),7.28-7.39(5H,m),7.52(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.07(1H, d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.15 (3H, dd, J = 13.1, 7.0 Hz), 1.56-1.67 (2H, m), 1.76-1.95 (2H, m), 2.13 (3H, s) , 2.55-2.77 (2H, m), 3.03-3.15 (5H, m), 3.21 (2H, t, J = 8.5 Hz), 3.42-3.56 (1H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.43-4.61 (2H, m), 4.76-4.88 (1H, m), 6.70-6.84 (3H, m), 6.92-7.02 (1H , m), 7.09 (1H, d, J = 8.5 Hz), 7.28-7.39 (5H, m), 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).

(29b)3-羥基-2-甲基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (29b) 3-hydroxy-2-methyl-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2, 3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

將實施例(29a)所獲得的化合物(62.6mg)溶解於乙醇(3mL)及乙酸乙酯(4mL)，添加7.5%鈀碳(12.5mg)並於氫氣環境下，於室溫攪拌18小時。追加7.5%鈀碳(12.5mg)後，於60℃氫氣環境下，再攪拌6小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(32.1mg)。 The compound (62.6 mg) obtained in Example (29a) was dissolved in ethanol (3 mL) and ethyl acetate (4 mL). After adding 7.5% palladium carbon (12.5 mg), the mixture was further stirred under a hydrogen atmosphere at 60 ° C for 6 hours. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.18(3H,dd,J=14.6,7.3Hz),1.53-1.67(2H,m),1.84-1.98(2H,m),2.13(3H,s),2.54-2.76(2H,m),2.84-2.93(1H,m),3.12(3H,s),3.15-3.29(3H,m),3.70-3.79(2H,m),3.96-4.06(1H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),4.74-4.85(1H,m),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.34-7.38(1H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18 (3H, dd, J = 14.6, 7.3 Hz), 1.53-1.67 (2H, m), 1.84-1.98 (2H, m), 2.13 (3H, s) , 2.54-2.76 (2H, m), 2.84-2.93 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.70-3.79 (2H, m), 3.96-4.06 (1H, m), 4.28 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74 - 4.85 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J) = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.34 - 7.38 (1H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例30) (Embodiment 30)

(實施例30-1)：實施例(30a)合成 (Example 30-1): Synthesis of Example (30a)

乙酸1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1- 側氧基丙烷-2-基酯 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5) -yl)oxy]phenyl}piperidin-1-yl)-1- Phenoxypropan-2-yl ester

(實施例30-2)：於實施例(30b)合成 (Example 30-2): Synthesis in Example (30b)

2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(30a)乙酸1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 (30a) 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

於實施例(1e)所獲得的化合物(150mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(77μL)，並於室溫攪拌5分鐘。其次添加(±)-2-乙醯氧基丙酸(37.4μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(115mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(77.5mg)。 Triethylamine (77 μL) was added to a solution of the compound (l. Next, add (±)-2-acetoxypropionic acid (37.4 μL), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (115 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.42-1.49(3H,m),1.51-1.63(2H,m),1.83-1.98(2H,br m),2.13(3H,s), 2.14(3H,s),2.63-2.79(2H,m),3.08-3.26(6H,m),3.88-3.99(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.70-4.79(1H,br m),5.40-5.50(1H,m),6.77(1H,d,J=9.2Hz),6.79-6.88(2H,m),7.05-7.15(2H,m),7.36(1H,d,J=7.3Hz),7.50-7.54(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.42-1.49 (3H, m), 1.51-1.63 (2H, m), 1.83-1.98 (2H, br m), 2.13 (3H, s), 2.14 (3H , s), 2.63-2.79 (2H, m), 3.08-3.26 (6H, m), 3.88-3.99 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.70-4.79 (1H, br m), 5.40-5.50 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.79-6.88 (2H, m), 7.05-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.50-7.54 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3) Hz).

(30b)2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (30b) 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(30a)所獲得的化合物(31.7mg)之四氫呋喃(4mL)與甲醇(1mL)之混合溶液中添加1N氫氧化鈉水溶液(188μL)，於室溫攪拌18小時。於減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(56.8mg)。 A 1 N aqueous sodium hydroxide solution (188 μL) was added to a mixed solution of the compound (3. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.35(3H,dd,J=13.4,6.7Hz),1.57-1.67(2H,m),1.86-1.98(2H,m),2.12(3H,s),2.68-2.79(2H,m),3.09-3.25(6H,m),3.79-3.86(1H,m),3.90-3.98(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.45-4.55(1H,m),4.68-4.80(1H,m),6.77(1H,d,J=8.5Hz),6.80-6.85(2H,m),7.05-7.12(2H,m),7.36(1H,d,J=7.3Hz),7.47-7.55(1H,m),7.59-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1H-NMR (400MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.67 (2H, m), 1.86-1.98 (2H, m), 2.12 (3H, s), 2.68-2.79(2H,m), 3.09-3.25(6H,m), 3.79-3.86(1H,m),3.90-3.98(1H,m), 4.29(2H,t,J=8.5Hz), 4.36( 2H, s), 4.45-4.55 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.05-7.12 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.47-7.55 (1H, m), 7.59-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 8.5Hz).

MS(APCI)m/z：577(M+H)+。 MS (APCI) m/z: 577 (M+H) + .

(實施例31) (Example 31)

(實施例31-1)：於實施例(31b)合成 (Example 31-1): Synthesis in Example (31b)

1-{5-[4-(1-{[(2S,4S)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 1-{5-[4-(1-{[(2S,4S)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2, 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

(實施例31-2)：於實施例(31c)合成 (Example 31-2): Synthesis in Example (31c)

1-{5-[4-(1-{[(2S,4S)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4- Methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例31-3)：於實施例(31d)合成 (Example 31-3): Synthesis in Example (31d)

1-[4-甲基-5-(4-{1-[(1-甲基-1H-吡咯-2-基)羰基]哌啶-4-基}苯氧基)-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[4-Methyl-5-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenoxy)-2,3-di Hydrogen-1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

(31a)(2S,4S)-4-氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (31a)(2S,4S)-4-fluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl)}- 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫 攪拌5分鐘。其次添加N-三級丁氧基羰基-順式-4-氟-L-脯胺酸(155mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(338mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. Next, N-tertiary butoxycarbonyl-cis-4-fluoro-L-proline (155 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.52-1.66(2H,br m),1.81-1.97(2H,br m),2.13(3H,s),2.17-2.32(1H,m),2.34-2.57(1H,br m),2.60-2.79(2H,br m),3.03-3.27(6H,m),3.72-3.99(3H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.61-4.87(2H,m),5.15(0.5H,br s),5.29(0.5H,br s),6.73-6.87(3H,m),7.01-7.14(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.52-1.66 (2H, br m), 1.81-1.97 (2H, br m), 2.13 (3H, s), 2.17-2.32 ( 1H,m),2.34-2.57(1H,br m), 2.60-2.79(2H,br m),3.03-3.27(6H,m),3.72-3.99(3H,m),4.29(2H,t,J = 8.5 Hz), 4.36 (2H, s), 4.61-4.87 (2H, m), 5.15 (0.5H, br s), 5.29 (0.5H, br s), 6.73-6.87 (3H, m), 7.01- 7.14(2H,m), 7.36(1H,d,J=7.9Hz), 7.52(1H,t,J=7.6Hz), 7.62(1H,t,J=7.6Hz),7.97(1H,d,J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(31b)1-{5-[4-(1-{[(2S,4S)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (31b) 1-{5-[4-(1-{[(2S,4S)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl -2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(31a)所獲得的化合物(338mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌5小時。於減壓下餾除溶媒，藉由將析出的固體以乙酸乙酯洗淨，獲得呈白色固體之標題化合物(308mg)。 4N hydrochloric acid was added to a solution of the compound (338 mg) obtained in Example (31a) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure, and the title compound (308 mg)

1H-NMR(400MHz,CDCl3)δ：1.61-1.74(2H,m),1.85-1.96(2H,m),2.13(3H,s),2.68-2.79(2H,m), 2.80-2.92(1H,m),3.02-3.25(8H,m),3.41-3.56(1H,m),3.84-4.00(2H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.72-4.86(1H,m),5.04-5.18(0.5H,br m),5.22-5.29(0.5H,br m),6.77(1H,d,J=8.5Hz),6.79-6.85(2H,m),7.04-7.15(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.74 (2H, m), 1.85-1.96 (2H, m), 2.13 (3H, s), 2.68-2.79 (2H, m), 2.80-2.92 ( 1H, m), 3.02-3.25 (8H, m), 3.41-3.56 (1H, m), 3.84-4.00 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s) , 4.72-4.86 (1H, m), 5.04-5.18 (0.5H, br m), 5.22-5.29 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.79-6.85 (2H, m), 7.04-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 ( 1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：620(M+H)+。 MS (APCI) m/z: 620 (M+H) + .

(31c)1-{5-[4-(1-{[(2S,4S)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (31c) 1-{5-[4-(1-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(31b)所獲得的化合物(308mg)溶解於甲醇(6mL)及二氯甲烷(2mL)溶液，添加7.5%鈀碳(75.0mg)、37%甲醛液(1.75mL)、鹽酸(288μL)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯並濾除不溶物後，將濾液於減壓下濃縮。於獲得的殘渣中添加1N氫氧化鈉水溶液而中和，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(262mg)。 The compound obtained in Example (31b) (308 mg) was dissolved in methanol (6 mL) and dichloromethane (2 mL), and 7.5% palladium carbon (75.0 mg), 37% formaldehyde solution (1.75 mL), hydrochloric acid (288 μL) And stirring under a hydrogen atmosphere at room temperature for 18 hours. After ethyl acetate was added to the reaction mixture and the insoluble material was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was neutralized by adding a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.56-1.67(2H,m),1.85-1.94(2H,m),2.13(3H,s),2.17-2.32(1H,m),2.39(3H,s),2.52-2.78(3H,br m),2.98-3.15(6H,m),3.17-3.26(2H,m),3.29-3.47(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.53-4.60(0.5H,br m),4.63-4.72(0.5H, br m),4.75-4.85(1H,m),5.04-5.11(0.5H,br m),5.16-5.25(0.5H,br m),6.74-6.85(3H,m),7.10(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.61(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.39 (3H, s), 2.52-2.78 (3H, br m), 2.98-3.15 (6H, m), 3.17-3.26 (2H, m), 3.29-3.47 (1H, m), 4.29 (2H, t, J = 8.5 Hz ), 4.36 (2H, s), 4.53-4.60 (0.5H, br m), 4.63-4.72 (0.5H, br m), 4.75-4.85 (1H, m), 5.04-5.11 (0.5H, br m) , 5.16-5.25 (0.5H, br m), 6.74-6.85 (3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t , J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：634(M+H)+。 MS (APCI) m/z: 634 (M+H) + .

(31d)1-[4-甲基-5-(4-{1-[(1-甲基-1H-吡咯-2-基)羰基]哌啶-4-基}苯氧基)-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (31d) 1-[4-Methyl-5-(4-{1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-4-yl}phenoxy)-2, 3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(31c)所獲得的化合物(262mg)之氯仿(15mL)溶液中歷經2小時以3次添加2,3-二氯-5,6-二氰基-1,4-苯醌(197mg)，於75℃攪拌6小時。於反應液中添加水，並以二氯甲烷提取。有機層以水洗淨3次及以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(34.7mg)。 To a solution of the compound obtained in Example (31c) (262 mg) in chloroform (15 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (197 mg) ), stirring at 75 ° C for 6 hours. Water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with water three times and washed with brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililili

1H-NMR(400MHz,CDCl3)δ：1.59-1.73(2H,m),1.85-1.95(2H,m),2.13(3H,s),2.69-2.79(1H,m),2.92-3.04(2H,m),3.12(3H,s),3.17-3.26(2H,m),3.80(3H,s),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.59-4.70(2H,m),6.07-6.10(1H,m),6.35-6.37(1H,m),6.68-6.71(1H,m),6.77(1H,d,J=8.5Hz),6.83(2H,d,J=8.5Hz),7.12(2H,d,J=8.5Hz),7.34-7.38(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.73 (2H, m), 1.85-1.95 (2H, m), 2.13 (3H, s), 2.69-2.79 (1H, m), 2.92-3.04 ( 2H,m), 3.12(3H,s), 3.17-3.26(2H,m), 3.80(3H,s), 4.29(2H,t,J=8.2Hz), 4.36(2H,s),4.59-4.70 (2H,m),6.07-6.10(1H,m),6.35-6.37(1H,m),6.68-6.71(1H,m),6.77(1H,d,J=8.5Hz),6.83(2H,d , J = 8.5 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.34 - 7.38 (1H, m), 7.49 - 7.55 (1H, m), 7.59 - 7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：612(M+H)+。 MS (APCI) m/z: 612 (M+H) + .

(實施例32) (Example 32)

1-{5-[4-(1-{[(2S)-1-乙醯基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S)-1-Ethylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2, 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(100μL)，並於室溫攪拌5分鐘。其次添加N-乙醯基-L-脯胺酸(69.7mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(153mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(186mg)。 Triethylamine (100 μL) was added to a solution of the compound (m. Next, N-acetyl-L-proline (69.7 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl Was guanidine (153 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.54-1.74(2H,m),1.80-2.03(5H,m),2.09-2.22(7H,m),2.57-2.76(2H,m),3.07-3.32(6H,m),3.48-3.58(1H,m),3.67-3.76(1H,m),4.02-4.15(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.68-4.79(1H,m),4.87-4.98(1H,m),6.74-6.87(3H,m),7.06-7.17(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07- 3.32(6H,m), 3.48-3.58(1H,m), 3.67-3.76(1H,m),4.02-4.15(1H,m), 4.29(2H,t,J=8.2Hz), 4.36(2H, s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, m), 7.36 (1H, d, J = 7.9 Hz) , 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：644(M+H)+。 MS (APCI) m/z: 644 (M+H) + .

(實施例33) (Example 33)

(實施例33-1)：於實施例(33b)合成 (Example 33-1): Synthesis in Example (33b)

1-{5-[4-(1-{[(2S,4R)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4R)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2, 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例33-2)：於實施例(33c)合成 (Example 33-2): Synthesis in Example (33c)

1-{5-[4-(1-{[(2S,4R)-1-乙醯基-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4R)-1-Ethyl-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(33a)(2S,4R)-4-氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (33a)(2S,4R)-4-fluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-) 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1e)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。其次添加N-三級丁氧基羰基-反式-4-氟-L-脯胺酸(155mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽 水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈黃色油狀物之標題化合物(327mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. Next, N-tertiary butoxycarbonyl-trans-4-fluoro-L-proline (155 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.47(9H,s),1.51-1.75(2H,m),1.80-2.02(2H,m),2.07-2.27(4H,m),2.38-2.59(1H,m),2.61-2.79(2H,m),3.12(3H,s),3.15-3.27(3H,m),3.58-4.07(3H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.69-4.98(2H,m),5.10-5.35(1H,m),6.73-6.88(3H,m),7.02-7.16(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 1.51-1.75 (2H, m), 1.80-2.02 (2H, m), 2.07-2.27 (4H, m), 2.38-2.59 ( 1H, m), 2.61-2.79 (2H, m), 3.12 (3H, s), 3.15-3.27 (3H, m), 3.58-4.07 (3H, m), 4.29 (2H, t, J = 8.5 Hz) , 4.36 (2H, s), 4.69-4.98 (2H, m), 5.10-5.35 (1H, m), 6.73-6.88 (3H, m), 7.02-7.16 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9Hz).

(33b)1-{5-[4-(1-{[(2S,4R)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (33b) 1-{5-[4-(1-{[(2S,4R)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl -2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(33a)所獲得的化合物(278mg)之二氯甲烷(1.5mL)溶液中添加4N鹽酸二烷溶液(3mL)，並於室溫攪拌5小時。於減壓下餾除溶媒，於殘渣中添加飽和碳酸氫鈉水溶液而中和，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，減壓下濃縮而獲得呈白色固體之標題化合物(155mg)。 4N hydrochloric acid was added to a solution of the compound (278 mg) obtained in Example (33a) in dichloromethane (1.5 mL) Alkane solution (3 mL) was stirred at room temperature for 5 h. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue to neutralize, and ethyl acetate was evaporated. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.59-1.75(2H,m),1.86-1.97(2H,m),2.13(3H,s),2.27-2.44(1H,m),2.64-2.80(2H,m),3.05-3.26(9H,m),3.31-3.51(1H,m),3.99-4.07(1H,m),4.16-4.26(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.71-4.82(1H,m),5.18-5.24(0.5H,br m),5.33-5.38(0.5H,br m),6.77(1H,d,J=8.5Hz),6.80-6.85(2H,m),7.03-7.14(2H,m),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.75 (2H, m), 1.86-1.97 (2H, m), 2.13 (3H, s), 2.27-2.44 (1H, m), 2.64-2.80 ( 2H, m), 3.05-3.26 (9H, m), 3.31-3.51 (1H, m), 3.99-4.07 (1H, m), 4.16-4.26 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.71-4.82 (1H, m), 5.18-5.24 (0.5H, br m), 5.33-5.38 (0.5H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03-7.14 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t , J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：620(M+H)+。 MS (APCI) m/z: 620 (M+H) + .

(33c)1-{5-[4-(1-{[(2S,4R)-1-乙醯基-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (33c) 1-{5-[4-(1-{[(2S,4R)-1-Ethyl-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy ]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(33b)所獲得的化合物(30.0mg)之二氯甲烷(2mL)溶液中添加乙酸酐(54.9μL)，並於室溫攪拌18小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(33.2mg)。 Acetic acid anhydride (54.9 μL) was added to a solution of the compound (3. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililililililililili

1H-NMR(400MHz,CDCl3)δ：1.46-1.60(2H,m),1.95-2.15(10H,m),2.62-2.78(2H,m),3.06-3.15(4H,m),3.15-3.26(2H,m),3.76-4.00(2H,m),4.04-4.32(3H,m),4.36(2H,s),4.63-4.78(1H,m),5.01-5.13(1H,m),5.23-5.29(0.5H,m),5.36-5.44(0.5H,m),6.70-6.84(3H,m),7.02-7.16(2H,m),7.32-7.40(1H,m),7.47-7.55(1H,m),7.57-7.65(1H,m),7.92-7.99(1H,m),8.02-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46-1.60 (2H, m), 1.95-2.15 (10H, m), 2.62-2.78 (2H, m), 3.06-3.15 (4H, m), 3.15- 3.26 (2H, m), 3.76-4.00 (2H, m), 4.04-4.32 (3H, m), 4.36 (2H, s), 4.63-4.78 (1H, m), 5.01-5.13 (1H, m), 5.23-5.29 (0.5H, m), 5.36-5.44 (0.5H, m), 6.70-6.84 (3H, m), 7.02-7.16 (2H, m), 7.32-7.40 (1H, m), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.92-7.99 (1H, m), 8.02-8.09 (1H, m).

MS(APCI)m/z：662(M+H)+。 MS (APCI) m/z: 662 (M+H) + .

(實施例34) (Example 34)

1-{5-[4-(1-{[(2S,4S)-1-乙醯基-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4S)-1-Ethyl-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(50.0mg)之二氯甲烷(2mL)溶液中添加三乙基胺(22.0μL)、乙酸酐(91.5μL)，並於室溫攪拌18小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(55.1mg)。 Triethylamine (22.0 μL) and acetic anhydride (91.5 μL) were added to a solution of the compound (5. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililililililili

1H-NMR(400MHz,CDCl3)δ：1.51-1.70(2H,m),1.78-2.02(3H,m),2.13(6H,s),2.17-2.35(1H,m),2.63-2.77(2H,m),3.12(3H,s),3.15-3.28(3H,m),3.83-4.06(3H,m),4.29(2H,t,J=8.5Hz),4.37(2H,s),4.65-4.80(1H,m),4.96-5.08(1H,m),5.22-5.29(0.6H,m),5.37-5.41(0.4H,m),6.73-6.86(3H,m),7.07-7.15(2H,m),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.51-1.70 (2H, m), 1.78-2.02 (3H, m), 2.13 (6H, s), 2.17-2.35 (1H, m), 2.63-2.77 ( 2H, m), 3.12 (3H, s), 3.15-3.28 (3H, m), 3.83-4.06 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65 -4.80 (1H, m), 4.96-5.08 (1H, m), 5.22-5.29 (0.6H, m), 5.37-5.41 (0.4H, m), 6.73-6.86 (3H, m), 7.07-7.15 ( 2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5) Hz), 8.07 (1H, d, J = 8.5Hz).

MS(APCI)m/z：662(M+H)+。 MS (APCI) m/z: 662 (M+H) + .

(實施例35)：於實施例(35b)合成 (Example 35): Synthesis in Example (35b)

(5S)-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基] 乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-2-酮 (5S)-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)] Ethyl}},3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-2-one

(35a)(2S)-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]-5-側氧基吡咯啶-1-甲酸苄酯 (35a)(2S)-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]-5-oxooxypyrrolidine-1-carboxylic acid benzyl ester

於實施例(1e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(4mL)溶液中添加三乙基胺(100μL)，並於室溫攪拌5分鐘。其次添加苄氧基-L-焦麩胺酸(116mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(153mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(221mg)。 Triethylamine (100 μL) was added to a solution of the compound (m. Next, benzyloxy-L-pyroglutamic acid (116 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl Was guanidine (153 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.47-1.65(2H,m),1.81-2.00(2H,m),2.12(3H,t,J=8.9Hz),2.22-2.36(1H,m),2.43-2.56(1H,m),2.60-2.83(3H,m),3.12(3H,s),3.16-3.27(3H,m),3.84-3.95(1H,m),4.07-4.16(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.67-4.75(1H,m),5.00-5.10(1H,m),5.19-5.35(2H,m),6.71-6.84(3H,m),6.98-7.05(1H,m),7.09(1H,d,J=8.5Hz),7.22-7.40(6H,m),7.50-7.55(1H,m),7.57-7.67(1H,m),7.95-8.00(1H, m),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.65 (2H, m), 1.81-2.00 (2H, m), 2.12 (3H, t, J = 8.9 Hz), 2.22-2.36 (1H, m) , 2.43-2.56 (1H, m), 2.60-2.83 (3H, m), 3.12 (3H, s), 3.16-3.27 (3H, m), 3.84-3.95 (1H, m), 4.07-4.16 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.75 (1H, m), 5.00-5.10 (1H, m), 5.19-5.35 (2H, m), 6.71 -6.84 (3H, m), 6.98-7.05 (1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.22-7.40 (6H, m), 7.50-7.55 (1H, m), 7.57-7.67 (1H, m), 7.95-8.00 (1H, m), 8.07 (1H, d, J = 7.9 Hz).

(35b)(5S)-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-2-酮 (35b)(5S)-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-2-one

將實施例(35a)所獲得的化合物(221mg)溶解於甲醇(3mL)及乙酸乙酯(3mL)，添加7.5%鈀碳(44.5mg)並於氫氣環境下，於室溫攪拌6小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(162mg)。 The compound (221 mg) obtained in Example (35a) was dissolved in methanol (3 mL) and ethyl acetate (3mL), and 7.5% palladium carbon (44.5 mg) was added and stirred at room temperature for 6 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.56-1.69(2H,m),1.87-1.99(2H,m),2.08-2.21(4H,m),2.33-2.57(3H,m),2.66-2.79(2H,m),3.12(3H,s),3.15-3.26(3H,m),3.82-3.91(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.50-4.58(1H,m),4.69-4.80(1H,m),5.81(1H,br s),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.57-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56-1.69 (2H, m), 1.87-1.99 (2H, m), 2.08-2.21 (4H, m), 2.33-2.57 (3H, m), 2.66- 2.79(2H,m), 3.12(3H,s), 3.15-3.26(3H,m),3.82-3.91(1H,m), 4.29(2H,t,J=8.2Hz), 4.36(2H,s) , 4.50-4.58 (1H, m), 4.69-4.80 (1H, m), 5.81 (1H, br s), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz) , 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J =8.5Hz), 8.07 (1H, d, J = 7.9Hz).

MS(APCI)m/z：616(M+H)+。 MS (APCI) m/z: 616 (M+H) + .

(實施例36) (Example 36)

(5S)-1-甲基-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-2-酮 (5S)-1-methyl-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-2-one

於實施例(1e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(4mL)溶液中添加三乙基胺(100μL)，並於室溫攪拌5分鐘。其次添加以文獻記載之方法(Bioorganic and Medicinal Chemistry Letters，2010，20，5080)合成的1-甲基-5-側氧基-L-脯胺酸(66.2mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(153mg)，並於室溫攪拌18小時。於反應混合物中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(5.3mg)。 Triethylamine (100 μL) was added to a solution of the compound (m. Next, 1-methyl-5-oxo-L-proline (66.2 mg) synthesized by the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2010, 20, 5080), 4-(4, chlorinated) was added. 6-dimethoxy-1,3,5-three -2-yl)-4-methyl Was guanidine (153 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.53-1.68(2H,m),1.89-2.02(3H,m),2.13(3H,s),2.29-2.42(2H,m),2.46-2.59(1H,m),2.65-2.79(2H,m),2.85(3H,d,J=11.0Hz),3.12(3H,s),3.16-3.28(3H,m),3.86-3.96(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.41-4.46(1H,m),4.72-4.82(1H,m),6.77(1H,d,J=8.5Hz),6.80-6.87(2H,m),7.07-7.13(2H,m),7.36(1H,d,J=7.9Hz),7.49-7.53(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.53-1.68 (2H, m), 1.89-2.02 (3H, m), 2.13 (3H, s), 2.29-2.42 (2H, m), 2.46-2.59 ( 1H, m), 2.65-2.79 (2H, m), 2.85 (3H, d, J = 11.0 Hz), 3.12 (3H, s), 3.16-3.28 (3H, m), 3.86-3.96 (1H, m) , 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.41-4.46 (1H, m), 4.72-4.82 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.87 (2H, m), 7.07-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.53 (1H, m), 7.58-7.65 (1H, m), 7.97 ( 1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

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

(實施例37) (Example 37)

(實施例37-1)：於實施例(37b)合成 (Example 37-1): Synthesis in Example (37b)

1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 1-{5-[4-(1-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2 ,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

(實施例37-2)：於實施例(37c)合成 (Example 37-2): Synthesis in Example (37c)

1-{5-[4-(1-{[(2S)-1-乙醯基-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S)-1-Ethyl-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]- 4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(37a)(2S)-4,4-二氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (37a) (2S)-4,4-difluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl)} -2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1e)所獲得的化合物(524mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(270μL)，並於室溫攪拌5分鐘。其次添加N-三級丁氧基羰基-4,4-二氟-L-脯胺酸(292mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(402mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈 白色固體之標題化合物(515mg)。 Triethylamine (270 μL) was added to a solution of the compound ( 524 mg. Next, N-tertiary butoxycarbonyl-4,4-difluoro-L-proline (292 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (402 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.47(9H,s),1.50-1.73(2H,m),1.81-1.99(2H,m),2.12(3H,s),2.21-2.49(1H,m),2.58-2.78(3H,m),3.06-3.32(6H,m),3.78-4.04(3H,m),4.28(2H,t,J=8.5Hz),4.36(2H,s),4.67-4.83(1H,m),4.86-4.99(1H,m),6.72-6.88(3H,m),7.02-7.15(2H,m),7.32-7.40(1H,m),7.47-7.56(1H,m),7.57-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 1.50-1.73 (2H, m), 1.81-1.99 (2H, m), 2.12 (3H, s), 2.21-2.49 (1H, m), 2.58-2.78 (3H, m), 3.06-3.32 (6H, m), 3.78-4.04 (3H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67 -4.83 (1H, m), 4.86-4.99 (1H, m), 6.72-6.88 (3H, m), 7.02-7.15 (2H, m), 7.32-7.40 (1H, m), 7.47-7.56 (1H, m), 7.57-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).

(37b)1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (37b) 1-{5-[4-(1-{[(2S)-4,4-Difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl Base-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(37a)所獲得的化合物(515mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌4小時。於減壓下餾除溶媒，藉由將析出的固體以乙酸乙酯洗淨，獲得呈白色固體之標題化合物(484mg)。 4N hydrochloric acid was added to a solution of the compound (515 mg) obtained in Example (37a) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure, and the title compound (484 mg)

1H-NMR(400MHz,DMSO-d6)δ：1.39-1.69(2H,m),1.76-1.88(2H,m),2.05(3H,s),2.53-2.69(1H,m),2.72-2.83(2H,m),2.92-3.23(7H,m),3.62-3.87(3H,m),4.23-4.36(4H,m),4.43-4.54(1H,m),4.96(0.5H,t,J=8.5Hz),5.04(0.5H,t,J=8.5Hz),6.71-6.83(3H,m),7.14-7.26(2H,m),7.48(1H,d,J=7.9Hz),7.55-7.60(1H,m),7.68-7.71(1H,m),7.84(1H,d,J=8.5Hz),7.97(1H,d,J=7.9Hz). 1 H-NMR (400MHz, DMSO -d 6) δ: 1.39-1.69 (2H, m), 1.76-1.88 (2H, m), 2.05 (3H, s), 2.53-2.69 (1H, m), 2.72- 2.83 (2H, m), 2.92-3.23 (7H, m), 3.62-3.87 (3H, m), 4.23-4.36 (4H, m), 4.43-4.54 (1H, m), 4.96 (0.5H, t, J = 8.5 Hz), 5.04 (0.5H, t, J = 8.5 Hz), 6.71-6.83 (3H, m), 7.14 - 7.26 (2H, m), 7.48 (1H, d, J = 7.9 Hz), 7.55 -7.60 (1H, m), 7.68-7.71 (1H, m), 7.84 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：638(M+H)+。 MS (APCI) m/z: 638 (M+H) + .

(37c)1-{5-[4-(1-{[(2S)-1-乙醯基-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (37c) 1-{5-[4-(1-{[(2S)-1-Ethyl-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy 4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(37b)所獲得的化合物(32.7mg)之二氯甲烷(3mL)溶液中添加三乙基胺(14.0μL)、乙酸酐(5.82μL)，並於室溫攪拌3小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(17.2mg)。 Triethylamine (14.0 μL) and acetic anhydride (5.82 μL) were added to a solution of the compound (32.7 mg). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlilililili

1H-NMR(400MHz,CDCl3)δ：1.53-1.67(2H,m),1.82-2.19(10H,m),2.59-2.81(2H,m),3.12(2H,s),3.16-3.28(6H,m),3.46-3.56(1H,m),4.24-4.32(2H,m),4.36(2H,s),4.66-4.78(1H,m),5.05-5.17(1H,m),6.74-6.87(3H,m),7.06-7.15(2H,m),7.36(1H,d,J=7.3Hz),7.49-7.55(1H,m),7.58-7.68(1H,m),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.67 (2H, m), 1.82-2.19 (10H, m), 2.59-2.81 (2H, m), 3.12 (2H, s), 3.16-3.28 ( 6H,m), 3.46-3.56(1H,m),4.24-4.32(2H,m),4.36(2H,s),4.66-4.78(1H,m),5.05-5.17(1H,m),6.74- 6.87 (3H, m), 7.06-7.15 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.58-7.68 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：680(M+H)+。 MS (APCI) m/z: 680 (M+H) + .

(實施例38) (Example 38)

1-{5-[4-(1-{[(2R)-1-乙醯基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2R)-1-Ethylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2, 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(150mg)之N,N-二甲基甲醯胺(4mL)溶液中添加三乙基胺(77.0μL)，並於室溫攪拌5分鐘。其次添加N-乙醯基-D-脯胺酸(59.3mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(115mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(109mg)。 Triethylamine (77.0 μL) was added to a solution of the compound (m. Next, N-acetyl-D-proline (59.3 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (115 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.54-1.74(2H,m),1.80-2.03(5H,m),2.09-2.22(7H,m),2.57-2.76(2H,m),3.07-3.32(6H,m),3.48-3.58(1H,m),3.67-3.76(1H,m),4.02-4.15(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.68-4.79(1H,m),4.87-4.98(1H,m),6.74-6.87(3H,m),7.06-7.17(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.54-1.74 (2H, m), 1.80-2.03 (5H, m), 2.09-2.22 (7H, m), 2.57-2.76 (2H, m), 3.07- 3.32(6H,m), 3.48-3.58(1H,m), 3.67-3.76(1H,m),4.02-4.15(1H,m), 4.29(2H,t,J=8.2Hz), 4.36(2H, s), 4.68-4.79 (1H, m), 4.87-4.98 (1H, m), 6.74-6.87 (3H, m), 7.06-7.17 (2H, m), 7.36 (1H, d, J = 7.9 Hz) , 7.52 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：644(M+H)+。 MS (APCI) m/z: 644 (M+H) + .

(實施例39) (Example 39)

(實施例39-1)：於實施例(39a)合成 (Example 39-1): Synthesis in Example (39a)

乙酸1-(4-{4-[(4-甲基-1-{[2-(乙基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 1-(4-{4-[(4-methyl-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5) -yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

(實施例39-2)：於實施例(39b)合成 (Example 39-2): Synthesis in Example (39b)

2-羥基-1-(4-{4-[(4-甲基-1-{[2-(乙基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(39a)乙酸1-(4-{4-[(4-甲基-1-{[2-(乙基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-1-側氧基丙烷-2-基酯 (39a) 1-(4-{4-[(4-methyl-1-{[2-(ethylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)-1-oxopropan-2-yl ester

於實施例(2d)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(30.0μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(44.9mg)及(±)-2-乙醯氧基丙酸(14.6mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(40.9mg)。 Triethylamine (30.0 μL) was added to a solution of the compound (20.0 mg), m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (44.9 mg) and (±)-2-ethoxypropoxypropionic acid (14.6 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAcqqqqqqq

1H-NMR(400MHz,CDCl3)：1.26(3H,t,J=6.7Hz),1.43-1.49(3H,m),1.50-1.60(2H,m),1.78-1.96(2H,m),2.12(3H,s),2.14(3H,s),2.60-2.77(2H,m), 3.15-3.24(5H,m),3.88-4.01(1H,br m),4.27(2H,t,J=8.2Hz),4.37(2H,s),4.68-4.80(1H,br m),5.40-5.48(1H,m),6.72-6.85(3H,m),7.06-7.15(2H,m),7.39(1H,d,J=6.7Hz),7.50(1H,t,J=7.0Hz),7.62(1H,t,J=7.0Hz),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ): 1.26 (3H, t, J = 6.7 Hz), 1.43-1.49 (3H, m), 1.50-1.60 (2H, m), 1.78-1.96 (2H, m), 2.12(3H,s), 2.14(3H,s), 2.60-2.77(2H,m), 3.15-3.24(5H,m),3.88-4.01(1H,br m),4.27(2H,t,J= 8.2 Hz), 4.37 (2H, s), 4.68-4.80 (1H, br m), 5.40-5.48 (1H, m), 6.72-6.85 (3H, m), 7.06-7.15 (2H, m), 7.39 ( 1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz).

(39b)2-羥基-1-(4-{4-[(4-甲基-1-{[2-(乙基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (39b) 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(ethylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(39a)所獲得的化合物(160mg)之四氫呋喃(10mL)與甲醇(2mL)之混合溶液中添加1N氫氧化鈉水溶液(390μL)，於室溫攪拌48小時。於減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(85.6mg)。 A 1 N aqueous sodium hydroxide solution (390 μL) was added to a mixed solution of the compound (m. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.35(3H,dd,J=13.4,6.7Hz),1.57-1.68(2H,m),1.87-2.00(2H,m),2.12(3H,s),2.65-2.82(2H,m),3.13-3.24(5H,m),3.76-3.85(1H,m),3.90-3.95(1H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.45-4.53(1H,m),4.68-4.80(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.07-7.12(2H,m),7.39(1H,d,J=7.9Hz),7.47-7.54(1H,m),7.59-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.68 (2H, m), 1.87-2. (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.13-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.45-4.53 (1H, m), 4.68-4.80 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 ( 2H,d,J=8.5Hz),7.07-7.12(2H,m),7.39(1H,d,J=7.9Hz),7.47-7.54(1H,m),7.59-7.66(1H,m),7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例40)：於實施例(40b)合成 (Example 40): Synthesis in Example (40b)

(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基} -4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-羥基丙烷-1-酮 (2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl} 4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-hydroxypropan-1-one

(40a)(2S)-2-(苄氧基)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (40a)(2S)-2-(Benzyloxy)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl) -2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(2d)所獲得的化合物(80.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(29.2μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(60.0mg)及O-苄基-D-丁酸(31.2mg)，於室溫攪拌24小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(77.8mg)。 Triethylamine (29.2 μL) was added to a solution of the compound (20.0 mg), m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl The guanidine oxime (60.0 mg) and O-benzyl-D-butyric acid (31.2 mg) were stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.47(3H,d,J=6.7Hz),1.50-1.62(2H,m),1.78-1.93(2H,br m),2.12(3H,s),2.59-2.75(2H,m),2.96-3.11(1H,m),3.13-3.25(4H,m),4.23-4.32(2H,m),4.33-4.41(4H,m),4.42-4.49(1H,m),4.56-4.68(1H,m),4.73-4.82(1H,m),6.77(1H,d,J=9.2Hz),6.81(2H,d,J=8.5Hz),7.07(2H,d,J=8.5Hz),7.32-7.36(5H,m),7.39(1H,d,J=6.7Hz),7.50(1H,t,J=7.0Hz),7.62(1H,t,J=7.0Hz),7.97(1H, d,J=8.5Hz),8.03(1H,d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.47 (3H, d, J = 6.7 Hz), 1.50-1.62 (2H, m), 1.78-1.93 (2H , br m), 2.12 (3H, s), 2.59-2.75 (2H, m), 2.96-3.11 (1H, m), 3.13 - 3.25 (4H, m), 4.23-4.32 (2H, m), 4.33 4.41 (4H, m), 4.42-4.49 (1H, m), 4.56-4.68 (1H, m), 4.73-4.82 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz), 7.32 - 7.36 (5H, m), 7.39 (1H, d, J = 6.7 Hz), 7.50 (1H, t, J = 7.0) Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 6.7 Hz).

(40b)(2S)-1-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-羥基丙烷-1-酮 (40b)(2S)-1-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethenyl}-4-methyl-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-hydroxypropan-1-one

將實施例(40a)所獲得的化合物(160mg)溶解於乙醇(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(15.6mg)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(45.9mg)。 The compound (160 mg) obtained in Example (40a) was dissolved in ethanol (2 mL) and ethyl acetate (2 mL), and then, 7.5% palladium carbon (15.6 mg) was added and stirred under a hydrogen atmosphere at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.35(3H,dd,J=13.4,6.7Hz),1.56-1.69(2H,m),1.86-1.98(2H,m),2.12(3H,s),2.66-2.79(2H,m),3.07-3.24(5H,m),3.76-3.85(1H,m),3.90-3.95(1H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.44-4.53(1H,m),4.69-4.82(1H,m),6.71-6.87(3H,m),7.05-7.12(2H,m),7.39(1H,d,J=7.3Hz),7.50(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=7.9Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.56-1.69 (2H, m), 1.86-1.98 (2H, m), 2.12 (3H, s), 2.66-2.79 (2H, m), 3.07-3.24 (5H, m), 3.76-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.44 - 4.53 (1H, m), 4.69 - 4.82 (1H, m), 6.71-6.87 (3H, m), 7.05-7.12 (2H , m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 7.9 Hz) ), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例41) (Example 41)

1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-甲氧基丙烷-1-酮 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)-2-methoxypropan-1-one

於實施例(1e)所獲得的化合物(43.0mg)之N,N-二甲基甲醯胺(2mL)溶液中添加三乙基胺(33.0μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(33.0mg)及2-甲氧基丙酸(9.93mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(27.7mg)。 Triethylamine (33.0 μL) was added to a solution of the compound (43.0 mg), m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (33.0 mg) and 2-methoxypropionic acid (9.93 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.39(3H,dd,J=12.8,6.7Hz),1.56-1.67(2H,m),1.85-1.94(2H,m),2.13(3H,s),2.57-2.80(2H,m),3.02-3.14(4H,m),3.17-3.24(2H,m),3.35(3H,dd,J=12.8,6.1Hz),4.09-4.39(6H,m),4.73-4.83(1H,m),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.61(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39 (3H, dd, J = 12.8, 6.7 Hz), 1.56-1.67 (2H, m), 1.85-1.94 (2H, m), 2.13 (3H, s) , 2.57-2.80 (2H, m), 3.02-3.14 (4H, m), 3.17-3.24 (2H, m), 3.35 (3H, dd, J = 12.8, 6.1 Hz), 4.09-4.39 (6H, m) , 4.73-4.83 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J=7.9Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例42) (Example 42)

(實施例42-1)：於實施例(42a)合成 (Example 42-1): Synthesis in Example (42a)

乙酸2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2- 側氧基乙酯 2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5) -yl)oxy]phenyl}piperidin-1-yl)-2- Ethyloxyethyl ester

(實施例42-2)：於實施例(42b)合成 (Example 42-2): Synthesis in Example (42b)

2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

(42a)乙酸2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙酯 (42a) 2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethyl ester

於實施例(1e)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(36.0μL)，並於室溫攪拌5分鐘。其次添加乙醯氧基乙酸(18.3mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(53.7mg)，並於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(65.6mg)。 Triethylamine (36.0 μL) was added to a solution of the compound (10.0 mg), m. Next, acetoxyacetic acid (18.3 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (53.7 mg) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.54-1.69(2H,m),1.84-1.96(2H,m),2.13(3H,s),2.20(3H,s),2.62-2.77(2H, m),3.07-3.25(6H,m),3.69-3.80(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.67-4.79(3H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.05(2H,t,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.69 (2H, m), 1.84-1.96 (2H, m), 2.13 (3H, s), 2.20 (3H, s), 2.62-2.77 (2H, m), 3.07-3.25 (6H, m), 3.69-3.80 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.67-4.79 (3H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05 (2H, t, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H) , t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：605(M+H)+。 MS (APCI) m/z: 605 (M+H) + .

(42b)2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 (42b) 2-Hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

於實施例(42a)所獲得的化合物(45.6mg)之四氫呋喃(2.5mL)與甲醇(1mL)之混合溶液中添加1N氫氧化鈉水溶液(226μL)，於室溫攪拌2.5小時。於減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(36.8mg)。 A 1 N aqueous sodium hydroxide solution (226 μL) was added to a mixed solution of the compound (45.6 mg) of THF (m. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.51-1.69(2H,m),1.85-1.96(2H,m),2.12(3H,s),2.67-2.84(2H,m),3.01-3.15(4H,m),3.15-3.27(2H,m),3.54-3.65(1H,m),3.71(1H,t,J=4.3Hz),4.20(2H,t,J=4.3Hz),4.23-4.31(2H,m),4.36(2H,s),4.70-4.78(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.0Hz),7.62(1H,t,J=7.0Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.69 (2H, m), 1.85-1.96 (2H, m), 2.12 (3H, s), 2.67-2.84 (2H, m), 3.01-3.15 ( 4H, m), 3.15-3.27 (2H, m), 3.54-3.65 (1H, m), 3.71 (1H, t, J = 4.3 Hz), 4.20 (2H, t, J = 4.3 Hz), 4.23-4.31 (2H, m), 4.36 (2H, s), 4.70-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.0 Hz), 7.62 (1H, t, J = 7.0 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：563(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例43) (Example 43)

2-[2-(甲基磺醯基)苯基]-1-{4-甲基-5-[4-(1-{[1R,3S,4R,5S]-1,3,4,5-四羥基環己基}羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基}乙酮 2-[2-(methylsulfonyl)phenyl]-1-{4-methyl-5-[4-(1-{[1R,3S,4R,5S]-1,3,4,5 -tetrahydroxycyclohexyl}carbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl}ethanone

於實施例(1e)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(36.0μL)，並於室溫攪拌5分鐘。其次添加(1R,3R,4R,5R)-(-)-奎尼酸(29.8mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(53.7mg)，於室溫攪拌15小時，再於75℃攪拌24小時。冷卻至室溫後，於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(13.0mg)。 Triethylamine (36.0 μL) was added to a solution of the compound (10.0 mg), m. Next, add (1R,3R,4R,5R)-(-)-quinic acid (29.8mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl The guanidine (53.7 mg) was stirred at room temperature for 15 hours and then at 75 ° C for 24 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.60-1.73(2H,m),1.84-1.97(2H,m),2.07-2.50(7H,m),2.70-2.82(2H,m),3.12(3H,s),3.21-3.23(2H,m),3.41-3.52(1H,m),3.69-3.77(1H,m),3.95-4.09(5H,m),4.18-4.24(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.56-4.75(2H,br m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz), 8.07(1H,d,J=7.3Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.73 (2H, m), 1.84-1.97 (2H, m), 2.07-2.50 (7H, m), 2.70-2.82 (2H, m), 3.12 ( 3H, s), 3.21-3.23 (2H, m), 3.41-3.52 (1H, m), 3.69-3.77 (1H, m), 3.95-4.09 (5H, m), 4.18-4.24 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.56-4.75 (2H, br m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz) , 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：679(M+H)+。 MS (APCI) m/z: 679 (M+H) + .

(實施例44) (Example 44)

(實施例44-1)：於實施例(44b)合成 (Example 44-1): Synthesis in Example (44b)

1-(4-甲基-5-{4-[1-(啉-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(4-methyl-5-{4-[1-( Phenan-2-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)phenyl Ethyl ketone

(實施例44-2)：於實施例(44c)合成 (Example 44-2): Synthesis in Example (44c)

1-[5-(4-{1-[(4-乙基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(4-ethyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

(44a)1-[5-(4-{1-[(4-苄基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (44a)1-[5-(4-{1-[(4-benzyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

於實施例(1e)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(72.0μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(53.7mg)及4-苄基-2-啉甲酸鹽酸鹽(40.0mg)，於室溫攪拌4小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無 水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(100mg)。 Triethylamine (72.0 μL) was added to a solution of the compound (10.0 mg), m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (53.7mg) and 4-benzyl-2- The morpholine hydrochloride (40.0 mg) was stirred at room temperature for 4 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.43-1.67(2H,m),1.79-1.90(2H,m),2.12(3H,s),2.20-2.33(1H,m),2.36-2.49(1H,m),2.55-2.75(3H,m),2.92-3.07(2H,m),3.10-3.20(4H,m),3.21(2H,t,J=8.5Hz),3.49-3.62(2H,m),3.65-3.75(1H,m),3.89-3.97(1H,m),4.04-4.13(1H,m),4.29(3H,t,J=8.5Hz),4.36(2H,s),4.66-4.74(1H,m),6.76(1H,d,J=8.5Hz),6.81(2H,d,J=7.9Hz),7.04-7.12(2H,m),7.28-7.40(5H,m),7.52(1H,t,J=7.0Hz),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.67 (2H, m), 1.79-1.90 (2H, m), 2.12 (3H, s), 2.20-2.33 (1H, m), 2.36-2.49 ( 1H, m), 2.55-2.75 (3H, m), 2.92-3.07 (2H, m), 3.10-3.20 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.49-3.62 (2H, m), 3.65-3.75 (1H, m), 3.89-3.97 (1H, m), 4.04-4.13 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.66 -4.74 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 7.9 Hz), 7.04-7.12 (2H, m), 7.28-7.40 (5H, m), 7.52 (1H, t, J = 7.0 Hz), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(44b)1-(4-甲基-5-{4-[1-(啉-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (44b) 1-(4-methyl-5-{4-[1-( Phenan-2-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)phenyl Ethyl ketone

將實施例(44a)所獲得的化合物(100mg)溶解於乙醇(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(20.1mg)並於氫氣環境下，於65℃攪拌3小時。於反應液中添加乙酸乙酯並濾除不溶物後，將濾液於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(46.9mg)。 The compound (100 mg) obtained in Example (44a) was dissolved in ethanol (2 mL) and ethyl acetate (2 mL), and 7.5% palladium carbon (20.1 mg) was added, and the mixture was stirred at 65 ° C for 3 hours under a hydrogen atmosphere. After ethyl acetate was added to the reaction mixture and the insoluble material was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified to mjjjjlililililililili

1H-NMR(400MHz,CDCl3)δ：1.59-1.72(2H,m),1.84-1.93(2H,m),2.13(3H,s),2.60-2.76(2H,m),2.82-2.99(2H,m),3.03-3.25(8H,m),3.62-3.71(1H,m), 3.83-3.90(1H,m),4.10-4.17(1H,m),4.22-4.31(3H,m),4.36(2H,s),4.69-4.77(1H,m),6.77(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.06-7.12(2H,m),7.36(1H,d,J=8.5Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.59-1.72 (2H, m), 1.84-1.93 (2H, m), 2.13 (3H, s), 2.60-2.76 (2H, m), 2.82-2.99 ( 2H, m), 3.03-3.25 (8H, m), 3.62-3.71 (1H, m), 3.83-3.90 (1H, m), 4.10-4.17 (1H, m), 4.22-4.31 (3H, m), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.06-7.12 (2H, m), 7.36 (1H, d, J = 8.5 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H , d, J = 8.5Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(44c)1-[5-(4-{1-[(4-乙基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (44c)1-[5-(4-{1-[(4-ethyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

於實施例(44b)所獲得的化合物(1.52g)之四氫呋喃(30mL)與甲醇(10mL)之混合溶液中添加乙酸(845μL)、乙醛(184μL)、三乙醯氧基硼氫化鈉(782mg)，於室溫攪拌18小時。將反應液於減壓下餾除溶媒，添加飽和碳酸氫鈉(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈淡黃色固體之標題化合物(558mg)。 Acetic acid (845 μL), acetaldehyde (184 μL), sodium triethoxysulfonate hydride (782 mg) was added to a mixed solution of the compound (1.52 g) obtained in the compound (44b) (30 mL) and methanol (10 mL). ), stirring at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure. EtOAc (EtOAc) The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAcjHHHHH

1H-NMR(400MHz,CDCl3)δ：1.11(3H,t,J=7.3Hz),1.60-1.73(2H,m),1.82-1.93(2H,m),2.12(3H,s),2.17-2.27(1H,m),2.33-2.39(1H,m),2.44-2.53(2H,m),2.60-2.81(3H,m),2.92-3.00(1H,m),3.01-3.13(4H,m),3.18-3.25(2H,m),3.64-3.77(1H,m),3.92-4.02(1H,m),4.06-4.17(1H,m),4.29(3H,t,J=8.5Hz),4.36(2H,s),4.68-4.79(1H,m),6.73-6.84(3H,m),7.05-7.13(2H,m),7.33-7.39(1H,m),7.50-7.54(1H,m),7.58-7.64(1H,m), 7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.60-1.73 (2H, m), 1.82-1.93 (2H, m), 2.12 (3H, s), 2.17 -2.27(1H,m), 2.33-2.39(1H,m),2.44-2.53(2H,m), 2.60-2.81(3H,m),2.92-3.00(1H,m),3.01-3.13(4H, m), 3.18-3.25 (2H, m), 3.64-3.77 (1H, m), 3.92-4.02 (1H, m), 4.06-4.17 (1H, m), 4.29 (3H, t, J = 8.5 Hz) , 4.36 (2H, s), 4.68-4.79 (1H, m), 6.73-6.84 (3H, m), 7.05-7.13 (2H, m), 7.33-7.39 (1H, m), 7.50-7.54 (1H, m), 7.58-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：646(M+H)+。 MS (APCI) m/z: 646 (M+H) + .

(實施例45) (Example 45)

(實施例45-1)：於實施例(45d)合成 (Example 45-1): Synthesis in Example (45d)

1-(4-甲基-5-{4-[1-(啉-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮 1-(4-methyl-5-{4-[1-( Phenyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethylsulfonyl)phenyl Ethyl ketone

(實施例45-2)：於實施例(45d)合成 (Example 45-2): Synthesis in Example (45d)

1-[5-(4-{1-[(4-乙基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮 1-[5-(4-{1-[(4-ethyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(ethyl Sulfhydryl)phenyl]ketone

(45a)(4-苄基啉-2-基)[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]甲酮 (45a) (4-benzyl 啉-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H )-based ketone

於1,2,3,6-四氫吡啶-4-基-硼酸 酯鹽酸鹽(CAS編號1121057-75-7)(369mg)之N,N-二甲基甲醯胺(10mL)溶液中添加三乙基胺(310μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(499mg)及4-苄基啉-2-甲酸(370mg)，於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取，有機層以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨。以無水硫酸 鈉乾燥後，藉由於減壓下濃縮，獲得呈茶色油狀物之標題化合物(390mg)。 1,2,3,6-tetrahydropyridin-4-yl-boronic acid Triethylamine (310 μL) was added to a solution of the ester hydrochloride (CAS No. 1111057-75-7) (369 mg) in N,N-dimethylformamide (10 mL) and stirred at room temperature for 5 min. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (499mg) and 4-benzyl Phenan-2-carboxylic acid (370 mg) was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The title compound (390 mg) was obtained as a brown oil.

1H-NMR(400MHz,CDCl3)δ：1.24(12H,s),1.56-1.69(2H,m),2.17-2.45(3H,m),2.63-2.73(1H,m),3.44-3.75(4H,m),3.84-4.15(4H,m),4.18-4.31(0.5H,m),6.42(0.5H,s),6.48(1H,s),7.28-7.35(5H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.24 (12H, s), 1.56-1.69 (2H, m), 2.17-2.45 (3H, m), 2.63-2.73 (1H, m), 3.44-3.75 ( 4H, m), 3.84-4.15 (4H, m), 4.18-4.31 (0.5H, m), 6.42 (0.5H, s), 6.48 (1H, s), 7.28-7.35 (5H, m).

(45b)5-(4-{1-[(4-苄基啉-2-基)羰基]-1,2,3,6-四氫吡啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (45b) 5-(4-{1-[(4-benzyl) Phenyl-2-yl)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid Tertiary butyl ester

於實施例(1a)所獲得的化合物(317mg)及實施例(45a)所獲得的化合物(390mg)之1,2-二甲氧基乙烷(10mL)溶液中添加碳酸鈉(249mg)之水溶液(3mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(64.1mg)，以微波反應裝置，於130℃反應1小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈茶色油狀物之標題化合物(356mg)。 An aqueous solution of sodium carbonate (249 mg) was added to a solution of the compound (317 mg) obtained in Example (1a) and the compound (390 mg) obtained in Example (45a) (1,2-dimethoxyethane (10 mL). (3 mL) and stirred at room temperature for 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (64.1 mg) was added, and the mixture was reacted at 130 ° C for 1 hour in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),2.06(3H,s),2.21-2.33(1H,m),2.35-2.60(3H,m),2.65-2.75(1H,m),2.87-2.98(1H,m),3.03(2H,t,J=8.5Hz),3.50-3.90(5H,m),3.92-4.39(6H,m),5.90(0.5H,s),5.96(0.5H,s),6.81(3H,d,J=8.5Hz),7.20-7.37(7H,m),7.68(1H,br s)。 1 H-NMR (400MHz, CDCl 3) δ: 1.56 (9H, s), 2.06 (3H, s), 2.21-2.33 (1H, m), 2.35-2.60 (3H, m), 2.65-2.75 (1H, m), 2.87-2.98 (1H, m), 3.03 (2H, t, J = 8.5 Hz), 3.50-3.90 (5H, m), 3.92-4.39 (6H, m), 5.90 (0.5H, s), 5.96 (0.5H, s), 6.81 (3H, d, J = 8.5 Hz), 7.20-7.37 (7H, m), 7.68 (1H, br s).

(45c)1-[5-(4-{1-[(4-苄基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮 (45c)1-[5-(4-{1-[(4-benzyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(ethyl Sulfhydryl)phenyl]ketone

於實施例(45b)所獲得的化合物(356mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌4小時。減壓下濃縮反應液，藉由減壓乾燥，獲得呈茶色固體之粗製之(4-苄基啉-2-基)[4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]甲酮鹽酸鹽(320mg)。 4N hydrochloric acid was added to a solution of the compound (356 mg) obtained in Example (45b) in dichloromethane (2 mL) Alkane solution (4 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and dried (EtOAc) 啉-2-yl)[4-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine- 1(2H)-yl]methanone hydrochloride (320 mg).

於獲得的化合物(1.15g)之N,N-二甲基甲醯胺(10mL)溶液中添加三乙基胺(580mL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(874mg)及[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(577mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈茶色液體之標題化合物(1.42g)。 Triethylamine (580 mL) was added to a solution of the obtained compound (1. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borane (874 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (577 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.9Hz),1.95-2.15(5H,m),2.21-2.33(1H,m),2.37-2.54(3H,m),2.67-2.79(1H,m),3.18-3.27(4H,m),3.51-3.89(5H,m),3.90-4.02(1H,m),4.07-4.40(6H,m),5.91(0.4H,br s),5.96(0.6H,br s),6.75-6.85(3H,m),7.29-7.35(5H,m),7.40(1H,d,J=7.9Hz),7.45-7.53(2H,m),7.57-7.65(1H,m),7.92-8.05(3H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.9 Hz), 1.95-2.15 (5H, m), 2.21-2.33 (1H, m), 2.37-2.54 (3H, m) , 2.67-2.79 (1H, m), 3.18-3.27 (4H, m), 3.51-3.89 (5H, m), 3.90-4.02 (1H, m), 4.07-4.40 (6H, m), 5.91 (0.4H , br s), 5.96 (0.6H, br s), 6.75-6.85 (3H, m), 7.29-7.35 (5H, m), 7.40 (1H, d, J = 7.9 Hz), 7.45-7.53 (2H, m), 7.57-7.65 (1H, m), 7.92-8.05 (3H, m).

(45d) (45d)

(45d-1)1-(4-甲基-5-{4-[1-(啉-2-基羰基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮及(45d-2)1-[5-(4-{1-[(4-乙基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮 (45d-1)1-(4-methyl-5-{4-[1-( Phenyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethylsulfonyl)phenyl Ethylketone and (45d-2)1-[5-(4-{1-[(4-ethyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(ethyl Sulfhydryl)phenyl]ketone

將實施例(45c)所獲得的化合物(1.42g)溶解於乙醇(10mL)及乙酸乙酯(10mL)，添加7.5%鈀碳(284mg)並於氫氣環境下，於60℃攪拌8小時。於反應液中添加乙酸乙酯並濾除不溶物後，將濾液於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得為白色固體之標題化合物45d-1(547mg)，為淡黃色固體之標題化合物45d-2(616mg)。 The compound obtained in Example (45c) (1.42 g) was dissolved in ethanol (10 mL) and ethyl acetate (10 mL), and 7.5% palladium carbon (284 mg) was added, and the mixture was stirred at 60 ° C for 8 hours under a hydrogen atmosphere. After ethyl acetate was added to the reaction mixture and the insoluble material was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by EtOAcjjjjjj elut elut elut elut elut elut .

(45d-1) (45d-1)

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.0Hz),1.60-1.72(2H,m),1.84-1.93(2H,m),2.12(3H,s),2.57-2.78(2H,m),2.81-2.98(2H,m),3.03-3.26(7H,m),3.60-3.71(1H,m),3.80-3.91(1H,m),4.08-4.18(1H,m),4.20-4.29(3H,m),4.37(2H,s),4.68-4.78(1H,m),6.77(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.05-7.15(2H,m),7.39(1H,d,J=7.9Hz),7.48-7.55(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.60-1.72 (2H, m), 1.84-1.93 (2H, m), 2.12 (3H, s), 2.57 -2.78 (2H, m), 2.81-2.98 (2H, m), 3.03-3.26 (7H, m), 3.60-3.71 (1H, m), 3.80-3.91 (1H, m), 4.08-4.18 (1H, m), 4.20-4.29 (3H, m), 4.37 (2H, s), 4.68-4.78 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz) ), 7.05-7.15(2H,m), 7.39 (1H,d,J=7.9Hz), 7.48-7.55(1H,m), 7.60-7.64(1H,m),7.97(1H,d,J=8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(45d-2) (45d-2)

1H-NMR(400MHz,CDCl3)δ：1.11(3H,t,J=7.3Hz),1.26(3H,t,J=7.3Hz),1.60-1.74(2H,m),1.81-1.95(2H,m),2.12(3H,s),2.16-2.25(1H,m),2.29-2.39(1H,m),2.43-2.54(2H,m),2.58-2.81(3H,m),2.93-3.29(6H,m),3.62-3.81(1H,m),3.93-4.01(1H,m),4.05-4.15(1H,m),4.22-4.33(3H,m),4.37(2H,s),4.68-4.78(1H,m),6.73-6.85(3H,m),7.05-7.15(2H,m),7.39(1H,d,J=7.9Hz),7.46-7.55(1H,m),7.57-7.66(1H,m),7.96(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.11 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.60-1.74 (2H, m), 1.81-1.95 (2H) , m), 2.12 (3H, s), 2.16-2.25 (1H, m), 2.29-2.39 (1H, m), 2.43-2.54 (2H, m), 2.58-2.81 (3H, m), 2.93-3.29 (6H, m), 3.62-3.81 (1H, m), 3.93-4.01 (1H, m), 4.05-4.15 (1H, m), 4.22-4.33 (3H, m), 4.37 (2H, s), 4.68 -4.78(1H,m),6.73-6.85(3H,m),7.05-7.15(2H,m),7.39(1H,d,J=7.9Hz),7.46-7.55(1H,m),7.57-7.66 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：660(M+H)+。 MS (APCI) m/z: 660 (M+H) + .

(實施例46) (Example 46)

1-[4-甲基-5-(4-{1-[(1-甲基吡咯啶-2-基)羰基]哌啶-4-基}苯氧基)-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[4-Methyl-5-(4-{1-[(1-methylpyrrolidin-2-yl)carbonyl]piperidin-4-yl}phenoxy)-2,3-dihydro- 1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(270mg)之N,N-二甲基甲醯胺(6mL)溶液中添加三乙基胺(140μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(207mg)及1-甲基吡咯啶-2-甲酸(77.3mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸 鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(106mg)。 Triethylamine (140 μL) was added to a solution of the compound (m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (207 mg) and 1-methylpyrrolidine-2-carboxylic acid (77.3 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.45-1.65(2H,m),1.76-2.00(2H,m),2.13(3H,s),2.18-2.28(1H,m),2.36(3H,d,J=6.1Hz),2.56-2.76(2H,m),3.03-3.25(9H,m),4.21-4.31(3H,m),4.36(2H,s),4.71-4.79(4H,br m),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.05-7.13(2H,m),7.36(1H,d,J=7.9Hz),7.49-7.55(1H,m),7.60-7.64(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.65 (2H, m), 1.76-2.00 (2H, m), 2.13 (3H, s), 2.18-2.28 (1H, m), 2.36 (3H, d, J = 6.1 Hz), 2.56-2.76 (2H, m), 3.03-3.25 (9H, m), 4.21-4.31 (3H, m), 4.36 (2H, s), 4.71-4.79 (4H, br m ), 6.76 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：616(M+H)+。 MS (APCI) m/z: 616 (M+H) + .

(實施例47) (Example 47)

1-{5-[4-(1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(37b)所獲得的化合物(272mg)之四氫呋喃(6mL)與甲醇(2mL)之混合溶液中添加乙酸(138μL)、甲醛液(37%)(45.1μL)、三乙醯氧基硼氫化鈉(128mg)，於室溫攪拌4小時。將反應液於減壓下濃縮後，添加飽和碳酸氫鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮 。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(57.6mg)。 Acetic acid (138 μL), formaldehyde solution (37%) (45.1 μL), and triethoxynitride boron were added to a mixed solution of the compound (272 mg) obtained in Example (37b) in tetrahydrofuran (6 mL) and methanol (2 mL). Sodium hydride (128 mg) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. EtOAc. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. . The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.59-1.72(2H,m),1.86-1.98(2H,m),2.13(3H,s),2.37-2.58(5H,m),2.62-2.79(3H,m),3.05-3.24(6H,m),3.48-3.62(2H,m),4.17-4.33(3H,m),4.36(2H,s),4.77-4.85(1H,m),6.76(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.04-7.14(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.59-1.72 (2H, m), 1.86-1.98 (2H, m), 2.13 (3H, s), 2.37-2.58 (5H, m), 2.62-2.79 ( 3H, m), 3.05-3.24 (6H, m), 3.48-3.62 (2H, m), 4.17-4.33 (3H, m), 4.36 (2H, s), 4.77-4.85 (1H, m), 6.76 ( 1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.04-7.14 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J =7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：652(M+H)+。 MS (APCI) m/z: 652 (M+H) + .

(實施例48) (Example 48)

1-[5-(4-{1-[(4-甲基啉-2-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(4-methyl) 啉-2-yl)carbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

於實施例(44b)所獲得的化合物(191mg)之四氫呋喃(6mL)與甲醇(2mL)之混合溶液中添加乙酸(106μL)、甲醛液(37%)(34.7μL)、三乙醯氧基硼氫化鈉(98.7mg)，並於室溫攪拌4小時。將反應液於減壓下濃縮後，添加飽和碳酸氫鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯 甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(58.6mg)。 Acetic acid (106 μL), formaldehyde solution (37%) (34.7 μL), triethoxynitride boron were added to a mixed solution of the compound (191 mg) obtained in Example (44b) in tetrahydrofuran (6 mL) and methanol (2 mL). Sodium hydride (98.7 mg) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was subjected to amine column chromatography (ethyl acetate / dichloro The title compound (58.6 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.61-1.76(2H,m),1.82-1.95(2H,m),2.12(3H,s),2.20-2.30(1H,m),2.33-2.44(4H,m),2.59-2.77(3H,m),2.86-2.94(1H,m),3.00-3.13(4H,m),3.21(2H,t,J=8.5Hz),3.67-3.80(1H,m),3.92-3.99(1H,m),4.06-4.15(1H,m),4.24-4.33(3H,m),4.36(2H,s),4.69-4.77(1H,m),6.73-6.85(3H,m),7.10(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.76 (2H, m), 1.82-1.95 (2H, m), 2.12 (3H, s), 2.20-2.30 (1H, m), 2.33-2.44 ( 4H, m), 2.59-2.77 (3H, m), 2.86-2.94 (1H, m), 3.00-3.13 (4H, m), 3.21 (2H, t, J = 8.5 Hz), 3.67-3.80 (1H, m), 3.92-3.99 (1H, m), 4.06-4.15 (1H, m), 4.24-4.33 (3H, m), 4.36 (2H, s), 4.69-4.77 (1H, m), 6.73-6.85 ( 3H, m), 7.10 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6) Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例49)：於實施例(49b)合成 (Example 49): Synthesis in Example (49b)

2-(環丙基胺基)-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 2-(cyclopropylamino)-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

(49a)(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙醛 (49a)(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}piperidin-1-yl)(sideoxy)acetaldehyde

於實施例18所獲得的化合物(243mg)之二氯甲烷(2mL)溶液中添加三氟乙酸(2mL)，並於室溫攪拌18小時。減壓下將反應液濃縮，添加飽和碳酸氫鈉水溶液(10mL) 而中和後、以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，藉由減壓下濃縮，獲得呈白色固體之標題化合物(343mg)。 Trifluoroacetic acid (2 mL) was added to aq. The reaction solution was concentrated under reduced pressure and aqueous saturated sodium hydrogen sulfate (10 mL) After neutralization, it was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.52-1.74(2H,m),1.81-1.97(2H,m),2.12(3H,s),2.65-2.89(2H,m),3.05-3.27(6H,m),4.19-4.33(3H,m),4.36(2H,s),4.68(1H,br s),6.71-6.87(3H,m),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.74 (2H, m), 1.81-1.97 (2H, m), 2.12 (3H, s), 2.65-2.89 (2H, m), 3.05-3. 6H, m), 4.19-4.33 (3H, m), 4.36 (2H, s), 4.68 (1H, br s), 6.71-6.87 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 ( 1H, d, J = 7.9 Hz).

(49b)(2-(環丙基胺基)-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 (49b) (2-(cyclopropylamino)-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethyl)}- 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

於實施例(49a)所獲得的化合物(100mg)之四氫呋喃(3mL)與甲醇(1mL)之混合溶液中添加乙酸(61.3μL)、環丙基胺(18.4μL)、三乙醯氧基硼氫化鈉(56.7mg)，並於室溫攪拌18小時。將反應液於減壓下濃縮後，添加飽和碳酸氫鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(二氯甲烷/乙酸乙酯)純化，獲得呈白色固體之標題化合物(2.5mg)。 Acetic acid (61.3 μL), cyclopropylamine (18.4 μL), triethoxycarbonylborohydride were added to a mixed solution of the compound (100 mg) obtained in Example (49a) in tetrahydrofuran (3 mL) and methanol (1 mL). Sodium (56.7 mg) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：0.35-0.46(4H,m),1.55-1.69(2H,m),1.82-1.95(2H,m),2.13(3H,s),2.18-2.25(1H,m),2.64-2.72(1H,m),3.04-3.15(4H,m),3.16-3.26(2H,m),3.44-3.60(3H,m),3.82-3.93(1H,m), 4.29(2H,t,J=8.5Hz),4.36(2H,s),4.73-4.83(1H,m),6.74-6.85(3H,m),7.09(2H,d,J=8.5Hz),7.33-7.39(1H,m),7.48-7.55(1H,m),7.58-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 0.35-0.46 (4H, m), 1.55-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.18-2.25 ( 1H, m), 2.64-2.72 (1H, m), 3.04-3.15 (4H, m), 3.16-3.26 (2H, m), 3.44-3.60 (3H, m), 3.82-3.93 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.73-4.83 (1H, m), 6.74-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.33 -7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：602(M+H)+。 MS (APCI) m/z: 602 (M+H) + .

(實施例50)：於實施例(50b)合成 (Example 50): Synthesis in Example (50b)

2-[(2-羥基乙基)胺基]-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 2-[(2-hydroxyethyl)amino]-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}- 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

(50a)(2-{[2-(苄氧基)乙基]胺基}-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 (50a) (2-{[2-(Benzyloxy)ethyl]amino}-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

於實施例(49a)所獲得的化合物(100mg)之四氫呋喃(3mL)與甲醇(1mL)之混合溶液中添加乙酸(61.3μL)、2-苄氧基-1-乙烷胺(40.5mg)、三乙醯氧基硼氫化鈉(56.7mg)，並於室溫攪拌3小時。將反應液於減壓下濃縮後，添加飽和碳酸氫鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈無色油狀物之標題化合物(36.3mg)。 Acetic acid (61.3 μL), 2-benzyloxy-1-ethaneamine (40.5 mg), and a mixture of tetrahydrofuran (3 mL) and methanol (1 mL) of the compound obtained in Example (49a), Sodium triethoxy borohydride (56.7 mg) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.49-1.63(2H,m), 1.81-1.92(2H,m),2.13(3H,s),2.59-2.76(2H,m),2.83-2.92(2H,m),3.00-3.15(4H,m),3.22(2H,t,J=8.5Hz),3.47-3.56(2H,m),3.62(2H,t,J=5.2Hz),3.77-3.90(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.55(2H,s),4.72-4.83(1H,m),6.77(1H,d,J=9.2Hz),6.81(2H,d,J=8.5Hz),7.08(2H,d,J=8.5Hz),7.22-7.39(6H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.63 (2H, m), 1.81-1.92 (2H, m), 2.13 (3H, s), 2.59-2.76 (2H, m), 2.83-2.92 ( 2H, m), 3.00-3.15 (4H, m), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.56 (2H, m), 3.62 (2H, t, J = 5.2 Hz), 3.77-3.90 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.55 (2H, s), 4.72-4.83 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.5 Hz), 7.22 - 7.39 (6H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 ( 1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(50b)2-[(2-羥基乙基)胺基]-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮 (50b) 2-[(2-Hydroxyethyl)amino]-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]acetamidine) }}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethanone

將實施例(50a)所獲得的化合物(36.3mg)溶解於甲醇(1mL)及二氯甲烷(1mL)，添加7.5%鈀碳(7.0mg)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯，濾除不溶物，藉由減壓下將濾液濃縮，獲得呈白色固體之標題化合物(24.6mg)。 The compound (36.3 mg) obtained in Example (50a) was dissolved in methanol (1 mL) and dichloromethane (1 mL), and 7.5% palladium carbon (7.0 mg) was added and stirred under a hydrogen atmosphere at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the title compound (24.6 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.65-1.80(4H,m),1.84-1.97(2H,m),2.12(3H,s),2.65-2.82(2H,m),3.11(3H,s),3.16-3.33(4H,m),3.64-3.75(1H,m),3.91-4.11(3H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.63-4.72(1H,m),6.73-6.85(3H,m),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.65-1.80 (4H, m), 1.84-1.97 (2H, m), 2.12 (3H, s), 2.65-2.82 (2H, m), 3.11 (3H, s), 3.16-3.33 (4H, m), 3.64-3.75 (1H, m), 3.91-4.11 (3H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.63 -4.72 (1H, m), 6.73-6.85 (3H, m), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：606(M+H)+。 MS (APCI) m/z: 606 (M+H) + .

(實施例51) (Example 51)

(實施例51-1)：於實施例(51c)合成 (Example 51-1): Synthesis in Example (51c)

(5S)-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-3-酮 (5S)-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-3-one

(實施例51-2)：於實施例(51d)合成 (Example 51-2): Synthesis in Example (51d)

(5S)-1-甲基-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-3-酮 (5S)-1-methyl-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-3-one

(51a)(2S,4R)-4-羥基-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸苄酯 (51a)(2S,4R)-4-hydroxy-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}}- Benzyl 2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylate

於實施例(1e)所獲得的(300mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(230μL)，並於室溫攪拌5分鐘。其次添加N-苄氧基羰基-L-羥基脯胺酸(176mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(159mg)、1-羥基苯并三唑一水合物(84.9mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下 濃縮。將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(170mg)。 Triethylamine (230 μL) was added to a solution of (300 mg) of N,N-dimethylformamide (5 mL) obtained in Example (1e), and stirred at room temperature for 5 min. Next, N-benzyloxycarbonyl-L-hydroxyproline (176 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylated imide hydrochloride (159 mg), 1- Hydroxybenzotriazole monohydrate (84.9 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then evaporated. concentrate. The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.64-1.92(2H,m),2.51-2.81(5H,m),2.59-2.79(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.54-3.67(1H,m),3.69-3.84(1H,m),4.07-4.19(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.49-5.23(6H,m),5.30(2H,s),6.71-6.90(4H,m),7.00-7.14(2H,m),7.27-7.40(5H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=6.7Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.64-1.92 (2H, m), 2.51-2.81 (5H, m), 2.59-2.79 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.54-3.67 (1H, m), 3.69-3.84 (1H, m), 4.07-4.19 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H , s), 4.49-5.23 (6H, m), 5.30 (2H, s), 6.71-6.90 (4H, m), 7.00-7.14 (2H, m), 7.27-7.40 (5H, m), 7.52 (1H) , t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 6.7 Hz).

(51b)(2S)-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]-4-側氧基吡咯啶-1-甲酸苄酯 (51b)(2S)-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]-4-oxoxypyrrolidine-1-carboxylic acid benzyl ester

將草醯氯(21.4μL)之二氯甲烷(2mL)溶液於氮氣環境下冷卻至-78℃，滴加二甲基亞碸(33.8μL)，攪拌15分鐘。滴加實施例(51a)所獲得的化合物(170mg)之二氯甲烷(4mL)溶液，再於-78℃攪拌15分鐘。添加三乙基胺(151μL)，於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(45.1mg)。 A solution of chloroform (21.4 μL) in dichloromethane (2 mL) was cooled to -78 ° C under nitrogen, and then dimethylamine (33.8 μL) was added dropwise and stirred for 15 minutes. A solution of the compound (170 mg) obtained in m. m. Triethylamine (151 μL) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.78-1.99(2H,m),2.13(3H,s),2.41-2.95(4H,m),3.06-3.28(6H,m),3.93-4.14(3H,m),4.23-4.32(3H,m),4.36(2H,s), 4.62-4.73(1H,m),5.07-5.35(4H,m),6.73-6.86(4H,m),7.04-7.13(2H,m),7.30-7.40(5H,m),7.52(1H,t,J=7.6Hz),7.61(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz)。 1H-NMR (400MHz, CDCl 3 ) δ: 1.78-1.99 (2H, m), 2.13 (3H, s), 2.41-2.95 (4H, m), 3.06-3.28 (6H, m), 3.93-4.14 (3H , m), 4.23-4.32 (3H, m), 4.36 (2H, s), 4.62-4.73 (1H, m), 5.07-5.35 (4H, m), 6.73-6.86 (4H, m), 7.04-7.13 (2H, m), 7.30-7.40 (5H, m), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz) , 8.08 (1H, d, J = 7.9 Hz).

(51c)(5S)-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-3-酮 (51c)(5S)-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-3-one

將實施例(51b)所獲得的化合物(45.1mg)溶解於甲醇(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(10.0mg)並於環境氣體下，於室溫攪拌18小時。於反應液中添加乙酸乙酯並濾除不溶物，藉由減壓下將濾液濃縮，獲得呈白色固體之標題化合物(40.0mg)。 The compound (45.1 mg) obtained in Example (51b) was dissolved in methanol (2mL) and ethyl acetate (2mL), and then, 7.5% palladium carbon (10.0 mg) was added and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. Ethyl acetate was added to the reaction mixture, and the title compound (40.0 mg) was obtained.

(51d)(5S)-1-甲基-5-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-3-酮 (51d)(5S)-1-methyl-5-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidin-3-one

於實施例(51c)所獲得的化合物(40.0mg)之二氯甲烷(1mL)與甲醇(2mL)之混合溶液中添加鹽酸(398μL)、甲醛液(37%)(242μL)、7.5%鈀碳(10.0mg)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮後，添加1N氫氧化鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(9.0mg)。 Hydrochloric acid (398 μL), formaldehyde solution (37%) (242 μL), and 7.5% palladium carbon were added to a mixed solution of the compound (40.0 mg) obtained in Example (51c) in dichloromethane (1 mL) and methanol (2 mL). (10.0 mg) was stirred at room temperature for 18 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililililililililili

1H-NMR(400MHz,CDCl3)δ：1.57-1.67(2H,m),1.88-1.99(2H,m),2.13(3H,s),2.48-2.78(7H,m),2.88-3.01(1H,m),3.12(3H,s),3.16-3.25(3H,m),3.50-3.63(1H,m),3.88-3.98(1H,m),4.16-4.22(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.76-4.87(1H,m),6.77(1H,d,J=8.5Hz),6.80-6.85(2H,m),7.07-7.15(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.9Hz),7.62(1H,t,J=7.9Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.67 (2H, m), 1.88-1.99 (2H, m), 2.13 (3H, s), 2.48-2.78 (7H, m), 2.88-3.01 ( 1H, m), 3.12 (3H, s), 3.16-3.25 (3H, m), 3.50-3.63 (1H, m), 3.88-3.98 (1H, m), 4.16-4.22 (1H, m), 4.29 ( 2H, t, J = 8.5 Hz), 4.36 (2H, s), 4.76-4.87 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.07-7.15 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

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

(實施例52) (Example 52)

1-{5-[4-(1-{[(4R)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(4R)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl -2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(33b)所獲得的化合物(123mg)溶解於甲醇(3mL)及二氯甲烷(1mL)之混合溶液，添加7.5%鈀碳(24.7mg)、37%甲醛液(277μL)、鹽酸(122μL)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯並濾除不溶物後，將濾液於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(93.6mg)。 The compound (123 mg) obtained in Example (33b) was dissolved in a mixed solution of methanol (3 mL) and dichloromethane (1 mL), and 7.5% palladium carbon (24.7 mg), 37% formaldehyde solution (277 μL), hydrochloric acid ( 122 μL) and stirred at room temperature for 18 hours under a hydrogen atmosphere. After ethyl acetate was added to the reaction mixture and the insoluble material was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified to mjjjjlilililililili

1H-NMR(400MHz,CDCl3)δ：1.57-1.70(2H,m), 1.86-2.00(2H,m),2.13(3H,s),2.18-2.34(2H,m),2.43(3H,d,J=9.2Hz),2.56-2.79(3H,m),3.07-3.27(6H,m),3.57-3.71(2H,br m),4.11-4.22(1H,br m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.77-4.86(1H,m),5.16-5.20(0.5H,m),5.30-5.35(0.5H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.06-7.13(2H,m),7.33-7.39(1H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.70 (2H, m), 1.86-2.00 (2H, m), 2.13 (3H, s), 2.18-2.34 (2H, m), 2.43 (3H, d, J = 9.2 Hz), 2.56-2.79 (3H, m), 3.07-3.27 (6H, m), 3.57-3.71 (2H, br m), 4.11-4.22 (1H, br m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.77-4.86 (1H, m), 5.16-5.20 (0.5H, m), 5.30-5.35 (0.5H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.06-7.13 (2H, m), 7.33 - 7.39 (1H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 ( 1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：634(M+H)+。 MS (APCI) m/z: 634 (M+H) + .

(實施例53) (Example 53)

1-{5-[4-(1-{[(2S)-4,4-二氟-1-(2-羥基乙基)吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-(2-hydroxyethyl)pyrrolidin-2-yl]carbonyl}piperidin-4-yl)benzene Oxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(37b)所獲得的化合物(74.2mg)之二氯甲烷(1mL)與甲醇(2mL)之混合溶液中添加鹽酸(71.3μL)、(三級丁基二甲基矽氧基)乙醛(222μL)、7.5%鈀碳(15mg)並於氫氣環境下，於室溫攪拌3日。於反應液中添加二氯甲烷並濾除不溶物，減壓下將濾液濃縮後，添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(6.8mg)。 Hydrochloric acid (71.3 μL), (tert-butyl dimethyl methoxy oxy) B was added to a mixed solution of the compound (74.2 mg) obtained in Example (37b) in dichloromethane (1 mL) and methanol (2 mL) Aldehyde (222 μL), 7.5% palladium on carbon (15 mg) was stirred at room temperature for 3 days under a hydrogen atmosphere. Methylene chloride was added to the reaction mixture, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by ethylamine EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.55-1.64(2H,m),1.87-1.98(2H,m),2.12(3H,s),2.24-2.41(1H,m),2.48-2.82(5H,m),2.85-2.98(1H,m),3.06-3.26(6H,m),3.46-3.76(3H,m),3.82-3.89(1H,m),3.95-4.03(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.74-4.84(1H,m),6.74-6.85(3H,m),7.05-7.13(2H,m),7.32-7.40(1H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.24-2.41 (1H, m), 2.48-2.82 ( 5H, m), 2.85-2.98 (1H, m), 3.06-3.26 (6H, m), 3.46-3.76 (3H, m), 3.82-3.89 (1H, m), 3.95-4.03 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.74-4.84 (1H, m), 6.74-6.85 (3H, m), 7.05-7.13 (2H, m), 7.32-7.40 ( 1H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9) Hz).

MS(APCI)m/z：682(M+H)+。 MS (APCI) m/z: 682 (M+H) + .

(實施例54)：於實施例(54b)合成 (Example 54): Synthesis in Example (54b)

1-{5-[4-(1-{[(2S,4R)-4-羥基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2, 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(54a)(2S,4R)-4-(苄氧基)-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (54a)(2S,4R)-4-(Benzyloxy)-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)) Tertyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(100μL)，並於室溫攪拌5分鐘。其次添加三級丁氧基羰基-O-苄基-L-4-羥基脯胺酸(142mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(153mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽 水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈無色油狀物之標題化合物(278mg)。 Triethylamine (100 μL) was added to a solution of the compound (m. Next, add tertiary butoxycarbonyl-O-benzyl-L-4-hydroxyproline (142 mg), 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (153 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.46(9H,s),1.54-1.71(2H,m),1.80-1.98(2H,m),2.12(3H,s),2.20-2.39(1H,m),2.56-2.79(2H,m),2.91-3.08(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.54-3.84(2H,m),4.03-4.33(4H,m),4.36(2H,s),4.42-4.63(2H,m),4.68-4.93(2H,m),6.73-6.87(3H,m),7.00-7.15(2H,m),7.29-7.37(6H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 (9H, s), 1.54-1.71 (2H, m), 1.80-1.98 (2H, m), 2.12 (3H, s), 2.20-2.39 (1H, m), 2.56-2.79 (2H, m), 2.91-3.08 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.54-3.84 (2H, m), 4.03 -4.33(4H,m), 4.36(2H,s),4.42-4.63(2H,m),4.68-4.93(2H,m),6.73-6.87(3H,m),7.00-7.15(2H,m) , 7.29-7.37 (6H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

(54b)1-{5-[4-(1-{[(2S,4R)-4-羥基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (54b) 1-{5-[4-(1-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl -2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(54a)所獲得的化合物(278mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)，於室溫攪拌18小時。於反應液中添加己烷(10mL)，減壓下餾除溶媒。殘渣以乙酸乙酯/己烷(1/1)洗淨而濾取，獲得為白色固體之粗製之1-{5-[4-(1-{[(2S,4R)-4-(苄氧基)吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽(259mg)。 4N hydrochloric acid was added to a solution of the compound (278 mg) obtained in Example (54a) in dichloromethane (2 mL) The alkane solution (4 mL) was stirred at room temperature for 18 h. Hexane (10 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate / hexane (1/1) and filtered to afford 1-[5-[4-(1-{[(2S,4R)-4-) benzyloxy as a white solid. Pyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2- (Methylsulfonyl) phenyl] ethyl ketone hydrochloride (259 mg).

將獲得的化合物(100mg)溶解於甲醇(2mL)及乙酸乙酯(2mL)，添加7.5%鈀碳(20.0mg)並於氫氣環境下，於室溫攪拌5小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮，藉由乾燥而獲得呈白色固體 之標題化合物(63.7mg)。 The obtained compound (100 mg) was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and 7.5% palladium carbon (20.0 mg) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give a white solid. The title compound (63.7 mg).

1H-NMR(400MHz,CDCl3)δ：1.59-1.70(2H,m),1.82-1.95(2H,m),1.98-2.08(2H,m),2.13(3H,s),2.29-2.36(1H,m),2.59-2.79(2H,m),3.02-3.27(6H,m),3.45-3.62(2H,m),4.11-4.21(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.49-4.59(1H,m),4.75-4.84(1H,m),6.77(1H,d,J=8.5Hz),6.80-6.85(2H,m),7.03-7.14(2H,m),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 ( 1H, m), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.03 -7.14(2H,m), 7.36(1H,d,J=7.3Hz), 7.52(1H,t,J=7.6Hz), 7.62(1H,t,J=7.6Hz),7.97(1H,d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例55) (Example 55)

1-{5-[4-(1-{[(2S,4R)-4-羥基-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4- Methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(54b)所獲得的1-{5-[4-(1-{[(2S,4R)-4-羥基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮(150mg)溶解於甲醇(3mL)及二氯甲烷(1mL)，添加7.5%鈀碳(30.0mg)、37%甲醛液(854μL)、鹽酸(141μL)並於氫氣環境下，於室溫攪拌8小時。於反應液中添加乙酸乙酯並濾除不溶物，將濾液於減壓下濃縮。於獲得的殘渣中添 加1N氫氧化鈉水溶液而中和，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(85.3mg)。 1-{5-[4-(1-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxyl group obtained in Example (54b) ]-4-Methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone (150 mg) was dissolved in methanol (3 mL) Methylene chloride (1 mL) was added, and 7.5% palladium carbon (30.0 mg), 37% formaldehyde solution (854 μL), and hydrochloric acid (141 μL) were added and stirred under a hydrogen atmosphere at room temperature for 8 hours. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. Add to the residue obtained It was neutralized by adding 1 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililililili

1H-NMR(400MHz,CDCl3)δ：1.59-1.70(2H,m),1.82-1.95(2H,m),1.98-2.08(2H,m),2.13(3H,s),2.29-2.36(1H,m),2.40(3H,d,J=8.5Hz),2.59-2.79(2H,m),3.02-3.27(6H,m),3.45-3.62(2H,m),4.11-4.21(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.49-4.59(1H,m),4.75-4.84(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.70 (2H, m), 1.82-1.95 (2H, m), 1.98-2.08 (2H, m), 2.13 (3H, s), 2.29-2.36 ( 1H, m), 2.40 (3H, d, J = 8.5 Hz), 2.59-2.79 (2H, m), 3.02-3.27 (6H, m), 3.45-3.62 (2H, m), 4.11-4.21 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.49-4.59 (1H, m), 4.75-4.84 (1H, m), 6.77 (1H, d, J = 8.5 Hz) ), 6.82 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例56) (Example 56)

2-[2-(甲基磺醯基)苯基]-1-(4-甲基-5-{4-[1-(3,3,3-三氟丙基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)乙酮 2-[2-(Methylsulfonyl)phenyl]-1-(4-methyl-5-{4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl Phenoxy}-2,3-dihydro-1H-indol-1-yl)ethanone

於實施例(1e)所獲得的化合物(100mg)之四氫呋喃(3mL)與甲醇(1mL)之混合溶液中添加三乙基胺(18.0μL)、乙酸(38.1μL)、3,3,3-三氟丙基醛(18.6mg)、三乙醯氧基硼氫化鈉(35.3mg)，於室溫攪拌18小時。將反應 液於減壓下濃縮後，將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(10.5mg)。 Triethylamine (18.0 μL), acetic acid (38.1 μL), 3,3,3-three were added to a mixed solution of the compound (100 mg) obtained in Example (1e) in tetrahydrofuran (3 mL) and methanol (1 mL). Fluoropropyl aldehyde (18.6 mg) and sodium triethoxysulfonium borohydride (35.3 mg) were stirred at room temperature for 18 hours. Will react After the residue was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.55-2.00(4H,m),2.13(3H,s),2.31-2.52(2H,m),2.61-2.69(2H,m),2.98-3.07(2H,m),3.12(3H,s),3.21(2H,t,J=8.2Hz),3.82-3.91(1H,m),4.01-4.18(1H,m),4.28(2H,t,J=8.2Hz),4.36(2H,s),5.48-5.59(1H,m),6.76-6.85(3H,m),7.12(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.53(1H,t,J=7.3Hz),7.61(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-2.00 (4H, m), 2.13 (3H, s), 2.31-2.52 (2H, m), 2.61-2.69 (2H, m), 2.98-3.07 ( 2H,m), 3.12(3H,s), 3.21(2H,t,J=8.2Hz),3.82-3.91(1H,m),4.01-4.18(1H,m),4.28(2H,t,J= 8.2 Hz), 4.36 (2H, s), 5.48-5.59 (1H, m), 6.76-6.85 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9) Hz), 7.53 (1H, t, J = 7.3 Hz), 7.61 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz) .

MS(APCI)m/z：601(M+H)+。 MS (APCI) m/z: 601 (M+H) + .

(實施例57) (Example 57)

1-[5-(4-{1-[(2S)-1,4-二烷-2-基甲基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2S)-1,4-two Alkan-2-ylmethyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加N,N-二異丙基乙基胺(94.9μL)，並於室溫攪拌5分鐘。其次添加碳酸鉀(15.3mg)、按照文獻記載之方法(Journal of Medicinal Chemistry，2011，54，7772)合成的[(2R)-1,4-二烷-2-基]甲基 甲烷磺酸(65.2mg)，並於80℃攪拌24小時。於反應液中添 加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈黃色固體之標題化合物(37.7mg)。 N,N-diisopropylethylamine (94.9 μL) was added to a solution of the compound (60.0 mg) obtained in Example (1e) (N. Stir for 5 minutes. Next, potassium carbonate (15.3 mg) was added, and [(2R)-1,4-di) synthesized according to the method described in the literature (Journal of Medicinal Chemistry, 2011, 54, 7732). Alkan-2-yl]methylmethanesulfonic acid (65.2 mg) was stirred at 80 ° C for 24 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.51-1.65(2H,m),1.74-1.85(2H,m),2.02-2.14(4H,m),2.17-2.32(1H,br m),2.37-2.53(2H,m),2.98-3.13(5H,m),3.14-3.25(2H,m),3.25-3.34(1H,m),3.56-3.64(1H,m),3.68-3.87(6H,m),4.28(2H,t,J=8.5Hz),4.36(2H,s),6.72-6.88(3H,m),7.12(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.96(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.51-1.65 (2H, m), 1.74-1.85 (2H, m), 2.02-2.14 (4H, m), 2.17-2.32 (1H, br m), 2.37 -2.53 (2H, m), 2.98-3.13 (5H, m), 3.14 - 3.25 (2H, m), 3.25-3.34 (1H, m), 3.56-3.64 (1H, m), 3.68-3.87 (6H, m), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72-6.88 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9) Hz).

MS(APCI)m/z：605(M+H)+。 MS (APCI) m/z: 605 (M+H) + .

(實施例58) (Example 58)

1-[5-(4-{1-[(2R)-1,4-二烷-2-基甲基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2R)-1,4-two Alkan-2-ylmethyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methyl Sulfhydryl)phenyl]ketone

於實施例(1e)所獲得的化合物(80.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加碳酸鉀(61.3mg)、按照文獻記載之方法(Journal of Medicinal Chemistry，2011，54，7772)合成的[(2S)-1,4-二烷-2-基]甲基 甲烷磺酸(43.5mg)，並於80℃攪拌15小時。於反應液中添加水而 以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(6.5mg)。 Potassium carbonate (61.3 mg) was added to a solution of the compound obtained in Example (1e) (80.0 mg) in N,N-dimethylformamide (3 mL), according to the method of the literature (Journal of Medicinal Chemistry, 2011) ,54,7772)Synthesized [(2S)-1,4-two Alkan-2-yl]methylmethanesulfonic acid (43.5 mg) was stirred at 80 ° C for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.53-1.66(2H,m),1.73-1.87(2H,m),2.02-2.16(4H,m),2.18-2.30(1H,m),2.39-2.54(2H,m),2.97-3.14(5H,m),3.14-3.25(2H,m),3.25-3.36(1H,m),3.54-3.66(1H,m),3.67-3.87(6H,m),4.28(2H,t,J=8.5Hz),4.36(2H,s),6.72-6.87(3H,m),7.12(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.96(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.66 (2H, m), 1.73-1.87 (2H, m), 2.02-2.16 (4H, m), 2.18-2.30 (1H, m), 2.39- 2.54(2H,m), 2.97-3.14(5H,m),3.14-3.25(2H,m),3.25-3.36(1H,m),3.54-3.66(1H,m),3.67-3.87(6H,m ), 4.28 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.72 - 6.87 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz) ).

MS(APCI)m/z：605(M+H)+。 MS (APCI) m/z: 605 (M+H) + .

(實施例59)：於實施例(59b)合成 (Example 59): Synthesis in Example (59b)

1-(5-{4-[1-(2-羥基乙基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(2-hydroxyethyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-inden-1-yl )-2-[2-(methylsulfonyl)phenyl]ethanone

(59a)1-(5-{4-[1-(2-{[三級丁基(二甲基)矽基]氧基}乙基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (59a) 1-(5-{4-[1-(2-{[Tris-butyl(dimethyl)indenyl)oxy}ethyl)piperidin-4-yl]phenoxy}-4 -methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(100mg)之四氫呋喃(3mL)與甲醇(1mL)之混合溶液中添加乙酸(63.5μL)、(三級丁基二甲基矽氧基)醛(48.3mg)、三乙醯氧基硼氫化 鈉(58.8mg)，並於室溫攪拌15小時。將反應液於減壓下濃縮，添加飽和碳酸氫鈉水溶液(10mL)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。 To a mixed solution of the compound (100 mg) obtained in Example (1e) (tetram. ), triethoxyhydrin hydroboration Sodium (58.8 mg) was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated.

將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(36.9mg)。 The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：0.08(6H,s),0.90(9H,s),1.86-1.94(2H,m),2.06(3H,s),2.29-2.39(2H,m),2.41-2.58(3H,m),2.72(2H,t,J=6.1Hz),3.13(3H,s),3.18-3.29(4H,m),3.85(2H,t,J=6.1Hz),4.29(2H,t,J=8.5Hz),4.37(2H,s),6.74-6.85(3H,m),7.14(2H,d,J=9.2Hz),7.37(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.60-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 0.08 (6H, s), 0.90 (9H, s), 1.86-1.94 (2H, m), 2.06 (3H, s), 2.29-2.39 (2H, m) , 2.41-2.58 (3H, m), 2.72 (2H, t, J = 6.1 Hz), 3.13 (3H, s), 3.18-3.29 (4H, m), 3.85 (2H, t, J = 6.1 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.74 - 6.85 (3H, m), 7.14 (2H, d, J = 9.2 Hz), 7.37 (1H, d, J = 7.9 Hz) ), 7.53 (1H, t, J = 7.6 Hz), 7.60-7.66 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

(59b)1-(5-{4-[1-(2-羥基乙基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (59b) 1-(5-{4-[1-(2-Hydroxyethyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indole- 1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(59a)所獲得的化合物(36.9mg)之四氫呋喃(1mL)溶液中添加氟化四丁基銨(1mol/L四氫呋喃溶液、23.7μL)，並於室溫攪拌15小時。減壓下將反應液濃縮，將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(27.8mg)。 To a solution of the compound (36.9 mg) obtained in EtOAc (MeOH) (EtOAc, m. The reaction mixture was concentrated under reduced EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.39-1.52(1H,m),1.62-1.75(1H,m),1.85-2.17(5H,m),2.36-2.49(2H,m),2.51-2.63(1H,m),2.73-2.84(2H,m),3.12(3H,s), 3.22(2H,t,J=8.5Hz),3.27-3.39(3H,m),3.74-3.83(2H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.77(1H,d,J=8.5Hz),6.80-6.85(2H,m),7.14(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.50-7.54(1H,m),7.57-7.68(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39-1.52 (1H, m), 1.62-1.75 (1H, m), 1.85-2.17 (5H, m), 2.36-2.49 (2H, m), 2.51- 2.63 (1H, m), 2.73-2.84 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.27-3.39 (3H, m), 3.74-3.83 (2H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.80-6.85 (2H, m), 7.14 (2H, d, J) = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.57-7.68 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H , d, J = 7.9Hz).

MS(APCI)m/z：604(M+H)+。 MS (APCI) m/z: 604 (M+H) + .

(實施例60) (Embodiment 60)

1-(5-{4-[1-(2-甲氧基乙基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indole-1 -yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(80.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加碳酸鉀(61.3mg)、2-溴乙基甲基醚(20.8μL)，並於80℃攪拌12小時。於反應液中添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色固體之標題化合物(46.2mg)。 Potassium carbonate (61.3 mg) and 2-bromoethyl methyl ether (20.8 μL) were added to a solution of the compound (80.0 mg) obtained from the compound (1j) in N,N-dimethylformamide (3 mL) And stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by ethylamine EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.59-1.68(2H,m),1.76-1.87(2H,m),2.40-2.49(5H,m),2.41-2.49(1H,m),2.61(2H,t,J=5.5Hz),3.02-3.14(5H,m),3.21(2H,t,J=7.9Hz),3.36(3H,s),3.54(2H,t,J=5.5Hz),4.28(2H,t,J=7.9Hz),4.36(2H,s),6.74-6.87(3H,m),7.13(2H,d,J= 8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.61(1H,t,J=7.6Hz),7.96(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.68 (2H, m), 1.76-1.87 (2H, m), 2.40-2.49 (5H, m), 2.41-2.49 (1H, m), 2.61 ( 2H, t, J = 5.5 Hz), 3.02-3.14 (5H, m), 3.21 (2H, t, J = 7.9 Hz), 3.36 (3H, s), 3.54 (2H, t, J = 5.5 Hz), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 6.74 - 6.87 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz) ), 7.52 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：563(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例61) (Example 61)

1-(5-{4-[1-(3,3-二氟丙基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(3,3-Difluoropropyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indole- 1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(80.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加N,N-二異丙基乙基胺(126μL)，並於室溫攪拌5分鐘。其次添加碳酸鉀(30.7mg)、按照文獻記載之方法(Journal of Organic Chemistry，2009，74,4547)合成的2-二氟乙基甲烷磺酸(105mg)，並於80℃攪拌12小時。於反應液中添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。獲得的殘渣以胺基管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(15.5mg)。 N,N-diisopropylethylamine (126 μL) was added to a solution of the compound (80.0 mg Stir for 5 minutes. Next, potassium carbonate (30.7 mg) and 2-difluoroethylmethanesulfonic acid (105 mg) synthesized according to the method described in the literature (Journal of Organic Chemistry, 2009, 74, 4547) were added, and stirred at 80 ° C for 12 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by mjjjlilililililili

1H-NMR(400MHz,CDCl3)δ：1.70-1.86(4H,m),2.13(3H,s),2.29(2H,t,J=5.5Hz),2.38-2.52(1H,m),2.69-2.83(2H,m),3.00-3.07(2H,m),3.12(3H,s),3.21(2H,t,J=8.5Hz),4.28(2H,t,J=8.5Hz),4.36(2H,s),5.75-5.80(0.2H,m),5.89-5.94(0.5H,m), 6.03-6.09(0.3H,m),6.73-6.85(3H,m),7.12(2H,d,J=8.5Hz),7.35-7.38(1H,m),7.49-7.55(1H,m),7.59-7.64(1H,m),7.96(1H,d,J=8.5Hz),8.08(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.70-1.86 (4H, m), 2.13 (3H, s), 2.29 (2H, t, J = 5.5 Hz), 2.38-2.52 (1H, m), 2.69 -2.83 (2H, m), 3.00-3.07 (2H, m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.28 (2H, t, J = 8.5 Hz), 4.36 ( 2H, s), 5.75-5.80 (0.2H, m), 5.89-5.94 (0.5H, m), 6.03-6.09 (0.3H, m), 6.73-6.85 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.35-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.08 (1H, d , J = 8.5Hz).

MS(APCI)m/z：569(M+H)+。 MS (APCI) m/z: 569 (M+H) + .

(實施例62)：於實施例(62b)合成 (Example 62): Synthesis in Example (62b)

(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酸 (4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}piperidin-1-yl)acetic acid

(62a)(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酸甲酯 (62a)(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 Methyl-phenyl]oxy}phenyl}piperidin-1-yl)acetate

於實施例(1e)所獲得的化合物(42.6mg)之二氯甲烷(3mL)溶液中添加溴乙酸甲酯(9.3μL)、三乙基胺(29.4μL)，並於室溫攪拌18小時。於反應液中添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(32.8mg)。 Methyl bromoacetate (9.3 μL) and triethylamine (29.4 μL) were added to a solution of the compound (4. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.78-1.91(4H,m),2.13(3H,s),2.23-2.32(2H,m),2.39-2.56(1H,m),3.00-3.08(2H,m),3.12(3H,s),3.21(2H,t,J=8.5Hz),3.26(2H,s),3.74(3H,s),4.28(2H,t,J=8.5Hz),4.36(2H,s),6.73-6.83(3H,m),7.13(2H,d,J=8.5Hz),7.36(1H,d, J=7.3Hz),7.52(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.96(1H,d,J=9.1Hz),8.07(1H,t,J=3.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.91 (4H, m), 2.13 (3H, s), 2.23-2.32 (2H, m), 2.39-2.56 (1H, m), 3.00-3.08 ( 2H,m), 3.12(3H,s), 3.21(2H,t,J=8.5Hz), 3.26(2H,s), 3.74(3H,s), 4.28(2H,t,J=8.5Hz), 4.36(2H, s), 6.73-6.83(3H,m), 7.13(2H,d,J=8.5Hz), 7.36(1H,d, J=7.3Hz),7.52(1H,t,J=7.3Hz ), 7.62 (1H, t, J = 7.3 Hz), 7.96 (1H, d, J = 9.1 Hz), 8.07 (1H, t, J = 3.9 Hz).

(62b)(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酸 (62b)(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}piperidin-1-yl)acetic acid

於實施例(62a)所獲得的化合物(32.8mg)之四氫呋喃(1mL)與甲醇(1mL)之混合溶液中添加2N氫氧化鈉水溶液(71.1μL)，於室溫攪拌18小時。減壓下將反應液濃縮，添加水而以二氯甲烷將水層洗淨。將獲得的水層以1N鹽酸中和後，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，藉由於減壓下濃縮、乾燥，獲得呈白色固體之標題化合物(12.2mg)。 A 2N aqueous sodium hydroxide solution (71.1 μL) was added to a mixed solution of the compound (32.8 mg), m. The reaction solution was concentrated under reduced pressure, and water was added and the aqueous layer was washed with dichloromethane. The obtained aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.62-2.14(7H,m),2.59-2.79(1H,m),3.00-3.24(5H,m),3.40(3H,s),3.55(2H,s),4.17-4.41(5H,m),6.58-6.86(3H,m),7.03-7.18(1H,m),7.25-7.38(1H,m),7.42-7.63(3H,m),7.92(1H,d,J=8.5Hz),8.03(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.62-2.14 (7H, m), 2.59-2.79 (1H, m), 3.00-3.24 (5H, m), 3.40 (3H, s), 3.55 (2H, s), 4.17-4.41 (5H, m), 6.58-6.86 (3H, m), 7.03-7.18 (1H, m), 7.25-7.38 (1H, m), 7.42-7.63 (3H, m), 7.92 ( 1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：563(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例63) (Example 63)

1-(4-甲基-5-{4-[1-(氧呾-3-基)哌啶-4-基]苯氧基}-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(4-Methyl-5-{4-[1-(oxaindole-3-yl)piperidin-4-yl]phenoxy}-2,3-dihydro-1H-indole-1- Base-2-(2-(methylsulfonyl)phenyl]ethanone

於實施例(1e)所獲得的化合物(50.0mg)之二氯甲烷(2mL)溶液中添加三乙醯氧基硼氫化鈉(27.3mg)、2-氧 雜環丁酮(2-oxetanone)(85.7mg)，並於室溫攪拌18小時。於反應液中添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(38.3mg)。 To a solution of the compound (50.0 mg) obtained in the compound (1j), methylene chloride (2 mL) 2-oxetanone (85.7 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.70-1.98(6H,m),2.13(3H,s),2.39-2.52(1H,m),2.80-2.92(2H,m),3.12(3H,s),3.22(2H,t,J=7.9Hz),3.45-3.53(1H,m),4.28(2H,t,J=7.9Hz),4.36(2H,s),4.63-4.71(4H,m),6.71-6.87(3H,m),7.13(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.70-1.98 (6H, m), 2.13 (3H, s), 2.39-2.52 (1H, m), 2.80-2.92 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 7.9 Hz), 3.45-3.53 (1H, m), 4.28 (2H, t, J = 7.9 Hz), 4.36 (2H, s), 4.63-4.71 (4H, m ), 6.71-6.87 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H) , t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：561(M+H)+。 MS (APCI) m/z: 561 (M+H) + .

(實施例64) (Example 64)

(實施例64-1)：於實施例(64a)合成 (Example 64-1): Synthesis in Example (64a)

1-{4-甲基-5-[4-(1-甲基-1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{4-methyl-5-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例64-2)：於實施例(64b)合成 (Example 64-2): Synthesis in Example (64b)

1-{4-甲基-5-[4-(1-甲基哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{4-Methyl-5-[4-(1-methylpiperidin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[ 2-(methylsulfonyl)phenyl]ethanone

(64a)1-{4-甲基-5-[4-(1-甲基-1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (64a) 1-{4-Methyl-5-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-2,3-dihydro- 1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1b)所獲得的化合物(200mg)、1-甲基-1,2,3,6-四氫吡啶-4-硼酸 酯(53.5mg)之1,2-二甲氧基乙烷(2mL)溶液中添加碳酸鈉(50.8mg)之水溶液(1mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(13.1mg)，以微波反應裝置，使於130℃反應1小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(40.7mg)。 Compound (200 mg) obtained in Example (1b), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid An aqueous solution (1 mL) of sodium carbonate (50.8 mg) was added to a solution of the ester (53.5 mg) in hexanes (2 mL) and stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (13.1 mg) was added, and the mixture was reacted at 130 ° C for 1 hour in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlilililililili

1H-NMR(400MHz,CDCl3)δ：1.47-1.62(2H,br m),2.12(3H,s),2.52-2.62(2H,br m),2.64-2.73(2H,br m),3.12(3H,s),3.21(2H,t,J=8.5Hz),3.49(3H,s),4.29(2H,t,J=8.5Hz),4.36(2H,s),5.98(1H,br s),6.75-6.86(3H,m),7.22-7.32(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.47-1.62 (2H, br m), 2.12 (3H, s), 2.52-2.62 (2H, br m), 2.64-2.73 (2H, br m), 3.12 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.49 (3H, s), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.98 (1H, br s ), 6.75-6.86 (3H, m), 7.22-7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：517(M+H)+。 MS (APCI) m/z: 517 (M+H) + .

(64b)1-{4-甲基-5-[4-(1-甲基哌啶-4-基)苯氧基 ]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (64b) 1-{4-methyl-5-[4-(1-methylpiperidin-4-yl)phenoxy ]-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(64a)所獲得的化合物(22.0mg)溶解於乙醇(2mL)及甲醇(1mL)，添加7.5%鈀碳(4.0mg)並於氫氣環境下，於室溫攪拌24小時。於反應液中添加甲醇並濾除不溶物，藉由減壓下將濾液濃縮，獲得呈白色固體之標題化合物(24.5mg)。 The compound (22.0 mg) obtained in Example (64a) was dissolved in ethanol (2 mL) and methanol (1 mL), and 7.5% palladium carbon (4.0 mg) was added and stirred at room temperature for 24 hours under hydrogen atmosphere. Methanol was added to the reaction mixture, and the title compound (24.5 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.38-1.83(3H,m),1.95-2.08(2H,m),2.11(3H,s),2.36-2.52(1H,br m),2.62-2.90(5H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.47-3.59(1H,m),4.29(2H,t,J=8.5Hz),4.37(2H,s),6.72-6.87(3H,m),7.16(1H,d,J=8.5Hz),7.23-7.31(1H,m),7.36(1H,d,J=7.3Hz),7.48-7.56(1H,m),7.58-7.67(1H,m),7.98(1H,t,J=7.9Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.38-1.83 (3H, m), 1.95-2.08 (2H, m), 2.11 (3H, s), 2.36-2.52 (1H, br m), 2.62-2.90 (5H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.47-3.59 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 6.72-6.87 (3H, m), 7.16 (1H, d, J = 8.5 Hz), 7.23-7.31 (1H, m), 7.36 (1H, d, J = 7.3 Hz), 7.48-7.56 (1H) , m), 7.58-7.67 (1H, m), 7.98 (1H, t, J = 7.9 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：519(M+H)+。 MS (APCI) m/z: 519 (M+H) + .

(實施例65) (Example 65)

1-(4-{4-[4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基]氧基]苯基}哌啶-1-基)-2-(啉-4-基)乙酮 1-(4-{4-[4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl Oxy]phenyl}piperidin-1-yl)-2-( Phenyl-4-yl)ethanone

於實施例(1e)所獲得的化合物(60.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(31.0μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三 -2-基)-4-甲基啉鎓(46.0mg)及啉-4-基乙酸(19.3mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(51.5mg)。 Triethylamine (31.0 μL) was added to a solution of the compound (m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (46.0mg) and Phenyl-4-ylacetic acid (19.3 mg) was stirred at room temperature for 18 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.49-1.68(2H,m),1.83-1.95(2H,m),2.13(3H,s),2.47-2.76(6H,m),3.03-3.33(8H,m),3.65-3.78(4H,m),4.13-4.23(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.70-4.78(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=7.9Hz),7.09(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.49-7.55(1H,m),7.60-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.68 (2H, m), 1.83-1.95 (2H, m), 2.13 (3H, s), 2.47-2.76 (6H, m), 3.03-3.33 ( 8H,m), 3.65-3.78(4H,m),4.13-4.23(1H,m), 4.29(2H,t,J=8.5Hz), 4.36(2H,s), 4.70-4.78(1H,m) , 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 7.9 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49 -7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例66) (Example 66)

N,N-二甲基-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N,N-Dimethyl-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(134mg)之二氯甲烷(4mL)溶液中添加二甲基胺鹽酸鹽(56.8mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(66.8mg)、3H-1,2,3- 三唑并[4,5-b]吡啶-3-醇(31.6mg)、N,N-二異丙基乙基胺(0.202mL)而於室溫攪拌。12小時後，將反應液減壓濃縮，殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(101mg)。 Dimethylamine hydrochloride (56.8 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (134 mg) m. Carboxylimine hydrochloride (66.8 mg), 3H-1, 2,3- Triazolo[4,5-b]pyridin-3-ol (31.6 mg), N,N-diisopropylethylamine (0.202 mL) was stirred at room temperature. After 12 hours, the reaction mixture was evaporated.

1H-NMR(400MHz,CDCl3)δ：1.60-1.77(2H,m),1.85-1.98(2H,m),2.12(3H,s),2.69-2.83(2H,m),3.01(3H,s),3.04(3H,s),3.12(3H,s),3.14-3.25(3H,m),3.72-3.80(1H,m),4.25-4.32(2H,m),4.36(2H,s),4.66-4.74(1H,m),6.74-6.85(3H,m),7.07-7.13(2H,m),7.34-7.38(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.95-8.00(1H,m),8.07-8.08(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 1.60-1.77 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.69-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.12 (3H, s), 3.14 - 3.25 (3H, m), 3.72-3.80 (1H, m), 4.25 - 4.32 (2H, m), 4.36 (2H, s) , 4.66-4.74 (1H, m), 6.74-6.85 (3H, m), 7.07-7.13 (2H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 ( 1H, m), 7.95-8.00 (1H, m), 8.07-8.08 (1H, m).

MS(APCI)m/z：604(M+H)+。 MS (APCI) m/z: 604 (M+H) + .

(實施例67) (Example 67)

N-乙基-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-ethyl-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(117mg)之二氯甲烷(4mL)溶液中添加乙基胺鹽酸鹽(24.8mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(77.8mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(27.6mg)、N,N-二異丙基乙基胺(0.106mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶 形固體之標題化合物(78.0mg)。 Ethylamine hydrochloride (24.8 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (117 mg. Carboxylimine hydrochloride (77.8 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (27.6 mg), N,N-diisopropylethyl The amine (0.106 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give white amorphous The title compound (78.0 mg) was obtained.

1H-NMR(500MHz,CDCl3)δ：1.20(3H,t,J=7.3Hz),1.60-1.79(2H,m),1.88-1.97(2H,m),2.12(3H,s),2.70-2.82(2H,m),3.09-3.25(6H,m),3.31-3.38(2H,m),4.25-4.32(2H,m),4.36(2H,s),4.65-4.72(1H,m),5.12-5.19(1H,m),6.75-6.85(3H,m),7.08-7.20(3H,m),7.34-7.38(1H,m),7.49-7.54(1H,m),7.59-7.64(1H,m),7.95-7.99(1H,m),8.06-8.09(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 1.20 (3H, t, J = 7.3 Hz), 1.60-1.79 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70 -2.82 (2H, m), 3.09-3.25 (6H, m), 3.31-3.38 (2H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.72 (1H, m) , 5.12-5.19(1H,m), 6.75-6.85(3H,m),7.08-7.20(3H,m),7.34-7.38(1H,m),7.49-7.54(1H,m),7.59-7.64( 1H, m), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).

MS(APCI)m/z：604(M+H)+。 MS (APCI) m/z: 604 (M+H) + .

(實施例68) (Example 68)

N-(2-氟乙基)-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-(2-fluoroethyl)-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(132mg)之二氯甲烷(4mL)溶液中添加2-氟乙基胺鹽酸鹽(34.2mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(87.8mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(31.2mg)、N,N-二異丙基乙基胺(0.120mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，而獲得呈白色非晶形固體之標題化合物(87.0mg)。 2-Hydroxyethylamine hydrochloride (34.2 mg), 1-ethyl-3-(3-dimethylamino) was added to a solution of the compound (132 mg) obtained from m. Propyl)carboxylimine hydrochloride (87.8 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (31.2 mg), N,N-diisopropyl Base ethylamine (0.120 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.60-1.81(2H,m),1.87-2.00(2H,m),2.12(3H,s),2.71-2.84(2H,m), 3.08-3.26(6H,m),3.56-3.70(2H,m),4.24-4.33(2H,m),4.36(2H,s),4.46-4.51(1H,m),4.57-4.63(1H,m),4.65-4.74(1H,m),5.07-5.15(1H,m),6.75-6.85(3H,m),7.08-7.13(2H,m),7.34-7.38(1H,m),7.48-7.56(2H,m),7.59-7.65(1H,m),7.95-8.00(1H,m),8.06-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.81 (2H, m), 1.87-2.00 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.08-3.26 ( 6H,m),3.56-3.70(2H,m),4.24-4.33(2H,m),4.36(2H,s),4.46-4.51(1H,m),4.57-4.63(1H,m),4.65- 4.74(1H,m), 5.07-5.15(1H,m), 6.75-6.85(3H,m),7.08-7.13(2H,m),7.34-7.38(1H,m),7.48-7.56(2H,m ), 7.59-7.65 (1H, m), 7.95-8.00 (1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：622(M+H)+。 MS (APCI) m/z: 622 (M+H) + .

(實施例69) (Example 69)

N-(2,2-二氟乙基)-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-(2,2-difluoroethyl)-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(138mg)之二氯甲烷(4mL)溶液中添加2,2-二氟乙烷-1-胺鹽酸鹽(42.2mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(91.8mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(32.6mg)、N,N-二異丙基乙基胺(0.125mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈淡黃色非晶形固體之標題化合物(110mg)。 2,2-difluoroethane-1-amine hydrochloride (42.2 mg), 1-ethyl-3-(3) was added to a solution of the compound (138 mg) in dichloromethane (4 mL) -Dimethylaminopropyl)carboxylimine hydrochloride (91.8 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (32.6 mg), N N-Diisopropylethylamine (0.125 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(500MHz,CDCl3)δ：1.61-1.79(2H,m),1.90-1.99(2H,m),2.12(3H,s),2.72-2.84(2H,m),3.09-3.25(6H,m),3.64-3.75(2H,m),4.26-4.31(2H,m),4.36(2H,s),4.66-4.72(1H,m),5.08-5.15(1H,m),5.75-6.01(1H,m),6.75-6.85(3H,m),7.08-7.13(2H,m), 7.34-7.38(1H,m),7.46-7.56(2H,m),7.59-7.64(1H,m),7.95-7.99(1H,m),8.06-8.09(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 1.61-1.79 (2H, m), 1.90-1.99 (2H, m), 2.12 (3H, s), 2.72-2.84 (2H, m), 3.09-3.25 ( 6H, m), 3.64-3.75 (2H, m), 4.26-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.08-5.15 (1H, m), 5.75- 6.01(1H,m), 6.75-6.85(3H,m),7.08-7.13(2H,m), 7.34-7.38(1H,m),7.46-7.56(2H,m),7.59-7.64(1H,m ), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).

MS(APCI)m/z：640(M+H)+。 MS (APCI) m/z: 640 (M+H) + .

(實施例70) (Embodiment 70)

N-甲基-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-methyl-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(136mg)之二氯甲烷(4mL)溶液中添加甲基胺鹽酸鹽(31.8mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(90.4mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(32.1mg)、N,N-二異丙基乙基胺(0.123mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(71.0mg)。 Methylamine hydrochloride (31.8 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (136 mg) in dichloromethane (4 mL) Carboxylimine hydrochloride (90.4 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (32.1 mg), N,N-diisopropylethyl The amine (0.123 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.58-1.81(2H,m),1.87-1.98(2H,m),2.12(3H,s),2.70-2.83(2H,m),2.89(3H,d,J=5.1Hz),3.08-3.25(6H,m),4.25-4.32(2H,m),4.36(2H,s),4.64-4.72(1H,m),5.11-5.19(1H,m),6.75-6.85(3H,m),7.08-7.22(3H,m),7.34-7.39(1H,m),7.50-7.56(1H,m),7.59-7.65(1H,m),7.95-8.00(1H,m),8.06-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 1.58-1.81 (2H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 2.89 (3H, d, J = 5.1 Hz), 3.08-3.25 (6H, m), 4.25 - 4.32 (2H, m), 4.36 (2H, s), 4.64 - 4.72 (1H, m), 5.11-5.19 (1H, m) , 6.75-6.85 (3H, m), 7.08-7.22 (3H, m), 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 ( 1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：590(M+H)+。 MS (APCI) m/z: 590 (M+H) + .

(實施例71) (Example 71)

2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基-N-丙基乙醯胺 2-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Oxy]phenyl]piperidin-1-yl)-2-oxo-N-propylacetamide

於實施例79所獲得的化合物(131mg)之二氯甲烷(4mL)溶液中添加n-丙基胺鹽酸鹽(43.4mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(87.1mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(30.9mg)、N,N-二異丙基乙基胺(0.119mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(92.0mg)。 N-propylamine hydrochloride (43.4 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (131 mg), m. Carboxylimine hydrochloride (87.1 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (30.9 mg), N,N-diisopropyl Ethylamine (0.119 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：0.96(3H,t,J=7.4Hz),1.52-1.80(4H,m),1.87-1.98(2H,m),2.12(3H,s),2.70-2.83(2H,m),3.08-3.31(8H,m),4.25-4.32(2H,m),4.36(2H,s),4.65-4.73(1H,m),5.11-5.19(1H,m),6.75-6.84(3H,m),7.08-7.24(3H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.95-8.00(1H,m),8.06-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 0.96 (3H, t, J = 7.4 Hz), 1.52-1.80 (4H, m), 1.87-1.98 (2H, m), 2.12 (3H, s), 2.70 -2.83 (2H, m), 3.08-3.31 (8H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.73 (1H, m), 5.11-5.19 (1H, m) , 6.75-6.84 (3H, m), 7.08-7.24 (3H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.95-8.00 ( 1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例72) (Example 72)

2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側 氧基-N-(丙烷-2-基)乙醯胺 2-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Oxy]phenyl]piperidin-1-yl)-2-side oxy-N-(propan-2-yl)acetamide

於實施例79所獲得的化合物(134mg)之二氯甲烷(4mL)溶液中添加異丙基胺鹽酸鹽(44.4mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(89.1mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(31.6mg)、N,N-二異丙基乙基胺(0.121mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(92.0mg)。 Add isopropylamine hydrochloride (44.4 mg), 1-ethyl-3-(3-dimethylaminopropyl) to a solution of the compound (134 mg) m. Carboxylimine hydrochloride (89.1 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (31.6 mg), N,N-diisopropyl The amine (0.121 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj

1H-NMR(500MHz,CDCl3)δ：1.19-1.24(6H,m),1.59-1.80(2H,m),1.88-1.97(2H,m),2.12(3H,s),2.70-2.81(2H,m),3.09-3.25(6H,m),4.00-4.10(1H,m),4.25-4.32(2H,m),4.36(2H,s),4.65-4.71(1H,m),5.13-5.19(1H,m),6.75-6.84(3H,m),6.99-7.14(3H,m),7.35-7.38(1H,m),7.49-7.54(1H,m),7.59-7.64(1H,m),7.95-7.99(1H,m),8.06-8.09(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 1.19-1.24 (6H, m), 1.59-1.80 (2H, m), 1.88-1.97 (2H, m), 2.12 (3H, s), 2.70-2.81 ( 2H, m), 3.09-3.25 (6H, m), 4.00-4.10 (1H, m), 4.25-4.32 (2H, m), 4.36 (2H, s), 4.65-4.71 (1H, m), 5.13 5.19 (1H, m), 6.75-6.84 (3H, m), 6.99-7.14 (3H, m), 7.35-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m ), 7.95-7.99 (1H, m), 8.06-8.09 (1H, m).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例73) (Example 73)

2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基-N-(2,2,2-三氟乙基)乙醯胺 2-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyloxy]phenyl}piperidin-1-yl)-2-oxo-N-(2,2,2-trifluoroethyl)acetamide

於實施例79所獲得的化合物(133mg)之二氯甲烷(4mL)溶液中添加2,2,2-三氟乙基胺鹽酸鹽(62.5mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(88.4mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(31.4mg)、N,N-二異丙基乙基胺(0.121mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(120mg)。 2,2,2-trifluoroethylamine hydrochloride (62.5 mg), 1-ethyl-3-(3-) was added to a solution of the compound (133 mg) obtained from m. Dimethylaminopropyl)carboxylimine hydrochloride (88.4 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (31.4 mg), N, N-Diisopropylethylamine (0.121 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.62-1.80(2H,m),1.90-2.00(2H,m),2.12(3H,s),2.73-2.85(2H,m),3.09-3.25(6H,m),3.87-4.03(2H,m),4.25-4.31(2H,m),4.36(2H,s),4.66-4.72(1H,m),5.09-5.16(1H,m),6.75-6.85(3H,m),7.08-7.13(2H,m),7.34-7.38(1H,m),7.50-7.55(1H,m),7.57-7.65(2H,m),7.96-7.99(1H,m),8.06-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.80 (2H, m), 1.90-2.00 (2H, m), 2.12 (3H, s), 2.73-2.85 (2H, m), 3.09-3.25 ( 6H, m), 3.87-4.03 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 4.66-4.72 (1H, m), 5.09-5.16 (1H, m), 6.75- 6.85(3H,m),7.08-7.13(2H,m),7.34-7.38(1H,m),7.50-7.55(1H,m),7.57-7.65(2H,m),7.96-7.99(1H,m ), 8.06-8.09 (1H, m).

MS(APCI)m/z：658(M+H)+。 MS (APCI) m/z: 658 (M+H) + .

(實施例74) (Example 74)

N-乙基-N-甲基-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-ethyl-N-methyl-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(0.14g)之二氯甲烷(4mL)溶液中添加N-甲基乙烷胺鹽酸鹽(0.072g)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(0.096g)、 3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(0.034g)、N,N-二異丙基乙基胺(0.130mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(125mg)。 N-methylethaneamine hydrochloride (0.072 g), 1-ethyl-3-(3-dimethyl group) was added to a solution of the compound (0.14 g Aminopropyl)carboxylimine hydrochloride (0.096 g), 3H-1,2,3-Triazolo[4,5-b]pyridin-3-ol (0.034 g), N,N-diisopropylethylamine (0.130 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.25(3H,q,J=7.3Hz),1.61-1.76(2H,m),1.85-1.98(2H,m),2.12(3H,s),2.68-2.82(2H,m),2.99(3H,d,J=7.8Hz),3.09-3.25(6H,m),3.27-3.55(2H,m),3.71-3.80(1H,m),4.24-4.32(2H,m),4.36(2H,s),4.65-4.74(1H,m),6.74-6.85(3H,m),7.07-7.13(2H,m),7.34-7.38(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.95-7.99(1H,m),8.05-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.25 (3H, q, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68 -2.82(2H,m), 2.99(3H,d,J=7.8Hz), 3.09-3.25(6H,m), 3.27-3.55(2H,m),3.71-3.80(1H,m),4.24-4.32 (2H,m), 4.36(2H,s),4.65-4.74(1H,m),6.74-6.85(3H,m),7.07-7.13(2H,m),7.34-7.38(1H,m),7.49 -7.55 (1H, m), 7.59-7.65 (1H, m), 7.95-7.99 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例75) (Example 75)

2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 2-(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Ethyl]phenyl]piperidin-1-yl)-2-oxoethoxyacetamide

於實施例79所獲得的化合物(0.140g)之二氯甲烷(4mL)溶液中添加氯化銨(0.067g)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(0.096g)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(0.034g)、N,N-二異丙基乙基胺(0.130mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之 標題化合物(76.0mg)。 Ammonium chloride (0.067 g), 1-ethyl-3-(3-dimethylaminopropyl)carboxylate was added to a solution of the compound (0.140 g) obtained from m. Imine hydrochloride (0.096 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.034 g), N,N-diisopropylethylamine ( 0.130 mL) and stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate) to afford white solid. The title compound (76.0 mg).

1H-NMR(400MHz,CDCl3)δ：1.61-1.81(2H,m),1.88-1.99(2H,m),2.12(3H,s),2.71-2.84(2H,m),3.09-3.26(6H,m),4.25-4.32(2H,m),4.36(2H,s),4.64-4.72(1H,m),4.93-5.01(1H,m),5.51-5.62(1H,m),6.75-6.85(3H,m),6.90-7.00(1H,m),7.08-7.13(2H,m),7.34-7.39(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.95-7.99(1H,m),8.06-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.81 (2H, m), 1.88-1.99 (2H, m), 2.12 (3H, s), 2.71-2.84 (2H, m), 3.09-3.26 ( 6H,m), 4.25-4.32(2H,m), 4.36(2H,s),4.64-4.72(1H,m),4.93-5.01(1H,m),5.51-5.62(1H,m),6.75- 6.85(3H,m), 6.90-7.00(1H,m),7.08-7.13(2H,m),7.34-7.39(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m ), 7.95-7.99 (1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：576(M+H)+。 MS (APCI) m/z: 576 (M+H) + .

(實施例76) (Example 76)

1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-(啉-4-基)乙烷-1,2-二酮 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyloxy]phenyl}piperidin-1-yl)-2-( Polin-4-yl)ethane-1,2-dione

於實施例79所獲得的化合物(750mg)之二氯甲烷(10mL)溶液中添加啉(227mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(499mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(177mg)、N,N-二異丙基乙基胺(0.680mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(460mg)。 Addition of the compound (750 mg) obtained in Example 79 to dichloromethane (10 mL) Porphyrin (227 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylated imide hydrochloride (499 mg), 3H-1,2,3-triazolo[4,5- b] Pyridin-3-ol (177 mg), N,N-diisopropylethylamine (0.680 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.59-1.75(2H,m),1.88-1.98(2H,m),2.12(3H,s),2.70-2.83(2H,m), 3.10-3.29(6H,m),3.43-3.48(2H,m),3.62-3.84(7H,m),4.25-4.32(2H,m),4.36(2H,s),4.64-4.72(1H,m),6.74-6.84(3H,m),7.07-7.13(2H,m),7.34-7.38(1H,m),7.50-7.55(1H,m),7.59-7.65(1H,m),7.95-7.99(1H,m),8.06-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.75 (2H, m), 1.88-1.98 (2H, m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.10-3.29 ( 6H,m),3.43-3.48(2H,m),3.62-3.84(7H,m),4.25-4.32(2H,m),4.36(2H,s),4.64-4.72(1H,m),6.74- 6.84(3H,m),7.07-7.13(2H,m),7.34-7.38(1H,m),7.50-7.55(1H,m),7.59-7.65(1H,m),7.95-7.99(1H,m ), 8.06-8.09 (1H, m).

MS(APCI)m/z：646(M+H)+。 MS (APCI) m/z: 646 (M+H) + .

(實施例77) (Example 77)

1-(四氫吖唉-1-基)-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙烷-1,2-二酮 1-(tetrahydroindol-1-yl)-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)ethane-1,2-dione

於實施例79所獲得的化合物(159mg)之二氯甲烷(4mL)溶液中添加四氫吖唉鹽酸鹽(51.6mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(106mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(37.5mg)、N,N-二異丙基乙基胺(0.144mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(108mg)。 To a solution of the compound (159 mg) obtained in m. m. m. m. Carboxylimine hydrochloride (106 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (37.5 mg), N,N-diisopropylethyl The amine (0.144 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.59-1.76(2H,m),1.87-1.96(2H,m),2.12(3H,s),2.32-2.43(2H,m),2.68-2.79(2H,m),3.10-3.25(6H,m),4.07-4.17(3H,m),4.25-4.38(6H,m),4.61-4.68(1H,m),6.74-6.84(3H,m),7.07-7.12(2H,m),7.34-7.38(1H,m),7.49-7.55(1H,m), 7.59-7.65(1H,m),7.95-7.99(1H,m),8.05-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.59-1.76 (2H, m), 1.87-1.96 (2H, m), 2.12 (3H, s), 2.32-2.43 (2H, m), 2.68-2.79 ( 2H,m),3.10-3.25(6H,m),4.07-4.17(3H,m), 4.25-4.38(6H,m),4.61-4.68(1H,m),6.74-6.84(3H,m), 7.07-7.12(2H,m),7.34-7.38(1H,m),7.49-7.55(1H,m), 7.59-7.65(1H,m),7.95-7.99(1H,m),8.05-8.09(1H , m).

MS(APCI)m/z：616(M+H)+。 MS (APCI) m/z: 616 (M+H) + .

(實施例78) (Example 78)

(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙酸乙基酯 (4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Ethyl]phenyl}piperidin-1-yl)(oxy)acetate

於實施例(1e)所獲得的化合物(215mg)中添加二氯甲烷(4mL)、N,N-二異丙基胺(0.208mL)、氯乙醛酸乙酯(0.062mL)而於室溫攪拌。2小時後，減壓濃縮，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(239mg)。 Methyl chloride (4 mL), N,N-diisopropylamine (0.208 mL) and ethyl chloroglyoxylate (0.062 mL) were added to the compound obtained in Example (1e). Stir. After 2 hours, the residue was evaporated.

1H-NMR(400MHz,CDCl3)δ：1.38(3H,t,J=7.0Hz),1.59-1.77(2H,m),1.86-1.97(2H,m),2.12(3H,s),2.69-2.82(2H,m),3.12(3H,s),3.15-3.26(3H,m),3.72-3.81(1H,m),4.24-4.40(6H,m),4.61-4.70(1H,m),6.74-6.79(1H,m),6.80-6.85(2H,m),7.08-7.13(2H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.95-8.00(1H,m),8.05-8.10(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.38 (3H, t, J = 7.0Hz), 1.59-1.77 (2H, m), 1.86-1.97 (2H, m), 2.12 (3H, s), 2.69 -2.82(2H,m), 3.12(3H,s),3.15-3.26(3H,m),3.72-3.81(1H,m),4.24-4.40(6H,m),4.61-4.70(1H,m) , 6.74-6.79 (1H, m), 6.80-6.85 (2H, m), 7.08-7.13 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.65 ( 1H, m), 7.95-8.00 (1H, m), 8.05-8.10 (1H, m).

(實施例79) (Example 79)

(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙酸 (4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}piperidin-1-yl)(oxy)acetic acid

於實施例78所獲得的化合物(237mg)之1,4-二烷(2mL)溶液中添加1N氫氧化鈉水溶液(1.17mL)而於室溫攪拌3小時。以1N鹽酸水溶液中和後，以乙酸乙酯提取。有機層以無水硫酸鈉乾燥後，過濾，減壓濃縮。藉由以乙酸乙酯進行再結晶而獲得呈黃色固體之標題化合物(204mg)。 1,4-two of the compound (237 mg) obtained in Example 78 A 1 N aqueous sodium hydroxide solution (1.17 mL) was added to a solution of hexane (2 mL) and stirred at room temperature for 3 hr. After neutralizing with a 1N aqueous hydrochloric acid solution, it was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The title compound (204 mg) was obtained as a yellow solid.

1H-NMR(400MHz,DMSO-d6)δ：1.39-1.57(2H,m),1.76-1.87(2H,m),1.98-2.08(4H,m),2.71-2.83(2H,m),3.13-3.40(6H,m),3.58-3.67(1H,m),4.21-4.40(4H,m),6.73-6.80(3H,m),7.14-7.21(2H,m),7.45-7.50(1H,m),7.55-7.61(1H,m),7.66-7.73(1H,m),7.81-7.87(1H,m),7.94-7.99(1H,m)。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.39-1.57 (2H, m), 1.76-1.87 (2H, m), 1.98-2.08 (4H, m), 2.71-2.83 (2H, m), 3.13-3.40(6H,m), 3.58-3.67(1H,m),4.21-4.40(4H,m),6.73-6.80(3H,m),7.14-7.21(2H,m),7.45-7.50(1H m), 7.55-7.61 (1H, m), 7.66-7.73 (1H, m), 7.81-7.87 (1H, m), 7.94-7.99 (1H, m).

(實施例80) (Embodiment 80)

(實施例80-1)：於實施例(80a)合成 (Example 80-1): Synthesis in Example (80a)

(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸乙酯 (4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyl oxy]-2-methylphenyl}piperidin-1-yl)(ethyloxy)acetate

(實施例80-2)：於實施例(80b)合成 (Example 80-2): Synthesis in Example (80b)

(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)( 側氧基)乙酸鈉 (4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Oxy]-2-methylphenyl}piperidin-1-yl) Sodium oxy) sodium acetate

(80a)(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸乙酯 (80a)(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Ethyl-oxy]-2-methylphenyl}piperidin-1-yl)(ethyloxy)acetate

於實施例(9c)所獲得的化合物(400mg)之二氯甲烷(8mL)溶液中添加三乙基胺(190μL)、氯乙醛酸乙酯(86.0μL)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。 Triethylamine (190 μL) and ethyl chloroglyoxylate (86.0 μL) were added to a solution of the compound (m. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated.

將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(399mg)。 The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.21-1.30(6H,m),1.60-1.74(2H,m),1.78-1.90(2H,m),2.12(3H,s),2.30(3H,s),2.71-2.83(1H,m),2.86-2.99(1H,m),3.15-3.29(5H,m),3.73-3.84(1H,m),4.27(2H,t,J=8.5Hz),4.33-4.38(4H,m),4.63-4.73(1H,m),6.66-6.70(2H,m),6.77(1H,d,J=8.5Hz),7.04(1H,d,J=8.5Hz),7.39(1H,d,J=7.9Hz),7.50(1H,t,J=7.6Hz),7.60-7.64(1H,m),7.97(1H,d,J=9.2Hz),8.03(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21-1.30 (6H, m), 1.60-1.74 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.71-2.83 (1H, m), 2.86-2.99 (1H, m), 3.15-3.29 (5H, m), 3.73-3.84 (1H, m), 4.27 (2H, t, J = 8.5 Hz) , 4.33-4.38 (4H, m), 4.63-4.73 (1H, m), 6.66-6.70 (2H, m), 6.77 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz ), 7.39 (1H, d, J = 7.9 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.60-7.64 (1H, m), 7.97 (1H, d, J = 9.2 Hz), 8.03 (1H) , d, J = 7.9 Hz).

(80b)(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1- 基)(側氧基)乙酸鈉 (80b)(4-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}piperidine-1- Sodium (sodium oxy) sodium acetate

於實施例(80a)所獲得的化合物(399mg)之四氫呋喃(2mL)與乙醇(2mL)之混合溶液中添加2N之氫氧化鈉水溶液(378μL)，並於室溫攪拌18小時。減壓下濃縮反應液，將獲得的殘渣以水洗淨後濾取，藉由減壓乾燥而獲得為淡桃色固體之標題化合物(433mg)。 A 2N aqueous solution of sodium hydroxide (378 μL) was added to a mixture of THF (2 mL) and THF (2 mL). The reaction mixture was concentrated under reduced pressure. EtOAc m.

1H-NMR(400MHz,DMSO-d6)δ：1.10(3H,t,J=7.3Hz),1.26-1.49(2H,m),1.55-1.69(2H,m),2.04(3H,s),2.26(3H,s),2.81-3.03(2H,m),3.19(2H,t,J=8.5Hz),3.29(2H,q,J=7.3Hz),3.37-3.48(1H,m),3.76-3.88(1H,m),4.21-4.41(5H,m),6.54-6.58(1H,m),6.66-6.68(1H,m),6.75(1H,d,J=8.5Hz),7.06(1H,d,J=8.5Hz),7.48-7.51(1H,m),7.55-7.60(1H,m),7.68-7.73(1H,m),7.82(1H,d,J=8.5Hz),7.91(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.10 (3H, t, J = 7.3 Hz), 1.26-1.49 (2H, m), 1.55-1.69 (2H, m), 2.04 (3H, s) , 2.26 (3H, s), 2.81-3.03 (2H, m), 3.19 (2H, t, J = 8.5 Hz), 3.29 (2H, q, J = 7.3 Hz), 3.37-3.48 (1H, m), 3.76-3.88(1H,m),4.21-4.41(5H,m),6.54-6.58(1H,m),6.66-6.68(1H,m),6.75(1H,d,J=8.5Hz),7.06( 1H,d,J=8.5Hz), 7.48-7.51(1H,m), 7.55-7.60(1H,m), 7.68-7.73(1H,m),7.82(1H,d,J=8.5Hz),7.91 (1H, d, J = 7.9Hz).

MS(APCI)m/z：605(M+H)+。 MS (APCI) m/z: 605 (M+H) + .

(實施例81) (Example 81)

(實施例81-1)：於實施例(81a)合成 (Example 81-1): Synthesis in Example (81a)

(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸乙酯 (4-{4-[(1-{[2-(methylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyl oxy]-2-methylphenyl}piperidin-1-yl)(ethyloxy)acetate

(實施例81-2)：於實施例(81b)合成 (Example 81-2): Synthesis in Example (81b)

(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基 -2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸 (4-{4-[(1-{[2-(methylsulfonyl)phenyl)ethinyl}-4-methyl) -2,3-dihydro-1H-indol-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)(oxy)acetic acid

(實施例81-3)：於實施例(81c)合成 (Example 81-3): Synthesis in Example (81c)

2-(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-N,N-二甲基-2-側氧基乙醯胺 2-(4-{4-[(1-{[2-(methylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]-2-ylphenyl}piperidin-1-yl)-N,N-dimethyl-2-oxoethoxyacetamide

(81a)(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸乙酯 (81a)(4-{4-[(1-{[2-(methylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 Ethyl-oxy]-2-methylphenyl}piperidin-1-yl)(ethyloxy)acetate

於實施例(8b)所獲得的化合物(200mg)之二氯甲烷(5mL)溶液中添加三乙基胺(100μL)、氯乙醛酸乙酯(44.1μL)，於室溫攪拌2小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(209mg)。 Triethylamine (100 μL) and ethyl chloroglyoxylate (44.1 μL) were added to a solution of the compound (m. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.38(3H,t,J=7.0Hz),1.60-1.76(2H,m),1.79-1.92(2H,m),2.12(3H,s),2.30(3H,s),2.70-2.83(1H,m),2.86-2.99(1H,m), 3.12(3H,s),3.15-3.29(3H,m),3.72-3.84(1H,m),4.24-4.42(6H,m),4.61-4.74(1H,m),6.64-6.71(2H,m),6.76(1H,d,J=8.5Hz),7.04(1H,d,J=7.9Hz),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.60-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.38 (3H, t, J = 7.0 Hz), 1.60-1.76 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.70-2.83 (1H, m), 2.86-2.99 (1H, m), 3.12 (3H, s), 3.15-3.29 (3H, m), 3.72-3.84 (1H, m), 4.24 -4.42 (6H, m), 4.61-4.74 (1H, m), 6.64-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.47-7.55 (1H, m), 7.60-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9Hz).

(81b)(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)(側氧基)乙酸 (81b)(4-{4-[(1-{[2-(Methylsulfonyl)phenyl)ethinyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]-2-methylphenyl}piperidin-1-yl)(oxy)acetic acid

於實施例(81a)所獲得的化合物(209mg)之四氫呋喃(2mL)與乙醇(2mL)之混合溶液中添加2N之氫氧化鈉水溶液(253μL)，並於室溫攪拌18小時。減壓下濃縮反應液，以1N鹽酸中和，再次減壓濃縮後，殘渣以水洗淨後濾取，藉由乾燥而獲得為白色固體之標題化合物(145mg)。 A 2N aqueous solution of sodium hydroxide (253 μL) was added to a mixture of THF (2 mL) and THF (2 mL). The reaction mixture was concentrated under reduced pressure. EtOAc m.

1H-NMR(400MHz,DMSO-d6)δ：1.22-1.51(2H,m),1.57-1.70(2H,m),2.04(3H,s),2.26(3H,s),2.44-2.62(1H,m),2.80-2.91(1H,m),2.94-3.05(1H,m),3.13-3.24(5H,m),3.76-3.92(1H,br m),4.22-4.39(5H,m),6.57(1H,dd,J=8.5,3.1Hz),6.67(1H,d,J=3.1Hz),6.74(1H,d,J=9.2Hz),7.06(1H,d,J=8.5Hz),7.48(1H,d,J=7.9Hz),7.53-7.60(1H,m),7.66-7.73(1H,m),7.83(1H,d,J=9.2Hz),7.96(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.22-1.51 (2H, m), 1.57-1.70 (2H, m), 2.04 (3H, s), 2.26 (3H, s), 2.44-2.62 ( 1H, m), 2.80-2.91 (1H, m), 2.94-3.05 (1H, m), 3.13-3.24 (5H, m), 3.76-3.92 (1H, br m), 4.22-4.39 (5H, m) , 6.57 (1H, dd, J = 8.5, 3.1 Hz), 6.67 (1H, d, J = 3.1 Hz), 6.74 (1H, d, J = 9.2 Hz), 7.06 (1H, d, J = 8.5 Hz) , 7.48 (1H, d, J = 7.9 Hz), 7.53-7.60 (1H, m), 7.66-7.73 (1H, m), 7.83 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J =7.9Hz).

(81c)2-(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-N,N-二甲基-2-側氧基乙醯胺 (81c) 2-(4-{4-[(1-{[2-(methylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-N,N-dimethyl-2-oxoethoxyacetamide

於實施例(81b)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(49.0μL)，並於室溫攪拌5分鐘。其次添加二甲基胺鹽酸鹽(11.6mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(27.3mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(16.1mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。 Triethylamine (49.0 μL) was added to a solution of the compound (70.0 mg), m. Next, dimethylamine hydrochloride (11.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylated imide hydrochloride (27.3 mg), 3H-1, 2, 3-Triazolo[4,5-b]pyridin-3-ol (16.1 mg) was stirred at room temperature for 18 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated.

藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，而獲得呈白色固體之標題化合物(46.6mg)。 The title compound (46.6 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.57-1.75(2H,m),1.79-1.92(2H,m),2.12(3H,s),2.30(3H,s),2.73-2.83(2H,m),3.01(3H,s),3.04(3H,s),3.12(3H,s),3.15-3.26(3H,m),3.72-3.82(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.67-4.77(1H,m),6.63-6.71(2H,m),6.76(1H,d,J=8.5Hz),7.04(1H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.49-7.55(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.57-1.75 (2H, m), 1.79-1.92 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.73-2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.12 (3H, s), 3.15-3.26 (3H, m), 3.72-3.82 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H, s), 4.67-4.77 (1H, m), 6.63-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d , J = 7.3 Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例82) (Example 82)

N-乙基-2-(4-{4-[(1-{[2-(甲基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2-側氧基乙醯胺 N-ethyl-2-(4-{4-[(1-{[2-(methylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例(81b)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(49.0μL)，並於室溫攪拌5分鐘。添加乙基胺鹽酸鹽(11.6mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(27.3mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(16.1mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，而獲得呈白色固體之標題化合物(23.5mg)。 Triethylamine (49.0 μL) was added to a solution of the compound (70.0 mg), m. Add ethylamine hydrochloride (11.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (27.3 mg), 3H-1,2,3- Triazolo[4,5-b]pyridin-3-ol (16.1 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (23.5 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.21(3H,t,J=6.7Hz),1.60-1.90(4H,m),2.12(3H,s),2.31(3H,s),2.69-2.85(1H,m),2.91-2.98(1H,m),3.10-3.25(6H,m),3.35(2H,q,J=6.7Hz),4.29(2H,t,J=8.5Hz),4.36(2H,s),4.64-4.76(1H,m),5.09-5.25(1H,m),6.62-6.71(2H,m),6.76(1H,d,J=8.5Hz),7.04(1H,d,J=9.2Hz),7.13-7.20(1H,m),7.36(1H,d,J=6.7Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=9.2Hz),8.07(1H,d,J=6.7Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 6.7 Hz), 1.60-1.90 (4H, m), 2.12 (3H, s), 2.31 (3H, s), 2.69-2.85 (1H, m), 2.91-2.98 (1H, m), 3.10-3.25 (6H, m), 3.35 (2H, q, J = 6.7 Hz), 4.29 (2H, t, J = 8.5 Hz), 4.36 ( 2H, s), 4.64-4.76 (1H, m), 5.09-5.25 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J=9.2Hz), 7.13-7.20(1H,m), 7.36(1H,d,J=6.7Hz), 7.52(1H,t,J=7.6Hz), 7.62(1H,t,J=7.6Hz) , 7.97 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 6.7 Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例83) (Example 83)

N-乙基-2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基 }-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-2-側氧基乙醯胺 N-ethyl-2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl)ethenyl) }-4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]-2-methylphenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例(80b)所獲得的化合物(100mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(66.0μL)，並於室溫攪拌5分鐘。添加乙基胺鹽酸鹽(15.6mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(36.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(21.7mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，而獲得呈白色固體之標題化合物(49.0mg)。 Triethylamine (66.0 μL) was added to a solution of the compound (100 mg), m. Ethylamine hydrochloride (15.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (36.7 mg), 3H-1,2,3- Triazolo[4,5-b]pyridin-3-ol (21.7 mg) was stirred at room temperature for 18 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (49.0 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.21(3H,t,J=7.3Hz),1.26(3H,t,J=7.3Hz),1.58-1.90(4H,m),2.12(3H,s),2.30(3H,s),2.73-2.83(1H,m),2.87-2.99(1H,m),3.09-3.26(5H,m),3.31-3.40(2H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.66-4.76(1H,m),5.13-5.24(1H,m),6.63-6.71(2H,m),6.77(1H,d,J=8.5Hz),7.04(1H,d,J=8.5Hz),7.11-7.22(1H,m),7.39(1H,d,J=7.9Hz),7.51(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.90 (4H, m), 2.12 (3H, s ), 2.30 (3H, s), 2.73-2.83 (1H, m), 2.87-2.99 (1H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t , J=8.5Hz), 4.37(2H, s), 4.66-4.76(1H,m), 5.13-5.24(1H,m),6.63-6.71(2H,m),6.77(1H,d,J=8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.11 - 7.22 (1H, m), 7.39 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.62 ( 1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例84) (Example 84)

2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌啶-1-基)-N,N-二甲基-2-側氧基乙醯胺 2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]-2-ylphenyl}piperidin-1-yl)-N,N-dimethyl-2-oxoethoxyacetamide

於實施例(80b)所獲得的化合物(100mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(66.0μL)，並於室溫攪拌5分鐘。其次添加二甲基胺鹽酸鹽(15.6mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(36.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(21.7mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，而獲得呈白色固體之標題化合物(24.5mg)。 Triethylamine (66.0 μL) was added to a solution of the compound (100 mg), m. Next, dimethylamine hydrochloride (15.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (36.7 mg), 3H-1, 2, 3-Triazolo[4,5-b]pyridin-3-ol (21.7 mg) was stirred at room temperature for 18 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (24.5 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.6Hz),1.51-1.76(2H,m),1.78-1.90(2H,m),2.12(3H,s),2.30(3H,s),2.74-2.84(1H,m),2.86-2.98(1H,m),3.02(3H,s),3.04(3H,s),3.16-3.27(5H,m),3.72-3.82(1H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.67-4.76(1H,m),6.62-6.71(2H,m),6.76(1H,d,J=8.5Hz),7.04(1H,d,J=8.5Hz),7.40(1H,d,J=7.9Hz),7.48-7.53(1H,m),7.60-7.66(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.6 Hz), 1.51-1.76 (2H, m), 1.78-1.90 (2H, m), 2.12 (3H, s), 2.30 (3H, s), 2.74-2.84 (1H, m), 2.86-2.98 (1H, m), 3.02 (3H, s), 3.04 (3H, s), 3.16-3.27 (5H, m), 3.72-3.82 (1H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.67-4.76 (1H, m), 6.62-6.71 (2H, m), 6.76 (1H, d, J = 8.5 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.48-7.53 (1H, m), 7.60-7.66 (1H, m), 7.97 (1H) , d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例85) (Example 85)

(實施例85-1)：於實施例(85a)合成 (Example 85-1): Synthesis in Example (85a)

(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙酸乙酯 (4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Ethyl]phenyl}piperidin-1-yl)(ethyloxy)acetate

(實施例85-2)：於實施例(85b)合成 (Example 85-2): Synthesis in Example (85b)

(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙酸鈉 (4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl) Sodium oxy]phenyl}piperidin-1-yl)(sodium oxy)acetate

(實施例85-3)：於實施例(85c)合成 (Example 85-3): Synthesis in Example (85c)

2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-N,N-二甲基-2-側氧基乙醯胺 2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]phenyl]piperidin-1-yl)-N,N-dimethyl-2-oxoethoxyacetamide

(85a)(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側 氧基)乙酸乙酯 (85a)(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}piperidin-1-yl) (side Ethyl acetate

於實施例(2d)所獲得的化合物(3.25g)之二氯甲烷(30mL)溶液中，冰冷下，添加二異丙基乙基胺(2.99mL)、乙醛酸乙酯(0.782mL)，並於室溫攪拌2小時。減壓下，餾除溶媒，以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(2.91g)。 To a solution of the compound (3.25 g) obtained from m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m It was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and purified mjjjjlilililililili

1H-NMR(400MHz,CDCl3)δ：1.28(3H,t,J=7.3Hz),1.38(3H,t,J=7.3Hz),1.61-1.76(2H,m),1.85-1.97(2H,m),2.11(3H,s),2.69-2.83(2H,m),3.16-3.29(5H,m),3.72-3.82(1H,m),4.22-4.41(6H,m),4.61-4.70(1H,m),6.77(1H,d,J=8.5Hz),6.82(2H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.39(1H,d,J=7.9Hz),7.47-7.54(1H,m),7.59-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), 1.61-1.76 (2H, m), 1.85-1.97 (2H) , m), 2.11 (3H, s), 2.69-2.83 (2H, m), 3.16-3.29 (5H, m), 3.72-3.82 (1H, m), 4.22-4.41 (6H, m), 4.61-4.70 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.47-7.54 (1H, m), 7.59-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(85b)(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)(側氧基)乙酸鈉 (85b)(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}piperidin-1-yl)(oxy)acetate sodium

於實施例(85a)所獲得的化合物(2.61g)之四氫呋喃(15mL)溶液中添加1N之氫氧化鈉水溶液(6.0mL)，並於室溫攪拌28小時。減壓下，餾除溶媒，藉由減壓乾燥而獲得呈白色固體之標題化合物(2.70g)。本化合物並未純化而用於下一步驟。 A 1N aqueous solution of sodium hydroxide (6.0 mL) was added to EtOAc (EtOAc m. The solvent was evaporated under reduced pressure. This compound was used in the next step without purification.

(85c)2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基 )-N,N-二甲基-2-側氧基乙醯胺 (85c) 2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole -5-yl)oxy]phenyl}piperidin-1-yl )-N,N-dimethyl-2-oxoethoxyacetamide

於實施例(85b)所獲得的化合物(450mg)之二氯甲烷(8mL)懸浮液中添加二異丙基乙基胺(0.377mL)、二甲基胺鹽酸鹽(240mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(211mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(100mg)，並於室溫攪拌10小時。減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷→甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(256mg)。 Diisopropylethylamine (0.377 mL), dimethylamine hydrochloride (240 mg), 1-B were added to a suspension of the compound (450 mg) obtained from m. 3-(3-dimethylaminopropyl)carboxylimine hydrochloride (211 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol ( 100 mg) and stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.60-1.78(2H,m),1.85-1.98(2H,m),2.12(3H,s),2.68-2.83(2H,m),3.01(3H,s),3.04(3H,s),3.15-3.26(5H,m),3.71-3.81(1H,m),4.20(2H,t,J=8.5Hz),4.37(2H,s),4.65-4.74(1H,m),6.75-6.84(3H,m),7.05(2H,d,J=8.5Hz),7.39(1H,d,J=7.3Hz),7.50(1H,t,J=7.3Hz),7.58-7.65(1H,m),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=8.5Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.60-1.78 (2H, m), 1.85-1.98 (2H, m), 2.12 (3H, s), 2.68 -2.83 (2H, m), 3.01 (3H, s), 3.04 (3H, s), 3.15-3.26 (5H, m), 3.71-3.81 (1H, m), 4.20 (2H, t, J = 8.5 Hz ), 4.37 (2H, s), 4.65-4.74 (1H, m), 6.75-6.84 (3H, m), 7.05 (2H, d, J = 8.5 Hz), 7.39 (1H, d, J = 7.3 Hz) , 7.50 (1H, t, J = 7.3 Hz), 7.58-7.65 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例86) (Example 86)

N-乙基-2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺 N-ethyl-2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide

於實施例(85b)所獲得的化合物(300mg)之二氯甲烷 (8mL)懸浮液中添加二異丙基乙基胺(0.252mL)、乙基胺鹽酸鹽(200mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(141mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(66.6mg)，並於室溫攪拌24小時。減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(201mg)。 Methylene chloride of the compound obtained in Example (85b) (300 mg) (8 mL) suspension was added with diisopropylethylamine (0.252 mL), ethylamine hydrochloride (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylate The amine hydrochloride (141 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (66.6 mg) was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.21(3H,t,J=7.3Hz),1.26(3H,t,J=7.3Hz),1.58-1.81(2H,m),1.88-1.99(2H,m),2.12(3H,s),2.70-2.83(2H,m),3.09-3.26(5H,m),3.31-3.40(2H,m),4.27(2H,t,J=8.5Hz),4.37(2H,s),4.65-4.74(1H,m),5.11-5.20(1H,m),6.77(1H,d,J=8.5Hz),6.81(2H,d,J=8.5Hz),7.08-7.19(3H,m),7.39(1H,d,J=7.3Hz),7.50(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.3 Hz), 1.58-1.81 (2H, m), 1.88-1.99 (2H , m), 2.12 (3H, s), 2.70-2.83 (2H, m), 3.09-3.26 (5H, m), 3.31-3.40 (2H, m), 4.27 (2H, t, J = 8.5 Hz), 4.37 (2H, s), 4.65-4.74 (1H, m), 5.11-5.20 (1H, m), 6.77 (1H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.08 -7.19 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：618(M+H)+。 MS (APCI) m/z: 618 (M+H) + .

(實施例87) (Example 87)

2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-N-甲基-2-側氧基乙醯胺 2-(4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]phenyl]piperidin-1-yl)-N-methyl-2-oxoethoxyacetamide

於實施例(85b)所獲得的化合物(250mg)之N,N-二甲基甲醯胺(5mL)懸浮液中添加二異丙基乙基胺(0.210mL)、甲基胺鹽酸鹽(138mg)、1-乙基-3-(3-二甲基胺基 丙基)羧醯亞胺鹽酸鹽(117mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(55.5mg)，於室溫攪拌12小時。於反應液中添加水，以乙酸乙酯提取，將有機層以水、飽和食鹽水洗淨後，以無水硫酸鈉乾燥。減壓下餾除溶媒，將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(185mg)。 To a suspension of the compound (250 mg) obtained in Example (85b), N,N-dimethylformamide (5 mL), diisopropylethylamine (0.210 mL), methylamine hydrochloride 138 mg), 1-ethyl-3-(3-dimethylamino group Propyl)carboxylimine hydrochloride (117 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (55.5 mg) was stirred at room temperature for 12 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAc m.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.9Hz),1.60-1.81(2H,m),1.87-1.99(2H,m),2.12(3H,s),2.70-2.85(2H,m),2.89(3H,d,J=4.9Hz),3.10-3.26(5H,m),4.27(2H,t,J=7.9Hz),4.37(2H,s),4.65-4.72(1H,m),5.11-5.19(1H,m),6.77(1H,d,J=9.2Hz),6.81(2H,d,J=9.2Hz),7.20-7.22(3H,m),7.39(1H,d,J=7.3Hz),7.50(1H,t,J=7.3Hz),7.62(1H,t,J=7.3Hz),7.97(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.9 Hz), 1.60-1.81 (2H, m), 1.87-1.99 (2H, m), 2.12 (3H, s), 2.70 -2.85 (2H, m), 2.89 (3H, d, J = 4.9 Hz), 3.10-3.26 (5H, m), 4.27 (2H, t, J = 7.9 Hz), 4.37 (2H, s), 4.65- 4.72 (1H, m), 5.11-5.19 (1H, m), 6.77 (1H, d, J = 9.2 Hz), 6.81 (2H, d, J = 9.2 Hz), 7.20-7.22 (3H, m), 7.39 (1H, d, J = 7.3 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.62 (1H, t, J = 7.3 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.03 (1H , d, J = 7.9Hz).

MS(APCI)m/z：604(M+H)+。 MS (APCI) m/z: 604 (M+H) + .

(實施例88)：於實施例(88d)合成 (Example 88): Synthesis in Example (88d)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-3-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-3-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

(88a)5-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (88a) 5-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyl oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl acrylate

於實施例(1b)所獲得的化合物(500mg)、1-三級丁氧基羰基-5,6-二氫-2H-吡啶-3-硼酸 酯(370mg)之1,2-二甲氧基乙烷(12mL)溶液中添加碳酸鈉(317mg)之水溶液(3mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(81.6mg)，以微波反應裝置，使於130℃反應1小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(272mg)。 The compound obtained in Example (1b) (500 mg), 1-tert-butoxycarbonyl-5,6-dihydro-2H-pyridine-3-boronic acid To a solution of the ester (370 mg) in 1,2-dimethoxyethane (12 mL) was added EtOAc (3 mL) EtOAc. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (81.6 mg) was added, and the mixture was reacted at 130 ° C for 1 hour in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.49(9H,s),2.12(3H,s),2.24-2.34(2H,br m),3.12(3H,s),3.17-3.26(2H,m),3.49-3.59(2H,br m),4.19-4.34(4H,m),4.37(2H,s),6.11(1H,br s),6.76-6.88(3H,m),7.23-7.32(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 (9H, s), 2.12 (3H, s), 2.24-2.34 (2H, br m), 3.12 (3H, s), 3.17-3.26 (2H, m ), 3.49-3.59 (2H, br m), 4.19-4.34 (4H, m), 4.37 (2H, s), 6.11 (1H, br s), 6.76-6.88 (3H, m), 7.23-7.32 (2H , m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz) ), 8.08 (1H, d, J = 7.9 Hz).

(88b)3-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-哌啶-1-甲酸三級丁酯 (88b) 3-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Butyl oxy]phenyl}-piperidine-1-carboxylic acid tert-butyl butyl ester

將實施例(88a)所獲得的化合物(272mg)溶解於四氫呋喃(3mL)及乙酸乙酯(3mL)，添加7.5%鈀碳(54.5mg)，氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯，濾除不溶物，藉由減壓下餾除溶媒，獲得呈白色固體之標題化合物(279mg)。 The compound (272 mg) obtained in Example (88a) was dissolved in tetrahydrofuran (3 mL) and ethyl acetate (3 mL), and 7.5% palladium carbon (54.5 mg) was added, and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the title compound (279 mg) was evaporated.

1H-NMR(400MHz,CDCl3)δ：1.46(9H,s),1.51-1.64(2H,m),1.71-1.78(1H,br m),1.89-2.02(2H,m),2.13(3H,s),2.56-2.79(3H,br m),3.12(3H,s),3.22(2H,t,J=8.5Hz),4.05-4.18(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.74-6.88(3H,m),7.13(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.97(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.46 (9H, s), 1.51-1.64 (2H, m), 1.71-1.78 (1H, br m), 1.89-2.02 (2H, m), 2.13 (3H) , s), 2.56-2.79 (3H, br m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 4.05-4.18 (1H, m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.74-6.88 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(88c)1-{4-甲基-5-[4-(哌啶-3-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (88c) 1-{4-methyl-5-[4-(piperidin-3-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2 -(methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(88b)所獲得的化合物(272mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌3小時。減壓下濃縮反應液後，添加乙酸乙酯並濾取不溶物。藉由將獲得的固體減壓乾燥而獲得呈白色固體之標題化合物(274mg)。 4N hydrochloric acid was added to a solution of the compound (272 mg) obtained in Example (88b) in dichloromethane (2 mL) Alkane solution (4 mL) was stirred at room temperature for 3 h. After concentrating the reaction mixture under reduced pressure, ethyl acetate was added and the insoluble material was filtered. The title compound (274 mg) was obtained as a white solid.

MS(APCI)m/z：505(M+H)+。 MS (APCI) m/z: 505 (M+H) + .

(88d)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-3-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (88d) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-3-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

於實施例(88c)所獲得的化合物(80.0mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(41.0μL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(61.4mg)及1,4-二烷-2-甲酸(23.0mg)，於室溫攪拌20小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉 乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(72.3mg)。 Triethylamine (41.0 μL) was added to a solution of the compound (80.0 mg), m. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Porphyrin (61.4mg) and 1,4-two Alkyl-2-carboxylic acid (23.0 mg) was stirred at room temperature for 20 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAcjjjjjjd

1H-NMR(400MHz,CDCl3)δ：1.51-1.75(2H,m),1.78-1.92(1H,m),2.00-2.09(1H,m),2.12(3H,d,J=6.7Hz),2.47-2.82(2H,m),2.86-3.17(4H,m),3.17-3.25(2H,m),3.65-4.09(7H,m),4.23-4.41(5H,m),4.58-4.71(1H,m),6.74-6.89(3H,m),7.12(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.51-1.75 (2H, m), 1.78-1.92 (1H, m), 2.00-2.09 (1H, m), 2.12 (3H, d, J = 6.7 Hz) , 2.47-2.82 (2H, m), 2.86-3.17 (4H, m), 3.17-3.25 (2H, m), 3.65-4.09 (7H, m), 4.23-4.41 (5H, m), 4.58-4.71 ( 1H, m), 6.74-6.89 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(實施例89) (Example 89)

1-{5-[4-(1-乙醯基哌啶-3-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-3-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2- [2-(methylsulfonyl)phenyl]ethanone

於實施例(88c)所獲得的化合物(153mg)之二氯甲烷(8mL)溶液中添加三乙基胺(86μL)，並於室溫攪拌5分鐘。添加乙酸酐(32.1μL)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(118mg)。 Triethylamine (86 μL) was added to a solution of the compound (l. Acetic anhydride (32.1 μL) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.49-1.72(2H,m), 1.76-1.88(1H,m),2.00-2.09(4H,m),2.13(3H,s),2.47-2.70(2H,m),3.01-3.10(1H,m),3.12(3H,s),3.16-3.26(2H,m),3.79-3.89(1H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),4.64-4.78(1H,m),6.73-6.86(3H,m),7.13(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.72 (2H, m), 1.76-1.88 (1H, m), 2.00-2.09 (4H, m), 2.13 (3H, s), 2.47-2.70 ( 2H, m), 3.01-3.10 (1H, m), 3.12 (3H, s), 3.16-3.26 (2H, m), 3.79-3.89 (1H, m), 4.29 (2H, t, J = 8.2 Hz) , 4.36 (2H, s), 4.64 - 4.78 (1H, m), 6.73 - 6.86 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：547(M+H)+。 MS (APCI) m/z: 547 (M+H) + .

(實施例90)：於實施例(90e)合成 (Example 90): Synthesis in Example (90e)

1-(5-{4-[1-(1,4-二烷-2-基羰基)吡咯啶-3-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)pyrrolidin-3-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

(90a)2-[2-(甲基磺醯基)苯基]-1-{4-甲基-5-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}乙酮 (90a) 2-[2-(Methylsulfonyl)phenyl]-1-{4-methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}ethanone

於實施例(1b)所獲得的化合物(300mg)、雙聯頻哪醇硼酸酯(167mg)、乙酸鉀(117mg)、二甲基亞碸(200μL)之1,4-二烷(10mL)溶液中添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(14.7mg)，氮氣環境下，使於100℃反應5小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣 以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(222mg)。 Compound (300 mg) obtained in Example (1b), bispinacol borate (167 mg), potassium acetate (117 mg), dimethyl hydrazine (200 μL) 1,4-two [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (14.7 mg) was added to a solution of alkane (10 mL) under nitrogen atmosphere at 100 The reaction was carried out at ° C for 5 hours. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.33(12H,s),2.08(3H,s),3.13(3H,s),3.21(2H,t,J=8.5Hz),4.29(2H,t,J=8.5Hz),4.37(2H,s),6.74-7.02(3H,m),7.26-7.44(2H,m),7.49-7.55(1H,m),7.62(1H,t,J=7.9Hz),7.73(1H,d,J=8.5Hz),7.95-8.04(1H,m),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.33 (12H, s), 2.08 (3H, s), 3.13 (3H, s), 3.21 (2H, t, J = 8.5Hz), 4.29 (2H, t , J=8.5Hz), 4.37(2H, s), 6.74-7.02(3H,m), 7.26-7.44(2H,m), 7.49-7.55(1H,m), 7.62(1H,t,J=7.9 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz).

(90b)3-{[(三氟甲基)磺醯基]氧基}-2,5-二氫-1H-吡咯-1-甲酸苄酯 (90b) 3-{[(Trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylic acid benzyl ester

將1-苄氧基羰基-3-吡咯啶酮(1.00g)之四氫呋喃(5mL)溶液冷卻至-78℃，滴加雙(三甲基矽基)醯胺鈉(1.6M四氫呋喃溶液、8.44mL)，於同溫下攪拌1小時。其次，滴加N-苯基雙(三氟甲烷磺醯亞胺)(1.79g)之四氫呋喃(10mL)溶液，冰冷下攪拌2小時。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈茶色油狀物之標題化合物(593mg)。 A solution of 1-benzyloxycarbonyl-3-pyrrolidone (1.00 g) in tetrahydrofuran (5 mL) was cooled to -78 ° C, and sodium bis(trimethylsulfonyl)amide (1.6 M tetrahydrofuran solution, 8.44 mL) was added dropwise. ), stirring at the same temperature for 1 hour. Next, a solution of N-phenylbis(trifluoromethanesulfonimide) (1.79 g) in tetrahydrofuran (10 mL) was added dropwise and stirred for 2 hr. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：4.30(4H,br m),5.17(2H,s),5.73(0.5H,s),5.78(0.5H,s),7.26-7.45(5H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 4.30 (4H, br m), 5.17 (2H, s), 5.73 (0.5H, s), 5.78 (0.5H, s), 7.26-7.45 (5H, m ).

(90c)3-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-2,5-二氫-1H-吡咯-1-甲酸苄酯 (90c) 3-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Benzyloxy]phenyl}-2,5-dihydro-1H-pyrrole-1-carboxylic acid benzyl ester

於實施例(90a)所獲得的化合物(100mg)及實施例(90b)所獲得的化合物(87.5mg)之1,2-二甲氧基乙烷(3 mL)溶液中添加碳酸鈉(58.0mg)之水溶液(1mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(15.0mg)，以微波反應裝置，使於130℃反應45分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(262mg)。 The compound obtained in Example (90a) (100 mg) and the compound obtained in Example (90b) (87.5 mg) of 1,2-dimethoxyethane (3) An aqueous solution (1 mL) of sodium carbonate (58.0 mg) was added to the solution and stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (15.0 mg) was added and reacted at 130 ° C for 45 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.11(3H,s),3.12(3H,s),3.22(2H,t,J=8.5Hz),4.29(2H,t,J=8.5Hz),4.33-4.43(4H,br m),4.48-4.60(2H,m),5.20(2H,s),6.01(0.5H,s),6.05(0.5H,s),6.74-6.88(3H,m),7.25-7.44(8H,m),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.99(1H,d,J=9.2Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.22 (2H, t, J = 8.5Hz), 4.29 (2H, t, J = 8.5Hz), 4.33-4.43(4H,br m),4.48-4.60(2H,m), 5.20(2H,s),6.01(0.5H,s),6.05(0.5H,s),6.74-6.88(3H,m) , 7.25-7.44 (8H, m), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).

(90d)1-{4-甲基-5-[4-(吡咯啶-3-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (90d) 1-{4-methyl-5-[4-(pyrrolidin-3-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2 -(methylsulfonyl)phenyl]ethanone

將實施例(90c)所獲得的化合物(26.2mg)溶解於乙醇(1.5mL)及乙酸乙酯(1.5mL)，添加7.5%鈀碳(5.5mg)並於氫氣環境下，於室溫攪拌18小時。於反應液中添加乙酸乙酯，濾除不溶物後，藉由將濾液於減壓下濃縮乾固而獲得呈黃色油狀物之標題化合物(19.4mg)。 The compound obtained in Example (90c) (26.2 mg) was dissolved in ethanol (1.5 mL) and ethyl acetate (1.5 mL), and 7.5% palladium carbon (5.5 mg) was added and stirred under a hydrogen atmosphere at room temperature. hour. Ethyl acetate was added to the reaction mixture, and the title compound (19.4 mg) was obtained as a yellow oil.

1H-NMR(400MHz,CDCl3)δ：1.78-1.97(2H,m),2.13(3H,s),2.18-2.38(1H,m),2.43-2.72(2H,m),3.06-3.26(7H,m),3.31-3.45(1H,m),4.28(2H,t,J=8.5Hz),4.36(2H,s),6.72-6.85(3H,m),7.10-7.20(2H,m), 7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.58-7.65(1H,m),7.96(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.97 (2H, m), 2.13 (3H, s), 2.18-2.38 (1H, m), 2.43-2.72 (2H, m), 3.06-3.26 ( 7H,m),3.31-3.45(1H,m), 4.28(2H,t,J=8.5Hz), 4.36(2H,s),6.72-6.85(3H,m),7.10-7.20(2H,m) , 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.58-7.65 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(90e)1-(5-{4-[1-(1,4-二烷-2-基羰基)吡咯啶-3-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (90e) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)pyrrolidin-3-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

於實施例(90d)所獲得的化合物(19.4mg)之N,N-二甲基甲醯胺(3mL)溶液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(16.4mg)及1,4-二烷-2-甲酸(6.27mg)，並於室溫攪拌15小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(5.8mg)。 To a solution of the compound (19.4 mg) obtained in Example (90d), N,N-dimethylformamide (3 mL), 4-(4,6-dimethoxy-1,3,5 -three -2-yl)-4-methyl Porphyrin (16.4mg) and 1,4-two Alkyl-2-carboxylic acid (6.27 mg) was stirred at room temperature for 15 h. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.88-2.09(1H,m),2.12(3H,s),2.20-2.40(1H,m),3.12(3H,s),3.16-3.25(2H,m),3.29-3.62(3H,m),3.66-4.02(8H,m),4.20-4.33(3H,m),4.37(2H,s),6.77(1H,d,J=8.5Hz),6.84(2H,t,J=8.5Hz),7.08-7.19(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.88-2.09 (1H, m), 2.12 (3H, s), 2.20-2.40 (1H, m), 3.12 (3H, s), 3.16-3.25 (2H, m), 3.29-3.62 (3H, m), 3.66-4.02 (8H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 6.84 (2H, t, J = 8.5 Hz), 7.08-7.19 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：605(M+H)+。 MS (APCI) m/z: 605 (M+H) + .

(實施例91) (Example 91)

1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯 基]乙酮 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-吲哚-1-yl}-2-[2-(methylsulfonyl)benzene Ethyl ketone

於實施例(1b)所獲得的化合物(200mg)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(150mg)之1,2-二甲氧基乙烷(6mL)溶液中添加碳酸鈉(127mg)之水溶液(2mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(32.6mg)，以微波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡茶色固體之標題化合物(120mg)。 The compound (200 mg) obtained in Example (1b), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 Add a solution of sodium carbonate (127 mg) (2 mL) to a solution of 6-dihydropyridine-1(2H)-yl]ethanone (150 mg) in 1,2-dimethoxyethane (6 mL). Stir for 5 minutes. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (32.6 mg) was added and reacted at 130 ° C for 15 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.14(1.5H,s),2.17(1.5H,s),2.48-2.62(2H,m),3.02-3.19(4H,m),3.22(2H,t,J=8.2Hz),3.65(1H,t,J=5.8Hz),3.81(1H,t,J=5.8Hz),4.20-4.24(2H,m),4.29(2H,t,J=8.2Hz),4.37(2H,s),5.94(0.5H,br s),6.00(0.5H,br s),6.79(1H,d,J=9.2Hz),6.81-6.86(2H,m),7.25-7.31(1H,m),7.36(1H,d,J=7.9Hz),7.51-7.55(1H,m),7.60-7.64(1H,m),7.99(1H,d,J=9.2Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 2.12 (3H, s), 2.14 (1.5H, s), 2.17 (1.5H, s), 2.48-2.62 (2H, m), 3.02-3.19 (4H, m), 3.22 (2H, t, J = 8.2 Hz), 3.65 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.20-4.24 (2H, m), 4.29 ( 2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.94 (0.5H, br s), 6.00 (0.5H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.81-6.86 (2H,m), 7.25-7.31(1H,m), 7.36(1H,d,J=7.9Hz),7.51-7.55(1H,m), 7.60-7.64(1H,m),7.99(1H,d , J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APC1)m/z：545(M+H)+。 MS (APC1) m / z: 545 (M + H) + .

(實施例92)：於實施例(92b)合成 (Example 92): Synthesis in Example (92b)

2-甲氧基-1-[4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]乙酮 2-methoxy-1-[4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]ethanone

(92a)2-[2-(甲基磺醯基)苯基]-1-{4-甲基-5-[4-(1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}乙酮鹽酸鹽 (92a) 2-[2-(Methylsulfonyl)phenyl]-1-{4-methyl-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)benzene Oxy]-2,3-dihydro-1H-indol-1-yl}ethanone hydrochloride

於實施例(1c)所獲得的化合物(219mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌3小時。減壓下濃縮反應液，殘渣以乙酸乙酯洗淨後濾取，藉由乾燥而獲得呈白色固體之標題化合物(326mg)。 4N hydrochloric acid was added to a solution of the compound (219 mg) obtained in Example (1c) in dichloromethane (2 mL) Alkane solution (4 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced vacuo.

MS(APCI)m/z：503(M+H)+。 MS (APCI) m/z: 503 (M+H) + .

(92b)2-甲氧基-1-[4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]乙酮 (92b) 2-methoxy-1-[4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3-di Hydrogen-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]ethanone

於實施例(92a)所獲得的化合物(150mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(77.0μL)，並於室溫攪拌5分鐘。其次添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(115mg)及甲氧基乙酸(26.0μL)，於室溫攪拌48小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析( 乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(69.5mg)。 Triethylamine (77.0 μL) was added to a solution of the compound (150 mg), m. Next, add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl The guanidine (115 mg) and methoxyacetic acid (26.0 μL) were stirred at room temperature for 48 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.49-2.60(2H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.45(3H,s),3.68(1H,t,J=5.5Hz),3.83(1H,t,J=5.5Hz),4.09-4.20(3H,m),4.21-4.25(1H,m),4.29(2H,t,J=8.2Hz),4.37(2H,s),5.93(0.4H,br s),5.99(0.6H,br s),6.79(1H,d,J=8.5Hz),6.84(2H,d,J=9.2Hz),7.24-7.32(2H,m),7.37(1H,d,J=7.9Hz),7.49-7.55(1H,m),7.60-7.64(1H,m),7.99(1H,d,J=9.2Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.49-2.60 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.45 (3H) , s), 3.68 (1H, t, J = 5.5 Hz), 3.83 (1H, t, J = 5.5 Hz), 4.09-4.20 (3H, m), 4.21-4.25 (1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 5.93 (0.4H, br s), 5.99 (0.6H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d , J=9.2Hz), 7.24-7.32(2H,m), 7.37(1H,d,J=7.9Hz), 7.49-7.55(1H,m), 7.60-7.64(1H,m),7.99(1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：575(M+H)+。 MS (APCI) m/z: 575 (M+H) + .

(實施例93) (Example 93)

(2S)-2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)丙烷-1-酮 (2S)-2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro) -1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)propan-1-one

於實施例(92a)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(230μL)，並於室溫攪拌5分鐘。其次添加L-乳酸(57.1μL)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(159mg)、1-羥基苯并三唑一水合物(84.9mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水 洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(146mg)。 Triethylamine (230 μL) was added to a solution of the compound (m. Next, L-lactic acid (57.1 μL), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (159 mg), 1-hydroxybenzotriazole monohydrate ( 84.9 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. Organic layer with water and saturated brine After washing, it was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlilililili

1H-NMR(400MHz,CDCl3)δ：1.36(3H,dd,J=14.6,6.7Hz),2.12(3H,s),2.48-2.63(2H,m),3.11(3H,s),3.22(2H,t,J=8.5Hz),3.56-3.65(1H,m),3.84-3.93(1H,m),3.98-4.15(1H,m),4.29(3H,t,J=8.5Hz),4.36(2H,s),4.44-4.61(1H,m),5.93(0.5H,br s),6.02(0.5H,br s),6.79(1H,d,J=8.5Hz),6.84(2H,d,J=9.2Hz),7.22-7.32(2H,m),7.36(1H,d,J=7.9Hz),7.47-7.55(1H,m),7.57-7.65(1H,m),7.99(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.36 (3H, dd, J = 14.6,6.7Hz), 2.12 (3H, s), 2.48-2.63 (2H, m), 3.11 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.56-3.65 (1H, m), 3.84-3.93 (1H, m), 3.98-4.15 (1H, m), 4.29 (3H, t, J = 8.5 Hz), 4.36 (2H, s), 4.44 - 4.61 (1H, m), 5.93 (0.5H, br s), 6.02 (0.5H, br s), 6.79 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.22 - 7.32 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.47 - 7.55 (1H, m), 7.57 - 7.65 (1H, m), 7.99 (1H) , d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：575(M+H)+。 MS (APCI) m/z: 575 (M+H) + .

(實施例94)：於實施例(94b)合成 (Example 94): Synthesis in Example (94b)

3-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)丙烷-1-酮 3-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)propan-1-one

(94a)1-[4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)-3-(丙-2-烯-1-基氧基)丙烷-1-酮 (94a) 1-[4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole -5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)-3-(prop-2-en-1-yloxy)propan-1-one

於實施例(92a)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫 攪拌5分鐘。其次添加3-烯丙氧基丙酸(81.7μL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(230mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(61.8mg)。 Triethylamine (150 μL) was added to a solution of the compound (300 mg), m. Next, 3-allyloxypropionic acid (81.7 μL) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (230 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.47-2.58(2H,m),2.63-2.75(2H,m),3.13(3H,s),3.22(2H,t,J=8.5Hz),3.69(1H,t,J=5.8Hz),3.77-3.85(3H,m),3.96-4.03(2H,m),4.09-4.15(1H,m),4.19-4.25(1H,m),4.29(2H,t,J=8.5Hz),4.36(2H,s),5.15-5.30(2H,m),5.85-5.99(2H,m),6.79(1H,d,J=8.5Hz),6.82-6.86(2H,m),7.21-7.31(2H,m),7.36(1H,d,J=7.9Hz),7.50-7.54(1H,m),7.59-7.66(1H,m),7.95-8.04(1H,m),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.47-2.58 (2H, m), 2.63-2.75 (2H, m), 3.13 (3H, s), 3.22 (2H, t, J=8.5 Hz), 3.69 (1H, t, J=5.8 Hz), 3.77-3.85 (3H, m), 3.96-4.03 (2H, m), 4.09-4.15 (1H, m), 4.19-4.25 (1H , m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 5.15-5.30 (2H, m), 5.85-5.99 (2H, m), 6.79 (1H, d, J = 8.5 Hz), 6.82-6.86 (2H, m), 7.21-7.31 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.54 (1H, m), 7.59-7.66 (1H, m) , 7.95-8.04 (1H, m), 8.07 (1H, d, J = 7.9 Hz).

(94b)3-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)丙烷-1-酮 (94b) 3-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)propan-1-one

於實施例(94a)所獲得的化合物(161mg)之四氫呋喃(3mL)溶液中添加1,3-二甲基巴比妥酸(82.2mg)、肆(三苯基膦)鈀(0)(15.2mg)，氮氣環境下，於90℃攪拌5小時。減壓下將反應液濃縮，將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷→甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(124mg)。 1,3-Dimethylbarbituric acid (82.2 mg), hydrazine (triphenylphosphine) palladium (0) (15.2) was added to a solution of the compound (161 mg) obtained in Example (94a) in tetrahydrofuran (3 mL). Mg), stirred at 90 ° C for 5 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.49-2.65(4H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.43-3.52(1H,m),3.65(1H,t,J=5.8Hz),3.83(1H,t,J=5.8Hz),3.86-3.93(2H,m),4.07-4.12(1H,m),4.22-4.33(3H,m),4.37(2H,s),5.93(0.5H,br s),6.01(0.5H,br s),6.79(1H,d,J=9.2Hz),6.84(2H,q,J=8.5Hz),7.19-7.31(2H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.60-7.64(1H,m),7.99(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.49-2.65 (4H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.43-3.52 (1H, m), 3.65 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 3.86-3.93 (2H, m), 4.07-4.12 (1H, m), 4.22 4.33(3H,m), 4.37(2H,s), 5.93(0.5H,br s),6.01(0.5H,br s),6.79(1H,d,J=9.2Hz),6.84(2H,q, J=8.5Hz), 7.19-7.31(2H,m), 7.49-7.55(1H,m), 7.59-7.65(1H,m), 7.60-7.64(1H,m),7.99(1H,d,J= 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：575(M+H)+。 MS (APCI) m/z: 575 (M+H) + .

(實施例95)：於實施例(95b)合成 (Example 95): Synthesis in Example (95b)

(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮 (2S)-2-hydroxy-1-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]propan-1-one

(95a)4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (95a) 4-{2-Methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester

於實施例(3b)所獲得的化合物(267mg)之1,2-二甲氧基乙烷(4mL)、水(2mL)溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-甲酸三級丁酯(193mg)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(42.4mg)、碳酸鈉(110mg)，而於微 波照射下於120℃攪拌30分鐘。冷卻至室溫後，以乙酸乙酯提取。有機層以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(319mg)。 4-(4,4,5,5-tetramethyl-) was added to a solution of the compound (267 mg) obtained in Example (3b) in 1,2-dimethoxyethane (4 mL), water (2 mL) 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester (193 mg), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium(II) chloride complex (42.4 mg), sodium carbonate (110 mg), and The mixture was stirred at 120 ° C for 30 minutes under wave irradiation. After cooling to room temperature, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.50(9H,s),2.13(3H,s),2.22(3H,s),2.28-2.36(2H,m),3.12(3H,s),3.18-3.26(2H,m),3.56-3.64(2H,m),3.98-4.05(2H,m),4.25-4.32(2H,m),4.37(2H,s),5.46-5.59(1H,m),6.61-6.66(1H,m),6.68-6.71(1H,m),6.77-6.81(1H,m),6.95-6.99(1H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.96-8.00(1H,m),8.06-8.10(1H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.50 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 2.28-2.36 (2H, m), 3.12 (3H, s), 3.18 -3.26(2H,m),3.56-3.64(2H,m),3.98-4.05(2H,m), 4.25-4.32(2H,m),4.37(2H,s),5.46-5.59(1H,m) , 6.61-6.66 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95-6.99 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 ( 1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).

(95b)(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮 (95b)(2S)-2-hydroxy-1-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl) }-2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]propan-1-one

於實施例(95a)所獲得的化合物(632mg)中添加4N鹽酸二烷溶液(10mL)而於室溫攪拌2小時。藉由將反應液減壓濃縮而獲得粗製之1-{4-甲基-5-[3-甲基-4-(1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽。 4N hydrochloric acid was added to the compound (632 mg) obtained in Example (95a) The alkane solution (10 mL) was stirred at room temperature for 2 hours. The crude 1-{4-methyl-5-[3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy group was obtained by concentrating the reaction mixture under reduced pressure. ]-2,3-Dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride.

於獲得的化合物(145mg)之二氯甲烷(4mL)溶液中添加85%L-乳酸水溶液(33.3mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(101mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(35.7mg)、N,N-二異丙基乙基胺(0.137mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之 標題化合物(51.0mg)。 85% L-lactic acid aqueous solution (33.3 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide was added to a solution of the obtained compound (145 mg) in dichloromethane (4 mL) Hydrochloride (101 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (35.7 mg), N,N-diisopropylethylamine (0.137 mL) Stir at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate) to afford white solid. The title compound (51.0 mg).

1H-NMR(400MHz,CDCl3)δ：1.34-1.40(3H,m),2.13(3H,s),2.19-2.24(3H,m),2.35-2.44(2H,m),3.12(3H,s),3.18-3.26(2H,m),3.56-3.62(1H,m),3.89-3.95(1H,m),3.98-4.07(1H,m),4.17-4.33(3H,m),4.37(2H,s),4.48-4.56(1H,m),5.50-5.63(1H,m),6.62-6.67(1H,m),6.69-6.72(1H,m),6.76-6.81(1H,m),6.94-6.99(1H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.05-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.34-1.40 (3H, m), 2.13 (3H, s), 2.19-2.24 (3H, m), 2.35-2.44 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.56-3.62 (1H, m), 3.89-3.95 (1H, m), 3.98-4.07 (1H, m), 4.17-4.33 (3H, m), 4.37 ( 2H, s), 4.48-4.56 (1H, m), 5.50-5.63 (1H, m), 6.62-6.67 (1H, m), 6.69-6.72 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99(1H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.05-8.10(1H , m).

MS(APCI)m/z：589(M+H)+。 MS (APCI) m/z: 589 (M+H) + .

(實施例96)：於實施例(96b)合成 (Example 96): Synthesis in Example (96b)

(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)丙烷-1-酮 (2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3 -dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)propan-1-one

(96a)1-{5-[4-(1-{[(4S)-2,2-二甲基-1,3-二氧戊環-4-基]羰基}-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (96a) 1-{5-[4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-1,2,3, 6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)benzene Ethyl ketone

於實施例(92a)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。其次，添加按照文獻記載之方法(Bioorganic and Medicinal Chemistry Letters，2004，14，3231)合成的(4S)-2,2-二甲基-1,3-二氧戊環-4-甲酸(100mg)、氯化 4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(231mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(242mg)。 Triethylamine (150 μL) was added to a solution of the compound (300 mg), m. Next, (4S)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid (100 mg) synthesized according to the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231) was added. , 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (231 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.38-1.45(6H,m),2.12(3H,s),2.48-2.64(1H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.62-3.75(1H,m),3.91-4.03(1H,m),4.09-4.22(2H,m),4.22-4.39(5H,m),4.40-4.51(1H,m),4.70-4.76(1H,m),5.96(1H,br s),6.00(1H,br s),6.79(1H,d,J=9.2Hz),6.84(2H,d,J=8.5Hz),7.22-7.32(2H,m),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.0Hz),7.62(1H,t,J=7.0Hz),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.38-1.45 (6H, m), 2.12 (3H, s), 2.48-2.64 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J=8.2Hz), 3.62-3.75 (1H, m), 3.91-4.03 (1H, m), 4.09-4.22 (2H, m), 4.22-4.39 (5H, m), 4.40-4.51 (1H, m) , 4.70-4.76 (1H, m), 5.96 (1H, br s), 6.00 (1H, br s), 6.79 (1H, d, J = 9.2 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.22-7.32(2H,m), 7.36(1H,d,J=7.9Hz), 7.52(1H,t,J=7.0Hz), 7.62(1H,t,J=7.0Hz),7.98(1H,d , J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(96b)(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基)丙烷-1-酮 (96b)(2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethyl)}- 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl)propan-1-one

於實施例(96a)所獲得的化合物(320mg)之二氯甲烷(1mL)與水(500μL)之混合溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌2小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，藉由減壓下濃縮，獲得呈白色固體之標題化合物(254mg)。 4N hydrochloric acid was added to a mixed solution of the compound (320 mg) obtained in Example (96a) in dichloromethane (1 mL) and water (500 μL) Alkane solution (2 mL) was stirred at room temperature for 2 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s), 2.48-2.66(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.59-3.73(5H,m),3.74-3.84(1H,m),4.02-4.17(1H,m),4.20-4.33(3H,m),4.37(2H,s),4.46-4.57(1H,m),5.93(0.4H,br s),6.00(0.6H,br s),6.76-6.90(3H,m),7.16-7.31(2H,m),7.37(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),7.99(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.48-2.66 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.59-3.73 (5H, m), 3.74-3.84 (1H, m), 4.02-4.17 (1H, m), 4.20-4.33 (3H, m), 4.37 (2H, s), 4.46-4.57 (1H, m), 5.93 (0.4H, br s), 6.00 (0.6H, br s), 6.76-6.90 (3H, m), 7.16-7.31 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H , t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例97) (Example 97)

2-羥基-3-甲氧基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮 2-hydroxy-3-methoxy-1-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl} -2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]propan-1-one

於實施例(95b)所獲得的1-{4-甲基-5-[3-甲基-4-(1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽(205mg)之二氯甲烷(4mL)溶液中添加2-羥基-3-甲氧基丙酸(53.4mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(92.4mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(56.8mg)、N,N-二異丙基乙基胺(0.194mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(167mg)。 1-{4-Methyl-5-[3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-2 obtained in Example (95b) , 2 -Dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride (205 mg) in dichloromethane (4 mL) -hydroxy-3-methoxypropionic acid (53.4 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (92.4 mg), 3H-1,2 3-Triazolo[4,5-b]pyridin-3-ol (56.8 mg), N,N-diisopropylethylamine (0.194 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.22(3H, s),2.34-2.43(2H,m),3.12(3H,s),3.18-3.26(2H,m),3.40(3H,s),3.49-3.81(3H,m),3.89-4.16(2H,m),4.22-4.29(3H,m),4.37(2H,s),4.57-4.67(1H,m),5.49-5.62(1H,m),6.62-6.67(1H,m),6.68-6.72(1H,m),6.76-6.81(1H,m),6.93-6.99(1H,m),7.34-7.39(1H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.06-8.10(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22 (3H, s), 2.34-2.43 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m) , 3.40 (3H, s), 3.49-3.81 (3H, m), 3.89-4.16 (2H, m), 4.22-4.29 (3H, m), 4.37 (2H, s), 4.57-4.67 (1H, m) , 5.49-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.93-6.99 (1H, m), 7.34-7.39 ( 1H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：619(M+H)+。 MS (APCI) m/z: 619 (M+H) + .

(實施例98) (Example 98)

1-{5-[4-[1-(1,4-二烷-2-基羰基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-[1-(1,4-di) Alkan-2-ylcarbonyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}- 2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(1b)所獲得的1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮(2.5g)及實施例(103b)所獲得的化合物(1.94g)之1,2-二甲氧基乙烷(50mL)溶液中添加碳酸鈉(1.59g)之水溶液(10mL)，並於室溫攪拌5分鐘。其次添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(408mg)，並以微波反應裝置，使於130℃反應45分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化， 獲得呈淡黃色固體之標題化合物(1.96g)。 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-inden-1-yl]-2-[2- obtained in Example (1b) Adding sodium carbonate to a solution of (methylsulfonyl)phenyl]ethanone (2.5 g) and the compound obtained in Example (103b) (1.94 g) in 1,2-dimethoxyethane (50 mL) An aqueous solution (10 mL) of 1.59 g) was stirred at room temperature for 5 min. Next, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (408 mg) was added and reacted at 130 ° C for 45 minutes in a microwave reactor. . After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate /hexane). The title compound (1.96 g) was obtained as a pale yellow solid.

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.46-2.57(1H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.62-3.99(9H,m),4.08-4.19(1H,m),4.23-4.41(6H,m),5.94(0.5H,br s),5.98(0.5H,br s),6.79(1H,d,J=8.5Hz),6.84(2H,d,J=8.5Hz),7.23-7.32(2H,m),7.37(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),7.99(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.46-2.57 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.62-3.99 (9H,m), 4.08-4.19(1H,m),4.23-4.41(6H,m),5.94(0.5H,br s),5.98(0.5H,br s),6.79(1H,d,J= 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.23 - 7.32 (2H, m), 7.37 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：617(M+H)+。 MS (APCI) m/z: 617 (M+H) + .

(實施例99) (Example 99)

N,N-二甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 N,N-Dimethyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

於實施例(102b)所獲得的化合物(232mg)之N,N-二甲基甲醯胺(4mL)溶液中添加二甲基胺鹽酸鹽(64.3mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(113mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(60.4mg)、N,N-二異丙基乙基胺(0.172mL)而室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(152mg)。 To a solution of the compound (232 mg) obtained in Example (102b), N,N-dimethylformamide (4mL), dimethylamine hydrochloride (64.3mg), 1-ethyl-3- 3-dimethylaminopropyl)carboxylimine hydrochloride (113 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (60.4 mg), N N-Diisopropylethylamine (0.172 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.20-2.23(3H,m),2.37-2.46(2H,m),3.00-3.09(6H,m), 3.12(3H,s),3.18-3.26(2H,m),3.57-3.63(1H,m),3.82-3.89(1H,m),4.02-4.07(1H,m),4.22-4.33(3H,m),4.37(2H,s),5.50-5.62(1H,m),6.62-6.67(1H,m),6.68-6.71(1H,m),6.76-6.81(1H,m),6.94-6.99(1H,m),7.34-7.39(1H,m),7.50-7.56(1H,m),7.59-7.65(1H,m),7.96-8.00(1H,m),8.06-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 2.12 (3H, s), 2.20-2.23 (3H, m), 2.37-2.46 (2H, m), 3.00-3.09 (6H, m), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.57-3.63 (1H, m), 3.82-3.89 (1H, m), 4.02-4.07 (1H, m), 4.22-4.33 (3H, m), 4.37 ( 2H, s), 5.50-5.62 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.50-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m).

MS(APCI)m/z：616(M+H)+。 MS (APCI) m/z: 616 (M+H) + .

(實施例100) (Embodiment 100)

N-乙基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 N-ethyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

於實施例(102b)所獲得的化合物(147mg)之二氯甲烷(4mL)溶液中添加乙基胺鹽酸鹽(40.7mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(95.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(34.0mg)、N,N-二異丙基乙基胺(0.131mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(84.0mg)。 Ethylamine hydrochloride (40.7 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (147 mg) obtained from m. Carboxylimine hydrochloride (95.7 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (34.0 mg), N,N-diisopropyl Ethylamine (0.131 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(500MHz,CDCl3)δ：1.21(3H,t,J=7.1Hz),2.13(3H,s),2.21-2.24(3H,m),2.37-2.50(2H,m),3.12(3H,s),3.19-3.25(2H,m),3.32-3.39(2H,m),3.83-3.87(1H,m),4.19-4.23(1H,m),4.24-4.32(3H,m), 4.36(2H,s),4.72-4.76(1H,m),5.52-5.59(1H,m),6.62-6.66(1H,m),6.68-6.71(1H,m),6.76-6.81(1H,m),6.94-6.98(1H,m),7.29-7.39(2H,m),7.50-7.54(1H,m),7.59-7.64(1H,m),7.96-8.00(1H,m),8.06-8.09(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 1.21 (3H, t, J = 7.1 Hz), 2.13 (3H, s), 2.21-2.24 (3H, m), 2.37-2.50 (2H, m), 3.12 (3H, s), 3.19-3.25 (2H, m), 3.32-3.39 (2H, m), 3.83-3.87 (1H, m), 4.19-4.23 (1H, m), 4.24-4.32 (3H, m) , 4.36 (2H, s), 4.72-4.76 (1H, m), 5.52-5.59 (1H, m), 6.62-6.66 (1H, m), 6.68-6.71 (1H, m), 6.76-6.81 (1H, m), 6.94-6.98 (1H, m), 7.29-7.39 (2H, m), 7.50-7.54 (1H, m), 7.59-7.64 (1H, m), 7.96-8.00 (1H, m), 8.06- 8.09 (1H, m).

MS(APCI)m/z：616(M+H)+。 MS (APCI) m/z: 616 (M+H) + .

(實施例101) (Example 101)

N-(2-氟乙基)-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 N-(2-fluoroethyl)-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl} -2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

於實施例(102b)所獲得的化合物(147mg)之二氯甲烷(4mL)溶液中添加2-氟乙基胺鹽酸鹽(49.7mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(95.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(34.0mg)、N,N-二異丙基乙基胺(0.131mL)而室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(95.0mg)。 2-Hydroxyethylamine hydrochloride (49.7 mg), 1-ethyl-3-(3-dimethylmethyl) was added to a solution of the compound (147 mg) obtained from m. Aminopropyl)carboxylimine hydrochloride (95.7 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (34.0 mg), N,N-di Isopropylethylamine (0.131 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.23(3H,s),2.38-2.51(2H,m),3.13(3H,s),3.19-3.26(2H,m),3.58-3.72(2H,m),3.83-3.89(1H,m),4.20-4.33(4H,m),4.37(2H,s),4.47-4.52(1H,m),4.59-4.63(1H,m),4.70-4.74(1H,m),5.51-5.60(1H,m),6.62-6.67(1H,m),6.68-6.71(1H,m),6.77-6.81(1H,m),6.95-7.00(1H,m), 7.34-7.39(1H,m),7.49-7.56(1H,m),7.57-7.72(2H,m),7.96-8.00(1H,m),8.06-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.23 (3H, s), 2.38-2.51 (2H, m), 3.13 (3H, s), 3.19-3.26 (2H, m) , 3.58-3.72 (2H, m), 3.83-3.89 (1H, m), 4.20-4.33 (4H, m), 4.37 (2H, s), 4.47-4.52 (1H, m), 4.59-4.63 (1H, m), 4.70-4.74 (1H, m), 5.51-5.60 (1H, m), 6.62-6.67 (1H, m), 6.68-6.71 (1H, m), 6.77-6.81 (1H, m), 6.95- 7.00 (1H, m), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.57-7.72 (2H, m), 7.96-8.00 (1H, m), 8.06-8.10 (1H, m ).

MS(APCI)m/z：634(M+H)+。 MS (APCI) m/z: 634 (M+H) + .

(實施例102) (Example 102)

(實施例102-1)：於實施例(102a)合成 (Example 102-1): Synthesis in Example (102a)

[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基](側氧基)乙酸乙酯 [4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole] -5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl](p-oxy)ethyl acetate

(實施例102-2)：於實施例(102b)合成 (Example 102-2): Synthesis in Example (102b)

[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基](側氧基)乙酸 [4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole] -5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl](a pendant oxy)acetic acid

(實施例102-3)：於實施例(102c)合成 (Example 102-3): Synthesis in Example (102c)

N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 N-methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3- Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

(102a)[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基) 苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基](側氧基)乙酸乙酯 (102a)[4-{2-Methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl](sideoxy Ethyl acetate

於實施例(95b)所獲得的1-{4-甲基-5-[3-甲基-4-(1,2,3,6-四氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽(425mg)之二氯甲烷(10mL)、N,N-二異丙基乙基胺(0.401mL)溶液中添加氯(側氧基)乙酸乙酯(0.111mL)而於室溫攪拌。30分鐘後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(462mg)。 1-{4-Methyl-5-[3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-2 obtained in Example (95b) , 3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride (425 mg) in dichloromethane (10 mL), N, N To a solution of diisopropylethylamine (0.401 mL), ethyl chloroacetate (0.11OmL) was added and stirred at room temperature. After 30 minutes, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.36-1.42(3H,m),2.13(3H,s),2.22(3H,s),2.37-2.46(2H,m),3.12(3H,s),3.18-3.25(2H,m),3.60-3.64(1H,m),3.81-3.86(1H,m),4.07-4.11(1H,m),4.19-4.24(1H,m),4.26-4.33(2H,m),4.33-4.40(4H,m),5.49-5.61(1H,m),6.62-6.67(1H,m),6.68-6.71(1H,m),6.76-6.81(1H,m),6.94-6.99(1H,m),7.34-7.39(1H,m),7.50-7.55(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.05-8.10(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36-1.42 (3H, m), 2.13 (3H, s), 2.22 (3H, s), 2.37-2.46 (2H, m), 3.12 (3H, s) , 3.18-3.25 (2H, m), 3.60-3.64 (1H, m), 3.81-3.86 (1H, m), 4.07-4.11 (1H, m), 4.19-4.24 (1H, m), 4.26-4.33 ( 2H,m),4.33-4.40(4H,m),5.49-5.61(1H,m),6.62-6.67(1H,m),6.68-6.71(1H,m),6.76-6.81(1H,m), 6.94-6.99 (1H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H , m).

(102b)[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基](側氧基)乙酸 (102b)[4-{2-Methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H -吲哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl](peroxy)acetic acid

於實施例(102a)所獲得的化合物(462mg)1,4-二烷(5mL)溶液中添加1N氫氧化鈉水溶液(1.5mL)而於室溫攪拌3小時。以1N鹽酸水溶液中和後，以乙酸乙酯提取。有機層以無水硫酸鈉乾燥後，過濾，藉由減壓濃縮而獲 得粗製之[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基](側氧基)乙酸。 Compound (462 mg) 1,4-two obtained in Example (102a) A 1 N aqueous sodium hydroxide solution (1.5 mL) was added to a solution of hexane (5 mL) and stirred at room temperature for 3 hr. After neutralizing with a 1N aqueous hydrochloric acid solution, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated.]]]]]]]]]]] Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl](lateral oxygen Base) acetic acid.

(102c)N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 (102c) N-methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2 ,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

於實施例(102b)所獲得的化合物(147mg)之二氯甲烷(4mL)溶液中添加甲基胺鹽酸鹽(33.7mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(95.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(34.0mg)、N,N-二異丙基乙基胺(0.131mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(38.0mg)。 Methylamine hydrochloride (33.7 mg), 1-ethyl-3-(3-dimethylaminopropyl) was added to a solution of the compound (147 mg) obtained from m. Carboxylimine hydrochloride (95.7 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (34.0 mg), N,N-diisopropyl Ethylamine (0.131 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.19-2.25(3H,m),2.37-2.51(2H,m),2.90(3H,d,J=5.1Hz),3.12(3H,s),3.18-3.26(2H,m),3.82-3.87(1H,m),4.18-4.33(4H,m),4.37(2H,s),4.72-4.76(1H,m),5.51-5.64(1H,m),6.61-6.67(1H,m),6.68-6.72(1H,m),6.76-6.81(1H,m),6.94-6.99(1H,m),7.30-7.40(2H,m),7.49-7.56(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 2.13 (3H, s), 2.19-2.25 (3H, m), 2.37-2.51 (2H, m), 2.90 (3H, d, J = 5.1Hz), 3.12 (3H, s), 3.18-3.26 (2H, m), 3.82-3.87 (1H, m), 4.18-4.33 (4H, m), 4.37 (2H, s), 4.72-4.76 (1H, m), 5.51 -5.64 (1H, m), 6.61-6.67 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.94-6.99 (1H, m), 7.30-7.40 (2H, m), 7.49-7.56 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：602(M+H)+。 MS (APCI) m/z: 602 (M+H) + .

(實施例103)：於實施例(103d)合成 (Example 103): Synthesis in Example (103d)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苄基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基 ]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]benzyl}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Phenyl]ethanone

(103a)5-(4-溴苄基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (103a) 5-(4-bromobenzyl)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(900mg)之1,2-二甲氧基乙烷(12mL)、水(6mL)溶液中添加1-溴-4-(氯甲基)苯(618mg)、肆(三苯基膦)鈀(0)(145mg)、碳酸鈉(664mg)而於100℃攪拌10小時。冷卻至室溫後，以乙酸乙酯提取，有機層以水及飽和食鹽水洗淨。以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(524mg)。 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole- 1-Bromo-4-(chloromethyl)benzene (618 mg), hydrazine (1,2-dimethoxyethane (12 mL), water (6 mL) was added to a solution of 1-butylic acid tert-butyl ester (900 mg). Triphenylphosphine) palladium (0) (145 mg) and sodium carbonate (664 mg) were stirred at 100 ° C for 10 hours. After cooling to room temperature, it was extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous sodium sulfate, it was filtered and evaporated. The residue was purified by EtOAcjjjjj elut elut

1H-NMR(400MHz,CDCl3)δ：1.52-1.59(9H,m),2.04(3H,s),2.94-3.03(2H,m),3.89(2H,s),3.91-4.04(2H,m),6.87-7.01(3H,m),7.32-7.39(2H,m),7.54-7.75(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.52-1.59 (9H, m), 2.04 (3H, s), 2.94-3.03 (2H, m), 3.89 (2H, s), 3.91-4.04 (2H, m), 6.87-7.01 (3H, m), 7.32-7.39 (2H, m), 7.54-7.75 (1H, m).

(103b)1,4-二烷-2-基[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]甲酮 (103b) 1,4-two Alkan-2-yl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H) Ketone

於1,4-二烷-2-甲酸(1.02g)之二氯甲烷(30mL)溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,6-四氫吡啶鹽酸鹽(1.73g)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(2.02g)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(0.958g)、N,N-二異丙基乙基胺(3.68 mL)而於室溫攪拌。12小時後，添加水而以二氯甲烷提取。以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(1.78g)。 1,4-two Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) to a solution of alkane-2-carboxylic acid (1.02 g) in dichloromethane (30 mL) -1,2,3,6-tetrahydropyridine hydrochloride (1.73 g), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (2.02 g), 3H-1,2,3-Triazolo[4,5-b]pyridin-3-ol (0.958 g), N,N-diisopropylethylamine (3.68 mL) was stirred at room temperature. After 12 hours, water was added and extracted with dichloromethane. After drying over anhydrous sodium sulfate, it was filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.22-1.28(12H,m),2.21-2.40(2H,m),3.44-4.36(11H,m),6.41-6.55(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.22-1.28 (12H, m), 2.21-2.40 (2H, m), 3.44 - 4.36 (11H, m), 6.41-6.55 (1H, m).

(103c)5-{4-[1-(1,4-二烷-2-基羰基)-1,2,3,6-四氫吡啶-4-基]苄基}-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (103c) 5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzyl}-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid Butyl ester

於實施例(103a)所獲得的化合物(453mg)之1,2-二甲氧基乙烷(8mL)、水(4mL)溶液中添加實施例(103b)所獲得的化合物(545mg)、肆(三苯基膦)鈀(0)(65.1mg)、碳酸鈉(239mg)而於100℃攪拌10小時。冷卻至室溫後，以乙酸乙酯提取，有機層以水及飽和食鹽水洗淨。以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈非晶形固體之標題化合物(561mg)。 The compound (545 mg) obtained in the example (103b), hydrazine was added to a solution of the compound (453 mg) obtained in the compound ( 323 mg) (1,2-dimethoxyethane (8 mL), water (4 mL). Triphenylphosphine) palladium (0) (65.1 mg) and sodium carbonate (239 mg) were stirred at 100 ° C for 10 hours. After cooling to room temperature, it was extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous sodium sulfate, it was filtered and evaporated. The residue was purified by EtOAcjjjjjj elut elut

1H-NMR(400MHz,CDCl3)δ：1.45-1.61(9H,m),2.06(3H,s),2.47-2.71(2H,m),2.95-3.04(2H,m),3.62-4.40(15H,m),5.96-6.06(1H,m),6.92-7.04(1H,m),7.06-7.13(2H,m),7.22-7.24(2H,m),7.60-7.75(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.61 (9H, m), 2.06 (3H, s), 2.47-2.71 (2H, m), 2.95-3.04 (2H, m), 3.62-4.40 ( 15H, m), 5.96-6.06 (1H, m), 6.92-7.04 (1H, m), 7.06-7.13 (2H, m), 7.22-7.24 (2H, m), 7.60-7.75 (1H, m).

(103d)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苄基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (103d) 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]benzyl}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonate) Phenyl]ethanone

於實施例(103c)所獲得的化合物(560mg)之乙酸乙 酯(10mL)溶液中添加7.5%鈀碳(50.0mg)而於氫氣環境下於室溫攪拌12小時。將反應液以矽藻土過濾後，藉由減壓濃縮而獲得粗製之5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苄基}-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(534mg)。 To a solution of the compound (560 mg) obtained in EtOAc (EtOAc) (EtOAc) After filtering the reaction mixture with diatomaceous earth, the crude 5-[4-[1-(1,4-di) was obtained by concentration under reduced pressure. Alkyl-2-ylcarbonyl)piperidin-4-yl]benzyl}-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (534 mg).

於獲得的化合物(528mg)之二氯甲烷溶液(10mL)中添加三氟乙酸(2.5mL)而於室溫攪拌。3小時後，以飽和碳酸氫鈉水中和，以二氯甲烷提取。有機層以無水硫酸鈉乾燥後，藉由過濾、減壓濃縮而獲得粗製之1,4-二烷-2-基(4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)甲基]苯基}哌啶-1-基)甲酮。 Trifluoroacetic acid (2.5 mL) was added to a dichloromethane solution (m. After 3 hours, it was neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then filtered and then evaporated. Alk-2-yl (4-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)methyl]phenyl}piperidin-1-yl)methanone.

於獲得的化合物(195mg)之二氯甲烷(5mL)溶液中添加[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(119mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(133mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(63.1mg)、N,N-二異丙基乙基胺(0.242mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色固體之標題化合物(243mg)。 [2-(Methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (119 mg), 1-ethyl-3 was added to a solution of the obtained compound (195 mg) in dichloromethane (5 mL) -(3-dimethylaminopropyl)carboxylated imine hydrochloride (133 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (63.1 mg) N,N-Diisopropylethylamine (0.242 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAcjjjjj elut elut

1H-NMR(500MHz,CDCl3)δ：1.54-1.74(2H,m),1.83-1.95(2H,m),2.09-2.16(3H,m),2.58-2.76(2H,m),3.00-3.22(5H,m),3.62-3.95(8H,m),4.08-4.15(2H,m),4.20-4.27(2H,m),4.27-4.38(3H,m),4.66-4.74(1H,m),6.96-7.01(1H,m),7.03-7.12(4H,m),7.34-7.38(1H,m),7.49-7.55(1H,m),7.58-7.64(1H,m),7.93-7.98(1H,m),8.05-8.10(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.83-1.95 (2H, m), 2.09-2.16 (3H, m), 2.58-2.76 (2H, m), 3.00- 3.22 (5H, m), 3.62-3.95 (8H, m), 4.08-4.15 (2H, m), 4.20-4.27 (2H, m), 4.27-4.38 (3H, m), 4.66-4.74 (1H, m ), 6.96-7.01 (1H, m), 7.03-7.12 (4H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.64 (1H, m), 7.93-7.98 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：617(M+H)+。 MS (APCI) m/z: 617 (M+H) + .

(實施例104) (Example 104)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苄基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]benzyl}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(ethylsulfonate) Phenyl]ethanone

於實施例(103d)所獲得的1,4-二烷-2-基(4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)甲基]苯基}哌啶-1-基)甲酮(200mg)之二氯甲烷(5mL)溶液中添加[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(130mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(137mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(64.7mg)、N,N-二異丙基乙基胺(0.249mL)而於於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(256mg)。 1,4-two obtained in the example (103d) Alkan-2-yl (4-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)methyl]phenyl}piperidin-1-yl)methanone ( [2-(ethylsulfonyl)phenyl]acetic acid (CAS number 1363179-47-8) (130 mg), 1-ethyl-3-(3-di) was added to a solution of 200 mg) in dichloromethane (5 mL) Methylaminopropyl)carboxylimine hydrochloride (137 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (64.7 mg), N,N- Diisopropylethylamine (0.249 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(500MHz,CDCl3)δ：1.21-1.28(3H,m),1.52-1.75(2H,m),1.83-1.94(2H,m),2.09-2.16(4H,m),2.58-2.76(2H,m),3.00-3.24(4H,m),3.66-3.97(8H,m),4.07-4.15(1H,m),4.19-4.25(2H,m),4.28-4.39(3H,m),4.66-4.74(1H,m),6.97-7.01(1H,m),7.03-7.12(4H,m),7.37-7.41(1H,m),7.47-7.53(1H,m),7.59-7.64(1H,m),7.93-7.97(1H,m),8.01-8.05(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 1.21-1.28 (3H, m), 1.52-1.75 (2H, m), 1.83-1.94 (2H, m), 2.09-2.16 (4H, m), 2.58- 2.76 (2H, m), 3.00-3.24 (4H, m), 3.66-3.97 (8H, m), 4.07-4.15 (1H, m), 4.19-4.25 (2H, m), 4.28-4.39 (3H, m ), 4.66-4.74 (1H, m), 6.97-7.01 (1H, m), 7.03-7.12 (4H, m), 7.37-7.41 (1H, m), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93-7.97 (1H, m), 8.01-8.05 (1H, m).

MS(APCI)m/z：631(M+H)+。 MS (APCI) m/z: 631 (M+H) + .

(實施例105)：於實施例(105d)合成 (Example 105): Synthesis in Example (105d)

1-{5-[4-(4-乙醯基哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(105a)5-(4-{4-[(苄氧基)羰基]哌-1-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (105a) 5-(4-{4-[(benzyloxy)carbonyl]piperidin -1-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於4-(4-溴苯基)哌-1-甲酸苄酯(CAS編號1150271-33-2)(2g)之1,4-二烷溶液中添加5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(1.33g)、碘化銅(I)(203mg)、N,N-二甲基甘胺酸(219mg)及碳酸銫(3.47g)，並於100℃攪拌12小時。將反應液冷卻至室溫，以矽藻土過濾。減壓下將濾液濃縮，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈非晶形固體之標題化合物(773mg)。 4-(4-bromophenyl)per Benzene-1-carboxylate (CAS No. 1150271-33-2) (2g) of 1,4-two 5-Hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tertiary butyl ester (1.33 g), copper (I) iodide (203 mg), N, N were added to the alkane solution. - dimethylglycine (219 mg) and cesium carbonate (3.47 g), and stirred at 100 ° C for 12 hours. The reaction solution was cooled to room temperature and filtered over Celite. The filtrate was concentrated under reduced pressure. EtOAc m.

1H-NMR(500MHz,CDCl3)δ：1.51-1.59(9H,m),2.09(3H,s),2.98-3.09(6H,m),3.63-3.69(4H,m),3.96-4.07(2H,m),5.16(2H,s),6.67-6.77(1H,m),6.77-6.89(4H,m),7.18-7.27(1H,m),7.29-7.40(4H,m),7.58-7.68(1H,m)。 1 H-NMR (500MHz, CDCl 3 ) δ: 1.51-1.59 (9H, m), 2.09 (3H, s), 2.98-3.09 (6H, m), 3.63-3.69 (4H, m), 3.96-4.07 ( 2H, m), 5.16 (2H, s), 6.67-6.77 (1H, m), 6.77-6.89 (4H, m), 7.18-7.27 (1H, m), 7.29-7.40 (4H, m), 7.58- 7.68 (1H, m).

(105b)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-甲酸苄酯 (105b) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyloxyphenyl Benzyl-1-carboxylate

於實施例(105a)所獲得的化合物(770mg)中添加4N 鹽酸二烷溶液(5mL)，並於室溫攪拌。3小時後，藉由將反應液濃縮而獲得粗製之4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-甲酸苄酯鹽酸鹽。 4N hydrochloric acid was added to the compound (770 mg) obtained in Example (105a) A solution of the alkane (5 mL) was stirred at room temperature. After 3 hours, the crude 4-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidyl was obtained by concentration. Benzyl -1-carboxylate hydrochloride.

於獲得的化合物之二氯甲烷溶液中添加[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(332mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(405mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(192mg)、N,N-二異丙基乙基胺(0.737mL)而於室溫攪拌。12小時後，添加水而以乙酸乙酯提取。有機層以硫酸鈉乾燥後、過濾，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色非晶形固體之標題化合物(520mg)。 [2-(Methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (332 mg), 1-ethyl-3-(3-dimethyl) was added to the obtained compound in dichloromethane. Aminopropyl)carboxylimine hydrochloride (405 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (192 mg), N,N-diiso Propylethylamine (0.737 mL) was stirred at room temperature. After 12 hours, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.14(3H,s),2.99-3.12(7H,m),3.16-3.24(2H,m),3.62-3.69(4H,m),4.24-4.30(2H,m),4.36(2H,s),5.16(2H,s),6.67-6.72(1H,m),6.80-6.90(4H,m),7.30-7.40(6H,m),7.48-7.55(1H,m),7.58-7.64(1H,m),7.91-7.96(1H,m),8.04-8.09(1H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 2.14 (3H, s), 2.99-3.12 (7H, m), 3.16-3.24 (2H, m), 3.62-3.69 (4H, m), 4.24-4.30 ( 2H, m), 4.36 (2H, s), 5.16 (2H, s), 6.67-6.72 (1H, m), 6.80-6.90 (4H, m), 7.30-7.40 (6H, m), 7.48-7.55 ( 1H, m), 7.58-7.64 (1H, m), 7.91-7.96 (1H, m), 8.04-8.09 (1H, m).

(105c)1-{4-甲基-5-[4-(哌-1-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (105c) 1-{4-methyl-5-[4-(piperider -1-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(105b)所獲得的化合物(200mg)之甲醇(8mL)、二氯甲烷(4mL)、乙酸(0.4mL)溶液中添加7.5%鈀碳(100mg)而於氫氣環境下，於室溫攪拌。5小時後，將反應液以矽藻土過濾、減壓濃縮。將殘渣以胺基矽膠層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(125mg)。 Add a 7.5% palladium on carbon (100 mg) to a solution of the compound (200 mg) obtained in Example (105b) in methanol (8 mL), dichloromethane (4 mL) Stir. After 5 hours, the reaction solution was filtered over EtOAc EtOAc. The residue was purified with EtOAc EtOAc EtOAc EtOAc

MS(APCI)m/z：506(M+H)+。 MS (APCI) m/z: 506 (M+H) + .

(105d)1-{5-[4-(4-乙醯基哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (105d) 1-{5-[4-(4-Ethyl) -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(105c)合成的化合物(70.0mg)之吡啶(0.8mL)溶液中添加乙酸酐(0.065mL)而於室溫攪拌。2小時後，添加水而以乙酸乙酯提取。有機層以鹽酸洗淨後，以無水硫酸鈉乾燥，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(66mg)。 To a solution of the compound (70.0 mg) in pyridine (0.8 mL). After 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with hydrochloric acid and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.14(3H,s),2.15(3H,s),3.03-3.13(7H,m),3.18-3.24(2H,m),3.59-3.64(2H,m),3.74-3.79(2H,m),4.25-4.30(2H,m),4.36(2H,s),6.69-6.73(1H,m),6.82-6.91(4H,m),7.34-7.38(1H,m),7.49-7.55(1H,m),7.59-7.64(1H,m),7.92-7.96(1H,m),8.05-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 2.14 (3H, s), 2.15 (3H, s), 3.03-3.13 (7H, m), 3.18-3.24 (2H, m), 3.59-3.64 (2H, m), 3.74-3.79 (2H, m), 4.25-4.30 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82-6.91 (4H, m), 7.34-7.38 ( 1H, m), 7.49-7.55 (1H, m), 7.59-7.64 (1H, m), 7.92-7.96 (1H, m), 8.05-8.09 (1H, m).

MS(APCI)m/z：548(M+H)+。 MS (APCI) m/z: 548 (M+H) + .

(實施例106) (Example 106)

1-(5-{4-[4-(1,4-二烷-2-基羰基)哌-1-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[4-(1,4-di) Alkan-2-ylcarbonyl)per -1-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(105c)所獲得的化合物(50.0mg)之二氯甲烷(2mL)溶液中添加1,4-二烷-2-甲酸(CAS編號 89364-41-0)(15mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(28mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(0.052g)、N,N-二異丙基乙基胺(0.0516mL)而於室溫攪拌整夜。將反應液濃縮後，殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(56.0mg)。 To a solution of the compound obtained in Example (105c) (50.0 mg) in dichloromethane (2 mL) Alkane-2-carboxylic acid (CAS No. 89364-41-0) (15 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (28 mg), 3H-1 2,3-Triazolo[4,5-b]pyridin-3-ol (0.052 g), N,N-diisopropylethylamine (0.0516 mL) was stirred at room temperature overnight. After the reaction mixture was concentrated, EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.15(3H,s),2.99-3.15(7H,m),3.17-3.25(2H,m),3.60-3.90(9H,m),3.92-3.98(1H,m),4.24-4.34(3H,m),4.36(2H,s),6.68-6.73(1H,m),6.81-6.91(4H,m),7.34-7.39(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m),7.92-7.97(1H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.99-3.15 (7H, m), 3.17-3.25 (2H, m), 3.60-3.90 (9H, m), 3.92-3.98 ( 1H,m),4.24-4.34(3H,m),4.36(2H,s),6.68-6.73(1H,m),6.81-6.91(4H,m),7.34-7.39(1H,m),7.49- 7.55 (1H, m), 7.59-7.65 (1H, m), 7.92-7.97 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：620(M+H)+。 MS (APCI) m/z: 620 (M+H) + .

(實施例107) (Example 107)

(實施例107-1)：於實施例(107a)合成 (Example 107-1): Synthesis in Example (107a)

乙酸2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)-2-側氧基乙酯 2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5) -yl)oxy]phenyl}peri -1-yl)-2-oxoethyl ester

(實施例107-2)：於實施例(107b)合成 (Example 107-2): Synthesis in Example (107b)

2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)乙酮 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}peri -1-yl) ethyl ketone

(107a)乙酸2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)-2-側氧基乙酯 (107a) 2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole)哚-5-yl)oxy]phenyl}peri -1-yl)-2-oxoethyl ester

於實施例(105c)所獲得的化合物(210mg)之二氯甲烷(4mL)溶液中添加(乙醯基氧基)乙酸(CAS編號13831-30-6)(58.0mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(119mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(56.0mg)、N,N-二異丙基乙基胺(0.161mL)而於室溫攪拌整夜。將反應液濃縮，殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(192mg)。 To a solution of the compound (210 mg) obtained in m. m. (m. 3-(3-Dimethylaminopropyl)carboxamide imine hydrochloride (119 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (56.0 mg N,N-diisopropylethylamine (0.161 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, EtOAc mjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.14(3H,s),2.20(3H,s),3.03-3.14(7H,m),3.17-3.25(2H,m),3.51-3.58(2H,m),3.73-3.81(2H,m),4.24-4.31(2H,m),4.36(2H,s),4.77(2H,s),6.68-6.74(1H,m),6.81-6.91(4H,m),7.33-7.38(1H,m),7.48-7.55(1H,m),7.58-7.65(1H,m),7.91-7.97(1H,m),8.04-8.10(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 2.14 (3H, s), 2.20 (3H, s), 3.03-3.14 (7H, m), 3.17-3.25 (2H, m), 3.51-3.58 (2H, m), 3.73-3.81 (2H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 4.77 (2H, s), 6.68-6.74 (1H, m), 6.81-6.91 (4H, m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.91-7.97 (1H, m), 8.04-8.10 (1H, m).

(107b)2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)乙酮 (107b) 2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-2,3-dihydro- 1H-indol-5-yl)oxy]phenyl}peri -1-yl) ethyl ketone

於實施例(107a)所獲得的化合物(188mg)之甲醇(2mL)溶液中添加碳酸鉀(214mg)而於室溫攪拌5小時。將 反應液濃縮，殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈白色固體之標題化合物(139mg)。 Potassium carbonate (214 mg) was added to a solution of the compound (m. will The reaction mixture was concentrated and purified mjjjjlilililililili

1H-NMR(400MHz,CDCl3)δ：2.14(3H,s),3.06-3.13(7H,m),3.18-3.25(2H,m),3.40-3.46(2H,m),3.60-3.65(1H,m),3.80-3.86(2H,m),4.20-4.23(2H,m),4.25-4.31(2H,m),4.36(2H,s),6.69-6.73(1H,m),6.82-6.92(4H,m),7.34-7.39(1H,m),7.59-7.65(1H,m),7.59-7.65(1H,m),7.93-7.97(1H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.14 (3H, s), 3.06-3.13 (7H, m), 3.18-3.25 (2H, m), 3.40-3.46 (2H, m), 3.60-3.65 ( 1H, m), 3.80-3.86 (2H, m), 4.20-4.23 (2H, m), 4.25-4.31 (2H, m), 4.36 (2H, s), 6.69-6.73 (1H, m), 6.82 6.92(4H,m),7.34-7.39(1H,m),7.59-7.65(1H,m),7.59-7.65(1H,m),7.93-7.97(1H,m),8.05-8.10(1H,m ).

MS(APCI)m/z：564(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例108)：於實施例(108b)合成 (Example 108): Synthesis in Example (108b)

1-{5-[4-(4-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 1-{5-[4-(4-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone salt Acid salt

(108a)(2S)-4,4-二氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (108a) (2S)-4,4-difluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl)} -2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin -1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(105c)所獲得的化合物(299mg)中添加二氯甲烷(4mL)、1-(三級丁氧基羰基)-4,4-二氟-L-脯胺酸(CAS編號203866-15-3)(178mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(170mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(80.5mg)、N,N-二異丙基乙基胺(0.309mL)而於室溫攪拌整夜。將反應液減壓濃縮，殘渣以矽膠 管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(407mg)。 To the compound (299 mg) obtained in Example (105c), dichloromethane (4 mL), 1-(tris-butoxycarbonyl)-4,4-difluoro-L-proline (CAS No. 203866- 15-3) (178 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (170 mg), 3H-1,2,3-triazolo[4 5-B]pyridin-3-ol (80.5 mg), N,N-diisopropylethylamine (0.309 mL) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dried. Purification by column chromatography (EtOAc/EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.59(9H,s),2.15(3H,s),2.29-2.50(1H,m),2.58-2.76(1H,m),3.00-3.27(8H,m),3.57-3.68(2H,m),3.72-4.02(4H,m),4.23-4.32(2H,m),4.36(2H,s),4.75-4.82(1H,m),4.87-4.95(1H,m),6.68-6.73(1H,m),6.81-6.91(4H,m),7.33-7.38(1H,m),7.49-7.55(1H,m),7.58-7.65(1H,m),7.91-7.97(1H,m),8.04-8.09(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.59 (9H, s), 2.15 (3H, s), 2.29-2.50 (1H, m), 2.58-2.76 (1H, m), 3.00-3.27 (8H, m), 3.57-3.68 (2H, m), 3.72-4.02 (4H, m), 4.23-4.32 (2H, m), 4.36 (2H, s), 4.75-4.82 (1H, m), 4.87-4.95 ( 1H, m), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.33-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.91-7.97 (1H, m), 8.04-8.09 (1H, m).

(108b)1-{5-[4-(4-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (108b) 1-{5-[4-(4-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone salt Acid salt

於實施例(108a)所獲得的化合物(402mg)之1,4-二烷(3mL)溶液中添加4N鹽酸二烷溶液(5mL)，並於室溫攪拌。3小時後，將反應液減壓濃縮。將丙酮添加於殘渣中，濾取析出的固體，藉由乾燥而獲得呈白色固體之標題化合物(345mg)。 1,4-two of the compound (402 mg) obtained in Example (108a) Add 4N hydrochloric acid to the solution of alkane (3mL) A solution of the alkane (5 mL) was stirred at room temperature. After 3 hours, the reaction solution was concentrated under reduced pressure. The title compound (345 mg) was obtained as a white solid.

1H-NMR(400MHz,CD3OD)δ：2.09(3H,s),2.66-2.81(1H,m),3.09-3.16(4H,m),3.17-3.31(3H,m),3.59-3.78(4H,m),3.77-4.22(6H,m),4.31-4.40(4H,m),5.12-5.21(1H,m),6.73-6.79(1H,m),6.97-7.04(2H,m),7.45-7.51(1H,m),7.55-7.63(3H,m),7.65-7.72(1H,m),7.91-7.97(1H,m),8.03-8.08(1H,m). 1 H-NMR (400 MHz, CD 3 OD) δ: 2.09 (3H, s), 2.66-2.81 (1H, m), 3.09-3.16 (4H, m), 3.17-3.31 (3H, m), 3.59-3.78 (4H,m),3.77-4.22(6H,m),4.31-4.40(4H,m),5.12-5.21(1H,m),6.73-6.79(1H,m),6.97-7.04(2H,m) , 7.45-7.51 (1H, m), 7.55-7.63 (3H, m), 7.65-7.72 (1H, m), 7.91-7.97 (1H, m), 8.03-8.08 (1H, m).

MS(APCI)m/z：639(M+H)+。 MS (APCI) m/z: 639 (M+H) + .

(實施例109) (Example 109)

1-{5-[4-(4-{[(2S)-1-乙醯基-4,4-二氟吡咯啶-2-基]羰基}哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-{[(2S)-1-Ethyl-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(108b)所獲得的化合物(84.0mg)之吡啶(1mL)溶液中添加乙酸酐(0.059mL)而於室溫攪拌2小時。於反應液中添加水後，以乙酸乙酯提取。有機層以鹽酸洗淨後，以無水硫酸鈉乾燥，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色固體之標題化合物(67.0mg)。 Acetic anhydride (0.059 mL) was added to a solution of the compound (m. After adding water to the reaction liquid, it was extracted with ethyl acetate. The organic layer was washed with hydrochloric acid and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(500MHz,CDCl3)δ：2.09(3H,s),2.15(3H,s),2.42-2.56(1H,m),2.59-2.71(1H,m),3.03-3.15(6H,m),3.15-3.29(3H,m),3.61-3.72(2H,m),3.83-3.97(3H,m),4.01-4.13(1H,m),4.24-4.31(2H,m),4.36(2H,s),5.04-5.11(1H,m),6.68-6.72(1H,m),6.81-6.91(4H,m),7.34-7.38(1H,m),7.49-7.54(1H,m),7.59-7.64(1H,m),7.92-7.97(1H,m),8.05-8.09(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 2.09 (3H, s), 2.15 (3H, s), 2.42-2.56 (1H, m), 2.59-2.71 (1H, m), 3.03-3.15 (6H, m), 3.15-3.29 (3H, m), 3.61-3.72 (2H, m), 3.83-3.97 (3H, m), 4.01-4.13 (1H, m), 4.24-4.31 (2H, m), 4.36 ( 2H, s), 5.04-5.11 (1H, m), 6.68-6.72 (1H, m), 6.81-6.91 (4H, m), 7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64(1H,m), 7.92-7.97(1H,m),8.05-8.09(1H,m).

MS(APCI)m/z：681(M+H)+。 MS (APCI) m/z: 681 (M+H) + .

(實施例110) (Embodiment 110)

1-{5-[4-(4-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(108b)所獲得的化合物(143mg)之甲醇(2mL)溶液中添加甲醛液(37%)(0.3mL)、7.5%鈀碳(20.0mg)、12N鹽酸(0.10mL)，而於氫氣環境下攪拌10小時。將反應液以矽藻土過濾，減壓濃縮。殘渣以胺基矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色固體之標題化合物(73.0mg)。 To a solution of the compound (143 mg) obtained in Example (108b) in methanol (2 mL), EtOAc (EtOAc) Stir under a hydrogen atmosphere for 10 hours. The reaction solution was filtered over EtOAc EtOAc. The residue was purified with EtOAc EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.15(3H,s),2.39(3H,s),2.44-2.61(1H,m),2.63-2.77(1H,m),2.99-3.17(8H,m),3.17-3.25(2H,m),3.46-3.58(2H,m),3.68-3.81(2H,m),3.82-3.94(2H,m),4.23-4.32(2H,m),4.36(2H,s),6.68-6.73(1H,m),6.81-6.93(4H,m),7.33-7.39(1H,m),7.49-7.56(1H,m),7.59-7.66(1H,m),7.92-7.97(1H,m),8.05-8.11(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.39 (3H, s), 2.44-2.61 (1H, m), 2.63-2.77 (1H, m), 2.99-3.17 (8H, m), 3.17-3.25 (2H, m), 3.46-3.58 (2H, m), 3.68-3.81 (2H, m), 3.82-3.94 (2H, m), 4.23-4.32 (2H, m), 4.36 ( 2H, s), 6.68-6.73 (1H, m), 6.81-6.93 (4H, m), 7.33-7.39 (1H, m), 7.49-7.56 (1H, m), 7.59-7.66 (1H, m), 7.92-7.97(1H,m), 8.05-8.11(1H,m).

MS(APCI)m/z：653(M+H)+。 MS (APCI) m/z: 653 (M+H) + .

(實施例111)：於實施例(111b)合成 (Example 111): Synthesis in Example (111b)

1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)-3-methylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)benzene Ethyl ketone

(111a)4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-甲酸三級丁酯 (111a) 4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}peri 1-carboxylic acid tert-butyl butyl ester

於實施例(3b)合成的化合物(200mg)之甲苯溶液中添加哌-1-甲酸三級丁酯(86.0mg)、二環己基[2’,4’,6’-三(丙烷-2-基)聯苯基-2-基]膦(18.0mg)、參(二亞苄基丙酮)二鈀(0)(17.0mg)、三級丁醇鈉(112mg)而於100℃攪拌10小時。冷卻至室溫後，過濾、減壓濃縮。殘渣藉由矽膠管柱層析(乙酸乙酯/己烷)純化，而獲得呈淡黃色固體之標題化合物(122mg)。 Adding piperidine to the toluene solution of the compound (200 mg) synthesized in Example (3b) 1-carboxylic acid tert-butyl butyl ester (86.0 mg), dicyclohexyl [2',4',6'-tris(propan-2-yl)biphenyl-2-yl]phosphine (18.0 mg), ginseng Dibenzylideneacetone)dipalladium(0) (17.0 mg) and sodium butoxide sodium (112 mg) were stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS(APCI)m/z：620(M+H)+。 MS (APCI) m/z: 620 (M+H) + .

(111b)1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (111b)1-{5-[4-(4-Ethyl) -1-yl)-3-methylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)benzene Ethyl ketone

於實施例(111a)所獲得的化合物(120mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(1.5mL)並於室溫攪拌。2小時後，藉由減壓濃縮而獲得粗製之呈固體之1-{4-甲基-5-[3-甲基-4-(哌-1-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (120 mg) obtained in Example (111a) in dichloromethane (1 mL) A solution of the alkane (1.5 mL) was stirred at room temperature. After 2 hours, a crude solid 1-{4-methyl-5-[3-methyl-4-(piperidin) was obtained by concentration under reduced pressure. -1-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride.

於獲得的化合物之二氯甲烷(1mL)溶液中添加吡啶(1mL)、乙酸酐(0.091mL)而於室溫攪拌2小時。添加水而以氯仿提取後，有機層以鹽酸洗淨，以硫酸鈉乾燥、過濾、減壓濃縮。殘渣藉由以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(85.0mg)。 Pyridine (1 mL) and acetic anhydride (0.091 mL) were added to a solution of the obtained compound in dichloromethane (1 mL). After adding water and extracting with chloroform, the organic layer was washed with hydrochloric acid, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.14(6H,s),2.28(3H,s),2.78-2.88(4H,m),3.12(3H,s),3.17-3.25(2H,m),3.56-3.62(2H,m),3.70-3.78(2H,m),4.24-4.32(2H,m), 4.36(2H,s),6.64-6.70(1H,m),6.71-6.77(2H,m),6.88-6.92(1H,m),7.34-7.38(1H,m),7.49-7.55(1H,m),7.58-7.65(1H,m),7.93-7.98(1H,m),8.05-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.14 (6H, s), 2.28 (3H, s), 2.78-2.88 (4H, m), 3.12 (3H, s), 3.17-3.25 (2H, m) , 3.56-3.62 (2H, m), 3.70-3.78 (2H, m), 4.24-4.32 (2H, m), 4.36 (2H, s), 6.64-6.70 (1H, m), 6.71-6.77 (2H, m), 6.88-6.92 (1H, m), 7.34-7.38 (1H, m), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.93-7.98 (1H, m), 8.05- 8.09 (1H, m).

MS(APCI)m/z：562(M+H)+。 MS (APCI) m/z: 562 (M+H) + .

(實施例112)：於實施例(112b)合成 (Example 112): Synthesis in Example (112b)

1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)-3-methylphenoxy]4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethyl ketone

(112a)4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}哌-1-甲酸三級丁酯 (112a) 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-2,3-dihydro-1H-indole-5- Ethyl]-2-methylphenyl} piperidine 1-carboxylic acid tert-butyl butyl ester

於藉由與實施例(1b)同樣的手法合成的1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮(548mg)中添加哌-1-甲酸三級丁酯(231mg)、三級丁醇鈉(298mg)、參(二亞苄基丙酮)二鈀(0)(47.0mg)、2-(二環己基膦基)-2’,4’,6’-三異丙基-1,1’-聯苯基(49.0mg)、甲苯(5mL)而於100℃攪拌10小時。冷卻至室溫後，過濾及減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色油狀物之標題化合物(328mg)。 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-inden-1-yl]- synthesized by the same method as in Example (1b) Piper added to 2-[2-(ethylsulfonyl)phenyl]ethanone (548 mg) 1-carboxylic acid tert-butyl butyl ester (231 mg), tertiary sodium butoxide (298 mg), ginseng (dibenzylideneacetone) dipalladium (0) (47.0 mg), 2-(dicyclohexylphosphino)-2 ',4',6'-Triisopropyl-1,1'-biphenyl (49.0 mg), toluene (5 mL) was stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc

MS(APCI)m/z：634(M+H)+。 MS (APCI) m/z: 634 (M+H) + .

(112b)1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯 基]乙酮 (112b) 1-{5-[4-(4-Ethyl) -1-yl)-3-methylphenoxy]4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethyl ketone

於實施例(112a)所獲得的化合物(327mg)之二氯甲烷溶液中添加4N鹽酸二烷溶液(4mL)而於室溫攪拌。3小時後，藉由減壓濃縮而獲得粗製之呈淡黃色固體之2-[2-(乙基磺醯基)苯基]-1-{4-甲基-5-[3-甲基-4-(哌-1-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}乙酮鹽酸鹽。 4N hydrochloric acid was added to a dichloromethane solution of the compound (327 mg) obtained in Example (112a) The alkane solution (4 mL) was stirred at room temperature. After 3 hours, a crude pale yellow solid of 2-[2-(ethylsulfonyl)phenyl]-1-{4-methyl-5-[3-methyl- 4-(piperider -1-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}ethanone hydrochloride.

於獲得的化合物中添加二氯甲烷(2mL)、吡啶(2mL)、乙酸酐(0.243mL)而於室溫攪拌3小時。將反應液直接藉由矽膠管柱層析(乙酸乙酯/氯仿)純化，而獲得呈白色固體之標題化合物(225mg)。 Dichloromethane (2 mL), pyridine (2 mL), and acetic anhydride (0.243 mL) were added to the obtained compound, and the mixture was stirred at room temperature for 3 hours. The title compound (225 mg) was obtained.

1H-NMR(500MHz,CDCl3)δ：1.26(3H,t,J=7.6Hz),2.12-2.15(6H,m),2.28(3H,s),2.79-2.88(4H,m),3.17-3.24(4H,m),3.56-3.61(2H,m),3.71-3.78(2H,m),4.24-4.30(2H,m),4.37(2H,s),6.64-6.69(1H,m),6.71-6.76(2H,m),6.88-6.92(1H,m),7.37-7.41(1H,m),7.48-7.53(1H,m),7.59-7.64(1H,m),7.93-7.97(1H,m),8.00-8.04(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.6 Hz), 2.12 - 2.15 (6H, m), 2.28 (3H, s), 2.79-2.88 (4H, m), 3.17 -3.24(4H,m),3.56-3.61(2H,m),3.71-3.78(2H,m), 4.24-4.30(2H,m),4.37(2H,s),6.64-6.69(1H,m) , 6.71-6.76 (2H, m), 6.88-6.92 (1H, m), 7.37-7.41 (1H, m), 7.48-7.53 (1H, m), 7.59-7.64 (1H, m), 7.93-7.97 ( 1H, m), 8.00-8.04 (1H, m).

MS(APCI)m/z：576(M+H)+。 MS (APCI) m/z: 576 (M+H) + .

(實施例113)：於實施例(113b)合成 (Example 113): Synthesis in Example (113b)

1-{5-[4-(4-乙醯基哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

(113a)5-[4-(4-乙醯基哌-1-基)苯氧基]-4-甲基 -2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (113a) 5-[4-(4-Ethylpiperazine) -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

將實施例(105a)所獲得的化合物(433mg)溶解於甲醇(6mL)、二氯甲烷(3mL)及乙酸(0.3mL)，添加7.5%鈀碳，並於氫氣環境下，於室溫攪拌。7小時後，將反應液以矽藻土過濾，濾液藉由減壓濃縮而獲得粗製之呈淡橙色油狀物之4-甲基-5-[4-(哌-1-基)苯氧基]-2,3-二氫-1H-吲哚-1-甲酸三級丁酯。於獲得的化合物之二氯甲烷(5mL)溶液中添加吡啶(3mL)、乙酸酐(0.752mL)而於室溫攪拌3小時。將反應液直接以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色固體之標題化合物(302mg)。 The compound (433 mg) obtained in Example (105a) was dissolved in methanol (6 mL), dichloromethane (3 mL), and acetic acid (0.3 mL), and then, 7.5% palladium carbon was added, and stirred under a hydrogen atmosphere at room temperature. After 7 hours, the reaction mixture was filtered over EtOAc EtOAc (EtOAc) -1-yl)phenoxy]-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester. Pyridine (3 mL) and acetic anhydride (0.752 mL) were added to a solution of the obtained compound in dichloromethane (5 mL). The reaction mixture was purified by EtOAcjjjjjjd

MS(APCI)m/z：452(M+H)+。 MS (APCI) m/z: 452 (M+H) + .

(113b)1-{5-[4-(4-乙醯基哌-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (113b) 1-{5-[4-(4-Ethyl sulfhydryl) -1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

於實施例(113a)所獲得的化合物(300mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)而於室溫攪拌。3小時後，藉由減壓濃縮而獲得粗製之1-(4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (300 mg) obtained in Example (113a) in dichloromethane (2 mL) The alkane solution (2 mL) was stirred at room temperature. After 3 hours, the crude 1-(4-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl} was obtained by concentration under reduced pressure. Piperidin-1-yl)ethanone hydrochloride.

於獲得的化合物中添加二氯甲烷(4mL)、[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(182mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(191mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(90mg)、二異丙基乙基胺(0.347mL)而於室溫攪拌12小時。將反應液減壓濃縮，殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(185mg)。 To the obtained compound, dichloromethane (4 mL), [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (182 mg), 1-ethyl-3-(3- Dimethylaminopropyl)carboxylimine hydrochloride (191 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (90 mg), diisopropyl Ethylamine (0.347 mL) was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.23-1.28(3H,m),2.12-2.16(6H,m),3.02-3.12(4H,m),3.16-3.25(4H,m),3.58-3.64(2H,m),3.74-3.80(2H,m),4.23-4.30(2H,m),4.37(2H,s),6.68-6.73(1H,m),6.81-6.91(4H,m),7.37-7.42(1H,m),7.47-7.53(1H,m),7.59-7.65(1H,m),7.92-7.96(1H,m),8.01-8.05(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.23-1.28 (3H, m), 2.12-2.16 (6H, m), 3.02-3.12 (4H, m), 3.16-3.25 (4H, m), 3.58- 3.64 (2H, m), 3.74-3.80 (2H, m), 4.23-4.30 (2H, m), 4.37 (2H, s), 6.68-6.73 (1H, m), 6.81-6.91 (4H, m), 7.37-7.42 (1H, m), 7.47-7.53 (1H, m), 7.59-7.65 (1H, m), 7.92-7.96 (1H, m), 8.01-8.05 (1H, m).

MS(APCI)m/z：562(M+H)+。 MS (APCI) m/z: 562 (M+H) + .

(實施例114)：於實施例(114d)合成 (Example 114): Synthesis in Example (114d)

1-(5-{[6-(4-乙醯基哌-1-基)吡啶-3-基]氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{[6-(4-ethenyl) -1-yl)pyridin-3-yl]oxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)benzene Ethyl ketone

(114a)4-(5-溴吡啶-2-基)哌-1-甲酸三級丁酯 (114a) 4-(5-bromopyridin-2-yl)peri 1-carboxylic acid tert-butyl butyl ester

於哌-1-甲酸三級丁酯(2.40g)與2,5-二溴吡啶(3.10g)之甲苯(35mL)溶液中添加參(二亞苄基丙酮)二鈀(0)(0.60g)、4,5-雙(二苯基膦基)-9,9-二甲基[口+山][口+星](1.10g)、三級丁醇鈉(3.80g)而於100℃攪拌10小時。冷卻至室溫後，以矽藻土過濾，將濾液減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈黃色固體之標題化合物(1.32g)。 Yupe Add bis(dibenzylideneacetone)dipalladium (0) (0.60 g) to a solution of 2-butyl butyl formate (2.40 g) and 2,5-dibromopyridine (3.10 g) in toluene (35 mL). 4,5-bis(diphenylphosphino)-9,9-dimethyl [mouth + mountain] [mouth + star] (1.10 g), sodium tert-butoxide (3.80 g) and stirred at 100 ° C 10 hour. After cooling to room temperature, it was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

(114b)1-[4-(5-溴吡啶-2-基)哌-1-基]乙酮 (114b) 1-[4-(5-bromopyridin-2-yl)peri -1-yl] ethyl ketone

於實施例(114a)所獲得的化合物(630mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)而於室溫 攪拌。3小時後，藉由減壓濃縮而獲得粗製之1-(5-溴吡啶-2-基)哌二鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (630 mg) obtained in Example (114a) in dichloromethane (2 mL) The alkane solution (4 mL) was stirred at room temperature. After 3 hours, the crude 1-(5-bromopyridin-2-yl)peridine was obtained by concentration under reduced pressure. Dihydrochloride.

於獲得的化合物中添加二氯甲烷(4mL)、三乙基胺(1.28mL)、乙酸酐(0.522mL)而於室溫攪拌。3小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈淡黃色固體之標題化合物(520mg)。 Dichloromethane (4 mL), triethylamine (1.28 mL), acetic anhydride (0.522 mL) were added to the obtained compound and stirred at room temperature. After 3 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.15(3H,s),3.45-3.50(2H,m),3.55-3.64(4H,m),3.71-3.77(2H,m),6.55-6.60(1H,m),7.55-7.60(1H,m),8.20-8.23(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, s), 3.45-3.50 (2H, m), 3.55-3.64 (4H, m), 3.71-3.77 (2H, m), 6.55-6. 1H, m), 7.55-7.60 (1H, m), 8.20-8.23 (1H, m).

(114c)5-{[6-(4-乙醯基哌-1-基)吡啶-3-基]氧基}-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (114c) 5-{[6-(4-Ethyl hydrazine) -1-yl)pyridin-3-yl]oxy}-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於實施例(114b)所獲得的化合物(750mg)之1,4-二烷(10mL)溶液中添加5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(789mg)、碘化銅(I)(100mg)、N,N-二甲基甘胺酸(108mg)、碳酸銫(1.72g)，而於100℃攪拌12小時。冷卻至室溫後，以矽藻土過濾，將濾液減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈淡黃色固體之標題化合物與原料之混合物(431mg)。 1,4-two of the compound (750 mg) obtained in the example (114b) 5-Hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tertiary butyl ester (789 mg), copper (I) iodide (100 mg), N was added to the solution of the alkane (10 mL). N-dimethylglycine (108 mg) and cesium carbonate (1.72 g) were stirred at 100 ° C for 12 hours. After cooling to room temperature, it was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

MS(APCI)m/z：453(M+H)+。 MS (APCI) m/z: 453 (M+H) + .

(114d)1-(5-{[6-(4-乙醯基哌-1-基)吡啶-3-基]氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 (114d) 1-(5-{[6-(4-Ethyl) -1-yl)pyridin-3-yl]oxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[2-(methylsulfonyl)benzene Ethyl ketone

於實施例(114c)所獲得的化合物(431mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌。3小時後，藉由將反應液濃縮而獲得粗製之1-(4- {5-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]吡啶-2-基}哌-1-基)乙酮二鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (431 mg) obtained in Example (114c) in dichloromethane (2 mL) A solution of the alkane (4 mL) was stirred at room temperature. After 3 hours, the crude 1-(4-{5-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]pyridine was obtained by concentrating the reaction mixture. 2-base}piper -1-yl)ethanone dihydrochloride.

於獲得的化合物之二氯甲烷(4mL)溶液中添加[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(0.220g)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(0.270g)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(0.130g)、N,N-二異丙基乙基胺(0.660mL)並於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(0.142g)。 [2-(Methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (0.220 g), 1-ethyl-3-(()) was added to a solution of the obtained compound in dichloromethane (4 mL) 3-dimethylaminopropyl)carboxylimine hydrochloride (0.270 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.130 g), N,N-Diisopropylethylamine (0.660 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjli

1H-NMR(400MHz,CDCl3)δ：2.15(3H,s),2.18(3H,s),3.10(3H,s),3.18-3.25(2H,m),3.39-3.45(2H,m),3.51-3.62(4H,m),3.72-3.79(2H,m),4.24-4.32(2H,m),4.35(2H,s),6.61-6.67(2H,m),7.13-7.18(1H,m),7.33-7.39(1H,m),7.48-7.55(1H,m),7.58-7.65(1H,m),7.90-7.98(2H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.15 (3H, s), 2.18 (3H, s), 3.10 (3H, s), 3.18-3.25 (2H, m), 3.39-3.45 (2H, m) , 3.51-3.62 (4H, m), 3.72-3.79 (2H, m), 4.24-4.32 (2H, m), 4.35 (2H, s), 6.61-6.67 (2H, m), 7.13-7.18 (1H, m), 7.33-7.39 (1H, m), 7.48-7.55 (1H, m), 7.58-7.65 (1H, m), 7.90-7.98 (2H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：549(M+H)+。 MS (APCI) m/z: 549 (M+H) + .

(實施例115) (Example 115)

(實施例115-1)：於實施例(115a)合成 (Example 115-1): Synthesis in Example (115a)

(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)(側氧基)乙酸乙酯 (4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}peri -1-yl)(sideoxy)ethyl acetate

(實施例115-2)：於實施例(115b)合成 (Example 115-2): Synthesis in Example (115b)

(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)(側氧基)乙酸 (4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl) Oxy]phenyl}peri -1-yl)(lateral oxy)acetic acid

(115a)(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)(側氧基)乙酸乙酯 (115a)(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}peri -1-yl)(sideoxy)ethyl acetate

於實施例(105b)所獲得的化合物(680mg)之甲醇(4mL)溶液中添加4N鹽酸二烷溶液(2mL)、7.5%鈀碳(50.0mg)而於氫氣環境下於室溫攪拌。4小時後，藉由將矽藻土過濾的濾液減壓濃縮而獲得粗製之1-{4-甲基-5-[4-(哌-1-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (680 mg) obtained in Example (105b) in methanol (4 mL) An alkane solution (2 mL), 7.5% palladium on carbon (50.0 mg) was stirred at room temperature under a hydrogen atmosphere. After 4 hours, the crude 1-(4-methyl-5-[4-(piperider) was obtained by concentrating the filtrate filtered from celite. -1-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride.

於0℃，於獲得的化合物(152mg)中添加二氯甲烷(3mL)、N,N-二異丙基乙基胺(0.147mL)、氯(側氧基)乙酸乙酯(0.0436mL)而升溫至室溫。於室溫攪拌3小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈非晶形固體之標題化合物(69.0mg)。 Dichloromethane (3 mL), N,N-diisopropylethylamine (0.147 mL), and ethyl chloride (ethyloxy)acetate (0.0436 mL) were added to the obtained compound (152 mg). Warm to room temperature. After stirring at room temperature for 3 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.38(3H,t,J=7.2Hz),2.14(3H,s),3.09-3.15(7H,m),3.18-3.25(2H,m),3.57-3.63(2H,m),3.77-3.82(2H,m),4.25-4.31(2H,m),4.32-4.39(4H,m),6.69-6.73(1H,m),6.81-6.91(4H,m),7.34-7.39(1H,m),7.49-7.55(1H,m),7.59-7.65(1H,m), 7.93-7.97(1H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.38 (3H, t, J = 7.2 Hz), 2.14 (3H, s), 3.09-3.15 (7H, m), 3.18-3.25 (2H, m), 3.57 -3.63 (2H, m), 3.77-3.82 (2H, m), 4.25-4.31 (2H, m), 4.32-4.39 (4H, m), 6.69-6.73 (1H, m), 6.81-6.91 (4H, m), 7.34-7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.93-7.97 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：606(M+H)+。 MS (APCI) m/z: 606 (M+H) + .

(115b)(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)(側氧基)乙酸 (115b)(4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}peri -1-yl)(lateral oxy)acetic acid

於實施例(115a)所獲得的化合物(67.0mg)之1,4-二烷(1mL)溶液中添加1N氫氧化鈉水溶液(1mL)而於室溫攪拌。5小時後，以1N鹽酸水溶液中和，濾取析出的固體，以水及氯仿洗滌，藉由乾燥而獲得呈白色固體之標題化合物(43.0mg)。 1,4-two of the compound (67.0 mg) obtained in the example (115a) A 1N aqueous solution of sodium hydroxide (1 mL) was added to a solution of hexane (1 mL) and stirred at room temperature. After 5 hours, the title compound (43.0 mg) was obtained as a white solid.

1H-NMR(400MHz,DMSO-d6)δ：2.06(3H,s),2.47-2.53(2H,m),3.13-3.28(7H,m),3.55-3.74(4H,m),4.22-4.35(4H,m),6.68-6.73(1H,m),6.80-6.86(2H,m),7.09-7.22(2H,m),7.45-7.50(1H,m),7.54-7.61(1H,m),7.68-7.70(1H,m),7.80-7.85(1H,m),7.93-7.99(1H,m)。 1 H-NMR (400MHz, DMSO -d 6) δ: 2.06 (3H, s), 2.47-2.53 (2H, m), 3.13-3.28 (7H, m), 3.55-3.74 (4H, m), 4.22- 4.35(4H,m), 6.68-6.73(1H,m), 6.80-6.86(2H,m),7.09-7.22(2H,m),7.45-7.50(1H,m),7.54-7.61(1H,m ), 7.68-7.70 (1H, m), 7.80-7.85 (1H, m), 7.93-7.99 (1H, m).

(實施例116)：於實施例(116d)合成 (Example 116): Synthesis in Example (116d)

1-{5-[4-(4-乙醯基哌-1-基)-3-氟苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)-3-fluorophenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethyl ketone

(116a)4-(4-溴-2-氟苯基)哌-1-甲酸三級丁酯 (116a) 4-(4-bromo-2-fluorophenyl)peri 1-carboxylic acid tert-butyl butyl ester

於4-溴-2-氟-1-碘苯(2.00g)之甲苯(15mL)溶液中添加哌-1-甲酸三級丁酯(1.24g)、參(二亞苄基丙酮)二鈀(0)(304mg)、(±)-2,2’-雙(二苯基膦基)-1,1’-聯萘(413mg) 、三級丁醇鈉(1.28g)而於100℃攪拌。10小時後，冷卻至室溫。矽藻土過濾後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色油狀物之標題化合物(542mg)。 Add pipeper to a solution of 4-bromo-2-fluoro-1-iodobenzene (2.00 g) in toluene (15 mL) 3-carboxylic acid tert-butyl ketone (1.24 g), ginseng (dibenzylideneacetone) dipalladium (0) (304 mg), (±)-2,2'-bis(diphenylphosphino)-1, 1'-binaphthyl (413 mg) and sodium tributoxide (1.28 g) were stirred at 100 °C. After 10 hours, it was cooled to room temperature. After filtering through celite, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS(APCI)m/z：359(M+H)+。 MS (APCI) m/z: 359 (M+H) + .

(116b)1-[4-(4-溴-2-氟苯基)哌-1-基]乙酮 (116b) 1-[4-(4-bromo-2-fluorophenyl)peri -1-yl] ethyl ketone

於實施例(116a)所獲得的化合物(542mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌。5小時後，藉由將反應液濃縮而獲得粗製之1-(4-溴-2-氟苯基)哌鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (542 mg) obtained in Example (116a) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After 5 hours, the crude 1-(4-bromo-2-fluorophenyl)peridine was obtained by concentrating the reaction mixture. Hydrochloride.

將獲得的化合物溶解於二氯甲烷(3mL)與吡啶(3mL)，添加乙酸酐(1.4mL)而於室溫攪拌。3小時後，將反應液減壓濃縮將獲得的殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈淡黃色固體之標題化合物(407mg)。 The obtained compound was dissolved in dichloromethane (3 mL) and pyridine (3 mL), and acetic acid (1.4 mL) was added and stirred at room temperature. After 3 hours, the reaction mixture was evaporated.

(116c)5-[4-(4-乙醯基哌-1-基)-3-氟苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (116c) 5-[4-(4-Ethylpicyl) -1-yl)-3-fluorophenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester

於實施例(116b)所獲得的化合物(407mg)之1,4-二烷(15mL)溶液中添加5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(673mg)、碘化銅(I)(51.0mg)、N,N-二甲基甘胺酸(55mg)、碳酸銫(880mg)而於100℃攪拌12小時。冷卻至室溫後，以矽藻土過濾，減壓濃縮。殘渣藉由以矽膠管柱層析(乙酸乙酯/氯仿)純化，而獲得呈茶色油狀物之原料與標題化合物之約1對1的混合物(428mg)。 1,4-two of the compound (407 mg) obtained in Example (116b) a solution of 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (673 mg) and copper (I) iodide (51.0 mg) in a solution of alkane (15 mL). N,N-dimethylglycine (55 mg) and cesium carbonate (880 mg) were stirred at 100 ° C for 12 hours. After cooling to room temperature, it was filtered over EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate / EtOAc)

MS(APCI)m/z：470(M+H)+。 MS (APCI) m/z: 470 (M+H) + .

(116d)1-{5-[4-(4-乙醯基哌-1-基)-3-氟苯氧基]-4- 甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (116d) 1-{5-[4-(4-Ethyl) -1-yl)-3-fluorophenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethyl ketone

於實施例(116c)所獲得的化合物(428mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(4mL)，並於室溫攪拌。3小時後，藉由將反應液濃縮而獲得粗製之1-(4-{2-氟-4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (428 mg) obtained in Example (116c) in dichloromethane (3 mL) A solution of the alkane (4 mL) was stirred at room temperature. After 3 hours, the crude 1-(4-{2-fluoro-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy group was obtained by concentrating the reaction mixture. Phenyl] -1-yl) ethyl ketone hydrochloride.

於獲得的化合物之二氯甲烷(6mL)溶液中添加[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(250mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(262mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(124mg)、N,N-二異丙基乙基胺(0.476mL)，而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色固體之標題化合物(46.0mg)。 Add [2-(ethylsulfonyl)phenyl]acetic acid (CAS number 1363179-47-8) (250 mg), 1-ethyl-3-(3) to a solution of the obtained compound in dichloromethane (6 mL) -Dimethylaminopropyl)carboxylimine hydrochloride (262 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (124 mg), N, N Diisopropylethylamine (0.476 mL), stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.23-1.29(3H,m),2.11(3H,s),2.13(3H,s),2.94-3.03(4H,m),3.16-3.25(4H,m),3.59-3.64(2H,m),3.75-3.80(2H,m),4.24-4.31(2H,m),4.37(2H,s),6.57-6.65(2H,m),6.75-6.80(1H,m),6.82-6.89(1H,m),7.37-7.42(1H,m),7.48-7.54(1H,m),7.59-7.66(1H,m),7.96-8.00(1H,m),8.01-8.06(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.23-1.29 (3H, m), 2.11 (3H, s), 2.13 (3H, s), 2.94-3.03 (4H, m), 3.16-3.25 (4H, m), 3.59-3.64 (2H, m), 3.75-3.80 (2H, m), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.57-6.65 (2H, m), 6.75-6.80 ( 1H, m), 6.82-6.89 (1H, m), 7.37-7.42 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.00 (1H, m), 8.01-8.06 (1H, m).

(實施例117)：於實施例(117c)合成 (Example 117): Synthesis in Example (117c)

1-{5-[4-(4-乙醯基哌-1-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-ethenyl) -1-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl) Phenyl]ketone

(117a)5-(4-溴-3-甲氧基苯氧基)-4-甲基1-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (117a) 5-(4-Bromo-3-methoxyphenoxy)-4-methyl1-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於1-溴-4-碘-2-甲氧基苯(CAS編號755027-18-0)(2g)之1,4-二烷(30mL)溶液中添加5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(1.91g)、碘化銅(I)(243mg)、N,N-二甲基甘胺酸(263mg)、碳酸銫(4.16g)而於100℃攪拌12小時。冷卻至室溫後，以矽藻土過濾，將濾液減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(1.42g)。 1,4-two of 1-bromo-4-iodo-2-methoxybenzene (CAS No. 755027-18-0) (2g) A solution of 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (1.91 g) and copper (I) iodide (243 mg) was added to the solution of the alkane (30 mL). N,N-dimethylglycine (263 mg) and cesium carbonate (4.16 g) were stirred at 100 ° C for 12 hours. After cooling to room temperature, it was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.48-1.64(9H,m),2.05(3H,s),2.98-3.07(2H,m),3.83(3H,s),3.97-4.11(2H,m),6.22-6.27(1H,m),6.51-6.58(1H,m),6.76-6.86(1H,m),7.33-7.38(1H,m),7.63-7.76(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.48-1.64 (9H, m), 2.05 (3H, s), 2.98-3.07 (2H, m), 3.83 (3H, s), 3.97-4.11 (2H, m), 6.22-6.27 (1H, m), 6.51-6.58 (1H, m), 6.76-6.86 (1H, m), 7.33-7.38 (1H, m), 7.63-7.76 (1H, m).

(117b)5-[4-(4-乙醯基哌-1-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (117b) 5-[4-(4-Ethyl) -1-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於實施例(117a)所獲得的化合物(400mg)之甲苯(2mL)溶液中添加1-(哌-1-基)乙酮(CAS編號13889-98-0)(177mg)、參(二亞苄基丙酮)二鈀(0)(42.0mg)、(±)-2,2’-雙(二苯基膦基)-1,1’-聯萘(57.0mg)、三級丁醇鈉(221mg)而於100℃攪拌10小時。冷卻至室溫後，以矽藻土過濾，將濾液減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈淡黃色油狀物之標題化合 物(232mg)。 To a solution of the compound obtained in Example (117a) (400 mg) in toluene (2 mL) -1-yl)ethanone (CAS No. 13889-98-0) (177 mg), ginseng (dibenzylideneacetone) dipalladium (0) (42.0 mg), (±)-2,2'-bis (two Phenylphosphino)-1,1'-binaphthyl (57.0 mg) and sodium tert-butoxide (221 mg) were stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.51-1.62(9H,m),2.09(3H,s),2.13(3H,s),2.92-3.06(6H,m),3.60-3.66(2H,m),3.76-3.85(5H,m),3.97-4.09(2H,m),6.27-6.32(1H,m),6.54-6.59(1H,m),6.71-6.73(2H,m),7.60-7.74(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.62 (9H, m), 2.09 (3H, s), 2.13 (3H, s), 2.92-3.06 (6H, m), 3.60-3.66 (2H, m), 3.76-3.85 (5H, m), 3.97-4.09 (2H, m), 6.27-6.32 (1H, m), 6.54-6.59 (1H, m), 6.71-6.73 (2H, m), 7.60- 7.74 (1H, m).

(117c)1-{5-[4-(4-乙醯基哌-1-基)-3-甲氧基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (117c)1-{5-[4-(4-Ethyl) -1-yl)-3-methoxyphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl) Phenyl]ketone

於實施例(117b)所獲得的化合物(210mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(4mL)而於室溫攪拌。1小時後，藉由減壓濃縮而獲得粗製之1-(4-{2-甲氧基-4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌-1-基)乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (210 mg) obtained in Example (117b) in dichloromethane (2 mL) The alkane solution (4 mL) was stirred at room temperature. After 1 hour, the crude 1-(4-{2-methoxy-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl) was obtained by concentration under reduced pressure. Oxy]phenyl}peri -1-yl) ethyl ketone hydrochloride.

於獲得的化合物中添加二氯甲烷(4mL)、[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(112mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(125mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(59.0mg)、二異丙基乙基胺(0.228mL)而於室溫攪拌12小時。將反應液減壓濃縮，殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(205mg)。 To the obtained compound, dichloromethane (4 mL), [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (112 mg), 1-ethyl-3-(3- Dimethylaminopropyl)carboxylimine hydrochloride (125 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (59.0 mg), diisopropyl The ethyl ethylamine (0.228 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced vacuo.

1H-NMR(500MHz,CDCl3)δ：2.13(3H,s),2.14(3H,s),2.93-3.01(4H,m),3.12(3H,s),3.19-3.24(2H,m),3.60-3.65(2H,m),3.76-3.81(2H,m),3.83(3H,s),4.26-4.31(2H,m),4.36(2H,s),6.30-6.36(1H,m), 6.55-6.59(1H,m),6.73-6.81(2H,m),7.34-7.39(1H,m),7.50-7.55(1H,m),7.59-7.65(1H,m),7.94-7.99(1H,m),8.05-8.10(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.14 (3H, s), 2.93-3.01 (4H, m), 3.12 (3H, s), 3.19-3.24 (2H, m) , 3.60-3.65 (2H, m), 3.76-3.81 (2H, m), 3.83 (3H, s), 4.26-4.31 (2H, m), 4.36 (2H, s), 6.30-6.36 (1H, m) , 6.55-6.59 (1H, m), 6.73-6.81 (2H, m), 7.34-7.39 (1H, m), 7.50-7.55 (1H, m), 7.59-7.65 (1H, m), 7.94-7.99 ( 1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：578(M+H)+。 MS (APCI) m/z: 578 (M+H) + .

(實施例118) (Example 118)

(實施例118-1)：於實施例(118c)合成 (Example 118-1): Synthesis in Example (118c)

1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-氟-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-fluoro-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(實施例118-2)：於實施例(118d)合成 (Example 118-2): Synthesis in Example (118d)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-氟-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-fluoro-2,3-dihydro-1H-indol-1-yl}-2-[ 2-(methylsulfonyl)phenyl]ethanone

(118a)5-(4-溴苯氧基)-4-氟-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (118a) 5-(4-Bromophenoxy)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於5-羥基-4-氟-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(500mg)及1-溴-4-碘苯(670mg)之二烷(12mL)溶液中添加碘化銅(I)(75.2mg)、N,N-二甲基甘胺酸(81.4mg)、碳酸銫(1.29g)，並於90℃攪拌5小時。於反應液中添加 飽和氯化銨水溶液(10mL)、飽和碳酸氫鈉水溶液(5mL)，並添加乙酸乙酯而提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(254mg)。 In the case of 5-hydroxy-4-fluoro-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester (500 mg) and 1-bromo-4-iodobenzene (670 mg) To the solution of the alkane (12 mL), copper (I) iodide (75.2 mg), N,N-dimethylglycine (81.4 mg), and cesium carbonate (1.29 g) were added, and the mixture was stirred at 90 ° C for 5 hours. A saturated aqueous ammonium chloride solution (10 mL) and a saturated aqueous sodium hydrogencarbonate solution (5 mL) were added to the mixture, and ethyl acetate was added to extract. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (254 mg) was obtained from m.

1H-NMR(400MHz,CDCl3)δ：1.56(9H,s),3.14(2H,t,J=8.9Hz),4.01-4.10(2H,m),6.81(2H,d,J=8.5Hz),6.85-6.96(1H,m),7.38(2H,d,J=8.5Hz),7.50-7.66(1H,br m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.56 (9H, s), 3.14 (2H, t, J = 8.9 Hz), 4.01-4.10 (2H, m), 6.81 (2H, d, J = 8.5 Hz ), 6.85-6.96 (1H, m), 7.38 (2H, d, J = 8.5 Hz), 7.50-7.66 (1H, br m).

(118b)1-[5-(4-溴苯氧基)-4-氟-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 (118b) 1-[5-(4-Bromophenoxy)-4-fluoro-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonyl) Phenyl]ketone

於實施例(118a)所獲得的化合物(254mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌18小時。減壓下濃縮反應液，藉由減壓乾燥，獲得白色固體之粗製之5-(4-溴苯氧基)-4-氟-2,3-二氫-1H-吲哚鹽酸鹽(202mg)。 4N hydrochloric acid was added to a solution of the compound (254 mg) obtained in Example (118a) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and evaporated to dryness crystals crystals crystals ).

於獲得的化合物(202mg)之N,N-二甲基甲醯胺(5mL)溶液中添加三乙基胺(160μL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(244mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(151mg)，並於室溫攪拌18小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(255mg)。 Triethylamine (160 μL) was added to a solution of the obtained compound (202 mg) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 5 min. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (244 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (151 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (255 mg) was obtained from m.

1H-NMR(400MHz,CDCl3)δ：3.12(3H,s),3.33(2H,t,J=8.5Hz),4.27-4.39(4H,m),6.83(2H,d,J=8.5Hz),6.91(1H,t,J=8.2Hz),7.35(1H,d,J=7.3Hz),7.40(2H,d,J=8.5Hz),7.50-7.65(2H,m),7.90(1H,d,J=9.2Hz),8.07(1H,d,J=9.2Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 3.12 (3H, s), 3.33 (2H, t, J = 8.5 Hz), 4.27-4.39 (4H, m), 6.83 (2H, d, J = 8.5 Hz ), 6.91 (1H, t, J = 8.2 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.50 - 7.65 (2H, m), 7.90 (1H) , d, J = 9.2 Hz), 8.07 (1H, d, J = 9.2 Hz).

(118c)1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-氟-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (118c) 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-fluoro-2,3-dihydro- 1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

添加實施例(118b)所獲得的化合物(155mg)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(115mg)之1,2-二甲氧基乙烷(10mL)溶液及碳酸鈉(97.7mg)之水溶液(2mL)，並於室溫攪拌5分鐘。添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(10.0mg)，以微波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(135mg)。 The compound (155 mg) obtained in Example (118b), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 was added. a solution of 6-dihydropyridine-1(2H)-yl]ethanone (115 mg) in 1,2-dimethoxyethane (10 mL) and an aqueous solution of sodium carbonate (97.7 mg) (2 mL) Stir for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (10.0 mg) was added, and the mixture was reacted at 130 ° C for 15 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.15(3H,d,J=11.6Hz),2.47-2.59(2H,m),3.12(3H,s),3.34(2H,t,J=8.2Hz),3.66(1H,t,J=5.8Hz),3.81(1H,t,J=5.8Hz),4.08-4.15(1H,m),4.19-4.24(1H,br m),4.29-4.37(4H,m),5.94(0.5H,br s),6.02(0.5H,br s),6.88-6.96(3H,m),7.29-7.37(3H,m),7.50-7.56(1H,m),7.59-7.67(1H,m), 7.90(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.15 (3H, d, J = 11.6 Hz), 2.47-2.59 (2H, m), 3.12 (3H, s), 3.34 (2H, t, J = 8.2 Hz ), 3.66 (1H, t, J = 5.8 Hz), 3.81 (1H, t, J = 5.8 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, br m), 4.29-4.37 (4H , m), 5.94 (0.5H, br s), 6.02 (0.5H, br s), 6.88-6.96 (3H, m), 7.29-7.37 (3H, m), 7.50-7.56 (1H, m), 7.59 - 7.67 (1H, m), 7.90 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

(118d)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-氟-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (118d) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-fluoro-2,3-dihydro-1H-indol-1-yl}- 2-[2-(methylsulfonyl)phenyl]ethanone

使實施例(118c)所獲得的化合物(135mg)溶解於甲醇(3mL)及乙酸乙酯(2mL)，氮氣環境下，於室溫攪拌。添加7.5%鈀碳(27.2mg)，並氫氣環境下，於室溫攪拌18小時。濾除不溶物，減壓下餾除溶媒。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(129mg)。 The compound (135 mg) obtained in Example (118c) was dissolved in methanol (3 mL) and ethyl acetate (2 mL). 7.5% palladium on carbon (27.2 mg) was added and stirred at room temperature for 18 hours under a hydrogen atmosphere. The insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.50-1.64(2H,m),1.80-1.93(2H,m),2.13(3H,s),2.54-2.73(2H,m),3.08-3.22(4H,m),3.33(2H,t,J=8.2Hz),3.87-3.98(1H,m),4.27-4.39(4H,m),4.72-4.83(1H,m),6.85-6.93(3H,m),7.12(2H,d,J=8.5Hz),7.35(1H,d,J=7.3Hz),7.54(1H,t,J=7.0Hz),7.63(1H,t,J=7.0Hz),7.88(1H,d,J=8.5Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.64 (2H, m), 1.80-1.93 (2H, m), 2.13 (3H, s), 2.54-2.73 (2H, m), 3.08-3.22 ( 4H, m), 3.33 (2H, t, J = 8.2 Hz), 3.87-3.98 (1H, m), 4.27-4.39 (4H, m), 4.72-4.83 (1H, m), 6.85-6.93 (3H, m), 7.12 (2H, d, J = 8.5 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.54 (1H, t, J = 7.0 Hz), 7.63 (1H, t, J = 7.0 Hz) , 7.88 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：551(M+H)+。 MS (APCI) m/z: 551 (M+H) + .

(實施例119)：於實施例(119c)合成 (Example 119): Synthesis in Example (119c)

1-乙醯基-4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-3-酮 1-ethenyl-4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole -5-yl)oxy]phenyl}piperidin-3-one

(119a)3-羥基-4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶 -1-甲酸三級丁酯 (119a) 3-Hydroxy-4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole哚-5-yl)oxy]phenyl}piperidine 1-carboxylic acid tert-butyl butyl ester

於實施例(1c)所獲得的化合物(500mg)之四氫呋喃(20mL)溶液中添加硼烷-四氫呋喃錯合物(1M四氫呋喃溶液、1.66mL)，並於室溫攪拌18小時。將反應液冷卻至0℃，添加5N氫氧化鈉水溶液(497μL)，並攪拌20分鐘。再添加30%過氧化氫水(235μL)，於50℃攪拌6小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(339mg)。 A borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 1.66 mL) was added to a solution of the compound (m. The reaction liquid was cooled to 0 ° C, and a 5N aqueous sodium hydroxide solution (497 μL) was added and stirred for 20 minutes. Further, 30% hydrogen peroxide water (235 μL) was added, and the mixture was stirred at 50 ° C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.53-1.83(4H,m),2.13(3H,s),2.45-2.52(1H,m),2.56-2.83(2H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.58-3.68(1H,br m),4.29(2H,t,J=8.5Hz),4.36(2H,s),6.79(1H,d,J=9.2Hz),6.85(2H,d,J=8.5Hz),7.16(2H,d,J=8.5Hz),7.36(1H,d,J=7.3Hz),7.47-7.55(1H,m),7.58-7.66(1H,m),7.98(1H,d,J=9.2Hz),8.07(1H,d,J=7.3Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.48 (9H, s), 1.53-1.83 (4H, m), 2.13 (3H, s), 2.45-2.52 (1H, m), 2.56-2.83 (2H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.5 Hz), 3.58-3.68 (1H, br m), 4.29 (2H, t, J = 8.5 Hz), 4.36 (2H, s) , 6.79 (1H, d, J = 9.2 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.47 - 7.55 (1H, m), 7.58-7.66 (1H, m), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz).

(119b)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3-側氧基哌啶-1-甲酸三級丁酯 (119b) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Tertiary butyl oxy]phenyl}-3-oxo-piperidine-1-carboxylic acid

將草醯氯(35.9μL)之二氯甲烷(6mL)溶液於氮氣環境下，冷卻至-78℃，滴加二甲基亞碸(59.4μL)，並攪拌15分鐘。於反應液中滴加實施例(119a)所獲得的化合物(200mg)之二氯甲烷(4mL)溶液，並於-78℃攪拌15分鐘 。添加三乙基胺(178μL)，並於室溫攪拌2小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(138mg)。 A solution of chloroform (35.9 μL) in dichloromethane (6 mL) was cooled to -78 ° C under nitrogen, and dimethyl hydrazide (59.4 μL) was added dropwise and stirred for 15 minutes. A solution of the compound obtained in Example (119a) (200 mg) in dichloromethane (4 mL). . Triethylamine (178 μL) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),2.10-2.36(5H,m),3.13(3H,s),3.21(2H,t,J=8.5Hz),3.43-3.55(1H,br m),3.57-3.65(1H,m),3.88-4.13(2H,br m),4.21-4.31(3H,m),4.36(2H,s),6.80(1H,d,J=8.5Hz),6.85(2H,d,J=8.5Hz),7.03(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.50-7.54(1H,m),7.59-7.67(1H,m),7.98(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.48 (9H, s), 2.10-2.36 (5H, m), 3.13 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 3.43-3.55 (1H, br m), 3.57-3.65 (1H, m), 3.88-4.13 (2H, br m), 4.21-4.31 (3H, m), 4.36 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.50 - 7.54 (1H, m), 7.59 - 7.67 (1H, m), 7.98 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz).

(119c)1-乙醯基-4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-3-酮 (119c) 1-Ethyl-4-(4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H) -吲哚-5-yl)oxy]phenyl}piperidin-3-one

於實施例(119b)所獲得的化合物(104mg)之二氯甲烷(1mL)溶液中添加4N鹽酸之二烷溶液(2mL)，並於室溫攪拌18小時。減壓下濃縮反應液，藉由減壓乾燥，獲得呈白色固體之粗製之4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-3-酮鹽酸鹽(93.5mg)。 Add 4N hydrochloric acid to a solution of the compound (104 mg) obtained in Example (119b) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and evaporated to dryness crystals crystals crystals }}-2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-3-one hydrochloride (93.5 mg).

於獲得的化合物(93.5mg)之二氯甲烷(5mL)溶液中添加三乙基胺(70μL)，並於室溫攪拌5分鐘。添加乙酸酐(15.9μL)，並於室溫攪拌4小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無 水硫酸鈉乾燥後，於減壓下濃縮。 Triethylamine (70 μL) was added to a solution of the obtained compound (93.5 mg) in dichloromethane (5 mL) and stirred at room temperature for 5 min. Acetic anhydride (15.9 μL) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with water and saturated saline to After drying over sodium sulfate, it was concentrated under reduced pressure.

將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(79.9mg)。 The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.16(3H,d,J=18.3Hz),2.20-2.44(1H,m),3.12(3H,s),3.22(2H,t,J=8.5Hz),3.46-3.54(1H,m),3.60-3.68(2H,m),3.83-3.93(1H,m),4.26(4H,td,J=17.1,7.3Hz),4.36(2H,s),6.80(1H,d,J=8.5Hz),6.85(2H,d,J=8.5Hz),7.02(2H,t,J=7.9Hz),7.36(1H,d,J=7.9Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.16 (3H, d, J = 18.3 Hz), 2.20-2.44 (1H, m), 3.12 (3H, s), 3.22 (2H) , t, J = 8.5 Hz), 3.46-3.54 (1H, m), 3.60-3.68 (2H, m), 3.83-3.93 (1H, m), 4.26 (4H, td, J = 17.1, 7.3 Hz), 4.36(2H, s), 6.80 (1H, d, J = 8.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.02 (2H, t, J = 7.9 Hz), 7.36 (1H, d, J) = 7.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9) Hz).

MS(APCI)m/z：561(M+H)+。 MS (APCI) m/z: 561 (M+H) + .

(實施例120) (Example 120)

1-(5-{4-[1-乙醯基-3-羥基哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{4-[1-Ethyl-3-hydroxypiperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-inden-1-yl )-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(119c)所獲得的化合物(20.0mg)之甲醇(2mL)溶液中添加氫化硼鈉(2.7mg)，並加熱回流40分鐘。於反應液中添加水而於減壓下濃縮，將殘渣以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈淡桃色固體之標題化 合物(19.9mg)。 Sodium borohydride (2.7 mg) was added to a solution of the compound (20.0 mg). Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methylene chloride) to afford titled pale pale solid. Compound (19.9 mg).

1H-NMR(400MHz,CDCl3)δ：1.60-1.75(2H,m),1.79-1.92(1H,m),2.13(3H,s),2.15(3H,d,J=7.3Hz),2.51-2.62(1H,m),2.91-3.02(1H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.57-3.67(1H,br m),3.79-4.07(1H,m),4.29(2H,t,J=8.2Hz),4.37(2H,s),4.68-4.95(1H,m),6.79(1H,d,J=8.5Hz),6.84-6.89(2H,m),7.15(2H,d,J=8.5Hz),7.36(1H,d,J=7.9Hz),7.53(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.99(1H,d,J=8.5Hz),8.08(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.60-1.75 (2H, m), 1.79-1.92 (1H, m), 2.13 (3H, s), 2.15 (3H, d, J = 7.3Hz), 2.51 -2.62 (1H, m), 2.91-3.02 (1H, m), 3.12 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.57-3.67 (1H, br m), 3.79-4.07 ( 1H, m), 4.29 (2H, t, J = 8.2 Hz), 4.37 (2H, s), 4.68-4.95 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 6.84-6.89 (2H , m), 7.15 (2H, d, J = 8.5 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz) ), 7.99 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：563(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例121)：於實施例(121c)合成 (Example 121): Synthesis in Example (121c)

1-甲基-4-{4[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-2-酮 1-methyl-4-{4[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5 -yl)oxy]phenyl}piperidin-2-one

(121a)4-甲基-5-[4-(1-甲基-2-側氧基-1,2-二氫吡啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (121a) 4-Methyl-5-[4-(1-methyl-2-oxooxy-1,2-dihydropyridin-4-yl)phenoxy]-2,3-dihydro-1H -吲哚-1-carboxylic acid tertiary butyl ester

添加實施例(1a)所獲得的化合物(200mg)、以文獻記載之方法(WO2009/74812)合成的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-2(1H)-酮(291mg)之1,2-二甲氧基乙烷(6mL)溶液及碳酸鈉(157mg)之水溶液(2mL)，並於室溫攪拌5分鐘。添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(16.2mg)，並以微 波反應裝置，使於130℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈茶色油狀物之標題化合物(104mg)。 The compound obtained in Example (1a) (200 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3, synthesized by the method described in the literature (WO2009/74812), was added. a solution of 2-dioxaborolan-2-yl)pyridine-2(1H)-one (291 mg) in 1,2-dimethoxyethane (6 mL) and aqueous sodium carbonate (157 mg) (2 mL) Stir at room temperature for 5 minutes. Add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (16.2 mg), and The wave reaction apparatus was allowed to react at 130 ° C for 15 minutes. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl3)δ：1.57(9H,s),2.07(3H,s),3.04(2H,t,J=8.9Hz),3.57(3H,s),3.95-4.09(2H,br m),6.41(1H,d,J=7.0Hz),6.75(1H,s),6.78-6.87(1H,m),6.91(2H,d,J=8.5Hz),7.31(1H,d,J=7.0Hz),7.50(2H,t,J=8.5Hz),7.70(1H,br s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.57 (9H, s), 2.07 (3H, s), 3.04 (2H, t, J = 8.9 Hz), 3.57 (3H, s), 3.95-4.09 (2H , br m), 6.41 (1H, d, J = 7.0 Hz), 6.75 (1H, s), 6.78-6.87 (1H, m), 6.91 (2H, d, J = 8.5 Hz), 7.31 (1H, d , J = 7.0 Hz), 7.50 (2H, t, J = 8.5 Hz), 7.70 (1H, br s).

(121b)4-甲基-5-[4-(1-甲基-2-側氧基哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (121b) 4-Methyl-5-[4-(1-methyl-2-oxopiperidin-4-yl)phenoxy]-2,3-dihydro-1H-indole-1- Butyl formate

於實施例(121a)所獲得的化合物(20.0mg)之甲醇(2mL)溶液中添加20%氫氧化鈀碳(3.0mg)，氫氣環境下，於室溫攪拌24小時。濾除不溶物，減壓下餾除溶媒。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(16.0mg)。 20% palladium hydroxide carbon (3.0 mg) was added to a solution of the compound (20.0 mg) obtained in m. The insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.57(9H,s),1.86-1.97(1H,m),2.05-2.11(4H,m),2.39-2.51(1H,m),2.63-2.75(1H,m),2.95-3.07(6H,m),3.27-3.44(2H,m),3.98-4.07(2H,br m),6.74-6.84(3H,m),7.04-7.12(2H,m),7.56-7.74(1H,br m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57 (9H, s), 1.86-1.97 (1H, m), 2.05-2.11 (4H, m), 2.39-2.51 (1H, m), 2.63-2.75 ( 1H, m), 2.95-3.07 (6H, m), 3.27-3.44 (2H, m), 3.98-4.07 (2H, br m), 6.74-6.84 (3H, m), 7.04-7.12 (2H, m) , 7.56-7.74 (1H, br m).

(121c)1-甲基-4-{4[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-2-酮 (121c) 1-Methyl-4-{4[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole哚-5-yl)oxy]phenyl}piperidin-2-one

於實施例(121b)所獲得的化合物(133mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌18小時。減壓下濃縮反應液，濾取獲得的固體，以乙酸乙酯洗淨，藉由乾燥獲得呈桃色固體之粗製之1-甲基-4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-2-酮鹽酸鹽(154mg)。 4N hydrochloric acid was added to a solution of the compound (133 mg) obtained in Example (121b) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the obtained solid was filtered, washed with ethyl acetate, and dried to give 1-methyl-4-{4-[(4-methyl-2,3 -Dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-2-one hydrochloride (154 mg).

於獲得的化合物(114mg)之N,N-二甲基甲醯胺(3mL)溶液中添加三乙基胺(130μL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(126mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(78.6mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(148mg)。 Triethylamine (130 μL) was added to a solution of the obtained compound (114 mg) in N,N-dimethylformamide (3 mL) and stirred at room temperature for 5 min. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (126 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (78.6 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to mjjjjlililililili

1H-NMR(400MHz,CDCl3)δ：1.88-2.02(1H,m),2.07-2.16(4H,m),2.40-2.51(1H,m),2.65-2.75(1H,m),2.98(3H,s),3.01-3.13(4H,m),3.22(2H,t,J=8.2Hz),3.30-3.44(2H,m),4.29(2H,t,J=8.2Hz),4.36(2H,s),6.78(1H,d,J=8.5Hz),6.84(2H,d,J=8.5Hz),7.10(2H,d,J=9.2Hz),7.36(1H,d,J=7.3Hz),7.52(1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.98(1H,d,J=9.2Hz),8.07(1H,d,J=7.3Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.88-2.02 (1H, m), 2.07-2.16 (4H, m), 2.40-2.51 (1H, m), 2.65-2.75 (1H, m), 2.98 ( 3H, s), 3.01-3.13 (4H, m), 3.22 (2H, t, J = 8.2 Hz), 3.30-3.44 (2H, m), 4.29 (2H, t, J = 8.2 Hz), 4.36 (2H , s), 6.78 (1H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 9.2 Hz), 7.36 (1H, d, J = 7.3 Hz) ), 7.52 (1H, t, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 9.2 Hz), 8.07 (1H, d, J = 7.3 Hz).

MS(APCI)m/z：533(M+H)+。 MS (APCI) m/z: 533 (M+H) + .

(實施例122)：於實施例(122b)合成 (Example 122): Synthesis in Example (122b)

N-(1-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}吡咯啶-3-基)乙醯胺 N-(1-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyloxy]phenyl}pyrrolidin-3-yl)acetamide

(122a)5-{4-[3-(乙醯基胺基)吡咯啶-1-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (122a) 5-{4-[3-(Ethylamino)pyrrolidin-1-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid Tertiary butyl ester

將實施例(1a)所獲得的化合物(600mg)、N-(吡咯啶-3-基)乙醯胺(247mg)、參(二亞苄基丙酮)二鈀(0)(68.0mg)、(±)-2,2’-雙(二苯基膦基)-1,1’-聯萘(92.4mg)、三級丁醇鈉(428mg)、甲苯(4mL)之混合物於100℃攪拌10小時。冷卻至室溫後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈橙色非晶形固體之標題化合物(240mg)。 The compound (600 mg) obtained in Example (1a), N-(pyrrolidin-3-yl)acetamide (247 mg), bis(dibenzylideneacetone) dipalladium (0) (68.0 mg), ( a mixture of ±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (92.4 mg), sodium tributoxide (428 mg), toluene (4 mL) was stirred at 100 ° C for 10 hours. . After cooling to room temperature, it was filtered and concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc)

MS(APCI)m/z：452(M+H)+。 MS (APCI) m/z: 452 (M+H) + .

(122b)N-(1-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}吡咯啶-3-基)乙醯胺 (122b) N-(1-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole) -5-yl)oxy]phenyl}pyrrolidin-3-yl)acetamide

於實施例(122a)所獲得的化合物(240mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(3mL)而於於室溫攪拌。3小時後，藉由減壓濃縮而獲得粗製之N-(1-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}吡咯啶-3-基)乙醯胺鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (240 mg) obtained in Example (122a) in dichloromethane (2 mL) The alkane solution (3 mL) was stirred at room temperature. After 3 hours, the crude N-(1-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl} was obtained by concentration under reduced pressure. Pyrrolidin-3-yl)acetamide hydrochloride.

於獲得的化合物中添加二氯甲烷(4mL)、[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(137mg)、1-乙基 -3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(153mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(72.3mg)、二異丙基乙基胺(0.277mL)而於室溫攪拌12小時。將反應液減壓濃縮，殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈茶色固體之標題化合物(142mg)。 Methylene chloride (4 mL), [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (137 mg), 1-ethyl group were added to the obtained compound. -3-(3-dimethylaminopropyl)carboxylimine hydrochloride (153 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (72.3 Mg), diisopropylethylamine (0.277 mL) and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced vacuo.

1H-NMR(400MHz,CDCl3)δ：1.98(3H,s),2.19(3H,s),2.24-2.36(1H,m),3.10(3H,s),3.15-3.32(4H,m),3.40-3.53(2H,m),4.23-4.30(2H,m),4.35(2H,s),4.59-4.68(1H,m),5.64-5.72(1H,m),6.49-6.56(2H,m),6.59-6.64(1H,m),6.83-6.89(2H,m),7.33-7.38(1H,m),7.48-7.55(1H,m),7.58-7.64(1H,m),7.88-7.93(1H,m),8.05-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.98 (3H, s), 2.19 (3H, s), 2.24-2.36 (1H, m), 3.10 (3H, s), 3.15-3.32 (4H, m) , 3.40-3.53 (2H, m), 4.23-4.30 (2H, m), 4.35 (2H, s), 4.59-4.68 (1H, m), 5.64-5.72 (1H, m), 6.49-6.56 (2H, m), 6.59-6.64 (1H, m), 6.83-6.89 (2H, m), 7.33-7.38 (1H, m), 7.48-7.55 (1H, m), 7.58-7.64 (1H, m), 7.88- 7.93 (1H, m), 8.05-8.09 (1H, m).

MS(APCI)m/z：548(M+H)+。 MS (APCI) m/z: 548 (M+H) + .

(實施例123)：於實施例(123b)合成 (Example 123): Synthesis in Example (123b)

1-{5-[4-(1,4-二氧-8-氮螺[4.5]癸-8-基)苯氧基]-4-甲基1-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1,4-Dioxo-8-azaspiro[4.5]dec-8-yl)phenoxy]-4-methyl1-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(123a)5-[4-(1,4-二氧-8-氮螺[4.5]癸-8-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (123a) 5-[4-(1,4-Dioxo-8-azaspiro[4.5]dec-8-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole 1-carboxylic acid tert-butyl butyl ester

將實施例(1a)所獲得的化合物(1g)、1,4-二氧-8-氮螺[4.5]癸烷(531mg)、參(二亞苄基丙酮)二鈀(0)(113mg)、2-(二環己基膦基)-2’,4’,6’-三異丙基-1,1’-聯苯基(118 mg)、三級丁醇鈉(594mg)、甲苯(5mL)之混合物於100℃攪拌10小時。冷卻至室溫後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(945mg)。 The compound (1 g) obtained in Example (1a), 1,4-dioxo-8-azaspiro[4.5]decane (531 mg), and bis(dibenzylideneacetone)dipalladium (0) (113 mg) 2-(Dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (118 A mixture of mg) sodium butoxide sodium (594 mg) and toluene (5 mL) was stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.55(9H,s),1.82-1.90(4H,m),2.09(3H,s),2.97-3.07(2H,m),3.17-3.27(4H,m),3.94-4.08(6H,m),6.66-6.83(3H,m),6.86-6.93(2H,m),7.57-7.72(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.55 (9H, s), 1.82-1.90 (4H, m), 2.09 (3H, s), 2.97-3.07 (2H, m), 3.17-3.27 (4H, m), 3.94-4.08 (6H, m), 6.66-6.83 (3H, m), 6.86-6.93 (2H, m), 7.57-7.72 (1H, m).

(123b)1-{5-[4-(1,4-二氧-8-氮螺[4.5]癸-8-基)苯氧基]-4-甲基1-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (123b) 1-{5-[4-(1,4-Dioxo-8-azaspiro[4.5]dec-8-yl)phenoxy]-4-methyl1-2,3-dihydro- 1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(123a)所獲得的化合物(263mg)之丙酮(3mL)溶液中添加4N鹽酸二烷溶液(3mL)而於室溫攪拌。3小時後，藉由減壓濃縮而獲得粗製之8-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-1,4-二氧-8-氮螺[4.5]癸烷鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (263 mg) obtained in Example (123a) in acetone (3 mL) The alkane solution (3 mL) was stirred at room temperature. After 3 hours, the crude 8-{4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-1 was obtained by concentration under reduced pressure. 4-Dioxo-8-azaspiro[4.5]decane hydrochloride.

於獲得的化合物之二氯甲烷(5mL)溶液中添加[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(241mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(216mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(76.6mg)、N,N-二異丙基乙基胺(0.294mL)而於室溫攪拌。12小時後，減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(305mg)。 Add [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (241 mg), 1-ethyl-3-(3) to a solution of the obtained compound in dichloromethane (5 mL) - dimethylaminopropyl)carboxylimine hydrochloride (216 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (76.6 mg), N, N-Diisopropylethylamine (0.294 mL) was stirred at room temperature. After 12 hours, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.85-1.86(4H,m),2.15(3H,s),3.11(3H,s),3.18-3.26(6H,m),3.99(4H,s), 4.23-4.31(2H,m),4.36(2H,s),6.70(1H,d,J=8.3Hz),6.79-6.84(2H,m),6.87-6.92(2H,m),7.34-7.38(1H,m),7.49-7.54(1H,m),7.59-7.64(1H,m),7.91-7.95(1H,m),8.05-8.09(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.85-1.86 (4H, m), 2.15 (3H, s), 3.11 (3H, s), 3.18-3.26 (6H, m), 3.99 (4H, s) , 4.23-4.31(2H,m), 4.36(2H,s), 6.70(1H,d,J=8.3Hz), 6.79-6.84(2H,m),6.87-6.92(2H,m),7.34-7.38 (1H, m), 7.49-7.54 (1H, m), 7.59-7.64 (1H, m), 7.91-7.95 (1H, m), 8.05-8.09 (1H, m).

MS(APCI)m/z：563(M+H)+。 MS (APCI) m/z: 564 (M+H) + .

(實施例124) (Example 124)

1-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-4-酮 1-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy Phenyl]piperidin-4-one

於實施例(123b)所獲得的化合物(302mg)之丙酮(8mL)溶液中添加35%鹽酸(8mL)而於外溫80℃攪拌3小時。冷卻至室溫後，減壓濃縮。殘渣以二氯甲烷提取後，有機層以無水硫酸鈉乾燥。過濾、減壓濃縮後，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得黃色非晶形固體之標題化合物(191mg)。 A solution of the compound (302 mg) obtained in Example (123b) (yield (3 mL) After cooling to room temperature, it was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. After filtration and concentrating under reduced pressure, EtOAc m.

MS(APCI)m/z：519(M+H)+。 MS (APCI) m/z: 519 (M+H) + .

(實施例125) (Embodiment 125)

1-{5-[4-(4-羥基哌啶-1-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(4-Hydroxypiperidin-1-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2 -(methylsulfonyl)phenyl]ethanone

於0℃，實施例124所獲得的化合物(191mg)之甲醇(3mL)、四氫呋喃(1.5mL)溶液中添加氫化硼鈉(27.9mg) 。於0℃攪拌1小時後，添加1N鹽酸水溶液。藉由減壓濃縮將有機溶媒餾除後，以二氯甲烷提取。有機層以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(143mg)。 Addition of sodium borohydride (27.9 mg) to a solution of the compound (191 mg) obtained in m. . After stirring at 0 ° C for 1 hour, a 1 N aqueous hydrochloric acid solution was added. The organic solvent was distilled off by concentration under reduced pressure, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified with EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.66-1.76(2H,m),1.97-2.05(2H,m),2.15(3H,s),2.80-2.89(2H,m),3.11(3H,s),3.17-3.24(2H,m),3.40-3.48(2H,m),3.78-3.87(1H,m),4.24-4.31(2H,m),4.36(2H,s),6.67-6.72(1H,m),6.79-6.84(2H,m),6.86-6.92(2H,m),7.34-7.38(1H,m),7.48-7.54(1H,m),7.58-7.64(1H,m),7.90-7.95(1H,m),8.05-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 1.66-1.76 (2H, m), 1.97-2.05 (2H, m), 2.15 (3H, s), 2.80-2.89 (2H, m), 3.11 (3H, s), 3.17-3.24 (2H, m), 3.40-3.48 (2H, m), 3.78-3.87 (1H, m), 4.24-4.31 (2H, m), 4.36 (2H, s), 6.67-6.72 ( 1H, m), 6.79-6.84 (2H, m), 6.86-6.92 (2H, m), 7.34-7.38 (1H, m), 7.48-7.54 (1H, m), 7.58-7.64 (1H, m), 7.90-7.95 (1H, m), 8.05-8.09 (1H, m).

MS(APCI)m/z：521(M+H)+。 MS (APCI) m/z: 521 (M+H) + .

(實施例126) (Example 126)

4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]-2-甲基苯基}-1-甲基哌-2-酮 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy 2-methylphenyl}-1-methylper 2-ketone

將藉由與實施例(1b)同樣的手法合成的1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(乙基磺醯基)苯基]乙酮(500mg)、1-甲基哌-2-酮(130mg)、參(二亞苄基丙酮)二鈀(0)(43.3mg)、(±)-2,2’-雙(二苯基膦基)-1,1’-聯萘(58.9mg)、三級丁醇鈉(273mg)、甲苯(5mL) 之混合物於100℃攪拌10小時。冷卻至室溫後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/氯仿)純化，獲得呈白色非晶形固體之標題化合物(53.0mg)。 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-inden-1-yl]- synthesized by the same method as in Example (1b) 2-[2-(ethylsulfonyl)phenyl]ethanone (500 mg), 1-methylperazine 2-ketone (130 mg), ginseng (dibenzylideneacetone) dipalladium (0) (43.3 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-linked A mixture of naphthalene (58.9 mg), sodium tributoxide (273 mg) and toluene (5 mL) was stirred at 100 ° C for 10 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.2Hz),2.13(3H,s),2.26(3H,s),3.03(3H,s),3.11-3.26(6H,m),3.39-3.44(2H,m),3.56(2H,s),4.24-4.31(2H,m),4.37(2H,s),6.65-6.71(1H,m),6.73-6.78(2H,m),6.89-6.94(1H,m),7.37-7.43(1H,m),7.47-7.55(1H,m),7.60-7.66(1H,m),7.94-7.99(1H,m),8.01-8.06(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 2.26 (3H, s), 3.03 (3H, s), 3.11-3.26 (6H , m), 3.39-3.44 (2H, m), 3.56 (2H, s), 4.24-4.31 (2H, m), 4.37 (2H, s), 6.65-6.71 (1H, m), 6.73-6.78 (2H , m), 6.89-6.94 (1H, m), 7.37-7.43 (1H, m), 7.47-7.55 (1H, m), 7.60-7.66 (1H, m), 7.94-7.99 (1H, m), 8.01 -8.06(1H,m).

MS(APCI)m/z：562(M+H)+。 MS (APCI) m/z: 562 (M+H) + .

(實施例127)：於實施例(127c)合成 (Example 127): Synthesis in Example (127c)

4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}啉-3-酮 4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy Phenyl] Karolin-3-one

(127a)4-甲基-5-[4-(3-側氧基啉-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (127a) 4-methyl-5-[4-(3-sideoxy) Benzyl-4-yl)phenoxy]-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(1.00g)及4-(4-溴苯基)啉-3-酮(1.13g)之二烷(15mL)溶液中添加碘化銅(I)(152mg)、N,N-二甲基甘胺酸(166mg)、碳酸銫(2.61g)，於100℃攪拌12小時。放冷後，於反應液依序添加飽和氯化銨水溶液、飽和碳酸氫鈉水溶液，以乙酸乙酯提取。有機層以水及飽和食鹽水洗 淨，以無水硫酸鈉乾燥後，於減壓下濃縮。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡紅色固體之含標題化合物的混合物(880mg)。 3-Hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester (1.00 g) and 4-(4-bromophenyl) Dioxa-3-one (1.13g) Copper (I) iodide (152 mg), N,N-dimethylglycine (166 mg), and cesium carbonate (2.61 g) were added to the solution of the alkane (15 mL), and the mixture was stirred at 100 ° C for 12 hours. After cooling, a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc)

MS(APCI)m/z：425(M+H)+。 MS (APCI) m/z: 425 (M+H) + .

(127b)4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}啉-3-酮 三氟乙酸鹽 (127b) 4-{4-[(4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl} Oxa-3-one trifluoroacetate

將實施例(127a)所獲得的混合物(365mg)溶解於二氯甲烷(5mL)，於室溫添加三氟乙酸，並於同溫下攪拌3小時。減壓下濃縮反應液，減壓下，藉由乾燥，獲得呈茶褐色油狀物之粗製之標題化合物(370mg)。本化合物直接使用於下一步驟。 The mixture obtained in Example (127a) (365 mg) was dissolved in dichloromethane (5mL), trifluoroacetic acid was added at room temperature, and stirred at the same temperature for 3 hours. The title compound (370 mg) was obtained. This compound was used directly in the next step.

(127c)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}啉-3-酮 (127c) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole-5- Alkyloxy]phenyl} Karolin-3-one

於實施例(127b)所獲得的化合物(195mg)之二烷(8mL)溶液中添加二異丙基乙基胺(0.206mL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(150mg)及[2-(甲基磺醯基)苯基]乙酸(109mg)，於室溫攪拌24小時。添加水並以乙酸乙酯提取3次，合併有機層，以水、飽和食鹽水洗淨後，以無水硫酸鈉乾燥，並餾除溶媒。藉由將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之含標題化合物的混合物(135mg)。 The compound obtained in Example (127b) (195 mg) Diisopropylethylamine (0.206 mL) and 4-(4,6-dimethoxy-1,3,5-trichloride) were added to the solution of the alkane (8 mL). -2-yl)-4-methyl Borax (150 mg) and [2-(methylsulfonyl)phenyl]acetic acid (109 mg) were stirred at room temperature for 24 hours. Water was added and extracted with ethyl acetate three times. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (methanol)

1H-NMR(400MHz,CDCl3)δ：2.11(3H,s),3.12(3H,s),3.17-3.27(2H,m),3.70-3.75(2H,m),3.99-4.05(2H,m),4.24-4.39(6H,m),6.81(1H,d,J=8.5Hz),6.89(2H,dd,J=8.5,2.1Hz),7.18-7.24(2H,m),7.36(1H,d,J=7.9 Hz),7.49-7.55(1H,m),7.58-7.65(1H,m),7.96-8.02(1H,m),8.07(1H,d,J=7.9Hz). 1 H-NMR (400MHz, CDCl 3) δ: 2.11 (3H, s), 3.12 (3H, s), 3.17-3.27 (2H, m), 3.70-3.75 (2H, m), 3.99-4.05 (2H, m), 4.24 - 4.39 (6H, m), 6.81 (1H, d, J = 8.5 Hz), 6.89 (2H, dd, J = 8.5, 2.1 Hz), 7.18-7.24 (2H, m), 7.36 (1H) , d, J = 7.9 Hz), 7.49-7.55 (1H, m), 7.58-7.65 (1H, m), 7.96-8.02 (1H, m), 8.07 (1H, d, J = 7.9 Hz).

MS(APCI)m/z：521(M+H)+。 MS (APCI) m/z: 521 (M+H) + .

(實施例128) (Embodiment 128)

4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}啉-3-酮 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy Phenyl] Karolin-3-one

於實施例(127b)所獲得的化合物(110mg)之二烷(8mL)溶液中添加二異丙基乙基胺(0.116mL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(85.1mg)及[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(63.0mg)，並於室溫攪拌24小時。添加水並以乙酸乙酯提取3次，合併有機層以水、飽和食鹽水洗淨後，以無水硫酸鈉乾燥，並餾除溶媒。藉由將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之含標題化合物的混合物(136mg)。 The compound (110 mg) obtained in the example (127b) Diisopropylethylamine (0.116 mL) and 4-(4,6-dimethoxy-1,3,5-trichloride) were added to the solution of the alkane (8 mL). -2-yl)-4-methyl Borax (85.1 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (63.0 mg) were stirred at room temperature for 24 hours. Water was added and extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (136 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.28(3H,t,J=7.9Hz),2.12(3H,s),3.16-3.26(4H,m),3.69-3.80(2H,m),3.99-4.07(2H,m),4.21-4.44(6H,m),6.81(1H,d,J=8.5Hz),6.89(2H,d,J=8.5Hz),7.15-7.30(2H,m),7.37-7.43(1H,m),7.48-7.54(1H,m),7.59-7.66(1H,m),7.96-8.05(2H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.28 (3H, t, J = 7.9 Hz), 2.12 (3H, s), 3.16-3.26 (4H, m), 3.69-3.80 (2H, m), 3.99 -4.07 (2H, m), 4.21-4.44 (6H, m), 6.81 (1H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m), 7.37-7.43 (1H, m), 7.48-7.54 (1H, m), 7.59-7.66 (1H, m), 7.96-8.05 (2H, m).

MS(APCI)m/z：535(M+H)+。 MS (APCI) m/z: 535 (M+H) + .

(實施例129)：於實施例(129c)合成 (Example 129): Synthesis in Example (129c)

1-{4-甲基-5-[4-(啉-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基)}-2-[2-(甲基磺醯基)苯基]乙酮 1-{4-methyl-5-[4-( Polin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl)}-2-[2-(methylsulfonyl)phenyl]ethanone

(129a)4-甲基-5-[4-(3-啉-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (129a) 4-methyl-5-[4-(3- Benzyl-4-yl)phenoxy]-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(1.00g)及4-(4-溴苯基)啉(1.46g)之二烷(15mL)溶液中添加碘化銅(I)(153mg)、N,N-二甲基甘胺酸(166mg)、碳酸銫(2.61g)，並於90℃攪拌25小時。放冷後，添加乙酸乙酯並攪拌30分鐘後，濾除不溶物。減壓下餾除溶媒，藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈茶褐色非晶形固體之含標題化合物的混合物(125mg)。 3-Hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl butyl ester (1.00 g) and 4-(4-bromophenyl) Porphyrin (1.46g) Copper (I) (153 mg), N,N-dimethylglycine (166 mg), and cesium carbonate (2.61 g) were added to a solution of the alkane (15 mL), and stirred at 90 ° C for 25 hours. After allowing to cool, ethyl acetate was added and stirred for 30 minutes, and then the insoluble material was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified from mjjjjjjjjj

MS(APCI)m/z：411(M+H)+。 MS (APCI) m / z: 411 (M + H) +.

(129b)4-甲基-5-[4-(啉-4-基)苯氧基]-2,3-二氫-1H-吲哚 三氟乙酸鹽 (129b) 4-methyl-5-[4-( Polin-4-yl)phenoxy]-2,3-dihydro-1H-indole trifluoroacetate

將實施例(129a)所獲得的混合物(370mg)溶解於二氯甲烷(5mL)，於室溫添加三氟乙酸(8mL)，並於同溫下攪拌3小時。減壓下濃縮反應液，減壓下，藉由乾燥，獲得呈茶褐色油狀物之粗製之標題化合物(385mg)。本 化合物直接使用於下一步驟。 The mixture (370 mg) obtained in Example (129a) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (8 mL) was added at room temperature, and stirred at the same temperature for 3 hours. The title compound (385 mg) was obtained. this The compound was used directly in the next step.

(129c)1-{4-甲基-5-[4-(啉-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基)}-2-[2-(甲基磺醯基)苯基]乙酮 (129c) 1-{4-methyl-5-[4-( Polin-4-yl)phenoxy]-2,3-dihydro-1H-indol-1-yl)}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(129b)所獲得的化合物(165mg)之二烷(8mL)溶液添加二異丙基乙基胺(0.180mL)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(132mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(91.6mg)，並於室溫攪拌48小時。添加水並以乙酸乙酯提取3次，合併有機層，以水、飽和食鹽水洗淨後，以無水硫酸鈉乾燥，並餾除溶媒。藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈褐色非晶形固體之標題化合物(21.0mg)。 The compound (165 mg) obtained in Example (129b) Add a solution of diisopropylethylamine (0.180 mL) and 4-(4,6-dimethoxy-1,3,5-three) in a solution of alkane (8 mL). -2-yl)-4-methyl Borax (132 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (91.6 mg) were stirred at room temperature for 48 hours. Water was added and extracted with ethyl acetate three times. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The title compound (21.0 mg) was obtained as a brown solid.

1H-NMR(400MHz,CDCl3)δ：2.15(3H,s),3.04-3.24(7H,m),3.82-3.89(6H,m),4.28(2H,t,J=7.9Hz),4.36(2H,s),6.69(1H,d,J=8.5Hz),6.79-6.89(4H,m),7.36(1H,d,J=7.9Hz),7.51(1H,t,J=7.3Hz),7.59-7.64(1H,m),7.93(1H,d,J=8.5Hz),8.05-8.09(1H,m). 1 H-NMR (400MHz, CDCl 3) δ: 2.15 (3H, s), 3.04-3.24 (7H, m), 3.82-3.89 (6H, m), 4.28 (2H, t, J = 7.9Hz), 4.36 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 6.79-6.89 (4H, m), 7.36 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.3 Hz) , 7.59-7.64 (1H, m), 7.93 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m).

MS(APCI)m/z：507(M+H)+。 MS (APCI) m / z: 507 (M + H) +.

(實施例130)：於實施例(130c)合成 (Example 130): Synthesis in Example (130c)

1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[(1'-Ethyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4-methyl- 2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

(130a)5-[(6-溴吡啶-3-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (130a) 5-[(6-Bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester

於5-羥基-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯(1g)及2-溴-5-氟吡啶(0.777g)之N,N-二甲基甲醯胺(5mL)溶液中添加碳酸銫(3.92g)，並以微波反應裝置於150℃使反應70分鐘。減壓下濃縮反應液，以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(0.580g)。 N,N- in 3-tert-butyl 5-hydroxy-4-methyl-2,3-dihydro-1H-indole-1-carboxylate (1 g) and 2-bromo-5-fluoropyridine (0.777 g) Dimethyl carbonate (3.92 g) was added to a solution of dimethylformamide (5 mL), and the reaction was allowed to proceed at 150 ° C for 70 minutes in a microwave reactor. The reaction mixture was evaporated to mjjjjjjjjjjj

MS(APCI)m/z：405(M+H)+。 MS (APCI) m/z: 405 (M+H) + .

(130b)1-{5-[(6-溴吡啶-3-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (130b) 1-{5-[(6-Bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2- (ethylsulfonyl)phenyl]ethanone

將實施例(130a)所獲得的化合物(400mg)溶解於二氯甲烷(10mL)，於室溫添加4N鹽酸二烷溶液(4.0mL)並攪拌4小時。將反應液濃縮，獲得粗製之5-[(6-溴吡啶-3-基)氧基]-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(335mg)。 The compound obtained in Example (130a) (400 mg) was dissolved in dichloromethane (10 mL), and 4N hydrochloric acid was added at room temperature. The alkane solution (4.0 mL) was stirred for 4 hours. The reaction solution was concentrated to give crude 5-[(6-bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indole hydrochloride (335 mg).

於獲得的化合物(335mg)之N,N-二甲基甲醯胺(5mL)溶液中添加4-甲基啉(0.216mL)並於室溫攪拌20分鐘。其次，添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(353mg)及[2-(乙基磺醯基)苯基]乙酸(CAS編號1363179-47-8)(269mg)，再於室溫攪拌3小時。減壓下濃縮反應液，以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(400mg)。 4-methyl group was added to a solution of the obtained compound (335 mg) in N,N-dimethylformamide (5 mL) The morpholine (0.216 mL) was stirred at room temperature for 20 min. Secondly, adding 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (353 mg) and [2-(ethylsulfonyl)phenyl]acetic acid (CAS No. 1363179-47-8) (269 mg) were stirred at room temperature for 3 hours. The reaction mixture was evaporated to drynessnessnessnessnessnessness

1H-NMR(400MHz,CDCl3)δ：1.27(3H,t,J=7.3Hz),2.10(3H,s),3.17-3.25(4H,m),4.29(2H,t,J=8.5Hz),4.37(2H,s),6.79(1H,d,J=9.1Hz),7.03(1H,dd,J=8.5,3.0Hz),7.34-7.41(2H,m),7.49-7.54(1H,m),7.60-7.65(1H,m),7.99-8.07(3H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.10 (3H, s), 3.17-3.25 (4H, m), 4.29 (2H, t, J = 8.5 Hz ), 4.37 (2H, s), 6.79 (1H, d, J = 9.1 Hz), 7.03 (1H, dd, J = 8.5, 3.0 Hz), 7.34 - 7.41 (2H, m), 7.49 - 7.54 (1H, m), 7.60-7.65 (1H, m), 7.99-8.07 (3H, m).

MS(APCI)m/z：515(M+H)+。 MS (APCI) m/z: 515 (M+H) + .

(130c)1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (130c) 1-{5-[(1'-Ethyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4- Methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone

於(實施例130b)所獲得的化合物(100mg)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(73.1mg)之1,2-二甲氧基乙烷(2mL)溶液中添加碳酸鈉(61.7mg)水溶液(1mL)及[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(15.8mg)，以微波反應裝置，使於100℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(甲醇/二氯甲烷)純化，獲得呈白色固體之標題化合物(70.0mg)。 Compound (100 mg) obtained in (Example 130b), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 Add a solution of sodium carbonate (61.7 mg) (1 mL) and [1] to a solution of 6-dihydropyridine-1(2H)-yl]ethanone (73.1 mg) in 1,2-dimethoxyethane (2 mL). 1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (15.8 mg) was reacted at 100 ° C for 15 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),2.12(3H,s),2.14(3H x 1/2,s),2.17(3H x 1/2,s),2.58-2.74(2H,br m),3.16-3.25(2H,m),3.66(1H,t,J=5.8Hz),3.83(1H,t,J=5.8Hz),4.09-4.20(2H,m),4.24-4.32(4H,m),4.37(2H,s),6.44-6.55(1H,br m),6.79(1H,d,J=8.5Hz),7.07-7.13(1H,m),7.28-7.34(1H, m),7.40(1H,d,J=7.9Hz),7.51(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),7.98-8.05(2H,m),8.26-8.28(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2, s), 2.58-2.74 (2H, br m), 3.16-3.25 (2H, m), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.09-4.20 ( 2H,m),4.24-4.32(4H,m),4.37(2H,s),6.44-6.55(1H,br m),6.79(1H,d,J=8.5Hz),7.07-7.13(1H,m ), 7.28-7.34 (1H, m), 7.40 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.98-8.05 (2H, m), 8.26-8.28 (1H, m).

MS(APCI)m/z：560(M+H)+。 MS (APCI) m / z: 560 (M + H) +.

(實施例131) (Example 131)

1-(5-{[6-(1-乙醯基哌啶-4-基)吡啶-3-基]氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(乙基磺醯基)苯基]乙酮 1-(5-{[6-(1-Ethylpiperidin-4-yl)pyridin-3-yl]oxy}-4-methyl-2,3-dihydro-1H-indole-1 -yl)-2-[2-(ethylsulfonyl)phenyl]ethanone

將實施例(130c)所獲得的化合物(54.0mg)溶解於二氯甲烷(5mL)及甲醇(5mL)，添加7.5%鈀碳(30.0mg)，並於氫氣環境下於室溫攪拌30分鐘。濾除不溶物，減壓下濃縮濾液而獲得呈白色固體之標題化合物(52.0mg)。 The compound obtained in Example (130c) (54.0 mg) was dissolved in dichloromethane (5 mL) and methanol (5mL), and then, 7.5% palladium carbon (30.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The title compound (52.0 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.26(3H,t,J=7.3Hz),1.62-1.79(2H,m),1.89-2.03(2H,m),2.12(6H,s),2.61-2.71(1H,m),2.85-2.95(1H,br m),3.15-3.25(5H,m),3.94(1H,d,J=13.4Hz),4.28(2H,t,J=8.5Hz),4.37(2H,s),4.76(1H,d,J=13.4Hz),6.77(1H,d,J=8.5Hz),7.02-7.10(2H,m),7.39(1H,d,J=7.6Hz),7.51(1H,t,J=7.6Hz),7.63(1H,t,J=7.6Hz),8.01(2H,dd,J=15.6,8.2Hz),8.25(1H,d,J=2.4Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.62-1.79 (2H, m), 1.89-2.03 (2H, m), 2.12 (6H, s), 2.61 -2.71(1H,m),2.85-2.95(1H,br m),3.15-3.25(5H,m),3.94(1H,d,J=13.4Hz), 4.28(2H,t,J=8.5Hz) , 4.37 (2H, s), 4.76 (1H, d, J = 13.4 Hz), 6.77 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.6 Hz), 8.01 (2H, dd, J = 15.6, 8.2 Hz), 8.25 (1H, d, J = 2.4) Hz).

MS(APCI)m/z：562(M+H)+。 MS (APCI) m/z: 562 (M+H) + .

(實施例132)：於實施例(132b)合成 1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (Example 132): Synthesis in Example (132b) 1-{5-[(1'-Ethyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4-methyl- 2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(132a)1-{5-[(6-溴吡啶-3-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (132a) 1-{5-[(6-Bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2- (methylsulfonyl)phenyl]ethanone

於(130b)所獲得的粗製之5-[(6-溴吡啶-3-基)氧基]-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(400mg)之N,N-二甲基甲醯胺(5mL)溶液中添加4-甲基啉(0.233mL)並於室溫攪拌20分鐘。其次，添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(381mg)及[2-(甲基磺醯基)苯基]乙酸(CAS編號142336-20-7)(272mg)，再於室溫攪拌3小時。減壓下濃縮反應液，以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(460mg)。 N of 5-[(6-bromopyridin-3-yl)oxy]-4-methyl-2,3-dihydro-1H-indole hydrochloride (400 mg) obtained in (130b) , 4-methyl dimethylformamide (5mL) solution was added 4-methyl The morpholine (0.233 mL) was stirred at room temperature for 20 min. Secondly, adding 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (381 mg) and [2-(methylsulfonyl)phenyl]acetic acid (CAS No. 142336-20-7) (272 mg) were stirred at room temperature for 3 hours. The reaction mixture was evaporated to drynessnessnessnessnessnessness

MS(APCI)m/z：501(M+H)+。 MS (APCI) m/z: 501 (M+H) + .

(132b)1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (132b) 1-{5-[(1'-Ethyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4- Methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於(132a)所獲得的化合物(190mg)及1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(143mg)之1,2-二甲氧基乙烷(2mL)溶液中添加碳酸鈉(121mg)水溶液(0.5mL)及[1,1’-雙(二苯基膦基)二 茂鐵]二氯化鈀(II)二氯甲烷錯合物(31.0mg)，並以微波反應裝置，使於100℃反應15分鐘。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈淡黃色固體之標題化合物(100mg)。 The compound (190 mg) obtained in (132a) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6 Add a solution of sodium carbonate (121 mg) (0.5 mL) and [1, 1' to a solution of dihydropyridine-1(2H)-yl]ethanone (143 mg) in 1,2-dimethoxyethane (2 mL). - bis(diphenylphosphino)di Molecular iron] palladium (II) chloride complex (31.0 mg) was reacted at 100 ° C for 15 minutes in a microwave reactor. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.12(3H,s),2.14(3H x 1/2,s),2.17(3H x 1/2,s),2.58-2.75(2H,m),3.12(3H,s),3.22(2H,t,J=8.2Hz),3.66(1H,t,J=5.8Hz),3.83(1H,t,J=5.8Hz),4.15-4.20(1H,br m),4.25-4.33(3H,m),4.37(2H,s),6.44-6.54(1H,m),6.79(1H,d,J=8.5Hz),7.10(1H,dd,J=8.5,2.4Hz),7.28-7.39(2H,m),7.53(1H,t,J=7.3Hz),7.63(1H,t,J=7.3Hz),8.00(1H,d,J=8.5Hz),8.07(1H,d,J=7.9Hz),8.28(1H,dd,J=7.9,2.4Hz). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.12 (3H, s), 2.14 (3H x 1/2, s), 2.17 (3H x 1/2, s), 2.58-2.75 (2H, m), 3.12(3H, s), 3.22 (2H, t, J = 8.2 Hz), 3.66 (1H, t, J = 5.8 Hz), 3.83 (1H, t, J = 5.8 Hz), 4.15 - 4.20 (1H, br m), 4.25-4.33 (3H, m), 4.37 (2H, s), 6.44-6.54 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.5, 2.4 Hz), 7.28-7.39 (2H, m), 7.53 (1H, t, J = 7.3 Hz), 7.63 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.07 (1H, d, J = 7.9 Hz), 8.28 (1H, dd, J = 7.9, 2.4 Hz).

MS(APCI)m/z：546(M+H)+。 MS (APCI) m/z: 546 (M+H) + .

(實施例133) (Example 133)

1-(5-{[6-(1-乙醯基哌啶-4-基)吡啶-3-基]氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[2-(甲基磺醯基)苯基]乙酮 1-(5-{[6-(1-Ethylpiperidin-4-yl)pyridin-3-yl]oxy}-4-methyl-2,3-dihydro-1H-indole-1 -yl)-2-[2-(methylsulfonyl)phenyl]ethanone

將實施例(132b)所獲得的化合物(30.0mg)溶解於二氯甲烷(5mL)及甲醇(5mL)，添加7.5%鈀碳(10.0mg)， 並於氫氣環境下於室溫攪拌2小時。濾除不溶物，減壓下濃縮濾液而獲得呈白色固體之標題化合物(25.0mg)。 The compound obtained in Example (132b) (30.0 mg) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and 7.5% palladium carbon (10.0 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The title compound (25.0 mg) was obtained as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.67-1.81(2H,m),1.90-2.03(2H,m),2.12(3H,s),2.13(3H,s),2.46-2.53(1H,m),2.62-2.71(1H,m),3.12(3H,s),3.17-3.25(3H,m),3.87-3.97(2H,m),4.30(2H,t,J=8.5Hz),4.36(2H,s),6.76(1H,d,J=8.5Hz),7.02-7.10(2H,m),7.36(1H,d,J=7.9Hz),7.50-7.55(1H,m),7.59-7.65(1H,m),7.99(1H,d,J=8.5Hz),8.05-8.09(1H,m),8.26(1H,d,J=2.4Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.67-1.81 (2H, m), 1.90-2.03 (2H, m), 2.12 (3H, s), 2.13 (3H, s), 2.46-2.53 (1H, m), 2.62-2.71 (1H, m), 3.12 (3H, s), 3.17-3.25 (3H, m), 3.87-3.97 (2H, m), 4.30 (2H, t, J = 8.5 Hz), 4.36 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 7.02-7.10 (2H, m), 7.36 (1H, d, J = 7.9 Hz), 7.50-7.55 (1H, m), 7.59- 7.65 (1H, m), 7.99 (1H, d, J = 8.5 Hz), 8.05-8.09 (1H, m), 8.26 (1H, d, J = 2.4 Hz).

MS(APCI)m/z：548(M+H)+。 MS (APCI) m/z: 548 (M+H) + .

(實施例134) (Example 134)

1-[5-(4-{1-[(2R)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2R)-1,4-two Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl] ketone

於實施例(1g-2)獲得的化合物(150mg)之氯仿(10mL)溶液中添加氧化錳(IV)(632mg)，並加熱回流36小時。於反應液中添加氯仿，進行矽藻土過濾，減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈黃色固體之標題化合物(23.1mg)。 Manganese (IV) oxide (632 mg) was added to a solution of the compound (1. Chloroform was added to the reaction mixture, and the mixture was filtered over Celite, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.54-1.74(2H,m),1.84-1.96(2H,m),2.39(3H,s),2.58-2.78(2H,m), 3.00-3.21(4H,m),3.63-3.99(6H,m),4.06-4.16(1H,br m),4.28-4.38(1H,br m),4.65-4.75(1H,br m),4.88(2H,s),6.76(1H,d,J=3.7Hz),6.81(2H,d,J=8.5Hz),6.97(1H,d,J=9.2Hz),7.06-7.12(2H,m),7.40(1H,d,J=6.7Hz),7.55-7.61(1H,m),7.62-7.68(2H,m),8.10-8.13(1H,m),8.21(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.54-1.74 (2H, m), 1.84-1.96 (2H, m), 2.39 (3H, s), 2.58-2.78 (2H, m), 3.00-3.21 ( 4H, m), 3.63-3.99 (6H, m), 4.06-4.16 (1H, br m), 4.28-4.38 (1H, br m), 4.65-4.75 (1H, br m), 4.88 (2H, s) , 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.06-7.12 (2H, m), 7.40 (1H, d, J = 6.7 Hz), 7.55 - 7.61 (1H, m), 7.62 - 7.68 (2H, m), 8.10 - 8.13 (1H, m), 8.21 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：617(M+H)+。 MS (APCI) m/z: 617 (M+H) + .

(實施例135) (Example 135)

1-[5-(4-{1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮 1-[5-(4-{1-[(2S)-1,4-two Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-1H-indol-1-yl]-2-[2-(methylsulfonyl)phenyl] ketone

於實施例(1g-1)獲得的化合物(300mg)之氯仿(10mL)溶液中添加2,3-二氯-5,6-二氰基-1,4-苯醌(231mg)，並加熱回流6小時。於反應液中添加氯仿，進行矽藻土過濾，減壓下濃縮。於殘渣中添加水，以乙酸乙酯提取。有機層以水洗淨2次及以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈淡褐色固體之標題化合物(90.3mg)。 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (231 mg) was added to a solution of the compound (300 mg) obtained in Example (1 g-1) in chloroform (10 mL). 6 hours. Chloroform was added to the reaction mixture, and the mixture was filtered over Celite, and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.52-1.73(2H,m),1.82-1.95(2H,m),2.39(3H,s),2.57-2.76(2H,m),3.04-3.24(4H,m),3.65-4.00(6H,m),4.07-4.18(1H,br m), 4.27-4.37(1H,br m),4.68-4.75(1H,br m),4.89(2H,s),6.77(1H,d,J=3.7Hz),6.79-6.84(2H,m),6.97(1H,d,J=9.2Hz),7.09(2H,d,J=8.5Hz),7.37-7.44(1H,m),7.55-7.62(1H,m),7.63-7.69(2H,m),8.09-8.15(1H,m),8.22(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.73 (2H, m), 1.82-1.95 (2H, m), 2.39 (3H, s), 2.57-2.76 (2H, m), 3.04-3.24 ( 4H,m), 3.65-4.00(6H,m),4.07-4.18(1H,br m), 4.27-4.37(1H,br m),4.68-4.75(1H,br m),4.89(2H,s) , 6.77 (1H, d, J = 3.7 Hz), 6.79-6.84 (2H, m), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.37-7.44 ( 1H, m), 7.55-7.62 (1H, m), 7.63-7.69 (2H, m), 8.09-8.15 (1H, m), 8.22 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：617(M+H)+。 MS (APCI) m/z: 617 (M+H) + .

(實施例136) (Example 136)

(2S)-2-羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2S)-2-hydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-1H-indole-5 -yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例10所獲得的化合物(72.8mg)之氯仿(5mL)溶液中添加2,3-二氯-5,6-二氰基-1,4-苯醌(60.2mg)，並於75℃攪拌6小時。將反應液冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(14.7mg)。 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (60.2 mg) was added to a solution of the compound obtained in Example 10 (72.8 mg) in chloroform (5 mL) at 75 ° C Stir for 6 hours. After cooling the reaction mixture to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.35(3H,dd,J=13.4,6.7Hz),1.57-1.70(2H,m),1.88-1.97(2H,m),2.39(3H,s),2.67-2.80(2H,m),3.08-3.18(4H,m),3.77-3.86(1H,m),3.90-3.98(1H,br m),4.44-4.54(1H,br m),4.71-4.82(1H,br m),4.88(2H,s),6.77(1H,d,J=4.3Hz), 6.82(2H,d,J=7.3Hz),6.97(1H,d,J=8.5Hz),7.05-7.13(2H,m),7.41(1H,d,J=7.3Hz),7.54-7.60(1H,m),7.62-7.69(2H,m),8.11(1H,t,J=4.3Hz),8.22(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, dd, J = 13.4, 6.7 Hz), 1.57-1.70 (2H, m), 1.88-1.97 (2H, m), 2.39 (3H, s) , 2.67-2.80(2H,m), 3.08-3.18(4H,m),3.77-3.86(1H,m),3.90-3.98(1H,br m),4.44-4.54(1H,br m),4.71- 4.82 (1H, br m), 4.88 (2H, s), 6.77 (1H, d, J = 4.3 Hz), 6.82 (2H, d, J = 7.3 Hz), 6.97 (1H, d, J = 8.5 Hz) , 7.05-7.13(2H,m), 7.41 (1H,d,J=7.3Hz), 7.54-7.60(1H,m), 7.62-7.69(2H,m),8.11(1H,t,J=4.3Hz ), 8.22 (1H, d, J = 8.5Hz).

MS(APCI)m/z：575(M+H)+。 MS (APCI) m/z: 575 (M+H) + .

(實施例137)：於實施例(137b)合成 (Example 137): Synthesis in Example (137b)

1-{5-[4-(1-{[(2S,4S)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4- Methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

(137a)(2S,4S)-4-氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (137a)(2S,4S)-4-fluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-) 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(139b)所獲得的化合物(300mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(231mg)及N-三級丁氧基羰基-cis-4-氟-L-脯胺酸(158mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(350mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. Add 4-(4,6-dimethoxy-1,3,5-three chloride) -2-yl)-4-methyl Borax (231 mg) and N-tertiary butoxycarbonyl-cis-4-fluoro-L-proline (158 mg) were stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s), 1.53-1.66(2H,m),1.81-1.97(2H,m),2.15-2.33(1H,m),2.39(3H,s),2.42-2.78(3H,m),3.07-3.25(4H,m),3.71-3.98(3H,m),4.62-4.83(2H,m),4.89(2H,s),5.15(0.5H,br s),5.30(0.5H,br s),6.77(1H,d,J=3.7Hz),6.81(2H,d,J=7.9Hz),6.98(1H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.41(1H,d,J=7.9Hz),7.58(1H,t,J=7.6Hz),7.62-7.69(2H,m),8.12(1H,d,J=7.9Hz),8.22(1H,d,J=9.2Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.48 (9H, s), 1.53-1.66 (2H, m), 1.81-1.97 (2H, m), 2.15-2.33 (1H, m), 2.39 (3H, s), 2.42 - 2.78 (3H, m), 3.07 - 3.25 (4H, m), 3.71-3.98 (3H, m), 4.62-4.83 (2H, m), 4.89 (2H, s), 5.15 (0.5H , br s), 5.30 (0.5H, br s), 6.77 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 7.9 Hz), 6.98 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62 - 7.69 (2H, m), 8.12 (1H, d , J = 7.9 Hz), 8.22 (1H, d, J = 9.2 Hz).

(137b)1-{5-[4-(1-{[(2S,4S)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (137b) 1-{5-[4-(1-{[(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy] -4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(137a)所獲得的化合物(350mg)之二氯甲烷(5mL)溶液中添加4N鹽酸二烷溶液(10mL)，於室溫攪拌10小時。於減壓下餾除溶媒，藉由將析出的固體以乙酸乙酯洗淨，獲得呈薄桃色固體之粗製之1-{5-[4-(1-{[(2S,4S)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽(334mg)。 4N hydrochloric acid was added to a solution of the compound (350 mg) obtained in Example (137a) in dichloromethane (5 mL) A solution of the alkane (10 mL) was stirred at room temperature for 10 h. The solvent was distilled off under reduced pressure, and the precipitated solid was washed with ethyl acetate to give a crude 1-[5-[4-(1-{[(2S,4S)-4-) Fluropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)benzene Ethyl ketone hydrochloride (334 mg).

於獲得的化合物(334mg)之四氫呋喃(6mL)與甲醇(2mL)之混合溶液中添加乙酸(175μL)、37%甲醛液(57μL)、三乙醯氧基硼氫化鈉(162mg)，並於室溫攪拌18小時。減壓下將反應液濃縮，添加飽和碳酸氫鈉(10mL.)而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以胺基矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固 體之標題化合物(240mg)。 To the mixed solution of the obtained compound (334 mg) in tetrahydrofuran (6 mL) and methanol (2 mL), acetic acid (175 μL), 37% formaldehyde solution (57 μL), sodium triethoxy hydride hydride (162 mg), and Stir for 18 hours. The reaction mixture was concentrated under reduced vacuoluent. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by an amine column chromatography (ethyl acetate / dichloromethane) to afford white solid. The title compound (240 mg).

1H-NMR(400MHz,CDCl3)δ：1.48-1.67(2H,m),1.83-1.95(2H,m),2.09-2.32(2H,m),2.39(6H,s),2.48-2.77(3H,m),2.96-3.17(5H,m),3.32-3.44(1H,m),4.50-4.60(0.5H,br m),4.63-4.72(0.5H,br m),4.76-4.84(1H,br m),4.88(2H,s),5.07(0.5H,br s),5.22(0.5H,br s),6.76(1H,d,J=3.7Hz),6.81(2H,d,J=8.5Hz),6.97(1H,d,J=9.2Hz),7.10(2H,d,J=9.2Hz),7.40(1H,d,J=8.5Hz),7.55-7.60(1H,m),7.63-7.68(2H,m),8.10-8.13(1H,m),8.21(1H,d,J=9.2Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.67 (2H, m), 1.83-1.95 (2H, m), 2.09-2.32 (2H, m), 2.39 (6H, s), 2.48-2.77 ( 3H,m), 2.96-3.17(5H,m),3.32-3.44(1H,m),4.50-4.60(0.5H,br m),4.63-4.72(0.5H,br m),4.76-4.84(1H , br m), 4.88 (2H, s), 5.07 (0.5H, br s), 5.22 (0.5H, br s), 6.76 (1H, d, J = 3.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 9.2 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.55-7.60 (1H, m), 7.63 -7.68 (2H, m), 8.10-8.13 (1H, m), 8.21 (1H, d, J = 9.2 Hz).

MS(APCI)m/z：632(M+H)+。 MS (APCI) m/z: 632 (M+H) + .

(實施例138)：於實施例(138b)合成 (Example 138): Synthesis in Example (138b)

(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-1H-吲哚-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

(138a)1-{5-[4-(1-{[(4S)-2,2-二甲基-1,3-二氧戊環-4-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (138a) 1-{5-[4-(1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]carbonyl}piperidin-4-yl) Phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(139b)所獲得的化合物(320mg)之N,N-二甲基甲醯胺(8mL)溶液中添加三乙基胺(150μL)，並於室溫攪拌5分鐘。依序添加按照文獻記載之方法(Bioorganic and Medicinal Chemistry Letters，2004，14，3231)合成 的(4S)-2,2-二甲基-1,3-二氧戊環-4-甲酸(100mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(231mg)，並於室溫攪拌18小時。於反應液中添加水並以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(320mg)。 Triethylamine (150 μL) was added to a solution of the compound (m. (4S)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid (100 mg) synthesized according to the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, 14, 3231) was added in order. , 4-(4,6-dimethoxy-1,3,5-three chloride -2-yl)-4-methyl Was guanidine (231 mg) and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.39-1.46(6H,m),1.50-1.75(2H,m),1.85-1.96(2H,m),2.39(3H,s),2.64-2.76(2H,m),3.01-3.22(4H,m),3.73(0.5H,t,J=4.9Hz),3.85(0.5H,t,J=4.9Hz),4.20-4.33(1H,m),4.39-4.52(1H,m),4.67-4.77(2H,m),4.88(2H,s),6.76(1H,d,J=3.7Hz),6.82(2H,d,J=8.5Hz),6.97(1H,d,J=9.2Hz),7.09(2H,d,J=7.3Hz),7.40(1H,d,J=7.3Hz),7.55-7.60(1H,m),7.63-7.68(2H,m),8.11(1H,d,J=9.2Hz),8.21(1H,d,J=9.2Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39-1.46 (6H, m), 1.50-1.75 (2H, m), 1.85-1.96 (2H, m), 2.39 (3H, s), 2.64-2.76 ( 2H, m), 3.01-3.22 (4H, m), 3.73 (0.5H, t, J = 4.9 Hz), 3.85 (0.5H, t, J = 4.9 Hz), 4.20-4.33 (1H, m), 4.39 -4.52 (1H, m), 4.67-4.77 (2H, m), 4.88 (2H, s), 6.76 (1H, d, J = 3.7 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 ( 1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.60 (1H, m), 7.63 - 7.68 (2H, m ), 8.11 (1H, d, J = 9.2 Hz), 8.21 (1H, d, J = 9.2 Hz).

(138b)(2S)-2,3-二羥基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)丙烷-1-酮 (138b)(2S)-2,3-dihydroxy-1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl)ethinyl}-) 1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)propan-1-one

於實施例(138a)所獲得的化合物(350mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌2.5小時。於反應液中添加水，以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，藉由減壓下濃縮，獲得呈白色固體之標題化合物(255mg)。 4N hydrochloric acid was added to a solution of the compound (350 mg) obtained in Example (138a) in dichloromethane (1 mL) Alkane solution (2 mL) was stirred at room temperature for 2.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.59-1.71(2H,m),1.88-2.00(2H,m),2.38(3H,s),2.69-2.83(2H,m),3.12(3H,s),3.13-3.23(1H,m),3.56-3.66(1H,m),3.72-3.81(1H,m),3.83-3.94(1H,m),4.50(1H,br s),4.69-4.78(1H,br m),4.88(2H,s),6.76(1H,d,J=4.0Hz),6.82(2H,d,J=8.5Hz),6.97(1H,d,J=9.2Hz),7.09(2H,d,J=8.5Hz),7.40(1H,d,J=7.6Hz),7.58(1H,t,J=7.6Hz),7.63-7.68(2H,m),8.11(1H,d,J=4.0Hz),8.22(1H,d,J=9.2Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.59-1.71 (2H, m), 1.88-2.00 (2H, m), 2.38 (3H, s), 2.69-2.83 (2H, m), 3.12 (3H, s), 3.13-3.23 (1H, m), 3.56-3.66 (1H, m), 3.72-3.81 (1H, m), 3.83-3.94 (1H, m), 4.50 (1H, br s), 4.69-4.78 (1H, br m), 4.88 (2H, s), 6.76 (1H, d, J = 4.0 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.63 - 7.68 (2H, m), 8.11 (1H, d , J = 4.0 Hz), 8.22 (1H, d, J = 9.2 Hz).

MS(APCI)m/z：591(M+H)+。 MS (APCI) m/z: 591 (M+H) + .

(實施例139)：於實施例(139d)合成 (Example 139): Synthesis in Example (139d)

1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 1-{5-[4-(1-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-1H -吲哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

(139a)4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (139a) 4-{4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-1H-indol-5-yl)oxy]phenyl } piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1d)所獲得的化合物(150mg)之二氯甲烷(10mL)溶液中添加2,3-二氯-5,6-二氰基-1,4-苯醌(84.5mg)，並加熱回流15小時。減壓下濃縮反應液，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡褐色固體之標題化合物(60.0mg)。 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (84.5 mg) was added to a solution of the compound (150 mg) obtained from m. Heat to reflux for 15 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s), 1.57-1.64(2H,m),1.76-1.84(2H,br m),2.39(3H,s),2.54-2.65(1H,br m),2.71-2.85(2H,br m),3.13(3H,s),4.08-4.32(2H,br m),4.89(2H,s),6.75-6.83(3H,m),6.98(1H,d,J=9.2Hz),7.10(2H,d,J=8.5Hz),7.40(1H,d,J=7.3Hz),7.55-7.67(3H,m),8.11(1H,d,J=7.9Hz),8.21(1H,d,J=9.2Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.57-1.64 (2H, m), 1.76-1.84 (2H, br m), 2.39 (3H, s), 2.54-2.65 (1H , br m), 2.71-2.85 (2H, br m), 3.13 (3H, s), 4.08-4.32 (2H, br m), 4.89 (2H, s), 6.75-6.83 (3H, m), 6.98 ( 1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.55-7.67 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz).

(139b)1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (139b) 1-{4-Methyl-5-[4-(piperidin-4-yl)phenoxy]-1H-indol-1-yl}-2-[2-(methylsulfonyl) Phenyl]ethanone hydrochloride

於實施例(139a)所獲得的化合物(58.0mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(2mL)，於室溫攪拌4小時。減壓下濃縮反應液，藉由乾燥而獲得呈白色固體之標題化合物(50.0mg)。 4N hydrochloric acid was added to a solution of the compound (58.0 mg) obtained in Example (139a) in dichloromethane (3 mL) A solution of the alkane (2 mL) was stirred at room temperature for 4 h. The title compound (50.0 mg) was obtained.

MS(APCI)m/z：503(M+H)+。 MS (APCI) m/z: 503 (M+H) + .

(139c)(2S)-4,4-二氟-2-[(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (139c)(2S)-4,4-difluoro-2-[(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl)} -1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl ester

於實施例(139b)所獲得的化合物(48.0mg)之N,N-二甲基甲醯胺(2.5mL)溶液中添加4-甲基啉(18.0mg)，並於室溫攪拌20分鐘。其次添加N-三級丁氧基羰基-4,4-二氟-L-脯胺酸(26.8mg)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(32.0mg)，於室溫攪拌3.5小時。減壓下將反應液濃縮，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(65.0mg)。 4-methyl group was added to a solution of the compound (48.0 mg) obtained in Example (139b) in N,N-dimethylformamide (2.5 mL) The morpholine (18.0 mg) was stirred at room temperature for 20 min. Next, N-tertiary butoxycarbonyl-4,4-difluoro-L-proline (26.8 mg) and 4-(4,6-dimethoxy-1,3,5-three chloride were added. -2-yl)-4-methyl The guanidine (32.0 mg) was stirred at room temperature for 3.5 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.47(9H,s), 1.53-1.64(4H,m),1.82-2.01(2H,m),2.39(3H,s),2.59-2.80(3H,m),3.13(3H,s),3.15-3.31(1H,br m),3.80-4.03(3H,m),4.68-4.84(1H,m),4.89(2H,s),6.75-6.85(3H,m),6.97(1H,d,J=8.5Hz),7.02-7.13(2H,m),7.41(1H,d,J=6.7Hz),7.55-7.69(3H,m),8.09-8.14(1H,m),8.22(1H,d,J=8.5Hz)。 1 H-NMR (400MHz, CDCl 3) δ: 1.47 (9H, s), 1.53-1.64 (4H, m), 1.82-2.01 (2H, m), 2.39 (3H, s), 2.59-2.80 (3H, m), 3.13 (3H, s), 3.15-3.31 (1H, br m), 3.80-4.03 (3H, m), 4.68-4.84 (1H, m), 4.89 (2H, s), 6.75-6.85 (3H , m), 6.97 (1H, d, J = 8.5 Hz), 7.02-7.13 (2H, m), 7.41 (1H, d, J = 6.7 Hz), 7.55-7.69 (3H, m), 8.09-8.14 ( 1H, m), 8.22 (1H, d, J = 8.5 Hz).

(139d)1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (139d) 1-{5-[4-(1-{[(2S)-4,4-Difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl -1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone hydrochloride

將實施例(139c)所獲得的化合物(55.0mg)溶解於二氯甲烷(3mL)，添加4N鹽酸二烷溶液(1mL)並於室溫攪拌2小時。減壓下濃縮反應液後，乾燥而獲得呈白色非晶形固體之標題化合物(45.0mg)。 The compound obtained in Example (139c) (55.0 mg) was dissolved in dichloromethane (3 mL), and 4N hydrochloric acid Alkane solution (1 mL) was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.43-1.76(5H,br m),1.83-2.09(2H,m),2.38(3H,s),2.43-2.59(1H,m),2.70-2.91(2H,m),3.12(3H,s),3.73-4.05(3H,br m),4.57-4.73(1H,m),4.88(2H,s),6.74-6.85(3H,m),6.97(1H,d,J=9.2Hz),7.04-7.15(2H,br m),7.40(1H,d,J=7.3Hz),7.55-7.69(3H,m),8.11(1H,d,J=7.9Hz),8.22(1H,d,J=9.2Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.76 (5H, br m), 1.83-2.09 (2H, m), 2.38 (3H, s), 2.43-2.59 (1H, m), 2.70-2.91 (2H,m), 3.12(3H,s),3.73-4.05(3H,br m),4.57-4.73(1H,m),4.88(2H,s),6.74-6.85(3H,m),6.97( 1H,d,J=9.2Hz), 7.04-7.15(2H,br m), 7.40(1H,d,J=7.3Hz),7.55-7.69(3H,m),8.11(1H,d,J=7.9 Hz), 8.22 (1H, d, J = 9.2 Hz).

MS(APCI)m/z：636(M+H)+。 MS (APCI) m/z: 636 (M+H) + .

(實施例140) (Embodiment 140)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonate) Mercapto)phenyl]ketone

於實施例(139b)所獲得的化合物(50.0mg)之二氯甲烷(3mL)溶液中添加4-甲基啉(20μL)，並於室溫攪拌20分鐘。添加乙酸酐(10.5μL)，於室溫攪拌2小時。減壓下將反應液濃縮，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色固體之標題化合物(50.0mg)。 4-methyl group was added to a solution of the compound obtained in Example (139b) (50.0 mg) in dichloromethane (3 mL) The morpholine (20 μL) was stirred at room temperature for 20 min. Acetic anhydride (10.5 μL) was added and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.48-1.69(2H,m),1.82-1.95(2H,m),2.13(3H,s),2.39(3H,s),2.57-2.75(2H,m),3.12(3H,s),3.16-3.24(1H,m),3.88-3.97(1H,br m),4.73-4.83(1H,br m),4.88(2H,s),6.75-6.85(3H,m),6.97(1H,d,J=9.2Hz),7.09(2H,d,J=8.5Hz),7.40(1H,d,J=7.9Hz),7.55-7.69(3H,m),8.11(1H,d,J=7.9Hz),8.21(1H,d,J=9.2Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.48-1.69 (2H, m), 1.82-1.95 (2H, m), 2.13 (3H, s), 2.39 (3H, s), 2.57-2.75 (2H, m), 3.12 (3H, s), 3.16-3.24 (1H, m), 3.88-3.97 (1H, br m), 4.73-4.83 (1H, br m), 4.88 (2H, s), 6.75-6.85 ( 3H, m), 6.97 (1H, d, J = 9.2 Hz), 7.09 (2H, d, J = 8.5 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.55-7.69 (3H, m), 8.11 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 9.2 Hz).

MS(APCI)m/z 545(M+H)+。 MS (APCI) m/z 545 (M+H) + .

(實施例141)：於實施例(141c)合成 (Example 141): Synthesis in Example (141c)

1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2-[2 -(methylsulfonyl)phenyl]ethanone

(141a)4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (141a) 4-{2-Methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-1H-indol-5-yl) Oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(8a)所獲得的化合物(3.50g)之二氯甲烷(50mL)溶液中添加2,3-二氯-5,6-二氰基-1,4-苯醌(1.95g)並加熱回流3小時。添加二氯甲烷(25mL)並攪拌5分鐘後，濾去不溶物而將反應液減壓下濃縮。將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，進一步將獲得的固體以甲醇洗淨後，藉由濾取而獲得呈白色固體之標題化合物(3.10g)。 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.95 g) was added to a solution of the compound (3.50 g) obtained from m. Heat to reflux for 3 hours. After adding dichloromethane (25 mL) and stirring for 5 minutes, the insoluble material was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc) elute

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.51-1.65(2H,m),1.67-1.79(2H,m),2.29(3H,s),2.39(3H,s),2.71-2.89(3H,m),3.12(3H,s),4.24(2H,br s),4.89(2H,s),6.64-6.70(2H,m),6.77(1H,d,J=3.7Hz),6.97(1H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),7.41(1H,d,J=7.9Hz),7.55-7.61(1H,m),7.62-7.68(2H,m),8.12(1H,d,J=7.9Hz),8.21(1H,d,J=8.5Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.67-1.79 (2H, m), 2.29 (3H, s), 2.39 (3H, s) , 2.71-2.89 (3H, m), 3.12 (3H, s), 4.24 (2H, br s), 4.89 (2H, s), 6.64-6.70 (2H, m), 6.77 (1H, d, J = 3.7 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.05 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.55 - 7.61 (1H, m), 7.62 7.68 (2H, m), 8.12 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz).

(141b)1-{4-甲基-5-[3-甲基-4-(哌啶-4-基)苯氧基]-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮鹽酸鹽 (141b) 1-{4-methyl-5-[3-methyl-4-(piperidin-4-yl)phenoxy]-1H-indol-1-yl}-2-[2-( Methylsulfonyl)phenyl]ethanone hydrochloride

於實施例(141a)所獲得的化合物(3.40g)之二氯甲烷(30mL)溶液中添加4N鹽酸二烷溶液(20mL)，並於室溫攪拌4小時。減壓下餾除溶媒，藉由乾燥而獲得標題化合物(3.30g)。 4N hydrochloric acid was added to a solution of the compound (3.40 g) obtained in Example (141a) in dichloromethane (30 mL) Alkane solution (20 mL) was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and the title compound (3.

MS(APCI)m/z：517(M+H)+。 MS (APCI) m/z: 517 (M+H) + .

(141c)1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 (141c) 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2 -[2-(methylsulfonyl)phenyl]ethanone

於實施例(141b)所獲得的化合物(3.10g)之二氯甲烷(50mL)溶液中添加4-甲基啉(1.2mL)，並於室溫攪拌 30分鐘。添加乙酸酐(0.640mL)，並於室溫攪拌4小時。減壓下將反應液濃縮，將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化後，藉由以乙醇洗淨而獲得呈白色固體之標題化合物(2.50g)。 4-methyl group was added to a solution of the compound (3.10 g) obtained in Example (141b) in dichloromethane (50 mL) The morpholine (1.2 mL) was stirred at room temperature for 30 min. Acetic anhydride (0.640 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.55-1.61(2H,m),1.74-1.86(2H,m),2.13(3H,s),2.29(3H,s),2.39(3H,s),2.57-2.67(1H,m),2.83-2.93(1H,m),3.13(3H,s),3.15-3.22(1H,m),3.94(1H,d,J=12.8Hz),4.79(1H,d,J=12.8Hz),4.88(2H,s),6.64-6.71(2H,m),6.75-6.79(1H,m),6.95-7.05(2H,m),7.40(1H,d,J=7.3Hz),7.55-7.61(1H,m),7.62-7.68(2H,m),8.09-8.14(1H,m),8.21(1H,d,J=8.5Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.61 (2H, m), 1.74-1.86 (2H, m), 2.13 (3H, s), 2.29 (3H, s), 2.39 (3H, s) , 2.57-2.67(1H,m),2.83-2.93(1H,m),3.13(3H,s),3.15-3.22(1H,m),3.94(1H,d,J=12.8Hz),4.79(1H ,d,J=12.8Hz),4.88(2H,s),6.64-6.71(2H,m),6.75-6.79(1H,m),6.95-7.05(2H,m),7.40(1H,d,J = 7.3 Hz), 7.55-7.61 (1H, m), 7.62-7.68 (2H, m), 8.09-8.14 (1H, m), 8.21 (1H, d, J = 8.5 Hz).

MS(APCI)m/z：559(M+H)+。 MS (APCI) m/z: 559 (M+H) + .

(實施例142)：於實施例(142c)合成 (Example 142): Synthesis in Example (142c)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(ethyl sulfonate) Mercapto)phenyl]ketone

(142a)4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (142a) 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethenyl}-4-methyl-1H-indol-5-yl)oxy]phenyl } piperidine-1-carboxylic acid tert-butyl butyl ester

分5次每隔1小時添加2,3-二氯-5,6-二氰基-1,4-苯醌(365mg)於實施例(2c)所獲得的化合物(400mg)之二氯甲烷(15mL)溶液中，並加熱回流5小時。放冷後，添加二氯甲烷，濾除不溶物並將反應液減壓下濃縮。將獲得的 殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，進一步將獲得的固體以甲醇洗淨後，藉由濾取而獲得呈白色固體之標題化合物(110mg)。 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (365 mg) of the compound obtained in Example (2c) (400 mg) m. 15 mL) of the solution and heated to reflux for 5 hours. After allowing to cool, dichloromethane was added, the insoluble material was filtered off, and the mixture was concentrated under reduced pressure. Will be obtained The residue was purified by EtOAc EtOAc EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.29(3H,t,J=7.3Hz),1.47(9H,s),1.51-1.64(2H,m),1.75-1.85(2H,m),2.39(3H,s),2.54-2.65(1H,br m),2.71-2.85(2H,br m),3.20(2H,q,J=7.3Hz),4.23(2H,br s),4.89(2H,s),6.73-6.83(3H,m),6.98(1H,d,J=8.5Hz),7.10(2H,d,J=8.5Hz),7.43(1H,d,J=7.9Hz),7.56(1H,t,J=7.9Hz),7.62-7.68(2H,m),8.07(1H,d,J=7.9Hz),8.21(1H,d,J=8.5Hz)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.29 (3H, t, J = 7.3 Hz), 1.47 (9H, s), 1.51-1.64 (2H, m), 1.75-1.85 (2H, m), 2.39 (3H, s), 2.54-2.65 (1H, br m), 2.71-2.85 (2H, br m), 3.20 (2H, q, J = 7.3 Hz), 4.23 (2H, br s), 4.89 (2H, s), 6.73-6.83 (3H, m), 6.98 (1H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.56 ( 1H, t, J = 7.9 Hz), 7.62 - 7.68 (2H, m), 8.07 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5 Hz).

(142b)2-[2-(乙基磺醯基)苯基]-1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-1H-吲哚-1-基}乙酮鹽酸鹽 (142b) 2-[2-(ethylsulfonyl)phenyl]-1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-1H-indole- 1-keto-ethanone hydrochloride

將實施例(142a)所獲得的化合物(110mg)溶解於二氯甲烷(5mL)，將4N鹽酸二烷溶液(2mL)於室溫攪拌3小時。減壓下餾除溶媒，藉由乾燥而獲得標題化合物(100mg)。 The compound obtained in Example (142a) (110 mg) was dissolved in dichloromethane (5 mL), 4N hydrochloric acid The alkane solution (2 mL) was stirred at room temperature for 3 h. The solvent was distilled off under reduced pressure, and the title compound (100 mg) was obtained.

MS(APCI)m/z：517(M+H)+。 MS (APCI) m/z: 517 (M+H) + .

(142c)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮 (142c) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-( Ethylsulfonyl)phenyl]ethanone

將實施例(142b)所獲得的化合物(100mg)溶解於二氯甲烷(10mL)，添加4-甲基啉(0.040mL)並於室溫攪拌30分鐘。其次，添加乙酸酐(0.021mL)並進一步於室溫攪拌3小時。減壓下將反應液濃縮，藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈白色 固體之標題化合物(90.0mg)。 The compound obtained in Example (142b) (100 mg) was dissolved in dichloromethane (10 mL) The morpholine (0.040 mL) was stirred at room temperature for 30 min. Next, acetic anhydride (0.021 mL) was added and further stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.24-1.31(3H,m),1.52-1.65(2H,br m),1.82-1.93(2H,m),2.13(3H,s),2.39(3H,s),2.56-2.74(2H,m),3.10-3.24(3H,m),3.88-3.96(1H,m),4.74-4.81(1H,m),4.89(2H,s),6.74-6.84(3H,m),6.96-7.00(1H,m),7.06-7.11(2H,m),7.41-7.45(1H,m),7.53-7.59(1H,m),7.63-7.68(2H,m),8.05-8.09(1H,m),8.22(1H,d,J=9.2Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.24-1.31 (3H, m), 1.52-1.65 (2H, br m), 1.82-1.93 (2H, m), 2.13 (3H, s), 2.39 (3H) , s), 2.56-2.74 (2H, m), 3.10-3.24 (3H, m), 3.88-3.96 (1H, m), 4.74-4.81 (1H, m), 4.89 (2H, s), 6.74-6.84 (3H,m), 6.96-7.00(1H,m),7.06-7.11(2H,m),7.41-7.45(1H,m),7.53-7.59(1H,m),7.63-7.68(2H,m) , 8.05-8.09 (1H, m), 8.22 (1H, d, J = 9.2Hz).

MS(APCI)m/z：559(M+H)+。 MS (APCI) m/z: 559 (M+H) + .

(實施例143) (Example 143)

1-{5-[4-(1-{[(2S)-1-乙醯基-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮 1-{5-[4-(1-{[(2S)-1-Ethyl-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]- 4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone

於實施例(139d)所獲得的化合物(30.0mg)之二氯甲烷(2mL)溶液中添加4-甲基啉(9.81μL)，並於室溫攪拌20分鐘。其次，添加乙酸酐(5.06μL)，並於同溫度攪拌2小時。減壓下餾除溶媒，藉由將獲得的殘渣以矽膠管柱層析(乙酸乙酯/二氯甲烷)純化，而獲得呈白色固體之標題化合物(30.0mg)。 4-methyl group was added to a solution of the compound (30.0 mg) obtained in Example (139d) in dichloromethane (2 mL) The morpholine (9.81 μL) was stirred at room temperature for 20 min. Next, acetic anhydride (5.06 μL) was added and stirred at the same temperature for 2 hours. The solvent was evaporated under reduced pressure, and then evaporated, m.

1H-NMR(400MHz,CDCl3)δ：1.51-1.60(4H,m),1.82-2.02(2H,br m),2.10(3H,s),2.39(3H,s),2.40-2.53(1H,br m),2.60-2.79(2H,br m),3.13(3H,s), 3.14-3.39(1H,br m),3.88-4.09(2H,br m),4.66-4.76(1H,m),4.89(2H,s),5.05-5.14(1H,m),6.75-6.85(3H,m),6.97(1H,d,J=8.5Hz),7.06-7.15(2H,m),7.41(1H,d,J=6.7Hz),7.58(1H,t,J=7.6Hz),7.62-7.67(2H,m),8.09-8.14(1H,m),8.21(1H,d,J=9.2Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.60 (4H, m), 1.82-2.02 (2H, br m), 2.10 (3H, s), 2.39 (3H, s), 2.40-2.53 (1H) , br m), 2.60-2.79 (2H, br m), 3.13 (3H, s), 3.14-3.39 (1H, br m), 3.88-4.09 (2H, br m), 4.66-4.76 (1H, m) , 4.89 (2H, s), 5.05-5.14 (1H, m), 6.75-6.85 (3H, m), 6.97 (1H, d, J = 8.5 Hz), 7.06-7.15 (2H, m), 7.41 (1H) , d, J = 6.7 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.62 - 7.67 (2H, m), 8.09 - 8.14 (1H, m), 8.21 (1H, d, J = 9.2 Hz) .

MS(APCI)m/z：678(M+H)+。 MS (APCI) m/z: 678 (M+H) + .

(實施例144) (Example 144)

2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺 2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-吲哚-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide

於實施例(102b)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(3mL)溶液中添加氯化銨(54.5mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(97.7mg)、HOBt‧H2O(52.0mg)、N,N-二異丙基乙基胺(0.148mL)而於室溫攪拌。12小時後，反應液以矽膠管柱層析(甲醇/乙酸乙酯)純化，獲得呈白色固體之標題化合物(144mg)。 Ammonium chloride (54.5 mg), 1-ethyl-3-(3-dimethyl methoxide) was added to a solution of the compound (200 mg) obtained in the compound (102b) in N,N-dimethylformamide (3 mL) Aminopropyl carboxy) carboxy quinone hydrochloride (97.7 mg), HOBt ‧ H 2 O (52.0 mg), N,N-diisopropylethylamine (0.148 mL) was stirred at room temperature. After 12 hours, the title compound was crystalljjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.13(3H,s),2.23(3H,s),2.37-2.51(2H,m),3.12(3H,s),3.18-3.26(2H,m),3.82-3.88(1H,m),4.16-4.24(2H,m),4.25-4.33(2H,m),4.37(2H,s),4.65-4.69(1H,m),5.52-5.60(2H,m),6.62-6.66(1H,m),6.68-6.72(1H,m),6.76-6.81(1H,m),6.95-6.99(1H,m),7.01-7.17(1H,m),7.34-7.39(1H,m), 7.49-7.55(1H,m),7.59-7.65(1H,m),7.96-8.01(1H,m),8.05-8.10(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.23 (3H, s), 2.37-2.51 (2H, m), 3.12 (3H, s), 3.18-3.26 (2H, m) , 3.82-3.88 (1H, m), 4.16-4.24 (2H, m), 4.25-4.33 (2H, m), 4.37 (2H, s), 4.65-4.69 (1H, m), 5.52-5.60 (2H, m), 6.62-6.66 (1H, m), 6.68-6.72 (1H, m), 6.76-6.81 (1H, m), 6.95-6.99 (1H, m), 7.01-7.17 (1H, m), 7.34 7.39 (1H, m), 7.49-7.55 (1H, m), 7.59-7.65 (1H, m), 7.96-8.01 (1H, m), 8.05-8.10 (1H, m).

MS(APCI)m/z：588(M+H)+。 MS (APCI) m/z: 588 (M+H) + .

(實施例145)：於實施例(145e)合成 (Example 145): Synthesis in Example (145e)

1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2- [3-(methylsulfonyl)pyridin-2-yl]ethanone

(145a)[3-(甲基磺醯基)吡啶-2-基]丙二酸二乙酯 (145a) [3-(Methylsulfonyl)pyridin-2-yl]malonic acid diethyl ester

將2-氯-3-(甲基磺醯基)吡啶(0.300g)、碘化銅(I)(0.149g)、丙二酸二乙酯(0.476mL)、碳酸銫(1.53g)及吡啶甲酸(0.193g)懸浮於1,4-二烷(7.5mL)，並於100℃攪拌7小時。將反應液於室溫靜置整夜後，於100℃攪拌4小時。於反應液中添加飽和氯化銨水溶液而以乙酸乙酯提取後，將有機層以飽和食鹽水洗淨。使有機層以硫酸鈉乾燥，於減壓下濃縮後，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色油狀物之標題化合物(0.091g)。 2-Chloro-3-(methylsulfonyl)pyridine (0.300 g), copper (I) iodide (0.149 g), diethyl malonate (0.476 mL), cesium carbonate (1.53 g) and pyridine Formic acid (0.193g) is suspended in 1,4-two The alkane (7.5 mL) was stirred at 100 ° C for 7 hours. The reaction solution was allowed to stand at room temperature overnight, and then stirred at 100 ° C for 4 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with saturated brine. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.30(6H,t,J=7.3Hz),3.12(3H,s),4.30(4H,q,J=7.3Hz),5.85(1H,s),7.50-7.54(1H,m),8.32-8.36(1H,m),8.83-8.85(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.30 (6H, t, J = 7.3 Hz), 3.12 (3H, s), 4.30 (4H, q, J = 7.3 Hz), 5.85 (1H, s), 7.50-7.54 (1H, m), 8.32-8.36 (1H, m), 8.83-8.85 (1H, m).

(145b)[3-(甲基磺醯基)吡啶-2-基]乙酸 (145b) [3-(Methylsulfonyl)pyridin-2-yl]acetic acid

將實施例(145a)所獲得的化合物(0.0533g)溶解於甲醇(1.5mL)，添加2N氫氧化鈉水溶液(0.75mL)後，於50℃ 攪拌2小時30分鐘。反應液於室溫靜置整夜後，添加1N鹽酸使中和。將反應液以二氯甲烷/乙醇(19：1)混合溶液提取3次，有機層以硫酸鈉使乾燥。藉由減壓下濃縮有機層而獲得呈黃色油狀物之標題化合物(0.0322g)。 The compound obtained in Example (145a) (0.0533 g) was dissolved in methanol (1.5 mL), and 2N aqueous sodium hydroxide (0.75 mL) was added at 50 ° C Stir for 2 hours and 30 minutes. After the reaction solution was allowed to stand at room temperature overnight, 1N hydrochloric acid was added to neutralize. The reaction solution was extracted three times with a dichloromethane/ethanol (19:1) mixture, and the organic layer was dried over sodium sulfate. The title compound (0.0322 g) was obtained.

1H-NMR(400MHz,CDCl3)δ：3.20(3H,s),4.45(2H,s),7.47-7.53(1H,m),8.36-8.39(1H,m),8.79-8.82(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 3.20 (3H, s), 4.45 (2H, s), 7.47-7.53 (1H, m), 8.36-8.39 (1H, m), 8.79-8.82 (1H, m).

(145c)4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (145c) 4-{4-[(4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(1d)所獲得的化合物(300mg)之乙醇(3.5mL)、水(1.5mL)混合物中添加氫氧化鉀(1.67g)並於90℃攪拌1.5小時。冷卻至室溫後，添加水並以乙酸乙酯提取。有機層以水、碳酸氫鈉水、飽和食鹽水洗淨，以無水硫酸鈉乾燥後，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(124mg)。 Potassium hydroxide (1.67 g) was added to a mixture of the compound (300 mg) obtained in Example (1d. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate water and brine, dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.51-1.65(2H,m),1.75-1.84(2H,m),2.04-2.07(4H,m),2.51-2.63(1H,m),2.71-2.85(2H,m),2.96-3.03(2H,m),3.58-3.64(2H,m),4.15-4.32(2H,m),6.45-6.49(1H,m),6.65-6.70(1H,m),6.76-6.81(2H,m),7.04-7.10(2H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.75-1.84 (2H, m), 2.04-2.07 (4H, m), 2.51-2.63 ( 1H, m), 2.71-2.85 (2H, m), 2.96-3.03 (2H, m), 3.58-3.64 (2H, m), 4.15-4.32 (2H, m), 6.45-6.49 (1H, m), 6.65-6.70 (1H, m), 6.76-6.81 (2H, m), 7.04-7.10 (2H, m).

(145d)4-{4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (145d) 4-{4-[(4-Methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-dihydro-1H-indole -5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(145c)所獲得的化合物(124mg)之N,N-二甲基甲醯胺(2mL)溶液中添加實施例(145b)所獲得的化 合物(72.0mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(87.3mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(41.3mg)、N,N-二異丙基乙基胺(0.106mL)而於室溫攪拌。12小時後，反應液以矽膠管柱層析(乙酸乙酯/己烷)純化後，再以胺基矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈非晶形固體之標題化合物(118mg)。 The compound obtained in Example (145b) was added to a solution of the compound (124 mg) obtained in Example (145 g) in N,N-dimethylformamide (2 mL). Compound (72.0 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylimine hydrochloride (87.3 mg), 3H-1,2,3-triazolo[4 5-B]pyridin-3-ol (41.3 mg), N,N-diisopropylethylamine (0.106 mL) was stirred at room temperature. After 12 hours, the reaction mixture was purified by EtOAc EtOAc EtOAc EtOAc (118 mg).

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.51-1.65(2H,m),1.76-1.84(2H,m),2.13(3H,s),2.55-2.65(1H,m),2.71-2.85(2H,m),3.19-3.28(5H,m),4.15-4.38(4H,m),4.61(2H,s),6.74-6.84(3H,m),7.07-7.14(2H,m),7.45-7.50(1H,m),7.91-7.96(1H,m),8.34-8.39(1H,m),8.78-8.82(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.48 (9H, s), 1.51-1.65 (2H, m), 1.76-1.84 (2H, m), 2.13 (3H, s), 2.55-2.65 (1H, m), 2.71-2.85 (2H, m), 3.19-3.28 (5H, m), 4.15-4.38 (4H, m), 4.61 (2H, s), 6.74-6.84 (3H, m), 7.07-7.14 ( 2H, m), 7.45-7.50 (1H, m), 7.91-7.96 (1H, m), 8.34-8.39 (1H, m), 8.78-8.82 (1H, m).

(145e)1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (145e) 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-inden-1-yl} -2-[3-(methylsulfonyl)pyridin-2-yl]ethanone

於實施例(145d)所獲得的化合物(117mg)之二氯甲烷(1.5mL)溶液中添加4N鹽酸二烷溶液(1.5mL)而於室溫攪拌。3小時後，藉由減壓濃縮而獲得粗製之1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮二鹽酸鹽(115mg)。 4N hydrochloric acid was added to a solution of the compound (117 mg) obtained in Example (145d) in dichloromethane (1.5 mL) The alkane solution (1.5 mL) was stirred at room temperature. After 3 hours, the crude 1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H-indole was obtained by concentration under reduced pressure. 1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone dihydrochloride (115 mg).

於獲得的化合物(115mg)之二氯甲烷(4mL)、N,N-二異丙基乙基胺(0.121mL)溶液中添加乙酸酐(0.0282mL)而於室溫攪拌1小時。將反應液濃縮後，殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈白色非晶形固體之標題化合物(98.0mg)。 Acetic acid anhydride (0.0282 mL) was added to a solution of the obtained compound (115 mg) in dichloromethane (4 mL) and N,N-diisopropylethylamine (0.121 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.82-1.93(2H,m),2.11-2.15(6H,m),2.55-2.75(3H,m),3.10-3.28(7H,m),3.88-3.96(1H,m),4.31-4.38(2H,m),4.61(2H,s),4.73-4.82(1H,m),6.73-6.85(3H,m),7.06-7.12(2H,m),7.44-7.50(1H,m),7.92-7.96(1H,m),8.34-8.38(1H,m),8.78-8.81(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.82-1.93 (2H, m), 2.11-2.15 (6H, m), 2.55-2.75 (3H, m), 3.10-3.28 (7H, m), 3.88- 3.96 (1H, m), 4.31-4.38 (2H, m), 4.61 (2H, s), 4.73-4.82 (1H, m), 6.73-6.85 (3H, m), 7.06-7.12 (2H, m), 7.44-7.50(1H,m), 7.92-7.96(1H,m),8.34-8.38(1H,m),8.78-8.81(1H,m).

MS(APCI)m/z：548(M+H)+。 MS (APCI) m/z: 548 (M+H) + .

(實施例146)：於實施例(146c)合成 (Example 146): Synthesis in Example (146c)

1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2 ,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

(146a)1-[5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (146a) 1-[5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[ 3-(methylsulfonyl)pyridin-2-yl]ethanone

於實施例(24a)所獲得的化合物(683mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(6mL)而於室溫攪拌3小時。將反應液減壓濃縮後，使懸浮於乙酸乙酯，藉由濾取，獲得呈淡灰色固體之5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(519mg)。 4N hydrochloric acid was added to a solution of the compound (683 mg) obtained in Example (24a) in dichloromethane (3 mL) The alkane solution (6 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then evaporated to ethyl acetate, and evaporated to give 5-(4-bromo-2,5-dimethylphenoxy)-4-methyl- 2,3-Dihydro-1H-indole hydrochloride (519 mg).

於獲得的化合物(518mg)之二氯甲烷(8mL)、N,N-二甲基甲醯胺(3mL)之溶液中添加實施例(145b)所獲得的化合物(324mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(404mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇 (191mg)、N,N-二異丙基乙基胺(0.734mL)，而於室溫攪拌。12小時後，將反應液減壓濃縮，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(597mg)。 The compound obtained by the example (145b) (324 mg), 1-ethyl- was added to the solution of the obtained compound (518 mg) in dichloromethane (8 mL), N,N-dimethylformamide (3 mL). 3-(3-dimethylaminopropyl)carboxamide imine hydrochloride (404 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (191 mg), N,N-diisopropylethylamine (0.734 mL), and stirred at room temperature. After 12 hours, the reaction mixture was evaporated.

1H-NMR(500MHz,CDCl3)δ：2.13(3H,s),2.22-2.25(6H,m),3.19-3.28(5H,m),4.31-4.37(2H,m),4.61(2H,s),6.49(1H,s),6.60(1H,d,J=8.8Hz),7.36(1H,s),7.45-7.49(1H,m),7.89-7.93(1H,m),8.34-8.38(1H,m),8.78-8.81(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 2.13 (3H, s), 2.22 - 2.25 (6H, m), 3.19-3.28 (5H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 6.49 (1H, s), 6.60 (1H, d, J = 8.8 Hz), 7.36 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).

MS(APCI)m/z：530(M+H)+。 MS (APCI) m/z: 530 (M+H) + .

(146b)4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-甲酸三級丁酯 (146b) 4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3 -Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl acrylate

將實施例(146a)所獲得的化合物(565mg)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-甲酸三級丁酯(396mg)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(87.1mg)、碳酸鈉(226mg)、二甲氧基乙烷(8mL)、水(4mL)之混合物於微波照射下，於120℃攪拌30分鐘。冷卻至室溫後，添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨後，以無水硫酸鈉乾燥，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈橙色非晶形固體之標題化合物(672mg)。 The compound (565 mg) obtained in Example (146a), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- Dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester (396 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex ( A mixture of 87.1 mg), sodium carbonate (226 mg), dimethoxyethane (8 mL) and water (4 mL) was stirred at 120 ° C for 30 minutes under microwave irradiation. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.50(9H,s),2.11-2.19(6H,m),2.23(3H,s),2.27-2.37(2H,m), 3.20-3.28(5H,m),3.57-3.64(2H,m),3.98-4.05(2H,m),4.30-4.37(2H,m),4.61(2H,s),5.47-5.57(1H,m),6.45(1H,s),6.59-6.64(1H,m),6.93(1H,s),7.44-7.50(1H,m),7.88-7.93(1H,m),8.33-8.38(1H,m),8.77-8.81(1H,m)。 1 H-NMR (400MHz, CDCl 3) δ: 1.50 (9H, s), 2.11-2.19 (6H, m), 2.23 (3H, s), 2.27-2.37 (2H, m), 3.20-3.28 (5H, m), 3.57-3.64 (2H, m), 3.98-4.05 (2H, m), 4.30-4.37 (2H, m), 4.61 (2H, s), 5.47-5.57 (1H, m), 6.45 (1H, s), 6.59-6.64 (1H, m), 6.93 (1H, s), 7.44-7.50 (1H, m), 7.88-7.93 (1H, m), 8.33-8.38 (1H, m), 8.77-8.81 ( 1H, m).

(146c)1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (146c) 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl Base-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(146b)所獲得的化合物(672mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(6mL)而於室溫攪拌4小時。添加乙酸乙酯而懸浮後，藉由濾取，獲得呈白色固體之1-{5-[2,5-二甲基-4-(1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮二鹽酸鹽(635mg)。 4N hydrochloric acid was added to a solution of the compound (672 mg) obtained in Example (146b) in dichloromethane (3 mL) The alkane solution (6 mL) was stirred at room temperature for 4 hours. After ethyl acetate was added and suspended, it was obtained by filtration to give 1-{5-[2,5-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl) as a white solid. Phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone dihalide Acid salt (635 mg).

於獲得的化合物(335mg)之二氯甲烷(6mL)、N,N-二異丙基胺(0.386mL)溶液中添加乙酸酐(0.0786mL)而於室溫攪拌2小時。將反應液減壓濃縮後，殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈白色固體之標題化合物(281mg)。 Acetic acid anhydride (0.0786 mL) was added to a solution of the obtained compound (335 mg) in methylene chloride (6 mL) and N,N-diisopropylamine (0.386 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced vacuo.

1H-NMR(500MHz,CDCl3)δ：2.12-2.18(9H,m),2.23(3H,s),2.32-2.42(2H,m),3.21-3.28(5H,m),3.61-3.66(1H,m),3.76-3.82(1H,m),4.06-4.11(1H,m),4.17-4.22(1H,m),4.31-4.37(2H,m),4.61(2H,s),5.51-5.61(1H,m),6.45(1H,s),6.59-6.64(1H,m),6.92(1H,s),7.45-7.49(1H,m),7.89-7.93(1H,m), 8.34-8.38(1H,m),8.77-8.82(1H,m). 1 H-NMR (500 MHz, CDCl 3 ) δ: 2.12-2.18 (9H, m), 2.23 (3H, s), 2.32-2.42 (2H, m), 3.21-3.28 (5H, m), 3.61-3.66 ( 1H, m), 3.76-3.82 (1H, m), 4.06-4.11 (1H, m), 4.17-4.22 (1H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 5.51- 5.61 (1H, m), 6.45 (1H, s), 6.59-6.64 (1H, m), 6.92 (1H, s), 7.45-7.49 (1H, m), 7.89-7.93 (1H, m), 8.34- 8.38 (1H, m), 8.77-8.82 (1H, m).

MS(APCI)m/z：574(M+H)+。 MS (APCI) m/z: 574 (M+H) + .

(實施例147)：於實施例(147d)合成 (Example 147): Synthesis in Example (147d)

1-{5-[4-(1-乙醯基哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-Ethylpiperidin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H-indole -1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone

(147a)1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮 (147a) 1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H) Ethyl

於4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,6-四氫吡啶鹽酸鹽(1.00g)、二氯甲烷(15mL)、N,N-二異丙基乙基胺(1.06mL)之混合物中添加乙酸酐(0.462mL)而於室溫攪拌。2小時後，減壓濃縮，殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(485mg)。 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.00 g To a mixture of dichloromethane (15 mL) and N,N-diisopropylethylamine (1.06 mL), acetic anhydride (0.462 mL) was added and stirred at room temperature. After 2 hours, the residue was evaporated.

1H-NMR(400MHz,CDCl3)δ：1.27(12H,s),2.07-2.14(3H,m),2.21-2.32(2H,m),3.44-3.49(1H,m),3.60-3.65(1H,m),3.98-4.02(1H,m),4.10-4.14(1H,m),6.40-6.56(1H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.27 (12H, s), 2.07-2.14 (3H, m), 2.21-2.32 (2H, m), 3.44-3.49 (1H, m), 3.60-3.65 ( 1H, m), 3.98-4.02 (1H, m), 4.10-4.14 (1H, m), 6.40-6.56 (1H, m).

(147b)5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (147b) 5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2 , 3-dihydro-1H-indole-1-carboxylic acid tertiary butyl ester

將實施例(147a)所獲得的化合物(200mg)、實施例(24a)所獲得的化合物(362mg)、[1,1’-雙(二苯基膦基)二 茂鐵]二氯化鈀(II)二氯甲烷錯合物(65.0mg)、碳酸鈉(169mg)、二甲氧基乙烷(8mL)、水(4mL)之混合物於微波照射下，於120℃攪拌30分鐘。冷卻至室溫後，添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨後，以無水硫酸鈉乾燥，過濾、減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈白色固體之標題化合物(170mg)。 The compound obtained in Example (147a) (200 mg), the compound obtained in Example (24a) (362 mg), [1,1'-bis(diphenylphosphino) a mixture of ferrocene]palladium(II) chloride complex (65.0 mg), sodium carbonate (169 mg), dimethoxyethane (8 mL), water (4 mL) under microwave irradiation at 120 Stir at °C for 30 minutes. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by EtOAcjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.51-1.61(9H,m),2.07-2.19(9H,m),2.26(3H,s),2.31-2.43(2H,m),3.00-3.08(2H,m),3.61-3.66(1H,m),3.76-3.82(1H,m),3.97-4.11(3H,m),4.17-4.22(1H,m),5.51-5.61(1H,m),6.35-6.45(1H,m),6.59-6.74(1H,m),6.92(1H,s),7.56-7.74(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51-1.61 (9H, m), 2.07-2.19 (9H, m), 2.26 (3H, s), 2.31-2.43 (2H, m), 3.00-3.08 ( 2H, m), 3.61-3.66 (1H, m), 3.76-3.82 (1H, m), 3.97-4.11 (3H, m), 4.17-4.22 (1H, m), 5.51-5.61 (1H, m), 6.35-6.45 (1H, m), 6.59-6.74 (1H, m), 6.92 (1H, s), 7.56-7.74 (1H, m).

(147c)5-[4-(1-乙醯基哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-甲酸三級丁酯 (147c) 5-[4-(1-Ethylpiperidin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H-indole 1-carboxylic acid tert-butyl butyl ester

於實施例(147b)所獲得的化合物(165mg)之二氯甲烷(2mL)、甲醇(3mL)溶液中添加10%鈀碳(30.0mg)而於氫氣環境下於室溫攪拌。10小時後，矽藻土過濾，並減壓濃縮。殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化，獲得呈無色油狀物之標題化合物(124mg)。 To a solution of the compound (165 mg) obtained from m. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m After 10 hours, the celite was filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.50-1.69(11H,m),1.74-1.87(2H,m),2.10(3H,s),2.15(3H,s),2.20(3H,s),2.25(3H,s),2.56-2.67(1H,m),2.80-2.91(1H,m),2.99-3.08(2H,m),3.12-3.22(1H,m),3.90-4.09(3H,m),4.76-4.84(1H,m),6.34-6.48(1H,m),6.52-6.73(1H,m), 6.96(1H,s),7.61-7.64(1H,m)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.69 (11H, m), 1.74-1.87 (2H, m), 2.10 (3H, s), 2.15 (3H, s), 2.20 (3H, s) , 2.25 (3H, s), 2.56-2.67 (1H, m), 2.80-2.91 (1H, m), 2.99-3.08 (2H, m), 3.12-3.22 (1H, m), 3.90-4.09 (3H, m), 4.76-4.84 (1H, m), 6.34-6.48 (1H, m), 6.52-6.73 (1H, m), 6.96 (1H, s), 7.61-7.64 (1H, m).

(147d)1-{5-[4-(1-乙醯基哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (147d) 1-{5-[4-(1-Ethylpiperidin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H -吲哚-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone

於實施例(147c)所獲得的化合物(124mg)之二氯甲烷(1mL)溶液中添加4N鹽酸二烷溶液(2mL)而於室溫攪拌。3小時後，添加乙酸乙酯而使懸浮，藉由濾取，獲得1-(4-{2,5-二甲基-4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮鹽酸鹽(102mg)。 4N hydrochloric acid was added to a solution of the compound (124 mg) obtained in Example (147c) in dichloromethane (1 mL) The alkane solution (2 mL) was stirred at room temperature. After 3 hours, ethyl acetate was added to suspend, and by filtration, 1-(4-{2,5-dimethyl-4-[(4-methyl-2,3-dihydro-1H-) was obtained. Indole-5-yl)oxy]phenyl}piperidin-1-yl)ethanone hydrochloride (102 mg).

將獲得的化合物(102mg)、[3-(甲基磺醯基)吡啶-2-基]乙酸鈉(70.0mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(70.7mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(33.5mg)、N,N-二異丙基乙基胺(0.128mL)、N,N-二甲基甲醯胺(2mL)、二氯甲烷(2mL)之混合物於室溫攪拌。12小時後，將反應液減壓濃縮，殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈白色固體之標題化合物(83.0mg)。 The obtained compound (102 mg), sodium [3-(methylsulfonyl)pyridin-2-yl]acetate (70.0 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxylate Indoleamine hydrochloride (70.7 mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (33.5 mg), N,N-diisopropylethylamine (0.128 mL), a mixture of N,N-dimethylformamide (2 mL), dichloromethane (2 mL). After 12 hours, the reaction mixture was evaporated.

1H-NMR(500MHz,CDCl3)δ：1.55-1.68(2H,m),1.75-1.86(2H,m),2.14(3H,s),2.17(3H,s),2.21(3H,s),2.22(3H,s),2.57-2.66(1H,m),2.81-2.91(1H,m),3.12-3.28(6H,m),3.91-3.98(1H,m),4.31-4.37(2H,m),4.61(2H,s),4.76-4.84(1H,m),6.46(1H,s),6.55-6.59(1H,m),6.97(1H,s),7.45-7.50(1H,m),7.87-7.92(1H,m),8.34-8.38(1H,m),8.78-8.81(1H,m). 1 H-NMR (500MHz, CDCl 3 ) δ: 1.55-1.68 (2H, m), 1.75-1.86 (2H, m), 2.14 (3H, s), 2.17 (3H, s), 2.21 (3H, s) , 2.22 (3H, s), 2.57-2.66 (1H, m), 2.81-2.91 (1H, m), 3.12-3.28 (6H, m), 3.91-3.98 (1H, m), 4.31-4.37 (2H, m), 4.61 (2H, s), 4.76-4.84 (1H, m), 6.46 (1H, s), 6.55-6.59 (1H, m), 6.97 (1H, s), 7.45-7.50 (1H, m) , 7.87-7.92 (1H, m), 8.34-8.38 (1H, m), 8.78-8.81 (1H, m).

MS(APCI)m/z：576(M+H)+。 MS (APCI) m/z: 576 (M+H) + .

(實施例148)：於實施例(148c)合成 (Example 148): Synthesis in Example (148c)

1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[3-(methylsulfonate Mercapto)pyridin-2-yl]ethanone

(148a)4-{4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (148a) 4-{4-[(4-Methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

使實施例(1d)所獲得的化合物(500mg)溶解於乙醇(6mL)及水(2mL)，添加氫氧化鉀(464mg)。將反應液於90℃攪拌4小時後，冷卻至室溫，並將反應液以水稀釋。水層以二氯甲烷提取3次，合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒。將獲得的殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈無色非晶形固體之標題化合物(301mg)。 The compound (500 mg) obtained in Example (1d) was dissolved in ethanol (6 mL) and water (2 mL), and potassium hydroxide (464 mg) was added. After the reaction mixture was stirred at 90 ° C for 4 hours, it was cooled to room temperature, and the reaction mixture was diluted with water. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over sodium sulfate. The residue obtained was purified by EtOAcqqqqqqq

1H-NMR(400MHz,CDCl3)δ：1.48(9H,s),1.50-1.65(2H,m),1.77-1.82(2H,m),2.00-2.10(3H,m),2.53-2.63(1H,m),2.72-2.84(2H,m),2.99(2H,t,J=8.5Hz),3.61(2H,t,J=8.5Hz),4.14-4.30(2H,m),6.47(1H,d,J=8.5Hz),6.67(1H,d,J=8.5Hz),6.78(2H,d,J=8.5Hz),7.07(2H,d,J=8.5Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48 (9H, s), 1.50-1.65 (2H, m), 1.77-1.82 (2H, m), 2.00-2.10 (3H, m), 2.53-2.63 ( 1H, m), 2.72-2.84 (2H, m), 2.99 (2H, t, J = 8.5 Hz), 3.61 (2H, t, J = 8.5 Hz), 4.14 - 4.30 (2H, m), 6.47 (1H) , d, J = 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz).

(148b)4-{4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (148b) 4-{4-[(4-Methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3-dihydro-1H-indole -5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(148a)所獲得的化合物(150mg)及[3-(甲基磺醯基)吡啶-2-基]乙酸鈉鹽(105mg)之二甲基甲醯胺(5mL)溶液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(152mg)，並於室溫攪拌15小時。減壓下濃縮反應液，將殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(193mg)。 Adding chlorine to a solution of the compound (150 mg) obtained in Example (148a) and [3-(methylsulfonyl)pyridin-2-yl]acetate sodium salt (105 mg) in dimethylformamide (5 mL) 4-(4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl The guanidine (152 mg) was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.61-1.44(11H,m),1.76-1.83(2H,m),2.13(3H,s),2.55-2.64(1H,m),2.73-2.83(2H,m),3.20-3.28(5H,m),4.11-4.36(4H,m),4.61(2H,s),6.74-6.83(3H,m),7.10(2H,d,J=9.1Hz),7.47(1H,dd,J=7.9,4.9Hz),7.94(1H,d,J=9.1Hz),8.36(1H,dd,J=8.2,1.5Hz),8.80(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.61-1.44 (11H, m), 1.76-1.83 (2H, m), 2.13 (3H, s), 2.55-2.64 (1H, m), 2.73-2.83 ( 2H,m), 3.20-3.28(5H,m),4.11-4.36(4H,m),4.61(2H,s),6.74-6.83(3H,m),7.10(2H,d,J=9.1Hz) , 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 9.1 Hz), 8.36 (1H, dd, J = 8.2, 1.5 Hz), 8.80 (1H, dd, J = 4.9) , 1.8Hz).

MS(APCI)m/z：606(M+H)+。 MS (APCI) m/z: 606 (M+H) + .

(148c)1-(5-{4-[1-(1,4-二烷-2-基羰基)哌啶-4-基]苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (148c)1-(5-{4-[1-(1,4-di) Alkyl-2-ylcarbonyl)piperidin-4-yl]phenoxy}-4-methyl-2,3-dihydro-1H-indol-1-yl)-2-[3-(methylsulfonate Mercapto)pyridin-2-yl]ethanone

於實施例(148b)所獲得的化合物(60.0mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌。攪拌2小時後，藉由將反應液濃縮，獲得粗製之1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (60.0 mg) obtained in Example (148b) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H- Indole-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone hydrochloride.

於獲得的化合物之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0436mL)，並於室溫攪拌1小時15分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基 )-4-甲基啉鎓(41.1mg)及1,4-二烷-2-甲酸(26.2mg)，並於室溫攪拌20小時。減壓下濃縮反應液，殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(65.8mg)。 Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.0436 mL) was stirred at room temperature for 1 h and 15 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Porphyrin (41.1mg) and 1,4-two Alkyl-2-carboxylic acid (26.2 mg) was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.65-1.76(2H,m),1.95-1.84(2H,m),2.14(3H,s),2.59-2.77(2H,m),3.03-3.29(6H,m),3.65-3.97(6H,m),4.07-4.16(1H,m),4.28-4.38(3H,m),4.61(2H,s),4.67-4.75(1H,m),6.74-6.83(3H,m),7.07-7.12(2H,m),7.48(1H,dd,J=8.5,4.9Hz),7.94(1H,d,J=8.5Hz),8.34-8.38(1H,m),8.78-8.81(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.65-1.76 (2H, m), 1.95-1.84 (2H, m), 2.14 (3H, s), 2.59-2.77 (2H, m), 3.03-3.29 ( 6H,m), 3.65-3.97(6H,m),4.07-4.16(1H,m), 4.28-4.38(3H,m),4.61(2H,s),4.67-4.75(1H,m),6.74- 6.83(3H,m),7.07-7.12(2H,m), 7.48(1H,dd,J=8.5,4.9Hz), 7.94(1H,d,J=8.5Hz),8.34-8.38(1H,m) , 8.78-8.81 (1H, m).

MS(APCI)m/z：620(M+H)+。 MS (APCI) m/z: 620 (M+H) + .

(實施例149)：於實施例(149b)合成 (Example 149): Synthesis in Example (149b)

1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2 ,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

(149a)(2S)-4,4-二氟-2-[(4-{4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]吡咯啶-1-甲酸三級丁酯 (149a)(2S)-4,4-difluoro-2-[(4-{4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]) Tertyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

於實施例(148b)所獲得的化合物(60.0mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌。攪拌2小時後，藉由將反應液濃縮，獲得粗製之 1-{4-甲基-5-[4-(哌啶-4-基)苯氧基]-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮鹽酸鹽。 4N hydrochloric acid was added to a solution of the compound (60.0 mg) obtained in Example (148b) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 1-{4-methyl-5-[4-(piperidin-4-yl)phenoxy]-2,3-dihydro-1H- Indole-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone hydrochloride.

於獲得的化合物之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0436mL)，並於室溫攪拌2小時。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(41.1mg)及1-(三級丁基羰基)-4,4-二氟-L-脯胺酸(49.8mg)，並於室溫攪拌18小時。減壓下濃縮反應液，將殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈淡茶色非晶形固體之標題化合物(100mg)。 Add N-methyl to a solution of the obtained compound in N,N-dimethylformamide (5 mL) The morpholine (0.0436 mL) was stirred at room temperature for 2 h. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (41.1 mg) and 1-(tert-butylcarbonyl)-4,4-difluoro-L-proline (49.8 mg) were stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.41-1.52(11H,m),1.83-1.99(2H,m),2.13(3H,s),2.29-2.47(1H,m),2.57-2.79(4H,m),3.19-3.28(5H,m),3.81-4.00(4H,m),4.34(2H,t,J=8.5Hz),4.62(2H,s),4.68-4.84(1H,m),6.73-6.85(3H,m),7.04-7.14(2H,m),7.48(1H,dd,J=7.9,4.9Hz),7.94(1H,d,J=8.5Hz),8.36(1H,dd,J=7.9,1.8Hz),8.80(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.41-1.52 (11H, m), 1.83-1.99 (2H, m), 2.13 (3H, s), 2.29-2.47 (1H, m), 2.57-2.79 ( 4H, m), 3.19-3.28 (5H, m), 3.81-4.00 (4H, m), 4.34 (2H, t, J = 8.5 Hz), 4.62 (2H, s), 4.68-4.84 (1H, m) , 6.73-6.85 (3H, m), 7.04-7.14 (2H, m), 7.48 (1H, dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.36 (1H, dd , J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).

MS(APCI)m/z：739(M+H)+。 MS (APCI) m/z: 739 (M+H) + .

(149b)1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (149b) 1-{5-[4-(1-{[(2S)-4,4-Difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl Base-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(149a)所獲得的化合物(73.2mg)之二氯甲烷(2mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌。攪拌2小時45分鐘後，將反應液濃縮，於殘渣中添加飽和碳酸氫鈉水溶液。將獲得的混合溶液以二氯甲烷提取3次，將合併的有機層以硫酸鈉乾燥後，減壓下餾 除溶媒。將獲得的殘渣以NH管柱層析(二氯甲烷)純化，獲得呈無色非晶形固體之標題化合物(54.5mg)。 4N hydrochloric acid was added to a solution of the compound (73.2 mg) obtained in Example (149a) in dichloromethane (2 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 2 hours and 45 minutes, the reaction solution was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted three times with dichloromethane, and the combined organic layers were dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.57-1.68(2H,m),1.87-1.98(2H,m),2.13(3H,s),2.21-2.35(1H,m),2.46-2.60(1H,m),2.66-2.79(2H,m),3.06-3.29(7H,m),3.39-3.50(1H,m),3.84-3.92(1H,m),4.16-4.25(1H,m),4.34(2H,t,J=8.5Hz),4.61(2H,s),4.74-4.78(1H,m),6.74-6.87(3H,m),7.06-7.13(2H,m),7.48(1H,dd,J=7.9,4.9Hz),7.94(1H,d,J=8.5Hz),8.36(1H,dd,J=7.9,1.8Hz),8.80(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.57-1.68 (2H, m), 1.87-1.98 (2H, m), 2.13 (3H, s), 2.21-2.35 (1H, m), 2.46-2. 1H, m), 2.66-2.79 (2H, m), 3.06-3.29 (7H, m), 3.39-3.50 (1H, m), 3.84-3.92 (1H, m), 4.16-4.25 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.74 - 4.78 (1H, m), 6.74 - 6.87 (3H, m), 7.06 - 7.13 (2H, m), 7.48 (1H, Dd, J = 7.9, 4.9 Hz), 7.94 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.80 (1H, dd, J = 4.9, 1.8 Hz).

MS(APCI)m/z：639(M+H)+。 MS (APCI) m/z: 639 (M+H) + .

(實施例150) (Embodiment 150)

1-{5-[4-(1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(149b)所獲得的化合物(50.0mg)之甲醇(4mL)溶液中添加37%甲醛溶液(0.2mL)、7.5%鈀碳(50.0mg)及4N鹽酸二烷溶液(0.1mL)，並於氫氣環境下，於室溫攪拌13小時。藉由過濾去除觸媒後，減壓下濃縮濾液。於獲得的殘渣中添加飽和碳酸氫鈉水溶液，進行以二氯甲烷提取3次。將合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒，將獲得的殘渣以管柱層析(乙酸乙酯/二 氯甲烷→甲醇/乙酸乙酯)純化，獲得呈白色非晶形固體之標題化合物(10.0mg)。 37% formaldehyde solution (0.2 mL), 7.5% palladium carbon (50.0 mg) and 4N hydrochloric acid were added to a solution of the compound (50.0 mg) obtained in the compound (149b) in methanol (4 mL). A solution of the alkane (0.1 mL) was stirred at room temperature for 13 hr. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, and the solvent was evaporated to dryness, and the obtained residue was purified by column chromatography (ethyl acetate / dichloromethane / methanol / ethyl acetate) The title compound (10.0 mg).

MS(APCI)m/z：653(M+H)+。 MS (APCI) m/z: 653 (M+H) + .

(實施例151)於實施例(151d)合成 (Example 151) Synthesis in Example (151d)

1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-4-基]乙酮 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-吲哚-1-yl}-2-[3-(methylsulfonyl)pyridin-4-yl]ethanone

(151a)[3-(甲基磺醯基)吡啶-4-基]乙酸乙酯 (151a) [3-(Methylsulfonyl)pyridin-4-yl]ethyl acetate

於(3-溴吡啶-4-基)乙酸乙酯(CAS編號51054-99-0)(300mg)之二甲基亞碸(2mL)溶液中添加甲烷亞磺酸鈉(Sodium methanesulphinate)(251mg)、L-脯胺酸鈉鹽(337mg)、碘化銅(234mg)而於微波照射下於110℃攪拌1小時。冷卻至室溫後，藉由將反應液直接使用矽膠管柱層析而純化，獲得呈白色固體之標題化合物(66.0mg)。 Sodium methanesulphinate (251 mg) was added to a solution of (3-bromopyridin-4-yl)acetate (CAS number 51054-99-0) (300 mg) in dimethyl sulfoxide (2 mL). L-guanidine sodium salt (337 mg) and copper iodide (234 mg) were stirred at 110 ° C for 1 hour under microwave irradiation. After cooling to room temperature, the title compound (66.0 mg)

1H-NMR(400MHz,CDCl3)δ：1.28-1.33(3H,m),3.20(3H,s),4.18-4.25(4H,m),7.30-7.34(1H,m),8.77-8.81(1H,m),9.21(1H,s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.28-1.33 (3H, m), 3.20 (3H, s), 4.18-4.25 (4H, m), 7.30-7.34 (1H, m), 8.77-8.81 ( 1H, m), 9.21 (1H, s).

(151b)[3-(甲基磺醯基)吡啶-4-基]乙酸鈉 (151b) [3-(Methylsulfonyl)pyridin-4-yl]acetate sodium

於實施例(151a)所獲得的化合物(66.0mg)之1,4-二烷(2mL)溶液中添加1N氫氧化鈉水溶液(0.271mL)而於室溫攪拌。4小時後，藉由減壓濃縮而獲得粗製之[3-( 甲基磺醯基)吡啶-4-基]乙酸鈉(68.0mg)。 1,4-two of the compound (66.0 mg) obtained in Example (151a) A 1N aqueous solution of sodium hydroxide (0.271 mL) was added to a solution of hexane (2 mL) and stirred at room temperature. After 4 hours, the crude sodium [3-(methylsulfonyl)pyridin-4-yl]acetate (68.0 mg) was obtained.

(151c)1-[5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[3-(甲基磺醯基)吡啶-4-基]乙酮 (151c) 1-[5-(4-Bromophenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[3-(methylsulfonyl) Pyridin-4-yl]ethanone

於實施例(1a)所獲得的化合物(1.16g)中添加4N鹽酸二烷溶液(10mL)而於室溫攪拌3小時。減壓濃縮，使析出的固體懸浮於乙酸乙酯，藉由濾取而獲得5-(4-溴苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(911mg)。 4N hydrochloric acid was added to the compound (1.16 g) obtained in the example (1a) The alkane solution (10 mL) was stirred at room temperature for 3 hours. The organic layer was concentrated under reduced pressure, and the precipitated solid was suspended in ethyl acetate to give 5-(4-bromophenoxy)-4-methyl-2,3-dihydro-1H-indole hydrochloride. (911mg).

將獲得的化合物(97.7mg)、實施例(151b)所獲得的化合物(68.0mg)、1-乙基-3-(3-二甲基胺基丙基)羧醯亞胺鹽酸鹽(82.4mg)、3H-1,2,3-三唑并[4,5-b]吡啶-3-醇(39.0mg)、N,N-二異丙基乙基胺(0.150mL)、N,N-二甲基甲醯胺(2mL)之混合物於室溫攪拌。12小時後，反應液以矽膠管柱層析(甲醇/氯仿)純化，獲得呈淡黃色固體之標題化合物與4-甲基-3-(甲基磺醯基)吡啶之混合物(61.0mg)。 The obtained compound (97.7 mg), the compound obtained in the example (151b) (68.0 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboxyxine imine hydrochloride (82.4) Mg), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (39.0 mg), N,N-diisopropylethylamine (0.150 mL), N, N A mixture of dimethylformamide (2 mL) was stirred at room temperature. After 12 hours, the reaction mixture was purified mjjjjjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.10(3H,s),3.18-3.27(5H,m),4.26-4.31(2H,m),4.34(2H,s),6.73-6.80(3H,m),7.28-7.40(3H,m),7.93-7.96(1H,m),8.79-8.82(1H,m),9.20(1H,s)。 1 H-NMR (400MHz, CDCl 3 ) δ: 2.10 (3H, s), 3.18-3.27 (5H, m), 4.26-4.31 (2H, m), 4.34 (2H, s), 6.73-6.80 (3H, m), 7.28-7.40 (3H, m), 7.93-7.96 (1H, m), 8.79-8.82 (1H, m), 9.20 (1H, s).

(151d)1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-4-基]乙酮 (151d) 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]-4-methyl-2,3-dihydro -1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-4-yl]ethanone

將實施例(147a)所獲得的化合物(61.1mg)與實施例(151c)所獲得的化合物(61.0mg)、[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷錯合物(9.93mg)、碳酸鈉 (25.8mg)、二甲氧基乙烷(3mL)、水(1.5mL)之混合物於微波照射下，於120℃攪拌30分鐘。冷卻至室溫後，添加水而以乙酸乙酯提取。有機層以水及飽和食鹽水洗淨後，以無水硫酸鈉乾燥，過濾、減壓濃縮。殘渣以矽膠管柱層析(甲醇/氯仿)純化，獲得呈白色固體之標題化合物(27.0mg)。 The compound obtained in Example (147a) (61.1 mg) and the compound obtained in Example (151c) (61.0 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium (II) dichloromethane complex (9.93 mg), sodium carbonate A mixture of (25.8 mg), dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120 ° C for 30 minutes under microwave irradiation. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjj

1H-NMR(400MHz,CDCl3)δ：2.11-2.18(6H,m),2.47-2.60(2H,m),3.19(3H,s),3.20-3.28(2H,m),3.63-3.68(1H,m),3.78-3.84(1H,m),4.10-4.14(1H,m),4.20-4.25(1H,m),4.25-4.32(2H,m),4.34(2H,s),5.92-6.02(1H,m),6.77-6.87(3H,m),7.24-7.32(3H,m),7.92-7.97(1H,m),8.78-8.82(1H,m),9.20(1H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.11-2.18 (6H, m), 2.47-2.60 (2H, m), 3.19 (3H, s), 3.20-3.28 (2H, m), 3.63-3.68 ( 1H, m), 3.78-3.84 (1H, m), 4.10-4.14 (1H, m), 4.20-4.25 (1H, m), 4.25-4.32 (2H, m), 4.34 (2H, s), 5. 6.02 (1H, m), 6.77-6.87 (3H, m), 7.24-7.32 (3H, m), 7.92-7.97 (1H, m), 8.78-8.82 (1H, m), 9.20 (1H, s).

MS(APCI)m/z：546(M+H)+。 MS (APCI) m/z: 546 (M+H) + .

(實施例152) (Example 152)

1-{5-[2,5-二甲基-4-(1-{[(2S)-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[2,5-Dimethyl-4-(1-{[(2S)-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)phenoxy]- 4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(158e)所獲得的化合物(100mg)之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0725mL)，並於室溫攪拌40分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(68.4mg)及1-甲基-L-脯胺酸(42.6mg)，並於室溫攪拌2小時30分鐘。減壓 下濃縮反應液，殘渣以管柱層析(乙酸乙酯/二氯甲烷)純化，獲得黃色非晶形固體之標題化合物(49.2mg)。 N-methyl group was added to a solution of the compound (100 mg) obtained in Example (158e) in N,N-dimethylformamide (5 mL) The morpholine (0.0725 mL) was stirred at room temperature for 40 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (68.4 mg) and 1-methyl-L-proline (42.6 mg) were stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：2.00-1.75(5H,m),2.16-2.24(12H,m),2.35-2.42(3H,m),2.58-2.68(1H,m),2.81-2.93(1H,m),3.03-3.29(9H,m),4.20-4.38(3H,m),4.61(2H,s),4.80-4.90(1H,m),6.46(1H,s),6.57(1H,d,J=8.5Hz),6.94-6.99(1H,m),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.34-8.37(1H,m),8.79(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.00-1.75 (5H, m), 2.16-2.24 (12H, m), 2.35-2.42 (3H, m), 2.58-2.68 (1H, m), 2.81 2.93 (1H, m), 3.03-3.29 (9H, m), 4.20-4.38 (3H, m), 4.61 (2H, s), 4.80-4.90 (1H, m), 6.46 (1H, s), 6.57 ( 1H,d,J=8.5Hz), 6.94-6.99(1H,m), 7.47(1H,dd,J=7.9,4.9Hz), 7.89(1H,d,J=8.5Hz),8.34-8.37(1H , m), 8.79 (1H, dd, J = 4.9, 1.8 Hz).

MS(APCI)m/z：645(M+H)+。 MS (APCI) m/z: 645 (M+H) + .

(實施例153) (Example 153)

1-[5-(2,5-二甲基-4-{1-[(1-甲基-1H-咪唑-5-基)羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-[5-(2,5-Dimethyl-4-{1-[(1-methyl-1H-imidazol-5-yl)carbonyl]piperidin-4-yl}phenoxy)-4- Methyl-2,3-dihydro-1H-indol-1-yl]-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(158e)所獲得的化合物(70.0mg)之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0507mL)，並於室溫攪拌25分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(47.9mg)及1-甲基-1H-咪唑-5-甲酸(21.8mg)，並於室溫攪拌70分鐘。減壓下濃縮反應液，將殘渣以NH管柱層析(乙酸乙酯/二氯甲烷)純化，獲得呈無色非晶形固體之標題化合物(51.8mg)。 Add N-methyl to a solution of the compound (70.0 mg) obtained in Example (158e), N,N-dimethylformamide (5 mL) The morpholine (0.0507 mL) was stirred at room temperature for 25 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (47.9 mg) and 1-methyl-1H-imidazole-5-carboxylic acid (21.8 mg) were stirred at room temperature for 70 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.63-1.77(2H,m), 1.81-1.93(2H,m),2.13-2.30(10H,m),2.83-3.31(8H,m),3.84(3H,s),4.34(2H,t,J=8.5Hz),4.51-4.80(3H,m),6.46(1H,s),6.58(1H,d,J=8.5Hz),7.00(1H,s),7.25(1H,s),7.43-7.54(2H,m),7.89(1H,d,J=8.5Hz),8.32-8.38(1H,m),8.77-8.81(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.63-1.77 (2H, m), 1.81-1.93 (2H, m), 2.13-2.30 (10H, m), 2.83-3.31 (8H, m), 3.84 ( 3H, s), 4.34 (2H, t, J = 8.5 Hz), 4.51-4.80 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 8.5 Hz), 7.00 (1H, s ), 7.25 (1H, s), 7.43 - 7.54 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.32 - 8.38 (1H, m), 8.77 - 8.81 (1H, m).

MS(APCI)m/z：642(M+H)+。 MS (APCI) m/z: 642 (M+H) + .

(實施例154)：於實施例(154b)合成 (Example 154): Synthesis in Example (154b)

1-{5-[4-(1-{[(2S,4R)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S,4R)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)-2,5-dimethylphenoxy] -4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

(154a)(2S,4R)-2-[(4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基1]-4-氟吡咯啶-1-甲酸三級丁酯 (154a)(2S,4R)-2-[(4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-) Ethyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl 1]-4-fluoropyrrolidine-1-carboxylic acid Butyl ester

於實施例(158e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.145mL)，並於室溫攪拌20分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(137mg)及1-(三級丁基羰基)-4-氟-L-脯胺酸(115mg)，並於室溫攪拌3小時20分鐘。減壓下濃縮反應液，殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈無色非晶形固體之標題化合物(188mg)。 Add N-methyl to a solution of the compound (200 mg) obtained in Example (158e) in N,N-dimethylformamide (5 mL) The morpholine (0.145 mL) was stirred at room temperature for 20 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (137 mg) and 1-(tert-butylcarbonyl)-4-fluoro-L-proline (115 mg) were stirred at room temperature for 3 hours and 20 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

MS(APCI)m/z：749(M+H)+。 MS (APCI) m/z: 749 (M+H) + .

(154b)1-{5-[4-(1-{[(2S,4R)-4-氟吡咯啶-2-基]羰基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (154b) 1-{5-[4-(1-{[(2S,4R)-4-fluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)-2,5-dimethylbenzene Oxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(154a)所獲得的化合物(188mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(2mL)，並於室溫攪拌。攪拌45分鐘後，將反應液濃縮，於殘渣中添加飽和碳酸氫鈉水溶液。將獲得的混合溶液以二氯甲烷提取3次，將合併的有機層以硫酸鈉乾燥後，藉由減壓下餾除溶媒，獲得呈淡黃色固體之標題化合物(138mg)。 4N Hydrochloric acid was added to a solution of the compound (188 mg) obtained in Example (154a) in dichloromethane (3 mL) A solution of the alkane (2 mL) was stirred at room temperature. After stirring for 45 minutes, the reaction solution was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted with methylene chloride (3 ml), and the combined organic layer was dried over sodium sulfate.

1H-NMR(400MHz,CDCl3)δ：1.54-1.97(4H,m),2.13-2.27(10H,m),2.32-2.45(1H,m),2.65-2.76(1H,m),2.85-2.95(1H,m),3.11-3.29(7H,m),3.33-3.49(1H,m),4.01-4.09(1H,m),4.19-4.27(1H,m),4.34(2H,t,J=8.5Hz),4.61(2H,s),4.76-4.83(1H,m),5.20-5.40(1H,m),6.47-6.44(1H,m),6.58(1H,d,J=8.5Hz),6.96(1H,d,J=8.5Hz),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.34-8.38(1H,m),8.79(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400MHz, CDCl 3) δ: 1.54-1.97 (4H, m), 2.13-2.27 (10H, m), 2.32-2.45 (1H, m), 2.65-2.76 (1H, m), 2.85- 2.95 (1H, m), 3.11-3.29 (7H, m), 3.33-3.49 (1H, m), 4.01-4.09 (1H, m), 4.19-4.27 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.76-4.83 (1H, m), 5.20-5.40 (1H, m), 6.47-6.44 (1H, m), 6.58 (1H, d, J = 8.5 Hz) , 6.96 (1H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34 - 8.38 (1H, m), 8.79 ( 1H, dd, J = 4.9, 1.8 Hz).

MS(APCI)m/z：649(M+H)+。 MS (APCI) m/z: 649 (M+H) + .

(實施例155) (Example 155)

1-{5-[4-(1-{[(2S,4R)-4-氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)-2,5-dimethyl Phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(154b)所獲得的化合物(129mg)之甲醇(6mL)溶液中添加37%甲醛溶液(0.2mL)、7.5%鈀碳(50.0mg)及4N鹽酸二烷溶液(0.2mL)，氫氣環境下，於室溫攪拌19小時。藉由過濾而去除觸媒後，減壓下濃縮濾液。於獲得的殘渣中添加飽和碳酸氫鈉水溶液，並以二氯甲烷進行3次提取。將合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒，將獲得的殘渣以管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈淡黃色非晶形固體之標題化合物(14.3mg)。 37% formaldehyde solution (0.2 mL), 7.5% palladium carbon (50.0 mg) and 4N hydrochloric acid were added to a solution of the compound (129 mg) in methanol (6 mL). The alkane solution (0.2 mL) was stirred at room temperature for 19 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extracted three times with dichloromethane. The combined organic layer was dried over sodium sulfate, and the solvent was evaporated to dryness, and the obtained residue was purified by column chromatography (ethyl acetate / dichloromethane / methanol / ethyl acetate) The title compound (14.3 mg) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.77-1.91(4H,m),2.09-2.30(10H,m),2.41-2.49(3H,m),2.58-2.71(2H,m),2.83-2.95(1H,m),3.06-3.28(7H,m),3.59-3.72(2H,m),4.16-4.24(1H,m),4.34(2H,t,J=8.5Hz),4.61(2H,s),4.78-4.88(1H,m),5.16-5.36(1H,m),6.42-6.50(1H,m),6.58(1H,d,J=8.5Hz),6.92-7.00(1H,m),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.36(1H,dd,J=8.2,1.8Hz),8.79(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.77-1.91 (4H, m), 2.09-2.30 (10H, m), 2.41-2.49 (3H, m), 2.58-2.71 (2H, m), 2.83 2.95 (1H, m), 3.06-3.28 (7H, m), 3.59-3.72 (2H, m), 4.16-4.24 (1H, m), 4.34 (2H, t, J = 8.5 Hz), 4.61 (2H, s), 4.78-4.88 (1H, m), 5.16-5.36 (1H, m), 6.42-6.50 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.92-7.00 (1H, m) , 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 8.2, 1.8 Hz), 8.79 (1H, dd, J = 4.9) , 1.8Hz).

MS(APCI)m/z：663(M+H)+。 MS (APCI) m/z: 663 (M+H) + .

(實施例156)：於實施例(156b)合成 (Example 156): Synthesis in Example (156b)

1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoropyrrolidin-2-yl]carbonyl}piperidin-4-yl)-2,5-dimethylphenoxy ]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone

(156a)(2S)-2-[(4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)羰基]-4,4-二氟吡咯啶-1-甲酸三級丁酯 (156a) (2S)-2-[(4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]] Ethyl}},3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)carbonyl]-4,4-difluoropyrrolidine-1-carboxylic acid Butyl ester

於實施例(158e)所獲得的化合物(200mg)之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.145mL)，並於室溫攪拌35分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(137mg)及1-(三級丁基羰基)-4,4-二氟-L-脯胺酸(99.4mg)，並於室溫攪拌15小時30分鐘。減壓下濃縮反應液，殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈淡黃色非晶形固體之標題化合物(236mg)。 Add N-methyl to a solution of the compound (200 mg) obtained in Example (158e) in N,N-dimethylformamide (5 mL) The morpholine (0.145 mL) was stirred at room temperature for 35 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (137 mg) and 1-(tert-butylcarbonyl)-4,4-difluoro-L-proline (99.4 mg) were stirred at room temperature for 15 h 30 min. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.41-1.62(11H,m),1.69-1.94(2H,m),2.14-2.25(9H,m),2.31-2.51(1H,m),2.62-2.95(3H,m),3.15-3.28(6H,m),3.84-3.99(3H,m),4.34(2H,t,J=8.2Hz),4.61(2H,s),4.73-4.97(2H,m),6.43-6.48(1H,m),6.58(1H,d,J=8.5Hz),6.86-7.05(1H,m),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.36(1H,dd,J=7.9,1.8Hz),8.79(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.41-1.62 (11H, m), 1.69-1.94 (2H, m), 2.14-2.25 (9H, m), 2.31-2.51 (1H, m), 2.62 2.95 (3H, m), 3.15-3.28 (6H, m), 3.84-3.99 (3H, m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.97 (2H, m), 6.43-6.48 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 6.86-7.05 (1H, m), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H) , d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).

MS(APCI)m/z：767(M+H)+。 MS (APCI) m/z: 767 (M+H) + .

(156b)1-{5-[4-(1-{[(2S)-4,4-二氟吡咯啶-2-基]羰 基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 (156b) 1-{5-[4-(1-{[(2S)-4,4-Difluoropyrrolidin-2-yl]carbonyl) }}piperidin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-( Methylsulfonyl)pyridin-2-yl]ethanone

於實施例(156a)所獲得的化合物(234mg)之二氯甲烷(3mL)溶液中添加4N鹽酸二烷溶液(3mL)，並於室溫攪拌。40分鐘攪拌後，將反應液濃縮，於殘渣中添加飽和碳酸氫鈉水溶液。將獲得的混合溶液以甲醇/二氯甲烷(5/95)提取3次，合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒。將獲得的殘渣以NH管柱層析(甲醇/二氯甲烷)純化，獲得呈淡黃色固體之標題化合物(179mg)。 4N hydrochloric acid was added to a solution of the compound (234 mg) obtained in Example (156a) in dichloromethane (3 mL) A solution of the alkane (3 mL) was stirred at room temperature. After stirring for 40 minutes, the reaction mixture was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The obtained mixed solution was extracted three times with methanol/dichloromethane (5/95), and the combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.60-1.71(2H,m),1.79-1.91(2H,m),2.12-2.37(10H,m),2.48-2.61(1H,m),2.66-2.76(1H,m),2.94-2.84(1H,m),3.06-3.28(7H,m),3.40-3.51(1H,m),3.83-3.94(1H,m),4.17-4.24(1H,m),4.34(2H,t,J=8.2Hz),4.61(2H,s),4.75-4.83(1H,m),6.42-6.47(1H,m),6.58(1H,d,J=8.5Hz),6.95(1H,s),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.34-8.37(1H,m),8.79(1H,dd,J=4.9,1.8Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60-1.71 (2H, m), 1.79-1.91 (2H, m), 2.12-2.37 (10H, m), 2.48-2.61 (1H, m), 2.66- 2.76 (1H, m), 2.94-2.84 (1H, m), 3.06-3.28 (7H, m), 3.40-3.51 (1H, m), 3.83-3.94 (1H, m), 4.17-4.24 (1H, m ), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.75-4.83 (1H, m), 6.42-6.47 (1H, m), 6.58 (1H, d, J = 8.5 Hz) , 6.95 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.34 - 8.37 (1H, m), 8.79 (1H, dd, J =4.9, 1.8Hz).

MS(APCI)m/z：667(M+H)+。 MS (APCI) m/z: 667 (M+H) + .

(實施例157) (Example 157)

1-{5-[4-(1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)-2,5-di Methylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[3-(methylsulphonyl)pyridin-2-yl]ethanone

於實施例(156b)所獲得的化合物(179mg)之甲醇(7mL)溶液中添加37%甲醛溶液(0.2mL)、7.5%鈀碳(50.0mg)及4N鹽酸二烷溶液(0.4mL)，氫氣環境下，於室溫攪拌12小時。藉由過濾而去除觸媒後，減壓下濃縮濾液。於獲得的殘渣中添加飽和碳酸氫鈉水溶液，並以二氯甲烷進行3次提取。將合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒，藉由將獲得的殘渣以管柱層析(乙酸乙酯/己烷→甲醇/乙酸乙酯)純化，獲得呈淡黃色非晶形固體之標題化合物(91.9mg)。 37% formaldehyde solution (0.2 mL), 7.5% palladium carbon (50.0 mg) and 4N hydrochloric acid were added to a solution of the compound (179 mg) in methanol (7 mL). The alkane solution (0.4 mL) was stirred at room temperature for 12 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and extracted three times with dichloromethane. After the combined organic layer was dried over sodium sulfate, the solvent was evaporated, and the residue obtained was purified by column chromatography (ethyl acetate /hexanes The title compound (91.9 mg) was obtained as crystals.

1H-NMR(400MHz,CDCl3)δ：1.68-1.57(2H,m),1.79-1.90(2H,m),2.11-2.27(9H,m),2.39-2.47(3H,m),2.47-2.59(2H,m),2.63-2.80(2H,m),2.84-2.94(1H,m),3.05-3.19(1H,m),3.21-3.28(5H,m),3.50-3.62(2H,m),4.19-4.38(3H,m),4.61(2H,s),4.80-4.87(1H,m),6.42-6.49(1H,m),6.57(1H,d,J=8.5Hz),6.95(1H,s),7.45-7.50(1H,m),7.89(1H,d,J=8.5Hz),8.34-8.39(1H,m),8.78-8.81(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.68-1.57 (2H, m), 1.79-1.90 (2H, m), 2.11-2.27 (9H, m), 2.39-2.47 (3H, m), 2.47- 2.59(2H,m), 2.63-2.80(2H,m),2.84-2.94(1H,m),3.05-3.19(1H,m),3.21-3.28(5H,m),3.50-3.62(2H,m ), 4.19-4.38 (3H, m), 4.61 (2H, s), 4.80-4.87 (1H, m), 6.42-6.49 (1H, m), 6.57 (1H, d, J = 8.5 Hz), 6.95 ( 1H, s), 7.45-7.50 (1H, m), 7.89 (1H, d, J = 8.5 Hz), 8.34 - 8.39 (1H, m), 8.78-8.81 (1H, m).

MS(APCI)m/z：681(M+H)+。 MS (APCI) m/z: 681 (M+H) + .

(實施例158)：於實施例(158f)合成 (Example 158): Synthesis in Example (158f)

1-(4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基苯基}哌啶-1-基)-2-甲氧基乙酮 1-(4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}-2,3 -dihydro-1H-indol-5-yl)oxyphenyl}piperidin-1-yl)-2-methoxyethyl ketone

(158a)5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-甲酸苄酯 (158a) 5-(4-Bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester

於實施例(24a)所獲得的化合物(15.0g)之二氯甲烷(30mL)溶液中添加4N鹽酸二烷溶液(30mL)，並於室溫攪拌。攪拌2小時後，藉由將反應液濃縮，獲得粗製之5-(4-溴-2,5-二甲基苯氧基)-4-甲基-2,3-二氫-1H-吲哚鹽酸鹽(12.8g)。 4N hydrochloric acid was added to a solution of the compound (15.0 g) obtained in Example (24a) in dichloromethane (30 mL) A solution of the alkane (30 mL) was stirred at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give crude 5-(4-bromo-2,5-dimethylphenoxy)-4-methyl-2,3-dihydro-1H-indole. Hydrochloride (12.8 g).

於獲得的化合物(5.00g)之四氫呋喃(75mL)溶液中添加氯甲酸苄酯(5.81mL)及飽和碳酸氫鈉水溶液(75mL)，並於室溫攪拌。4小時30分鐘後，於反應混合物中添加水，並以乙酸乙酯進行3次提取，將合併的有機層以硫酸鈉乾燥後，減壓下餾除溶媒。使獲得的殘渣溶解於二氯甲烷，並添加己烷。濾取析出的固體，藉由使乾燥，獲得呈無色固體之標題化合物(5.77g)。 Benzyl chloroformate (5.81 mL) and a saturated aqueous solution of sodium hydrogencarbonate (75 mL) were added and the mixture was stirred at room temperature. After 4 hours and 30 minutes, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated. The obtained residue was dissolved in dichloromethane, and hexane was added. The title compound (5.77 g) was obtained as a colorless solid.

1H-NMR(400MHz,CDCl3)δ：2.08(3H,s),2.26-2.21(6H,m),3.07(2H,t,J=8.5Hz),4.12(2H,t,J=8.5Hz),5.20-5.35(2H,m),6.44(1H,s),6.52-6.72(1H,m),7.21-7.45(6H,m),7.65-7.71(1H,m). 1 H-NMR (400MHz, CDCl 3 ) δ: 2.08 (3H, s), 2.26-2.21 (6H, m), 3.07 (2H, t, J = 8.5 Hz), 4.12 (2H, t, J = 8.5 Hz ), 5.20-5.35 (2H, m), 6.44 (1H, s), 6.52-6.72 (1H, m), 7.21-7.45 (6H, m), 7.65-7.71 (1H, m).

MS(APCI)m/z：466(M+H)+。 MS (APCI) m/z: 466 (M+H) + .

(158b)5-{4-[1-(三級丁氧基羰基)-1,2,3,6-四氫吡啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-甲酸苄酯 (158b) 5-{4-[1-(tertiary butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2,5-dimethylphenoxy}-4 -methyl-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester

於實施例(158a)合成的化合物(2.00g)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,6-二氫吡啶-1(2H)-甲酸三級丁酯(1.59g)及肆(三苯基膦)鈀(248mg)之1,2-二 甲氧基乙烷(100mL)溶液中添加磷酸三鉀(2.73g)之水溶液(10mL)，並於90℃攪拌16小時。冷卻至室溫後，將有機層以硫酸鈉乾燥後，減壓下餾除溶媒。將獲得的殘渣以管柱層析(乙酸乙酯/己烷)純化，獲得呈無色固體之標題化合物(1.93g)。 Compound (2.00 g) synthesized in Example (158a), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- Dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester (1.59g) and hydrazine (triphenylphosphine)palladium (248mg) 1,2-di An aqueous solution (10 mL) of tripotassium phosphate (2.73 g) was added to a solution of methoxyethane (100 mL), and stirred at 90 ° C for 16 hours. After cooling to room temperature, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by EtOAcjjjjjjjj

1H-NMR(400MHz,CDCl3)δ：1.50(9H,s),2.08-2.16(6H,m),2.24(3H,s),2.29-2.37(2H,m),3.08(2H,t,J=8.5Hz),3.54-3.65(2H,m),4.02(2H,s),4.12(2H,t,J=8.5Hz),5.21-5.34(2H,m),5.48-5.57(1H,m),6.40(1H,s),6.53-6.73(1H,m),6.92(1H,s),7.19-7.45(5H,m),7.64-7.71(1H,m)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.50 (9H, s), 2.08-2.16 (6H, m), 2.24 (3H, s), 2.29-2.37 (2H, m), 3.08 (2H, t, J=8.5Hz), 3.54-3.65(2H,m), 4.02(2H,s), 4.12(2H,t,J=8.5Hz),5.21-5.34(2H,m),5.48-5.57(1H,m ), 6.40 (1H, s), 6.53 - 6.73 (1H, m), 6.92 (1H, s), 7.19-7.45 (5H, m), 7.64 - 7.71 (1H, m).

(158c)4-{2,5-二甲基-4-[(4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (158c) 4-{2,5-Dimethyl-4-[(4-methyl-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1- Butyl formate

於實施例(158b)所獲得的化合物(1.92g)之甲醇(60mL)溶液中添加10%鈀碳(100mg)，並於氫氣環境下，於室溫攪拌10小時15分鐘。藉由過濾而去除觸媒後，減壓下濃縮反應液，獲得呈無色非晶形固體之粗製之標題化合物(1.49g)。 To a solution of the compound (1.92 g) obtained from m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m After the catalyst was removed by filtration, the title compound (1.49 g) was obtained.

1H-NMR(400MHz,CDCl3)δ：1.50-1.48(9H,m),1.57-1.76(4H,m),2.12(3H,s),2.19(3H,s),2.24(3H,s),2.69-2.86(3H,m),3.08(2H,t,J=8.2Hz),3.72(2H,t,J=8.2Hz),4.14-4.36(2H,m),6.41(1H,s),6.57(1H,d,J=8.5Hz),6.71(1H,d,J=8.5Hz),6.98(1H,s). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50-1.48 (9H, m), 1.57-1.76 (4H, m), 2.12 (3H, s), 2.19 (3H, s), 2.24 (3H, s) , 2.69-2.86 (3H, m), 3.08 (2H, t, J = 8.2 Hz), 3.72 (2H, t, J = 8.2 Hz), 4.14 - 4.36 (2H, m), 6.41 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.71 (1H, d, J = 8.5 Hz), 6.98 (1H, s).

MS(APCI)m/z：437(M+H)+。 MS (APCI) m/z: 437 (M+H) + .

(158d)4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯 基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯 (158d) 4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonate) Benzylpyridin-2-yl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester

於實施例(158c)所獲得的化合物(700mg)及[3-(甲基磺醯基)吡啶-2-基]乙酸鈉鹽(456mg)之二甲基甲醯胺(10mL)溶液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(666mg)，並於室溫攪拌17小時30分鐘。減壓下濃縮反應液，殘渣以管柱層析(乙酸乙酯/二氯甲烷)純化，獲得黃色非晶形固體之標題化合物(1.03g)。 Adding chlorine to a solution of the compound obtained in Example (158c) (700 mg) and [3-(methylsulfonyl)pyridin-2-yl]acetate sodium salt (456 mg) in dimethylformamide (10 mL) 4-(4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl Was guanidine (666 mg) and stirred at room temperature for 17 hours and 30 minutes. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.49(9H,s),1.60-1.76(4H,m),2.17(3H,s),2.20(3H,s),2.22(3H,s),2.70-2.85(3H,m),3.20-3.29(5H,m),4.18-4.38(4H,m),4.61(2H,s),6.45(1H,s),6.57(1H,d,J=8.5Hz),6.99(1H,s),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.35(1H,dd,J=7.9,1.8Hz),8.79(1H,dd,J=4.9,1.8Hz)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 (9H, s), 1.60-1.76 (4H, m), 2.17 (3H, s), 2.20 (3H, s), 2.22 (3H, s), 2.70 -2.85(3H,m), 3.20-3.29(5H,m),4.18-4.38(4H,m),4.61(2H,s),6.45(1H,s),6.57(1H,d,J=8.5Hz ), 6.99 (1H, s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.35 (1H, dd, J = 7.9, 1.8 Hz), 8.79 (1H, dd, J = 4.9, 1.8 Hz).

(158e)1-{5-[2,5-二甲基-4-(哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮鹽酸鹽 (158e) 1-{5-[2,5-Dimethyl-4-(piperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole-1 -yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone hydrochloride

於實施例(158d)所獲得的化合物(1.02g)之二氯甲烷(10mL)溶液中添加4N鹽酸二烷溶液(10mL)，並於室溫攪拌。攪拌2小時後，藉由將反應液濃縮而獲得粗製之標題化合物(1.03g)。 4N hydrochloric acid was added to a solution of the compound (1.02 g) obtained in Example (158d) in dichloromethane (10 mL) A solution of the alkane (10 mL) was stirred at room temperature. After stirring for 2 hours, the title compound (1.03 g) was obtained.

MS(APCI)m/z：534(M+H)+。 MS (APCI) m/z: 534 (M+H) + .

(158f)1-(4-{2,5-二甲基-4-[(4-甲基-1-{[3-(甲基磺醯基)吡啶-2-基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基苯 基}哌啶-1-基)-2-甲氧基乙酮 (158f) 1-(4-{2,5-Dimethyl-4-[(4-methyl-1-{[3-(methylsulfonyl)pyridin-2-yl]ethenyl}- 2,3-dihydro-1H-indol-5-yl)oxybenzene 哌piperidin-1-yl)-2-methoxyethyl ketone

於實施例(158e)所獲得的化合物(100mg)之N,N-二甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0725mL)，並於室溫攪拌55分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(68.4mg)及甲氧基乙酸(19.3mg)，於室溫攪拌14小時。減壓下濃縮反應液，殘渣以管柱層析(乙酸乙酯/己烷→甲醇/乙酸乙酯)純化，獲得呈淡黃色非晶形固體之標題化合物(88.8mg)。 N-methyl group was added to a solution of the compound (100 mg) obtained in Example (158e) in N,N-dimethylformamide (5 mL) The morpholine (0.0725 mL) was stirred at room temperature for 55 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (68.4 mg) and methoxyacetic acid (19.3 mg) were stirred at room temperature for 14 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.62-1.70(2H,m),1.78-1.85(2H,m),2.17(3H,s),2.19-2.26(6H,m),2.63-2.72(1H,m),2.83-2.92(1H,m),3.06-3.19(1H,m),3.20-3.29(5H,m),3.44-3.53(3H,m),3.96-4.23(3H,m),4.34(2H,t,J=8.2Hz),4.61(2H,s),4.73-4.81(1H,m),6.45(1H,s),6.57(1H,d,J=8.5Hz),6.96(1H,s),7.47(1H,dd,J=7.9,4.9Hz),7.89(1H,d,J=8.5Hz),8.33-8.38(1H,m),8.77-8.82(1H,m). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.70 (2H, m), 1.78-1.85 (2H, m), 2.17 (3H, s), 2.19-2.26 (6H, m), 2.63-2.72 ( 1H,m),2.83-2.92(1H,m),3.06-3.19(1H,m), 3.20-3.29(5H,m),3.44-3.53(3H,m),3.96-4.23(3H,m), 4.34 (2H, t, J = 8.2 Hz), 4.61 (2H, s), 4.73-4.81 (1H, m), 6.45 (1H, s), 6.57 (1H, d, J = 8.5 Hz), 6.96 (1H) , s), 7.47 (1H, dd, J = 7.9, 4.9 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.33-8.38 (1H, m), 8.77-8.82 (1H, m).

MS(APCI)m/z：606(M+H)+。 MS (APCI) m/z: 606 (M+H) + .

(實施例159) (Example 159)

1-(5-{4-[1-(1H-咪唑-5-基羰基)哌啶-4-基]-2,5-二甲基苯氧基}-4-甲基-2,3-二氫-1H-吲哚-1-基)-2-[3-(甲基磺醯基)吡啶-2-基]乙酮 1-(5-{4-[1-(1H-imidazol-5-ylcarbonyl)piperidin-4-yl]-2,5-dimethylphenoxy}-4-methyl-2,3- Dihydro-1H-indol-1-yl)-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone

於實施例(158e)所獲得的化合物(80.0mg)之N,N-二 甲基甲醯胺(5mL)溶液中添加N-甲基啉(0.0580mL)，並於室溫攪拌60分鐘。於反應液中添加氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓(54.7mg)及4-咪唑甲酸(22.2mg)，並於室溫攪拌20小時。減壓下濃縮反應液，殘渣以NH管柱層析(乙酸乙酯/二氯甲烷→甲醇/乙酸乙酯)純化，獲得呈無色固體之標題化合物(32.7mg)。 N-methyl was added to a solution of the compound (80.0 mg) obtained in Example (158e) in N,N-dimethylformamide (5 mL) The morpholine (0.0580 mL) was stirred at room temperature for 60 min. Adding 4-(4,6-dimethoxy-1,3,5-three chloride) to the reaction solution -2-yl)-4-methyl Borax (54.7 mg) and 4-imidazolecarboxylic acid (22.2 mg) were stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

1H-NMR(400MHz,CDCl3)δ：1.68-1.94(4H,m),2.13-2.29(10H,m),2.79-3.31(8H,m),4.34(2H,t,J=8.5Hz),4.55-4.89(3H,m),6.46(1H,s),6.58(1H,d,J=9.1Hz),6.95-7.06(1H,m),7.38-7.50(2H,m),7.62-7.75(2H,m),7.89(1H,d,J=8.5Hz),8.36(1H,dd,J=7.9,1.2Hz),8.79(1H,dd,J=4.9,1.2Hz). 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.68-1.94 (4H, m), 2.13-2.29 (10H, m), 2.79-3.31 (8H, m), 4.34 (2H, t, J = 8.5 Hz) , 4.55-4.89 (3H, m), 6.46 (1H, s), 6.58 (1H, d, J = 9.1 Hz), 6.95-7.06 (1H, m), 7.38-7.50 (2H, m), 7.62-7.75 (2H, m), 7.89 (1H, d, J = 8.5 Hz), 8.36 (1H, dd, J = 7.9, 1.2 Hz), 8.79 (1H, dd, J = 4.9, 1.2 Hz).

MS(APCI)m/z：628(M+H)+。 MS (APCI) m/z: 628 (M+H) + .

(試驗例1) (Test Example 1)

對RORγt基因導入細胞之IL-17產生的抑制效果 Inhibitory effect of IL-17 production by RORγt gene introduction into cells

(1)RORγt基因導入細胞之製作 (1) Production of RORγt gene into cells

基於編碼小鼠(Mus musculus)RORgamma t蛋白質之全長胺基酸序列的mRNA之鹼基序列(GenBank登錄號AF163668：http：//www.metalife.com/Genbank/5679306)，藉由PCR法而取得編碼全長蛋白質的mRNA之cDNA。獲得的cDNA插入為表現載體(vector)的pUNO載體(InvivoGen公司)，而構築小鼠RORγt表現載體。構築的小鼠RORγt表現載體係導入至EL4細胞(小鼠T淋巴瘤細胞株)，以選擇培養基(於DMEM培養基中添加胎牛血清、殺稻瘟菌素S(Blasticidin S)、盤尼西林、鏈黴素者)培養 而取得RORγt基因導入細胞。 Based on the base sequence of the mRNA encoding the full length amino acid sequence of the mouse (Mus musculus) RORgamma t protein (GenBank Accession No. AF163668: http://www.metalife.com/Genbank/5679306), obtained by PCR A cDNA encoding the mRNA of a full-length protein. The obtained cDNA was inserted into a pUNO vector (InvivoGen) which is a expression vector, and a mouse RORγt expression vector was constructed. The constructed mouse RORγt expression vector was introduced into EL4 cells (mouse T lymphoma cell line) to select medium (added fetal bovine serum, blasticidin S (Blasticidin S), penicillin, Streptomyces in DMEM medium Cultivation The RORγt gene was introduced into the cells.

(2)IL-17產生抑制作用之評價 (2) Evaluation of IL-17 production inhibition

試驗化合物之IL-17產生抑制作用係將前述之RORγt基因導入細胞以佛波醇12-十四酸酯13-乙酸酯(phorbol 12-Myristate 13-acetate(PMA))及離子黴素(ionomycin)刺激之際之IL-17產生來測定。即，將RORγt基因導入細胞以前述選擇培養基調製，分注於96孔平底盤(Corning公司)內每1孔各75000個。此時，同時添加各種濃度之試驗化合物。於5%CO2濃度之保溫箱中於37℃培養1小時後，將PMA以終濃度25ng/mL、離子黴素以終濃度125ng/mL添加於各孔，合計100μL，於5%CO2濃度之保溫箱中於37℃培養20小時。之後，回收培養上清液，將上清液中之小鼠IL-17濃度，使用HTRF小鼠IL-17套組(Cisbio公司)，以EnVison(Perkin-Elmer公司)作時間分解螢光而測定。關於試驗化合物所致的IL-17產生抑制作用，係由試驗化合物存在下之試驗化合物濃度對IL-17產生量作半對數座標圖(semilogarithmic plot)的圖，將相當於試驗化合物非存在下之IL-17產生量之50%的IL-17產生量之試驗化合物濃度作為IC50值而算出。將IL-17產生抑制作用之結果示於表1。 The IL-17 production inhibitory effect of the test compound is the introduction of the aforementioned RORγt gene into cells such as phorbol 12-Myristate 13-acetate (PMA) and ionomycin. The IL-17 production at the time of stimulation was measured. Namely, the RORγt gene was introduced into cells and prepared in the above-mentioned selection medium, and dispensed into 75,000 cells per well in a 96-well flat bottom plate (Corning). At this time, test compounds of various concentrations were simultaneously added. After incubating at 37 ° C for 1 hour in an incubator with 5% CO 2 concentration, PMA was added to each well at a final concentration of 25 ng/mL and ionomycin at a final concentration of 125 ng/mL, totaling 100 μL at a concentration of 5% CO 2 . Incubate at 37 ° C for 20 hours in an incubator. Thereafter, the culture supernatant was collected, and the concentration of mouse IL-17 in the supernatant was measured by time-degrading fluorescence using EnVison (Perkin-Elmer) using an HTRF mouse IL-17 kit (Cisbio). . Regarding the inhibition of IL-17 production by the test compound, a graph of the semi-logothmic plot of the concentration of the test compound in the presence of the test compound on the IL-17 production amount, which corresponds to the absence of the test compound. The test compound concentration of the IL-17 production amount of 50% of the IL-17 production amount was calculated as the IC 50 value. The results of inhibition of IL-17 production are shown in Table 1.

於本試驗，本發明之化合物顯示優異的IL-17產生抑制作用。據此，有用於作為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病(克隆氏病或潰瘍性大腸炎等)、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎等之自體免疫疾病或IL-17之產生為病態發病參與的大腸癌之治療劑及/或預防劑。 In the present test, the compound of the present invention showed an excellent inhibitory effect on IL-17 production. Accordingly, it is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease or ulcerative colitis, etc.), and repair syndrome , systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft versus host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid Nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. Autoimmune diseases or the production of IL-17 is a pathologically involved colorectal cancer Therapeutic agents and/or prophylactic agents.

(試驗例2) (Test Example 2)

對IL-23誘導性小鼠乾癬樣皮膚炎模式的抑制效果 Inhibitory effect of IL-23-induced mouse dry dermatitis model

已知IL-23誘導性小鼠乾癬樣皮膚炎模式依存於IL-17(The Journal of Immunology,186,1495-1502(2011))(The Journal of Immunology,186,4481-4489(2011))。 The IL-23-inducible mouse xerodermatitis pattern is known to be dependent on IL-17 (The Journal of Immunology, 186, 1495-1502 (2011)) (The Journal of Immunology, 186, 4481-4489 (2011)).

實驗中使用BALB/c小鼠(日本Charles River公司)之7週齡以後的雄性小鼠5~10隻。第0日至第3日為止，麻醉下1日1次連日對小鼠單耳皮內投予小鼠IL-23(R&D Systems公司，以磷酸鹽緩衝食鹽水調製為50μg/mL)，1μg/隻，而誘發皮膚炎(The Journal of Experimental Medicine,203,2577-2587(2006))(Nature,445,648-651(2007))。對照組同樣地皮內投予牛血清白蛋白(Sigma公司，以磷酸鹽緩衝食鹽水調製為50μg/mL)1μg/隻。皮膚炎之評價係於小鼠IL-23最終投予24小時後(第4日)，將使用厚度量規而測量的耳殼厚度減去第0日之IL-23投予開始前之耳殼厚度的耳殼肥厚作為指標。試驗化合物懸浮於0.5%甲基纖維素溶液或9~10%(科利當(Kollidon)(註冊商標))VA64溶液。試驗化合物或溶媒係第0日至第3日為止每1日2次經口投予。關於試驗化合物所致的皮膚炎抑制效果，依據下述式算出作為抑制率(%)。皮膚炎抑制效果之結果示於表2。 In the experiment, 5 to 10 male mice of 7 weeks old after BALB/c mice (Charles River, Japan) were used. From day 0 to day 3, mouse IL-23 (R&D) was administered to mice in a single ear for 1 day under anesthesia. Systems Inc., modulating dermatitis induced by phosphate buffered saline (50 μg/mL), 1 μg/mouse (The Journal of Experimental Medicine, 203, 2577-2587 (2006)) (Nature, 445, 648-651 (2007)) . In the control group, bovine serum albumin (Sigma, 50 μg/mL in phosphate buffered saline) was administered intradermally at 1 μg/mouse. The dermatitis was evaluated after the final administration of mouse IL-23 for 24 hours (Day 4), and the thickness of the ear shell measured using the thickness gauge minus the IL-23 on day 0 was administered to the ear shell before the start. Thickness of the ear shell is used as an indicator. The test compound was suspended in a 0.5% methylcellulose solution or 9-10% (Kollidon (registered trademark)) VA64 solution. The test compound or the vehicle is administered orally twice a day from the 0th to the 3rd day. The dermatitis-inhibiting effect by the test compound was calculated as the inhibition rate (%) according to the following formula. The results of the dermatitis inhibitory effect are shown in Table 2.

抑制率(%)=100×(溶媒投予時之耳殼肥厚-試驗化合物投予時之耳殼肥厚)/(溶媒投予時之耳殼肥厚-對照組之耳殼肥厚) Inhibition rate (%) = 100 × (ear shell hypertrophy when the vehicle is administered - ear shell hypertrophy when the test compound is administered) / (ear shell hypertrophy when the vehicle is administered - the ear shell hypertrophy of the control group)

如上述顯示，本發明之化合物具有皮膚炎抑制效果，對乾癬為有效的。 As shown above, the compound of the present invention has a dermatitis-inhibiting effect and is effective for dryness.

製劑例1：膠囊劑 Formulation Example 1: Capsule

實施例1-1或2之化合物 50mg Compound of Example 1-1 or 2 50 mg

將上述處方之粉末混合，通過60網目的篩後，將此粉末置入250mg之明膠膠囊，作成膠囊劑。 The powder of the above prescription was mixed, passed through a sieve of 60 mesh, and the powder was placed in a 250 mg gelatin capsule to prepare a capsule.

製劑例2：錠劑 Formulation Example 2: Lozenges

將上述處方之粉末混合，使用玉米澱粉糊而造粒、乾燥後，藉由打錠機打錠，而作成1錠200mg之錠劑。因應必要可對此錠劑施予糖衣。 The powder of the above-mentioned prescription was mixed, granulated using a corn starch paste, and dried, and then ingot was tableted by a tableting machine to prepare a tablet of 200 mg in one tablet. A sugar coating may be applied to the tablet as necessary.

[產業上之可利用性] [Industrial availability]

本發明之通式(I)所表示的化合物或其同位素標識化合物或彼等之藥學上可容許的鹽具有優異的視網酸受體關連孤兒受體γt抑制作用及IL-17產生抑制作用，而有用作為醫藥。 The compound represented by the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has excellent retinol receptor-related orphan receptor γt inhibitory action and IL-17 production inhibitory action, And useful as medicine.

Claims (45)

一種通式(I)所表示的化合物或其藥學上可容許的鹽， 式中，R1表示C1-C6烷基、C3-C6環烷基或苯基，R2表示氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基，R3表示氫原子、C2-C7羧基烷基或羥基，R4表示鹵素原子或C1-C6烷基，R5表示氫原子或C1-C6烷基，R6表示氫原子、鹵素原子或C1-C6烷基，Q1表示氮原子或式=CH-所表示的基，Q2表示氮原子或式=CH-所表示的基，式-U-T-所表示的基表示式-CH2-CH2-所表示的基或式-CH=CH-所表示的基，Y表示亞甲基或氧原子，V表示氮原子或式=C(R7)-所表示的基，R7表示氫原子、鹵素原子、C1-C6烷基、C3-C6環烷基、C2-C6烯基、C1-C6烷氧基、C1-C6鹵化烷氧基、(C1-C6烷氧基)-(C1-C6烷基)基、(C1-C6烷氧基)-(C1-C6烷氧基)基、C2-C7烷基羰基、四氫呋喃基或氧唉基氧基 (oxetyloxy)，E表示可獨立經1至4個選自取代基群組A的基取代的哌啶-1-基、哌啶-3-基、哌啶-4-基、1,2,3,6-四氫吡啶-4-基、哌-1-基、啉-4-基、吡咯啶-1-基或吡咯啶-3-基，取代基群組A表示由C1-C6烷基、C1-C6鹵化烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、羧基甲基、羥基、單-C2-C7烷基羰基胺基、側氧基、環氧丙烷-3-基、(1,4-二烷-2-基)甲基、與E之亞甲基部位以第2位鍵結而構築螺環接結構的1,3-二氧戊環及式-L-R8所表示的基所構成的群組，L表示羰基、草醯基或磺醯基，R8表示C1-C6烷基、C1-C6羥基烷基、C1-C6二羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、二(C1-C6烷氧基)-(C1-C6烷基)基、(C1-C6烷氧基)-(C1-C6羥基烷基)基、C3-C6羥基環烷基、C1-C6氰基烷基、C1-C6烷氧基、羥基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、(C2-C7烷羰氧基)-(C1-C6烷基)基、(單-C3-C6環烷基胺基)-(C1-C6烷基)基、(C2-C7羥基烷羰氧基)-(C1-C6烷基)基、(單-C1-C6羥基烷基胺基)-(C1-C6烷基)基、四羥基環己基、四氫呋喃-2-基、四氫呋喃-3-基、環氧丙烷-2-基、環氧丙烷-3-基、1,4-二烷-2-基、四氫吖唉-1-基、啉-4-基、(啉-4-基)甲基、可獨立地經1或2個C1-C6烷基取代的吡咯-2-基、可獨立地經1或2個C1-C6烷基取代的啉-2-基、可 獨立地經1或2個C1-C6烷基取代的咪唑-5-基、或可獨立地經1至5個選自鹵素原子、C1-C6烷基、羥基、C1-C6羥基烷基、C2-C7烷基羰基及側氧基的基取代的吡咯啶-2-基。 a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, In the formula, R 1 represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a phenyl group, and R 2 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group. a group, R 3 represents a hydrogen atom, a C 2 -C 7 carboxyalkyl group or a hydroxyl group, R 4 represents a halogen atom or a C 1 -C 6 alkyl group, R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 6 represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group, Q 1 represents a nitrogen atom or a group represented by the formula =CH-, and Q 2 represents a nitrogen atom or a group represented by the formula =CH-, represented by the formula -UT- The base is represented by the formula -CH 2 -CH 2 - or the group represented by the formula -CH=CH-, Y represents a methylene group or an oxygen atom, and V represents a nitrogen atom or a formula = C(R 7 )- a group represented by R 7 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a C 1 -C 6 alkoxy group, a C 1 - C 6 halogenated alkoxy, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) a C 2 -C 7 alkylcarbonyl group, a tetrahydrofuranyl group or an oxetyloxy group, and E represents a piperidin-1-yl group which may be independently substituted with 1 to 4 groups selected from the substituent group A, Piperidin-3-yl, piperidin-4-yl, 1,2,3,6-tetrahydro Pyridin-4-yl, piperazine -1-base, Polin-4-yl, pyrrolidin-1-yl or pyrrolidin-3-yl, the substituent group A represents a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 hydroxyl group Alkyl, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, carboxymethyl group, hydroxyl group, mono-C 2 -C 7 alkylcarbonylamino group, pendant oxy group, epoxy Propane-3-yl, (1,4-di a group consisting of a 1,3-dioxolane having a spiro-ring structure and a group represented by the formula -LR 8 bonded to the methylene moiety of E at the 2nd position Group, L represents a carbonyl group, a sulfhydryl group or a sulfonyl group, and R 8 represents a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 1 -C 6 dihydroxyalkyl group, (C 1 -C 6 Alkoxy)-(C 1 -C 6 alkyl) group, di(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, (C 1 -C 6 alkoxy)- (C 1 -C 6 hydroxyalkyl) group, C 3 -C 6 hydroxycycloalkyl group, C 1 -C 6 cyanoalkyl group, C 1 -C 6 alkoxy group, hydroxyl group, amine group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di-(C 1 -C 6 alkyl)amino group, (C 2 -C 7 alkylcarbonyloxy)-(C 1 -C 6 alkyl) group, (mono-C 3 -C 6 cycloalkylamino)-(C 1 -C 6 alkyl) group, (C 2 -C 7 hydroxyalkylcarbonyloxy)-(C 1 -C 6 alkyl) group, (mono-C 1 -C 6 hydroxyalkylamino)-(C 1 -C 6 alkyl) group, tetrahydroxycyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl , propylene oxide-2-yl, propylene oxide-3-yl, 1,4-two Alkan-2-yl, tetrahydroinden-1-yl, Porphyrin-4-yl, ( Phenyl-4-yl)methyl, pyrrol-2-yl which may be independently substituted with 1 or 2 C 1 -C 6 alkyl groups, may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups a pyridin-2-yl group, an imidazole-5-yl group which may be independently substituted by 1 or 2 C 1 -C 6 alkyl groups, or may independently be substituted with 1 to 5 selected from a halogen atom, a C 1 -C 6 alkyl group a pyridyl-2-yl group substituted with a hydroxy group, a C 1 -C 6 hydroxyalkyl group, a C 2 -C 7 alkylcarbonyl group and a pendant oxy group. 如請求項1之化合物或其藥學上可容許的鹽，其中R1為甲基或乙基。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl or ethyl. 如請求項1或2之化合物或其藥學上可容許的鹽，其中R2為氫原子。 A compound according to claim 1 or 2, wherein R 2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 如請求項1至3中任一項之化合物或其藥學上可容許的鹽，其中R3為氫原子。 The compound of any one of claims 1 to 3, wherein R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 如請求項1至4中任一項之化合物或其藥學上可容許的鹽，其中R4為甲基。 The compound of any one of claims 1 to 4, wherein R 4 is methyl, or a pharmaceutically acceptable salt thereof. 如請求項1至5中任一項之化合物或其藥學上可容許的鹽，其中R5為氫原子或甲基。 The compound of any one of claims 1 to 5, wherein R 5 is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. 如請求項1至6中任一項之化合物或其藥學上可容許的鹽，其中R6為氫原子。 The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom. 如請求項1至7中任一項之化合物或其藥學上可容許的鹽，其中Q1為式=CH-所表示的基。 The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Q 1 is a group represented by the formula: CH-. 如請求項1至8中任一項之化合物或其藥學上可容許的鹽，其中Q2為式=CH-所表示的基。 The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Q 2 is a group represented by the formula =CH-. 如請求項1至9中任一項之化合物或其藥學上可容許的鹽，其中式-U-T-所表示的基為式-CH2-CH2-所表示的基。 The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the group represented by the formula -UT- is a group represented by the formula -CH 2 -CH 2 -. 如請求項1至10中任一項之化合物或其藥學上可容許的鹽，其中Y為氧原子。 The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom. 如請求項1至11中任一項之化合物或其藥學上可容許的鹽，其中V為式=C(R7)-所表示的基。 The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein V is a group represented by the formula: C(R 7 )-. 如請求項1至12中任一項之化合物或其藥學上可容許的鹽，其中R7為氫原子、鹵素原子、C1-C6烷基或C1-C6烷氧基。 The compound of any one of claims 1 to 12, wherein R 7 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or a pharmaceutically acceptable salt thereof. 如請求項1至12中任一項之化合物或其藥學上可容許的鹽，其中R7為氫原子或甲基。 The compound of any one of claims 1 to 12, wherein R 7 is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. 如請求項1至11中任一項之化合物或其藥學上可容許的鹽，其中V為氮原子。 The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein V is a nitrogen atom. 如請求項1至15中任一項之化合物或其藥學上可容許的鹽，其中E為經1個式-L-R8所表示的基取代的哌啶-4-基、1,2,3,6-四氫吡啶-4-基或哌-1-基。 The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein E is a piperidin-4-yl group, 1, 2, 3 substituted by a group represented by the formula -LR 8 6-tetrahydropyridin-4-yl or piperidine -1- base. 如請求項1至15中任一項之化合物或其藥學上可容許的鹽，其中E為經1個式-L-R8所表示的基取代的哌啶-4-基或1,2,3,6-四氫吡啶-4-基。 The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein E is a group-substituted piperidin-4-yl or 1,2,3 represented by the formula -LR 8 6-tetrahydropyridin-4-yl. 如請求項1至15中任一項之化合物或其藥學上可容許的鹽，其中取代基群組A為式-L-R8所表示的基。 The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein the substituent group A is a group represented by the formula -LR 8 . 如請求項1至18中任一項之化合物或其藥學上可容許的鹽，其中L為羰基或草醯基。 The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein L is a carbonyl group or a sulfhydryl group. 如請求項1至19中任一項之化合物或其藥學上可容許的鹽，其中R8為C1-C6烷基、C1-C6羥基烷基、(C1-C6烷氧基)-(C1-C6烷基)基、胺基、單-C1-C6烷基胺基、單-C1-C6鹵化烷基胺基、二-(C1-C6烷基)胺基、啉-2-基、或獨立經1至3個選自鹵素原子及C1-C6烷基的基取代的吡咯啶-2-基。 The compound of any one of claims 1 to 19, wherein R 8 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, (C 1 -C 6 alkoxy), or a pharmaceutically acceptable salt thereof ()-(C 1 -C 6 alkyl) group, amine group, mono-C 1 -C 6 alkylamino group, mono-C 1 -C 6 halogenated alkylamino group, di-(C 1 -C 6 Alkyl) amine group, A phenyl-2-yl group, or a pyrrolidin-2-yl group independently substituted with 1 to 3 groups selected from a halogen atom and a C 1 -C 6 alkyl group. 如請求項1至19中任一項之化合物或其藥學上可容許的鹽，其中R8為甲基、1-羥基乙基、甲氧基甲基、甲基胺基、乙基胺基、2,2-二氟乙基胺基、啉-2-基或4,4-二氟-1-甲基吡咯啶-2-基。 The compound of any one of claims 1 to 19, wherein R 8 is methyl, 1-hydroxyethyl, methoxymethyl, methylamino, ethylamino, or a pharmaceutically acceptable salt thereof, 2,2-difluoroethylamino group, Orido-2-yl or 4,4-difluoro-1-methylpyrrolidin-2-yl. 一種化合物或其藥學上可容許的鹽，其係：1-[5-(4-{1-[(2S)-1,4-二烷-2-基羰基]哌啶-4-基}苯氧基)-4-甲基-2,3-二氫-1H-吲哚-1-基]-2-[2-(甲基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-甲酸三級丁酯、2-甲氧基-1-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)乙酮、1-{5-[4-(1-{[(2S)-4,4-二氟-1-甲基吡咯啶-2-基]羰基}哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、N-(2,2-二氟乙基)-2-(4-{4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基)-2-側氧基乙醯胺、2-(4-{4-[(1-{[2-(乙基磺醯基)苯基]乙醯基}-4-甲基-2,3-二氫-1H-吲哚-5-基)氧基]苯基}哌啶-1-基 )-N-甲基-2-側氧基乙醯胺、(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮、N-乙基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、1-{5-[4-(4-乙醯基哌-1-基)-3-甲基苯氧基]4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[(1’-乙醯基-1’,2’,3’,6’-四氫-2,4’-聯吡啶-5-基)氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基} -2-[3-(甲基磺醯基)吡啶-2-基]乙酮。 A compound or a pharmaceutically acceptable salt thereof, which is 1-[5-(4-{1-[(2S)-1,4-di) Alkyl-2-ylcarbonyl]piperidin-4-yl}phenoxy)-4-methyl-2,3-dihydro-1H-indol-1-yl]-2-[2-(methylsulfonate) Phenyl)phenyl]ethanone, 1-{5-[4-(1-epiphenylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indole哚-1-yl}-2-[2-(methylsulfonyl)phenyl]ethanone, 4-{2-methyl-4-[(4-methyl-1-{[2-(A 3-sulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidine-1-carboxylic acid tert-butyl butyl ester, 2-methoxy 1-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indole- 5-yl)oxy]phenyl}piperidin-1-yl)ethanone, 1-{5-[4-(1-{[(2S)-4,4-difluoro-1-methylpyrrolidine) -2-yl]carbonyl}piperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(methylsulfonate) Mercapto)phenyl]ethanone, N-(2,2-difluoroethyl)-2-(4-{4-[(4-methyl-1-{[2-(methylsulfonyl)) Phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}piperidin-1-yl)-2-oxoethoxyacetamide, 2-( 4-{4-[(1-{[2-(ethylsulfonyl)phenyl]ethinyl}-4-methyl-2,3-dihydro-1H-indol-5-yl)oxy (phenyl)piperidin-1-yl)-N-methyl-2-oxoethoxyacetamide, (2S)-2-hydroxy-1-[4-{2-methyl- 4-[(4-Methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]benzene }},6-dihydropyridine-1(2H)-yl]propan-1-one, N-ethyl-2-[4-{2-methyl-4-[(4-methyl-1) -{[2-(methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine -1(2H)-yl]-2-oxoethoxyacetamide, N-methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-( Methylsulfonyl)phenyl]ethenyl}-2,3-dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)- 2-yloxyacetamide, 1-{5-[4-(4-ethenyl) -1-yl)-3-methylphenoxy]4-methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl Ethylketone, 1-{5-[(1'-ethylindolyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-5-yl)oxy]-4 -methyl-2,3-dihydro-1H-indol-1-yl}-2-[2-(ethylsulfonyl)phenyl]ethanone, 1-{5-[4-(1- Acetylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(methylsulfonyl)phenyl] Ethyl Ketone, 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-( Ethylsulfonyl)phenyl]ethanone, 1-{5-[4-(1-ethinylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro- 1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone, or 1-{5-[4-(1-ethenyl-1,2) ,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl} -2- [3-(Methylsulfonyl)pyridin-2-yl]ethanone. 一種1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[2-(Methylsulfonyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof. 一種(2S)-2-羥基-1-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]丙烷-1-酮、或其藥學上可容許的鹽。 (2S)-2-Hydroxy-1-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethenyl}- 2,3-Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]propan-1-one, or its pharmaceutically acceptable Salt. 一種N-甲基-2-[4-{2-甲基-4-[(4-甲基-1-{[2-(甲基磺醯基)苯基]乙醯基}-2,3-二氫-1H-吲哚-5-基)氧基]苯基}-3,6-二氫吡啶-1(2H)-基]-2-側氧基乙醯胺、或其藥學上可容許的鹽。 N-methyl-2-[4-{2-methyl-4-[(4-methyl-1-{[2-(methylsulfonyl)phenyl]ethinyl}-2,3 -Dihydro-1H-indol-5-yl)oxy]phenyl}-3,6-dihydropyridine-1(2H)-yl]-2-oxoethoxyacetamide, or a pharmaceutically acceptable compound thereof Allowable salt. 一種1-{5-[4-(1-乙醯基哌啶-4-基)-3-甲基苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(甲基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 1-{5-[4-(1-Ethylpiperidin-4-yl)-3-methylphenoxy]-4-methyl-1H-indol-1-yl}-2-[ 2-(methylsulfonyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof. 一種1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-1H-吲哚-1-基}-2-[2-(乙基磺醯基)苯基]乙酮、或其藥學上可容許的鹽。 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-1H-indol-1-yl}-2-[2-(ethyl Sulfosyl)phenyl]ethanone, or a pharmaceutically acceptable salt thereof. 一種1-{5-[4-(1-乙醯基哌啶-4-基)苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或其藥學上可容許的鹽。 1-{5-[4-(1-Ethylpiperidin-4-yl)phenoxy]-4-methyl-2,3-dihydro-1H-indol-1-yl}-2 -[3-(Methylsulfonyl)pyridin-2-yl]ethanone, or a pharmaceutically acceptable salt thereof. 一種1-{5-[4-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-2,5-二甲基苯氧基]-4-甲基-2,3-二氫-1H-吲哚-1-基}-2-[3-(甲基磺醯基)吡啶-2-基]乙酮、或其藥學上可容許的鹽。 1-{5-[4-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-dimethylphenoxy]-4-methyl- 2,3-Dihydro-1H-indol-1-yl}-2-[3-(methylsulfonyl)pyridin-2-yl]ethanone, or a pharmaceutically acceptable salt thereof. 一種醫藥組成物，其含有選自如請求項1至29中任一項之化合物或其藥學上可容許的鹽作為有效成分。 A pharmaceutical composition containing a compound selected from any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof as an active ingredient. 如請求項30之醫藥組成物，其中醫藥組成物係用以治療及/或預防藉由視網酸受體關聯孤兒受體γt抑制作用而可治療及/或預防的疾病。 The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is for treating and/or preventing a disease treatable and/or preventable by retinoid acid receptor-associated orphan receptor γt inhibition. 如請求項30之醫藥組成物，其中醫藥組成物係用於藉由Th17細胞分化之抑制及/或IL-17產生之抑制而可進行症狀之治療、改善、減輕及/或預防的疾病之治療及/或預防。 The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is used for the treatment of a disease which can be treated, ameliorated, alleviated and/or prevented by inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. And / or prevention. 如請求項30之醫藥組成物，其中醫藥組成物係用於乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌之治療及/或預防。 The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is used for dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis , cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer treatment and / or prevention. 如請求項30之醫藥組成物，其中醫藥組成物係用於乾癬或乾癬性關節炎之治療及/或預防。 The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is for the treatment and/or prevention of dryness or dryness arthritis. 一種視網酸受體關聯孤兒受體γt抑制劑，其含有如請求項1至29中任一項之化合物或其藥學上可容許的鹽作為有效成分。 A retinoid acid receptor-associated orphan receptor γt inhibitor comprising the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof as an active ingredient. 一種如請求項1至29中任一項之化合物或其藥學上可容許的鹽之用途，其係用以製造醫藥組成物。 A use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition. 如請求項36之用途，其中醫藥組成物係用以治療及/或預防乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌之組成物。 The use of claim 36, wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, repairing Syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, A composition of spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. 如請求項36之用途，其中醫藥組成物係用以治療及/或預防乾癬或乾癬性關節炎之組成物。 The use of claim 36, wherein the pharmaceutical composition is for treating and/or preventing a composition of dry or dry arthritis. 一種選自如請求項1至29中任一項之化合物或其藥學上可容許的鹽，其係用於藉由視網酸受體關聯孤兒受體γt抑制作用而被治療及/或預防的疾病之治療及/或預防之方法中的用途。 A compound selected from any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in a disease which is treated and/or prevented by retinoid receptor associated with orphan receptor γt inhibition Use in methods of treatment and/or prevention. 一種選自如請求項1至29中任一項之化合物或其藥學上可容許的鹽，其係用於乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌之治療及/或預防之方法中的用途。 A compound selected from any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, Inflammatory bowel disease, Shering's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, white spot, Kawasaki Treatment, and/or prevention of Shig's disease, Behcet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer The use of the method. 一種疾病之治療及/或預防方法，其係將選自如請求項 1至29中任一項的化合物或其藥學上可容許的鹽之藥理有效量投予至溫血動物。 A method of treating and/or preventing a disease, which is selected from the group consisting of A pharmacologically effective amount of a compound of any one of 1 to 29, or a pharmaceutically acceptable salt thereof, is administered to a warm-blooded animal. 如請求項41之方法，其中疾病為藉由視網酸受體關聯孤兒受體γt抑制作用而被治療及/或預防者。 The method of claim 41, wherein the disease is treated and/or prevented by inhibition of retinoic acid receptor-associated orphan receptor γt. 如請求項41之方法，其中疾病為乾癬、乾癬性關節炎、僵直性脊椎炎、多發性硬化症、類風濕性關節炎、炎症性腸病、修格連氏症候群、全身性紅斑狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、氣喘、I型糖尿病、移植物抗宿主病(GvHD)、斑禿、白斑、川崎氏病、貝塞氏症、絲球體腎炎、心肌病、再生不良性貧血、橋本氏病、硬皮症、巨細胞性動脈炎、接觸性皮膚炎、視神經炎或大腸癌。 The method of claim 41, wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Shering's syndrome, systemic lupus erythematosus, chronic Obstructive Pulmonary Disease (COPD), atopic dermatitis, asthma, type I diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, cardiomyopathy, dysplasia Anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. 如請求項41之方法，其中疾病為乾癬或乾癬性關節炎。 The method of claim 41, wherein the disease is dry or dry arthritis. 如請求項41至44中任一項之方法，其中溫血動物為人類。 The method of any one of claims 41 to 44, wherein the warm-blooded animal is a human.
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