TW201213319A - Tricyclic compounds, preparation process and pharmaceutical use thereof - Google Patents

Tricyclic compounds, preparation process and pharmaceutical use thereof Download PDF

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TW201213319A
TW201213319A TW100134936A TW100134936A TW201213319A TW 201213319 A TW201213319 A TW 201213319A TW 100134936 A TW100134936 A TW 100134936A TW 100134936 A TW100134936 A TW 100134936A TW 201213319 A TW201213319 A TW 201213319A
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group
compound
formula
azabicyclo
pharmaceutically acceptable
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TW100134936A
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Chinese (zh)
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fang-long Yang
Qing Dong
xue-jun Zhang
Jin-Dong Liang
Jiang Fan
Bo-Nian Liu
si-shun Kang
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Shanghai Hengrui Pharm Co Ltd
Jiangsu Hengrui Medicine Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Abstract

The present disclosure relates to tricyclic compounds, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel tricyclic compounds presented by formula (I), preparation processes and pharmaceutical compositions containing the same, and their use as a therapeutic agent, especially use as GPR119 agonists and the use as drugs for treatment treating diabetes and metabolic syndrome diseases in which each substitute group of general formula (I) is as defined in the specification.

Description

201213319 六、發明說明： 【發明所屬之技術領域】 本發明涉及一種新的三環類衍生物、其製備方法及含 有該衍生物的醫藥組成物以及其作為治療劑特別是作為3 G P R119激動劑和在製備治療抗糖尿病和代謝性综合症的 疾病的藥物的用途》 ’ 【先前技術】201213319 VI. Description of the Invention: [Technical Field] The present invention relates to a novel tricyclic derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a 3 GP R119 agonist And the use of a medicament for the preparation of a disease for treating anti-diabetic and metabolic syndrome" 'Prior Art】

II型糖尿病的-個典型症狀是伴隨患者表現 素耐受的同時騰腺点細胞無法分泌出足夠量的 於這-點可將臨床上治療π型糖尿病的藥物 兩土 -種是用來改善肝臟、肌肉等器官組織的騰島素耐為受兩症^ ，樂物，第▲二種是作用於胰腺^細胞促進其分泌姨島素的 藥物。目前，已經開發出了多種治療藥物用來實現這一目 的，如胰高血糖素樣多肽—i類似物（GLP4 ^A typical symptom of type 2 diabetes is that the patient's phenotype is unable to secrete a sufficient amount of the drug at the same time. The muscle tissue of the muscles and other organs of the island is affected by two syndromes, music, and ▲ the two are drugs that act on the pancreatic cells to promote their secretion of gualin. At present, a variety of therapeutic drugs have been developed to achieve this, such as glucagon-like polypeptide-i analog (GLP4 ^

時由於其作用機制為葡萄糖依賴性，在臨床治療使用過程 中可能不會使患者出現低錢的症狀，因而成為理想的户 療藥物。在對GUM研究基礎上，又開發出了二肽基肽^ IJKDPPimp制劑’也成功的成為新型π型糖尿病治療用 藥。隨著研究的進，深人’尤其是對胰腺^細胞分泌騰 島素過程的研究，使得一種G蛋白偶聯受體GpRU9成為一 個潛在的II型糖尿病治療的新靶點。 G蛋白偶聯受體119(GPR119)是經人類基因測序分析 發現的一種孤兒受體，其基因定位於X染色體，主要表達 於胰腺組織中的胰島点細胞以及腸道細胞。經過進一步研 95344 4 201213319 究，發現油醯乙醇胺（0ΕΑ)和脂肪酸衍生物油醯溶血卵磷脂 是GPR119的内源性配體。藉由與GPR119結合並激動 GPR119能提高/3細胞内的環磷酸腺苷（camp)濃度，激發 細胞内的刺激-分泌偶聯，促進約離子内流’從而促進膜島 素囊泡分泌到胞外。 GPR119的組織細胞表達特點與功能均提示，啟動該受 體可促進GLP-1及胰島素分泌’有助於血糖控制。這一概 念已被用於與糖尿病相關的藥理學研究中。在對分離大鼠 胰島的離體灌流試驗中，GPR119激動劑可刺激胰島素的第 一時相和第二時相分泌’且這種促胰島素分泌作用具有葡 萄糖依賴性。此外，GPR119激動劑還可促進小鼠腸道[細 胞系分泌GLP-1。GPR119激動劑對糖尿病的治療作用已在 動物實驗中得到了論證。給大鼠口服GpR119激動劑可顯著 提高血液迴圈中的胰島素、GLP-1和GIP水準，同時降低 大鼠在接受糖耐量試驗後的血糖濃度。給予糖尿病大鼠 (ZDF rat)每日口服GPR119激動劑持續治療4週，苴空腹 血糖水準賴降低，糖耐量試驗的耐受性顯著提高，糖化 =紅蛋白水準顯著改善，同時伴有胰島素含量顯著增加， 二姨島功能有所改善。上述試驗結果均表明，應用 19激動劑可改善試驗動物的糖尿病症狀。 主要病的新型製劑，119糊^ 種制= 素（包括GLIM和GIP)和胰島素有多 似物未Γ必的作用。這一特徵是耐Dpp—4降解的GLrM類 4抑制劑所不具備的。此外，動物試驗提示， 95344 5 201213319 GPR119激動劑還具有控制體重的潛能。這一新型作用機制 可能為糖尿病治療帶來更新、更強的降糖效果，從而有助 於增加糖尿病藥物治療的多樣性，以滿足不同患者的需求。 目前公開了-系列的GPRU9激動劑的專利申請其 中包括 W02009055331、W02008070692 和 W02009126535。 儘管目前已公開了 -系列的治療糖尿病和代謝性综 合症的疾病的GPR119激動劑，但仍需要開發新的具有更好 的藥效的化合物，經過不斷努力，本發明設計具有通式⑴ 所示的結構的化合物，並發現具有_結構㈣合物表現 出優異的效果和作用。 【發明内容】 本發明的目的在於提供—種通式⑴所㈣化合物， 以及它們的錢異频、對㈣、非對映體、消旋體和可 藥用的鹽，以及代謝產物和代謝前體或前藥。Since the mechanism of action is glucose-dependent, it may not cause symptoms of low-cost patients during clinical treatment, and thus it is an ideal household medicine. Based on the GUM study, the dipeptide-based peptide IJKDPPimp preparation was also developed as a new type of π-type diabetes treatment. With the advancement of research, deep humans, especially the study of the process of insulin secretion by pancreatic cells, make G-protein coupled receptor GpRU9 a potential new target for the treatment of type II diabetes. G-protein coupled receptor 119 (GPR119) is an orphan receptor discovered by human gene sequencing analysis. Its gene is located on the X chromosome, mainly expressed in pancreatic islet cells and intestinal cells in pancreatic tissue. After further research 95344 4 201213319, it was found that oil 醯 ethanolamine (0ΕΑ) and fatty acid derivative oil lysolysed lecithin are endogenous ligands of GPR119. By binding to GPR119 and agonizing GPR119, it can increase the concentration of cyclic adenosine monophosphate in /3 cells, stimulate intracellular stimulation-secretion coupling, and promote the influx of about ions, thereby promoting the secretion of membrane vesicles into cells. outer. The tissue cell expression characteristics and functions of GPR119 suggest that initiation of this receptor promotes GLP-1 and insulin secretion, which contributes to glycemic control. This concept has been used in pharmacological studies related to diabetes. In an ex vivo perfusion test for isolating rat islets, the GPR119 agonist stimulates the first phase of insulin and the second phase of secretion' and this insulinotropic secretion has glucose dependence. In addition, GPR119 agonists can also promote the secretion of GLP-1 in the intestinal tract of mice [cell lineage. The therapeutic effects of GPR119 agonists on diabetes have been demonstrated in animal experiments. Oral administration of GpR119 agonists to rats significantly increased insulin, GLP-1, and GIP levels in the blood circulation, while reducing blood glucose concentrations in rats after receiving the glucose tolerance test. Diabetic rats (ZDF rats) were given oral GPR119 agonist daily for 4 weeks, the fasting blood glucose level decreased, the tolerance of glucose tolerance test was significantly improved, the saccharification=red albumin level was significantly improved, and the insulin content was significantly increased. Increased, the function of Erqi Island has improved. The above test results show that the application of 19 agonists can improve the symptoms of diabetes in test animals. A new type of preparation for major diseases, 119 pastes, ginseng (including GLIM and GIP), and insulin have many effects. This feature is not available in Drl-4 degrading GLrM class 4 inhibitors. In addition, animal testing suggests that 95344 5 201213319 GPR119 agonists also have the potential to control body weight. This new mechanism of action may lead to newer, more hypoglycemic effects in the treatment of diabetes, which will help increase the diversity of diabetes medications to meet the needs of different patients. Patent applications for the GPRU9 agonist of the series are currently disclosed, including W02009055331, W02008070692, and W02009126535. Although a series of GPR119 agonists for the treatment of diseases of diabetes and metabolic syndrome have been disclosed, there is still a need to develop new compounds with better pharmacodynamics, and the design of the present invention has been shown in the general formula (1) through continuous efforts. The structure of the compound and found to have a _ structure (tetra) compound exhibits excellent effects and effects. SUMMARY OF THE INVENTION The object of the present invention is to provide a compound of the formula (1) (IV), and their heteropoly, para (IV), diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and before metabolism. Body or prodrug.

(I) 其中： mu自環烧基'雜環基、芳基或雜芳基，其中該環 院基、雜環基、芳基或雜芳基各自獨立地視需要進一步被 一個或多個選自㈣、氰基、縣、絲、烯基、炔基、 函代烷基、羥烷基、環烷基、雜環基、芳基、雜芳基、一⑽ -NW、-C⑻R2、-C(0)0R2 “c(〇)NR3R4、_nr3c(〇)r4、 -NR3S(0)„R4、-S⑻ns(Q)mNR3R4 的取代基所取代； 95344 6 201213319 環B選自雜環基、芳基或雜芳基，其中該芳基或雜芳 基各自獨立地視需要進一步被一個或多個選自鹵素、氰 基、硝基、烧基、稀基、块基、画代烧基、經烧基、環烧 基、雜環基、芳基、雜芳基、=〇、-0R2、-(CH2)mNR3R4、_nr3r4、 -C(0)R2、-C(0)0R2、-C(〇)NR3R4、-NR3C(0)R4、-NR3S(0)nR4、 -S(0)mR2或-S(0)mNR3R4的取代基所取代； 環C選自：(I) wherein: mu is self-cyclic alkyl 'heterocyclyl, aryl or heteroaryl, wherein the ring, heterocyclyl, aryl or heteroaryl are each independently selected one or more as needed From (iv), cyano, county, silk, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, mono(10)-NW, -C(8)R2, -C (0)0R2 Substituted by a substituent of "c(〇)NR3R4, _nr3c(〇)r4, -NR3S(0)„R4, -S(8)ns(Q)mNR3R4; 95344 6 201213319 Ring B is selected from heterocyclic group, aryl group Or a heteroaryl group, wherein the aryl or heteroaryl group is independently further optionally, if necessary, one or more selected from the group consisting of halogen, cyano, nitro, alkyl, dilute, block, exemplified, burned Base, cycloalkyl, heterocyclic, aryl, heteroaryl, =〇, -0R2, -(CH2)mNR3R4, _nr3r4, -C(0)R2, -C(0)0R2, -C(〇) Substituted by a substituent of NR3R4, -NR3C(0)R4, -NR3S(0)nR4, -S(0)mR2 or -S(0)mNR3R4; Ring C is selected from:

L2選自一個鍵或-(CH2；^-4-’其中任意的一個-ch2-視需 要進一步被一個或多個〇、N(R7)或S所代替，或任意的一 個-CH2-視需要進一步被一個或多個選自烷基或鹵素的取 代基所取代； 當選自一個鍵時，則環A為芳基或雜芳基； R1選自烷基、環烷基、雜環基、芳基、雜芳基、_c(〇)R2 或-C(0)0R2，其中該烷基、環烷基、雜環基、芳基或雜芳 基各自獨立地視需要進一步被一個或多個選自鹵素、氰 基、硝基、烷基、滷代烷基、羥基、羥烷基、烯基、炔基、 環烷基、雜環基、芳基、雜芳基、-OR2、-NR3r4、_C(〇)r2、 -C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、-NR3S(0)mR4、-S(0)mR2 7 95344 201213319 或-S(0)mNR3R4的取代基所取代； R2選自氫原子、鹵素、氰基、硝基、燒基、_代燒茂、 經烧基、院氧基、環院基、雜環基、芳基或雜芳夷 ^ 該烷基、羥烷基、烷氧基' 環烷基或雜環基各自^立=中 需要進一步被一個或多個選自齒素、氰基、硝基、羥=現 烷基、烷氧基、烯基、炔基、環烷基、雜環基、# 二、 芳基的取代基所取代；L2 is selected from a bond or -(CH2; ^-4-' wherein any one -ch2- is further replaced by one or more 〇, N(R7) or S, or any one -CH2- as needed Further substituted by one or more substituents selected from alkyl or halogen; when selected from a bond, ring A is aryl or heteroaryl; R1 is selected from alkyl, cycloalkyl, heterocyclyl, aromatic Or a heteroaryl group, _c(〇)R2 or -C(0)0R2, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently selected one or more as needed From halogen, cyano, nitro, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR2, -NR3r4, _C(〇)r2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -S(0)mR2 7 95344 201213319 or -S(0)mNR3R4 Substituted by a substituent; R2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a decyl group, a decyl group, an alkoxy group, a ring-based group, a heterocyclic group, an aryl group or a heterocyclic group. ^ The alkyl, hydroxyalkyl, alkoxy 'cycloalkyl or heterocyclic group each need further Substituted by one or more substituents selected from the group consisting of dentate, cyano, nitro, hydroxy=present alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, #二, aryl ;

R3和R4各自獨立地選自氫原子、烷基、烯基、炔基、 環烷基、雜環基、芳基或雜芳基，其中該烷基、烯基、炔 基、環烷基、雜環基、芳基或雜芳基各自獨立視需要進一 步被一個或多個選自烷基、齒素、氧代、烯基、炔基、硝 基、氰基、環烷基、雜環基、芳基、雜芳基、_〇R7、_nr8r9、 -C(0)R7、-C(0)0R7、-C(0)NR8R9、-NR8C(0)R9、-NR8S(〇)mR9、 -S(0)mR7或-S(0)mNR8R9的取代基所取代； 或者，R3和R4與相連接的氮原子形成雜環基，其中該 雜環基内含有一個或多個N、〇或S(0)m雜原子，並且該雜 環基視需要進一步被一個或多個選自烷基、鹵素、氧代、 烯基、炔基、硝基、氰基、環烷基、雜環基、芳基、雜芳 基、-OR7、-NR8R9、-C(0)R7、、_c(〇)nr8r9、 -NRC(0)R、-NR8S(0)mR9、-S(〇)raR7 或-S(〇)nNR8R9 的取代基 所取代； R5選自氫原子或烷基； R6選自氫原子、烷基、豳素、函代烷基、烯基、炔基、 硝基、氰基、環烷基、雜環基、芳基、雜芳基、_〇R2、_NR3R4、 8 95344 201213319 -C(0)R2、-C(0)0R2、-c(o)nr3r4、-nr3c(o)r4、-nr3s(o%r4、 -S(0)nR或-S(0)inNR3R4 ;或者兩個r6 一起形成氧代； R7、R8和R9各自獨立的選自氫原子、烷基、環烷基、 雜環基、芳基或雜芳基； Z 選自單鍵、雙鍵、-C(〇)-、-C=C(R7)、-〇-、_n(R7)_ 或-C(0)-N(R7)-，當q為〇時，z不能為雙鍵； m是0、1或2 ; P為0、1或2 ; q為0、1或2 ; r為0、1或2 ; s為0、1或2 ;且 u為0、1或2。 本發明涉及一種通式（I)所示的化合物或其可藥用的 鹽’其中包括通式（II)所示的化合物或其可藥用的趟.R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, The heterocyclic group, the aryl group or the heteroaryl group are each further independently selected from one or more selected from the group consisting of an alkyl group, a dentate, an oxo group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, and a heterocyclic group. , aryl, heteroaryl, _〇R7, _nr8r9, -C(0)R7, -C(0)0R7, -C(0)NR8R9, -NR8C(0)R9, -NR8S(〇)mR9, - Substituting a substituent of S(0)mR7 or -S(0)mNR8R9; or R3 and R4 form a heterocyclic group with a nitrogen atom to which the ring is attached, wherein the heterocyclic group contains one or more N, 〇 or S (0)m hetero atom, and the heterocyclic group is further selected from one or more selected from the group consisting of an alkyl group, a halogen, an oxo group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -OR7, -NR8R9, -C(0)R7, _c(〇)nr8r9, -NRC(0)R, -NR8S(0)mR9, -S(〇)raR7 or -S Substituting (n) a substituent of nNR8R9; R5 is selected from a hydrogen atom or an alkyl group; R6 is selected from a hydrogen atom, an alkyl group, a halogen, a haloalkyl group, an alkenyl group Alkynyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, _〇R2, _NR3R4, 8 95344 201213319 -C(0)R2, -C(0)0R2, -c( o) nr3r4, -nr3c(o)r4, -nr3s(o%r4, -S(0)nR or -S(0)inNR3R4; or two r6 together form an oxo; R7, R8 and R9 are each independently selected From a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; Z is selected from the group consisting of a single bond, a double bond, -C(〇)-, -C=C(R7), -〇-, _n(R7)_ or -C(0)-N(R7)-, when q is 〇, z cannot be a double bond; m is 0, 1 or 2; P is 0, 1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2; and u is 0, 1 or 2. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof Including the compound of the formula (II) or its pharmaceutically acceptable hydrazine.

(II) 其中： 環A選自：(II) where: ring A is selected from:

95344 9 20121331995344 9 201213319

R10相同或不同地選自鹵素、氰基、烷基、鹵代烷基、 羥烷基、環烷基、雜環基、芳基、雜芳基或-OR2 ; R選自氫原子、鹵素、氰基、硝基、烷基、烯基、炔 基、齒代烷基、羥烷基、環烷基、雜環基、芳基、雜芳基、 -OR、-NR3R4、-C(〇)R2、-c(〇)〇R2、-c(〇)NR3R4、-NR3C(0)R4、 -NR3S(0)mR4、-SCO)# 或-s(〇)nNR3R4 ; L!、L2 ’ R1至R5的定義如通式（1)化合物中所述； m是0、1或2 ; η是 0、1、2、3 或 4; Ρ為0、1或2 ;且 q為0、1或2。 本發明涉及一種通式（I)所示的化合物或其可藥用的 鹽，其中包括通式（III)所示的化合物或其可藥用的鹽.R10 is the same or differently selected from halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -OR2; R is selected from a hydrogen atom, a halogen, a cyano group , nitro, alkyl, alkenyl, alkynyl, dentate alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -NR3R4, -C(〇)R2 -c(〇)〇R2, -c(〇)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -SCO)# or -s(〇)nNR3R4 ; L!, L2 'R1 to R5 The definition is as described in the compound of the formula (1); m is 0, 1 or 2; η is 0, 1, 2, 3 or 4; Ρ is 0, 1 or 2; and q is 0, 1 or 2. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (III) or a pharmaceutically acceptable salt thereof.

(ΙΠ) \r， 95344 10 201213319 其中： 環A選自：(ΙΠ) \r, 95344 10 201213319 where: Ring A is selected from:

環B選自：Ring B is selected from:

相同或不同地選自鹵素、氰基、烷基、函代烷基、 羥烷基、％烷基、雜環基、芳基、雜芳基或_〇R2 ; R選自氫原子、彘素、氰基、硝基、烷基、烯基、炔 基、iS代烷基、羥烷基、環烷基、雜環基、芳基、雜芳基、 -OR2、-NR3R4、-C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、 -M3S(0)mR4、-S(0%R2 或-S(0)nNR3R4 ; Z 選自單鍵、雙鍵、-C(0)---C=C(R7)、-0---N(R7)- 或-C(0)-N(R7)-，當q為〇時，Z不能為雙鍵； L·、L2，R1至R4、R7的定義如通式（I)化合物中所述； m是0、1或2 ; 11 95344 201213319 η是 0、1、2、3 或 4; P為0、1或2 ;且 u為〇、ι或2。 本發明涉及一種通式（I)所示的化合物或其可藥用的 鹽’其中包括通式（IV )所示的化合物或其可藥用的鹽：The same or differently selected from the group consisting of halogen, cyano, alkyl, functional alkyl, hydroxyalkyl, % alkyl, heterocyclic, aryl, heteroaryl or 〇R2; R is selected from a hydrogen atom, a halogen , cyano, nitro, alkyl, alkenyl, alkynyl, iS alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR2, -NR3R4, -C(0 R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -M3S(0)mR4, -S(0%R2 or -S(0)nNR3R4; Z is selected from a single bond , double bond, -C(0)---C=C(R7), -0---N(R7)- or -C(0)-N(R7)-, when q is 〇, Z cannot Is a double bond; L·, L2, R1 to R4, R7 are as defined in the compound of formula (I); m is 0, 1 or 2; 11 95344 201213319 η is 0, 1, 2, 3 or 4; P is 0, 1 or 2; and u is 〇, ι or 2. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (IV) or Its pharmaceutically acceptable salt:

(IV) r N—R1(IV) r N-R1

其中： 環A選自：Where: Ring A is selected from:

環B選自：Ring B is selected from:

95344 12 201213319 R11選自氫原子、鹵素、氰基、硝基、烷基、烯基、炔 基、齒代烷基、羥烷基、環烷基、雜環基、芳基、雜芳基、 -OR2、-NR3R4、-C(0)R2、-C(0)0R2、-C(0)NR3R4、 -NR3C(0)R4、-NR3S(0)mR4、-S(0)mR2 或-S(0)mNR3R4 ;95344 12 201213319 R11 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a dentylalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR2, -NR3R4, -C(0)R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -S(0)mR2 or -S (0) mNR3R4;

Li、L2 ’ R1至R5的定義如通式（！）化合物中所述； m是0、1或2 ; π是 0、1、2、3 或 4;Li, L2' R1 to R5 are as defined in the compound of the formula (!); m is 0, 1 or 2; π is 0, 1, 2, 3 or 4;

P為0、1或2，p與q相加至少為i ; r為0、1或2’ms相加至少為1;且 s為 〇、]_ 或 2。 本發明涉及一種通式r τ Ν ~ λ Λ(Ι)所示的化合物或其可藥用的P is 0, 1 or 2, p is added to q at least i; r is 0, 1 or 2'ms is added at least 1; and s is 〇, ]_ or 2. The present invention relates to a compound represented by the formula r τ Ν ~ λ Λ (Ι) or a pharmaceutically acceptable compound thereof

其中包括通式（V 〇1厅不的化合物或其可藥用的鹽：These include compounds of the formula (V 〇1) or pharmaceutically acceptable salts thereof:

95344 13 201213319 環B選自：95344 13 201213319 Ring B is selected from:

R為雜芳基，其中該雜芳基視需要進一步被一個或多 個選自S素、烷基或齒代烷基的取代基所取代； R1()為鹵素； R"選自氫原子、鹵素、氰基、烷基、-C(0)R2、-C(0)0R2、 - c(o)nr3r4、 -NR3C(0)R4、-NR3S(0)mR4、-S(0)mR2 或-S(0)_R3R4 ; m是0、1或2 ; n是 0、1、2、3或 4 ; R2至R4的定義如通式（I I)化合物中所述。 本發明涉及一種通式（I)所示的化合物或其可藥用的 鹽’其中包括通式（VI)所示的化合物或其可藥用的鹽：R is a heteroaryl group, wherein the heteroaryl group is further substituted with one or more substituents selected from the group consisting of S, alkyl or dentate alkyl as desired; R1() is a halogen; R" is selected from a hydrogen atom, Halogen, cyano, alkyl, -C(0)R2, -C(0)0R2, -c(o)nr3r4, -NR3C(0)R4, -NR3S(0)mR4, -S(0)mR2 or -S(0)_R3R4; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; R2 to R4 are as defined in the compound of the formula (II). The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (VI) or a pharmaceutically acceptable salt thereof:

其中：環B、R、R1D或η的定義如通式（V)化合物中所 述。 本發明涉及一種通式（I)所示的化合物或其可藥用的 95344 14 201213319 鹽，其中包括通式（VII)所示的化合物或其可藥用Wherein: the ring B, R, R1D or η is as defined in the compound of the formula (V). The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable 95344 14 201213319 salt thereof, which comprises a compound of the formula (VII) or a pharmaceutically acceptable substance thereof

其中：環B、R1、R10或n的定義如通式（V)中所述。 本發明涉及一種通式（I)所示的化合物或其可藥用的 鹽’其中包括通式（VIII)所示的化合物或其可藥用的越：Wherein: the ring B, R1, R10 or n is as defined in the formula (V). The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (VIII) or a pharmaceutically acceptable compound thereof:

其中：環B、R1、R1Q或η的定義如通式（V)中所述。 本發明的較佳方案’一種通式（vii)所示的化合物或 其可藥用的鹽，其中環β為苯基。 本發明的較佳方案’一種通式（νπι)所示的化合物或 其可藥用的鹽，其中環Β為Wherein: the ring B, R1, R1Q or η is as defined in the formula (V). Preferred Embodiments of the Invention A compound of the formula (vii) or a pharmaceutically acceptable salt thereof, wherein the ring β is a phenyl group. A preferred embodiment of the invention, a compound of the formula (νπι) or a pharmaceutically acceptable salt thereof, wherein the ring is

本發明的較佳方案，一種通式（VII)或通式（VIII)所 述的化合物或其可藥用的鹽，其中： R選自氫原子、鹵素、氰基、烷基、-C(0)R2、 -C(0)NR3R4、-c(〇)OR2、 m是ο、1或2。 S(0)mR2 ; 95344 201213319 本發明的較佳方案，一種通式（VII)或通式（VIII)所 述的化合物或其可藥用的鹽，其中Ru為-S(0)mR2，m是1 或2。 —本發明的較佳方案，一種通式所示的化合物或其 可藥用的鹽’其#環a為雜環基、芳基或雜芳基。 —本發明的較佳方案’―種通式⑴所示的化合物或其 可藥用的鹽，其中環八為雜環基、芳基或雜芳基，環A視A preferred embodiment of the invention, a compound of the formula (VII) or formula (VIII), or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an alkyl group, and -C ( 0) R2, -C(0)NR3R4, -c(〇)OR2, m is ο, 1 or 2. S(0)mR2; 95344 201213319 A preferred embodiment of the invention, a compound of the formula (VII) or formula (VIII), or a pharmaceutically acceptable salt thereof, wherein Ru is -S(0)mR2,m Is 1 or 2. - A preferred embodiment of the invention, a compound of the formula or a pharmaceutically acceptable salt thereof, wherein #环a is a heterocyclic group, an aryl group or a heteroaryl group. - A preferred embodiment of the invention - a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein the ring VIII is a heterocyclic group, an aryl group or a heteroaryl group, and the ring A is regarded

為要被個或多個選自齒素、氰基、-C(0)R2、-C(0)NR3R4、 C(0)0R或-S(0)mR2的取代基所取代。 “本發明的較佳方案，-種通式⑴所示的化合物或其 可藥用的*其中環A為雜環基或雜芳基環A視需要被 一個ΚΟ%!?2取代，m是1或2。 —不赞㈣難方案，—贿式⑴所㈣化合物或其 可樂用的鹽，其中環八視需要被一個或多個氰基或豳素所 取代。 本發明的較佳方案，一锸s斗 、一 系種通式⑴、（II)、（III)或 (IV)所示的化合物或其可单 Γυ 用的鹽，其中Li為一個鍵或 一LH2- 0 一種通式（D、（II)、（III)或（IV) 的鹽’其中1^為-〇-、-CH2-、 本發明的較佳方案， 所示的化合物或其可藥用 -N(R7)-CH2-或-〇-CH2-。 本發明的較佳方案，一錄 ⑯-AWU 人& 種通式 0)^11)4111)4(] 所不的化合物或其可藥用的赜 士欲ηΒΑΑ± ^ 其中 R 為-C(0)0R2。 本發明的較佳方案，一種 硬通式（Ι)、（Π)、（ΙΙΙ)或（] 95344 16 201213319 所示的化合物或其可藥用的鹽，其中Rl為·To be substituted by one or more substituents selected from the group consisting of dentate, cyano, -C(0)R2, -C(0)NR3R4, C(0)0R or -S(0)mR2. "A preferred embodiment of the present invention, a compound of the formula (1) or a pharmaceutically acceptable compound thereof wherein ring A is a heterocyclic group or a heteroaryl ring A is optionally substituted by a ΚΟ%!?2, m is 1 or 2. - 不赞(四) difficult scheme, bribe (1) (4) a compound or a salt thereof for use in cola, wherein the ring is required to be substituted by one or more cyano or halogen. A compound represented by the formula (1), (II), (III) or (IV) or a monovalent salt thereof, wherein Li is a bond or a formula of LH2- 0 ( A salt of D, (II), (III) or (IV) wherein 1 is -〇-, -CH2-, a preferred embodiment of the invention, or a pharmaceutically acceptable -N(R7)- CH2- or -〇-CH2-. A preferred embodiment of the invention, a 16-AWU human & formula 0) ^ 11) 4111) 4 () compound or its medicinal gentleman desire ηΒΑΑ± ^ wherein R is -C(0)0R2. A preferred embodiment of the invention, a compound of the formula (Ι), (Π), (ΙΙΙ) or () 95344 16 201213319 or a pharmaceutically acceptable compound thereof Salt, where Rl is

鲁Lu

_本發明的較佳方案，—種通式⑴、⑴）、（1⑴或（ιν) 所示的化合物或其可藥㈣鹽，其中絲或雜芳基， 其中該烧基或雜芳基視需要進—步被—個或多個選自齒 素、羥基、烷基或g代烷基的取代基所取代。 一本發明的較佳方案’—種通式⑴、⑴）、〇⑴或（ιν) 所示的化合物或其可藥用的鹽，其中^為 KI.a preferred embodiment of the invention, a compound of the formula (1), (1)), (1(1) or (ιν) or a pharmacologically acceptable salt thereof, wherein a silk or a heteroaryl group, wherein the alkyl or heteroaryl group It is required to be further substituted by one or more substituents selected from the group consisting of dentate, hydroxyl, alkyl or gamma alkyl. A preferred embodiment of the invention - a general formula (1), (1)), hydrazine (1) or (ιν) A compound or a pharmaceutically acceptable salt thereof, wherein ^ is KI.

R1〇)n I， -K 0R1〇)n I, -K 0

10 或 ; R相同或不同地選自齒素、烷基、環烷基或鹵代烷基 的取代基所取代；且 π是 〇、1、2、3 或 4。 本發月的較佳方案’一種通式（II)所示的化合物或其 可藥用的鹽，其中P和q為0或卜 本發明的較佳方案，一種通式（ΠΙ)所示的化合物或 其可樂用的鹽，其中ζ選自—個單鍵或一〇_。 本發明的典型化合物包括，但不限於： 17 95344 20121331910 or R is substituted with a substituent selected from the group consisting of dentate, alkyl, cycloalkyl or haloalkyl; and π is 〇, 1, 2, 3 or 4. A preferred embodiment of the present invention is a compound of the formula (II) or a pharmaceutically acceptable salt thereof, wherein P and q are 0 or a preferred embodiment of the invention, a formula of the formula (ΠΙ) A salt for a compound or a cola thereof, wherein the hydrazine is selected from a single bond or a hydrazine. Typical compounds of the invention include, but are not limited to: 17 95344 201213319

實施例編號 化合物結構與命名 1 inn vCTO〇*N N ο (3a疋6550-5-1:2-溴-4-[(4-曱磺醯基哌嗪 -1-基）曱基]苯氧基]-2-(5-乙基嘧啶-2-基） _3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]D比口各 2 Ν / ·0 (3以?，63^-5-(:2-溴-4-[(4-曱磺醯基哌嗪 -1-基）曱基]苯氧基]-2-(5-乙基嘧啶-2-基） _3, 3a，4, 5, 6, 6<3-六氮~1Η-環戍並[c]°比口各 3 (3Μ，6a«-5-[2-氯-4-[(4-曱磺醯基哌嗪 -1-基）曱基]苯氧基]-2-(5-乙基嘧啶-2-基） -3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]α比口各 4 F (3城63«-5-[2,6-二氟-4-(4-曱磺醯基苯 基）苯氧基]-2-(5-乙基B密咬-2-基） _3, 3<9, 4, 5, 6, 6习-六說-1H-環戍並[〇]°比口各 5 ^'〇 (33尤 6a«-5-[[2,6-二氟-4-(4-甲磺醯基苯 基）苯氧基]曱基]-2-(5-乙基嘧啶-2-基） -3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[<:]°比口各 18 95344 201213319EXAMPLES No. Compound Structure and Nomenclature 1 inn vCTO〇*NN ο (3a疋6550-5-1: 2-Bromo-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy ]-2-(5-ethylpyrimidin-2-yl) _3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]D is 2 Ν / ·0 (3 ?,63^-5-(:2-Bromo-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethylpyrimidin-2-yl) ) _3, 3a,4, 5, 6, 6<3-hexanitrogen~1Η-cycloindole[c]°3 (3Μ,6a«-5-[2-chloro-4-[(4- Sulfosylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3,3a,4,5, 6, 6a-hexahydro-1H- Cyclopenta[c]α is 4 F (3 city 63 «-5-[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]-2-(5- Ethyl B-Bite-2-yl) _3, 3<9, 4, 5, 6, 6 Xi-Six--1H-cyclic 戍[〇]° than each mouth 5 ^'〇 (33 especially 6a«- 5-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-2-(5-ethylpyrimidin-2-yl)-3, 3a,4 , 5, 6, 6a-hexahydro-1H-cyclopenta[<:]° ratio 18 99344 201213319

6 (3a7?，6a5〇-5-[2-溴-4-[ (4-甲橫醯基0辰嗓 -卜基）曱基]苯氧基]-3, 3a，4, 5, 6, 6a-六氫 -1H-環戊並[c]n比洛-2-缓酸第三丁酯 7 )、〇會仝 (1尤55*)-6-[ [2-氣-4-[ (4-甲績酿基旅嘻_1_ 基）曱基]本氧基]曱基]-3-(5-乙基癌咬-2-基）-3-氮雜雙環並[3. 1.0]己烷 8 F Η^νΛΧ^ ^S"o (1疋5幻-6-[[2,6-二氟-4-(4-甲磺醯基苯 基）本氧基]曱基]-3-(5-乙基癌咬-2-基）-3-氮雜雙環並[3.1.0]己烷 9 3-L2, 6-二氟-4-(4-曱續酿基苯基）苯氧基] -8-氮雜雙環並[3. 2. Π辛烷-8-羧酸第=丁酯 10 3-[2, 6-二氟-4-(4-甲續醯基苯基）苯氧基] -8-(5-乙基嘧啶-2-基）-8-氮雜雙環並 _ [3.2.1]辛烷 95344 19 2012133196 (3a7?,6a5〇-5-[2-bromo-4-[(4-methyl fluorenyl)] phenoxy]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]nbilo-2-sodium tartrate 7), 〇 同 (1 especially 55*)-6-[ [2- gas-4-[ ( 4-甲 酿 嘻 嘻 _ _ _ ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] Alkyl 8 F Η^νΛΧ^ ^S"o (1疋5幻-6-[[2,6-difluoro-4-(4-methylsulfonylphenyl)-hydroxy]indolyl]-3- (5-ethylcarban-2-yl)-3-azabicyclo[3.1.0]hexane 9 3-L2,6-difluoro-4-(4-anthracenephenyl)phenoxy -8-Azabicyclo[3. 2. Octane-8-carboxylic acid = butyl ester 10 3-[2,6-difluoro-4-(4-methylnonylphenyl)benzene Oxy]-8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane 95344 19 201213319

11 ，'srcr〇C _ ° η^ν^ν>λ 3-[2-氯-4-[(4-甲磺醯基哌嗪-1-基）曱基] 苯氧基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環 並[3.2. 1]辛烷 12 (1尤 5幻-3-(5-乙基嘧啶-2-基）-6-[[5-(4-曱磺醯基苯基）吼嗪-2-基]氧甲基]-3-氮雜 雙環並[3. 1. 0]己烷 13 ΓΥ〇、Ά v〇^ Λ (1^550-3-(5-乙基嘧啶-2-基）-6-[[6-(4-曱磺醯基苯基）-3-吼啶基]氧甲基]-3-氮雜 雙環並[3. 1. 0]己烷 14 vCnc〇X人冬 / .0 (3a_/?，6a«-5-[2-溴-4-[(4-曱磺醯基哌嗪 -1-基）曱基]笨氧基]-3, 3a，4, 5, 6, 6a-六氫 -1)7-環戊並[c] αΛ^_2-敌酸第三丁酉旨 15 ，s'c〇X*u /、·0 (35尤6a«-5-[2-氯-4-[(4-曱磺醯基哌嗪 -1-基）曱基]苯氧基]-3, 35, 4, 5, 6, 6a-六氫 -1H-環戊並〇]吡咯-2-羧酸第三丁酯 20 95344 20121331911 , 'srcr〇C _ ° η^ν^ν>λ 3-[2-chloro-4-[(4-methylsulfonylpiperazin-1-yl)indolyl]phenoxy]-8-( 5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane 12 (1 especially 5 magic-3-(5-ethylpyrimidin-2-yl)-6-[[5 -(4-oxasulfonylphenyl)pyridazin-2-yl]oxymethyl]-3-azabicyclo[3.1.0]hexane 13 ΓΥ〇, Ά v〇^ Λ (1^ 550-3-(5-ethylpyrimidin-2-yl)-6-[[6-(4-oxasulfonylphenyl)-3-acridinyl]oxymethyl]-3-azabicyclo [3. 1. 0] Hexane 14 vCnc〇X human winter / .0 (3a_/?,6a«-5-[2-bromo-4-[(4-oxasulfonylpiperazin-1-yl)曱基] 笨 oxy]-3, 3a,4, 5, 6, 6a-hexahydro-1)7-cyclopenta[c] αΛ^_2-dicarboxylic acid third butyl quinone 15 , s'c〇X *u /, ·0 (35 especially 6a«-5-[2-chloro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-3, 35, 4, 5, 6, 6a-hexahydro-1H-cyclopentazepine]pyrrole-2-carboxylic acid tert-butyl ester 20 95344 201213319

16 F (17Ρ，55·)-6-[[2, 6-二氟-4-(4-曱磺醯基苯 基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己 烷-3-羧酸第三丁酯 17 F h又Λ (1 尤 5Λ-6-[[4-(4-氰基苯基）-2, 6-二氟-苯 氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯 18 3-[2, 6-二氟-4-(4-曱確酿基苯基）苯氧基] -8-氮雜雙環並[3. 2.1]辛烷-8-羧酸第三丁酯 19 (1疋 5|5*)_6_[[2, 6-二氟_4_(4_曱續酿基苯 基）苯氧基]甲基]-3-氮雜雙環並[3.1.0]己 烷-3-羧酸-1-曱基環丙基酯 20 〇XVxu F 9-[2, 6-二氟-4-(4-曱磺醯基苯基）笨氧 基]-7-氧雜-3-氮雜雙環並[3. 3.1 ]壬烧-3-羧酸第三丁酯 21 9534416 F (17Ρ,55·)-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1.0 ] Hexane-3-carboxylic acid tert-butyl ester 17 F h Λ (1 Λ5Λ-6-[[4-(4-cyanophenyl)-2,6-difluoro-phenoxy]indolyl ]-3-Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 18 3-[2,6-difluoro-4-(4-indoleylphenyl)benzene Oxy] -8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 19 (1疋5|5*)_6_[[2, 6-difluoro_4_(4_曱) Continuation of phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid-1-mercaptocyclopropyl 20 〇XVxu F 9-[2, 6-Difluoro-4-(4-oxasulfonylphenyl) phenyloxy]-7-oxa-3-azabicyclo[3.3.1] oxime-3-carboxylic acid tert-butyl ester 21 95344

t 201213319t 201213319

21 (1疋55)-6-[[2, 6-二氟-4-(4-甲磺醯基苯 基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己 烷-3-羧酸-1-曱基環丁基酯 22 Ν (1 尤 550-3-(5-乙基嘧啶-2-基）-6-[ [6-(3-°比啶基）-3-。比啶基]氧甲基]-3-氮雜雙環並 [3.1. 0]己烷 23 〇> (1尤 5Λ-3-(5-乙基嘧啶-2-基）-6-[[5-(3-氟-4-吼啶基）吼嗪-2-基]氧曱基]-3-氮雜雙 環並[3.1.0]己烷 24 (1疋550-3-(5-乙基嘧啶-2-基）-6-[(5-嘧啶 -5-基-吡啶-2-基）氧甲基]-3-氮雜雙環並 [3. 1. 0]己烷 25 F Η IX /S〇21 (1疋55)-6-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0] Alkyl-3-carboxylic acid-1-decylcyclobutyl ester 22 Ν (1 eu 550-3-(5-ethylpyrimidin-2-yl)-6-[ [6-(3-°-pyridyl)) -3-.pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 23 〇> (1 especially 5Λ-3-(5-ethylpyrimidin-2-yl)-6 -[[5-(3-fluoro-4-acridinyl)pyridazin-2-yl]oxyindolyl]-3-azabicyclo[3.1.0]hexane 24 (1疋550-3-( 5-ethylpyrimidin-2-yl)-6-[(5-pyrimidin-5-yl-pyridin-2-yl)oxymethyl]-3-azabicyclo[3.1.0]hexane 25 F Η IX /S〇

22 95344 20121331922 95344 201213319

(1尤5幻-3-(5-乙基嘧啶-2-基）-6-[[2-氟 -4-(4-T磺醯基苯基）苯氧基]曱基]-3-氮雜 雙環並[3. 1. 0]己烷 26 (3成6Μ)-2-(5-乙基嘧啶-2-基）-5-[2-氟 -4-(4-甲磺醯苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]n比嘻 27 '^：xQNl：r (33疋 6a®-2-(5-乙基嘧啶-2-基）-5-[2-氟 -4_(4-曱磺醯苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯 28 F H (1疋 5Λ-6-[[2, 6-二氟-4-(3-氟-4-吡啶基) 苯氧基]甲基]-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1.0]己烷 29 (1疋5幻-6-[[2, 6-二氟-4-(4-甲磺醯基苯 基）苯氧基]甲基]-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 30 F(1 especially 5 magic-3-(5-ethylpyrimidin-2-yl)-6-[[2-fluoro-4-(4-Tsulfonylphenyl)phenoxy]indolyl]-3- Azabicyclo[3.1.0]hexane 26 (3-6 Μ)-2-(5-ethylpyrimidin-2-yl)-5-[2-fluoro-4-(4-methanesulfonate) Phenyloxy]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]n than 嘻27 '^:xQNl:r (33疋6a®-2-(5 -ethylpyrimidin-2-yl)-5-[2-fluoro-4_(4-oxasulfonylphenyl)phenoxy]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclo Pentico[c]pyrrole 28 FH (1疋5Λ-6-[[2,6-difluoro-4-(3-fluoro-4-pyridyl)phenoxy]methyl]-3-(5-B Pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 29 (1疋5幻-6-[[2,6-difluoro-4-(4-methylsulfonylphenyl) Phenoxy]methyl]-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 30 F

23 95344 20121331923 95344 201213319

(1及，55}_6-[[2, 6_二氟_4_(4_甲確酿基苯 基）笨氧基]曱基]_3-[3-氟-5-(三氟曱 基）-2-吡啶基]-3-氮雜雙環並[3. 1. 0]己烷 31 F H XT 4-[4-[[(1疋 5Λ-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3.1.0]己烷-6-基]曱氧基] _3, 5-二氟-苯基]节腈 32 F 4-[4-[[(l疋 55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]甲氧基] -3, 5-二氟-苯基]-2-IL-节腈 33 。，/ / .0 (1 疋 55)-3-(5-乙基嘧啶-2-基）-6-[[4-(4-甲磺醯苯基）苯氧基]甲基]-3-氮雜雙環並 [3. 1.0]己烷 34 V N-i， 5-[(1尤 5«-6-[[2, 6-二氟-4-(4-甲磺醯基 苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1.0] 己烷-3-基]-3-異丙基-1，2, 4-噁二唑 24 95344 201213319(1 and, 55}_6-[[2,6-difluoro_4_(4_methyl-phenylene)phenyloxy]indolyl]-3-[3-fluoro-5-(trifluoromethyl) -2-pyridyl]-3-azabicyclo[3.1.0]hexane 31 FH XT 4-[4-[[(1疋5Λ-3-(5-ethylpyrimidin-2-yl)) 3-Azabicyclo[3.1.0]hexane-6-yl]nonyloxy]_3,5-difluoro-phenyl]ffinonitrile 32 F 4-[4-[[(l疋55)- 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]-3,5-difluoro-phenyl]-2- IL-nickel nitrite 33, / / .0 (1 疋 55)-3-(5-ethylpyrimidin-2-yl)-6-[[4-(4-methylsulfonylphenyl)phenoxy] Methyl]-3-azabicyclo[3.1.0]hexane 34 V Ni, 5-[(1 especially 5«-6-[[2, 6-difluoro-4-(4-methylsulfonyl) Phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole 24 95344 201213319

35 NC 4-[5-[[(1尤 5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]甲氧基]-2-0比啶基]苄腈 36 F Η IX (1尤5幻-6-[(2, 6-二氟-4-嘧啶-5-基-苯氧 基）曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3.1.0]己烷 37 〇 Η Τ〇λ^νΛ^ 3-[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧 基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環並 [3.2. 1]辛烷 38 c/5-(3ay?，6沾)-5-[2-氟-4-[ (4-曱磺醯基哌 嗪-1-基）甲基]苯氧基]-3, 35, 4, 5, 6, 65-六 氫-1H-環戊並[c]吡咯-2-羧酸第三丁酯 39 >οό：^νΑΛ 0 tra/35~(33及，6a5)_5_[2-亂_4_[ (4-曱續酿基 哌嗪-1-基）甲基]苯氧基]-3, 3a，4, 5, 6, 6a-六氩-1H-環戊並[c]吡咯-2-羧酸第三丁酯35 NC 4-[5-[[(1)5-5-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy) ]-2-0-pyridyl]benzonitrile 36 F Η IX (1 especially 5 magic-6-[(2, 6-difluoro-4-pyrimidin-5-yl-phenoxy)indolyl]-3- (5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 37 〇Η Τ〇λ^νΛ^ 3-[2,6-difluoro-4-(4-曱Sulfomethylphenyl)phenoxy]-8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane 38 c/5-(3ay?,6 dip) -5-[2-Fluoro-4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy]-3, 35, 4, 5, 6, 65-hexahydro-1H- Cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 39 >οό:^νΑΛ 0 tra/35~(33和,6a5)_5_[2-乱____ Pyrazin-1-yl)methyl]phenoxy]-3,3a,4,5, 6, 6a-hexa-argon-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester

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40 Νχν:在A：r F 4-[4-[ [(3出?，6^5)-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並比 洛_5-基]氧基]-3, 5-二敦-苯基]苯腈 41 F 9-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧 基]-3-(5-乙基嘧啶-2-基）7-氧雜-3-氮雜雙 環並[3. 3. 1]壬烷 42 °r°i\ 0"s\ 3-[[2, 6_二氟-4-(4-曱續酿基苯基）苯氧基] 甲基]-8-氮雜雙環並[3. 2.1]辛烷-8-羧酸第 三丁酯 43 /、 3_[[2，6-二氣_4-(4-曱確酿基苯基）苯氧基] 曱基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環並 [3.2. 1]辛烷 44 / '0 (1 疋 5^-3-(5-乙基嘧啶-2-基）-6-[[5-(4-曱磺醯基苯基)-2-吼啶基]氧曱基]-3-氮雜 雙環並[3. 1.0]己烷 26 95344 20121331940 Νχν: at A:r F 4-[4-[ [(3 out?, 6^5)-2-(5-ethylpyrimidin-2-yl)-3, 3a,4, 5, 6, 6a -hexahydro-1H-cyclopentabicyclo-5-yl]oxy]-3, 5-di-phenyl]benzonitrile 41 F 9-[2,6-difluoro-4-(4-A Sulfomethylphenyl)phenoxy]-3-(5-ethylpyrimidin-2-yl)7-oxa-3-azabicyclo[3.3.1]nonane 42 °r°i\ O'quot;s\ 3-[[2,6-Difluoro-4-(4-fluorenylphenyl)phenoxy]methyl]-8-azabicyclo[3.2.1]octane-8 -carboxylic acid tert-butyl ester 43 /, 3_[[2,6-diox_4-(4-indolylphenyl)phenoxy]indolyl]-8-(5-ethylpyrimidine-2 -yl)-8-azabicyclo[3.2.1]octane 44 / '0 (1 疋5^-3-(5-ethylpyrimidin-2-yl)-6-[[5-(4- Sulfosylphenyl)-2-acridinyl]oxanyl]-3-azabicyclo[3.1.0]hexane 26 95344 201213319

45 γ43νΛ^ nJT (1疋5«-3-(5-乙基嘧啶-2-基）-6-[(5-噠嗪 -4-基-2-吡啶基）氧曱基]-3-氮雜雙環並 [3. 1.0]己烷 46 “ Η Ν=ν' CN (3a疋 63^-2-(5-乙基嘧啶-2-基）-5-[4-(四 β坐—1—基）苯氧基]_3, 3a，4，5，6，6a_六氮-1H-環戊並[c]^p各 47 N-/ Η Ν=ν r . (3dP，6a5〇-2-(5-乙基嘧啶-2-基）-5-[4-(四 〇坐一1一基）苯氧基]_3，3a，4，5，6，6<3_六氮-1H-環戊並[c]D比洛 48 3-異丙基-5-[(iy?，55)-6-[[5-(4-甲磺醯基 苯基）-2-n比啶基]氧曱基]-3-氮雜雙環並 [3. 1. 0]己烧-3_基]-1，2, 4_α惡二β坐 49 Η (1 疋 550-3-(5-乙基嘧啶-2-基）-6-[[6-(4-吡啶基）-3-吡啶基]氧曱基]-3-氮雜雙環並· [3.1. 0]己烧45 γ43νΛ^ nJT (1疋5«-3-(5-ethylpyrimidin-2-yl)-6-[(5-pyridazin-4-yl-2-pyridyl)oxyindolyl]-3-nitrogen Heterobicyclo[3.1.0]hexane 46 " Η Ν=ν' CN (3a疋63^-2-(5-ethylpyrimidin-2-yl)-5-[4-(tetra-β-s--1) Phenyloxy]_3,3a,4,5,6,6a-hexanitro-1H-cyclopenta[c]^p each 47 N-/ Η Ν=ν r . (3dP,6a5〇-2- (5-ethylpyrimidin-2-yl)-5-[4-(tetramethylene-1-yl)phenoxy]_3,3a,4,5,6,6<3_hexanitro-1H-ring Pentacene [c]D piroxime 48 3-isopropyl-5-[(iy?,55)-6-[[5-(4-methylsulfonylphenyl)-2-n-pyridyl]oxy Mercapto]-3-azabicyclo[3.1.0]hexa-3-yl]-1,2,4_α oxadi-β-spin 49 Η (1 疋550-3-(5-ethylpyrimidine- 2-yl)-6-[[6-(4-pyridyl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3.

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50 Λ (1尤550-6-1^2-氯-4-(4-曱磺醯基苯基）苯 氧基]甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜 雙環並[3. 1.0]己烷 51 jrQ 〇 2-[(1疋 55*)-6-[[2,6-二氟-4-(4-甲磺醯基 苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1.0] 己烧_3_基]_1，3-苯並°惡°坐 52 F /S.0 (iy?，5^-3-(5-溴嘧啶-2-基）-6-[[2, 6-二氟 -4-(4-曱磺醯基苯基）苯氧基]曱基]-3-氮雜 雙環並[3.1.0]己烷 53 F (為尤知«-5-[2, 6-二氟-4-(4-甲磺醯基苯 基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊 並[c]吡咯-2-羧酸第三丁酯 54 〇 F 以15-6?3疋知51>5-[2,6-二氟-4-[(4-甲磺醯 基哌嗪-1-基）曱基]苯氧基]-2-(5-乙基嘧啶 -2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c] 〇比口各50 Λ (1 especially 550-6-1^2-chloro-4-(4-oxasulfonylphenyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3 -azabicyclo[3.1.0]hexane 51 jrQ 〇2-[(1疋55*)-6-[[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy Methyl]-3-azabicyclo[3.1.0] hexanyl _3_yl]-1,3-benzo[0]°°52 F /S.0 (iy?,5^-3-( 5-bromopyrimidin-2-yl)-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 0] Hexane 53 F (especially known as «-5-[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]-3, 3a, 4, 5, 6, 6a - hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 54 〇F with 15-6?3疋知51>5-[2,6-difluoro-4-[(4 -Metsulfonylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a,4, 5, 6, 6a-hexahydro-1H -cyclopenta[c]

28 95344 201213319 螓28 95344 201213319 螓

S〇 F 55 化3775-6^尤知幻-5-[2,6-二氟-4-[(4-曱磺 醯基哌嗪-1-基）甲基]苯氧基]-2-(5-乙基嘧 〇定_2-基）-3, 3a, 4, 5, 6, 6a-六氮-1H-環戊並 [c]B比口各 56 F η xr 0 4-[4-[[(1 疋 5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]甲氧基] -3, 5-二氟^苯基]节胺 57 νγ、Ύ ^γΝ^α F 4-[5-氣-4-[[(1疋 550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱氧 基]-2-氧-1-°比咬基]-2-氟-节腈 58 η2〇^ (1疋5«-6-[[2, 5-二氟-4-(4-曱磺醯基苯 基）苯氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷 59 (為疋知«-2-(5-乙基嘧啶-2-基）-5-[4-(4-曱磺醯基苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六 氫-1H-環戊並[c]n比洛 29 95344 201213319S〇F 55 3775-6^尤知幻-5-[2,6-Difluoro-4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy]-2- (5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 6a-hexanitro-1H-cyclopenta[c]B than the mouth each 56 F η xr 0 4-[4 -[[(1 疋5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy] -3, 5- Difluoro(phenyl) stilbene 57 νγ, Ύ ^γΝ^α F 4-[5-gas-4-[[(1疋550-3-(5-ethylpyrimidin-2-yl)-3-) Heterobicyclo[3.1.0]hexane-6-yl]nonyloxy]-2-oxo-1-° ratio thiol]-2-fluoro-quiniononitrile 58 η2〇^ (1疋5«- 6-[[2, 5-Difluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo And [3.1.0]hexane 59 (for the known «-2-(5-ethylpyrimidin-2-yl)-5-[4-(4-oxasulfonylphenyl)phenoxy]-3 , 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]nbilo 29 95344 201213319

60 0^F Η (U 550-6-1:(2, 6-二氟-4-噠嗪-4-基-苯氧 基）曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3.1.0]己烷 61 N。〜:在’X F (¾疋知5)-5-[2, 6-二氟-4-(4-氰基苯基）苯 氧基]-2-(5-乙基嘧啶-2-基） -3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[匚]°比口各 62 F 2-[2, 6-二it-4-(4-曱續酿基苯基）苯氧 基]-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯 63 %:， F 2_[2，6_二敗_4_(4_曱績酿基苯基）苯氧 基]-7-(5-乙基嘧啶-2-基）-7-氮雜螺環 [3.5]壬烷 64 N»N义 2-[[4-(四唑-1-基）苯氧基]曱基]-7-氮雜螺 環[3. 5]壬烷-7-羧酸第三丁酯 65 n=n II 义 2-[4-(四唑-1-基）苯氧基]-7-氮雜螺環 [3. 5]壬烷-7-羧酸第三丁酯 30 95344 20121331960 0^F Η (U 550-6-1: (2, 6-difluoro-4-pyridazin-4-yl-phenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl) )-3-Azabicyclo[3.1.0]hexane 61 N.~: in 'XF (3⁄4疋知5)-5-[2,6-difluoro-4-(4-cyanophenyl) Phenoxy]-2-(5-ethylpyrimidin-2-yl)-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[匚]° ratio 62 F 2- [2,6-Di-it-4-(4-anthracenylphenyl)phenoxy]-7-azaspiro[3. 5]decane-7-carboxylic acid tert-butyl ester 63%: , F 2_[2,6_二败_4_(4_曱 酿 phenyl)phenoxy]-7-(5-ethylpyrimidin-2-yl)-7-azaspiro[3.5] Decane 64 N»N- 2,2-[[4-(tetrazol-1-yl)phenoxy]indolyl]-7-azaspiro[3. 5]decane-7-carboxylic acid tert-butyl Ester 65 n=n II 2-(4-(tetrazol-1-yl)phenoxy]-7-azaspiro[3. 5]decane-7-carboxylic acid tert-butyl ester 30 95344 201213319

66 F Cl〆^ (1^ 5»-6-[[4-(6-氯-3-吼啶基）-2, 6-二氟 -苯氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1.0]己烷 67 ,Ν'Ν 〇 2-[2-[4-(四唑-1-基）苯氧基]乙基]-7-氮雜 螺環[3. 5]壬烷-7-羧酸第三丁酯 68 Λ (1疋5^-3-(5-乙基嘧啶-2-基）-6-[[2-甲基 -4-(4-曱磺醯基苯基）苯氧基]曱基]-3-氮雜 雙環並[3. 1.0]己烷 69 Η_Νχ7α (1尤 5^-3-(5-氯嘧啶-2-基）-6-[(1无)-1-[2,6-二氟-4-(4-曱續酿基苯基）笨 氧基]乙基]-3-氮雜雙環並[3.1.0]己烷 70 (IT?，5®-6-[[3,5-二氟-4-(4-甲磺醯基苯 基）苯氧基]甲基]-3-(5-乙基嘧啶-2-基)-3_ 氮雜雙環並[3.1.0]己烷 31 95344 20121331966 F Cl〆^ (1^ 5»-6-[[4-(6-chloro-3-acridinyl)-2,6-difluoro-phenoxy]indolyl]-3-(5-B Pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 67 , Ν'Ν 〇2-[2-[4-(tetrazol-1-yl)phenoxy]ethyl] -7-azaspiro[3. 5]decane-7-carboxylic acid tert-butyl ester 68 Λ (1疋5^-3-(5-ethylpyrimidin-2-yl)-6-[[2 -Methyl-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 69 Η_Νχ7α (1 especially 5^-3-(5- Chloropyrimidin-2-yl)-6-[(1)-1-[2,6-difluoro-4-(4-indolylphenyl)phenyloxy]ethyl]-3-aza Bicyclo[3.1.0]hexane 70 (IT?,5®-6-[[3,5-difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3- (5-ethylpyrimidin-2-yl)-3_azabicyclo[3.1.0]hexane 31 95344 201213319

71 (li?，5Λ-6-[[3, 5-二氟-4-(4-吡啶基）苯氧 基]曱基]-3-(5-乙基嘧啶-2_基）-3-氮雜雙 環並[3. 1. 0]己烷 72 7_(5-乙基°密咬_2-基）-2-[2-[4-(四〇坐-1_ 基）苯氧基]乙基]-7-氮雜螺環[3. 5]壬烷 73 4-[4-[[(1 尤 55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱氧基]苯 基]苯曱腈 74 (li?，5^-3-(5-乙基嘧啶-2-基）-6-[[4-(4-乙續酿基苯基）-2, 6-二氣-苯氧基]曱基]-3-氮雜雙環並[3.1.0]己烷 75 #-[[(1尤5Λ-3-(5-乙基嘧啶-2-基）-3-氮雜 雙環並[3.1.0]己烷-6-基]甲基]-5-(4-甲磺 醯基苯基）哌嗪-2-胺71 (li?,5Λ-6-[[3,5-difluoro-4-(4-pyridyl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexane 72 7_(5-ethyl ° 密_2-yl)-2-[2-[4-(tetramethylene-1_yl)phenoxy]B ]-7-azaspiro[3. 5]nonane 73 4-[4-[[(1 尤55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo) [3. 1. 0]Hex-6-yl]decyloxy]phenyl]benzonitrile 74 (li?,5^-3-(5-ethylpyrimidin-2-yl)-6-[[ 4-(4-Ethyl phenyl)-2,6-dioxa-phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 75 #-[[(1 especially 5Λ) -3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methyl]-5-(4-methanesulfonylphenyl)per Pyrazin-2-amine

32 95344 20121331932 95344 201213319

76 , Η)ΓΝχΧ rNjrN"'·· ^ ν〇^ ^'0 Λ4[(1)?，55)-3-(5-乙基嘧啶-2-基）-3-氮雜 雙環並[3.1.0]己烷-6-基]甲基]-於曱基 -5-(4-甲磺醯基苯基）哌嗪-2-胺 77 (1^55)-3-(5-乙基嘧啶-2-基）-6-[[4-(4-甲磺醯基苯基）***-1-基]曱基]-3-氮雜雙 環並[3. 1.0]己烷 78 Ο (1疋5«-6-[[4-(4-曱磺醯基笨基）苯氧基] 甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第 三丁酯 rr0、々 79 nh2 4-[4-[[(17?，55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱氧基]苯 基]苯曱醯胺 80 vO^丫、 33 95344 20121331976 , Η)ΓΝχΧ rNjrN"'·· ^ ν〇^ ^'0 Λ4[(1)?,55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 0]Hex-6-yl]methyl]-indolyl-5-(4-methylsulfonylphenyl)piperazin-2-amine 77 (1^55)-3-(5-ethylpyrimidine) -2-yl)-6-[[4-(4-methylsulfonylphenyl)triazol-1-yl]indolyl]-3-azabicyclo[3.1.0]hexane 78 Ο (1疋5«-6-[[4-(4-oxasulfonyl) phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid III Butyl ester rr0, 々79 nh2 4-[4-[[(17?,55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane -6-yl]nonyloxy]phenyl]benzamide 80 vO^丫, 33 95344 201213319

(1疋55)-3-(5-乙基嘧啶-2-基）-6-[(1Λ〇-1-[4_(4-曱確酿基苯基）苯氧基]乙 基]-3-氮雜雙環並[3. 1. 0]己烷 81 Λ 3-異丙基-5-[(1兄55·)-6-[[5-(4-曱磺醢基 苯基）吼嗪-2-基]氧甲基]-3-氮雜雙環並 [3. 1. 0]己烷-3-基]-1，2, 4-噁二唑 82 %j〇r° (1 疋 550-3-(5-乙基嘧啶-2-基）-6-[ [4-(5-甲磺醯基-2-吡啶基）苯氧基]甲基]-3-氮雜 雙環並[3. 1.0]己烷 83 、/、 9-[ [6-(4-曱磺醯基苯基）-3-°比啶基]氧 基]-7-氧雜-3-氮雜雙環並[3. 3.1]壬烷-3-羧酸第三丁酯 84 λ (1 疋 5«-6-[(li?)-l-[4-(4-曱磺醯基苯基） 苯氧基]乙基]-3-氮雜雙環並[3.1.0]己烷 -3-羧酸第三丁酯 85 °^°XXX 义 Λ 34 95344 201213319(1疋55)-3-(5-ethylpyrimidin-2-yl)-6-[(1Λ〇-1-[4_(4-indolylphenyl)phenoxy]ethyl]-3 -azabicyclo[3.1.0]hexane 81 Λ 3-isopropyl-5-[(1 brother 55·)-6-[[5-(4-oxasulfonylphenyl)pyridazine -2-yl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4-oxadiazole 82%j〇r° (1 疋550 -3-(5-ethylpyrimidin-2-yl)-6-[ [4-(5-methylsulfonyl-2-pyridyl)phenoxy]methyl]-3-azabicyclo[3] 1.0]hexane 83, /, 9-[ [6-(4-oxasulfonylphenyl)-3-°pyridinyl]oxy]-7-oxa-3-azabicyclo[3 3.1] tert-butyl-3-carboxylic acid tert-butyl ester 84 λ (1 疋5«-6-[(li?)-l-[4-(4-oxasulfonylphenyl)phenoxy]B 3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 85 °^°XXX Λ 34 95344 201213319

9-[4-(4-甲磺醯基苯基）苯氧基]-7-氧雜-3-氮雜雙環並[3. 3. 1]壬烷-3-羧酸第三丁酯 86 Η 3-異丙基-5-1:(1^55)-641:4-(4-甲磺醯基 苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 0] 己烧_3_基]-1，2, 4_β惡二β坐 87 ΟΗ [2-[[(1 兄 550-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1. 0]己烷-6-基]曱氧基]-5-(4-曱磺醯基苯基）苯基]曱醇 88 η H j〇T 1-[2-[[(1疋55')-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱氧基] -5-(4-曱磺醯基苯基）苯基]-趴曱基-曱胺 89 Ν<:?γ，α (1 尤 5^-3-(5-氯嘧啶-2_基）-6-[[4-(4-甲 磺醯基苯基）苯氧基]甲基]-3-氮雜雙環並 [3.1. 0]己烷9-[4-(4-Methanesulfonylphenyl)phenoxy]-7-oxa-3-azabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester 86 Η 3-isopropyl-5-1: (1^55)-641: 4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 0] 烧烧_3_基]-1,2, 4_β 恶二β坐87 ΟΗ [2-[[(1 brother 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo) And [3. 1. 0]hexane-6-yl]nonyloxy]-5-(4-oxasulfonylphenyl)phenyl]nonanol 88 η H j〇T 1-[2-[[ (1疋55')-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonyloxy]-5-(4 -nonylsulfonylphenyl)phenyl]-indolyl-decylamine 89 Ν<:?γ,α (1 尤5^-3-(5-chloropyrimidin-2-yl)-6-[[4 -(4-Methanesulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane

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90 V-矿 0 (1尤 5^-3-(5-乙基嘧啶-2-基)-6-[ [4-(2-氟-4-甲磺醯基苯基）苯氧基]曱基]-3-氮雜 雙環並[3. 1. 0]己烷 91 0 (1尤 5Λ-3-(5-乙基嘧啶-2-基）-6-[[4-(2-曱基-6-甲磺基-3-吡啶基）苯氧基]曱基]-3-氮雜雙環並[3.1.0]己烷 92 CN r,,，-CW Λ 2-[[(1疋5^-3-(5-乙基嘧啶-2-基）-3-氮雜 雙環並[3. 1.0]己烷-6-基]甲氧基]-5-(4-曱 磺醯基苯基）苯腈 Η)Γ人 ’Η 人 93 0 (1疋5幻-6-[[4-(4-甲磺醯基苯基）苯氧基] 甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-曱酸異 丙酯 94 ^ h90 V-mine 0 (1 especially 5^-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(2-fluoro-4-methylsulfonylphenyl)phenoxy]anthracene 3-azabicyclo[3.1.0]hexane 91 0 (1 especially 5Λ-3-(5-ethylpyrimidin-2-yl)-6-[[4-(2-mercapto) -6-Methanesulfonyl-3-pyridyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 92 CN r,,,-CW Λ 2-[[1疋5 ^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]-5-(4-oxasulfonylphenyl) Benzonitrile, Γ人'Η人 93 0 (1疋5幻-6-[[4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3] 1. 0] hexane-3-indole isopropyl ester 94 ^ h

36 95344 20121331936 95344 201213319

(1^5^-3-(5-曱基-2-吡啶基）-6-[ [4-(4-曱磺醯基苯基）苯氧基]甲基]-3-氮雜雙環並 [3.1. 0]己烷 95 y 0 3-異丙基-5-[(l兄55·)-6-[[4-(5-曱磺醯基 -2-吼啶基）苯氧基]曱基]-3-氮雜雙環並 [3. 1. 0]己烷-3-基]-1，2, 4-噁二唑 96 F (1 疋 5^-3-(5-乙基嘧啶-2-基）-6-[ [4-(3-氟-4-甲基亞磺醯基-苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷 97 χ 〇Τ (1疋 5^-3-(5-乙基嘧啶-2-基）-6-[ [4-(3-氟-4-曱磺醯基-苯基）苯氧基]曱基]-3-氮雜 雙環並[3.1.0]己烷 98 0 (1尤 5«-6-[[2,6-二氟-4-(5-曱磺醯基-2-"比啶基）苯氧基]曱基]-3-氮雜雙環並 [3. 1. 0]己烷-3-羧酸第三丁酯 37 95344 201213319(1^5^-3-(5-decyl-2-pyridyl)-6-[[4-(4-oxasulfonylphenyl)phenoxy]methyl]-3-azabicyclo [3.1. 0] Hexane 95 y 0 3-isopropyl-5-[(l-branches 55·)-6-[[4-(5-nonylsulfonyl-2-acridinyl)phenoxy] Mercapto]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4-oxadiazole 96 F (1 疋5^-3-(5-ethylpyrimidine) -2-yl)-6-[[4-(3-fluoro-4-methylsulfinyl-phenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 97 χ 〇Τ (1疋5^-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(3-fluoro-4-oxasulfonyl-phenyl)phenoxy]indole Benzyl-3-azabicyclo[3.1.0]hexane 98 0 (1 especially 5«-6-[[2,6-difluoro-4-(5-sulfonyl)-2-" Pyridyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 37 95344 201213319

99 N-^ ν-ΝΛ〇Ν b 3-乙基-5-[(l尤5幻-6-[[6-(4-曱磺醯基苯 基）-3-吡啶基]氧甲基]-3-氮雜雙環並 [3. 1· 0]己烷-3-基-1，2, 4-噁二唑 100 η)ΓΛν 3-環丙基-5-[(l疋5«-6-[[6-(4-曱磺醢基 苯基）-3-。比啶基]氧曱基]-3-氮雜雙環並 [3· 1. 0]己烷-3-基]-1，2, 4-噁二唑 101 (1尤5«-3-(5-乙基嘧啶-2-基）-6-[[4-(3-氟-4-吼啶基）苯氧基]曱基]-3-氮雜雙環並 [3. 1. 0]己烷 102 〇 1-[4-[5-[[(1疋 55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲氧 基]-2-°比啶基]苯基]乙酮 103 38 95344 20121331999 N-^ ν-ΝΛ〇Ν b 3-ethyl-5-[(l especially 5 magic-6-[[6-(4-oxasulfonylphenyl)-3-pyridyl]oxymethyl] 3-Azabicyclo[3.1·0]hexane-3-yl-1,2,4-oxadiazole 100 η)ΓΛν 3-cyclopropyl-5-[(l疋5«-6 -[[6-(4-oxasulfonylphenyl)-3-.pyridyl]oxyindolyl]-3-azabicyclo[3·1.0]hexane-3-yl]-1 , 2, 4-oxadiazole 101 (1 especially 5«-3-(5-ethylpyrimidin-2-yl)-6-[[4-(3-fluoro-4-acridinyl)phenoxy] Mercapto]-3-azabicyclo[3.1.0]hexane 102 〇1-[4-[5-[[(1疋55)-3-(5-ethylpyrimidin-2-yl)) 3-Azabicyclo[3.1.0]hexane-6-yl]methoxy]-2-pyridinyl]phenyl]ethanone 103 38 95344 201213319

(1兄 550-3-(5-曱基嘧啶-2-基）-6-[ [6-(4-甲磺醯基苯基）-3-°比啶基]氧曱基]-3-氮雜 雙環並[3. 1.0]己烷 104 (17?，5Λ-3-(5-氯嘧啶-2-基）-6-[[6-(4-甲 磺醯基苯基）-3-吼啶基]氧甲基]-3-氮雜雙 環並[3. 1. 0]己烷 105 。、W ή /S〇 N (1 疋 5^-3-(5-乙基嘧啶-2-基）-6-[[4-(6-曱磺醯基-3-咕啶基）苯氧基]甲基]-3-氮雜 雙環並[3. 1.0]己烷 106 νσσ H (1^ 5^-3-(5-乙基嘧啶-2-基）-6-[ [1-(4-甲磺醯基苯基）-4-哌啶基]氧甲基]-3-氮雜 雙環並[3. 1.0]己烷 107 ,NH2 4广 N 人NJ [2-[[(1疋5«-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環[3.1. 0]己烷-6-基]曱氧基]-5-(4-曱 磺醯基苯基）苯基]甲胺(1 brother 550-3-(5-decylpyrimidin-2-yl)-6-[ [6-(4-methylsulfonylphenyl)-3-°pyridinyl]oxanyl]-3- Azabicyclo[3.1.0]hexane 104 (17?,5Λ-3-(5-chloropyrimidin-2-yl)-6-[[6-(4-methylsulfonylphenyl)-3- Acridine]oxymethyl]-3-azabicyclo[3.1.0]hexane 105., W ή /S〇N (1 疋5^-3-(5-ethylpyrimidin-2- -6-[[4-(6-oxasulfonyl-3-acridinyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane 106 νσσ H (1^ 5^-3-(5-ethylpyrimidin-2-yl)-6-[ [1-(4-methylsulfonylphenyl)-4-piperidinyl]oxymethyl]-3-azabicyclo And [3.1.0]hexane 107, NH2 4 broad N human NJ [2-[[(1疋5«-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1. 0 Hexyl-6-yl]nonyloxy]-5-(4-oxasulfonylphenyl)phenyl]methylamine

39 95344 201213319 108 〇,^ Η /b (1 疋 5^-3-(5-乙基嘧啶-2-基）-6-[[6-(4-甲基亞磺醯基）-3-°比啶基]氧甲基]-3-氮雜 雙環並[3.1.0]己烷 109 (1疋 550-3-(5-乙基嘧啶-2-基）-6-[ [6-(3-氟-4-«比啶基）-3-°比啶基]氧曱基]-3氮雜雙 環並[3. 1.0]己烷 110 (1尤55)-3-(5-環丙基嘧啶-2-基）-6-[[6-(4-甲續醯基苯基）_3-°比0定基]氧曱 基]-3-氮雜雙環並[3. 1. 0]己烷 111 (1: 55)-3-(5-環丙基嘧啶-2-基）-6-[[6-(3-氟-4-比啶基）-3-比啶基]氧甲基]-3 氮雜雙環並[3. 1.0]己烷 112 N^p 40 95344 201213319 (1尤 55)-3-(5-甲基嘧啶-2-基）-6-[[6-(3-氟-4-n比啶基）-3-吡啶基]氧甲基]-3氮雜雙 環並[3. 1.0]己烷 113 (1足 550-3-(5-丙基嘧啶-2-基）-6-[ [6-(3-氟-4-n比啶基）-3-吼啶基]氧曱基]-3氮雜雙 環並[3.1. 0]己烷 114 νΛ7α (iyP，5«-3-(5-氯嘧啶-2-基）-6-[[6-(3-氟 -4-吡啶基）-3-吡啶基]氧甲基]-3氮雜雙環 並[3.1.0]己烷 rr° " 115 r° 4-[4-[[(1疋 55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3.1.0]己烷-6-基]曱氧基苯基] 苯曱酸乙酯 116 〇^〇H OH 4-[4-[[(1疋 5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3.1. 0]己烷-6-基]曱氧基苯基] 苯甲酸 41 95344 20121331939 95344 201213319 108 〇,^ Η /b (1 疋5^-3-(5-ethylpyrimidin-2-yl)-6-[[6-(4-methylsulfinyl)-3-° Pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 109 (1疋550-3-(5-ethylpyrimidin-2-yl)-6-[ [6-(3 -fluoro-4-«pyridyl)-3-°t-pyridyl]oxyindolyl]-3azabicyclo[3.1.0]hexane 110 (1 especially 55)-3-(5-cyclopropyl Pyrimidin-2-yl)-6-[[6-(4-methyl-decylphenyl)_3-° ratio 0]oxycarbonyl]-3-azabicyclo[3.1.0]hexane 111 (1: 55)-3-(5-cyclopropylpyrimidin-2-yl)-6-[[6-(3-fluoro-4-pyridyl)-3-pyridyl]oxymethyl] -3 azabicyclo[3.1.0]hexane 112 N^p 40 95344 201213319 (1 especially 55)-3-(5-methylpyrimidin-2-yl)-6-[[6-(3-fluoro -4-n-pyridyl)-3-pyridyl]oxymethyl]-3azabicyclo[3.1.0]hexane 113 (1 foot 550-3-(5-propylpyrimidin-2-yl) -6-[ [6-(3-Fluoro-4-n-pyridyl)-3-acridinyl]oxyindol]-3 azabicyclo[3.1.0]hexane 114 νΛ7α (iyP,5« -3-(5-chloropyrimidin-2-yl)-6-[[6-(3-fluoro-4-pyridyl)-3-pyridyl]oxymethyl]-3azabicyclo[3.1.0 ]hexane rr° " 115 r° 4-[4- [[(1疋55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonyloxyphenyl]benzoic acid B Ester 116 〇^〇H OH 4-[4-[[(1疋5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo][3.1. 0]hexane-6- Alkyloxyphenyl]benzoic acid 41 95344 201213319

117 η;Γν 叉？ (1疋5^-6-1^6-(4-111甲磺醢基苯基）-3-吡啶 基]氧甲基]-3-氮雜雙環[3. 1. 0]己烷-3-曱 酸異丙酯 118 /Η F 5-[(1疋5幻-6-[[4-(3-氟-4-曱亞磺醯基-苯 基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己 烷-3-基]-3-異丙基-1，2, 4-噁二唑 119 〇 崎义 Η Η (1疋5Λ-6-[[6-(5-曱磺醯基吲哚啉-1-基） 嘧啶-4-基]胺基]-3-氮雜雙環並[3. 1.0]己 烷-3-羧酸第三丁酯 120 〇 梦Λ (1尤5«-6-[乙基-[6-(5-曱磺醯基吲哚啉 -1-基）嘧啶-4-基]胺基]-3-氮雜雙環並 [3.1. 0]己烷-3-羧酸第三丁酯 121 Η/.νλΧ vcA H ，S..o (1疋 5iS*)_6-[[2, 6-二氣-4_(5_曱續酿基_2_ °比啶基）苯氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷117 η; Γν fork? (1疋5^-6-1^6-(4-111Methanesulfonylphenyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3 -isopropyl phthalate 118 /Η F 5-[(1疋5幻-6-[[4-(3-fluoro-4-indolyl)-phenyl)phenoxy]indolyl]-3 -Azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole 119 〇崎义Η Η (1疋5Λ-6-[[6- (5-nonylsulfonyl porphyrin-1-yl)pyrimidin-4-yl]amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 120 nightmare Λ (1 especially 5«-6-[ethyl-[6-(5-oxasulfonyl porphyrin-1-yl)pyrimidin-4-yl]amino]-3-azabicyclo[3. 0] hexane-3-carboxylic acid tert-butyl ester 121 Η/.νλΧ vcA H , S..o (1疋5iS*)_6-[[2, 6-digas-4_(5_曱Continuous _2_ °pyridyl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane

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122 W、ή /5>'b (U 55〇-6-[[4-(1-曱磺醯基-3, 6-二氫-2及-吼啶-4-基）苯氧基]甲基]-3-(5-乙基嘧啶 -2-基）-3-氮雜雙環並[3. 1. 0]己烷 123 〇 F 5-[(1疋 55·)-6-[[4-(3-氟-4-曱磺醯基-苯 基）苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己 烷-3-基]-3-異丙基-1，2, 4-噁二唑 124 F γΆ 0 5-[(17?，55)-6-[[2, 6-二氟-4-(5-曱磺醯基 -2-n比啶基）苯氧基]曱基]-3-氮雜雙環並 [3. 1. 0]己烷-3-基]-3-異丙基-1，2, 4-噁二唑 125 η卞 0 2-甲基-1-[(1尤55')_6_[[6-（4-曱續酿基苯 基）-3-比啶基]氧甲基]-3-氮雜雙環並 [3.1.0]己烷-3-基]丙基-2-醇 126 H,广N今F Λ122 W, ή /5 > 'b (U 55〇-6-[[4-(1-sulfonyl-3,6-dihydro-2 and-acridin-4-yl)phenoxy] A 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 123 〇F 5-[(1疋55·)-6-[[4 -(3-fluoro-4-oxasulfonyl-phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1 , 2, 4-oxadiazole 124 F γΆ 0 5-[(17?,55)-6-[[2,6-difluoro-4-(5-nonylsulfonyl-2-n-pyridinyl) Phenoxy]indenyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole 125 η卞0 2- Methyl-1-[(1 especially 55')_6_[[6-(4-anthracenylphenyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0] Hex-3-yl]propyl-2-ol 126 H, broad N today F Λ

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(1 疋 5^)-3-(2-氟-2-曱基-丙基）-6-[ [6-(4-曱磺醯基苯基）-3-"比啶基]氧曱基]-3-氮雜 雙環並[3. 1. 0]己烷 127 又。冬 νΟ^ 〆、'〇 (li?，5Λ-6-[[4-(5-甲磺醯基l-2-n比啶基）苯 氧基]甲基]-3-氮雜雙環並[3.1. 0]己烷-3-羧酸第三丁酯 128 rr°-a (1 尤 55)-3-(5-乙基嘧啶-2-基）-6-[[6-(l-曱續酿基-3, 6-二氮-2分-0比0定-4-基）-3-π比咬 基]氧曱基]-3-氮雜雙環並[3. 1.0]己烷 129 0 5-[(1^56)-6-[[6-(1-曱磺醯基-3, 6-二氫 -2及-吡啶-4-基）-3-吡啶基]氧曱基]-3-氮雜 雙環並[3.1. 0]己烷-3-基]-3-異丙基 -1，2, 4-噁二嗤 130 。HxrVF ,00 Η Zb (1疋 5^-3-(2-氟-2-曱基-丙基）-6-[ [4-(5-甲磺醯基-2-他啶基）苯氧基]甲基]-3-氮雜 雙環並[3. 1.0]己烷(1 疋5^)-3-(2-fluoro-2-indolyl-propyl)-6-[ [6-(4-oxasulfonylphenyl)-3-"pyridyl]oxyquinone Alkyl-3-azabicyclo[3.1.0]hexane 127 again.冬νΟ^ 〆, '〇(li?,5Λ-6-[[4-(5-methylsulfonyl l-2-n-pyridyl)phenoxy]methyl]-3-azabicyclo[ 3.1. 0] Hexane-3-carboxylic acid tert-butyl ester 128 rr°-a (1 especially 55)-3-(5-ethylpyrimidin-2-yl)-6-[[6-(l-曱) Continuing broth-3,6-diaza-2-0-0-0 -4-yl)-3-π ratio methoxyl]-3-azabicyclo[3.1.0]hexane129 0 5-[(1^56)-6-[[6-(1-oxasulfonyl-3,6-dihydro-2 and-pyridin-4-yl)-3-pyridyl]oxycarbonyl] 3-Azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiindole 130. HxrVF , 00 Η Zb (1疋5^-3- (2-fluoro-2-indolyl-propyl)-6-[[4-(5-methylsulfonyl-2-heptinyl)phenoxy]methyl]-3-azabicyclo[3] 1.0] Hexane

44 95344 20121331944 95344 201213319

131 Ά矿。H /S'b 5幻-6-[[2, 6-二氟-4-(1-甲磺醯基 -3, 6-二氫-2及-吡啶-4-基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-2-甲基-丙 烧-2-醇 132 0 (1尤 5»-6-[[2,6-二氟-4-(1 曱磺醯基 1-3, 6-二氫-2H-吡啶-4-基）苯氧基曱基] _3-(2-敗-2-曱基-丙基）-3-氮雜雙環並 [3.1.0]己烷 133 ry-r %ΧΧΝ "〇Τ 5-[(1尤5®-6-[[6-(3-氟-4-曱磺醯基-苯 基)-3-吼啶基]氧曱基]-3-氮雜雙環並 [3.1. 0]己烷-3-基]-3-異丙基-1，2, 4-噁二唑 134 0 5-[(1疋5幻-6-[[6-(5-曱磺醯基-2-吡啶 基)-3-吼啶基]氧曱基]-3-氮雜雙環並 [3.1. 0]己烧_3_基]_3_異丙基_1，2, 4_β惡二°坐 135 0 45 95344 201213319131 antimony ore. H /S'b 5 Magic-6-[[2, 6-Difluoro-4-(1-methanesulfonyl-3,6-dihydro-2 and-pyridin-4-yl)phenoxy]indole 3-Azabicyclo[3.1.0]hexane-3-yl]-2-methyl-propan-2-ol 132 0 (1 especially 5»-6-[[2,6 -difluoro-4-(1 sulfonyl 1-3,6-dihydro-2H-pyridin-4-yl)phenoxyindenyl] _3-(2-fail-2-mercapto-propyl) -3-Azabicyclo[3.1.0]hexane 133 ry-r %ΧΧΝ "〇Τ 5-[(1 especially 5®-6-[[6-(3-fluoro-4-sulfonyl) -phenyl)-3-acridinyl]oxycarbonyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole 134 0 5-[(1疋5幻-6-[[6-(5-oxasulfonyl-2-pyridyl)-3-acridinyl]oxyindolyl]-3-azabicyclo[33.1] 0]已烧_3_基]_3_isopropyl_1,2, 4_β恶二°坐135 0 45 95344 201213319

(1尤5Λ-3-異丙基-6-[[6-(4-甲磺醯基苯 基）-3-吼啶基]氧曱基]-3-氮雜雙環並 [3. 1. 0]己烷 136 F λ (1尤55)-6-[[2, 6-二氟-4-(1-曱磺醯基 -3, 6-二氫比咬-4-基）苯氧基]甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷 137 vW 0 (1疋 5^-3-(5-乙基嘧啶-2-基）-6-[ [6-(1-曱磺醯基-4-哌啶基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷 138 rr-r N (1 疋 55)-3-(5-氯嘧啶-2-基）-6-[[6-(1-甲 續酿基-3, 6-二氮-2·^_π比咬基）-3-°比咬 基]氧曱基]-3-氮雜雙環並[3. 1.0]己烷 139 V^N今 F N 0 (1153)-3-(2-氟-2-甲基-丙烷)-6-[[6-(1-曱確酿基-3，6_二氮_2及_11比咬-4-基）-3-α比π定 基]氧甲基]-3-氮雜雙環並[3.1. 0]己烷(1 Λ5Λ-3-isopropyl-6-[[6-(4-methylsulfonylphenyl)-3-acridinyl]oxyindolyl]-3-azabicyclo[3. 0]hexane 136 F λ (1 especially 55)-6-[[2, 6-difluoro-4-(1-indolesulfonyl-3,6-dihydropyridin-4-yl)phenoxy ]methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 137 vW 0 (1疋5^-3-(5-ethylpyrimidine- 2-yl)-6-[[6-(1-oxasulfonyl-4-piperidyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 138 Rr-r N (1 疋55)-3-(5-chloropyrimidin-2-yl)-6-[[6-(1-methyl mercapto-3,6-diaza-2·^_π ratio bite Base)-3-° ratio octyl]oxycarbonyl]-3-azabicyclo[3.1.0]hexane 139 V^N FN 0 (1153)-3-(2-fluoro-2-methyl -propane)-6-[[6-(1-indole- 3,6-dinitro-2 and _11 butyl-4-yl)-3-α ratio π-decyl]oxymethyl]-3 - azabicyclo[3.1.0]hexane

46 95344 20121331946 95344 201213319

140 F «W r'o (1尤5幻-6-[[2, 6-二氟-4-(1-曱磺醯基 -3, 6-二氩-2及-吡啶-4-基）苯氧基]曱 基]-3-(5-氣-嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷 141 0ΎΝ J r'o (li?，55)-6-[[4-(l-甲磺醯基-3, 6-二氫-2及-0比咬-4-基）苯氧基]甲基]-3-(5-氣-α密唆-2-基）-3-氮雜雙環並[3. 1. 0]己烷 142 f 順式-(1疋5^-3-(5-乙基嘧啶基-2-基） -6-[ [6_(1_甲績酿基-3，6-二氮Hn比咬-4-基）-3-吡啶基]氧曱基]-3-氮雜雙環並 [3.1. 0]己烷 143 1 3-異丙基-5-[順式-(1尤5®-6-[[4-(5-曱磺 醯基-2-吼啶基）苯氧基]曱基]-3-氮雜雙環 並[3. 1. 0]己烷-3-基]-1，2, 4-噁二唑 或其可藥用的鹽。 47 95344 201213319 本發明涉及-種製備通式⑴所雜化合物或其可藥 用鹽的方法，該方法包括：140 F «W r'o (1 especially 5 phantom-6-[[2, 6-difluoro-4-(1-oxasulfonyl-3,6-di-argon-2 and -pyridin-4-yl)) Phenoxy]fluorenyl]-3-(5-a-pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 141 0ΎΝ J r'o (li?,55)-6- [[4-(l-methylsulfonyl-3,6-dihydro-2 and-0-buty-4-yl)phenoxy]methyl]-3-(5-gas-α 唆-2 -yl)-3-azabicyclo[3.1.0]hexane 142 f cis-(1疋5^-3-(5-ethylpyrimidin-2-yl)-6-[ [6_ (1_A-flavor-3,6-diazaHn than -4-yl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3.1.0]hexane 143 1 3- Isopropyl-5-[cis-(1 especially 5®-6-[[4-(5-oxasulfonyl-2-acridinyl)phenoxy]indolyl]-3- azabicyclo [3. 1. 0]Hex-3-yl]-1,2,4-oxadiazole or a pharmaceutically acceptable salt thereof. 47 95344 201213319 The present invention relates to the preparation of a compound of the formula (1) or A method of medicinal salt, the method comprising:

(ΙΑ) (IB) 將通式（IA)化合物與通式（IB)化合物反應，得到通式 (I)化合物； 其中：PG為離去基團，較佳為鹵素或者磺醯基； 裱A、環B、環C、R1、乜和L2的定義與通式d)化合 物一致。 本發明涉及一種製備通式（1)所示的化合物或其可藥 用鹽的方法’該方法包括： ’(ΙΑ) (IB) reacting a compound of the formula (IA) with a compound of the formula (IB) to give a compound of the formula (I): wherein: PG is a leaving group, preferably a halogen or a sulfonyl group; The definitions of Ring B, Ring C, R1, 乜 and L2 are identical to the compounds of formula d). The present invention relates to a process for producing a compound of the formula (1) or a pharmaceutically acceptable salt thereof. The method comprises:

^ 將通式（1C)化合物與通式（Π))化合物在纪類催化劑 的條件下反應，得到通式（I)化合物； 其中：Li為一個鍵；X為鹵素；環A、環B、環c、R1 和的定義與通式（I)化合物一致。 本發明涉及一種製備通式（I)所述的化合物或其鹽的 製備方法，包括以下步驟：^ A compound of the formula (1C) is reacted with a compound of the formula (Π)) under the conditions of a catalyst to obtain a compound of the formula (I): wherein: Li is a bond; X is a halogen; ring A, ring B, The definition of ring c, R1 and is identical to the compound of formula (I). The present invention relates to a process for the preparation of a compound of the formula (I) or a salt thereof, comprising the steps of:

(IE)(IE)

(IF) 48 95344 201213319 將通式（IE)化合物與通式（IF)化合物在鹼性條件下 發生親核取代反應，得到通式（I)化合物。 其中：PG為離去基團，較佳為鹵素或者磺醯基； 環A、環B、環C、R1、和L2的定義與通式（I)化合 物一致。 本發明涉及一種製備通式（I)所述的化合物或其鹽的 製備方法，包括以下步驟：(IF) 48 95344 201213319 A nucleophilic substitution reaction of a compound of the formula (IE) with a compound of the formula (IF) under basic conditions affords a compound of the formula (I). Wherein: PG is a leaving group, preferably a halogen or a sulfonyl group; and the definitions of ring A, ring B, ring C, R1, and L2 are the same as those of the compound of the formula (I). The present invention relates to a process for the preparation of a compound of the formula (I) or a salt thereof, comprising the steps of:

(M) (IJ) 通式化合物（IH)與化合物（IJ)進行Suzuki反應，得 到通式（I)化合物。 其中：為一個鍵；X為鹵素；環A、環B、環C、R1 和L2的定義與通式（I)化合物一致。 本發明的另一方面涉及通式（I)所示的化合物或其可 藥用的鹽在製備GPR119激動劑中的用途。 本發明的另一方面涉及通式（I)所示的化合物或其可 藥用的鹽，作為GPR119激動劑的藥物。 本發明還涉及本發明化合物或其可藥用的鹽在製備 治療糖尿病和代謝綜合症的疾病的藥物中的用途。 本發明還涉及本發明化合物或其可藥用的鹽作為治 療糖尿病和代謝綜合症的疾病的藥物。 進一步，本發明的另一方面涉及一種醫藥組成物，其 含有治療有效劑量的通式（I)所示的化合物或其可藥用的 49 95344 201213319 鹽及其可藥用的載劑或賦形劑。該醫藥組成物用作咖19 激動劑的藥物。該醫藥組成物在製備治療Gp_激動劑中 的用途。該醫藥組成物在製備治療糖尿病和代謝综合 赫的藥物中的的用途。該組合物作為料糖尿病和代謝 綜合症的疾病的藥物。(M) (IJ) The compound of the formula (IH) is subjected to a Suzuki reaction with the compound (IJ) to give a compound of the formula (I). Wherein: a bond; X is a halogen; and the definitions of ring A, ring B, ring C, R1 and L2 are identical to the compound of formula (I). Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a GPR119 agonist. Another aspect of the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which is a medicament for a GPR119 agonist. The invention further relates to the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease of diabetes and metabolic syndrome. The present invention also relates to a compound of the present invention or a pharmaceutically acceptable salt thereof as a medicament for treating diseases of diabetes and metabolic syndrome. Further, another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable 49 95344 201213319 salt thereof, and a pharmaceutically acceptable carrier or form thereof Agent. The pharmaceutical composition is used as a drug for a gamma 19 agonist. The use of the pharmaceutical composition for the preparation of a therapeutic Gp-agonist. The use of the pharmaceutical composition for the preparation of a medicament for the treatment of diabetes and metabolic synthesis. This composition is used as a drug for diseases of diabetes and metabolic syndrome.

本發㈣ϋ面涉m隸尿師代謝綜合 症的疾病的方法，财法包括給予需要治療的患者有效治 療量的通式(I)所示的化合物或其可藥用的鹽，或含有通式 (I)所示的化合物或其可藥用的鹽的醫藥組成物。 工 广的—方面涉及作為治療糖尿病和代謝綜合 ==物的通式⑴所示的化合物或其可藥用的鹽， 有通式⑴所示的化合物或其可藥用的鹽的醫藥組成 物0 本發明的另一方面涉及一種調節姨島素的方法，該方 法包括給予需要治療的患者有效治療量的通式⑴所示的 化合物或其可藥用的鹽，或含有通式⑴所示的 可藥用的鹽的醫藥組成物。 丹 1 的另—方面涉及作為調節胰島素的藥物的通 式⑴所不的化合物或其可藥㈣鹽，或 的化合物或其可藥用的鹽的醫藥組成物。 ）所不 發明的詳細說明 除非有槪陳m彳下㈣錢料㈣ 中的術語具有下述含義。 曰 “烧基”指飽和的脂族烴基團’包括I至2。個碳原 95344 50 201213319 子的直鏈和支鏈基團。較佳含有1至丨2個碳原子的烷基， 非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁 基、異丁基、第三丁基、仲丁基、正戊基、丨，卜二甲基丙 基、1，2-二甲基丙基、2, 2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1_乙基-2-甲基丙基、 1’ 1,2-三甲基丙基、1，1—二曱基丁基、12_二曱基丁基、 2, 2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基 _ 戊基、3-甲基戊基、4-甲基戊基、2, 3-二曱基丁基、正庚 基、2-曱基己基、3-甲基己基、4-甲基己基、5-甲基己基、 2, 3-二甲基戊基、2, 4-二曱基戊基、2, 2-二曱基戊基、3, 3〜 一甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2, 3-二 甲基己基、2, 4-二甲基己基、2, 5-二甲基己基、2, 2-二甲 基己基、3, 3-二甲基己基、4, 4-二甲基己基、2-乙基己基、 3-乙基己基、4-乙基己基、2-曱基-2-乙基戊基、2-甲基—3〜 乙基戊基、正壬基、2-甲基-2-乙基己基、2-曱基-3-乙基 傷 己基、二乙基戊基、正癸基、3, 3-二乙基己基、2, 2〜 二乙基己基，及其各種支鏈異構體等。更較佳的是含有1 至6個碳原子的低級烷基’非限制性實施例包括曱基、乙 基、正丙基、異丙基、正丁基、異丁基、第三丁基、仲丁 基、正戊基、1，1-二曱基丙基、1，2-二甲基丙基、2, 2一二 甲基丙基、1-乙基丙基、2-甲基丁基、3-曱基丁基、正己 基、1-乙基-2-曱基丙基、1，1,2-三甲基丙基、i i一二甲基 丁基、1，2-二甲基丁基、2, 2-二曱基丁基、l 3一二甲基丁 基、2-乙基丁基、2_甲基戊基、3-甲基戊基、4-甲基戊基、 95344 51 201213319 2,3-二甲基丁基等。烷基可以是取代的或未取代的，當被 取代時，取代基可以在任何可使用的連接點上被取代，較 佳為一個或多個以下基團，獨立地選自烷基、烯基、炔基、 烧氧基、院硫基、院基胺基、i素、硫醇、經基、硝基、 氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜 環烧氧基、環烧硫基、雜環烧硫基、氧代、-OR2、_NR3r4、 -C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(〇)R4、-NR3S(0)mR4、 -S(0)mR2 或-S(0)mNR3R4。 ® “環烧基”指飽和或部分不飽和單環或多環環狀烴 馨 取代基’其包括3至20個碳原子，較佳包括3至12個石炭 原子，更較佳環烷基環包含3至1〇個碳原子。單環環烷基 的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯 基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯 基、環辛基等。多環環烷基包括螺環、稠環和橋環的環烷 基。 _ “螺環院基”指5至20員，單環之間共用一個碳原 子（稱螺原子）的多環基團，這些可以含有—個或多個冑 鲁 鍵，但沒有-個環具有完全共概的冗電子系統。較佳為6 至14員’更k佳為7至ig員^根據環與環之間共用螺原 子的數目將螺環燒基分為單螺環烧基、雙螺環烧基基或多 螺環烧基’較佳為單螺妓絲雙螺觀基。更較佳為4 員/4員、4員/5員、4員/6員、5員/5員或5員/6 環烷基。螺環烷基的非限制性實施例包含 、 95344 52 201213319 “稠環烷基”指5至20員，系統中的每個環與體系 中的其他環共用毗鄰的一對碳原子的全碳多環基團，其中 一個或多個環可以含有一個或多個雙鍵，但沒有一個環具 有完全共軛的7Γ電子系統。較佳為6至14員，更較佳為 7至10員。根據組成環的數目可以分為雙環、三環、四環 • 或多環稠環烷基，較佳為雙環或三環，更較佳為5員/5員 或5員/6員雙環烷基。稠環烷基的非限制性實施例包含 “橋環烷基”指5至20員，任意兩個環共用兩個不 直接連接的碳原子的全碳多環基團，這些可以含有一個或 g 多個雙鍵，但沒有一個環具有完全共軛的7Γ電子系統。較 佳為6至14員，更較佳為7至10員。根據組成環的數目 可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、 三環或四環，更有選為雙環或三環。橋環烷基的非限制性 實施例包含 知和总。 53 95344 201213319 該祕基環可以稠合科基、料基或雜環烧基環 上’其中與母體結構連接在-起的環為環烧基非限制性 實施例包括節滿基、四氫蔡基、苯並環庚烧基等。環炫基 可以是視需要取代的或未取代的，當被取代時，取代基較 佳為一個或多個以下基團，獨立地選自烷基、烯基、炔基、 烧氧基、院硫基、烧基胺基、鹵素、硫醇、經基、硝，基、 氰基、環烧基、雜環烷基、芳基、雜芳基、環烷氧基、雜 環烧氧基、環烧硫基、雜環垸硫基、氧代、-0R2、、 _ —C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、-NR3S(0)mR4、 -S(0)mR2 或-S(0)fflNR3R4。 彿基指由至少兩個碳原子和至少一個碳-碳雙鍵 組成的如上述定義的烷基。例如乙烯基、卜丙烯基、2_丙 烯基、1-，2-或3-丁烯基等。烯基可以是取代的或未取代 的，當被取代時，取代基較佳為一個或多個以下基團，獨 立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、 Φ 鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳 基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環燒 硫基、-OR2、-NR3R4、-C(〇)R2、-C(〇)〇R2、-C(〇)NR3R4、 -Nr3C(〇)R4、-NR3S(0%R4、-S(0)nR24_S(0)»NR3R4。 炔基”指至少兩個碳原子和至少一個碳-碳三鍵組 成的如上所定義的烷基。例如乙炔基、1-丙炔基、2-丙块 基、1-，2-或3-丁炔基等。炔基可以是取代的或未取代的， 當被取代時，取代基較佳為一個或多個以下基團，獨立地 選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵 54 95344 201213319 素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、 雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、 -OR2、-NR3R4、-C(0)R2、-C(0)〇R2、-C(〇)NR3R4、-nr3c(〇)r4、 -NR3S(0)mR4、-S(0)mR2 或。 “雜環基’’指飽和或部分不飽和單環或多環環狀烴 取代基，其包括3至20個環原子，其中一個或多個環原子 選自氮、氧或S(0),(其中m是整數〇至2)的雜原子，但 不包括-0_0_、-0-S—或-的環部分，其餘環原子為碳。 較佳包括3至12個環原子，其中至4個是雜原子，更較佳 環烷基環包含3至10個環原子。單環環烷基的非限制性實 施例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉 基、高哌嗪基、1’2, 3, 6-四氫n比啶基等。多環環烷基包括 螺環、稠環和橋環的雜環基。“螺雜環基，，指5至2〇員， 單環之間共用一個原子（稱螺原子）的多環雜環基團，其中 一個或多個環原子選自氮、氧或s(〇)p(其中ρ是整數〇至 Φ 2)的雜原子，其餘環原子為碳。這些可以含有一個或多個 雙鍵，但沒有一個環具有完全共軛的疋電子系統。較佳為 6至14員，更較佳為7至1〇員。根據環與環之間共用螺 原子的數目將螺環烷基分為單螺雜環基、雙螺雜環基或多 螺雜環基，較佳為單螺環烷基和雙螺環烷基。更較佳為4 員/4員、4員/5員、4員/6員'5員/5員或5員/6員單螺 環烷基。螺環烷基的非限制性實施例包含 55 95344 201213319The method of the present invention relates to a method for treating a disease of a metabolic syndrome of a genital division, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a formula A pharmaceutical composition of the compound (I) or a pharmaceutically acceptable salt thereof. The invention relates to a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, which is a compound for the treatment of diabetes and metabolism. 0 Another aspect of the present invention relates to a method for modulating phytosin comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof, or a compound of the formula (1) A medicinal composition of a pharmaceutically acceptable salt. Another aspect of Dan 1 relates to a pharmaceutical composition which is a compound of the formula (1) which is not a drug for regulating insulin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Detailed Description of the Invention Unless otherwise stated, the terms in (4) Money (4) have the following meanings.曰 "Acrylate" means a saturated aliphatic hydrocarbon group 'includes I to 2. Linear and branched groups of carbonogen 95344 50 201213319. Preferred are alkyl groups having from 1 to 2 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, hydrazine, bisdimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methyl butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1' 1,2-trimethylpropyl, 1,1-didecylbutyl, 12-didecylbutyl, 2,2-Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methyl-pentyl, 3-methylpentyl, 4-methylpentyl, 2 , 3-dimercaptobutyl, n-heptyl, 2-decylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2, 4 - Dimercaptopentyl, 2,2-didecylpentyl, 3,3~monomethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-di Methylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2 -ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-mercapto-2-ethylpentyl, 2-methyl-3~ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-mercapto-3-ethylhexyl, diethylpentyl, n-decyl, 3 , 3-diethylhexyl, 2, 2~ diethylhexyl, and various branched isomers thereof. More preferably, the lower alkyl group having from 1 to 6 carbon atoms' non-limiting examples include mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Sec-butyl, n-pentyl, 1,1-dimercaptopropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Base, 3-mercaptobutyl, n-hexyl, 1-ethyl-2-mercaptopropyl, 1,1,2-trimethylpropyl, ii-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-didecylbutyl, l 3 -dimethylbenzyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 95344 51 201213319 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, thiol, aminyl, i, thiol, thio, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic sulfuryl, oxo, -OR2, _NR3r4, -C(0)R2, -C(0)0R2, -C(0)NR3R4, - NR3C(〇)R4, -NR3S(0)mR4, -S(0)mR2 or -S(0)mNR3R4. ® "cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon aryl substituent which comprises from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably a cycloalkyl ring. Contains 3 to 1 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. _ "Spiral ring base" means 5 to 20 members, a polycyclic group sharing a carbon atom (called a spiro atom) between the single rings, which may contain one or more ruthenium bonds, but no - ring A completely redundant electronic system. Preferably, the number of members from 6 to 14 is more preferably from 7 to ig. According to the number of common snail atoms between the ring and the ring, the spiro group is divided into a single spiro group, a double spiro group or a multi-snail. The cycloalkyl group 'is preferably a single-spindle double-spinning base. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 cycloalkyl groups. Non-limiting examples of spirocycloalkyl include, 95344 52 201213319 "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an adjacent carbon atom with all other rings in the system. A cyclic group in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated 7-inch electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicycloalkyl group. . Non-limiting examples of fused cycloalkyl groups include "bridged cycloalkyl" refers to 5 to 20 members, any two rings sharing two carbon-free, all-carbon polycyclic groups, which may contain one or Multiple double bonds, but none of the rings have fully conjugated 7-inch electronic systems. Preferably, it is from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include the know and total. 53 95344 201213319 The substituent ring may be fused to a thiol, a sulfhydryl or a heterocyclic alkyl ring. The ring in which the parent structure is attached is a cycloalkyl group. Non-limiting examples include a tetrabasic, tetrahydro-Craft. Base, benzocycloheptyl and the like. The cyclononyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and Thio group, alkylamino group, halogen, thiol, thiol, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, Cyclosulfanyl, heterocyclic thiol, oxo, -0R2, _ -C(0)R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NR3S( 0) mR4, -S(0)mR2 or -S(0)fflNR3R4. Buddhism refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, a vinyl group, a propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group or the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino group, Φ halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocyclic thiol group, -OR2, -NR3R4, -C(〇)R2, -C(〇)〇R2, -C(〇)NR3R4, -Nr3C(〇)R4, -NR3S(0%R4,- S(0)nR24_S(0)»NR3R4. Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propane Block base, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo 54 95344 201213319 素, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Sulfur, -OR2, -NR3R4, -C(0)R2, -C(0)〇R2, -C(〇)NR3R4, -nr3c(〇)r4, -NR3S(0)mR4, -S(0) mR2 or "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S ( 0), (where m is an integer 〇 to 2) hetero atom, but excluding the ring moiety of -0_0_, -0-S- or -, the remaining ring atoms are carbon. Preferably including 3 to 12 ring atoms, Wherein to 4 are heteroatoms, more preferably the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl, homopiperazinyl, 1'2,3,6-tetrahydron-pyridyl, etc. Polycyclic cycloalkyl includes spiro, fused, and bridged heterocyclic groups. A cyclic group, which refers to a 5 to 2 member, a polycyclic heterocyclic group sharing an atom (called a spiro atom) between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or s(〇)p ( Where ρ is an integer 〇 to Φ 2) of the heteroatoms, and the remaining ring atoms are carbon. These may contain one or more pairs , but none of the rings have a fully conjugated ruthenium electronic system. Preferably, it is from 6 to 14 members, more preferably from 7 to 1 member. The spirocycloalkyl group is divided according to the number of common snail atoms between the ring and the ring. Monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl, preferably monospirocycloalkyl and dispirocycloalkyl. More preferably 4 members/4 members, 4 members/5 members, 4 Member/6 member '5 member/5 member or 5 member/6 member monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl group include 55 95344 201213319

稍雜壞基指5至20員，系統中的每個環與體系中的其 他環共祕義-對原子㈣環雜環基團，—個或多個環 可以含有-個衫個雙鍵，但沒有—個環具有完全共概的 π電子系統’其中一個或多個環原子選自氣、氧或抑乂A slightly heterozygous base refers to 5 to 20 members, and each ring in the system is synonymous with other rings in the system - for an atomic (tetra) ring heterocyclic group, one or more rings may contain - a double bond, But no—a ring has a completely common π-electron system' in which one or more ring atoms are selected from gas, oxygen, or sputum

(其中Ρ疋整數0至2)的雜原子，其餘環原子為碳。較佳 為6至14員’更較佳為7至1()員。根據組成環的數目可 以！^雙環、三環、四環❹環稠雜環烧基，較佳為雙環 或:壤’更較佳為5 s/5貝或5員/6貢雙環娜環基。铜 雜環基的非限制性實施例包含A hetero atom (wherein Ρ疋 integer 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members' more preferably 7 to 1 () members. According to the number of constituent rings! The bicyclic, tricyclic, tetracyclic anthracene ring heterocyclic alkyl group, preferably bicyclic or: soil' more preferably 5 s/5 shell or 5 member/6 tributary bicycloadenyl group. Non-limiting examples of copper heterocyclic groups include

連接的：二！5至14員’任意兩個環共用兩個不直 二=二環基團’這些可以含有-個_ 的雜原子，装^ @氧或（)m(其中m是整數0至2 7至10昌7 '衣、子為碳。較佳為6至14員’更較4 7至H)員。7至Π)員。根據組成環的數目可以分為心 95344 56 201213319 二環、四環或多環橋魏基，較佳為雙環、三環或四環， 更有選為雙&或二環。橋環燒基的非限制性實施例包含·· ^ % ^ ^ 4 =雜環基環可㈣合於綠、㈣基或賴基環上，其中 、母體結構連接在—起的環為雜環基，非限制性實施例包Connected: two! 5 to 14 members 'any two rings share two non-straight two = bicyclic groups' These may contain - _ of a hetero atom, ^ ^ oxygen or () m (where m is an integer 0 to 2 7 to 10 Chang 7 'clothes, children are carbon. It is better to be 6 to 14 members 'more than 4 7 to H). 7 to Π). According to the number of constituent rings, it can be divided into core 95344 56 201213319 bicyclic, tetracyclic or polycyclic bridge Wei, preferably bicyclic, tricyclic or tetracyclic, more preferably double & or bicyclic. A non-limiting example of a bridged ring group comprises ·· ^ % ^ ^ 4 = a heterocyclyl ring may be bonded to a green, (tetra) or lysine ring wherein the parent structure is attached to the ring Base, non-limiting embodiment package

等雜％基可以疋視需要取代的或未取代的，當被取代時， 取代基較佳為-個❹個町_，獨立地選***基、稀 基、炔基、錄基、⑽基、料絲、㈣、硫醇、經 基、罐基、氰基、祕基、雜錢基、絲、雜芳基、環 烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、氧代、_〇R2、 -NR3R4、-c(0)R2、-C(0)0R2、~C(〇)NR3R4、_NR3C(〇)r4、 -NR3S(0)raR4、-s(〇)mR2 或-S(0)撕3R4。The isomeric group may be substituted or unsubstituted, and when substituted, the substituent is preferably - a group of _, independently selected from the group consisting of an alkyl group, a dilute group, an alkynyl group, a benzyl group, and a (10) group. , filament, (d), mercaptan, mercapto, tank, cyano, thiol, hexanyl, silk, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfur, oxo, _〇R2, -NR3R4, -c(0)R2, -C(0)0R2, ~C(〇)NR3R4, _NR3C(〇)r4, -NR3S(0)raR4, -s( 〇) mR2 or -S(0) tear 3R4.

“芳基”指6炱14員全碳單環或稠合多環（也就是共 用毗鄰碳原子對的環）基團，具有共軛的π電子體系的多 環（即其帶有相鄰對碳原子的環）基團，較佳為6至1〇員， 例如苯基和萘基。所述芳基環可以稠合於雜芳基、雜環某 或環烷基環上，其中與母體結構連接在一起的環為芳美 環’非限制性實施例也含："Aryl" means a 6-membered, all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups, having a polycyclic ring of a conjugated π-electron system (ie, with adjacent pairs) The ring group of a carbon atom is preferably 6 to 1 member such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a mersene ring. Non-limiting examples also include:

95344 57 20121331995344 57 201213319

芳基可以是取代1¾未取代的，#被取代時，取代基較佳 為-個或多個以下基團’獨立地選自絲、縣、快基、 院氧基、烧硫基、燒基胺基、鹵素、硫醇、㈣、墙基、The aryl group may be a substituted 13⁄4 unsubstituted, and when # is substituted, the substituent is preferably one or more of the following groups 'independently selected from the group consisting of a silk, a county, a fast radical, an alkoxy group, a sulfur-burning group, and a pyridyl group. Amine, halogen, thiol, (iv), wall base,

氰基m雜批基、芳基、雜芳基、環院氧基、雜 %<烷氧基、裱烷硫基、雜環烷硫基、_〇R2、_NR3R4、_c(〇)r2、 -C(0)0R2、-C(0)NR3R4、_NR3C⑼r4、_NR3S(〇乂r4、 或-S(0)nNR3R4。 m 雜矛基 托包含1至4個雜原子，5至14個 的雜芳族體系，其中雜原子包括氧、硫和氮嗜佳為 1〇員。雜芳基較佳為是5員或6員，例如咬喃基、嘆吩基、 咬基tb洛基、N-统基η比略基、β密咬基"比嗓基、味嗅 土、四錢等。該雜芳基環可㈣合於芳基、雜環 垸基環上，其中與母體結構連接在―起的環 ^衣 非限制性實施例包含： 方基環，Cyano m hetero-batch, aryl, heteroaryl, cyclooxyl, hetero- < alkoxy, nonylthio, heterocycloalkylthio, _〇R2, _NR3R4, _c(〇)r2 -C(0)0R2, -C(0)NR3R4, _NR3C(9)r4, _NR3S(〇乂r4, or -S(0)nNR3R4. m spear base contains 1 to 4 heteroatoms, 5 to 14 heteroaryls a family system in which a hetero atom includes oxygen, sulfur and nitrogen as a member. The heteroaryl group is preferably 5 or 6 members, such as a thiol group, a thiophene group, a bite base tb-lole group, and an N-system. The base η is slightly singular, β is a bite base " 嗓 嗓, 味 snug, tetraki, etc. The heteroaryl ring can be (iv) bonded to an aryl or heterocyclic fluorenyl ring, wherein the parent structure is attached to A non-limiting embodiment of the ring includes: a square base ring,

取 雜芳基可叹财絲代料林 代基較佳為-個或多個以下„，獨立_自^時， 炔基、烧氧基、烧硫基、燒基胺基、函素、土 :土 硝基、氰基、賴基、雜觀基 ^、里基、 方暴雜方基、環烷氧 95344 58 201213319 基、雜環烧氧基、環烧硫基、雜環烧硫基、_〇R2、-NR3R4、 -C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、-NR3S(0)mR4、 -S(0；LR2 或-S(0)»NR3R4。 “燒氧基”指-0-(烧基）和-〇-(未取代的環烧基），其 中烷基的定義如上所述。非限制性實施例包含甲氧基、乙 氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、 環己氧基等。烷氧基可以是視需要取代的或未取代的，當 被取代時’取代基較佳為一個或多個以下基團，獨立地選 聲 自為烧基、稀基、快基、烧氧基、烧硫基、烧基胺基、南 素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、 雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、 -OR2、-NR3R4、-C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、 -NR3S(0)mR4、-S(0)mR2 或-SCOXNRY。 鹵代烧基指烧基被一個或多個齒素取代。 “羥基”指-0H基團。 $ “羥烷基”指烷基被羥基取代。 “鹵素”指氟、氣、溴或填。 “胺基”指-NH2。 “氰基”指-CN。 “硝基”指-N〇2。 “苄基”指-CH2-苯基。 “氧代”指=0。 “羧酸”指-C(0)0H。 “羧酸酯”指-C(0)0(烷基）或（環烷基）。 59 95344 201213319 “視需要”或“視需要地”意味著隨後所描述地事 件或環境可以但不必發生，該說明包括該事件或環境發生 或不發生地場合。例如，“視需要被烷基取代的雜環基團” 意味著烷基可以但不必須存在，該說明包括雜環基團被烷 基取代的情形和雜環基團不被烷基取代的情形。 “取代的”指基團中的一個或多個氫原子，較佳為最 多5個，更較佳為1至3個氫原子彼此獨立地被相應數目 的取代基取代。不言而喻，取代基僅處在它們的可能的化 # 學位置，本領域技術人員能夠在不付出過多努力的情況下 φ 確定（藉由實驗或理論）可能或不可能的取代。例如，具有 游離氫的胺基或羥基與具有不飽和（如烯屬）鍵的碳原子結 合時可能是不穩定的。 “醫藥組成物”表示含有一種或多種本文所述化合 物或其生理學上/可藥用的鹽或前體藥物與其他化學組分 的混合物，以及其他組分例如生理學/可藥用的載體和賦形 I 劑。醫藥組成物的目的是促進對生物體的給藥，利於活性 V · 成分的吸收進而發揮生物活性。 — m和R2至R4的定義如通式（I)化合物中所述。 本發明化合物的合成方法 為了完成本發明的目的，本發明採用如下技術方案： 本發明通式（I)所述的化合物或其鹽的製備方法，包 括以下步驟： 60 95344 201213319Preferably, the heteroaryl group is preferably one or more of the following, independent, from alkaloid, alkoxy, thiol, alkyl, cycline, earth: soil Nitro, cyano, lysyl, hydrazino, ruthenium, cyclamate, cycloalkoxy 95344 58 201213319 base, heterocyclic alkoxy, cycloalkylthio, heterocyclic thiol, _〇 R2, -NR3R4, -C(0)R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -S(0; LR2 or -S( 0)»NR3R4. "Alkoxy" means -0-(alkyl) and -〇-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, Ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted when substituted When the substituent is preferably one or more of the following groups, independently selected from the group consisting of a pyridyl group, a dilute group, a fast group, an alkoxy group, a sulfur-burning group, an alkyl group, a sulfhydryl group, a thiol group, a hydroxyl group, and a hydroxyl group. , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Base, cycloalkylthio, heterocycloalkylthio, -OR2, -NR3R4, -C(0)R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NR3S( 0) mR4, -S(0)mR2 or -SCOXNRY. A halogenated group means that the alkyl group is substituted by one or more dentates. "Hydroxy" means an -OH group. ""Hydroxyalkyl" means an alkyl group by a hydroxyl group. "Halogen" means fluorine, gas, bromine or filled. "Amine" means -NH2. "Cyano" means -CN. "Nitro" means -N〇2. "Benzyl" means -CH2-phenyl. "Oxo" means = 0. "Carboxylic acid" means -C(0)0H. "Carboxylic acid ester" means -C(0)0(alkyl) or (cycloalkyl). 59 95344 201213319 "As needed "Or "as needed" means that the event or environment described subsequently can, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic groups that are optionally substituted with alkyl groups" This means that an alkyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. "Substituted" means one or more hydrogens in the group. Atom, preferably up to 5, more preferably 1 to 3 hydrogen The subunits are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible positions, and those skilled in the art can determine φ without much effort (by experimentation) Or theoretically possible or impossible substitution. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond. "Pharmaceutical composition" means containing one or A plurality of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or mixture of prodrugs thereof with other chemical components, and other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active V· component to exert biological activity. - m and R2 to R4 are as defined in the compounds of formula (I). Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention employs the following technical scheme: The method for producing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps: 60 95344 201213319

將通式（IG)化合物與磺醯氣反應，得到磺醯基保護的 通式（IB)化合物；關於由其相應的醇形成績酸g旨參見r κThe compound of the formula (IG) is reacted with a sulfonium gas to give a sulfonyl group-protected compound of the formula (IB); with respect to its corresponding alcohol form acid g, see r κ

Crossland 和 K.L. Servis，/. 见，1970，35 3195-3196 ;或者將通式（IG)化合物自化，得到通式（IB) 化合物； 將通式（IA)化合物與通式（IB )化合物在驗性條件下 發生親核取代反應，得到通式（I)化合物；提供鹼性條件的 試劑包括但不限於碳酸鹽，較佳為碳酸鉀或碳酸鎚。關於 磺酸酯置換的反應條件，參見P. J· Gilligan等，乂#ec/. 0?挪.，1992，35，4344-436卜 當PG為羥基，-bH基團也含有羥基時，通式（ία)化 合物與通式（IB)化合物在三苯基膦和偶氮二甲酸二異丙醋 的存在下發生Mitsunobu反應，得到通式通式（I)化合物； 關於Mitsunobu反應的綜述參見D. L. Hughes 无eac42，335。 化合物a與化合物b發生親核取代反應，得到通式 (IA)化合物，化合物a為親核試劑，含有親核基團。 61 95344 201213319Crossland and KL Servis, /. See, 1970, 35 3195-3196; or self-generating a compound of the general formula (IG) to give a compound of the formula (IB); a compound of the formula (IA) and a compound of the formula (IB) A nucleophilic substitution reaction occurs under the conditions of the assay to give a compound of the formula (I); reagents which provide basic conditions include, but are not limited to, carbonates, preferably potassium carbonate or carbonated hammers. For the reaction conditions for sulfonate replacement, see P. J. Gilligan et al., 乂#ec/. 0?, No., 1992, 35, 4434-436. When PG is a hydroxyl group and the -bH group also contains a hydroxyl group, The Mitsunobu reaction of a compound of the formula (ία) with a compound of the formula (IB) in the presence of triphenylphosphine and diisopropyl azodicarboxylate gives a compound of the formula (I); for a review of the Mitsunobu reaction see DL Hughes has no eac42,335. The compound a and the compound b undergo a nucleophilic substitution reaction to obtain a compound of the formula (IA), which is a nucleophilic reagent and contains a nucleophilic group. 61 95344 201213319

當L1為一個化學鍵時，通式（ΙΑ)化合物的製備方法 視需要藉由以下兩種流程製備而得：化合物c和化合物d 在鈀類催化劑催化下’較佳為pd(pph3)44 pdCl2(pph3)2， 在鹼性條件下發生Suzuki偶合反應，得到通式（IA)化合 物；相鄰類似的’化合物e和化合物f也發生Suzuki偶合 反應’得到通式（IA)化合物；上述的Suzuki偶合反應發生 在取代的芳基硼酸或雜芳基硼酸和取代的芳基溴或雜芳基 鹵化物（溴化物或氯化物）之間，得到通式（IA)化合物；關 於 Suzuki 反應條件，參見 N. Miyaura 和 A. Suzuki,When L1 is a chemical bond, the preparation method of the compound of the formula (ΙΑ) can be obtained by the following two processes: compound c and compound d are preferably pd(pph3)44 pdCl2 under the catalysis of a palladium catalyst ( Pph3)2, Suzuki coupling reaction occurs under basic conditions to obtain a compound of the formula (IA); adjacent similar 'compounds e and compound f also undergo Suzuki coupling reaction' to obtain a compound of the formula (IA); the above-mentioned Suzuki coupling The reaction takes place between a substituted aryl boronic acid or a heteroaryl boronic acid and a substituted aryl bromide or heteroaryl halide (bromide or chloride) to give a compound of the formula (IA); for Suzuki reaction conditions, see N Miyaura and A. Suzuki,

Rev., 1995, 95, 2457-2483; A. Suzuki, J. 物a刪67?⑽.1999，576，147-168。 其中：PG為離去基團，較佳為鹵素或者磺醯基； 環A、環B、環C、R1、和L2的定義與通式（I)化合 物一致。 本發明通式（I)所述的化合物或其鹽的製備方法，包 括以下步驟：Rev., 1995, 95, 2457-2483; A. Suzuki, J. A. 67. (10). 1999, 576, 147-168. Wherein: PG is a leaving group, preferably a halogen or a sulfonyl group; and the definitions of ring A, ring B, ring C, R1, and L2 are the same as those of the compound of the formula (I). A method for producing a compound of the formula (I) or a salt thereof according to the present invention comprises the following steps:

(IC) (1D) (!) 將通式（1C)化合物與通式（ID)化合物在驗性條件下 反應，得到通式（I)化合物；關於Suzuki反應條件，參見 N. Miyaura 和 A. Suzuki, 1995，95， 95344 62 201213319 2457-2483; A. Suzuki，j 〇rgan〇metaUicChem. 1999 576, 147-168。通式⑽化合物可以藉由化合物g與化合 物h在鹼性條件下發生親核取代反應製備而得。、σ 其中：L為一個鍵；X為鹵素；環人、環Β、環c、Ri 和L2的定義與通式（I)化合物一致。 本發明通式（I)所述的化合物或其鹽的製備方法，包 括以下步驟： i(IC) (1D) (!) The compound of the formula (1C) is reacted with a compound of the formula (ID) under the test conditions to give a compound of the formula (I); for the Suzuki reaction conditions, see N. Miyaura and A. Suzuki, 1995, 95, 95344 62 201213319 2457-2483; A. Suzuki, j 〇rgan〇metaUicChem. 1999 576, 147-168. The compound of the formula (10) can be produced by subjecting the compound g to the nucleophilic substitution reaction of the compound h under basic conditions. σ where: L is a bond; X is a halogen; the ring, ring, ring c, Ri and L2 are as defined for the compound of formula (I). A method for producing a compound of the formula (I) or a salt thereof according to the present invention comprises the following steps:

GyL,H+ pgx^pgGyL, H+ pgx^pg

將通式（IE)化合物與通式（if)化合物在鹼性條件下 發生親核取代反應’得到通式（I)化合物；提供驗性條件的 試劑包括但不限於碳酸鹽’較佳為碳酸鉀或碳酸铯。關於 磺酸酯置換的反應條件，參見P. J. Gilligan等，乂』 〔加/»·，1992’ 35’ 4344-4361。通式（IE)化合物可以藉由 化合物j與化合物k在驗性條件下發生親核取代反應製備 而得。 其中：PG相同或不同，為離去基團，較佳為鹵素或者 續酿基； 環A、環B、環C、R1、Li和L2的定義與通式⑴化合 物一致。 本發明通式（I)所述的化合物或其鹽的製備方法，包 63 95344 201213319 括以下步驟 则 (U) 化合物（1C)與聯硼酸頻那醇酯在二（— (I> 鐵二氯化鈀的催化下，得到化合物（IH).笨膦基）二茂 合物（IJ)進行Suzuki反應，得到通式（I) δ物（丨1〇與化 其中：L丨為一個鍵；X為鹵音·# _物。 和Lz的定義與通式（I)化合物一致。 β、環C、R1 鹽 的製備方法， 包 本發明通式（I)所述的化合物或其 括以下步驟： ⑽汾一⑽分分分 化合物m在三氟醋酸或鹽酸的酸性條件二 氧基幾基，得到化合物n;化合物n視 第二 試劑反應，親電試㈣括但秘於 *要與各種親電 鹼性條件下加熱反應；2)氣F酸甲酯；：南：：芳基’ 取代基鹵化物；4)醯氣和磺醯氯；5)異物或 酸西t ^ ~吳虱酸酯和異硫說 I西曰。與親電試劑的反應可在適合的溶劑如二氯尹烷、讯 四氫呋喃、乙腈或二甲基亞颯_在本領域技術人八 知的條件下進行。 & 化合物η也可以與溴化氰反應，得到相應的氰基胺衍 生物’該氰基胺衍生物可進一步轉化為雜環，包括但 於。惡二嗅。 、 64 95344 201213319 其中：環A、環B、環C、R1、Li和L2的定義與通式（i) 化合物一致。 【實施方式】 以下結合實施例用於進一步描述本發明，但這些實施 例並非限制著本發明的範圍。 實施例 化合物的結構是藉由核磁共振（NMR)或/和質譜（MS) 來確定的。NMR位移（6 )以i〇_6 (ppm)的單位給出。NMR的 • 測定是用Bruker AVANCE-400核磁儀’測定溶劑為氘代二鲁 曱基亞颯⑽S0-成），氘代氯仿（CDC10，氘代曱醇（CD3〇D)， 内標為四甲基矽烷（TMS)。 MS的測定用FINNIGAN LCQAd (ESI)質譜儀（生產商：A compound of the formula (IE) is subjected to a nucleophilic substitution reaction with a compound of the formula (if) under basic conditions to give a compound of the formula (I); reagents providing assay conditions include, but are not limited to, carbonates, preferably carbonic acid. Potassium or strontium carbonate. For the reaction conditions for the sulfonate replacement, see P. J. Gilligan et al., ed/, · 1992' 35' 4344-4361. The compound of the formula (IE) can be obtained by nucleophilic substitution reaction of the compound j with the compound k under the test conditions. Wherein: PG is the same or different and is a leaving group, preferably a halogen or a continuation base; and the definitions of ring A, ring B, ring C, R1, Li and L2 are identical to the compound of formula (1). The preparation method of the compound of the formula (I) or a salt thereof of the present invention, package 63 95344 201213319 includes the following steps: (U) the compound (1C) and the boronic acid pinacol ester in the second (->I> iron dichloride Under the catalysis of palladium, the compound (IH). stupidyl) dicarboxylate (IJ) is subjected to Suzuki reaction to obtain the general formula (I) δ (wherein: 丨1〇 and crystallization: L丨 is a bond; X The formula of the formula (I) is the same as the compound of the formula (I), and the compound of the formula (I) of the present invention or the steps thereof are as follows: (10) 汾1 (10) is divided into compound m in the acidic condition of trifluoroacetic acid or hydrochloric acid to form a dioxyl group to obtain compound n; compound n is reacted according to the second reagent, electrophilic test (four) includes but secretive * with various electrophilic Heating reaction under alkaline conditions; 2) gas F acid methyl ester;: south:: aryl 'substituent halide; 4) helium and sulfonium chloride; 5) foreign matter or acid west t ^ ~ urate and Isosulfur said I Xiqiao. The reaction with the electrophile can be carried out in a suitable solvent such as dichloroindan, tetrahydrofuran, acetonitrile or dimethylhydrazine in a state known to those skilled in the art. & Compound η can also be reacted with cyanogen bromide to give the corresponding cyanoamine derivative. The cyanoamine derivative can be further converted to a heterocyclic ring, including but. Two evil sniffers. 64 95344 201213319 wherein: ring A, ring B, ring C, R1, Li and L2 are as defined for the compound of formula (i). The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. EXAMPLES The structure of the compounds was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (6) is given in units of i 〇 6 (ppm). NMR • The determination is based on the Bruker AVANCE-400 nuclear magnetic instrument's determination solvent for deuterated ruthenium sulfonium (10) S0-form), deuterated chloroform (CDC10, deuterated sterol (CD3〇D), internal standard is four Base decane (TMS). MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer:

Thermo,型號：Finnigail LCQ advantage MAX)。 HPLC的測定使用安捷倫1200DAD高壓液相色譜儀 (Sunf ire C18 15〇χ4· 6mm 色譜管柱）和 Waters 2695-2996 φ 高壓液相色譜儀（Gimini Cl8 l5〇x4.6mm色譜管柱）。 _ 薄層色譜矽膠板使用煙臺黃海HSGF254或青島GF254 石夕膠板’薄層色譜法（TLC)使用的矽膠板採用的規格是 0. 15mm至0. 2mm，薄層色譜分離純化產品採用的規格是〇. 4 mm 至 0· 5mm。 色譜管柱—般使用煙臺黃海矽膠200至300目矽膠為 載體。 本發明的已知的起始原料可以採用或按照本領域已 知的方法來合成，或可購買自ABCRGmbH&Co. KG，Acros 65 95344 201213319Thermo, model: Finnigail LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 15〇χ4·6 mm chromatography column) and a Waters 2695-2996 φ high pressure liquid chromatograph (Gimini Cl8 l5〇x4.6 mm chromatography column). _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Yes 4. 4 mm to 0·5 mm. The chromatographic column is generally used as a carrier for Yantai Huanghai Silicone 200 to 300 mesh silicone. The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCRGmbH & Co. KG, Acros 65 95344 201213319

Organics ’ Aldrich Chemical Company ’ 韶遠化學科技 (Accela ChemBio Inc)、達瑞化學品等公司。 氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬 氣或氮氣氣球。 氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 加壓氫化反應使用Parr 3916EKX型氫化儀和清藍 QL-500型氫氣發生器或HC2-SS型氫化儀。 氫化反應通常抽真空，充入氫氣，反複操作3次。 鲁 微波反應使用CEM Discover-S 908860型微波反應器。鲁 實施例中無特殊說明，反應在氮氣氛或氬氣氛下進 行。 實施例中無特殊說明，溶液是指水溶液。 實施例中無特殊說明，反應的溫度為室溫。 室溫為最適宜的反應溫度，為20°C至30eC。 實施例中的反應進程的監測採用薄層色譜法（TLC)， φ 反應所使用的展開劑的體系有：二氣甲烷和曱醇體系，正 己烧和乙酸乙酯體系，溶劑的體積比根據化合物的極性不 擊 同而進行調節。 純化化合物採用的管柱色譜的洗脫劑的體系和薄層 色譜法的展開劑體系包括：A :二氯甲烷和甲醇體系，B : 正己燒和乙酸乙酯體系，溶劑的體積比根據化合物的極性 不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性 或酸性試劑進行調節。 實施例1，2 66 95344 201213319 201213319 基哌嗪〜1-基）甲 4,5, 6, 6a-六氫 尤知幻-5 ~ [ 2-漠-4-[ (4-曱續職 基]苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3a， ~111-環戊並|»比11各 1〜基）甲基] &六氫-1H- cis-6^iP,知W-5-[2-溴-4-[(4-甲磺醯基哌嚷 苯氧基]-2-(5-乙基嘧啶_2_基）_3, 35,4, 5, 6, 6 環戊並[c]°比洛Organics' Aldrich Chemical Company ’Accela ChemBio Inc., Dari Chemicals and other companies. An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus. The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. The microwave reaction was performed using a CEM Discover-S Model 908860 microwave reactor. There is no special explanation in the examples, and the reaction is carried out under a nitrogen atmosphere or an argon atmosphere. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, from 20 ° C to 30 eC. The reaction process in the examples was monitored by thin layer chromatography (TLC). The system of the developing agent used for the φ reaction was: di-methane and decyl alcohol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent was based on the compound. The polarity is adjusted without the same polarity. Purification compounds using column chromatography eluent systems and thin layer chromatography developers include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, the volume ratio of the solvent according to the compound The polarity is adjusted to adjust, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment. Example 1, 2 66 95344 201213319 201213319 Piperazine~1-yl)methyl 4,5, 6, 6a-hexahydro-preferential-5 ~ [ 2- Desert-4-[(4-曱) Phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a, ~111-cyclopenta[»11-11 1~yl)methyl] & hexahydro-1H-cis- 6^iP, know W-5-[2-bromo-4-[(4-methylsulfonylpiperazinyloxy)-2-(5-ethylpyrimidin-2-yl)_3, 35,4, 5, 6, 6 cyclopenta[c]° bilo

第一步 (3狄6351) 1’ 2, 3, 3a，4, 5, 6, 6a-八氫環戊並[小比哈-5-醇 冰浴下，將 c/s~(3a&gt;P，6a«-5-羥基-3, 3a，4, 5, 6, 65-六氫—環戊並[啦嘻-2-緩酸第三丁酯la(2.20g，0.01 67 95344 201213319 mol，採用公知的方法 “Bioorganic &amp; Medicinal Chemistry Letters (2010)，20(5)，1674-1676” 製備而 得）溶解於20mL二氯曱烷中，滴加入30mL的4M鹽酸甲醇 溶液，升至室溫，攪拌反應12小時。減壓濃縮反應液，得 到粗品標題產物6¾尤^3幻-1，2, 3, 3a，4, 5, 6, 6a-八氣環戊 並[〇]°比略-5-醇lb(l. 50 g，黃色固體），產物不經純化直 接進行下一步反應。 第二步 _ 6¾尤 5a5^-2-(5-乙基°密咬-2-基）-3, 35, 4, 5, 6, 6a-六氫 -1H-環戊並[c]n比略-5-醇 將粗品^5^-1，2, 3, 3a，4, 5, 6, 6(3-八氫環戊並[c] 吡咯-5-醇 lb(l. 50g，9. 20mmol)溶解於 20mL N，N-二曱基乙 龜胺中’依次加2-氯-5-乙基密咬（1· 30g，9. 20mmol)和 碳酸鉀（2. 50g’ 18. 40mmol) ’升至150°C攪拌反應12小時。 過濾，加入50mL水，用乙酸乙酯萃取（5〇mLx3)，合併有機 φ 相，依次用水（2〇mLx3)，飽和氣化胺溶液（4〇mLx3)洗滌， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產 物6¾疋鈿5&gt;2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫 -1H-環戊並[c]吡咯-5-醇lc(2.20 g，黃色液體），產物不 經純化直接進行下一步反應。 MS m/z (ESI)： 234.1 [M+l] 第三步 [(3af, 6a5〇-2-(5-乙基嘧啶-2-基）-3, 33, 4, 5, 6, 6a-六氫 環戊並[c]吡咯-5-基]甲績酸酐 95344 68 201213319 冰浴下’將粗品（办疋知5&gt;2-(5-乙基嘧啶-2-基）-3,3a，4，5，6，6a-六氫-1H-環戍並各醇 lc(1.80g， 7. 70mmol)溶解於2〇mL無水二氣曱烧中，加入三乙胺（2mL， 14. 50mmol) ’ 滴加入甲磺醯氣（〇. 65mL，8. 50mmol)，升至 室溫’攪拌反應12小時。加入飽和碳酸氫鈉溶液30mL， 一氣曱烧萃取（10mLx3)，合併有機相，依次用水（20mLx3)， 飽和氯化鈉溶液（2〇mLx3)洗滌，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，得到粗品標題產物6a5*)-2-(5-❿ 乙基喷啶-2-基）-3,3a，4, 5,6, 6a-六氫-1H-環戊並[c]吡咯 _5_基]曱磺酸酐id( 1.60 g，黃色固體），產物不經純化直 接進行下一步反應。 MS m/z (ESI)： 312.1 [M+l] 第四步 4-甲磺醯基哌嗪-1-羧酸第三丁酯 冰浴下’將哌嗪-1-羧酸第三丁酯（4〇g，22mmol)溶解 ^ 於300mL無水二氣甲烷中，加入三乙胺（61mL，44mmol)， 滴加入含曱磺醯氣（29. 60g，25. 80mmol)的二氯曱烷溶夜， 滴加完畢後升至室溫，攪拌反應12小時，析出大量固體。 過;慮’；慮液用飽和氣化錄溶液（1 〇〇mLx3)洗條，無水硫酸鎮 乾燥’過遽，濾液減壓濃縮，得到粗品標題產物4-甲磺隨 基派嗪-1-羧酸第三丁酯le(52g，白色固體），產物不經纯 化直接進行下一步反應。 MS m/z (ESI)： 165.1 [M+l-100] 第五步 69 95344 201213319 1-甲磺醯基哌嘹 冰浴下，將4-甲磺醯基哌嗪__丨_羧酸第三丁酯le(4g， 1.50mmol)溶解於4〇mL二氣甲烷中滴加入4〇虹鹽酸 曱醇/谷液，升至室溫，攪拌反應12小時，析出大量固體。 過濾，付到粗品標題產物1-曱磺醯基哌嗪If(2. 90g，白 色固體），產物不經純化直接進行下一步反應。 第六步The first step (3 Di 6351) 1' 2, 3, 3a, 4, 5, 6, 6a-octahydrocyclopenta [small Biha-5-alcoholic ice bath, c/s~(3a&gt;P , 6a«-5-hydroxy-3, 3a, 4, 5, 6, 65-hexahydro-cyclopenta[lathene-2-sodium tartrate la (2.20g, 0.01 67 95344 201213319 mol, using A well-known method "Bioorganic & Medicinal Chemistry Letters (2010), 20 (5), 1674-1676" prepared) was dissolved in 20 mL of dichloromethane, and 30 mL of a 4 M hydrochloric acid methanol solution was added dropwise, and the temperature was raised to room temperature. The reaction was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure to give crude titled product: </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> - Alcohol lb (1.50 g, yellow solid), the product is directly subjected to the next reaction without purification. The second step is _63⁄4 especially 5a5^-2-(5-ethyl lymid-2-yl)-3, 35, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]n than slightly 5-alcohol will be crude ^5^-1,2, 3, 3a,4, 5, 6, 6 ( 3-octahydrocyclopenta[c]pyrrole-5-ol lb (1.50 g, 9.20 mmol) was dissolved in 20 mL of N,N-dimercaptoamine to sequentially add 2-chloro-5-ethyl Bite (1·30g, 9.20mmol) and potassium carbonate (2. 50g' 18. 40mmol The temperature was stirred at 150 ° C for 12 hours. Filtration, adding 50 mL of water, extracting with ethyl acetate (5 〇 mL x 3), combining the organic φ phase, followed by water (2 〇 mL x 3), saturated gasified amine solution (4 〇) The extract was washed with MgSO.sub.3 (MgSO.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss - hexahydro-1H-cyclopenta[c]pyrrole-5-ol lc (2.20 g, yellow liquid), the product was taken to the next step without purification. MS m/z (ESI): 234.1 [M+l] The third step [(3af, 6a5〇-2-(5-ethylpyrimidin-2-yl)-3, 33, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-5-yl] Ajic acid 95344 68 201213319 Under ice bath 'will be crude (do not know 5> 2-(5-ethylpyrimidin-2-yl)-3,3a,4,5,6,6a-hexahydro-1H-ring The hydrazine alcohol lc (1.80 g, 7.70 mmol) was dissolved in 2 mL of anhydrous dioxane, and triethylamine (2 mL, 14. 50 mmol) was added. The methylsulfonate gas was added dropwise (〇. 65 mL, 8. 50 mmol), warmed to room temperature and stirred for 12 hours. 30 mL of a saturated sodium hydrogencarbonate solution was added, and the mixture was combined with EtOAc (EtOAc) (EtOAc (EtOAc) The crude title product 6a5*)-2-(5-fluorenylethylpyridin-2-yl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole_5 was obtained. _ base] hydrazine sulfonic anhydride id ( 1.60 g, yellow solid), the product was directly subjected to the next reaction without purification. MS m/z (ESI): 312.1 [M+l] Step 4 4-Methylsulfonylpiperazine-1-carboxylic acid tert-butyl ester. (4〇g, 22mmol) dissolved in 300mL anhydrous di-methane, added triethylamine (61mL, 44mmol), and added dropwise to the chlorinated sulfonium (29. 60g, 25.80mmol) of dichloromethane After the completion of the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 12 hours to precipitate a large amount of solid. After the filter was treated with a saturated gasification solution (1 〇〇mLx3), dried over anhydrous sulfuric acid, and the filtrate was concentrated under reduced pressure to give the crude title product 4-methanesulfonylpyrazine-1- The butyl ketone carboxylate (52 g, white solid) was taken directly to the next step without purification. MS m/z (ESI): 165.1 [M+l-100] Step 5 69 95344 201213319 1-Methylsulfonylpiperazine ice bath, 4-methylsulfonylpiperazine __丨-carboxylic acid Tributyl ester le (4 g, 1.50 mmol) was dissolved in 4 mL of di-methane, and 4 〇 曱 曱 曱 / / 谷 谷 谷 谷 谷 谷 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Filtration was carried out to give the title compound (1. 90 g, white solid). Step 6

2-溴-4-[(4-甲磺醯基哌嗪―卜基）甲基]苯酚 ® 將粗品卜甲磺醯基哌嗪lf(400mg，2mmol)溶解於10mL 二氯乙烷中’依次加3-溴-4-羥基-苯曱醛（402mg ’ 2mmol) 和三乙醯氧基硼氫化鈉（848mg，4mmol)，升至8(TC攪拌反 應5小時。加入l〇mL飽和碳酸氫鈉溶液調節pH值至9， 二氣甲烷萃取（20mLx3)，無水硫酸鎂乾燥，過濾，濾液減 壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘 物，得到標題產物2-溴-4-[(4-甲磺酿基哌嗪_1-基）曱基] ^ 苯紛lg(300mg，白色固體），產率：43. 0%。 MS m/z (ESI): 348.6 [M+l] 第七步 尤 635·)_5-[2-溴-4-[(4-曱績醯基旅°秦_1-基）曱 基]苯氧基]-2_(5_乙基喊咬基）_3，3习，4，5，6，6沒_/、鼠 -1H-環戊並[c]吡咯2-Bromo-4-[(4-methanesulfonylpiperazine-byl)methyl]phenol® The crude methanesulfonyl piperazine lf (400 mg, 2 mmol) was dissolved in 10 mL of dichloroethane. Add 3-bromo-4-hydroxy-benzofural (402 mg '2 mmol) and sodium triethoxysulfonium borohydride (848 mg, 4 mmol), and bring to 8 (TC stirring reaction for 5 hours. Add 1 mL of saturated sodium bicarbonate The solution was adjusted to pH 9, to di-methane (20 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. -4-[(4-Methanesulfonylpiperazin-1 -yl)indolyl] ^ Benzene lg (300 mg, white solid), yield: 43. 0%. MS m/z (ESI): 348.6 [ M+l] The seventh step is especially 635·)_5-[2-bromo-4-[(4-曱曱醯基旅°秦_1-yl) fluorenyl]phenoxy]-2_(5_ethyl Shouting bite base) _3, 3 ha, 4, 5, 6, 6 no _ /, rat -1H-cyclopenta[c] pyrrole

CiWJaiP，知W_5-[2-溴-4-[(4-甲磺醯基哌嗪-1-基）曱基] 苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H- 環戊並[c] °比咯 70 95344 201213319 將2-溴-4-[(4-曱磺醯基哌嗪-1-基）曱基]苯酚lg (500mg，1.44mmol)和粗品 ci&gt;s-[(3a足 6aiS)-2-(5-乙基嘴 咬_2-基）-3, 3a，4, 5, 6, 6a_六氫-1H-環戊並[c]°比略-5-基] 甲續酸酐ld(536mg，1· 72mmol)溶解於10mL乙腈中，再加 入碳酸铯（936mg，2. 88mmol)，升至80°C擾拌反應4小時， 再50°C反應12小時。過濾，濾液減壓濃縮，用矽膠管柱 色譜法以洗脫劑體系A純化所得殘餘物，得到一對非對映 異構體產物，分別是尤鈿W-5-[2-溴-4-[(4-甲 • 磺醯基哌嗪-1-基）曱基]苯氧基]-2-(5-乙基嘧啶-2- 基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並各 1 (300mg， 白色固體），cis-a5尤知W-5-[2-溴-4-[(4-甲磺醯基哌嘻 -1-基）曱基]苯氧基]-2-(5-乙基*»密咬-2-基）-3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並[c]B比ρ各2(8mg，白色固 體）。 MS m/z (ESI): 564.1 [M+l] φ 14 丽R (400 MHz, CDCIO (5 8. 18 (d，2H)，7. 51 (d，1H)， 7.15 (d, 1H), 6.82 (d, 1H), 4.96-4.95 (m, 1H), 3.75- 3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.46 (s, 2H), 3.25 (s, 4H), 3. 10-3. 09 (m, 2H), 2. 78 (s, 3H), 2. 54 (s, 4H), 2.46 (q, 2H), 2.29-2.20 (m, 2H), 1.90-1.86 (m, 2H), 1.19 (t, 3H). 2!H 丽R (400 MHz, CDC10 5 8. 19 (d, 2H), 7. 51 (d，1H), 7.14 (d, 1H), 6.82 (d, 1H), 4.90-4.86 (m, 1H), 3.90- 3.84 (m, 2H), 3.65-3.60 (m, 2H), 3.43 (s, 2H), 3.25 71 95344 201213319 (s, 4H), 2.93-2.90 (m, 2H), 2. 78 (s, 3H), 2. 54 (s, 4H), 2.46 (q, 2H), 2.44-2.30 (m, 2H), 2.20-1.95 (m, 2H), 1. 19 (t, 3H). 實施例3 疋知W-5- [2-氣-4-[(4-甲磺醯基哌嗪_1 一基）曱基]笨 氧基]-2-(5_乙基嘧啶-2-基）-3, 3及4, 5, 6, 6a-六氫-1H_ 環戊並[^7]0比洛CiWJaiP, known as W_5-[2-bromo-4-[(4-methylsulfonylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3 , 3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c] ° ratio 70 95344 201213319 2-bromo-4-[(4-oxasulfonylpiperazin-1-yl) Mercapto]phenol lg (500mg, 1.44mmol) and crude ci&gt;s-[(3a foot 6aiS)-2-(5-ethyl-mouth bite_2-yl)-3, 3a,4, 5, 6, 6a _ hexahydro-1H-cyclopenta[c]° ratio -5-yl] methylene anhydride ld (536 mg, 1.72 mmol) was dissolved in 10 mL of acetonitrile, then cesium carbonate (936 mg, 2.88 mmol), liter The reaction was stirred for 4 hours at 80 ° C and 12 hours at 50 ° C. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give a pair of diastereomer products, respectively, 钿W-5-[2-bromo-4- [(4-Methoxysulfonylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a,4, 5, 6, 6a- Hexahydro-1H-cyclopentazone 1 (300 mg, white solid), cis-a5, especially known as W-5-[2-bromo-4-[(4-methylsulfonylpiperazin-1-yl)indolyl Phenoxy]-2-(5-ethyl*»Bitter-2-yl)-3, 3a,4, 5, 6, 6a-hexahydro-1Η-cyclopenta[c]B ratio ρ 2 (8 mg, white solid). MS m/z (ESI): 564.1 [M+l] φ 14 丽 R (400 MHz, CDCIO (5 8. 18 (d, 2H), 7. 51 (d, 1H), 7.15 (d, 1H), 6.82 (d, 1H), 4.96-4.95 (m, 1H), 3.75- 3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.46 (s, 2H), 3.25 (s, 4H), 3. 10-3. 09 (m, 2H), 2. 78 (s, 3H), 2. 54 (s, 4H), 2.46 (q, 2H), 2.29-2.20 (m, 2H), 1.90-1.86 (m , 2H), 1.19 (t, 3H). 2!H R (400 MHz, CDC10 5 8. 19 (d, 2H), 7. 51 (d,1H), 7.14 (d, 1H), 6.82 (d , 1H), 4.90-4.86 (m, 1H), 3.90- 3.84 (m, 2H), 3.65-3.60 (m, 2H), 3.43 (s, 2H), 3.25 71 95344 201213319 (s, 4H), 2.93- 2.90 (m, 2H), 2. 78 (s, 3H), 2. 54 (s, 4H), 2.46 (q, 2H), 2.44-2.30 (m, 2H), 2.20-1.95 (m, 2H), 1. 19 (t, 3H). Example 3 WW-5- [2-Ga-4-[(4-methylsulfonylpiperazin-1-yl)indolyl] phenyloxy]-2- (5-ethylpyrimidin-2-yl)-3, 3 and 4, 5, 6, 6a-hexahydro-1H_cyclopenta[^7]0bi Luo

第一步 (3af，685^-5-漠-2，（5-乙基喊咬-2-基）-3, 3a，4, 5, 6, 6a- 六氫~1H-環戊並[c]吡咯 將 6¾疋知59-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯_5_醇lc(8〇〇mg，3.43mm〇1)溶解 72 95344 201213319 於10mL二氯乙烧中，加入四溴化碳（1. 70 g，5. lOmmol)， 冰浴降至0°C，滴加5mL三苯基膦（1.35 g，5. lOmmol)的 二氯曱烷溶液，升至室溫攪拌反應12小時。加入10mL水 洗滌，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠管 柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產物 ^5&quot;)-5-漠-2_(5_乙基〇密〇定-2_基）_3，3a，4，5，6，6a-六氫-1H-環戊並各3a(200mg，白色固體），產率： 20. 0%。 • MS m/z (ESI): 298.0 [M+l] 第二步 2-氯-4-[(4-曱磺醯基哌嗪-1-基）曱基]笨酚 將1-曱石黃醢基痕0秦If(2 g，lOmmol)和3-氣-4-經基-苯曱醛（1. 56 g，lOmmol)加入20mL二氯乙烷中，升至80 °(：攪拌反應2小時，冷卻至室溫，再加入三乙醯氧基硼氫 化鈉（4. 23 g ’ 20ramol)，80°C擾拌反應5小時。加入100mL $ 飽和碳酸氫鈉溶液，二氯曱烷萃取（50mLx3)，有機相用飽 和氯化納溶液洗條（50mLx3)，無水硫酸鎮乾燥，過渡，滤 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得 殘餘物，得到標題產物2-氯-4-[(4-甲磺醯基哌嗪-1-基） 曱基]苯酚3b(2 g，白色固體），產率：66. 7%。 MS ra/z (ESI): 305.0 [M+l] 第三步 6¾足知5&gt;5-[ 2-氯-4-[ (4-曱磺醯基哌嗪-1 -基）曱基]苯 氧基]-2-(5-乙基嘴〇定-2-基）-3，35,4，5，6，63-六氮_111- 73 95344 201213319 環戊並[c] °比洛 將（3a·/?，6aiS*)_5-漠- 2-(5-乙基嘴定-2-基）-3, 3a，4, 5, 6，6a-六氫-1H-環戊並[c]比洛 3a( 1 OOmg， 0. 33mmol)和2-氯-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯酚 3b(102mg ’ 0. 33mmol)溶解於5mLN，N-二甲基曱醯胺中，再 加入碳酸絶（214mg，0. 66mmol)，升溫至回流攪拌反應5 小時。過濾、，加入30mL水，乙酸乙醋萃取（10mLx4)，合併 有機相，依次用水（5mLx3)，飽和氣化納溶液洗滌 ♦ (10mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄 肇 層色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物 6¾尤知5&gt;5-[2-氯-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯 氧基]-2-（5-乙基定-2-基）-3, 3a，4, 5, 6, 6a-六氩-1H-環戊並[c]吡咯3(50mg，白色固體），產率：29. 0%。 MS m/z (ESI): 519.7 [M+l] 1H NMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 7.27 (d, 1H), φ 7.09 (d, 1H), 6.84 (d, 1H), 4.90-4.87 (m, 1H), 3.90-3.85 (ra, 2H), 3.65-3.61 (m, 2H), 3.44 (s, 2H), _ 3.25 (s, 4H), 2.93-2.91 (in, 2H), 2.78 (s, 3H), 2.55 (s, 4H), 2.47 (q, 2H), 2.44-2.32 (m, 2H), 2.20-1.97 (in, 2H), 1. 19 (t, 3 H). 實施例4 (&lt;?3足沒3|51)_5_[2，6_二氟_4_(4_甲增酿基苯基）苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c] 〇比口各 74 95344 201213319The first step (3af, 685^-5-di-2, (5-ethyl shit-2-yl)-3, 3a, 4, 5, 6, 6a-hexahydro~1H-cyclopenta[c Pyrrole will be known as 59⁄4疋59-2-(5-ethylpyrimidin-2-yl)-3, 3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-5-ol Lc (8〇〇mg, 3.43mm〇1) dissolved 72 95344 201213319 In 10mL of dichloroethene, add carbon tetrabromide (1. 70 g, 5. lOmmol), ice bath to 0 ° C, drop 5 mL of a solution of triphenylphosphine (1.35 g, 5.0 mmol) in dichloromethane, stirred at room temperature for 12 hours, washed with 10 mL of water, dried over anhydrous magnesium sulfate, filtered, and evaporated. Chromatography to purify the obtained residue in eluent system B to give the title product: &quot;5&quot;)-5------ 6a-Hexahydro-1H-cyclopentazone 3a (200 mg, white solid), Yield: 20. 0%. • MS m/z (ESI): 298.0 [M+l] Step 2 2-Chloro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl] phenol Trace 0 Qin If (2 g, 10 mmol) and 3-gas-4-carbyl-benzofural (1.56 g, 10 mmol) were added to 20 mL of dichloroethane and raised to 80 ° (: stirring reaction for 2 hours, After cooling to room temperature, sodium triethoxysulfonate (4.23 g '20ramol) was added, and the reaction was stirred for 5 hours at 80 ° C. Add 100 mL of saturated sodium bicarbonate solution and dichloromethane extraction (50 mL x 3) The organic phase is washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sulphuric acid, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by eluent column chromatography with eluent system A to give the title product 2-chloro -4-[(4-Methanesulfonylpiperazin-1-yl)indolyl]phenol 3b (2 g, white solid), yield: 66. 7%. MS / / (ESI): 305.0 [M +l] The third step 63⁄4 is known as 5&gt; 5-[2-chloro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-2-(5-ethyl Mouth -2--2-yl)-3,35,4,5,6,63-hexanitro_111- 73 95344 201213319 Cyclopenta[c] °Biluo (3a·/?,6aiS*)_5- Desert - 2-(5-ethyl-n-but-2-yl)-3, 3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c] piroxa 3a (100 mg, 0.33 mmol) and 2-chloro-4-[(4-oxasulfonylpiperazine- 1-Base)methyl]phenol 3b (102 mg '0.33 mmol) was dissolved in 5 mL of N,N-dimethyldecylamine, and then carbonic acid (214 mg, 0.66 mmol) was added thereto, and the mixture was heated to reflux and stirred for 5 hours. Filtration, adding 30mL of water, ethyl acetate extraction (10mLx4), the organic phase was combined, washed with water (5mLx3), saturated sodium hydride solution ♦ (10mLx3), dried over anhydrous magnesium sulfate, filtered, filtrate concentrated under reduced pressure, thin Purification of the obtained residue by EtOAc (EtOAc) eluted to elute to afford the title product </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 5-[2-chloro-4-[(4-oxasulfonylpiperazin-1-yl)methyl] Phenoxy]-2-(5-ethyl-den-2-yl)-3, 3a,4,5, 6, 6a-hexa-ar-H-H-cyclopenta[c]pyrrole 3 (50 mg, white solid) Yield: 29.0% MS m/z (ESI): 519.7 [M+l] 1H NMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 7.27 (d, 1H), φ 7.09 (d, 1H), 6.84 (d, 1H), 4.90-4.87 (m, 1H), 3.90-3.85 (ra, 2H), 3.65-3.61 (m, 2H), 3.44 (s, 2H), _ 3.25 ( s, 4H), 2.93-2.91 (in, 2H), 2.78 (s, 3H), 2.55 (s, 4H), 2.47 (q, 2H), 2.44-2.32 (m, 2H), 2.20-1.97 (in, 2H), 1. 19 (t, 3 H). Example 4 (&lt;?3 foot not 3|51)_5_ [2,6-Difluoro_4_(4-methyl-1-bromophenyl)phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a,4, 5, 6, 6a- Hexahydro-1H-cyclopenta[c] oxime ratio each mouth 74 95344 201213319

第'·~步 6¾尤^35^-5-(4-溴-2, 6-二氟-苯氧基）-2-(5-乙基嘧啶 -2_基）_3，3s, 4，5，6，6s-六氣-1H_環戊並[c]a比嘻 將（3af，6a5&quot;)-5-漠-2-(5-乙基n密咬-2-基）-3，3a，4，5，6, 6习-六氮-111-¾戊並[c]。比洛 3a(60mg，The first '·~ step 63⁄4 especially ^35^-5-(4-bromo-2,6-difluoro-phenoxy)-2-(5-ethylpyrimidin-2-yl)_3,3s, 4,5 ,6,6s-hexa-1H-cyclopenta[c]a than hydrazine (3af,6a5&quot;)-5-indistance-2-(5-ethyln-secre-2-yl)-3,3a , 4, 5, 6, 6 Xi-hexanitro-111-3⁄4 pentylene [c]. Bilo 3a (60mg,

0. 20mmol)和 4-漠-2, 6-二I-苯紛（42mg，0. 20mmol)溶解 於5mLN, N-二曱基曱醯胺中，再加入碳酸鉀（I30mg， 0. 40匪〇1) ’升溫至150°C攪拌反應5小時。加入30mL水， 乙酸乙酯萃取（10mLx4)，合併有機相，依次用水（10mLx2)， 飽和氣化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，得到粗品標題產物6¾尤知5&gt;5-(4-溴 -2, 6-二氣-苯氧基）-2-(5-乙基，咬-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡p各 4a(80mg，淡 黃色固體），產物不經純化直接進行下一步反應。 MS m/z (ESI)： 426.1 [M+l] 75 95344 201213319 第二步 (^3皮，^5&quot;)-5-[2，6-二敗-4-(4-曱續酿基苯基）笨氧 基]-2-(5-乙基0密咬-2-基）-3, 33, 4, 5, 6, 6a-六氫-1H-環 戊並|»比〇各 將粗品（办及，知5&quot;)_5-(4-漠_2，6_二氣-苯氧 基）-2-(5-乙基定-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊 並[c]°比洛4a(85mg，0.20ramol)，（4-曱續醯基苯基）爛酸 (48mg’0.24mmol)和1，1’ -二（二苯膦基）二茂鐵二氣化把 隹 （15mg ’ 0. 20mmol)溶解於lOmLl，4-二〇惡烧中，再加入碳酸 铯（195mg，0. 60mmol)，升溫110°C授拌反應3小時。過遽， 濾液減壓濃縮，用薄層色譜法以洗脫劑體系A純化所得殘 餘物，得到標題產物知幻-5-[2, 6-二氟-4-(4-甲磺醢 基苯基）苯氧基]-2-(5-乙基〇密0定-2-基）-3, 3a, 4, 5, 6, 6a- 六氫-1H-環戊並[c&gt;比嘻4(60mg，白色固體），產率：60. 0%。 MS m/z (ESI): 500.2 [M+l] φ !H NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 8.01 (d, 2H), 7.69 (t, 2H), 7.14 (d, 2H), 4.97-4.93 (m, 1H), 3.87-3.82 (m, 2H), 3.73-3.69 (m, 2H), 3.10 (s, 3H), 2.85-2.82 (in, 2H), 2.48 (q, 2H), 2.37-2.33 (m, 2H), 2.02-1.99 (m, 2H), 1.20 (t, 3H). 實施例5 6¾尤知5&gt;5-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]甲 基]-2-(5-乙基哺咬-2-基）-3, 33, 4, 5, 6, 6a-六氫-1H-環 戊並[c]^p各 76 95344 2012133190. 20mmol) and 4-di-2,6-di-I-benzene (42mg, 0.20mmol) were dissolved in 5mL of N,N-didecylguanamine, and then added potassium carbonate (I30mg, 0. 40匪) 〇 1) 'The temperature was raised to 150 ° C and the reaction was stirred for 5 hours. After adding 30 mL of water and ethyl acetate (10 mL×4), the organic phase was combined, washed with water (10 mL×2), EtOAc (EtOAc) Know 5&gt;5-(4-Bromo-2,6-dioxa-phenoxy)-2-(5-ethyl, guan-2-yl)-3, 3a, 4, 5, 6, 6a-six Hydrogen-1H-cyclopenta[c]pyridinium 4a (80 mg, light yellow solid). MS m/z (ESI): 426.1 [M+l] 75 95344 201213319 The second step (^3 skin, ^5&quot;)-5-[2,6-di-s--4-(4-anthracene benzene) Base) phenyloxy]-2-(5-ethyl 0 dimethyl-2-yl)-3, 33, 4, 5, 6, 6a-hexahydro-1H-cyclopenta- (To do, know 5 &quot;)_5-(4-Mo _2,6_di- phenoxy)-2-(5-ethyl-den-2-yl)-3, 3a,4, 5, 6 , 6a-hexahydro-1H-cyclopenta[c]° pir 4a (85mg, 0.20ramol), (4-anthracenylphenyl) rotten acid (48mg '0.24mmol) and 1,1' - two (Diphenylphosphino) Ferrocene Di-Gasification Dissolve hydrazine (15 mg '0.20 mmol) in 10 mL of 1,2-dioxin, add cesium carbonate (195 mg, 0.60 mmol), and raise the temperature by 110 °C. Mix and react for 3 hours. After the hydrazine, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by eluent eluting with EtOAc (EtOAc) to afford the title product, ss.-5-[2,6-difluoro-4-(4-methanesulfonylbenzene) Phenyloxy]-2-(5-ethylindole quinone-2-yl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c&gt; (60 mg, white solid), yield: 60. 0%. MS m/z (ESI): 500.2 [M+l] φ.H NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 8.01 (d, 2H), 7.69 (t, 2H), 7.14 (d, 2H), 4.97-4.93 (m, 1H), 3.87-3.82 (m, 2H), 3.73-3.69 (m, 2H), 3.10 (s, 3H), 2.85-2.82 (in, 2H), 2.48 (q, 2H), 2.37-2.33 (m, 2H), 2.02-1.99 (m, 2H), 1.20 (t, 3H). Example 5 63⁄4, especially 5&gt;5-[[2,6-difluoro-4-( 4-methanesulfonylphenyl)phenoxy]methyl]-2-(5-ethyl-carto-2-yl)-3, 33, 4, 5, 6, 6a-hexahydro-1H-cyclo戊和[c]^p76 76344 201213319

第一步 (3ai*?，6a5*)-5-亞曱基-1，3, 3a，4, 6, 6a-六氫-環戊並[^吼 咯-2-羧酸第三丁酯 將甲基三苯基溴化磷（3. 93 g，llmmol)溶解於15mL 四氫呋喃中，冷卻至0°C，將5mL含第三丁醇卸（丨.12 g， lOmmol)的四氫呋喃溶液加入到反應液中，保持攪拌反 應0.5小時。再升至室溫攪拌反應0.5小時，然後加熱至 回流反應1小時。將反應液冷卻至0°C，加入5mL 5-酮 -1，3, 3a，4, 6, 6a-六氫-環戊並[c]°比咯-2-羧酸第三丁酯 5a(l. 12 g，5mmol，採用公知的方法 “Bioorganic &amp; Medicinal Chemistry Letters (2010), 20(5), 1674-1676”製備而得）的四氫呋喃溶液，除去冰浴，升溫 至回流反應4小時。加入30mL水，用乙酸乙酯萃取 77 95344 201213319 (50mLx3)，合併有機相，飽和氣化鈉溶液洗滌（5〇mLx3)， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用夕膠管柱色雄 法以洗脫劑體系8純化所得殘餘物，得到標2^色°曰 (3说6喊-5-亞曱基-1’ 3, 3a，4, 6, 6a_六氫_環戊並[c]吡 洛-2-減第三丁醋5b(0.7Gg，黃色液體），產率：62.5%。 MS m/z (ESI): 168.1 [M-55] 第二步 ⑽，6必-5-(經基曱基）-3, 3a，4, 5, 6, 6a_六氫♦環戊 擊 並[c] °比咯_2'緣酸第三丁醋 將21mL 1M硼烷的四氫呋喃溶液溶解於2〇乩四氫呋 »南中，冷卻至（TC，將2, 3-丁二烯（2mL，2〇· 2〇_)分批 加入到上述體系中，保持〇。(：攪拌反應3小時。將含 (3城6必-5-亞曱基-1，3’ 3見4, 6, 6a-六氩-環戊並[c]吡 酸第三TSI5bU g’4.5()_)的四氫吱喃溶液 15mL慢慢滴加到反應液中，升至室溫攪拌反應12小時。 參反應液冷卻i rc，慢慢加入1〇mL1〇%氣氧化納溶液 加入7就過氧化氫溶液，升至室溫。反應液減壓濃縮， 水相用乙酸乙酯萃取⑽Lx3)，合併有機相，無水硫酸鎮 乾燥，過遽，濾液減壓濃縮’得到粗品標題產物⑽，、 6价5-(減甲基）-3, 3a，4, 5, 6, 6a_六氫鲁環戊並 轉-2-紐第三丁醋5c(G. 9() g，黃色液體）， 83· 3%。 MS ra/z (ESI)： 186.1 [M-55] 第三步 95344 78 201213319 6¾尤甲石頁蕴氧基甲基）-3, 3a，4, 5, 6, 6a-六氫 -1 Η，環戊並[c&gt;比洛-2-羧酸第三丁酯 冰浴下，將（3a#，6avS)-5-(M基甲基）-3, 3a，4, 5, 6’ 6a-六氫-1 Η-環戊並[c]吡咯-2-羧酸第三丁醋 5c(0. 90 g，3· 73mmol)溶解於50mL無水二氯曱烷中，加 入三乙胺（0. 75 g ’ 7. 46mmol)，滴加入曱磺醯氣（〇. 45mL， 5. 60mmol)，攪拌反應2小時，再升至室溫反應12小時。 加入二氯甲烷50mL，依次用水（50mLx2)，飽和氣化鈉溶液 馨 （50mLx2)洗滌，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，修 得到粗品標題產物知W-5-(甲續醯氧基曱 基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吼咯-2-羧酸第三 丁酯5d(l g，黃色液體），產物不經純化直接進行下一步 反應。 MS m/z (ESI): 264.1 [M-55] 第四步 6¾尤知5·&gt;5_[(4-溴-2, 6-二氟-苯氧基）曱基]-擊 3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[C]0比各-2-缓酸第三丁酉旨 將粗品知幻-5-(曱磺醯氧基甲基）-3, 3見4, 5, 6, 6a-六氫-1H-環戊並〇&gt;比洛-2-敌酸第三丁酯 5d(320mg，lmmol)和 4-溴-2, 6-二氟-笨酚（230mg， 1. lOmmol)溶解於lOmLN，N-二曱基曱酿胺中，再加入碳酸 铯（650mg’2ramol)，升溫至90°C攪拌反應2小時。加入15mL 水’乙酸乙酯萃取（30mLx2)，合併有機相，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，得到粗品標題產物 95344 £；The first step (3ai*?, 6a5*)-5-arylene-1,3,3a,4,6,6a-hexahydro-cyclopenta[^-pyrrole-2-carboxylic acid tert-butyl ester will Methyltriphenylphosphonium bromide (3.93 g, llmmol) was dissolved in 15 mL of tetrahydrofuran, cooled to 0 ° C, and 5 mL of a solution containing a third butanol (丨.12 g, 10 mmol) in tetrahydrofuran was added to the reaction. In the solution, the stirring reaction was kept for 0.5 hours. The reaction was further stirred at room temperature for 0.5 hour, and then heated to reflux for 1 hour. The reaction solution was cooled to 0 ° C, and 5 mL of 5-keto-1,3,3a,4,6,6a-hexahydro-cyclopenta[c][rho]butrol-2-carboxylic acid tert-butyl ester 5a ( l. 12 g, 5 mmol, a tetrahydrofuran solution prepared by a known method "Bioorganic &amp; Medicinal Chemistry Letters (2010), 20 (5), 1674-1676"), the ice bath was removed, and the temperature was raised to reflux for 4 hours. Add 30mL of water, extract 77 95344 201213319 (50mLx3) with ethyl acetate, combine the organic phase, wash with saturated sodium carbonate solution (5〇mLx3), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained by purifying the eluent system 8 was used to obtain the standard 2 color 曰 (3 said 6 shouting-5-arylene-1' 3, 3a, 4, 6, 6a_hexahydro-cyclopenta[ c] pirox-2-reduced third vinegar 5b (0.7 Gg, yellow liquid), yield: 62.5% MS m/z (ESI): 168.1 [M-55] second step (10), 6 must-5 - (via fluorenyl)-3, 3a,4, 5, 6, 6a_hexahydro ♦ ring penton and [c] ° ratio of _2' acid acid third vinegar 21mL 1M borane in tetrahydrofuran solution Dissolved in 2 〇乩 tetrahydrofuran» South, cooled to (TC, 2,3-butadiene (2mL, 2〇·2〇_) was added to the above system in batches to maintain hydrazine. (: Stirring reaction 3 hours. Will contain (3 city 6 must-5-arylene-1,3' 3 see 4, 6, 6a-hexa-argon-cyclopenta[c]pyrrolic acid third TSI5bU g'4.5()_) 15 mL of the tetrahydrofuran solution was slowly added dropwise to the reaction solution, and the reaction was stirred at room temperature for 12 hours. The reaction solution was cooled to i rc, and 1 mL of 1% by volume of oxygen was slowly added. The sodium solution was added to a solution of hydrogen peroxide, and the mixture was warmed to room temperature. The reaction mixture was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (10), and then evaporated. Title product (10), 6-valent 5-(sub-methyl)-3, 3a, 4, 5, 6, 6a_hexahydrolucyclopenta-trans-2-non-butadiene vinegar 5c (G. 9() g , yellow liquid), 83·3%. MS ra/z (ESI): 186.1 [M-55] Step 3 95344 78 201213319 63⁄4尤甲石页氧氧 methyl)-3, 3a,4, 5, 6, 6a-hexahydro-1 fluorene, cyclopenta[c&gt;, bis-butyl carboxylic acid, tert-butyl ester, (3a#, 6avS)-5-(M-methyl)-3, 3a,4,5,6' 6a-hexahydro-1 fluorene-cyclopenta[c]pyrrole-2-carboxylic acid terpene vinegar 5c (0. 90 g, 3.73 mmol) dissolved in 50 mL of anhydrous dichloropurine To the alkane, triethylamine (0.75 g '7.46 mmol) was added, and hydrazine sulfonium (〇.45 mL, 5.60 mmol) was added dropwise, and the reaction was stirred for 2 hours, and then further warmed to room temperature for 12 hours. 50 mL of methyl chloride, washed with water (50 mL×2), saturated sodium carbonate solution (50 mL×2), dried over anhydrous magnesium sulfate, filtered, The crude title product was obtained to obtain W-5-(methyl hydrazinyl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid. Third butyl ester 5d (lg, yellow liquid), the product was directly subjected to the next reaction without purification. MS m/z (ESI): 264.1 [M-55] The fourth step 63⁄4 knows 5·&gt;5_[(4-bromo-2,6-difluoro-phenoxy)indolyl]-- 3, 3a , 4, 5, 6, 6a-hexahydro-1H-cyclopenta[C] 0 is more than each of the 2-butylic acid tributyl sulfonate to the crude product -5-(sulfonyloxymethyl)-3 , 3 see 4, 5, 6, 6a-hexahydro-1H-cyclopentazepine&gt; piroxicam-2-butyrate 3d (320mg, lmmol) and 4-bromo-2,6-difluoro - Phenol (230 mg, 1.10 mmol) was dissolved in 10 mL of N,N-didecylamine, and cesium carbonate (650 mg '2ramol) was added thereto, and the mixture was heated to 90 ° C and stirred for 2 hours. After adding 15 mL of water, ethyl acetate (30 mL×2), EtOAc (EtOAc m.

Ss1 79 201213319 6¾兄^6&gt;5-[(4-溴-2, 6-二氟-苯氧基）曱 基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[c]0比略-2-緩酸第= 丁酯5e(400mg ’黃色液體），產物不經純化直接進行下一 步反應。 MS m/z (ESI): 378 [M-55] 第五步 (办尤^W-5-[[2, 6-二氟-4-(甲磺醯基苯基）苯氧基]甲 基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]〇tb略-2-繞酸第二 # 丁醋 一 將粗品(^3兄沒(4-漠-2, 6-二氟-苯氧基）曱 基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並各-2-竣酸第三 丁酯5e(400mg，0. 93mmol)，（4-曱續醯基苯基）蝴酸 (310mg，1. 57mmol)和 1，Γ -二（二苯膦基）二茂鐵二氣化 把（68mg，0. 09mmol)溶解於30mLl，4-二0惡燒中，再加入碳 酸鉋（910mg ’ 2. 78mmol)，升溫120〇C攪拌反應3小時。過 φ 濾，加入20mL水，乙酸乙酯萃取（3〇mLx2)，合併有機相， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產 物6¾兄知5&gt;5-[[2, 6-二氟〜4-(曱磺醯基苯基）笨氧基]甲 基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯-2-幾酸第三 丁酯5f(400mg，棕色油狀物），產率：85. 1%。 MS m/z (ESI): 452. 1 [M-55] 第六步 6¾兄如5&gt;5-[[2, 6-二氟-4-(甲磺醯基苯基）苯氧基]曱 基]-1，2, 3, 3a，4, 5, 6, 6a-八氫環戊並[c]°比口各 80 95344 201213319 將6¾尤知幻-5-[ [2, 6-二敗-4-(甲續醯基苯基）苯氧 基]甲基]-3, 33, 4, 5, 6, 6沒-六氫-1H-環戊並[c]吡洛_2_叛 酸第三丁酯5f (400mg，0. 80mmol)溶解於1〇mL甲醇中，滴 加入5mL2 Μ鹽酸甲醇溶液，攪拌反應48小時。滴加飽和 氫氧化鈉溶液至反應液pH為10,二氯甲烧萃取（3〇mLx3)， 合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得 到粗品標題產物（办兄知5·&gt;5-[ [2, 6-二氟-4-(曱續g篮基笨 基）本氧基]甲基]-1，2, 3, 3a，4, 5, 6, 6a-八氫環戊並[c]η比 咯5g(300mg ’棕色油狀物），產物不經純化直接進行下一 步反應。 MS m/z (ESI)： 408.1 [M+l] 第七步 6¾疋知幻-5-[[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]甲 基]-2-(5-乙基喊唆-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環 戊並[c ] °比洛 將粗品5-[ [2, 6-二氟-4-(甲磺醯基笨基）笨氧基]曱 基]-1，2, 3, 3a, 4, 5, 6, 6a-八氫環戊並[c]D比咯 5g(250mg， 0. 60mmol)溶解於i〇mLN，N-二曱基乙醯胺中，依次加2-氯 -5-乙基-嘧啶（87mg，0. 60mmol)和碳酸鉀（210mg， 1. 50mmol)，升至15〇。(：攪拌反應6小時。冷卻至室溫，加 入20mL水’用乙酸乙酯萃取（30mLx3)，合併有機相，無水 硫酸鎮乾燥’過渡，濾、液減壓濃縮，用石夕膠管柱色譜法以 洗脫劑體系B純化所得殘餘物，得到標題產物 6¾兄知5&gt;5-[[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]甲 81 95344 201213319 基]_2-(5-乙基嘴咬-2-基）-3, 3a，4, 5, 6, 6a-六氫-1 Η-環 戊並[c]吡咯5(80mg，白色固體），產率：25%。 MS m/z (ESI): 514.2 [M+l] !H NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 8.01 (d, 2H), 7.69 (d, 2H), 7.20-7.10 (m, 2H), 4.14 (d, 2H), 3.85-3.70 (m, 2H), 3.57-3.46 (in, 2H), 3. 10(s, 3H), 2.93-2.82 (id, 2H), 2.48 (t, 2H), 2.27-2.23 (m, 2H), 1.88-1.82 (in, 1H), 1.45-1.40 (m, 2H), 1.19 (t, 3H).Ss1 79 201213319 63⁄4兄^6&gt;5-[(4-Bromo-2,6-difluoro-phenoxy)indolyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopentyl And [c] 0 is slightly quaternized with 2-butylic acid = butyl ester 5e (400 mg 'yellow liquid), and the product is directly subjected to the next reaction without purification. MS m/z (ESI): 378 [M-55] The fifth step (does well ^W-5-[[2,6-difluoro-4-(methylsulfonylphenyl)phenoxy]methyl) ]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]〇tb slightly-2-succinic acid ## 醋 vinegar one will be crude (^3 brother not (4-mo -2,6-difluoro-phenoxy)indolyl]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta-butyric acid tert-butyl ester 5e (400 mg, 0. 93mmol), (4-indolylphenyl)folic acid (310mg, 1.57mmol) and 1, hydrazine-bis(diphenylphosphino)ferrocene di-gasification (68mg, 0. 09mmol) Dissolved in 30 mL of 1,2- dioxin, then added carbonic acid planing (910 mg ' 2.78 mmol), and stirred at 120 ° C for 3 hours. Filtered by φ, added with 20 mL of water, and extracted with ethyl acetate (3 〇 mL x 2) The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and then evaporated. ]methyl]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 5f (400 mg, brown oil), yield : 85. 1%. MS m/z (ESI): 452. 1 [M-55] The sixth step 63⁄4 brother as 5&gt;5-[[2, 6-difluoro-4-( Sulfhydrylphenyl)phenoxy]indolyl]-1,2,3,3a,4,5, 6, 6a-octahydrocyclopenta[c]° ratio 80 95344 201213319 will be 63⁄4 -5-[ [2, 6-dioxa-4-(methyl decylphenyl)phenoxy]methyl]-3, 33, 4, 5, 6, 6-hexahydro-1H-cyclopentyl And [c] pirox-2_teric acid tert-butyl ester 5f (400 mg, 0.80 mmol) was dissolved in 1 mL of methanol, and 5 mL of 2 Μ hydrochloric acid methanol solution was added dropwise, and the reaction was stirred for 48 hours. Saturated sodium hydroxide was added dropwise. The solution is brought to a pH of 10, and the mixture is extracted with dichloromethane (3 mL mL). The organic phase is combined, dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure to give the crude title product (bringing 5·&gt;5-[ [2,6-difluoro-4-(anthracene g)-based oxy]methyl]-1,2,3,3a,4,5, 6, 6a-octahydrocyclopenta[c η 咯 5g (300mg 'brown oil), the product was directly subjected to the next reaction without purification. MS m / z (ESI): 408.1 [M + l] The seventh step 63⁄4 疋 幻 -5 - [[ 2,6-Difluoro-4-(4-oxasulfonylphenyl)phenoxy]methyl]-2-(5-ethylhhhyl-2-yl)-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c] ° bilo will be crude 5-[[2,6-difluoro-4-(methane) Stupid base] phenyloxy] fluorenyl]-1,2,3,3a, 4, 5, 6, 6a-octahydrocyclopenta[c]D than 5g (250mg, 0. 60mmol) dissolved in i To 〇mLN,N-dimercaptoacetamide, 2-chloro-5-ethyl-pyrimidine (87 mg, 0.60 mmol) and potassium carbonate (210 mg, 1. 50 mmol) were successively added to 15 〇. (: Stirring reaction for 6 hours. Cooling to room temperature, adding 20 mL of water 'extracted with ethyl acetate (30 mL×3), combining the organic phases, drying with anhydrous sulfuric acid 'transition, filtering, liquid concentration under reduced pressure, using Shixi rubber column chromatography The obtained residue was purified with eluent system B to give the titled product: </ </ RTI> </ RTI> </ RTI> </ RTI> 5-[[2,6-difluoro-4-(4-indolesulfonylphenyl)phenoxy]-methyl 81 95344 201213319 2,2-(5-ethyl-n-butyl-2-yl)-3,3a,4,5,6,6a-hexahydro-1 fluorene-cyclopenta[c]pyrrole 5 (80 mg, white solid), Yield: 25% MS m/z (ESI): 514.2 [M+l] &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&& , 7.20-7.10 (m, 2H), 4.14 (d, 2H), 3.85-3.70 (m, 2H), 3.57-3.46 (in, 2H), 3. 10(s, 3H), 2.93-2.82 (id, 2H), 2.48 (t, 2H), 2.27-2.23 (m, 2H), 1.88-1.82 (in, 1H), 1.45-1.40 (m, 2H), 1.19 (t, 3H).

實施例6 (3ai?，685·)-5-[2-溴-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯 氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並比咯-2-羧酸第Example 6 (3ai?,685·)-5-[2-bromo-4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy]-3, 3a, 4, 5 , 6, 6a-hexahydro-1H-cyclopentapyrol-2-carboxylic acid

第一步 (3aA 6aS)-5-甲磺醯氧基-3, 3a，4, 5, 6, 6a-六氫-1H-環戊 並[c]吡咯-2-羧酸第三丁醋 冰浴下，將（3a:6a«-5-羥基-3,3a，4,5,6,6a_六氳-環戊並k]吡咯-2-羧酸第三丁酯la(25g，120mraol)溶解 95344 82 201213319 於50mL無水二氯曱院中，加入三乙胺（35 g’ 440mmol)， 滴加入曱續醢氯（20mL，230匪ol)，擾样反應2小時，再升 至室溫反應12小時。反應液用飽和碳酸氫鈉溶液 (200mLx3)洗滌，無水硫酸鎂乾燥，過濾，濾液減壓濃縮， 得到粗品標題產物（3a^ 6&amp;5·)-5-甲磺醯氧基 -3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並|&gt;]吡咯-2-羧酸第三丁 酯6a(30 g，淺黃色固體），產物不經純化直接進行下一步 反應。 讎 第二步 (3a左，6a5〇-5-[2-漠-4-[(4-曱續酿基π辰唤一1一基）甲基]笨 氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]n比略_2_緩酸第 三丁酯 將2-漠-4-[(4_甲確醯基旅嗪-1-基）曱基]苯紛a (230mg，0. 70mmol)和粗品（3af, 6β5·)-5-曱績醯氧基 -3, 3a，4, 5, 6, 6a-六氫-1 Η-環戊並[c]°比略-2-綠酸第三丁 φ 酯6a(24〇mg ’ 0· 8〇mmol)溶解於10mL乙腈中，再加入碳酸 鉋（445mg ’ 1· 40mmol)，升至85°C攪拌反應6小時。過濟， 濾液減壓濃縮，用薄層色譜法以展開劑體系B純化所得殘 餘物，得到標題產物（38^685)-5-1^2-溴-4-[(4-曱續酿武 派°秦-1-基）甲基]苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊 並[c]吡咯-2-羧酸第三丁酯6(300mg，白色固體），產率. 93. 0〇/〇。 MS m/z (ESI): 558.2 [M+l] Ή NMR (400 MHz, CDCh) 5 7.48 (s, 1H), 7.21-7 23 (m 95344 83 201213319 1H), 7.03 (d, 1H), 4.97-5.02 (m, 1 H), 3.40-3.43 (m, 4H) 3.08-3.12 (m, 6H), 2.86 (s, 3H), 2.80 (m, 2H), 2.42-2.43 (ra, 4H), 1.97-2.02 (m, 2H), 1.77-1.82 (in, 2H), 1.39 (s, 9H). 實施例7 (U 5«-6-[[2-氯-4-[(4-曱磺醯基哌嗪-1-基）曱基]苯氧 基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷First step (3aA 6aS)-5-methanesulfonyloxy-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid terpene vinegar ice Under the bath, (3a:6a«-5-hydroxy-3,3a,4,5,6,6a_hexa-cyclopenta-k]pyrrole-2-carboxylic acid tert-butyl ester la (25g, 120mraol) Dissolve 95344 82 201213319 In 50 mL of anhydrous dichlorohydrazine, add triethylamine (35 g' 440 mmol), add hydrazine (20 mL, 230 匪ol) dropwise, react with the reaction for 2 hours, and then raise to room temperature. After 12 hours, the reaction mixture was washed with EtOAc EtOAc EtOAc. , 3a,4,5, 6, 6a-hexahydro-1Η-cyclopentazone|&gt;]pyrrole-2-carboxylic acid tert-butyl ester 6a (30 g, pale yellow solid), product was directly purified without purification One step reaction. 雠Second step (3a left, 6a5〇-5-[2-漠-4-[(4-曱 酿 酿 π 辰 一 一 一 一) methyl] 笨 oxy]-3, 3a , 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]n ratio slightly _2_slow acid tert-butyl ester 2- 2--4-(4-_ _ 醯 醯 旅 旅 - 1-yl) fluorenyl] benzene a (230 mg, 0.70 mmol) and crude (3 Af, 6β5·)-5-曱 醯oxy-3, 3a,4, 5, 6, 6a-hexahydro-1 Η-cyclopenta[c]° ratio -2-chloro acid third φ Ester 6a (24 〇 mg '0·8 〇 mmol) was dissolved in 10 mL of acetonitrile, and then added with carbonic acid (445 mg '1.40 mmol), and the mixture was stirred at 85 ° C for 6 hours. After the reaction, the filtrate was concentrated under reduced pressure. The resulting residue was purified by EtOAc (EtOAc) eluting Phenyloxy]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 6 (300 mg, white solid), yield 93. 0〇/〇 MS m/z (ESI): 558.2 [M+l] Ή NMR (400 MHz, CDCh) 5 7.48 (s, 1H), 7.21-7 23 (m 95344 83 201213319 1H), 7.03 (d, 1H), 4.97-5.02 (m, 1 H), 3.40-3.43 (m, 4H) 3.08-3.12 (m, 6H), 2.86 (s, 3H), 2.80 (m, 2H), 2.42- 2.43 (ra, 4H), 1.97-2.02 (m, 2H), 1.77-1.82 (in, 2H), 1.39 (s, 9H). Example 7 (U 5«-6-[[2-chloro-4- [(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1 . 0] Hexane

第一步 5 -节基-4，6_二叛基-3a, 6a_二氫_1Η-°比B各並[3, 4_c]n比〇坐 -3-曱酸乙酯 將1-苄基°比°各-2, 5-二酮7a(5 g，26. 70mmol)溶解於 30mL曱苯中，加入重氣乙酸乙酯（2. 9mL，28mmol)，升溫 至100°C，攪拌反應5小時。減壓濃縮反應液，用矽膠管 84 95344 201213319 柱色5普法以洗脫劑體系B純化所得殘餘物，得到標題產物 5-苄基-4, 6-二羰基-3a，6a-二氫-1H-吡咯並[3, 4-c]吡唑 -3-曱酸乙酯7b(6. 70 g ’白色固體），產率：91. 9%。 M5 m/z (Ε5Ί) : 302. 1 [M+1 ] 'H NMR (400 MHz, CDCh) δ 7.36-7.28 (m, 5H), 7. 14 (s, 1H), 4.90-4.87 (in, 1H), 4.64 (s, 2H), 4.57-4.54 (m, 1H), 4.33 (q, 2H), 1.36 (t, 3H). 第二步 _ (1尤55)-3-苄基2, 4-二羰基-3-氮雜雙環並[3. 1. 〇]己烷 - 6 -曱酸乙酉旨 將5-&gt;基-4，6-二幾基-3a, 6a_二氮_1Η-°比略並 [3, 4-c]°比。坐-3-曱酸乙酯7b(2. 10 g ’ 7mmol)置於反應瓶 中’加熱至190°C，於190〇C反應1小時。冷至室溫，加入 200mL乙酸乙酯，用矽膠管柱色譜法以洗脫劑體系b純化 所得殘餘物，得到標題產物（1尤5«-3-苄基2, 4-二羰基 φ 氮雜雙環並[3. 1. 0]己烷-6-甲酸乙酯7c(ll g，白色固 體），產率：57. 9%。 M5 ra/z (Ε5Ί)： 274. 1 [M+1] *H NMR (400 MHz, CDCh) δ 7.33-7.28 (m, 5H), 4.52 (s, 2H), 4.19 (q, 2H), 2.88-2.87 (m, 2H), 2.29-2.27 (m, 1H), 1.28 (t, 3H). 第三步 [(1尤5«-3-苄基-3-氮雜雙環並[3.1. 0]己烷-6-基]曱醇 將四氫鋁鋰（3 g，81mmol)溶解於200mL四氫呋喃中， 85 95344 201213319 慢慢加入5011^(1^550-3-苄基2, 4-二羰基-3-氮雜雙環並 [3.1.0]己烷-6-甲酸乙酯7(：(5.40§，2〇111111〇1)的四氫呋喃 溶液，加畢，回流反應5小時，降溫至50°C，攪拌反應16 小時。冷至室溫，冰水浴下緩慢滴入6mL飽和氯化銨溶液， 過濾，收集濾液，無水硫酸鎂乾燥，過濾，減壓濃縮濾液， 得到標題產物[(1尤5«-3-苄基-3-氮雜雙環並[3. 1. 0]己 烷-6-基]甲醇7d(3. 70 g，棕色油狀物），產率：91.1%。 IS m/z (E5I): 204. 1 [M+l] 鲁 第四步 [(1^ 550-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱醇 將[(1疋55V3-苄基-3-氮雜雙環並[3.1. 0]己烷-6-基]曱醇7d(3. 70 g，18. 30mmol)溶解於150mL曱醇中，依 次加入鈀/碳（200mg，10%)和曱酸銨（6. 90 g， 109. 80mmol)，回流反應1小時。冷至室溫，過濾，減壓濃 縮濾液，得到粗品標題產物[(1兄5«-3-氮雜雙環並[3. 1. 0] φ 己烷-6-基]曱醇7e(2· 3 g ’無色油狀物），產物不經純化 直接進行下一步反應。 WS m/z (Ε5Ί): 114. 1 [M+l] 第五步 [(1及，55〇-3-(5-乙基癌咬-2-基）-3-氮雜雙環並[3. 1. 0]己 烧-6-基]甲醇 將粗品[(1兄550-3-氮雜雙環並[3. 1. 0]己烷-6-基] 甲醇7e(500mg，4. 42mmol)溶解於5mLN, N-二曱基乙醯胺 中’依次加入2-氯-5-乙基-喷咬（630mg，4. 42mmol)和碳 86 95344 201213319 酸鉀（916mg，6. 63mmol)，升至150°C攪拌反應6小時。加 入50mL水，用乙酸乙酯萃取（30mLx3)，合併有機相，無水 硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 [(1足550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烷-6-基]甲醇7f(l g，褐色油狀），產物不經純化直接進 行下一步反應。 MS m/z (ESI): 220.1 [M+l] 第六步 [(1尤5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烷-6-基]曱磺酸曱酯 將粗品[(1兄55&quot;)-3-(5-乙基鳴咬-2-基）_3_氣雜雙環 並[3. 1. 〇]己烧-6-基]甲醇 7f(l g，4. 40mmol)溶解於 10mL 無水二氣甲烷中，加入三乙胺（893mg，8.83麵ol)，滴加入 曱確醯氣（759mg，6. 62mmol)，授拌反應12小時。加入飽 和碳酸氫鈉溶液30mL，二氯曱烷萃取（10mLx3)，合併有機 • 相’依次用水（20mLx3)，飽和氯化鈉溶液洗滌（20mLx3)， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產 物[(1疋5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己燒-6-基]甲磺酸曱酯7g(700mg，褐色油狀），產物不經 純化直接進行下一步反應。 MS m/z (ESI): 298.1 [M+l] 第七步 (1足551)-6-[[2-氣-4-[(4-曱磺醯基哌嗪-1-基）曱基]苯氧 基]甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 87 95344 201213319 烧 將粗品[(1疋55*)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1. 0]己烧-6-基]曱續酸曱 g旨 7g( 1 OOmg，0. 34mmol) 和2-氣-4-[(4-甲磺醯基哌嗪-1-基）甲基]苯酚3b(102mg， 0. 34mmol)溶解於5mLN，N-二曱基乙醢胺中，再加入碳酸絶 (221mg ’ 0. 68mmol)，升溫至15〇。(：攪拌反應8小時。加入 25mL水，乙酸乙酯萃取（20mLx3)，合併有機相，依次用飽 和氯化銨溶液（10mLx3) ’飽和氣化鈉溶液洗滌（10πιίχ3)， ^ 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜法以 展開劑體系A純化所得殘餘物，得到標題產物 (1尤55·)-6-[[2_氯-4-[(4-甲磺醯基哌嗪_丨_基）曱基]苯氧 基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己 烧7(70mg，白色固體），產率：42. 〇%。 MS m/z (ESI): 492 [M+l] 1H NMR (400 MHz, CDCh) &lt;5 8. 19 (s, 2H), 7. 35 (s, 1H), φ 7.12-1.07 (m, 1H), 6.87 (d, 1H), 4.02 (d, 2H), 3.94 (d, 2H), 3.55 (d, 2H), 3.47(s, 2H), 3.28-3.25 (m, 4 H), 2.79 (s, 3H), 2.56-2.55 (m, 4H), 2.46 (q, 2H), 1.78-1.77 (m, 2H), 1.20 (q&gt; 0.89-0.86 (m, 1H). 實施例8 (1兄55·)-6-[[2, 6-二氟-4-(4一甲磺醯基苯基）苯氧基]甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3.丨.ο]己烷 95344 88 201213319The first step 5 - benzyl-4,6_bis-rebase-3a, 6a_dihydro-1Η-° ratio B and [3, 4_c]n ratio 〇 曱 曱 曱 曱 1- 1-benzyl The base ratio of each -2, 5-dione 7a (5 g, 26.70 mmol) was dissolved in 30 mL of toluene, and ethyl acetate (2.9 mL, 28 mmol) was added, and the mixture was heated to 100 ° C, and stirred. 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc 9%。 Pyrrolo[3,4-c]pyrazole-3-furoate ethyl ester 7b (6. 70 g 'white solid), yield: 91.9%. M5 m/z (Ε5Ί) : 302. 1 [M+1 ] 'H NMR (400 MHz, CDCh) δ 7.36-7.28 (m, 5H), 7. 14 (s, 1H), 4.90-4.87 (in, 1H), 4.64 (s, 2H), 4.57-4.54 (m, 1H), 4.33 (q, 2H), 1.36 (t, 3H). The second step _ (1 especially 55)-3-benzyl 2, 4 -dicarbonyl-3-azabicyclo[3. 1. oxime] hexane-6-decanoate 酉 将 5-&gt; yl-4,6-diyl-3a, 6a-diaza_1Η- ° is slightly smaller than [3, 4-c] °. Ethyl -3-decanoate 7b (2. 10 g '7 mmol) was placed in a reaction flask to be heated to 190 ° C and reacted at 190 ° C for 1 hour. After cooling to room temperature, 200 mL of ethyl acetate was added, and the residue obtained was purified by eluent column chromatography eluting with eluent system b to give the title product (1 especially 5 «-3-benzyl 2, 4-dicarbonyl φ aza Bicyclo[3.1.0] hexane-6-carboxylate ethyl ester 7c (ll g, white solid), yield: 57. 9%. M5 ra/z (Ε5Ί): 274. 1 [M+1] *H NMR (400 MHz, CDCh) δ 7.33-7.28 (m, 5H), 4.52 (s, 2H), 4.19 (q, 2H), 2.88-2.87 (m, 2H), 2.29-2.27 (m, 1H) , 1.28 (t, 3H). The third step [(1 especially 5«-3-benzyl-3-azabicyclo[3.1.0]hexane-6-yl]nonanol lithium tetrahydrogenate (3 g, 81 mmol) dissolved in 200 mL of tetrahydrofuran, 85 95344 201213319 slowly added 5011^(1^550-3-benzyl 2, 4-dicarbonyl-3-azabicyclo[3.1.0]hexane-6- Ethyl formate 7 (: (5.40 §, 2〇111111〇1) in tetrahydrofuran, add, reflux reaction for 5 hours, cool to 50 ° C, stir the reaction for 16 hours. Cool to room temperature, slowly drip into the ice water bath 6 mL of a saturated ammonium chloride solution, filtered, and the filtrate was collected, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title product [(1,5,3-benzyl-3-azabicyclo[3. 0 Hexane-6-yl]methanol 7d (3. 70 g, brown oil), yield: 91.1%. IS m/z (E5I): 204. 1 [M+l] Lu fourth step [( 1^ 550-3-azabicyclo[3.1.0]hexane-6-yl]nonanol [(1疋55V3-benzyl-3-azabicyclo[3.1. 0]hexane- 6-yl]nonanol 7d (3. 70 g, 18.30 mmol) was dissolved in 150 mL of decyl alcohol, and palladium on carbon (200 mg, 10%) and ammonium citrate (6. 90 g, 109.80 mmol) were added in that order. The reaction was refluxed for 1 hour, cooled to room temperature, filtered, and the filtrate was evaporated. Alcohol 7e (2·3 g 'colorless oil), the product was directly subjected to the next reaction without purification. WS m/z (Ε5Ί): 114. 1 [M+l] Step 5 [(1 and, 55〇) -3-(5-ethylcarban-2-yl-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]methanol will be crude [(1 brother 550-3-azabicyclo) And [3. 1. 0]Hex-6-yl]methanol 7e (500 mg, 4.42 mmol) was dissolved in 5 mL of N,N-dimercaptoacetamide 'in order of 2-chloro-5-ethyl-spray Bite (630 mg, 4.42 mmol) and carbon 86 95344 201213319 potassium (916 mg, 6.63 mmol), and the mixture was stirred at 150 ° C for 6 hours. After adding 50 mL of water and extracting with ethyl acetate (30 mL×3), EtOAcjjjjjjjjjjjjjjj Benzyl-3-azabicyclo[3.1.0]hexane-6-yl]methanol 7f (1 g, mp.). : 220.1 [M+l] The sixth step [(1 especially 5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl ] 曱 sulfonate decyl sulfonate will be crude [(1 brother 55 &quot;) -3- (5-ethyl ketone-2-yl) _3_ oxabicyclo[3. 1. 〇] hexane-6-yl] Methanol 7f (lg, 4.40 mmol) was dissolved in 10 mL of anhydrous methylene methane, triethylamine (893 mg, 8.83 s) was added, and hydrazine (759 mg, 6.62 mmol) was added dropwise, and the reaction was stirred for 12 hours. After adding 30 mL of a saturated sodium hydrogencarbonate solution, a mixture of dichloromethane and EtOAc (3 mL, EtOAc, EtOAc (EtOAc) The crude title product [(1疋5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 0] hexyl -6-yl] decyl methanesulfonate 7 g (700 mg, brown oil), product was taken to the next step without purification. MS m/z (ESI): 298.1 [M+l] (1 551)-6-[[2-Ga-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]methyl]-3-(5-ethylpyrimidine) -2-yl)-3-azabicyclo[3.1.0]hexene 87 95344 201213319 The crude product will be calcined [(1疋55*)-3-(5-ethylpyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexan-6-yl]pyrene sulphate 7g (1 OOmg, 0.34mmol) and 2-ox-4-[(4-methylsulfonylpiperazine) 1-yl)methyl]phenol 3b (102 mg, 0.34 mmol) was dissolved in 5 mL of N,N-dimercaptoacetamide, and then carbonic acid (221 mg '0.68 mmol) was added thereto, and the temperature was raised to 15 Torr. The reaction was stirred for 8 hours, and 25 mL of water was added, and ethyl acetate (20 mL×3) was added, and the organic phase was combined, washed with saturated aqueous ammonium chloride (10 mL×3), saturated sodium sulfate solution (10πιίχ3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj _丨_基)曱基]benzene Oxy]mercapto]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] hexane 7 (70 mg, white solid), yield: 42. 〇 %. MS m/z (ESI): 492 [M+l] 1H NMR (400 MHz, CDCh) &lt;5 8. 19 (s, 2H), 7. 35 (s, 1H), φ 7.12-1.07 (m, 1H), 6.87 (d, 1H), 4.02 (d, 2H), 3.94 (d, 2H), 3.55 (d, 2H), 3.47(s, 2H), 3.28-3.25 (m, 4 H), 2.79 ( s, 3H), 2.56-2.55 (m, 4H), 2.46 (q, 2H), 1.78-1.77 (m, 2H), 1.20 (q&gt; 0.89-0.86 (m, 1H). Example 8 (1 brother 55 ·)-6-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3- Azabicyclo[3.丨.ο]hexane 95344 88 201213319

第一步 [(17?，5幻-6-[(4-溴-2，6-二氟-苯氧基）曱基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 將[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1· 0]己烧-6-基]曱石黃酸曱酯7g(150mg，0. 51mmol)和 4-溴-2, 6-二氟-苯紛（105mg ’ 0. 51mmol)溶解於 5mLN，N-二 甲基甲醯胺中，再加入碳酸鉋（329mg，1. 02mmol)，升溫至 90°C攪拌反應4小時。加入20mL水，乙酸乙酯萃取 (20mLx2)，合併有機相，無水硫酸鎂乾燥，過濾，濾液減 壓濃縮，用薄層色譜法以展開劑體系B純化所得殘餘物， 得到標題產物[(1尤5«-6-[(4-溴-2,6-二氟-苯氧基）甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 8a(58mg’ 無色油狀），產率：42.0°/〇。。 MS m/z (ESI)： 412.0 [M+l] 第二步 (1疋55*)-6-[[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]甲 89 95344 201213319 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烧 將[(17?，5 5&quot;) - 6-[(4-溴-2，6_ 二氣-苯氧基）曱 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷 8a(85mg，〇. 15 mol)，（4-曱磺醢基苯基）硼酸（35mg， 0. 18mmol)和1，Γ -二（二苯膦基）二茂鐵二氣化鈀 (llmg，0. 〇2mmol)溶解於5mLl，4-二噁烷中，再加入碳酸 铯（143mg，0.42mmol)，升溫120°C攪拌反應6小時。加入 20mL水’乙酸乙酯萃取（2〇mLx2) ’合併有機相，無水硫酸 # 鎂乾燥’過濾，濾液減壓濃縮，用薄層色譜法以展開劑體 系B純化所得殘餘物，得到標題產物（iy?，55〇-6-[[2,6-二 氟-4-(4-曱磺醯基苯基）苯氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烧8(20mg，白色固體），產 率：28. 0%。 MS m/z (ESI): 486.2 [M+l] Ή NMR (400 MHz, CDCh) d 8. 18 (s, 2H), 8. 02 (d, 2H), 7. 70-7. 73 (m, 2H), 7. 18 (d, 2H), 4. 14-4. 16 (m, 2H), 3.88-3.91 (m, 2H), 3.55-3.58 (m, 2H), 3.10 (s, 3H), 2.46-2.48 (m, 2H), 1.73(d, 2H), 1.25-1.29 (in, 1H), 1. 16-1.20 (m, 3H). 實施例9 3-[2, 6-二氟-4-(4-甲續酿基苯基）苯氧基]-8-氮雜雙環並 [3.2. 1]辛烷-8-羧酸第三丁酯 90 95344 201213319First step [(17?,5 Magic-6-[(4-Bromo-2,6-difluoro-phenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexane will [(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·0]hex- 6-yl] fluorite xanthate 7g (150mg, 0.51mmol) and 4-bromo-2,6-difluoro-benzene (105mg '0. 51mmol) dissolved in 5mL N,N-dimethylformamidine The amine was added with a carbonic acid planer (329 mg, 1.02 mmol), and the mixture was heated to 90 ° C, and the reaction was stirred for 4 hours. 20 mL of water and ethyl acetate (20 mL×2) was added, and the organic phases were combined, dried over anhydrous magnesium sulfate Concentration by pressure, the residue obtained was purified by EtOAc (EtOAc) (EtOAc) -3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 8a (58 mg of colorless oil), yield: 42.0 / /. MS m /z (ESI): 412.0 [M+l] The second step (1疋55*)-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]- 89 95344 201213319 基]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇] 己烧[[17?,5 5&quot;) - 6-[(4-Bromo-2,6-dioxa-phenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇] Alkane 8a (85 mg, 〇. 15 mol), (4-oxasulfonylphenyl)boronic acid (35 mg, 0.18 mmol) and 1, bismuth-bis(diphenylphosphino)ferrocene dipalladium (llmg) , 0. 〇 2 mmol) was dissolved in 5 mL of 1,4-dioxane, and then cesium carbonate (143 mg, 0.42 mmol) was added, and the reaction was stirred at 120 ° C for 6 hours. Add 20 mL of water 'ethyl acetate extract (2 〇 mL x 2) 'The combined organic phase, anhydrous sulfuric acid #MgSO4 was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford title product (iy?, 55〇-6-[[2,6 -difluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0 Calcined 8 (20 mg, white solid), yield: 28. 0%. MS m/z (ESI): 486.2 [M+l] NMR (400 MHz, CDCh) d 8. 18 (s, 2H) , 8. 02 (d, 2H), 7. 70-7. 73 (m, 2H), 7. 18 (d, 2H), 4. 14-4. 16 (m, 2H), 3.88-3.91 (m , 2H), 3.55-3.58 (m, 2H), 3.10 (s, 3H), 2.46-2.48 (m, 2H), 1.73(d, 2H), 1.25-1.29 (in, 1H), 1. 16-1.20 (m, 3H). Example 9 3-[2,6-Difluoro-4-(4-methylhydrophenyl)phenoxy]-8-azabicyclo[3.2.1] Octane-8-carboxylic acid tert-butyl ester 90 95344 201213319

第一步first step

3-羥基-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯 將8-氮雜雙環並[3. 2.1]辛烷-3-醇9a(5 g， 39.40mmol)溶解於50mL曱醇中，冰浴下，依次加入三乙胺 (7. 90 g，78. 70mmol)和二碳酸二第三丁酯（10. 30 g， 47.28mmol)，升至室溫攪拌反應2小時。過濾，加入100mL 飽和碳酸氫鈉溶液，用乙酸乙酯萃取（100mLx3)，合併有機 相，用飽和氯化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，得到粗品標題產物3-羥基-8-氮雜 雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯9b(8. 10 g，白色固 體），產物不經純化直接進行下一步反應。 MS m/z (ESI): 172.1 [M-55] 第二步 3-甲磺醯氧基-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁 酯 冰浴下，將粗品3-羥基-8-氮雜雙環並[3. 2. 1]辛烷 -8-羧酸第三丁酯9b(50. 60 g，0. 22 mol)溶解於200mL無 91 95344 201213319 水二氣甲烷中’加入三乙胺（48. 50 g，0.48 mol)，滴加入 曱磺醢氣（20mL，0.24 mol)，升至室溫攪拌反應12小時。 加入10mL水，有機相依次用1 μ鹽酸（20mLx3)，飽和氣化 鈉溶液（20mLx3)洗滌，無水硫酸鎂乾燥，過濾，濾液減壓 濃縮，得到粗品標題產物3-甲磺醯氧基-8-氮雜雙環並 [3. 2. 1]辛烷-8-羧酸第三丁酯9c(62. 70 g，白色固體）， 產物不經純化直接進行下一步反應。 MS m/z (ESI): 250.1 [M-55] 鲁 第三步 ^ 3-(4-溴-2, 6-二氟-苯氧基）-8-氮雜雙環並[3. 2. 1]辛烷 -8-羧酸第三丁酯 將3-曱續醯氧基-8-氮雜雙環並[3. 2. 1]辛烧-8-緩酸 第三丁酯 9c(600mg，1. 96mmol)和 4-溴-2, 6-•二氟ί-苯紛 (450mg ’ 2. 16mmol)溶解於5mLN，Ν-二甲基甲酿胺中，再加 入碳酸铯（1.92g，5.89_〇1) ’升溫至80。(：搜拌反應1小 φ 時’再於50°C攪拌反應12小時。過濾，濾液加入5〇mL水， 用乙酸乙酯萃取（30mLx3)，合併有機相，用無水硫酸鎮乾 φ 燥’過濾，濾液減壓濃縮’用薄層色譜法以展開劑體系B 純化所得殘餘物，得到標題產物3-(4-溴-2, 6-二氟-苯氧 基）-8-氮雜雙環並[3. 2· 1]辛烷-8-羧酸第三丁醋 9d(470mg，白色固體），產率：57. 3%。 第四步 3-[2, 6-二氟-4-(4-甲橫酿基本基）苯氧基]~8~氮雜雙環並 [3· 2· 1]辛烷-8-羧酸第三丁酯 95344 92 201213319 將3-(4-溴-2, 6-二氟-苯氧基）-8-氮雜雙環並[3. 2« I；] 辛烧-8、羧酸第三丁酯9d(72〇mg，l 7〇 ^οΐ)，（4-甲磺隨 基苯基）硼酸（413mg，2.05mmol)和1，1，-二（二苯膦基）二 茂鐵二氯化把（124mg，0. 17mmol)溶解於7mLl，4-二°惡燒和 水的混合溶劑（V/V = 5:2)中，加入碳酸鉋（1.60 g， 5. 10腿〇1) ’升至i2(Tc攪拌反應4小時。過濾，濾液加入 20mL水’用乙酸乙酯萃取（15mLx3)，合併有機相，依次用 水（5mLx3) ’餘和氯化納溶液洗務（5mLx3)，無水硫酸鎮乾 ® 燥’過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B 純化所得殘餘物，得到標題產物3-[2, 6-二氟-4-(4-甲磺 酸基苯基）苯氧基]-8-氮雜雙環並[3.2. 1]辛烷-8-羧酸第 三丁酯9(260mg，白色固體），產率：29. 0%。 MS m/z (ESI)：438.2 [M-55] *Η NMR (400 MHz, DMSO) (5 8.02 (s, 4H), 7.67 (d, 2H), 4.61-4.58 (m, 1H), 4.13 (s, 2H), 2.08 (s, 2H), 1.86 φ (s, 2H), 1.68-1. 64 (m, 4H), 1.39(s, 9H), 1.24(s, 3H). 實施例10 3-[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]-8_(5-乙基嘧 啶-2-基）-8-氮雜雙環並[3. 2. 1]辛烷3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 8-azabicyclo[3.2.1]octane-3-ol 9a (5 g , 39.40 mmol) was dissolved in 50 mL of decyl alcohol, and triethylamine (7. 90 g, 78.70 mmol) and dibutyl succinate (10. 30 g, 47.28 mmol) were added to the ice bath. The reaction was stirred at room temperature for 2 hours. Filtration, 100 mL of saturated sodium bicarbonate solution, and ethyl acetate (100 mL×3), EtOAc (EtOAc) 3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 9b (8. 10 g, white solid). MS m/z (ESI): 172.1 [M-55] Step 2 3-Methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ice The crude 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 9b (50.60 g, 0.22 mol) was dissolved in 200 mL without a bath. 95344 201213319 In a water-digestible methane, triethylamine (48.50 g, 0.48 mol) was added, and hydrazine sulfonate (20 mL, 0.24 mol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. 10 mL of water was added, and the organic phase was washed with EtOAc EtOAc (EtOAc) - azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 9c (62.70 g, white solid). MS m/z (ESI): 250.1 [M-55] Step 3: 3-(4-bromo-2,6-difluoro-phenoxy)-8-azabicyclo[3. 2. 1 ] Octadecyl-8-carboxylic acid tert-butyl ester 3- 曱 醯 -8 -8 -8 -8-8- azabicyclo[3.2.1] octyl-8-acidic acid tert-butyl ester 9c (600 mg, 1 . 96mmol) and 4-bromo-2,6-•difluoro-benzene (450mg ' 2. 16mmol) dissolved in 5mL N, Ν-dimethyl amide, and then added cesium carbonate (1.92g, 5.89_ 〇 1) 'Raise to 80. (: Mixing reaction 1 small φ' and stirring the reaction at 50 ° C for 12 hours. Filtration, adding 5 mL of water to the filtrate, extracting with ethyl acetate (30 mL×3), combining the organic phases, and drying with anhydrous sulfuric acid. Filtration and concentration of the filtrate under reduced pressure. The residue obtained was purified by EtOAc (EtOAc). [3. 2·1] Octane-8-carboxylic acid terpene vinegar 9d (470 mg, white solid), yield: 57. 3%. Step 4 3-[2,6-difluoro-4-( 4-methyl-branched base) phenoxy]~8-azabicyclo[3·2·1]octane-8-carboxylic acid tert-butyl ester 95344 92 201213319 3-(4-bromo-2, 6-Difluoro-phenoxy)-8-azabicyclo[3. 2« I;] octyl-8, carboxylic acid tert-butyl ester 9d (72〇mg, l 7〇^οΐ), (4 -Methanesulfonate phenyl)boronic acid (413 mg, 2.05 mmol) and 1,1,-bis(diphenylphosphino)ferrocene dichloride (124 mg, 0.17 mmol) were dissolved in 7 mL of 1,2-di Add a carbonic acid planer (1.60 g, 5. 10 leg 〇1) to the mixed solvent of oxalic acid and water (V/V = 5:2) and raise it to i2 (Tc stirred for 4 hours. Filter, add 20 mL of water to the filtrate) Extracted with ethyl acetate (15 mL×3), and the organic phase was combined and washed sequentially with water (5 mL×3) &lt;RTI ID=0.0&gt;&gt; The obtained residue was purified to afford titled product 3-[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]-8-azabicyclo[3. ] Octane-8-carboxylic acid tert-butyl ester 9 (260 mg, white solid), yield: 29.0%. MS m/z (ESI): 438.2 [M-55] * NMR (400 MHz, DMSO ) (5 8.02 (s, 4H), 7.67 (d, 2H), 4.61-4.58 (m, 1H), 4.13 (s, 2H), 2.08 (s, 2H), 1.86 φ (s, 2H), 1.68- 1. 64 (m, 4H), 1.39(s, 9H), 1.24(s, 3H). Example 10 3-[6,6-Difluoro-4-(4-oxasulfonylphenyl)phenoxy -8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane

93 95344 201213319 ο93 95344 201213319 ο

第一步 3-[2’6-二韻基苯基）笨氧基]十氮雜雙環並 [3. 2. 1 ]辛烧The first step 3-[2'6-dihypophenyl)aloxy]dodezabicyclo[3.2.1]xin

將3-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]_8_氮 雜雙環並[3·2·1]辛烷-8-羧酸第三丁酯9(13〇呢， 0:26咖〇1)溶解於5mL曱醇中，滴加入3此2 M氣化氫的甲 醇溶液，攪拌反應4小時。反應液減壓濃縮，得到粗品標 4產物3-[2, 6-二氟-4-(4-甲項醯基苯基）苯氧基]氮 雜雙環並[3. 2. 1 ]辛烧l〇a(98mg，白色固體），產物不經純 化直接進行下一步反應。 第二步 3~[2, 6~一氣_4_(4-曱續酿基本基）笨氧基]_8_(5-乙基喷 啶-2-基）-8-氮雜雙環並[3. 2. 1]辛烷 將粗品3-[2,6-二氟-4_(4—曱磺醢基苯基）苯氧 基]-8-氮雜雙環並[3.2. 1]辛烷 l〇a(103mg，0.25romol)溶 解於2mLN, N-二甲基乙醯胺中，依次加2_氯一5_乙基—嘧啶 (35mg，〇.25議1)和破酸舒（162mg，〇·49_υ，升至 150 。(:攪拌反應4小時。加入5齡水，用乙酸乙醋萃取 (2〇mLx3)，合併有機相，依次用水(論3) ’飽和氣化鈉 94 95344 201213319 溶液洗務（20mLx3)，無水硫酸鎮乾燥，過遽，據液減塵濃 縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到 標題產物3-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧 基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環並[3· 2· 1]辛烷 10(60mg，白色固體），產率：48. 0%。 MS m/z (ESI): 500.2 [M+l] *H NMR (400 MHz, DMSO) δ 8.26 (s, 2H), 7.99 (s, 4H), 7. 67(d, 2H), 4. 62(s, 2H), 4. 52 (s, 1H), 3. 26 (s, 3H), • 2.34 (q, 2H), 2.13 (t, 2H), 1.99-1.94 (m, 6H), 1.12 (t, 3H). 實施例11 3-[2_氯_4_[(4_甲續酿基派°秦_1-基）曱基]苯氧基]-8-（5_ 乙基嘧啶_2-基）-8-氮雜雙環並[3.2. 1]辛烷3-[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]_8-azabicyclo[3·2·1]octane-8-carboxylic acid tert-butyl Ester 9 (13 〇, 0:26 Curry 1) was dissolved in 5 mL of methanol, and 3 of this 2 M vaporized hydrogen in methanol was added dropwise, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure to give the crude product, 3-[2,6-difluoro-4-(4-methylphenylphenyl)phenoxy]azabicyclo[3.2.1] l 〇 a (98 mg, white solid). The second step is 3~[2, 6~一气_4_(4-曱 酿 基本 ))]]]]]]]]] 1] octane will be crude 3-[2,6-difluoro-4_(4-sulfonylphenyl)phenoxy]-8-azabicyclo[3.2.1]octane l〇a ( 103mg, 0.25romol) was dissolved in 2mL of N, N-dimethylacetamide, followed by 2_chloro-5-ethyl-pyrimidine (35mg, 〇.25 1) and saponin (162mg, 〇·49_υ) , Increase to 150. (: Stir the reaction for 4 hours. Add 5 weeks of water, extract with ethyl acetate (2 〇 mLx3), combine the organic phase, and then use water (3) 'saturated sodium sulphide 94 95344 201213319 solution wash ( 20 mL x 3), anhydrous sulphuric acid, dried, saponified, concentrated by liquid dusting, and purified to give the title product 3-[2,6-difluoro-4-(4- Methanesulfonylphenyl)phenoxy]-8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3·2·1]octane 10 (60 mg, white solid) Rate: 48.0% MS m/z (ESI): 500.2 [M+l] *H NMR (400 MHz, DMSO) δ 8.26 (s, 2H), 7.99 (s, 4H), 7. 67 (d , 2H), 4. 62(s, 2H), 4. 52 (s, 1H), 3. 26 (s, 3H), 2.34 (q, 2H), 2.13 (t, 2H), 1.99-1.94 (m, 6H), 1.12 (t, 3H). Example 11 3-[2_氯_4_[(4_甲续) °秦_1-yl)fluorenyl]phenoxy]-8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane

第一步 3-[2-氣-4-[(4-曱磺醯基哌嗪-1-基）曱基]苯氧基]-8-氮 雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯 將3_甲磺醯氧基-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸 95 95344 201213319 第三丁酯 9c(600mg，1. 96mmol)和 2-氯-4-[ (4-甲續醯基 哌嗪-1-基）甲基]苯酚3b(660mg ’ 2. 16mmol)溶解於i〇mL N，二甲基甲醢胺中，加入碳酸絶（1· 92 g，5. 89mmol)， 升溫至150°C攪拌反應5小時。過濾，濾液加入50mL水， 用乙酸乙酯萃取（30mLx3)，合併有機相，依次用水 (10mLx3)，飽和氣化鈉溶液洗滌（10mLx3)，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體 系B純化所得殘餘物，得到標題產物3-[2-氯-4-[(4-曱磺 # 醯基哌嗪-1-基）曱基]苯氧基]-8-氮雜雙環並[3.2. 1]辛烷 鲁 -8-叛酸第三丁醋lla(750mg，白色固體），產率：75.0%。 MS m/z (ESI)： 414. 2[M+1-100] 第二步 3-[2-氣-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯氧基]-8-氮 雜雙環並[3. 2.1]辛烷 將3-[2-氣-4_[(4-甲磺醯基哌嗪-1-基）甲基]苯氧 φ 基]氮雜雙環並[3. 2. 1]辛烧-8-羧酸第三丁酯 lla(700mg，1.36mmol)溶解於 5mL 甲醇中，滴加 3mL 2M 鲁 氯化氫甲醇溶液’攪拌反應4小時。反應液減壓濃縮，用 矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標 題產物3-[2-氯-4-[(4-甲磺醯基哌嗪-1-基）甲基]苯氧 基]-8-氮雜雙環並[3. 2. 1]辛烷llb(120mg，白色固體）， 產率：21. 0%。 MS m/z (ESI)： 414.2 [M+l] 第三步 96 95344 201213319 3-[2-氯-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯氧基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環並[3. 2. 1]辛烷 將3-[2-氯-4-[(4-甲磺醯基哌嗪-1-基）曱基]笨氧 基]-8-氮雜雙環並[3. 2· 1]辛烷 llb(120mg ’ 0.29mmol)溶 解於3mL N，N-二甲基乙醯胺中，依次加2-氣-5-乙基-嘧啶 (41mg，0. 29mmol)和碳酸鏠（188mg，0. 57mmol)，升至 150 °(：攪拌反應5小時。加入20mL水，用乙酸乙酯萃取 (10mLx3)，合併有機相，依次用水（5mLx3)，飽和氯化納溶 # 液洗滌（5mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮， 用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到 標題產物3-[2 -亂-4 -[(4-曱續酿基痕D秦-1-基）曱基]苯氧 基]-8-(5-乙基喷咬-2-基）-8-氮雜雙環並[3. 2. 1]辛院 ll(110mg，白色固體），產率：73%。 MS m/z (ESI): 520.2 [M+l] 1H NMR (400 MHz, DMSO) δ 8.30 (s, 2H), 7.30 (s, 1H), φ 7.27 (d, 1H), 7.18 (d, 1H), 4.94-4.89 (m, 1H), 4.67 (s, 2H), 3.44(s, 2H), 3.09-3.08 (m, 4H), 2. 86 (s, 3H), 2.47-2.43 (m, 6H), 2.10-2.09 (m, 2H), 1.99-1.93 (m, 4H), 1.64-1.62 (ra, 2H), 1.23-1.18 (m, 3H). 實施例12 (1^ 55)-3-(5-乙基嘧啶-2-基）_6_[ [5-(4-甲磺醯基苯基） °比嗓-2_基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷 97 95344 201213319First step 3-[2-Ga-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-8-azabicyclo[3.2.1]octane -8-carboxylic acid tert-butyl ester 3-methanesulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid 95 95344 201213319 tert-butyl ester 9c (600 mg, 1 . 96mmol) and 2-chloro-4-[(4-methylsulfonylpiperazin-1-yl)methyl]phenol 3b (660mg ' 2. 16mmol) dissolved in i〇mL N, dimethylformamide Among them, carbonic acid (1·92 g, 5.89 mmol) was added, and the mixture was heated to 150 ° C and stirred for 5 hours. Filtration, the filtrate was added to 50 mL of water, and extracted with ethyl acetate (30 mL×3), and the organic phase was combined, washed with water (10 mL×3), and then with saturated sodium carbonate solution (10 mL×3), dried over anhydrous magnesium sulfate, filtered, Column chromatography Chromatography of the obtained residue to afford the title product 3-[2-chloro-4-[(4-sulfonyl-hydrazinopiperazin-1-yl)indolyl]phenoxy] -8-Azabicyclo[3.2.1]octanelu-8-rebel tartrate lla (750 mg, white solid), yield: 75.0%. MS m/z (ESI): 414. 2[M+1-100] Step 2 3-[2- -4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy 3-[2- gas-4_[(4-methanesulfonylpiperazin-1-yl)methyl]phenoxy φyl]aza Bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester lla (700 mg, 1.36 mmol) was dissolved in 5 mL of methanol, and 3 mL of 2M solution of hydrogen chloride in methanol was added dropwise and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj Methyl]phenoxy]-8-azabicyclo[3.2.1]octane 11b (120 mg, white solid), Yield: 21. 0%. MS m/z (ESI): 414.2 [M+l]. Step 3 96 95344 201213319 3-[2-chloro-4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy -8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane 3-[2-chloro-4-[(4-methanesulfonyl) Pyrazin-1-yl)indolyl] phenoxy]-8-azabicyclo[3. 2·1]octane llb (120 mg '0.29 mmol) was dissolved in 3 mL of N,N-dimethylacetamide Add 2-gas-5-ethyl-pyrimidine (41 mg, 0.25 mmol) and cesium carbonate (188 mg, 0.57 mmol) to 150 ° (: stirring reaction for 5 hours. Add 20 mL of water with ethyl acetate The organic phase was extracted (10 mL×3), and then washed with water (5 mL×3), saturated sodium chloride solution (5 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification of the obtained residue to give the title product 3-[2----- 4-[(4- 曱 酿 痕 秦 秦 -1- -1- 基 基 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 5 5 5咬-2-yl)-8-azabicyclo[3.2.1] 辛院ll (110mg, white solid), yield: 73%. MS m/z (ESI): 520.2 [M+l] 1H NMR (400 MHz, DMSO) δ 8.30 (s, 2H), 7.30 (s, 1H), φ 7.27 (d, (H, 1H) , 2.47-2.43 (m, 6H), 2.10-2.09 (m, 2H), 1.99-1.93 (m, 4H), 1.64-1.62 (ra, 2H), 1.23-1.18 (m, 3H). Example 12 ( 1^ 55)-3-(5-ethylpyrimidin-2-yl)_6_[ [5-(4-methylsulfonylphenyl) ° 嗓-2_yl]oxyindolyl]-3-aza Double ring and [3. 1. 0] hexane 97 95344 201213319

Tf 12a 12 • 第-步 · (1尤5«-6-[(5-溴吼嗪-2-基）氧曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 將[(1尤550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己院-6-基]甲醇 7f(660mg，3mmol)溶解於 20mL 無 水四氫σ夫喃中，加入氫化納（120mg，3mmol) ’室溫搅拌0. 5 小時。冰浴下，加入2，5-二漠°比°秦（713mg，3mmo 1)，升至 φ 室溫攪拌反應12小時。反應液減壓濃縮，加入水10mL， $ 用乙酸乙酯萃取（20mLx3)，合併有機相，依次用水 (20mLx3)，飽和氣化納溶液洗務（20mLx3)，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體 系B純化所得殘餘物，得到標題產物（1尤5«-6-[(5-溴吡 嗪-2-基）氧曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷 12a(170mg，白色固體），產率：15. 0%。 第二步 (1尤550-3-(5-乙基嘧啶-2-基）-6-[ [5-(4-甲磺醯基苯基） 98 95344 201213319 吡嗪-2-基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷 將（U，55·)-6-[(5-溴咕嗪-2-基）氧曱基]-3-(5-乙基 嘧啶_2-基）-3-氮雜雙環並[3.1.0]己烷123(170呢， 0. 45醒〇1)，（4-甲磺醯基笨基）硼酸（117mg，0. 58mmol)， 二（三苯膦基）二氣化纪（l〇〇mg，〇. 14mmol)和 1. 50mL2 Μ 碳酸鈉溶液溶解於20mLN, Ν-二曱基甲醯胺中，升至85°C攪 拌反應5小時。加入水l〇〇mL’用乙酸乙酯萃取（2〇mLx3)， 合併有機相，依次用水（20mL&gt;&lt;3)，飽和氯化鈉溶液洗滌 馨 （20mLx3)，無水硫酸鎂乾燥，過遽，濾液減壓濃縮，用石夕 膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題 產物（1皮，55)-3-(5-乙基嘴咬-2-基）-6-[[5-(4-曱續酿基 苯基）吡嗪-2-基]氧曱基]-3-氮雜雙環並[3. 1.〇]己烷 12(100mg，白色固體），產率：50. 0%。 MS m/z (ESI): 452.2 [M+l] 1H NMR (400 MHz, CDC13) (5 8. 55 (d, 1H), 8.33 (d, 1H), φ 8.19 (s, 2H), 8.13 (d, 2H), 8.07-8.00 (m, 2H), 4.33 (d, 2H), 3.98 (d, 2H), 3.60 (d, 2H), 3. 09 (s, 3H), 2.47 (q, 2H), 1.79 (s, 2H), 1.25 (s, 1H), 1.18 (t, 3H). 實施例13 (1^ 55)-3-(5-乙基嘧咬-2-基）-6-[ [6-(4-甲續醯基苯 基）-3-°比°定基]氧曱基]-3-氮雜雙環並[3. 1. 〇]己炫Tf 12a 12 • Step - (1 especially 5«-6-[(5-bromopyridazin-2-yl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-nitrogen Heterobicyclo[3.1.0]hexane will [(1 especially 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.]]院-6 5小时。 After the addition of 2,5-two in the ice bath, add 2,5-two in the ice bath. Add the sodium hydride (120mg, 3mmol) to a solution of sodium hydride (120mg, 3mmol). The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The saturated gasified sodium solution was washed (20 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product (1 especially 5 «-6 -[(5-bromopyrazin-2-yl)oxyindenyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 12a (170 mg , white solid), yield: 15. 0%. The second step (1 especially 550-3-(5-ethylpyrimidin-2-yl)-6-[ [5-(4-methylsulfonylphenyl) ) 98 95344 201213319 Pyrazine-2- (U,55·)-6-[(5-bromopyridazin-2-yl)oxyindenyl]-3, oxymethyl]-3-azabicyclo[3.1.0]hexane -(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 123 (170, 0. 45 awake 1), (4-methylsulfonyl phenyl) boric acid (117mg, 0. 58mmol), bis(triphenylphosphino)digassing (l〇〇mg, 〇. 14mmol) and 1.50mL2 Μ sodium carbonate solution dissolved in 20mLN, Ν-dimercaptocarboxamide The reaction was stirred for 5 hours at 85 ° C. Water (1 mL mL) was extracted with water, and the organic phase was combined, washed sequentially with water (20 mL &gt;&lt; 3), saturated sodium chloride solution (20 mL×3), dried over anhydrous magnesium sulfate, EtOAc (EtOAc m. Ethyl acetophenone-2-yl)-6-[[5-(4-fluorenylphenyl)pyrazin-2-yl]oxyindolyl]-3-azabicyclo[3. 1.〇 Hexane 12 (100 mg, white solid), yield: 50. 0%. MS m/z (ESI): 452.2 [M+l] 1H NMR (400 MHz, CDC13) (5 8. 55 (d, 1H) ), 8.33 (d, 1H), φ 8.19 (s, 2H), 8.13 (d, 2H), 8.07-8.00 (m, 2H), 4.33 (d, 2H), 3.98 (d, 2H), 3.60 (d, 2H), 3. 09 (s, 3H), 2.47 (q, 2H), 1.79 (s, 2H), 1.25 (s, 1H), 1.18 (t, 3H). Example 13 (1^ 55)-3-(5-Ethylpyridin-2-yl)-6-[ [6-(4-醯 醯 苯基 phenyl)-3-° ratio ° ] base] oxoyl]-3-azabicyclo[3. 1. 〇]

99 95344 20121331999 95344 201213319

第一步 (1友，550-6-[ (6-氯-3-0比咬基）氧甲基]_3-（5-乙基嚷咬〜2、 • 基）-3-氮雜雙環並[3· 1.0]己烷 將[(1尤5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烧-6-基]甲醇 7f(436mg，2ramol)溶解於 15mL 甲 笨中，加入6-氣η比咬-3-醇（200mg，1. 55mmol)，再加入三 笨基膦（609mg，2. 33mmol)和N，N，N’，N’ -四甲基偶氮二 甲醯胺（401mg ’ 2. 33mmol)，加熱至60°C攪拌3小時。反 應液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所 φ 得殘餘物，得到標題產物（1尤55〇-6-[(6-氣-3-吡啶基）氧 曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 13a(300mg，白色固體），產率：61. 〇〇%。 MS m/z (ESI):331. 1 [M+l] 第二步 (1兄5«-3-(5-乙基嘧啶-2-基）-6-[[6_(4_甲磺醯基苯 基）-3-吡啶基]氧曱基]_3_氮雜雙環並[3. h 〇]己烷 將（1兄550-6-1: (6-氣-3-吡啶基）氧曱基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3· h 〇]己烷13a(15〇mg， 100 95344 201213319 〇.45mmol) ’（4-甲磺醯基苯基）硼酸（117mg，0.58mm〇l)， 一（二本膦基）二氯化把（lOOmg，0. 14mmol)和 1. 5〇inL2 Μ 碳酸鈉溶液溶解於20mLN，N-二甲基甲醯胺中，升至85°C授 拌反應5小時。加入i〇〇mL水，用乙酸乙酯萃取（8〇fliLx3)， 合併有機相’依次用水（2〇mLx3)，飽和氣化鈉溶液洗滌 (30mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，μ 層色譜法以展開劑體系Β純化所得殘餘物，得到禪^用缚 (1尤551)-3-(5-乙基嘴唆-2-基）-6-[ [6-(4-甲續隨我^物 基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1· 〇]己&amp; 13(110mg，白色固體），產率：55. 0%。 MS m/z (ESI): 451.2 [M+l] 2H)， 1H), 63''3. 58 (m， 2H)， 4 丽R (400 MHz，CDC13) δ 8.43 (d，1H)，8. 2〇 8.16-8. 12 (m，2H)，8.03-8.00 (m，2H)，7.74 7.30 (dd, 1H), 4.04 (d, 2H), 4.00 (d, 2H), 3 (m, 2H), 3.09(s, 3H), 2. 48 (q, 2H), 1.81-1.78 1.27-1.25 (m, 1H), 1.19 (t, 3H). 實施例14 (3a^ 685^-5-[2-漠-4-[(4-甲確酿基娘嗪-l-基）甲 氧基]_3, 3a，4, 5, 6, 6a-六氫-1ZM裒戊並[c]°比。各〜9 , ^ 丁酯 扣琰峻第 95344 101 201213319The first step (1 friend, 550-6-[(6-chloro-3-0 than octyl)oxymethyl]_3-(5-ethyl 嚷 bit~2, • yl)-3-azabicyclo [3·1.0]hexane will [(1 especially 5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]methanol 7f (436 mg, 2ramol) was dissolved in 15 mL of a solution, and 6-gas η was added to the octa-3-ol (200 mg, 1.55 mmol), followed by tris-phenylphosphine (609 mg, 2.33 mmol) and N,N. N',N'-tetramethylazolylamine (401 mg '2.33 mmol), heated to 60 ° C and stirred for 3 hours. The reaction was concentrated under reduced pressure using a silica gel column chromatography to eluent system B Purification of the residue afforded the title product (1 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Azabicyclo[3.1.0]hexane 13a (300 mg, white solid), yield: 61. 〇〇%. MS m/z (ESI): 331. 1 [M+l] 1 brother 5«-3-(5-ethylpyrimidin-2-yl)-6-[[6_(4_methylsulfonylphenyl)-3-pyridyl]oxyindolyl]_3_azabicyclo [3. h 〇] Hexane (1 brother 550-6-1: (6-gas-3-pyridyl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-nitrogen Heterobicyclo and [3· h 〇]hexane 13a (15 〇 mg, 100 95344 201213319 〇.45 mmol) '(4-methylsulfonylphenyl)boronic acid (117 mg, 0.58 mm 〇l), one (two phosphino) dichlorination (lOOmg, 0. 14mmol) and 1.5〇inL2 Μ The sodium carbonate solution was dissolved in 20mL of N,N-dimethylformamide, and it was stirred at 85 ° C for 5 hours. Add i〇〇mL water, use Ethyl acetate extraction (8 〇fli Lx3), and the organic phase was combined with water (2 〇 mL×3), saturated sodium sulfate solution (30 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained by purifying the obtained system is obtained by using zen (1 551)-3-(5-ethyl-anthran-2-yl)-6-[[6-(4-) -3 -pyridyl]oxymethyl]-3-azabicyclo[3.1·〇]hexan &amp; 13 (110 mg, white solid), yield: 55.0%. MS m/z (ESI) ): 451.2 [M+l] 2H), 1H), 63''3. 58 (m, 2H), 4 Li R (400 MHz, CDC13) δ 8.43 (d, 1H), 8. 2〇 8.16-8 . 12 (m, 2H), 8.03 - 8.00 (m, 2H), 7.74 7.30 (dd, 1H), 4.04 (d, 2H), 4.00 (d, 2H), 3 (m, 2H), 3.09(s, 3H), 2. 48 (q, 2H), 1.81-1.78 1.27-1. 25 (m, 1H), 1.19 (t, 3H). Example 14 (3a^ 685^-5-[2-di-4-[(4-methyl sylylene-l-yl)methoxy) ]_3, 3a, 4, 5, 6, 6a-hexahydro-1ZM pentylene [c] ° ratio. Each ~9, ^ Butyl ester buckles 琰 第 95534 101 201213319

第四步 ο 第一步 (3ae，6a»S)-5-苯曱叛基-3, 3a，4, 5, 6, 6a-六氫-環戊並[c] 吡咯-2-羧酸第三丁酯 將（3a足685^-5-經基-3, 3a，4, 5, 6, 6s-六氫-環戊並 [c]^°各-2-叛酸第三丁酯la(5 g，22mmol)溶解於i〇〇mL 四氩呋喃中，依次加入苯甲酸（2.96g，24.20mraol)，三苯 基膦（8. 65 g，33mmol)和偶氮二甲酸二乙酯（4. 2mL， Φ 26.4〇mmol) ’升溫至50°C，攪拌反應3小時。減壓濃縮反 應液，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘 物，得到標題產物（3a尤6a«-5-苯甲羧基 -3, 3艮4, 5, 6, 6a-六氫-環戊並|&gt;]吡咯-2-羧酸第三丁酯 14a(5. 70 g，無色黏稠液體），產率：78. 5%。 第二步 (3a及，6a5&quot;)-5-經基-3, 3a，4, 5, 6, 65_六氫-環戊並[c]n比洛 -2-羧酸第三丁酯 將（3a/?，6a5*)-5-苯甲羧基-3, 35, 4, 5, 6, 6沒-六氫-環 102 95344 201213319 戊並[c]°比咯羧酸第三丁酯 I4a(5.70 g，17.20mmol) 溶解於150mL曱醇和水（v/V = 2:1)混合溶劑中，加入氫化 鋼（3. 40g’ 86mmol)，攪拌反應2小時。減壓濃縮反應液， 加入50mL水，滴加1 μ鹽酸至反應液pH約為3，用乙酸 乙酯萃取（100mLx2)，合併有機相，用無水硫酸鎂乾燥，過 濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純 化所得殘餘物，得到標題產物（3a尤635·)-5-羥基 -3, 3a，4, 5, 6, 6a-六氫-環戊並[c]吡咯-2-羧酸第三丁酯 14b(3. 60 g，白色固體），產率：92. 1%。 第三步 (3a足6^50-5-甲磺醯氧基-3, 3a，4, 5, 6, 6a-六氫-環戊並[c] 吡咯-2-羧酸第三丁酯 冰浴下’將（3ay?，55； 6a«-5-羥基-3, 3a，4, 5, 6, 6a-六 氫-環戊並[c&gt;比咯-2-羧酸第三丁酯I4b(200mg，0. 88mmol) 溶解於10mL無水二氯甲烷中，加入三乙胺（178mg， 1.76imnol) ’滴加甲磺醯氯（i2〇mg，lmmol)，升至室溫反應 12小時。反應液用飽和氯化鈉溶液洗滌（2〇mLx3)，無水硫 酸鎂乾综’過遽，濾液減壓濃縮，得到粗品標題產物 (3ay?，6a«-5-曱磺醯氧基-3, 3a，4, 5, 6, 6a-六氫-環戊並[c] 匕略-2-叛酸第三丁酯i4c(270mg，無色油狀），產物不經 純化直接進行下一步反應。 第四步 (33疋655*)-5-[2-溴〜4-[(4-曱磺醯基哌嗪-1-基）甲基]苯 氧基]-3, 3a，4, 5, 6, 6a-六氫-1丑-環戊並[c]吡咯-2-羧酸第 103 95344 201213319 三丁酯 將2-溴-4-[(4-曱磺醯基哌嗪-i-基）曱基]苯酚lk (254mg，0.73mmol)和粗品（35皮，63^-5-甲磺醯氧基 -3, 3a，4, 5, 6, 6a-六氫-環戊並[c]吡咯-2-羧酸第三丁酯 14c(270mg ’ 0. 88mmol)溶解於l〇mL乙腈中，加入碳酸鉋 (475mg，1. 46mmol)，升至80°C攪拌反應4小時。過濾， 濾液減壓濃縮，用薄層色譜法以展開劑體系B純化所得殘 ^ 餘物，得到標題產物（3ai?，635·)-5-[2-溴-4-[(4-甲磺醯基 °辰°秦-1-基）曱基]苯氧基]-3, 3a, 4, 5, 6, 6a-六氫-1於環戊 並[c]吡咯-2-羧酸第三丁酯14(280mg，白色固體），產率： 50· 0%。 MS m/z (ESI)： 560.2 [M+l] *H NMR (400 MHz, i/-DMS0) &lt;5 7.49 (d, 1H), 7.22-7.24 (in, 1H), 7.04 (d, 1H), 4.96 (Z?r. s, 1H), 3.50 (t, 2H), 3.44 (s, 2H), 3.10-3.25 (in, 2H), 3.08-3.11 (m, 4H), % 2.86 (s, 3H), 2.73 s, 2H), 2.43 (br. s, 4H), 2.20(Z?r. s, 2H), 1.69(Z?r. s, 2H), 1.37 (s, 9H). 實施例15 6a5&quot;)-5-[2-氣-4-[(4-曱續醯基0底唤-1-基）甲基]苯 氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並竣酸第 三丁酯The fourth step ο the first step (3ae, 6a»S)-5-benzoquinone-3, 3a, 4, 5, 6, 6a-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid Tributyl ester will be (3a 685^-5-radio-3, 3a, 4, 5, 6, 6s-hexahydro-cyclopenta[c]^°-2-pyrrolic acid tert-butyl ester la ( 5 g, 22 mmol) was dissolved in i〇〇mL tetrahydrofuran, followed by benzoic acid (2.96 g, 24.20 mraol), triphenylphosphine (8.65 g, 33 mmol) and diethyl azodicarboxylate (4 2mL, Φ 26.4〇mmol) 'When the temperature is raised to 50 ° C, the reaction is stirred for 3 hours. The reaction mixture is concentrated under reduced pressure. The residue obtained is purified eluting with eluent column chromatography to afford the title product (3a 6a) «-5-Benzylcarboxy-3,3艮4, 5, 6, 6a-hexahydro-cyclopentapine|&gt;]pyrrole-2-carboxylic acid tert-butyl ester 14a (5. 70 g, colorless viscous liquid ), yield: 78. 5%. The second step (3a and, 6a5 &quot;)-5-radio-3, 3a, 4, 5, 6, 65_hexahydro-cyclopenta[c]n bilo Tert-butyl 2-carboxylate will be (3a/?,6a5*)-5-benzylcarboxy-3, 35, 4, 5, 6, 6-hexahydro-cyclo 102 95344 201213319 pent[c] °Comparyl carboxylic acid tert-butyl ester I4a (5.70 g, 17.20 mmol) dissolved in 150 mL of sterol and water (v/V = 2:1) To the mixed solvent, hydrogenated steel (3.40 g '86 mmol) was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and 50 mL of water was added, and 1 μ hydrochloric acid was added dropwise until the pH of the reaction mixture was about 3, and extracted with ethyl acetate ( The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, -3, 3a, 4, 5, 6, 6a-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 14b (3. 60 g, white solid), yield: 92.1% The third step (3a foot 6^50-5-methanesulfonyloxy-3,3a,4,5, 6, 6a-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester Under ice bath 'will (3ay?, 55; 6a«-5-hydroxy-3, 3a, 4, 5, 6, 6a-hexahydro-cyclopenta[c&gt; tert-but-2-carboxylic acid tert-butyl ester I4b (200 mg, 0.88 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and then triethylamine (178 mg, 1.76 imnol) was added dropwise with methanesulfonium chloride (i2 mg, 1 mmol) and allowed to react at room temperature for 12 hours. The reaction solution was washed with a saturated sodium chloride solution (2 mL mL), dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give crude title product (3y?, 6a«-5-sulfonyloxy-3). 3a, 4, 5, 6, 6a-hexahydro-cyclopenta[c] oxime-2-teric acid tert-butyl ester i4c (270 mg, colorless oil), the product was directly subjected to the next reaction without purification. Four steps (33疋655*)-5-[2-bromo~4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenoxy]-3, 3a,4, 5, 6 , 6a-hexahydro-1 ugly-cyclopenta[c]pyrrole-2-carboxylic acid 103 95344 201213319 tributyl ester 2-bromo-4-[(4-oxasulfonylpiperazine-i-yl) Mercapto]phenol lk (254 mg, 0.73 mmol) and crude product (35 pi, 63^-5-methanesulfonyloxy-3, 3a, 4, 5, 6, 6a-hexahydro-cyclopenta[c]pyrrole 2-carboxylic acid tert-butyl ester 14c (270 mg '0.88 mmol) was dissolved in 1 mL of acetonitrile, and carbonic acid (475 mg, 1.46 mmol) was added thereto, and the mixture was stirred at 80 ° C for 4 hours, filtered, and the filtrate was reduced. Concentration by pressure, purification of the residue by thin layer chromatography using EtOAc EtOAc (EtOAc) °Qin-1-yl)fluorenyl]phenoxy]-3, 3a, 4, 5, 6, 6a-hexahydro-1 in cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 14 (280 mg, white solid), yield: 50·0%. MS m/z ( ESI): 560.2 [M+l] *H NMR (400 MHz, i/-DMS0) &lt;5 7.49 (d, 1H), 7.22-7.24 (in, 1H), 7.04 (d, 1H), 4.96 (Z ?r. s, 1H), 3.50 (t, 2H), 3.44 (s, 2H), 3.10-3.25 (in, 2H), 3.08-3.11 (m, 4H), % 2.86 (s, 3H), 2.73 s , 2H), 2.43 (br. s, 4H), 2.20 (Z?r. s, 2H), 1.69 (Z?r. s, 2H), 1.37 (s, 9H). Example 15 6a5&quot;)-5 -[2- gas-4-[(4-曱 醯 0 底 -1- -1- -1- 基 基) methyl] phenoxy]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-ring Tert-butyl pentanoic acid

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1a OH Hm7~pH -* C &gt;第一步1a OH Hm7~pH -* C &gt; first step

5spXc^x^ 15 第一步 (33及，6^51)-5-溴-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]°比洛 -2-羧酸第三丁酯5spXc^x^ 15 First step (33 and, 6^51)-5-bromo-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]°bilo-2- Tert-butyl carboxylate

將6a«-5-羥基-3, 3a，4, 5, 6, 6a-六氫-環戊並 鲁 [c]吡咯-2-羧酸第三丁酯la(2. 30g，lOmmol)溶解於40mL 二氯乙烧中，加入四演化碳（6. 60g，20mmol)，冰浴降至0 °C，滴加25mL三苯基膦（5. 20g，20mmol)的二氣曱烧溶液， 升至室溫攪拌反應12小時。用水洗滌（20mLx2)，無水硫酸 鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫 劑體系B純化所得殘餘物，得到標題產物（33^63^)-5-溴 ~3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯-2-羧酸第三丁 酯15a(l. 30 g，淡黃色液體），產率：44. 5%。 MS m/z (ESI): 236.0 [M-55] 第二步 (3说65^-5-1:2-氯-4-[(4-曱磺醯基哌嗪-1-基）曱基]苯 氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯-2-羧酸第 三丁酯 將（3a^，635)-5-溴-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並 [c]0比》各-2-敌酸第三丁酯15a(l g ’ 3.40mmol)和2-氣 105 95344 201213319 _4_[(4-曱磺醯基哌嗪一卜基）曱基]苯酚33(1 〇5 g， 3.40mmol)溶解於i〇mu，N-二曱基曱醯胺中，再加入碳酸 鉋（2.20 g，6.80mmol)，升溫至15(TC攪拌反應6小時。 加入50mL水’乙酸乙酯萃取（3〇mLx3)，合併有機相，飽和 氣化胺溶液洗滌（30mLx5)，無水硫酸鎂乾燥，過濾，濾液 減壓濃縮’用石夕膠管柱色譜法以洗脫劑體系A純化所得殘 餘物，得到標題產物（3a^6a«-5-[2-氯-4-[(4-甲磺酿基 派嗪-1-基）甲基]苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊 • 並[c]吡咯-2-羧酸第三丁酯15(1. 20 g，白色固體），產率： 68· 0%。 MS m/z (ESI): 514.2 [M+l] !H NMR (400 MHz, CDCh) δ 7.33 (d, 1H), 7.08 (d, 1H), 6.82 (d, 1H), 4.87-4.84 (m, 1H), 3.62-3.57 (m, 2H), 3.46 (s, 2H) 3.39-3.37 (m, 2H), 3.25-3.28 (m, 4H), 2.79 (s, 3H), 2.78-2.75 (ra, 2H) ,2.57-2.55 (m, 4H), φ 2.25-2.22 ( m, 2H), 1.92-1.89 (m, 2H), 1.46 (s, 9H). 實施例16 (1疋5«-6-[[2,6-二氟-4_(4-甲磺醯基苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1. 〇]己烷-3-羧酸第三丁酯Dissolving 6a«-5-hydroxy-3,3a,4,5,6,6a-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester la (2.30 g, 10 mmol) In 40 mL of dichloroethane, add four evolution carbon (6. 60 g, 20 mmol), drop to 0 ° C in an ice bath, and add 25 mL of triphenylphosphine (5. 20 g, 20 mmol) in dioxane to the solution. The reaction was stirred at room temperature for 12 hours. The title compound (33^63^)-5-bromo~3 was obtained as the title product (33^63^)-5-bromo~3~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 15a (l. 30 g, pale yellow liquid), yield: 44. 5 %. MS m/z (ESI): 236.0 [M-55] Step 2 (3) 65^-5-1: 2-chloro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl Phenoxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3a^,635)-5-bromo -3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c] 0 ratio, each of the tert-butyl esters of tert-butyl acid 15a (lg ' 3.40 mmol) and 2-gas 105 95344 201213319 _4_[(4-oxasulfonylpiperazine-indolyl) decyl]phenol 33 (1 〇 5 g, 3.40 mmol) was dissolved in i〇mu, N-didecyl decylamine, and then added with carbonic acid planing (2.20 g, 6.80 mmol), warmed to 15 (TC stirring reaction for 6 hours. Add 50 mL of water 'ethyl acetate extract (3 〇 mL x 3), combine the organic phase, wash with saturated gasified amine solution (30 mL×5), dry over anhydrous magnesium sulfate , filtration, and concentration of the filtrate under reduced pressure. The residue obtained was purified from the eluent system A to afford the title product (3a^6a«-5-[2-chloro-4-[(4-methane) Arylpyrazine-1-yl)methyl]phenoxy]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta-[c]pyrrole-2-carboxylic acid tert-butyl Ester 15 (1. 20 g, white solid), Yield: 68·0%. MS m/z (ESI): 514.2 [M+l] !H NMR (400 MHz, CDCh) δ 7.33 (d, 1H), 7.08 (d, 1H), 6.82 (d, 1H), 4.87-4.84 (m, 1H), 3.62-3.57 (m, 2H), 3.46 (s, 2H) 3.39-3.37 (m, 2H), 3.25-3.28 (m, 4H), 2.79 (s, 3H), 2.78-2.75 (ra, 2H), 2.57-2.55 (m, 4H), φ 2.25 -2.22 (m, 2H), 1.92-1.89 (m, 2H), 1.46 (s, 9H). Example 16 (1疋5«-6-[[2,6-difluoro-4_(4-methane) Nonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. oxime]hexane-3-carboxylic acid tert-butyl ester

106 95344 201213319106 95344 201213319

(1兄550-6-(羥基甲基）-3-氮雜雙環並[3. 1. 〇]己烷-3-羧 酸第三丁酯(1 brother 550-6-(hydroxymethyl)-3-azabicyclo[3. 1. oxime] hexane-3-carboxylic acid tert-butyl ester

將[(1尤5iS)-3-氮雜雙環並[3. 1. 〇]己烧-6-基]曱醇 7e(l. 44 g，12. 70mmol)溶解於36mL甲醇中’依次加入三 乙胺（2· 50 g，25. 40mmol)，氫氧化鈀（260mg，cat.)和二 碳酸二第三丁酯（3.30g，15.20mmol)，攪拌反應12小時〇 過濾，濾液減壓濃縮，得到粗品標題產物（1尤550-6-(經基 曱基）_3-氮雜雙環並[3. 1. 0]己烧-3-竣酸第三丁 g旨 16a(2. 70g，黃色液體），產物不經純化直接進行下一步 反應。 MS m/z (ESI): 158.1 [M-55] 第二步 (1尤5Λ-6-(曱磺醯氧基曱基）-3-氮雜雙環並[3. ι· 〇]己燒 -3-羧酸第三丁酯 冰浴下，將粗品（1足55)-6-(羥基甲基）-3-氮雜雙環 107 95344 201213319 並[3.1.0]己烷-3-羧酸第三丁酯 16a(2.70g，12.70mmol) 溶解於30mL無水二氯甲烷中，加入三乙胺（2. 57g， 25. 40mmol)，滴加入 5mL 曱續醯氯（1. 74g，15. 20mmol)的 二氣甲烷溶液，升至室溫反應12小時。加入飽和氣化銨溶 液20mL，萃取分液，水相用二氯曱烷（20mLxl)萃取，合併 有機相，依次用飽和氯化銨溶液（20mLx2)，飽和氯化鈉溶 液（10mLx2)洗滌，無水硫酸鎂乾燥，過濾，濾液減壓濃縮， 得到粗品標題產物（17?，5«-6-(甲磺醯氧基曱基）-3-氮雜 ® 雙環並[3· 1.0]己烷-3-羧酸第三丁酯16b(3g，黃色油狀），φ 產物不經純化直接進行下一步反應。 MS m/z (ESI): 236.1 [M-55] 第三步 (1足550-6-1 (4-溴-2, 6-二氟-苯氧基）曱基]一3_氮雜雙環 並[3· 1. 0]己烧-3-竣酸第三丁醋 將粗品（1尤5iS)-6-(甲續酿氧基曱基）-3-氮雜雙環並 Φ [3.1.〇]己烷-3-羧酸第三丁酯161)(22,6.90匪〇1)和4-溴 -2, 6-二氟-苯酚（1.44 g，6. 90mmol)溶解於 4〇mLN，N-二曱籲 基曱醯胺中，再加入碳酸鉋（4· 50 g，13. 80mmol)，升溫至 150 C揽摔反應5小時。加入10OmL水，乙酸乙g旨萃取 (30mLx4)，合併有機相’飽和氣化銨溶液洗條（4〇mLx5)， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產 物（1友，550-6-IX4-溴-2, 6-二氟-苯氧基）甲基]氮雜雙 環並[3. 1. 0]己烧-3-竣酸第三丁酯16c(2. 20 g，黃色液 體），產物不經純化直接進行下一步反應。 95344 108 201213319 MS m/z (ESI): 350 [M-55] 第四步 (1尤55&quot;)-6-[ [2, 6-二氟-4-(4-甲續醯基苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1.0]己院-3-緩酸第三丁醋 將粗品（1尤5l9)-6-[(4-溴-2, 6-二I-苯氧基）曱基]一3一 氮雜雙環並[3. 1.0]己烷-3-羧酸第三丁酯16c(2g，5mmol)， (4-曱確醢基苯基）删酸（1.20g，6mmol)和1，1’ -二（二苯 膦基）二茂鐵二氯化把（365mg ’ 0. 50mmol)溶解於4〇mLl，4- 二噁烷中，再加入碳酸鉋（3.20 g，1〇丽〇1)，升溫至回流 擾拌反應3小時。顧，缝減壓濃縮，㈣膠f柱色譜 法以洗脫繼系B純化所得殘餘物 ⑽ 5幻-6-[[2, 6-二氟-4-(4n 酸第三丁酯16(2 g 甲磺醯基苯基）笨氧基1曱 基]-3-氣雜雙環並[3.1.G]己境、3、 白色固體），產率：84. 30/〇。 MS m/z (ESI): 424.1 [M-55][(1 especially 5iS)-3-azabicyclo[3. 1. 〇]hexan-6-yl] sterol 7e (1.44 g, 12.70 mmol) was dissolved in 36 mL of methanol' Ethylamine (2·50 g, 25.40 mmol), palladium hydroxide (260 mg, cat.) and dibutyl butyl dicarbonate (3.30 g, 15.20 mmol), stirred for 12 hours, filtered, and concentrated. The crude title product is obtained (1 especially 550-6-(by fluorenyl)_3-azabicyclo[3.1.0]hexa -3-decanoic acid tertidine g 16a (2. 70g, yellow liquid The product was directly subjected to the next reaction without purification. MS m/z (ESI): 158.1 [M-55] The second step (1 especially 5Λ-6-(sulfonyloxycarbonyl)-3-aza Bicyclo[3. ι·〇] hexane-carboxylic acid tert-butyl ester in ice bath, the crude product (1 foot 55)-6-(hydroxymethyl)-3-azabicyclo 107 95344 201213319 and [ 3.1.0] Hexane-3-carboxylic acid tert-butyl ester 16a (2.70 g, 12.70 mmol) was dissolved in 30 mL of anhydrous dichloromethane, triethylamine (2. 57 g, 25. 40 mmol) was added, and 5 mL of hydrazine was added dropwise. Continue to dichloride (1.74g, 15.20mmol) of di-methane solution, and raise to room temperature for 12 hours. Add 20mL of saturated ammonium sulfate solution, extract and separate. The extract was extracted with dichloromethane (20 mL×1), EtOAc (EtOAc m. Title product (17?,5«-6-(methylsulfonyloxyindenyl)-3-aza®bicyclo[3·1.0]hexane-3-carboxylic acid tert-butyl ester 16b (3 g, yellow oil The φ product was directly subjected to the next reaction without purification. MS m/z (ESI): 236.1 [M-55] The third step (1 550-6-1 (4-bromo-2, 6-difluoro) -phenoxy)indolyl]-3_azabicyclo[3·1] hexyl -3-decanoic acid tert-butyl vinegar crude product (1 especially 5iS)-6-(methyl ethoxylated oxime Benzyl-3-azabicyclo-p-[3.1.〇]hexane-3-carboxylic acid tert-butyl ester 161) (22,6.90匪〇1) and 4-bromo-2,6-difluoro-phenol ( 1.44 g, 6. 90 mmol) was dissolved in 4 mL of N,N-dioximide, and then added with carbonic acid planer (4·50 g, 13.80 mmol), and the temperature was raised to 150 C for 5 hours. 10OmL water, acetic acid, ethyl acetate (30mLx4), combined with organic phase 'saturated ammonium hydride solution strip (4〇mLx5), dried over anhydrous magnesium sulfate, filtered, filtered Concentration under reduced pressure gave the crude title product (1, 550-6-IX 4-bromo-2, 6-difluoro-phenoxy)methyl] azabicyclo[3. 1. The third butyl citrate 16c (2.20 g, yellow liquid) was subjected to the next reaction without purification. 95344 108 201213319 MS m/z (ESI): 350 [M-55] Step 4 (1 especially 55&quot;)-6-[ [2, 6-Difluoro-4-(4-methylphenyl) Phenoxy]fluorenyl]-3-azabicyclo[3.1.0]hexyl-3-lowic acid tert-butyl vinegar crude product (1 especially 5l9)-6-[(4-bromo-2, 6- Di-I-phenoxy)indenyl]- 3 -azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 16c (2 g, 5 mmol), (4-decylphenyl) Acid-depleted (1.20g, 6mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloride (365mg '0.50mmol) was dissolved in 4〇mL,4-dioxane, and then added Carbonate planer (3.20 g, 1 〇 〇 1), warmed to reflux and stirred for 3 hours. Gu, sewing under reduced pressure, (4) gel f column chromatography to elute the residue obtained by purification of step B (10) 5 magic-6-[[2, 6-difluoro-4-(4n acid tert-butyl ester 16 (2) g methanesulfonyl phenyl) phenyloxy 1 fluorenyl]-3- oxabicyclo[3.[g], 3, white solid), yield: 84.30 / 〇. MS m/z (ESI): 424.1 [M-55]

!H NMR (400 MHz, i/-DMSO) &lt;5 7 〇〇 , 4.06 01’ 肌 3.39(d，2H)，.38^4H)，7.65(d’1H)， (s，2H)，1.36 (s，9H)’ G.9(H).89 3(m2i)二 5H)’ h56 實施例17 ⑽ 5Λ+[[4-(4-氰絲基)乂 6_ 基]-3-氮雜雙環並[3.1. ο。 氧土]甲 UJ己烷-3-鲮酸第三丁酯!H NMR (400 MHz, i/-DMSO) &lt;5 7 〇〇, 4.06 01' Muscle 3.39 (d, 2H), .38^4H), 7.65 (d'1H), (s, 2H), 1.36 (s,9H)' G.9(H).89 3(m2i)二5H)' h56 Example 17 (10) 5Λ+[[4-(4-cyanomethyl)乂6_yl]-3-azabicyclo And [3.1. ο. Oxygen soil] A UJ hexane-3-decanoic acid tert-butyl ester

95344 109 20121331995344 109 201213319

將（li?，55〇-6-[(4-溴-2, 6-二氟-苯氧基）甲基]-3-氮 雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯16c(300mg， 0. 74imio1) ’（4-氰基苯基）棚酸（131mg，0. 89mmol)和 1，1’ _二（二苯膦基）二茂鐵二氣化lG(54mg，0. 07mmol)溶 ® 解於3mLl，4-二°惡烧和2mL水的混合溶劑中，再加入三水 合磷酸鉀（591mg，2. 22mmol)，升溫至120°C攪拌反應7小 時。過濾、，加入20mL水，乙酸乙酯萃取（20mLx3)，合併有 機相，飽和氣化鈉溶液洗滌（15mLx3)，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B純化 所得殘餘物，得到標題產物（1^55·)-6-[[4-(4-氰基苯 基）-2, 6-二氟-苯氧基]甲基]-3-氣雜雙環並[3. 1. 0]己烧 _ -3-羧酸第三丁酯17(70mg ’白色固體），產率：22%。 MS m/z (ESI): 371.1 [M-55] *Η NMR (400 MHz, d/-DMSO) δ 8.21 (d, 4H), 7.65 (d, 2H), 4. 06(d, 2H), 3.40 (d, 2H), 3. 25 (s, 2H), 1.56(t, 2H), 1.35 (s, 9H), 0.93-0.89 (m, 1H). 實施例18 3-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]-8-氮雜雙環並 [3. 2. 1]辛烷-8-羧酸第三丁酯 110 95344 201213319Will (li?,55〇-6-[(4-bromo-2,6-difluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate Acidic tert-butyl ester 16c (300 mg, 0.74 imio1) '(4-cyanophenyl) shed acid (131 mg, 0.89 mmol) and 1,1'-bis(diphenylphosphino)ferrocene lG (54 mg, 0.07 mmol) dissolved in a mixed solvent of 3 mL of 1,2-dioxacin and 2 mL of water, and then added potassium phosphate trihydrate (591 mg, 2.22 mmol), and the temperature was raised to 120 ° C to stir the reaction. </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> The resulting residue was purified to give the title product (1^55·)-6-[[4-(4-cyanophenyl)-2,6-difluoro-phenoxy]methyl]-3- Gas-heterobicyclo[3.1.0]hexane- -3-carboxylic acid tert-butyl ester 17 (70 mg 'white solid), yield: 22%. MS m/z (ESI): 371.1 [M-55 ] *Η NMR (400 MHz, d/-DMSO) δ 8.21 (d, 4H), 7.65 (d, 2H), 4. 06(d, 2H), 3.40 (d, 2H), 3. 25 (s, 2H), 1.56(t, 2H), 1.35 (s, 9H), 0.93-0.89 (m, 1H). Example 18 3-[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]-8-azabicyclo[3.2.1]octine Alkyl-8-carboxylic acid tert-butyl ester 110 95344 201213319

第三步third step

第一步 3_溴-8-氮雜雙環並[3· 2. 1 ]辛烧-8-竣酸第三丁酉旨 將粗品3-羥基-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第 三丁酯9b(2.20 g，9. 7〇顏〇1)溶解於20mL二氣甲烷中， 加入四溴化碳（4. 80 g，14· 50imnol) ’冰浴下，滴加入20mL 翁 三苯基膦（3.81 g，14. 50mmol)的二氯曱烷溶液，升至室溫 攪拌反應12小時。反應液減壓濃縮，用矽膠管柱色譜法以 洗脫劑體系B純化所得殘餘物，得到標題產物3-溴-8-氮 雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯I8a(1.96g，黃色 液體），產率：70. 0%。 第二步 3-(4-溴-2, 6-二氟-苯氧基）-8-氮雜雙環並[3. 2. 1]辛烷 -8-羧酸第三丁酯 將3-溴-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯 111 95344 201213319 18a(500mg，1. 73mmol)和 4-溴-2, 6-二氟-苯酚（361mg， 1.73mmol)溶解於5mLN，N-二曱基甲醯胺中，再加入碳酸鉀 (716mg，5. 19mmol)，升溫至120°C攪拌反應4小時。加入 50mL水，用乙酸乙醋萃取（20mLx3)，合併有機相，依次用 水（10mLx3)，飽和氣化鈉溶液洗滌（10mLx3)，無水硫酸鎂 乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以展開劑 體系B純化所得殘餘物，得到標題產物3-(4-溴-2, 6-二氟 -苯氧基）-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯 # 18b(330mg，黃色液體），產率：46.3%。 第三步 3-[2, 6-二氟-4-(4-曱續醢基苯基）苯氧基]-8-氮雜雙環並 [3. 2. 1]辛烧-8-羧酸第三丁酯 將3-(4-溴-2, 6-二氟-苯氧基）-8-氮雜雙環並[3. 2. 1 ] 辛烧-8-缓酸第三丁酯18b(390mg，〇. 93mmol)，（4-曱確醯 基苯基）蝴酸（224mg，1. 12mmol)和1，1’ -二（二笨膦基）二 φ 茂鐵二氣化鈀（68mg，0. 09mmol)溶解於6mLl，4-二嗯烧和 水（V/V = 5:1)混合溶劑中，再加入三水合破酸钾（743mg， 2. 29mmol)，升溫至120°C攪拌反應4小時。過濾、，加入2〇mL 水’用乙酸乙醋萃取（20mLx3) ’合併有機相，飽和氣化納 溶液洗滌（10mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓濃 縮’用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物， 得到標題產物3-[2, 6-二氟-4-(4-曱磺醯基苯基）笨氧 基]-8-氮雜雙環並[3. 2. 1]辛烧-8-竣酸第三丁醋 18(170mg，白色固體），產率：37. 〇%。 95344 112 201213319 MS m/z (ESI): 438.2 [M-55] Ή NMR (400 MHz, (/-DMSO) δ 8.01-7.97 (m, 4H), 7.66 (d, 2H), 4. 59 (s, 1H), 4. 11 (s, 2H), 3. 32 (s, 3H), 2. 19 (d, 2H), 2.10-2.06 (m, 2H), 1.99-1.93 (s, 4H), 1.40 (s, 9H). 實施例19 (1疋5«-6-[[2, 6-二氟-4-(4_甲磺醯基苯基）苯氧基]甲 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸-1-曱基環丙基酯The first step 3_bromo-8-azabicyclo[3·2.1]octane-8-decanoic acid tributyl hydrazine is intended to be a crude 3-hydroxy-8-azabicyclo[3.2.1] Octane-8-carboxylic acid tert-butyl ester 9b (2.20 g, 7.9 〇 〇 1) was dissolved in 20 mL of di-methane, and added to carbon tetrabromide (4. 80 g, 14.50 imnol) 'ice bath Next, 20 mL of a solution of trimethylphosphine (3.81 g, 14.50 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjj The third butyl ester I8a (1.96 g, yellow liquid), yield: 70. 0%. Step 2 3-(4-Bromo-2,6-difluoro-phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3-bromo -8-Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 111 95344 201213319 18a (500 mg, 1.73 mmol) and 4-bromo-2,6-difluoro-phenol ( 361 mg, 1.73 mmol) was dissolved in 5 mL of N,N-dimercaptocaramine, and potassium carbonate (716 mg, 5.19 mmol) was added thereto, and the mixture was heated to 120 ° C and stirred for 4 hours. Add 50mL of water, extract with ethyl acetate (20mLx3), combine the organic phase, wash with water (10mLx3), saturated sodium carbonate solution (10mLx3), dry over anhydrous magnesium sulfate, filtered, filtrate concentrated under reduced pressure, chromatographic column chromatography The residue obtained was purified by EtOAc EtOAc (EtOAc (MeOH) - carboxylic acid tert-butyl ester # 18b (330 mg, yellow liquid), yield: 46.3%. Step 3 3-[2,6-Difluoro-4-(4-indolylphenyl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylic acid The third butyl ester will be 3-(4-bromo-2,6-difluoro-phenoxy)-8-azabicyclo[3.2.1]octane-8-acidified tert-butyl ester 18b ( 390 mg, 〇. 93 mmol), (4-indolylphenyl)folic acid (224 mg, 1.12 mmol) and 1,1'-di(diphosphino)di-ruthenium dipentide palladium (68 mg, 0. 09mmol) dissolved in 6mLl, 4- dioxin and water (V / V = 5:1) mixed solvent, then added potassium sulphate trihydrate (743mg, 2. 29mmol), heated to 120 ° C stirring reaction 4 hours. Filtration, adding 2 mL of water 'extracted with ethyl acetate (20 mL×3) 'The organic phase was combined, washed with saturated sodium carbonate solution (10 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to afford the title product 3-[2,6-difluoro-4-(4-oxasulfonylphenyl) phenoxy]-8-azabicyclo[3. 2. 1] octyl-8-decanoic acid butyl vinegar 18 (170 mg, white solid), yield: 37. 〇%. </ RTI> </ RTI> <RTIgt; , 1H), 4. 11 (s, 2H), 3. 32 (s, 3H), 2. 19 (d, 2H), 2.10-2.06 (m, 2H), 1.99-1.93 (s, 4H), 1.40 (s, 9H). Example 19 (1疋5«-6-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-aza Bicyclo[3.1.0]hexane-3-carboxylic acid-1-mercaptocyclopropyl ester

(1足55&quot;)-6-[ [2, 6-二氟-4-(4-甲續醯基苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己烧 冰浴下，將（1疋5«-6-[[2,6-二氟-4-(4-甲磺醯基笨 基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三 丁酯16(1. 10 g，2. 30mmol)溶解於5mL二氯曱烧中，滴加 入20mL4 Μ鹽酸曱醇溶液’升至室溫，攪拌反應12小時。 減壓濃縮反應液’得到粗品標題產物（1尤55·)-6-[[2, 6-二 氟-4-(4-曱磺醯基苯基）苯氧基]甲基]-3-氮雜雙環並 113 95344 201213319 [3. 1· 0]己烷19a(800mg，白色固體），產物不經純化直接 進行下一步反應。 第二步 (1尤5Λ-6-[[2, 6-二氟-4-(4-甲績酿基笨基）苯氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己烧-3-羧酸-1-甲基環丙基醋 將粗品（1疋5幻-6-[[2, 6-二氟-4~(4-曱磺醯基苯基） 本氧基]曱基]-3-氮雜雙環並[3. 1. 0]己院i9a(150mg， 〇. 36mraol) ’ 三乙胺（73mg ’ 0· 72romol)加入至 8niL 二氯甲院 中，冰浴下，加入lmLU-曱基環丙基）（4-硝基笨基）碳酸 酯19b(102mg，0.43mmol，採用公知的方法“專利 WO2010009195製備而得）的二氣甲燒溶液，升至室溫授掉 反應12小時。過濾’加入l〇〇mL二氣甲烷，依次用1 M 氫氧化鋼溶液（10inL)，1Μ鹽酸（l〇mL)，飽和氯化鈉溶液洗 滌（10mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用 薄層色s普法以展開劑體系B純化所得殘餘物，得到標題產 _ 物（1兄550-6-1^2, 6-二氟-4-(4-曱磺醯基笨基）苯氧基]甲 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸-1-曱基環丙基酿 19(100mg，白色固體），產率：58.8%。 MS ra/z (ESI): 424.2 [M-53] 'H NMR (400 MHz, d-dUSO) δ 7.98 (d, 4H), 7.65 (d, 2H), 4.05 (d, 2H), 3.41 (d, 2H), 3.35-3.28 (ra, 5H), 1.55 (s，2H)，1.42 (s, 3H), 0.91-0.90 (m, 1H)，0.74-0.72 (m，2H)，0.57-0.56(m，2H). 實施例20 114 95344 201213319 9-[2,6-二氟-4-(4-甲磺醢基苯基）苯氧基]_7_氧雜―3_氮 雜雙環並[3. 3. 1]壬烷-3-羧酸第三丁酯(1 foot 55 &quot;)-6-[ [2, 6-difluoro-4-(4-methylthenylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. 0 Under the calcined ice bath, (1疋5«-6-[[2,6-difluoro-4-(4-methylsulfonyl)phenyloxy]methyl]-3-azabicyclo And [3. 1. 0] hexane-3-carboxylic acid tert-butyl ester 16 (1. 10 g, 2. 30 mmol) was dissolved in 5 mL of dichloropyrene, and 20 mL of 4 hydrazine hydrochloride solution was added dropwise. The reaction was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give the crude title product (1 </ RTI> </ RTI> -6-[[2,6-difluoro-4-(4-indolesulfonylphenyl)phenoxy) Methyl]-3-azabicyclohexane 113 95344 201213319 [3. 1·0]hexane 19a (800 mg, white solid), the product was directly subjected to the next reaction without purification. The second step (1 especially 5 Λ - 6-[[2,6-Difluoro-4-(4-methylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexacarb-3-carboxylate Acid-1-methylcyclopropyl vinegar will be crude (1疋5幻-6-[[2,6-difluoro-4~(4-oxasulfonylphenyl) hydroxy]indolyl]-3 -Azabicyclo[3. 1. 0] 院院i9a (150mg, 〇. 36mraol) 'Triethylamine (73mg ' 0· 72romol) added to 8niL dichlorocarbyl, ice bath , adding lmLU-mercaptocyclopropyl)(4-nitrophenyl)carbonate 19b (102 mg, 0.43 mmol, prepared by the known method "patent WO2010009195"), and then raised to room temperature. The reaction was carried out for 12 hours. Filtering was carried out by adding 1 mL of methane methane, followed by 1 M aqueous solution of oxidized steel (10 inL), 1 Μ hydrochloric acid (10 mL), and saturated sodium chloride solution (10 mL×2), dried over anhydrous magnesium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the obtained residue by a thin layer of EtOAc EtOAc EtOAc EtOAc苯 醯 )) phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid-1-mercaptocyclopropyl 19 (100 mg, white solid ), yield: 58.8%. MS ra/z (ESI): 424.2 [M-53] 'H NMR (400 MHz, d-dUSO) δ 7.98 (d, 4H), 7.65 (d, 2H), 4.05 ( d, 2H), 3.41 (d, 2H), 3.35-3.28 (ra, 5H), 1.55 (s, 2H), 1.42 (s, 3H), 0.91-0.90 (m, 1H), 0.74-0.72 (m, 2H), 0.57-0.56 (m, 2H). Example 20 114 95344 201213319 9-[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]_7_oxa-3 _ aza double ring And [3.3.1] decane-3-carboxylic acid tert-butyl ester

第一步 9-羥基-7-氧雜-3-氮雜雙環並[3. 3. 1]壬-3-羧酸第三丁酯 將3-苄基-7-氧雜-3-氮雜雙環並[3. 3. 1]壬-9-醇 20a(2 g，8. 57mmol，採用公知的方法“專利 W02010009195”製備而得）溶解於50mL甲醇中，依次加入 三乙胺（1. 73 g，17. 14mmol)和二碳酸二第三丁酯（2. 25 g， 10. 29mmol)，再加入氫氧化把（1. 81 g，2. 57mmol)，置換 氫氣3次，攪拌反應12小時。過濾，濾液減壓濃縮，得到 粗品標題產物9-羥基-7-氧雜-3-氮雜雙環並[3. 3. 1]壬 -3-羧酸第三丁酯20b(2. 31 g，黃色液體），產物不經純化 直接進行下一步反應。 MS m/z (ESI): 242.2 [M+l] 第二步 115 95344 201213319 9-曱磺醯氧基-7-氧雜-3-氮雜雙環並[3. 3· 1]壬-3-羧酸第 三丁酯 冰浴下，將粗品9-羥基-7-氧雜-3-氮雜雙環並[3. 3. 1]First step 9-hydroxy-7-oxa-3-azabicyclo[3.3.1]indole-3-carboxylic acid tert-butyl ester 3-benzyl-7-oxa-3-aza Bicyclo[3.3.1]壬-9-ol 20a (2 g, 8.57 mmol, prepared by the known method "patent W02010009195") was dissolved in 50 mL of methanol, and then added triethylamine (1. 73). g, 17. 14 mmol) and di-tert-butyl dicarbonate (2.25 g, 10.29 mmol), further added with hydrogen peroxide (1.81 g, 2.57 mmol), substituted hydrogen three times, stirred for 12 hours . Filtration and concentration of the filtrate under reduced pressure afforded crude title product 9-hydroxy-7-oxa-3-azabicyclo[3.3.1]indole-3-carboxylic acid tert-butyl ester 20b (2. 31 g, Yellow liquid), the product was directly subjected to the next reaction without purification. MS m/z (ESI): 242.2 [M+l] Step 2 115 95344 201213319 9-sulfonyloxy-7-oxa-3-azabicyclo[3. 3·1]壬-3- The crude 9-hydroxy-7-oxa-3-azabicyclo[3.3.1]

壬-3-羧酸第三丁酯20b(2. 09 g ’ 8. 57mmol)溶解於50mL 無水一氯曱烧中’加入三乙胺（1.73g，17. 14mmo 1)，滴加 甲磺醯氣（1.47 g，l2_86mmol)，升至室溫反應12小時。 加入水50mL，萃取分液，水相用二氣甲烷（5〇mLx2)萃取， 合併有機相，依次用飽和碳酸氫鈉溶液（3〇raL)，飽和氯化 Φ 納溶液洗務（3〇mL) ’無水硫酸鎂乾燥，過濾，遽液減壓濃 縮’得到粗品標題產物9-曱續醯氧基-7-氧雜-3-氮雜雙環 _ 並[3. 3. 1]壬-3-羧酸第三丁酯20c(2. 16 g，黃色油狀）， 產物不經純化直接進行下一步反應。 第三步 9-(4-溴-2, 6-二氟-笨氧基）-7-氧雜-3-氮雜雙環並[3. 3. 1] 壬-3-羧酸第三丁酯 0 將粗品9-甲續醯氧基-7-氧雜-3-氮雜雙環並[3. 3. 1 ] 壬-3-羧酸第三丁酯 20c(l g ’ 3. llmm〇i)和 4-溴-2, 6-二 # 氟-苯酚（0· 71 g，3.41mmol)溶解於4〇mLN，N-二甲基曱醯 胺中’再加入碳酸铯（2. 03 g，6. 22mmol)，升溫至90°C撥 拌反應2小時’再升溫至150°C攪拌反應5小時。加入6〇mL 水’乙酸乙醋萃取（50mLx3)，合併有機相，飽和氣化鈉溶 液洗滌（50mL) ’無水硫酸鎮乾燥’過濾，濾液減壓濃縮， 用石夕膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到 標題產物9-(4-溴-2, 6-二氟-苯氧基）_7_氧雜_3_氮雜雙 95344 116 201213319 環並[3.3. 1]壬-3-羧酸第三丁酯20d(0.32g，黃色固體）， 產率：23%。 MS m/z (ESI): 379.1 [M-55] 第四步 9-[2,6-二氟-4-(4-甲磺醯基苯基）苯氧基μ7_氧雜氣 雜雙環並[3. 3. 1]壬烷-3-羧酸第三丁醋 將9-(4-溴-2, 6-二氟-苯氧基）-7-氧雜-3-氮雜雙j牙 並[3.3.1]壬-3-羧酸第三丁酯 20(1(0.32 8,〇.74111111〇1), φ (4-甲績醯基苯基）蝴酸（178mg，0. 89mmol)和 1，1，_二（_ 本鱗基）一戊鐵·一氣化把（54ing ’ 0. 〇7nuno 1)溶解於2〇mL 1，4-二嗔烧中’再加入碳酸铯（0. 72 g，2. 22mmol)，升溫 至120°C授拌反應3小時。加入20mL水，乙酸乙酯萃取 (30mLx3)，合併有機相，飽和氣化鈉溶液洗滌（30mL),無 水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法 以洗脫劑體系B純化所得殘餘物，得到標題產物9-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]-7-氧雜-3-氮雜雙環並 • [3·3. 1]壬烷-3-羧酸第三丁酯20(0. 18g，白色固體），產 率：48. 7%。 MS ra/z (ESI): 454.1 [M-55] lH NMR (400 MHz，CDCh) (5 8.01-8. 04 (m，2H)，7. 70-7.72 (in, 2H), 7.19-7.21 (m, 2H), 4.27-4.63 (m, 7H), 3.85-3.94 (m, 2H), 3.16-3.19 (m, 1H), 3.11 (s, 3H), 3.03-3.07 (m, 1H), 1.49 (s, 9H). 實施例21 117 95344 201213319 (1及，55')-6-[[2,6_二敗-4-(4-曱橫醯基苯基）苯氧基]甲 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸-1-曱基環丁基酯Indole-3-carboxylic acid tert-butyl ester 20b (2. 09 g ' 8. 57 mmol) was dissolved in 50 mL of anhydrous monochlorohydrazine. Adding triethylamine (1.73 g, 17.14 mmo 1), adding methotrexate Gas (1.47 g, l2_86 mmol) was allowed to react to room temperature for 12 hours. Add 50mL of water, extract and separate the liquid, extract the aqueous phase with di-methane (5〇mLx2), combine the organic phase, and then wash it with saturated sodium bicarbonate solution (3〇raL), saturated chlorinated Φ nano solution (3〇mL) 'Dry anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude title product 9-</RTI> </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; The carboxylic acid tert-butyl ester 20c (2.16 g, yellow oil) was taken to the next step without purification. The third step is 9-(4-bromo-2,6-difluoro-indolyl)-7-oxa-3-azabicyclo[3.3.1] indole-3-carboxylic acid tert-butyl ester 0 will be crude 9-methyl decyloxy-7-oxa-3-azabicyclo[3.3.1] indole-3-carboxylic acid tert-butyl ester 20c (lg ' 3. llmm〇i) and 4-Bromo-2,6-di #fluoro-phenol (0·71 g, 3.41 mmol) was dissolved in 4 mL of N,N-dimethyl decylamine and then cesium carbonate (2.03 g, 6. 22 mmol), the temperature was raised to 90 ° C and the reaction was stirred for 2 hours. The temperature was further raised to 150 ° C and the reaction was stirred for 5 hours. Add 6 mL of water 'acetic acid ethyl acetate (50 mL×3), combine the organic phase, wash with saturated sodium carbonate solution (50 mL) and dry with anhydrous sulfuric acid. The filtrate is concentrated under reduced pressure and eluted with Shixi rubber column chromatography. The resulting residue was purified to give the title product 9-(4-bromo-2,6-difluoro-phenoxy)_7-oxa-3-azabis 95344 116 201213319 ring [3.3. 1]壬3-carboxylic acid tert-butyl ester 20d (0.32 g, yellow solid), yield: 23%. MS m/z (ESI): 379.1 [M-55] Step 4 9-[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy[7]-oxo heterobicyclo and [3. 3. 1] decane-3-carboxylic acid tert-butyl vinegar 9-(4-bromo-2,6-difluoro-phenoxy)-7-oxa-3-aza double j And [3.3.1] indole-3-carboxylic acid tert-butyl ester 20 (1 (0.32 8, 〇.74111111〇1), φ (4-methylphenyl) phenyl acid (178 mg, 0.89 mmol) And 1,1,_ two (_ squaring), a pentane, a gasification (54ing '0. 〇7nuno 1) dissolved in 2 〇mL 1,4-dioxinone' and then added cesium carbonate (0. 72 g, 2. 22 mmol), and the mixture was heated to 120 ° C for 3 hours. Add 20 mL of water, ethyl acetate (30 mL×3), and the organic phase was combined, washed with saturated sodium sulfate (30 mL) Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting from EtOAc EtOAc EtOAc EtOAc Oxy]-7-oxa-3-azabicyclo[3.3.1]decane-3-carboxylic acid tert-butyl ester 20 (0. 18 g, white solid), yield: 48. MS ra/z (ESI): 454.1 [M-55] lH NMR (400 MHz, CDCh) (5 8. 01-8. 04 (m, 2H), 7. 70-7.72 (in, 2H), 7.19-7.21 (m, 2H), 4.27-4.63 (m, 7H), 3.85-3.94 (m, 2H), 3.16 -3.19 (m, 1H), 3.11 (s, 3H), 3.03-3.07 (m, 1H), 1.49 (s, 9H). Example 21 117 95344 201213319 (1 and, 55')-6-[[2 , 6_2, 4-(4-indolyl phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid-1-pyrene Butyl butyl ester

第一步 (1-曱基環丁基）（4-硝基苯基）碳酸酯 將氯碳酸-(4-硝基苯基）醋（1. 68 g，8. 36mmol)溶解 於20mL二氣曱烷中，依次加入粗品卜曱基環丁基醇 21a(600mg，6.97mmo卜採用公知的方法“專利 W02010009195” 製備而得），4-二甲胺基0比唆（60mg，cat.) 和5mL三曱基吡啶，攪拌反應12小時。滴加1 Μ鹽酸淬 滅反應，分液，合併有機相，無水硫酸鎮乾燥，過遽，渡 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系Β純化所得 殘餘物，得到標題產物（1-甲基環丁基）（4-硝基苯基）碳酸 酯21b(0.40 g，無色液體），產率：24%。 第二步 (1足5«-6-[[2, 6-二氟-4-(4-曱磺醯基苯基）笨氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸-1-曱基環丁基酯 118 95344 201213319 冰浴下’將（1^550-6-(^2, 6-二氟-4-(4-曱續醯基苯 基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 〇]己烧I9a(i66mg， 0. 40mmol)，三乙胺（81mg ’ 0. 80mmol)溶解於 i〇mL 二氣甲 烷中’加入2mLU-甲基環丁基）（4-硝基苯基）碳酸酯 21b(100mg ’ 0.40刪〇1)的二氯甲烷溶液’升至室溫撥拌反 應15小時。加入40mL二氯曱烷，依次用1 μ氫氧化鈉溶 液（10mLx2)，1Μ鹽酸（l〇mL)，飽和氣化鈉溶液洗條 (10mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄 • 層色譜法以展開劑體系B純化所得殘餘物，得到標題產物 (1及，550-64 [2, 6-二氟-4-(4-曱石黃酿基苯基）苯氧基]甲 基]_3 -氣雜雙％並[3. 1. 0]己烧-3-叛酸-1-甲基環丁基酉旨 21(82mg，白色固體），產率：58. 8%。 MS m/z (ESI): 492.2 [M+l] 1H NMR (400 MHz, CDCh) &lt;5 8.01-8.04 (m, 2H), 7. 7〇-7.73 (in, 2H), 7.17-7.27 (m, 2H), 4.08-4.10 (m, 2H), 馨 3.60-3.62 (m, 2H), 3.37-3.41 (m, 2H), 3.10 (s, 3H) 2.28-2.31 (m, 2H), 2.08-2.13 (in, 2H), 1.76-1.78 (in, 1H), 1.64-1.66 (m, 1H), 1.57 (s, 3H), 1.25-1.27 (m, 2H), 1. 13-1. 15 (m, 1H). 實施例2 2 (1^ 55^-3-(5-乙基嘴咬-2-基）-6-[ 啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷 95344 119 201213319The first step (1-fluorenylcyclobutyl) (4-nitrophenyl) carbonate dissolves chlorocarbonic acid-(4-nitrophenyl) vinegar (1. 68 g, 8.36 mmol) in 20 mL of two gas. In decane, crude decylcyclobutyl alcohol 21a (600 mg, 6.97 mmo was prepared by the known method "patent W02010009195"), 4-dimethylamino 0 唆 (60 mg, cat.) and 5 mL of three were sequentially added. Pyrithione was stirred for 12 hours. The reaction mixture was quenched with 1 EtOAc, EtOAc (EtOAc)EtOAc. (1-Methylcyclobutyl)(4-nitrophenyl)carbonate 21b (0.40 g, colorless liquid), yield: 24%. The second step (1 foot 5«-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl) phenyloxy] fluorenyl]-3-azabicyclo[3. 1 0] Hexane-3-carboxylic acid-1-decylcyclobutyl ester 118 95344 201213319 Under the ice bath 'will (1^550-6-(^2, 6-difluoro-4-(4-) Nonylphenyl)phenoxy]methyl]-3-azabicyclo[3. 1. oxime] hexane I9a (i66 mg, 0. 40 mmol), triethylamine (81 mg '0. 80 mmol) dissolved in i 〇mL di-methane in 'add 2mLU-methylcyclobutyl) (4-nitrophenyl) carbonate 21b (100mg '0.40 deleted 1) in dichloromethane solution's warmed to room temperature and stirred for 15 hours Add 40 mL of dichloromethane, and then use 1 μl of sodium hydroxide solution (10 mL×2), 1 Μ hydrochloric acid (10 mL), and a saturated sodium carbonate solution (10 mL×2), dried over anhydrous magnesium sulfate. The residue obtained was purified by thin layer chromatography using EtOAc EtOAc (EtOAc) (md. And the yield: 58.8%. The yield of the methyl group of the methyl group of the group of the group of the group of the group of the group of the group. MS m/z (ESI): 492.2 [M+l] 1H NMR (400 MHz, CDCh) &lt;5 8.01-8.04 (m, 2H), 7. 7〇-7.73 (in, 2H), 7.17-7.27 (m, 2H), 4.08-4.10 ( m, 2H), Xin 3.60-3.62 (m, 2H), 3.37-3.41 (m, 2H), 3.10 (s, 3H) 2.28-2.31 (m, 2H), 2.08-2.13 (in, 2H), 1.76- 1.78 (in, 1H), 1.64-1.66 (m, 1H), 1.57 (s, 3H), 1.25-1.27 (m, 2H), 1. 13-1. 15 (m, 1H). Example 2 2 ( 1^ 55^-3-(5-ethyl-n-butyl-2-yl)-6-[pyridyl]oxymethyl]-3-azabicyclo[3. 1. 0]hexane 95344 119 201213319

將（iy?，5«-6-[(6-氯-3-°比啶基）氧甲基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷13a(100mg， 0. 30mmol) ’ 3-°比咬侧酸（48· 30mg，0· 39mmol)，二（三苯膦 基）二氣化把（100mg，0. 14mniol)和1. 5mL2 Μ碳酸鈉溶液溶 解於20mLN，N-二曱基曱醯胺中，升至85°C攪拌反應12小 時。加入水100mL ’用乙酸乙酯萃取（5〇mLx3)，合併有機 φ 相’依次用水（20mLx3) ’飽和氣化鈉溶液洗滌（20mLx3)， 無水硫酸錢乾燥，過滤，遽液減壓濃縮，用薄層色譜法以 展開劑體系B純化所得殘餘物，得到標題產物 (1尤5«-3-(5-乙基嘧啶-2-基）-6-[[6-(3-吡啶基）-3-吡 啶基]氧曱基]-3-氮雜雙環並[3. 1. 〇]己烷22(5〇mg，白色 固體），產率：44· 6%。 MS m/z (ESI): 374.2 [M+l] H NMR (400 MHz, CDCh) δ 9. 13 (d, 1H), 8.60 (dd, 1H), 8.41 (d，1H)，8. 32-8.23 (m，1H)，8. 17 (s，2H)，7.68 95344 120 201213319 (d, 1H), 7.38 (dd, 1H), 7.29 (dd, 1H), 4.00 (dd, 4H), 3.58 (dd, 2H), 2.46 (q, 2H), 1.98 (s, 1H), 1.77 (dd, 2H), 1. 18 (t, 3H). 實施例23 (1^ 550-3-(5-乙基嘧啶-2-基）-6-[ [5-(3-氟-4-n比啶基） 吼嗪-2-基]氧曱基1-3-氮雜雙環並「3. 1.01己露…Will (iy?,5«-6-[(6-chloro-3-pyridinyl)oxymethyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3 1. 0] Hexane 13a (100mg, 0. 30mmol) ' 3-° ratio biting acid (48·30mg, 0·39mmol), bis(triphenylphosphino) di-gasification (100mg, 0. 14mniol And 1.5 mL of 2 Μ sodium carbonate solution dissolved in 20 mL of N,N-didecyl decylamine, and stirred to 85 ° C for 12 hours. Add water 100 mL 'Extracted with ethyl acetate (5 〇 mL x 3), combined organic The φ phase was washed with water (20 mL×3) in a saturated sodium sulphate solution (20 mL×3), dried over anhydrous sulphuric acid, filtered, and concentrated under reduced pressure. (1 especially 5«-3-(5-ethylpyrimidin-2-yl)-6-[[6-(3-pyridyl)-3-pyridyl]oxyindolyl]-3-azabicyclo[ 3. 〇]hexane 22 (5 〇 mg, white solid), yield: 44· 6%. MS m/z (ESI): 374.2 [M+l] H NMR (400 MHz, CDCh) δ 9 . 13 (d, 1H), 8.60 (dd, 1H), 8.41 (d, 1H), 8. 32-8.23 (m, 1H), 8. 17 (s, 2H), 7.68 95344 120 201213319 (d, 1H ), 7.38 (dd, 1H), 7.29 (dd, 1H), 4.00 ( Dd, 4H), 3.58 (dd, 2H), 2.46 (q, 2H), 1.98 (s, 1H), 1.77 (dd, 2H), 1. 18 (t, 3H). Example 23 (1^ 550- 3-(5-ethylpyrimidin-2-yl)-6-[ [5-(3-fluoro-4-n-pyridyl)pyridazin-2-yl]oxyindolyl 1-1-3 azabicyclo "3. 1.01 has revealed...

將（1兄5Λ-6-[(5-溴吨嗪-2-基）氧曱基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷12a(100mg， 0. 27mmol)’（3-氣比咬基）硼酸（75mg，0. 53mmol)，二（三 苯膦基）二氣化鈀（50mg，〇.〇7mmol)和lmL2 Μ碳酸鈉溶液 溶解於10mLN，N-二曱基甲醯胺中，升至85°C攪拌反應3 小時。加入30mL水’用乙酸乙酯萃取（3〇mLx3)，合併有機 相’依次用水（20mLx2)，飽和氯化鈉溶液洗滌（2〇mLx2)， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜法以 展開劑體系B純化所得殘餘物，制標題產物 (U 5幻-3-(5-乙基錢|基）_6_[[5_(3_襄_4_〇比啶基）Will (1 brother 5Λ-6-[(5-bromooxazin-2-yl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 〇]hexane 12a (100 mg, 0. 27 mmol) '(3-gas ratio), boric acid (75 mg, 0.53 mmol), bis(triphenylphosphino) di-palladium (50 mg, 〇.〇 7 mmol) and lmL2 Μ sodium carbonate solution was dissolved in 10 mL of N,N-dimercaptocarhamamine, and the reaction was stirred for 3 hours at 85 ° C. Add 30 mL of water 'extracted with ethyl acetate (3 〇 mL x 3), and combine the organic phase' with water (20mLx2), washed with saturated sodium chloride solution (2〇mLx2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin-layer chromatography to afford the title product (U 5 illusion) -3-(5-ethylqan|yl)_6_[[5_(3_襄_4_〇比基基)

121 95344 201213319 吡嗪-2-基]氧甲基]-3-氮雜雙環並[3. L 〇]己烷23(7〇mg， 白色固體），產率：67. 3%。 MS m/z (ESI)： 393.2 [M+l] HNMR(400 MHz, CDCh) δ 8. 73-8. 72 (m, 1H), 8.58-8.51 (m, 2H), 8.37 (d, 1H), 8.18 (s, 2H), 8.00 (dd, 1H), 4.35 (d, 2H), 3.97 (d, 2H), 3.61-3.56 Cm, 2H), 2.48 (q, 2H), 1.80-1.76 (m, 2H), 1.31^1.26 (m, 1H), 1.19 (t, 3H). ^ 實施例24 -2-基）氧甲基]-3_氮雜雙環並[3. L 〇]己烷121 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. MS m/z (ESI): 393.2 [M+l] HNMR (400 MHz, CDCh) δ 8. 73-8. 72 (m, 1H), 8.58-8.51 (m, 2H), 8.37 (d, 1H) , 8.18 (s, 2H), 8.00 (dd, 1H), 4.35 (d, 2H), 3.97 (d, 2H), 3.61-3.56 Cm, 2H), 2.48 (q, 2H), 1.80-1.76 (m, 2H), 1.31^1.26 (m, 1H), 1.19 (t, 3H). ^ Example 24-2-yl)oxymethyl]-3_azabicyclo[3.L 〇]hexane

將（1尤550-64(5-溴吡嗪-2-基）氧甲基]_3_(5_乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1·〇]己烷12a(170mg， 〇.45mmol) ’ 嘧啶-5-基-硼酸（73mg，〇.59mmol)，二（三苯 膦基）二氣化鈀（35mg，0. 05mmol)和1. 5mL 2 Μ碳酸鈉溶液 溶解於6mLN，N-二甲基甲醯胺中，升至85°C攪拌反應5小 122 95344 201213319 時。加入30mL水，用乙酸乙酯萃取（30mLx3)’合併有機相， 依次用水（20mLx2) ’飽和氯化鈉溶液洗滌（20mLx2)，無水 硫酸鎂乾燥，過濾’濾液減壓濃縮，用矽膠管枉色譜法以 洗脫劑體系A純化所得殘餘物，得到標題產物 (1足55)-3-(5-乙基嘧啶-2-基）-6-[(5-嘧啶-5-基比啶 -2-基）氧曱基]-3-氮雜雙環並[3· ΐ·〇]己烷24(110mg，淡 黃色固體），產率：65. 0%。 MS m/z (ESI): 376.2 [M+l] • !H NMR (400 MHz, CDCh) δ 9.27 (s, 2H), 9.25 (s, 1H), 8. 53(d, 1H), 8. 36(d, 1H), 8. 17 (d, 2H), 4. 34 (d, 2H), 3.95 (d, 2H), 3.57 (d, 2H), 2.46 (q, 2H), 1.78-1.77 (m, 2H), 1.30-1.26 (m, 1H), 1.18 (t，3H). 實施例25 (1足55)-3-(5-乙基嘧啶-2-基）-6-[ [2-氟-4-(4-曱磺醯基 苯基）苯氧基]甲基]-3-氮雜雙環並[3.丨.〇]己烷Will (1 especially 550-64(5-bromopyrazin-2-yl)oxymethyl]_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·〇]hexane 12a(170mg, 〇.45mmol) 'Pyridine-5-yl-boronic acid (73mg, 〇.59mmol), bis(triphenylphosphino) dipalladium (35mg, 0.05mmol) and 1. 5mL 2 Μ sodium carbonate The solution was dissolved in 6 mL of N,N-dimethylformamide and raised to 85 ° C to stir the reaction at 5 hours 122 95344 201213319. Add 30 mL of water and extract with ethyl acetate (30 mL×3). Combine the organic phase, then use water (20 mL×2) The mixture was washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 3-(5-ethylpyrimidin-2-yl)-6-[(5-pyrimidin-5-ylpyridin-2-yl)oxyindolyl]-3-azabicyclo[3·ΐ·〇] Hexane 24 (110 mg, pale yellow solid), Yield: 65.0%. MS m/z (ESI): 376.2 [M+l] </ s> NMR (400 MHz, CDCh) δ 9.27 (s, 2H) , 9.25 (s, 1H), 8. 53(d, 1H), 8. 36(d, 1H), 8. 17 (d, 2H), 4. 34 (d, 2H), 3.95 (d, 2H) , 3.57 (d, 2H), 2.46 (q, 2H), 1.78-1.7 7 (m, 2H), 1.30-1.26 (m, 1H), 1.18 (t, 3H). Example 25 (1 foot 55)-3-(5-ethylpyrimidin-2-yl)-6-[ [ 2-fluoro-4-(4-oxasulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3.丨.〇]hexane

• 95344 201213319 第一步 2-氟-4-(4-曱磺醯苯基）苯酚 將 4-溴-2-氟-苯酚 25a(478mg，2. 50mmol)溶於 15mL 曱醇和水的混合溶劑中（V/V=4:l)，加入（4-曱磺醯笨基） 硼酸（1 g，5mmol)和碳酸鈉（269mg，2. 50mmol)，加入四三 苯基膦鈀（200mg ’ 0. 14mmol)，微波12(TC反應10分鐘。 依次加入50mL水和30mL乙酸乙酯，滴加1 Μ鹽酸至反應 液pH為3。過濾，濾液用乙酸乙酯萃取（3〇mLx3)，合併有 機相，用飽和氣化鈉溶液洗滌（3〇mL)，無水硫酸鎂乾燥，鲁 過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B 純化所得殘餘物，得到標題產物2-氟-4-(4-曱磺醯苯基） 苯酚25b(82mg，白色固體），產率：56. 1%。 MS ra/z (ESI): 284.1 [M+18] 第二步 (1足55^-3-(5-乙基喷e定-2-基）-6-[ [2-氟-4-(4-甲績酿基 苯基）笨氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷 將[(1尤55^-13-(5-乙基，咬-2-基）-3-氮雜雙環並 鲁 [3. 1. 0]己烧-6-基]甲續酸曱酯7g(ll〇mg，lmmol)和2-氟 -4-(4-甲確醯苯基）笨驗25b(133rag，0.50mmol)溶解於 10mLN，N-二曱基曱醯胺中，加入碳酸鉀（138mg，lmmol)， 升溫至100°C攪拌反應5小時。加入15raL水，用乙酸乙酿 萃取（30mLx3) ’合併有機相，無水硫酸鎮乾燥’過濾，濾 液減壓濃縮，用曱第三醚和甲醇（V/V = 50:1)混合溶劑洗 滌純化所得殘餘物，得到標題產物（1尤5 51) - 3 - (5 -乙基嘧咬 124 95344 201213319 -2-基）-6-[[2-氟-4-(4-曱磺醯基苯基）苯氧基]曱基]_3一 氮雜雙環並[3. 1.0]己烷25(135mg，白色固體），產率： 57.5%。 MS m/z (ESI): 468.2 [M+l] !H NMR (400 MHz, CDCh) 5 8. 18 (s, 2H), 7. 99 (d, 2H), 7.71 (d, 2H), 7.35-7.39 (m, 2H), 7.07 (t, 1H), 4.07 (d, 2H), 3.98 (d, 2H), 3.59 (d, 2H), 3. 10 (s, 3H), 2.47 (q, 2H), 1.79(s, 2H), 1. 25-1. 28 (m, 1H), 1. 19 (t, 3H).• 95344 201213319 First Step 2-Fluoro-4-(4-oxasulfonylphenyl)phenol 4-Bromo-2-fluoro-phenol 25a (478 mg, 2.50 mmol) was dissolved in 15 mL of a mixture solvent of decyl alcohol and water. (V/V=4:1), adding (4-oxasulfonyl) boronic acid (1 g, 5 mmol) and sodium carbonate (269 mg, 2.50 mmol), and adding tetrakistriphenylphosphine palladium (200 mg '0. 14mmol), microwave 12 (TC reaction for 10 minutes. Add 50 mL of water and 30 mL of ethyl acetate in turn, add 1 Μ hydrochloric acid to the reaction solution pH 3. Filter, extract the filtrate with ethyl acetate (3 〇mLx3), and combine the organic phase It was washed with a saturated sodium carbonate solution (3 mL), dried over anhydrous magnesium sulfate, and then filtered, and then filtered and evaporated. 4-(4-indolesulfonylphenyl) phenol 25b (82 mg, white solid), yield: 56.1%. MS / / (ESI): 284.1 [M+18] ^-3-(5-Ethyl eodyl-2-yl)-6-[ [2-fluoro-4-(4-methylphenyl)phenyl]oxy]methyl]-3-aza Bicyclo[3.1.0]hexane will [(1 especially 55^-13-(5-ethyl, guan-2-yl)-3-azabicyclohexene [3. 1. 0] hexane-6 -甲 曱 曱 7g (ll 〇 mg, lmmol) and 2-fluoro-4-(4-methyl phenyl phenyl) stupid 25b (133rag, 0.50mmol) dissolved in 10mL N, N-dimercaptopurine To the amine, potassium carbonate (138 mg, 1 mmol) was added, and the mixture was heated to 100 ° C and stirred for 5 hours. 15 raL of water was added, and extracted with acetic acid (30 mL×3), the organic phase was combined, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. Purification of the obtained residue by washing with a mixture solvent of hexanes and methanol (V/V = 50:1) to give the title product (1 especially 5 51) - 3 - (5 - ethyl pyrimidine 124 95344 201213319 -2- 6-[[2-fluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 25 (135 mg, white solid) Yield: 57.5%. MS m/z (ESI): 468.2 [M+l].H NMR (400 MHz, CDCh) 5 8. 18 (s, 2H), 7. 99 (d, 2H), 7.71 (d, 2H), 7.35-7.39 (m, 2H), 7.07 (t, 1H), 4.07 (d, 2H), 3.98 (d, 2H), 3.59 (d, 2H), 3. 10 (s, 3H ), 2.47 (q, 2H), 1.79(s, 2H), 1. 25-1. 28 (m, 1H), 1. 19 (t, 3H).

實施例26，27 ira/Js-Uay?, 6^5)-2-(5-乙基痛咬-2-基）-5-[2-氟-4-(4-甲 磺醯苯基）苯氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[c&gt;比咯 c/s-(3^?，6a«-2-(5-乙基嘧啶-2-基）-5-[2-氟-4-(4-甲磺 醯苯基）苯氧基]-3, 3本4, 5, 6, 6a-六氫-1H-環戊並[c&gt;比咯Example 26, 27 ira/Js-Uay?, 6^5)-2-(5-ethylheptan-2-yl)-5-[2-fluoro-4-(4-methanesulfonylphenyl) Phenoxy]-3,3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c&gt; ratio 咯c/s-(3^?,6a«-2-(5-ethylpyrimidine) -2-yl)-5-[2-fluoro-4-(4-methylsulfonylphenyl)phenoxy]-3,3,4,5, 6, 6a-hexahydro-1H-cyclopenta[ c&gt;

ί/·肌s-(3城 6Μ)-2-(5-乙基嘧啶-2-基）-5-[2-氟-4-(4-甲 磺醯苯基）苯氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[c&gt;比咯 〔/•5-(33/?，635&lt;)-2-（5-乙基痛唆-2-基）_5-[2-氟-4-(4-甲續 醯苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯 125 95344 201213319 將（3a)?, 6a«-5-溴-2-(5-乙基嘧啶-2-基）-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並比哈 3a(340mg， 1. 15mmol)和 2-氟-4-(4-甲磺酿苯基）笨紛 25b(300mg， 1· 13mm〇l)溶於30mL N，N-二曱基甲醯胺中，再加入碳酸鉀 (172mg，1· 24mmol)，升溫至60°C攪拌反應1小時，再升 溫至120°C擾拌反應1小時。加入50mL水，乙酸乙酯萃取 (30mLx3)，合併有機相，用飽和氣化鈉溶液洗滌（3〇mL)， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜 ® 法以洗脫劑體系B純化所得殘餘物，得到一對非對映異構 體，分別是6a5&gt;2〜（5-乙基嘧啶-2-基）-5-[2-氟-4-(4-甲磺醯苯基）笨氧基]_3, 3沒，4, 5, 6, 6a_ 六氫-1H-環戊並[c]吡咯26(54mg，白色固體），產率： 29.5%。635·)-2-(5-乙基嘧啶_2_基5一[2_氟 -4-(4-曱磺醯苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1Η-環 戊並[c]吡咯27(160mg，白色固體），產率：1〇 〇%。 • MS m/z (ESI): 482.2 [M+l] 26 4 NMR (400 MHz, CDC10 (5 8. 20 (s，2H)，8. 07-7.90 (m, 2H), 7.77-7.65 (m, 2H), 7.41-7.27 (m, 2H), 7.03 (t，1H)，5. 10-4. 93 3.75 (dd，2H)，3. 53 (dd， 2H)，3.09 (s，5H)，2.48 (q，2H)，2.32 (dd，2H)， 2.04-1.85 (m，2H)，1.19 (t，3H). 27 4 NMR (400 MHz，CDCh) ά 8. 19 (s，2H)，8. 02-7. 92 (m, 2H), 7.73-7.64 (m, 2H), 7.34-7.27 (m, 2H), 7.06-6.94 (m, 1H), 4.94 (s，in)，3 84 (dd，2H), 3.67 95344 126 201213319 (dd, 2H), 3.08 (s, 3H), 2.89 (d, 2H), 2.53-2.33 (m, 4H), 2.03-1.90 (m, 2H), 1.20 (t, 3H).ί/·肌s-(3C6Μ)-2-(5-ethylpyrimidin-2-yl)-5-[2-fluoro-4-(4-methylsulfonylphenyl)phenoxy]-3 , 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c&gt; than ole[/•5-(33/?,635&lt;)-2-(5-ethyl pain 唆-2- _5-[2-Fluoro-4-(4-methylindole phenyl)phenoxy]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole 125 95344 201213319 Will (3a)?, 6a«-5-bromo-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopentadol Ha 3a (340mg, 1. 15mmol) and 2-fluoro-4-(4-methanesulfonylphenyl) cumbersome 25b (300mg, 1.13mm〇l) dissolved in 30mL N,N-dimercaptocarboxamide Further, potassium carbonate (172 mg, 1.25 mmol) was further added, and the mixture was heated to 60 ° C to stir the reaction for 1 hour, and then heated to 120 ° C to disturb the reaction for 1 hour. Add 50 mL of water, and extract with ethyl acetate (30 mL×3). The organic phase is combined, washed with a saturated sodium carbonate solution (3 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure and washed with a silica gel column chromatography The obtained residue was purified by de-batch system B to give a pair of diastereomers, respectively 6a5 &gt; 2~(5-ethylpyrimidin-2-yl)-5-[2-fluoro-4-(4-methyl) Sulfonylphenyl) phenyloxy]_3,3,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole 26 (54 mg, white solid), yield: 29.5%. 635·)-2-(5-ethylpyrimidin-2-yl-5-[2-fluoro-4-(4-oxasulfonylphenyl)phenoxy]-3, 3a,4, 5, 6, 6a - hexahydro-1 fluorene-cyclopenta[c]pyrrole 27 (160 mg, white solid), yield: 1% mp.: MS m/z (ESI): 482.2 [M+l] 26 4 NMR (400 MHz , CDC10 (5 8. 20 (s, 2H), 8. 07-7.90 (m, 2H), 7.77-7.65 (m, 2H), 7.41-7.27 (m, 2H), 7.03 (t, 1H), 5 10-4. 93 3.75 (dd, 2H), 3.53 (dd, 2H), 3.09 (s, 5H), 2.48 (q, 2H), 2.32 (dd, 2H), 2.04-1.85 (m, 2H) ), 1.19 (t, 3H). 27 4 NMR (400 MHz, CDCh) ά 8. 19 (s, 2H), 8. 02-7. 92 (m, 2H), 7.73-7.64 (m, 2H), 7.34-7.27 (m, 2H), 7.06-6.94 (m, 1H), 4.94 (s, in), 3 84 (dd, 2H), 3.67 95344 126 201213319 (dd, 2H), 3.08 (s, 3H), 2.89 (d, 2H), 2.53-2.33 (m, 4H), 2.03-1.90 (m, 2H), 1.20 (t, 3H).

實施例28 (1及，551)-6-[ [2, 6-二氟-4-(3-氟-4-0比《定基）苯氧基]甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己院Example 28 (1 and 551)-6-[ [2,6-Difluoro-4-(3-fluoro-4-0-"predoxy)phenoxy]methyl]-3-(5-ethyl Pyrimidin-2-yl)-3-azabicyclo[3. 1. 〇]

將[(1 兄 55·)-6-[(4-溴-2, 6-二氟-苯氧基）甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3.1. 0]己烧8a(100mg， 0.24 mol)’（3-氟-4-吡啶基）硼酸（34mg，〇.24mmol)和 1，1 _一（一本膦基）二茂鐵二氯化纪（3. 50mg，0. Olmmol) 溶解於lOmLl，4-二噁烷中，再加入三水合填酸鉀 (191. 50mg，0· 72mmol)，升溫至回流攪拌反應5小時。過 濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B純化所 得殘餘物，得到標題產物（1疋5«-6-[[2, 6-二氟-4-(3-氟 -4-吡啶基）苯氧基]甲基]-3-(5-乙基嘧啶_2_基）_3_氮雜 雙環並[3· 1· 0]己烷28(60mg，白色固體），產率：57. 6%。 MS m/z (ESI)： 427.2 [M+l] 95344 127 201213319 'H NMR (400 MHz, CDCh) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.19 (s, 2H), 7.36-7.34 (m, 1H), 7.22 (d, 2H), 4.16 (d, 2H), 3.92 (d, 2H), 3. 57 (d, 2H), 2.47 (q, 2H), 1.74 (s, 2H), 1.20-1. 17 (in, 4H). 實施例29 (1尤551)-6-[[2,6-二氟-4-(4-曱磺醯基苯基）苯氧基]曱 基]-3-(5-丙基喊咬-2-基）-3-氮雜雙環並[3. 1· 0]己烧[(1 broth 55·)-6-[(4-bromo-2,6-difluoro-phenoxy)methyl]-3-(5-ethylpyrimidin-2-yl)-3-aza Bicyclo and [3.1. 0] hexane 8a (100 mg, 0.24 mol) of '(3-fluoro-4-pyridyl)boronic acid (34 mg, 〇.24 mmol) and 1,1 _(a phosphino) ferrocene Dichlorobenzene (3. 50 mg, 0. Olmmol) was dissolved in 10 mL of 4-dioxane, and potassium sulfate trihydrate (191.50 mg, 0·72 mmol) was added thereto, and the mixture was heated to reflux and stirred for 5 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to purified to afford titled product (1 疋5 «-6-[[2,6-difluoro-4-(3-fluoro-4) -pyridyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)_3_azabicyclo[3·1·0]hexane 28 (60 mg, white solid), yield : 57. 6% MS m/z (ESI): 427.2 [M+l] 95344 127 201213319 'H NMR (400 MHz, CDCh) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.19 (s , 2H), 7.36-7.34 (m, 1H), 7.22 (d, 2H), 4.16 (d, 2H), 3.92 (d, 2H), 3. 57 (d, 2H), 2.47 (q, 2H), 1.74 (s, 2H), 1.20-1. 17 (in, 4H). Example 29 (1 especially 551)-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl) Phenoxy]indenyl]-3-(5-propyl-chary-2-yl)-3-azabicyclo[3.1·0]hexa

將（1尤550-6-1^2, 6-二氟-4-(4-曱磺醯基苯基）苯氧 基]甲基]_3-氮雜雙環並[3. 1. 0]己烧19a(150mg， 0· 36mmol) ’ 2-氯-5-丙基-σ密咬（56mg，0. 36mmol)和碳酸卸 (149mg，1. lOmmol)溶於5mLN，N-二甲基曱醢胺中，升溫至 150°C擾拌反應8小時。冷卻，加入20mL水，用乙酸乙醋 萃取（10mLx3)，合併有機相，用飽和氯化銨溶液洗務 (10mLx5)，無水硫酸鎮乾燥，過濾，濾液減壓濃縮，用薄 層色譜法以展開劑體系B純化所得殘餘物，得到標題產物 (1^550-6-1^2, 6-二氟-4-(4-曱磺醢基苯基）苯氧基]甲 128 95344 201213319 基]_3-(5_丙基喊淀_2-基）-3_氛雜雙极並[3. 1. 0]己烧 29(100mg，白色固體），產率：55. 5%。 MS m/z (ESI): 500.2 [M+l] !H NMR (400 MHz, CDCh) δ 8.16 (s, 2H), 8.02 (q, 2H), 7.71(q, 2H), 7. 17 (d, 2H), 4. 14 (d, 2H), 3.90 (d, 2H), 3.56 (d, 2H), 3. 10(s, 3H), 2. 39 (t, 2H), 1.72(s, 2H), 1.59-1.53 (m, 2H), 1.24-1.21 (m, 1H), 0.93 (t, 3H). 實施例30 (1尤55·)-6-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]曱 基]-3-[3-氟-5-(三氟曱基）-2-°比啶基]-3-氮雜雙環並 [3. 1· 0]己烷Will (1 especially 550-6-1^2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]methyl]_3-azabicyclo[3.1.0] 19a (150mg, 0·36mmol) '2-chloro-5-propyl-σ-bite (56mg, 0.36mmol) and carbonic acid (149mg, 1.10mmol) dissolved in 5mL N,N-dimethylhydrazine In the amine, the temperature was raised to 150 ° C and the reaction was stirred for 8 hours. After cooling, 20 mL of water was added, and extracted with ethyl acetate (10 mL×3), the organic phase was combined, washed with saturated ammonium chloride solution (10 mL×5), dried over anhydrous sulfuric acid, Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel eluting to afford to afford the title product (1^550-6-1^2, 6-difluoro-4-(4-sulfonyl) Phenyl)phenoxy]methyl 128 95344 201213319 base]_3-(5_propyl sulphate_2-yl)-3_heterobipolar [3. 1. 0] hexane 29 (100 mg, white solid) ), Yield: 55. 5%. MS m/z (ESI): 500.2 [M+l] NMR (400 MHz, CDCh) δ 8.16 (s, 2H), 8.02 (q, 2H), 7.71 ( q, 2H), 7. 17 (d, 2H), 4. 14 (d, 2H), 3.90 (d, 2H), 3.56 (d, 2H), 3. 10(s, 3H), 2. 39 ( t, 2H), 1.72(s, 2H), 1.59-1.53 (m, 2H), 1.24-1.21 (m, 1H), 0.93 (t, 3H). Example 30 (1) 55·)-6-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-[3-fluoro-5-(trifluoromethyl) -2-°-pyridyl]-3-azabicyclo[3.1·0]hexane

將（1足5«-6-[[2,6-二氟-4-(4-曱磺醯基苯基）苯氧 基]曱基]-3-氮雜雙環並[3· 1.0]己烷19a(20mg ’ 0. 05mmol) ’ 三乙胺（12mg，0. 12mmol)溶解於 5mL 二氣曱院 中，冰浴下，滴加入2, 3-二氟-5-(三氟曱基）吡啶（9mg， 0. 05mmol)，升至室溫授拌反應2小時，再加入碳酸鉀 129 95344 201213319 (13mg，0. 10_1)，室溫攪拌12小時。過濾，濾液減壓濃 縮，用薄層色譜法以展開劑體系B純化所得殘餘物，得到 標題產物（1皮，55·)-6-[[2, 6-二氟-4-(4-曱橫醢基苯基）苯 氧基]曱基]-3-[3-氟-5-(三氟曱基）-2-〇比啶基]-3-氮雜雙 環並[3. 1. 0]己烷30 (20mg，白色固體），產率：76. 〇%。 MS m/z (ESI): 543.1 [M+l] 'H NMR (400 MHz, CDCh) δ 8. 17 (s, 1H), 8.03-8.01 (ra, 2H), 7.71 (q, 2H), 7.33-7.30 (m, 1H), 7.19 (d, 2H), 鲁 4. 14 (d, 2H), 4. 07-4. 04 (m, 2H), 3. 71 (d, 2H), 3. l〇 (s, 3H), 1.76 (d, 2H), 1.25-1.22 (m, 1H). 實施例31 4-[4-[ [ (1尤550-3-(5-乙基密咬-2-基）-3-氣雜雙環並 [3. 1·〇]己烷-6-基]甲氧基]-3, 5-二氟-苯基]苄腈.Will (1 foot 5«-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3·1.0] Alkane 19a (20 mg '0.05 mmol) 'Triethylamine (12 mg, 0.12 mmol) was dissolved in 5 mL of dioxane, and 2, 3-difluoro-5-(trifluoromethyl) was added dropwise in an ice bath. Pyridine (9 mg, 0.05 mmol) was stirred at room temperature for 2 hours, then added potassium carbonate 129 95344 201213319 (13 mg, 0. 10_1), stirred at room temperature for 12 hours, filtered, and concentrated. Chromatography Purification of the obtained residue in EtOAc EtOAc EtOAc (EtOAc: EtOAc曱]][3-fluoro-5-(trifluoromethyl)-2-indolyl]-3-azabicyclo[3.1.0]hexane 30 (20 mg, white solid) Yield: 76. 〇% MS m/z (ESI): 543.1 [M+l] 'H NMR (400 MHz, CDCh) δ 8. 17 (s, 1H), 8.03-8.01 (ra, 2H) , 7.71 (q, 2H), 7.33-7.30 (m, 1H), 7.19 (d, 2H), Lu 4. 14 (d, 2H), 4. 07-4. 04 (m, 2H), 3. 71 (d, 2H), 3. l〇(s, 3H), 1.76 (d, 2H), 1.25-1.22 (m, 1H). Example 31 4-[4-[ [ (1 especially 550-3-( 5-ethyl crypto-2-yl And gas -3- azabicyclo [3.1 · square] hexane-6-yl] methoxy] -3, 5-difluoro - phenyl] benzonitrile.

將[(17?，5«-6-[(4-溴-2,6-二氟-苯氧基）甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷8a(100mg， 〇. 24 mol)，（4-氰基苯基）硼酸（43mg，0. 29mmol)和 1，1，~ 130 95344 201213319 二（二苯膦基）二茂鐵二氯化鈀（17mg，〇· 〇2mmol)溶解於 lOmLl，4-二0惡烧中，再加入碳酸铯（238mg，0. 70mmol)，升 溫至120 C搜掉反應2小時。冷卻，加入20mL水，用乙酸 乙酯萃取（20mLx2) ’合併有機相’用飽和氯化鈉溶液洗滌 (10mLx2) ’無水硫酸鎂乾燥’過濾，濾液減壓濃縮，用薄 層色譜法以展開劑體系B純化所得殘餘物，得到標題產物 4 [4 [ [ (5vS)-3_(5_乙基响咬-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]曱氧基]-3, 5-二氟-苯基]节腈 φ 31(59mg，白色固體），產率：56. 0%。 MS m/z (ESI): 433.2 [M+l] !HNMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 7.73-7.75 (m, 2H), 7. 67-7. 63 (m, 2H), 7. 14-7. 16 (m, 2H), 4.13-4.15 (m, 2H), 3.88-3.91 (m, 2H), 3.55-3.57 (m, 2H), 2.44-2.49 (ra, 2H), 1.72 (d, 2H), 1.17-1.20 (m, 4H). 實施例32 4-[4-[[(1足550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1· 0]己烷-6-基]甲氧基]-3, 5-二氟-苯基]-2-氟-苄腈[(17?,5«-6-[(4-Bromo-2,6-difluoro-phenoxy)methyl]-3-(5-ethylpyrimidin-2-yl)-3-aza Bicyclo[3.1.0]hexane 8a (100 mg, 〇. 24 mol), (4-cyanophenyl)boronic acid (43 mg, 0.25 mmol) and 1,1,~130 95344 201213319 bis(diphenyl) Phosphono)ferrocene palladium dichloride (17 mg, 〇·〇 2 mmol) was dissolved in 10 mL of 1,2-dioxaldehyde, then cesium carbonate (238 mg, 0.70 mmol) was added, and the temperature was raised to 120 C. After cooling, add 20 mL of water, and extract with ethyl acetate (20 mL×2). &lt;&quot;&quot;&quot;&quot;&quot;&quot&&&&&&&&&&&&&&&&&&& The resulting residue was purified to give the title product 4 [4 [ [ (5vs) - 3 - (5-ethyl-b.). -6-yl] decyloxy]-3, 5-difluoro-phenyl] sulphononitrile φ 31 (59 mg, white solid), yield: 56.0%. MS m/z (ESI): 433.2 [M +l] !HNMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 7.73-7.75 (m, 2H), 7. 67-7. 63 (m, 2H), 7. 14-7. 16 (m, 2H), 4.13-4.15 (m, 2H), 3.88-3.91 (m, 2H), 3.55- 3.57 (m, 2H), 2.44-2.49 (ra, 2H), 1.72 (d, 2H), 1.17-1.20 (m, 4H). Example 32 4-[4-[[(1 foot 550-3-( 5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·0]hexane-6-yl]methoxy]-3, 5-difluoro-phenyl]-2-fluoro -benzonitrile

95344 131 20121331995344 131 201213319

第一步first step

(4-氰基-3-敦-苯基）硼酸 將2-(2-二曱胺基乙氧基）-N，N-二曱基-乙胺 (0. 5mL，2. 53mmol)溶於20mL四氫吱。南中，冰浴下，加入 2. 53mL2 Μ異丙基氯化鎂，攪拌20分鐘。再加入2-氟-4-碘-苄腈32a(500mg，2. 02 mol)，升溫至15°C反應2小時。 將反應液冷卻至0°C，再加入三異丙氧基硼烷（0. 9mL， 4. 05丽〇1)，升至室溫反應2小時。加入5mL 1 Μ鹽酸，用 乙酸乙S旨萃取（30mLx2)，合併有機相，無水硫酸納乾燥， 過濾，濾液減壓濃縮，得到標題粗產物（4-氰基-3-氟-苯基） 硼酸32b(310mg，黃色油狀），產物不經純化直接進行下一 步反應。 第二步 4-[4-[[(1尤5«-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]甲氧基]-3, 5-二氟-苯基]-2-氟-苄腈 將[(1尤5«-6-[(4-溴-2,6-二氟-苯氧基）曱 基]-3-(5 -乙基喊咬-2-基）-3 -氮雜雙環並[3. 1. 0]己院 8a(100mg，0· 24 mol)，粗品（4-氰基-3-氟-苯基）硼酸 32b(48mg，0. 30mmol)和 1，Γ -二（二苯膦基）二茂鐵二氣 132 95344 201213319 化鈀（18mg，0. 02mmol)溶解於l〇mLl，4-二噁烷中’再加入 碳酸铯（238mg’0.70mmol)，升溫至120°C攪拌反應2小時。 冷卻，加入20mL水，用乙酸乙酯萃取（2〇mLx2)，合併有機 相，用飽和氯化鈉溶液洗滌（l〇mLx2)，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B純化 所得殘餘物’得到標題產物4-[4-[[(1足550-3-(5-乙基喷 啶-2-基）-3-氮雜雙環並[3· 1. 0]己烷-6-基]甲氧基]-3,5-二氟-苯基]-2-氟-苄腈32(10mg，白色固體），產率：9.1%。 • MS m/z (ESI): 451.2 [M+l] !H NMR (400 MHz, CDCh) δ 8. 21 (s, 2H), 7. 69-7. 72 (m, 1H), 7.38-7.43 (m, 2H), 7. 14-7. 16 (ra, 2H), 4.13-4.16 (m, 2H), 3.96 (d, 2H), 3. 63 (d, 2H), 2.48-2.52 (m, 2H), 1.76 (d, 2H), 1.26 (d, 1H), 1.18-1.21 (m, 3H). 實施例33 (ly?, 5kS〇-3-（5 -乙基嘴淀-2-基）-6-[[4-（4-曱績酿苯基）笨 氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷(4-Cyano-3-d-phenyl)boronic acid 2-(2-didecylaminoethoxy)-N,N-didecyl-ethylamine (0.5 mL, 2.53 mmol) was dissolved 20 mL of tetrahydroanthraquinone. In the middle, under ice bath, add 2. 53 mL of 2 isopropyl isopropylmagnesium chloride and stir for 20 minutes. Further, 2-fluoro-4-iodo-benzonitrile 32a (500 mg, 2.02 mol) was added, and the mixture was heated to 15 ° C for 2 hours. The reaction solution was cooled to 0 ° C, and triisopropoxyborane (0.9 mL, 4.05 〇1) was added, and the mixture was allowed to react at room temperature for 2 hours. 5 mL of 1 hydrazine hydrochloride was added, and extracted with ethyl acetate (30 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product (4-cyano-3-fluoro-phenyl) boric acid 32b (310 mg, yellow oil), product was taken to the next step without purification. The second step is 4-[4-[[(1)5«-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl] Methoxy]-3, 5-difluoro-phenyl]-2-fluoro-benzonitrile [(1 especially 5«-6-[(4-bromo-2,6-difluoro-phenoxy)anthracene] ]]-3-(5-ethyl-challenyl-2-yl)-3-azabicyclo[3. 1. 0] hexyl 8a (100mg, 0·24 mol), crude (4-cyano- 3-fluoro-phenyl)boronic acid 32b (48 mg, 0.30 mmol) and 1, hydrazine-bis(diphenylphosphino)ferrocene dihide 132 95344 201213319 palladium (18 mg, 0.02 mmol) dissolved in l〇mLl , and then added cesium carbonate (238 mg '0.70 mmol) in 4-dioxane, and the mixture was heated to 120 ° C and stirred for 2 hours. After cooling, 20 mL of water was added, and the mixture was extracted with ethyl acetate (2 mL mL). It is washed with a saturated sodium chloride solution (10 mL mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and the residue obtained is purified by thin layer chromatography to afford the title product 4-[4-[[ (1 foot 550-3-(5-ethylpiperidin-2-yl)-3-azabicyclo[3·1.0]hexane-6-yl]methoxy]-3,5-di Fluoro-phenyl]-2-fluoro-benzonitrile 32 (10 mg, white solid), yield: 9.1%. MS m/z (ESI): 451.2 [M+l] !H NMR (400 MHz, CDCh) δ 8. 21 (s, 2H), 7. 69-7. 72 (m, 1H), 7.38-7.43 (m, 2H), 7. 14 -7. 16 (ra, 2H), 4.13-4.16 (m, 2H), 3.96 (d, 2H), 3. 63 (d, 2H), 2.48-2.52 (m, 2H), 1.76 (d, 2H) , 1.26 (d, 1H), 1.18-1.21 (m, 3H). Example 33 (ly?, 5kS〇-3-(5-ethyl-n-but-2-yl)-6-[[4-(4 - 酿 酿 phenyl) stupidoxy] methyl]-3-azabicyclo[3. 1. 0] hexane

133 95344 201213319133 95344 201213319

第一步 4-(4_曱磺醯基苯基）苯酚 將4-溴苯紛33a(100mg，〇. 58mmol)，（4-曱續醢基笨The first step 4-(4_nonylsulfonylphenyl)phenol 4-bromobenzene 33a (100mg, 〇. 58mmol), (4-曱 醢 笨 笨 笨

基）硼酸（127mg ’ 0. 64mmol)和1，1，—二（二苯鱗基）二茂鐵 二氯化I巴（42mg，0. 05mmol)溶解於i〇mL 14-二噪烧中， 再加入二水合礎酸钟（462mg ’ 1. 73mmol)，升溫至12(TC撥Boric acid (127 mg '0.64 mmol) and 1,1,-bis(diphenyl) ferrocene dichloride I bar (42 mg, 0.05 mmol) were dissolved in i〇mL 14-diode. Add the dihydrate acid clock (462mg ' 1.73mmol) and heat up to 12 (TC dial

拌反應2小時。加入25mL水，乙酸乙酯萃取（5〇mLx2)，合 併有機相。水相用5%氫氧化鈉溶液洗滌（i〇mL)，滴加3 Μ 鹽酸至反應液pH值為6至7，乙酸乙酯萃取（5〇mLx2)，合 併有機相’無水硫酸鎂乾燥’過濾，濾液減壓濃縮，得到 標題粗產物4-(4-曱續酿基苯基）苯酌 33b( 135mg，灰色固 體），產物不經純化直接進行下一步反應。 MS m/z (ESI): 266.1 [M+18] 第二步 (1疋550-3-(5-乙基嘧啶-2-基）-6-[ [4-(4-甲磺醯苯基）笨 氧基]曱基]-3-氮雜雙環並[3· 1.0]己烷 將[(1尤55·)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烧-6-基]甲績酸甲酯7g(l〇〇mg，0. 40mmol)和粗 品4-(4-甲磺醯基苯基）苯酚33b(120mg ’ 0. 40mmol)溶解 134 95344 201213319 於lOmLN’N-二曱基乙醢胺中，再加入碳酸鉋（262mg， 0.80mmol)，升溫至12(TC擾拌反應1〇小時◊加入25乩水， 乙酸乙醋萃取（20mLx3) ’合併有機相，用飽和氯化鈉溶液 洗務（10mLx3) ’無水硫酸鎮乾燥，過濾，濾液減壓濃縮， 用薄層色譜法以展開劑體系B純化所得殘餘物，得到標題 產物（1兄55)-3-(5-乙基癌咬-2-基）-6-[[4-(4-曱確醯苯 基）苯氧基]甲基]-3-氮雜雙環並[3. 1·〇]己烷33( 70mg，白 色固體），產率：38. 7%。 • MS m/z (ESI): 450.2 [M+l] !HNMR (400 MHz, CDCla) 5 8.21 (s, 2H), 7.97-7.99 (m, 2H), 7.73-7.74 (m, 2H), 7.55-7.57 (m, 2H), 7.00-7.02 (m, 2H), 4.00-4.03 (in, 4H), 3.62-3.65 (in, 2H), 3.09 (s, 3H), 2.46-2.52 (m, 2H), 1.79 (s, 2H), 1.24-1.26 (m，1H)，1. 18-1.23 (m，3H). 實施例34 ^ 5-[(lT?，5«-6-[[2,6-二氟-4-(4-甲磺醯基苯基）苯氧基] 曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基 -1，2, 4-°惡二°坐Mix and react for 2 hours. 25 mL of water was added, and ethyl acetate was extracted (5 〇 mL x 2), and the organic phase was combined. The aqueous phase was washed with 5% sodium hydroxide solution (i〇mL), 3 Μ hydrochloric acid was added dropwise until the pH of the reaction mixture was 6 to 7, ethyl acetate was extracted (5 〇mL×2), and the organic phase was dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; MS m/z (ESI): 266.1 [M+18] Step 2 (1疋550-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(4-methylsulfonylphenyl) ) oxy]] fluorenyl]-3-azabicyclo[3·1.0]hexane will [(1 especially 55·)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo And [3. 1. 0]hexa-6-yl]methyl acid methyl ester 7g (l〇〇mg, 0. 40mmol) and crude 4-(4-methylsulfonylphenyl)phenol 33b (120mg ' 0. 40mmol) Dissolved 134 95344 201213319 In 10 mL of N'N-dimercaptoacetamide, add carbonic acid planer (262 mg, 0.80 mmol), and warm to 12 (TC stir-fry reaction for 1 hour, add 25 乩 water, acetic acid Ethyl acetate extraction (20 mL x 3) 'The organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sulphuric acid, filtered, and the filtrate was concentrated under reduced pressure. The title product (1 brother 55)-3-(5-ethylcarban-2-yl)-6-[[4-(4-oxalylphenyl)phenoxy]methyl]-3-nitro Heterobicyclo[3.1·〇]hexane 33 (70 mg, white solid), yield: 38. 7%. • MS m/z (ESI): 450.2 [M+l] !HNMR (400 MHz, CDCla ) 5 8.21 (s, 2H), 7.97-7.99 (m, 2H), 7.73-7.74 ( m, 2H), 7.55-7.57 (m, 2H), 7.00-7.02 (m, 2H), 4.00-4.03 (in, 4H), 3.62-3.65 (in, 2H), 3.09 (s, 3H), 2.46- 2.52 (m, 2H), 1.79 (s, 2H), 1.24-1.26 (m, 1H), 1.18-1.23 (m, 3H). Example 34^ 5-[(lT?,5«-6- [[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane-3-yl]- 3-isopropyl-1,2, 4-°

135 95344 201213319135 95344 201213319

(1疋55〇-6-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己烷-3-甲腈 將（1疋55·)-6-[[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧 # 基]曱基]-3-氮雜雙環並[3. 1. 0]己烷19a(250mg， 0· 70mmol)和溴化氰（114mg，lmmol)溶解於10mL氯仿中， 再加入碳酸鉀（398mg，2. 50mmol)，升溫至回流攪拌反應 48小時。過濾，濾液減壓濃縮，得到標題粗產物 (1足55*)-6-[[2, 6-二氟-4-(4-曱確酿基苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1.0]己烷-3-曱腈34a(230mg，白色 固體），產物不經純化直接進行下一步反應。 • MS m/z (ESI): 422.1 [M+18] 第二步 5-[(1疋，55|)-6-[[2,6'~二氟-4-（4-甲續醢基苯基）苯氧基] 曱基]-3-氮雜雙環並[3. 1· 0]己烷-3-基]-3-異丙基 -1，2, 4-噁二唑 將（1兄55·)-6-[[2, 6-二氟-4-(4-甲磺醢基苯基）苯氧 基]曱基]-3-氮雜雙環並[3. 1. 〇]己烷-3二曱腈34a(200mg， 〇. 50 mol)和 Ν’ -羥基·2-甲基-丙脒（36mg，0.54mmol)溶 解於1 OmL四風α夫喃中，加入〇· 54mL 1Μ氯化辞的四氫夫〇南 136 95344 201213319 溶液’沉降15分鐘。將上述混合物溶於15mL 4M氯化氫的 乙醇和水的混合溶劑中（v/v = 1:1)，升溫至回流攪拌反應 1小時。加入過量的碳酸鈉中和反應，過濾’加入乙酸乙 酉旨20mL ’用飽和氯化鈉溶液洗滌（2〇mLx2)，無水硫酸鎂乾 燥’過遽，濾液減壓濃縮，用薄層色譜法以展開劑體系B 純化所得殘餘物’得到標題產物5_[〇尤5幻_6_[[2, 6_二 氟-4-(4-甲磺醯基苯基）苯氧基]甲基]_3一氮雜雙環並 [3. 1.0]己烷-3-基]-3-異丙基-1，2,4-噁二唑 34(102mg， • 白色固體），產率：42. 0%。 MS m/z (ESI)： 490.2 [M+l] WNMRUOOMHz，CDCh) (5 8.02-8.04 (m，2H)，7.70-7. 72 (m, 2H), 7.18-7.20 (in, 2H), 4.13-4.15 (m, 2H), 3.83-3.85 (in, 2H), 3.66-3.69 (in, 2H), 3.10 (s, 3H), 2.90-2.94 (m, 1H), 1.79 (s, 2H), 1.29-1.31 (m, 6H), 1.21 (s, 1H). 實施例35 4-[5-[ [(1疋55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己貌-6-基]曱氧基]-2-π比唆基]节腈(1疋55〇-6-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. 0] Hexane-3-carbonitrile will be (1疋55·)-6-[[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy#yl]indolyl]-3-nitrogen Heterobicyclo[3.1.0]hexane 19a (250 mg, 0·70 mmol) and cyanogen bromide (114 mg, 1 mmol) were dissolved in 10 mL of chloroform, then potassium carbonate (398 mg, 2.50 mmol) was added and the mixture was warmed to reflux. The reaction was stirred for 48 hours. Filtration and the filtrate was concentrated under reduced pressure to give the crude title compound (1.sup.5*)-6-[[2,6-difluoro-4-(4-indoleylphenyl)phenoxy] Benzyl]-3-azabicyclo[3.1.0]hexane-3-indanonitrile 34a (230 mg, white solid), product was taken to the next step without purification. MS m/z (ESI): 422.1 [M+18] The second step 5-[(1疋,55|)-6-[[2,6'~difluoro-4-(4-methyln-decylphenyl)phenoxy] fluorenyl] 3-Azabicyclo[3.1·0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole (1 brother 55·)-6-[[2 , 6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. oxime]hexane-3 dinitrile 34a (200 mg, 〇. 50 mol) and Ν'-hydroxy-2-methyl-prop (36 mg, 0.54 mmol) was dissolved in 10 mL of tetragen alpha fusole, and added to 54·54 mL of 1 Μ tetrahydrofuran 136 95344 201213319 solution 'sedimented for 15 minutes. The above mixture was dissolved in 15 mL of 4 M hydrogen chloride in ethanol. In a mixed solvent with water (v/v = 1:1), the mixture was heated to reflux and stirred for 1 hour. The reaction was neutralized by adding an excess of sodium carbonate, and filtered by adding 'acetic acid ethyl acetate 20 mL' to wash with a saturated sodium chloride solution (2) 〇mLx2), dried over anhydrous magnesium sulfate 'over hydrazine, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography to afford the title product 5 </ </ Fluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]_3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2, 4-oxadiazole 34 (102 mg, • white solid), yield: 40.0%. MS m/z (ESI): 490.2 [M+l] WNMRUOOMHz, CDCh) (5 8.02-8.04 (m, 2H) , 7.70-7. 72 (m, 2H), 7.18-7.20 (in, 2H), 4.13-4.15 (m, 2H), 3.83-3.85 (in, 2H), 3.66-3.69 (in, 2H), 3.10 ( s, 3H), 2.90-2.94 (m, 1H), 1.79 (s, 2H), 1.29-1.31 (m, 6H), 1.21 (s, 1H). Example 35 4- [5-[ [(1疋55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.]]]-]-6-yl]]oxy]- 2-π-pyrimidyl] nitrite

137 95344 201213319137 95344 201213319

將（1疋55·)-6-[(6-氯-3-°比啶基）氧曱基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. h 〇]己烷13a(13〇mg， 0. 39mmol) ’（4-氰基苯基）硼酸（75mg，〇. 51mm〇1)，二（三 參苯鱗基）二氣化把（l〇〇mg，〇. Ummol)和1. 5mL 2M碳酸鈉溶 液溶解於20mLN，N-二曱基甲醯胺中，升至85〇c攪拌反應 20小時。加入i〇〇mL水’用乙酸乙酯萃取（5〇mLx3)，合併 有機相，用飽和氣化鈉溶液洗滌（15mLx2)，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B 純化所得殘餘物’得到標題產物4-[5-[[( 1亿55)-3-(5-乙 基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烧-6-基]甲氧 φ 基]-2-吡啶基]苄腈35(109mg，白色固體），產率：70. 0%。 MS m/z (ESI): 398.2 [M+l] 】H NMR (400 MHz，CDCh) (5 8.40 (d，1H)，8· 17 (s，2H)， 8.05 (d, 2H), 7.71 (dd, 3H), 7.28 (dd, 1H), 4.00 (dd, 4H), 3.58 (d, 2H), 2.46 (q, 2H), 1.78 (s, 2H), 1.64 (s, 1H), 1.18 (t, 3H). 實施例36 (1A*，55·)-6-[(2, 6-二氟-4-痛咬-5-基-苯氧基）甲基]一3_ (5-乙基嘴咬-2-基）-3-氮雜雙環並[3. 1. 〇]己烧 95344 138 201213319(1疋55·)-6-[(6-chloro-3-°pyridyl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3 h 〇]hexane 13a (13〇mg, 0. 39mmol) '(4-cyanophenyl)boronic acid (75mg, 〇. 51mm〇1), bis(tris-benzene fluorenyl) di-gasification (l 〇〇mg, 〇. Ummol) and 1.5 mL of 2M sodium carbonate solution were dissolved in 20 mL of N,N-dimercaptocarbamide, and the mixture was stirred at 85 ° C for 20 hours. The mixture was extracted with ethyl acetate (5 mL mL), and the organic phase was combined, washed with saturated aqueous sodium chloride (15 mL×2), dried over anhydrous magnesium sulfate Purification of the residue obtained in the solvent system B afforded the title product 4-[5-[[(1,5,5,5)-3-(5-ethylpyrimidin-2-yl)-3- azabicyclo[3. 0 。 。 -6-6-yl] methoxy phthalyl]-2-pyridyl] benzonitrile 35 (109 mg, white solid), yield: 70. 0%. MS m/z (ESI): 398.2 [M+l]]H NMR (400 MHz, CDCh) (5 8.40 (d,1H),8·17 (s,2H), 8.05 (d, 2H), 7.71 ( Dd, 3H), 7.28 (dd, 1H), 4.00 (dd, 4H), 3.58 (d, 2H), 2.46 (q, 2H), 1.78 (s, 2H), 1.64 (s, 1H), 1.18 (t , 3H). Example 36 (1A*, 55·)-6-[(2,6-difluoro-4-glycyl-5-yl-phenoxy)methyl]-3_ (5-ethyl mouth Bite-2-yl)-3-azabicyclo[3. 1. 〇] hexane 95344 138 201213319

將[(1尤5«-6-[(4-溴-2,6-二氟-苯氧基）曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷8a(100mg，[(1 especially 5«-6-[(4-bromo-2,6-difluoro-phenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo And [3. 1. 0] hexane 8a (100mg,

0. 24 mol)，α密°定-5-基-硼酸（36mg，0. 29mmol)和 1，1’ -二（二苯膦基）二茂鐵二氯化鈀（18mg，0. 02mmol)溶解於 5mL 1，4-二噁烷和lmL水的混合溶劑中，升溫至120°C攪 拌反應8小時。加入20mL水，用乙酸乙酯萃取（20mLx3)， 合併有機相，用飽和氯化鈉溶液洗滌（5mLx3)，無水硫酸鈉 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 B純化所得殘餘物，得到標題產物（1尤5«-6-[(2,6-二氟 -4-嘧啶-5-基-苯氧基）曱基]-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1.0]己烷36(65mg，白色固體），產率：66.0%。 MS m/z (ESI): 410.2 [M+l] 丽R (400 MHz，CDC13) (5 9.20 (s，3H)，8.20 (s，2H)， 7.77 (d, 2H), 4. 12(d, 2H), 3.73 (d, 2H), 3. 44 (d, 2H), 2.40 (q, 2H), 1.71 (s, 2H), 1.11 (t, 3H), 0.90-0.89 (m, 1H). 實施例37 139 95344 201213319 3-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]_8_(5_乙基嘧 唆-2-基）-8-氮雜雙環並[3. 2· 1 ]辛烧0. 24 mol), α密定-5-yl-boronic acid (36 mg, 0.25 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (18 mg, 0.02 mmol) The mixture was dissolved in a mixed solvent of 5 mL of 1,4-dioxane and 1 mL of water, and the mixture was heated to 120 ° C and stirred for 8 hours. Add 20 mL of water, extract with ethyl acetate (20 mL×3), EtOAc (3 mL, EtOAc) The obtained residue was purified to give the title product (1,5,6--6-[(2,6-difluoro-4-pyrimidin-5-yl-phenoxy)indolyl]-3-(5-ethylpyrimidine- 2-Alkyl)-3-azabicyclo[3.1.0]hexane 36 (65 mg, white solid), yield: 66.0% MS m/z (ESI): 410.2 [M+l] MHz, CDC13) (5 9.20 (s, 3H), 8.20 (s, 2H), 7.77 (d, 2H), 4. 12(d, 2H), 3.73 (d, 2H), 3. 44 (d, 2H ), 2.40 (q, 2H), 1.71 (s, 2H), 1.11 (t, 3H), 0.90-0.89 (m, 1H). Example 37 139 95344 201213319 3-[2,6-Difluoro-4- (4-methylsulfonylphenyl)phenoxy]_8_(5-ethylpyrimidin-2-yl)-8-azabicyclo[3. 2·1 ]xin

第一步 3-[4-(4-甲續醢基苯基）-2, 6-二氣-苯氧基]-8-氮雜雙環 並[3.2.1]辛烷 將3-[2,6_二氟-4-(4-曱磺醯基苯基）苯氧基]—8_氮 雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯18(l〇〇mg， 0. 20mmol)溶解於2mL 2M氣化氫曱醇溶液，搜拌反應5小 時。反應液減壓濃縮，得到標題粗產物3_[4-(4-曱續醯基 苯基）-2, 6-二氟-苯氧基]-8-氮雜雙環並[3. 2. 1 ]辛烧 鲁 37a(85mg，白色固體），產物不經純化直接進行下一步反 應0 第二步 3-[2,6-二氟-4-(4-甲磺醯基苯基）苯氧基]-8_(5一乙基嘧 啶-2-基）-8-氮雜雙環並[3. 2· 1]辛烷 將粗品3-[4-(4-甲磺醯基苯基）-2, 6-二氟-苯氧基] -8-氮雜雙環並[3. 2. 1]辛燒 37a(85mg，0. 20 mol)，2-氯 140 95344 201213319 -5-乙基-嘧啶（42mg，0. 30mmol)和碳酸鉀（82mg，0. 60 mol) 溶解於3mL N，N-二甲基甲醯胺中，升溫至i〇(Tc攪拌反應 12小時。加入20mL水，用乙酸乙酯萃取（2〇mLx3)，合併 有機相，用飽和氣化鈉溶液洗滌（5mLx3)，無水硫酸鈉乾 燥’過濾’濾液減壓濃縮，用薄層色譜法以展開劑體系B 純化所得殘餘物’得到標題產物3-[2, 6-二氟-4-(4-曱磺 酿基苯基）苯氧基]-8-(5-乙基嘧啶-2-基）-8-氮雜雙環並 [3. 2· 1]辛烷37(35mg，白色固體），產率：34. 0%。 • MS m/z (ESI): 500.2 [M+l] 'H NMR (400 MHz, CDCh) δ 8. 26 (s, 2H), 7. 99 (t, 4H), 7. 67 (d, 2H), 4. 63 (s, 2H), 4. 58 (t, 1H), 3. 26 (s, 3H), 2.43 (q, 2H), 2.33 (d, 2H), 2.02-1.99 (m, 2H), 1.97-1.94 (m, 4H), 1.30-1.23 (m, 3H). 實施例38，39 c/s-(3a)P，6a5*)-5-[2-氟-4-[(4-甲磺醯基哌嗪-1-基）甲基] φ 苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並[c]吡咯_2-羧酸 第三丁酯 i/*a/?s-(3a兄 6^50-5-(:2-氟-4-[(4-甲磺醯基哌嗪-1-基）甲 基]苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]e比咯一2- 缓酸第三丁酯The first step 3-[4-(4-methyl-decylphenyl)-2,6-dioxa-phenoxy]-8-azabicyclo[3.2.1]octane will be 3-[2, 6_Difluoro-4-(4-oxasulfonylphenyl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 18 (l〇 〇mg, 0. 20mmol) was dissolved in 2mL of 2M gasified hydroquinone solution, and the reaction was mixed for 5 hours. The reaction mixture was concentrated under reduced pressure to give the crude title compound 3-[4-(4-indoleylphenyl)-2,6-difluoro-phenoxy]-8-azabicyclo[3.2.1] Xinshoulu 37a (85mg, white solid), the product was directly subjected to the next step without purification. The second step 3-[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy] -8_(5-ethylpyrimidin-2-yl)-8-azabicyclo[3. 2·1]octane will be crude 3-[4-(4-methylsulfonylphenyl)-2, 6 -difluoro-phenoxy]-8-azabicyclo[3.2.1]octane 37a (85 mg, 0.20 mol), 2-chloro 140 95344 201213319 -5-ethyl-pyrimidine (42 mg, 0. 30mmol) and potassium carbonate (82mg, 0. 60mol) dissolved in 3mL N,N-dimethylformamide, heated to i〇 (Tc stirred reaction for 12 hours. Add 20mL water, extracted with ethyl acetate (2 〇 mLx3), the organic phase was combined, washed with a saturated sodium sulphate solution (5 mL×3), dried over anhydrous sodium sulfate, filtered, filtered, and concentrated under reduced pressure. The product 3-[2,6-difluoro-4-(4-sulfonylsulfophenyl)phenoxy]-8-(5-ethylpyrimidin-2-yl)-8-azabicyclo[3] . 2·1]octane 3 7 (35 mg, white solid), Yield: 34.0%. MS m/z (ESI): 500.2 [M+l] 'H NMR (400 MHz, CDCh) δ 8. 26 (s, 2H), 7. 99 (t, 4H), 7. 67 (d, 2H), 4. 63 (s, 2H), 4. 58 (t, 1H), 3. 26 (s, 3H), 2.43 (q, 2H ), 2.33 (d, 2H), 2.02-1.99 (m, 2H), 1.97-1.94 (m, 4H), 1.30-1.23 (m, 3H). Example 38, 39 c/s-(3a)P, 6a5*)-5-[2-Fluoro-4-[(4-methylsulfonylpiperazin-1-yl)methyl] φ phenoxy]-3, 3a, 4, 5, 6, 6a-six Hydrogen-1Η-cyclopenta[c]pyrrole_2-carboxylic acid tert-butyl ester i/*a/?s-(3a brother 6^50-5-(:2-fluoro-4-[(4-A) Sulfopyryl piperazin-1-yl)methyl]phenoxy]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]e ratio 1- 2 Tributyl ester

141 95344 201213319141 95344 201213319

ΟΟ

15a 38a15a 38a

第一步 # 2-氟-4-[(4-甲磺醯基哌嗪-1-基）甲基]苯酚 肇 將粗品1-甲磺醯基哌嗪lf(4· 30g。，〇. 〇2mol)溶解於 40mL二氯乙烧中，加入3-氟-4-羥基-苯曱醛（3g，0. 〇2 mol) ’升至80°C攪拌反應2小時。冷卻至室溫’冰浴下， 加入乙醯基硼氫化鈉（8. 50g，0. 〇4mol)，升至80°C攪拌反 應3小時，再降至50°C反應12小時。降至室溫，冰浴下， 滴加100mL 10%氫氧化鈉溶液，滴加1〇%氯化氫溶液至反應 φ 液邱為7，二氣甲统萃取（100mLx3)，合併有機相，無水 硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物2_ Φ 氟一4-[(4-甲磺醯基哌嗪一 1—基）曱基]苯酚38a(3. 8〇 g，白 色固體），產物不經純化直接進行下一步反應。 MS m/z (ESI): 289.1 [M+l] 第二步 氟-4-[(4-甲磺醯基哌嗪4—基）曱基] 苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H_環戊並[c]吡咯_2_羧酸 第三丁酯 95344 142 201213319 6a5&quot;)-5-[2-氟-4-[ (4-曱石黃醯基α辰嗓-1-基）曱 基]笨氧基]-3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並[c]吡咯-2- 羧酸第三丁酯 將粗品2-氟-4-[(4-曱磺醯基哌嗪-1-基）甲基]苯酚 38a(200mg，0. 69mmol) -3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯-2-羧酸第三丁 酯 15a(200mg，0. 69mmol)溶於 5mL N，N-二甲基甲醢胺中， 再加入碳酸鉀（192mg，1. 39mmol)，升溫至150°C擾拌反應 ⑩ 4小時。加入10mL水，乙酸乙酯萃取（10mLx3)，合併有機 _ 相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用製備分離 法純化所得殘餘物，得到兩種是構型翻轉的異構體，分別 是6a«-5-[2-氟-4-[(4-曱磺醯基哌嗪-1-基） 曱基]苯氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯 -2-羧酸第三丁酯38(60mg，白色固體），產率：21. 0%。 65«-5-[2-氟-4-[(4-曱磺醯基哌嗪-1-基）曱 基]苯氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[(^&gt;比咯-2-羧酸第三丁酯39(10mg，白色固體），產率：3. 0%。 隹 MS m/z (ESI): 498.3 [M+l] 38 4 NMR (400 MHz, CDC13) 5 7. 07-7. 04 (m，1H)，6.94 (d, 1H), 6.85(t, 1H), 4. 84-4. 78 (m, 1H), 3. 57 (s, 2H), 3.46 (s, 2H), 3.38-3.36 (m, 2H), 3.26-3.23 (in, 3H), 2.78 (s, 3H), 2.70 (s, 2H), 2.55-2.53 (in, 4H) , 2.27 (s, 2H), 1.85 (s, 3H), 1.46 (s, 9H). 391!!丽R(400 MHz，CDC13) 5 7. 09-7. 05 (m，1H)，6.95 143 95344 201213319 (d, 1H), 6.86 (t, 1H), 4.91-4.89 (m, 1H), 3.52-3.47 Cm, 4H), 3.26-3.23 (m, 6H), 2.91 (s, 2H), 2.78 (s, 3H), 2.56-2.53 (in, 4H), 2. 24-2. 19 (m, 2H), 1.82-1.78 (m, 2H), 1.46 (s, 9H). 實施例40 4-[4-[[(33疋 63^-2-(5-乙基嘧啶-2-基）-3, 3a, 4, 5, 6, 6a-/、氫-1H-環戊並〇&gt;比咯-5-基]氧基]_3, 5_二氟_苯基]苯腈First step #2-Fluoro-4-[(4-methanesulfonylpiperazin-1-yl)methyl]phenol oxime will be crude 1-methanesulfonyl piperazine lf (4·30g., 〇. 〇 2 mol) was dissolved in 40 mL of dichloroethene, and 3-fluoro-4-hydroxy-phenylfurfural (3 g, 0. 〇 2 mol) was added. The reaction was stirred at 80 ° C for 2 hours. After cooling to room temperature in an ice bath, sodium acetoxyborohydride (8.50 g, 0.4 mol) was added, and the mixture was stirred at 80 ° C for 3 hours, and then reduced to 50 ° C for 12 hours. At room temperature, add 100 mL of 10% sodium hydroxide solution dropwise in an ice bath, add 1% by weight of hydrogen chloride solution to the reaction φ solution, Qiqiu 7, extract by two gas system (100mLx3), combine the organic phase, anhydrous magnesium sulfate Drying, filtration, and EtOAc EtOAc (EtOAc) The product was directly subjected to the next reaction without purification. MS m/z (ESI): 289.1 [M+l] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 6, 6a-hexahydro-1H_cyclopenta[c]pyrrole_2_carboxylic acid tert-butyl ester 95344 142 201213319 6a5&quot;)-5-[2-fluoro-4-[(4-曱石黄醯基α嗓 嗓-1-yl) fluorenyl] phenoxy]-3, 3a,4, 5, 6, 6a-hexahydro-1 fluorene-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2-fluoro-4-[(4-oxasulfonylpiperazin-1-yl)methyl]phenol 38a (200 mg, 0.69 mmol) -3, 3a, 4, 5, 6, 6a-hexahydro-1H - cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 15a (200 mg, 0.69 mmol) was dissolved in 5 mL of N,N-dimethylformamide, then potassium carbonate (192 mg, 1.39 mmol) ), the temperature was raised to 150 ° C and the reaction was stirred for 10 4 hours. After adding 10 mL of water and ethyl acetate (10 mL×3), the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative separation to obtain two isomers which were inverted. 6a«-5-[2-Fluoro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-3, 3a, 4, 5, 6, 6a-six Hydrogen-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 38 (60 mg, white solid), yield: 21. 0%. 65«-5-[2-Fluoro-4-[(4-oxasulfonylpiperazin-1-yl)indolyl]phenoxy]-3, 3a, 4, 5, 6, 6a-hexahydro- 1H-cyclopenta[(^&gt; tert-butan-2-carboxylic acid tert-butyl ester 39 (10 mg, white solid), yield: 3. 0%. 隹MS m/z (ESI): 498.3 [M+ l] 38 4 NMR (400 MHz, CDC13) 5 7. 07-7. 04 (m, 1H), 6.94 (d, 1H), 6.85(t, 1H), 4. 84-4. 78 (m, 1H ), 3. 57 (s, 2H), 3.46 (s, 2H), 3.38-3.36 (m, 2H), 3.26-3.23 (in, 3H), 2.78 (s, 3H), 2.70 (s, 2H), 2.55-2.53 (in, 4H), 2.27 (s, 2H), 1.85 (s, 3H), 1.46 (s, 9H). 391!! Li R (400 MHz, CDC13) 5 7. 09-7. 05 ( m,1H), 6.95 143 95344 201213319 (d, 1H), 6.86 (t, 1H), 4.91-4.89 (m, 1H), 3.52-3.47 Cm, 4H), 3.26-3.23 (m, 6H), 2.91 ( s, 2H), 2.78 (s, 3H), 2.56-2.53 (in, 4H), 2. 24-2. 19 (m, 2H), 1.82-1.78 (m, 2H), 1.46 (s, 9H). Example 40 4-[4-[[(33疋63^-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 6a-/, hydrogen-1H-cyclopentane 〇&gt;Byr-5-yl]oxy]_3,5-difluoro-phenyl]benzonitrile

將粗品（3a7?，63^-5-(4-溴-2, 6-二氟-苯氧基）-2- (5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]The crude product (3a7?, 63^-5-(4-bromo-2,6-difluoro-phenoxy)-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]

0比咯 4a(210mg ’ 0. 50mol)，（4-氰基苯基）硼酸（ii〇mg ’ 0· 75咖〇1)和1，1，-二（二苯膦基）二茂鐵二氯化鈀（36mg， 0.05111111〇1)溶解於2〇1111^1，4-二°惡烧中’升溫至12〇。(；授掉 反應3小時。過濾，加入20mL水’用乙酸乙酯萃取 (50mLx3) ’合併有機相，無水硫酸鈉乾燥，過濾，，渡液減 壓濃縮’用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘 物，得到標題產物4-[4-[[(3a尤6a«“2-(5-乙基咳咬_2_ 基）_3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c] 各—5-基]氧 基]-3, 5-二氟-苯基]苯腈40(80mg，白色固體），產率 95344 144 201213319 36. 4%。 MS m/z (ESI): 447.2 [M+l] ^ NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 7.72 (d, 2H), 7.59 (d, 2H), 7.09-7.14 (m, 2H), 4.93-4.96 (m, 1H), 3.82-3.87 (m, 2H), 3.69-3.73 (in, 2H), 2.84-2.87 (in, 2H), 2.49 (q, 2H), 2.33-2.36 (m, 2H), 1.97-2.02 (m, 2H), 1.21 (t, 3H). 實施例41 • 9-[2’ 6_二氟-4—(4-曱磺醯基苯基）苯氧基]-3-(5-乙基嘧修 咬-2-基）7-氧雜-3-氮雜雙環並[3. 3. 1]壬烷0 to 4a (210 mg '0.50 mol), (4-cyanophenyl)boronic acid (ii〇mg '0·75 curry 1) and 1,1,-bis(diphenylphosphino)ferrocene Palladium chloride (36 mg, 0.05111111〇1) was dissolved in 2〇1111^1,4-dioxacin' to raise the temperature to 12〇. The reaction was allowed to stand for 3 hours. Filtration and addition of 20 mL of water was extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified to give the title product 4-[4-[[(3a s. 6a) "2-(5-ethyl cough _2 yl) _3, 3a, 4, 5, 6, 6a- Hydrogen-1H-cyclopenta[c]-(5-yl)oxy]-3,5-difluoro-phenyl]benzonitrile 40 (80 mg, white solid), yield: 95344 144. MS m/z (ESI): 447.2 [M+l] NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 7.72 (d, 2H), 7.59 (d, 2H), 7.09-7.14 (m, 2H), 4.93-4.96 (m, 1H), 3.82-3.87 (m, 2H), 3.69-3.73 (in, 2H), 2.84-2.87 (in, 2H), 2.49 (q, 2H), 2.33-2.36 ( m, 2H), 1.97-2.02 (m, 2H), 1.21 (t, 3H). Example 41: 9-[2' 6-difluoro-4-(4-oxasulfonylphenyl)phenoxy ]-3-(5-Ethylpyrimidin-2-yl)7-oxa-3-azabicyclo[3.3.1]decane

第一步 7-氧雜-3-氮雜雙環並[331]壬_9_醇 將3-节基+氧雜-3-氮雜雙環並[3 31]壬一9_醇他First step 7-oxa-3-azabicyclo[331]indole-9-ol will be 3-mercapto +oxa-3-azabicyclo[3 31]indole-9-ol

製借8 Μ&quot;1&quot;1。1’採用公知的方法“專利W02G1G_195” 脅而得）溶解於30fflL甲醇中，加入氫氧減（i.8ig， 95344 145 201213319 2· 57mmol) ’置換氫氣3次，攪拌反應12小時。過濾，遽 液減壓濃縮，得到粗品標題產物7-氧雜-3-氮雜雙環並 [3. 3. 1]壬-9-醇41a(l. 38g，棕色液體），產物不經純化直 接進行下一步反應。 MS m/z (ESI): 144.1 [M+l] 第二步 3-(5-乙基嘧啶-2-基）-7-氧雜-3-氤雜雙環並[3. 3. i]壬 -9-醇 鲁 將粗品7-氧雜-3-氮雜雙環並[3.3. 1]壬-9-醇41a (1. 23g，8· 57mmol)溶解於20mL乙二酸二曱酯中，加入2-氣-5-乙基嘧啶（1. 23g，8. 57mmol)和碳酸鉀（1. 78g， 12. 86mmol) ’ 150°C攪拌反應7小時。加入水30mL，用乙 酸乙酯萃取（50mLx3)，合併有機相，用飽和氣化鈉溶液洗 滌（30mL)，無水硫酸鎂乾燥，過濾’濾液減壓濃縮，得到 粗品標題產物3-(5-乙基嘧啶-2-基）-7-氧雜-3-氮雜雙環 • 並[3.3. 1]壬-9-醇41b(1.26 g，黃色油狀），產物不經純 化直接進行下一步反應。 MS m/z (ESI): 250.2 [M+l] 第三步 [3-(5-乙基嘧啶-2-基）-7-氧雜_3-氮雜雙環並[3. 3. 1]壬 -9-基]甲基磺酸酯 冰浴下，將粗品3-(5-乙基β密咬一2-基）-7-氧雜-3-氮 雜雙環並[3. 3. 1]壬-9-醇 41b(l· 26g，5· 05mmol)溶解於 50mL二氣甲烷中，加入三乙胺（1. 02g，10. lOmmol)，滴加 146 95344 201213319 曱石黃醯氯（0. 87g，7. 58mmol)，升至室溫，反應2小時。加 入水10mL，用二氣曱烷萃取（20mLx3)，合併有機相，用飽 和氣化鈉溶液（30mL)洗務，無水硫酸鎮乾燥，過遽，濾液 減壓濃縮’得到粗品標題產物[3 - ( 5 -乙基嘴唆-2 -基）- 7 -氧雜-3-氮雜雙環並[3.3. 1]壬-9-基]曱基磺酸酯41c (0.71 g，黃色油狀），產物不經純化直接進行下一步反應。 MS m/z (ESI): 328.1 [M+l] 第四步 • 9-(4_溴-2, 6-二氟-苯氧基）-3-(5-乙基嘧啶-2-基）_7_氧 籲 雜-3-氮雜雙環並[3. 3. 1]壬烷 將粗品[3-(5-乙基嘧啶-2-基）-7-氧雜-3-氮雜雙環 並[3.3. 1]壬-9-基]甲基續酸西旨 41c(500mg，1. 53mmol)， 4-溴-2, 6-二氟-苯盼（350mg ’ 1. 68mmol)和碳酸鉀（420mg， 3. 05mmol)溶解於20mL术二曱基曱醯胺中，升溫至150 °C擾拌反應7小時。加入50mL水，用乙酸乙S旨萃取 (50mLx3)，合併有機相，用飽和氣化納溶液洗條（50mL)， ^ ® 無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜 法以洗脫劑體系B純化所得殘餘物，得到標題產物9-(4-漠-2,6-二I-苯氧基）-3-(5 -乙基^密鳴^-基）-7-氧雜-3-氮雜雙環並[3.3.1]壬烷41(1(20〇11^，淡黃色固體），產率： 29.9%。 MS m/z (ESI): 440.1 [M+l] 第五步 9-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]-3-(5-乙基嘧 147 95344 201213319 咬-2-基）7-氧雜-3-氮雜雙環並[3.3. 1]壬烷 將9 (4漠-2, 6-一氟-苯氧基）-3-(5-乙基嚷咬-2-基） -7-氧雜-3-氮雜雙環並[3. &amp;丨]壬烷41d(5〇mg，〇. llmm〇1)， (4-甲石頁醯基苯基）硼酸（28mg ’ ΐ4_〇ι)和i，i，-二（二 苯膦基）二茂鐵二氣化把（5mg，0. OlmmoL)溶解於5mLl, 4-一噁烧中，再加入墙酸钟（47mg，〇· 22mmol)，升溫至120 C攪拌反應5小時。加入i〇mL水，乙酸乙酯萃取（2〇mLx3)， 合併有機相，飽和氣化鈉溶液洗滌（2〇mL)，無水硫酸鎂乾 • 燥，過濾，濾液減壓濃縮，製備純化所得殘餘物，得到標 題產物9-[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]-3-(5_ 乙基°密啶-2-基）7-氧雜-3-氮雜雙環並[3. 3. 1]壬烷41 (22mg，白色固體），產率：39.3%。 MS m/z (ESI)： 454.1 [M-55] ^NMR (400 MHz, CDCh) δ 8.13-8.22 (ra, 2H), 8.02-8.04 (in, 2H), 7.70-7.73 (m, 2H), 7.18-7.23 (ra, 2H), 5.07-5.11 (in, 1H), 4.77-4.80 (m, 1H), 4.63-4.66 (m, 1H), 4.31-4.34 (m, 1H), 4.17-4.20 (m, 1H), 3.87-3.90 (m, 1H), 3.71-3.78 (m, 2H), 3.28-3.32 (m, 1H), 3.11 (s, 3H), 2.44-2.50 (m, 2H), 2.20 (s, 1H), 0.96 (s, 1H), 1. 17-1.20 (m, 3H). 實施例42 3-[[2, 6-二敦-4-(4-甲續酿基苯基）苯氧基]曱基]-8-氮雜 雙環並[3·2. 1]辛烷-8-羧酸第三丁酯 148 95344 201213319Borrowing 8 Μ&quot;1&quot;1.1' is obtained by using the well-known method "patent W02G1G_195") dissolved in 30fflL methanol, adding hydrogen and oxygen minus (i.8ig, 95344 145 201213319 2·57mmol) 'replacement hydrogen 3 times The reaction was stirred for 12 hours. Filtration and concentrating under reduced pressure afforded the crude title product 7-oxa-3-azabicyclo[3.3.1]--9-ol 41a (l. 38 g, brown liquid) Carry out the next reaction. MS m/z (ESI): 144.1 [M+l] Step 2 3-(5-ethylpyrimidin-2-yl)-7-oxa-3-indolebicyclo[3. 3. i] -9-Alcohol The crude 7-oxa-3-azabicyclo[3.3.1]non-9-ol 41a (1. 23 g, 8.57 mmol) was dissolved in 20 mL of dinonyl oxalate and added. 2-Gapent-5-ethylpyrimidine (1.23 g, 8.57 mmol) and potassium carbonate (1.78 g, 12.86 mmol) were stirred at 150 ° C for 7 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, washed with a saturated sodium sulfate solution (30 mL), dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give crude title product 3-(5-B Pyrimidin-2-yl)-7-oxa-3-azabicyclo-[3.3.1]non-9-ol 41b (1.26 g, yellow oil). MS m/z (ESI): 250.2 [M+l]. Step 3 [3-(5-ethylpyrimidin-2-yl)-7-oxa~3-azabicyclo[3.3.1]壬-9-yl]methanesulfonate, the crude 3-(5-ethylβ-density 2-yl)-7-oxa-3-azabicyclo[3.3.1 1 ] 壬-9-ol 41b (1·26g, 5· 05mmol) was dissolved in 50mL of di-methane, added triethylamine (1. 02g, 10.10mmol), and added 146 95344 201213319 曱石黄醯氯 (0 87 g, 7.58 mmol), warmed to room temperature and allowed to react for 2 hours. 10 mL of water was added, and the mixture was extracted with dioxane (20 mL×3). The organic phase was combined, washed with saturated sodium sulfate (30 mL), dried over anhydrous sulphuric acid, and the filtrate was concentrated under reduced pressure to give crude title product [3 - (5-Ethylhydrazine-2-yl)-7-oxa-3-azabicyclo[3.3.1]fluoren-9-yl]decyl sulfonate 41c (0.71 g, yellow oil) The product was directly subjected to the next reaction without purification. MS m/z (ESI): 328.1 [M+l] Step 4: 9-(4-bromo-2,6-difluoro-phenoxy)-3-(5-ethylpyrimidin-2-yl) _7_oxooxa-3-azabicyclo[3.3.1]nonane will be crude [3-(5-ethylpyrimidin-2-yl)-7-oxa-3-azabicyclo[ 3.3. 1]壬-9-yl]methyl-reductive acid 41c (500mg, 1.53mmol), 4-bromo-2,6-difluoro-benzene (350mg ' 1.68mmol) and potassium carbonate (420mg , 3. 05 mmol) was dissolved in 20 mL of dimethyl decylamine, and the temperature was raised to 150 ° C to disturb the reaction for 7 hours. Add 50mL of water, extract with ethyl acetate (50mLx3), combine the organic phase, wash the strip with saturated sodium hydride solution (50mL), dry with anhydrous sodium sulfate, filter, filtrate concentrate under reduced pressure, using gel column chromatography The obtained residue was purified to give the titled product 9-(4-di-2,6-di-I-phenoxy)-3-(5-ethyl) Oxy-3-azabicyclo[3.3.1]nonane 41 (1 (20 〇 11^, pale yellow solid), yield: 29.9%. MS m/z (ESI): 440.1 [M+l] The fifth step is 9-[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]-3-(5-ethylpyrimidine 147 95344 201213319 biti-2-yl) 7-oxo Hetero-3-azabicyclo[3.3.1]decane will be 9 (4-indol-2,6-fluoro-phenoxy)-3-(5-ethylindole-2-yl)-7- Oxa-3-azabicyclo[3. &amp;丨]decane 41d (5〇mg, 〇. llmm〇1), (4-methylsulfonylphenyl)boronic acid (28mg ' ΐ4_〇ι And i,i,-bis(diphenylphosphino)ferrocene di-gasification (5mg,0. OlmmoL) was dissolved in 5mLl, 4-monomethane, and then added to the wall acid clock (47mg, 〇·22mmol) ), the temperature was raised to 120 C and the reaction was stirred for 5 hours. i〇mL water was added, and ethyl acetate was added. (2 〇 mLx3), the organic phase was combined, washed with a saturated aqueous sodium chloride solution (2 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the purified residue to give the title product 9-[2, 6-Difluoro-4-(4-oxasulfonylphenyl)phenoxy]-3-(5-ethyl-[upperidine-2-yl)7-oxa-3-azabicyclo[3. 3. 1] decane 41 (22 mg, white solid), yield: 39.3%. MS m/z (ESI): 454.1 [M-55] NMR (400 MHz, CDCh) δ 8.13-8.22 (ra, 2H ), 8.02-8.04 (in, 2H), 7.70-7.73 (m, 2H), 7.18-7.23 (ra, 2H), 5.07-5.11 (in, 1H), 4.77-4.80 (m, 1H), 4.63-4.66 (m, 1H), 4.31-4.34 (m, 1H), 4.17-4.20 (m, 1H), 3.87-3.90 (m, 1H), 3.71-3.78 (m, 2H), 3.28-3.32 (m, 1H) , 3.11 (s, 3H), 2.44-2.50 (m, 2H), 2.20 (s, 1H), 0.96 (s, 1H), 1. 17-1.20 (m, 3H). Example 42 3-[[2 , 6-Dutung-4-(4-methyl-bromophenyl)phenoxy]indolyl]-8-azabicyclo[3·2.1]octane-8-carboxylic acid tert-butyl ester 148 95344 201213319

第一步first step

3-氧-8-氮雜雙環並[3.2. 1]辛烷-8-羧酸第三丁酯 將3-羥基-8-氮雜雙環並[3.2. 1]辛烷-8-羧酸第三丁 酯9b(5g，21. 90mmol)溶解於50mL二氯甲烧中，加入氣鉻 酸吡啶（7. 10g，32. 90mmol)，室溫攪拌反應12小時。過濾， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所 得殘餘物，得到標題產物3-氧-8-氮雜雙環並[3. 2. 1]辛烷 -8-羧酸第三丁酯42a(4· 50 g，淡綠色固體），產率：91. 0%。 MS m/z (ESI)： 170.1 [M-55] 第二步 3-亞甲基-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁酯 冰浴下’將1M第三丁醇鉀的四氫呋喃溶液19. 8mL加 入至100mL含曱基三苯基溴化膦（7. 142，19. 8〇111〇1)的四氫 呋喃溶液中，攪拌1小時，再加入3_氧_8_氮雜雙環並 [3. 2· 1]辛烷-8-羧酸第三丁酯 42a(3g，13. 30mol) ’ 缓慢 95344 149 201213319 升至室溫攪拌反應12小時。加入50mL水，用乙酸乙酯萃 取（30mLx3)，合併有機相，有機相依次用水（10mLx3)，飽 和氯化鈉溶液洗務（10mLx3)，無水硫酸鈉乾燥，過濾，濾 液減壓濃縮，得到粗品標題產物3-亞甲基-8-氮雜雙環並 [3. 2. 1]辛烷-8-羧酸第三丁酯42b(2. 30 g，無色液體）， 產物不經純化直接進行下一步反應。 第三步 3-（羥基甲基）-8-氮雜雙環並[3. 2. 1]辛烷-8-羧酸第三丁3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid Tributyl ester 9b (5 g, 21.90 mmol) was dissolved in 50 mL of methylene chloride, pyridine (2. 10 g, 32.90 mmol) was added, and the reaction was stirred at room temperature for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc. 0%。 The acid tert-butyl ester 42a (4 · 50 g, pale green solid), yield: 91.0%. MS m/z (ESI): 170.1 [M-55] Step 2 3-Methylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester under ice bath '1 mL of 1 M potassium butoxide potassium tetrahydrofuran solution was added to 100 mL of a solution containing decyltriphenylphosphonium bromide (7. 142, 19.8 〇 111 〇 1) in tetrahydrofuran, stirred for 1 hour, and then added 3_Oxygen_8_azabicyclo[3. 2·1]octane-8-carboxylic acid tert-butyl ester 42a (3 g, 13.30 mol) ' Slow 95344 149 201213319 The reaction was stirred at room temperature for 12 hours. Add 50 mL of water, and extract with ethyl acetate (30 mL×3). The organic phase is combined, and the organic phase is washed with water (10 mL×3) The title product is 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 42b (2. 30 g, colorless). One step reaction. The third step 3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tertidine

醋 ⑩ 冰浴下，將1 Μ硼烷的四氫呋喃溶液6. 2mL加入至l〇mL 粗品3-亞曱基-8-氮雜雙環並[3·2. 1]辛烷_8_羧酸第三丁 酯42b(lg，4. 76mol)的四氫呋喃溶液，緩慢升至室溫攪拌 反應12小時。緩慢加入5mL水，再加入14mL2M氫氧化鈉 洛液和7mL30%過氧化氫溶液，反應液加熱至5〇〇c，攪拌i 小時。ms旨萃取（3()mLx3) ’合併有機相，有機相依 次用水（1〇mLx3)，飽和氯化納溶液⑽⑽洗條，無水硫 酸納乾燥’過濾、’渡液減壓濃縮，得到粗品標題產物3-(經· 基甲基）_8_氮雜雙環並[3· 2.1]辛18-紐第三丁醋 42c(〇.81 g ’無色液體），產物不經純化直接進行下一步 第四步 2. 1]辛燒-8-繞酸 3'(曱顧氧基甲基）〜8_氮雜雙環並[3. 第三丁酯 冰浴下’將粗* 3'⑽基甲基）1氮雜雙環並[3 21] 95344 150 201213319In a vinegar 10 ice bath, 6. 2 mL of a 1 Μ borane in tetrahydrofuran solution was added to 10 mL of crude 3-mercapto-8-azabicyclo[3.2] octane _8-carboxylic acid A solution of tributyl ester 42b (lg, 4.76 mol) in tetrahydrofuran was slowly stirred to room temperature and stirred for 12 hours. Slowly add 5 mL of water, then add 14 mL of 2M sodium hydroxide solution and 7 mL of 30% hydrogen peroxide solution. The reaction solution was heated to 5 ° C and stirred for 1 hour. Ms extract (3 () mL x 3) 'The organic phase was combined, the organic phase was washed with water (1 〇 mL x 3), saturated sodium chloride solution (10) (10), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title. The product 3-(carbylmethyl)_8-azabicyclo[3.2.1]octyl 18-nuclear butyl vinegar 42c (〇.81 g 'colorless liquid), the product was directly subjected to the next step without purification. Step 2. 1] octyl-8-acid 3' (reacting oxymethyl) ~8_azabicyclo[3. The third butyl ester under ice bath will be thick * 3 '(10) methyl) 1 azabicyclo[3 21] 95344 150 201213319

辛烷-8-羧酸第三丁酯42c(500mg，2. 19mmol)溶解於5mL 無水二氯甲烧中’加入三乙胺（663mg，6. 57mmol)，滴加入 甲磺醯氣（300mg，2_ 63mmol)，升至室溫攪拌反應12小時。 加入1 OmL水，有機相依次用1Μ鹽酸（5mLx3 )，飽和氣化鈉 溶液洗滌（5mLx3) ’無水硫酸鎮乾燥，過濾，濾液減壓濃縮， 得到粗品標題產物3_(甲續蕴氧基曱基），8-氮雜雙環並 [3.2.1]辛烷-8-羧酸第三丁酯42(1(62〇11^，無色液體），產 物不經純化直接進行下一步反應。 • 第五步 3-[(4-溴-2, 6-二氟-苯氧基）曱基]-8-氮雜雙環並[3. 2. 1] 辛烷-8-羧酸第三丁酯 將粗品3-(曱磺醯氧基曱基）-8-氮雜雙環並[3. 2. 1] 辛烧-8-竣酸第三丁醋424(60〇111运，1.88111111〇1)和4-溴-2,6-二氟-苯酚（469mg，2. 25mmol)溶解於5mL乙二酸二曱酯 中，再加入碳酸鉀，5. 64mmol)，升溫至i5〇t：擾拌 反應4小時。加入20mL水’用乙酸乙酯萃取（2〇mLX3)，合 併有機相，有機相依次用水（10mLx3)，飽和氯化鈉溶液洗 滌（10mLx3)，用無水硫酸鈉乾燥’過濾，濾液減壓濃縮， 用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到 標題產物3-[(4-溴-2,6-二氟-苯氧基）曱基]-8_氮雜雙環 並[3.2.1]辛烷-8-羧酸第三丁酯426(15〇1^，白色固體）， 產率：18. 0°/〇。 MS m/z (ESI): 376.0 [M-55] 第六步 95344 151 201213319 3-[ [2, 6-二氟-4-(4-甲績醢基苯基）苯氧基]曱基]-8-氮雜 雙環並[3. 2. 1 ]辛院-8-敌酸第三丁酉旨 將3-[(4-漠-2, 6-二苯氧基）甲基]-8-氮雜雙環並 [3· 2. 1]辛烷-8-羧酸第三丁酯 42e(150mg，0. 35 mol)，（4-曱磺醯基苯基）硼酸（83mg，0.42mmol)和1，Γ -二（二苯膦 基）二茂鐵二氣化鈀（26mg，0. 04mmol)溶解於6mLl,4-二噁 烧和水的混合溶劑（V/V = 5:1)中，加入三水合填酸鉀 (279mg，1· 05mmol)，升至120°C攪拌反應7小時。過濾， # 濾液加入20mL水，用乙酸乙酯萃取（20mLx3)，合併有機 鲁 相’依次用水（5mLx3) ’飽和氣化鈉溶液洗滌（5mLx3)，無 水硫酸鈉乾燥’過濾，濾液減壓濃縮，用薄層色譜法以展 開劑體系B純化所得殘餘物，得到標題產物3-[ [2, 6-二氣 -4-(4-甲確醯基苯基）苯氧基]甲基]-8-氮雜雙環並[3. 2. 1] 辛烧-8-叛酸第三丁酯42(130mg，白色固體），產率：73. 〇%。 MS m/z (ESI): 452.1 [M-55] φ Ή NMR (400 MHz, t/-DMS0) δ 7. 99 (s, 4H), 7.65 (d, 2H), 4.18-4.17 (m, 2H), 4.11-4.06 (m, 2H), 3.22 (s, 3H), · 2.08-2.07 (m, 2H), 2.05-2.01 (m, 1H), 1.99-1.92 (m, 2H), 1.62-1.60 (m, 2H), 1.56-1.52 (m, 2H), 1.43 (s, 9H). 實施例43 3-[ [2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]曱基]-8_(5_ 乙基嘧啶-2-基）-8-氮雜雙環並[3. 2. 1]辛烷 152 95344 201213319Octane-8-carboxylic acid tert-butyl ester 42c (500 mg, 2.19 mmol) was dissolved in 5 mL of anhydrous methylene chloride. Add triethylamine (663 mg, 6.57 mmol), and add methyl sulfonate (300 mg, 2_63 mmol), the reaction was stirred at room temperature for 12 hours. 1 OmL of water was added, and the organic phase was washed with 1 hr of hydrochloric acid (5 mL×3), and then with saturated aqueous sodium chloride (5 mL×3). , 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 42 (1 (62 〇 11 ^, colorless liquid), the product was directly subjected to the next reaction without purification. Step 3-[(4-Bromo-2,6-difluoro-phenoxy)indolyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3-(oxasulfonyloxyindenyl)-8-azabicyclo[3.2.1]octane-8-decanoic acid butyl vinegar 424 (60〇111, 1.88111111〇1) and 4- Bromo-2,6-difluoro-phenol (469 mg, 2.25 mmol) was dissolved in 5 mL of didecyl oxalate, then potassium carbonate (5. 64 mmol) was added, and the mixture was warmed to i5 〇t: the mixture was stirred for 4 hours. The mixture was extracted with EtOAc (2 mL EtOAc). The resulting residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) 3)] Octane-8-carboxylic acid tert-butyl ester 426 (15 〇 1 ^, white solid), Yield: 18. 0 ° / 〇. MS m/z (ESI): 376.0 [M-55]. Step 6 95344 151 201213319 3-[ [2, 6-difluoro-4-(4-methylphenyl)phenoxy]indolyl] -8-Azabicyclo[3.2.1]Xinyuan-8-dibasic acid tributyl hydrazine is intended to 3-[(4-di-2,6-diphenoxy)methyl]-8-nitrogen Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 42e (150 mg, 0.35 mol), (4-oxasulfonylphenyl)boronic acid (83 mg, 0.42 mmol) and 1 , Γ-bis(diphenylphosphino)ferrocene dipalladium palladium (26 mg, 0.04 mmol) was dissolved in 6 mL of a mixed solvent of dioxin and water (V/V = 5:1), added Potassium acid trihydrate (279 mg, 1.05 mmol) was added and the mixture was stirred at 120 ° C for 7 hours. Filtration, # filtrate was added to 20 mL of water, extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed with water (5 mL×3), saturated sodium sulfate solution (5 mL×3), dried over anhydrous sodium sulfate. The resulting residue was purified by EtOAc EtOAc (EtOAc) - azabicyclo[3.2.1]octane-8-t-acid tert-butyl ester 42 (130 mg, white solid), yield: 73. 〇%. MS m/z (ESI): 452.1 [M-55] φ Ή NMR (400 MHz, t/-DMS0) δ 7. 99 (s, 4H), 7.65 (d, 2H), 4.18-4.17 (m, 2H ), 4.11-4.06 (m, 2H), 3.22 (s, 3H), · 2.08-2.07 (m, 2H), 2.05-2.01 (m, 1H), 1.99-1.92 (m, 2H), 1.62-1.60 ( m, 2H), 1.56-1.52 (m, 2H), 1.43 (s, 9H). Example 43 3-[[2,6-difluoro-4-(4-indolesulfonylphenyl)phenoxy ]]yl]-8_(5-ethylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane 152 95344 201213319

3-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]曱基]_8_氮雜 雙環並[3.2.1]辛烷 將3-[ [2, 6-二氟-4-(4-甲磺醯基苯基）笨氧基]甲基] -8-氮雜雙環並[3· 2.1]辛烷-8-羧酸第三丁酯42(70mg， 0. 14mmol)溶解於2mL 2M氣化氫曱醇溶液，擾拌反應12 小時。反應液減壓濃縮，得到標題粗產物3-[[2,6-二 -4-(4-曱磺醯基苯基）苯氧基]甲基]-8-氮雜雙環並[3. 2. 1] 辛烷43a(55mg，白色固體）’產物不經純化直接進行下一 步反應。 第二步 3-[[2, 6-二氟-4-(4-甲磺醯基苯基）笨氧基]曱基]-8-(5- 乙基癌啶-2-基）-8-氮雜雙環並[3.2. 1]辛烷 將粗品3-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基] 甲基]-8-氮雜雙環並[3. 2. 1 ]辛烧 43a(55mg，0. 12 mol)， 2-氯-5-乙基-喷咬（26mg，〇. 19则1〇1)和碳酸鉋（inmg，0. 36 mol)溶解於5mL况#一二甲基曱醯胺中，升溫至i2〇°C攪拌 153 95344 201213319 反應4小時。加入20mL水，用乙酸乙酯萃取（20mLx3)，合 併有機相’依次用水（5mLx3)，飽和氯化鈉溶液洗務 (5mLx3)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層 色譜法以展開劑體系B純化所得殘餘物，得到標題產物 3-[[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]甲基]_8_(5_ 乙基嘧啶-2-基）-8-氮雜雙環並[3· 2. 1]辛烷43(31mg，白 色固體），產率：48. 0%。 MS m/z (ESI): 514.2 [M+l] # *11 NMR (400 MHz, d-dWSO) δ 8.25 (s, 2H), 7. 99 (s, 4H), 7. 65(d, 2H), 4. 59(s, 2H), 4.21 (t, 2H), 3. 27 (s, 3H), 2.45-2.42 (m, 2H), 2.14-2.11 (m, 2H), 2.03-2.01 (m, 1H), 1.76-1.74 (m, 2H), 1.62-1.58 (m, 2H), 1.30-1.26 (m, 2H), 1. 15-1. 12 (m, 3H). 實施例44 (1疋550-3-(5-乙基嘧啶-2-基）-6-[[5-(4-甲磺醯基苯 基）-2-°比咬基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烧3-[[2,6-Difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]_8_azabicyclo[3.2.1]octane will be 3-[ [2, 6-Difluoro-4-(4-methylsulfonylphenyl) phenyloxy]methyl]-8-azabicyclo[3·2.1]octane-8-carboxylic acid tert-butyl ester 42 (70 mg , 0. 14 mmol) was dissolved in 2 mL of 2M gasified hydroquinone solution, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound, 3-[[2,6-di-4-(4-oxasulfonylphenyl)phenoxy]methyl]-8-azabicyclo[3. 1] Octane 43a (55 mg, white solid) product was taken directly to the next step without purification. Step 2 3-[[2,6-Difluoro-4-(4-methylsulfonylphenyl) phenyloxy] decyl]-8-(5-ethylcarbanidin-2-yl)-8 -Azabicyclo[3.2.1]octane will be crude 3-[[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-8-azabicyclo And [3. 2. 1 ] Xin Shao 43a (55mg, 0. 12 mol), 2-chloro-5-ethyl-penetration (26mg, 〇. 19, 1〇1) and carbonic acid planing (inmg, 0. 36 mol) was dissolved in 5 mL of #1 dimethyl decylamine, and the temperature was raised to i2 〇 ° C to stir 153 95344 201213319 for 4 hours. Add 20 mL of water, extract with ethyl acetate (20 mL×3), and combine the organic phase with water (5 mL×3), washed with saturated sodium chloride solution (5 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAc (EtOAc) -2-yl)-8-azabicyclo[3·2]octane 43 (31 mg, white solid), yield: 40.0%. MS m/z (ESI): 514.2 [M+l] # *11 NMR (400 MHz, d-dWSO) δ 8.25 (s, 2H), 7. 99 (s, 4H), 7. 65(d, 2H ), 4. 59(s, 2H), 4.21 (t, 2H), 3. 27 (s, 3H), 2.45-2.42 (m, 2H), 2.14-2.11 (m, 2H), 2.03-2.01 (m , 1H), 1.76-1.74 (m, 2H), 1.62-1.58 (m, 2H), 1.30-1.26 (m, 2H), 1. 15-1. 12 (m, 3H). Example 44 (1疋550-3-(5-ethylpyrimidin-2-yl)-6-[[5-(4-methylsulfonylphenyl)-2-° ratio octyl]oxymethyl]-3-azabicyclo And [3. 1. 0] burned

154 95344 201213319 第一步 (1尤550-6-1:(5-溴-2-*1比啶基）氧曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 將[(1^ 550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷_6_基]曱醇 7f(590mg’2. 69mmol)溶解於 10mL 况#•二甲基曱醯胺中，滴加入5mL含60%氫化鈉（129mg， 5. 38mmol)的术於二甲基甲醢胺溶液，攪拌1小時，反應 液變成淡黃色，升溫至50°C攪拌反應0. 5小時。冷卻至室 φ 溫，再滴加入5mL2, 5-二溴D比咬（637mg，2. 69mmol)的况鲁 二甲基曱醯胺溶液，攪拌12小時。加入lOOmL水，用乙酸 乙酯萃取（50mLx5)，合併有機相，用飽和氯化鈉溶液洗滌 (50mL)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠 管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產 物（1疋55V6_[(5-溴-2-比啶基）氧甲基]-3-(5-乙基嘧啶 -2-基）-3-氮雜雙環並[3. 1· 0]己烧44a(219mg，白色固體）， 產率：21. 9%。 ▲154 95344 201213319 First step (1 especially 550-6-1: (5-bromo-2-*1-pyridyl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-nitrogen Heterobicyclo[3.1.0]hexane will [(1^ 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane_6 _ base] sterol 7f (590mg '2. 69mmol) was dissolved in 10mL of dimethyl decylamine, adding 5mL of 60% sodium hydride (129mg, 5. 38mmol) to dimethylformamidine The amine solution was stirred for 1 hour, the reaction liquid turned pale yellow, and the temperature was raised to 50 ° C. The reaction was stirred for 0.5 hours. The mixture was cooled to room temperature φ, and 5 mL of 2,5-dibromo D ratio (637 mg, 2.69 mmol) was added dropwise. The solution was stirred for 12 hours, and the mixture was stirred for 12 hr. The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting eluting eluting eluting eluting eluting eluting eluting eluting eluting -ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0] hexane 44a (219 mg, white solid), yield: 21.9%.

A W ^ MS m/z (ESI): 377.2 [M+l] 第二步 (1及，55&quot;)-3-(5-乙基〇密咬-2-基）-6-[[5-(4-甲續酿基苯 基）-2-β比咬基]氧甲基]-3-氣雜雙環並[3. 1. 0]己恢 將（1足55&quot;)-6-[(5-漠-2-°比咬基）氧甲基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3.1. 0]己烷44a(200mg， 0. 53mmol)，（4-曱續醯基苯基）删酸（139mg，0. 69mmol)， 二（三苯膦基）二氯化鈀（lOOmg，0. 14mmol)和2mL2M碳酸 155 95344 201213319 納溶液溶解於lOmL乙二醇二曱鍵中，升至80°C授拌反應 12小時。加入l〇〇mL水，用乙酸乙酯萃取（30mLx5)，合併 有機相’用飽和氯化鈉溶液洗滌（50mL)，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B純化 所得殘餘物’得到標題產物（1^5^-3-(5-乙基嘧咬-2一 基）-6-[[5-(4-甲磺醯基苯基）-2-吡啶基]氧曱基]一氮雜 雙環並[3· 1. 0]己烷44(110mg，白色固體），產率：46.⑽。 MS m/z (ESI)： 451.2 [M+l] Ή NMR (400 MHz, CDCh) δ 8.38 (d, 1H), 8.17 (s, 2H), 8.01 (d, 2H), 7.82 (dd, 1H), 7.73-7.69 (m, 2H), 6.87 Cd, 1H), 4.30 (d, 2H), 3.96 (d, 2H), 3. 57 (d, 2H), 3. 〇9 (s, 3H), 2.46 (q, 2H), 1.77-1.74 (m, 2H), i 31_i „ 1H), 1.18 (t, 3H). · 實施例45 基）氧甲基]-3-氮雜雙環並[3. 1.0]己烷 (1疋550-3-(5-乙基嘧啶-2-基）-6-[(5-噠嗪基_2_吡啶AW ^ MS m/z (ESI): 377.2 [M+l] The second step (1 and, 55 &quot;)-3-(5-ethyl guanidine-2-yl)-6-[[5-( 4-methyl phenyl phenyl)-2-β ratio thiol]oxymethyl]-3- oxabicyclo[3. 1. 0] hex will be (1 foot 55 &quot;) -6-[(5 -indifferent to -2-methylpyrimidin-2-yl)-3-azabicyclo[3. , (4-曱-decylphenyl)-decanoic acid (139mg, 0.69mmol), bis(triphenylphosphino)palladium dichloride (100mg, 0.45mmol) and 2mL2M carbonic acid 155 95344 201213319 nano solution dissolved in lOmL In the ethylene glycol dioxime bond, the reaction was carried out for 12 hours at 80 ° C. The mixture was extracted with ethyl acetate (30 mL×5), and the combined organic layer was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered, Purification of the residue obtained by solvent system B to give the title product (1^5^-3-(5-ethyl-pyrimidin-2-yl)-6-[[5-(4-methylsulfonylphenyl)-2 -pyridyl]oxycarbonyl]-azabicyclo[3·1.0]hexane 44 (110 mg, white solid), yield: 46. (10) MS m/z (ESI): 451.2 [M+l Ή NMR (400 MHz, CDCh) δ 8.38 (d, 1H), 8.17 (s, 2H), 8.01 (d, 2H), 7.82 (dd, 1H), 7.73-7.69 (m, 2H), 6.87 Cd, 1H), 4.30 (d, 2H), 3.96 (d, 2H), 3. 57 (d, 2H), 3. 〇9 (s, 3H), 2.46 (q, 2H), 1.77-1.74 (m, 2H ), i 31_i „ 1H), 1.18 (t, 3H). · Example 45 yl)oxymethyl]-3-azabicyclo[3.1.0]hexane (1疋550-3-(5-B) Pyrimidin-2-yl)-6-[(5-oxazinyl-2-pyridine)

95344 156 201213319 將（1尤55〇-6-[(6-氯-3-吼啶基）氧曱基]_3_(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷13a(200mg， 0. 60mmol)，三第三丁基（噠嗪-4-基）錫（557mg，1. 50mmol) 和二（三苯膦基）二氣化鈀（50mg，0. 06mmol)溶解於l〇mL 1，4-二噁烷中，升至110°C攪拌反應20小時。反應液冷卻 後加入100mL乙酸乙酯’依次用水（30mLx2)，飽和氣化納溶 液洗滌（30mL) ’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用 矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到梗 Φ 題產物（1兄550-3-(5-乙基痛咬-2-基）-6-[一某 -2-°比咬基）氧甲基]-3-氮雜雙環並[3· 1· 〇]己貌45(8〇mg 黃色固體），產率：35.7%。 MS m/z (ESI): 375.2 [M+l] 4 匪R (400 MHz, CDC13) δ 9.76 (s，1H)，9·24 (d 1H) 8. 46 (d，1H)，8. 18 (s，2H)，8. 01 (d，1H)，7· 81 (d 1H)’ 7.32 (dd，1H)，4.05 (d，2H)，3.99 (d，2H)，3 60 (d 2H), 2.47 (q, 2H), 1.82-1.76 (m, 2H), 1.69-1 59 ^ 1H), 1.18 (t, 3H). m， 實施例46 (3习疋635*)-2-(5-乙基哺咬-2-基）-5-[4—(四嗤〜i一灵）笨氧^ 基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊&amp;[c]n比口各95344 156 201213319 (1 especially 55〇-6-[(6-chloro-3-acridinyl)oxyindolyl]_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] Hexane 13a (200 mg, 0. 60 mmol), tri-tert-butyl (pyridazin-4-yl) tin (557 mg, 1.50 mmol) and bis(triphenylphosphino) di-palladium (50 mg) 0. 06mmol) was dissolved in l〇mL 1,4-dioxane, and the reaction was stirred at 110 ° C for 20 hours. After the reaction solution was cooled, 100 mL of ethyl acetate was added, followed by water (30 mL×2), saturated sodium carbonate solution. Wash (30 mL), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by eluent column chromatography with eluent column chromatography to obtain the product of stalk Φ (1 brother 550-3-(5-B) Base pain bite-2-yl)-6-[一某-2-° ratio biting base)oxymethyl]-3-azabicyclo[3·1· 〇] appearance 45 (8〇mg yellow solid) Yield: 35.7% MS m/z (ESI): 375.2 [M+l] 4 匪R (400 MHz, CDC13) δ 9.76 (s, 1H), 9·24 (d 1H) 8. 46 (d , 1H), 8. 18 (s, 2H), 8. 01 (d, 1H), 7· 81 (d 1H)' 7.32 (dd, 1H), 4.05 (d, 2H), 3.99 (d, 2H) , 3 60 (d 2H), 2.47 (q, 2H), 1.82-1.76 (m, 2H), 1.69-1 59 ^ 1H), 1.18 (t, 3H). m, Example 46 (3 疋 635*)-2-(5-ethyl gnat-2-yl)-5-[4—(four嗤~i一灵) 笨氧^基]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopentane &amp; [c]n

95344 157 201213319 ηΝΦ- 步 2 0 ο 40 第一步 4_(四峻-1-基）苯紛 將4-胺基苯盼46a(5 g，45. 80mmol)溶解於42mL乙 馨酸中，依次加入原曱酸三乙酯（24. 40mL，146.50mmol)和疊 肇 氮化鈉（3. 73 g，57. 30mmol)，攪拌10分鐘，升至80°C授 拌反應1. 5小時。加入30mL水和17mL 6 Μ鹽酸，冰浴下， 緩慢加入6mL25%的亞硝酸納溶液，析出白色固體，抽遽， 用水洗滌（60mLx2)，得到標題產物粗品4-(四氮唑-1-基） 苯酚46b(6. 30 g ’灰白色固體），產率：85. 0%。 MS ra/z (ESI): 163.0 [M+l] 第二步 (33疋 635^-2-(5-乙基，咬-2-基）-5-[4-(四0坐-1-基）苯氧 _ 基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]n比咯 將粗品 cis-KSay?，635^-2-(5-乙基嘧咬-2-基）- 3, 3a，4, 5, 6, 6a-六氩-1H-環戊並[c]吡洛-5-基]曱續酸酐 ld(160mg，0.51mmol)溶解於15虬况於二曱基甲醯胺中， 攪拌，加入粗品4-(四唾-1-基）笨紛46b(75mg ’ 0. 46mm〇i) 和碳酸鉀（141mg，1. 02mmol)，升溫至1〇〇。0攪拌反應2小 時。反應液減壓漢縮’加入5〇mL水，乙酸乙酯萃取 158 95344 201213319 (20mLx4)，合併有機相，用水洗滌（2〇mLx3),無水硫酸鎂 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 B純化所得殘餘物’得到標題產物（以幻_2_(5_乙基嘧 嘴-2-基）-5-[4-(四氮唑_丨_基）苯氧基]_3, 3a，4, 5, 6, 6a_ 六氫-1H-環戊並[c]吡咯46(17mg，白色固體），產率： 10. 0%。 MS m/z (ESI)： 378.2 [M+l] 1H 丽R(400 MHz，CDCIO 6 9.93(s，1H)，8. 21 (s，2H)， • 7.77(d, 2H), 7. 14(d, 2H), 5.07-4.98 (m, 1H), 3.78- 3.70 (m, 2H), 3.41-3.36 (m, 2H), 2.94-2.89 (m, 2H), 2.43-2.38 (m, 2H), 1.94-1.90 (m, 2H), 1.22(s, 3H), 1. 15-1. 10(ra, 2H). 實施例47 (3a^，6^51)-2-(5-乙基**密咬-2-基）-5-[4-(四0坐-1-基）苯氧 基]-3,3&lt;3,4,5,6,63-六氫-111-環戊並[〇]11比口各95344 157 201213319 ηΝΦ- Step 2 0 ο 40 First step 4_(tetrajun-1-yl)benzene The 4-aminobenzene 46a (5 g, 45.80 mmol) was dissolved in 42 mL of octanoic acid and added sequentially. 5小时。 The original solution of tridecanoic acid (24. 40mL, 146.50mmol) and sodium arsenide (3. 73 g, 57. 30mmol), stirred for 10 minutes, the temperature was raised to 80 ° C. 30 mL of water and 17 mL of 6 hydrazine hydrochloride were added, and 6 mL of a 25% sodium nitrite solution was slowly added thereto under ice-cooling to precipitate a white solid, which was washed with water and washed with water (60 mL×2) to give the crude title product 4-(tetrazol-1-yl) 0%。 Phenol 46b (6. 30 g 'gray white solid), yield: 85.0%. MS ra/z (ESI): 163.0 [M+l] The second step (33疋635^-2-(5-ethyl, hexane-2-yl)-5-[4-(四零坐-1- Phenyloxy-3-yl]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]n ratio will be crude cis-KSay?, 635^-2-(5-B Pyrimidine-2-yl)- 3, 3a,4, 5, 6, 6a-hexa-argon-1H-cyclopenta[c]pyrrole-5-yl]anthracene anhydride ld (160 mg, 0.51 mmol) dissolved The mixture was stirred and added to the crude 4-(tetras-s-l-yl) succinim 46b (75 mg '0. 46mm 〇i) and potassium carbonate (141 mg, 1.02 mmol). The temperature was raised to 1 Torr. 0 The reaction was stirred for 2 hours. The reaction solution was depressurized and condensed into 5 liters of water, ethyl acetate was extracted 158 95344 201213319 (20 mL x 4), the organic phases were combined, washed with water (2 〇 mL x 3), anhydrous sulfuric acid The magnesium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin-layer chromatography to afford the title product (yield _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -(tetrazolium-hydrazinyl)phenoxy]_3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole 46 (17 mg, white solid), yield: 10. 0% MS m/z (ESI): 378.2 [M+l] 1H Li R (400 MHz, CDCIO 6 9.93 (s,1H), 8. 21 (s,2H), 7.77(d, 2H), 7. 14(d, 2H), 5.07-4.98 (m, 1H), 3.78- 3.70 (m, 2H), 3.41-3.36 (m, 2H), 2.94-2.89 (m, 2H), 2.43-2.38 (m, 2H), 1.94-1.90 (m, 2H), 1.22(s, 3H), 1. 15-1. 10 (ra, 2H). Example 47 (3a^, 6^51)-2-(5-ethyl ** dimethyl-2-yl)-5-[4-(tetrakis-1-yl)benzene Oxy]-3,3&lt;3,4,5,6,63-hexahydro-111-cyclopenta[〇]11

將粗品知59-5-漠-2-(5-乙基，淀-2-基）-3,33,4,5,6,63-六氫-111-環戊並[(^]吡咯3&amp;(23711^， 159 95344 201213319 0. 80mmol)溶解於15mL况於二甲基曱醯胺中，攪拌，加入 粗品4-(四唑-1-基）苯酚46b(117mg，0. 72mmol)和碳酸鉀 (221mg ’ 1. 60mmol) ’升溫至12(TC攪拌反應2. 5小時。反 應液減壓濃縮，加入50mL水，乙酸乙酯萃取（20mLx3)，合 併有機相，用水洗滌（2〇mLx2)，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘 餘物’得到標題產物（33^, 6319)-2-(5-乙基哺咬-2-基）一5一 [4-(四唾-1-基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-in-環戊並 鲁 [c]吡咯47(40mg，白色固體），產率：15. 0%。 MS m/z (ESI): 378.2 [M+l] 1H NMR (400 MHz，CDC13) (5 9. 61 (s，1H)，8. 19 (s，2h) 7.68 (d，2H)，7.00 (d，2H)，5.04-4.94 (m，1H), 3· 77__ 3.69 (m，2H)，3.67-3.60 (m，2H)，2.97-2.90 (m，2H) 2.48-2.45 (m，2H)，1.93-1.88 (m，2H)，1.29 (s，3H) 1. 23-1. 18 (m，2H).The crude product is known as 59-5-moly-2-(5-ethyl, phospho-2-yl)-3,33,4,5,6,63-hexahydro-111-cyclopenta[(^]pyrrole 3&amp (23711^, 159 95344 201213319 0. 80 mmol) dissolved in 15 mL of dimethyl decylamine, stirred, and added crude 4-(tetrazol-1-yl)phenol 46b (117 mg, 0.72 mmol) and carbonic acid Potassium (221 mg ' 1.60 mmol) was heated to 12 (TC stirring reaction for 2.5 hours. The reaction mixture was concentrated under reduced pressure, then 50 mL water, ethyl acetate (20mL×3), and the organic phase was combined and washed with water (2 〇mLx2) Drying over anhydrous magnesium sulfate, filtration, EtOAc EtOAc (EtOAc) a 5-[4-(tetras-s-l-yl)phenoxy]-3,3a,4,5,6,6a-hexahydro-in-cyclopenta[c]pyrrole 47 (40 mg, <RTIgt; , 2h) 7.68 (d, 2H), 7.00 (d, 2H), 5.04-4.94 (m, 1H), 3· 77__ 3.69 (m, 2H), 3.67-3.60 (m, 2H), 2.97-2.90 (m , 2H) 2.48-2.45 (m, 2H), 1.93-1.88 (m, 2H) , 1.29 (s, 3H) 1. 23-1. 18 (m, 2H).

實施例48 3-異丙基-5-[(1尤55')-6-[[5-(4-甲磺醯基苯基）_2_比。定 基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-12, 嗓 二〇坐Example 48 3-Isopropyl-5-[(1 especially 55')-6-[[5-(4-methylsulfonylphenyl)_2_ ratio. Alkyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl]-12, 嗓

95344 160 20121331995344 160 201213319

第一步 (1疋550-(6-羥曱基）-3-氮雜雙環並[3. 1. 0]己烷-3-曱腈 # 將碳酸氫鈉（2. 52g ’ 3〇mmol)溶解于5mL水中，攪:拌， 冰水浴下，滴加入15mL粗品[(1^5^)-3-氮雜雙環並 [3. 1· 0]己烷-6-基]甲醇7e(l. 13g，lOmmol)的二氯曱烷溶 液’再滴加入1· 50mL溴化氰（1. 27g，12mmol)的二氣甲烷 溶液，0°C反應40分鐘’再升溫至2(TC攪拌2小時。加入 10mL水’分液，水相用二氣甲烷萃取（30mLx3)，合併有機 相’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標 鲁 題產物（1亿5«-(6-羥曱基）-3-氮雜雙環並[3. 1. 〇]己烷 -3-曱腈48a(1.10g，桔黃色油狀物），產物不經純化直接 進行下一步反應。 MS m/z (ESI): 139.1 [M+l] 第二步 [(1疋55)-3-(3-異丙基-1，2, 4--°惡二唾-5-基）-3-氮雜雙 環並[3. 1. 0]己烧-6-基]曱醇 將粗品（1足5«-(6-羥甲基）-3-氮雜雙環並[3. 1. 〇] 己烧-3-曱腈48a(415mg，3mmol)和W -羥基-2-曱基-丙 161 95344 201213319 胺（368mg ’ 3. 60mmol)溶解於i5mL四氫吱喊中，攪拌，滴 加入3. 60mL 1M氣化亞鋅的四氫呋喃溶液，有大量白色固 體生成。反應液減壓濃縮，加入4. 50niL 4M氯化氫的乙醇 溶液，升溫至80°C反應2小時。冷卻，加入破酸納固體至 反應液pH為6，過濾，用乙酸乙酯萃取（5〇mLxl)，無水硫 酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗 脫劑體系B純化所得殘餘物，得到標題產物 (3-異丙基-1，2, 4—噁二唑-5-基）-3-氮雜雙環並[3. 1. 〇] 鲁己烷_6_基]曱醇48b(270mg ’無色油狀物），產率：40. 〇%。 _ MS m/z (ESI): 224. 1 [M+l] 第三步 [(li?，55)-3-(3-異丙基-1，2, 4--噁二唑-5-基）-3-氮雜雙 環並[3. 1. 0]己烧-6-基]甲基磺酸曱酯 冰浴下，將[(1疋55)-3-(3-異丙基-1,2,4--噁二唑-5-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲醇48b(250mg， φ 1. 则ιοί)溶解於30mL無水二氣甲烷中，加入三乙胺 (6.4mL，3.30mmol)，滴加入曱磺醯氣（0 2mL，2. 20mmol)，籲 升至室溫，攪拌反應3小時。反應液減壓濃縮，加入水 30mL，用乙酸乙酯萃取（30mLx3)，合併有機相，無水硫酸 鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 [(1亿55)-3-(3-異丙基-1，2, 4—噁二唑-5-基）-3-氮雜雙 環並[3. 1· 0]己烷-6-基]甲基磺酸曱酯48c(330mg，黃色油 狀）’產物不經純化直接進行下一步反應。 MS m/z (ESI): 302.1 [M+l] 162 95344 201213319 第四步 6-(4-甲磺醯基苯基）吡啶_3一醇 將（4-甲橫醯基苯基）蝴酸48d(lg，5mmol)和6-氣°比唆 -3-醇（650mg，5mmol)溶解於3〇mL乙二醇二甲醚中，加入 四三苯基膦鈀（288mg，0. 25mmol)和2M碳酸鈉溶液7. 5mL， 100°C微波反應30分鐘。反應液減壓濃縮，加入水15〇ιηί， 滴加1M鹽酸至反應液pH值為5至6,用乙酸乙酯萃取 (50mLx3)，合併有機相，無水硫酸鎂乾燥，過濾，濾液減 • 壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘 _ 物’得到標題產物6-(4-曱磺醯基苯基）吡啶-3-醇48e (420mg，白色固體），產率：37. 5%。 MS ra/z (ESI): 249.6 [M+l] 第五步 3-異丙基-5-[(l兄55&quot;)-6-[[5-(4-甲續醯基苯基）-2-〇比咬 基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-1，2, 4-噁 二口坐 將粗品[(1尤 55^-3-(3-異丙基-1, 2, 籲 基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱基磺酸曱酯48c (330mg ’ 1. lOmmol)溶解於l5mLyV, #-二甲基曱醯胺中，擾 拌，加入6-(4-曱磺醯基笨基）吡啶-3-醇48e(275mg， 1. lOmmol)和碳酸|f(456nig，3. 30mmol)，升溫至 90°C授拌 反應16小時。加入lOOmL水，乙酸乙酯萃取（8〇mLx2)，合 併有機相，用水洗滌（5OmL&gt;&lt;2)，無水硫酸鎂乾燥，過濾、， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所 163 95344 201213319 得殘餘物，得到標題產物3-異丙基-5-[(1τ?，550-6-1^5-(4-曱磺醯基苯基）-2-吡啶基]氧曱基]-3-氮雜雙環並 [3. 1. 0]己烷-3-基]-1，2, 4-噁二唑 48(120mg，白色固體）， 產率：24. 0%。 MS m/z (ESI): 455.2 [M+l] 1H 丽R(400 MHz，CDC13) (5 8.42(d，1H)，8.15(d，2H)， 8.03 (d, 2H), 7.76 (d, 1H), 7.32 (dd, 1H), 4.05 (d, 2H), 3.88 (d, 2H), 3.67-3.71 (m, 2H), 3.09 (s, 3H), Φ 2.90-2.92 (m, 1H), 1.80-1.84 (m, 2H), 1.29 (d, 6H), 1.24-1.28 (m, 1H). 實施例49 (1尤55*)-3-(5-乙基嘧啶-2-基）-6-[[6-(4-吡啶基）-3-吡 啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷The first step (1疋550-(6-hydroxydecyl)-3-azabicyclo[3.1.0]hexane-3-indoleonitrile # sodium bicarbonate (2. 52g '3〇mmol) Dissolve in 5mL of water, stir: mix, add 15mL of crude [(1^5^)-3-azabicyclo[3.1·0]hexane-6-yl]methanol 7e (l. 13 g, 10 mmol) of dichloromethane solution was further added dropwise to 50 mL of cyanogen bromide (1. 27 g, 12 mmol) in dioxane. The mixture was reacted at 0 ° C for 40 minutes and then warmed to 2 (TC stirred for 2 hours). Add 10 mL of water's liquid, extract the aqueous phase with di-methane (30 mL×3), combine the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to give the crude product (100 million-(6-hydroxyl) Benzyl)-3-azabicyclo[3. 1. oxime]hexane-3-indanonitrile 48a (1.10 g, orange oil). The product was taken to the next step without purification. MS m/z (ESI): 139.1 [M+l] The second step [(1疋55)-3-(3-isopropyl-1,2,4--- oxadisin-5-yl)-3-aza Bicyclo[3.1.0]hexan-6-yl]nonanol will be crude (1 foot 5«-(6-hydroxymethyl)-3-azabicyclo[3. 1. 〇] hexane- 3-indene nitrile 48a (415 mg, 3 mmol) and W-hydroxy-2-indolyl-propanoid 161 95344 201213319 Amine (368 mg ' 3. 60 mmol) was dissolved in i5 mL of tetrahydro hydrazine, stirred, and added dropwise to a solution of 3.60 mL of 1M vaporized ZnZ in tetrahydrofuran. A large amount of white solid was formed. 50 mM 4M hydrogen chloride in ethanol, the temperature was raised to 80 ° C for 2 hours. After cooling, add the acid-degraded solid to pH 6 of the reaction mixture, which was filtered, extracted with ethyl acetate (5 mL mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc Heterobicyclo[3. 1. 〇] ruthene_6_yl] decyl alcohol 48b (270 mg 'colorless oil), yield: 40. 〇%. _ MS m/z (ESI): 224. [M+l] The third step [(li?,55)-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3. 1. 0] hexyl-6-yl]methyl sulfonate under ice bath, [(1疋55)-3-(3-isopropyl-1,2,4-oxadiazole-5 -yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanol 48b (250mg, φ 1. then ιοί) dissolved in 30mL anhydrous di-methane, added triethyl (6.4mL, 3.30mmol), was added dropwise Yue sulfonylurea gas (0 2mL, 2. 20mmol), called on warmed to room temperature, stirred for 3 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methylsulfonate oxime ester 48c (330 mg, The yellow oily product was directly subjected to the next reaction without purification. MS m/z (ESI): 302.1 [M+l] 162 95344 201213319 Step 4 6-(4-Methanesulfonylphenyl)pyridine-3-ol (4-methyl-decylphenyl) 48d (lg, 5mmol) and 6-gas ratio of indole-3-ol (650mg, 5mmol) were dissolved in 3〇mL of ethylene glycol dimethyl ether, tetrakistriphenylphosphine palladium (288mg, 0.25mmol) and 2M sodium carbonate solution 7. 5mL, microwave reaction at 100 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) was evaporated. EtOAc EtOAc EtOAc EtOAc. Concentration, purification of the obtained residue by EtOAc EtOAc EtOAc EtOAc (EtOAc) : 37. 5%. MS ra/z (ESI): 249.6 [M+l] Step 5 3-isopropyl-5-[(l brother 55&quot;)-6-[[5-(4-methyl-decylphenyl)- 2-〇 咬 ] ] ] ] ] ] ] ] ] 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 ^-3-(3-Isopropyl-1, 2, octyl)-3-azabicyclo[3.1.0]hexane-6-yl]nonylsulfonate oxime ester 48c (330 mg ' 1 lOmmol) dissolved in l5mLyV, #-dimethyl decylamine, scrambled, added 6-(4-oxasulfonylpyridyl)pyridin-3-ol 48e (275mg, 1. lOmmol) and carbonic acid|f (456 nig, 3.30 mmol), and the mixture was heated to 90 ° C for 16 hours. Add 100 mL of water, ethyl acetate (8 〇 mL x 2), and the organic phases were combined, washed with water (5OmL &gt;&lt; 2), anhydrous magnesium sulfate Drying, filtration, and concentrating the filtrate under reduced pressure, and purifying 163 95344 201213319 by eluent column chromatography to afford the title product 3-isopropyl-5-[(1τ?,550-6 -1^5-(4-oxasulfonylphenyl)-2-pyridyl]oxyindolyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2 , 4-oxadiazole 48 (120 mg, white solid), Yield: 24.0% MS m/z (ESI): 455.2 [M+l] 1H R (400 MHz, CDC13) (5 8.42 (d, 1H), 8.15 (d, 2H), 8.03 (d, 2H), 7.76 (d, 1H), 7.32 (dd, 1H), 4.05 (d, 2H) , 3.88 (d, 2H), 3.67-3.71 (m, 2H), 3.09 (s, 3H), Φ 2.90-2.92 (m, 1H), 1.80-1.84 (m, 2H), 1.29 (d, 6H), 1.24-1.28 (m, 1H). Example 49 (1 especially 55*)-3-(5-ethylpyrimidin-2-yl)-6-[[6-(4-pyridyl)-3-pyridyl Oxymethyl]-3-azabicyclo[3.1.0]hexane

將（17?，5«-6-[ (6-氯-3-吼啶基）氧曱基]-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷13a(99mg， 0.30ramol)，（4-°比°定基）删酸（44. 30mg，0. 36mmol)溶解於 6mL乙二醇二甲謎和水（V/V = 1:1)的混合溶劑中，再依次 加入破酸鉀（83mg，0. 60mmol)和四三苯膦把（35mg， 164 95344 201213319 0. 03mmol)，125°c微波反應30分鐘。加入lOmL水，用乙 酸乙酯萃取（25mLx3)，合併有機相，無水硫酸鎂乾燥，過 濾’濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所 得殘餘物，得到標題產物（1^550-3-(5-乙基嘧啶-2-基）-6-[ [6-(4-°比啶基）-3-吨啶基]氧曱基]-3-氮雜雙環並 [3.1.0]己烷 49(50mg，白色固體），產率·· 44. 6%。 MS m/z (ESI): 373.7 [M+l](17?,5«-6-[(6-Chloro-3-acridinyl)oxyindolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] Hexane 13a (99mg, 0.30ramol), (4-° ratio ° base) acid deletion (44. 30mg, 0.36mmol) dissolved in 6mL ethylene glycol meditation and water (V/V = 1 In a mixed solvent of :1), potassium bromate (83 mg, 0.60 mmol) and tetratriphenylphosphine (35 mg, 164 95344 201213319 0. 03 mmol) were added in sequence, and microwave reaction was carried out for 30 minutes at 125 ° C. 10 mL of water was added. The title compound (1^550-3-) was obtained. The title compound was obtained from ethyl acetate (ethyl acetate). (5-ethylpyrimidin-2-yl)-6-[ [6-(4-°-pyridyl)-3-tonidyl]oxyindolyl]-3-azabicyclo[3.1.0] Alkane 49 (50 mg, white solid), mp. 44. 6% MS m/z (ESI): 373.7 [M+l]

'H NMR (400 MHz, CDCh) δ 8.58 (d, 2H), 8.40 (d, 2H), B. 18(s, 2H), 7. 99(m, 3H), 4.09 (d, 2H), 3.88 (d, 2H), 3. 64(d, 2H), 2.49(m, 2H), 1.85(d, 2H), 1. 19 (m, 4H). 實施例50 (U5«-6-[[2-氯-4-(4-曱磺醯基苯基）苯氧基]曱基]'H NMR (400 MHz, CDCh) δ 8.58 (d, 2H), 8.40 (d, 2H), B. 18(s, 2H), 7. 99(m, 3H), 4.09 (d, 2H), 3.88 (d, 2H), 3. 64(d, 2H), 2.49(m, 2H), 1.85(d, 2H), 1. 19 (m, 4H). Example 50 (U5«-6-[[2 -chloro-4-(4-oxasulfonylphenyl)phenoxy]indolyl]

〜3-(5-乙基痛咬-2-基）_3-氣雜雙環並[3. 1. 0]己烧~3-(5-ethylheptan-2-yl)_3-heterobicyclo[3. 1. 0] hexane

第一步 2-氯-4-(4-曱磺醯基苯基）苯酚 將 4-溴-2-氯-苯酴 50a(500mg，2.40mol)，（4-曱確 165 95344 201213319 醯基苯基）侧酸（531mg，2. 60mmol)，1，1，-二（二苯膦基） 二茂鐵二氣化鈀（35mg，0. 05mmol)和三水合磷酸鉀（1· 3〇g, 4.80mmol)溶解於50mLl，4-二噁烧中，升溫至回流攪拌反 應5小時。過濾，濾液減壓濃縮，用薄層色譜法以展開劑 體系B純化所得殘餘物，得到標題產物2-氣-4-(4-曱續醯 基苯基）苯紛50b(400mg，白色固體），產率：58. 7%。 MS m/z (ESI): 300.1 [M+18] 第二步 參 （1疋55)-6-[ [2-氣-4-(4-曱石黃醯基苯基）苯氧基]曱基]_3- (5-乙基响咬-2-基）-3-氮雜雙環並[3. 1. 〇]己烧 鲁 將粗品[(1疋55〇-3-(5-乙基β密唆-2-基）-3-氣雜雙環 並[3.1.0]己烷-6-基]曱磺酸甲酯7运（10511^，0.35111111〇1) 和2-氣-4-(4-曱續酿基苯基）苯紛501)(10〇111£，0.35111111〇1) 溶解於5mL况於二曱基乙醯胺中，再加入碳酸鉋（230mg， 0.70mmol)，升溫至150°C攪拌反應8小時。冷卻，加入25mL 水’用乙酸乙酯萃取（10mLx4)，合併有機相，用飽和氣化 錢溶液洗務（10mLx5)，無水硫酸鎮乾燥，過濾、，濾液減壓 # 濃縮，用薄層色譜法以展開劑體系B純化所得殘餘物，得 到標題產物（1及，551)-6-[ [2-氯-4-(4-曱續酿基苯基）苯氧 基]曱基]_3_(5-乙基喻咬-2-基）-3-氮雜雙環並[3. 1. 〇]己 烷50(100mg，白色固體），產率：58.4%。 MS ra/z (ESI): 484.2 [M+l] 1H NMR (400 MHz, CDCh) δ 8. 19 (s, 2H), 8. 00 (q, 2H), 7.72 (q, 2H), 7.64 (d, 1H), 7.47-7.44 (m, 1H), 7.02 166 95344 201213319 (d, 1H), 4. 11 (d, 2H), 3. 99 (d, 2H), 3. 60 (d, 2H), 3. 09 (s, 3H), 2.47 (q, 2H), 1.83-1.82 (m, 2H), 1.28-1.25 (m, 1H), 1.19 (t, 3H). 實施例51 2-[(l尤55*)-6-[[2,6-二氟-4-(4-甲磺醯基苯基）苯氧基] 曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-1，3-苯並噁唑The first step of 2-chloro-4-(4-oxasulfonylphenyl)phenol 4-bromo-2-chloro-phenylhydrazine 50a (500mg, 2.40mol), (4-曱 165 95344 201213319 decyl benzene a side acid (531 mg, 2.60 mmol), 1,1,-bis(diphenylphosphino)ferrocene di-palladium (35 mg, 0.05 mmol) and potassium phosphate trihydrate (1.3 g, 4.80 mmol) was dissolved in 50 mL of 1,2-dioxane, and the mixture was heated to reflux and stirred for 5 hours. Filtration and concentrating the filtrate under reduced pressure, and the residue obtained was purified by EtOAc EtOAc (EtOAc) , yield: 58.7%. MS m/z (ESI): 300.1 [M+18] 2nd step (1疋55)-6-[ [2- gas-4-(4-carbazinylphenyl)phenoxy]indolyl] _3-(5-Ethyl ringing-2-yl)-3-azabicyclo[3. 1. 〇] hexene ruthenium crude [(1疋55〇-3-(5-ethylβ密唆) 2-yl)-3- oxabicyclo[3.1.0]hexane-6-yl] sulfonate methyl ester 7 (10511^, 0.35111111〇1) and 2-gas-4-(4-曱Continuous phenyl) benzene 501) (10 〇 111 £, 0.35111111 〇 1) Dissolved in 5 mL of dimercaptoacetamide, then added carbonic acid planer (230 mg, 0.70 mmol), heated to 150 ° C stirring Reaction for 8 hours. Cooling, add 25 mL of water 'extracted with ethyl acetate (10 mL×4), combine the organic phase, wash with saturated gasification solution (10 mL×5), dry over anhydrous sulfuric acid, filter, filtrate decompression #concentrate, using thin layer chromatography The obtained residue was purified to give the titled product (1, 551)-6-[[2-chloro-4-(4-indoleylphenyl)phenoxy]indolyl]_3_(5) -ethyl-b-yl-2-yl)-3-azabicyclo[3. 1. oxime]hexane 50 (100 mg, white solid), yield: 58.4%. MS ra/z (ESI): 484.2 [M+l] 1H NMR (400 MHz, CDCh) δ 8. 19 (s, 2H), 8. 00 (q, 2H), 7.72 (q, 2H), 7.64 ( d, 1H), 7.47-7.44 (m, 1H), 7.02 166 95344 201213319 (d, 1H), 4. 11 (d, 2H), 3. 99 (d, 2H), 3. 60 (d, 2H) , 3. 09 (s, 3H), 2.47 (q, 2H), 1.83-1.82 (m, 2H), 1.28-1.25 (m, 1H), 1.19 (t, 3H). Example 51 2-[(l Especially 55*)-6-[[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. 0] Alkan-3-yl]-1,3-benzoxazole

將粗品（1及，55&quot;)-6-[ [2，6-二氟-4-(4-曱石黃酿基苯基） 苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷19a(20mg， 0. 05mmol) ’ 三乙胺（15mg，0. 15mmol)加入至 5mL 二氣曱烧 中’冰洛下’加入lmL 2-氣-1，3-苯並0惡嗤（8mg’ 〇· 〇5mm〇i) 的二氯曱烷溶液，升至室溫攪拌反應2小時，再加入碳酸 鉀（13mg，0. lOmmol)，攪拌反應12小時。過濾，渡液減壓 濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得 到標題產物2-[(1疋55&quot;)-6-[[2, 6-二氟-4-(4-甲磺醯基苯 基）苯氧基]甲基]-3-氮雜雙環並[3· ΐ·〇]己烷-3—基μι、 苯並噁唑51(20mg，白色固體），產率：41· 6%。 MS m/z (ESI): 497.2 [M+l] 95344 167 201213319 Ή NMR (400 MHz, CDCh) δ 8.02 (q, 2H), 7.71 (q, 2H), 7.39 (d, 1H), 7.26 (d, 1H), 7.20-7.16 (m, 3H), 7.04-7. 02(m, 1H), 4.15((1, 2H), 3.96 (d, 2H), 3.75 (d, 2H), 3.10 (s, 3H), 1.82-1.81 (m, 2H), 1.26-1.25 (m, 1H). 實施例52 (1 尤 5«-3-(5-溴嘧啶-2-基）-6-[[2, 6-二氟-4-(4-甲磺醯 基苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷The crude product (1 and 55&quot;)-6-[[2,6-difluoro-4-(4-carbophyllin)phenoxy]indolyl]-3-azabicyclo[3] 1.0] Hexane 19a (20 mg, 0.05 mmol) 'Triethylamine (15 mg, 0.15 mmol) was added to 5 mL of dioxane in the 'under ice' to add 1 mL of 2-gas-1,3-benzox. A solution of chloroform (8 mg of 〇·〇5mm〇i) in dichloromethane was stirred at room temperature for 2 hours, then potassium carbonate (13 mg, 0.1 mmol) was added and the mixture was stirred for 12 hours. Filtration, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford to afford the title product 2-[(1疋55&quot;)-6-[[2,6-difluoro-4-( 4-methylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3·ΐ·〇]hexane-3-ylpyr, benzoxazole 51 (20 mg, white solid), Yield: 41·6%. MS m/z (ESI): 497.2 [M+l] 95344 167 201213319 Ή NMR (400 MHz, CDCh) δ 8.02 (q, 2H), 7.71 (q, 2H), 7.39 (d, 1H), 7.26 (d , 1H), 7.20-7.16 (m, 3H), 7.04-7. 02(m, 1H), 4.15((1, 2H), 3.96 (d, 2H), 3.75 (d, 2H), 3.10 (s, 3H), 1.82-1.81 (m, 2H), 1.26-1.25 (m, 1H). Example 52 (1 especially 5«-3-(5-bromopyrimidin-2-yl)-6-[[2, 6 -difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane

將粗品（1尤5^-641:2, 6-二氟-4-(4-甲磺醯基苯基） 苯氧基]曱基]-3-氮雜雙環並[3.1.〇]己烷19&amp;(2〇11^， 0. 05mmol)，5-溴-2-氣-嘧啶（i2mg，〇. 〇6mmol)和碳酸铯 (41mg ’ 0. 13mmol)加入至5mL^於二曱基乙醯胺中，升至 150°C攪拌反應8小時。冷卻，加入25mL水，用乙酸乙酉旨 萃取（10raLx4)，合併有機相，用飽和氣化銨溶液洗滌 (10mLx5)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層 色譜法以展開劑體系A純化所得殘餘物，得到標題產物 (1 尤 550-3-(5-溴嘧啶-2-基）-6一[[2, 6-二氟-4-(4-曱磺醯 168 95344 201213319 基苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷52 (20mg ’白色固體），產率：8〇.⑽。 MS m/z (ESI)： 536.5 [M+l] !H NMR (400 MHz, CDCh) δ 8.32 (s, 2H), 8.02 (d, 2H), 7. 70 (d, 2H), 7. 18 (d, 2H), 4. 14 (d, 2H), 3. 90 (d, 2H), 3.58 (d, 2H), 3.10 (s, 3H), 1.77-1.75 (m, 2H), 1.18-1.16 (m, 1H). 實施例53 (3a&gt;?，知5*)-5-[2, 6-二氟-4-(4-甲續醯基笨基）苯氧基]-3, 3a，4, 5, 6, 6a-六氳-1H-環戊並|»比略-2-竣酸第三丁酯The crude product (1 especially 5^-641: 2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.〇]hexane 19&amp;(2〇11^, 0. 05mmol), 5-bromo-2-a-pyrimidine (i2mg, 〇. 〇6mmol) and cesium carbonate (41mg '0.13mmol) were added to 5mL^ in dimethyl hydrazine The mixture was stirred and stirred at 150 ° C for 8 hours. After cooling, 25 mL of water was added, and the mixture was extracted with ethyl acetate (10 raL×4). The organic phase was combined, washed with saturated aqueous ammonium sulfate (10 mL×5), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to purified crystals eluted to afford to afford the title product (1 550-3-(5-bromopyrimidin-2-yl)-6-[[2, 6- Fluoro-4-(4-oxasulfonyl 168 95344 201213319 phenyl) phenoxy] decyl]-3-azabicyclo[3.1.0]hexane 52 (20 mg 'white solid), yield: 8 10.(10) MS m/z (ESI): 536.5 [M+l] !H NMR (400 MHz, CDCh) δ 8.32 (s, 2H), 8.02 (d, 2H), 7. 70 (d, 2H) , 7. 18 (d, 2H), 4. 14 (d, 2H), 3. 90 (d, 2H), 3.58 (d, 2H), 3.10 (s, 3H), 1.77-1.75 (m, 2H) , 1.18-1.16 (m, 1H). Example 53 (3a&gt;?, know 5*)-5-[2, 6- Fluoro-4-(4-methyl sulfhydryl)phenoxy]-3, 3a,4, 5, 6, 6a-hexafluoro-1H-cyclopentapine|» 比略-2-竣酸三Butyl ester

第一步 六氫-1H-環戊並[c]吡咯—2-羧酸第三丁酯 將（3ai?，鈿«-5-溴-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c] 吡咯-2-羧酸第三丁酯153(1舀，3.5〇111111〇1)，4-溴-2,6-二氟 -苯酚（0. 72 g，3. 50mmol)和碳酸鉀（966mS，7. Ommol)加入 169 95344 201213319 至10mL况於二曱基乙醯胺中，升至10(TC攪拌反應12小 時。冷卻，加入20mL水，用乙酸乙酯萃取（20mLx3)，合併 有機相，無水硫酸鎂乾燥’過濾，濾液減壓濃縮，用矽膠 管柱色譜法以洗脫劑體系8純化所得殘餘物，得到標題產 物（办尤知«-5-(4-溴-2, 6-二氟-苯氧基）-3, 3a，4, 5, 6, 6a_ 六氫-1H-環戊並[c]吡咯―2-羧酸第三丁酯53a(lg，白色固 體），產率：68· 5%。 MS ra/z (ESI): 364.0 [M-55]The first step of hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3ai?, 钿«-5-bromo-3, 3a, 4, 5, 6, 6a-hexahydrogen -1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 153 (1舀, 3.5〇111111〇1), 4-bromo-2,6-difluoro-phenol (0. 72 g, 3 50mmol) and potassium carbonate (966mS, 7. Ommol) was added to 169 95344 201213319 to 10mL in diamyl acetamide, raised to 10 (TC stirred for 12 hours. Cooled, added 20mL water, extracted with ethyl acetate (20 mL×3), the organic phase was combined, dried over anhydrous magnesium sulfate <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -Bromo-2,6-difluoro-phenoxy)-3,3a,4,5, 6, 6a_ hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 53a (lg , white solid), Yield: 68· 5%. MS / / (ESI): 364.0 [M-55]

第二步 (办足知5·)-5-[2, 6-二氟一4_(4-甲磺醯基笨基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並比咯-2-羧酸第三丁酯 將（3a兄知5)-5-(4-溴6-二氟-苯氧基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]°比咯-2-羧酸第三丁酯 53a(500mg，1. 20 mol)，（4_曱磺酿基苯基）硼酸（311mg， 1. 56mmol)，1，1’ -二（二本鱗基） 一戊鐵·一氣化把（88mg ’The second step (hand to know 5·)-5-[2,6-difluoro- 4_(4-methanesulfonylphenyl)phenoxy]-3, 3a,4, 5, 6, 6a-six Hydrogen-1H-cyclopentapyrol-2-carboxylic acid tert-butyl ester (3a brother 5)-5-(4-bromo 6-difluoro-phenoxy)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]°, tert-but-2-carboxylic acid, tert-butyl ester 53a (500 mg, 1.20 mol), (4_sulfonyl phenyl) boric acid (311 mg) , 1.56mmol),1,1'-two (two scales), a pentane, a gasification (88mg'

0. 12mmol)和三水合磷酸鉀（958呃，3. 60则ϊ〇1)溶解於lOmL 1, 4-二噁烷中，升溫至回流攪拌反應12小時。過濾，濾液 減壓濃縮，用矽膠管枉色譜法以洗脫劑體系B純化所得殘 餘物，得到標題產物（3a尤知5〇-5-[2, 6-二氟-4-(4-曱確醯 基苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]吼咯 -2-羧酸第三丁酯53(380mg，白色固體），產率：64. 0%。 MS m/z (ESI): 438.1 [M-55] Ή NMR (400 MHz, CDCh) δ 8.01 (d, 2H), 7.75 (d, 2H), 7.17-7.15 (m, 2H), 4.92-4.89 (m, 1H), 3.62-3.57 (m, 170 95344 201213319 2H)，3.45-3.42 (m，2H)，3.10 (s，3H)，2.69 (s，2H) 2.26-2. 25 (m，2H)，1.92-1.89 (m，2H)，1.48 (s，9H) 實施例54, 55 6^15-(办_/?，知15)-5-[2,6-二氟-4-[(4-甲續酿基0辰*1秦1基） 曱基]苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3a, 4, 5, 6, 65-六0. 12 mmol) and potassium phosphate trihydrate (958 呃, 3.60 ϊ〇1) were dissolved in 10 mL of 1, 4-dioxane, and the mixture was heated to reflux and stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc Benzyl phenyl)phenoxy]-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 53 (380 mg, white Yield: 64. 0%. MS m/z (ESI): 438.1 [M-55] NMR (400 MHz, CDCh) δ 8.01 (d, 2H), 7.75 (d, 2H), 7.17- 7.15 (m, 2H), 4.92-4.89 (m, 1H), 3.62-3.57 (m, 170 95344 201213319 2H), 3.45-3.42 (m, 2H), 3.10 (s, 3H), 2.69 (s, 2H) 2.26-2. 25 (m, 2H), 1.92-1.89 (m, 2H), 1.48 (s, 9H) Example 54, 55 6^15-(do _/?, know 15)-5-[2, 6-Difluoro-4-[(4-methyl aryl-based 0 **1-methyl 1 yl) fluorenyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4 , 5, 6, 65-six

氳-1H-環戊並[c]*1比哈 疋知5·)-5-[2, 6-二氟-4-[(4-甲磺醯基哌嗪一1 一基） 曱基]笨氧基]-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6沒-六氮 -1H-環戊並[c]e比17各氲-1H-cyclopenta[c]*1 is more specific than 疋 疋 5·)-5-[2,6-difluoro-4-[(4-methanesulfonylpiperazine-l-yl) fluorenyl] Phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a,4, 5, 6, 6--hexanitro-1H-cyclopenta[c]e is 17

第一步 2，6-二氣-4-[(4-曱礦酿基派嗓-1-基）甲基]本紛 將粗品1-曱項醢基0底嗪If (636mg，3. 20mmol)和3, 5-二氟-4-羥基-苯曱醛（500mg，3. 20mmol)溶解於10mL二氣 171 95344 201213319 乙烷中’升溫至80°C攪拌反應2小時，冷卻至室溫，加人 三乙醯氧基蝴氫化鈉（1· 40g，6. 40mmol)，升溫至8〇°c授 拌反應12小時。加入1 〇mL飽和碳酸氫鈉溶液至反應液pjj 值為9 ’二氣甲烧萃取（20mLx3)，無水硫酸鎮乾燥，過溃， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所 得殘餘物，得到標題產物2,6-二氟-4-[(4-甲磺醯基哌。秦 -1-基）甲基]苯紛54a(500mg，白色固體），產率：51%。 第二步 φ 口/15-(3&lt;3尤知5')-5-[2,6-二氟-4-[(4-曱確醯基哌嗪-1_基） 甲基]苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3a, 4, 5, 6, 63~六 鲁 氫-1H-環戊並[c]吡咯 知5*)-5-[2, 6-二氟-4-[(4-曱磺醯基派嘻一1〜 基）甲基]苯氧基]-2-(5-乙基嘧啶-2-基）-3, 3沒，4, 5, 6, 六氫-1H-環戊並[^^吼略 將2, 6-二敗-4-[(4-甲續醯基派唤-1-基）曱基]笨紛 54a(100mg’ 0. 33mmol)’（3a尤知S)-5-溴-2-(5-乙基喷η定、 基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]n比ρ各 3a(97mg， φ 0. 33mmol)和碳酸奸（91mg，0. 66mmol)溶解於 5mL 况仏二 甲基曱醯胺中，升至100°C攪拌反應12小時。冷卻，加人 20mL水，用乙酸乙酯萃取（20mLx3)，合併有機相，用飽和 氯化鈉溶液洗滌（20mL)，無水硫酸鎂乾燥，過濾，據液減 壓濃縮，用薄層色譜法以展開劑體系B純化所得殘餘物， 得到一對非對映異構體產物，分別是知5·)-5-[2,6-二氟-4-[(4-甲磺醯基哌嗪-1-基）曱基]笨氧基]-2- 172 95344 201213319 (5-乙基喊咬-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戍並[c] 吡咯 54(30mg，白色固體），i/*5/7sK3a兄知5&quot;)-5-[2, 6-二 氟一4-[(4-曱磺醯基哌嗪-1-基）曱基]苯氧基]-2-(5-乙基 嘧啶-2-基）-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並[c]吡咯55 (10mg，白色固體）。 MS m/z (ESI): 522.3 [M+l] 54 ^ NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 6.85 (d, 2H), 4.84-4.78 (m, 1H), 3.83-3.78 (m, 2H), 3.70-3.66 φ (m, 2H), 3.45(s, 2H), 3. 27-3. 25 (m, 4H), 2. 79 (s, 5H), 2.56-2.54 (m, 4H), 2.48-2.46 (in, 2H), 2. 32-2.29 (m, 2H), 1.95-1.92 (m, 2H), 1.20 (t, 3H). 55 !H NMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 6.91-6.86 (m, 2H), 4.92 (s, 1H), 3.70-3.67 (m, 2H), 3.52-3.47 (in, 4H), 3.28-3.25 (m, 4H), 3.13-3.11 (m, 2H), 2.79 (s, 3H), 2.57-2.55 (m, 4H), 2.47-2.45 (m, 2H), 2.32-2.29 (in, 2H), 1.78-1.13 (m, 2H), 1.20-1.17 (t, 3H). • 實施例56 4-[4-[ [(1^ 55)-3-(5-乙基哺咬-2-基）-3-氮雜雙環並 [3. 1· 0]己烷-6-基]曱氧基]-3, 5-二氟-苯基]苄胺The first step 2,6-diox-4-[(4-曱-mineral-based 嗓-1-yl)methyl] will be the crude product 1-曱 醢 0 0 base azine If (636mg, 3. 20mmol And 3, 5-difluoro-4-hydroxy-phenylfurfural (500 mg, 3.20 mmol) dissolved in 10 mL of two gas 171 95344 201213319 ethane 'heated to 80 ° C, stirred for 2 hours, cooled to room temperature, Add sodium triethoxyphosphonium hydride (1·40 g, 6.40 mmol), and warm to 8 ° C to carry out a reaction for 12 hours. Add 1 〇mL of saturated sodium bicarbonate solution to the reaction liquid pjj value of 9 'two gas-burning extraction (20mLx3), anhydrous sulfuric acid drying, over-crushing, the filtrate is concentrated under reduced pressure, using gel column chromatography to eluent system The residue obtained was purified to give the title compound 2,6-difluoro-4-[(4-methylsulfonylpiped-qin-l-yl)methyl]benzene 54a (500 mg, white solid). 51%. The second step φ mouth /15-(3&lt;3 especially know 5')-5-[2,6-difluoro-4-[(4-indole-piperazine-l-yl)methyl]phenoxy 2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 63~liuluhydro-1H-cyclopenta[c]pyrrole 5*)-5-[ 2,6-Difluoro-4-[(4-oxasulfonylpyrylene-1-yl)methyl]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3 ,4, 5, 6, hexahydro-1H-cyclopenta[^^吼 will be 2,6-di-f--4-[(4- 醯 醯 派 派 -1- -1- 基 基)]] 54a (100 mg '0.33 mmol)' (3a is known as S)-5-bromo-2-(5-ethyl oxime, yl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H - cyclopenta[c]n ratio ρ3a (97mg, φ 0.33mmol) and carbonated (91mg, 0.66mmol) were dissolved in 5mL of dimethyl decylamine, and stirred to 100 ° C to stir the reaction 12 hours. The mixture was cooled with EtOAc (EtOAc) (EtOAc)EtOAc. The residue obtained by purifying the system B was purified to obtain a pair of diastereomers, respectively, which were known as 5·)-5-[2,6-difluoro-4-[(4-methylsulfonylpiperazine)- 1-yl) fluorenyl] phenyloxy]-2- 172 95344 201213319 (5-ethyl shrine-2-yl)-3, 3a,4, 5, 6, 6a-hexahydro-1H-cycloindole [c] Pyrrole 54 (30 mg, white solid), i/*5/7sK3a, brother 5&quot;)-5-[2,6-difluoro-4-[(4-oxasulfonylpiperazin-1-yl)曱]]phenoxy]-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole 55 (10 mg , white solid). MS m/z (ESI): 522.3 [M+l] 54 NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 6.85 (d, 2H), 4.84-4.78 (m, 1H), 3.83-3.78 (m, 2H), 3.70-3.66 φ (m, 2H), 3.45(s, 2H), 3. 27-3. 25 (m, 4H), 2. 79 (s, 5H), 2.56-2.54 (m , 4H), 2.48-2.46 (in, 2H), 2. 32-2.29 (m, 2H), 1.95-1.92 (m, 2H), 1.20 (t, 3H). 55 !H NMR (400 MHz, CDCh) δ 8. 18 (s, 2H), 6.91-6.86 (m, 2H), 4.92 (s, 1H), 3.70-3.67 (m, 2H), 3.52-3.47 (in, 4H), 3.28-3.25 (m, 4H), 3.13-3.11 (m, 2H), 2.79 (s, 3H), 2.57-2.55 (m, 4H), 2.47-2.45 (m, 2H), 2.32-2.29 (in, 2H), 1.78-1.13 ( m, 2H), 1.20-1.17 (t, 3H). • Example 56 4-[4-[ [(1^ 55)-3-(5-ethyl)-2-yl)-3-aza Bicyclo[3.1·0]hexane-6-yl]nonyloxy]-3,5-difluoro-phenyl]benzylamine

173 95344 201213319173 95344 201213319

NCNC

3131

FF

將4-[4-[ [ (1^ 55^-3-(5-乙基癌咬-2-基）-3-氮雜雙 環並[3. 1· 0]己烷-6-基]曱氧基]-3, 5-二氟-苯基]苄腈31 (20mg ’ 46 y mol)和氫氧化卸（3. 89mg，69“ mol)溶解於 20mL曱醇中’再加入lmL 30%過氧化氫，攪拌反應2小時。 Φ 冷卻’加入50mL水’用乙酸乙酯萃取（3〇mLx2)，合併有機 相’無水硫酸鎂乾燥’過濾，濾液減壓濃縮，得到標題產 物4-[4-[[(1兄550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1· 0]己烷-6-基]甲氧基]-3, 5-二氟-苯基]苄胺56 (15mg，白色固體），產率：75. 0%。 MS m/z (ESI): 451.5 [M+l] Ή NMR (400 MHz, CDCh) δ 8.21 (s, 2H), 7.89 (d, 2H), 參 7.60-7.62 (m, 2H), 7.17-7.19 (m, 2H), 4.12-4.14 (m, 2H), 3.94-3.97 (m, 2H), 3.60-3.62 (m, 2H), 2.46-2.52 (m, 2H), 1.75(s, 2H), 1.26(s, 1H), 1.17-1. 22 (m, 3H). 實施例57 4-[5-氯-4-[ [(1尤55&quot;)-3-(5-乙基痛淀-2-基）-3-氮雜雙環 並[3. 1.0]己烷-6-基]甲氧基]-2-氧-1-吡啶基]-2-氟-苄 腈 174 95344 2012133194-[4-[[(1^55^-3-(5-ethylcarban-2-yl)-3-azabicyclo[3.1·0]hexane-6-yl]曱Oxy]-3, 5-difluoro-phenyl]benzonitrile 31 (20 mg '46 y mol) and hydrolytic (3.39 mg, 69" mol) dissolved in 20 mL of sterol' plus 1 mL of 30% Hydrogen peroxide, stirring reaction for 2 hours. Φ Cooling 'Addition of 50 mL of water' was extracted with ethyl acetate (3 〇 mL×2), and the combined organic phases were dried over anhydrous magnesium sulfate. [[(1 brother 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1] 0]hexane-6-yl]methoxy]-3, 5- Difluoro-phenyl]benzylamine 56 (15 mg, mp. , 2H), 7.89 (d, 2H), Ref. 7.60-7.62 (m, 2H), 7.17-7.19 (m, 2H), 4.12-4.14 (m, 2H), 3.94-3.97 (m, 2H), 3.60- 3.62 (m, 2H), 2.46-2.52 (m, 2H), 1.75 (s, 2H), 1.26 (s, 1H), 1.17-1. 22 (m, 3H). Example 57 4-[5-chloro -4-[ [(1 especially 55&quot;)-3-(5-ethyloxan-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]- 2-oxo-1-pyridyl]-2-fluoro-benzonitrile 174 95344 2012133 19

NC·NC·

ClCl

Cl 57a 57bCl 57a 57b

參Reference

4-(5-氣-4-經基-2-氧-1-11比'1定基）-2-氟-节腈 將 5-氯-4-經基-1及-°比咬-2-酮 57a(177mg，1. 21mmol)， 2-氟-4-蛾-苄腈（30Omg，1. 21 mmol)，1，10-二氣雜菲 (44mg，0. 24mmol)，碳酸鉀（334mg ’ 2. 40mmol)和峨化亞銅 (46mg，0. 24mmol)加入至20mL二曱基亞石風中，升至140°C 擾拌反應3小時。冷卻，加入50mL水，滴加1 Μ氯化氫溶 液至反應液pH值為2，用乙酸乙酯萃取（100mLx2)，合併 有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠 管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產 物4-(5-氯-4-經基-2-氧-1-π比唆基）-2-氟-节猜57b(71mg’ 黃色固體），產率：22.0%。 MS m/z (ESI): 265.1 [M+1] 第二步 4-[5-氣-4-[ [(1足55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 175 95344 201213319 並[3. 1. 0]己烷-6-基]曱氧基]-2-氧-1-吡啶基]-2-氟-节 腈 將4-(5-氯-4-經基-2-氧-1-〇比淀基）-2-氟-节腈57b (71mg，0. 30mmol)’粗品[(1足 55^-3-(5-乙基嘧啶-2-基）-3- 氮雜雙環並[3. 1.0]己烷-6-基]曱磺酸曱酯7g(80mg，4-(5-Gas-4-Phenyl-2-oxo-1-11 is more than '1'-)-Fluoro-nodal nitrile 5- 5-chloro-4-yl-1 and -° ratio -2- Ketone 57a (177 mg, 1.21 mmol), 2-fluoro-4-moth-benzonitrile (30 mg, 1.21 mmol), 1,10-diphenanthrene (44 mg, 0.25 mmol), potassium carbonate (334 mg) 2. 40 mmol) and cuprous copper (46 mg, 0.24 mmol) were added to 20 mL of dimercapite, and the mixture was stirred at 140 ° C for 3 hours. After cooling, add 50 mL of water, add 1 Μ of hydrogen chloride solution to the reaction solution, pH 2, extract with ethyl acetate (100 mL×2), combine the organic phase, dry over anhydrous magnesium sulfate, and filter. The residue obtained was purified by eluent system B to give the title product 4-(5-chloro-4-y- </RTI> Solid), Yield: 22.0%. MS m/z (ESI): 265.1 [M + 1] Step 2 4-[5- -4- -4-[ [(1) s. Azabicyclohexene 175 95344 201213319 and [3. 1. 0]Hex-6-yl]nonyloxy]-2-oxo-1-pyridyl]-2-fluoro- nitrite will be 4-(5-chloro- 4-Phenyl-2-oxo-1-indenyl amide)-2-fluoro-phthonitrile 57b (71 mg, 0.30 mmol) 'crude [(1 foot 55^-3-(5-ethylpyrimidine-2) -yl)-3-azabicyclo[3.1.0]hexane-6-yl]phosphonium sulfonate 7 g (80 mg,

0. 30mmol)和碳酸絶（I75mg，0.62mmol)加入至 i〇mL 二曱基曱醯胺中，升至90°C攪拌反應6小時。冷卻，加入 50mL水’用乙酸乙酯萃取（2〇mLx2)，合併有機相，無水硫 # 酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑 體系B純化所得殘餘物，得到標題產物4-[5-氣-4-[[(1疋55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己 烧-6-基]甲氧基]-2-氧-l-n比咬基]-2-氟-苄腈57(10mg，淺 黃色固體），產率：8.0%。 MS m/z (ESI)： 466.2 [M+l] Ή NMR (400 MHz, CDCh) ά 8.20 (s, 2H), 8.05 (s, 1H), 等 7.60-7.64 (m, 1H), 7.02-7.06 (m, 2H), 6.51 (s, 1H), 4.10-4.12 (m, 2H), 3.99-4.02 (m, 2H), 3.59-3.62 (in, 2H), 2.45-2.51 (m, 2H), 1.83 (s, 2H), 1.27 (s, 1H), 1. 17-1.21 (m, 3H). 實施例58 (1足55*)-6-[[2,5-二氟-4-(4-曱磺醯基苯基）苯氧基]曱 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 176 95344 2012133190. 30 mmol) and carbonic acid (I75 mg, 0.62 mmol) were added to i〇mL dimethyl decylamine, and the reaction was stirred at 90 ° C for 6 hours. After cooling, 50 mL of water was added and extracted with ethyl acetate (2 mL mL). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 4-[5-gas-4-[[(1疋55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.]] 6-yl]methoxy]-2-oxo-ln butyl]-2-fluoro-benzonitrile 57 (10 mg, pale yellow solid), yield: 8.0%. MS m/z (ESI): 466.2 [M+l] Ή NMR (400 MHz, CDCh) ά 8.20 (s, 2H), 8.05 (s, 1H), etc. 7.60-7.64 (m, 1H), 7.02-7.06 (m, 2H), 6.51 (s, 1H), 4.10-4.12 (m, 2H), 3.99-4.02 (m, 2H), 3.59-3.62 (in, 2H), 2.45-2.51 (m, 2H), 1.83 (s, 2H), 1.27 (s, 1H), 1. 17-1.21 (m, 3H). Example 58 (1 foot 55*)-6-[[2,5-difluoro-4-(4- Sulfosylphenyl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 176 95344 201213319

第一步first step

2, 5-二氟-4-(4-曱磺醯基苯基）苯酚 將 4-溴-2, 5-二氟-苯紛 58a(500mg，2. 34imnol)，（4-甲磺醯基苯基）硼酸（479mg，2. 34mmol)，1，Γ -二（二苯膦 基）二茂鐵二氯化鈀（175mg，0. 20mmol)和碳酸铯（2. 34 g， 7mmol)溶解於20mL 1，4-二噁烷中，升溫至120°C攪拌反應 2小時。冷卻，加入60mL水，用乙酸乙酯萃取（20mLx2)， 合併有機相，滴加4M氫氧化鈉溶液至反應液pH值為3， 萃取分離，水相滴加1Μ氯化氫溶液至反應液pH值為6， 用乙酸乙酯萃取（50mLx2)，合併有機相，無水硫酸鎂乾燥， 過遽’遽液減堡濃縮*得到粗品標題產物2，5_·—亂_4_(4_ 曱磺醯基苯基）苯酚58b(900mg，灰色固體），產率：66. 0%。 MS m/z (ESI): 302.1 [M+18] 第二步 (17?，5«-6-[ [2, 5-二氟-4-(4-曱磺醯基苯基）苯氧基]曱 177 95344 201213319 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1〇]己烷 將粗品2, 5-二氟-4-(4-曱磺醯基苯基）苯酚58b (lOOmg，0.35mmol)，粗品[(1尤 5i9)_3_(5_乙基嘧啶_2一 基）-3-氮雜雙環並[3. 1. 〇]己烷-6-基]甲磺酸曱酯7g (105mg，0.35mmol)和碳酸铯（339mg，0.7Ommol)加入至 lOmL水#-二曱基曱醯胺中，升至卯力攪拌反應3小時。 冷卻，加入40mL水，用乙酸乙酯萃取（4〇mLx2)，合併有機 相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜 ^ 法以展開劑體系B純化所得殘餘物，得到標題產物 (U 550-6-[[2, 5-二氟-4-(4-甲磺醯基笨基）苯氧基]甲基] -3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷58 (30mg，白色固體），產率：17. 7%。 MS m/z (ESI): 486.2 [M+l] 4 丽R (400 MHz, CDC13) (5 8.21 (s，2H)，8.00 (d，2H)， 7.70 (d, 2H), 7.18-7.23 (m, 1H), 6.79-6.83 (m, 1H), φ 4. 02-4. 06(m, 4H), 3. 62-3. 64(m, 2H), 3.09 (s, 3H), 2.46-2.52 (m, 2H), 1.82 (s, 2H), 1.24-1.27 (m, 1H), 1. 18-1. 22 (m, 3H). 實施例59 (3a尤知5^-2-(5-乙基痛咬-2-基）-5-[4-(4-甲確醯基苯基） 本氧基]-3, 3a, 4, 5, 6, 6a-六氫-1H-環戊並比口各2,5-difluoro-4-(4-oxasulfonylphenyl)phenol 4-bromo-2,5-difluoro-benzophenone 58a (500 mg, 2.34 imnol), (4-methylsulfonyl) Phenyl)boronic acid (479 mg, 2.34 mmol), 1, fluorene-bis(diphenylphosphino)ferrocene palladium dichloride (175 mg, 0.20 mmol) and cesium carbonate (2. 34 g, 7 mmol) were dissolved in In 20 mL of 1,4-dioxane, the mixture was heated to 120 ° C and stirred for 2 hours. After cooling, add 60 mL of water, extract with ethyl acetate (20 mL×2), combine the organic phase, add 4M sodium hydroxide solution to the pH of the reaction solution, extract, and add 1 Μ hydrogen chloride solution to the pH of the reaction solution. 6. Extract with ethyl acetate (50 mL×2), combine the organic phases, dry over anhydrous magnesium sulfate, and then dry over 遽 遽 遽 减 减 * * * 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 4 4 4 4 4 4 ) ) ) ) ) ) ) ) ) ) ) 0%。 Phenol 58b (900mg, gray solid), yield: 66.0%. MS m/z (ESI): 302.1 [M+18] Step 2 (17?,5«-6-[ [2, 5-difluoro-4-(4-oxasulfonylphenyl)phenoxy) ]曱177 95344 201213319 基]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1〇]hexane The crude product 2, 5-difluoro-4-(4- Sulfosylphenyl)phenol 58b (100 mg, 0.35 mmol), crude [(1 especially 5i9)_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇] 7 g of alkyl-6-yl]methanesulfonate (105 mg, 0.35 mmol) and cesium carbonate (339 mg, 0.70 mmol) were added to 10 mL of water #-didecylguanamine, and the mixture was stirred for 3 hours. After cooling, 40 mL of water was added, and the mixture was extracted with ethyl acetate (4 mL mL), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Title product (U 550-6-[[2,5-difluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl) 3-Azabicyclo[3.1.0]hexane 58 (30 mg, white solid), yield: 17.7%. MS m/z (ESI): 486.2 [M+l] 4 400 MHz, CDC13) (5 8.21 (s, 2H), 8.00 (d, 2H), 7.70 (d, 2H), 7.18- 7.23 (m, 1H), 6.79-6.83 (m, 1H), φ 4. 02-4. 06(m, 4H), 3. 62-3. 64(m, 2H), 3.09 (s, 3H), 2.46-2.52 (m, 2H), 1.82 (s, 2H), 1.24-1.27 (m, 1H), 1. 18-1. 22 (m, 3H). Example 59 (3a, especially 5^-2- (5-ethylheptan-2-yl)-5-[4-(4-methyl-decylphenyl) hydroxy]-3, 3a, 4, 5, 6, 6a-hexahydro-1H- Cyclopentyl

95344 178 20121331995344 178 201213319

第一步 (3a^ ^350-5-(4-演笨氧基）-2-(5-乙基Ρ密咬-2-基）-鲁 3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並[c]吡咯 鲁 將（3a尤沒35&quot;)-5_漠-2-(5-乙基η密咬_2-基）一 3, 3a，4, 5, 6, 6a-六氫-1Η-環戊並[c]n比β各 3a(300mg， lmmol) ’ 4-溴苯酚（175mg，lmmol)和碳酸鉀（28〇mg，2mmol) 加入至lOmL^yV-二甲基甲醯胺中’升至12〇。〇攪拌反應5 小時。冷卻，加入15mL水’用乙酸乙酯萃取（3〇mLx3)，合 併有機相’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物（3a尤知5^-5-(4-演苯氧基）_2-(5-乙基喊咬 -2-基）_3，3习，4，5，6，63_六氮_1H~環戊並[c]»比洛 59a (350mg，棕色油狀），產品不經純化直接進行下一步反應。 MS m/z (ESI): 388.1 [M+l] 第二步 (3a足知5)-2-(5-乙基p密淀-2-基）-5-[4-(4-曱續酿基苯基） 苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[^]β比洛 將粗品（33疋知5&quot;)_5_(4_&gt;臭本氧基）-2-(5-乙基喊淀 -2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]n比咯 59a 179 95344 201213319 (350mg，0. 90mmol)，（4-曱橫醯基苯基）蝴酸（216mg， 1. lOmmol)，1，Γ -二（二苯膦基）二茂鐵二氣化ls(66mg， 0. 09mmol)和碳酸鉋（880mg，2. 70mmol)溶解於 i5mLl，4-二 噁烷中，升溫至120°C攪拌反應5小時。冷卻’加入20mL 水，用乙酸乙酯萃取（30mLx3) ’合併有機相，飽和氣化鈉 溶液洗滌（20mLx3)，無水硫酸鎂乾燥’過濾，濾液減壓濃 縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物， 得到標題產物（3a)?，知^-2-(5-乙基嘧啶-2-基）-5-[4-(4-# 甲磺醯基苯基）苯氧基]-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並 [匸]°比咯59(3〇11^，白色固體），產率：7.2%。 MS m/z (ESI): 464. 2 [M+l] Ή NMR (400 MHz, CDCh) δ 8. 19 (s, 2H), 7.97 (d, 2H), 7.71 (d, 2H), 7.51 (d, 2H), 6.90 (d, 2H), 4.89-4.94 (m, 1H), 3.79-3.84 (m, 2H), 3.65-3.68 (in, 2H), 3.09 (s, 3H), 2.88-2.92 (m, 2H), 2.48 (q, 2H), 2.38-2.45 赢(m, 2H), 1.92-1.97 (m, 2H), 1.20 (t, 3H). 實施例60 (1^ 560-6-(^(2, 6-二氟-4-噠嗪-4-基-苯氧基）曱基]_3_ (5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷The first step (3a^^350-5-(4-desyloxy)-2-(5-ethyl guanidine-2-yl)-Lu 3, 3a, 4, 5, 6, 6a-six Hydrogen-1Η-cyclopenta[c]pyrrole will be (3a especially 35&quot;)-5_ desert-2-(5-ethyl η 密_2-yl)-3, 3a, 4, 5, 6 , 6a-hexahydro-1Η-cyclopenta[c]n ratio β each 3a (300mg, lmmol) '4-bromophenol (175mg, 1mmol) and potassium carbonate (28〇mg, 2mmol) added to lOmL^yV- In dimethylformamide, the temperature was increased to 12 Torr. The reaction was stirred for 5 hours. After cooling, 15 mL of water was added, and extracted with ethyl acetate (3 〇mL×3). The organic phase was combined and dried over anhydrous magnesium sulfate. Concentration to obtain the crude title product (3a, especially 5^-5-(4- phenoxy)_2-(5-ethyl-chal-2-yl)_3,3,4,5,6,63_ Hexanitro-1H~cyclopenta[c]»Bilo 59a (350 mg, brown oil), product was taken to the next step without purification. MS m/z (ESI): 388.1 [M+l] (3a is known as 5)-2-(5-ethylp-melt-2-yl)-5-[4-(4-anthracenylphenyl)phenoxy]-3, 3a, 4, 5 , 6, 6a-hexahydro-1H-cyclopenta[^]βpirin will be crude (33疋知5&quot;)_5_(4_&gt;odorooxy)-2-(5-ethyl -2--2-yl)-3,3a,4,5, 6, 6a-hexahydro-1H-cyclopenta[c]n ratio 159a 179 95344 201213319 (350mg,0. 90mmol), (4-曱横Nonylphenyl)folic acid (216 mg, 1.10 mmol), 1, Γ-bis(diphenylphosphino)ferrocene digasification ls (66 mg, 0.99 mmol) and carbonic acid planer (880 mg, 2.70 mmol) Dissolved in i5 mL of 1,4-dioxane, and warmed to 120 ° C to stir the reaction for 5 hours. Cooled 'Add 20 mL of water, extract with ethyl acetate (30 mL×3). Combine the organic phase, wash with saturated sodium carbonate solution (20 mL×3), Drying over anhydrous magnesium sulfate <filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to the titled product (3a) with the eluent column chromatography to give the title product (3a). -yl)-5-[4-(4-#methylsulfonylphenyl)phenoxy]-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[匸]° ratio 59 (3〇11^, white solid), yield: 7.2%. MS m/z (ESI): 464. 2 [M+l] NMR (400 MHz, CDCh) δ 8. 19 (s, 2H ), 7.97 (d, 2H), 7.71 (d, 2H), 7.51 (d, 2H), 6.90 (d, 2H), 4.89-4.94 (m, 1H), 3.79-3.84 (m, 2H), 3.65- 3.68 (in, 2H), 3.09 (s, 3H), 2.88-2.92 (m, 2 H), 2.48 (q, 2H), 2.38-2.45 win (m, 2H), 1.92-1.97 (m, 2H), 1.20 (t, 3H). Example 60 (1^ 560-6-(^(2) , 6-difluoro-4-pyridazin-4-yl-phenoxy)indolyl]_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane

180 95344 201213319180 95344 201213319

將 4-漠_2，6_ — 氣-笨盼 60a(lOOmg ’ 0. 48ππη〇1)，三 第三丁基（達唤-4-基）錫（196mg，0. 53mmol)和 1，1’ 一二 (二苯膦基）二茂鐵二氯化ls(10mg，0. Olmmol)溶解於5mL 1，4-二噁烷中，升溫至110°C攪拌反應10小時。冷卻，加 入10mL水，用乙酸乙酯萃取（20mLx3)，合併有機相，飽和 氯化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥，過濾，濾液 減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘 餘物，得到標題產物2, 6-二氟-4-噠嗪-4-基-苯酚60b (72mg，淺黃色固體），產率：72. 7%。 MS m/z (ESI): 208.8 [M+l] 第二步 (1兄5«-6-[(2, 6-二氟-4-噠嗪~4-基-笨氧基）曱基]ΙΟ-乙 基嘧啶-2-基 ）-3-氮雜 雙環並 [3. 1. 0] 己烷 將2,6-二氟-4-建嗓-4-基-笨紛601)(45111尽， 〇.22minol) ’ 粗品[(1^55^-.3-(5-乙基喊咬-2-基）_3_氮雜 雙環並[3. 1. 0]己烧-6-基]甲續酸甲醋7g(64mg，0. 22mmol) 和碳酸I色（141mg，0. 43mmol)加入至10mL况二曱基曱酿 181 95344 201213319 胺中，升至9(TC攪拌反應3小時。冷卻，加入2〇mL水， 用乙酸乙酯萃取（30mLx3)，合併有機相，飽和氯化鈉溶液 洗滌（30mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮， 用碎膠管柱色s普法以洗脫劑體系B純化所得殘餘物，得到 才示《|產物（1疋55&quot;)-6-[(2, 6-二說-4-健嗪-4-基-苯氧基）甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3, 1. 〇]己烷60 (15mg，白色固體），產率：16. 9%。 MS m/z (ESI)： 410.2 [M+l] 鲁 *11 NMR (400 MHz, CDCh) δ 9.41-9.43 (m, 1H), 9.26-9.28 (m, 1H), 8. 17-8. 19 (m, 2H), 7.58-7.60 (m, 1H), 7.24-7.26 (m, 2H), 4.17-4.19 (m, 2H), 3.90-3.93 (m, 2H), 3.56-3.59 (m, 2H), 2.44-2.50 (m, 2H), 1.63-1.65 (m, 2H), 1.23-1.26 (m, 1H), 1.16-1.20 (ra, 3H). 實施例61 (办疋知«-5_[2, 6-二氟-4-(4-氰基苯基）苯氧基]-2-(5-^ 乙基嘴°定-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c]°比哈4-Si_2,6_-gas-stupid 60a (100 mg '0. 48ππη〇1), tri-tert-butyl (D--4-yl) tin (196 mg, 0.53 mmol) and 1,1' The bis(diphenylphosphino)ferrocene dichloride ls (10 mg, 0. Olmmol) was dissolved in 5 mL of 1,4-dioxane, and the mixture was warmed to 110 ° C and stirred for 10 hours. After cooling, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title compound: 2, 6-difluoro-4-pyridazin-4-yl-phenol 60b (72 mg, pale yellow solid). MS m/z (ESI): 208.8 [M+l] Step 2 (1 brother 5«-6-[(2,6-difluoro-4-pyridazin~4-yl-phenyloxy)indolyl] ΙΟ-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane will be 2,6-difluoro-4-indol-4-yl-stupid 601) (45111 , 〇.22minol) '粗品[(1^55^-.3-(5-ethyl shouting-2-yl)_3_azabicyclo[3. 1. 0]hexa-6-yl] 7 g (64 mg, 0.22 mmol) of a continuous acid methyl vinegar and a color (141 mg, 0.43 mmol) of carbonic acid were added to 10 mL of the diterpene broth 181 95344 201213319 amine, and the mixture was raised to 9 (TC stirring reaction for 3 hours. Cooling, 2 mL of water was added, and extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by de-batch system B to obtain "|product (1疋55&quot;)-6-[(2,6-di-yt-4-phenylazin-4-yl-phenoxy)methyl]- 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3, 1. oxime]hexane 60 (15 mg, white solid), yield: 16.9%. MS m/z ( ESI): 410.2 [M+l] Lu*11 NMR (400 MHz, CDCh) δ 9.41-9.43 (m, 1H), 9.2 6-9.28 (m, 1H), 8. 17-8. 19 (m, 2H), 7.58-7.60 (m, 1H), 7.24-7.26 (m, 2H), 4.17-4.19 (m, 2H), 3.90 -3.93 (m, 2H), 3.56-3.59 (m, 2H), 2.44-2.50 (m, 2H), 1.63-1.65 (m, 2H), 1.23-1.26 (m, 1H), 1.16-1.20 (ra, 3H). Example 61 (Knowing ««-5_[2,6-Difluoro-4-(4-cyanophenyl)phenoxy]-2-(5-^ 乙嘴°定-2- Base)-3, 3a,4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]°biha

將粗品（33^&gt;，635')_5_(4-演-2，6_二說_苯氧基）-2-(5-乙基嘧啶-2-基）-3, 3a，4, 5, 6, 6a-六氫-1H-環戊並[c] 182 95344 201213319 吡咯 4a(210mg，0. 50mmol)，（4-氰基笨基）硼酸（ii〇mg， 0· 75mmol)，1，Γ -二（二苯膦基）二茂鐵二氯化鈀（36mg， 0. 05mmol)和磷酸鉀（400mg，1· 50mmol)溶解於 2〇mLi, 4-二 噁烷中’升溫120°C攪拌反應3小時。過濾，濾液加入2〇mL 水，乙酸乙酯萃取（50mLx3)，合併有機相，無水硫酸鎮乾 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體 系B純化所得殘餘物，得到標題產物（3a&gt;?，6-二氟-4-(4-氰基苯基）苯氧基]-2-(5-乙基嘧啶-2〜基） 鲁-3, 3a，4, 5, 6, 6a-六氳-1H-環戊並[c]°比洛 61 (80mg，白色 固體），產率：36. 4%。 MS m/z (ESI): 447.2 [M+l] ^NMR (400 MHz, CDCh) ^ 8.22 (s, 2H), 7.74-7.72 (m, 2H), 7. 61-7. 59 (m, 2H), 7. 14-7. 09 (m, 2H), 4.96-4.93 (m, 1H), 3.87-3.69 (m, 4H), 2.85 (s, 2H), 2.52-2.46 (m, 2H), 2.36-2.33 (m, 2H), 2.02-1.97 (m, 2H), 1.21-1.19 (m, 3H) 實施例62 2-[2, 6-二氟-4-(4-甲磺醯基苯基）笨氧基]-7-氮雜螺環 [3. 5]壬烷-7-羧酸第三丁酯The crude product (33^&gt;, 635') _5_(4-act-2,6_bis _phenoxy)-2-(5-ethylpyrimidin-2-yl)-3, 3a, 4, 5 , 6, 6a-hexahydro-1H-cyclopenta[c] 182 95344 201213319 pyrrole 4a (210 mg, 0.50 mmol), (4-cyanophenyl)boronic acid (ii〇mg, 0·75 mmol), 1, Γ-bis(diphenylphosphino)ferrocene palladium dichloride (36 mg, 0.05 mmol) and potassium phosphate (400 mg, 1.50 mmol) dissolved in 2 〇mLi, 4-dioxane, 'temperature rise 120 ° C The reaction was stirred for 3 hours. Filtration, the filtrate was added with 2 mL of water, and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sulphuric acid, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B. The title product was obtained (3a&gt;?,6-difluoro-4-(4-cyanophenyl)phenoxy]-2-(5-ethylpyrimidin-2-yl) ru-3, 3a, 4, 5 , 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 NMR (400 MHz, CDCh) ^ 8.22 (s, 2H), 7.74-7.72 (m, 2H), 7. 61-7. 59 (m, 2H), 7. 14-7. 09 (m, 2H), 4.96-4.93 (m, 1H), 3.87-3.69 (m, 4H), 2.85 (s, 2H), 2.52-2.46 (m, 2H), 2.36-2.33 (m, 2H), 2.02-1.97 (m, 2H) ), 1.21-1.19 (m, 3H) Example 62 2-[2,6-Difluoro-4-(4-methylsulfonylphenyl) phenyloxy]-7-azaspiro[3. ] decane-7-carboxylic acid tert-butyl ester

95344 183 20121331995344 183 201213319

• 第一步 鲁 4-曱烯基哌啶-1-羧酸第三丁酯 將三苯基曱基溴化膦（1. 80g，0. 05 mol)加入至100mL 四氫呋喃中，冰浴下，加入第三丁醇鉀（5. 60g，0. 05 mol)， 攪拌30分鐘，加熱回流1小時，再冰浴冷卻至0°C，滴加 20mL 4-氧基旅咬-1-叛酸第三丁酯62a(5g，0. 03 mol)的 四氳吱喃溶液，升溫至回流擾拌反應4小時。加入100mL ▲ 水，乙酸乙i旨萃取（100mLx3)，合併有機相，無水硫酸鎂乾 • φ 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體 系B純化所得殘餘物，得到標題產物4-甲烯基哌啶-1-羧 酸第三丁酯62b(4. 20g，無色油狀），產率：86. 0%。 第二步 2-氧基-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯 將4-甲烯基哌啶-1-羧酸第三丁酯62b(l g，5. lOmmol) 和鋅-銅（4. 30 g，66mmol)加入至20mL乙鍵中，滴加10mL 三氯乙醯氯（4.70g，26mmol)的况於二甲基曱醯胺，攪拌 184 95344 201213319 反應12小時。冰浴下，加入100mL飽和碳酸氫鈉溶液，過 渡’乙酸乙酯萃取（50mLx3)，合併有機相，無水硫酸鎂乾 燥’濾液減壓濃縮。加入5〇mL 2 Μ氣化銨的曱醇溶液，分 批加入活化鋅粉（16g’0.25mol)，室溫反應12小時。過濾， 遽液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所 得殘餘物，得到標題產物2-氧基-7-氮雜螺環[3. 5]壬烷 敌酸第三丁酯62c(600mg，白色固體），產率：50.0%。 第三步 鲁 2~經基-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯 將2-氧基-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯 62c(60〇mg，2. 53mmol)溶解於i〇mL曱醇中，冰浴下，加 入蝴氫化鈉（187mg，5. 06mmol)，升至室溫，攪拌反應12 小時。加入20mL 1 Μ鹽酸，乙酸乙酯萃取（50mLx3)，合併 有機相’飽和氣化鈉溶液洗滌〇00mLx3)，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，得到粗品標題產物2-羥基-7- % 氮雜螺環[3· 5]壬烧羧酸第三丁酯62d(410mg，無色固 體），產率：68%。 MS m/z (ESI): 186.1 [M-55] 第四步 2曱項醯基氧基-7-氮雜螺環[3· 5]壬烷_7_羧酸第三丁酯 冰浴下，將粗品2-羥基_7_氮雜螺環[3. 5]壬烷_7_羧 酸第三丁醋62d(200mg，〇. 82mmol)溶解於5mL無水二氣甲 烷中，加入二乙胺（248mg，2. 46mmol)，滴加甲磺醯氣 (I4lmg’ 1.24顏〇1)，升至室溫，攪拌反應丨5小時。加入 185 95344 201213319 1 OmL水，乙酸乙酯萃取（20mLx3)，合併有機相，依次用水 (5mLx3)，飽和氣化鈉溶液洗條（5mLx3)，無水硫酸納乾燥， 過濾，濾液減壓濃縮，得到粗品標題產物2-甲磺醢基氧基 -氮雜螺環[3. 5]壬烧-7-紱酸第三丁 g旨62e(215mg ’無色 油狀物），產物不經純化直接進行下一步反應。 第五步 2，6_一敗_4-（曱續酿基笨基）苯紛 將 4-溴-2, 6-二氟-苯齡 62f (500mg，2. 83mmol)，（4~ 鲁 曱績酿基苯基）侧酸（690mg，3. 40mmol)，1，1’ -二（二笨鱗 基）二茂鐵二氯化把（204mg，0. 28mmol)和三水合鱗酸却 (1. 90 g’7· 20mmol)溶解於 12mLl，4-二噁炫和水（v/V = 5:1) 混合溶劑中，升溫至120°C攪拌反應5小時。加入20mL水， 乙酸乙酯萃取（20mLx3)，合併有機相，用飽和氣化鈉溶液 洗滌（10mLx3)，無水硫酸鈉乾燥’過濾，濾液減壓濃縮， 得到粗品標題產物2, 6-二氟-4-(曱績醯基苯基）苯酚62g ^ (570mg ’棕色固體）’產物不經純化直接進行下一步反應。 MS m/z (ESI): 302.1 [M+18] _ 第六步 2-[2, 6-二氟-4-(4-甲磺醯基苯基）苯氧基]_7_氮雜螺環 [3· 5]壬烷-7-羧酸第三丁酯 將粗品2-甲磺醯基氧基-7-氮雜螺環[3.5]壬烷-7-羧 酸第二丁酯 62e(215mg’ 0. 67mmol)，粗品 2, 6-二氟-4-(甲 磺醯基苯基）苯酚62g(191mg’ 0. 67mmol)和碳酸鉀（277mg， 2mmo 1)溶解於2 〇mL 二甲基甲醯胺中，升溫至1〇〇。〇， 186 95344 201213319 授拌反應12小時。加入2〇mL水’用乙酸乙酿萃取（5〇mLx2)， 合併有機相，依次用水（1〇mLx3)，飽和氯化鈉溶液洗滌 (10mLx3)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄 層色譜法以展開劑體系B純化所得殘餘物，得到標題產物 2-[2’6-二氟-4-(4-曱磺醯基笨基）苯氧基μ7_氮雜螺環 [3.5]壬烷-7-綾酸第三丁酯62(25〇!^，白色固體），產率： 73. 0〇/〇。 MS m/z (ESI): 408.2 [M+l-100] • *H NMR (400 MHz, d-dWSO) δ 7. 99 (s, 4H), 7.64 (d, 2H) 4.83-4.80 (m，1H)，3.32 (s，3H), 3.25-3. Η (m，2H)’ 2.33-2.28 (m，2H)，1.96-1.91 (m，2H)，1.53—i (m 2H)，1.47-1.35 (m，9H)，1.30-1.26 (m，2H), 1 15-i i2 (m, 2H). 實施例63 2-[2, 6-二氟-4-(4-曱磺醯基苯基）笨氧基]_7_(5_乙基嘧 α定-2-基）-7-氮雜螺環[3. 5]壬燒• The first step of the 4-butenylpiperidine-1-carboxylic acid tert-butyl ester, triphenylsulfonium bromide (1. 80g, 0.05 mol) was added to 100mL of tetrahydrofuran, under ice bath, Add potassium tert-butoxide (5. 60g, 0.05 mol), stir for 30 minutes, heat to reflux for 1 hour, then cool to 0 ° C in an ice bath, add 20 mL of 4-oxybend brittle--1-reacid A solution of tributyl ester 62a (5 g, 0.03 mol) in tetrahydrofuran was heated to reflux to react for 4 hours. Add 100 mL of ▲ water, extract with acetic acid (100 mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, φ dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by eluent column chromatography with eluent column chromatography. 0%。 The title product was obtained by the title product: 4-methyl-l-piperidine-l-carboxylic acid tert-butyl ester 62b (4. 20 g, colorless oil). Second step 2-oxy-7-azaspirocyclo[3.5.nonane-7-carboxylic acid tert-butyl ester 4-methylenylpiperidine-1-carboxylic acid tert-butyl ester 62b (lg 5, lOmmol) and zinc-copper (4. 30 g, 66 mmol) were added to 20 mL of the ethyl bond, and 10 mL of trichloroacetonitrile chloride (4.70 g, 26 mmol) was added dropwise to the dimethyl decylamine. 95344 201213319 Reaction 12 hours. Under ice-cooling, a solution of EtOAc (EtOAc m. A solution of 5 〇 mL of 2 hydrazine hydride in methanol was added, and activated zinc powder (16 g' 0.25 mol) was added in portions and allowed to react at room temperature for 12 hours. After filtration, the mash was concentrated under reduced pressure, and the obtained residue was purified to the titled product 2-oxy-7-azaspiro[3. Butyl ester 62c (600 mg, white solid), yield: 50.0%. The third step is 2-2, alkyl-7-azaspiro[3.5]decane-7-carboxylic acid, tert-butyl ester, 2-oxo-7-azaspiro[3. 5]decane -7-carboxylic acid tert-butyl ester 62c (60 〇mg, 2.53 mmol) was dissolved in i〇mL sterol, and added to sodium hydrogen hydride (187 mg, 5.06 mmol) under ice-cooling. Reaction for 12 hours. After adding 20 mL of 1 hydrazine hydrochloric acid, ethyl acetate (50 mL×3), and the organic phase was washed with saturated sodium sulfate solution 〇 00mL×3, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2-hydroxy-7- % azaspiro[3·5]pyrene carboxylic acid tert-butyl ester 62d (410 mg, colorless solid), yield: 68%. MS m/z (ESI): 186.1 [M-55] The fourth step 2 醯 醯 氧基 ethoxy-7-azaspiro[3·5]decane_7_carboxylic acid tert-butyl ester under ice bath The crude 2-hydroxy-7-azaspiro[3.5.nonane_7-carboxylic acid terpene vinegar 62d (200 mg, 〇. 82 mmol) was dissolved in 5 mL of anhydrous di-methane, and diethylamine was added. (248 mg, 2.46 mmol), methyl sulfonate (I4lmg ' 1.24 〇 1) was added dropwise, and the mixture was allowed to warm to room temperature, and the reaction was stirred for 5 hours. 185 95344 201213319 1 OmL of water, ethyl acetate extraction (20mLx3), the organic phase was combined, washed with water (5mLx3), saturated sodium carbonate solution (5mLx3), dried in anhydrous sodium sulfate, filtered, concentrated The crude title product 2-methanesulfonyloxy-aza spiro[3. 5]pyrazine-7-decanoic acid tert-butyl-g 62e (215 mg of <RTI ID=0.0> One step reaction. The fifth step 2, 6_ one defeat _4-(continuous brewing base) benzene will be 4-bromo-2,6-difluoro-benzene age 62f (500mg, 2.83mmol), (4~ reckless Synthetic phenyl) side acid (690mg, 3.40mmol), 1,1'-di(diphenyl) ferrocene dichloride (204mg, 0.28mmol) and sulphate trihydrate (1 90 g'7·20 mmol) was dissolved in a mixed solvent of 12 mL of 1,2-dioxane and water (v/V = 5:1), and the mixture was heated to 120 ° C and stirred for 5 hours. After adding 20 mL of water and ethyl acetate (20 mL×3), the organic phase was combined, washed with a saturated sodium sulfate solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2, 6-difluoro- 4-(Compound decylphenyl)phenol 62 g ^ (570 mg 'brown solids' product was directly subjected to the next reaction without purification. MS m/z (ESI): 302.1 [M+18] _ Step 6 2-[2,6-difluoro-4-(4-methylsulfonylphenyl)phenoxy]_7_aza-spiro [3·5] tert-butane-7-carboxylic acid tert-butyl ester crude 2-methylsulfonyloxy-7-azaspiro[3.5]decane-7-carboxylic acid second butyl ester 62e (215 mg '0. 67 mmol), crude 2,6-difluoro-4-(methylsulfonylphenyl)phenol 62 g (191 mg '0.77 mmol) and potassium carbonate (277 mg, 2mmo 1) dissolved in 2 〇mL dimethyl In methotrexate, the temperature is raised to 1 Torr. 〇, 186 95344 201213319 The reaction was allowed to react for 12 hours. Add 2 mL of water to extract with ethyl acetate (5 〇 mL×2), and combine the organic phases, which are washed with water (1 mL mL 3), saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate The resulting residue was purified by EtOAc (EtOAc) (EtOAc). [3.5] decane-7-decanoic acid tert-butyl ester 62 (25 〇!^, white solid), yield: 73. MS m/z (ESI): 408.2 [M+l-100] • *H NMR (400 MHz, d-dWSO) δ 7. 99 (s, 4H), 7.64 (d, 2H) 4.83-4.80 (m, 1H), 3.32 (s, 3H), 3.25-3. Η (m, 2H)' 2.33-2.28 (m, 2H), 1.96-1.91 (m, 2H), 1.53 - i (m 2H), 1.47-1.35 (m, 9H), 1.30-1.26 (m, 2H), 1 15-i i2 (m, 2H). Example 63 2-[2,6-difluoro-4-(4-oxasulfonylphenyl) ) 笨 oxy]_7_(5_ethylsulfonyl-1,3-yl)-7-azaspiro[3. 5] 壬

95344 187 201213319 2-[2, 6-二氟-4-(4-甲續醯基苯基）苯氧基]一7_氮雜螺環 [3. 5]壬烷 將2-[2, 6-二氟-4-(4-曱磺醯基苯基）苯氧基]—7-氮 雜螺環[3. 5]壬烷-7-羧酸第三丁酯62(150mg，0.29mmol) 溶解於2mL 4 Μ鹽酸曱醇溶液，攪拌反應12小時。反應液 減壓濃縮，得到粗品標題產物2-[2, 6-二氟-4-(4-曱續酿 基苯基）苯氧基]-7-氮雜螺環[3· 5]壬烷63a(120mg，白色 固體），產物不經純化直接進行下一步反應。 第二步 2-[2’ 6-二氟-4-(4-甲績醯基笨基）苯氧基]-7-(5-乙基嘧 啶-2-基）-7-氮雜螺環[3. 5]壬烷 將粗品2-[2, 6-二氣-4-(4-甲續酿基苯基）苯氧基]95344 187 201213319 2-[2,6-Difluoro-4-(4-methyln-decylphenyl)phenoxy]-7-azaspiro[3.5.nonane] 2-[2, 6 -Difluoro-4-(4-oxasulfonylphenyl)phenoxy]-7-azaspiro[3. 5]nonane-7-carboxylic acid tert-butyl ester 62 (150 mg, 0.29 mmol) Dissolved in 2 mL of 4 hydrazine hydrochloride solution and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude title product 2-[2,6-difluoro-4-(4-indoleylphenyl)phenoxy]-7-azaspiro[3·5]decane 63a (120 mg, white solid). The second step is 2-[2' 6-difluoro-4-(4-carbamicindolyl)phenoxy]-7-(5-ethylpyrimidin-2-yl)-7-aza spiro ring [3. 5] decane will be crude 2-[2,6-diox-4-(4-methylphenyl)phenoxy]

-7-氮雜螺環[3. 5]壬烧 63a(120mg，〇. 27mmol)溶解於 5mL 况二曱基曱醯胺中’依次加入2-氯-5-乙基-嘧咬（42mg， 0.29mmol)和碳酸絶（263mg，0.81mmol)，升至 150。〇授摔 反應5小時。冷至室溫，加入1 OmL水，用乙酸乙g旨萃取 (10mLx3)，合併有機相，依次用水（5mLx3)，飽和氣化納溶 液洗條（5mLx3)，無水硫酸鎮乾燥，過濾，濾液減麗漢縮， 用薄層色譜法以展開劑體系B純化所得殘餘物，得到標題 產物2-[2, 6-二氟-4-(4-甲讀醯基苯基）苯氧基]·_7_(5一乙 基嘴咬-2-基）-7-氣雜螺環[3. 5]壬烧63(75mg，黃色固 體），產率：69. 0%。 MS m/z (ESI): 234.1 [M+l] NMR (400 MHz，cZ-DMSO) &lt;5 8. 25 (s’ 2H)，7. 99 (s，4H)， 95344 188 201213319 7.64(d，2H)，4.86-4.84 (m，lH)，3.32(s，3H)，3.25-3· 14 (m，2H)，2. 33-2· 28 (m，2H)，2. 08-2. 〇6 (m，2H)， 1.96-1.91 (m，2H)，1.53-1.50 (m，2H)，1.30一 1.26 (m， 2H)，1.21-1.19 (m，2H), 1.13-1.12 (m，3H). 實施例64 2-[[4-(四唑-l-基）笨氧基]曱基]_7—氮雜螺瓖[3· 5]壬烷 —7-羧酸第三丁酯-7-azaspiro[3. 5]pyrazine 63a (120 mg, 〇. 27 mmol) was dissolved in 5 mL of dimethyl decyl amide. Add 2-chloro-5-ethyl-pyrimidine (42 mg, 0.29 mmol) and carbonic acid (263 mg, 0.81 mmol) were raised to 150. He gave a reaction for 5 hours. Cool to room temperature, add 1 OmL of water, extract with acetic acid (10mLx3), combine the organic phase, then wash with water (5mLx3), saturated sodium carbonate solution (5mLx3), dry anhydrous sulfuric acid, filter, filtrate minus The resulting residue was purified by EtOAc (EtOAc) elut elut (5-Ethyl acetonate-2-yl)-7- oxaspiro[3. 5] oxime 63 (75 mg, yellow solid), yield: 69. 0%. MS m/z (ESI): 234.1 [M+l] NMR (400 MHz, cZ-DMSO) &lt;5 8. 25 (s' 2H), 7.99 (s, 4H), 95344 188 201213319 7.64 (d , 2H), 4.86-4.84 (m, lH), 3.32 (s, 3H), 3.25-3· 14 (m, 2H), 2. 33-2· 28 (m, 2H), 2. 08-2. 〇6 (m, 2H), 1.96-1.91 (m, 2H), 1.53-1.50 (m, 2H), 1.30-1.26 (m, 2H), 1.21-1.19 (m, 2H), 1.13-1.12 (m, 3H). Example 64 2-[[4-(tetrazol-l-yl)phenyloxy]indolyl]-7-azaspiro[3·5]decane-7-carboxylic acid tert-butyl ester

第一步 2-(經基甲基）-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯 將4-曱烯基哌啶-1-羧酸第三丁酯62b(5〇〇mg， 2. lOmmol)溶解於20mL四氫呋喃中，冰浴下，加入9-硼雜 又環[3. 3· 1 ]壬烧（12. 7mL，6. 30mmol)，升至室溫，攪拌 反應12小時。冰浴下，加入lmL水，2mL 3 M氫氧化鈉和 2mL過氧化風’繼續反應1小時。加入別紅水，用乙酸乙 酉曰萃取（20mLx3)，合併有機相，飽和氣化鈉溶液洗滌 (30mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用矽 膠管柱色譜法以洗脫劑體系8純化所得殘餘物，得到標題 產物2-(羥基曱基）-7-氮雜螺環[3. 5]壬烷_7_羧酸第三丁 95344 189 201213319 酯64a(550mg，無色黏稠），產率：1〇〇 〇%。 MS m/z (ESI): 200.1 [M-55] 第二步 2-[[4-(四唾+基）苯氧基]甲基]_7_氮雜螺環[3 5]壬烷 —7-羧酸第三丁酯 將2-(羥基甲基）-7-氮雜螺環[3 5]壬烷_7_羧酸第三 丁酯64a(200mg，0. 78mmol)溶解於15mL甲苯中，攪拌， 加入粗品4—(四氮唑-卜基）笨酚46b(127mg，0.78mm〇l), 再依-人加入二笨基膦（4limg，ι· 57mm〇i)和偶氮二甲酸二異 丙酯（238mg，1. 18mmol)，攪拌反應16小時。反應液減壓 濃縮，用矽膠管柱色譜法以洗脫劑體系β純化所得殘餘 物’得到標題產物2-[[4-(四唑-1-基）苯氧基]甲基]-7-氮 雜螺環[3. 5]壬烷-7-羧酸第三丁酯64(110mg，白色固體）， 產率：34. 0%。 MS m/z (ESI): 400.2 [M+l] φ NMR (400 MHz, CDCh) 5 8. 90 (s, 1H), 7. 60-7. 58 (m, 2H), 7.07-7.05 (in, 2H), 4.00 (d, 2H), 3.85-3.81 (in, 2H), 3.32-3.30 (m, 2H), 2.79-2.76 (m, 1H), 2.04-2.01 (m，2H), 1.73-1.70 (m, 2H)，1.65-1.61 (m, 2H), 1.55-1.51 (m, 2H), 1.46 (s, 9H). 實施例65 2-[4-(四唑-1-基）苯氧基]-7—氮雜螺環[3.5]壬烷-7-羧酸 第三丁酯 190 95344 201213319First step 2-(transmethyl)-7-azaspiro[3.5.nonane-7-carboxylic acid tert-butyl ester 4-nonenylpiperidine-1-carboxylic acid tert-butyl Ester 62b (5 〇〇 mg, 2. lOmmol) was dissolved in 20 mL of tetrahydrofuran, and added to a mixture of 9-bora-cyclo-[3. 3·1] oxime (12.7 mL, 6.30 mmol). The reaction was stirred at room temperature for 12 hours. Under ice bath, 1 mL of water, 2 mL of 3 M sodium hydroxide and 2 mL of peroxidic air were added to continue the reaction for 1 hour. Add red water, extract with ethyl acetate (20mLx3), combine the organic phase, wash with saturated sodium carbonate solution (30mLx2), dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, use the gel column chromatography to eluent The obtained residue was purified to give the titled product 2-(hydroxy-decyl)-7- aza-spiro[3. 5] decane_7-carboxylic acid tert-butyl 95344 189 201213319 ester 64a (550 mg, colorless viscous) , Yield: 1%. MS m/z (ESI): 200.1 [M-55] Step 2 2-[[4-(tetras-s-yl)phenoxy]methyl]_7_azaspiro[3 5]decane-7 -Dibutyl carboxylic acid tert-butyl 2-(hydroxymethyl)-7-azaspiro[3 5 ]decane-7-carboxylic acid 64a (200 mg, 0.78 mmol) was dissolved in 15 mL of toluene Stirring, adding the crude 4-(tetrazolium-bu)phenol 46b (127mg, 0.78mm〇l), and then adding the stupylphosphine (4limg, ι· 57mm〇i) and azodicarboxylic acid Diisopropyl ester (238 mg, 1.18 mmol) was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and then purified, m. 0%。 Aza-spiro[3. 5] decane-7-carboxylic acid tert-butyl ester 64 (110 mg, white solid), yield: 34.0%. MS m/z (ESI): 400.2 [M+l] φ NMR (400 MHz, CDCh) 5 8. 90 (s, 1H), 7. 60-7. 58 (m, 2H), 7.07-7.05 (in , 2H), 4.00 (d, 2H), 3.85-3.81 (in, 2H), 3.32-3.30 (m, 2H), 2.79-2.76 (m, 1H), 2.04-2.01 (m, 2H), 1.73-1.70 (m, 2H), 1.65-1.61 (m, 2H), 1.55-1.51 (m, 2H), 1.46 (s, 9H). Example 65 2-[4-(tetrazol-1-yl)phenoxy ]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester 190 95344 201213319

OHOH

將粗品2-羥基-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁 醋62d(150mg，0. 62mmol)溶解於15mL曱苯中，擾拌，加 φ 入粗品4-(四氮α坐-1-基）苯紛46b(101mg，0. 62minol)，再 依次加入三苯基膦（328mg，1. 25mmol)和偶氮二曱酸二異丙 酉旨（189mg，0. 93mmol)，加熱至65°C，擾拌反應3小時。 反應液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化 所得殘餘物，得到標題產物2-[4-(四唑-1-基）苯氧基]-7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯65(100mg，白色固 體），產率：96.0%。 ^ MS m/z (ESI): 286.1 [M+l-100] 沱丽R(400 MHz，CDC10 5 8.89(s，1H)，7. 60-7. 56 (m， 2H), 6.98-6.95 (m, 2H), 4.78-4.75 (m, 1H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 2H), 2.49-2.45 (m, 2H), 2.02-1.98 (m, 2H), 1.60-1.56 (m, 4H), 1.47 (s, 9H). 實施例66 (1^ 55·)-6-[[4-(6-氯-3-咬啶基）-2, 6-二氟-苯氧基]曱 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 191 95344 201213319The crude 2-hydroxy-7-azaspiro[3.5.nonane-7-carboxylic acid terpene vinegar 62d (150 mg, 0.62 mmol) was dissolved in 15 mL of toluene, and the mixture was stirred and φ was added to the crude product. 4-(tetrazole α-s-l-yl)benzene 46b (101 mg, 0.62 min), followed by triphenylphosphine (328 mg, 1.25 mmol) and diisopropyl azodicarboxylate (189 mg) , 0. 93 mmol), heated to 65 ° C, and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj [3. 5] Decane-7-carboxylic acid tert-butyl ester 65 (100 mg, white solid), yield: 96.0%. ^ MS m/z (ESI): 286.1 [M+l-100] 沱 R (400 MHz, CDC10 5 8.89 (s, 1H), 7. 60-7. 56 (m, 2H), 6.98-6.95 ( m, 2H), 4.78-4.75 (m, 1H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 2H), 2.49-2.45 (m, 2H), 2.02-1.98 (m, 2H), 1.60-1.56 (m, 4H), 1.47 (s, 9H). Example 66 (1^55·)-6-[[4-(6-Chloro-3-acridinyl)-2,6-difluoro -phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 191 95344 201213319

FF

將[(1^ 55V6-[(4-溴-2, 6-二氟-苯氧基）曱基]-3_ (5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷8a(70mg， 0. 17mmol)，（6-氯-3-吡啶基）硼酸（27mg，0. 17mmol)， 1，Γ -二（二苯膦基）二茂鐵二氣化鈀（12. 40mg，0. 02mmol) 和碳酸鉋（167mg，0.51mmol)溶解於l〇mL 1,4-二噁烷中， 升溫至120°C，攪拌反應2小時。加入50mL水，用乙酸乙 酯萃取（20mLx2)，合併有機相，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，用薄層色譜法以展開劑體系B純化所得殘 餘物，得到標題產物（1尤550-6-1^4-(6-氣-3-吡啶基）-2, 6-二氟-苯氧基]甲基]-3_(5-乙基喷咬-2-基）-3-氮雜雙 環並[3. 1.0]己烷66(20mg，褐色固體），產率：26.7%。 MS m/z (ESI): 443.2 [M+l] 'H NMR (400 MHz, CDCh) &lt;5 8.54 (s, 2H), 8.16 (s, 2H), 7.76-7.78 (m, 1H), 7.40-7.42 (ra, 1H), 7.10-7.12 (m, 1H), 4. 12-4. 14 (m, 2H), 3.87-3.90 (m, 2H), 3.53-3.56 (m, 2H), 2.43-2. 49 (m, 2H), 1.72(s, 2H), 1.26 (s, 1H), 1· 16-1· 20 (m, 3H). 實施例67 192 95344 201213319 2-[2-[4-(四唑-1-基）苯氧基]乙基]-7-氮雜螺環[3. 5]壬 烷-7-羧酸第三丁酯[(1^55V6-[(4-Bromo-2,6-difluoro-phenoxy)indolyl]-3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇]hexane 8a (70 mg, 0.17 mmol), (6-chloro-3-pyridyl)boronic acid (27 mg, 0.17 mmol), 1, Γ-bis(diphenylphosphino)ferrocene Palladium (12. 40 mg, 0.02 mmol) and carbonic acid planer (167 mg, 0.51 mmol) were dissolved in 1 mL of 1,4-dioxane, and the temperature was raised to 120 ° C, and the reaction was stirred for 2 hours. 50 mL of water was added thereto. Ethyl acetate (20 mL×2), EtOAc EtOAc (EtOAc m. ^4-(6-Ga3-pyridyl)-2,6-difluoro-phenoxy]methyl]-3_(5-ethylpiper-2-yl)-3-azabicyclo[ 3. 1.0] Hexane 66 (20 mg, brown solid), yield: 26.7%. MS m/z (ESI): 443.2 [M+l] 'H NMR (400 MHz, CDCh) &lt;5 8.54 (s, 2H), 8.16 (s, 2H), 7.76-7.78 (m, 1H), 7.40-7.42 (ra, 1H), 7.10-7.12 (m, 1H), 4. 12-4. 14 (m, 2H), 3.87-3.90 (m, 2H), 3.53-3.56 (m, 2H), 2.43-2. 49 (m, 2H), 1.72(s, 2H), 1.26 (s, 1H), 1· 16-1· 20 (m, 3H). Example 67 192 95344 201213319 2-[2-[4-(tetrazol-1-yl)phenoxy]ethyl]-7-azaspiro[ 3. 5] Decane-7-carboxylic acid tert-butyl ester

第一步 2-(2-乙氧基-2-氧-亞乙基）-7-氮雜螺環[3. 5]壬烷-7-羧 酸第三丁酯First step 2-(2-ethoxy-2-oxo-ethylidene)-7-azaspiro[3. 5]decane-7-carboxylic acid tert-butyl ester

將60%氫化納（92mg，2. 30mmol)加入至1 〇mL苯中，緩 慢滴加入膦醯基乙酸三乙酯（414/z L，2. 10匪〇1)，攪拌1 小時，緩慢加入2-氧基-7-氮雜螺環[3. 5]壬烷-7-羧酸第 三丁酯62c(500mg，2. lOmmol)，升溫至65°C，攪拌反應 30分鐘。冷卻至室溫，加入20mL水，用乙酸乙酯萃取 (100mLx2)，合併有機相，依次用水（50mLx2)，飽和氯化納 溶液洗滌（50mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃 縮’得到粗品標題產物2-(2-乙氧基_2-氧-亞乙基）-7-氮 雜螺環[3. 5]壬烷-7-羧酸第三丁酯67a(700mg，黃色油 狀）’產物不經純化直接進行下一步反應。 第二步 2-(2-乙氧基-2-氧-乙基）-7-氮雜螺環[3. 5]壬烷_7_羧酸 193 95344 201213319 第三丁酯 將粗品2-(2-乙氧基-2-氧-亞乙基）-7-氮雜螺環[3. 5] 壬烧-7-羧酸第三丁酯67a(700mg，2. 30mmol)溶於50mL甲 醇中，加入鈀/碳（70mg，10%)，加壓氫化，反應12小時。 冷至室溫，過濾，濾液減壓濃縮，得到粗品標題產物2-(2~ 乙氧基-2-氧-乙基）-7-氮雜螺環[3. 5]壬烧-7-叛酸第三丁 酯67b(598mg，淡黃色油狀物），產物不經純化直接進行下 一步反應。 ® MS ra/z (ESI): 212.2 [M+l-100] 第三步 · 2-(2-經基）-7-氣雜螺環[3· 5]壬燒-7-缓酸第三丁酉旨 將四氫鋁鋰（146mg ’ 3. 84mmol)溶解於20mL四氫咬。南 中’冰浴下，慢慢加入10mL 2-(2-乙氧基-2-氧-乙基）~7-氮雜螺環[3. 5]壬烷-7-羧酸第三丁酯67b(598mg， 1. 92minol)的四氫呋喃溶液，加畢，反應12小時。緩慢滴 φ 入〇. 5mL飽和氯化録溶液，過濾，收集濾、液，無水硫酸鎂 乾燥’過;慮’遽液減屋濃縮’付到粗品標題產物2_(2_經 鲁 基）_7-氮雜螺環[3. 5]壬烧-7-叛酸第三丁醋67c(500mg， 無色油狀物），產物不經純化直接進行下一步反應。 MS m/z (ESI): 214.1 [M-55] 第四步 2-[2-[4-(四唑-1-基）苯氧基]乙基]-7-氮雜螺環[3. 5]壬 烷-7-羧酸第三丁酯 將粗品2-(2-羥基）-7-氮雜螺環[3. 5]壬烷-7-羧酸第 194 95344 201213319 三丁酯67c(200mg，0.74mmol)溶解於i5mL甲苯中，攪拌， 加入粗品4-(四唑-1-基）苯酚46b(108mg，0. 67mmol)，再 依次加入二苯基膦（387mg，1. 48mmol)和偶氮二甲酸二異丙 酉旨（0· 2mL，1. llmmol)，室溫授拌12小時，再加熱至65°C， 擾拌反應2小時。反應液減壓漢縮，用石夕膠管柱色譜法以 洗脫劑體系B純化所得殘餘物，得到標題產物2-[2-[4-(四 唑-1-基）苯氧基]乙基]-7-氮雜螺環[3. 5]壬烷-7-羧酸第 三丁酯67(40mg，黃色固體），產率·· 13· 〇%。 鲁 MS m/z (ESI): 414.2 [M+1] 1H NMR (400 MHz，CDC13) 5 8· 89 (s，1H)，7. 59-7. 56 (m， 2H)，7.05-7.01 (m，2H)，3.96 (t，2H)，3.38-3.23 (m， 4H)，2.45(dt’ 1H)，2.08-1.99 (m，2H)，l.93(dd，2H)， 1.62-1.56 (m, 2H), 1.52-1.47 (m, 2H), I.45 (s, 9H), 1.40 (d, 2H). 實施例68 φ (1尤55&quot;)-3-(5-乙基嘧啶-2-基）-6-[[2-曱基-4_(4一曱磺醯 基苯基）苯氧基]甲基]-3-氮雜雙環並[3. ί ο]己烷60% sodium hydride (92mg, 2.30mmol) was added to 1 〇mL of benzene, triethyl phosphinoacetate (414 / z L, 2. 10 匪〇 1) was slowly added dropwise, stirred for 1 hour, slowly added 2-Oxo-7-azaspirocyclo[3. 5]decane-7-carboxylic acid tert-butyl ester 62c (500 mg, 2.10 mmol), warmed to 65 ° C, and stirred for 30 min. After cooling to room temperature, 20 mL of water was added, and the mixture was combined with ethyl acetate (100 mL×2), and the organic phase was washed with water (50 mL×2) The crude title product 2-(2-ethoxy-2-oxo-ethylidene)-7-azaspiro[3.5.nonane-7-carboxylic acid tert-butyl ester 67a (700 mg, yellow oil. The product was directly subjected to the next reaction without purification. The second step 2-(2-ethoxy-2-oxo-ethyl)-7-azaspiro[3. 5]decane_7_carboxylic acid 193 95344 201213319 The third butyl ester will be crude 2-( 2-ethoxy-2-oxo-ethylidene-7-azaspiro[3. 5] tert-butyl -7-carboxylic acid tert-butyl ester 67a (700 mg, 2.30 mmol) was dissolved in 50 mL of methanol. Palladium on carbon (70 mg, 10%) was added, and hydrogenation under pressure was carried out for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to give the crude title product 2-(2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The acid tert-butyl ester 67b (598 mg, pale yellow oil) was taken to the next step without purification. ® MS ra/z (ESI): 212.2 [M+l-100] Step 3 · 2-(2-Phase)-7-Gasspiro[3·5]壬烧-7------------ Ding Yu intended to dissolve lithium tetrahydrogenate (146 mg ' 3. 84 mmol) in 20 mL tetrahydrogen bite. Under the ice bath in South China, slowly add 10 mL of 2-(2-ethoxy-2-oxo-ethyl)-7-azaspiro[3.5.nonane-7-carboxylic acid tert-butyl ester. A solution of 67b (598 mg, 1.92 minol) in tetrahydrofuran was added and the mixture was reacted for 12 hours. Slowly drop φ into the 〇. 5mL saturated chlorinated solution, filter, collect the filtrate, liquid, dry magnesium sulphate 'over; consider ' 遽 liquid reduced house concentration' to the crude title product 2_ (2_ by Luji) _7- Azaspirocyclo[3. 5]pyrrol-7-rebel acid butyl vinegar 67c (500 mg, colorless oil). MS m/z (ESI): 214.1 [M-55] Step 4 2-[2-[4-(tetrazol-1-yl)phenoxy]ethyl]-7-azaspiro[3. 5] tert-butane-7-carboxylic acid tert-butyl ester crude 2-(2-hydroxy)-7-azaspiro[3. 5]decane-7-carboxylic acid 194 95344 201213319 tributyl ester 67c ( 200 mg, 0.74 mmol) was dissolved in EtOAc (5 mL). Diisopropyl azodicarboxylate (0.2 mL, 1.1 mmol) was stirred at room temperature for 12 hours, then heated to 65 ° C, and the reaction was stirred for 2 hours. The reaction mixture was subjected to reduced pressure. ]-7-Azaspiro[3. 5]decane-7-carboxylic acid tert-butyl ester 67 (40 mg, yellow solid), yield ···········鲁 MS m/z (ESI): 414.2 [M+1] 1H NMR (400 MHz, CDC13) 5 8· 89 (s, 1H), 7. 59-7. 56 (m, 2H), 7.05-7.01 ( m, 2H), 3.96 (t, 2H), 3.38-3.23 (m, 4H), 2.45 (dt' 1H), 2.08-1.99 (m, 2H), 1.93 (dd, 2H), 1.62-1.56 ( m, 2H), 1.52-1.47 (m, 2H), I.45 (s, 9H), 1.40 (d, 2H). Example 68 φ (1 especially 55&quot;)-3-(5-ethylpyrimidine- 2-yl)-6-[[2-indolyl-4_(4-indolylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3. ί]hexane

195 95344 201213319 第一步 2-甲基-4-(4-曱磺醢基苯基）苯酚 將 4-溴-2-曱基-苯酚 68a(300mg，1. 60mmol)，（4-曱 續醯基苯基）硼酸（321mg，1. 60mmol)’ 1，Γ -二（二苯膦基） 二茂鐵二氯化把（117mg，0. 16mmol)和碳酸铯（1· 57g， 4. 81mmol)溶解於lOmLl，4-二0惡烧中，升溫至120°C，授拌 反應2小時。加入50mL水，用乙酸乙醋萃取（20mLx2)，合 併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物2-甲基-4-(4-甲磺醯基苯基）苯酚68b (350mg，黃色固體）’產物不經純化直接進行下一步反應。 MS m/z (ESI)： 280.1 [M+18] 第二步 (1尤5«-3-(5-乙基嘧啶—2-基）-6-[[2-甲基〜4-(4-甲磺醯 基苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 〇]己烷 將粗品2-甲基-4-(4-曱磺醯基苯基）笨酚68b(1〇〇mg， 0.38nm〇l)溶解於5mL况於二曱基曱醯胺中，依次加入粗195 95344 201213319 The first step 2-methyl-4-(4-oxasulfonylphenyl)phenol 4-bromo-2-indolyl-phenol 68a (300 mg, 1.60 mmol), (4-曱 continued Phenyl) boric acid (321 mg, 1.60 mmol)' 1, Γ-bis(diphenylphosphino)ferrocene dichloride (117 mg, 0.16 mmol) and cesium carbonate (1·57 g, 4.81 mmol) Dissolved in 10 mL, 4- dioxin, heated to 120 ° C, and stirred for 2 hours. After adding 50 mL of water, the mixture was extracted with EtOAc (EtOAc (EtOAc) The phenol 68b (350 mg, yellow solid) product was directly subjected to the next reaction without purification. MS m/z (ESI): 280.1 [M+18] Step 2 (1 especially 5 «-3-(5-ethylpyrimidin-2-yl)-6-[[2-methyl~4-(4) -Methanesulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3. 1. oxime]hexane The crude 2-methyl-4-(4-oxasulfonylphenyl) Stupid phenol 68b (1 〇〇 mg, 0.38 nm 〇l) was dissolved in 5 mL of dimethyl decyl amide and added in turn.

口口 KU，55·)-3-(5-乙基嘧啶_2_基）一3_氮雜雙環並[3. h 己院6基]甲續酸甲g旨％⑴3mg，〇.38mmol)和碳酸鎚 (248mg ’ 〇.76mmol) ’升溫至90°C，擾拌反應4小時。. 入5GmL水_/用乙駿乙§旨萃取（4GmLx2)，合併有機相，奔 ’過據，濾液減壓濃縮，用薄層色譜法以展 、化所彳于殘餘物，得到標題產物（1尤55^-3-(5 乙基0f 咬-2-基「Γς) ^ [[2~甲基-4-(4-甲磺醢基苯基）苯簞 土 Γ雜雙環並[3·1·〇]己烷68(130mg，白色固體 196 95344 201213319 產率：73. 8%。 MS m/z (ESI): 464.2 [M+l] !H NMR (400 MHz, CDCh) δ 8.23 (s, 2H), 7.96-7.99 (m, 2H), 7.72-7.74 (m, 2H), 7.40-7.42 (m, 2H), 6.88-6.90 (m, 1H), 4. 01-4. 03 (m, 4H) 3. 60-3. 62 (m, 2H), 3. 09 (s, 3H), 2.49-2.51 (m, 2H), 2.31 (s, 3H), 1.82 (s, 2H), 1.26 (s, 1H), 1. 19-1.24 (m, 3H). 實施例69 • (1 疋 550-3-(5-氯嘧啶〜2-基）-6-[(lA〇-i-[2, 6-二氟-4-(4- 曱磺醯基苯基）苯氧基]乙基]-3-氮雜雙環並[3. i. 〇]己烷Oral KU, 55·)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.h hexyl 6-methyl]methyl-reacting methic acid %(1)3mg, 〇.38mmol) The mixture was heated to 90 ° C with a carbonated hammer (248 mg '〇.76 mmol), and the reaction was stirred for 4 hours. Into 5GmL of water _ / extracted with jun jun jie (4GmLx2), the organic phase was combined, the crystallization was carried out, the filtrate was concentrated under reduced pressure, and the residue was obtained by thin layer chromatography to obtain the title product. 1 especially 55^-3-(5 ethyl 0f bit-2-yl "Γς) ^ [[2~methyl-4-(4-methylsulfonylphenyl) benzoquinone oxacyclobi[3· 1·〇]hexane 68 (130 mg, white solid 196 95344 201213319 Yield: 73.8%) MS m/z (ESI): 464.2 [M+l] !H NMR (400 MHz, CDCh) δ 8.23 (s , 2H), 7.96-7.99 (m, 2H), 7.72-7.74 (m, 2H), 7.40-7.42 (m, 2H), 6.88-6.90 (m, 1H), 4. 01-4. 03 (m, 4H) 3. 60-3. 62 (m, 2H), 3. 09 (s, 3H), 2.49-2.51 (m, 2H), 2.31 (s, 3H), 1.82 (s, 2H), 1.26 (s , 1H), 1. 19-1.24 (m, 3H). Example 69 • (1 疋550-3-(5-chloropyrimidin~2-yl)-6-[(lA〇-i-[2, 6 -difluoro-4-(4-oxasulfonylphenyl)phenoxy]ethyl]-3-azabicyclo[3.i. 〇]hexane

第一步 (1足55)-6-甲醯基-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第 三丁酯First step (1 foot 55)-6-methionyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

乾冰浴下，將草醯氣（143mg，0. 13mmol)溶解於6mL 197 95344 201213319 二氯曱烷中’緩慢滴加二甲基亞砜(19〇mg，2 44mm〇1)，攪 拌反應10分鐘，隨後滴加4mL粗品（1疋5幻_6_(羥基甲基） -3-氮雜雙環並[3.1.〇]已烷_3_羧酸第三丁酯16&amp;(2〇〇呢， 0.94mm〇l)的二氣曱烧溶液，麟反應3q分鐘。再滴加三 乙胺（470mg，4.69ram〇l)，逐漸升至室溫，擾拌反應2小時。 加入10mL水泮滅反應’二氯甲烷萃取，合併有機 相’飽和氯化鈉溶液洗滌（20IUL)，無水硫酸鈉乾燥，過濾， 濾、液減壓濃縮，得到粗品標題產物⑽⑹.甲醯基_3_ 氣雜雙％並[3· 1.0]己坡―3_敌酸第三丁醋69a(21〇mg，淺 育色黏稠物），產物不經純化直接進行下一步反應。 第二步 (1尤55)-6-(1-羥基乙基；)_3_氮雜雙環並[3. h 〇]己烷一3_ 綾酸第三丁酯 冰浴下’將粗品（1足5^)-6-甲醯基-3-氮雜雙環並 [3. 1. 0]己烷-3-羧酸第三丁酯 69a(200mg，0. 94mmol)溶解 鲁 於5此四虱0夫畴中’緩慢滴加〇· 6此3M甲基漠化鎮，升至 室溫’攪拌反應2小時。加入5mL飽和氣化銨溶液淬滅反 應，乙酸乙酯萃取（20mLx4)，合併有機相，飽和氣化鈉溶 液洗滌（20mL) ’無水硫酸鈉乾燥，過濾，濾液減壓濃縮， 得到粗品標題產物（1皮，55^-6-(1-經基乙基）-3-氮雜雙環 並[3. 1. 0]己烷-3-羧酸第三丁酯69b(180mg，淺黃色液 體），產物不經純化直接進行下一步反應。 MS m/z (ESI): 172.1 [M-55] 第三步 198 95344 201213319 (lie，5«-6-U-曱磺醯基乙基）-3-氮雜雙環並[3. 1. 0]己烷 -3-羧酸第三丁酯 冰浴下，將粗品（1尤5«-6-(1-羥基乙基）-3-氮雜雙 環並[3. 1.0]己烷-3-羧酸第三丁酯 69b(180mg，0.79romol) 溶解於5mL無水二氯甲烧中，加入三乙胺（i6〇mg，1. 58mmol) 和4-二甲胺基吡啶（5mg，cat.)，滴加入甲磺醯氣（140mg， 1. 19mmol) ’升溫至室溫，攪拌反應12小時。加入i〇mL 水’用二氯曱烷萃取（20mLx3)，用飽和氯化鈉溶液洗滌 (20mLx2) ’無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物（1尤55^-6-(1-甲磺醯基乙基）-3-氮雜雙環 並[3. 1. 0]己烧-3-叛酸第三丁醋69c(190mg，黃色液體）， 產物不經純化直接進行下一步反應。 MS m/z (ESI): 250.1 [M-55] 第四步 (1兄5«-6-[l-(4-溴-2,6-二氟-苯氧基）乙基]-3〜氮雜雙 環並[3. 1. 0]己烷-3-羧酸第三丁酯 將4-溴-2, 6-二氟-苯紛（180mg，0. 87minol)溶解於云此 况於二曱基曱醯胺中，依次加入粗品（丨兄^曱磺醯 基乙基）-3-氮雜雙環並[3· 1. 〇]己烷-3-羧酸第三丁能69c (190mg，〇· 79mmol)和碳酸鉋（510mg，1_ 58mmol)，升至 100 C授拌反應2小時。加入20mL水，用乙酸乙酸萃取 (20mLx3) ’合併有機相，用飽和氣化鈉溶液洗滌（2〇ml^幻， 無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管杈色譜 法以洗脫劑體系B純化所得殘餘物，得到標題產物 95344 199 201213319 (1尤55·)-6-[1-(4-溴-2, 6-二氟-苯氧基）乙基]-3-氮雜雙 環並[3. 1. 0]己烷-3-羧酸第三丁酯69d( 190mg，白色固 體），產率：57· 6%。 MS m/z (ESI): 364.0 [M-55] 第五步 (1尤 550-6-((1^0-1-(2, 6-二氟-4-(4-甲4酿基苯基）苯氧 基]乙基]-3-氮雜雙環並[3. 1. 0]己炫-3-叛酸第三丁酉旨 將（1兄55)-641-(4-溴-2, 6-二氟-苯氧基）乙基]-3-• 氮雜雙環並[3· 1. 0]己烷-3-羧酸第三丁酯69d(190mg， 0. 45mmol) ’（4-甲磺醯基苯基）硼酸（i〇9mg，〇. 55mmol)， 1，Γ -二（二苯膦基）二茂鐵二氣化鈀（33mg，〇. 05mm〇1)和 碳酸鉋（440mg，1. 35mmol)溶解於6mLl，4-二噁烷中，升溫 至120°C，擾拌反應5小時。加入1 〇mL水，用乙酸乙g旨萃 取（20mLx3)’合併有機相，用飽和氯化鈉溶液洗滌（2〇此）， 無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜 g 法以洗脫劑體系B純化所得殘餘物，得到標題產物 (1及，55|)-6-[(1&gt;?)-1-[2,6-二氟-4-（4-曱績醯基苯基）笨氧 _ 基]乙基]-3-氮雜雙環並[3.1. 0]己烧-3-叛酸第三丁酯 69e(120mg，白色固體），產率：59. 1%。 MS m/z (ESI): 438.1 [M-55] 第六步 (1皮，55·)-6-[(1Α〇-1-[2, 6-二氟-4-(4-曱續醢基苯基）苯氧 基]乙基]-3-氮雜雙環並[3. 1.0]己烷 冰浴下’將（1^55)-6-((1^0-1-(2, 6-二氟-4-(4-甲 200 95344 201213319 續醯基苯基）苯氧基]乙基]-3-氮雜雙環並[3. i. 〇]己烧-3- 叛酸第三丁酯69(120mg，0. 24mmol)溶解於2mL二氣甲院 t，滴加入5mL4 Μ鹽酸曱醇溶液，升溫至室溫，攪拌反應 2小時。減壓濃縮反應液，得到粗品標題產物（1^5^)-6- [(1及)-1-[2,6-二氟-4-(4-曱磺醯基苯基）苯氧基]乙基] -3-氮雜雙環並[3. 1.0]己燒69f(100mg ’白色固體），產物 不經純化直接進行下一步反應。 第七步 _ (1足 55)-3-(5-氯嘴咬-2-基)-6-[(1 皮)-1-[2, 6-二氣-4-(4- _ 曱續醯基苯基）苯氧基]乙基]-3-氮雜雙環並[3. 1. 〇]己烧 將粗品（1无，55)-6-[(1^&gt;)-1-[2，6-二氟-4-(4-曱續酉篮 基苯基）苯氧基]乙基]-3-氮雜雙環並[3. 1. 〇]己烷69f (lOOmg ’ 0. 23mmol)溶解於5mL况#-二曱基乙醯胺中，依 次加入2, 5-二氯嘧啶（42mg，0. 28mmol)和火#-二異丙基乙 胺（90mg，0. 70mmol)，升溫至140°C，攪拌反應7小時。 φ 加入25mL水，用乙酸乙酯萃取（30mLx3)，合併有機相，依 次用1M氯化氫溶液（15mL)，飽和碳酸氫鈉溶液（i5mL)，飽 · 和氯化鈉溶液洗滌（15mLx2)，無水硫酸鈉乾燥，過濾、，滤 液減壓濃縮，用石夕膠管柱色譜法以洗脫劑體系B純化所得 殘餘物，得到標題產物（1^5^)-3-(5-氯嘴咬-2-基）-6-[(1及)-1-[2, 6-二氟-4-(4-曱橫酿基苯基）笨氧基]乙基] -3-氮雜雙環並[3. 1. 0]己烷69(52mg，白色固體），產率： 44. 4%。 MS m/z (ESI): 506.1 [M+l] 95344 201 201213319 1H NMR (400 MHz, CDCh) δ 8. 29 (s, 2H), 8.06-8.08 (m, 2H), 7.75-7.77 (m, 2H), 7.22-7.24 (m, 2H), 3.93-3.96 (in, 2H), 3.85-3.88 (m, 1H), 3.61-3.64 (m, 1H), 3.51-3.54 (m, 1H), 3.14 (s, 3H), 1.65-1.70 (m, 2H), 1.52-1.53 (m, 3H), 1.08-1. 10 (ra, 1H). 實施例70 (1^ 550-64(:3, 5-二氟-4-(4-甲磺醯基苯基）苯氧基]甲 基]-3-(5-乙基嘧啶-2-基）_3-氮雜雙環並[3. 1. 〇]己烷Under dry ice bath, the grass helium (143 mg, 0.13 mmol) was dissolved in 6 mL of 197 95344 201213319 dichloromethane, and dimethyl sulfoxide (19 〇 mg, 2 44 mm 〇1) was slowly added dropwise, and the reaction was stirred for 10 minutes. Then, 4 mL of crude product (1疋5 phantom_6_(hydroxymethyl)-3-azabicyclo[3.3.〇]hexane _3_carboxylic acid tert-butyl ester 16 &amp; (2 ,, 0.94) was added dropwise. Mm〇l) of the two gas smoldering solution, the reaction was carried out for 3 minutes. Then triethylamine (470mg, 4.69ram〇l) was added dropwise, gradually raised to room temperature, and the reaction was stirred for 2 hours. Add 10 mL of water to quench the reaction. The organic phase was washed with a saturated aqueous sodium chloride solution (20 IUL), dried over anhydrous sodium sulfate, filtered, filtered, and evaporated to give the title compound (10) (6). 3· 1.0]Hippo-3_dicarboxylic acid third vinegar 69a (21〇mg, light coloring viscous material), the product is directly subjected to the next reaction without purification. The second step (1 especially 55)-6-( 1-hydroxyethyl;)_3_azabicyclo[3.h 〇]hexane-3_ decanoic acid tert-butyl ester under ice bath 'will be crude (1 foot 5^)-6-methyl decyl-3- Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 69a (2 00mg, 0. 94mmol) dissolved in 5 of the four 虱 0 domain, 'slow drop 〇 · 6 this 3M methyl desertification town, rose to room temperature' stirring reaction for 2 hours. Add 5mL saturated ammonium hydride solution quenched The reaction was quenched, EtOAc (EtOAc (EtOAc)EtOAc. (1-Phenylethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 69b (180 mg, pale yellow liquid). Reaction MS m/z (ESI): 172.1 [M-55] Step 3 198 95344 201213319 (lie, 5«-6-U-sulfonylethyl)-3-azabicyclo[3. 0] Hexane-3-carboxylic acid tert-butyl ester in ice bath, the crude product (1 especially 5«-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylic acid tert-butyl ester 69b (180 mg, 0.79 romol) was dissolved in 5 mL of anhydrous methylene chloride, and triethylamine (i6 〇mg, 1.58 mmol) and 4-dimethylaminopyridine (5 mg, cat) were added. .), adding methanesulfonate (140 mg, 1.19 mmol) dropwise. Warming to room temperature and stirring for 12 hours. After adding i〇mL water, it was extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product (1 especially 55^-6 -(1-Methanesulfonylethyl)-3-azabicyclo[3.1.0]hexacarb-3-carboxylic acid terpene vinegar 69c (190 mg, yellow liquid), product was directly purified without purification The next step is to react. MS m/z (ESI): 250.1 [M-55] Step 4 (1 brother 5 «-6-[l-(4-bromo-2,6-difluoro-phenoxy)ethyl]-3~ Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester dissolves 4-bromo-2,6-difluoro-benzene (180 mg, 0.87 min) in the cloud. In the decyl decylamine, the crude product (丨 曱 曱 曱 曱 乙基 乙基 ethyl)-3-azabicyclo[3· 1. 〇]hexane-3-carboxylic acid tert-butyl 69c (190 mg, 〇·79mmol) and carbonated planer (510mg, 1_58mmol), and stirred up to 100 C for 2 hours. Add 20mL of water and extract with acetic acid (20mLx3) 'The organic phase is combined and washed with saturated sodium carbonate solution (2〇 The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-Bromo-2,6-difluoro-phenoxy)ethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 69d (190 mg, white Solid), Yield: 57·6% MS m/z (ESI): 364.0 [M-55] Step 5 (1 especially 550-6-((1^0-1-(2, 6-difluoro) -4-(4-methyl 4-bromophenyl)phenoxy]ethyl]-3-nitrogen Bicyclo[3.1.0]Hyunxu-3-Resin 3D Dingzhi (1 brother 55)-641-(4-bromo-2,6-difluoro-phenoxy)ethyl]-3 -• Azabicyclo[3·1]hexane-3-carboxylic acid tert-butyl ester 69d (190mg, 0. 45mmol) '(4-methylsulfonylphenyl)boronic acid (i〇9mg, 〇 . 55mmol), 1, Γ-bis(diphenylphosphino)ferrocene di-palladium (33mg, 〇. 05mm〇1) and carbonate planer (440mg, 1.35mmol) dissolved in 6mL, 4-dioxane The temperature was raised to 120 ° C, and the reaction was stirred for 5 hours. 1 mL of water was added and extracted with acetic acid (20 mL×3). The organic phase was combined and washed with a saturated sodium chloride solution (2 〇), anhydrous sodium sulfate The title compound (1 and, 55|)-6-[(1&gt;?)-1-[[ 2,6-difluoro-4-(4-indolylphenyl) oxo-yl]ethyl]-3-azabicyclo[3.1.0]hexa--3-teric acid tert-butyl ester 69e (120 mg, white solid), Yield: 59.1%. MS m/z (ESI): 438.1 [M-55] Step 6 (1, 55·)-6-[(1Α〇-1- [2, 6-difluoro-4-(4-anthracenylphenyl)phenoxy ]ethyl]-3-azabicyclo[3.1.0]hexane under ice bath '(1^55)-6-((1^0-1-(2, 6-difluoro-4-() 4-A 200 95344 201213319 Continuation of nonylphenyl)phenoxy]ethyl]-3-azabicyclo[3.i. 〇]hexacarb-3-tert-butyl tert-butyl ester 69 (120 mg, 0. 24 mmol) was dissolved in 2 mL of Erqijiayuan t, and 5 mL of a 4 Μ guanidine hydrochloride solution was added dropwise, and the mixture was warmed to room temperature, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (1·5^)-6-[(1)-1-1-[2,6-difluoro-4-(4-oxasulfonylphenyl)phenoxy Ethyl]-3-azabicyclo[3.1.0]hexane 69f (100 mg of 'white solid). The seventh step _ (1 foot 55) -3- (5-chloro-mouth bit-2-yl)-6-[(1 skin)-1-[2, 6-two gas-4-(4- _ 曱Nonylphenyl)phenoxy]ethyl]-3-azabicyclo[3. 1. oxime] hexane is crude (1 no, 55)-6-[(1^&gt;)-1-[ 2,6-Difluoro-4-(4-indolyl phenyl)phenoxy]ethyl]-3-azabicyclo[3. 1. oxime]hexane 69f (100 mg '0. 23 mmol Dissolved in 5 mL of #-dimercaptoacetamide, and sequentially added 2,5-dichloropyrimidine (42 mg, 0.28 mmol) and fire #-diisopropylethylamine (90 mg, 0.70 mmol), and warmed up. The reaction was stirred for 7 hours at 140 °C. Φ Add 25mL of water, extract with ethyl acetate (30mLx3), combine the organic phase, then use 1M hydrogen chloride solution (15mL), saturated sodium bicarbonate solution (i5mL), saturated and sodium chloride solution (15mLx2), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified eluting with eluent column chromatography to afford the title product (1^5^)-3-(5-chloropurine -2- -6-[(1 and)-1-[2,6-difluoro-4-(4-indolylphenyl)phenyloxy]ethyl]-3-azabicyclo[3. 1. 0% hexane 69 (52 mg, white solid), yield: 44. 4%. MS m/z (ESI): 506.1 [M+l] 95344 201 201213319 1H NMR (400 MHz, CDCh) δ 8. 29 (s, 2H), 8.06-8.08 (m, 2H), 7.75-7.77 (m, 2H), 7.22-7.24 (m, 2H), 3.93-3.96 (in, 2H), 3.85-3.88 (m, 1H), 3.61-3.64 (m, 1H), 3.51-3.54 (m, 1H), 3.14 ( s, 3H), 1.65-1.70 (m, 2H), 1.52-1.53 (m, 3H), 1.08-1. 10 (ra, 1H). Example 70 (1^ 550-64(:3, 5- Fluoro-4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.indole]hexane

第一步 3，5-二1-4-（4_甲橫酿基苯基）苯盼The first step 3,5-di1-4-(4-methyl-bromophenyl)

將 4-漠-3, 5-二氟-苯紛 70a(500mg，2. 40mmol)，（4- 曱續酿基苯基）硕酸（478mg，2. 40mmol) ’ 1，1’ -二（二苯膦 基）二茂鐵二氣化ls(174mg，0. 24mmol)和碳酸铯（2. 34 g， 7. 20mmol)溶解於i〇mL 1，4-二噁烷中，升溫至120°C，攪 拌反應2小時。加入5〇mL水，用乙酸乙醋萃取（20mLx2)， 合併有機相’無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得 到粗品標題產物3, 5-二氟-4-(4-曱磺醯基苯基）苯酚70b 202 95344 201213319 (519mg，黃色固體）’產物不經純化直接進行下一步反 MS m/z (ESI): 283.0 [M-l] 第二步 ⑽5«-3-(5-乙基対_2_基）_6_[[2_甲基_4_(4_甲續酿 基苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷只 將粗品3, 5-二氟-4-(4-甲磺醯基苯基）苯酚7〇b (lOOmg，0.35mmol)溶解於5mL况趴二曱基甲醯胺中，依 次加入粗品[(17?，550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 傷並[3.1.0]己烷_6 一基]曱磺酸曱酯7g(105mg，〇.35mmol) 和碳酸铯（230mg，0. 70mmol)，升溫至90°C，攪拌反應4 小時。加入50mL水，用乙酸乙酯萃取（4〇mLx2)，合併有機 相，無水硫酸鎮乾燥’過濾，濾液減壓濃縮，用薄層色譜 法以展開劑體系B純化所得殘餘物，得到標題產物 (17P，550-3-(5-乙基嘧啶-2-基）-6-[[2-曱基-4-(4-曱磺醯 基苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烧70 φ (68mg ’白色固體），產率：40. 0%。 MS m/z (ESI): 486.2 [M+l] 'H NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 8.00 (d, 2H), 7.65 (d, 2H), 6.57-6.59 (m, 2H), 4.00-4.02 (m, 2H), 3.93-3.96 (in, 2H), 3.60-3.63 (m, 2H), 3.10 (s, 3H), 2.46-2.52 (m, 2H), 1.77 (s, 2H), 1.24-1.27 (ra, 1H), 1. 18-1.22 (in, 3H). 實施例71 (1足5«-6-[[3, 5-二氟-4-(4-比啶基）苯氧基]曱基]-3- 203 95344 201213319 (5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷4-Di-3,5-difluoro-benzophenone 70a (500 mg, 2.40 mmol), (4-anthracenylphenyl) fulvic acid (478 mg, 2.40 mmol) ' 1,1' -di ( Diphenylphosphino)ferrocene di-gasified ls (174 mg, 0.25 mmol) and cesium carbonate (2. 34 g, 7. 20 mmol) were dissolved in i〇mL 1,4-dioxane and warmed to 120°. C, the reaction was stirred for 2 hours. After adding 5 mL of water, it was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3, 5-difluoro-4-(4-indenesulfonium) Phenyl phenyl) phenol 70b 202 95344 201213319 (519 mg, yellow solid) 'The product was taken directly to the next step without purification. m/z (ESI): 283.0 [Ml] The second step (10) 5 «-3-(5-ethyl対_2_yl)_6_[[2_methyl_4_(4_methyl-bromophenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane only crude 3 , 5-difluoro-4-(4-methylsulfonylphenyl)phenol 7〇b (100 mg, 0.35 mmol) was dissolved in 5 mL of dimercaptomethionine, and the crude product was added in sequence [(17?, 550). 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo-injured [3.1.0]hexane-6-yl] sulfonate decyl sulfonate 7g (105mg, 〇.35mmol) and cesium carbonate (230 mg, 0. 70 mmol), the mixture was warmed to 90 ° C, and the reaction was stirred for 4 hours. 50 mL of water was added and extracted with ethyl acetate (4 mL mL). The resulting residue was purified by EtOAc EtOAc (EtOAc) 3-(5-ethylpyrimidin-2-yl)-6-[[2-indolyl-4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[ 3. 1. 0] 70 φ (68 mg 'white solid), yield: 40. 0%. MS m/z (ESI): 486.2 [M+l] 'H NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 8.00 (d, 2H), 7.65 (d, 2H), 6.57-6.59 (m, 2H), 4.00-4.02 (m, 2H), 3.93-3.96 (in, 2H), 3.60-3.63 (m, 2H), 3.10 (s, 3H), 2.46-2.52 (m, 2H), 1.77 (s, 2H), 1.24-1.27 (ra, 1H), 1. 18-1.22 (in, 3H). Example 71 (1 foot 5«-6-[[3, 5-difluoro-4-(4-pyridyl)phenoxy]indolyl]-3- 203 95344 201213319 (5-ethylpyrimidin-2- Benzyl-3-azabicyclo[3.1.0]hexane

將[(1尤5Λ-6-Κ4-溴-2, 6-二氟-苯氧基）曱基]-3-® (5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷8a(90mg， 2. 19mmol)，4-°比咬基删酸（27mg’ 2. 19mmol)，1，1’ -二（二 苯膦基）二茂鐵二氣化ls(16mg，0. 22mmol)和碳酸錄 (214mg，6. 58mmol)溶解於 lOmLl，4-二°惡烧中，升溫 120 °〇攪拌反應2小時。加入50mL水，用乙酸乙酯萃取 (40mLx2) ’合併有機相，無水硫酸鈉乾燥，過濾，濾液減 壓濃縮，用薄層色譜法以展開劑體系B純化所得殘餘物， % 得到標題產物（1疋5«-6-[[3, 5-二氟-4-(4-吡啶基）苯氧 基]曱基]_3-(5-乙基癌°定-2-基）-3~氮雜雙環並[3· 1. 0]己 烷71(70mg，白色固體），產率·· 22.0%。 MS m/z (ESI): 409.2 [M+l] 'H NMR (400 MHz, CDCh) 5 8.70 (s, 2H), 8.20 (s, 2H), 7.47 (s, 2H), 7.21-7.23 (m, 2H), 4.15-4.17 (m, 2H), 3.91-3.94 (m, 2H), 3.57-3.60 (m, 2H), 2.45-2.51 (m, 2H), 1.74 (s, 2H), 1.26 (s, 1H), 1.17-1.21 (m, 3H). 實施例72 204 95344 基）苯氧基]乙 201213319 7-(5-乙基嘧啶-2-基）-2-[2-[4-(四崃 基]-7-氮雜螺環[3.5]$#[(1 especially 5Λ-6-Κ4-bromo-2,6-difluoro-phenoxy)indolyl]-3-® (5-ethylpyrimidin-2-yl)-3-azabicyclo[ 3. 1. 0] Hexane 8a (90mg, 2.19mmol), 4-° than bite-based acid (27mg' 2. 19mmol), 1,1'-bis(diphenylphosphino)ferrocene The ls (16 mg, 0.22 mmol) and the carbonated product (214 mg, 6.58 mmol) were dissolved in 10 mL, 4-dioxacin, and the mixture was heated to 120 ° and stirred for 2 hours. After adding 50 mL of water and extracting with ethyl acetate (40 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.疋5«-6-[[3, 5-difluoro-4-(4-pyridyl)phenoxy]indolyl]_3-(5-ethylcarboxy-2-yl)-3~aza Bicyclo[3·1.0]hexane 71 (70 mg, white solid), yield: 22.0%. MS m/z (ESI): 409.2 [M+l] 'H NMR (400 MHz, CDCh) 5 8.70 (s, 2H), 8.20 (s, 2H), 7.47 (s, 2H), 7.21-7.23 (m, 2H), 4.15-4.17 (m, 2H), 3.91-3.94 (m, 2H), 3.57- 3.60 (m, 2H), 2.45-2.51 (m, 2H), 1.74 (s, 2H), 1.26 (s, 1H), 1.17-1.21 (m, 3H). Example 72 204 95344 phenyl) B 201213319 7-(5-ethylpyrimidin-2-yl)-2-[2-[4-(tetradecyl)-7-azaspiro[3.5]$#

第一步first step

2-(7-氮雜螺環[3. 5]壬烷-2-基)心’ ^ 將粗品2-(2-羥基）-7-氮雜螺環[3. 5]壬姨7缓3文第 三丁酯67c(200mg，0. 74mmol)溶解於1〇汕 &gt;氣甲烧中’ 滴加入三氟乙酸（114/zL，1.48mmol)，攪拌反應2小時。 反應液減壓濃縮，得到粗品標題產物2-(7-氮雜螺5] 壬烧-2-基）乙醇72a(200mg，黃色油狀物）’產物不Ί屯化 直接進行下一步反應。 第二步 2-[7-(5-乙基嘧啶-2-基）-7-氮雜螺環[3.5]安炫~2_基]乙 醇 將粗品2-(7-氮雜螺環[3. 5]壬烷-2-基）心醇72a (200mg，1. i8mmol)溶解於i〇mL光#-二曱基f醯胺中，依 久加入2-氯-5-乙基、濟咬（i68mg，1. 18mm〇l)和兔西夂鉀 (408mg，2. 90mmol)，升溫至i3〇ec，攪拌反應3小時。加 入50mL水，用乙酸乙酯萃取（5〇mLx3)，合併有機相，用飽 95344 205 201213319 和氯化鈉溶液洗滌（50mLx3)，無水硫酸鎂乾燥，過濾，濾 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系8純化所得 殘餘物，得到標題產物2_[7_(5_乙基嘧啶_2_基）_7_氮雜 螺環[3.5]壬烷-2-基]乙醇72b(136nig，白色固體），產率： 42. 0%。 MS m/z (ESI): 276.2 [M+1] 第三步 φ Κ5—乙基嘧啶基）-2-[2~[4-(四唑-1-基）苯氧基]乙 基]-7-氮雜螺環[3. 5]壬烷 將2-[7-(5-乙基射-2-基）-7-氮雜螺環[3. 5]壬烷 2-基]乙醇72b(136mg，0.49mmol)溶解於i5mL甲笨中， 攪拌，加入粗品4-(四唑-1-基）苯酚46b(72mg，〇 44mm〇1)， 再依-人加入二笨基膦（256mg’ 〇· 98賴〇1)和偶氮二曱酸二異 丙醋（145eL ’ 〇. 74_1)，室溫擾拌12小時，再加熱至 6代，攪拌反應2小時。反應液減壓濃縮，用薄層色譜法 _ 卩展開劑體系B純化所得殘餘物，得到標題產物卜（5_乙 基喷咬-2-基）-2-[2-[4-(四唾+基）苯氧基]乙基]_7-氮 雜螺環[3.5]壬烧72(17mg，白色固體），產率：8%。 WS m/z (ESI): 420.2 [M+l] 1H NMR (400 MHz, CDCh) ,5 8. 89 (s, 1H), 8. 15 (s 2H) H7.53(m，2H)，7.07-7.01(m，2H)，3.97(t，’2H)’， 3.Π-3.70 (m，2H)，3.69-3. 62 (m，2H)，2.46 (td 3H) 2. 13-2. 04 (m, 2H), 1.95 (dd, 2H), 1.71-1.64 (m 2η/ 1.59-1.49 (m, 4H), 1.17 (t, 3H). 95344 206 201213319 實施例73 4-[4-[[(li?，5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]曱氧基]苯基]苯曱腈2-(7-Azaspiro[3. 5]decane-2-yl) heart ' ^ The crude 2-(2-hydroxy)-7-azaspiro[3. 5]壬姨7 is slowed down 3 The third butyl ester 67c (200 mg, 0.74 mmol) was dissolved in 1 〇汕 > gas toluene', trifluoroacetic acid (114/zL, 1.48 mmol) was added dropwise, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (yield: 2-(7-azaspiro- 5) oxime-2-yl)ethanol 72a (200 mg, yellow oil). The second step 2-[7-(5-ethylpyrimidin-2-yl)-7-azaspiro[3.5]Anxun~2_yl]ethanol will be the crude 2-(7-azaspiro[3] 5] decane-2-yl)ol 200a (200mg, 1. i8mmol) was dissolved in i〇mL light #-dimercaptofamine, long-term addition of 2-chloro-5-ethyl, bite (i68 mg, 1.18 mm 〇l) and rabbit bismuth potassium (408 mg, 2.90 mmol), the temperature was raised to i3 〇ec, and the reaction was stirred for 3 hours. Add 50mL of water, extract with ethyl acetate (5〇mLx3), combine the organic phase, wash with 95344 205 201213319 and sodium chloride solution (50mLx3), dry over anhydrous magnesium sulfate, filter, filtrate concentrate under reduced pressure Chromatography The residue obtained was purified using eluent system 8 to give the title product: 2-[7-(5-ethylpyrimidin-2-yl)-7-azaspirocyclo[3.5]decane-2-yl]ethanol 72b (136nig) , white solid), yield: 42.0%. MS m/z (ESI): 276.2 [M+1] </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 7-Azaspiro[3.5.nonane] 2-[7-(5-Ethyl-2-yl)-7-azaspiro[3. 5]decane-2-yl]ethanol 72b (136 mg, 0.49 mmol) was dissolved in i5 mL of a solution, stirred, and the crude 4-(tetrazol-1-yl)phenol 46b (72 mg, 〇 44 mm 〇 1) was added, and then bis-phenylphosphine (256 mg' was added. 〇·98 〇 〇 1) and azobisphthalic acid diisopropyl vinegar (145eL '〇. 74_1), stir-fry for 12 hours at room temperature, then heat to 6 generations, and stir the reaction for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjjjjjjjjjj Benzyloxy]ethyl]-7-azaspiro[3.5] oxime 72 (17 mg, white solid), yield: 8%. WS m/z (ESI): 420.2 [M+l] 1H NMR (400 MHz, CDCh), 5 8. 89 (s, 1H), 8. 15 (s 2H) H7.53 (m, 2H), 7.07 -7.01 (m, 2H), 3.97 (t, '2H)', 3. Π - 3.70 (m, 2H), 3.69-3. 62 (m, 2H), 2.46 (td 3H) 2. 13-2. 04 (m, 2H), 1.95 (dd, 2H), 1.71-1.64 (m 2η/ 1.59-1.49 (m, 4H), 1.17 (t, 3H). 95344 206 201213319 Example 73 4-[4-[[ (li?,5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonyloxy]phenyl]phenylhydrazine Nitrile

第一步 4-(4-羥基苯基）苯曱腈 將（4-氰基苯基）棚酸73a(lg，6. 80mmol)，4-演苯紛 (911mg，5. 30mmol)，1，Γ -二（二苯膦基）二茂鐵二氯化把 (387mg，0. 53mmol)和三水合填酸鉀（4. 23g，4. 23mmol)溶 解於15mLl，4-二噁烷中，升溫至回流攪拌反應12小時。 過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B 純化所得殘餘物，得到標題產物4-(4-羥基笨基）苯曱腈 73b(840mg，白色固體），產率：83.0%。 MS m/z (ESI): 193.8 [M-l] 第二步 4-[4-[[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]曱氧基]苯基]苯曱腈 將4-(4-羥基苯基）笨曱腈731)(10〇11^，0.5〇111111〇1)溶 207 95344 201213319 解於5mL况趴二甲基甲醯胺中，依次加入粗品[(1^ 5«-3〜 (5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱 磺酸曱酯7居（13711^’0.46賴〇1)和碳酸铯（325呃，1111111〇1)， 升溫至80 C ’授摔反應12小時。加入20mL水，用乙酸乙 醋萃取（20mLx3) ’合併有機相，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所 得殘餘物’得到標題產物4-[4-[[(1兄5«-3-(5-乙基喷咬 φ -2~基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲氧基]苯基]苯 甲腈73( 35mg，白色固體），產率：19. 0%。 MS m/z (ESI)： 397.2 [M+l] NMR (400 MHz，CDC13) (5 8.20 (s，2H)，7.71-7. 63(m， 4H), 7.53 (d, 2H), 7.00 (d, 2H), 4.02-3.97 (m, 4H), 3.63-3.60 (m, 2H), 2.51-2.45 (m, 2H), 1.78 (s, 2H), 1.26-1. 18 (m, 4H) 實施例74The first step of 4-(4-hydroxyphenyl)benzonitrile is (4-cyanophenyl) succinic acid 73a (lg, 6.80 mmol), 4- benzene (911 mg, 5.30 mmol), 1, Γ-bis(diphenylphosphino)ferrocene dichloride (387 mg, 0.53 mmol) and potassium sulfate trihydrate (4.23 g, 4.23 mmol) were dissolved in 15 mL of 1,4-dioxane and warmed up. The reaction was stirred at reflux for 12 hours. Filtration and concentrating the filtrate under reduced pressure. EtOAc (EtOAc): 83.0%. MS m/z (ESI): 193.8 [Ml] Step 2 4-[4-[[(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.0]Hex-6-yl]decyloxy]phenyl]benzonitrile was dissolved in 4-(4-hydroxyphenyl)acridonitrile 731) (10〇11^, 0.5〇111111〇1) 207 95344 201213319 The solution was dissolved in 5 mL of dimethylformamide, and the crude product [(1^ 5«-3~(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] was sequentially added. Hexane-6-yl] sulfonate sulfonate 7 (13711^'0.46 lysine 1) and cesium carbonate (325 呃, 1111111〇1), heated to 80 C 'rejection reaction for 12 hours. Add 20 mL of water, It was extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system B to give the title product 4-[4- [[(1 brother 5«-3-(5-ethyl squirt φ -2~yl)-3-azabicyclo[3. 1.]] hexyl-6-yl] methoxy]phenyl Benzoonitrile 73 (35 mg, white solid), Yield: 10.0%. MS m/z (ESI): 397.2 [M+l] NMR (400 MHz, CDC13) (5 8.20 (s, 2H), 7.71-7. 63(m, 4H), 7.53 (d, 2H), 7.00 (d, 2H), 4.02-3.97 (m, 4H) , 3.63-3.60 (m, 2H), 2.51-2.45 (m, 2H), 1.78 (s, 2H), 1.26-1. 18 (m, 4H) Example 74

(1足55*)-3-(5_乙基癌咬-2-基）-6-[ [4-(4-乙續酿基苯 基）-2,6-二氟-苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烧(1 foot 55*)-3-(5_ethylcarban-2-yl)-6-[ [4-(4-ethyl phenyl)-2,6-difluoro-phenoxy] Methyl]-3-azabicyclo[3. 1. 0] hexane

95344 208 201213319 第一步 4-(4-乙磺醯基苯基）-2, 6-二氟-笨酚 將 4-溴-2, 6-二氟-苯紛 74a(500mg，2. 39mmol)，（4- 乙績醯基苯基）硼酸（512mg，2. 39mmol)，1，Γ -二（二苯膦 基）二茂鐵二氯化把（175mg，0. 20mmol)和碳酸絶（2. 34 g， 7. 18mmol)溶解於l〇mL 1，4-二噁烷中，升溫至12(TC，擾 拌反應2小時。加入50mL水，用乙酸乙酯萃取（20mLx2)， 合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得 _ 到粗品標題產物4-(4_乙續酿基苯基）-2，6-二氧-苯盼 74b(200mg，灰色固體），產物不經純化直接進行下一步反 應。 MS m/z (ESI): 297.0 [M-l] 第二步 (IT?, 5vS)-3-(5 -乙基癌咬-2~基）_6_[[4_(4_乙績酿基苯 基）-2, 6-二氟-苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷 $ 將粗品4-(4-乙磺醯基苯基）-2, 6-二氟-笨酚74b (100mg ’ 0. 30mmol)溶解於l〇mL况二甲基曱醯胺中，依 次加入粗品[(1^ 55*)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1.0]己烷-6-基]甲磺酸曱酯 7g(100mg，0.30mmol) 和石炭酸铯（328mg，lmmol)，升至90°C擾拌反應2小時。加 入50mL水，用乙酸乙酯萃取（40mLx2)，合併有機相，無水 硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開 劑體系B純化所得殘餘物，得到標題產物（1^550-3-(5-乙基嘧啶-2-基）-6-[[4-(4-乙磺醯基苯基）-2, 6-二氟-苯 209 95344 201213319 氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷74( 20mg，白色固 體），產率：12.5%。 MS m/z (ESI): 500.2 [M+l] 丽R (400 MHz, CDCh) 5 8. 18 (s，2H)，7. 97-7. 99 (m， 2H), 7.69-7.72 (m, 2H), 7. 17-7. 19 (m, 2H), 4.14-4.16 (m, 2H), 3.88-3.91 (m, 2H), 3.55-3.57 (m, 2H), 3.14-3.19 (m, 2H), 2.43-2.50 (m, 2H), 1.72 (s, 2H), 1.30-1.34(m, 3H), 1.26-1.23 (m, 1H), 1.17-1.20 (m, 3H).95344 208 201213319 First step 4-(4-ethylsulfonylphenyl)-2,6-difluoro-indolyl 4-bromo-2,6-difluoro-benzene 74a (500 mg, 2.39 mmol) , (4-ethylidene phenyl)boronic acid (512 mg, 2.39 mmol), 1, fluorene-bis(diphenylphosphino)ferrocene dichloride (175 mg, 0.20 mmol) and carbonic acid (2) 34 g, 7. 18 mmol) dissolved in 1 mL of 1,4-dioxane, warmed to 12 (TC, scrambled for 2 h. Add 50 mL of water, extract with ethyl acetate (20 mL×2), combined organic phase Drying over anhydrous sodium sulfate, filtration, and EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The next reaction was carried out without purification. MS m/z (ESI): 297.0 [Ml] The second step (IT?, 5vS)-3-(5-ethylcarcinoid bite-2~yl)_6_[[4_( 4_B-branched phenyl)-2,6-difluoro-phenoxy]methyl]-3-azabicyclo[3.1.0]hexane $ crude 4-(4-ethanesulfonyl) Phenyl)-2,6-difluoro-indolol 74b (100 mg '0.30 mmol) was dissolved in 1 mL of dimethyl decylamine, and the crude product [(1^55*)-3-(5) was added in sequence. -ethylpyrimidin-2-yl)-3- 7 g (100 mg, 0.30 mmol) of heterobicyclo[3.1.0]hexane-6-yl]methanesulfonate and cesium carbate (328 mg, 1 mmol), and the mixture was stirred at 90 ° C for 2 hours. Add 50 mL of water. The extract was extracted with ethyl acetate (40 mL×2), EtOAcjjjjjjjjjjj -(5-ethylpyrimidin-2-yl)-6-[[4-(4-ethanesulfonylphenyl)-2,6-difluoro-benzene 209 95344 201213319 oxy]methyl]-3- Azabicyclo[3.1.0]hexane 74 (20 mg, white solid), yield: 12.5%. MS m/z (ESI): 500.2 [M+l] R (400 MHz, CDCh) 5 8. 18 (s, 2H), 7. 97-7. 99 (m, 2H), 7.69-7.72 (m, 2H), 7. 17-7. 19 (m, 2H), 4.14-4.16 (m, 2H), 3.88-3.91 (m, 2H), 3.55-3.57 (m, 2H), 3.14-3.19 (m, 2H), 2.43-2.50 (m, 2H), 1.72 (s, 2H), 1.30-1.34 ( m, 3H), 1.26-1.23 (m, 1H), 1.17-1.20 (m, 3H).

實施例75 於[[(li?，5^-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己烧-6-基]曱基]-5-(4_曱續酿基苯基）°底嗓-2-胺Example 75 on [[(li?,5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexa-6-yl]]] -5-(4_曱 酿 酿 phenyl) ° 嗓 嗓-2-amine

第一步 (1疋5«-6-(溴甲基）-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 210 95344 201213319 並[3. 1. 0]己烷First step (1疋5«-6-(bromomethyl)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo 210 95344 201213319 and [3. 1. 0]hexane

將粗品[(1足55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1.0]己烧-6-基]甲磺酸甲酯7g(219mg，lmm〇1)和四 溴化碳（500mg，1.· 50mm〇l)溶解於5mL二氣曱烷中，加入三 苯基膦（393mg，1. 50mmol)，攪拌反應3小時 。加入50mL 水，用二氣甲烷萃取（l〇mLx2)，合併有機相，無水硫酸鎂 乾燥’過滤’遽液減壓濃縮，用矽膠管柱色譜法以洗脫劑 體系B純化所得殘餘物，得到標題產物（丨兄5幻_6_(溴甲 _ 基）-3_(5_乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 75a(260mg，無色晶體），產率：92 2%。 MS m/z (ESI): 284.0 [M+l] 第二步 5-溴娘嗪〜2-胺 冰浴下，將哌嗪-2-胺75b(ll. 87g，12. 50mmol)溶解 於300mL二氯曱烷中，分批加入N-溴代丁二醯亞胺（22. 20 • g，125醒〇1) ’攪拌反應2小時。加入i〇〇mL飽和碳酸鈉溶 液淬滅反應’分液’有機相依次用飽和碳酸鈉溶液洗滌 (50mLxl)，水洗滌（50mLx2)，無水硫酸鈉乾燥，過濾，濾 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得 殘餘物，得到標題產物5-溴哌嗪-2-胺75c(13g，黃色固 體），產率：60. 0%。 MS m/z (ESI): 173.9 [M+l] 第三步 5-(4-曱確酿基苯基）派嗓-2-胺 211 95344 201213319 將5-溴哌嗪-2-胺75c(lg，5. 60mmol)，（4一甲磺醯基 苯基）硼酸（1. I4g，5. 60mmol)，二（三苯膦基;)二氯化鈀 (130mg，0· 12mmol)和 8mL 2M 碳酸納溶液溶解於 28mLi 4- 二噁烷和曱醇的混合溶劑（V/V = 5:2)中，升至1〇〇£&gt;c攪拌 反應3小時。加入15mL水，抽濾，濾餅用水洗務（4〇mLx2)， 濾餅用120raL乙酸乙酯打漿，攪拌2〇分鐘，抽濾，得到粗 品標題產物5-(4-甲磺醯基苯基）哌嗪_2_胺75d(14〇g， 黃色固體），產物不經純化直接進行下一步反應。 ® MS m/z (ESI)： 250.1 [M+l] 第四步 一 趴[[(1尤55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1· 0] 己烷-6-基]甲基]-5-(4-甲磺醯基苯基）哌嗪-2-胺 將粗品5-(4-甲磺醯基苯基）哌嗪-2-胺75d(100mg， 0.40mmol)溶解於2mL况於二甲基曱醢胺中，加入60%氫化 鈉（40mg，lmmol) ’升至4(TC攪拌反應0. 5小時。冷卻至 • 至溫’加入（1尤55^-6-(^臭曱基）-3-(5-乙基痛咬基）-3_ 氮雜雙環並[3. 1. 0]己烷75a(80mg，0. 28mmol)，攪拌反應 _ 40分鐘。加入30mL水，用乙酸乙酯萃取（50mLx2)，合併 有機相，用飽和氣化鈉溶液洗滌（20mLxl)，無水硫酸鈉乾 燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A 純化所得殘餘物，得到標題產物#-[[(1^550-3-(5-乙基 嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6-基]甲基]-δα-甲磺醯基苯基 ） 哌嗪-2-胺 75(30mg ， 淡黃 色固體）， 產 率：23. 8%。 212 95344 201213319 MS m/z (ESI): 451.2 [M+l] 丽R (400 MHz, CDCla) 5 8.56 (s，1H)，8.22 (s，2H)， 8.11(d, 2H), 8.03(d, 3H), 3. 99 (d, 2H), 3. 61 (d, 2H), 3. 51-3.38 (m, 2H)，3.12 (s，3H), 2.50 (q, 2H)，1.74 (s, 3H), 1.22 (t, 3H), 1.13 (m, 1H). 實施例76 於[[(1^ 55&quot;)-3-(5 -乙基σ密咬-2-基）-3-氣雜雙環並[3. 1. 〇] 己烧-6-基]曱基]-yV~曱基-5-(4-曱續醢基苯基）派唤-2_胺The crude product [(1 foot 55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl methanesulfonate 7 g (219 mg, Lmm 〇 1) and carbon tetrabromide (500 mg, 1. 50 mm 〇l) were dissolved in 5 mL of dioxane, triphenylphosphine (393 mg, 1.50 mmol) was added, and the reaction was stirred for 3 hours. Add 50 mL of water, extract with methane (1 〇 mL×2), combine the organic phases, dry the 'filter' with anhydrous magnesium sulfate, concentrate under reduced pressure, and purify the residue by eluent column chromatography with eluent system B to obtain the residue. The title product (丨兄5幻_6_(bromomethyl)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 75a (260 mg, colorless crystals ), yield: 92 2%. MS m / z (ESI): 284.0 [M + l] The second step 5 - bromozin ~ 2-amine ice bath, piperazine-2-amine 75b (ll. 87g, 12. 50mmol) was dissolved in 300mL of dichloromethane, and N-bromosuccinimide was added in portions (22. 20 • g, 125 〇 1). Stirring reaction for 2 hours. Add i〇〇mL The saturated organic sodium carbonate solution was quenched and the organic phase was washed with saturated sodium carbonate solution (50 mL×1), washed with water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with a silica gel column chromatography. The resulting residue was purified by EtOAc (EtOAc): EtOAc (EtOAc) ] The third step 5-(4-曱 酿 phenyl) pie 嗓-2 -Amine 211 95344 201213319 5-Bromopiperazine-2-amine 75c (lg, 5.60 mmol), (4-methanesulfonylphenyl)boronic acid (1.14 g, 5.60 mmol), bis(triphenylphosphine) Base;) palladium dichloride (130 mg, 0.12 mmol) and 8 mL of 2M sodium carbonate solution dissolved in a mixed solvent of 28mLi 4-dioxane and decyl alcohol (V/V = 5:2), raised to 1〇〇 The reaction was stirred for 3 hours. 15 mL of water was added, suction filtered, and the filter cake was washed with water (4 〇mL×2). The filter cake was beaten with 120 raL of ethyl acetate, stirred for 2 minutes, and filtered to give the crude title product 5- (4-Methanesulfonylphenyl)piperazine-2-amine 75d (14 g, yellow solid), product was taken to the next step without purification. MS m/z (ESI): 250.1 [M+l The fourth step is a step [[(1 especially 55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·0] hexane-6-yl]methyl -5-(4-Methanesulfonylphenyl) piperazine-2-amine The crude 5-(4-methylsulfonylphenyl) piperazine-2-amine 75d (100 mg, 0.40 mmol) was dissolved in 2 mL In the case of dimethyl decylamine, 60% sodium hydride (40 mg, 1 mmol) was added to '4' (TC stirring reaction 0.5 hr. Cooling to • to temperature) was added (1 especially 55^-6-(^ Skunk base 3- (5-ethyl-bite pain yl) -3_ azabicyclo [3. 1. 0] hexane 75a (80mg, 0. 28mmol), _ the reaction was stirred for 40 minutes. Add 30 mL of water, extract with ethyl acetate (50 mL×2), and the organic phase is combined, washed with a saturated sodium carbonate solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give the title product #-[[(1^550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime]hexane-6-yl. Methyl]-δα-methylsulfonylphenyl) piperazine-2-amine 75 (30 mg, pale yellow solid), Yield: 23.8%. 212 95344 201213319 MS m/z (ESI): 451.2 [M+l] 丽R (400 MHz, CDCla) 5 8.56 (s,1H), 8.22 (s,2H), 8.11(d, 2H), 8.03(d , 3H), 3. 99 (d, 2H), 3. 61 (d, 2H), 3. 51-3.38 (m, 2H), 3.12 (s, 3H), 2.50 (q, 2H), 1.74 (s , 3H), 1.22 (t, 3H), 1.13 (m, 1H). Example 76 in [[(1^ 55&quot;)-3-(5-ethyl σ-Bitter-2-yl)-3- gas Heterobicyclo[3. 1. 〇] hexyl-6-yl] fluorenyl]-yV~ fluorenyl-5-(4-anthracenylphenyl)--2-amine

# 將#-[[(1疋55)-3-(5-乙基喊咬-2-基）-3-氮雜雙環 並[3. 1. 0]己烷-6-基]曱基]-5-(4-甲石黃醯基苯基）旅嗓-2-胺75(36mg ’ 0. 08mmol)溶解於lmL Λ I-二甲基曱醯胺中， 加入60%氫化納（l〇mg ’ 0· 25mmol)，擾拌反應〇. 5小時， 再加入碘曱烷（14mg ’ 0. 10_〇1)，攪拌反應2〇分鐘。加入 3〇mL水，用乙酸乙酯萃取（5〇mLx2)，合併有機相，用飽和 氯化鈉溶液洗滌（20mLxl)，無水硫酸鈉乾燥，過濾.，滹液 減壓濃縮，用薄層色譜法以展開劑體系△純化所得= 物，得到標題產物於[[(1疋5«-3-(5-乙基嘧啶、2〜義、 氮雜雙環並[3. 1.0]己烷-6-基]曱基]甲基—5 土 〜甲續 95344 213 201213319 醯基苯基）哌嗪-2-胺76(17mg，淡黃色固體），產率：45. 9°/〇。 MS m/z (ESI): 465.2 [M+l] 沱匪R (400 MHz，CDCIO (5 8. 60 (s，1H)，8. 18 (d，3H)， 8. 12 (d, 2H), 8. 03 (d, 2H), 3. 94 (d, 2H), 3. 68 (d, 2H), 3.56 (d, 2H), 3. 25(s, 3H), 3. 12 (s, 3H), 2.48 (q, 2H), 1.73 (s, 2H), 1.20 (t, 3H), 1.14-1.02 (m, 1H). 實施例77#将#-[[(1疋55)-3-(5-ethyl-snack-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]indenyl] -5-(4-methylglycosylphenyl) 嗓-2-amine 75 (36 mg '0.08 mmol) was dissolved in 1 mL of Λ I-dimethyl decylamine, and 60% sodium hydride (l 〇 mg ' 0·25 mmol), the reaction was stirred for 5 hours, then iodonane (14 mg '0. 10_〇1) was added, and the reaction was stirred for 2 minutes. Add 3 mL of water, extract with ethyl acetate (5 〇 mL×2), combine the organic phase, wash with a saturated sodium chloride solution (20 mL×l), dry over anhydrous sodium sulfate, and filtered. The obtained product was purified by a solvent system Δ to give the title product in [[(1疋5«-3-(5-ethylpyrimidine, 2~, azabicyclo[3.1.0]hexane-6- m ] ] 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 344 (ESI): 465.2 [M+l] 沱匪R (400 MHz, CDCIO (5 8. 60 (s, 1H), 8. 18 (d, 3H), 8. 12 (d, 2H), 8. 03 (d, 2H), 3. 94 (d, 2H), 3. 68 (d, 2H), 3.56 (d, 2H), 3. 25(s, 3H), 3. 12 (s, 3H), 2.48 (q, 2H), 1.73 (s, 2H), 1.20 (t, 3H), 1.14-1.02 (m, 1H). Example 77

(1尤550-3-(5-乙基嘧啶-2-基）-6-[ [4-(4-甲磺醯基苯基） ***-1-基]甲基]-3-氮雜雙環並[3. 1. 0]己烷(1 especially 550-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(4-methylsulfonylphenyl)triazol-1-yl]methyl]-3-aza Bicyclo[3.1.0]hexane

參 第一步 (1尤550-6-(疊氮曱基）-3-(5-乙基嘧啶-2-基）-3-氮雜雙 214 95344 201213319 環並[3· 1· 〇]己烧 將粗品[(1兄55)-3-(5-乙基响唆-2-基）-3-氮雜雙j事 並[3.1.0]己烷-6-基]曱磺酸曱酯 7g(2.20g，7.40irnn〇1^ 和疊氮化鈉（1. 20g，18mmol)溶解於i〇mLU-二甲基甲酿 胺中，升至8(TC攪拌反應12小時。加入2〇mL水，用己駿 乙酯萃取（20mLx3)，合併有機相，無水硫酸鎂乾燥，過淚， 濾液減壓濃縮，得到粗品標題產物（1尤55^-6-(疊氮甲茂） -3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷77a _ (380mg，褐色油狀），產率：23.0°/〇。 MS m/z (ESI): 245.1 [M+l] 第二步 三曱基-[2-(4-甲續醯基）乙炔基]石夕烧 將卜溴-4-曱磺醯基-苯77b(lg，4.20mmol)，三乙胺 (1.20g，12. 60mmol) ’ 碘化亞銅（71mg，0.40mmol)和二 苯膦基）二氯化鈀（118mg，0.20mmol)溶解於lOmL二氣曱燒 φ 中’冰浴冷卻下，滴加乙炔基（三曱基）矽烷（458mg， 4. 70mmol)，升至室溫，攪拌反應12小時。加入i〇mL水， 用乙酸乙酯萃取（l〇mLx2)，合併有機相，依次用1M氯化銨 溶液（10mLx2) ’飽和氣化鈉溶液洗滌(^04x2)，無水硫酸 鈉乾燥’過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫 劑體系β純化所得殘餘物，得到標題產物三曱基-[2_(4- 甲磺醯基）乙炔基]矽烷77c(lg，淡黃色固體），產率·· 93. 4%。 MS m/z (ESI): 270.1 [M+18] 215 95344 201213319 第三步 1-乙炔基-4-甲績醯基-苯 將三曱基-[2-(4-甲確酿基）乙快基]石夕烧77c(lg ’ 4mmol)碳酸卸（2. 20g，16mmol)溶解於20mL曱醇中，授拌 反應12小時。過濾，濾液減壓濃縮，用碎膠管柱色譜法以 洗脫劑體系B純化所得殘餘物，得到標題產物卜乙炔基-4-曱續醯基-苯77d(400mg，黃色固體），產率：56.3%。 MS ra/z (ESI)： 198.1 [M+18] 第四步 (1兄550-3-(5-乙基嘧啶-2-基）-6-[[4-(4-曱磺醯基苯基） ***-1-基]曱基]-3-氮雜雙環並[3. 1.0]己烷 將粗品（1尤55)-6-(疊氮甲基）-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷 77a(100mg，0.40mmol)， 1-乙快基-4-甲續酿基-苯77d(74mg，0. 40mmol)，溴化亞 銅（12mg’ 0· 08mmol)和三乙胺（81mg，0. 80mmol)溶解於 5mL 乙腈中，滴加lmL水，攪拌反應12小時。加入20mL水， 用乙酸乙酯萃取（20mLx3)，合併有機相，無水硫酸鈉乾燥， 過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B 純化所得殘餘物，得到標題產物（1兄550-3-(5-乙基嘧啶 -2-基）-6-[ [4-(4-曱磺醯基苯基）***-1-基]曱基]-3-氮 雜雙環並[3. 1. 0]己烷77(85mg，白色固體），產率：55. 0%。 MS ra/z (ESI)： 424.2 [M+l] Ή NMR (400 MHz, CDCh) 5 8. 18 (s, 2H), 8.07-8.00 (m, 4H), 7.97 (s, 1H), 4.42 (d, 2H), 3.98 (d, 2H), 3.59 216 95344 201213319 (d, 2H), 3. 10(s, 3H), 2. 50-2. 45 (m, 2H), 1.87(s, 2H), 1. 34-1. 31 (m, 1H), 1. 19 (t, 3H). 實施例78 (1兄5«-6-[[4-(4-曱磺醯基苯基）苯氧基]曱基]-3-氮雜 雙環並[3. 1. 0]己烷-3-羧酸第三丁酯The first step (1 especially 550-6-(azidoindolyl)-3-(5-ethylpyrimidin-2-yl)-3-azapine 214 95344 201213319 环[3·1· 〇] The crude product [(1 brother 55)-3-(5-ethyloxan-2-yl)-3-aza-bi-[3.1.0]hexane-6-yl]indolesulfonate 7g (2.20g, 7.40irnn〇1^ and sodium azide (1. 20g, 18mmol) were dissolved in i〇mLU-dimethylamine, and raised to 8 (TC stirred for 12 hours. Add 2〇mL The mixture was extracted with EtOAc (EtOAc) (EtOAc) (5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] hexane 77a _ (380 mg, brown oil), yield: 23.0° / 〇. MS m/z ( ESI): 245.1 [M+l] The second step of tridecyl-[2-(4-methyl-decyl)ethynyl] Shih-hsing will be bromo-4-indenesulfonyl-benzene 77b (lg, 4.20 Methyl) (1.20 g, 12.60 mmol) 'Copper iodide (71 mg, 0.40 mmol) and diphenylphosphino)palladium dichloride (118 mg, 0.20 mmol) dissolved in 10 mL of dioxane φ 'Iceyl group (trimethyl sulfhydryl) is added dropwise under ice cooling (458 mg, 4. 70 mmol), warmed to room temperature, and stirred for 12 hr. EtOAc (EtOAc) (EtOAc (EtOAc) The saturated sodium carbonate solution was washed (^04x2), dried under anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography using eluent column chromatography to give the title product tris-yl-[2_( 4-methanesulfonyl)ethynyl]decane 77c (lg, pale yellow solid), mp. 93. 4%. MS m/z (ESI): 270.1 [M+18] 215 95344 201213319 - ethynyl-4-methylindolyl-benzene-tris-yl-[2-(4-methyl-furanyl)ethyl-carbyl]zexi-burn 77c (lg '4mmol) carbonic acid unloading (2. 20g, 16mmol) Dissolved in 20 mL of decyl alcohol and allowed to react for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by column chromatography using eluent column chromatography to give the title product ethethyl-4- hydrazine. - Benzene 77d (400 mg, yellow solid), yield: 56.3%. MS / / (ESI): 198.1 [M+18] Step 4 (1 brother 550-3-(5-ethylpyrimidin-2-yl) )-6-[[4-(4-oxasulfonylphenyl) triazole -1-yl]fluorenyl]-3-azabicyclo[3.1.0]hexane will be crude (1 especially 55)-6-(azidomethyl)-3-(5-ethylpyrimidin-2- 3-Azabicyclo[3.1.0]hexane 77a (100 mg, 0.40 mmol), 1-ethyl carbyl-4-methyl aryl-benzene 77d (74 mg, 0.40 mmol), bromide Copper (12 mg '0·08 mmol) and triethylamine (81 mg, 0.80 mmol) were dissolved in 5 mL of acetonitrile, and 1 mL of water was added dropwise, and the reaction was stirred for 12 hours. After adding 20 mL of water, the mixture was extracted with ethyl acetate (20 mL×3), EtOAcjjjjjjjjjjjjjj 1 brother 550-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(4-oxasulfonylphenyl)triazol-1-yl]indolyl]-3-azabicyclo [3. 1. 0] Hexane 77 (85 mg, white solid), yield: 55.0%. MS, m/z (ESI): 424.2 [M+l] NMR (400 MHz, CDCh) 5 8 18 (s, 2H), 8.07-8.00 (m, 4H), 7.97 (s, 1H), 4.42 (d, 2H), 3.98 (d, 2H), 3.59 216 95344 201213319 (d, 2H), 3. 10(s, 3H), 2. 50-2. 45 (m, 2H), 1.87(s, 2H), 1. 34-1. 31 (m, 1H), 1. 19 (t, 3H). Example 78 (1 brother 5«-6-[[4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane-3- Tert-butyl carboxylate

將粗品4-(4-甲磺醯基苯基）苯酚33b(250mg， 0.80mmol)溶解於5mL况二甲基甲醯胺中，依次加入粗 品（1尤5«-6-(曱磺醯氧基甲基）-3-氮雜雙環並[3. 1. 0]己 # 烷-3-羧酸第三丁酯16b(293mg，0.80mmol)和碳酸铯 (656mg，1. 60mmol)，升至90°C擾拌反應4小時。加入50mL 水，用乙酸乙酯萃取（40mLx2)，合併有機相，無水硫酸鎂 乾燥，過濾，濾液減壓濃縮，得到標題產物（1^550-6-[[4-(4-曱磺醯基苯基）苯氧基]甲基]-3-氮雜雙環並 [3. 1.0]己烷-3-羧酸第三丁酯78(200mg，白色固體），產 率：56. 0%。 MS m/z (ESI): 388.1 [M-55] 4 丽R(400 MHz，CDCh) 5 7.97-7. 99 (m，2H)，7.72-7. 75 217 95344 201213319 (m, 2H), 7.55-7.57 (m, 2H), 6.98-7.00 (in, 2H), 3.86-4.00 (m, 2H), 3.62-3.72 (m, 2H), 3.39-3.40 (m, 2H), 3.09(s, 3H), 1.59(s, 2H), 1.40 (s, 9H), 1. 17 (s, 1H). 實施例79 4-[4-[[(l尤5«-3-(5-乙基嘧啶-2-基）-3_氮雜雙環並 [3. 1.0]己烷-6-基]甲氧基]苯基]苯曱醯胺The crude 4-(4-methylsulfonylphenyl)phenol 33b (250 mg, 0.80 mmol) was dissolved in 5 mL of dimethylformamide, and the crude product was added in sequence (1 especially 5 «-6-(sulfonate) Methyl)-3-azabicyclo[3.1.0]hexa-3-carboxylic acid tert-butyl ester 16b (293 mg, 0.80 mmol) and cesium carbonate (656 mg, 1.60 mmol), The mixture was stirred for 4 hours at 90 ° C. 50 mL of water was added, and ethyl acetate (40 mL) was evaporated. 4-(4-oxasulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 78 (200 mg, white solid) Yield: 56.0% MS m/z (ESI): 388.1 [M-55] 4 R (400 MHz, CDCh) 5 7.97-7. 99 (m, 2H), 7.72-7. 75 217 95344 201213319 (m, 2H), 7.55-7.57 (m, 2H), 6.98-7.00 (in, 2H), 3.86-4.00 (m, 2H), 3.62-3.72 (m, 2H), 3.39-3.40 (m, 2H ), 3.09(s, 3H), 1.59(s, 2H), 1.40 (s, 9H), 1. 17 (s, 1H). Example 79 4-[4-[[(l especially 5«-3- (5-ethylpyrimidin-2-yl)-3_azabicyclo[3.1.0]hexane-6-yl]methoxy]phenyl]benzoquinone

將4-[4-[[(1足550-3-(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3. 1. 0]己烷-6-基]甲氧基]苯基]苯甲腈73(5mg， 12.60//111〇1)和氫氧化鉀（1呢’18.90训〇1)溶解於51111乙 醇中，加入過氧化氫0.50mL，攪拌反應12小時。反應液 減壓濃縮’加入20mL水，用乙酸乙酯萃取（2〇mLx2)，合併 有機相’無水硫酸鎂乾燥，過濾’濾液減壓濃縮’用薄層 色譜法以展開劑體系B純化所得殘餘物，得到標題產物 4-[4-[[(1尤55)-3-(5-乙基°密咬-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]甲氧基]苯基]苯曱醯胺79(3mg，白色 固體），產率·· 57· 7%。 MS m/z (ESI): 415.2 [M+l] 95344 218 201213319 !H NMR (400 MHz, CDCh) δ 8.20 (s, 2H), 7. 99(s, 1H), 7.91-7.94 (m, 2H), 7.65-7.70 (m, 4H), 7.32(s, 1H), 7.03-7.05 (m, 2H), 3.97-3.99 (m, 2H), 3.78-3.81 (m, 2H), 3.45-3.48 (in, 2H), 2.38-2.40 (m, 2H), 1.77 (s, 2H), 1. 13 (s, 1H), 1. 09-1. 11 (m, 3H). 實施例80 (1 左，550-3-(5-乙基喷咬-2-基）-6-[(17?)_1-[4-（4-甲績酸 基苯基）苯氧基]乙基]-3-氮雜雙環並[3. 1. 0]己烷4-[4-[[(1) 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy) ]Phenyl]benzonitrile 73 (5 mg, 12.60//111〇1) and potassium hydroxide (1'18.90) 1 were dissolved in 51,11 ethanol, 0.50 mL of hydrogen peroxide was added, and the reaction was stirred for 12 hours. The liquid was concentrated under reduced pressure, and then the mixture was extracted with ethyl acetate (2 mL), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and filtrate was concentrated under reduced pressure. To give the title product 4-[4-[[(1)5-(5-ethyl))-azabicyclo[3.1.0]hexane-6-yl Methoxy]phenyl]benzoinamine 79 (3 mg, white solid), mp. 57. s. MS m/z (ESI): 415.2 [M+l] 95344 218 201213319 !H NMR ( 400 MHz, CDCh) δ 8.20 (s, 2H), 7. 99(s, 1H), 7.91-7.94 (m, 2H), 7.65-7.70 (m, 4H), 7.32(s, 1H), 7.03-7.05 (m, 2H), 3.97-3.99 (m, 2H), 3.78-3.81 (m, 2H), 3.45-3.48 (in, 2H), 2.38-2.40 (m, 2H), 1.77 (s, 2H), 1 . 13 (s, 1H), 1. 09-1. 11 (m, 3H). Example 80 (1 left, 550-3-(5-ethyl ace-2-yl)-6-[(1 7?)_1-[4-(4-Propanylphenyl)phenoxy]ethyl]-3-azabicyclo[3.1.0]hexane

(1尤5Λ-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烷-6-笨甲醛 乾冰浴下，將草醯氯（174mg，1.37mmol)溶解於10mL 二氯曱烷中，緩慢滴加二曱基亞砜（232mg，2.97mio1)，反 應10分鐘後’滴加5mL粗品[(1^ 550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲醇7f(250mg， 1.14丽〇1)的二氣甲烷溶液，攪拌反應3〇分鐘。再滴加三 乙胺（576mg，5. 71咖〇1)，逐漸升至室溫，攪拌反應2小時'。 95344 219 201213319 加入10mL水淬滅反應，二氯曱烷萃取（2〇mLx3)，合併有機 相’飽和氯化鈉溶液洗滌（20mLx2)，無水硫酸鎂乾燥，過 濾’滤液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純 化所得殘餘物，得到標題產物（1疋55·)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6-苯曱醛80a(100mg，白 色固體），產率：40.3%。 MS m/z (ESI)： 218.2 [M+l] ^ 第二步 l-[(u，550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己烧-6-基]乙醇 冰浴下，將（1^55^-3-(5-乙基喷°定-2-基）-3-氮雜雙 環並[3. 1. 0]己烧-6-苯曱路80a(100mg，0. 46mmol)加入至 5mL四氫呋喃中，緩慢滴加0· 3mL 3M曱基溴化鎂，逐漸升 至室溫，攪拌反應2小時。加入15mL飽和氣化銨溶液淬滅 反應，乙酸乙酯萃取（30mLx2)，合併有機相，無水硫酸鎂 φ 乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 1-[(1尤5«_3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇] 己烷-6-基]乙醇80b(100mg ’白色固體），產物不經純化直 接進行下一步反應。 MS m/z (ESI)： 234.2 [M+l] 第三步 (liP, 55)-6-(1-氣乙基）-3-(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3. 1. 0]己烷 冰浴下，將尤55)-3-(5-乙基嘧啶-2-基）-3-氮 220 95344 201213319 雜雙環並[3. 1.0]己烷-6-基]乙醇 80b(100mg，〇.43mmol) 溶解於10mL無水二氯甲烷中，加入三乙胺（〇. lmL， 0. 86mmol) ’滴加入曱橫酿乳（〇. imL，〇. 64mmol) ’升至室 溫’攪拌反應2小時。加入二氯甲烷1〇mL，用飽和氯化鈉 溶液洗滌（20mLx2) ’無水硫酸鎂乾燥，過濾，濾液減壓濃 縮，得到粗品標題產物（1^550-6-0-氣乙基）-3-(5-乙基 嘧啶-2-基)-3-氮雜雙環並[3· 1· 〇]己烷80c(100mg，黃色 液體），產物不經純化直接進行下一步反應。 鳙 MS m/z (ESI): 252.1 [M+l] 第四步 (1疋 55)-3-(5-乙基嘧唆-2-基）-6-[(1 及)_i_[4_(4一甲續醯 基苯基）苯氧基]乙基]-3-氮雜雙環並[3. 1. 〇]己烷 將粗品4-(4-曱石黃酿基苯基）苯驗33b(109mg，(1 especially 5Λ-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-benzaldehyde in a dry ice bath, the grass is chlorine (174 mg, 1.37 mmol) was dissolved in 10 mL of dichloromethane, and dimercaptosulfoxide (232 mg, 2.97 mio1) was slowly added dropwise. After 10 minutes of reaction, '5 mL of crude product was added dropwise [(1^ 550-3-(5-ethylpyrimidine) a 2-methane solution of 2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanol 7f (250 mg, 1.14 〇1), stirred for 3 〇 minutes. Add triethylamine (576 mg, 5. 71 Curry 1), gradually warm to room temperature, and stir the reaction for 2 hours'. 95344 219 201213319 Add 10 mL of water to quench the reaction, dichloromethane extraction (2 〇 mL x 3), combine organic The mixture was washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product (1 疋 55·) 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1.indole]hexane-6-phenylfurfural 80a (100 mg, white solid), yield: 40.3%. MS m/z (ESI): 218.2 [M+l] </RTI> Step 2 l-[(u,550-3-(5-ethylpyrimidin-2-yl)-3- aza And [3. 1. 0] hexyl-6-yl] ethanol in an ice bath, (1^55^-3-(5-ethyl oxime-2-yl)-3-azabicyclo[ 3. 1. 0] hexyl-6-benzoquinone 80a (100mg, 0.46mmol) was added to 5mL of tetrahydrofuran, slowly added 0. 3mL 3M mercapto magnesium bromide, gradually rose to room temperature, stirring reaction 2 The reaction was quenched by the addition of 15 mL of aq. EtOAc. EtOAc (EtOAc) _3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] hexane-6-yl]ethanol 80b (100 mg of 'white solid). One step reaction MS m/z (ESI): 234.2 [M+l] Step 3 (liP, 55)-6-(1-ethylethyl)-3-(5-ethylpyrimidin-2-yl)- 3-Azabicyclo[3.1.0]hexane under ice bath, will be especially 55)-3-(5-ethylpyrimidin-2-yl)-3-nitrogen 220 95344 201213319 heterobicyclo[3. 1.0] Hexane-6-yl]ethanol 80b (100 mg, 〇.43 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and triethylamine (〇.lmL, 0.86 mmol) was added to the mixture. imL, . 64mmol) 'was raised to room temperature' reaction was stirred for 2 hours. After adding 1 mL of dichloromethane, it was washed with a saturated sodium chloride aqueous solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give the crude title product (1^ 550-6-0- -(5-ethylpyrimidin-2-yl)-3-azabicyclo[3·1·〇]hexane 80c (100 mg, yellow liquid).鳙MS m/z (ESI): 252.1 [M+l] The fourth step (1疋55)-3-(5-ethylpyrimidin-2-yl)-6-[(1 and)_i_[4_( 4-methyl-phenylphenyl)phenoxy]ethyl]-3-azabicyclo[3. 1. oxime] hexane will be crude 4-(4-aragonite yellow phenyl) benzene test 33b (109mg,

0. 44mmol)溶解於10mL U-二曱基甲醯胺中，依次加入粗 品（1尤55)-6-(1-氯乙基）-3-(5-乙基喊咬-2-基）-3-氮雜 雙環並[3. 1. 0]己烷80c(100mg，〇· 4〇mmol)和礙酸鉋 (325mg，lmmol)，升至110°C攪拌反應4小時。加入50mL 水’用乙酸乙酯萃取（30mLx2)，合併有機相，用飽和氣化 鈉溶液洗滌（20mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓 濃細’付到標題產物（1^55)-3-(5-乙基嘴咬-2_基）_6 -[(li?)-l-[4-(4-甲磺醯基苯基）苯氧基]乙基]-3-氮雜雙環 並[3· 1· 0]己烷80( 70mg，白色固體），產率：38. 0%。 MS m/z (ESI): 464.2 [M+l] 1H NMR (400 MHz, ci-DMSO) 8.20 (s, 2H), 7.95 (dd, 4H), 221 95344 201213319 7.69(d，2H)，7.07(d，2H),4.25-4.32 (m，lH)，3.73-3.78 (m，2H)，3. 39-3.45 (m，2H)，3.24 (s，3H)，2 40 (Q，2H)，1.73-1. 77 (m，2H)，1.32 (d，3H)，l.li (t，3H) 0-92-0.95 (m, 1H). 實施例81 異丙基-5-[(li?，5«~6-[ [5-(4-甲磺醯基苯基）吡嗪一2_ 基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-基；hi，2, 4-惡0. 44 mmol) was dissolved in 10 mL of U-dimercaptocarhamamine, and the crude product (1 especially 55)-6-(1-chloroethyl)-3-(5-ethyl-chary-2-yl) was added in order. 3-Azabicyclo[3.1.0]hexane 80c (100 mg, 〇·4 〇 mmol) and acid turbid (325 mg, 1 mmol) were stirred at 110 ° C for 4 hours. After adding 50 mL of water, the mixture was extracted with ethyl acetate (30 mL×2), and the organic phase was combined, washed with a saturated sodium carbonate solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give the title product (1^55) -3-(5-ethyl-mouth bit-2_yl)_6-[(li?)-l-[4-(4-methylsulfonylphenyl)phenoxy]ethyl]-3-aza 0%。 Bicyclo[3·1·0]hexane 80 (70 mg, white solid), yield: 38.0%. MS m/z (ESI): 464.2 [M+l] 1H NMR (400 MHz, ci-DMSO) 8.20 (s, 2H), 7.95 (dd, 4H), 221 95344 201213319 7.69 (d, 2H), 7.07 ( d, 2H), 4.25-4.32 (m, lH), 3.73-3.78 (m, 2H), 3. 39-3.45 (m, 2H), 3.24 (s, 3H), 2 40 (Q, 2H), 1.73 -1. 77 (m, 2H), 1.32 (d, 3H), l.li (t, 3H) 0-92-0.95 (m, 1H). Example 81 isopropyl-5-[(li?, 5«~6-[ [5-(4-methylsulfonylphenyl)pyrazine-2-yl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl; Hi,2, 4- evil

二唾Two saliva

eib 第一步 _ 5-(4-甲續醢基苯基）α比唤-2-醇 將3. 8mL濃硫酸冷卻至〇°C，分批加入亞硝*酸納 (520mg，7. 60mmol)，升溫至50°C攪拌，使固體全部溶解， 再冷卻至0°C，滴加11. 2mL粗品5-(4-曱磺醯基苯基）略喚 -2-胺75d(1.40g，5. 60mmol)的濃硫酸溶液’保持内溫在 0°C-5°C ’室溫攪拌15分鐘，再升溫至45。0攪拌30分鐘。 反應液緩慢倒入300mL冰水中，攪拌，滴加12. 5 Μ氮氧化Eib first step _ 5-(4-methyl decyl phenyl) α bis- -2-ol 3.8 mL concentrated sulfuric acid was cooled to 〇 ° C, and nitrous acid sodium sulphate (520 mg, 7.60 mmol) was added in portions. The mixture was heated to 50 ° C and stirred to dissolve all the solids, and then cooled to 0 ° C, and 11.2 mL of crude 5-(4-oxasulfonylphenyl) amin-2-amine 75d (1.40 g, 5. 60 mmol) concentrated sulfuric acid solution 'Keep the internal temperature at 0 ° C -5 ° C ' room temperature for 15 minutes, then warm to 45 ° 0 for 30 minutes. The reaction solution was slowly poured into 300 mL of ice water, stirred, and added dropwise.

95344 222 201213319 鈉溶液至反應液pH為4，抽濾，濾餅用水洗滌（5〇mLx2)， 得到粗品標題產物5-(4-Τ磺醯基苯基）吡嗪_2_醇81b (1.20g’黃色固體）’產物不經純化直接進行下一步反應。 MS m/z (ESI): 251.0 [M+l] 第二步 3-異丙基-5-[(1尤55〇-6-[[5-(4-甲磺醯基苯基）吼嗪-2-基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-1，2, 4-噁 二嗤 將粗品[(1及，55^-3-(3-異丙基-1, 2, 4—°惡二峻-5-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲基磺酸甲酯48c (200mg，0. 66mmol)溶解於5mL况二曱基曱醯胺中，授 拌，加入5-(4-曱磺醯基苯基）吡嗪-2-醇81b(166mg， 0· 66mmol)和碳酸鉀（275mg，1. 98mmol)，升溫至 8(TC 攪拌 反應1小時。加入20mL水’乙酸乙酯萃取（20mLx2)，合併 有機相，用飽和氯化鈉溶液洗滌（20mL)，無水硫酸納乾燥， 過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B 純化所得殘餘物，得到標題產物3-異丙基-5-[(1足55·)_6-[[5-(4-甲磺醢基苯基）吡嗪-2-基]氧曱基]-3-氮雜雙環並 [3· 1. 0]己烧-3-基]-1，2, 4-p惡二唾 81(48mg，白色固體）， 產率：16. 0%。 MS m/z (ESI): 456.1 [M+l] 1H NMR (400 MHz, CDCh) δ 8.60 (s, 1H), 8.37 (s, 1H), 8. 17 (d, 2H), 8. 08 (d, 2H), 4. 37 (d, 2H), 3. 90 (d, 2H), 3.72 (d, 2H), 3.13 (s, 3H), 2.97-2.87 (m, 1H), 1.84 223 95344 201213319 (s, 2H), 1.33 (d, 6H), 0.92 (s, 1H). 實施例82 (1尤55)-3-(5-乙基嘧啶-2-基）-6-[[4-(5-曱磺醯基-2-吡 啶基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷95344 222 201213319 Sodium solution to pH 4 of the reaction solution, suction filtration, filter cake washed with water (5 〇mL×2) to give the crude title product 5-(4-oxasulfonylphenyl)pyrazine-2-alcohol 81b (1.20 g' yellow solid) 'The product was directly subjected to the next reaction without purification. MS m/z (ESI): 251.0 [M+l] Step 2 3-isopropyl-5-[(1,5,5--6-[[5-(4-methylsulfonylphenyl)pyridazine) -2-yl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4-oxadiazine will be crude [(1 and, 55^- 3-(3-Isopropyl-1, 2, 4-°Ethyl-5-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methylsulfonate Ester 48c (200 mg, 0.66 mmol) was dissolved in 5 mL of dimethyl decylamine, and mixed with 5-(4-oxasulfonylphenyl)pyrazine-2-ol 81b (166 mg, 0·66 mmol) And potassium carbonate (275 mg, 1.98 mmol), warmed to 8 (TC stirred for 1 hour. Add 20 mL of water to ethyl acetate (20 mL×2), and the organic phase was combined and washed with saturated sodium chloride solution (20 mL) Drying with sodium sulfate, filtration, and concentration of the filtrate under reduced pressure. Purified residue eluted with EtOAc EtOAc (EtOAc) 5-(4-Methanesulfonylphenyl)pyrazin-2-yl]oxyindenyl]-3-azabicyclo[3·1]]pyrrol-3-yl]-1,2, 4 -p dioxin 81 (48 mg, white solid), Yield: 16.0%. MS m/z (ESI): 456.1 [M+l] 1H NMR (400 MHz, CDCh ) δ 8.60 (s, 1H), 8.37 (s, 1H), 8. 17 (d, 2H), 8. 08 (d, 2H), 4. 37 (d, 2H), 3. 90 (d, 2H) ), 3.72 (d, 2H), 3.13 (s, 3H), 2.97-2.87 (m, 1H), 1.84 223 95344 201213319 (s, 2H), 1.33 (d, 6H), 0.92 (s, 1H). Example 82 (1 especially 55)-3-(5-ethylpyrimidin-2-yl)-6-[[4-(5-nonylsulfonyl-2-pyridyl)phenoxy]indolyl]-3 -azabicyclo[3.1.0]hexane

6262

第一步 4-(5-曱續醯基-2-°比咬基）苯驗 將 2-溴-5-甲磺醯基-吡啶 82a(100mg，425 #111〇1)， (4-經基苯基）硼酸（58mg，425// mol)，1，1，-二（二苯膦基） 二茂鐵二氣化鈀（30mg，42· 5emol)和碳酸铯（414mg， 1. 28mmol)溶解於5mLl，4-二噁烷中，升溫6〇°C攪拌反應2 小時。加入10mL水，用乙酸乙酯萃取（2〇mLx2)，合併有機 相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜 法以展開劑體系B純化所得殘餘物，得到標題產物4_(5一 甲磺醯基-2-°比啶基）苯酚82b(20mg，黃色固體），產率： 18. 00/〇。 MS m/z (ESI): 250.1 [M+l] 第二步 224 95344 201213319 (1尤5Λ-3-(5-乙基嘧啶-2-基）-6-[ [4-(5-甲磺醯基-2-吡 咬基）笨氧基]甲基]-3-氮雜雙環並[3. l 0]己烷 將4-(5-曱磺醯基-2-吡啶基）苯酚82b(20mg，92. 30 //mol)溶解於5mL Λ； 二曱基曱醯胺中，依次加入粗品 [(1尤550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烧-6-基]甲磺酸尹酯7苣（27.4〇11^，92.30//11]〇1)和碳酸鉋 (60mg，184. 50//mol)，升至1〇〇。(：攪拌反應4小時。加入 10mL水’用乙酸乙醋萃取（2〇mLx2)，合併有機相，無水硫 ^ 酸鎂乾燥，過濾’濾液減壓濃縮’用薄層色譜法以展開劑 體系A純化所得殘餘物，得到標題產物（1尤550-3-(5-乙基 喊唆-2-基）-6-[[4-(5-曱石黃醯基-2-°比贫基）笨氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己炫82(2Omg，白色固體），產 率：48· 7%。 MS m/z (ESI): 451. 2 [M+1] *H NMR (400 MHz, CDCh) 5 9. 14 (s, 1H), 8. 20-8.23 (ra, φ 3H), 8.04-8.06 (m, 2H), 7.84-7.86 (m, 1H), 7.02-7.04 (m, 2H), 4.00-4.02 (m, 4H) » 3. 61-3. 63 (m, 2H), 3.13 (s, 3H), 2. 46-2. 50 (m, 2H), 1.79(s, 2H), 1.24(s, 1H), 1. 18_1. 24 (in, 3H). 實施例83 9-[ [6-(4-曱磺醯基苯基）-3-吼啶基]氧基]-7-氧雜—3一氛 雜雙環並[3.3· 1]壬烷-3-羧酸第三丁酉旨 95344 225 201213319The first step 4-(5-曱 醯 -2- -2- 比 咬 ) ) ) 苯 苯 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- Phenyl) boric acid (58 mg, 425 / / mol), 1,1,-bis (diphenylphosphino) ferrocene dipalladium (30 mg, 42 · 5emol) and cesium carbonate (414 mg, 1. 28 mmol) The solution was dissolved in 5 mL of 1,2-dioxane, and the reaction was stirred at a temperature of 6 ° C for 2 hours. After adding 10 mL of water and extracting with ethyl acetate (2 mL mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (5-Methanesulfonyl-2-pyridinyl)phenol 82b (20 mg, yellow solid), Yield: 18. 00 / 〇. MS m/z (ESI): 250.1 [M+l] Step 2 224 95344 201213319 (1 Λ5Λ-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(5-methane)醯-yl-2-pyridyl) phenyloxy]methyl]-3-azabicyclo[3.l 0]hexane 4-(5-nonylsulfonyl-2-pyridyl)phenol 82b ( 20 mg, 92. 30 //mol) was dissolved in 5 mL of hydrazine; in the dimercaptoamine, the crude product was added in sequence [(1 especially 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo) And [3. 1. 0] hexyl-6-yl]ylidene mesylate 7 (17.4〇11^, 92.30//11]〇1) and carbonate planer (60mg, 184.50//mol), Raise to 1 〇〇. (: Stirring reaction for 4 hours. Add 10 mL of water 'extracted with ethyl acetate (2 〇 mL x 2), combine the organic phases, dry anhydrous magnesium sulphate, filter 'filtrate under reduced pressure' with thin layer chromatography The residue obtained was purified by the solvent system A to give the titled product (1 550-3-(5-ethyl- yin-2-yl)-6-[[4-(5- fluorene fluorenyl-2-) Phenoxy] fluorenyl]-3-azabicyclo[3.1.0]hexan 82 (2Omg, white solid), yield: 48·7% MS m/z (ESI) : 451. 2 [M+1] *H NMR (400 MHz, CDCh) 5 9. 14 (s, 1H), 8. 20-8.23 (ra, φ 3H), 8.04-8.0 6 (m, 2H), 7.84-7.86 (m, 1H), 7.02-7.04 (m, 2H), 4.00-4.02 (m, 4H) » 3. 61-3. 63 (m, 2H), 3.13 (s , 3H), 2. 46-2. 50 (m, 2H), 1.79(s, 2H), 1.24(s, 1H), 1. 18_1. 24 (in, 3H). Example 83 9-[ [6 -(4-oxasulfonylphenyl)-3-oxaridinyloxy]-7-oxa-3-heterobicyclo[3.3·1]decane-3-carboxylic acid tertidine 95344 225 201213319

20d 第一步 Θ320d first step Θ3

9-[ [6-(4-甲基硫基苯基）-3-α比咬基]氧基]_7-氧雜-3-氮 雜雙環並[3.3. 1]壬烧-3-叛酸第三丁酉旨 將9-(4-溴_2, 6-二氟-苯氧基）-7-氧雜氮雜雙環 並[3. 3. 1 ]壬-3-竣酸第三丁酯 20d(300mg，0. 75mmol)，（4- 曱基硫基苯基）棚酸（151mg ’ 0. 90mmol)和1, 1’ -二（二苯 膦基）二茂鐵二氣化鈀（55mg，〇. 〇8mmol)溶解於15mLl，4-二噁烷中，再加入碳酸鉋（〇.73g，2. 25mmol)，升溫至120 °C攪拌反應2小時。加入20mL水，乙酸乙酯萃取（30mLx3)， 合併有機相，飽和氣化鈉溶液洗滌（3〇mL)，無水硫酸鈉乾 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體 系B純化所得殘餘物，得到標題產物9_[[6_(4一甲基硫基 苯基）-3-咐咬基]氧基]_7_氧雜_3_氮雜雙環並[3. &amp;丨]壬 烧-3-羧酸第三丁酯83a(152mg，灰色固體），產率：42. 6%。 MS m/z (ESI): 443.2 [M+l] 第二步 9-[[6 -（4-甲磺醯基苯基）_3_0比啶基;I氧基]_7_氧雜一3 一氮 雜雙環並[3. 3. 1]壬烷-3-羧酸第三丁酯 226 95344 201213319 冰洛下，將9-[[6-(4-甲基硫基苯基）-3-吡啶基]氧 基]-7-氧雜-3-氮雜雙環並[3. 3. 1]壬烷-3-羧酸第三丁酯 83a(150mg，0.34mmol)溶解於5mL二氣甲烷令，加入間氯 過氧苯甲酸（182mg，0· 75mmol)，升至室溫攪摔反應2小 時。反應液用飽和亞硫酸鈉溶液洗滌（10mL)，無水硫酸鈉 乾燥，過濾、，濾液減壓濃縮，用薄層色譜法以展開劑體系 B純化所付殘餘物，得到標題產物9_ [[ 6-(4-甲確酿基苯 基）-3-吡啶基]氧基]-7-氧雜-3-氮雜雙環並[3. 3.丨]壬烷 # 羧酸第三丁酯83(5mg，白色固體），產率：&amp; 1%。 MS m/z (ESI): 475.6 [M+l] !H NMR (400 MHz, ci-DMSO) δ 8.53-8.54 (m, 1H), 8.27-8.29 (m, 2H), 7.98-8.07 (m, 3H), 7.65-7.68 (m, 1H), 4.86-4.88 (m, 1H), 4.24-4.38 (m, 2H), 3.94-4.01 (m, 2H), 3.68-3.73 (m, 2H), 3.33 (s, 3H), 3.14-3.29 (m, 2H), 1.89-1.91 (m, 2H), 1.40 (s, 9H). 實施例84 (1足55·)-6-[(1Α〇-1-[4-(4-曱磺醯基苯基）苯氧基]乙 基]-3-氮雜雙環並[3. 1. 〇]己烧-3-敌酸第三丁醋9-[ [6-(4-Methylthiophenyl)-3-α 咬 ]]oxy]_7-oxa-3-azabicyclo[3.3. 1] 壬 -3- 叛 叛The third batch is intended to be 9-(4-bromo-2,6-difluoro-phenoxy)-7-oxaazabicyclo[3.3.1]indole-3-decanoic acid tert-butyl ester 20d (300 mg, 0.75 mmol), (4-nonylthiophenyl) shed acid (151 mg '0.90 mmol) and 1,1'-bis(diphenylphosphino)ferrocene dipalladium (55 mg, 〇. 8 mmol) was dissolved in 15 mL of 1,2-dioxane, and then carbonic acid (73 g, 2.25 mmol) was added thereto, and the mixture was heated to 120 ° C and stirred for 2 hours. Add 20 mL of water, extract with ethyl acetate (30 mL×3), combine the organic phase, wash with saturated sodium carbonate solution (3 〇mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified to give the title product 9-[[6-(4-methylthiophenyl)-3-indenyl]oxy]-7-oxax-3-azabicyclo[3. &amp; 6%] 壬 -3- -3- carboxylic acid tert-butyl ester 83a (152 mg, gray solid), yield: 42.6%. MS m/z (ESI): 443.2 [M+l]. Step 2 9-[[6-(4-methylsulfonylphenyl)_3-0-pyridinyl; Ioxy]_7_oxa-3-nitrogen Heterobicyclo[3.3.1]decane-3-carboxylic acid tert-butyl ester 226 95344 201213319 Under ice, 9-[[6-(4-methylthiophenyl)-3-pyridyl ]]oxy]-7-oxa-3-azabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester 83a (150 mg, 0.34 mmol) was dissolved in 5 mL of methane methane and added m-Chloroperoxybenzoic acid (182 mg, 0.75 mmol) was stirred at room temperature for 2 hours. The reaction mixture was washed with aq. EtOAc EtOAc (EtOAc) -Methoxyphenyl)-3-pyridyl]oxy]-7-oxa-3-azabicyclo[3. 3.丨]decane #carboxylic acid tert-butyl ester 83 (5mg, white Solid), Yield: &amp; 1%. MS m/z (ESI): 475.6 [M+l] &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& 3H), 7.65-7.68 (m, 1H), 4.86-4.88 (m, 1H), 4.24-4.38 (m, 2H), 3.94-4.01 (m, 2H), 3.68-3.73 (m, 2H), 3.33 ( s, 3H), 3.14-3.29 (m, 2H), 1.89-1.91 (m, 2H), 1.40 (s, 9H). Example 84 (1 foot 55·)-6-[(1Α〇-1-[ 4-(4-oxasulfonylphenyl)phenoxy]ethyl]-3-azabicyclo[3. 1. 〇] hexane--3-carboxylic acid tert-butyl vinegar

227 95344 201213319227 95344 201213319

第一步 (1尤5«-6-曱醯基-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第 三丁酯 乾冰浴下，將草醯氯（2. 14 g，16. 90mmol)加入至20mL 參 二氯曱烷中，緩慢滴加二曱基亞颯（2. 86 g，35. 60mmol)， 鲁 反應1小時，隨後滴加40mL(l兄5«-6-(羥基曱基）-3-氮 雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯16a(3 g ’ 14mmol) 的二氯甲烷，攪拌反應2小時。再滴加三乙胺（7. 12g ’ 70. 30mmol)，逐漸升至室溫，攪拌反應2小時。加入20mL 飽和氯化銨溶液淬滅反應，有機相無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，得到粗品標題產物（1兄55·)-6-甲醯基-3-_ 氮雜雙環並[3. 1.0]己烷-3-羧酸第三丁酯84a(3g，黃色油 狀），產物不經純化直接進行下一步反應。 琴 MS m/z (ESI): 156.1 [M-55] 第二步 (1^ 5«-6-(l-羥基乙基）-3-氮雜雙環並[3. 1. 0]己烷-3- 羧酸第三丁酯 冰浴下，將粗品（1^550-6-曱醯基-3-氮雜雙環並 [3. 1· 0]己烷-3-羧酸第三丁酯84a(3g，14. 20mmol)加入至 20mL四氫呋喃中，緩慢滴加3M曱基溴化鎂（3. 39g， 228 95344 201213319 28.40mmol)，逐漸升至室溫，攪拌反應2小時。加入20mL 水，乙酸乙酯萃取（40mLx2)，合併有機相，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，得到粗品標題產物（1左，550-6-( 1-羥基乙基）-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯 84b(2. 80 g，黃色油狀），產物不經純化直接進行下一步 反應。 MS m/z (ESI): 172.1 [M-55] 第三步 籲 （1疋551)-6-(l -氯乙基）-~3 -氮雜雙環並[3. 1. 0]己烧竣 酸第三丁酯 將粗品（1尤550-6-(1-羥基乙基）-3-氮雜雙環並 [3.1.0]己烷-3-羧酸第三丁酯841)(2.8(^，13丽〇1)溶解於 60mL無水二氣曱烧中，加入三乙胺（2. 67g，26. 40mmol)， 滴加入曱磺醯氣（2.27g，19.80mmol)，攪拌反應12小時。 加入60mL水，二氣曱院萃取（50mLx2)，合併有機相，無水 硫酸鎮乾餘，過丨慮5遽液減壓濃縮*得到粗品標題產物 • · (1兄55^-6-(1-氣乙基）-3-氮雜雙環並[3. 1. 0]己烷-3-羧 酸第三丁酯84c(3. 30g，黃色液體），產物不經純化直接進 行下一步反應。 MS m/z (ESI): 190.0 [M-55] 第四步 (1疋5«-6-[(1皮)-1-[4-(4-曱磺醯基苯基）苯氧基]乙 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯 將粗品4-(4-曱磺醯基苯基）苯酚33b(346mg， 229 95344 201213319 1. 39mmol)溶解於5mL况二曱基曱醯胺中，依次加入粗 品（1兄550-6-(1-氯乙基）-3-氮雜雙環並[3. 1. 0]己烷-3-竣酸第三丁醋84c(342mg，1. 39mmol)和碳酸鉋（908mg， 2. 79mmol)，升至100°C攪拌反應2小時。加入10mL水， 用乙酸乙酯萃取（10mLx2)，合併有機相，用飽和氯化鈉溶 液洗條（20mLx2)，無水硫酸鎮乾燥，過濾、，濾、液減壓濃縮， 得到標題產物（1兄550-6-1:(1友)-1-[4-(4-曱磺醯基苯基） 苯氧基]乙基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁 ® 酯84(217mg，黃色固體），產率：34. 0%。 MS m/z (ESI): 402.1 [M-55] NMR (400 MHz, CDCh) δ 7.97-7.99 Cm, 2H), 7.72-7.74 (m, 2H), 7.54-7.56 (m, 2H), 6.97-6.99 (in, 2H), 4.05-4.18 (m, 1H), 3.61-3.67 (m, 2H), 3.35-3.37 (m, 2H), 3. 10(s, 3H), 1.60(s, 3H), 1.42 (s, 9H), 1.39(s, 2H), 1.26 (s, 1H). • 實施例85 9-[4-(4-甲磺醯基苯基）苯氧基]-7-氧雜-3-氮雜雙環並 [3. 3. 1]壬烷-3-羧酸第三丁酯The first step (1 especially 5«-6-mercapto-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in the dry ice bath, the grass is chlorine (2. 14 g, 16.90 mmol) was added to 20 mL of dichloromethane, and dimercaptopurine (2.86 g, 35.60 mmol) was slowly added dropwise, and the reaction was carried out for 1 hour, followed by dropwise addition of 40 mL (l brother 5«). 6-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 16a (3 g '14 mmol) in dichloromethane, and the mixture was stirred for 2 hr. Add triethylamine (7. 12g '70. 30mmol), gradually increase to room temperature, and stir the reaction for 2 hours. Add the reaction solution by adding 20 mL of saturated ammonium chloride solution, dry the organic phase with anhydrous magnesium sulfate, filter, and decompress the filtrate. Concentration to give the crude title product (1 g. 55·)-6-carbazin-3--azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 84a (3 g, yellow oil) The product was directly subjected to the next reaction without purification. Qin MS m/z (ESI): 156.1 [M-55] The second step (1^5«-6-(l-hydroxyethyl)-3-azabicyclo And [3. 1. 0] hexane-3-carboxylic acid tert-butyl ester in ice bath, the crude product (1^550-6-mercapto-3-azabicyclo[3.1·0] Alkyl-3-carboxylic acid Butyl ester 84a (3 g, 14.20 mmol) was added to 20 mL of tetrahydrofuran, 3M mercapto magnesium bromide (3. 39 g, 228 95344 201213319 28.40 mmol) was slowly added dropwise, gradually warmed to room temperature, and the reaction was stirred for 2 hours. Water, ethyl acetate (40 mL×2), EtOAcjjjjjjjjjjjjjj Bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 84b (2. 80 g, yellow oil), product was taken to the next step without purification. MS m/z (ESI): 172.1 [M-55] The third step is to call (1疋551)-6-(l-chloroethyl)-~3-azabicyclo[3.1.0]hexa-butyric acid tert-butyl ester. (1 especially 550-6-(1-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 841) (2.8 (^, 13 丽〇1) dissolved To 60 mL of anhydrous dioxane, triethylamine (2.67 g, 26.40 mmol) was added, and sulfonium oxime (2.27 g, 19.80 mmol) was added dropwise, and the reaction was stirred for 12 hours. 60 mL of water was added, and the gas was added to the hospital. Extraction (50mLx2), combined organic phase, anhydrous sulphuric acid, dry, and dehydrated Reduced to give the crude title product • · (1 brother 55^-6-(1-gasethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 84c ( 3. 30 g, yellow liquid), the product was directly subjected to the next reaction without purification. MS m/z (ESI): 190.0 [M-55] Step 4 (1疋5«-6-[(1)-1-[4-(4-oxasulfonylphenyl)phenoxy] Ethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester crude 4-(4-oxasulfonylphenyl)phenol 33b (346 mg, 229 95344 201213319 1. 39 mmol) was dissolved in 5 mL of dimethyl decylamine, and the crude product was added in sequence (1 brother 550-6-(1-chloroethyl)-3-azabicyclo[3.1.0]hexane- 3-decanoic acid butyl vinegar 84c (342 mg, 1.39 mmol) and carbonic acid planing (908 mg, 2.79 mmol), and the mixture was stirred at 100 ° C for 2 hours, and then added with 10 mL of water and extracted with ethyl acetate (10 mL×2). The organic phase was combined, washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, filtered, and concentrated under reduced pressure to give the title product (1 brother 550-6-1: (1 friend)-1- [4-(4-oxasulfonylphenyl) phenoxy]ethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 84 (217 mg, Yield: 34.0% MS m/z (ESI): 402.1 [M-55] NMR (400 MHz, CDCh) δ 7.97-7.99 Cm, 2H), 7.72-7.74 (m, 2H) , 7.54-7.56 (m, 2H), 6.97-6.99 (in, 2H), 4.05-4.18 (m, 1H), 3.61-3.67 (m , 2,,,,,,,,,,,,, • Example 85 9-[4-(4-Methanesulfonylphenyl)phenoxy]-7-oxa-3-azabicyclo[3.3.1]nonane-3-carboxylic acid Tributyl ester

230 95344 201213319 將粗品9-甲磺醢氧基-7-氧雜-3-氮雜雙環並[3. 3. 1] 壬-3-竣酸第三丁醋 2〇c(i42mg，0. 44mmol)和 4-(4-甲績 醯基苯基）苯龄（l〇〇mg，〇· 4〇mmol)溶解於5mL况yV-二甲基 乙醢胺中’再加入碳酸铯（262mg，0. 80mmol)，升溫至18〇 C ’擾拌反應7小時。加入l5mL水，乙酸乙酯萃取（2〇mLx3)， 合併有機相，飽和氣化鈉溶液洗滌（2〇mLx2)，無水硫酸鈉 乾燥’過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 B純化所得殘餘物，得到標題產物9-[4-(4-甲續醯基苯基） 苯氧基]-7-氧雜-3-氮雜雙環並[3. 3. 1]壬烷-3-竣酸第三 丁酯85(20mg ’白色固體），產率：1〇. 5%。 MS m/z (ESI)： 418.1 [M-55] H NMR (400 MHz, CDCI3) δ 7. 98-8. 00 (m, 2H), 7 72-7 74 (m, 2H), 7.57-7.59 (m, 2H), 7.05-7.07 (m, 2H), 4.60-4.64 (m, 2H), 4.59-4.60 (m, 1H), 4.13-4.22 (m, 2H), 3.82-3.90 (m, 2H), 3.25-3.28 (m, 1H), 3.18-3.20 (m, _ 1H), 3. 17 (s, 3H), 1. 96-1· 98 (m, 2H)，1. 5〇 (s，9h) 實施例86 3-異丙基-5-[(1兄5Λ-6-[ [4-(4-曱磺醯基苯基）笨氧基] 甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-1，2, 4-嗔二嗤230 95344 201213319 Crude 9-methanesulfonyloxy-7-oxa-3-azabicyclo[3.3.1] 壬-3-decanoic acid tert-butyl vinegar 2〇c (i42 mg, 0.44 mmol And 4-(4-methyl-decylphenyl) benzene (l〇〇mg, 〇·4〇mmol) dissolved in 5mL of yV-dimethylacetamide' plus cesium carbonate (262mg, 0 80mmol), warmed to 18〇C 'scrambled reaction for 7 hours. Add l5mL of water, extract with ethyl acetate (2〇mLx3), combine the organic phase, wash with saturated sodium carbonate solution (2〇mLx2), dry over anhydrous sodium sulfate 'filtered, concentrate the filtrate under reduced pressure, use thin layer chromatography to develop the solvent The obtained residue was purified to give the title product 9-[4-(4-methyl-n-decylphenyl)phenoxy]-7-oxa-3-azabicyclo[3.3.1]nonane. -3-butyl citrate 85 (20 mg 'white solid), yield: 1 〇. 5%. MS m/z (ESI): 418.1 [M-55] H NMR (400 MHz, CDCI3) δ 7. 98-8. 00 (m, 2H), 7 72-7 74 (m, 2H), 7.57-7.59 (m, 2H), 7.05-7.07 (m, 2H), 4.60-4.64 (m, 2H), 4.59-4.60 (m, 1H), 4.13-4.22 (m, 2H), 3.82-3.90 (m, 2H) , 3.25-3.28 (m, 1H), 3.18-3.20 (m, _ 1H), 3. 17 (s, 3H), 1. 96-1· 98 (m, 2H), 1.5 〇 (s, 9h) Example 86 3-Isopropyl-5-[(1 brother 5Λ-6-[[4-(4-oxasulfonylphenyl) phenyloxy]methyl]-3-azabicyclo[3] 1. 0]Hex-3-yl]-1,2,4-anthracene

95344 231 20121331995344 231 201213319

第一步 (1兄55)-6-(: [4-（4-曱磺醯基苯基）笨氧基]曱基]-3-氮雜 雙環並[3. 1.0]己烷 將（1疋551)-6-[ [4_(4一甲磺醯基笨基）笨氧基]甲基] -3-氮雜雙環ϋ[3. 1· 〇]己烷-3-羧酸第三丁酯78(200mg， _ 0. 45mmol)溶解於20mL5 M氯化氫的乙酸乙酯溶液，攪拌反 應12小時。反應液減壓濃縮’得到粗品標題產物 (1疋5«-6-[[4-(4-曱磺醯基苯基）苯氧基]曱基]一3_氮雜 雙環並[3. 1.0]己烷86a(200mg，白色固體）’產物不經純 化直接進行下一步反應。 MS m/z (ESI): 344.1 [M+l] 第二步 φ (1及，55')-6-[[4-(4-曱磺醢基苯基）苯氧基]曱基]_3_氮雜 雙環並[3. 1·0]己烷-3-甲腈 將粗品（1尤55*)-6-[[4-(4-甲磺醯基苯基）笨氧基]甲 基]-3-氣雜雙環並[3. 1. 0]己燒 86a(88mg，25. 60 # mol) 溶解於10mL氣仿中，依次加入溴化亞銅（37mg，38#mol；) 和碳酸鉀（128mg ’ lmraol)，升至60°C下，攪拌反應48小 時。反應液減壓濃縮’得到粗品標題產物（1尤5幻-6_ [[4-(4-甲續酿基苯基）苯氧基]甲基]-3-氣雜雙環並 [3. 1.0]己院-3-曱腈86b(90mg ’黃色固體）’產物不經純 95344 232 201213319 化直接進行下一步反應。 第三步 3-異丙基-5-[(1尤551)-6-[[4-(4-曱磺醯基苯基）苯氧基] 甲基卜3—氮雜雙環並[3. 1. 0]己烷-3-基]-1，2, 4-噁二唑 將粗品（1疋55·)-6-[[4-(4-曱磺醯基苯基）苯氧基]曱 基]-3-氮雜雙環並[31〇]己烷_3_甲腈86b(1〇〇mg， 0. 02mmol)溶解於i〇mL四氫η夫喃中，依次加入n，_經基一2_ 曱基-丙胺（30mg，0.03mmol)和氯化鋅（4〇mg，〇.〇3mm〇l)，The first step (1 brother 55)-6-(: [4-(4-oxasulfonylphenyl) phenyloxy] fluorenyl]-3-azabicyclo[3.1.0]hexane will (1疋551)-6-[ [4_(4-Methanesulfonyl)-phenyl]oxy]methyl]-3-azabicycloindole [3. 1· 〇]hexane-3-carboxylic acid tert-butyl Ester 78 (200 mg, _ 0. 45 mmol) was dissolved in 20 mL of ethyl acetate (5 mL), and the mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude title product (1 疋 5 « -6-[[4-(4) - oxime sulfhydryl phenyl) phenoxy] fluorenyl]- 3 - azabicyclo[3.1.0]hexane 86a (200 mg, white solid) product was directly subjected to the next reaction without purification. MS m / z (ESI): 344.1 [M+l] Second step φ (1 and, 55')-6-[[4-(4-oxasulfonylphenyl)phenoxy]indolyl]_3_aza Bicyclo[3.1·0]hexane-3-carbonitrile will be crude (1 especially 55*)-6-[[4-(4-methylsulfonylphenyl) phenyloxy]methyl]-3 - gas heterobicyclo and [3. 1. 0] hexane 86a (88mg, 25.60 # mol) dissolved in 10mL of air, followed by the addition of cuprous bromide (37mg, 38 #mol;) and potassium carbonate (128mg 'lmraol), the temperature was raised to 60 ° C, and the reaction was stirred for 48 hours. The reaction liquid was concentrated under reduced pressure to give a crude product. The product (1 especially 5 phantom-6_ [[4-(4-methyl phenyl) phenoxy]methyl]-3- oxabicyclo[3.1.0] hexanyl-3-carbonitrile 86b ( 90mg 'yellow solid' product was directly subjected to the next reaction without pure 95344 232 201213319. The third step 3-isopropyl-5-[(1 yu 551)-6-[[4-(4-sulfonate) Phenyl)phenoxy]methyldi-3-azabicyclo[3.1.0]hexane-3-yl]-1,2,4-oxadiazole will be crude (1疋55·)- 6-[[4-(4-oxasulfonylphenyl)phenoxy]indolyl]-3-azabicyclo[31〇]hexane_3_carbonitrile 86b (1〇〇mg, 0. 02mmol) was dissolved in i〇mL tetrahydronaphthol, followed by n, _ benzyl- 2 fluorenyl-propylamine (30mg, 0.03mmol) and zinc chloride (4〇mg, 〇.〇3mm〇l),

攪拌反應12小時。反應液減壓濃縮，加入1〇mL4M氣化氫 的乙醇和水的混合溶液（V/V = 1:1)，回流i小時。加入碳 酉文氫納至反應液pH為7’過濾，用乙酸乙酯萃取（2〇mLx2)， 合併有機相，無水硫酸鎂乾燥，過濾，渡液減壓濃縮，用 薄層色譜法以展關齡B純化所得殘餘物，得到標題產 物3_異丙基_5—[⑽⑹+[[4|甲賴基苯基）苯氧 基]曱基]-3-氮雜雙環並[3. 1.0]己烷1 一基]_U2,4一鳴二 唑86(3mg ’白色固體），產率：2.0%。 MS m/z (ESI): 454.2 [M+l] NMR (400 MHz, CDCh) ^ 7. 97-7. 99 (m, 2H), 7.72-7.74 (m, 2H), 7.55-7.57 (m, 2H), 6.98^7.00 (m, 2H), 3.97-3.99 (m, 2H), 3.86-3.88 (m, 2H), 3.67-3.69 (m, 2H), 3.09 (s, 3H)，2.89-2.92 (m，ih)，l 79 (s，2H)，137 (s, 1H), 1.28-1.34 (m, 6H). ’ * 實施例87 [2-[[(ld3-(5-乙基錢-2_基氮雜雙環並[3i〇] 95344 233 201213319 己烷-6-基]甲氧基]-5-(4-曱磺醯基苯基）苯基]曱醇The reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and a mixture of 1 mL of 4M hydrogenated hydrogen and water (V/V = 1:1) was added and refluxed for one hour. Add the carbon hydrazine to the reaction solution to pH 7', extract with ethyl acetate (2 〇mLx2), combine the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure, using thin layer chromatography The obtained residue was purified to give the title product: 3- isopropyl_5-[(10)(6)+[[4]methylphenylphenylphenoxy]indolyl]-3-azabicyclo[3. Hexane 1 -yl]_U2,4-monodiazole 86 (3 mg 'white solid), yield: 2.0%. MS m/z (ESI): 454.2 [M+l] NMR (400 MHz, CDCh) </ RTI> 7.97-7. 99 (m, 2H), 7.72-7.74 (m, 2H), 7.55-7.57 (m, 2H), 6.98^7.00 (m, 2H), 3.97-3.99 (m, 2H), 3.86-3.88 (m, 2H), 3.67-3.69 (m, 2H), 3.09 (s, 3H), 2.89-2.92 ( m, ih), l 79 (s, 2H), 137 (s, 1H), 1.28-1.34 (m, 6H). ' * Example 87 [2-[[(ld-(5-ethyl--2) _Alkylheterobicyclo[3i〇] 95344 233 201213319 Hex-6-yl]methoxy]-5-(4-oxasulfonylphenyl)phenyl]nonanol

第一步 5-溴-2-[ [(1及，5iS)-3-(5-乙基0^^-2-基）-3-氣雜雙環並 [3. 1. 0]己烷-6-基]甲氧基]苯曱醛 將5-漠-2-經基-苯甲搭87a(500mg，2. 50mmol)溶解 於20mL况趴二曱基曱醢胺中，依次加入粗品[(1^55)-3-(5-乙墓嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱 續酸甲醋 7g(740mg，2. 50mmol)和碳酸钟（690mg，5mmol)， _ 升至ll〇°C攪拌反應4小時。加入100mL水，用乙酸乙酯 萃取（50mLx2)，合併有機相，用飽和氯化鈉溶液洗滌 (50mLx2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物5-溴-2-[[(1尤5^-3-(5-乙基嘧啶-2-基） -3-氮雜雙環並[3. 1.0]己烷-6-基]甲氧基]苯曱醛87b (550mg，橙黃色固體），產率：55. 0%。 第二步 2-[[(1尤5«-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己烷_6_基]曱氧基]-5-(4-甲磺醯基苯基）苯甲醛 234 95344 201213319 將粗品5-溴-2-[[(l疋550-3-(5-乙基嘧啶_2-基）-3-氮 雜雙環並[3. 1.0]己烷-6-基]曱氧基]苯曱醛87b(550mg， 1.37mmol)，（4-曱基醯基苯基）硼酸（330mg，1.64mmol)和 1’ 1 —二（二苯膦基）二茂鐵二氯化|e(l〇〇mg，0. 14mm〇l) 溶解於20mLl, 4-二嗯烧中，再加入碳酸鉋（1. 33g， 4· lQmmol) ’升溫至i20°C攪拌反應5小時。加入50mL水， 乙酸乙酯萃取（5〇mLx3)，合併有機相，無水硫酸鈉乾燥， 過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A 純化所得殘餘物，得到標題產物2-[[(1尤5^-3-(5-乙基 鲁 嘧啶-2-基）-3-氮雜雙環並[3· 1.0]己烷-6-基]甲氧基] (4-曱磺醯基笨基）苯曱醛87c(500mg，白色固體），產率： 76. 9%。 MS m/z (ESI):478. 2 [M+l] 第三步 [2-[[(1亿55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3.1.0]己烷-6-基]曱氧基]-5-(4-甲磺醯基苯基）笨基]曱 醇 · 將2-[[(1尤55&quot;)-3-(5-乙基α密咬-2-基）-3-氮雜雙環 並[3. 1· 0]己烷-6-基]甲氧基]-5-(4-甲磺醯基笨基）苯甲 酸· 87c(120mg，0. 25mmol)溶解於15mL甲醇中，加入蝴氣 化鈉（19mg，0. 50mmol)，升至回流攪:拌反應2. 5小時。加 入20mL水，用二氯甲烧萃取（30mLx2)，合併有機相，無水 硫酸鈉乾燥，過濾，濾液減壓濃縮，得到標題產物 [2-[[(1尤5Λ-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 235 95344 201213319 [3· 1· 0]己烷-6-基]曱氧基]-5-(4-曱磺醯基笨基）笨基]曱 醇87(110mg，白色固體），產率：91. 7%。 MS m/z (ESI): 480.2 [M+l] 1H NMR (400 MHz, d-MSO) δ 8.21 (s, 2H), 7.93 (dd, 4H), 7.78 (d, 1H), 7.61 (dd, 1H), 7.08 (d, 1H), 5.13 (t, 1H), 4.60 (d, 2H), 4. 04 (d, 2H), 3.80 (d, 2H), 3.46 (d, 2H), 3.24(s, 3H), 2. 42 (q, 2H), 1.79(s, 2H), 1.12 (t, 3H), 1.08-1. 12 (m, 1H).The first step is 5-bromo-2-[[(1,5iS)-3-(5-ethyl0^^-2-yl)-3- oxabicyclo[3.1.0]hexane- 6-yl]methoxy]benzofural 5-(5-hydroxy-2-yl-benzyl) 87a (500 mg, 2.50 mmol) was dissolved in 20 mL of dimethyl decylamine, and the crude product was added sequentially [( 1^55)-3-(5-b-tolypyrimidin-2-yl)-3-azabicyclo[3. 1. 0]hexane-6-yl]-decanoic acid methyl vinegar 7g (740mg, 2. 50 mmol) and a carbonic acid clock (690 mg, 5 mmol), _ was raised to ll ° ° C and stirred for 4 hours. After adding 100 mL of water, the mixture was extracted with ethyl acetate (50 mL×2). [[(1 especially 5^-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]phenylfurfural 87b (550mg , orange-yellow solid), yield: 55.0%. The second step 2-[[(1 especially 5«-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] Hexyl-6-yl]decyloxy]-5-(4-methylsulfonylphenyl)benzaldehyde 234 95344 201213319 The crude product 5-bromo-2-[[(l疋550-3-) (5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonyloxy]benzaldehyde 87b (550 mg, 1.37 mmol), (4-mercapto) Nonylphenyl)boronic acid (330 mg, 1.64 mmol) and 1'1-bis(diphenylphosphino)ferrocene dichloride|e(l〇〇mg, 0.45 mm〇l) dissolved in 20 mLl, 4- In the second burning, add the carbonic acid planer (1. 33g, 4· lQmmol). Warm up to i20 ° C and stir the reaction for 5 hours. Add 50mL of water, extract with ethyl acetate (5〇mLx3), combine the organic phase, anhydrous sodium sulfate Dry, filter 'filtrate Concentration by pressure, the residue obtained was purified by eluent column chromatography eluting with eluent system A to give the title product 2-[[(1)5-5-(5-ethylpyrimidin-2-yl)-3- Azabicyclo[3·1.0]hexane-6-yl]methoxy](4-oxasulfonyl) phenylfurfural 87c (500 mg, white solid), yield: 76. 9%. m/z (ESI): 478. 2 [M+l] The third step [2-[[(1 billion 55)-3-(5-ethylpyrimidin-2-yl)-3- azabicyclo[ 3.1.0]Hex-6-yl]decyloxy]-5-(4-methylsulfonylphenyl) phenyl] decyl alcohol · 2-[[(1 especially 55&quot;)-3-(5 -ethyl alpha dimethyl-2-yl)-3-azabicyclo[3.1. 0]hexane-6-yl]methoxy]-5-(4-methylsulfonyl)phenyl Formic acid · 87c (120mg, 0.25mmol) was dissolved in 15mL of methanol, added with sodium sulphate (19mg, 0. 50mmol), and then stirred to reflux. Stirring reaction 2. 5 hours. Add 20mL of water, use dichloromethane The mixture was extracted (30 mL×2), EtOAcjjjjjjjjjjjj Azabicyclo and 235 95344 201213319 [3·1·0]hexane-6-yl]nonyloxy]-5-(4-oxasulfonyl) Yl] Yue alcohol 87 (110mg, white solid), yield: 917%. MS m/z (ESI): 480.2 [M+l] 1H NMR (400 MHz, d-MSO) δ 8.21. (s, 2H), 7.93 (dd, 4H), 7.78 (d, 1H), 7.61 (dd, 1H), 7.08 (d, 1H), 5.13 (t, 1H), 4.60 (d, 2H), 4. 04 (d, 2H), 3.80 (d, 2H), 3.46 (d, 2H), 3.24(s , 3H), 2. 42 (q, 2H), 1.79(s, 2H), 1.12 (t, 3H), 1.08-1. 12 (m, 1H).

實施例88 l-[2-[ [(1尤550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]曱氧基]-5-(4-曱磺醯基笨基）笨基] 甲基-甲胺Example 88 l-[2-[ [(1) 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]decyloxy ]-5-(4-sulfonyl sulfhydryl) stupid base] methyl-methylamine

將2-[ [(1疋551)-3-(5-乙基喊咬-2-基）-3-氮雜雙環 並[3. 1. 0]己烷-6-基]曱氧基]-5-(4-甲磺醯基苯基）苯甲 酿 87c(95mg ’ 〇. 20mmol)和曱胺鹽酸鹽（16mg ’ 0. 24mmol) 溶解於10mL甲醇中’升至回流攪拌反應2〇分鐘，加入硼 氫化納（llmg ’ 〇.3〇mmol)，繼續回流攪拌反應2.5小時。 236 95344 201213319 加入20mL水，用一氯曱烧萃取（3〇mLx2)，合併有機相，無 水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以洗 脫劑體系A純化所得殘餘物’得到標題產物ι_[2-[[(ι及，551) -3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6-基] 曱氧基]-5-(4-甲磺醯基苯基）苯基]一舲曱基-甲胺88(15mg， 白色固體），產率：15.3%。 MS ra/z (ESI): 493.2 [M+l] 1H NMR (400 MHz, d-MSO) δ 8.21 (s, 2H), 7.91 (dd, 鲁 4H), 7.72 (d, 2H), 7.16 (d, 1H), 5.61 (s, 1H), 4.06 (d, 2H), 3. 79(d, 2H), 3. 46 (d, 2H), 3. 36 (s, 3H), 3.24 (s, 3H), 2.41 (q, 2H), 1. 94-2. 04 (m, 2H), 1.79(s, 2H), 1. 11 (t, 3H), 1. 08-1. 12 (m, 1H). 實施例89 (1^ 55)-3-(5-氣嘧啶-2-基）-6-[[4-(4-甲磺醢基苯基）苯 氧基]曱基]-3-氮雜雙環並[3.1. 0]己烷2-[[(1疋551)-3-(5-ethyl-chal-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]decyloxy] -5-(4-Methanesulfonylphenyl)benzil 87c (95mg '〇. 20mmol) and guanamine hydrochloride (16mg '0.24mmol) dissolved in 10mL of methanol' Minutes, sodium borohydride (llmg '〇.3〇mmol) was added, and the reaction was further stirred under reflux for 2.5 hours. 236 95344 201213319 Add 20mL of water, extract with trichloromethane (3〇mLx2), combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by eluent system A using thin layer chromatography 'Get the title product ι_[2-[[(ι), 551) -3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] hexane-6-yl ]] methoxy]-5-(4-methylsulfonylphenyl)phenyl]-indenyl-methylamine 88 (15 mg, white solid), yield: 15.3%. MS ra/z (ESI): 493.2 [M+l] 1H NMR (400 MHz, d-MSO) δ 8.21. (s, 2H), 7.91 (dd, Lu 4H), 7.72 (d, 2H), 7.16 (d , 1H), 5.61 (s, 1H), 4.06 (d, 2H), 3. 79(d, 2H), 3. 46 (d, 2H), 3. 36 (s, 3H), 3.24 (s, 3H ), 2.41 (q, 2H), 1. 94-2. 04 (m, 2H), 1.79(s, 2H), 1. 11 (t, 3H), 1. 08-1. 12 (m, 1H) Example 89 (1^55)-3-(5-Azapirin-2-yl)-6-[[4-(4-methylsulfonylphenyl)phenoxy]indolyl]-3-nitrogen Heterobicyclic and [3.1. 0] hexane

將粗品（1尤5«-6-[[4-(4-曱磺醯基苯基）苯氧基]甲 基]~3-氮雜雙環並[3. 1. 0]己烧86a(50mg，0· 15mmol)溶解 237 95344 201213319 於5mL况舲二曱基曱醯胺中，依次加入2, 5-二氣，咬The crude product (1 especially 5«-6-[[4-(4-oxasulfonylphenyl)phenoxy]methyl]~3-azabicyclo[3. 1. 0]hexa burned 86a (50mg , 0·15mmol) Dissolved 237 95344 201213319 In 5mL of bismuthyl decylamine, add 2, 5-two gas, bite

(22mg’ 0. 15mmol)和碳酸絶（119mg’ 0. 36mmol)，升至 i20°C 攪拌反應2小時。加入10mL水，用乙酸乙酯萃取（20mLx2)， 合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得 到粗品標題產物（1兄5«-3-(5-氯嘧啶-2-基）-6-[[4-(4-甲續醯基苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烧 89(10mg，黃色固體），產率：15. 0%。 MS m/z (ESI): 457.1 [M+l] *H NMR (400 MHz, CDCh) ά 8.23 (s, 2H), 7.97-7.99 (m, 2H), 7.72-7.74 (m, 2H), 7.55-7.57 (m, 2H), 7.00-7.02 (m，2H)，3. 94-3. 99 (m，4H)，3.58-3.60 (m，2H), 3.09 (s, 3H), 1.78 (s, 2H), 1.21 (s, 1H). 實施例90 (1及，51$')-3-(5-乙基喊咬-2-基）-6-[[4-(2-氟-4-甲續酿基 苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 〇]己烷(22 mg'0. 15 mmol) and carbonic acid (119 mg'0. 36 mmol), and the mixture was stirred at i20 ° C for 2 hours. After adding 10 mL of water, the mixture was extracted with EtOAc (EtOAc) (EtOAcjjjjjjjjjjjj -6-[[4-(4-methyl-n-decylphenyl)phenoxy]methyl]-3-azabicyclo[3.1.0] hexane 89 (10 mg, yellow solid) Rate: 15.0% MS m/z (ESI): 457.1 [M+l] *H NMR (400 MHz, CDCh) ά 8.23 (s, 2H), 7.97-7.99 (m, 2H), 7.72-7.74 (m, 2H), 7.55-7.57 (m, 2H), 7.00-7.02 (m, 2H), 3. 94-3. 99 (m, 4H), 3.58-3.60 (m, 2H), 3.09 (s, 3H), 1.78 (s, 2H), 1.21 (s, 1H). Example 90 (1 and, 51$')-3-(5-ethyl shrine-2-yl)-6-[[4- (2-fluoro-4-methyl chlorophenyl)phenoxy]methyl]-3-azabicyclo[3. 1. oxime] hexane

201213319 1-溴-2-氟-4-曱磺醯基-苯 將2-氟-4-曱石黃醯基-苯胺90a(1000mg，5. 29mmol)溶 解於30mL乙腈中，依次加入亞硝酸第三丁酯（1. 2mL， 9. 25mmol)和漠化綱（1500mg ’ 6. 60mmol)，升至 65°C 反應 1 小時。加入100mL20%的鹽酸溶液，用乙酸乙酯萃取 (40mLx3)，合併有機相，用飽和氯化鈉溶液洗滌（5〇mLx2)， 無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到標題產物1-溴-2-氟-4-曱項醯基-苯90b(1300mg，淺黃色固體），產 φ 率：1 000/〇。 MS m/z (ESI): 252.0 [M+l] 第二步 4-(2-氟-4曱磺醯基-苯基）苯酚 將 1_&gt;臭-2-氟-4-甲績酿基-笨 90b(250mg，lmmol)， 4-經基苯棚酸（150mg，l.lOmmol)和1，丨’—二（二苯膦基） 二茂鐵二氯化把（75mg，〇· lOmmol)溶解於2〇mLl，4-二噁炫 中，再加入碳酸铯（970mg，3mmol)，升溫至ii〇°c擾拌反 ® 應4小時。加入10mL水，乙酸乙酯萃取（2〇mLx3)，合併有 機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管 枉色譜法以洗脫劑體系B純化所得殘餘物，得到標題產物 4-（2-甲基-6-曱基磺基-3-吡啶基）笨酚9〇c(17〇mg，白色 固體），產率：63. 0%。 MS m/z (ESI)： 284.0 [M+18] 第三步 (1疋5«-3-（5-乙基嘧啶-2-基）-6-[[4〜（2_氟_4_甲磺醯基 95344 239 201213319 苯基）苯氧基]曱基]-3_氮雜雙環並[3. 1. 0]己烷 將4-(2-曱基-6-甲基磺基-3-吡啶基）苯酚90c (130mg，0.50mmol)溶解於151〇1^於二甲基甲醯胺中，依 次加入粗品[(1及，550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1. 0]己烧-6-基]曱續酸甲醋 7g(i5〇mg，〇. 50mmol) 和碳酸鉀（140mg’0. lOmmol)，升至liot：攪拌反應4小時。 加入10mL水，用乙酸乙酯萃取（2〇mLx2)，合併有機相，無 水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法 • 以洗脫劑體系A純化所得殘餘物，得到標題產物（1及，5幻_3_ (5-乙基嘧啶-2-基）-6-[ [4-(2-氟-4-曱磺醯基苯基）苯氧 基]曱基]-3-氮雜雙環並[3. 1.〇]己烷9〇(13〇mg，白色固 體），產率：56.5%。 MS m/z (ESI): 468.1 [M+l] NMR (400 MHz, i/-DMS0) δ 8.21 (s, 2H), 7.79-7 87 (m, 3H), 7.55-7.57 (m, 2H), 7.08-7.11 (m, 2H), 3.99- φ 4.01 (m，2H) ’ 3.79-3.82 (m, 2H)，3.46-3.48 (m，2H), 3.31 (s, 3H), 2.39-2.45 (m, 2H), 1.78 (s, 2H), 1. is (s, 1H), 1. 10-1. 14 (m，3H). 實施例91 (1兄5«-3-(5-乙基嘧啶-2-基）-6一[[4_(2_曱基一6_甲磺基 -3-吡啶基）苯氧基]曱基]—3-氮雜雙環並[3·丨· 0]己烷 95344 240 201213319201213319 1-Bromo-2-fluoro-4-oxasulfonyl-benzene 2-Fluoro-4-valerium xanthyl-aniline 90a (1000 mg, 5.29 mmol) was dissolved in 30 mL of acetonitrile, followed by the addition of nitrite The ester (1.2 mL, 9.25 mmol) and the desertification (1500 mg ' 6. 60 mmol) were reacted to 65 ° C for 1 hour. After adding 100 mL of a 20% hydrochloric acid solution, and extracting with ethyl acetate (40 mL×3), the organic phase is combined, washed with a saturated sodium chloride solution (5 〇mL×2), dried over anhydrous sodium sulfate, filtered, Bromo-2-fluoro-4-indolyl-benzene 90b (1300 mg, pale yellow solid), yield φ: 1 000 / 〇. MS m/z (ESI): 252.0 [M+l] Step 2 4-(2-Fluoro-4-sulfonyl-phenyl)phenol 1_&gt;Smelly-2-fluoro-4-methyl-branched- Stupid 90b (250mg, 1mmol), 4-phenylbenzene phthalic acid (150mg, 1.0mmol) and 1, 丨'-bis(diphenylphosphino)ferrocene dichloride (75mg, 〇·lOmmol) In 2 mL mL, 4-dioxane, additional cesium carbonate (970 mg, 3 mmol) was added, and the temperature was raised to ii 〇 °c to disturb the reaction for 4 hours. After adding 10 mL of water and ethyl acetate (2 mL mL), the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. 4-(2-methyl-6-mercaptosulfo-3-pyridinyl) phenol 9 〇c (17 mg, white solid), yield: 63.0%. MS m/z (ESI): 284.0 [M+18] Step 3 (1疋5«-3-(5-ethylpyrimidin-2-yl)-6-[[4~(2_fluoro_4_) Methanesulfonyl 95344 239 201213319 Phenyl)phenoxy]fluorenyl]-3_azabicyclo[3.1.0]hexane 4-(2-mercapto-6-methylsulfo-3 -pyridyl)phenol 90c (130 mg, 0.50 mmol) was dissolved in 151 mmol in dimethylformamide, and the crude product was added sequentially [(1 and 550-3-(5-ethylpyrimidin-2-yl)) -3-Azabicyclo[3.1.0]hexan-6-yl]sutonic acid methyl vinegar 7g (i5〇mg, 〇. 50mmol) and potassium carbonate (140mg '0. lmmol), rose to liot : stirring the reaction for 4 hours. Add 10 mL of water, extract with ethyl acetate (2 〇 mL x 2), combine the organic phase, dry over anhydrous sodium sulfate, and filter, and concentrate the filtrate under reduced pressure, using gel column chromatography • eluent system A The obtained residue was purified to give the title product (1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Benzyl]-3-azabicyclo[3. 1. oxime] hexane 9 〇 (13 〇 mg, white solid), yield: 56.5% MS m/z (ESI): 468.1 [M+ l] NMR (400 MHz, i/-DMS0) δ 8.21 (s, 2H), 7.79-7 87 (m, 3H) , 7.55-7.57 (m, 2H), 7.08-7.11 (m, 2H), 3.99- φ 4.01 (m, 2H) ' 3.79-3.82 (m, 2H), 3.46-3.48 (m, 2H), 3.31 (s , 3H), 2.39-2.45 (m, 2H), 1.78 (s, 2H), 1. is (s, 1H), 1. 10-1. 14 (m, 3H). Example 91 (1 brother 5« -3-(5-ethylpyrimidin-2-yl)-6-[[4_(2_fluorenyl-6-methylsulfo-3-pyridyl)phenoxy]indolyl]-3-azabicyclo And [3·丨· 0]hexane 95344 240 201213319

第一步 3-溴-2-甲基_6—曱磺基—吡啶 將 3, 6-二漠-2-曱基吡啶 91a(3〇〇mg，1. 2〇mm〇1)溶解 於10mL二曱基亞砜中，依次加入曱磺酸鈉（567mg， 4.80mmol)和碘化亞酮（339mg，16〇mm〇1)，升至 125。(：微 波反應40分鐘。加入3〇此水，用乙酸乙酯萃取（40mLx2)， 合併有機相’用飽和氣化鈉溶液洗滌（3〇mLx2)，無水硫酸 納乾燥，過滤’遽液減壓濃縮，用矽膠管柱色譜法以洗脫 劑體系B純化所得殘餘物，得到標題產物3_溴_2_曱基_6_ 曱磺基-吡啶91b(80mg，黃色液體），產率：26.7%。 MS m/z (ESI): 251. 0 [M+1] 第二步 4-(2-曱基-6-曱基磺基-3-吼啶基）苯酚 將 3-漠-2-甲基-6-甲磺基-吼啶 91b(86mg，0. 34mmol)， 4-羥基苯硼酸（47mg，0. 34mmol)和1，Γ -二（二苯膦基）二 茂鐵二氯化鈀（25mg，0. 〇3mmol)溶解於5mLl，4-二噁烧中， 241 95344 201213319 再加入碳酸铯（336g，1. 03mm〇l)，升溫至12〇。(：攪拌反應2 小時。加入lOmL水，乙酸乙酯萃取（2〇mLx3)，合併有機相， 無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用石夕膠管柱色譜 法以洗脫劑體系A純化所得殘餘物，得到標題產物4_(2_ 曱基-6-曱基磺基-3-吡啶基）笨酚91c(4〇mg，白色固體）， 產率：44· 0%。 MS m/z (ESI)： 263.9 [M+l] 第三步 •⑽5Λ_3一(5-乙基射-2_基）-6-[[4-(2-甲基+曱續基 -3-吡啶基）苯氧基]曱基]-3-氮雜雙環並[3·丨· 〇]己烷 將4-(2-曱基-6-甲基績基-3^^定基）苯紛91c(45呢， 0.17mm〇l)溶解於5mL况妗二甲基曱醯胺中，依次加入粗 品[(U 55)-3-(5-乙基。密咬-2、基）_3_氣雜雙環並[3. h 〇] 己烧-6-基]甲續酸7g(5img，〇· 17随〇1)和碳酸絶（167呢， 0. 50mi〇1)，升至uot攪拌反應4小時。加入1〇乩水， 春用乙酸乙S旨萃取（施Lx2)，合併有機相，無水硫酸納乾燥， 過滤，濾液減壓濃縮，用石夕膠管枝色譜法以洗脫劑體系a 純化所得殘餘物，得到標題產物（1疋5幻_3_(5_乙基嘧啶 -2-基）-6-[[4-(2-甲基-6-曱磺基~3_吡啶基）笨氧基]甲 基]-3-氮雜雙環並[^.0]己烷9l(15mg，白色固體），產 率：18. 90/〇。 MS m/z (ESI)： 465.0 [M+l] iNMRUOOMHz，CDC13) (5 8.25(s，2H)，7·97_7 95 (m 1H), 7.75-7.73 (ra, 1H), 7.26-7.24 (,, 2H), 7.00-6.98 95344 242 201213319 (m, 2H), 4.12-3.92 (in, 4H), 3. 67 (in, 2H), 3. 27 (s, 3H), 2.60 (s, 3H), 2.52-2.50 (m, 2H), 1.82 (s, 2H), 1.26 (s, 1H), 1.25~1. 19 (m, 3H) 實施例92 2-[[(l兄5vS)-3〜（5-乙基嘴淀-2-基）-3-氮雜雙環並[3 i 〇] 己烷-6-基]甲氧基]-5-(4-甲磺醯基苯基）苯睛The first step 3-bromo-2-methyl-6-oxime sulfo-pyridine dissolves 3,6-dioxa-2-mercaptopyridine 91a (3 〇〇mg, 1.2 〇mm〇1) in 10 mL In the dimercaptosulfoxide, sodium sulfonate (567 mg, 4.80 mmol) and iodide (339 mg, 16 〇 mm 〇 1) were successively added to rise to 125. (: Microwave reaction for 40 minutes. Add 3 liters of this water, extract with ethyl acetate (40 mL×2), and combine the organic phase 'washed with saturated sodium carbonate solution (3 〇mLx2), dried over anhydrous sodium sulfate, filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS m/z (ESI): 251. 0 [M+1] The second step 4-(2-mercapto-6-fluorenylsulfonyl-3-acridinyl)phenol 3-3--2- -6-methylsulfonyl-acridine 91b (86 mg, 0.34 mmol), 4-hydroxybenzeneboronic acid (47 mg, 0.34 mmol) and 1, bis-di(diphenylphosphino)ferrocene palladium dichloride (25 mg, 0. 〇 3 mmol) was dissolved in 5 mL of 1,2-dioxane, 241 95344 201213319 and then cesium carbonate (336 g, 1.03 mm 〇l) was added, and the temperature was raised to 12 Torr. (: The reaction was stirred for 2 hours. Water, ethyl acetate extraction (2 mL mL), EtOAc (EtOAc) (2_ 曱基-6-曱Sulfo-3-pyridyl) phenol 91c (4 〇 mg, white solid), Yield: 44·0%. MS m/z (ESI): 263.9 [M+l] Step 3 • (10) 5Λ_3 one (5) -ethyl-2-phenyl)-6-[[4-(2-methyl+decyl-3-pyridyl)phenoxy]indolyl]-3-azabicyclo[3·丨· 〇]Hexane was dissolved in 5 mL of dimethyl decylamine by 4-(2-indolyl-6-methyldiphenyl-3)-based benzene 91c (45, 0.17 mm 〇l). The crude product [(U 55)-3-(5-ethyl. 密-2, yl)_3_ oxabicyclo[3.h 〇] hexyl-6-yl]carboxamide 7g (5img, 〇· 17 with 〇 1) and carbonic acid (167, 0. 50mi 〇 1), rose to uot to stir the reaction for 4 hours. Add 1 〇乩 water, spring with acetic acid B S extraction (application Lx2), combined organic phase Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue obtained was purified by eluent to give the title product (1 疋5 _3_(5-ethylpyrimidin-2-) 6-[[4-(2-methyl-6-sulfonyl~3_pyridyl) phenyloxy]methyl]-3-azabicyclo[^.0]hexane 9l (15mg , white solid), Yield: 18.90 / 〇. MS m/z (ESI): 465.0 [M+l] iNMRUOOMHz, CDC13) (5 8.25(s, 2H), 7.97_7 95 (m 1H), 7.75-7.73 (ra, 1H), 7.26-7.24 (,, 2H), 7.00-6.98 95344 242 201213319 (m, 2H ), 4.12-3.92 (in, 4H), 3. 67 (in, 2H), 3. 27 (s, 3H), 2.60 (s, 3H), 2.52-2.50 (m, 2H), 1.82 (s, 2H) ), 1.26 (s, 1H), 1.25~1. 19 (m, 3H) Example 92 2-[[(l brother 5vS)-3~(5-ethyl-n-but-2-yl)-3-nitrogen Heterobicyclo[3 i 〇] hexane-6-yl]methoxy]-5-(4-methanesulfonylphenyl) benzene

(5-溴-2-[[ (1^551)-3-(5 -乙基痛α定-2-基）-3-氮雜雙環並 [3.1.0]己烷-6-基]曱氧基]苯腈 將[(1疋55)-3-(5-乙基痛咬-2-基）-3-氮雜雙環並 [3. 1.0]己烧-6-基]曱續酸甲酯7g(500mg，1. 68mmol)溶解 於20mL况I-二曱基甲醯胺中，加入碳酸鉀（46〇mg， 3.37mmol)和 2-氰基-4-漠苯驗（430mg，2.19mmol)，升至 110 C授拌反應2. 5小時。加入20mL水，用乙酸乙醋萃取 (40mLx2)，合併有機相，用飽和氣化鈉溶液洗滌（5〇‘）， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到標題產物（5_ 95344 243 201213319 溴-2-[ [(1兄55*)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烧-6-基]甲氧基]苯乙腈92a(500mg，棕色液 體），產率：74. 6%。 MS m/z (ESI): 400.9 [M+l] 第二步 2-[[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇] 己烷-6-基]曱氧基]-5-(4-曱磺醯基苯基）苯腈 將（5_溴-2-[[(1足55)-3-(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1. 0]己烷-6-基]甲氧基]苯乙腈92a(500mg， 1.25mmol)，（4-甲磺醯基笨基）硼酸（25〇mg，i.25mmol)， 二（三苯膦基）二氯化鈀（92mg，0. 13mmol)和碳酸铯（1220mg， 3. 75mmol)溶解於30mLl，4-二噁烧中，升至ii〇°c撥拌反應 5小時。過濾，濾液減壓濃縮’用矽膠管柱色譜法以洗脫 劑體系A純化所得殘餘物，得到標題產物2-[[(ι兄55&quot;)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6-基]曱 % 氧基]_5_(4_曱磺醯基苯基）苯腈101(350mg，白色固體）， 產率：59. 3%。 MS m/z (ESI): 475.0 [M+l] ]Η NMR (400 MHz, CDCh) δ 8. 21-8. 20 (m, 3H), 8. 05-7. 98 (m, 5H), 7.40-7.38 (m, 1H), 4.21-4.19 (in, 2H), 3.82-3.79 (m, 2H), 3.48-3.46 (m, 2H), 3.31 (s, 3H), 2.44- 2.38 (ra, 2H), 1.83 (s, 2H), 1.14 (s, 1H), 1.13-1.09 (m, 3H) 實施例93 244 95344 201213319 C1&amp; 55·)-6-[[4-(4-曱磺醯基苯基）苯氧基]甲基]-3-氮雜 雙環並[3. 1. 0]己烷-3-曱酸異丙酯(5-Bromo-2-[[(1^551)-3-(5-ethyl-anthracene-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]indole Oxy]benzonitrile will [(1疋55)-3-(5-ethylheptan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl] Ester 7g (500mg, 1.68mmol) was dissolved in 20mL of I-dimercaptocaramine, adding potassium carbonate (46〇mg, 3.37mmol) and 2-cyano-4-inverteum (430mg, 2.19mmol) The mixture was heated to 110 C to give a reaction of 2.5 hours. Add 20 mL of water, extract with ethyl acetate (40 mL×2), combine the organic phases, wash with saturated sodium carbonate solution (5 〇 '), dry over anhydrous magnesium sulfate, filter The filtrate was concentrated under reduced pressure to give the title product (5_95344 243 201213319 bromo-2-[[(1), 55*)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0]Hex-6-yl]methoxy]phenylacetonitrile 92a (500 mg, brown liquid), yield: 74.6% MS m/z (ESI): 400.9 [M+l] 2-[[(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] hexane-6-yl] decyloxy]-5- (4-oxasulfonylphenyl)benzonitrile (5-bromo-2-[[(1)55)-3-(5-ethylpyrimidin-2-yl)-3- azabicyclo[3 1. 0] Hexane - 6-yl]methoxy]phenylacetonitrile 92a (500 mg, 1.25 mmol), (4-methylsulfonylphenyl)boronic acid (25 mg, i.25 mmol), bis(triphenylphosphino)palladium dichloride (92 mg, 0.13 mmol) and cesium carbonate (1220 mg, 3.75 mmol) were dissolved in 30 mL of 1,2-dioxane, and the mixture was stirred to ii 〇 °c for 5 hours. Filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography using eluent system A to give the title product 2-[[(m.ss. 55 &quot;)-3-(5-ethylpyrimidin-2-yl)-3- azabicyclo[3] 1. 〇] hexane-6-yl] 曱% oxy]_5_(4_nonylsulfonylphenyl) benzonitrile 101 (350 mg, white solid), Yield: 59. 3%. MS m/z (ESI): 475.0 [M+l] ] NMR (400 MHz, CDCh) δ 8. 21-8. 20 (m, 3H), 8. 05-7. 98 (m, 5H), 7.40-7.38 ( m, 1H), 4.21-4.19 (in, 2H), 3.82-3.79 (m, 2H), 3.48-3.46 (m, 2H), 3.31 (s, 3H), 2.44- 2.38 (ra, 2H), 1.83 ( s, 2H), 1.14 (s, 1H), 1.13-1.09 (m, 3H) Example 93 244 95344 201213319 C1&amp;55·)-6-[[4-(4-oxasulfonylphenyl)phenoxy Methyl]-3-azabicyclo[3.1.0]hexane-3-indole isopropyl ester

將粗品（1足55·)-6-[[4-(4-甲磺醯基苯基）苯氧基]甲 基]-3-氮雜雙環並[3. 1. 〇]己烧86a(85mg，0· 22mmol)溶解 於5mL 一氯甲烧中’依次加入三乙胺（7〇mg，0· 70mmol)和 氣代曱酸異丙酯（3〇mg，〇. 25imo1)，室溫擾拌反應12小 時。加入lOmL水’用乙酸乙酯萃取（2〇mLx2)，合併有機相， 無水硫酸鎂乾燥，過濾、，濾液減壓濃縮，得到粗品標題產 物（1足550-641:4-(4-甲磺醯基苯基）苯氧基]甲基]-3-氮 雜雙環並[3. 1.0]己烷-3-曱酸異丙酯93(40mg，白色固 體），產率：40. 0%。 MS m/z (ESI): 430.0 [M+l] !H NMR (400 MHz, CDCh) δ 7. 99-7. 97 (m, 2H), 7.75-7.72 (m, 2H), 7.57-7.53 (m, 2H), 7.01-6.98 (ra, 2H), 4.94-4.89 (m, 1H), 4.00-3.88 (m, 2H), 3. 76-3.67 (in, 2H), 3.47-3.44 (m, 2H), 3.09 (s, 3H), 1.62 (s, 2H), 1.25-1.23 (m, 6H), 1.17 (s, 1H) 245 95344 201213319 實施例94 (1尤550-3-(5-曱基-2-吡啶基）-6-[ [4-(4-曱磺醯基苯基） 苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷The crude product (1 foot 55·)-6-[[4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3. 1. 〇] hexane 86a ( 85mg, 0·22mmol) dissolved in 5mL of chloroformate's sequential addition of triethylamine (7〇mg, 0·70mmol) and isopropyl phthalate (3〇mg, 〇. 25imo1), disturbed at room temperature Reaction for 12 hours. After adding 10 mL of water, it was extracted with ethyl acetate (2 mL mL), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product (1 550-641: 4-(4-methane) % phenyl) phenoxy]methyl]-3-azabicyclo[3.1.0]hexane-3-indole isopropyl ester 93 (40 mg, white solid), yield: 40. 0%. MS m/z (ESI): 430.0 [M+l] &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& m, 2H), 7.01-6.98 (ra, 2H), 4.94-4.89 (m, 1H), 4.00-3.88 (m, 2H), 3. 76-3.67 (in, 2H), 3.47-3.44 (m, 2H ), 3.09 (s, 3H), 1.62 (s, 2H), 1.25-1.23 (m, 6H), 1.17 (s, 1H) 245 95344 201213319 Example 94 (1 especially 550-3-(5-mercapto- 2-pyridyl)-6-[ [4-(4-oxasulfonylphenyl) phenoxy]methyl]-3-azabicyclo[3.1.0]hexane

將粗品（1尤55·)-6-[[4-(4-甲磺醯基苯基）苯氧基]甲 基]-3-氮雜雙環並[3. 1. 0]己炫· 86a(100mg，0· 26mmol)溶 解於10mL 1，4-二噁院中，依次加入三（二亞苄基丙酮）二 le(23mg，0. 03mmol) ’ 2, 2’ -雙-(二苯膦基）-1，Γ -聯萘 (32mg，0· 05mmol)和 2-溴-5-甲基吡啶（5〇mg，0· 29_〇1)，The crude product (1 especially 55·)-6-[[4-(4-methylsulfonylphenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexa-86a (100 mg, 0 · 26 mmol) was dissolved in 10 mL of 1,4-dioxin, and then added tris(dibenzylideneacetone) dile (23 mg, 0.03 mmol) ' 2, 2'-bis-(diphenylphosphine) Base)-1, Γ-binaphthyl (32 mg, 0.05 mmol) and 2-bromo-5-methylpyridine (5 〇 mg, 0·29_〇1),

升至100°C攪拌反應8小時。過濾，濾液減壓濃縮，用薄 層色谱法以展開劑體系A純化所得殘餘物，得到標題產物 (1尤550-3-(5-曱基-2-°比咬基）-6~[[4-(4-甲磺醯基笨基） 苯氧基]甲基]-3-氮雜雙環並[3. 1.〇]己烷94(3〇mg，白色 固體），產率：26. 5°/〇。 MS m/z (ESI): 435.0 [M+l] 沱丽R(400 MHz，CDC13) (5 7.99-7.97 (m，3H)，7. 7心7.72 (m, 2H), 7. 57-7. 54 (m, 2H), 7. 28~7. 27 (m, 2H), 7 〇2-7.00 (m, 2H), 3.99-3.97 (in, 2H), 3.83-3.81 (m, 2H) 3.49-3.46 (m, 2H), 3.09 (s, 3H)，2.19 (s，3H) 1 78 95344 246 201213319 (s, 2H), 1.33-1.29 (m, 1H) 實施例95 3-異丙基-5-[(l)P，55·)-6-[[4-(5-曱磺醯基-2-吡啶基）笨 氧基]曱基]-3-氮雜雙環並[3· 1. 〇]己烷-3-基]-1，2, 4-噁The reaction was stirred at 100 ° C for 8 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford the title product (1 550-3-(5-mercapto-2-one ratio)-6~[[ 4-(4-Methanesulfonyl phenyl) phenoxy]methyl]-3-azabicyclo[3. 1. oxime] hexane 94 (3 〇 mg, white solid), yield: 26. 5°/〇. MS m/z (ESI): 435.0 [M+l] R R (400 MHz, CDC13) (5 7.99-7.97 (m, 3H), 7. 7 hearts 7.72 (m, 2H), 7. 57-7. 54 (m, 2H), 7. 28~7. 27 (m, 2H), 7 〇2-7.00 (m, 2H), 3.99-3.97 (in, 2H), 3.83-3.81 ( m, 2H) 3.49-3.46 (m, 2H), 3.09 (s, 3H), 2.19 (s, 3H) 1 78 95344 246 201213319 (s, 2H), 1.33-1.29 (m, 1H) Example 95 3- Isopropyl-5-[(l)P,55.)-6-[[4-(5-nonylsulfonyl-2-pyridyl)phenyloxy]indolyl]-3-azabicyclo[ 3· 1. 〇]Hex-3-yl]-1,2, 4-Evil

將4-(5-曱磺醯基-2-吡啶基）苯酚82b(42mg， 0. 17mmol)溶解於5mL况趴二曱基曱醯胺中，依次加入粗 品[[(U，55)-3-(3-異丙基-1，2, 4—噁二唑-5-基）-3-氮雜 雙環並[3.1· 0]己烧-6-基]曱基磺酸曱酯48c(50mg， φ 0. 和碳酸鉋（l〇8mg，0· 33mmol)，升至 1HTC 搜拌 反應4小時。加入i〇mL水，用乙酸乙酯萃取（2〇mLx2)，合 併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄 層色譜法以展開劑體系A純化所得殘餘物，得到標題產物 3-異丙基-5-[(1及，[4-(5-甲確醢基比〇定基）苯 氧基]曱基]-3-氮雜雙環並[3. 1. 0]己嫁-3-基]-1，2, 4-°惡 二唑95(40rag，白色固體），產率：53. 0%。 MS m/z (ESI)： 455.0 [M+l] NMR (400 MHz, CDCh) (5 9. 16 (s, 1H), 8.24-8.22 (in, 247 95344 201213319 1H), 8.07-8.05 (m, 2H), 7.87-7.85 (m, 1H), 7.02-7.01 (m, 2H), 4.02-4.00 (m, 2H), 3.92-3.90 (m, 2H), 3.73-3.70 (m, 2H), 3.14 (s, 3H), 2.96-2.90 (m, 1H), 1.81 (s, 2H), 1.32-1.30 (m, 6H), 1.26-1.24 (m, 1H) 實施例96 (1_^&gt;，51$*)-3_(5_乙基〇^咬-2-基）-6_[[4-(3-氣-4_甲基亞·®^ 醯基-苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷4-(5-Indolyl-2-pyridyl-2-pyridyl)phenol 82b (42 mg, 0.17 mmol) was dissolved in 5 mL of dimethyl decylamine, and the crude product [[(U, 55)-3] was sequentially added. -(3-isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1·0]hexa-6-yl]decylsulfonate 48c (50mg , φ 0. and carbonic acid planing (l〇8mg, 0·33mmol), and raised to 1HTC for 4 hours. Add i〇mL water, extract with ethyl acetate (2〇mLx2), combine the organic phase, anhydrous sodium sulfate Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue obtained was purified by EtOAc EtOAc (EtOAc) 〇 〇 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Yield: 53.0% MS m/z (ESI): 455.0 [M+l] NMR (400 MHz, CDCh) (5 9. 16 (s, 1H), 8.24-8.22 (in, 247 95344 201213319 1H), 8.07-8.05 (m, 2H), 7.87-7.85 (m, 1H), 7.02-7.01 (m, 2H), 4.02-4.00 (m, 2H), 3.92-3.90 (m, 2H), 3.73- 3.70 (m, 2H), 3.14 (s, 3H), 2.96-2.90 (m, 1H), 1.81 (s, 2H), 1.32-1.30 ( m, 6H), 1.26-1.24 (m, 1H) Example 96 (1_^&gt;, 51$*)-3_(5_ethyl〇^bit-2-yl)-6_[[4-(3- -4-4_Methyl y·®^ fluorenyl-phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane

FF

將卜氟-2-甲硫基苯96a(5. 12g，35·30_〇1)溶解於 40mL二氣曱烧中，依次加入液溴（ι gmL，35. 30mm〇l)，授 拌反應12小時。加入i〇〇mL飽和碳酸氫鈉水溶液，用乙酸 乙醋萃取（100mLx2) ’合併有機相’用飽和氣化鈉溶液洗滌 (50mLx2) ’無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽 膠官柱色谱法以洗脫劑體系B純化所得殘餘物，得到標題 產物4_&gt;臭-2-氣-1-曱基亞續酿-苯96b(1000mg，白色固 95344 248 201213319 體），產率：12. 6%。 MS m/z (ESI)： 236.8 [M+l] 第二步 4-(3-氟-4-甲基亞磺醯基-笨基）笨酚 將4-溴-2-氟-卜曱基亞磺醯-苯96b(1000mg， 4. 20mmol) ’ 4-羥基苯硼酸（582mg，4. 20mmol)和 1，1，-二 (二苯膦基）二茂鐵二氣化纪（300mg，0.40mmol)溶解於 20mL 1，4-二噁烷中，再加入碳酸铯（4. 12 g，12. 60mmol)， φ 升溫至120°C授拌反應2小時。加入20mL水，乙酸乙酯萃 取（20mLx2)，合併有機相，無水硫酸鈉乾燥，過濾，濾液 減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得殘 餘物，得到標題產物4-(3-氟-4-甲基亞續醯基-苯基）苯驗 96c(210mg，黃色固體），產率·· 20. 0%。 MS m/z (ESI): 250.9 [M+l] 第三步 (1及，551)-3-(5-乙基喊唆-2-基）-6-[ [4-(3-氟-4-甲基亞橫 _ 醯基-苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷 將4-(3-氟-4-曱基亞磺醯基-苯基）笨酚96c(50mg， 0. 20mmol)溶解於5mL爪於二甲基甲醯胺中，依次加入粗 品[(1疋5«-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0] 己烧-6-基]甲續酸曱酯7g(59mg，0. 20mmol)和碳酸铯 (130mg，0. 40mmol)，升至110°C擾拌反應4小時。加入l〇mL 水，用乙酸乙酯萃取（20mLx2)，合併有機相，無水硫酸鈉 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 249 95344 201213319 A純化所得殘餘物得到標題產物（17?，5Λ_3_(5—乙基嘧啶 -2-基）-6-[ [4-(3-氟-4-甲基亞磺醯基-笨基）笨氧基]甲 基]-3-氮雜雙環並[3· 1. 〇]己烧96(50mg，白色固體），產 率：45. 0%。 MS m/z (ESI)： 452.0 [M+l] ]H NMR (400 MHz, CDCh) 5 8. 18 (s, 2H), 7.90-7.86 (m, 1H), 7.58-7.51 (m, 3H), 7.31-7.28 (m, 1H), 7.27-6.99 (m, 2H), 3.98-3.97 (m, 4H), 3.60-3.58 (m, 2H), 2.87 # (s, 3H), 2.50-2.45 (m, 2H), 1.77 (s, 2H), 1.26-1.24 (m, 1H), 1.23-1. 17 (m, 3H) 實施例97 (1^ 55)-3-(5-乙基嘧啶—2-基）-6-[ [4-(3-氟-4-曱磺醯基 -苯基）苯氧基]甲基]—3-氮雜雙環並[3. h 〇]己烷Dissolve the fluoro--2-methylthiobenzene 96a (5. 12g, 35·30_〇1) in 40mL of dioxane, and then add liquid bromine (ι gmL, 35. 30mm〇l) to the reaction. 12 hours. Add 〇〇mL saturated sodium bicarbonate solution, extract with ethyl acetate (100 mL×2), and combine with the organic phase. Wash with saturated sodium sulphate solution (50 mL×2) dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by column chromatography using eluent B to give the titled product 4_&gt; odor-2- s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s .6%. MS m/z (ESI): 236.8 [M+l] Step 2 4-(3-Fluoro-4-methylsulfinyl-phenyl) phenoxyphenol 4-bromo-2-fluoro-didecylsulfin醯-Benzene 96b (1000 mg, 4. 20 mmol) '4-Hydroxybenzeneboronic acid (582 mg, 4.20 mmol) and 1,1,-bis(diphenylphosphino)ferrocene digassing (300 mg, 0.40 mmol) The solution was dissolved in 20 mL of 1,4-dioxane, and cesium carbonate (4.12 g, 12.60 mmol) was further added, and the temperature was raised to 120 ° C to carry out a reaction for 2 hours. After adding 20 mL of water and ethyl acetate (20 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give the title product 4- (3-Fluoro-4-methylindolyl-phenyl)benzene 96c (210 mg, yellow solid), mp. MS m/z (ESI): 250.9 [M+l] Step 3 (1 &, 551) -3-(5-ethyl yin-2-yl)-6-[ [4-(3-fluoro- 4-methyl yttrium _ fluorenyl-phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane 4-(3-fluoro-4-mercaptosulfinyl) Mercapto-phenyl) phenol phenol 96c (50 mg, 0.20 mmol) was dissolved in 5 mL of dimethylformamide, and the crude product was added sequentially [(1疋5«-3-(5-ethylpyrimidin-2-) Benzyl-3-azabicyclo[3.1.0]hexan-6-yl]methyl decanoate 7g (59mg, 0.20mmol) and cesium carbonate (130mg, 0. 40mmol), raised to 110 ° C The mixture was stirred for 4 hours. The mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. The obtained residue was purified to give the title product (17?,5?-??(5-ethylpyrimidin-2-yl)-6-[[4-(3-fluoro-4-methylsulfinyl)-phenyl) Methyl]-3-azabicyclo[3· 1. oxime] hexane 96 (50 mg, white solid), yield: 45.0%. MS m/z (ESI): 452.0 [M+l] ]H NMR (400 MHz, CDCh) 5 8. 18 (s, 2H), 7.90-7.86 (m, 1H), 7.58-7.51 (m, 3H ), 7.31-7.28 (m, 1H), 7.27-6.99 (m, 2H), 3.98-3.97 (m, 4H), 3.60-3.58 (m, 2H), 2.87 # (s, 3H), 2.50-2.45 ( m, 2H), 1.77 (s, 2H), 1.26-1.24 (m, 1H), 1.23-1. 17 (m, 3H) Example 97 (1^ 55)-3-(5-ethylpyrimidine-2 -yl)-6-[ [4-(3-fluoro-4-oxasulfonyl-phenyl)phenoxy]methyl]-3-azabicyclo[3.h 〇]hexane

第一步 (li?，550-3-(5-乙基嘧啶-2-基）-6-[ [4-(3-氟-4-甲磺醯基 -苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷 將（liP, 5«-3-(5-乙基嘧啶-2-基）-6-[[4-(3-氟_4_ 250 95344 201213319 曱基亞磺醯基-苯基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 〇] 己烷96(40mg ’ 0. 09mmol)溶解於5mL二氯曱烧中，加入間 氣過氧苯甲酸（23mg，0. 13匪〇1)，室溫攪拌反應3小時。 加入10mL二氯曱烷’用飽和碳酸鈉溶液洗滌（i〇mLx2)，無 水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展 開劑體系A純化所得殘餘物，得到標題產物（1兄55)-3-(5-乙基嘧啶-2-基）-6-[ [4-(3-氟-4-甲磺醯基-苯基）苯氧基] 曱基]-3-氮雜雙環並[3. 1.0]己烷97(10mg，白色固體）， φ 產率：25. 0%。 MS m/z (ESI): 468.0 [M+l] *H NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 7.99-7.95 (m, 1H), 7.55-7.49 (m, 3H), 7.43-7.40 (m, 1H), 7.01-6.99 (m, 2H), 3. 99-3. 97 (in, 4H), 3. 66 (m, 2H), 3. 25 (s, 3H), 2.50-2.49 (in, 2H), 1.80 (s, 2H), 1.26-1.25 (in, 1H), 1. 20-1. 18 (m, 3H) 實施例98 • (1^ 5«-6-[[2, 6-二氟-4-(5-曱磺醯基-2-吡啶基）苯氧基] 曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯First step (li?, 550-3-(5-ethylpyrimidin-2-yl)-6-[[4-(3-fluoro-4-methylsulfonyl-phenyl)phenoxy]fluorenyl) ]-3-Azabicyclo[3.1.0]hexane will (liP, 5«-3-(5-ethylpyrimidin-2-yl)-6-[[4-(3-fluoro_4_) 95 95 344 During the calcination, add m-benzoic acid (23 mg, 0.13匪〇1), and stir the reaction for 3 hours at room temperature. Add 10 mL of dichloromethane to wash with saturated sodium carbonate solution (i〇mLx2), anhydrous sodium sulfate Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue obtained was purified to the titled product (1 g. 55)-3-(5-ethylpyrimidin-2-yl)-6-[ [4-(3-Fluoro-4-methylsulfonyl-phenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 97 (10 mg, white solid), φ yield :25. 0%. MS m/z (ESI): 468.0 [M+l] *H NMR (400 MHz, CDCh) δ 8.22 (s, 2H), 7.99-7.95 (m, 1H), 7.55-7.49 ( m, 3H), 7.43-7.40 (m, 1H), 7.01-6.99 (m, 2H), 3. 99-3. 97 (in, 4H), 3. 66 (m, 2H), 3. 25 ( s, 3H), 2.50-2.49 (in, 2H), 1.80 (s, 2H), 1.26-1.25 (in, 1H), 1. 20-1. 18 (m, 3H) Example 98 • (1^ 5 «-6-[[2,6-Difluoro-4-(5-nonylsulfonyl-2-pyridyl)phenoxy]indolyl]-3-azabicyclo[3. 1. 0] Alkyl-3-carboxylic acid tert-butyl ester

251 5； 95344 201213319251 5; 95344 201213319

第一步 (1 尤 5»-6-[ [2, 6-二氟-4-(4, 4, 5, 5-四曱基-1，3, 2-二氧 代硼酸-2-基）苯氧基]甲基]-3-氮雜雙環並[3. 1.〇]己烷 -3-羧酸第三丁酯 φ 將（U5«-6-[(4-溴-2, 6-二氟-苯氧基）甲基]-3-氮 雜雙環並[3. 1. 0]己烧-3-幾酸第三丁酯16c(2g，5mmol)， 聯硼酸頻那醇醋（1· 90g ’ 7mmol)，醋酸鉀（1. 50 g，15mmol) 和1，1’ _二（二苯膦基）二茂鐵二氯化把（360mg，0.50mmol) 溶解於50mLl，4-二噁烷中，升溫至95。(：，攪拌反應2. 5 小時。加入30mL水，乙酸乙酯萃取（5〇mLx2)，合併有機相， 無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產 物（1 疋 550-6-(^2, 6-二氟-4-(4, 4, 5, 5-四甲基-1，3, 2-二· 氧代硼酸-2-基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 〇]己 烷-3-羧酸第三丁酯98a(2.20g，黃色油狀物），產物不經 純化直接進行下一步反應。 MS m/z (ESI)： 396.1 [M-55] 第二步 (1尤55&quot;)-6-[[2, 6-二氟-4-(5-曱確酿基咬基）笨氧基] 曱基]-3-氮雜雙環並[3. 1· 0]己统-3-羧酸第三丁醋 95344 252 201213319 將粗品（1皮，55^-6-(^ [2, 6-二氟-4-(4, 4, 5, 5-四曱基 -1，3, 2-二氧代硼酸-2-基）苯氧基]甲基]-3-氮雜雙環並 [3. 1. 0]己烧-3-竣酸第三丁醋 98a(2. 20g，4· 87mmol)，3-甲續酿基-6-溴-〇比咬（1. 20g，4. 87mmol) ’碳酸铯（4. 70g， 14.60丽〇1)和1，1’-二（二苯膦基）二茂鐵二氣化鈀（3.50 g，0. 40mmol)溶解於50mLl，4-二噁烧中，升溫至li〇°c， 攪拌反應2小時。加入30mL水，乙酸乙酯萃取（5〇mLx2)， 合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用 φ 薄層色譜法以展開劑體系B純化所得殘餘物，得到標題產 物（1疋[2, 6-二It-4-(5-甲續醯基-2-〇比咬基）苯氧 基]甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯98 (1. 90g，淺黃色固體），產率：82. 0%。 MS ra/z (ESI): 481.2 [M+l] 泔丽R(400 MHz，CDC13) 6 9.17(s，1H)’ 8. 30-8. 28 (m， 1H), 7.85-7.83 (m, 1H), 7.70-7.68 (m, 2H), 4.14-4.12 (m, 2H), 3.60-3.57 (m, 2H), 3.38-3.35 (m, 2H), 3.15 * (s, 3H), 1.72 (s, 2H), 1.44 (s, 9H), 1.14 (s, 1H) 實施例9 9 3-乙基-5-[(1Λ 551)-6-[[6-(4-曱磺醯基苯基）-3-11比啶基] 氧曱基]-3-氮雜雙環並[3· 1. 0]己烷-3-基-1，2, 4-嗯二唑The first step (1 especially 5»-6-[ [2, 6-difluoro-4-(4, 4, 5, 5-tetradecyl-1,3,2-dioxoboronic acid-2-yl) Phenoxy]methyl]-3-azabicyclo[3. 1.〇]hexane-3-carboxylic acid tert-butyl ester φ (U5«-6-[(4-bromo-2, 6- Difluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexa-butylic acid tert-butyl ester 16c (2g, 5mmol), boronic acid pinnacol vinegar (1 · 90g '7mmol), potassium acetate (1. 50 g, 15mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloride (360mg, 0.50mmol) dissolved in 50mLl,4-dioxin In the alkane, the temperature was raised to 95. (:, the reaction was stirred for 2.5 hours. EtOAc (3 mL). Product (1 疋 550-6-(^2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy Methyl]-3-azabicyclo[3. 1. oxime] hexane-3-carboxylic acid tert-butyl ester 98a (2.20 g, yellow oil). MS m/z (ESI): 396.1 [M-55] Step 2 (1 especially 55&quot;)-6-[[2, 6-difluoro-4-(5- Indeed, the base of the base is styrene] fluorenyl]-3-azabicyclo[3.1·0]hex-3-carboxylic acid third vinegar 95344 252 201213319 will be crude (1 skin, 55^- 6-(^ [2, 6-Difluoro-4-(4, 4, 5, 5-tetradecyl-1,3,2-dioxoboronic acid-2-yl)phenoxy]methyl]- 3-Azabicyclo[3.1.0]hexahydro-3-phthalic acid terpene vinegar 98a (2. 20g, 4.87mmol), 3-methyl aryl-6-bromo-pyrene ratio ( 1. 20g, 4. 87mmol) 'Carbonate (4. 70g, 14.60 Radisson 1) and 1,1'-bis(diphenylphosphino)ferrocene dipalladium (3.50 g, 0.40 mmol) dissolved The temperature was raised to 5 °C, and the reaction was stirred for 2 hours. 30 mL of water was added, and ethyl acetate was extracted (5 mL mL). Concentration and purification of the obtained residue by EtOAc EtOAc (EtOAc) Oxy]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 98 (1. 90 g, pale yellow solid), yield: 82.0%. MS ra/z (ESI): 481.2 [M+l] 泔 R (400 MHz, CDC13) 6 9.17(s,1H)' 8. 30-8. 28 (m, 1H), 7.85-7.83 (m, 1H), 7.70-7.68 (m, 2H), 4.14-4.12 (m, 2H), 3.60-3.57 (m, 2H), 3.38-3.35 (m, 2H), 3.15 * (s, 3H), 1.72 (s , 2H), 1.44 (s, 9H), 1.14 (s, 1H) Example 9 9 3-ethyl-5-[(1Λ 551)-6-[[6-(4-oxasulfonylphenyl) -3-11-pyridyl]oxyindolyl]-3-azabicyclo[3·1]hex-3-yl-1,2,4-oxadiazole

253 95344 201213319253 95344 201213319

(17?，5Λ-6-[ [6-(4-曱磺醯基苯基）-3-。比啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯 將6_(4_曱續酿基苯基）〇比〇定-3_醇48e(2500mg ’ lOmmol)溶解於50mL术於二甲基甲醯胺中，依次加入粗品 (1疋5Λ-6-(甲磺醯氧基曱基）-3-氮雜雙環並[3. 1. 0]己烷 -3-缓酸第三丁醋 16b(2900mg，lOmmol)和碳酸鉀（4150mg， 30匪〇1)，升至80°C攪拌反應12小時。加入lOOmL水，過 遽，遽餅溶於1 OOmL二氯甲烧中，無水硫酸鈉乾燥，過遽， 濾液減壓濃縮，得到標題產物（1尤5«-6- [ [ 6-(4-甲磺醯基 苯基）_3-°比咬基]氧甲基]-3 -氮雜雙環並[3. 1. 0]己烧-3-羧酸第三丁酯99a(2600mg，淡黃色固體），產率：60. 0%。 第二步 (1尤55〇-6-[[6-(4-甲磺醯基苯基）-3-°比啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷鹽酸鹽 將（1兄5Λ-6-[[6-(4-曱磺醯基苯基）-3-π比啶基]氧 254 95344 201213319 甲基]-3-氮雜雙環並[3. 1. 〇]己烧-3-叛酸第三丁酯99a(17?,5Λ-6-[ [6-(4-oxasulfonylphenyl)-3-.pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 3-carboxylic acid tert-butyl ester 6_(4_曱 酿 酿 phenyl) 〇 〇 -3 -3 -3 -3 _ _ _ e e 48e (2500mg ' lOmmol) dissolved in 50mL in dimethylformamide, added sequentially Crude (1疋5Λ-6-(methylsulfonyloxyindenyl)-3-azabicyclo[3.1.0]hexane-3-buffered acid butyl vinegar 16b (2900mg, lOmmol) and carbonic acid Potassium (4150mg, 30匪〇1), stirred to 80 ° C for 12 hours, adding 100 mL of water, simmering, simmering in 100 mL of methylene chloride, drying over anhydrous sodium sulfate, decanting, filtrate decompression Concentration to give the title product (1 especially 5«-6-[[6-(4-methylsulfonylphenyl)_3-) ratio oxymethyl]-3-azabicyclo[3. 0] hexane-carboxylic acid tert-butyl ester 99a (2600 mg, pale yellow solid), yield: 60. 0%. The second step (1 especially 55〇-6-[[6-(4-methane) Nonylphenyl)-3-°pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane hydrochloride (1 brother 5Λ-6-[[6-(4) - oxasulfonylphenyl)-3-πpyridinyl]oxy 254 95344 201213319 methyl]-3-azabicyclo[3. 1. 〇]hex -3- Acid tert-butyl ester 99a

(2600mg，5.85mmol)溶解於 5〇mL 乙酸乙酯，加入 i〇mL5M 氯化氫的乙酸乙酯溶液，搜拌反應3小時。反應液減壓濃 縮，得到粗品標題產物（1兄5«-6-[[6-(4-甲磺醯基苯基） -3-啦啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷鹽酸99b (2680mg，淡黃色固體），產物不經純化直接進行下一步反 應。 MS m/z (ESI): 345.0 [M+l] • 第三步 籲 (1及，55&lt;)-6-[[6-(4-甲石黃醯基苯基）-3-〇比唆基]氧曱基]-3-氮雜雙環並[3· 1· 0]己烷-3-曱腈 將粗品標題產物（1及，55)-6-1^ [6-(4-曱績g藍基苯基）_3_ 吡啶基]氧曱基]-3-氮雜雙環並[3. 1.0]己烷鹽酸99b (2680mg ’ 5. 85mmol)溶解於20mL二氣甲烧中，冰浴下加入 30mL碳酸氫鈉（3000mg，35. 8mmol)的水溶液，攪拌3〇分 鐘，再加入2mL溴化氰（682mg ’ 6. 44mmol)的二氣甲烷溶 馨液，室溫擾拌反應12小時。加入20mL水，用二氯曱烧萃零 取（60mLx4)，合併有機相，無水硫酸鈉乾燥，過濾，濾液 減壓濃縮，用矽膠管柱色譜法以展開劑體系A純化所得殘 餘物，得到標題產物（1尤55*)-6-[[6-(4-甲磺醯基苯基）-3-°比咬基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烧-3-曱腈99c (1700mg，白色固體），產率：78. 7%。 MS m/z (ESI): 370.0 [M+l] 第四步 255 95344 201213319 3-乙基-5-[ (1左，55)-6- [ [ 6-(4-曱續醯基苯基）-3-π比咬基] 氧甲基]-3-氮雜雙環並[3. 1. 〇]己烷-3-基-1，2,4-噁二唑 將（1及，550-6-[[6-(4-曱磺醯基苯基）-3-η比啶基]氧 甲基]-3-氮雜雙環並[3. 1. 0]己烧-3-曱腈99c(369mg， 1. OOmraol)溶解於15mL四氫呋喃中，依次加入ν’ -羥基-2-甲基-丙胺（106mg，1. 2mmol)和氯化鋅（1. 2mL，1. 2mmol) 的四氫呋喃溶液’攪拌反應12小時。反應液減壓濃縮，加 入10mL 4M氯化氫的乙醇和水的混合溶液（v/V = 1:1)，回 _ 流2小時。加入碳酸氫鈉至反應液pH為7,過濾，用二氣 曱烷萃取（20mLx3) ’合併有機相，無水硫酸鎂乾燥，過遽， 濾液減壓濃縮’用薄層色譜法以展開劑體系A純化所得殘 餘物’得到標題產物3-乙基-5-[(1尤55·)-6-[[6-(4~甲續 醯基苯基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1· 〇]己燒 -3-基-1，2, 4-噁二唑99(60mg，白色固體），產率：13.⑽。 MS m/z (ESI): 441.1 [M+l] φ Ή NMR (400 MHz, CDCh) 5 8. 40 (d, 1H), 8. 13 (d, 2H) 8.01 (d，2H)，7.72 (d, 1H)，7.28 (dd，1H)，4.03 (d’ 2H)，3.87 (d，2H)，3.69 (d，2H)，3.08 (s，3H), 2.58(2600 mg, 5.85 mmol) was dissolved in 5 mL of ethyl acetate, and a solution of 5 mL of hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude title product (1,5,6--6-[[6-(4-methylsulfonylphenyl)-3-oxaridinyl]oxymethyl]-3-azabicyclo and [3. 1.0] Hexane hydrochloride 99b (2680 mg, pale-yellow solid). The product was taken to the next step without purification. MS m/z (ESI): 345.0 [M+l] • The third step (1 and, 55&lt;)-6-[[6-(4-methylglycosylphenyl)-3-indolyl]indolyl]-3-azabicyclo[3·1·0]hexane-3- The phthalonitrile will be the crude title product (1 and, 55)-6-1^ [6-(4-曱克g-L-phenylphenyl)_3_pyridyl]oxyindolyl]-3-azabicyclo[3. ]] hexane hydrochloride 99b (2680 mg ' 5. 85 mmol) was dissolved in 20 mL of methane, and an aqueous solution of 30 mL of sodium hydrogencarbonate (3000 mg, 35.8 mmol) was added in an ice bath, stirred for 3 minutes, and 2 mL of cyanogen bromide was added. (682 mg ' 6. 44 mmol) of di-methane methane solution, and reacted at room temperature for 12 hours. Add 20 mL of water, distillate with dichloromethane to remove (60 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography *)-6-[[6-(4-Methanesulfonylphenyl)-3-° ratio octyl]oxymethyl]-3-azabicyclo[3. 1. 0]hexene-3-曱carbonitrile 99c (1700 mg, white solid), yield: 78. 7%. MS m/z (ESI): 370.0 [M+l] Step 4 255 95344 201213319 3-ethyl-5-[ (1 left, 55)-6- [ [ 6-(4-曱 醯 醯 phenyl)-3-π ratio octyl] oxymethyl]-3-azabicyclo[3. 1. 〇]hexane-3- Base-1,2,4-oxadiazole (1 and, 550-6-[[6-(4-oxasulfonylphenyl)-3-n-pyridyl]oxymethyl]-3-nitrogen Heterobicyclo[3.1.0]hexacarbyl-3-carbonitrile 99c (369 mg, 1. OOmraol) was dissolved in 15 mL of tetrahydrofuran, followed by ν'-hydroxy-2-methyl-propylamine (106 mg, 1.2 mmol) And stirring with zinc chloride (1.2 mL, 1.2 mmol) in tetrahydrofuran solution for 12 hours. The reaction solution was concentrated under reduced pressure, and 10 mL of 4M hydrogen chloride in a mixture of ethanol and water (v/V = 1:1) was added. The mixture was refluxed for 2 hours. Sodium bicarbonate was added until the pH of the reaction mixture was 7 and filtered. The mixture was extracted with dioxane (20 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Purification of the residue obtained by developing solvent system A The title product 3-ethyl-5-[(1 especially 55·)-6-[[6-(4-~-n-decylphenyl)-3-pyridyl]oxymethyl]-3-azabicyclo [3. 1· 〇] hexyl-3-yl-1,2,4-oxadiazole 99 (60 mg, white solid), Yield: 13. (10). MS m/z (ESI): 441.1 [M+l] φ Ή NMR (400 MHz, CDCh) 5 8. 40 (d, 1H), 8. 13 (d, 2H) 8.01 (d, 2H), 7.72 ( d, 1H), 7.28 (dd, 1H), 4.03 (d' 2H), 3.87 (d, 2H), 3.69 (d, 2H), 3.08 (s, 3H), 2.58

Cdd, 2H), 1.89-1.70 (m, 3H), 1.27 (t, 3H) 實施例100 3-環丙基-5-[(l疋55·)-6-[[6-(4-甲磺醯基苯基定 基]氧甲基]-3-氮雜雙環並[3· 1·0]己烷-3—基；μι 2,4、嗓 二口坐 95344 256 201213319Cdd, 2H), 1.89-1.70 (m, 3H), 1.27 (t, 3H) Example 100 3-cyclopropyl-5-[(l疋55·)-6-[[6-(4-methane) Nonylphenyl phenyl]oxymethyl]-3-azabicyclo[3·1·0]hexane-3-yl; μι 2,4, 嗓二口坐95344 256 201213319

• 將（1足5幻-6-[[6-(4-甲磺醯基苯基）-3-吡啶基]氧 曱基]-3-氮雜雙環並[3. h 〇]己烷_3_甲腈99c(3〇〇mg， 0. 81mmol)溶解於15mL四氫呋喃中，依次加入環丙曱醯胺 肟（98. Omg’ 〇.98111111〇1)和氯化鋅（lmL，〇.98丽〇1)，攪拌反 應12小時。反應液減壓濃縮，加入1〇此氣化氫的乙醇 和水的混合溶液（V/V = 1:1)，回流2小時。加入碳酸氫鈉 至反應液pH為7，過濾，用乙酸乙酯萃取（2〇mLx2)，合併 有機相’無水硫酸鎮乾燥，過渡，濾液減壓濃縮，用薄層 色譜法以展開劑體系A純化所得殘餘物，得到標題產物3_ 環丙基 氧曱基]-3-氮雜雙環並[3.1.0]己烷〜3〜基_1，24_鳴二唆 99(50mg，白色固體），產率：11. 〇%。 MS m/z (ESI): 453.1 [M+l] WMRUOOMHz，CDCh) 5 8.41 (s，1H)，8 15(d，2H)， 8.02(d，2H)，7.75 (d, 1H)，7.32 (d，1H)，4 〇3(山 2H)， 3.84 (d, 2H), 3.65 (d, 2H), 3. 〇8 (s&gt; 3H^ 1.87-1.86 95344 257 201213319 (m，1H), 1.79-1. 77 (m，2H)，1.26-1· 22 (m，1H), 0.96〜 0.93 (m, 4H) 實施例101 (1尤 55〇-3-(5-乙基哺〇定_2-基）-6-[ [4-(3-氣-4-0比咬基） 苯氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷• Will (1 foot 5 phantom-6-[[6-(4-methylsulfonylphenyl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3.h 〇]hexane_ 3_carbonitrile 99c (3〇〇mg, 0. 81mmol) was dissolved in 15mL of tetrahydrofuran, and then cyclopropamidamine (98. Omg' 〇.98111111〇1) and zinc chloride (lmL, 〇.98) were added in sequence. Lishen 1), the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and a mixture of ethanol and water (V/V = 1:1) of this hydrogenated hydrogen was added, and refluxed for 2 hours. The pH of the solution was 7, filtered, extracted with ethyl acetate (2 〇 mL×2), the organic phase was combined and dried over anhydrous sulphuric acid, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography to afford The title product 3_cyclopropyloxyindenyl]-3-azabicyclo[3.1.0]hexane~3~yl-1,24_sound succinimide 99 (50 mg, white solid), yield: 11. MS m/z (ESI): 453.1 [M+l] WMRUOOMHz, CDCh) 5 8.41 (s, 1H), 8 15 (d, 2H), 8.02 (d, 2H), 7.75 (d, 1H), 7.32 (d,1H),4 〇3 (Mountain 2H), 3.84 (d, 2H), 3.65 (d, 2H), 3. 〇8 (s&gt; 3H^ 1.87-1.86 95344 257 201213319 (m, (H), 1.79-1. 〇定_2-yl)-6-[ [4-(3-Ga-4-0-bite) phenoxy]indolyl]-3-azabicyclo[3. 1. 0]hexane

第一步 (1尤55〇-6-[(4-溴苯氧基）甲基]-3-(5-乙基嘧啶-2-基） -3-氮雜雙環並[3. 1. 0]己烷 將[(1尤55*)_3_(5_乙基嘴咬-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]甲磺酸甲酯7g(800mg，2· 69mmol)溶解 於5inL况.一甲基曱酿胺中’加入碳酸絶（175Oing， 5. 38mmol)和 4-溴苯酚（465mg，2. 69mmol)，升至 120〇C 撥 拌反應6小時。加入20mL水’用乙酸乙酯萃取（4〇mLx2)， 合併有機相，用飽和氯化鈉溶液洗滌（50mL)，無水硫酸鎂 乾燥，過濾，濾液減壓濃縮，得到標題產物（1及，5幻_6_[(4-溴苯氧基）曱基]-3-(5-乙基嘧啶2-基）-3-氮雜雙環並 [3.1. 0]己烧 l〇la(990mg ’ 白色固體），產率：98. 〇%。 258 95344 201213319 MS m/z (ESI): 376.1 [M+l] 第二步 (1无，55^-3-(5-乙基响〇定-2-基）-6-[ [4-(3-氟-4-〇比咬基） 苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷 將（1疋5«-6-[(4-溴苯氧基）甲基]-3-(5-乙基嘧啶2-基）-3-氮雜雙環並[3. 1. 0]己烧 101a(100mg，0. 27mmol)， (3-氟-4-吡啶基）硼酸（38mg，0. 27mmol)，二（三苯膦基） 二氯化把（4mg，0. Olmmol)和三水合磷酸卸（215mg， φ 〇.81mmol)溶解於5mLl，4-二噁烷中，升至100°C攪拌反應 鲁 12小時。過濾，濾液減壓濃縮，用薄層色譜法以展開劑體 系B純化所得殘餘物，得到標題產物（1尤5«-3-(5-乙基嘧 咬_2-基）-6-[ [4-(3-氟-4-0比咬基）苯氧基]曱基]-3-氮雜 雙環並[3. 1.0]己烷101(65mg，白色固體），產率：62.0%。 MS ra/z (ESI): 391. 0 [M+l] 4 MIR (400 MHz, CDCh) δ 8. 91-8. 44 (m，2H)，8. 19 (s， 2H), 7. 59-7. 57 (m, 2H), 7. 40-7. 37 (ra, 1H), 7.02-7.00 ® (m, 2H), 4.00-3.98 (m, 4H), 3.61-3.58 (m, 2H), 2.50- · 2.45 (m, 2H), 1.77 (s, 2H), 1.27-1.23 (m, 1H), 1.21-1.17 (m, 3H) 實施例102 1-[4-[5-[[(1足5«-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1· 0]己烷-6-基]曱氧基]-2-吡啶基]苯基]乙酮 259 95344 201213319The first step (1 especially 55〇-6-[(4-bromophenoxy)methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0 Hexane will [[1 especially 55*)_3_(5-ethyl-n-butyl-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methyl methanesulfonate 7g (800mg, 2.69mmol) was dissolved in 5inL. In monomethylamine, 'added carbonic acid (175Oing, 5. 38mmol) and 4-bromophenol (465mg, 2.69mmol), and raised to 120〇C The reaction was stirred for 6 hrs. EtOAc (EtOAc (EtOAc)EtOAc. (1 and 5 _6_[(4-bromophenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. (990 mg 'white solid), yield: 98. 〇%. 258 95344 201213319 MS m/z (ESI): 376.1 [M+l] The second step (1 no, 55^-3-(5-ethyl ring) 〇定-2-yl)-6-[ [4-(3-fluoro-4-pyranyl) phenoxy]methyl]-3-azabicyclo[3.1.0]hexane will (1疋5«-6-[(4-Bromophenoxy)methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] hexane 101a (100 mg, 0. 27 mmol), (3-fluoro-4-pyridyl)boronic acid (38 mg, 0.25 mmol), bis(triphenylphosphino) dichloride (4 mg, 0. Olmmol) and phosphoric acid trihydrate (215mg, φ 〇.81mmol) were dissolved in 5mL of 1,4-dioxane, and stirred at 100 ° C for 12 hours. Filtered, the filtrate was concentrated under reduced pressure, using thin layer chromatography The residue obtained by purifying the solvent system B was purified to give the title product (1,5,3-(5-ethyl-pyridin-2-yl)-6-[[4-(3-fluoro-4-0) Phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane 101 (65 mg, white solid), yield: 62.0%. MS / / (ESI): 391. 0 [M+ l] 4 MIR (400 MHz, CDCh) δ 8. 91-8. 44 (m, 2H), 8. 19 (s, 2H), 7. 59-7. 57 (m, 2H), 7. 40- 7. 37 (ra, 1H), 7.02-7.00 ® (m, 2H), 4.00-3.98 (m, 4H), 3.61-3.58 (m, 2H), 2.50- · 2.45 (m, 2H), 1.77 (s , 2H), 1.27-1.23 (m, 1H), 1.21-1.17 (m, 3H) Example 102 1-[4-[5-[[(1)5«-3-(5-ethylpyrimidine-2 -yl)-3-azabicyclo[3.1. 0]hexane-6-yl]nonyloxy]-2-pyridyl]phenyl]ethanone 259 95344 201213319

• 第一步 _ l-[4-(5-經基-2-°比β定基）苯基]乙酮 將2-溴-5-羥基-吡啶（213mg，1. 22mmol)，4-乙醯苯 硼酸（200mg，1.22mmol)和1，Γ -二（三苯膦基）二氯化鈀 (50mg，0· 12imnol)溶解於511^况於二曱基曱醯胺中，再加 入2 Μ碳酸鈉溶液（lmL，3. 66mmol)，升溫至120〇C微波反 應1小時。加入20mL水，滴加5M鹽酸至反應液pH為3 _ 至5’乙酸乙S曰萃取（20mLx2)，合併有機相，依次用水 (20mLxl) ’飽和氣化鈉溶液洗滌（2〇mLxl) ’無水硫酸鈉乾 · 燥，過濾，濾液減壓濃縮，得到標題產物羥基_2一 吡啶基）笨基]乙酮l〇2a(3〇〇mg，黃色固體），產率：1〇〇%。 第二步 卜[445-[[(1疋55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]甲氧基]-2-吡啶基]苯基]乙酮 將1-[4-(5-羥基-2-吡啶基）苯基]乙酮i〇2a(180mg， 0.84mmol)溶解於8mL况於二曱基曱醯胺中，依次加入粗 260 95344 201213319 品[(liP, 560-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己烧-6-基]曱續酸甲酉旨7g(250mg，0. 84mmol)和碳酸鉀 (235mg，1.70mmol)’升至85eC攪拌反應3小時。加入50mL 水，用乙酸乙酯萃取（50mLx2)，合併有機相，依次用水 (50mLxl) ’飽和氣化鈉溶液洗條（5〇mLxl)，無水硫酸鈉乾 燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A 純化所得殘餘物，得到標題產物1-[4-[5-[[(1亿550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱 # 氧基]_2—吡啶基]苯基]乙酮102(120mg，白色固體），產 率：34. 6〇/〇。 MS m/z (ESI)： 415. 1 [M+l] Ή NMR (400 MHz, CDCh) 5 8.56 (d, 1H), 8.50 (d, 1H), 8.46(d, 1H), 8. 17(s, 2H), 7. 36 (d, 2H), 7. 18 (d, 2H), 4.04 (d, 2H), 3.99(d, 2H), 3.60 (d, 2H), 2.47 (q, 2H), 2.15 (s, 3H), 1.80-1.78 (m, 2H), 1.27-1.25 (m, 1H), 1.19 (t, 3H) 實施例103 (1尤550-3-(5-甲基嘧啶—2-基）-6-[ [6-(4-甲磺醯基苯 基）_3—°比啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷• First step _ l-[4-(5-Pyridyl-2-° ratio β-based) phenyl] ethyl ketone 2-bromo-5-hydroxy-pyridine (213 mg, 1.22 mmol), 4-ethyl hydrazine Phenylboronic acid (200mg, 1.22mmol) and 1, bismuth-bis(triphenylphosphino)palladium dichloride (50mg, 0·12imnol) are dissolved in 511 conditions in dimethyl decylamine, followed by 2 Μ carbonic acid The sodium solution (1 mL, 3.66 mmol) was heated to 120 ° C for 1 hour. Add 20 mL of water, add 5M hydrochloric acid to the reaction solution to pH 3 _ to 5' acetic acid ethyl acetonitrile extraction (20mLx2), combine the organic phase, and then wash with water (20mLxl) 'saturated sodium carbonate solution (2〇mLxl) The sodium sulfate was dried and filtered, and the filtrate was evaporated to ethylamine. The second step is [445-[[(1疋55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]- Oxy]-2-pyridyl]phenyl]ethanone 1-[4-(5-hydroxy-2-pyridyl)phenyl]ethanone i〇2a (180 mg, 0.84 mmol) was dissolved in 8 mL of two In the decylguanamine, the crude product 260 95344 201213319 [(liP, 560-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] hexane- 6-Based] Acidic hydrazine 7g (250mg, 0.84mmol) and potassium carbonate (235mg, 1.70mmol) were stirred at 85eC for 3 hours. Add 50mL of water, extract with ethyl acetate (50mLx2), combine The organic phase was washed with water (50 mL×1), saturated aqueous sodium chloride (5 mL mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 1-[4-[5-[[(100 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl) [M+l] 曱 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 415 NMR NMR (400 MHz, CDCh) 5 8.56 (d, 1H), 8.50 (d, 1H) , 8.46(d, 1H), 8. 17(s, 2H), 7. 36 (d, 2H), 7. 18 (d, 2H), 4.04 (d, 2H), 3.99(d, 2H), 3.60 (d, 2H), 2.47 (q, 2H), 2.15 (s, 3H), 1.80-1.78 (m, 2H), 1.27-1.25 (m, 1H), 1.19 (t, 3H) Example 103 (1 550-3-(5-methylpyrimidin-2-yl)-6-[[6-(4-methylsulfonylphenyl)_3-pyridinyl]oxymethyl]-3-azabicyclo [3. 1. 0] Hexane

261 95344 201213319261 95344 201213319

第一步 # [(1疋5^-3-(5-T基嘧啶-2-基）-3-氮雜雙環並[3· 1. 0]己 烷-6-基]曱醇 將粗品[(1尤550-3-氮雜雙環並[3. 1. 0]己烷-6-基] 甲醇7e(453mg，4mmol)溶解於5mL #，#-二甲基乙醢胺中， 依次加入2-氣-5-甲基-嘴咬（514mg，4mmol)和碳酸斜 (829mg，6mmol)，升至140°C擾拌反應2小時。加入50mL 水，用乙酸乙酯萃取（30mLx3)，合併有機相，無水硫酸鎂 φ 乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑 體系A純化所得殘餘物，得到標題產物[(1^550-3-(5-甲 基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱醇 103a(0.41 g，淺黃色固體），產率：51. 0°/〇。 MS m/z (ESI): 206.0 [M+l] 第二步 [(1足55·)-3-(5-甲基嘧啶-2-基）-3-氮雜雙環並[3· 1· 0]己 烷-6-基]曱磺酸曱酯 將（1尤550-3-(5-曱基嘧啶-2-基）-3-氮雜雙環並 262 95344 201213319First Step # [(1疋5^-3-(5-T-Pyrylpyrimidin-2-yl)-3-azabicyclo[3·1]]hex-6-yl]nonanol will be crude [ (1 especially 550-3-azabicyclo[3.1.0]hexane-6-yl] Methanol 7e (453 mg, 4 mmol) was dissolved in 5 mL of #,#-dimethylacetamide, and then added 2 - gas-5-methyl-mouth bite (514 mg, 4 mmol) and carbonic acid (829 mg, 6 mmol), and stirred to 140 ° C for 2 hours. Add 50 mL of water, extract with ethyl acetate (30 mL x 3), and combine organic The residue was dried over anhydrous magnesium sulfate (MgSO4), filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-A)-3-azabicyclo[3.1.0]hexane-6-yl]nonanol 103a (0.41 g, pale-yellow solid), yield: 51. z (ESI): 206.0 [M+l] The second step [(1 foot 55·)-3-(5-methylpyrimidin-2-yl)-3-azabicyclo[3·1·0] Alkyl-6-yl]anthracene sulfonate will (1 especially 550-3-(5-mercaptopyrimidin-2-yl)-3-azabicyclo 262 95344 201213319

[3. 1. 0]己烧-6-基]曱醇 103a(0· 41 g ’ 2mmol)溶解於 2〇mL 無水二氣甲烧中’加入三乙胺（0. 8mL，6mmo 1)，滴加入甲 磺醯氣（0. 3mL ’ 3mmol) ’攪拌反應12小時。加入飽和碳酸 氫鈉溶液30mL ’二氯曱烷萃取（l〇mLx3)，合併有機相，依 次用水（20mLx3)，飽和氣化鈉溶液洗滌（20mLx3)，無水硫 酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 [(1足55)-3-(5-曱基嘴咬-2-基）-3-氮雜雙環並[3. 1. 0]己 烧-6-基]曱石黃酸曱醋103b(400mg，白色固體），產率： φ 70.0%。 φ MS in/z (ESI): 284. 0 [M+l] 第三步 (17?，550-3-(5-曱基嘧啶-2-基）-6-[ [6-(4-曱磺醯基苯 基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷 將粗品[(1尤55·)-3-(5曱基嘧啶-2-基）-3-氮雜雙環 並[3· 1. 〇]己烷-6-基]曱磺酸甲酯 l〇3b(130mg，0· 46mmol) 和6-(4-甲續醯基苯基）π比咬-3-醇48e(114mg，0. 46mmol) ^ ® 溶解於10mLN，N-二甲基乙醯胺中，再加入碳酸鉀（127mg， 〇. 92mmol) ’升溫至80°C攪拌反應1小時。加入25mL水， 乙酸乙酯萃取（20mLx3)，合併有機相，依次用飽和氣化銨 溶液（10mLx3) ’飽和氣化鈉溶液洗滌（l〇mLx3)，無水硫酸 鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體 系A純化所得殘餘物，得到標題產物（丨尤55)-3-(5-曱基嘧 啶-2-基）-6-[[6_(4-曱磺醯基苯基）-3-批啶基]氧甲基] -3-氮雜雙環並[3. 1.0]己烷103(1 l〇mg，白色固體）’產 263 95344 201213319 率：56. 0〇/〇。 MS m/z (ESI): 437.0 [M+l] 'H 丽R(400 MHz，CDC13) 6 8.42-8.40 (m，1H)，8.16-8. 12 (m, 4H), 8.02-8.00 (m, 2H), 7.74-7.72 (m, 1H), 7.31-7. 29 (in, 1H), 4. 04 (d, 2H), 3.98 (d, 2H), 3. 60 (d, 2H), 3.08 (s, 3H), 2.12 (s, 2H), 1.78 (s, 2H), 1.26-1.25 (m, 2H) 實施例104 (1及，55&quot;)-3-(5 -氣喷α定-2-基）-6-[[6-(4-甲績酿基苯 基）-3-吡啶基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷[3. 1. 0] hexyl-6-yl] decyl alcohol 103a (0· 41 g '2 mmol) was dissolved in 2 mL of anhydrous dimethyl ketone, adding triethylamine (0.8 mL, 6 mmo 1), Methanesulfonate (0.3 mL '3 mmol) was added dropwise and the reaction was stirred for 12 hours. Adding saturated sodium bicarbonate solution (30 mL) of dichloromethane (1 mL mL), EtOAc (EtOAc, m. , the crude title product [(1 foot 55)-3-(5-mercaptopurine-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl] fluorite yellow Acid vinegar 103b (400 mg, white solid), yield: φ 70.0%. φ MS in/z (ESI): 284. 0 [M+l] The third step (17?,550-3-(5-decylpyrimidin-2-yl)-6-[ [6-(4-曱) Sulfhydrylphenyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane will be crude [(1 especially 55·)-3-(5-mercaptopyrimidine- 2-yl)-3-azabicyclo[3· 1. 〇]hexane-6-yl] sulfonate methyl ester l〇3b (130 mg, 0·46 mmol) and 6-(4-methyl fluorenyl) Phenyl) π is more than butyl-3-ol 48e (114 mg, 0.46 mmol) ^ ® dissolved in 10 mL of N,N-dimethylacetamide, then potassium carbonate (127 mg, 〇. 92 mmol) The reaction was stirred for 1 hour, and 25 mL of water was added, and ethyl acetate (20 mL×3) was added, and the organic phase was combined and washed successively with saturated aqueous ammonium sulfate solution (10 mL×3), saturated sodium sulfate solution (l〇mL×3), dried over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel eluting to afford to afford the title product ( 丨 55 55) -3-(5- decylpyrimidin-2-yl)-6-[[6_ (4-oxasulfonylphenyl)-3-butidyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 103 (1 l〇mg, white solid) 'produced 263 95344 201213319 Rate: 56.0 〇/〇. MS m/z (E SI): 437.0 [M+l] 'H R (400 MHz, CDC13) 6 8.42-8.40 (m, 1H), 8.16-8. 12 (m, 4H), 8.02-8.00 (m, 2H), 7.74 -7.72 (m, 1H), 7.31-7. 29 (in, 1H), 4. 04 (d, 2H), 3.98 (d, 2H), 3. 60 (d, 2H), 3.08 (s, 3H) , 2.12 (s, 2H), 1.78 (s, 2H), 1.26-1.25 (m, 2H) Example 104 (1 and, 55 &quot;)-3-(5 - gas jet alpha-but-2-yl)-6 -[[6-(4-Methylphenyl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3.1.0]hexane

第First

xr 第二 # ^s；〇Xr second # ^s;〇

46e __ 第三·#46e __ third·#

CI 第一步 [(1尤5^-3-(5-氯嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 -6-基]甲醇 264 95344 201213319 將粗品[(1疋55^)-3-氮雜雙環並[3. 1. 0]己烷-6-基] 甲醇7e(350mg，3. lOmmol)溶解於15mL况#-二甲基乙醯 胺中，依次加入2, 5-二氯-。密〇定（462mg，3. lOmmol)和碳酸 鉀（641mg，4. 60mmol)，升至140°C攪拌反應1小時。加入 5〇mL水，用乙酸乙酯萃取（3〇mLx3)，合併有機相，無水硫 酸鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗 脫劑體系A純化所得殘餘物，得到標題產物[(1^5^)-3-(5~氯嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲醇 • l〇4a(0.40g，白色固體），產率：60.0%。 鲁 MS ra/z (ESI)： 226.0 [M+l] 第二步 [(1疋550-3-(5-氣嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 -6-基]曱磺酸曱酯 將（1兄5-3-(5-氣β密°定-2-基）_3-氮雜雙環並 [3. 1. 〇]己烧-6-基]曱醇 l〇4a(0. 38g，1. 68mmol)溶解於 φ 20mL無水二氯甲烧中，加入三乙胺（0. 7mL，5. 04mmol)， 滴加入曱磺醯氣（〇. 2mL，2. 52mmol)，攪拌反應1小時。加 入飽和碳酸氫鈉溶液30mL，二氯甲烷萃取（10mLx3)，合併 有機相，依次用水（2〇mLx3)，飽和氯化鈉溶液洗滌 (20mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物[(li?，550-3-(5-氣嘧啶-2-基）-3-氮雜雙環 並[3. 1.0]己燒~6-基]曱績酸曱酯l〇4b(370mg，白色固 體），產率：72.5%。 MS m/z (ESI)： 304.1 [M+l] 265 95344 201213319 第三步 (1疋550-3-(5-氣嘧啶-2-基）一6_[[6_(4一曱磺醢基苯 基）-3-吡啶基]氧曱基μ3—氮雜雙環並[3. 1〇]己烷 將粗品[(1尤5^)-3-(5-氣嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己院-6-基]甲磺酸曱酯 1〇4b(18〇mg，〇60mm〇i) 和6-(4-甲橫醯基苯基）〇比咬令醇48e(i5〇mg，〇· 6〇mm〇i) 各解於15mL况#-二曱基乙酿胺中 ，再加入碳酸鉀（165mg， 匕20&quot;1&quot;101)，升溫至80°C攪拌反應1小時。加入25mL水， 乙酸乙醋萃取（20mLx3)，合併有機相，依次用飽和氣化銨鲁 溶液（10mLx3)，飽和氣化鈉溶液洗滌（1〇mLx3)，無水硫酸 鎂乾燥，過濾’濾液減壓濃縮，用薄層色譜法以展開劑體 系A純化所得殘餘物，得到標題產物（1兄55·)—3-(5-氣嘧啶 -2-基）-6-[[6-(4-曱磺醯基苯基）-3-。比啶基]氧甲基]-3-氮雜雙環並[3. 1· 〇]己烷l〇4(120mg，白色固體），產率： 44· 0%。 _ MS m/z (ESI): 4570 [M+l] !H NMR (400 MHz, CDCh) δ 8.41 (d, 1H), 8.23 (s, 2H), ® 8.12 (d, 2H), 8.00 (d, 2H), 7.73 (d, 1H), 7.31-7.29 (m, 1H), 4.02(d, 2H), 3. 93 (d, 2H), 3. 58 (d, 2H), 3.08 (s, 3H), 1.80 (s, 2H), 1.25-1.21 (m, 1H) 實施例105 (1足55)-3-(5-乙基喷咬-2-基）_6_[[4-(6 -曱續酿基-3-0比 啶基）笨氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷 266 95344 201213319CI first step [(1 especially 5^-3-(5-chloropyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanol 264 95344 201213319 [(1疋55^)-3-azabicyclo[3.1.0]hexane-6-yl]methanol 7e (350mg, 3.10mmol) was dissolved in 15mL of #-dimethylacetamide 2, 5-Dichloro-. dimethyl sulfonate (462 mg, 3.10 mmol) and potassium carbonate (641 mg, 4.60 mmol) were added, and the reaction was stirred at 140 ° C for 1 hour. 5 mL of water was added with acetic acid. The ethyl ester was extracted (3 〇 mL×3), the organic phase was combined, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product [(1^5) ^)-3-(5-chloropyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanol • l〇4a (0.40 g, white solid) Rate: 60.0%. Lu MS ra/z (ESI): 226.0 [M+l] The second step [(1疋550-3-(5-apyrimidin-2-yl)-3-azabicyclo[3] 1. 0] Hexane-6-yl] sulfonate oxime ester (1 brother 5-3-(5-gas β-denidine-2-yl)_3-azabicyclo[3. 1. 〇 ] 己 -6-yl] decyl alcohol l 〇 4a (0. 38g, 1. 68mmol) dissolved in φ 20mL anhydrous dichloromethane Triethylamine (0.7 mL, 5.04 mmol) was added, and hydrazine sulfonium (〇. 2 mL, 2.52 mmol) was added dropwise, and the reaction was stirred for 1 hour. 30 mL of saturated sodium hydrogencarbonate solution was added and extracted with dichloromethane. 10mLx3), the organic phase was combined, washed with water (2 mL mL), EtOAc (EtOAc) (5-Azoxypyrimidin-2-yl)-3-azabicyclo[3.1.0]hexanyl~6-yl] hydrazinyl ester l〇4b (370 mg, white solid), yield: 72.5%. MS m/z (ESI): 304.1 [M+l] 265 95344 201213319 The third step (1疋550-3-(5-apyrimidin-2-yl)-6_[[6_(4- sulfonylbenzene) ))-3-pyridyl]oxanyl μ3-azabicyclo[3. 1〇]hexane will be crude [(1 especially 5^)-3-(5-apyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexyl-6-yl]methanesulfonate 1〇4b (18〇mg,〇60mm〇i) and 6-(4-methyl-cyanophenyl)〇 bite Let alcohol 48e (i5〇mg, 〇·6〇mm〇i) be dissolved in 15mL of #-dimercaptoamine, then add potassium carbonate (165mg, 匕20&quot;1&quot;101), and heat up to 80° C stirring Reaction for 1 hour. Add 25 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated ammonium sulfate solution (10 mL×3), saturated sodium carbonate solution (1〇mL×3), dry over anhydrous magnesium sulfate, filter Concentration and purification of the obtained residue by EtOAc EtOAc (EtOAc) Sulfohydroxyphenyl)-3-. Pyridyl]oxymethyl]-3-azabicyclo[3.1·〇]hexane l〇4 (120 mg, white solid), yield: 44.0%. _ MS m/z (ESI): 4570 [M+l] !H NMR (400 MHz, CDCh) δ 8.41 (d, 1H), 8.23 (s, 2H), ® 8.12 (d, 2H), 8.00 (d , 2H), 7.73 (d, 1H), 7.31-7.29 (m, 1H), 4.02(d, 2H), 3. 93 (d, 2H), 3. 58 (d, 2H), 3.08 (s, 3H) ), 1.80 (s, 2H), 1.25-1.21 (m, 1H) Example 105 (1 foot 55)-3-(5-ethyl aceton-2-yl)_6_[[4-(6 - 曱Styrene-3-0-pyridyl)phenyloxy]indolyl]-3-azabicyclo[3. 1. 0]hexane 266 95344 201213319

第一步 5-漠-2-曱硫基-η比咬The first step 5-wet-2-曱thio-η ratio bite

將 2, 5-二溴吡啶 i〇5a(lg，4· 20mmol)溶解於 i〇mL 况舲二曱基甲醯胺中，加入甲基硫化鈉（3〇〇mg，4. 2〇mm〇1)， 室溫反應0· 5小時。加入3〇mL水，用乙酸乙酯萃取 (20mLx2) ’合併有機相’用飽和氣化鈉溶液洗滌（2〇mLx2)， 無水硫酸鈉乾燥’過濾’濾液減壓濃縮，得到標題產物5_ 溴-2-曱硫基-吡啶105b(800mg，白色固體），產率：1〇〇%。 MS m/z (ESI): 203.8 [M+l] 第二步 5-溴-2-曱磺醯基-吡啶 將 5_漠-2-甲硫基-〇比0定 105b(800mg ’ 3. 90mmol)溶解 於8mL異丙醇中，加入過硫酸氫鉀（4. 80g，7.80mmol)，攪 267 95344 201213319 拌反應12小時。反應液減壓濃縮，用薄層色譜法以展開劑 體糸B純化所得殘餘物，得到標題產物5-漠-2-甲績酿基-吡啶105c(120mg，黃色固體），產率：13. 0%。 MS in/z (ESI): 235.9 [M+l] 第三步 4-(6 -曱確醯基-3-e比咬基）苯紛 將 5-溴-2-甲續醯基-〇比咬 l〇5c(400mg，1. 70mmol)， (4-羥基苯）硼酸（234mg，1. 70mrool)，二（三苯膦基）二氣化 鲁鈀（25mg，0. 03mmol)和三水合磷酸鉀（1400mg，5. lOmmol) · 溶解於5mL 1，4-二噁烷中，升至l〇(TC攪拌反應12小時。 過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B 純化所得殘餘物，得到標題產物4-(6-甲磺醯基-3-吡咬基） 苯105d(400mg ’白色固體），產率：95.2%。 MS m/z (ESI): 250.0 [M+1] 第四步 φ (1尤5^-3-(5-乙基嘧啶-2-基）-6-[ [4-(6-甲磺醯基-3-吡 α定基）本氧基]甲基]-3-氮雜雙環並[3. 1. 〇]己院 鲁 將4-(6-曱續醯基-3-°比咬基）苯i〇5d(i〇〇mg， 0.40mm〇l)溶解於5mL况趴二曱基甲醯胺中，依次加入粗 品[(1尤560-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3· ι·〇] 己烷-6-基]甲磺酸曱酯7g(119mg，〇 4〇mra〇1)和碳酸鉋2, 5-dibromopyridine i〇5a (lg, 4·20 mmol) was dissolved in i〇mL state dimethyl carbamide, and sodium methyl sulfide (3 〇〇 mg, 4.2 〇mm〇) was added. 1), the reaction at room temperature for 0.5 hours. After adding 3 mL of water, extracting with ethyl acetate (20 mL×2) and EtOAc (2 mL), EtOAc (EtOAc) 2-decylthio-pyridine 105b (800 mg, white solid), yield: 1%. MS m/z (ESI): 203.8 [M+l]. Step 2 5-bromo-2-indolesulfonyl-pyridine. 5_Methyl-2-methylthio-indole ratio 0 to 105b (800 mg ' 3. 90 mmol) was dissolved in 8 mL of isopropanol, potassium hydrogen persulfate (4.80 g, 7.80 mmol) was added, and the reaction was stirred for 267 95344 201213319 for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj 0%. MS in/z (ESI): 235.9 [M+l] The third step 4-(6 - 曱 醯 -3- -3-e 比 咬 ) ) ) 将 将 将 5 5 5 5 5 5 5 5 5 5 5咬l〇5c (400mg, 1.70mmol), (4-hydroxyphenyl)boronic acid (234mg, 1.70mrool), bis(triphenylphosphino) di-gasified ruthenium palladium (25mg, 0.03mmol) and phosphoric acid trihydrate Potassium (1400 mg, 5.10 mmol) · Dissolved in 5 mL of 1,4-dioxane, raised to 1 〇 (TC stirred for 12 hours. Filtration 'The filtrate was concentrated under reduced pressure, using a cartridge column chromatography to eluent system The residue was purified to give the title compound 4-(6-methanesulfonyl-3-pyrimidinyl) benzene 105d (400 mg &lt;RTI ID=0.0&gt; M+1] The fourth step φ (1 especially 5^-3-(5-ethylpyrimidin-2-yl)-6-[[4-(6-methylsulfonyl-3-pyridinyl)-based oxygen ]]methyl]-3-azabicyclo[3. 1. 〇] 己院鲁 4-(6-曱 continued 醯--3-° than bite) benzophene 5d (i〇〇mg, 0.40 mm〇l) was dissolved in 5 mL of dimercaptocarhamamine, and the crude product was added in sequence [(1 especially 560-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3· Ig·〇] hexane-6-yl] decyl methanesulfonate 7g (119mg, 〇4〇mra〇1) and carbonic acid plane

(260rag，0.80mni〇l)，升至80°C攪拌反應12小時。加入10mL 水，用乙酸乙酯萃取（2〇mLx2)，合併有機相，無水硫酸鈉 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 268 95344 201213319 A純化所得殘餘物得到標題產物（1尤551)_3_(5_乙基嘧啶 -2-基）-6-[[4-(6-曱磺醯基-3-啦啶基）苯氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷i〇5(120mg，白色固體），產率： 66.7%。 MS m/z (ESI): 451. 1 [M+l] *H NMR (400 MHz, CDCh) δ 8.90 (s, 1H), 8.31 (s, 2H), 8.13-8.06 (m, 2H), 7.56-7.54 (m, 2H), 7.04-7.02 (m, 2H), 4.16-4.14 (m, 2H), 4.00-3.98 (m, 2H), 3.78-3.75 • (m, 2H), 3. 26(s, 3H), 2. 55-2. 54 (m, 2H), 1.87(s, 1H), 1. 24-1. 23 (m, 5H) 實施例106 (1兄55|)-3-(5~乙基喊咬-2-基）_6_[[1-（4-甲續酿基苯 基）-4-哌啶基]氧甲基]-3-氮雜雙環並[3. i. 〇]己烷(260rag, 0.80mni〇l), the reaction was stirred at 80 ° C for 12 hours. After adding 10 mL of water and extracting with ethyl acetate (2 mL mL), the organic phase was combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin-layer chromatography to afford the title 268 95344 201213319 A Product (1 especially 551)_3_(5-ethylpyrimidin-2-yl)-6-[[4-(6-oxasulfonyl-3-oxaridinyl)phenoxy]indolyl]-3-nitrogen Heterobicyclo[3.1.0]hexane i〇5 (120 mg, white solid), yield: 66.7%. MS m/z (ESI): 451. 1 [M+l] *H NMR (400 MHz, CDCh) δ 8.90 (s, 1H), 8.31 (s, 2H), 8.13-8.06 (m, 2H), 7.56 -7.54 (m, 2H), 7.04-7.02 (m, 2H), 4.16-4.14 (m, 2H), 4.00-3.98 (m, 2H), 3.78-3.75 • (m, 2H), 3. 26(s , 3H), 2. 55-2. 54 (m, 2H), 1.87(s, 1H), 1. 24-1. 23 (m, 5H) Example 106 (1 brother 55|)-3-(5 ~Ethyl ketone-2-yl)_6_[[1-(4-methylphenyl)-4-piperidinyl]oxymethyl]-3-azabicyclo[3. i. 〇] Hexane

第一步 4-羥基哌啶-1-羧酸第三丁酯 269 95344 201213319 將4-氧代°底咬_1_緩酸第三丁@旨l〇6a(10g，50mmol) 溶解於1 OOmL甲醇中’加入蝴氫化納（2. 84g，75mmol)，授 拌反應2小時。加入30mL水，用乙酸乙酯萃取（2〇mLx2)， 合併有機相’用飽和氣化鈉溶液洗滌（20mLx2)，無水硫酸 鈉乾燥，過濾’濾液減壓濃縮，得到標題產物4-羥基哌啶 基-1-幾酸第三丁S旨106b(10. 50 g，白色固體），產率： 1001 MS m/z (ESI): 102.1 [M+1-100] • 第二步 4-羥基哌啶三氟乙酸鹽 將4-經基痕咬基-1-竣酸第三丁g旨l〇6b(4650mg， 23. lOmmol)溶解於100mL二氯曱院中，加入三氟乙酸 (26. 30 g，231mmol) ’攪拌反應2小時。反應液減壓濃縮， 得到標題產物4-羥基哌啶三氟乙酸鹽106c(5200mg，淡黃 色油狀物），產率：100%。 第三步 1-(4-曱磺醯基苯基）哌啶-4-醇 將4-羥基哌啶三氟乙酸鹽l〇6c(3230mg，15mmol)， 1-氟-4-曱磺醯基苯（2610mg，15mmol)及碳酸鉀（6220mg， 45ramol)溶解於50mL况二甲基甲醯胺中，升至90°C，攪 拌反應12小時。加入300mL水，用乙酸乙酯萃取 (100mLx3) ’合併有機相，無水硫酸鈉乾燥，過濾，濾液減 壓濃縮’用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘 物，得到標題產物1-(4-曱磺醯基苯基）哌啶-4-醇106d 270 95344 201213319 (3400mg，淺黃色固體），產率：78. 3%。 MS m/z (ESI): 250.0 [M+l] 第四步 (1皮，550-3-(5-乙基嘧咬-2-基）-6-[[i-(4-曱橫醢基苯 基）-4-哌啶基]氧曱基]-3-氮雜雙環並[3. 1. 〇]己烷 將1-(4-曱崎酿基苯基）〇辰〇定-4-醇i〇6d(100mg， 0. 39mmol)溶解於3mL四氫呋喃中，冷卻至〇°c，依次加入 15-冠-5(86mg，0· 39mmol)和氫化鈉（I6mg，0. 39mmol)，攪 # 拌30分鐘’再加入粗品[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3_ 1. 0]己烷-6-基]曱磺酸曱酯7g (116mg，0. 39mmol)，微波升至l〇(TC攪拌反應0· 5小時。 加入10mL飽和氯化銨溶液，用乙酸乙酯萃取（15mLx3)，合 併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用石夕First step 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 269 95344 201213319 4 oxo bottom bit _1_slow acid third butyl @ 〇 l 〇 6a (10g, 50mmol) dissolved in 100 mL Adding hydrogenated naphthalene (2. 84 g, 75 mmol) in methanol and mixing for 2 hours. The title product, 4-hydroxypiperidine, was obtained by the addition of 30 mL of water, EtOAc (EtOAc (EtOAc). Benzene-1-carboxylic acid tert-butyl S. 106b (10. 50 g, white solid), Yield: 1001 MS m/z (ESI): 102.1 [M+1-100] The pyridine trifluoroacetate salt is dissolved in 100 mL of dichlorohydrazine, and the trifluoroacetic acid (26.30) is added to the base of the 4-aminoglycolate-1-butyric acid tributyl sulfonate (4650 mg, 23.10 mmol). g, 231 mmol) 'Stirring reaction for 2 hours. The reaction mixture was concentrated to dryness crystals crystal crystal crystal crystal crystal crystal crystal crystal The third step is 1-(4-oxasulfonylphenyl)piperidin-4-ol 4-hydroxypiperidine trifluoroacetate l〇6c (3230 mg, 15 mmol), 1-fluoro-4-indenesulfonyl Benzene (2610 mg, 15 mmol) and potassium carbonate (6220 mg, 45 ramol) were dissolved in 50 mL of dimethylformamide, and the mixture was warmed to 90 ° C, and the reaction was stirred for 12 hours. After adding 300 mL of water and extracting with ethyl acetate (100 mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system A to give title product 1 -(4-oxasulfonylphenyl)piperidin-4-ol 106d 270 95344 201213319 (3400 mg, pale yellow solid), yield: 78.3%. MS m/z (ESI): 250.0 [M+l] The fourth step (1 skin, 550-3-(5-ethylpyridine-2-yl)-6-[[i-(4-曱横醢) Phenyl)-4-piperidinyl]oxanyl]-3-azabicyclo[3. 1. oxime]hexane 1-(4-曱崎-brown phenyl) 〇辰〇定-4 - alcohol i 〇 6d (100 mg, 0. 39 mmol) was dissolved in 3 mL of tetrahydrofuran, cooled to 〇 ° C, and then added 15 - crown -5 (86 mg, 0. 39 mmol) and sodium hydride (I6 mg, 0. 39 mmol), stir #混搅拌30分钟'Add the crude product [(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3_1.0]hexane-6-yl] sulfonic acid The oxime ester 7g (116mg, 0. 39mmol), was added to the oxime (1 hr). The reaction mixture was stirred for EtOAc. , filtration, filtrate concentrated under reduced pressure, with Shi Xi

I 膠管柱色譜法以展開劑體系A純化所得殘餘物得到標題產 物（1尤550-3-(5-乙基嘧啶-2-基）-6-[[ 1-(4-曱磺醯基苯 I 基）-4-哌啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷1〇6 (62mg，白色固體），產率：34. 6%。 MS m/z (ESI): 457.2 [M+l] NMR (400 MHz, CDCh) δ 8.16 (s, 2H), 7.74 (d, 2H), 6.92 (d, 2H), 3.90 (d, 2H), 3.69-3.65 (m, 2H), 3.56-3.52 (in, 3H), 3.45 (d, 2H), 3.18-3.15 (in, 2H), 3.00 (s, 3H), 2.48-2.42 (dd, 2H), 1.97-1.93 (m, 2H), 1.71-1.68 (m, 2H), 1.25 (s, 2H), 1. 17 (t, 3H), 0. 99 (t, 1H) 實施例107 271 95344 201213319 [2-[[(1^ 5lS)-3-(5-乙基喊β定-2-基）-3-氮雜雙環[3. 1. 0] 己烷-6-基]甲氧基]-5-(4-甲磺醯基笨基）苯基]甲胺I Hose column chromatography Purify the obtained residue in a solvent system A to give the title product (1 550-3-(5-ethylpyrimidin-2-yl)-6-[[ 1-(4- sulfonyl benzene benzene) Im)-4-piperidinyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 1〇6 (62 mg, white solid), yield: 34. 6% MS m/z (ESI): 457.2 [M+l] NMR (400 MHz, CDCh) δ 8.16 (s, 2H), 7.74 (d, 2H), 6.92 (d, 2H), 3.90 (d, 2H), 3.69-3.65 ( m, 2H), 3.56-3.52 (in, 3H), 3.45 (d, 2H), 3.18-3.15 (in, 2H), 3.00 (s, 3H), 2.48-2.42 (dd, 2H), 1.97-1.93 ( m, 2H), 1.71-1.68 (m, 2H), 1.25 (s, 2H), 1. 17 (t, 3H), 0. 99 (t, 1H) Example 107 271 95344 201213319 [2-[[( 1^ 5lS)-3-(5-ethyl-Sn-decyl-2-yl)-3-azabicyclo[3. 1. 0] hexane-6-yl]methoxy]-5-(4- Methyl sulfonyl phenyl] methylamine

將2-[[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1. 0]己烷-6-基]甲氧基]-5-(4-甲磺醯基苯基）苯曱 醛 87c(100mg，0· 20mmol)和氨水（5mg，0. 30mmol)溶解於 lOmL甲醇中，升至回流攪拌反應20分鐘，加入硼氫化鈉 (16mg，0· 40mmol)，繼續回流擾拌反應2. 5小時。加入20mL 水，用二氯甲烷萃取（30mLx2)，合併有機相，無水硫酸鈉 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以洗脫劑體系 A純化所得殘餘物，得到標題產物l-[2-[[(lA&gt;，55^)-3-(5-乙 基嘧啶-2-基 ）-3-氮雜 雙環並 [3. 1. 0] 己烷-6-基] 甲氧 基]-5-(4-甲磺醯基苯基）苯基]-沪曱基-甲胺88(10mg，白 色固體），產率：10. 0%。 MS ra/z (ESI): 479.2 [M+l] ^ NMR (400 MHz, CDCh) δ 8. 20-8. 18 (m, 2H), 7.99-7.94 (m, 5H), 7.77-7.75 (m, 1H), 7.19-7.17 (m, 1H), 4.14 272 95344 201213319 (m, 4H), 4.08-4.07 (m, 4H), 3.84-3.81 (m, 2H), 3.24 (s, 3H), 2. 42-2. 38 (m, 2H), 1.83(s, 2H), 1. 16 (s, 1H), 1. 12-1. 09 (in, 3H) 實施例10 8 (1尤5^-3-(5-乙基嘧啶-2-基）-6-[[6-(4-甲基亞磺醯 基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷2-[[(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]-5 -(4-Methanesulfonylphenyl) phenylfurfural 87c (100 mg, 0·20 mmol) and aqueous ammonia (5 mg, 0.30 mmol) were dissolved in 10 mL of methanol, and the mixture was stirred under reflux for 20 minutes, and sodium borohydride was added. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The residue obtained was purified by eluent system A to give the title product l-[2-[[(lA&gt;, 55^)-3-(5-ethylpyrimidin-2-yl)-3- azabicyclo and [3. 1. 0] hexane-6-yl] methoxy]-5-(4-methylsulfonylphenyl)phenyl]-histyl-methylamine 88 (10 mg, white solid) Rate: 10. 0%. MS ra/z (ESI): 479.2 [M+l] NMR (400 MHz, CDCh) δ 8. 20-8. 18 (m, 2H), 7.99-7.94 (m, 5H ), 7.77-7.75 (m, 1H), 7.19-7.17 (m, 1H), 4.14 272 95344 201213319 (m, 4H), 4.08-4.07 (m, 4H), 3.84-3.81 (m, 2H), 3.24 ( s, 3H), 2. 42-2. 38 (m, 2H), 1.83(s, 2H), 1. 16 (s, 1H), 1. 12- 1. 09 (in, 3H) Example 10 8 (1 especially 5^-3-(5-ethylpyrimidin-2-yl)-6-[[6-(4-methylsulfinyl)-3 -pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane

第一步 6-（4-曱基亞續醯苯基）°比唆-3-醇 • 將6-(4-曱基硫苯基）吡啶-3-醇（0. 04 g，〇. 20則1〇1) 溶解於5mL二氣曱烷中，加入間氯過氧苯曱酸（28mg， 〇 · 12mmo 1) ’反應1小時。加入1 〇 〇mL飽和碳酸氫鈉水溶液， 用乙酸乙酯萃取（100mLx2)，合併有機相，用飽和氣化納溶 液洗條（5mLx2)，無水硫酸鈉乾燥，過濾，渡液減壓濃縮， 用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到 標題產物6-(4-甲基亞續醯苯基）*&gt;比咬-3-醇l〇8a(l8. 40mg， 白色固體），產率：39. 0%。 MS ra/z (ESI): 234.0 [M+l] 95344 273 201213319 第二步 (1尤550-3-(5-乙基嘧啶-2-基）-6-[[6-(4-曱基亞磺醯 基）-3一°比啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷 將6-(4-甲基亞磺醯苯基）吡啶-3-醇l〇8a(115mg， 0.50inmol)溶解於i5mL况於二甲基甲醯胺中，依次加入粗 品[(1尤550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇] 己烧-6-基]曱續酸甲g旨7g(149mg，〇. 50mmol)和碳酸釺 (138mg ’ lmmol)，升至80°C攪拌反應4小時。加入10mL # 水，用乙酸乙酯萃取（20mLx2)，合併有機相，無水硫酸鈉 鲁 乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系 A純化所得殘餘物得到標題產物（1尤55*)Κ5-乙基嘴咬 -2_基）_6_[[ 6-（4-曱基亞項酿基）_3_0比咬基]氧曱基]~3-氮雜雙環並[3. 1.0]己烷108(120mg ’白色固體），產率： 55. 0%。 MS m/z (ESI): 435.2 [M+l] *H NMR (400 MHz, d-MSO) δ 8.39 (d, 1H), 8.21 (s, 2H), 攀 8.08 (d, 2H)，7. 72-7. 69 (m, 3H), 7.29-7.27 (m, 1H),鲁 4.02 (d, 3H), 3.65 (s, 2H), 2.75 (s, 3H), 2.50-2.48 (m, 2H), 1.82 (s, 2H), 1.24-1.17 (in, 5H) 實施例109 (1兄 55)-3-(5-乙基嘧啶-2-基）-6-[[6-(3-1-4-°比啶 基）_3_吡啶基]氧曱基]-3氮雜雙環並[3. 1.0]己烷 274 95344 201213319The first step is 6-(4-fluorenyl phenyl) 唆-3-ol • 6-(4-mercaptothiophenyl)pyridin-3-ol (0. 04 g, 〇. 20 Then 1〇1) was dissolved in 5 mL of dioxane, and m-chloroperoxybenzoic acid (28 mg, 〇·12 mmo 1) was added to react for 1 hour. Add 1 mL of a saturated aqueous solution of sodium hydrogencarbonate, and extract with ethyl acetate (100 mL×2). The organic phase is combined, washed with a saturated sodium chloride solution (5 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained by purifying the column chromatography with eluent system A afforded the title product 6-(4-methyl succinylphenyl)*&gt;biter-3-ol l8a (l.40 mg, white) Solid,) Yield: 39.0%. MS ra/z (ESI): 234.0 [M+l] 95344 273 201213319 The second step (1 especially 550-3-(5-ethylpyrimidin-2-yl)-6-[[6-(4-fluorenyl) Sulfosyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 6-(4-methylsulfinylphenyl)pyridine-3 - Alcohol 10 8 (115 mg, 0.50 inmol) was dissolved in i5 mL in dimethylformamide, and the crude product was added in sequence [(1 550-3-(5-ethylpyrimidin-2-yl)-3-nitrogen) Heterobicyclo[3. 1. 〇] hexyl-6-yl] benzoic acid yg 7g (149mg, 〇. 50mmol) and cesium carbonate (138mg 'lmmol), the reaction was stirred at 80 ° C for 4 hours. After adding 10 mL of water, the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.尤55*)Κ5-ethyl mouth bite-2_base)_6_[[ 6-(4-mercapto-sub-branched)_3_0 than bite-based]oxycarbonyl]~3-azabicyclo[3. 1.0 Hexane 108 (120 mg 'white solid), Yield: 55.0%. MS m/z (ESI): 435.2 [M+l] *H NMR (400 MHz, d-MSO) δ 8.39 (d, 1H ), 8.21 (s, 2H), climb 8.08 (d, 2H), 7. 72-7. 69 (m , 3H), 7.29-7.27 (m, 1H), Lu 4.02 (d, 3H), 3.65 (s, 2H), 2.75 (s, 3H), 2.50-2.48 (m, 2H), 1.82 (s, 2H) , 1.24-1.17 (in, 5H) Example 109 (1 brother 55)-3-(5-ethylpyrimidin-2-yl)-6-[[6-(3-1-4-°-pyridyl) _3_pyridyl]oxycarbonyl]-3 azabicyclo[3.1.0]hexane 274 95344 201213319

將6-(3-氟-4-吡啶基）吡啶-3-醇l〇9a(100mg， • 〇.53mmol)溶解於5mL Λ舲二曱基甲醯胺中，依次加入粗 品[(1足55)-3-(5-乙基嘧啶-2-基）_3_氮雜雙環並[3· ι 〇] 己烷-6-基]甲磺酸甲酯7g(150mg，〇. 53mmol)和碳酸鉀 (22〇mg，1· 58則1〇1) ’升至85。〇攙拌反應3小時。加入3〇mL 水，用乙酸乙酯萃取（2〇mLx3)，合併有機相，依次用水 (30raLxl)，飽和氣化鈉溶液洗滌（3〇mLxl)，無水硫酸鈉乾 燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以展開劑體 φ 系A純化所得殘餘物得到標題產物（1疋550-3-(5-乙基喷 啶-2-基）-6-[ [6-(3-氟-4-吡咬基）-3-吡啶基]氧甲基]一3 氣雜雙環並[3. 1. 0]己烧109(100mg，白色固體），產率： 48. 8%。 MS m/z (ESI): 392.1 [M+l] !H NMR (400 MHz, CDCh) 5 8.53 (d, 1H), 8.49 (d, 1H) 8.44 (d, 1H), 8.18 (s, 2H), 7.99 (dd, 1H), 7.87 (d 1H), 7.28 (dd, 1H), 4.03 (d, 2H), 3.99 (d, 2H), 3.59 (d, 2H), 2.46 (q, 2H), 1.78-1.76 (m, 2H), 1.25-1.23 95344 275 201213319 (m, 1H), 1. 18 (t, 3H) 實施例110 ⑽別+⑸環絲較-2-基）-6-[[6〜（4、ψ俩基苯 基）-3-吼啶基]氧甲基]-3-氮雜雙環並[3· 1〇]己烧6-(3-Fluoro-4-pyridinyl)pyridin-3-ol 10 9 (100 mg, • 53.53 mmol) was dissolved in 5 mL of decylcarbamamine, and the crude product was added in sequence [(1 foot 55) -3(5-ethylpyrimidin-2-yl)_3_azabicyclo[3· ι 〇] hexane-6-yl]methyl methanesulfonate 7g (150mg, 〇. 53mmol) and potassium carbonate (22〇mg, 1.58 is 1〇1) 'Up to 85. The reaction was stirred for 3 hours. After adding 3 mL of water, and extracting with ethyl acetate (2 〇 mL×3), the organic phase was combined, washed with water (30 raLxl), saturated sodium carbonate solution (3 mL mL), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography eluting with </RTI> </ RTI> </ RTI> </ RTI> A to give the title product (1 疋 550 -3- Fluor-4-pyridyl)-3-pyridyl]oxymethyl]- 3 gas heterobicyclo[3. 1. 0] hexane 109 (100 mg, white solid), yield: 48.8%. m/z (ESI): 392.1 [M+l] !H NMR (400 MHz, CDCh) 5 8.53 (d, 1H), 8.49 (d, 1H) 8.44 (d, 1H), 8.18 (s, 2H), 7.99 (dd, 1H), 7.87 (d 1H), 7.28 (dd, 1H), 4.03 (d, 2H), 3.99 (d, 2H), 3.59 (d, 2H), 2.46 (q, 2H), 1.78- 1.76 (m, 2H), 1.25-1.23 95344 275 201213319 (m, 1H), 1. 18 (t, 3H) Example 110 (10) Other + (5) ring filaments than 2-yl)-6-[[6~( 4, benzyl phenyl)-3-acridinyl]oxymethyl]-3-azabicyclo[3·1〇] hexane

第一步 2-氯_5-環丙基-嘧啶 將2-氣-5-溴-嘧啶（387mg，2mmol)溶解於7 6mL甲苯 φ 中，依次加入環丙基硼酸（223mg，2.60mmol),磷酸鉀（148 g ’ 7mmol)，二環己院基填（56mg，0. 20mmol)和醋酸把 (22. 40mg，0. l〇mm〇i)，升至 i2(TC 微波反應 0. 2 小時。冷 至室溫，加入l〇mL水，用乙酸乙酯萃取（20mLx3)，合併有 機相，用飽和氣化鈉溶液洗滌（5〇mLxl)，無水硫酸鎂乾燥， 過濾減壓濃縮濾液，用矽膠管柱色譜法以洗脫劑體系B純 化所得殘餘物’得到標題產物2-氯環丙基-嘧啶11a (270mg ’白色固體），產率：87. 7%。 MS m/z (ESI): 155.0 [M+l] 276 95344 201213319 第二步 [(liP，550-3-(5-環丙基嘧啶-2-基）-3-氮雜雙環並[3· 1. 〇] 己烧-6-基]曱醇 將粗品[(1尤5«-3-氮雜雙環並[3. ι 0]己烷_6_基] 曱醇7e(373mg，3. 30mmol)溶解於1〇mL况趴二曱基曱醯 胺中’依次加入2-氯_5-ί哀丙基-喷u定ii〇a(51〇mg， 3. 30mmol)和碳酸鉀（684mg，4. 95mmol)，升至 15(TC 攪拌 反應2小時。反應液減壓濃縮，加入2〇mL水，用乙酸乙酯 攀 萃取（2〇mLx6) ’合併有機相’無水硫酸鎂乾燥，過濾，濾 液減壓濃縮，用石夕膠管柱色譜法以洗脫劑體系B純化所得 殘餘物，得到標題產物[(1^55^-3-(5-環丙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6一基]曱醇ii〇b(〇. 63g， 黃色固體），產率：82.7%。 MS m/z (ESI): 232.1 [M+l] 第三步 φ [(1尤55)-3-(5-環丙基嘧啶-2-基）-3-氮雜雙環並[3· 1. 〇] 己烷-6-基]曱磺酸曱酯 將[(1^ 55)-3-(5-環丙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]曱醇 ll〇b(0.63g，2.73mmol)溶解於 10mL無水二氯甲烧中’加入三乙胺（750mg，5. 46min〇l)， 滴加入甲續醢氯（0. 3mL，4. 08mmol)，授拌反應0. 5小時。 加入30mL水’擾拌30分鐘，分液，水相用二氯甲燒萃取 (10mLx3) ’合併有機相，用水洗條（lOmLxl)，無水硫酸錤 乾燥’過遽，滤液減壓濃縮，得到粗品標題產物[(1及， 277 95344 201213319 C5-環丙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷-6-基] 甲磺酸甲酯110c(760mg ’黃色固體），產物不經純化直接 進行下一步反應。 MS m/z (ESI): 310. 1 [M+1] 第四步 (1尤55)-3-(5-環丙基嘧啶-2-基）-6-[ [6-(4-曱磺醯基苯 基）-3-°比啶基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷 將粗品[(li?，5«-3-(5-環己基嘧啶-2-基）-3-氮雜雙 _ 環並[3. 1. 0]己烷-6-基]曱磺酸曱酯ll〇c(223mg， 0. 72mmol)和6-(4-甲磺醯基笨基）吡啶-3-醇48e(180mg， 0· 72賴〇1)溶解於2mL况二曱基曱醯胺中’再加入碳酸 鉀（300mg，2. 17mmol)，升溫至9〇°C攪拌反應5小時。加 入20mL水，二氣曱烷萃取（2〇mLx3)，合併有機相，無水硫 酸鎂乾燥’過濾’濾液減壓濃縮，用薄層色譜法以展開劑 體系A純化所得殘餘物，得到標題產物（丨尤550-3-(5-環丙 φ 基嘧啶_2_基）一6-[ [6-(4-曱磺醯基苯基）-3-吡啶基]氧甲 基]-3-氮雜雙環並[3.1.〇]己烷ii〇(i6〇mg，白色固體）， 產率：47. 9%。 MS m/z (ESI): 463.1 [M+1] !H NMR (400 MHz, CDCh) δ 8.45 (s, 1H), 8.16 (d, 4H), 8. 03(d, 2H), 7. 76(d, 1H), 7.32 (d, 1H), 4. 06 (d, 2H), 3. 99 (d, 2H), 3. 60 (d, 2H), 3. 11 (s, 3H), 1. 81 (s, 2H), 1.74-1.72 (m, 1H), 1.27-1.25 (m, 1H), 0.93 (d, 2H), 0.60 (d, 2H) 278 95344 201213319 實施例111 (1友，551)-3-(5-環丙基嘴咬-2-基）-6-[[6-(3-|1-4-'1比咬 基）-3-吡啶基]氧曱基]-3氮雜雙環並[3. 1. 0]己烷The first step 2-chloro-5-cyclopropyl-pyrimidine 2-oxa-5-bromo-pyrimidine (387 mg, 2 mmol) was dissolved in 7 6 mL of toluene φ, and then cyclopropylboronic acid (223 mg, 2.60 mmol) was added. Potassium phosphate (148 g '7 mmol), dicyclohexylamine (56 mg, 0.20 mmol) and acetic acid (22. 40 mg, 0.1 mmmm), raised to i2 (TC microwave reaction 0.2 hours) The mixture was cooled to room temperature, and then added with EtOAc EtOAc (EtOAc (EtOAc) The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) : 155.0 [M+l] 276 95344 201213319 The second step [(liP,550-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3· 1. 〇] hexane- 6-yl]sterol The crude product [(1 especially 5«-3-azabicyclo[3. ι 0]hexane_6_yl] sterol 7e (373 mg, 3.30 mmol) was dissolved in 1 〇 mL. In the case of indole quinone amide, 2-chloro-5- lysyl propyl- sulphide ii 〇 a (a) (51 〇 mg, 3. 30 mmol) and carbonic acid Potassium (684 mg, 4.95 mmol), raised to 15 (TC stirred for 2 hours. The reaction was concentrated under reduced pressure. EtOAc (2 mL), EtOAc (EtOAc) Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product [(1^55^-3-(5-cyclopropylpyrimidin-2-yl) -3 azabicyclo[3. 1. oxime] hexane-6-yl] sterol ii 〇 b (〇. 63 g, yellow solid), yield: 82.7% MS m/z (ESI): 232.1 [M+l] The third step φ [(1 especially 55)-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3· 1. 〇] hexane-6- [(1^55)-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonanol Ll〇b (0.63g, 2.73mmol) was dissolved in 10mL of anhydrous methylene chloride. Add triethylamine (750mg, 5.46min〇l) 5小时。 Add 30mL of water 'scrambled for 30 minutes, liquid, the aqueous phase was extracted with methylene chloride (10mLx3) 'combined organic phase, washed with water (lOmLxl), dried anhydrous barium sulfate 'After 遽, the filtrate was concentrated under reduced pressure to give the crude title product [(1 &, 277 95344 201213319 C5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime]hexane-6 Methyl methanesulfonate 110c (760 mg 'yellow solid), the product was taken to the next step without purification. MS m/z (ESI): 310. 1 [M+1] Step 4 (1 especially 55)-3-(5-cyclopropylpyrimidin-2-yl)-6-[ [6-(4-曱) Sulfhydrylphenyl)-3-°-pyridyl]oxycarbonyl]-3-azabicyclo[3.1.0]hexane will be crude [(li?,5«-3-(5-ring) Hexylpyrimidin-2-yl)-3-azabi-cyclo[3.1.0]hexane-6-yl]decylsulfonate 〇〇c (223 mg, 0. 72 mmol) and 6-(4 -Methanesulfonylpyridyl)pyridin-3-ol 48e (180 mg, 0·72 lysine 1) was dissolved in 2 mL of dimethyl decylamine and then potassium carbonate (300 mg, 2.17 mmol) was added and the temperature was raised to The reaction was stirred for 5 hours at 9 ° C. Add 20 mL of water, dioxane extraction (2 〇 mL x 3), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, filtered, and concentrated under reduced pressure. The obtained residue was purified to give the title product (H. s. 550.sup.5-(5-cyclopropyl-pyrimidin-2-yl)- 6-[[6-(4-oxasulfonylphenyl)-3-pyridyl Oxymethyl]-3-azabicyclo[3.1.〇]hexane ii 〇 (i6〇mg, white solid), Yield: 47. 9% MS m/z (ESI): 463.1 [M+ 1] !H NMR (400 MHz, CDCh) δ 8.45 (s, 1H), 8.16 (d, 4H), 8. 03(d, 2H), 7. 76(d, 1H), 7.32 (d, 1H), 4. 06 (d, 2H), 3. 99 (d, 2H), 3. 60 (d, 2H), 3. 11 (s, 3H), 1. 81 (s, 2H), 1.74- 1.72 (m, 1H), 1.27-1.25 (m, 1H), 0.93 (d, 2H), 0.60 (d, 2H) 278 95344 201213319 Example 111 (1 friend, 551)-3-(5-cyclopropyl Mouth bit-2-yl)-6-[[6-(3-|1-4-'1 octyl)-3-pyridyl]oxycarbonyl]-3 azabicyclo[3. 1. 0 Hexane

將 6-(3-氟-4-°比°定基）°比淀-3-醇 109a(150mg， 0. 79mmo 1)溶解於5mL况二曱基甲醯胺中，依次加入粗 品[(1兄550-3-(5-環丙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]曱磺酸曱酯 110c(244mg，0.79mmol) 和碳酸鉀（327mg，2.37mmol)，升至80°C攪拌反應12小時。 反應液減壓濃縮，加入10mL水，用二氯曱烷萃取（15mLx3)， 合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用 矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物得到標題 產物（1皮，55)-3-(5-環丙基响咬-2-基）-6-[ [6-(3-氟-4-0比 啶基）-3-吡啶基]氧曱基]-3氮雜雙環並[3. 1. 〇]己烷11〇 (150mg，淡黃色固體），產率：47.2%。 MS m/z (ESI): 404.1 [M+l] ^ NMR (400 MHz, CDCh) δ 8.49-8.47 (m, 3H), 8. 12 (s, 2H), 7.99 (t, 1H), 7.87 (d, 1H), 7.26 (d, 1H), 4. 03 279 95344 201213319 (d, 2H), 3.96 (d, 2H), 3.57 (d, 2H), 1.77 (s, 2H), 1.69-1.67 (m，1H), 1.25 (m, 1H)，0.89 (d，2H)，0.56 (d, 2H) 實施例112 (1 兄 55)-3-(5-甲基嘧啶一2_基）-6-[[6-(3-氟-4-吡啶 基）_3~°比啶基]氧甲基]-3氮雜雙環並[3. 1. 〇]己烷6-(3-Fluoro-4-° ratio of base) ° is dissolved in 5 mL of dimercaptocarhamamine, and then added to the crude product [(1 brother) 550-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]phosphonium sulfonate 110c (244 mg, 0.79 mmol) and potassium carbonate (327mg, 2.37mmol), the reaction was stirred at 80 ° C for 12 hours. The reaction was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration by pressure, the residue obtained was purified by eluent column chromatography eluting with eluent system A to give the title product (1 pi, 55) -3- (5-cyclopropyl-b- -2- yl)-6-[[6 -(3-Fluoro-4-0-pyridyl)-3-pyridyl]oxyindolyl]-3azabicyclo[3. 1. oxime]hexane 11 〇 (150 mg, pale yellow solid), yield : 47.2% MS m/z (ESI): 404.1 [M+l]^ NMR (400 MHz, CDCh) δ 8.49-8.47 (m, 3H), 8. 12 (s, 2H), 7.99 (t, 1H ), 7.87 (d, 1H), 7.26 (d, 1H), 4. 03 279 95344 201213319 (d, 2H), 3.96 (d, 2H), 3.57 (d, 2H), 1.77 (s, 2H), 1.69 -1.67 (m,1H), 1.25 (m, 1H), 0.89 (d,2H), 0.56 (d, 2H) Example 112 (1 brother 55)-3-(5-methylpyrimidin-2-yl)-6-[[6-(3-fluoro-4-pyridyl)_3~~pyridyl]oxymethyl] -3 azabicyclo[3. 1. oxime] hexane

將6-(3-氟-4-吡啶基）吡啶-3-醇109a(150mg， 〇. 79mmol)溶解於5mL况二甲基甲醯胺中，依次加入粗 品[(1^ 550-3-(5-曱基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇] 馨 己烧-6-基]甲石黃酸甲酯l〇3b(224mg，0. 79mmol)和碳酸卸 (327mg，2. 37ramol)，升至8(TC攪拌反應12小時。反應液 減壓濃縮’加入lOmL水’用二氯曱烷萃取（i5mLx3)，合併 有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用碎膠 管柱色譜法以洗脫劑體系A純化所得殘餘物得到標題產物 (1兄55*)-3-(5-甲基,咬-2-基）-6-[[6-(3-氟-4-'1比。定 基）-3-°比啶基]氧曱基]-3氮雜雙環並[3. 1.0]己烷112 (150mg，淡黃色固體），產率：50. 3%。 MS m/z (ESI): 378.0 [M+l] 280 95344 201213319 ]HNMR (400 MHz, CDCh) ά 8.49-8.47 (m, 3H), 8. 15 (s, 2H), 7.99 (t, 1H), 7.87 (d, 1H), 7.26 (d, 1H), 4.03 (d, 2H)，3.96 (d，2H)，3.58 (d，2H), 2.12 (s, 3H)，1.78 (s, 2H), 1. 25-1.23 (m, 1H) 實施例113 (1足 55^-3-(5-丙基癌咬-2-基）-6-[ [6-(3-氟-4-°比咬 基）-3-°比咬基]氧曱基]_3氮雜雙環並[3. 1.0]己炫6-(3-Fluoro-4-pyridyl)pyridin-3-ol 109a (150 mg, 〇. 79 mmol) was dissolved in 5 mL of dimethylformamide, and the crude product was added sequentially [(1^ 550-3-( 5-decylpyrimidin-2-yl)-3-azabicyclo[3. 1. oxime] eugenol-6-yl]methylglycinate l〇3b (224 mg, 0.79 mmol) and carbonic acid Discharge (327 mg, 2.37 ramol), to 8 (TC stirring reaction for 12 hours. The reaction mixture was concentrated under reduced pressure of &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&&& The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluted eluted eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut 6-(3-Fluoro-4-'1 ratio. benzyl)-3-° ratio pyridine]oxycarbonyl]-3 azabicyclo[3.1.0]hexane 112 (150 mg, pale yellow solid). Rate: 50.3% MS m/z (ESI): 378.0 [M+l] 280 95344 201213319 ]HNMR (400 MHz, CDCh) ά 8.49-8.47 (m, 3H), 8. 15 (s, 2H) , 7.99 (t, 1H), 7.87 (d, 1H), 7.26 (d, 1H), 4.03 (d, 2H), 3.96 (d, 2H), 3.58 (d, 2H), 2.12 (s, 3H), 1.78 (s, 2H), 1. 25-1.23 (m, 1H) Example 113 (1 foot 55^-3-(5-propyl) Carcinoma bite-2-yl)-6-[ [6-(3-fluoro-4-° ratio bite base)-3-° ratio bite base] oxo group]_3 azabicyclo[3.1.0]

第一步 鲁 [(1足550-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並[3. 1· 0]己 烧-6-基]甲醇 將粗品[(1疋5«-3-氮雜雙環並[3. 1 · 0]己烷-6-基] 曱醇7e(566mg，5mmol)溶解於l〇mL况二甲基乙醯胺 中，依次加入2-氣-5-丙基-喷咬（783mg，5mmol)和碳酸卸 (1040mg ’ 7. 50mmol) ’升至140°C攪拌反應4小時。反應 液減壓濃縮’加入20mL水’用乙酸乙酯萃取（2〇mLX3)，合 併有機相，無水硫酸錢乾燥，過濾、，遽液減壓漢縮，用石夕 膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題 95344 281 201213319 產物[(1^ 551)-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並 [3.1.0]己烷-6-基]曱醇113&amp;(0.88 8，黃色固體），產率： 75. 6%。 MS ra/z (ESI)： 234.1 [M+l] 第二步 [(1兄5Λ-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烷-6-基]甲磺酸甲酯 將（1疋55)-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並 ^ [3.1.0]己烷-6-基]甲醇113&amp;(0.88舀，3.77麵〇1)溶解於 10mL無水二氣甲烷中，加入三乙胺（1· ifflL，7. 54则1〇1)， 冰浴下’滴加入甲確醯氣（0. 4mL，5. 66ππηο1)，撥拌反應 0. 5小時。加入30mL水，攪拌30分鐘，水相用二氯甲烷 萃取（20mLxl)，合併有機相，依次用水（i〇mLxl)，飽和氯 化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥，過濾，濾液減 壓濃縮，得到粗品標題產物[(1尤55)-3-(5-丙基嘧啶-2-φ 基）-3-氮雜雙環並[3.1.0]己烷-6-基]曱磺酸曱酯113b (1200mg ’黃色固體）’產率：100%。 _ MS m/z (ESI): 312.1 [M+l] 第三步 (1^&gt;，55|)-3-(5-丙基〇密咬-2-基）-6-[[6-(3-氟-4-°比11定 基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1. 0]己烷 將 6-(3-氟定基）〃比咬-3-醇 i〇9a(100mg， 0. 53mmol)溶解於5mL况yV-二甲基曱醯胺中，依次加入粗 品[(1尤55)-3-(5-丙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 282 95344 201213319 己烧-6-基]曱續酸曱酯ii3b(i64mg，0· 53mmol)和碳酸_ (218mg ’ 1.58imn〇l)，升至8(TC攪拌反應12小時。反應液 減壓濃縮，加入l〇mL水，用二氯甲烷萃取（i5mLx3)，合併 有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠 管柱色譜法以洗脫劑體系A純化所得殘餘物得到標題產物 (1兄55')-3-(5-丙基嘴〇定-2-基）-6-[[6-(3-敗-4：-'11比咬 基）-3-°比啶基]氧曱基]-3氮雜雙環並[3· 1.〇]己烷113 (lOOmg，淺黃色固體），產率：46. 9%。 MS m/z (ESI): 406.1 [M+l] 'H NMR (400 MHz, CDCh) 5 8.51-8.49 (m, 3H), 8. 15 (s, 2H), 7.99 (t, 1H), 7.87 (d, 1H), 7.28 (d, 1H), 4.03 (d, 2H), 3.97(d, 2H), 3. 58 (d, 2H), 2. 39 (t, 2H), 1.78 (s, 2H), 1.56-1.54 (m, 2H), 1.25-1.23 (m, 1H), 0.92 Ct, 3H) 實施例114The first step is Lu [(1 foot 550-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[3.1·0]hexa-6-yl]methanol to crude [[1疋5«-3-Azabicyclo[3. 1 · 0]hexane-6-yl] sterol 7e (566 mg, 5 mmol) was dissolved in 1 mL of dimethyl acetamide, and then added 2- Gas-5-propyl-penetration (783 mg, 5 mmol) and carbonic acid unloading (1040 mg '7.550 mmol) 'When the temperature was raised to 140 ° C, the reaction was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure '20 mL of water' and extracted with ethyl acetate. (2 〇 mL X3), the organic phase was combined, dried over anhydrous sulphuric acid, filtered, and the residue was evaporated to dryness. The residue obtained was purified by eluent column chromatography to afford title product 95344 281 201213319 [ (1^ 551)-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonanol 113 &amp; (0.88 8, yellow solid), Yield: 75.6%. MS ra/z (ESI): 234.1 [M+l] Step 2 [(1 brother 5Λ-3-(5-propylpyrimidin-2-yl)-3-azabicyclo) And [3. 1. 0]Hex-6-yl]methyl methanesulfonate (1疋55)-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[J][3.1 .0]hexane-6-yl]methanol 113 &amp; (0.88 舀, 3.77 〇1) In 10 mL of anhydrous di-methane, add triethylamine (1·ifflL, 7.54, 1〇1), and add amethyst (0.4 mL, 5.66ππηο1) to the ice bath. 0. 5小时。 After adding 30mL of water, stirring for 30 minutes, the aqueous phase was extracted with dichloromethane (20mLxl), the organic phase was combined, washed with water (i〇mLxl), saturated sodium chloride solution (20mLx3), dried over anhydrous magnesium sulfate Filtration and concentration of the filtrate under reduced pressure afforded crude title product [(1,5,5)-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-曱 曱 sulfonate sulfonate 113b (1200 mg 'yellow solid') yield: 100%. _ MS m/z (ESI): 312.1 [M+l] The third step (1^&gt;, 55|)-3 -(5-propylindole-2-yl)-6-[[6-(3-fluoro-4-° ratio 11-decyl)-3-pyridyl]oxymethyl]-3-azabicyclo [3. 1. 0] Hexane 6-(3-fluoro-decyl) hydrazine is dissolved in 5 mL of yV-dimethyl decylamine in the same manner as octa-3-ol i 〇 9a (100 mg, 0.53 mmol). Add the crude [(1 especially 55)-3-(5-propylpyrimidin-2-yl)-3-azabicyclo[3. 1. 0] 282 95344 201213319 hexane-6-yl] hydrazide Ester ii3b (i64mg, 0·53mmol) and carbonated _ ( 218 mg ' 1.58 imn 〇 l), raised to 8 (TC stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. The residue obtained gave the title product (1 br. 55') -3-(5-propyl-n-but-but-2-yl)-6-[[6-(3-----4:-'11 ratio). 3- 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. MS m/z (ESI): 406.1 [M+l] &quot;H NMR (400 MHz, CDCh) 5 8.51-8.49 (m, 3H), 8. 15 (s, 2H), 7.99 (t, 1H), 7.87 (d, 1H), 7.28 (d, 1H), 4.03 (d, 2H), 3.97(d, 2H), 3. 58 (d, 2H), 2. 39 (t, 2H), 1.78 (s, 2H) ), 1.56-1.54 (m, 2H), 1.25-1.23 (m, 1H), 0.92 Ct, 3H) Example 114

(li1?, 55^-3-(5-氯嘧啶-2-基）-6-[[6-(3-氟-4-吼啶基）-3-吡啶基]氧甲基]_3氮雜雙環並[3. 1.0]己烷(li1?, 55^-3-(5-chloropyrimidin-2-yl)-6-[[6-(3-fluoro-4-acridinyl)-3-pyridyl]oxymethyl]_3 aza Bicyclo[3.1.0]hexane

95344 201213319 將6-(3-氟-4-吡啶基）吡啶-3-醇109a(100mg， 0. 53mmol)溶解於5mL况於二曱基曱醯胺中，依次加入粗 品[(1尤5^-3-(5-氣嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己 烧-6-基]曱績酸甲酯l〇4b(160mg，0. 53mmol)和碳酸钟 (218mg，1. 58mmol)，升至80°C攪拌反應16小時。反應液 減壓濃縮，加入10mL水，用乙酸乙酯萃取（15mLx3)，合併 有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠 管柱色譜法以洗脫劑體系A純化所得殘餘物得到標題產物 (1)?，55*)-3-(5-氣鳴咬-2-基）-6-[ [ 6_(3-氣-4-°比β定基）-3-擊 吡啶基]氧甲基]-3氮雜雙環並[3. 1.0]己烷114(160mg， 淡黃色固體），產率：76.4%。 MS m/z (ESI): 398.1 [M+l] !HNMR (400 MHz, CDCh) (5 8.49-8.47 (m, 3H), 8.22 (s, 2H), 7.99 (t, 1H), 7.87 (d, 1H), 7.26 (d, 1H), 4.03 (d, 2H), 3.95 (d, 2H), 3.58 (d, 2H), 1.79 (s, 2H), • 1.23-1.21 (m, 1H) 實施例115 ® 4-[4-[ [(1尤55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1_ 0]己烧-6-基]曱氧基笨基]苯甲酸乙酯95344 201213319 6-(3-Fluoro-4-pyridinyl)pyridin-3-ol 109a (100 mg, 0. 53 mmol) was dissolved in 5 mL of dimethyl decylamine, and the crude product was added sequentially [(1 especially 5^) -3-(5-apyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl ester l〇4b (160 mg, 0.45 mmol) The carbonic acid clock (218 mg, 1.58 mmol) was stirred at 80 ° C for 16 hours. The reaction mixture was evaporated to dryness. The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting from EtOAc EtOAc EtOAc EtOAc EtOAc 6_(3-gas-4-° ratio β-based)-3-pyridylpyridyl]oxymethyl]-3azabicyclo[3.1.0]hexane 114 (160 mg, pale yellow solid), yield: 76.4 %. MS m/z (ESI): 398.1 [M+l].HNMR (400 MHz, CDCh) (5 8.49-8.47 (m, 3H), 8.22 (s, 2H), 7.99 (t, 1H), 7.87 (d , 1H), 7.26 (d, 1H), 4.03 (d, 2H), 3.95 (d, 2H), 3.58 (d, 2H), 1.79 (s, 2H), • 1.23-1.21 (m, 1H) 115 ® 4-[4-[ [(1 especially 55)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1_ 0]hexa-6-yl]oxyl Ethyl benzoate

95344 284 20121331995344 284 201213319

將（1疋55·)-6-[(4-溴苯氧基）曱基]-3-(5-乙基嘧啶2-基）-3-氮雜雙環並[3· 1. 0]己烷 l〇la(i5〇mg，0· 40mmol)， 4-硼酸-苯曱酸乙酯（78mg，0. 40mmol)，二（三苯膦基）二氯 _ 化把（6mS ’ 〇· Olmmol)和三水合碌卸（319mg，1. 20mmol) 溶解於5mL 1，4-二噁烷中，升至i〇(TC攪拌反應12小時。 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系β純化 所得殘餘物，得到標題產物4-[4-[[(1尤5«-3-(5-乙基嘧 啶-2-基）-3-氮雜雙環並[3· 1· 〇]己烷-6-基]曱氧基苯基] 苯曱酸乙酯115(93mg，白色固體），產率：52. 。 MS m/z (ESI): 444.2 [M+l] φ NMR (400 MHz, CDCh) δ 8.19 (s, 2H), 8.13 (d, 2H), 7.62 (d, 2H), 7.57 (d, 2H), 6.99 (d, 2H), 4.43-4.38 (m, 2H), 4. 00-3. 97 (m, 4H), 3. 61-3. 59 (m, 2H) 2 50- 2.45 (m, 2H), 1.77 (s, 2H) , 1.42 (t, 3H), 1.26-1.23 (m, 1H), 1. 19 (t, 3H). 實施例116 4-[4-[[(U5S)-3-(5-乙基鳴咬-2-基氮雜雙環並 [3. 1.0]己烷-6-基]甲氧基苯基]笨曱酸 95344 285 201213319(1疋55·)-6-[(4-Bromophenoxy)indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3·1]] Alkane l〇la (i5〇mg, 0·40mmol), 4-boronic acid-benzoic acid ethyl ester (78mg, 0.40mmol), bis(triphenylphosphino)dichloro-chemical (6mS ' 〇· Olmmol) It was dissolved in 5 mL of 1,4-dioxane and dissolved in 5 mL of 1,4-dioxane. The mixture was stirred for 12 hours. The filtrate was concentrated under reduced pressure and purified by thin layer chromatography. The resulting residue was purified to give the title product 4-[4-[[(1,5,5,3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3·1· 〇]] Ethyl hexyl-6-yl] decyloxyphenyl] phenyl decanoate 115 (93 mg, white solid), yield: 52. MS m/z (ESI): 444.2 [M+l] φ NMR (400 MHz, CDCh) δ 8.19 (s, 2H), 8.13 (d, 2H), 7.62 (d, 2H), 7.57 (d, 2H), 6.99 (d, 2H), 4.43-4.38 (m, 2H), 4 00-3. 97 (m, 4H), 3. 61-3. 59 (m, 2H) 2 50- 2.45 (m, 2H), 1.77 (s, 2H) , 1.42 (t, 3H), 1.26- 1.23 (m, 1H), 1. 19 (t, 3H). Example 116 4-[4-[[(U5S)-3-(5-ethylheptin-2-ylazabicyclo[3. 1.0]hexane-6-yl]methoxyphenyl] Yue acid 95344 285 201 213 319

將4-[4-[[(1尤550-3-(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3. 1. 0]己烷-6-基]曱氧基苯基]苯甲酸乙酯115 (50mg ’ 0. 13mmol)溶解於2mL四氫呋喃中，加入2mL 10〇/〇 的氫氧化經水溶液，升至5(TC攪拌反應4小時。加入2roL2M 的鹽酸，用乙酸乙酯萃取（5mLx3)，合併有機相，無水硫酸 鎂乾燥，過滤，濾液減壓濃縮，用薄層色譜法以展開劑體 φ 系A純化所得殘餘物，得到標題產物4-[4-[[(1尤55&quot;)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烷_6_基]曱 氧基苯基]苯曱酸116(23mg，白色固體），產率：5〇. 〇0/〇。 MS in/z (ESI): 416. 1 [M+l] H NMR (4GG MHz, CDC13) δ 11. 05 (s，iH)，8. 35 (s，2H)， 8.02(d，2H)，7.64 (d，2H)，7.59 (d，2H)，6.99 (d，2H)， 4.25-4.22 (m, 4H), 3.68-3.56 (m, 2H), 2.78-2.73 (m, 2H), 1.97 (s, 2H), 1.62-1.59 (m, 1H), 1.29 (t, 3H). 實施例117 95344 286 201213319 (1尤5iS)-6-[ [6-(4-m甲石黃酿基苯基）-3-°比。定基]氧曱基] -3-氮雜雙環[3. 1. 0]己烷-3-曱酸異丙酯4-[4-[[(1) 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]decyloxy Ethyl phenyl] benzoate 115 (50 mg '0.13 mmol) was dissolved in 2 mL of tetrahydrofuran, 2 mL of 10 〇 / 〇 NaOH aqueous solution was added, and the temperature was raised to 5 (TC stirring reaction for 4 hours. 2 roL 2 M hydrochloric acid was added, with acetic acid The ethyl ester was extracted (5 mL×3), and the combined organics were evaporated, evaporated, evaporated, evaporated, evaporated, evaporated (1 especially 55&quot;)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇]hexane_6_yl]decyloxyphenyl]benzoic acid 116 (23 mg, white solid), Yield: 5 〇. 〇0/〇. MS in /z (ESI): 416. 1 [M+l] H NMR (4GG MHz, CDC13) δ 11. 05 (s, iH), 8.35 (s, 2H), 8.02 (d, 2H), 7.64 (d, 2H), 7.59 (d, 2H), 6.99 (d, 2H), 4.25-4.22 (m, 4H), 3.68 -3.56 (m, 2H), 2.78-2.73 (m, 2H), 1.97 (s, 2H), 1.62-1.59 (m, 1H), 1.29 (t, 3H). Example 117 95344 286 201213319 (1 especially 5iS )-6-[ [6-(4-mmethytylphenyl)-3-° ratio. Alkyl] oxo] 3-Azabicyclo[3.1.0]hexane-3-indole isopropyl ester

第一步 (1疋55)-6-(羥曱基）-3-氮雜雙環並[3. 1. 0]己烧-3-甲酸 異丙酯 將粗品[(1及，550-3-氮雜雙環並[3· 1. 〇]己烷-6-基] φ 甲醇7e(650mg，5. 70mmol)溶解於15mL吡啶中，加入氯甲 酸異丙酯（0· 7mL，5. 70mmol)，攪拌反應4小時。加入50mL 水，用乙酸乙酯萃取（30mLx3)，合併有機相，無水硫酸鎂 乾燥，過濾’濾液減壓濃縮，得到標題產物（1尤550-6-(羥 曱基）-3-氮雜雙環並[3. 1. 0]己院-3-曱酸異丙酯117a (0· 99g，黃色液體），產率：95. 0%。 MS ra/z (ESI): 200. 1 [M+l] 第二步 (1疋55)-6-(甲磺醯基氧曱基）-3-氮雜雙環並[3. i. 〇]己烷 287 95344 201213319 -3_甲酸異丙酯 將（liP，55)-6-(羥曱基）-3-氮雜雙環並[3. 1. 〇]己烷 -3-曱酸異丙酯117a(0. 96 g，4. 80mmol)溶解於i5mL無水 二氣曱烷中’加入三乙胺（2mL，14. 40mmol)，滴加入甲磺 醯氯（0. 6mL，7. 20mmol)，擾拌反應12小時。加入飽和碳 酸氫鈉溶液30mL，二氯曱烷萃取（10mLx3)，合併有機相， 依次用水（20mLx3)，飽和氯化鈉溶液洗務（20mLx3)，無水 硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 ^ (1疋5«-6-(甲磺醯基氧甲基）-3-氮雜雙環並[3. 1,〇]己烧鲁 -3-甲酸異丙酯117b(1300mg，黃色液體），產率：97 〇%。 MS m/z (ESI): 278.0 [M+l] 第三步 (1足55*)-6-[ [6-(4-m甲續醯基苯基）-3-n比π定基]氧甲 基]-3-氮雜雙環[3. 1. 0]己烷-3-曱酸異丙酿 將6-(4-曱磺醯基苯基）吡啶_3-醇48e(249mg，lmmQl；) # 溶解於12乩况於二甲基曱醯胺中，依次加入粗品 (1疋55)-6-(甲磺醯基氧甲基）_3_氮雜雙環並[3· i 〇]己俨 _ 3甲酸異丙酯ll7b(1277mg，lmmol)和碳酸卸（276mg， ，升至80。(：攪拌反應12小時。加入1〇虬水，g用乙 酸乙醋萃取（2〇mLx2)，合併有機相，無水硫酸納乾燥，過 濾，濾液減壓濃縮，用矽膠薄層色譜法以洗脫劑體系A矣° 化所得殘餘物得到標題產物（1疋551)_6〜[[6_(4_m曱磺職純 基笨基）—3_°比啶基]氧甲基]—3-氮雜雙環[3. 1.0]己燒 曱酸異丙酯117(150mg，淺黃色固體），產率：35 〇%。 95344 288 201213319 MS m/z (ESI): 431.1 [M+l] !H NMR (400 MHz, CDCh) δ 8. 40 (d, 1H), 8. 15-8. 12 (m, 2H), 8.02-8.00 (m, 2H), 7.74-7.72 (m, 1H), 7.31-7.29 (m, 1H), 4.93-4.86 (m, 1H), 4.06-3.93 (m, 2H), 3.76-3.66 (m, 2H), 3.47-3.41 (m, 2H), 3.08 (s, 3H), 1.63 (s, 2H), 1.25-1.19 (m, 6H), 1.18-1.15 (m, 1H) 實施例118 5-[(1尤5«-6-[[4-(3-氟-4-曱亞磺醯基-苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異丙基-1，2, 4- 噁二吐The first step (1疋55)-6-(hydroxyindole)-3-azabicyclo[3.1.0]hexa- -3-carboxylic acid isopropyl ester will be crude [(1 and, 550-3- Azabicyclo[3·1·〇]hexane-6-yl] φ Methanol 7e (650 mg, 5.70 mmol) was dissolved in 15 mL of pyridine, and isopropyl chloroformate (0.7 mL, 5.70 mmol) was added. The reaction was stirred for 4 hours, 50 mL of water was added, and ethyl acetate (30 mL EtOAc) was evaporated. 3-Azabicyclo[3. 1. 0] hexyl-3- decanoate 117a (0·99 g, yellow liquid), yield: 95. 0%. MS ra/z (ESI): 200 . 1 [M+l] The second step (1疋55)-6-(methylsulfonyloxyindolyl)-3-azabicyclo[3.i. 〇]hexane 287 95344 201213319 -3_carboxylic acid Isopropyl ester (liP, 55)-6-(hydroxyindole)-3-azabicyclo[3. 1. oxime]hexane-3-decanoate 117a (0. 96 g, 4. 80 mmol) was dissolved in i5 mL of anhydrous dioxane. Add triethylamine (2 mL, 14.40 mmol), add methanesulfonium chloride (0.6 mL, 7.20 mmol) dropwise, and stir the reaction for 12 hours. Add saturated hydrogen carbonate. Sodium solution 30mL, two The decane was extracted (10 mL×3), and the organic phase was combined, washed with water (20 mL×3), EtOAc (EtOAc) -6-(Methanesulfonyloxymethyl)-3-azabicyclo[3. 1, 〇] hexane ruthenium-3-carboxylic acid isopropyl ester 117b (1300 mg, yellow liquid), yield: 97 〇% MS m/z (ESI): 278.0 [M+l] The third step (1 foot 55*)-6-[ [6-(4-m-methyl-decylphenyl)-3-n ratio π-based] Oxymethyl]-3-azabicyclo[3.1.0]hexane-3-furic acid isopropyl 6-(4-oxasulfonylphenyl)pyridine-3-ol 48e (249 mg, lmmQl ;) # dissolve in 12 于 in dimethyl decylamine, add the crude (1疋55)-6-(methylsulfonyloxymethyl)_3_azabicyclo[3·i 〇]俨 _ 3 isopropyl formate ll7b (1277 mg, 1 mmol) and carbonic acid unloaded (276 mg, to 80. (: stirring reaction for 12 hours. Add 1 〇虬 water, g with ethyl acetate extraction (2 〇 mL x 2), combined The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and the residue obtained by the eluent thin layer chromatography using the eluent system A 得到Product (1疋551)_6~[[6_(4_m曱) is a benzyl group] Ester 117 (150 mg, pale yellow solid), yield: 5%. 95344 288 201213319 MS m/z (ESI): 431.1 [M+l] !H NMR (400 MHz, CDCh) δ 8. 40 (d, 1H), 8. 15-8. 12 (m, 2H), 8.02 -8.00 (m, 2H), 7.74-7.72 (m, 1H), 7.31-7.29 (m, 1H), 4.93-4.86 (m, 1H), 4.06-3.93 (m, 2H), 3.76-3.66 (m, (H, 2H) 1 especially 5«-6-[[4-(3-fluoro-4-indolizinyl-phenyl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane-3 -yl]-3-isopropyl-1,2,4-dioxin

將4-(3-氟-4-曱基亞確酿基-莩基）苯紛96c(50mg， 0. 20mmol)溶解於5mL况於二曱基曱酿胺中，依次加入粗 品[[(1尤55^-3-(3-異丙基-1，2, 4--B惡二嗤-5-基）-3-氮雜 雙環並[3· 1. 0]己烧-6-基]曱基績酸曱醋48c(60mg， 0· 20mmol)和碳酸铯（130mg，0· 42mmol)，升至 ll〇°C 攪拌 反應4小時。加入10mL水’用乙酸乙酯萃取（2〇mLx2)，合 289 95344 201213319 併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄 層色5眷法以展開劑體系A純化所得殘餘物得到標題產物 5-[(1疋55')-6-[[4-(3-氟-4-曱亞磺醯基-苯基）苯氧基]甲 基]_3-氮雜雙環並[3. 1· 〇]己烧-3-基]-3-異丙基_i，2, 4- 噁二唑118(10mg，白色固體），產率：15. 〇〇/0。 MS m/z (ESI): 456.2 [M+l] iNMRMOOMHz，CDCl〇 (5 7. 90-7. 88 (m，1H), 7. 58-7.52 (m, 3H), 7.31-7.27 (m, 1H), 6.98-6.96 (m, 2H), 3.98-修 3.94 (m, 4H), 3.76-3.74 (m, 2H), 2.98-2.96 (in, 1H), 2.87 (s, 3H), 1.83 (s, 2H), 1.34-1.32 (m, 6H), 1.26-1.24 (m, 1H) 實施例119 (IT?, 55^-6-[[6-(5-甲磺醯基吲哚啉-1-基）嘧啶-4-基]胺 基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯4-(3-Fluoro-4-indolyl-furanyl-fluorenyl)benzene 96c (50mg, 0.20mmol) was dissolved in 5mL of dimercaptoamine, and the crude product [[(1) Especially 55^-3-(3-isopropyl-1,2,4--Boxadiazin-5-yl)-3-azabicyclo[3·1]]hexa-6-yl]曱基绩酸曱 vinegar 48c (60mg, 0·20mmol) and cesium carbonate (130mg, 0·42mmol), raised to ll ° ° C stirred reaction for 4 hours. Add 10mL water 'extracted with ethyl acetate (2 〇 mLx2) 289 95344 201213319 and the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 6-[[4-(3-Fluoro-4-indolylsulfonyl-phenyl)phenoxy]methyl]_3-azabicyclo[3. 1·〇]hexan-3-yl]- 1-isopropyl-i,2,4-oxadiazole 118 (10 mg, white solid), yield: 15. 〇〇/0. MS m/z (ESI): 456.2 [M+l] iNMRMOOMHz, CDCl 〇(5 7. 90-7. 88 (m,1H), 7. 58-7.52 (m, 3H), 7.31-7.27 (m, 1H), 6.98-6.96 (m, 2H), 3.98-repair 3.94 ( m, 4H), 3.76-3.74 (m, 2H), 2.98-2.96 (in, 1H), 2.87 (s, 3H), 1.83 (s, 2H), 1.34-1.32 ( m, 6H), 1.26-1.24 (m, 1H) Example 119 (IT?, 55^-6-[[6-(5-methylsulfonylpurolin-1-yl)pyrimidin-4-yl] Amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

290 95344 201213319 (1: 55)-3-氮雜雙環並[3. 1. 〇]己烷-6_胺 將[(1兄550-3-苄基-3-氮雜雙環並[3. 1. 〇]己烷-6-硝基119a(5. 50g ’ 25· 20mmol)溶解於i〇〇mL曱醇中，依次 加入氫氧化鈀（lOOOmg ’ 10%)，氫化反應36小時。過濾， 減壓濃縮濾液’得到粗品標題產物（1疋5^)-3-氮雜雙環並 [3. 1 · 0]己烧_6_胺119b( 1. 70 g，無色油狀物），產物不經 純化直接進行下一步反應。 MS m/z (ESI): 141.2 [M+42] • 第二步 (1无，55^-6-(胺基）-3-氮雜雙環並[3. i. 〇]己烧_3-竣酸第 三丁酯 將（1兄550-3-氮雜雙環並[3. 1.0]己烷-6_胺U9b (1.70运’17.3〇111111〇1)溶解於6〇11^曱苯中，加入苯甲醛（2.50 g ’ 25. 40mmol)，升溫130°C攪拌反應3小時。加入二碳酸 二第三丁酯（3. 80g，17. 30mmol) ’攪拌反應12小時。反應 液濃縮，加入10mL飽和硫酸氫鈉溶液，攪拌反應〇. 5小時 _ 後，加入5mL 1M的氫氧化鈉溶液，二氯曱烷萃取（2〇mLx2), 合併有機相’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用 矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標 題產物（1^55)-6-(胺基）-3-氮雜雙環並[3·ι 〇]己尸3 羧酸第三丁酯119c(140 g，黃色固體），產率：5〇 7%。 MS m/z (ESI): 199. 1 [M+l] 第三步 痛咬-4-基）-5-甲續酿基-〇弓卜朵琳 * 95344 291 201213319 將5-甲續醯基-α弓卜朵琳1 i9d(210mg，1. 06 mol)，氫 化納（64mg，1. 6〇随0〇和 4, 6-二氣嘧啶（313mg，2. lOmmol) 溶解於lOmL四氫呋喃中’室溫攪拌反應4小時。加入2〇乩 水，乙酸乙酯萃取（20inLx2) ’合併有機相，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮’用矽膠管柱色譜法以洗脫劑體 系A純化所得殘餘物，得到標題產物i-(6_氣定_4一 基）-5-曱續醯基-吲哚琳119e(300mg，黃色固體），產率： 90.9%。 ^ MS m/z (ESI): 310.0 [M+l] · 第四步 (1尤55)-6-1^ [6-(5-甲績醯基°引°朵琳-1-基）痛咬-4-基]胺 基]-3-氮雜雙環並[3. 1_ 0]己烷-3-羧酸第三丁酯 將（1尤550-6-(胺基）-3-氮雜雙環並[3.1. 0]己烷-3-綾酸第三丁酯119c(280mg，0. 90mmol)溶解於5mL况二 甲基甲酼胺中，依次加入1-(6-氯，咬-4-基）-5-曱確酿基 •-吲哚琳 119e(140mg，0. 71mmol)和碳酸鉀（250mg， 1. 80mmol)，升至80°C攪拌反應3小時。加入20mL水，用着 乙酸乙酯萃取（20mLx2)，合併有機相，無水硫酸鈉乾燥， 過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A 純化所得殘餘物，得到標題產物（1兄5«-6-[ [6-(5-甲確醯 基吲哚啉-1-基）嘧啶-4-基]胺基]-3-氮雜雙環並[3. 1.〇] 己烷-3-羧酸第三丁酯119(70mg，白色固體），產率：21.〇%。 MS m/z (ESI): 472.2 [M+l] Ή NMR (400 MHz, CDCh) δ 8.58 (d, 1H), 8.32 (s, 1H), 95344 292 201213319 7.79-7.72 (m, 2H), 5.78 (s, 1H), 4.12 (t, 2H), 3.76 (d, 1H), 3.65 (d, 1H), 3.52-3.46 (m, 2H), 3.34-3.30 (m, 2H), 3.03 (s, 3H), 2.34 (s, 1H), 1.85 (d, 1H), 1.46-1.41 (in, 10H) 實施例120 (1足55^-6-[乙基-[6-(5-甲續醯基吲嗓琳一基）嘴咬_4_ 基]胺基]-3-氮雜雙環並[3. 1. 0]己燒-3-叛酸第三丁醋290 95344 201213319 (1: 55)-3-Azabicyclo[3. 1. 〇]hexane-6-amine will [(1 brother 550-3-benzyl-3-azabicyclo[3. 1 〇]hexane-6-nitro119a (5. 50g '25·20mmol) was dissolved in i〇〇mL sterol, palladium hydroxide (100 mg '10%) was added successively, hydrogenation reaction for 36 hours. Filtration, subtraction Concentration of the filtrate to give the crude title product (1疋5^)-3- azabicyclo[3. 1 · 0]hexane _6_amine 119b ( 1. 70 g, colorless oil) Purification was carried out directly to the next reaction. MS m/z (ESI): 141.2 [M+42] • The second step (1 none, 55^-6-(amino)-3-azabicyclo[3. 〇] 烧烧_3- decyl citrate will dissolve (1 brother 550-3-azabicyclo[3.1.0]hexane-6-amine U9b (1.70 运 '17.3〇111111〇1) in 6 To the benzene, add benzaldehyde (2.50 g '25.40 mmol), stir the reaction at 130 ° C for 3 hours, add ditributyl dicarbonate (3.80 g, 17.30 mmol) and stir the reaction for 12 hours. The reaction solution was concentrated, 10 mL of saturated sodium hydrogen sulfate solution was added, and the reaction was stirred for 5 hours. Then, 5 mL of 1 M sodium hydroxide solution was added, and dichloromethane was extracted (2 mL). The title compound (1^55)-6-(amino group) was obtained by chromatography. -3-Azabicyclo[3·ι 〇] cadaver 3 carboxylic acid tert-butyl ester 119c (140 g, yellow solid), yield: 5 〇 7% MS m/z (ESI): 199. 1 [M+l] The third step is bite-4-base)-5-A continued brewing base-〇弓布多琳* 95344 291 201213319 5-A continued 醯基-α弓卜朵琳1 i9d (210mg 1. 06 mol), sodium hydride (64 mg, 1.6 〇 with 0 〇 and 4, 6-di-pyrimidine (313 mg, 2. 10 mmol) dissolved in 10 mL of tetrahydrofuran 'Stirring reaction at room temperature for 4 hours. Add 2 〇 Hydrophobic, ethyl acetate extraction (20 inLx2) 'The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system A to give the title product i-( 6_气定_4一基)-5-曱 continued 醯-吲哚 119 119e (300 mg, yellow solid), yield: 90.9%. ^ MS m/z (ESI): 310.0 [M+l] The fourth step (1 especially 55)-6-1^ [6-(5-A performance 醯基°引°朵琳-1-基) pain Butyl-4-yl]amino]-3-azabicyclo[3. 1_ 0]hexane-3-carboxylic acid tert-butyl ester (1 especially 550-6-(amino)-3-aza Bicyclo[3.1. 0]hexane-3-decanoate tert-butyl ester 119c (280 mg, 0.90 mmol) was dissolved in 5 mL of dimethylformamide, followed by 1-(6-chloro, bite-4 -Base) -5- 酿 酿 • 吲哚 吲哚 119 119 119 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 119 119 119 119 119 119 119 119 119 119 119 119 。 。 。 。 。 After adding 20 mL of water and extracting with ethyl acetate (20 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give the title product. (1 brother 5«-6-[ [6-(5-(a)-indolyl phthalolin-1-yl)pyrimidin-4-yl]amino]-3-azabicyclo[3. 1.〇] Hexane-3-carboxylic acid tert-butyl ester 119 (70 mg, white solid), yield: 21.%. MS m/z (ESI): 472.2 [M+l] NMR (400 MHz, CDCh) δ 8.58 (d, 1H), 8.32 (s, 1H), 95344 292 201213319 7.79-7.72 (m, 2H), 5.78 (s, 1H), 4.12 (t, 2H), 3.76 (d, 1H), 3.65 (d , 1H), 3.52-3.46 (m, 2H), 3.34-3.30 (m, 2H), 3.03 (s, 3H), 2.34 (s, 1H), 1.85 (d, 1H), 1.46-1.41 (in, 10H Example 120 (1 foot 55^-6-[ethyl-[6-(5-methyl- 醯 醯 吲嗓 一 ))) mouth bite _4_ yl]amino]-3-azabicyclo[3] 1. 0] burned -3- retinoic acid third vinegar

將（17?，550-6-[ [6-(5-甲礦酿基吲η朵琳一基）β密咬 -4-基]胺基]-3-氮雜雙環並[3.1· 0]己烷-3-羧酸第三丁醋 119(60mg ’ 0· 13mmol)溶解於5mL况#-二曱基甲酿胺中， 加入60%氫化鈉（26mg，0· 65mmol)，攪拌反應〇. 5小時， 再加入碘乙烷（〇· lmL，0. 26mmol)，攪拌反應4小時。加入 5mL水，用二氯甲烷萃取（5mLx2)，合併有機相，用飽和氣 化鈉溶液洗滌（5mL&gt;&lt;l)，無水硫酸鈉乾燥，過濾.，濾液減壓 濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得 到標題產物（1尤55)-6-[乙基-[6-(5-f磺醯基呷哚啉 95344 293 201213319 基）嘧咬-4-基]胺基]-3-氮雜雙環並[3. 1. 〇]己烧-3-叛酸 第三丁酯120(60mg，淡黃色固體）’產率·· 90.0%。 MS m/z (ESI): 500.2 [M+l] !Η NMR (400 MHz, CDCb) δ 8.54 (d, 1H), 8. 43 (s, 1H), 7.78-7.74 (m, 2H), 5.92 (s, 1H), 4.10 (t, 2H), 3.91-3.90 (m, 1H), 3.76 (d, 1H), 3.65 (d, 1H), 3.58-3.55 (m, 3H), 3. 29(q, 2H), 3. 02 (s, 3H), 2.30 (s, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.47 (s, 9H), 1.18 (t, 3H) 鲁 實施例121 (ld6-[[2,6-二氟-4-(5-甲罐醢基比唆基）苯氧基] 甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3·丨·0]己烷Will (17?, 550-6-[ [6-(5-(5-(5-(5-))]]]]]]]]]] Hexane-3-carboxylic acid terpene vinegar 119 (60 mg '0·13 mmol) was dissolved in 5 mL of #-dimercaptoamine, 60% sodium hydride (26 mg, 0·65 mmol) was added, and the reaction was stirred. After 5 hours, additional ethyl iodide (〇·lmL, 0.25 mmol) was added, and the reaction was stirred for 4 hours. 5 mL of water was added and extracted with dichloromethane (5 mL×2), and the organic phases were combined and washed with saturated sodium carbonate solution (5 mL &gt;&lt;l), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to purified to afford titled product (1 s. -(5-fsulfonylporphyrin 95344 293 201213319 yl) pyrimidine-4-yl]amino]-3-azabicyclo[3. 1. 〇] hexane-3 retinoic acid Ester 120 (60 mg, pale yellow solid) <yield············································· 43 (s, 1H), 7.78-7.74 (m, 2H), 5.92 (s, 1H), 4.10 (t, 2H), 3.91-3.90 (m, 1H), 3.76 (d, 1H), 3.65 (d, 1H), 3.58-3.55 (m, 3H), 3. 29(q, 2 H), 3. 02 (s, 3H), 2.30 (s, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.47 (s, 9H), 1.18 (t, 3H) Lu Example 121 (ld6-[[2,6-Difluoro-4-(5-methylcansylpyridyl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3-nitrogen Heterobicyclo[3·丨·0]hexane

第一步 (1尤 5«-6-[[2, 6-二氟-4-(4, 4, 5, 5-四甲基一1，3, 2_二氧 代硼酸-2-基）笨氧基]曱基]_3_(5-乙基嘧啶-2-基）-3-氮 雜雙環並[3. 1. 〇]己烧 95344 294 201213319 將[(1尤55·)-6-[(4-溴-2, 6-二氟-苯氧基）曱基]-3-(5-乙基喊淀-2-基）-3__氮雜雙環並[3.丨.〇]己烷8a(85mg， 〇· 15 mol) ’ 聯硼酸頻那醇酯（93mg，0. 36mmol)和 1，1，-二（二苯膦基）二茂鐵二氯化鈀（18mg，〇. 〇2mm〇1)溶解於 5此二曱基亞硬中’再加入醋酸鉀（72mg，0. 73mmol)，升 溫110 C擾拌反應6小時。加入2〇mL水，乙酸乙酯萃取 (20mLx2)，合併有機相，無水硫酸鎂乾燥，過濾，濾液減 壓濃縮，得到標題產物（丨足二氟_4_ φ (4, 4, 5, 5_四曱基-1，3, 2-二氧代硼酸-2-基）苯氧基]甲基] -3-(5-乙基嘴咬-2-基）-3-氮雜雙環並[3. 1. 〇]己烷121a (70mg，白色固體），產率：67. 1%。 第二步 (U 5«-6-[[2, 6-二氟-4-(5-甲磺醯基-2-吼啶基）苯氧基] 甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷 將（1尤 5«-6-[ [2, 6-二氟-4-（4, 4, 5, 5-四曱基 鲁 —1，3, 2-二氧代硼酸-2-基）苯氧基]甲基]-3-(5-乙基&quot;密咬 -2-基）-3-氣雜雙環並[3. 1. 〇]己烧 121a(70mg，0. 15mraol) 溶解於5mL术於二甲基甲醯胺中，再加入碳酸鉋（i5〇mg， 0.46mmol)，2-溴-5-甲磺醯基-吡啶（36mg，0. 15mmol)及 1，1 -二（二苯膦基）二戊鐵二氣化把（12mg，0. 02mmol)，， 升溫至110°C授拌反應4小時。加入2〇mL水，乙酸乙酯萃 取（20mLx2) ’合併有機相’無水硫酸鎂乾燥，過濾，濾液 減壓濃縮，用薄層色譜法以展開劑體系B純化所得殘餘 物’得到標題產物（1尤55·)-6-[[2,6-二氟-4-(5-甲磺醯基 295 95344 201213319 產率·· 13. 5% -2-錢基）苯氧基]甲基]-3-(5 乂基錢I基）_3—氣雜 雙環並[3· 1. 0]己烷121(10mg，白色固體） ’ MS m/z (ESI): 487.2 [M+l] ’HNMRUOOMHz，CDC13) 5 9. 17-9.16(m，1H) 8 29_8 28 (m，1H)，8. 27 (s，2H)，7. 84-7. 82 (m，1H), 7 7〇一γ 67 (ra，2H)，4.19-4.17(m，2H)，3.88~3.85(m，2H)，3 55_ 3.52 (m, 2H), 3.15 (s, 3H), 2.48-2.42 (m, 2H), l 71 (s, 2H), 1.26 (s, 1H), 1.19-1.15 (m, 3H)The first step (1 especially 5«-6-[[2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxoboronic acid-2-yl) Stupid oxy] fluorenyl]_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇] hexane 95344 294 201213319 will [(1 especially 55·)-6-[ (4-Bromo-2,6-difluoro-phenoxy)indolyl]-3-(5-ethyl-oxo-2-yl)-3__azabicyclo[3.丨.〇]hexane 8a (85 mg, 〇·15 mol) 'Binnaborate boranoate (93 mg, 0.36 mmol) and 1,1,-bis(diphenylphosphino)ferrocene palladium dichloride (18 mg, 〇. 〇 2 mm 〇1) Dissolved in 5 dimethyl sulfoxides, then added potassium acetate (72 mg, 0.73 mmol), and stirred at 110 C for 6 hours. Add 2 mL of water, extract with ethyl acetate (20 mL×2), and combine The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to give the title product (d.d. 2-yl)phenoxy]methyl]-3-(5-ethyl-n-butyl-2-yl)-3-azabicyclo[3. 1. oxime]hexane 121a (70 mg, white solid) Yield: 67.1%. The second step (U 5 «-6-[[2,6-difluoro-4-(5-methylsulfonyl-2-acridinyl)phenoxy]] 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane will (1 especially 5«-6-[[2,6-difluoro- 4-(4, 4, 5, 5-tetradecyl-l,3,2-dioxoboronic acid-2-yl)phenoxy]methyl]-3-(5-ethyl&quot; -2-yl)-3-heterobicyclo[3. 1. 〇] hexane 121a (70mg, 0.15mraol) dissolved in 5mL in dimethylformamide, then added carbonic acid planing (i5〇mg , 0.46 mmol), 2-bromo-5-methanesulfonyl-pyridine (36 mg, 0.15 mmol) and 1,1-di(diphenylphosphino)dipentane di-gasification (12 mg, 0.02 mmol) The temperature was raised to 110 ° C and the reaction was stirred for 4 hours. 2 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue obtained by the solvent system B to give the title product (1 y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y 2-Mecyl)phenoxy]methyl]-3-(5-mercapto-l-l-yl)_3-heterobicyclo[3·1.0]hexane 121 (10 mg, white solid) ' MS m/z (ESI): 487.2 [M+l] 'HNMRUOOMHz, CDC13) 5 9. 17-9.16(m,1 H) 8 29_8 28 (m, 1H), 8. 27 (s, 2H), 7. 84-7. 82 (m, 1H), 7 7〇 γ 67 (ra, 2H), 4.19-4.17 (m , 2H), 3.88~3.85(m, 2H), 3 55_ 3.52 (m, 2H), 3.15 (s, 3H), 2.48-2.42 (m, 2H), l 71 (s, 2H), 1.26 (s, 1H), 1.19-1.15 (m, 3H)

實施例122 (1^ 55〇-6-[[4-(l -曱續酿基-3, 6-二氫-2皮-«比u定_4一基）苯 氧基]甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. h 〇] 己烷Example 122 (1^55〇-6-[[4-(l - 曱 酿 -3 -3,6-dihydro-2 pi-« u 定 _4 yl) phenoxy]methyl]- 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.h 〇] hexane

第一步 4-U-羥基〜苯基）_3, 6_二氫_2及-吡啶-1-羧酸第三丁酯 296 95344 201213319 將 4-溴-苯盼 122a(519mg，3mmol)和 4-(4, 4, 5, 5-四 甲基-1，3, 2-二氧硼酸醋-2-基）-3, 6-二氳-2皮-〇比嘴&gt;1-叛 酸第三丁酯（973 g’3. 15mmol)溶解於50mL乙醇和甲苯（v/v =1:4)混合溶劑中，依次加入飽和碳酸鈉溶液（3. 3mL， 6. 60mmol)和二茂鐵二氣化鈀（220mg，0· 30mmol)，升溫至 100°C，擾拌反應2小時。加入50mL水，乙酸乙g旨萃取 (50mLx3) ’合併有機相，依次用水（50mLxl)，飽和氯化納 溶液洗滌（5QmLxl)，無水硫酸鎂乾燥，過濾，濾液減壓濃 φ 縮’用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物， 得到標題產物4-(4-經基-苯基）-3, 6-二氫-2及-°比咬-丨〜叛 酸第三丁酯122b(0. 60mg，白色固體），產率：73.20/〇。 MS m/z (ESI): 274.3 [M-l] 第二步 4-[4-[ [(1尤55^-3-(5-乙基嘴咬-2-基）-3-氮雜雙環並 [3. 1. 0]己烧-6-基]甲氧基]-苯基]-3, 6-二氫-2及比咬 羧酸第三丁酯 馨 將4-(4_經基-苯基）-3, 二氫-2及-°比咬-1-羧酸第三 丁酯122b(412mg，1.50mmol)溶解於i〇mL况趴二甲基甲 醯胺中，加入[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3.1.〇]己烷-6-基]曱磺酸甲酯78(4〇411^，1.36111111〇1) 和碳酸鉀（563mg，4. 08_〇1)，升溫至1〇〇。〇，攪拌反應3 小時。加入50mL水’乙酸乙酯萃取（5〇mLx4)，合併有機相， 依次用水（50mLxl) ’飽和氣化鈉溶液洗滌（50mLxi)，無水 硫酸鎂乾燥’過濾，濾液減壓濃縮，用矽膠管柱色譜法以 95344 297 201213319 洗脫劑體系B純化所得殘餘物，得到標題產物4-[4-[[(1尤55&quot;)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇] 己烧-6-基]曱氧基]-苯基]_3, 6-二氫-2/Γ-η比咬-1-叛酸第 三丁酯122c(467mg，白色固體），產率：79. 2%。 MS m/z (ESI): 477.2 [M+l] 第三步First step 4-U-hydroxy-phenyl)_3,6-dihydro-2 and -pyridine-1-carboxylic acid tert-butyl ester 296 95344 201213319 4-Bromo-benzone 122a (519 mg, 3 mmol) and 4 -(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborate-2-yl)-3,6-diindole-2-bibi mouth&gt;1-remediation Tributyl ester (973 g'3. 15 mmol) was dissolved in 50 mL of a mixed solvent of ethanol and toluene (v/v = 1:4), followed by saturated sodium carbonate solution (3.3 mL, 6.60 mmol) and ferrocene The palladium (220 mg, 0. 30 mmol) was vaporized, the temperature was raised to 100 ° C, and the reaction was stirred for 2 hours. Add 50mL of water, extract with acetic acid (50mLx3) 'The organic phase is combined, washed with water (50mLxl), saturated sodium chloride solution (5QmLxl), dried over anhydrous magnesium sulfate, filtered, and the filtrate is reduced in concentration and reduced by 矽The residue obtained was purified by column chromatography using eluent system B to give the title product 4-(4-carbo-phenyl)-3,6-dihydro-2 and -° ratio bite-oxime to tartrate third Ester 122b (0. 60 mg, white solid). Yield: 73.20. MS m/z (ESI): 274.3 [Ml]. Step 2 4-[4-[[(1,5^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 3. 1. 0] hexyl-6-yl] methoxy]-phenyl]-3,6-dihydro-2 and butyl carboxylic acid tert-butyl phthalate 4-(4- mercapto-benzene Base-3, dihydro-2 and -° ratio bitrate-1-carboxylic acid tert-butyl ester 122b (412 mg, 1.50 mmol) was dissolved in i〇mL condition dimethylformamide, added [(1疋550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.indole]hexane-6-yl]methyl sulfonate 78 (4〇411^, 1.36111111〇1) And potassium carbonate (563 mg, 4. 08_〇1), the temperature was raised to 1 〇〇. 〇, the reaction was stirred for 3 hours. Add 50 mL of water 'ethyl acetate extraction (5 〇 mL x 4), the organic phase was combined, and then water (50 mL×l) 'Saturated sodium sulphate solution (50 mL xi), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc. -[[(1 especially 55&quot;)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. 1. 〇] hexyl-6-yl] decyloxy]-benzene Base]_3,6-dihydro-2/Γ-η ratio bite-1-reactic acid tert-butyl ester 122c (467mg White solid), yield:. 79 2% MS m / z (ESI):. 477.2 [M + l] Step

(1/?，55·)-6-[ [4-(1，2, 3, 6-四氫〇比咬-4-基）苯氧基]甲 基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3· 1. 〇]己烷 將4-[4-[[(1友，550-3-(5-乙基喷唆-2-基）~3-氮雜雙 壤並[3. 1. 0]己烧-6-基]甲氧基]-苯基]-3, 6-二氫比 啶-1-羧酸第三丁酯 122c(450mg，〇· 95mmol)溶解於 l〇mL 二氯甲燒中，加入lmL三氟醋酸，擾拌反應2小時。滴加 1M飽和碳酸鈉溶液至反應液PH為1〇，乙酸乙酯萃取 (50mLx4)，合併有機相，依次用水（50mLxl)，飽和氯化鈉 溶液洗務（50mLxl)，無水硫酸鎮乾燥，過濾、，遽液減塵滚 縮’付到粗品標題產物（1尤55^-6-[ [4-( 1，2, 3，6-四氫π比〇定 -4-基）笨氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3· 1. 〇]己烧122d(396mg，黃色固體），產物不經純化直 接進行下一步反應。 MS m/z (ESI): 377.3 [M+l] 第四步 (1足 5iS)-6-[ [4-(1-甲讀醯基-3, 6-二氫比咬-4-基）苯 氧基]甲基]-3_(5-乙基嘴咬-2-基）-3-氣雜雙環並[3. 1. 0] 己烷 298 95344 201213319 將粗品（1足55)-6-[[4-(1，2, 3, 6-四氫《比啶-4-基）苯 氧基]曱基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0] 己烷122d(356mg，0.94mmol)溶解於10mL二氯曱烷中，加 入二乙胺（287mg，2. 84賴〇 1) ’冰浴下慢慢滴加甲績酿氯 (161mg’ i.41mmol)，〇°C攪拌反應1小時。加入50mL水， 二氯f烷萃取（60mLx4)，合併有機相，依次用水（60mLxl)， 飽和氣化鈉溶液洗滌（60mLxl)，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所 ® 得殘餘物，得到標題產物（1兄55V6-[[4~(1-甲磺醯基 _ -3, 6-二氫-2及-吡啶-4-基）苯氧基]曱基]-3-(5-乙基嘧啶 -2-基）-3-氮雜雙環並[3. 1. 0]己烷122(67mg，白色固體）， 產率：15. 7%。 MS ffl/z (ESI): 455·2 [M+1] lHNMR (400 MHz, CDCh) 5 8.22 (s, 2H), 7.33 (d, 2H), 6.90 (d, 2H), 6.02 (s, 1H), 4.01-3.95 (m, 6H), 3.63 φ (d, 2H), 3. 57-3. 55 (t, 2H), 2. 89 (s, 3H), 2. 67 (s, 2H), 2.53-2.48 (q, 2H), 1.78 (s, 2H), 1.24-1.20 (m, 4H) · 實施例123 5-[(l足5«-6-[[4-(3-氟-4-甲磺醯基-苯基）苯氧基]曱 基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基-1,2,4- 噁二唑(1/?,55·)-6-[ [4-(1,2,3,6-tetrahydroindole than -4-yl)phenoxy]methyl]-3-(5-ethylpyrimidine) -2-yl)-3-azabicyclo[3· 1. 〇]hexane will be 4-[4-[[(1 friend, 550-3-(5-ethyl spur-2-yl)~ 3-Aza-dish and [3.1.0]hexa-6-yl]methoxy]-phenyl]-3,6-dihydroabiridin-1-carboxylic acid tert-butyl ester 122c (450 mg , 〇·95mmol) dissolved in l〇mL of methylene chloride, add 1mL of trifluoroacetic acid, and stir the reaction for 2 hours. Add 1M saturated sodium carbonate solution to the reaction solution pH 1〇, ethyl acetate extraction (50mLx4) The organic phase was combined, washed successively with water (50 mL×l), saturated sodium chloride solution (50 mL×l), dried over anhydrous sulphuric acid, filtered, and sputum dust-reduced and rolled to the crude title product (1 especially 55^-6- [[4-( 1,2, 3,6-tetrahydropi-pyridin-4-yl) phenyloxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-aza Double-ring [3· 1. 〇] hexanes 122d (396mg, yellow solid), the product was taken to the next step without purification. MS m/z (ESI): 377.3 [M+l] Step 4 (1 foot 5iS) )-6-[ [4-(1-methyl-decyl-3,6-dihydropyridin-4-yl)phenoxy]methyl]-3_(5-ethyl-mouth bite-2 -yl)-3-cycloheterobicyclo[3. 1. 0] hexane 298 95344 201213319 The crude product (1 foot 55)-6-[[4-(1,2, 3, 6-tetrahydro) 4-yl)phenoxy]indolyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 122d (356mg, 0.94mmol) dissolved Diethylamine (287 mg, 2.84 lysine 1) was added to 10 mL of dichloromethane. The chloroform (161 mg 'i.41 mmol) was slowly added dropwise under ice-cooling, and the reaction was stirred for 1 hour at 〇 °C. After adding 50 mL of water and dichlorofane extraction (60 mL×4), the organic phase was combined, washed with water (60 mL×l), saturated sodium carbonate solution (60 mL×l), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by eluent system A to give the title product (1 br. 55V6-[[4~(1-methylsulfonyl)--3,6-dihydro-2 and -pyridin-4-yl Phenoxy]indenyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 122 (67 mg, white solid), yield: 15 7% MS ffl/z (ESI): 455·2 [M+1] lHNMR (400 MHz, CDCh) 5 8.22 (s, 2H), 7.33 (d, 2H), 6.90 (d, 2H), 6.02 (s, 1H), 4.01-3.95 (m, 6H), 3.63 φ (d, 2H), 3 57-3. 55 (t, 2H), 2. 89 (s, 3H), 2. 67 (s, 2H), 2.53-2.48 (q, 2H), 1.78 (s, 2H), 1.24-1.20 ( m, 4H) · Example 123 5-[(l-foot 5«-6-[[4-(3-fluoro-4-methylsulfonyl-phenyl)phenoxy]indolyl]-3-aza Bicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole

299 95344 201213319299 95344 201213319

將5-[(1尤5«-6-[[4~(3-氟-4-甲亞磺醯基-苯基）苯 氧基]甲基]-3-氮雜雙環並[3.1.0]己烷-3-基]-3-異丙基 -1，2,4-噁二唑118(5111§，0.0111]11]〇1)溶解於51111况於二曱 基曱醯胺中，加入間氣過氧苯曱酸（5mg，0. 02mmol)，攪拌 反應12小時。加入lOmL飽和亞硫酸溶液，用乙酸乙酯萃 取（10mLx2)，合併有機相，無水硫酸鈉乾燥，過濾，濾液 減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘 物’得到標題產物5-[(1兄5«-6-[[4-(3-氟~4〜曱確醯基-苯基）苯氧基]甲基]-3-氮雜雙環並[3. 1·〇]己烧一3_基]—3一 異丙基-1,2,4-噁二唑123(31^’白色固體），產率：6〇.〇0/〇。 MS m/z (ESI): 472. 1 [M+1] ]HNMR (400 MHz, CDCh) &lt;5 7. 99-7. 97 (ra, 1H), 7 55-7 51 (m，3H)，7.49-7.43(ra，lH)，7.0〇s6.98(m，2H) 3 98-3.85(m，4H)，3.69-3.67 (m，2H)，3.25(s，3H) 2 92- 2.88 (m, 1H), 1.79 (s, 2H), 1*33-1.26 (m, 6H), 1 25 (m, 1H) 實施例124 5-[(1足550-6-1^2, 6-二氟-4_(5-甲續鼴基_2〜0比咬基）苯 氧基]甲基]-3-氮雜雙環並[3.1. 0]已境_3~基]異丙基 -1，2, 4-噁二唑 95344 300 2012133195-[(1 especially 5«-6-[[4~(3-fluoro-4-methylsulfinyl-phenyl)phenoxy]methyl]-3-azabicyclo[3.1.0] ]Hex-3-yl]-3-isopropyl-1,2,4-oxadiazole 118 (5111§, 0.0111]11]〇1) dissolved in 51111 in dimercaptoamine, added m-P-benzoic acid (5 mg, 0.02 mmol), and the reaction was stirred for 12 hr. EtOAc (EtOAc) was evaporated. Concentration, purification of the residue obtained by thin layer chromatography to a solvent system A to give the title product 5-[(1 brother 5«-6-[[4-(3-fluoro~4~曱-decyl-phenyl)) Phenoxy]methyl]-3-azabicyclo[3.1·〇]hexa-3_yl]-3-isopropyl-1,2,4-oxadiazole 123 (31^' white Solid), Yield: 6 〇.〇0/〇 MS m/z (ESI): 472. 1 [M+1] ]HNMR (400 MHz, CDCh) &lt;5 7. 99-7. 97 (ra , 1H), 7 55-7 51 (m, 3H), 7.49-7.43 (ra, lH), 7.0〇s6.98 (m, 2H) 3 98-3.85 (m, 4H), 3.69-3.67 (m, 2H), 3.25(s,3H) 2 92- 2.88 (m, 1H), 1.79 (s, 2H), 1*33-1.26 (m, 6H), 1 25 (m, 1H) Example 124 5-[ (1 foot 550-6-1^2, 6-Difluoro-4_(5-methyl-indenyl 2~0-bito) phenoxy]methyl]-3-azabicyclo[3.0.1] _3~yl]isopropyl -1,2,4-oxadiazole 95344 300 201213319

F h,/-n^nKF h, /-n^nK

第一步 5-[(1疋5«-6-[(4-溴-2,6-二氟-苯氧基）曱基]-3-氮雜雙 環並[3. 1. 0]己院_3_基]_3 -異丙基_1，2, 4_β惡二。坐 將粗品[(1及，5異丙基_1，2，4--σ惡二π坐-5-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]曱基磺酸曱酯48c (1600mg，5. 31mmol)溶解於15mL #，二甲基甲醯胺中， 授拌，加入2, 6-二氟-4-溴-苯盼（1100mg，5. 31mmol)和碳 酸鉋（3460mg，10. 60mmol)，升溫至90°C攪拌反應4小時。 加入100mL水，乙酸乙S旨萃取（80mLx2)，合併有機相，用 水洗務（50mLx2)，無水硫酸鎭乾燥，過遽，爐液減壓濃縮， 用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到 標題產物5-[(1兄5«-6-[(4-溴-2,6-二氟-苯氧基）甲 基]-3-氮雜雙環並[3. 1. 0]己烧-3-基]-3-異丙基-1，2, 4_ 噁二唑124a(1100mg，白色固體），產率：50. 0%。 301 95344 201213319 MS m/z (ESI): 416.1 [M+l] 第二步 5-[(l兄 5«-6-[[2, 6-二氟-4-(4, 4, 5, 5-四甲基-1，3, 2-二 氧代硼酸酯-2-基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己 炫*-3-基]-3-異丙基-1，2, 4-α惡二吐 將5-[(1兄5«-6-[(4-溴-2, 6-二氟-苯氧基）曱基] -3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基-1，2, 4-噁二 唑 124a(1100mg，2. 70 mol)，聯硼酸頻那醇酯（l〇l〇mg， w 3. 90mmol)和1，Γ -二（二苯膦基）二茂鐵二氯化鈀（194mg， 0. 50mmol)溶解於20mL二甲基亞礙中，再加入醋酸鉀 (781mg’7. 80mmol)，升溫110°C攪拌反應6小時。加入50mL 水’乙酸乙酯萃取（50mLx2)，合併有機相，無水硫酸鎂乾 燥’過濾，濾液減壓濃縮，得到標題產物5-[(1疋5«-6-[[2, 6-二氟-4-(4, 4, 5, 5-四甲基-1，3, 2-二氧代棚酸酯-2-基）苯氧基]甲基]-3-氮雜雙環並[3. 1· 0]己烷-3-基]-3-異 .丙基-1，2, 4-噁二唑124b(1200mg，褐色液體），產率：67. 1% MS m/z (ESI): 462.2 [M+l] 第三步 5-[(l/?，55〇-6-[[2, 6-二氟-4-(5-甲磺醯基-2-吡啶基）笨 氧基]曱基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異丙基 -1，2, 4-°惡二°垒 將 5-[(1尤 5幻-6-[[2, 6-二氟-4-(4, 4, 5, 5-四曱基 -1，3, 2-二氧代硼酸酯-2-基）苯氧基]甲基]-3-氮雜雙環並 [3. 1. 0]己烧-3-基]-3-異丙基-1，2, 4-°惡二唾 I24b(400mg， 302 95344 201213319 0. 19mmol)溶解於5mLyV，•二甲基甲醯胺中，再加入碳酸鉋 (848mg ’ 2. 60mmol) ’ 2-漠-5-曱績醯基~ι»比咬（2〇5mg， 0· 86麵〇1)及1，1 -二（二本鱗基）一戊鐵二氣化把（63mg， 0.08ramol)，’升溫至ll〇°c攪拌反應4小時。加入20mL水， 乙酸乙醋萃取（20mLx2)，合併有機相，無水硫酸鎖乾燥， 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系B純化 所得殘餘物，得到標題產物5-[(1亿5«-6-[[2,6-二氟 -4-(5-曱磺醯基-2-吡啶基）苯氧基]甲基]-3-氮雜雙環並 • [3.1.0]己烷-3-基]-3-異丙基-1，2,4-噁二唑124(2〇11^， 白色固體），產率：5. 0%。 MS m/z (ESI): 491.1[M+1] 'H NMR (400 MHz, CDCh) &lt;5 9. 17 (s, 1H), 8.29-8. 27 (m, 1H), 7.85-7.83 (in, 1H), 7.70-7.68 (m, 2H), 4.17-4.16 (ni, 2H), 3.78-3.76 (m, 2H), 3.65-3.63 (m, 2H), 3.15 (s, 3H), 2.90-2.87 (m, 1H), 1.76 (s, 2H), 1.29-1.27 • Cm, 6H), 1. 20-1. 18 (in, 1H) 實施例125 2-曱基-1-[(1兄55·)-6-[[6-（4-甲磺醯基苯基）_3-吼啶基] 氧曱基]-3-氮雜雙環並[3· 1· 〇]己烧基]丙基一2_醇The first step 5-[(1疋5«-6-[(4-bromo-2,6-difluoro-phenoxy)indolyl]-3-azabicyclo[3. 1.]] _3_基]_3 -isopropyl-1,2,4_β dioxin. Sit will be crude [(1 and 5 isopropyl_1,2,4--σ oxa 2 π--5-yl)- 3-Azabicyclo[3.1.0]hexane-6-yl]nonylsulfonate oxime ester 48c (1600 mg, 5.31 mmol) was dissolved in 15 mL of #, dimethylformamide, and mixed, 2 6-Difluoro-4-bromo-benzophenone (1100 mg, 5.31 mmol) and carbonic acid planer (3460 mg, 10.60 mmol), and the mixture was heated to 90 ° C and stirred for 4 hours. Add 100 mL of water, ethyl acetate was extracted ( 80mLx2), the organic phase was combined, washed with water (50mLx2), dried with anhydrous sulphate, dried over EtOAc, EtOAc EtOAc. [(1 brother 5«-6-[(4-bromo-2,6-difluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexa-3-yl] -3-isopropyl-1,2,4-oxadiazole 124a (1100 mg, white solid), yield: 50. 0%. 301 95344 201213319 MS m/z (ESI): 416.1 [M+l] Step 5-[(l brother 5«-6-[[2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxo) Borate-2-yl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexyl*-3-yl]-3-isopropyl-1,2, 4-恶二二吐吐 will be 5-[(1 brother 5«-6-[(4-bromo-2,6-difluoro-phenoxy)indolyl]-3-azabicyclo[3. 1. 0] Hex-3-yl]-3-isopropyl-1,2,4-oxadiazole 124a (1100 mg, 2.70 mol), pinacol borate (l〇l〇mg, w 3. 90 mmol And 1, bis-bis(diphenylphosphino)ferrocene palladium dichloride (194 mg, 0.50 mmol) was dissolved in 20 mL of dimethyl sulphate, then potassium acetate (781 mg '7. 80 mmol) was added, and the temperature was raised. The reaction was stirred at 110 ° C for 6 hours, extracted with 50 mL of EtOAc EtOAc (EtOAc (EtOAc) [[2, 6-Difluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxosuccin-2-yl)phenoxy]methyl]-3 - azabicyclo[3.1]0-hexane-3-yl]-3-iso-propyl-1,2,4-oxadiazole 124b (1200 mg, brown liquid), yield: 67. % MS m/z (ESI): 462.2 [M+l] Step 3 5-[(l/?,55〇-6-[[2,6-difluoro-4-(5-methylsulfonyl)- 2-pyridyl)phenyloxy]indolyl]-3-azapine Cyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-° dioxin will be 5-[(1 especially 5 magic-6-[[2, 6- Difluoro-4-(4,4,5,5-tetradecyl-1,3,2-dioxoborate-2-yl)phenoxy]methyl]-3-azabicyclo[ 3. 1. 0] hexyl-3-yl]-3-isopropyl-1,2,4-° dioxin I24b (400 mg, 302 95344 201213319 0. 19 mmol) dissolved in 5 mL yV, • dimethyl In the guanamine, add the carbonic acid planer (848mg ' 2. 60mmol) ' 2- desert-5- 曱 醯 ~ ~ι» bite (2〇5mg, 0·86面〇1) and 1,1 - two ( Two squaring bases), a ferric pentoxide gasification (63 mg, 0.08 ramol), was heated to ll 〇 °c and stirred for 4 hours. After adding 20 mL of water and ethyl acetate (20 mL×2), the organic phase is combined, dried with anhydrous sulphuric acid, filtered, and the filtrate is concentrated under reduced pressure. 100 million «6-[[2,6-difluoro-4-(5-nonylsulfonyl-2-pyridyl)phenoxy]methyl]-3-azabicyclo[3.1.0 Hex-3-yl]-3-isopropyl-1,2,4-oxadiazole 124 (2〇11^, white solid), yield: 5. 0%. MS m/z (ESI) : 491.1[M+1] 'H NMR (400 MHz, CDCh) &lt;5 9. 17 (s, 1H), 8.29-8. 27 (m, 1H), 7.85-7.83 (in, 1H), 7.70- 7.68 (m, 2H), 4.17-4.16 (ni, 2H), 3.78-3.76 (m, 2H), 3.65-3.63 (m, 2H), 3.15 (s, 3H), 2.90-2.87 (m, 1H), 1.76 (s, 2H), 1.29-1.27 • Cm, 6H), 1. 20-1. 18 (in, 1H) Example 125 2-mercapto-1-[(1 brother 55·)-6-[[ 6-(4-Methanesulfonylphenyl)-3-pyridinyl]oxycarbonyl]-3-azabicyclo[3·1·〇]hexanyl]propyl-2-ol

303 95344 201213319303 95344 201213319

將（1尤5«-6-[ [6-(4-曱磺醢基苯基）-3-吡啶基]氧 曱基]-3-氮雜雙環並[3. 1. 0]己烷鹽酸99b(0. 41 溶解於15mL甲醇和二氣甲烷（V/V=2:l)的混合溶劑中’加 入三乙胺（0. 4mL，3mmoi)，加入2, 2~二甲基環氧乙烷 ^ (3l6mL，4. 40mmol)，擾拌反應72小時。反應液減壓濃縮’ 加入水10mL，二氯甲烷萃取（20mLx2)，合併有機相，依次 ^ 用水（20mLxl)，飽和氣化鈉溶液洗滌（20mLxl)，無水硫酸 鎂乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫 劑體系A純化所得殘餘物，得到標題產物（2-甲基-1-[(1^ 55V6_[[6〜（4-甲磺醯基苯基）~3-比啶基]氧甲基] 、3〜氮雜雙環並[3. 1.0]己烷-3-基]丙基-2-醇125(270mg， 黃色固體），產率：64H . MS m/z (ESI): 417.2 [M+1] NMR (400 MHz，CDC13) 5 8.40 (s，1H)，8· 13 (d，2H), φ 8.00 (d, 2H), 7.73 (d, 2H), 7.27 (d, 1H), 3.93 (d, 2H), 3. 33(br. s, 2H), 3. 08 (s, 3H), 2. 73-2. 55 (m, 4H), 1.79 (br. s, 1H), 1.55 (s, 2H)，1.19 (s，6H) 實施例126 (1疋，55〇-3-(2-氟~2-甲基-丙基）_6-[[6-(4-甲確酿基苯 基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3.1.0]已烷 304 95344 201213319(1 especially 5«-6-[ [6-(4-oxasulfonylphenyl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3.1.0]hexane hydrochloride 99b (0. 41 dissolved in a mixed solvent of 15 mL of methanol and di-methane (V/V = 2:1) 'Addition of triethylamine (0.4 mL, 3 mmoi), add 2, 2~ dimethyl epoxy Alkane (3l6mL, 4.40mmol), the reaction was stirred for 72 hours. The reaction solution was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; After washing (20 mL×1), dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated,,,,,,,,,,,,,, [[6~(4-Methanesulfonylphenyl)~3-pyridyl]oxymethyl], 3~azabicyclo[3.1.0]hexane-3-yl]propyl-2-ol 125 (270 mg, mp. , φ 8.00 (d, 2H), 7.73 (d, 2H), 7.27 (d, 1H), 3.93 (d, 2H), 3. 33(br. s, 2H), 3. 08 (s, 3H), 2. 73-2. 55 (m, 4H), 1.79 (br. s, 1H), 1.55 (s, 2H), 1.19 (s, 6H) Example 126 (1疋, 55〇-3-(2-Fluoro~2-methyl-propyl)_6-[[6-(4-) Phenyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 305 95344 201213319

將（2-甲基550-6-^6-(4-甲磺醢基苯基） -3-吼唆基]氧曱基]-3-氮雜雙環並[3.〖.〇]己烷_3_基]丙 基-2-醇125(0. 21 g，0. 50mmol)溶解於5mL二氯甲烷中， 加入雙（2-甲氧基乙基）胺基三氟化硫（I33mg，0. 60mmol)， 攪拌反應2小時。滴加飽和碳酸氫鈉溶液至反應液PH為 7,二氯曱烧萃取（10mLx3)，合併有機相，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化 所得殘餘物，得到標題產物（〗足5®-3-(2-氟-2-曱基 基）-6~[ [6-(4-甲確醯基笨基）-3-°比咬基]氧甲基]〜3-氮雜 雙環並[3. 1.0]己烷126(80nig，白色固體），產率：38. 3%。 MS m/z (ESI): 419.2 [M+l] (400 MHz，CDC13)占 8.41 (d, 1H), 8.13 (d，2H) 8.00(d，2H)，7.72 (d, 1H)，7.28 (d，1H)，3.91 (d，2H) 3.17 (d, 2H), 3.08 (s, 3H), 2.57-2.47 (m, 4H), χ n (br. s, 1H), 1.44 (s, 2H), 1.32 (d, 6H) 實施例127 (1/?，55〇-6-[ [4-(5-甲續醢基l-2-n比咬基）笨氧基]甲 基]-3-氮雜雙環並[3· 1· 0]己烷-3-羧酸第三丁酉旨 95344 305 201213319(2-Methyl 550-6-^6-(4-methylsulfonylphenyl)-3-indolyl]oxyindolyl]-3-azabicyclo[3.]. _3_yl]propyl-2-alcohol 125 (0. 21 g, 0.50 mmol) was dissolved in 5 mL of dichloromethane, and bis(2-methoxyethyl)aminosulfur trifluoride (I33 mg, 0. 60mmol), the reaction was stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise to a solution of pH 7 and then extracted with dichloromethane (10mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate and filtered. The residue obtained was purified by thin layer chromatography using EtOAc (EtOAc) (EtOAc).笨 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ESI): 419.2 [M+l] (400 MHz, CDC13) occupies 8.41 (d, 1H), 8.13 (d, 2H) 8.00 (d, 2H), 7.72 (d, 1H), 7.28 (d, 1H), 3.91 (d, 2H) 3.17 (d, 2H), 3.08 (s, 3H), 2.57-2.47 (m, 4H), χ n (br. s, 1H), 1.44 (s, 2H), 1.32 (d, 6H) Example 127 (1/?, 55〇-6-[[4-(5-methyl-indolyl l-2-n ratio)] oxy]methyl] 3-Azabicyclo[3·1·0]hexane-3-carboxylic acid tert-butylation 95344 305 201213319

將4-(5-甲磺醯基-2-吡啶基）苯酚82b(450mg， 1. 81mmol)溶解於5mL况#-二曱基曱醯胺中，依次加入粗 品（1尤5«-6-(甲磺醯氧基甲基）—3-氮雜雙環並[3. 1. 〇]己 烧-3-緩酸第三丁酯16b(526mg，1.81roniol)和碳酸铯 (1180mg ’ 3. 61酿〇1) ’升至u〇°C攪拌反應4小時。加入 10mL水，用乙酸乙酯萃取（2〇mLx2)，合併有機相，無水硫 酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗 脫劑體系A純化所得殘餘物，得到標題產物（1尤5Λ-6-[[4-(5-甲磺醯基卜2-°比啶基）苯氧基]甲基]-3-氮雜雙環 並[3· 1. 0]己烷-3-羧酸第三丁酯127(600mg，白色固體）， 產率：74.8%。 MS m/z (ESI): 445.2 [M+l] lH NMR (400 MHz, CDCh) 5 9. 17 (s, 1H), 8. 27-8. 24 (m, 1H), 8.08-8.06 (m, 2H), 7.89-7.86 (m, 1H), 7.03-7.01 (m, 2H), 4.02-3.90 (ra, 4H), 3.41-3.39 (in, 2H), 3.14 (s, 3H), 1.60 (s, 2H), 1.45 (s, 9H), 1. 19-1. 15 (m, 1H) 實施例128 306 95344 201213319 -3-氮雜雙環[3. 1.〇]己晚4-(5-Methanesulfonyl-2-pyridyl)phenol 82b (450 mg, 1.81 mmol) was dissolved in 5 mL of #-didecylguanamine, and the crude product was added in sequence (1 especially 5 «-6- (Methanesulfonyloxymethyl)-3-azabicyclo[3. 1. oxime] hexane--3-glycolic acid tert-butyl ester 16b (526 mg, 1.81 roniol) and cesium carbonate (1180 mg ' 3. 61 The mixture was stirred for 1 hour. The reaction was stirred for 4 hours. Add 10 mL of water and extracted with ethyl acetate (2 mL mL). The resulting residue was purified by column chromatography eluting to afford the title product (1:5--6-[[4-(5-methylsulfonyl) 2-pyridinyl)phenoxy]methyl] 3-Azabicyclo[3·1]hexane-3-carboxylic acid tert-butyl ester 127 (600 mg, white solid), yield: 74.8% MS m/z (ESI): 445.2 [M +l] lH NMR (400 MHz, CDCh) 5 9. 17 (s, 1H), 8. 27-8. 24 (m, 1H), 8.08-8.06 (m, 2H), 7.89-7.86 (m, 1H ), 7.03-7.01 (m, 2H), 4.02-3.90 (ra, 4H), 3.41-3.39 (in, 2H), 3.14 (s, 3H), 1.60 (s, 2H), 1.45 (s, 9H), 1. 19-1. 15 (m, 1H) Example 128 306 95344 201213319 -3-Azabicyclo [3. 1.〇] It’s late

(1兄5S1)〜3-(5-乙基嘧咬-2-基）-6-((( 1’ -（甲續醯基）-1，2，3’，6，-四氫-[2,4’_聯0也咬基]_5-基）氧基）甲基）(1 brother 5S1)~3-(5-Ethylpyridin-2-yl)-6-(((1'-(methylthenyl)-1,2,3',6,-tetrahydro-[ 2,4'_0 is also biting base]_5-yl)oxy)methyl)

0 128 第一步 4~(5〜羥基―2-吡啶基）-3, 6-二氫_2於吡啶~1-羧酸第三丁0 128 first step 4~(5~hydroxy-2-pyridyl)-3,6-dihydro-2 in pyridine~1-carboxylic acid third

酯 將5、經基-2-溴-α比咬（2. 56 g ’ 14. 70mmol)溶解於 80mL乙醇和甲苯（V/V=l:3)的混合溶劑中，依次加入 4 (4’ 4, 5, 5-四甲基-1，3, 2-二氧棚酸醋_2-基）-3, 6-二氫 一2#—°比啶-1-羧酸第三丁酯（5g ’ 16. 20mmol)，2M的碳酸鈉 (14*7inL，29. 40mmol)水溶液，二茂鐵二氯化鈀（1.08g， 1· Wnm〇1) ’升溫至i〇(rc，攪拌反應3小時。減壓濃縮反 應液’用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘 物’得到標題產物4-(5-羥基-2-批啶基）-3,6-二氫-2於吡 307 95344 201213319 啶-1-羧酸第三丁酯128a(3. 6 g，白色固體），產率：90. 0%。 MS m/z (ESI): 277.1 [Μ+1] 第二步 4-[5-[[(l尤5Λ-3_(5-乙基嘧啶基）-3-氮雜雙環並 [3. 1· 0]己院-6-基]曱氧基]-2-°比咬基]-3, 6-二氫-2及-吼 咬-1，羧酸第三丁酯The ester was dissolved in a mixed solvent of 80 mL of ethanol and toluene (V/V=l:3) by substituting a base-2-bromo-α ratio (2. 56 g ' 14.70 mmol), and sequentially adding 4 (4'). 4,5,5-tetramethyl-1,3,2-dioxanthene-2-yl)-3,6-dihydro-2#-°-pyridyl-1-carboxylic acid tert-butyl ester ( 5g ' 16. 20mmol), 2M sodium carbonate (14*7 inL, 29.40 mmol) aqueous solution, ferrocene palladium dichloride (1.08 g, 1·Wnm〇1) 'warmed to i〇 (rc, stirring reaction 3 The reaction mixture was concentrated under reduced pressure to purify the residue obtained from eluent system B to give the title product 4-(5-hydroxy-2-b- hexyl)-3,6-dihydro-2. Pyridine 307 95344 201213319 pyridine-1-carboxylic acid tert-butyl ester 128a (3.6 g, white solid), yield: 90.0%. MS m/z (ESI): 277.1 [Μ+1] Step 4-[5-[[(l especially 5Λ-3_(5-ethylpyrimidinyl)-3-azabicyclo[3.1·0]hexyl-6-yl]decyloxy]-2- ° than bite base]-3, 6-dihydro-2 and - bite-1, carboxylic acid tert-butyl ester

將4-(5-羥基-2-吡啶基）-3, 6-二氫-2及-吡啶-1-羧酸 第三丁酯128a(2g，7. 20fflmol)溶解於20mL况於二甲基甲 醯胺中，加入[(1尤5«-3-(5-乙基嘧啶-2-基）-3-氮雜雙環 並[3. 1. 0]己烷-6-基]曱磺酸甲酯 7g (2. 15mg，7. 20mmol) 和碳酸鉀（2· 98mg，21.60mmol)，升至80°C擾拌反應4小 時。冷卻，加入10mL水攪拌，析出固體，過濾，濾餅用正 己烧（50mL)洗條，真空乾燥得到標題產物4-[5_ [[(1友，551)-3-(5-乙基哺咬-2-基）-3-氮雜雙環並[3. 1. 0] 己烷-6-基]甲氧基]~2-吡啶基]-3, 6-二氫-2皮-吡啶-1-羧 酸第三丁酯128b(2. 10 g，白色固體），產率：61. 0%。 第三步 (1足 550-3-(5-乙基嘧啶-2-基）-6-[[6-(1，2, 3, 6-四氫0比 啶-4-基）-3-吡啶基]氧曱基]-3-氮雜雙環[3. 1· 0]己烷鹽 酸鹽 將4-[5-[[(1足5«-3-(5-乙基嘧啶-2-基）-3_氮雜雙 環並[3.1. 0]己烷-6-基]甲氧基]-2-吡啶基]-3, 6-二氫 -2及-吡啶-1-羧酸第三丁酯I28b(2. 10 g，4. 40mmol)溶解 於120mL乙酸乙酯和二氣曱烷（v/v = 5:1)的混合溶劑中， 308 95344 201213319 慢慢加入50mL5 Μ的鹽酸乙酸乙酯溶液，攪拌反應2小時， 減壓濃縮，得到標題產物（1^550-3-(5-乙基嘧啶*~2-基）-6-[[6~(1，2, 3, 6-四氛0比α定-4-基）-3-0比咬基]氧甲 基]-3-氮雜雙環[3. 1.0]乙烷128c(2.4g，白色固體），產 率：100% 。 第四步 (1尤515)-3-（5-乙基痛咬-2-基）-6-(((1’-（甲石黃醜基） -1，2，3，6’-四氫-咬基]-5-基）氧基）甲基） 馨 -3-氮雜雙環[3. 1. 0]己烷將（1尤5^-3-(5-乙基嘧啶-2-基） -6-[ [6-(1，2, 3, 6-四氫吼咬-4-基）-3-0比咬基]氧甲基]〜3、 氮雜雙環[3. 1. 0]己烷鹽酸鹽i28c(268mg，0. 65mmol)溶解 於15mL二氣甲烷中，加入三乙胺（270/zL，1.95mmol)，冰 浴下’再滴加入甲磺醯氣（80//L，0. 97mmol)，升至室溫， 攪拌反應6小時。加入水i〇mL，二氣甲烷萃取（20mLx3)， 合併有機相，用飽和氣化鈉溶液洗滌（l〇roL)，無水硫酸鎂 _ 乾燥，過濾，濾液減壓濃縮，用矽膠管枉色譜法以洗脫劑 體系A純化所得殘餘物，得到標題產物（1兄55·)_3_(5_乙基 嘧啶-2-基）-6-(((1’-(甲磺醯基）_1’，2’，3’，6，-四氫-[2, 4’ -聯吨啶基]-5-基）氧基）曱基）_3_氮雜雙環[3. ι 0] 己院128(20mg，白色固體），產率：6.8%。 MS m/z (ESI): 456.3 [M+l] 4 腿R(400 MHz, CDCl〇 (5 8.26(s，1H)，8.17(s, 2H)， 7.32 (d, 1H), 7.17 (d, 1H), 6.49 (s, lfl), 4.08-3.88 (m, 6H), 3. 58-3. 50 (in, 4H), 2.85(s, 3H), 2. 76 (s, 2H), 309 95344 201213319 2.46 (t, 2H), 1.75 (s, 2H), 1.25-1.18 (m, 4H)Dissolving 4-(5-hydroxy-2-pyridyl)-3,6-dihydro-2 and-pyridine-1-carboxylic acid tert-butyl ester 128a (2 g, 7.20 ffl mol) in 20 mL of dimethyl In the formamide, [(1 especially 5«-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]anthracenesulfonic acid was added. Methyl ester 7g (2. 15mg, 7.20mmol) and potassium carbonate (2. 98mg, 21.60mmol), and stirred to 80 ° C for 4 hours. After cooling, add 10mL of water to stir, precipitate solid, filter, filter cake The mixture was washed with hexane (50 mL) and dried in vacuo to give the title product 4-[5_[[(1, 551)-3-(5-ethyl-dozen-2-yl)-3-azabicyclo[3. 1. 0] Hexa-6-yl]methoxy]~2-pyridyl]-3,6-dihydro-2pi-pyridine-1-carboxylic acid tert-butyl ester 128b (2. 10 g, white Solid), yield: 61.0%. The third step (1 foot 550-3-(5-ethylpyrimidin-2-yl)-6-[[6-(1,2, 3, 6-tetrahydro) 0-pyridin-4-yl)-3-pyridyl]oxycarbonyl]-3-azabicyclo[3.1·0]hexane hydrochloride will 4-[5-[[(1 foot5«-) 3-(5-ethylpyrimidin-2-yl)-3_azabicyclo[3.1.0]hexane-6-yl]methoxy]-2-pyridyl]-3,6-dihydro- 2 and -pyridine-1-carboxylic acid tert-butyl ester I28b (2. 10 g, 4. 40 mmol Dissolved in a mixed solvent of 120 mL of ethyl acetate and dioxane (v/v = 5:1), 308 95344 201213319 slowly added 50 mL of a 5 Μ solution of ethyl acetate in hydrochloric acid, stirred for 2 hours, and concentrated under reduced pressure. The title product was obtained (1^550-3-(5-ethylpyrimidin*~2-yl)-6-[[6~(1,2, 3, 6-tetravalent 0 to α-4-yl)- 3-0 butyl group] oxymethyl]-3-azabicyclo[3.1.0]ethane 128c (2.4g, white solid), yield: 100%. Step 4 (1 especially 515)-3- (5-ethylheptan-2-yl)-6-(((1'-(methyl sulphate)-1,2,3,6'-tetrahydro- dimethyl]-5-yl)oxy) Methyl) mann-3-azabicyclo[3.1.0]hexane will (1 especially 5^-3-(5-ethylpyrimidin-2-yl)-6-[ [6-(1,2 , 3,6-tetrahydroindole-4-yl)-3-0 ratio octyl]oxymethyl]~3, azabicyclo[3.1.0]hexane hydrochloride i28c (268 mg, 0. 65 mmol) was dissolved in 15 mL of di-methane, triethylamine (270/zL, 1.95 mmol) was added, and methanesulfonate (80//L, 0.97 mmol) was added dropwise under ice-cooling to room temperature. The reaction was stirred for 6 hours. Add water i〇mL, di-methane extraction (20mLx3), combine the organic phase, wash with saturated sodium carbonate solution (l〇roL), anhydrous magnesium sulfate _ dry, filter, the filtrate is concentrated under reduced pressure, using a gelatin tube chromatography The obtained residue was purified with eluent system A to give the title product (1 s. 55.) _3_(5-ethylpyrimidin-2-yl)-6-(((1'-(methylsulfonyl))', 2',3',6,-Tetrahydro-[2,4'-bi-oxaridinyl]-5-yl)oxy)indolyl)_3_azabicyclo[3. ι 0] 院院128(20mg , white solid), yield: 6.8%. MS m/z (ESI): 456.3 [M+l] 4 leg R (400 MHz, CDCl 〇 (5 8.26 (s, 1H), 8.17 (s, 2H), 7.32 (d, 1H), 7.17 (d, (H, 6H) 201213319 2.46 (t, 2H), 1.75 (s, 2H), 1.25-1.18 (m, 4H)

實施例129 5-[(l兄 5Λ-6-[[6-(1-曱磺醯基-3, 6-二氫-2多咐咬-4-基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1. 〇]己院_3_ 基]-3-異丙基-1, 2, 4-噁二唑Example 129 5-[(l brother 5Λ-6-[[6-(1-oxasulfonyl-3,6-dihydro-2polyglyth-4-yl)-3-pyridyl]oxymethyl) ]-3-Azabicyclo[3. 1. 〇] 己院_3_基]-3-isopropyl-1, 2, 4-oxadiazole

第一步 4-[5-[[(1尤 5«-3-(3-異丙基-1，2,4-噁二唑-5-基）-3-氣 雜雙環並[3. 1. 0]己烷-6-基]曱氧基]-2-吡啶基]一3, 6一一二 氫-2)7-吡啶-1-羧酸第三丁酯 將粗品[(1兄5«-3-(3-異丙基-1，2,4--噁二唑_5一 基）-3-氮雜雙環並[3. 1.0]己烷-6-基]甲基磺酸甲醋48c (263mg, 0. 87mmol)，4-(5-羥基-2-吡啶基）_3, 6-二氮一2皮一 吡啶-1-羧酸第三丁酯128a(200mg，0· 73min〇l)和碳酸舒 (302mg，2. 19mmol)溶解於lOmL 於·二甲基甲醯胺令’授 95344 310 201213319 拌，升溫至80°C攪拌反應2小時。加入50mL水，乙酸乙 酯萃取（50mLx2)，合併有機相，用飽和氣化鈉溶液洗滌 (50mLx2)，無水硫酸鎂乾燥’過濾，濾液減壓濃縮，得到 粗品標題產物4-[5-[[(1尤550-3-(3-異丙基-1，2, 4-噁二 唑-5-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲氧基]-2-吡 啶基]-3, 6-二氫-2及-吡啶-1-羧酸第三丁酯129a(350mg， 黃色油狀物），產物不經純化直接進行下一步反應。 第二步 ® 5-[(1 足 5幻-6_[[6-(1，2, 3, 6-四氫吼啶-4-基）-3-吡啶基] 氧曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基 -1，2, 4-嗯二唑鹽酸鹽 將粗品 4-[5-[ [(1 皮，519)-3-(3-異丙基-1，2, 4-β惡二峻 -5-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲氧基]-2-吡啶 基]-3, 6—二氫-2及-吡啶-1-羧酸第三丁酯129a(350mg， 〇· 73mmol)溶解於20mL甲醇中，加入1 OmL 5M鹽酸乙酸乙 # 酯溶液，攪拌反應6小時。反應液減壓濃縮，得到粗品標 題產物 5-[(1兄 [6-(1，2, 3, 6-四氫®比变-4-基）-3- β比啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異 丙基-1，2, 4-噁二唑鹽酸鹽129b(305mg ’黃色固體），產物 不經純化直接進行下一步反應。 第三步 5~[(1 及，55&quot;)-6-[[6-(1-甲續疏基-3, 6-二氫-2及-〇比唆-4-基）-3-吡啶基]氧f基]-3-氮雜雙環並[3· 1. 0]己烷-3-基]~3-異丙基-1，2, 惡二唾 311 95344 201213319 將 5-[(1 足 55·)-6-[[6-(1, 2, 3, 6-四氫°比啶-4-基）-3-°比啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異 丙基-1，2, 4-°惡二吐鹽酸鹽129b(305mg，0. 73mmol)溶解於 20mL二氯甲烷中，加入三乙胺（305#L，2. 19mmol)，冰浴 下，再滴加入甲磺醯氯（84//L，1. lOmmol)，升至室溫，攪 拌反應6小時。加入水50mL，二氣甲烧萃取（10mLx3)，合 併有機相，用飽和氣化鈉溶液洗滌（2〇mLx3)，無水硫酸鎂 φ 乾燥’過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑 體系A純化所得殘餘物，得到標題產物5-[(1足5幻_6_ [[6-(1-甲磺醯基-3, 6-二氫-2皮-吡啶-4-基）-3-吡啶基]氧 甲基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異丙基 -1，2,4-噁二唑129(4〇111§，白色固體），產率：11.9%。 MS m/z (ESI): 460.1 [M+l] *Η NMR (400 MHz, CDCls) d 8.29 (d, 1H), 7.39 (d&gt; 1H), 7. 24 (d, 1H), 6. 57 (s, 1H), 4. 06 (d, 2H), 4. 02 (d, 2H), i 3. 89 (d, 2H), 3. 71 (d, 2H), 3. 58 (t, 2H), 2. 94 (q, 1H), 2. 90 (s, 3H), 2. 81 (d, 2H), 1. 82 (s, 2H), 1. 32 (d, 6H), 1.25 (t, 1H) 實施例130 ㈤，55)-3-(2-氟-2-甲基一丙基磺醯基_2_ 吡啶基）苯氧基]甲基]_3_氮雜雙環並[31〇]己烷The first step 4-[5-[[(1 especially 5«-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3- oxabicyclo][3. 1 . 0]Hex-6-yl]nonyloxy]-2-pyridyl]-3,6-dihydro-2)7-pyridine-1-carboxylic acid tert-butyl ester will be crude [[1 brother 5 «-3-(3-Isopropyl-1,2,4-oxadiazole-5-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methylsulfonate A Vinegar 48c (263 mg, 0.87 mmol), 4-(5-hydroxy-2-pyridyl)_3,6-diaza-2 picopyridine-1-carboxylic acid tert-butyl ester 128a (200 mg, 0·73 min 〇 l) and carbonated (302mg, 2.19mmol) dissolved in lOmL of dimethyl dimethyl amide to '95344 310 201213319 mix, warmed to 80 ° C and stirred for 2 hours. Add 50mL of water, ethyl acetate extraction ( 50 mL x 2), the organic phase was combined, washed with a saturated sodium sulfate solution (50 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 4-[5-[[(1) 550-3-(3) -isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy]-2-pyridinyl] -3,6-Dihydro-2 and -pyridine-1-carboxylic acid tert-butyl ester 129a (350 mg, yellow oil), product Step reaction. Step 2® 5-[(1 foot 5 幻-6_[[6-(1,2, 3, 6-tetrahydroacridin-4-yl)-3-pyridyl] oxinyl]- 3-Azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazolate hydrochloride crude 4-[5-[ [(1 519)-3-(3-isopropyl-1,2,4-βoxadis-5-yl)-3-azabicyclo[3.1.0]hexane-6-yl] Methoxy]-2-pyridyl]-3,6-dihydro-2 and-pyridine-1-carboxylic acid tert-butyl ester 129a (350 mg, 〇·73 mmol) was dissolved in 20 mL of methanol, and 1 mL of 5 M hydrochloric acid was added. The acetic acid ethyl ester solution was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to give the crude title product 5-[(1[[--[1,2,3,6-tetrahydro-)--4-yl)- 3-β-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole hydrochloride 129b (305 mg 'yellow solid'), the product was directly subjected to the next reaction without purification. The third step 5~[(1 and, 55&quot;)-6-[[6-(1-methyl succinyl-3, 6-di Hydrogen-2 and -p-pyridin-4-yl)-3-pyridyl]oxyf-yl]-3-azabicyclo[3·1.0]hex-3-yl]~3-isopropyl -1,2, evil two saliva 311 95344 201213319 will be 5-[(1 foot 55·) -6-[[6-(1, 2, 3, 6-tetrahydropyridin-4-yl)-3-° ratio pyridine]oxymethyl]-3-azabicyclo[3.1.0] Hexane-3-yl]-3-isopropyl-1,2,4-° oxadihydrochloride 129b (305 mg, 0.73 mmol) was dissolved in 20 mL of dichloromethane and triethylamine (305#) L, 2.19 mmol), under ice-cooling, methanesulfonium chloride (84 / /L, 1.10 mmol) was added dropwise, and the mixture was warmed to room temperature, and the reaction was stirred for 6 hours. 50 mL of water was added, and the mixture was extracted with a gas-fired gas (10 mL×3). The organic phase was combined and washed with a saturated sodium carbonate solution (2 〇mL×3), dried over anhydrous magnesium sulfate (yield) filtered and concentrated under reduced pressure, using a silica gel column chromatography. The residue obtained was purified by eluent system A to give the title product 5-[(1,5,5,6-[[6-(1-methylsulfonyl-3,6-dihydro-2pi-pyridin-4-yl) )-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole 129 (4〇 111 §, white solid), Yield: 11.9% MS m/z (ESI): 460.1 [M+l] * NMR (400 MHz, CDCls) d 8.29 (d, 1H), 7.39 (d &gt; 1H) , 7. 24 (d, 1H), 6. 57 (s, 1H), 4. 06 (d, 2H), 4. 02 (d, 2H), i 3. 89 (d, 2H), 3. 71 (d, 2H), 3. 58 (t, 2H), 2. 94 (q, 1H), 2. 90 (s, 3H), 2. 81 (d, 2H), 1. 82 (s, 2H) , 1. 32 (d, 6H), 1.25 (t, 1H) Example 130 (V), 55)-3-(2-Fluoro-2-methyl-propylsulfonyl-2-ylpyridyl)phenoxy] Methyl]_3_azabicyclo[31〇]hexane

95344 312 20121331995344 312 201213319

ο 第一步 (1疋55*)-6-[[4-(5-甲％酿基~2-°比唆基）苯氧基]甲基]一 氮雜雙環並[3. 1. 〇]己燒 將（1尤5«-6-[[4-(5-曱磺醯基卜2_0比啶基）苯氧基] 甲基]-氮雜雙ί哀並[3. 1. 0]己烧-3-幾酸第三丁醋127 (350mg ’ 0. 78_〇1)溶解於5mL鹽酸甲醇溶液中，攪拌反應 5小時。加入1〇‘飽和碳酸氫鈉溶液，用乙酸乙酯萃取 (20mLx2) ’合併有機相’無水硫酸鈉乾燥，過濾，濾液減 • 壓濃縮’得到標題產物（1兄55*)-6-[[4-(5-曱磺醯基-2-吡 咬基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0]己烷130a (170mg ’白色固體），產率·· 62.0%。 MS m/z (ESI)： 445.2 [M+l] 第二步 2-甲基-1-[(1足5幻_6-[[4-(5-甲磺醯基-2-吡啶基）苯氧 基]曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]丙烷-2-醇 將（1疋5«-6-[[4_(5-曱磺醯基-2-比啶基）苯氧基] 甲基]-3-氮雜雙環並[3. 1.0]己烷 130a(0.07g，0.20mmol) 313 95344 201213319 溶解於51^甲醇中，加入2,2-二甲基環氧乙烷（22111名， 0· 30mmol)，攪拌反應16小時。加入水10mL，二氣曱烷萃 取（10mLx3)，合併有機相，依次用水（20mLx3)，飽和氯化 鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥，過濾，濾液減壓 濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘 物，得到標題產物2-甲基-1-[(1尤5ν9)-6-[[4-(5-曱磺醯 基-2-吼啶基）苯氡基]甲基]-3-氮雜雙環並[3. 1. 0]己烷 -3-基]丙烷-2-醇13Gb(130rag，黃色固體），產率·· 64. 9%。 • MS m/z (ESI): 417.1 [M+l] 第三步 · (1尤519)-3-(2~氟-2-甲基-丙基）-6-[[4-（5-曱續醯基-2_ 吡啶基）苯氧基]甲基]-3~氮雜雙環並[3. 1.0]己烷 將2-曱基疋55〇-6-[ [4-(5-甲確醜基~2-n比咬 基）苯氧基]甲基]氮雜雙環並[3. 1.0]己烷-3-基]丙烷 -2-醇 130b(0. 13g ’ 0. 30mmol)溶解於 5mL 二氣曱院中，加 參入雙（2-甲氧基乙基）胺基三氟化硫（69mg，0. 30麵〇1)，攪 拌反應2小時》加入水10mL ’二氣甲烷萃取（i〇mLx3)，合鲁 併有機相，依次用水（20mLx3)，飽和氣化鈉溶液洗滌 (20mLx3) ’無水硫酸鎂乾燥’過渡，濾、液減壓濃縮，用薄 層色譜法以展開劑體系A純化所得殘餘物，得到標題產物 (1兄55)-3-(2-氟-2-曱基-丙基）-6-[[4-(5-曱續醯基-2-。比啶基）苯氧基]甲基]-3-氮雜雙環並[3. 1.0]己烷130 (20mg，白色固體），產率：38. 3%。 MS m/z (ESI): 419.1 [M+l] 314 95344 201213319 4 丽R(400 MHz，CDCi3) (5 9. 14(s，1H)，8.22-8.20(m， 1H), 8.05-8.03 (m, 2H), 7.86-7.83 (m, 1H), 7.02-7.00 (m, 2H), 3.89-3.87 (m, 2H), 3.18-3.16 (m, 2H), 3.13 (s, 3H), 2. 57 (s, 1H), 2. 51-2. 46 (ra, 2H), 1. 71 (s, 2H), 1.43-1.26 (m, 8H) 實施例131 1-[(1兄 5幻-6-[[2, 6-二氟-4-(1-曱磺醯基-3, 6-二氫-2/i-吡啶-4-基）笨氧基]曱基]-3-氤雜雙環並[3. 1. 0]己烷-3-• 基]-2-曱基-丙烧-2-醇ο First step (1疋55*)-6-[[4-(5-methyl-branched ~2-° thiol)phenoxy]methyl]azabicyclo[3. 1. 〇 It has been burned (1 especially 5«-6-[[4-(5-oxasulfonyl) 2_0-pyridyl)phenoxy]methyl]-azapine [3. 1. 0] The calcined -3-acidic third butyl vinegar 127 (350 mg '0. 78_〇1) was dissolved in 5 mL of methanolic hydrochloric acid solution, and the reaction was stirred for 5 hours. 1 〇 'saturated sodium hydrogencarbonate solution was added and extracted with ethyl acetate. (20mLx2) 'Consolidated organic phase' dried over anhydrous sodium sulfate, filtered, filtrate reduced by pressure to give the title product (1 brother 55*)-6-[[4-(5-sulfonyl-2-yl) Phenoxy]methyl]-3-azabicyclo[3.1.0]hexane 130a (170 mg 'white solid), yield · · 62.0%. MS m/z (ESI): 445.2 [M +l] The second step 2-methyl-1-[(1 foot 5 幻_6-[[4-(5-methylsulfonyl-2-pyridyl)phenoxy]indolyl]-3-nitrogen Heterobicyclo[3.1.0]hexane-3-yl]propan-2-ol (1疋5«-6-[[4_(5-indolesulfonyl-2-pyridyl)phenoxy) Methyl]-3-azabicyclo[3.1.0]hexane 130a (0.07g, 0.20mmol) 313 95344 201213319 dissolved in 51^ methanol, added 2,2-dimethyl Ethylene oxide (22111, 0·30 mmol), stirred for 16 hours. Add 10 mL of water, dioxane extract (10 mL×3), and combine the organic phases, then wash with water (20mL×3), saturated sodium chloride solution (20mL×3) After drying over anhydrous magnesium sulfate, the mixture was filtered, and the filtrate was evaporated to dryness, and the residue obtained was purified by eluent column chromatography to afford the title product 2-methyl-1-[(1 especially 5ν9)-6-[ [4-(5-oxasulfonyl-2-acridinyl)phenylhydrazinyl]methyl]-3-azabicyclo[3.1.0]hexane-3-yl]propan-2-ol 13Gb (130rag, yellow solid), yield · 64.9%. • MS m/z (ESI): 417.1 [M+l] Step 3 · (1 especially 519)-3-(2~fluoro-2 -Methyl-propyl)-6-[[4-(5-indolyl-2-ylpyridyl)phenoxy]methyl]-3~azabicyclo[3.1.0]hexane 2-曱基疋55〇-6-[ [4-(5-甲其丑基~2-n ratio) phenoxy]methyl]azabicyclo[3.1.0]hexane-3-yl] Propane-2-ol 130b (0.13g '0. 30mmol) was dissolved in 5mL of dioxane, added with bis(2-methoxyethyl)amine trifluoride (69mg, 0. 30 side) 〇 1), stir the reaction for 2 hours" add water 10mL 'two gas Methane extraction (i〇mLx3), Helu and organic phase, followed by washing with water (20mLx3), saturated sodium carbonate solution (20mLx3) 'drying with anhydrous magnesium sulfate', filtering, liquid concentration under reduced pressure, using thin layer chromatography Purification of the residue obtained from the solvent system A afforded the title product (1 s. 55) -3-(2-fluoro-2-mercapto-propyl)-6-[[4-(5- 曱 醯 醯 -2- . Benzidyl)phenoxy]methyl]-3-azabicyclo[3.1.0]hexane 130 (20 mg, white solid), yield: 38.3%. MS m/z (ESI): 419.1 [M+l] 314 95344 201213319 4 R (400 MHz, CDCi3) (5 9. 14 (s, 1H), 8.22-8.20 (m, 1H), 8.05-8.03 ( m, 2H), 7.86-7.83 (m, 1H), 7.02-7.00 (m, 2H), 3.89-3.87 (m, 2H), 3.18-3.16 (m, 2H), 3.13 (s, 3H), 2. 57 (s, 1H), 2. 51-2. 46 (ra, 2H), 1. 71 (s, 2H), 1.43-1.26 (m, 8H) Example 131 1-[(1 brother 5 fantasy-6 -[[2,6-difluoro-4-(1-oxasulfonyl-3,6-dihydro-2/i-pyridin-4-yl)phenyloxy]indolyl]-3-indole bicyclic And [3. 1. 0]hexane-3-•yl]-2-mercapto-propan-2-ol

第一步 4-(3, 5-二氟-4-羥基-苯基）-3, 6-二氫-2#-吡啶-1-羧酸第 三丁酯 將2, 6-二氟-4-溴-苯紛（1040mg，5mmol)溶解於6mL乙 醇中，加入4-(4, 4, 5, 5-四曱基-1，3, 2-二氧硼酸酯-2-基） 315 95344 201213319 -3, 6-二氮-2及-吡啶-卜羧酸第三丁酯（170〇g，5. 50mmol)， 加入2 Μ碳酸鈉（5mL ’ lOramol)的水溶液，二茂鐵二氣化把 (366mg ’ 0. 5mmol)，升溫至100°C，微波攪拌反應1小時。 減壓濃縮反應液，用矽膠管柱色譜法以洗脫劑體系B純化 所得殘餘物，得到標題產物4-(3,5-二氟-4-羥基-苯 基）-3, 6-二氫-2#-吡啶-1-甲酸第三丁 131a(772mg，白色 固體），產率：49. 5%。 MS m/z (ESI): 312.2 [M+l] 第二步 2, 6-二氟-4-(1, 2, 3, 四氫吼咬~4-基）苯酷 將4-(3, 5-二氟-4-羥基-笨基）-3, 6-二氫-2及-吡啶 -1-羧酸第三丁酯131a(0. 77g，2. 47mmol)溶解於5mL乙酸 乙酯中’慢慢加入5M的鹽酸乙酸乙酯溶液，室溫反應i. 5 小時，減壓濃縮’得到標題產物2, 6-二氟-4〜（1，2, 3, 6〜四 氫°比啶-4-基）苯酚131b(0. 611g，黃色固體），產率：⑽。 | MS m/z (ESI): 204.2 [M+l] 第三步 2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫-2及-吡啶-4-基）苯酚 將2, 6-二氟-4-( 1，2, 3, 6-四氫π比咬-4-基）笨盼i31b (0. 61g ’ 2.47mmol)溶解於l〇m乙二氯曱烷中，冰浴下，加 入三乙胺（1200mg ’ 9. 88mmol)及甲磺醯氣（621mg，First step 4-(3,5-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2#-pyridine-1-carboxylic acid tert-butyl ester 2,6-difluoro-4 -Bromo-benzene (1040 mg, 5 mmol) was dissolved in 6 mL of ethanol, and 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborate-2-yl) 315 95344 was added. 201213319 -3, 6-diaza-2 and -pyridine-polycarboxylic acid tert-butyl ester (170〇g, 5.50mmol), adding 2 Μ sodium carbonate (5mL 'lOramol) aqueous solution, ferrocene di-gasification (366 mg '0.5 mmol) was heated to 100 ° C and stirred under microwave for 1 hour. The reaction mixture was concentrated under reduced pressure, and then purified, m.jjjjjjjjjjjjjjjjjjj -2#-pyridine-1-carboxylic acid tert-butyl 131a (772 mg, white solid), yield: 49.5%. MS m/z (ESI): 312.2 [M+l] The second step 2, 6-difluoro-4-(1, 2, 3, tetrahydrobite~4-yl) benzene will be 4-(3, 3-Difluoro-4-hydroxy-phenyl)-3,6-dihydro-2 and-pyridine-1-carboxylic acid tert-butyl ester 131a (0.77 g, 2.47 mmol) was dissolved in 5 mL of ethyl acetate ' Slowly add 5M ethyl acetate solution, react at room temperature for 1.5 hours, concentrate under reduced pressure to give the title product 2, 6-difluoro-4~(1,2,3,6~tetrahydropyridinium 4-yl)phenol 131b (0.161 g, yellow solid), yield: (10). MS m/z (ESI): 204.2 [M+l] Step 3 2, 6-difluoro-4-(1-methylsulfonyl-3,6-dihydro-2 and -pyridin-4-yl Phenol will dissolve 2,6-difluoro-4-(1,2,3,6-tetrahydropi-buty-4-yl) stupid i31b (0. 61g ' 2.47mmol) in l〇m ethylene dichloride In decane, triethylamine (1200 mg '9.88 mmol) and methanesulfonate (621 mg,

5. 43mmo 1)’攪拌反應12小時。加入1〇此水，用二氣甲烧 萃取（50mLx3)，合併有機相，減壓濃縮，用矽膠管柱色譜 法以洗脫劑體系B純化所得殘餘物，得到的固體溶解於3mL 95344 316 201213319 二氯甲烷中，加入10mL甲醇，再加入3mL 2M氫氧化鈉溶 液’攪拌反應1小時。反應液減壓濃縮，加入10mL水，滴 加2M鹽酸至反應液pH為2至3,用二氣曱烷萃取（5〇mLx3)， 合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，標 題產物2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫-2F吡啶-4-基）苯紛131c(0. 50g ’白色固體），產率：89. 〇%。 第四步 (1 尤 5Λ-6-[[2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫-2及-吡 咬-4-基）笨氧基]甲基]-3-氮雜雙環並[3.1. 〇]己燒-3-緩 酸第三丁酯 將2, 6-一氣_4-(1-曱確酿基-3, 6-二氫-2必··。比咬-4-基）苯酚131c(377mg，1.30imnol)溶解於7mL火尽·二甲基 甲醯胺中，加入（1尤5«-6-(甲磺醯氧基曱基）-3〜氮雜雙環 並[3. 1. 0]己院-3-羧酸第三丁酿 16b(415mg，1. 42顏〇1)5. 43mmo 1)' Stirring reaction for 12 hours. 1 Torr of this water was added, and the mixture was extracted with a methane (50 mL×3). The organic phase was combined and concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system B. The obtained solid was dissolved in 3 mL 95344 316 201213319 To the dichloromethane, 10 mL of methanol was added, and then 3 mL of a 2 M sodium hydroxide solution was added to stir the reaction for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. EtOAc (EtOAc m. , the title product 2,6-difluoro-4-(1-methylsulfonyl-3,6-dihydro-2Fpyridin-4-yl)benzene 131c (0. 50 g 'white solid), yield: 89 〇%. The fourth step (1 especially 5Λ-6-[[2,6-difluoro-4-(1-methylsulfonyl-3,6-dihydro-2 and-pyridin-4-yl))] Methyl]-3-azabicyclo[3.1. 〇] hexane--3-glycolic tert-butyl ester 2,6-one gas _4-(1-indole- 3,6-dihydro- 2 must be more than bit -4-yl) phenol 131c (377mg, 1.30imnol) dissolved in 7mL of chlorhexidine dimethylformamide, added (1 especially 5«-6-(methylsulfonyloxy oxime) Base)-3~azabicyclo[3. 1. 0] hexan-3-carboxylic acid third butyl 16b (415mg, 1.42 〇1)

和碳酸鉀（518mg ’ 3· 75ramol)，升至80°C，攪拌反應16小 時。反應液減壓濃縮，加入50mL水，用乙酸乙離萃取 (50mLx3)，合併有機相，無水硫酸鎂乾燥，過遽，濟液咸 壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化戶斤得殘餘 物，得到標題產物（1尤5«-6-[[2,6-二氟-4、（丨、甲續酿其 -3, 6-二氫比咬-4-基）笨氧基]曱基]-3-氡雜雙環並 [3.1.0]己烷-3-羧酸第三丁酯131以0.5〇8，白色固體） 產率：82. 6%。 MS m/z (ESI): 220.2 [M+1] 第五步 95344 317 201213319 (1疋 5Λ-6-[[2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫-2#-吡 啶-4-基）苯氧基]曱基]-3-氮雜雙環[3. 1. 0]乙烷 將（17?，55*)_6~[[2，6~一既~4_(1-甲續酿基-3，6_二氮 -2τ7-吡啶-4-基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 0]己烷 -3-叛酸第三丁醋131d(0. 50g，l. lOmmol)溶解於5mL乙酸 乙酯中，慢慢加入5M的鹽酸乙酸乙酯溶液，攪拌反應1 小時，減壓濃縮’得到標題產物（1尤5Λ-6-[[2, 6-二氟 -4-(1-甲磺醯基-3, 6-二氫-2展-比啶-4-基）苯氧基]甲 ® 基]-3-氮雜雙環[3. 1. 0]乙烷I31e(0.45 g，黃色固狀物）， 產率：100% 〇 MS m/z (ESI): 385. 1 [M-fl] 第六步 卜[(1尤55)-6-(1:2, 6-二氟-4-(卜甲磺醯基-3, 6-二氫-2万-吡啶基）苯氧基]曱基]-3-氮雜雙環並[3.1.0]己烷-3- 基]-2-甲基-丙烧-2-醇 釀將（1疋5Λ-6-[[2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫 -2及-吡啶-4-基）笨氧基]曱基]-3-氮雜雙環[3. 1. 0]乙烷 131e(450mg，lmmol)溶解於lOmL曱醇和二氣甲烷（V/V = 1:1)混合溶劑中，加入三乙胺（〇.41^，3111111〇1)，加入2,2~· 二曱基環氧乙烷（560mL，7.76mmol)，攪拌反應72小時。 反應液減壓濃縮，加入水lOtnL，二氣曱烧萃取（10mLx3)， 合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用 矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標 題產物1-[ (1及,5幻-6-[ [2, 6-二氟-4-(1-甲續醯基-3, 6- 318 95344 201213319 二氫-2汉-η比啶-4-基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 〇] 己烧-3-基]-2-曱基-丙烧-2-醇131(460mg，黃色固體）， 產率：100%。 MS m/z (ESI): 457.2 [M+l] *Η NMR (400 MHz, CDCh) (5 6.90-6.88 (m, 2H), 6.05-6.03 (m, 1H), 3.95-3.93 (m, 4H), 3.51 (t, 2H), 3.00 (br. s, 2H), 2. 86(s, 3H), 2. 50-2. 35 (in, 6H), 1.79-1.77 (m, ^ 1H), 1.50 (br. s, 1H), 1.35 (s, 2H), 1.32 (s, 6H) 實施例132 (1兄5幻-6-[[2,6-二氟-4-(1 甲磺醯基 1-3,6-二氫-2{{-吡 啶-4-基）苯氧基甲基]-3-(2-氟-2-甲基-丙基）-3 -氮雜雙 環並[3.1.0]己烷With potassium carbonate (518 mg '3·75 ramol), the temperature was raised to 80 ° C, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 50 mL of water was added, and then extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, and dried over EtOAc EtOAc EtOAc. The residue is obtained, and the title product is obtained (1 especially 5«-6-[[2,6-difluoro-4, (丨, 甲 酿 其 -3 -3,6- dihydrogen -4- base) stupid Oxy] fluorenyl]-3-oxabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 131 as 0.5 〇8, white solid) Yield: 82.6%. MS m/z (ESI): 220.2 [M+1] Step 5 95344 317 201213319 (1疋5Λ-6-[[2,6-difluoro-4-(1-methylsulfonyl-3, 6-) Dihydro-2#-pyridin-4-yl)phenoxy]indolyl]-3-azabicyclo[3.1.0]ethane will be (17?,55*)_6~[[2,6~ a ~4_(1-methyl succinyl-3,6-diaza-2τ7-pyridin-4-yl)phenoxy]indolyl]-3-azabicyclo[3.1.0]hexane -3-Resin acid butyl vinegar 131d (0. 50g, 1.0 mol) was dissolved in 5 mL of ethyl acetate, and 5 M hydrochloric acid ethyl acetate solution was slowly added, and the reaction was stirred for 1 hour, and concentrated under reduced pressure to give the title product. (1 especially 5Λ-6-[[2,6-difluoro-4-(1-methylsulfonyl-3,6-dihydro-2-dipyridin-4-yl)phenoxy]methyl) ]-3-Azabicyclo[3.1.0]ethane I31e (0.45 g, yellow solid), Yield: 100% 〇MS m/z (ESI): 385. 1 [M-fl] Six steps [(1 especially 55)-6-(1:2,6-difluoro-4-(bethanesulfonyl-3,6-dihydro-2,4-pyridyl)phenoxy]fluorenyl) ]-3-Azabicyclo[3.1.0]hexane-3-yl]-2-methyl-propan-2-ol can be (1疋5Λ-6-[[2,6-difluoro- 4-(1-Methanesulfonyl-3,6-dihydro-2 and -pyridin-4-yl) phenyloxy]indolyl]-3-azabicyclo[3. 1. 0]B 131e (450mg, 1mmol) was dissolved in 10mL of decyl alcohol and di-methane (V/V = 1:1) mixed solvent, adding triethylamine (〇.41^, 3111111〇1), adding 2,2~· Ethylene oxide (560 mL, 7.76 mmol), and the reaction was stirred for 72 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. Concentration, the residue obtained was purified by eluent column chromatography eluting with eluent system A to give the title product 1-[(1,5,6--6-[[2,6-difluoro-4-(1-) Mercapto-3, 6- 318 95344 201213319 Dihydro-2 Han-n-pyridin-4-yl)phenoxy]methyl]-3-azabicyclo[3. 1. 〇] 烧烧-3- 2-mercapto-propan-2-ol 131 (460 mg, yellow solid), Yield: 100%. MS m/z (ESI): 457.2 [M+l] * NMR (400 MHz, CDCh (5 6.90-6.88 (m, 2H), 6.05-6.03 (m, 1H), 3.95-3.93 (m, 4H), 3.51 (t, 2H), 3.00 (br. s, 2H), 2. 86 ( s, 3H), 2. 50-2. 35 (in, 6H), 1.79-1.77 (m, ^ 1H), 1.50 (br. s, 1H), 1.35 (s, 2H), 1.32 (s, 6H) Example 132 (1 brother 5 Fanta-6-[[2,6-difluoro-4-(1 methanesulfonyl) 1-3,6-dihydro-2{{-pyridyl 4-yl) phenoxymethyl] -3- (2-fluoro-2-methyl - propyl) -3 - azabicyclo [3.1.0] hexane

將 1〜[(1疋 55〇~6-[[2, 6-二氟-4~(1-甲磺醯基-3, 6-二氫〜2及-比啶-4-基）苯氧基]甲基]-3-氮雜雙環並[3. 1. 0] 己烷-3-基]-2-甲基-丙烷-2-醇 131(〇.37g，0.80mm〇l)溶 解於5mL二氣甲烷申，加入雙（2-甲氧基乙基）胺基三氟化 硫（221mg，lmmol)，攪拌反應2小時。滴加飽和碳酸氫鈉 溶液至反應液pH為7，二氣曱烷萃取（i〇mLx3)，合併有機 319 95344 201213319 相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層色譜 法以展開劑體系A純化所得殘餘物，得到標題產物 日 (1 尤 5Λ-6-[[2,6-二氟-4-(1 甲確醯基卜3,6-二氣~2H-°比 °定-4-基）苯氧基甲基]-3-(2-氟-2-曱基-丙基）一3一氣雜雙 環並[3. 1. 0]己烷132(150mg，白色固體），產率：4〇. 9%。 MS m/z (ESI): 459.1 [M+l] NMR (400 MHz, CDCh) δ 6. 90-6. 88 (m, 2H), 6. 05-6. 031~[(1疋55〇~6-[[2,6-difluoro-4~(1-methylsulfonyl-3,6-dihydro~2 and-bipyridin-4-yl)phenoxy) Methyl]methyl]-3-azabicyclo[3.1.0]hexane-3-yl]-2-methyl-propan-2-ol 131 (〇.37g, 0.80mm〇l) is dissolved in 5 mL of dioxane, adding bis(2-methoxyethyl)aminosulfur trifluoride (221 mg, 1 mmol), stirring for 2 hours, adding saturated sodium bicarbonate solution until the pH of the reaction solution was 7, 2 gas The decane extract (i〇mLx3), the organic phase 319 95344 201213319 phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography to afford the title product (1) 5Λ-6-[[2,6-difluoro-4-(1 甲 醯 醯 3 3 3,6-二气~2H-° ratio -4-yl)phenoxymethyl]-3-( 2-fluoro-2-indolyl-propyl)-3-mono-heterobicyclo[3.1.0]hexane 132 (150 mg, white solid), yield: 4 〇. 9%. MS m/z (ESI ): 459.1 [M+l] NMR (400 MHz, CDCh) δ 6. 90-6. 88 (m, 2H), 6. 05-6. 03

(m, lti), 3.95-3.90 (ra, 4H), 3.51 (t, 2H), 3.10 (br. M 擊 s, 2H), 2.86 (s, 3H), 2.60-2.45 (m, 6H), 1.67 (br. s, 1H), 1.37-1.25 (m, 8H) 實施例133 5-[(1兄550-6-^6-(3-氟-4-曱磺醯基-笨基）-3-。比啶基] 氧甲基]-3-氮雜雙環並[3. 1. 〇]己烷-3-基]-3-異丙基 -1，2, 4-噁二唑(m, lti), 3.95-3.90 (ra, 4H), 3.51 (t, 2H), 3.10 (br. M s, 2H), 2.86 (s, 3H), 2.60-2.45 (m, 6H), 1.67 (br. s, 1H), 1.37-1.25 (m, 8H) Example 133 5-[(1 brother 550-6-^6-(3-fluoro-4-sulfonyl-phenyl)-3- -pyridyl]oxymethyl]-3-azabicyclo[3. 1. 〇]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole

I … 133bI ... 133b

第一步 320 95344 201213319 2-(3-氟-4-亞甲磺醯基-苯基）-4, 4, 5, 5_四甲基一^ 3, 2_二 氧代硼酸 將4-溴-2-氟-1-甲基亞磺醯〜笨96b(23〇mg，〇. 97_〇1)， 聯删酸頻那醇酯（302mg，1. 19mmol)，醋酸鉀（291mg， 2. 97mrool)和1，1’ -二（二笨膦基）二茂鐵二氣化鈀（72mg， 0. 01 fflino 1)溶解於25mL 1，4-二°惡燒中，升溫至95°C，撥拌 反應2小時。加入30mL水，乙酸乙酯萃取（50mLx2)，合併 有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，用薄層 色譜法以展開劑體系B純化所得殘餘物，得到標題產物 2-(3-氟-4-亞曱磺醯基-苯基）~4, 4, 5, 5-四甲基-1，3, 2-二 氧代硼酸133a(195mg ’黃色固體），產率：71. 〇%。 MS m/z (ESI)： 285.1 [M+l] 第二步 6-(3-氟-4-亞甲續醯基-苯基 &gt;比咬-3-經基 將2-(3-氟-4-亞甲項醯基-苯基）-4, 4, 5, 5-四甲基 -1，3, 2-二氧代硼酸 133a(190mg，0. 67mmol)，3-羥基-6-演-°比咬（116mg ’ 0. 67nmiol)，碳酸絶（654mg，2mmol)和 1，Γ -二（二苯膦基）二茂鐵二氣化鈀（49mg，0. Olmrool)溶 解於5mL 1，4-二噁烷中，升溫至ll〇°C，攪拌反應4小時。 加入30mL水，乙酸乙酯萃取（50mLx2)，合併有機相，無水 硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品標題產物 6-(3-氟-4-亞曱磺醯基-苯基）吡啶-3-羥基133b(90mg，褐 色油狀物），產物不經純化直接進行下一步反應。 MS m/z (ESI): 252.0 [M+l] 321 95344 201213319 第三步 5-[(1^ 551)-6-[ [6-(3-H-亞甲磧醯基-苯基）-3-«&gt;比咬基] 氧甲基]-3-氮雜雙環並[3· 1. 0]己烷-3-基]-3-異丙基 -1，2, 4-°惡二唾 將粗品6-(3-氟-4-亞甲續醯基-苯基）η比咬-3-羥基 133b(90mg ’ 0. 30mmol) ’ [(1尤 55)-3-(3-異丙基-1, 2, 4- °惡一°坐_5 -基）-3_氮雜雙環並[3. 1· 0]己烧_6~基]曱基續酸 _ 甲酯 48c(108mg，0· 30mmol)和碳酸铯（233mg，0· 60mmol) 溶解於5mL #-二甲基甲醯胺中，升溫至ii〇°c，攪拌反 應4小時。加入30mL水，乙酸乙醋萃取（50mLx2)，合併有 機相’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到粗品 標題產物5-[(1兄5»S)-6-[[6-（3-氟-4-亞甲續酿基-苯 基）-3〜吡啶基]氧甲基]-3-氮雜雙環並[3. 1.0]己烷-3-基]-3-異丙基-1，2, 4-噁二唑133c(163mg，灰色固體），產 物不經純化直接進行下一步反應。 _ MS m/z (ESI): 457.2 [M+1] 第四步 5-[(1)?，5«-6-[[6-(3-氟-4-曱磺醯基-笨基）-3-吡啶基] 氧曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基 -1，2, 4-β惡二0坐 將粗品5-[(1及，55&quot;)-6_[ [6-(3-IL-4-亞甲續酿基-苯基） -3-吡啶基]氧曱基]_3_氮雜雙環並[3. 1.0]己烷-3-基]-3-異丙基-1，2, 4-°惡二。坐 133c(163mg，0. 35mmol)溶解於 5mL 二氯甲烷中，加入間氯過氧苯甲酸（184mg，0. 90mmol)，攪 322 95344 201213319 拌反應12小時。反應液減壓濃縮，用薄層色譜法以展開劑 體系B純化所得殘餘物，得到標題產物5-[(1兄550-6-[[6-(3-氟-4-甲磺醯基-苯基）〜3_吡啶基]氧曱基]-3-氮雜 雙環並[3. 1. 0]己烧-3-基]~3_異丙基-1，2, 4-β惡二β坐133 (5mg ’白色固體），產率：3. 0%。 MS ra/z (ESI): 473.2 [M+l] 'H NMR (400 MHz, CDCla) δ 8. 40-8. 39 (m, 1H), 8.00-7.92 (m, 1H), 7.89-7.87 (m, 2H), 7.74-7.72 (ra, 1H), 7.30-7.27 (m, 1H), 4.05-4.03 (m, 2H), 3.90-3.87 (m, 2H), 3.70-3.68 (m, 2H), 3.26 (s, 3H), 2.92-2.89 (m, 1H), 1.82 (s, 2H), 1.30-1.28 (m, 6H), 1.26 (s, 1H) 實施例134 5-[(l疋5«-6-[[6-(5-甲磺醯基-2-吡啶基）-3-吡啶基]氧 甲基]-3-氮雜雙環並[3. 1. 0]己烷-3-基]-3-異丙基 -1，2, 4-噁二唑First step 320 95344 201213319 2-(3-Fluoro-4-methanesulfonyl-phenyl)-4, 4, 5, 5_tetramethyl-(3,2-dioxaboronic acid 4-bromo 2-fluoro-1-methylsulfinium oxime~ stupid 96b (23〇mg, 〇. 97_〇1), conjugated acid pinacol ester (302mg, 1.19mmol), potassium acetate (291mg, 2. 97mrool) and 1,1'-di(diphenylphosphino)ferrocene dipalladium (72mg, 0.011 fflino 1) were dissolved in 25mL of 1,4-two-degree methane and heated to 95 ° C. Mix and react for 2 hours. After adding 30 mL of water and ethyl acetate (50 mL×2), the organic phase was combined, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. -Fluoro-4-ylidenesulfonyl-phenyl)~4,4,5,5-tetramethyl-1,3,2-dioxaborate 133a (195 mg 'yellow solid), yield: 71. 〇%. MS m/z (ESI): 285.1 [M+l]. Step 2 6-(3-fluoro-4-methylene-decyl-phenyl). -4-Methylene fluorenyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborate 133a (190 mg, 0.67 mmol), 3-hydroxy-6- -° ratio bite (116 mg '0.77 nmiol), carbonic acid (654 mg, 2 mmol) and 1, bis-bis(diphenylphosphino)ferrocene dipalladium (49 mg, 0. Olmrool) dissolved in 5 mL 1 The temperature was raised to ll 〇 ° C, and the reaction was stirred for 4 hr. The mixture was stirred for 4 hr. The title product, 6-(3-fluoro-4-sulfoniumsulfonyl-phenyl)pyridin-3-hydroxy 133b (90 mg, brown oil). ESI): 252.0 [M+l] 321 95344 201213319 Third Step 5-[(1^ 551)-6-[ [6-(3-H-Methylenesulfonyl-phenyl)-3-«&gt; Than the base] Oxymethyl]-3-azabicyclo[3·1]Hex-3-yl]-3-isopropyl-1,2,4-° dioxin will be crude 6- (3-fluoro-4-methylene hydrazino-phenyl) η than bite-3-hydroxy 133b (90 mg ' 0. 30mmol) '[(1 especially 55)-3-(3-isopropyl-1, 2, 4- ° 恶一°坐_5-yl)-3_ azabicyclo[3. 1· 0 _ _6~yl] hydrazino acid _ methyl ester 48c (108mg, 0 · 30mmol) and cesium carbonate (233mg, 0. 60mmol) dissolved in 5mL #-dimethylformamide, heated to ii〇 The reaction was stirred for 4 hours, then added with 30 mL of water and ethyl acetate (50 mL×2), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 5-[(1 brother 5»S) -6-[[6-(3-Fluoro-4-methylene)-phenylpyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3- 3- isopropyl-1,2,4-oxadiazole 133c (163 mg, m.p.), m. ] Step 4 5-[(1)?,5«-6-[[6-(3-Fluoro-4-sulfonyl-phenyl)-3-pyridyl]oxanyl]-3-nitrogen Heterobicyclo[3.1.0]Hex-3-yl]-3-isopropyl-1,2,4-β oxa 2 will sit the crude 5-[(1 and 55&quot;)-6_[ [6-(3-IL-4-methylene recalcyl-phenyl)-3-pyridyl]oxycarbonyl]_3_azabicyclo[3.1.0]hexane-3-yl]-3- Isopropyl-1,2, 4- Oxadiazol. 133c (163 mg, 0.35 mmol) was dissolved in 5 mL of dichloromethane, m-chloroperoxybenzoic acid (184 mg, 0. 90 mmol) was added, and the mixture was stirred for 322 95344 201213319 for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified, m.jjjjjjjjjjjjjj Phenyl)~3_pyridyl]oxycarbonyl]-3-azabicyclo[3.1.0]hexa-3-yl]~3_isopropyl-1,2,4-β坐 133 (5 mg 'white solid), yield: 3. 0%. MS / / (ESI): 473.2 [M+l] 'H NMR (400 MHz, CDCla) δ 8. 40-8. 39 ( m, 1H), 8.00-7.92 (m, 1H), 7.89-7.87 (m, 2H), 7.74-7.72 (ra, 1H), 7.30-7.27 (m, 1H), 4.05-4.03 (m, 2H), 3.90-3.87 (m, 2H), 3.70-3.68 (m, 2H), 3.26 (s, 3H), 2.92-2.89 (m, 1H), 1.82 (s, 2H), 1.30-1.28 (m, 6H), 1.26 (s, 1H) Example 134 5-[(l疋5«-6-[[6-(5-Methanesulfonyl-2-pyridyl)-3-pyridyl]oxymethyl]-3- Azabicyclo[3.1.0]hexane-3-yl]-3-isopropyl-1,2,4-oxadiazole

323 95344 201213319 第一步 (5-溴-2-吡啶基）-三丁基-錫 乾冰浴下，將2,5-二溴-吡啶134&amp;(〇.202,〇.84咖〇1) 溶解於10mL曱笨中’滴加2M 丁基鋰（〇. 5mL，0. 93mm〇l), 攪拌1小時，再滴加三丁基氣化錫（286mg，〇· 88ram〇1)，擾 拌反應1小時，升至室溫’加入1 〇mL飽和氯化鍵溶液，乙 酸乙酯萃取（30mLx3)，合併有機相，用飽和氣化鈉溶液洗 滌（lOmLxl) ’無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得 到粗品標題產物（5-溴-2-β比啶基）-三丁基-錫i34b(〇. 31 g，無色液體）’產物不經純化直接進行下一步反應。 MS m/z (ESI): 448·0 [M+1] 第二步 5-漠-2-(5-甲續酿基-2-°比咬基比咬 將粗品（5_漠_2-°比咬基）-三丁基-錫134b(189mg， 〇.42mmol)，5-曱磺醯基-2-溴-吡啶（lOOmg，0.42mmol)和 四三笨基膦把（l〇mg，〇· 〇lmm〇l)溶解於l〇mL甲苯中，升溫 至120〇C，攪拌反應15小時。加入100mL乙酸乙酯，用飽 和氯化鈉溶液洗滌（20mLx2)，無水硫酸鎂乾燥，過濾，濾 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得 殘餘物，得到標題產物5-溴-2-(5-曱磺醯基-2-吡啶基）吡 °定134c(83mg，白色固體），產率：63. 4%。 MS m/z (ESI): 312.9 [M-l] 第三步 6 -（5-f續酿基_2-°比变基）σ比咬-3-經基 324 95344 201213319 將5-溴-2-(5-曱磺醯基-2-吡啶基）吡啶134c(200mg， 0. 64mmol)，聯硼酸頻那醇酯（211mg ’ 〇. 83mmol)，醋酸鉀 (188mg，1.92mmol)和 1,1’ -二（二苯膦基）二茂鐵二氯化 鈀（26mg，〇.〇3minol)溶解於l〇mL 1,4-二噁烷中，升溫至 95°C，攪拌反應2小時。加入80mL乙酸乙酯，用飽和氯化 鈉溶液洗滌（20rnLx2)，無水硫酸鎂乾燥，過濾，濾液減壓 濃縮’得到的粗品溶解於lOffiL四氫呋喃中，冰浴冷卻，依 次滴加0. 4mL 5M氫氧化納溶液，〇. 3niL30%過氧化氫溶液， 室溫授摔反應15小時。加入1 OmL水’分液，滴加1 μ鹽酸 至水層pH為7，乙酸乙酯萃取（30mLx3) ’合併有機相，用 飽和氣化鈉溶液洗滌（2〇mLx2)，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，得到粗品標題產物6-(5-曱磺醯基-2-吼啶 基）吼啶〜3-羥基134d(30mg，灰色固體），產物不經純化直 接進行下一步反應。 MS m/z (ESI)： 251.0 [M+l] φ 第四步 5-[(1亿55*)~6-[[6-(5-甲續醯基-2-°比°定基）-3-吼啶基]氧— 甲基]-3-氮雜雙環並[3· 1. 0]己烷-3-基]-3-異丙基 〜1，2, 4-噁二唑 將粗品6-(5-甲確醯基-2-°比啶基）吡啶-3-羥基I34d (30mg，〇· 12mmol)，[(1疋 5^-3-(3-異丙基-1，2, 4-惡二唑 -5-基）-3-氮雜雙環並[3. 1· 〇]己烷-6-基]曱基磺酸曱酯 48c(39mg ’ 〇· 13minol)和碳酸絶（78fflg，0. 24mmol)溶解於 lOmLyV，#-二甲基甲醯胺中，升溫至u〇°c，攪拌反應2小 325 95344 201213319 時。加入20mL水，乙酸乙酯萃取（30mLx3)，合併有機相， 用飽和氯化鈉溶液洗滌（20mLx2)，無水硫酸鎮乾燥，過遽， 慮液減壓濃縮，用薄層色譜法以展開劑體系B純化所得殘 餘物’得到標題產物[β-(5_曱續酿基-2-°比啶基）-3-°比啶基]氧曱基]-3-氮雜雙環並[3. 1. 〇]己燒 -3-基]-3-異丙基-1，2,4-噁二唑I34(8mg，白色固體），產 率：14. 5%。 MS m/z (ESI): 456.2 [M+l] H NMR (400 MHz, CDCh) δ 9. 13 (s, 1H)&gt; 8. 56-8. 54 (m 1H), 8.47-8.45 (m, 1H), 8.39 (s, lH), 8.29-8.27 1H), 7.33-7.31 (m, 1H), 4.07-4.05 (m，2H), 3.90-3.87 (m，2H)，3. 7卜3.68 (m, 2H)，3.14 (s，3H)，2.90-2.89 (m, 1H), 1.65-1.63 (m, 1H), 1.30-1.28 (m, 6H), 1.27-1.25 (m, 2H) 實施例135 鲁 U尤55)-3-異丙基-6-[[6-(4-甲續醯基苯基）_3_。比嘴基] 氧甲基]-3-氣雜雙環並[3· 1〇]己炫323 95344 201213319 The first step (5-bromo-2-pyridyl)-tributyl-tin dry ice bath, 2,5-dibromo-pyridine 134 &amp; (〇.202, 〇.84 curry 1) dissolved 2M butyl lithium (〇. 5mL, 0. 93mm〇l) was added dropwise in 10 mL of hydrazine, stirred for 1 hour, and then tributyltin hydride (286 mg, 〇·88ram〇1) was added dropwise, and the reaction was disturbed. 1 hour, rise to room temperature 'Add 1 〇mL saturated chlorination solution, extract with ethyl acetate (30mL×3), combine the organic phase, wash with saturated sodium carbonate solution (10 mL×l), dry over anhydrous magnesium sulfate, filter, filtrate minus Concentration under pressure gave the crude title product (5-bromo-2-[pi]pyridinyl)-tributyl-tin i34b (.31 g, colorless liquid). MS m/z (ESI): 448·0 [M+1] The second step 5 - desert -2- (5-methyl nitrate--2-° ratio bite base bite will be crude (5_ desert_2- ° 咬 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 〇· 〇lmm〇l) was dissolved in 10 mL of toluene, heated to 120 ° C, and stirred for 15 hours. Add 100 mL of ethyl acetate, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous magnesium The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc , white solid), Yield: 63. 4%. MS m/z (ESI): 312.9 [Ml] The third step 6 - (5-f continuation base 2 - ° ratio base) σ ratio bite-3 - bromo 324 95344 201213319 5-bromo-2-(5-nonylsulfonyl-2-pyridinyl)pyridine 134c (200 mg, 0.64 mmol), boranoic acid pinacol ester (211 mg ' 〇. 83 mmol), Potassium acetate (188 mg, 1.92 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (26 mg, 〇.〇3 minol) dissolved in 1 mL of 1,4-dioxane The temperature was raised to 95 ° C, and the reaction was stirred for 2 hours. 80 mL of ethyl acetate was added, washed with a saturated sodium chloride solution (20 rnLx2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in loffiL tetrahydrofuran. The ice bath was cooled, and then 0. 4mL of 5M sodium hydroxide solution was added dropwise, 3niL 30% hydrogen peroxide solution, and the reaction was dropped for 15 hours at room temperature. 1 mL of water was added to dispense liquid, and 1 μ hydrochloric acid was added dropwise to the water layer. The mixture was extracted with ethyl acetate (30 mL×3).曱 醯 醯 吼 吼 吼 吼 吼 吼 〜 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 。 。 。 。 。 。 。 。 。 。 。 。 。 The fourth step is 5-[(1 billion 55*)~6-[[6-(5-methyl-indolyl-2-° ratio]-based)-3-acridinyl]oxy-methyl]-3-nitrogen Heterobicyclo[3·1.0]hexane-3-yl]-3-isopropyl~1,2,4-oxadiazole will be crude 6-(5-methyl-decyl-2-pyridine Pyridyl-3-hydroxy I34d (30 mg, 〇·12 mmol), [(1疋5^- 3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1·〇]hexane-6-yl]decylsulfonate 48c (39mg '〇·13minol) and carbonic acid (78fflg, 0.24mmol) were dissolved in lOmLyV, #-dimethylformamide, and the temperature was raised to u〇°c, and the reaction was stirred at 2 325 95344 201213319. Add 20mL of water, extract with ethyl acetate (30mLx3), combine the organic phase, wash with saturated sodium chloride solution (20mLx2), dry over anhydrous sulfuric acid, simmer, concentrate under reduced pressure, using thin layer chromatography to develop the system Purification of the residue obtained by B to give the title product [β-(5 曱 曱 -2- -2- ° 啶 ) ) ) -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 5%] Benzene-3-yl]-3-isopropyl-1,2,4-oxadiazole I34 (8 mg, white solid), yield: 14.5%. MS m/z (ESI): 456.2 [M+l] H NMR (400 MHz, CDCh) δ 9. 13 (s, 1H)&gt; 8. 56-8. 54 (m 1H), 8.47-8.45 (m , 1H), 8.39 (s, lH), 8.29-8.27 1H), 7.33-7.31 (m, 1H), 4.07-4.05 (m, 2H), 3.90-3.87 (m, 2H), 3. 7 b 3.68 ( m, 2H), 3.14 (s, 3H), 2.90-2.89 (m, 1H), 1.65-1.63 (m, 1H), 1.30-1.28 (m, 6H), 1.27-1.25 (m, 2H) Example 135 Lu U especially 55)-3-isopropyl-6-[[6-(4-methyl-decylphenyl)_3_. Than mouth base] oxymethyl]-3-gas heterobicyclo[3·1〇]

將（1尤5^-6-[[6-(4-曱磺醯基笨基）_3_^啶基]氧 95344 326 201213319 曱基]-3-氮雜雙環並[3. h 〇]己烷鹽酸99b(11〇mg， 0. 32mmol)溶解於2〇mL二氣曱烷中，依次加入異丁醛 (35mg，0.48mmol)和醋酸（38mg，〇.64mmol)，攪拌反應 30 分鐘。再加入三乙醯氧基硼氫化鈉（135mg，〇. 64mmol)，攪 拌反應12小時。加入水i〇mL，二氣曱烷萃取（2〇mLx3) ’ 合併有機相’用飽和氣化鈉溶液洗滌（2〇mLxl)，無水硫酸 鎮乾燥’過濾’濾液減壓濃縮，用薄層色譜法以展開劑體 系A純化所得殘餘物，得到標題產物異丙基 * -6_[ [6一（4_曱磺醯基苯基）-3-吡啶基]氧甲基]-3-氮雜雙 環並[3.1.0]己烷135(6011^，白色固體），產率：46.9〇/〇。 MS ra/z (ESI)： 401.1 [M+l] 'H NMR (400 MHz, CDCh) δ 8.37 (s, 1H), 8.13 (d, 2H), 8.00(d, 2H), 7.73 (d, 1H), 7. 29 (s, 1H), 3. 99 (d, 2H), 3. 08(s, 3H), 2.90(s, 2H), 2. 73 (s, 2H), 2. 17 (s, 1H), 2.09 (s, 3H), 1.81 (s, 2H), 1.05 (d, 6H) φ 實施例136 (1^ 55·)-6-[[2, 6-二氟-4-(卜甲磺醯基-3, 6-二氫-2及-吡善 啶-4-基）苯氧基]甲基]_3_(5-乙基嘧啶-2-基）-3-氮雜雙 環並[3. 1.0]己烷Will (1 especially 5^-6-[[6-(4-oxasulfonyl)]_3_^yl]oxy 95344 326 201213319 fluorenyl]-3-azabicyclo[3.h 〇]hexane Hydrochloric acid 99b (11 mg, 0. 32 mmol) was dissolved in 2 mL of dioxane, and isobutyraldehyde (35 mg, 0.48 mmol) and acetic acid (38 mg, 〇.64 mmol) were added in that order, and the reaction was stirred for 30 minutes. Sodium triethoxysulfonium borohydride (135 mg, 〇. 64 mmol), stirred for 12 hours. Water i 〇 mL, dioxane extraction (2 〇 mL x 3) 'The combined organic phase' was washed with saturated sodium carbonate solution ( 2 〇mLxl), anhydrous sulphuric acid-drying 'filtered' filtrate was concentrated under reduced pressure, and the obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) Nonylphenyl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane 135 (6011^, white solid), yield: 46.9 〇/〇. MS ra/z (ESI): 401.1 [M+l] 'H NMR (400 MHz, CDCh) δ 8.37 (s, 1H), 8.13 (d, 2H), 8.00 (d, 2H), 7.73 (d, 1H), 7. 29 (s, 1H), 3. 99 (d, 2H), 3. 08(s, 3H), 2.90(s, 2H), 2. 73 (s, 2H), 2. 17 (s, 1H), 2.09 (s, 3H), 1.81 (s, 2H), 1 .05 (d, 6H) φ Example 136 (1^55·)-6-[[2,6-Difluoro-4-(buxosulfonyl-3,6-dihydro-2 and-pyridyl) Pyridin-4-yl)phenoxy]methyl]_3_(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane

201213319201213319

第一步first step

4-[4-[[(1尤55·)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烧_6-基]甲氧基]-3, 5-二象-苯基]-3, 6-二氫 -2及-吡啶-1-羧酸第三丁酯 將4-(3, 5-二氟-4-羥基-苯基）-3, 6-二氫-2万比啶 -1-竣酸第三丁酯 131a(466mg，1. 50mmol)溶解於 10mL 水菸二曱基曱醯胺中，加入[(1兄55)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]甲磺酸曱酯7g (404mg，1. 36mmol)和碳酸鉀（563mg，4. 08mmol)，升溫至 100°C，攪拌反應3小時。加入25mL水，乙酸乙酯萃取 (50mLx4)，合併有機相，依次用水（50mLxl)，飽和氯化納 溶液洗滌（50mLxl)，無水硫酸鎂乾燥，過濾，濾液減壓濃 縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物， 得到標題產物4-[4-[[(1疋550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱氧基]-3, 5-二氟-苯 基]-3,6-二氫-2分-吡啶-1-羧酸第三丁酯1363(38〇11^，無 色黏稠液體），產率：59. 8%。 328 95344 201213319 MS m/z (ESI): 513.2 [M+l] 第二步 (1/?，55&quot;)-6-[[2, 6- — ，2, 3, 6-四氫D比咬-4-基）苯氧 基]甲基]-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. ι· 〇]己 烧4-[4-[[(1 especially 55·)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexa-[6-yl]methoxy] 3-(3,5-difluoro-4-hydroxy-benzene, tert-butyl 3-, 3-dihydro-phenyl]-3,6-dihydro-2 and-pyridine-1-carboxylic acid Base,-3,6-dihydro-2,000-bipyridin-1-carboxylic acid, tert-butyl ester 131a (466 mg, 1.50 mmol) was dissolved in 10 mL of smokylidene guanamine, added [(1 brother 55) 3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanesulfonate 7 g (404 mg, 1.36 mmol) and potassium carbonate ( 563 mg, 4.08 mmol), the temperature was raised to 100 ° C, and the reaction was stirred for 3 hours. After adding 25 mL of water and ethyl acetate (50 mL×4), the organic phase was combined, washed with water (50 mL×l), EtOAc (EtOAc) The obtained residue was purified with EtOAc EtOAc (EtOAc). . 0]Hex-6-yl]decyloxy]-3,5-difluoro-phenyl]-3,6-dihydro-2-pyridine-3-carboxylic acid tert-butyl ester 1363 (38〇) 11^, colorless viscous liquid), yield: 59.8%. 328 95344 201213319 MS m/z (ESI): 513.2 [M+l] Step 2 (1/?, 55&quot;)-6-[[2 , 6- — , 2, 3, 6-tetrahydro D is more than -4-yl)phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[ 3. ι· 〇] already burned

將4-[4-[[(1尤550-3-(5-乙基嘧啶-2-基）-3~氮雜雙 環並[3_ 1. 0]己烷-6-基]曱氧基]一3, 5-二氟_苯基]-3, 6''二 氫-2於吡啶-1-羧酸第三丁酯i36a(380mg，0· 74mmol)溶解 於10mL二氣曱烷中，加入imL三氟醋酸，攪拌反應2小時。 滴加1M飽和碳酸鈉溶液至反應液pH為10,乙酸乙酯萃取 (50mLx4) ’合併有機相’依次用水（5〇mLxl) ’飽和氯化納 溶液洗滌（30mLxl)，無水硫酸鎂乾燥，過濾，濾液減壓濃 縮，得到粗品標題產物（1疋550-6-1^2, 6-二氟Μα， 2, 3, 6〜四 氫吡啶-4-基）苯氧基] 甲基]-3-(5-乙 基嘧啶 -2-基）-3-氮雜雙環並[3. 1·〇]己烷I36b(0.27g，黃色油狀 物）’產物不經純化直接進行下一步反應。 MS m/z (ESI)： 413.3 [Μ+1] Φ 第三步 (U，5«-6-[[2, 6-二氟-4-(1-甲磺醯基-3, 6-二氫比 咬-4-基）苯氧基]曱基]_3_(5_乙基嘧啶_2_基）-3_氮雜雙 環並[3. 1. 0]己垸 將粗品（1忆 55*)-6-[[2, 6-二氟-4-(1，2, 3, 6-四氫n比 唆-4-基）苯氧基]甲基]一3~(5-乙基唆咬-2-基）-3-氮雜雙 環並[3· 1· 〇]己烷 l36b(270mg，0. 65mmol)溶解於 10mL 二 329 95344 201213319 氣甲烧中’加入三乙胺（197mg，1. 95廳〇 1) ’冰浴下慢慢滴 加曱續酿氯（112mg ’ 〇, 98mmol)，0°C授拌反應]•小時。加 入50mL水’二氯曱烷萃取（5〇mLx3)，合併有機相，依次用 水GOmLxU ’飽和氣化鈉溶液洗滌（5〇mLxl)，無水硫酸錢 乾燥’過濾，濾液減壓濃縮，用矽膠營挺 體系A純化所得殘餘物，得到標題產物（丨友礅法以洗脫劑 二敦-4-( 1-甲續醯基-3, 6-二氫-2及-%0定 ）6 [[2, 64-[4-[[(1 especially 550-3-(5-ethylpyrimidin-2-yl)-3~ azabicyclo[3_1.0]hexyl-6-yl] decyloxy]] a 3,5-difluoro-phenyl]-3,6''dihydro-2-pyridine-3-carboxylic acid tert-butyl ester i36a (380 mg, 0.77 mmol) was dissolved in 10 mL of dioxane, added imL trifluoroacetic acid, stirring reaction for 2 hours. Add 1M saturated sodium carbonate solution to the reaction solution pH 10, ethyl acetate extraction (50mLx4) 'combined organic phase' followed by washing with water (5〇mLxl) 'saturated sodium chloride solution (30 mL×1), dried over anhydrous magnesium sulfate, filtered and evaporated. Phenoxy]methyl]-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·〇]hexane I36b (0.27 g, yellow oil) The next reaction was carried out without purification. MS m/z (ESI): 413.3 [Μ+1] Φ The third step (U,5«-6-[[2, 6-difluoro-4-(1-A) Sulfhydryl-3,6-dihydrobiti-4-yl)phenoxy]indenyl]_3_(5-ethylpyrimidin-2-yl)-3_azabicyclo[3. 1. 0]垸 垸 will be crude (1 recall 55*)-6-[[2, 6-difluoro-4-(1,2, 3, 6-tetrahydro n ratio唆-4-yl)phenoxy]methyl]-3~(5-ethylindole-2-yl)-3-azabicyclo[3·1· 〇]hexane l36b (270 mg, 0. 65mmol) dissolved in 10mL two 329 95344 201213319 gas-fired 'added triethylamine (197mg, 1. 95 hall 〇 1) ' slowly added to the ice under the ice bath (112mg ' 〇, 98mmol), 0° C mixing reaction]•hour. Add 50mL water 'dichlorodecane extraction (5〇mLx3), combine the organic phase, and then wash with water (5〇mLxl) with water saturated solution of GOmLxU ', saturated with sulfuric acid, 'filter, The filtrate was concentrated under reduced pressure, and the obtained residue was purified using EtOAc EtOAc (EtOAc EtOAc) -%0 fixed)6 [[2, 6

基]-3-(5-乙基喊咬-2-基）-3-氮雜雙壤你「）本氧基]曱 136(130mg，白色固體），產率：40.8%。 」 MS m/z (ESI): 491.1 [M+l]]]-3-(5-ethyl-chick-2-yl)-3-aza-bi-salt you ") oxy] 曱 136 (130 mg, white solid), yield: 40.8%." MS m/ z (ESI): 491.1 [M+l]

Ή NMR (400 MHz, i/-DMSO) δ 8.21 (s, 〇UN 印），6.94 (d，2H)， 6.10 (s, 1H), 4.10 (d, 2H), 4.00 (s, on, 3. 89 (d, 2H), 3.58-3.54 (m, 4H), 2.90 (s, 3H), 2 r〇 , * b2 (s, 2H), 2. 53- 2.47 (q, 2H), 1.71 (s, 2H), 1.30-^ί 0n ^ A*2〇 (m, 4H) 實施例137NMR NMR (400 MHz, i/-DMSO) δ 8.21 (s, 〇UN), 6.94 (d, 2H), 6.10 (s, 1H), 4.10 (d, 2H), 4.00 (s, on, 3. 89 (d, 2H), 3.58-3.54 (m, 4H), 2.90 (s, 3H), 2 r〇, * b2 (s, 2H), 2. 53- 2.47 (q, 2H), 1.71 (s, 2H), 1.30-^ί 0n ^ A*2〇(m, 4H) Example 137

(1 尼 5«_3-(5-乙基嘧啶-2-基）-6-[[6 啶基）-3-吡啶基]氧甲基]-3-氮雜雙 (1 -甲續酿基-4-嘛_ J裒並[3. 1. 0]己烷(1 Nie 5«_3-(5-ethylpyrimidin-2-yl)-6-[[6 pyridine)-3-pyridyl]oxymethyl]-3-aza bis (1-methyl aryl) -4- Well _ J裒 and [3. 1. 0] Hexane

95344 330 201213319 將（1/?，550-3-(5-乙基嘧啶-2-基）-6-[ [6-( 1-甲磺醯 基-3，6_二氮比咬-4_基）-3_B比ϋ定基]氧曱基]-氮雜 雙環並[3· 1. 0]己烷128(100mg，0. 22顏〇1)溶解於20mL曱 醇中，加入鈀/碳（20mg，10%)，攪拌反應12小時。過濾， 濾餅用二氯甲烷洗滌（20mLx3)，濾液減壓濃縮，用矽膠管 柱色譜法以洗脫劑體系A純化所得殘餘物’得到標題產物 (1尤5Λ-3-(5-乙基嘧啶-2-基）-6-[[6_(1-甲磺醯基-4-哌 啶基）-3-吡啶基]氧f基]-3-氮雜雙環並[3. 1.〇]己烷137 鲁 （30mg，白色固體），產率：29.8%。 MS m/z (ESI): 458.2 [M+l] 4 腿R (400 MHz, CDCla) (5 8.27 (d，1H)，8. 21 (s，2H)， 7.22 (d, 1H), 7.13 (d, 1H), 3.99 (dd, 5H), 3.61 (d, 2H), 2.94-2.74 (m, 5H), 2.50 (q, 2H), 2.20-2.00 (m, 3H), 1.98-1.85 (m, 2H), 1.78 (s, 2H), 1.22 (t, 3H), 0.92 (t, 2H) 鲁 實施例138 (1尤5«-3-(5-氣嘧啶-2-基）-6-[[6-(1-曱磺醯基-3,6-二 氫比啶-4-基）-3-批啶基]氧甲基]-3-氮雜雙環並 [3. 1.0]己烷95344 330 201213319 Will (1/?,550-3-(5-ethylpyrimidin-2-yl)-6-[ [6-( 1-methylsulfonyl-3,6-diazepine bite-4_) ))-3_B ϋ 基 ] 曱 曱 ] ] ] ] ] 3 3 3 3 3 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( , 10%), the reaction was stirred for 12 hours. Filtration, the filter cake was washed with dichloromethane (20 mL×3), the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give the title product (1) Λ5Λ-3-(5-ethylpyrimidin-2-yl)-6-[[6-(1-methylsulfonyl-4-piperidyl)-3-pyridyl]oxyfyl]-3-nitrogen Heterobicyclo[3. 1.]hexane 137 ru (30 mg, white solid), yield: 29.8% MS m/z (ESI): 458.2 [M+l] 4 leg R (400 MHz, CDCla) (5 8.27 (d, 1H), 8. 21 (s, 2H), 7.22 (d, 1H), 7.13 (d, 1H), 3.99 (dd, 5H), 3.61 (d, 2H), 2.94-2.74 ( m, 5H), 2.50 (q, 2H), 2.20-2.00 (m, 3H), 1.98-1.85 (m, 2H), 1.78 (s, 2H), 1.22 (t, 3H), 0.92 (t, 2H) Example 138 (1 especially 5«-3-(5-apyrimidin-2-yl)-6-[[6-(1-oxasulfonyl-3,6-dihydropyridin-4-yl) -3-triazinyl]oxymethyl]-3- Heteroaryl bicyclo [3. 1.0] hexane

331 95344 201213319331 95344 201213319

6-(1，2, 3, 6-四氫吡啶-4-基）吡啶-3-經基 將4-(5-羥基-2-吡啶基）-3, 6-二氫-2)7-吡啶-1-羧酸 第三丁酯128a(552mg ’ 2mmol)溶解於2〇‘二氯甲烧中， 加入2mL二氟醋酸’擾掉反應12小時。反應液減壓濃縮， 得到粗品標題產物6-(1，2，3，6〜四氫β比咬-4-基）处咬_3_ 經基138a(500mg ’黃綠色油狀物），產物不經純化直接進 行下一步反應。 φ MS ra/z (ESI): 177.0 [M+l] 第二步 [6_(1-甲續醯基-3, 6-二氫-211-«»比咬-4-基）-3-〇比咬基]甲 續酸酉旨 將6-(1，2, 3, 6-四氫吡啶-4-基）吡啶-3-羥基138a (352mg，2mmol)溶解於10mL二氣曱烷中，冰浴下，加入甲 續醢氣（344mg ’ 3mmol)和三乙胺（607mg，6mmol)，0°C 擾拌 反應2小時。加入50mL水，用二氯甲烷萃取（50mLx3)，合 併有機相，依次用水（50mLxl)，飽和氣化納溶液洗條 332 95344 201213319 (50mLxl)，無水硫酸鎂乾燥，過滤，遽液減壓濃縮，用石夕 膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題 產物[6-(1-甲磺醯基-3, 6-二氫-2H-吡啶-4-基）-3-吡啶基] 甲磺酸酯138b(339mg，淡黃色固體），產率：51. 1%。 MS m/z (ESI): 333.0 [M+l] 第三步 6-(1-曱續酿基_3,6-二氫-211-〇比咬-4-基）°比唆-3-醇 將[6-(1-甲石黃醢基-3, 6-二氫-2Η-0比咬-4-基）-3-0比 籲啶基]曱磺酸酯138b(l g’ 3mmol)溶解於3mL二氯曱烷中， 加入10mL甲醇，再依次加入氫氧化鈉（360mg，9mmol)和 2mL水，升至40°C，攪拌反應2小時。加入20mL水，滴加 1 Μ鹽酸至反應液pH為6，反應液減壓濃縮，過濾，乾燥， 得到標題產物甲石黃酿基_3, 6~二氫-2H-°比咬-4〜基） 吡啶-3-醇138c(620mg，白色固體），產率：81. 3%。 MS m/z (ESI): 255.2 [M+l] 第四步 (1兄 55)-3-(5-氯嘴n定-2-基）-6-[ [6-(1-曱確醯基—3 一 ，丨&quot;1_&gt; 氫-2及-吡啶-4-基）-3-吡啶基]氧甲基]-3-氮雜雙環並 [3· ΙΟ]己烷 將6-(1-曱磺醯基-3, 6-二氬-2H-吡啶-4-基）吡啶 醇138c(381fflg，1.50fflrool)溶解於15mL况於二甲基甲醯 胺中，依次加入[(1足55)-3-(5-氣嘧啶_2_基）-3-氮雜雙環 並[3· 1.0]己烷-6-基]甲磺酸甲酯 1〇4b(5〇lmg，1. 65mm〇1) 和碳酸鉀（518mg，3. 75imol)，升溫至i〇(^c，攪拌反應i 95344 333 201213319 小時。降溫至85°C，攪拌反應12小時。加入50mL水，二 氣曱烷萃取（60mb&lt;3)，合併有機相，依次用水（30mLxl)， 飽和氯化納溶液洗蘇（30mLx2)，無水硫酸鎂乾燥，過濾、， 濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所 得殘餘物，得到標題產物（1疋5«-3-(5-氯嘧啶-2-基）-6-[[.6_(1-曱石黃醢基-3，6-二氫_2及-0比0定-4-基）-3-°比咬基]氣 甲基]-3-氮雜雙環並[3. 1.0]己烷138(380mg，白色固體）， 產率：54. 8%。6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-3-yl) 4-(5-hydroxy-2-pyridyl)-3,6-dihydro-2)7- Pyridine-1-carboxylic acid tert-butyl ester 128a (552 mg '2 mmol) was dissolved in 2 〇 'dichloromethane, and 2 mL of difluoroacetic acid was added to disturb the reaction for 12 hours. The reaction solution was concentrated under reduced pressure to give the crude title product 6-(1,2,3,6~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The next reaction was carried out directly by purification. φ MS ra/z (ESI): 177.0 [M+l] The second step [6_(1-methyl-indolyl-3,6-dihydro-211-«» than -4-yl)-3-〇 6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-3-hydroxy 138a (352 mg, 2 mmol) was dissolved in 10 mL of dioxane, ice. Under a bath, helium (344 mg '3 mmol) and triethylamine (607 mg, 6 mmol) were added and the reaction was stirred at 0 °C for 2 hours. After adding 50 mL of water, and extracting with dichloromethane (50 mL×3), the organic phase was combined, and then washed with water (50 mL×l), EtOAc EtOAc EtOAc EtOAc The residue obtained was purified by eluent from EtOAc EtOAc (EtOAc) 1%。 Pyridyl] mesylate 138b (339 mg, pale yellow solid), yield: 51.1%. MS m/z (ESI): 333.0 [M+l] The third step 6-(1- 曱 酿 _ _ 3,6-dihydro-211-〇 咬 -4- -4- base) ° 唆 -3- The alcohol dissolves [6-(1-methylglycosyl-3,6-dihydro-2Η-0-biti-4-yl)-3-0pyridinyl]anthracene sulfonate 138b (1 g' 3 mmol) To 3 mL of dichloromethane, 10 mL of methanol was added, and then sodium hydroxide (360 mg, 9 mmol) and 2 mL of water were successively added, and the mixture was warmed to 40 ° C, and the reaction was stirred for 2 hours. 20 mL of water was added, 1 Μ hydrochloric acid was added dropwise to the pH of the reaction mixture, the reaction mixture was concentrated under reduced pressure, filtered, and dried to give the title product, s,,,,,,,,,,,,,,,,, Pyridine-3-ol 138c (620 mg, white solid), yield: 81.3%. MS m/z (ESI): 255.2 [M+l] Step 4 (1 brother 55)-3-(5-chloro-n-n-but-2-yl)-6-[ [6-(1-曱定醯Base-3, 丨&quot;1_&gt; Hydrogen-2 and -pyridin-4-yl)-3-pyridyl]oxymethyl]-3-azabicyclo[3·ΙΟ]hexane 6-(1 -Indolyl-3,6-di-argon-2H-pyridin-4-yl)pyridinol 138c (381fflg, 1.50fflrool) was dissolved in 15 mL of dimethylformamide, and sequentially added [(1 foot 55) )-3-(5-amphazin-2-yl)-3-azabicyclo[3·1.0]hexane-6-yl]methyl methanesulfonate 1〇4b (5〇lmg, 1. 65mm〇) 1) and potassium carbonate (518mg, 3. 75imol), warmed to i〇 (^c, stirring reaction i 95344 333 201213319 hours. Cooling to 85 ° C, stirring reaction for 12 hours. Add 50mL water, dioxane extraction ( 60mb&lt;3), the organic phase was combined, washed with water (30mLxl), saturated sodium chloride solution (30mLx2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using a gel column chromatography to eluent system The residue obtained is purified to give the title product (1疋5«-3-(5-chloropyrimidin-2-yl)-6-[[.6_(1-曱石黄醢基-3,6-dihydro-2 and -0 is 0 to -4-base) -3-° than bite Methyl]-3-azabicyclo[3.1.0]hexane 138 (380 mg, white solid), yield: 54.8%.

MS m/z (ESI): 462.2 [M+l] 4 丽R(400 MHz，J-DMSO) d 8.26(s, 1H)，8. 22(s，2H)， 7.31 (d, 1H), 7.16 (d, 1H), 6.49 (s, 1H), 4.00-3.91 (m, 6H), 3.53-3.52 (m, 4H), 2. 86 (s, 3H), 2.76 (m, 2H), 1.77 (m, 2H), 1.19 (m, 1H) 實施例139 (1尤550-3-(2-氟-2-甲基-丙烷）-6-[ [6-(1-甲磺醯基 -3, 6-二氫-2及-吡啶-4-基）-3-吡啶基]氧甲基]-3-氮雜雙 環並[3. 1. 0]己烷MS m/z (ESI): 462.2 [M+l] 4 R (400 MHz, J-DMSO) d 8.26 (s, 1H), 8. 22 (s, 2H), 7.31 (d, 1H), 7.16 (d, 1H), 6.49 (s, 1H), 4.00-3.91 (m, 6H), 3.53-3.52 (m, 4H), 2. 86 (s, 3H), 2.76 (m, 2H), 1.77 (m , 2H), 1.19 (m, 1H) Example 139 (1 especially 550-3-(2-fluoro-2-methyl-propane)-6-[ [6-(1-methylsulfonyl-3, 6 -dihydro-2 and-pyridin-4-yl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane

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(1足550-6-1^6-(1-甲磺醯基_3, 6_二氫一2及一吡啶-4-基）-3-吡啶基]氧曱基]〜3〜氮雜雙環並[3. 1. 0]己烷-3-羧 酸第三丁酯(1 foot 550-6-1^6-(1-methylsulfonyl-3,6-dihydro-2 and pyridin-4-yl)-3-pyridyl]oxanyl]~3~aza Bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

將6-(1-曱磺醯基-3, 6~二氫-2H-吡啶-4-基）吡啶-3-羥基 138c(280mg ’ 1. 10mm〇i)，（i亿 55)-6-(甲磺醯氧基曱 基）-3-氮雜雙環並[3. 1.〇]己烷_3_羧酸第三丁酯16b (417mg，1. 43mmol)和碳酸鉀（455mg，3. 3〇mmol)溶解於 8mL 况二甲基甲醯胺中’升至，攪拌反應8小時β加入 100mL水’用乙酸乙酯萃取（5〇mLx3)，合併有機相，用餘 和氯化鈉溶液洗滌（50mLxl)，無水硫酸鈉乾燥，過滤’遽、 液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所得 殘餘物，得到標題產物（1^55)-641:6-(1-曱磺醢基_3,6_ 二氫-2及-吡啶-4-基）-3-吡啶基]氧甲基]-3-氮雜雙環並 [3. 1. 0]己烷-3-羧酸第三丁酯139a(360mg，白色固體）’ 產率：73. 0%。 MS m/z (ESI): 394.1 [M-55] 第二步 335 95344 201213319 1-[(1尤550-6-^6-(卜甲磺醯基-3, 6-二氫-2分-吡啶-4-基）-3-吡啶基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-基] 丙烷-2-醇 將（1兄5«-6-[[6-(1-曱磺醯基-3,6-二氫-2皮-吡啶 -4-基）-3-吡啶基]氧曱基]-3-氮雜雙環並[3. 1. 0]己烷-3-羧酸第三丁酯139a(360mg，0.80mmol)溶解於15mL 4M鹽 酸1，4-二噁烷溶液中，攪拌反應1小時，反應液減壓濃縮， 在殘餘物中加入20mL曱醇和三乙胺（242mg，2. 40mmol)， ® 再加入2, 2-二甲基環氧乙烧（173mg，2. 40mmol)，升至33 °C，攪拌反應12小時。反應液減壓濃縮，用矽膠管柱色譜鲁 法以洗脫劑體系A純化所得殘餘物，得到標題產物 1-[(1皮，551)-6-[[6-(1-曱續醢基-3,6_二氫-2及~〇比啶-4-基）-3~吡啶基]氧甲基]-3-氮雜雙環並[3. 1. 〇]己烷-3-基] 丙院-2-醇139b(200mg，白色固體），產率：60. 〇%。 MS ra/z (ESI): 422.2 [M+l] , 第三步 (1尤55)-3-(2-氟-2-甲基-丙烧）-β-[[6_(卜甲績醯基鲁 _3, 6-二氫-2士吡啶-4-基）-3'•吡啶基]氧曱基]一3_氮雜雙 環並[3. 1. 〇]己烷 乾冰浴下，將甲磺醯基_3,6_ 二氫-2#-吡啶-4-基）-3-吡啶基]氧曱基]_3_氮雜雙環並 [3. 1· 0]己烧-3-基]丙烧-2-醇 139b(20〇mg，〇. 47mmol)溶 解於20mL二氣f烷t，加入雙（2-?氧基乙基）胺基三氟化 硫（157邶，0· 71mm〇l)，升至室溫，攪拌反應2小時。加入 95344 336 201213319 50mL飽和碳酸氫鈉溶液，二氣曱烷萃取（5〇mLx3)，合併有 機相，用飽和氯化納容液洗務（5〇mLxi),無水硫酸錢乾燥， 過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A 純化所得殘餘物’得到標題產物（1兄55·)_3_(2-氟-2-曱基一 丙烷）-6-[[6-(1-甲磺醢基~3, 6-二氫-2及-吡啶-4-基）-3-吡啶基]氧甲基]-3-氮雜雙環並[3. 1.〇]己烷I39(99rog，白 色固體），產率：50. 0%。 MS m/z (ESI): 424.2 [M+l] _ Ή NMR (400 MHz, CDCh) 5 8.25 (d, 1H), 7.32 (d, 1H), 7. 16(dd, 1H), 6. 63-6. 37 (m, 1H), 4.20-3.94 (m, 2H), 3.94-3.77 (m, 2H), 3.53 (t, 2H), 3.16 (d, 2H), 3.00-2.83 (in, 3H), 2.83-2.72 (m, 2H), 2.56 (s, 1H), 2.53-2.37 (ra, 3H), 1.77-1.59 (m, 1H), 1.42 (br. s, 2H), 1. 38-1. 17 (in, 6H) 實施例1406-(1-Indolyl-3,6-dihydro-2H-pyridin-4-yl)pyridine-3-hydroxyl 138c (280 mg ' 1.10 mm〇i), (i billion 55)-6- (Methanesulfonyloxyindenyl)-3-azabicyclo[3. 1.indole]hexane_3_carboxylic acid tert-butyl ester 16b (417 mg, 1.43 mmol) and potassium carbonate (455 mg, 3. 3〇mmol) dissolved in 8mL of dimethylformamide, 'rise up, stir the reaction for 8 hours, add βmL of water', extract with ethyl acetate (5〇mLx3), combine the organic phase, use the residual sodium chloride solution After washing (50 mL×1), dried over anhydrous sodium sulfate, EtOAc (EtOAc m. 1-nonylsulfonyl-3,6-dihydro-2 and-pyridin-4-yl)-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3 - carboxylic acid tert-butyl ester 139a (360 mg, white solid)' yield: 73.0%. MS m/z (ESI): 394.1 [M-55] The second step 335 95344 201213319 1-[(1 especially 550-6-^6-(b-methylsulfonyl-3,6-dihydro-2 points - Pyridin-4-yl)-3-pyridyl]oxoyl]-3-azabicyclo[3.1.0]hexane-3-yl]propan-2-ol (1 brother 5«-6 -[[6-(1-oxasulfonyl-3,6-dihydro-2pi-pyridin-4-yl)-3-pyridyl]oxyindolyl]-3-azabicyclo[3. 1 0] Hexane-3-carboxylic acid tert-butyl ester 139a (360 mg, 0.80 mmol) was dissolved in 15 mL of 4M hydrochloric acid 1,4-dioxane solution, and the reaction was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure. 20 mL of decyl alcohol and triethylamine (242 mg, 2.40 mmol) were added, and then 2,2-dimethylepoxyethane (173 mg, 2.40 mmol) was added thereto, and the mixture was heated to 33 ° C, and the reaction was stirred for 12 hours. The liquid was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc (EtOAc) 3,6-dihydro-2 and ~p-pyridin-4-yl)-3~pyridyl]oxymethyl]-3-azabicyclo[3. 1. 〇]hexane-3-yl] propyl院-2-ol 139b (200mg, white solid), yield: 60. 〇%. MS ra / z (ESI): 422.2 [M+l], the third step (1 especially 55)-3-(2 -Fluoro-2-methyl-propanone)-β-[[6_(布甲绩醯基鲁_3,6-Dihydro-2spyridin-4-yl)-3'•pyridyl]oxyindolyl] 3_Azabicyclo[3. 1. 〇]hexane in a dry ice bath, methanesulfonyl-3,6-dihydro-2#-pyridin-4-yl)-3-pyridyl]oxycarbonyl] _3_Azabicyclo[3.1·0]hexa-3-yl]propan-2-ol 139b (20 〇mg, 〇. 47 mmol) was dissolved in 20 mL of di-halogenane a, and added to bis(2- ? oxyethyl)aminosulfur trifluoride (157 邶, 0 · 71mm 〇l), raised to room temperature, stirred for 2 hours. Add 95344 336 201213319 50mL saturated sodium bicarbonate solution, dioxane extraction ( 5〇mLx3), the organic phase was combined, washed with saturated sodium chloride solution (5〇mLxi), dried with anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system A. Residue 'obtained the title product (1 brother 55·)_3_(2-fluoro-2-mercapto-propane)-6-[[6-(1-methylsulfonyl~3,6-dihydro-2 and - Pyridin-4-yl)-3-pyridyl]oxymethyl]-3-azabicyclo[3. 1. oxime hexane I39 (99 rog, white solid), yield: 50. 0%. MS m/z (ESI): 424.2 [M+l] _ NMR (400 MHz, CDCh) 5 8.25 (d, 1H), 7.32 (d, 1H), 7. 16 (dd, 1H), 6. 63 -6. 37 (m, 1H), 4.20-3.94 (m, 2H), 3.94-3.77 (m, 2H), 3.53 (t, 2H), 3.16 (d, 2H), 3.00-2.83 (in, 3H) , 2.83-2.72 (m, 2H), 2.56 (s, 1H), 2.53-2.37 (ra, 3H), 1.77-1.59 (m, 1H), 1.42 (br. s, 2H), 1. 38-1. 17 (in, 6H) Example 140

(1 尤 55)-6-1:(2, 6-二氟-4-(1-曱磺醯基一3, 6-二氫-2沪吡 啶-4-基）苯氧基]甲基]-3-(5-氯-嘧啶-2-基）-3-氮雜雙環· 並[3.1.0]己烷(1 especially 55)-6-1: (2,6-difluoro-4-(1-sulfonyl-1,6-dihydro-2-pyridin-4-yl)phenoxy]methyl] -3-(5-chloro-pyrimidin-2-yl)-3-azabicyclo]-[3.1.0]hexane

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第一步 • 4-[4-[ [ (1兄 5iS)-3-(5-氯-定~2-基）-3-氣雜雙環並 _ [3. 1. 0]己烧-6-基]甲氧基]-3, 5-二氟-笨基]-3, 6-二氫 -2及-°比咬-1-緩酸第三丁酯 將4-(3, 5-二氟-4-羥基-苯基）-3, 6-二氫-2#-吡啶 -1-羧酸第三丁酯 131a(684mg，2. 20mmol)溶解於 20mL 况二曱基曱醯胺中，加入[(1^ 550-3-(5-氣嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烧-6-基]甲石黃酸104(607mg， 癟 2咖〇1)和碳酸鉀（829mg ’ 6mmol)，升溫至9(TC，攪拌反應 12小時。加入5〇mL水，二氯曱烷萃取（5〇mLx4)，合併有 · 機相’依次用水（5〇mLxl)，飽和氣化鈉溶液洗滌（5〇mLxi)， 無水硫酸鎮乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜 法以洗脫劑體系B純化所得殘餘物，得到標題產物 4-[4-[[(1疋550-3-(5-氯-嘧啶-2-基）-3-氮雜雙環並 [3. h 〇]己燒一6一基]甲氧基]-3, 5-二氟-苯基]-3, 6-二氫 一2於吡啶-1~羧酸第三丁酯140a(797mg，白色固體），產 率·· 76. 8%。 338 95344 201213319 MS m/z (ESI)： 519.2 [M+l] 第二步 (1 及，55·)-6-[[2, 6-二氟~4-(1，2, 3, 6-四氫σ比咬基）苯氧 基]曱基]-3-(5~氣-續咬-2-基）-3-氮雜雙環並[3. 1. 0]己 烷 將4-[4-[[(1足5«-3-(5-氣-嘧啶-2-基）-3-氮雜雙 環並[3. 1.0]己烷-6-基]甲氧基]-3, 5-二氟-苯基]-3, 6-二 氫-2及-比啶-1-羧酸第三丁酯i4〇a(780mg，1. 50mmol)溶解 鲁於20mL —鼠甲燒中’加入2mL三氟醋酸’授拌反應1小時。 加入50mL水，滴加1M飽和碳酸鈉溶液至反應液pH為9 至10，二氣曱烷萃取（6〇mLx4)，合併有機相，依次用水 (50mLxl)，飽和氯化鈉溶液洗滌（5〇mLxl)，無水硫酸鎂乾 燥，過濾，濾液減壓濃縮，得到粗品標題產物（1足5幻_6_ [[2, 6〜二氟-4-(1，2, 3, 6-四氫吼啶-4-基）笨氧基]甲 基]-3-(5-氣〜嘧啶-2-基）-3-氮雜雙環並[3. 1〇]己烷 • 140b(622mg，淡黃色固體），產物不經純化直接 步反應^ MS m/z (ESI)： 419.1 [ΜΗ] 第三步 (1尤5«-6-[[2, 6-二氟-4-(1-曱磺醯基〜3, 6-二氫〜2皮_吡 咬-4-基）苯氧基]甲基]_3_(5_氯、射_2_基）氣雜雙= 並[3. 1.0]己烷 將粗品（U5«-6-[[2, 6-二氟-4-(1，2, 3’ 6-四氫吼 咬-4-基）苯氧基]曱基]_3_(5_氯〜錢基）—3—氮雜雙環 95344 339 201213319 並[3.1. 0]己院 140b(610mg，1. 50mmol)溶解於 2〇此一患 求Va 曱炫中，加入三乙胺（455mg，4. 50mmol)，冰浴下慢慢滴加 曱磺醯氯（258mg，2.25ramol)，（TC攪拌反應2小時。加入 100mL水’二氯曱院萃取（6〇mLx4)，合併有機相，依次用 水（lOOmLxl)，飽和氣化鈉溶液洗滌（1〇〇mLxl)，無水硫酸 鎂乾燥，過濾’濾液減壓濃縮，用矽膠管柱色譜法以洗脫 劑體系B純化所得殘餘物，得到標題產物（丨尤5幻 [[2,6一二氟—4-(1一甲磺醢基-3,6-二氫-2#_吡啶-4-基）苯 氧基]曱基]-3-(5-氣K2-基）氮雜雙環並[3. h 〇] 己烷140(470mg’白色固體），產率：63. 4%。 MS m/z (ESI): 497.1 [m+1] HNMR(400 MHz, i/-DMS0) (5 8.22 (s, 2H), 6.92 (d, 2H), 6.05-6.07 (m, 1H), 4.02 (d, lH), 3.95-3.97 (m, 2H), 3.83 (d, 2H), 3.49-3.54 (m, 4H), 2.86 (s, 3H), 2.57- 2.58 (m，2H), 1.69 (s, 2H), 16 (m, 1H) 實施例141 (1 尤 550-6-^4-(1-^磺醯基__3, 6_二氫比啶_4_基）苯 氧基]甲基]錢—2〜基）_3_氮雜雙環並[3· h 〇]The first step • 4-[4-[ [ (1 brother 5iS)-3-(5-chloro-butened~2-yl)-3- gas heterobicyclo and _ [3. 1. 0] hexane-6- Methoxy]-3, 5-difluoro-styl]-3,6-dihydro-2 and -° ratio nitrile-butylic acid tert-butyl ester 4-(3, 5-difluoro -4-hydroxy-phenyl)-3,6-dihydro-2#-pyridine-1-carboxylic acid tert-butyl ester 131a (684 mg, 2.20 mmol) was dissolved in 20 mL of dimethyl decylamine, added [(1^ 550-3-(5-apyrimidin-2-yl)-3-azabicyclo[3.1.0]hexa-6-yl]methoric acid 104 (607 mg, 瘪2 coffee) 〇1) and potassium carbonate (829mg '6mmol), warmed to 9 (TC, stirred for 12 hours. Add 5 〇mL water, dichloro decane extraction (5 〇mLx4), combined with the machine phase' sequentially with water (5 〇mLxl), washed with saturated sodium sulphate solution (5 〇mLxi), dried over anhydrous sulphuric acid, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system B to give title product 4- [4-[[(1疋550-3-(5-chloro-pyrimidin-2-yl)-3-azabicyclo[3.h 〇]hexa-hexyl]methoxy]-3, 5-Difluoro-phenyl]-3,6-dihydro-2 in pyridine-1~carboxylic acid tert-butyl ester 140a (797 mg, white solid), yield · 76. 8%. 338 95344 201213319 MS m/z (ESI): 519.2 [M+l] The second step (1 and, 55·)-6-[[2, 6-difluoro~4-(1, 2, 3, 6-tetrahydro σ ratio butyl) phenoxy] fluorenyl]-3-(5~ gas-continuation-2-yl)-3-azabicyclo[3. 1. 0] The alkane will be 4-[4-[[(1)5«-3-(5-a-pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methoxy ]-3, 5-Difluoro-phenyl]-3,6-dihydro-2 and-bipyridine-1-carboxylic acid tert-butyl ester i4〇a (780 mg, 1.50 mmol) dissolved in 20 mL - mouse Add a solution of '2 mL of trifluoroacetic acid' in the torrefaction for 1 hour. Add 50 mL of water, add 1 M saturated sodium carbonate solution to the reaction solution at pH 9 to 10, dioxane extraction (6 〇mLx4), and combine the organic phases. , washed with water (50 mL×l), saturated sodium chloride solution (5 mL mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product (1 s. 5 _6_[[2, 6~ 4-(1,2,3,6-tetrahydroacridin-4-yl)phenyloxy]methyl]-3-(5-a-pyrimidin-2-yl)-3-azabicyclo[ 3. 1 〇]hexane = 140b (622 mg, light yellow solid), the product was directly purified without purification. MS m/z (ESI): 419.1 [ΜΗ] Three steps (1 especially 5«-6-[[2,6-difluoro-4-(1-oxasulfonyl~3,6-dihydro~2pi-pyridin-4-yl)phenoxy] Methyl]_3_(5_Chloro, shot_2_yl) gas hetero double = and [3. 1.0] hexane will be crude (U5«-6-[[2, 6-difluoro-4-(1,2) , 3' 6-tetrahydroindole-4-yl)phenoxy]indolyl]_3_(5-chloro-h- yl)-3-azabicyclo 95344 339 201213319 and [3.1. 0] syllabus 140b (610mg , 1. 50mmol) dissolved in 2 〇 求 求 V V V V V V V V V V V V V V V V V V V V The reaction was stirred for 2 hours. Add 100 mL of water to dichlorohydrazine (6 〇mLx4), and combine the organic phase, and then wash with water (100 mL×1), saturated sodium carbonate solution (1 〇〇mL×1), dry over anhydrous magnesium sulfate, and filtered. The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product ([2,6-difluoro- 4-(1,1,1,1,5,5,6-di-hydrogen) -2#_pyridin-4-yl)phenoxy]indolyl]-3-(5-gas K2-yl)azabicyclo[3.h 〇]hexane 140 (470 mg 'white solid), yield : 63. 4% MS m/z (ESI): 497.1 [m+1] HNMR (400 MHz, i/-DMS0) (5 8.22 (s, 2H), 6.92 (d, 2H), 6.05-6.07 ( m, 1H), 4.02 (d, lH), 3.95-3.97 (m, 2H), 3.83 (d, 2H), 3.49-3.54 (m, 4H), 2.86 (s, 3H), 2.57- 2.58 (m, 2H), 1.69 (s, 2H), 16 (m, 1H) Example 141 (1 especially 550-6-^4-(1-^sulfonyl__3,6-dihydropyridyl_4_yl) Phenoxy]methyl]methanol-2~yl)_3_azabicyclo[3·h 〇]

340 95344 201213319340 95344 201213319

第一步 4-[4-[[(1亿550-3-(5-氯-嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]曱氧基]-苯基]-3, 6-二氫-2F吡啶-1- 羧酸第三丁酯 將4-(4-羥基-苯基）-3, 6-二氫-2及-吡啶-1-羧酸第三 丁酯 122b(500mg，1.82mmol)溶解於 20mL 况#~二甲基甲 醯胺中，加入[(1尤5^-3-(5-氯嘧啶-2-基）-3-氮雜雙環並 [3. 1. 0]己烷-6-基]曱磺酸104(607mg，2mmol)和碳酸鉀 (753mg，5. 46mmol)，升溫至100°C，擾拌反應2小時。加 入50mL水，二氣甲烧萃取（50mLx4)，合併有機相，依次用 水（50mLxl)，飽和氯化納溶液洗滌（50mLxl)，無水硫酸鎂 乾燥，過濾，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑 體系B純化所得殘餘物，得到標題產物4-[4-[[(1兄5«-3-(5_氯-嘧啶-2-基）-3-氮雜雙環並[3. 1.0]己烷-6-基]曱氧 基]-苯基]-3, 6-二氫-2及-吡啶-1-羧酸第三丁酯141a (566mg，白色固體），產率：64. 4%。 MS m/z (ESI): 483.5 [M+l] 341 95344 201213319 第二步The first step is 4-[4-[[(100-(5-chloro-pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]) Oxy]-phenyl]-3,6-dihydro-2Fpyridine-1-carboxylic acid tert-butyl ester 4-(4-hydroxy-phenyl)-3,6-dihydro-2 and -pyridine- 1-carboxylic acid tert-butyl ester 122b (500 mg, 1.82 mmol) was dissolved in 20 mL of ## dimethylformamide and added [(1 especially 5^-3-(5-chloropyrimidin-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-yl]anthracenesulfonic acid 104 (607 mg, 2 mmol) and potassium carbonate (753 mg, 5.46 mmol), warmed to 100 ° C, scrambled reaction 2 </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> The residue obtained was purified by column chromatography using eluent B to give the title product 4-[4-[[(1), 5, 3-(5-chloro-pyrimidin-2-yl)-3-azabicyclo and [3. 1.0] Hexane-6-yl]decyloxy]-phenyl]-3,6-dihydro-2 and-pyridine-1-carboxylic acid tert-butyl ester 141a (566 mg, white solid) Rate: 64. 4%. MS m/z (ESI): 483.5 [M+l] 341 95344 201213319 Step 2

(1疋55^-6-[ [4-(1，2, 3, 6-四氫〇比咬-4-基）笨氧基]甲 基]-3-(5-氯-嘧啶-2-基）-3-氮雜雙環並[3. 1. 〇]己烧 將4-[4-[[(1及，550-3-(5-氣-嘯咬-2-基）-3-氮雜雙 環並[3. 1. 0]己院-6-基]甲氧基]-苯基]-3, 6-二氩-2)7-η比 咬-1-幾酸第三丁酯 141a(540mg，1· 12mmol)溶解於 2〇mL 二氣甲烷中，加入2mL三氟醋酸，攪拌反應2小時。滴加 1 Μ飽和碳酸鈉溶液至反應液pH為9至10,二氯甲烷萃取 (60mLx4)，合併有機相，依次用水（50mLxl)，飽和氣化納 溶液洗滌（50raL&gt;d)，無水硫酸鎂乾燥，過濾，濾液減壓濃 β 縮，得到粗品標題產物（1亿55V6-[[4-(l，2, 3, 6-四氫。比啶 -4-基）笨氧基]曱基]-3-(5-氯-嘧啶-2-基）-3-氣雜雙環並 [3.1.0]己烷1411)(30611^’白色固體），產物不經純化直接 進行下一步反應。 MS m/z (ESI): 383.2 [M+l] 第三步 (li?，5«-6-[[4-(卜甲磺醯基-3, 6-二氫-2於吡啶-4~·基）苯· 氧基]▼基]-3-(5-氣-嘧啶_2-基）-3-氮雜雙環並[3.丨· 0] 己烷 將粗品（1兄5«-6-[[4-(1，2, 3, 6-四氩11比咬-4-基）苯 氧基]甲基]-3-(5-氣-嘧啶-2-基）-3-氮雜雙環並[3.丨.0] 己烷141b(300mg，0. 78mmol)溶解於20mL二氯甲燒中’加 入三乙胺（237rog，2.34imio1) ’冰浴下慢慢滴加甲確酿氮 (134mg，1. i7mm〇l)，（TC攪拌反應2小時。加入50mL水’ 95344 342 201213319 一氯甲烷萃取（60mLx4)，合併有機相，依次用水（50mLxl)， 飽和氣化鈉溶液洗滌（50mLxl)，無水硫酸鎂乾燥，過濾， 據液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系A純化所 得殘餘物，得到標題產物（ΐ7?，55·)-6-[[4-(1-甲磺醢基 一3, 6-二氫-2#-吡啶-4-基）苯氧基]甲基]-3-(5-氯-嘧啶 —2-基）-3-氮雜雙環並[3. 1.0]己烷141(227mg，白色固 體）’產率：63.2%。 • MS m/z (ESI)： 461.5 [M+l] ^NMR (400 MHz，ίΖ-MSO) 5 8.26 (s，2H)，7.33 (d，2H)， φ 6.91 (d, 2H), 6.02 (br, 1H), 3.95-3.99 (m, 6H), 3.54-3.62 (m, 4H), 2.89 (s, 3H), 2.67 (br, 2H), 1.78 (s, 2H), 1.22 (br, 1H) 實施例142 順式-(1及，550-3-(5-乙基嘲咬基-2-基）-6-[ 甲續醢 基-3, 6-二氫咬-4-基）-3_0比°定基]氧曱基氮雜 % 雙環並[3.1.0]己烷(1疋55^-6-[[4-(1,2,3,6-tetrahydroindole is more than -4-yl) phenyloxy]methyl]-3-(5-chloro-pyrimidine-2- Benzyl-3-azabicyclo[3. 1. 〇] hexane will be 4-[4-[[(1,, 550-3-(5- qi- 咬 -2--2-yl)-3-) Heterobicyclo[3. 1. 0]hexyl-6-yl]methoxy]-phenyl]-3,6-diargon-2)7-n ratio bita-1-carboxylic acid tert-butyl ester 141a (540 mg, 1.1 mmol) was dissolved in 2 mL of di-methane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. 1 Torr of saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 9 to 10, and dichloromethane was extracted ( The organic phase was combined, washed with water (50 mL×1), and then evaporated to NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-(l,2,3,6-tetrahydro.pyridin-4-yl)phenyloxy]indolyl]-3-(5-chloro-pyrimidin-2-yl)-3-oxabicyclo[ 3.1.0] Hexane 1411) (30611^' white solid), product was taken to the next step without purification. MS m/z (ESI): 383.2 [M+l] The third step (li?, 5«- 6-[[4-(b-sulfonyl-3,6-dihydro-2 in pyridin-4~-yl)benzene-oxy]▼-yl]-3-(5-a-pyrimidine-2- )-3-Azabicyclo[3.丨·0] Hexane will be crude (1 brother 5«-6-[[4-(1,2, 3, 6-tetra-argon 11 to bit-4-yl) Phenoxy]methyl]-3-(5-a-pyrimidin-2-yl)-3-azabicyclo[3.丨.0] Hexane 141b (300 mg, 0.78 mmol) was dissolved in 20 mL of dichloro Add a triethylamine (237rog, 2.34imio1) in the A-burning. Slowly add a fixed amount of nitrogen (134mg, 1. i7mm〇l) under ice bath. (TC stir the reaction for 2 hours. Add 50mL of water' 95344 342 201213319 The organic phase was extracted with chloroform (60 mL×4), and then washed with water (50 mL×l), saturated sodium sulfate solution (50 mL×l), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified to give the title product (????, 55.)-6-[[4-(1-methylsulfonyl-1,6-dihydro-2#-pyridin-4-yl)benzene. Oxy]methyl]-3-(5-chloro-pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane 141 (227 mg, white solid) yield: 63.2%. m/z (ESI): 461.5 [M+l] NMR (400 MHz, ίΖ-MSO) 5 8.26 (s, 2H), 7.33 (d, 2H), φ 6.91 (d, 2H), 6.02 (br, 1H), 3.95-3.99 (m, 6H), 3.54 -3.62 (m, 4H), 2.89 (s, 3H), 2.67 (br, 2H), 1.78 (s, 2H), 1.22 (br, 1H) Example 142 cis-(1 and, 550-3-( 5-ethyl benzyl-2-yl)-6-[methyl hydrazino-3,6-dihydro -4-yl)-3_0 ratio ° alkyl] oxindyl alkidine % bicyclo[3. 0]hexane

95344 343 20121331995344 343 201213319

142b142b

HO ΗHO Η

142e 第三步142e Step 3

第一步 順式-（1^55)-3〜苄基2, 4-二羰基-3-氮雜雙環並[3. 1.0] 己烷-6-甲酸乙酯 將5-苄基-4, 6-二羰基-3a，6a-二氳-1H-吡嘻並 [3,4-c]吡唑-3-曱酸乙酯7b(2. 10 g，7mmol)置於反應瓶 中’加熱至19(TC，於19(TC下反應1小時。冷至室溫，加 入200mL乙酸乙酯，用矽膠管柱色譜法以洗脫劑體系b純 化所得殘餘物’得到標題產物順式-(1疋5Λ-3-苄基2, 4-二幾基-3-氮雜雙環並[3. 1.〇]己烷-6-曱酸乙酯142a(2 S ’白色固體），產率：12.8%。 ^ m/z (ESI)： 274.1 [M+l] 第二步 [順式苄基-3-氮雜雙環並[3. 1·0]己烷-6-基] 甲醇 將四氫鋁鋰（1. 12 g，29. 28mmol)溶解於35raL四氫呋 °南中’降溫至Ot，慢慢加入i5mL順式-(1尤5«-3-节基 2, 4一二羰基-3-氮雜雙環並[3. 1. 0]己烷-6-甲酸乙酯142a 344 95344 201213319 (2g，7.32mm〇l)的四氫呋喃溶液，加畢，升至室溫’攪拌 10分鐘’加熱至回流反應3小時。加入5mL 1M氫氧化鈉 溶液，再加入5mL乙醇，過濾，依次用10mL甲醇’ 10mL 二氣甲垸洗滌濾餅，合併濾液，減壓濃縮濾液，加入20mL 水’用乙酸乙酯萃取（30mLx3)，合併有機相，依次用水 (20mLx3)，飽和氣化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾 燥’過滤’濾液減壓濃縮，得到粗品標題產物[順式 -(1尤5«-3〜苄基-3-氮雜雙環並[3. 1. 0]己垸-6-基]甲醇 鲁丨421)(1. 45 g，淡黃色油狀物），產物不經純化直接進行下 一步反應。 M51 m/z (E5I)： 204. 5 [M+1] 第三步 [順式-(1尤56V3-氮雜雙環並[3. 1. 0]己烷-6-基]曱醇 .將粗品[順式-(1尤5«-3-苄基-3-氮雜雙環並[3. 1. 〇] 己烷-6-基]曱醇142b(1.45g，7. 13mmol)溶解於50mL曱醇 φ 中’依次加入鈀/碳（300mg，10%)，氫氣置換3次，攪拌反 應12小時。過濾，減壓濃縮濾液，得到粗品標題產物[順 式-(1兄5Λ-3-氮雜雙環並[3.1.0]己烷-6-基]甲醇142c (0. 8 g，淡黃色油狀物），產物不經純化直接進行下一步反 應。 M51 ra/z (ESI): 114.4 [M+1] 第四步 [順式-(1^ 550-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並 [3. 1.0]己烷-6-基]曱醇 345 95344 201213319 將粗品[順式-(1兄5«S)-3-氮雜雙環並[3· i. 〇]己烧 -6-基]甲醇 142c(300mg，2. 65mmol)溶解於 2〇mL 乙腈中， 依次加入2-氯-5-乙基-嘧啶（451mg，3. 18丽〇1)和碳酸鉀 (1· 10g，7. 95mmol)，升溫至回流，授拌反應4小時。減壓 濃縮反應液’用梦膠管柱色譜法以洗脫劑體系B純化所得 殘餘物’得到標題產物[順式-(1^55)-3-(5-乙基嘧啶-2- 基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]甲醇I42d(324mg， 白色固體），產率：56. 0%。 • MS m/z (ESI): 220.5 [M+1] 第五步 孀 曱續酸[順式-(1兄55^-3-(5-乙基癌咬-2-基）-3-氮雜雙環 並[3·1·0]己烷-6-基]甲基酯 冰浴下，將粗品[順式-(1尤55^-3-(5-乙基嘧啶-2-基）_3_氮雜雙環並[3. 1.0]己烷-6-基]曱醇142d(159 g， 0· 72mmol)溶解於l5mL二氯甲烷中，加入三乙胺（183mg， • 1. 81mmol)，再滴加入甲磺醯氣（I24mg，1· OSmmol)，升至 室溫，攪拌反應1小時。加入10mL飽和碳酸氫鈉溶液，用 _ 二氯甲烷萃取（20mLx3)，合併有機相，依次用水（20mLx3)， 飽和氣化鈉溶液洗滌（20mLx3)，無水硫酸鎂乾燥，過濾， 濾液減壓濃縮，得到粗品標題產物曱磺酸[順式-(1兄5幻-3 -(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1· 〇]己烷-6-基]甲 基酯142e(180mg，白色固體），產物不經純化直接進行下 一步反應。 MS m/z (ESI)： 298.1 [M+l] 346 95344 201213319 第六步 順式-(1足5iS)-3-(5 -乙基嘴唆基-2-基）-6-[[6_(1_甲續酿 基-3, 6-二氫-2及-〇比0定-4-基）-3-°比咬基]氧曱基]_3-敗雜 雙環並[3. 1. 0]己烷 將6-(1-甲磺醯基-3, 6-二氫-2H-吡啶-4-基）吡啶-3-醇 138c(3160mg，0. 63mmol)，曱續酸[順式-(1尤 551)-3-(5-乙基嘧啶-2-基）-3-氮雜雙環並[3. 1. 0]己烷-6-基]曱基酯 142e(180mg，0. 63mmol)和碳酸鉀（174mg，1· 26mmol)溶解 • 於8mL yV，於二曱基甲醯胺中，升溫至90°C，攪拌反應3 小時。減壓濃縮反應液，加入25mL水，用二氯甲烷萃取 (60mLx3)，合併有機相，依次用水（30mLxl)，飽和氣化鈉 溶液洗滌（30mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃 縮，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物， 得到標題產物順式-(1尤550-3-(5-乙基嘧啶基-2-基）一6_ [[6-(1-曱續醢基-3, 6-二氫-2及比咬-4-基）-3-〇比咬基]氧 φ 曱基]-3-氮雜雙環並[3.1.0]己烧142(50mg，白色固體）， 產率：20%。 MS m/z (ESI): 456. 2 _] !H 丽R(400 MHz，cH)MSO) 5 8.22(d，1H)，7.86(s，2H)， 7. 28 (dd，1H)，7.12 (dd，1H)，6.45 (s，1H)，4. 12-3.93 (m, 4H), 3. 81-3. 73 (m, 4H), 3. 56-3. 45 (m, 2H), 2. 85 (s, 3H), 2.73 (s, 2H), 2.46 (m, 2H), 2.00 (s, 2H), 1.54-1.46 (m, 1H), 1.18 (t, 3H) 實施例143 347 95344 201213319 3-異丙基-5-[順式-(ΙΑ, 55·)-6-[[4-(5-f續醯基_2-σ比咬 基）苯氧基]甲基]-3-氮雜雙環並[3· 1. 0]己烧_3一基] -1,2,4-°惡二。生The first step is cis-(1^55)-3~benzyl 2,4-dicarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylate ethyl 5-benzyl-4, 6-Dicarbonyl-3a,6a-dioxin-1H-pyrido[3,4-c]pyrazole-3-furoate ethyl ester 7b (2. 10 g, 7 mmol) was placed in a reaction flask 'heated to 19 (TC, 19 hours at TC (cooled to room temperature, 200 mL of ethyl acetate was added, and the residue obtained was purified by eluent column chromatography with eluent system b) to give the title product cis- (1 疋5Λ-3-Benzyl 2, 4-diyl-3-azabicyclo[3. 1.]]hexane-6-decanoic acid ethyl ester 142a (2 S 'white solid), yield: 12.8% ^ m/z (ESI): 274.1 [M+l] The second step [cis benzyl-3-azabicyclo[3.1·0]hexane-6-yl]methanol lithium tetrahydrogenate (1. 12 g, 29.28 mmol) dissolved in 35raL tetrahydrofuran South 'cooled to Ot, slowly added i5mL cis-(1 especially 5«-3-pyringyl 2, 4-dicarbonyl-3- Azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester 142a 344 95344 201213319 (2g, 7.32mm〇l) in tetrahydrofuran solution, added to room temperature, stirred for 10 minutes, heated to reflux Reaction for 3 hours. Add 5mL of 1M sodium hydroxide solution, plus 5 mL of ethanol was added, filtered, and the filter cake was washed with 10 mL of methanol '10 mL of dimethyl hydrazine. The filtrate was combined. The filtrate was concentrated under reduced pressure. The mixture was extracted with 20 mL of water and extracted with ethyl acetate (30 mL×3). The organic phase was combined and then water (20 mL×3) The saturated sodium carbonate solution was washed (20 mL×3), dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the crude title product [ cis-(1 especially 5«-3~benzyl-3-azabicyclo[3] 1. 0] hexamethylene-6-yl]methanol ruthenium 421) (1. 45 g, pale yellow oil). The product was taken to the next step without purification. M.sub.5 m/z (E5I): 204. 5 [M+1] The third step [cis-(1 especially 56V3-azabicyclo[3.1.0]hexane-6-yl]sterol. The crude product [cis-(1 especially 5«) 3-Benzyl-3-azabicyclo[3. 1. oxime] hexane-6-yl]nonanol 142b (1.45 g, 7.13 mmol) was dissolved in 50 mL of decyl φ. (300 mg, 10%), hydrogen was replaced 3 times, and the reaction was stirred for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure to give the crude title product [ </ RTI> </ RTI> </ RTI> </ RTI> -6-yl]methanol 142c (0.8 g, pale yellow oil), product was directly purified without purification Step reaction. M51 ra/z (ESI): 114.4 [M+1] Step 4 [cis-(1^ 550-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3. ]Hex-6-yl]nonanol 345 95344 201213319 The crude product [cis-(1 brother 5«S)-3-azabicyclo[3·i. 〇]hexan-6-yl]methanol 142c ( 300 mg, 2.65 mmol) was dissolved in 2 mL of acetonitrile, followed by 2-chloro-5-ethyl-pyrimidine (451 mg, 3.18 〇1) and potassium carbonate (1·10 g, 7.95 mmol), and warmed up. To reflux, the reaction was allowed to react for 4 hours. The reaction mixture was concentrated under reduced pressure to purify the residue obtained from the eluent system B with the aid of the gel column chromatography to give the title product [cis-(1^55)-3-(5- Ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]methanol I42d (324 mg, white solid), yield: 56.0%. z (ESI): 220.5 [M+1] The fifth step of the subsequent acid [cis-(1 brother 55^-3-(5-ethylcarban-2-yl)-3-azabicyclo[ 3·1·0]hexane-6-yl]methyl ester, the crude product [cis-(1 especially 55^-3-(5-ethylpyrimidin-2-yl)_3_ azabicyclo) And [3.1.0]hexane-6-yl]nonanol 142d (159 g, 0·72 mmol) was dissolved in 15 mL of dichloromethane, and triethylamine (183 mg, • 1. 81 mmol), add methyl sulfonium oxime (I24 mg, 1 · OSmmol), warm to room temperature, stir the reaction for 1 hour, add 10 mL of saturated sodium bicarbonate solution, extract with _ dichloromethane (20 mL x 3), combine The organic phase was washed with water (20 mL×3), EtOAc (EtOAc) (EtOAc) (5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1·〇]hexane-6-yl]methyl ester 142e (180 mg, white solid). One step reaction MS m/z (ESI): 298.1 [M+l] 346 95344 201213319 The sixth step cis-(1 foot 5iS)-3-(5-ethyl-mercapto-2-yl)-6- [[6_(1_甲再酿基-3,6-dihydro-2 and -〇 is 0--4-yl)-3-° than biting base] oxoyl]_3--heterobicyclo[3 1. 0] Hexane 6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-3-ol 138c (3160 mg, 0.63 mmol), succinic acid [cis-(1 especially 551)-3-(5-ethylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]decyl ester 142e (180 mg , 0. 63mmol) and potassium carbonate (174mg, 1· 26 mmol) Dissolved • At 8 mL yV, in dimethylformamide, the temperature was raised to 90 ° C, and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained is purified by eluent column chromatography using eluent column chromatography to give the title product cis-(1 550-3-(5-ethylpyrimidin-2-yl)- 6-[[6-( 1-曱 醢 -3-3,6-dihydro-2 and butyl-4-yl)-3-〇 咬 ] ] ] ] ] ] ] ] ] 氧 氧 氧 氧 氧 氧 氧 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 142 (50 mg, white solid), Yield: 20%. MS m/z (ESI): 456. 2 _] !H R (400 MHz, cH)MSO) 5 8.22 (d, 1H), 7.86 (s , 2H), 7. 28 (dd, 1H), 7.12 (dd, 1H), 6.45 (s, 1H), 4. 12-3.93 (m, 4H), 3. 81-3. 73 (m, 4H) , 3. 56-3. 45 (m, 2H), 2. 85 (s, 3H), 2.73 (s, 2H), 2.46 (m, 2H), 2.00 (s, 2H), 1.54-1.46 (m, 1H), 1.18 (t, 3H) Example 143 347 95344 201213319 3-Isopropyl-5-[cis-(ΙΑ, 55·)-6-[[4-(5-f 醯 醯_2- σ 咬 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 苯 苯 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Health

第一步 順式-(1尤55〇-(6-經曱基）-3-氮雜雙環並[3. 1· 〇]己燒-3- 甲腈 冰浴下，將[順式-(1)Ρ，55·)-3-氮雜雙環並[3.丨·0]己 φ 烷-6-基]曱醇 142c(500mg，4.41mmol)溶解于 48mL 水和二 氯甲烷（V/V = 1:5)混合溶劑中，加入碳酸鉀（1. 52g， 11. 02mmol)和溴化氰（537mg，5. 07mmol)，擾拌反應 1 小 時’升至室溫，攪拌1小時。加入20mL水，分液，水相用 二氣曱烷萃取（30mLx3)，合併有機相，無水硫酸鎂乾燥， 過濾，濾液減壓濃縮，得到粗品標題產物順式-(1疋5 51) - (6 -羥曱基）-3-氮雜雙環並[3.1.〇]己烷-3-甲腈143&amp;(40〇1112, 淡黃色油狀物），產物不經純化直接進行下一步反應。 MS m/z (ESI): 139.1 [M+l] 348 95344 201213319 第二步 [順式-(1足5^-3-(3-異丙基-1，2, 4—噁二唑-5-基）-3-氮 雜雙環並[3.1. 0]己烷-6-基]曱醇 將粗品順式~(1友，55*)-(6-經曱基）-3-氣雜雙環並The first step is cis-(1 especially 55〇-(6-pyridyl)-3-azabicyclo[3.1·〇]hexacarb-3-carbonitrile under ice bath, [cis-( 1) Ρ, 55·)-3-Azabicyclo[3.丨·0]hexacyclo-6-yl]nonanol 142c (500 mg, 4.41 mmol) dissolved in 48 mL of water and dichloromethane (V/V = 1:5) To a mixed solvent, potassium carbonate (1.52 g, 11.02 mmol) and cyanogen bromide (537 mg, 5.07 mmol) were added, and the mixture was stirred for 1 hour to rise to room temperature and stirred for 1 hour. After adding 20 mL of water, the mixture was separated, and the aqueous layer was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6-Hydroxymethyl)-3-azabicyclo[3.1.oxime]hexane-3-carbonitrile 143 &amp; (40 〇 1112, pale yellow oil). MS m/z (ESI): 139.1 [M+l] 348 95344 201213319 The second step [cis-(1 foot 5^-3-(3-isopropyl-1,2,4-oxadiazole-5) -yl)-3-azabicyclo[3.1.0]hexane-6-yl]nonanol will be crude cis-(1 friend, 55*)-(6-pyridyl)-3-heterobicyclo and

[3, 1. 0]己烧-3~ 甲腈 I43a(410mg，2. 97mmol)溶解於 i5mL 四氫呋喃中，加入N，-羥基-2-甲基-丙胺（334mg， 3.27mmol)和氣化鋅（445mg，3.27mm〇1)，攪拌反應1小時。 減壓濃縮反應液，加入l〇mL水和乙醇（V/V = 1:1)混合溶 鲁劑’再加入lmL濃鹽酸，升溫至8(TC ’攪拌反應1小時。_ 減壓濃縮反應液’滴加飽和碳酸氫鈉溶液至反應液pH為7 至8 ’加入20mL水，用乙酸乙酯萃取（50inLx3)，合併有機 相，用飽和氣化鈉溶液洗滌（30mLx2)，無水硫酸鎂乾燥， 過遽’減壓濃縮濾液’用石夕膠管柱色譜法以洗脫劑體系B 純化所彳于殘餘物，得到標題產物[順式_(1充，5幻_3_(3-異丙 基-1’ 2, 4—噁二唑-5-基）-3-氮雜雙環並[3. 1. 〇]己烷-6- # 基]曱醇143b(380mS，淡黃色油狀物），產率：57· 0%。 MS ra/z (ESI)： 224.1 [M+l] # 第三步 [順式-⑽5«-3-(3-異丙基—1，2, 4一惡二唾_5_基）_3—氮 雜雙環並[3.1.0]己烷一 6 一基]曱基磺酸曱酯 冰冷下’將[順式-(1疋異丙基—U4—噁 二嗤+基）-3-氮雜雙環並[3.丨，Q]已炫_6_基]甲醇礙 (35〇mg，1.57mmol)溶解於15fflL二氯甲烷中，加入三乙胺 (397mg，3. 92嶋1)，滴加入甲磺醯氣(233mg，2. 〇4mffl〇1)， 95344 349 201213319 攪拌反應1小時。加入20mL飽和碳酸氫鈉溶液，用二氯甲 烷萃取（30mLx3)，合併有機相，用飽和氣化鈉溶液洗滌 (30mLx2)，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，得到 粗品標題產物[順式-(1尤55)-3-(3-異丙基-1，2, 4—噁二 唑-5-基）-3-氮雜雙環並[3. 1· 0]己烷-6-基]甲基續酸甲酯 143c(392mg ’淡黃色油狀物），產物不經純化直接進行下 一步反應。 MS m/z (ESI): 302.5 [M+l] ^ 第四步 · 3異丙基-5-[順式-(1疋，55&quot;)-6-[ [4-(5-甲礦酿基-2-〇比0定 基）苯氧基]曱基]-3-氮雜雙環並[3. 1. 〇]己烷-3-基] 一1，2, 4-噁二唑 將粗品[順式—（1兄55^3-(3-異丙基-1，2, 4—噁二唑 -5-基）-3-氮雜雙環並[3. 1. 〇]己烷_6_基]甲基磺酸甲酯 143c(392mg，1· 57mmol)，4—(5_甲磺醯基_2_吡啶基）苯酚 參 82b(473mg，1. 57ramol)和碳酸鉀（433mg，3· 14_〇1)溶解 於10mL 二曱基曱酿胺中’升溫至赃，擾拌反應3鲁 小時。加入50虬水，用二氯曱烷萃取（8〇mLx2)，合併有機 相用飽和氯化納溶液洗膝（3GmLx2)，無水硫酸鎮乾燥， 過濾；慮液減壓遭縮，用石夕膠管柱色譜法以洗脫劑體系B 純化所得軸物，制標财物3_異丙基+[順式 (1疋551) 6 [[4-(5-甲續驢基-卜比嘴基）苯氧基]曱 (400mg’白色固體），產率：56.0%。 350 95344 201213319 MS m/z (ESI): 455.1 [M+l] Ή NMR (400 MHz, g^-DMSO) δ 9.14 (d, 1H), 8.21 (dd, 1H), 8.06-7.98 (m, 2H), 7.84 (d, 1H), 7.02-6.95 (in, 2H), 4.03 (d, 2H), 3.88-3.80 (m, 2H), 3.80-3.73 (m, 2H), 3.13 (s, 3H), 2.87 (td, 1H), 2.07-2.00 (in, 2H), 1.60 (t, 1H), 1.26 (d, 6H) 測試例： 生物學評價 _ 以下方法用來測定本發明化合物對GPR119的激動活 性。實驗方法簡述如下： 在96孔板中接種倉鼠beta胰島細胞（HIT-T15)(購 於ATCC，貨號CRL-1777)，接種細胞密度為2xl04。細胞 在37 C ’ 5%C〇2條件下培養48小時後’移去培養液，加入 100 刺激緩衝液（Hanks, 5mMHEPES，0.5mMIBMX，[3, 1. 0] hexane-3-carbonitrile I43a (410 mg, 2.97 mmol) was dissolved in i5 mL of tetrahydrofuran, and N,-hydroxy-2-methyl-propylamine (334 mg, 3.27 mmol) and zinc hydride ( 445 mg, 3.27 mm 〇 1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and 1 mL of water and ethanol (V/V = 1:1) were added to dissolve the solvent. Then, 1 mL of concentrated hydrochloric acid was added, and the temperature was raised to 8 (TC' stirring reaction for 1 hour. _ The reaction solution was concentrated under reduced pressure. Adding saturated sodium bicarbonate solution to a pH of 7 to 8 ′ of the reaction mixture, adding 20 mL of water, and extracting with ethyl acetate (50 inLx3), and the organic phase is combined, washed with saturated sodium carbonate solution (30 mL×2), dried over anhydrous magnesium sulfate. The title product was obtained by purifying the residue under reduced pressure and the residue was purified by eluent column chromatography to give the title product [cis _ (1 cum, 5 phantom _3_(3-isopropyl)- 1' 2,4-oxadiazol-5-yl)-3-azabicyclo[3. 1. oxime hexane-6- # benzyl] sterol 143b (380mS, light yellow oil), produced Rate: 57·0%. MS ra/z (ESI): 224.1 [M+l] # Third step [cis-(10)5«-3-(3-isopropyl-1,2,4-dioxin _5_基)_3—Azabicyclo[3.1.0]hexane-6-yl]decylsulfonic acid decyl ester under ice cooling '[cis-(1疋isopropyl-U4-oxadiazine+) ))-3-azabicyclo[3.丨,Q]有炫_6_yl]methanol (35〇mg, 1.57mmol) is dissolved in 15fflL of dichloromethane, plus Triethylamine (397 mg, 3.92嶋1), added with methanesulfonate (233 mg, 2. 〇4mffl〇1), 95344 349 201213319, stirred for 1 hour, added with 20 mL of saturated sodium bicarbonate solution, with dichloromethane The organic phase was extracted (30 mL×3), EtOAc (3 mL, EtOAc) -isopropyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1·0]hexane-6-yl]methyl-postanoic acid methyl ester 143c (392 mg ' The product was taken to the next step without purification. MS m/z (ESI): 302.5 [M+l] ^ Step 4 · 3 isopropyl-5-[cis--(1疋,55&quot;)-6-[ [4-(5-methyl-branched--2-indole-based 0-butyl)phenoxy]indolyl]-3-azabicyclo[3. 1. 〇]hexane- 3-yl]-1,2,4-oxadiazole will be crude [cis-(1 brother 55^3-(3-isopropyl-1,2,4-oxadiazol-5-yl)-3) -Azabicyclo[3. 1. 〇]hexane_6_yl]methyl methanesulfonate 143c (392 mg, 1. 57 mmol), 4-(5-methylsulfonyl-2-pyridyl)phenol Reference 82b (473mg, 1. 57ramol) and potassium carbonate (433m g,3·14_〇1) Dissolved in 10 mL of dimercaptoamine, 'heated to 赃, and disturbed for 3 hrs. Add 50 虬 water, extract with dichloro decane (8 〇mLx2), combine the organic phase with a saturated sodium chloride solution to wash the knee (3GmLx2), dry anhydrous sulfuric acid, filter; consider the liquid reduced pressure, use Shixi hose Purification of the obtained shaft by column chromatography with eluent system B, labeling property 3_isopropyl + [cis (1疋551) 6 [[4-(5-methyl-indolyl-bubi)) phenoxy Base] 曱 (400 mg 'white solid), yield: 56.0%. </ RTI> </ RTI> <RTIgt; ), 7.84 (d, 1H), 7.02-6.95 (in, 2H), 4.03 (d, 2H), 3.88-3.80 (m, 2H), 3.80-3.73 (m, 2H), 3.13 (s, 3H), 2.87 (td, 1H), 2.07-2.00 (in, 2H), 1.60 (t, 1H), 1.26 (d, 6H) Test Example: Biological Evaluation _ The following method was used to determine the agonistic activity of the compound of the present invention against GPR119. The experimental methods are briefly described as follows: Hamster beta-islet cells (HIT-T15) (purchased from ATCC, Cat. No. CRL-1777) were inoculated into 96-well plates at a seed density of 2 x 104. The cells were cultured for 48 hours at 37 C '5% C〇2, and the medium was removed, and 100 stimulation buffer (Hanks, 5 mM HEPES, 0.5 mM IBMX, was added).

0. 1%BSA, pH 7. 4)，並於室溫孵育15分鐘。在孔中加入不 φ 同濃度藥物，畔育30分鐘後，移去緩衝液，加入75/zL 預冷的裂解液’並在冰上孵育20分鐘，適當地振盪。將 96孔板以13000 rpm的轉速離心1〇分鐘。取5〇/zL樣品 上清，按照 cAMP ELISA 試劑盒（Cell Biolabs，Inc.)標準 步驟檢測cAMP含量，化合物的EC5〇值可藉由CAMP含量計 算得出。 351 95344 201213319 受試化合物的ec5。值如下表所示： 化合物編號 EC5〇(HIT-T15)/(/zM) 實施例4 0.021 實施例8 0. 004 實施例12 0. 006 實施例13 0. 012 實施例25 0. 020 實施例33 0. 009 實施例34 0. 012 實施例41 0. 027 實施例48 0. 071 實施例52 0. 061 實施例56 0. 042 實施例74 0. 062 實施例75 0. 094 實施例78 0. 062 實施例80 0. 071 實施例81 0. 078 實施例82 0. 028 實施例89 0. 038 實施例90 0. 027 實施例91 0. 011 實施例93 0. 028 實施例95 0. 036 實施例96 0. 051 實施例97 0. 046 實施例103 0. 048 實施例104 0. 038 實施例105 0. 064 實施例108 0. 047 實施例110 0. 016 實施例113 0. 075 實施例118 0. 043 352 95344 201213319 實施例121 0. 052 實施例122 0. 005 實施例123 0. 056 實施例124 0. 038 實施例126 0.058 實施例127 0. 048 實施例128 0. 011 實施例129 0. 069 實施例130 0. 068 實施例132 0. 009 實施例133 0. 052 實施例134 0. 057 實施例136 0. 004 實施例137 0. 058 實施例138 0. 005 實施例139 0. 021 結論：本發明實施例化合物均具有較好的胰島素激動活性。 藥效學測試 1. 研究目的 # 以ICR小鼠為受試動物，觀察本發明待測實施例化合 物單次單劑量給藥對糖負荷小鼠血糖值的影響。 2. 受試化合物 實施例化合物 8、13、25、33、82、95、97、12卜 122、 128 、 136 和 138 3.試驗動物 健康ICR小鼠（體重20至24 g左右）130隻，雌雄各 半，購自上海西普爾-必凱實驗動物有限公司，動物生產許 353 95344 201213319 可證號：SCXK(滬）2008-0016。 4. 藥物配製 稱取適量化合物以0.5%羥曱基纖維素鈉水溶液配製 成3mg/m 1的混懸液。 5. 試驗方法 5. 1分組 雌雄鼠共130隻，過夜禁食16小時。稱重後測定基 礎血糖值，根據血糖高低隨機分組為Blank組（5雌5雄）、 • 12個本發明待測化合物分為12個組（分別5雌5雄）。 5. 2劑量設置 給藥劑量為30mg/kg，Blank組給予0. 5 °/。羥曱基纖維 素納水溶液。 5.3給藥方法 灌胃給藥，給藥15分鐘後按4 g/kg給予20%的葡萄 糖溶液（每隻小鼠給予0. 4mL)。 | 5. 4血糖值的測定 按劑量給藥，測定血糖值（-15分鐘）。 給藥15分鐘後按4 g/kg給予20 %的葡萄糖溶液，並 在0、15、30、45、60和120分鐘時使用羅氏羅康全血糖 測定儀測定各小鼠的血糖值。 5.5資料統計 使用Excel統計軟體：平均值以avg計算；SD值以 STDEV計算；組間差異P值以TTEST計算。 AUC計算公式： 354 95344 201213319 AUC= ( &quot;t 1 5min +&quot;t Omin ) X〇 · 2 5 / 2 + ( &quot;t 30min+&quot;t 15min ) X 0 . 2 5 / 2 + ( &quot;t 45min + t30min)xO. 2 5 / 2 + ( 160min+145min ) XO . 2 5 / 2 + ( 1120mi n+160min ) X 1 / 2 其中&quot;t〇Diin，&quot;tl5min，Ϊ30πύη, &quot;t45min，t6〇rain, &quot;tl20min 為不同時間點 測得的企糖值。 6.試驗結果 實施例編號 30分鐘内血糖下降率％ 8 15. 62 13 16. 92 25 10. 12 33 11. 09 82 10. 75 95 16. 11 97 10. 78 121 14. 55 122 14. 96 128 17. 51 136 16. 70 138 18. 66 結果表明：本發明測試的化合物均有明顯的降低小鼠血糖 φ 升高的作用。 【圖式簡單說明】 無 【主要元件符號說明】 無 355 953440. 1% BSA, pH 7.4) and incubated for 15 minutes at room temperature. The drug of the same concentration was added to the well. After 30 minutes of incubation, the buffer was removed, 75/zL of pre-chilled lysate was added and incubated on ice for 20 minutes, and shaken appropriately. The 96-well plate was centrifuged at 13,000 rpm for 1 minute. The 5 〇/zL sample supernatant was taken and the cAMP content was measured according to the cAMP ELISA kit (Cell Biolabs, Inc.). The EC5 enthalpy of the compound can be calculated from the CAMP content. 351 95344 201213319 The ec5 of the test compound. The values are shown in the following table: Compound No. EC5(HIT-T15)/(/zM) Example 4 0.021 Example 8 0. 004 Example 12 0. 006 Example 13 0. 012 Example 25 0. 020 Example 33 0. 009 Example 34 0. 012 Example 41 0. 027 Example 48 0. 071 Example 52 0. 061 Example 56 0. 042 Example 74 0. 062 Example 75 0. 094 Example 78 0 062 Example 80 0. 071 Example 81 0. 078 Example 82 0. 028 Example 89 0. 038 Example 90 0. 027 Example 91 0. 011 Example 93 0. 028 Example 95 0. 036 Example 96 0. 051 Example 97 0. 046 Example 103 0. 048 Example 104 0. 038 Example 105 0. 064 Example 108 0. 047 Example 110 0. 016 Example 113 0. 075 Example 118 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. 069 Example 130 0. 068 Example 132 0. 009 Example 133 0. 052 Example 134 0. 057 Example 136 0. 004 Example 137 0. 058 Example 138 0.005 Example 139 0.021 CONCLUSION: Example Compound preferred embodiment of the present invention have insulin agonist activity. Pharmacodynamic Test 1. Research Objective # ICR mice were used as test animals, and the effect of single-dose administration of the compounds of the present invention to the blood glucose level of sugar-loaded mice was observed. 2. Test compound Examples Compounds 8, 13, 25, 33, 82, 95, 97, 12, 122, 128, 136 and 138 3. Test animals Healthy ICR mice (body weight 20 to 24 g or so) 130, Both male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production Xu 353 95344 201213319 certificate number: SCXK (Shanghai) 2008-0016. 4. Preparation of the drug A suitable amount of the compound was weighed into a suspension of 3 mg/m 1 in an aqueous solution of 0.5% hydroxymercaptocellulose. 5. Test methods 5. 1 group A total of 130 male and female rats were fasted for 16 hours overnight. The blood glucose levels were measured after weighing, and were randomly grouped into the Blank group (5 females and 5 males) according to the high blood sugar level, and 12 compounds of the present invention were divided into 12 groups (5 females and 5 males, respectively). 5度之间。 The dose was administered at a dose of 30 mg / kg, the Blanc group was given 0. 5 ° /. An aqueous solution of hydroxydecyl cellulose. 5.3 Administration method Administration by intragastric administration, after 15 minutes of administration, 20% of a glucose solution (0.4 mL per mouse) was administered at 4 g/kg. 5. Determination of blood glucose level The blood glucose level (-15 minutes) was measured by dosing. After 15 minutes of administration, 20% glucose solution was administered at 4 g/kg, and blood glucose values of each mouse were measured at 0, 15, 30, 45, 60 and 120 minutes using a Roche Rocco whole blood glucose meter. 5.5 Data statistics Using Excel statistical software: the average value is calculated by avg; the SD value is calculated by STDEV; the difference P value between groups is calculated by TTEST. AUC calculation formula: 354 95344 201213319 AUC= ( &quot;t 1 5min +&quot;t Omin ) X〇· 2 5 / 2 + ( &quot;t 30min+&quot;t 15min ) X 0 . 2 5 / 2 + ( &quot ;t 45min + t30min)xO. 2 5 / 2 + ( 160min+145min ) XO . 2 5 / 2 + ( 1120mi n+160min ) X 1 / 2 where &quot;t〇Diin,&quot;tl5min,Ϊ30πύη, &quot; T45min, t6〇rain, &quot;tl20min are the sugar values measured at different time points. 6. Test results Example number of blood glucose drop rate within 30 minutes % 8 15. 62 13 16. 92 25 10. 12 33 11. 09 82 10. 75 95 16. 11 97 10. 78 121 14. 55 122 14. 96 128 17. 51 136 16. 70 138 18. 66 The results showed that the compounds tested in the present invention all significantly reduced the blood glucose φ increase in mice. [Simple description of the diagram] None [Key component symbol description] None 355 95344

Claims (1)

201213319 七、申請專利範圍： 1. 一種通式（I)所示的化合物或其可藥用的鹽：201213319 VII. Patent Application Range: 1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: (I) 其中： 環A選自環烷基、雜環基、芳基或雜芳基，其中該 環烷基、雜環基、芳基或雜芳基各自獨立地視需要進一 步被一個或多個選自鹵素、氰基、硝基、烧基、稀基、0 炔基、齒代烷基、羥烷基、環烷基、雜環基、芳基、雜 芳基、-OR2、-NR3R4、-C(0)R2、-C(0)0R2、-C(0)NR3R4、 -NR3C(0)R4、-NVSCOW、-S(0%R2 或-S(0)JR3R4 的取 代基所取代； 環B選自雜環基、芳基或雜芳基，其中該芳基或雜 芳基各自獨立地視需要進一步被一個或多個選自鹵素、 氰基、硝基、烧基、稀基、快基、_代烧基、經烧基、 環烷基、雜環基、芳基、雜芳基、=0、-OR2、-(CHOoNRl4、 · -C(0)R2、-C(0)0R2、-C(0)NR3R4、-NR3C(0)R4、-NfSCO^R4、 -SCOW或-S(0)mNR3R4的取代基所取代； 環C選自： 1 95344 201213319(I) wherein: ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently further optionally one or more Selected from halogen, cyano, nitro, alkyl, dilute, 0 alkynyl, dentate alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR2, -NR3R4 Substituted by a substituent of -C(0)R2, -C(0)0R2, -C(0)NR3R4, -NR3C(0)R4, -NVSCOW, -S(0%R2 or -S(0)JR3R4 The ring B is selected from a heterocyclic group, an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group is each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, alkyl, and dilute groups, as needed. , fast radical, _alkyl, pyrenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -OR2, -(CHOoNRl4, · -C(0)R2, -C(0 Substituting a substituent of 0R2, -C(0)NR3R4, -NR3C(0)R4, -NfSCO^R4, -SCOW or -S(0)mNR3R4; Ring C is selected from: 1 95344 201213319 2選自一個鍵或-(CHOh-，其中任意的—個. 視需要進一步被一個或多個〇、N(R7Us所代替，或 任意的〜個-CH2-視需要進-步被1或多個炫基 或齒素的取代基所取代； 、 當^選自一個鍵時，則環A為芳基或雜芳其. R1選自烷基、環烷基、雜環基、芳基、、 或-c⑻⑽，其中魏基、環烧基、雜環ς、 方土或雜芳基各自獨立地視需要進一步被一個或多個 選自卣素、氰基、硝基、烷基、_代烷基、羥基、羥姨 基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、_〇R2， -nr3r4 , -C(〇)R2 , -C(0)0R2 &gt; -C(0)NR3R4 . -NR3C(0)R4、 ’3S(0)mR4、_S⑼#或_v〇)idNr3r4的取代基所取代； R選自氫原子、鹵素、氰基、硝基、烷基、鹵代烷 基、經院基、烷氧基、環烷基、雜環基、芳基或雜芳基， 其中該烧基、羥烷基、烷氧基、環烷基或雜環基各自獨 立地視需要進一步被一個或多個選自齒素、氰基、硝 基、羥基、烷基、烷氧基、烯基、炔基、環烷基、雜環 基、芳基或雜芳基的取代基所取代； 2 95344 201213319 R3和R4各自獨立地選自氫原子、烷基、烯基、炔 基、環燒基、雜環基、芳基或雜芳基，其中該燒基、、 基、炔基、魏基、雜環基、芳基或雜芳基各自獨立視 需要進-步被-個或多個選***基、齒素、氧代、稀基、 炔基、硝基、氰基、祕基、雜環基、芳基、雜芳基、 -、-⑽f，〇她7、、c⑻nr8r9、 -帆⑼R9、-m〇)U⑻mR7或〜s⑻她9的取 代基所取代；2 is selected from a bond or - (CHOh-, any of which - as needed further by one or more 〇, N (R7Us instead, or any ~-CH2- as needed - 1 or more Substituted by a substituent or a dentate substituent; when ^ is selected from a bond, then ring A is aryl or heteroaryl. R1 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, Or -c(8)(10), wherein the wei group, the cycloalkyl group, the heterocyclic oxime, the smectite or the heteroaryl are each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, alkyl, alkyl. Base, hydroxy, hydroxydecyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, _〇R2, -nr3r4, -C(〇)R2, -C(0)0R2 &gt ; -C(0)NR3R4 . -NR3C(0)R4, '3S(0)mR4, _S(9)# or _v〇) Substituted by a substituent of idNr3r4; R is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, An alkyl group, a haloalkyl group, a transatom group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, hydroxyalkyl group, alkoxy group, cycloalkyl group or heterocyclic group are each independently Further need to be further selected by one or more selected from dentate, cyano, Substituted by a substituent of a nitro, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; 2 95344 201213319 R3 and R4 are each independently selected from hydrogen An atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the group, the alkynyl group, the thiol group, the heterocyclic group, the aryl group or the heteroaryl group Each of them is independently selected from one or more selected from the group consisting of an alkyl group, a dentate, an oxo group, a dilute group, an alkynyl group, a nitro group, a cyano group, a thiol group, a heterocyclic group, an aryl group, a heteroaryl group, -, - (10) f, 〇 her 7, c (8) nr8r9, - sail (9) R9, -m 〇) U (8) mR7 or ~ s (8) substituted with 9 substituents; 或者，R3和R4與相連接的氮原子形成雜環基，其 中該雜環基内含有一個或多個N、〇或娜雜原子， =且為雜％基視需要進—步被一個或多個選***基、齒 j A氧代、稀基、炔基、硝基、氰基、環烧基、雜環基、 方基、雜芳基、，7、,v、-ww、__or7、 - C=r^、，8c⑼r9、，8s⑼mR9、_s(〇)^ S(〇)mNRR9的取代基所取代； R5選自氫原子或烷基； 笑、碰Γ自^原子、燒基、自素、函代垸基、婦基、炔 二氰基:環烧基、雜環基、芳基、雜芳基、I -NR3S(〇)mR4〇)RS(〇^ ' 'C(0)NR3R4' -NR3«°)R4' 形成氧代；、）mR或1(0)^^4;或者兩個R6—起 R7、R8和r9各自 雜環基m雜&amp;選自氫原子、烧基、環烧基、 z選自單鍵、=侧…〇w)、_G_、_N(R&gt; 95344 3 201213319 或-C(0)-N(R7)-，當 m是0、1或2 ; P為0、1或2 ; q為〇、1或2 ; r為0、1或2 ; s為0、1或2 ; u為0、1或2。 q為〇時 ，z不能為雙鍵； 且 2.Alternatively, R3 and R4 form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, fluorene or naphthene atoms, and is a heterogeneous group which is required to be stepped by one or more One selected from the group consisting of a pyridyl group, a dentate, a methoxy group, a dilute group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, a aryl group, a heteroaryl group, 7, 7, v, -ww, __or7, - C=r^,, 8c(9)r9,,8s(9)mR9, _s(〇)^ S(〇)substituted by a substituent of mNRR9; R5 is selected from a hydrogen atom or an alkyl group; laughing, touching from a ^ atom, a pyridyl group, a self-priming , ketone, keto, alkyne dicyanyl: cycloalkyl, heterocyclic, aryl, heteroaryl, I -NR3S(〇)mR4〇)RS(〇^ ' 'C(0)NR3R4' -NR3 «°) R4' forms oxo; , ) mR or 1 (0) ^^4; or two R6 - R7, R8 and r9 each heterocyclic group m hetero-amp; selected from hydrogen atom, alkyl group, a cycloalkyl group, z is selected from a single bond, = side...〇w), _G_, _N (R&gt; 95344 3 201213319 or -C(0)-N(R7)-, when m is 0, 1 or 2; P is 0, 1 or 2; q is 〇, 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2; u is 0, 1 or 2. When q is 〇, z cannot be a double bond; 2. 如申請專利範圍第i箱&amp;、+ ^ 1項所述的通式（I)所示的化合物或 、可藥用的鹽’其中包括通式（π)所示的化合物或其可 藥用的鹽：A compound represented by the formula (I) or a pharmaceutically acceptable salt as described in the above-mentioned Patent Application No. 1 box &amp;, +^1, which comprises a compound represented by the formula (π) or a pharmaceutically acceptable compound thereof Salt: (II)(II) 其中： 環Α選自：Where: the ring is selected from: 環B選自： 4 95344 201213319Ring B is selected from: 4 95344 201213319 R10相同或不同地選自鹵素、氰基、烷基、鹵代烷 基、羥烷基、環烷基、雜環基、芳基、雜芳基或-OR2 ;R10 is the same or differently selected from the group consisting of halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -OR2; R11選自氫原子、鹵素、氰基、硝基、烷基、烯基、 炔基、鹵代烷基、羥烷基、環烷基、雜環基、芳基、雜 芳基、-OR2、-NR3R4、-C(〇)R2、-C(0)0R2、-C(〇)NR3R4、 -NR3C(0)R4、-NR3S(0%R4、-S(0)mR2 或-S(0)mNR3R4 ; L^L^R1至R5的定義如申請專利範圍第i項中所 述； m是0、1或2 ; η是 0、1、2、3 或4;R11 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR2, -NR3R4 , -C(〇)R2, -C(0)0R2, -C(〇)NR3R4, -NR3C(0)R4, -NR3S (0%R4, -S(0)mR2 or -S(0)mNR3R4; L^L^R1 to R5 are as defined in the scope of claim i; m is 0, 1 or 2; η is 0, 1, 2, 3 or 4; Ρ為〇、1或2 ;且 q為〇、ι或2。 •如申請專利範圍第1項所述的通式（I)所示的化合物或 其可藥用的鹽，其中包括通式（III)所示的化合物或其 可樂用的鹽： 其中：Ρ is 〇, 1 or 2; and q is 〇, ι or 2. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, which comprises a compound represented by the formula (III) or a salt thereof; V u 95344 5 (III) 201213319 環A選自：V u 95344 5 (III) 201213319 Ring A is selected from: Rl〇)n (R1〇)n (R10)n (R10)nRl〇)n (R1〇)n (R10)n (R10)n Rl〇)n ^ / (R10)n . 環B選自： / ’Rl〇)n ^ / (R10)n . Ring B is selected from: / ’ R相同或不同地選自鹵素、氰基、烷基、齒代烷 基、經1烷基、環烷基、雜環基、芳基、雜芳基或_〇R2 ; R選自氫原子、鹵素、氰基、硝基、烷基、烯基、 炔基、齒代烷基、羥烷基、環烷基、雜環基、芳基、雜 芳基、-OR2、-NR3R4、-C(〇)R2、-C(〇)〇R2、_c(〇)NR3R4、 -NR3C(0)R4、-NR3S(0)mR4、-s(〇)mR2 或_s(〇)mNR3R4 ; 2選自單鍵、雙鍵、-(：(0)-、-〇(：(1〇、-0-、*^(1〇-或-C(0)-N(R7)- ’當Q為0時，z不能為雙鍵； L·、L·、R1至R4、R7的定義如申請專利範圍第i項 中所述； m是0、1或2 ; 95344 6 201213319 η是 0、1、2、3或 4; ρ為0、1或2 ;且 u為0、1或2。 4.如申請專利範圍第1項所述的通式（I)所示的化合物或 其可藥用的鹽，其中包括通式（IV)所示的化合物或其可 藥用的鹽：R is the same or differently selected from the group consisting of halogen, cyano, alkyl, dentate alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or 〇R2; R is selected from a hydrogen atom, Halogen, cyano, nitro, alkyl, alkenyl, alkynyl, dentylalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR2, -NR3R4, -C ( 〇) R2, -C(〇)〇R2, _c(〇)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -s(〇)mR2 or _s(〇)mNR3R4; 2 selected from the list Key, double key, -(:(0)-, -〇(:(1〇,-0-,*^(1〇- or -C(0)-N(R7)- ' when Q is 0, z cannot be a double bond; L·, L·, R1 to R4, R7 are as defined in item i of the patent application; m is 0, 1 or 2; 95344 6 201213319 η is 0, 1, 2, 3 Or 4; ρ is 0, 1 or 2; and u is 0, 1 or 2. 4. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, as described in claim 1, wherein Including a compound of the formula (IV) or a pharmaceutically acceptable salt thereof: (IV) 其中： 環Α選自：(IV) where: the ring is selected from: R10)n (R10)n (R10)n (R10)n (R1〇)nR10)n (R10)n (R10)n (R10)n (R1〇)n 環B選自：Ring B is selected from: R1()相同或不同地選自鹵素、氰基、烷基、鹵代烷 7 95344 201213319 基、羥烷基、環烷基、雜環基、芳基、雜芳基或_0R2; R選自虱原子、齒素、氰基、石肖基、烧基、婦基、 炔基、齒代烷基、羥烷基、環烷基、雜環基、芳基、雜 芳基、-OR2、-NR3R4、-C(0)R2、-C⑼OR2、-C(0)NR3R4、 -NR3C(0)R4、-NR3S(0)mR4、-S(0)mR2 或-S(0)mNR3R4 ; 、L·、R1至R5的定義如申請專利範圍第i項中所 述；R1() is the same or differently selected from the group consisting of halogen, cyano, alkyl, haloalkane 7 95344 201213319, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or _0R2; , dentate, cyano, schiffki, alkyl, keto, alkynyl, dentate alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR2, -NR3R4, -C (0) R2, -C(9)OR2, -C(0)NR3R4, -NR3C(0)R4, -NR3S(0)mR4, -S(0)mR2 or -S(0)mNR3R4; , L·, R1 to R5 The definition is as described in item i of the patent application scope; m是0、1或2 ; n是 〇、1、2、3或4; ρ為0、1或2，ρ與q相加至少為1 ; q為0、1或2 ; r為〇、ι或2，！&gt;與8相加至少為1;且 s為〇、1或2。 5.=申請專利範圍第2項所述的通式（II)所示的化合物 或其可藥用的鹽，其中包括通式（v)所示的化合物或其 可藥用的鹽：m is 0, 1 or 2; n is 〇, 1, 2, 3 or 4; ρ is 0, 1 or 2, ρ is added to q at least 1; q is 0, 1 or 2; r is 〇, ι Or 2,! &gt; Adding to 8 is at least 1; and s is 〇, 1 or 2. 5. The compound of the formula (II) or the pharmaceutically acceptable salt thereof according to the second aspect of the invention, which comprises the compound of the formula (v) or a pharmaceutically acceptable salt thereof: 其中： 環A選自：Where: Ring A is selected from: (R10)n(R10)n (R1〇)n (R10)n(R1〇)n (R10)n (R1〇)n 95344 8 201213319(R1〇)n 95344 8 201213319 環B選自：Ring B is selected from: R為雜芳基，其中該雜芳基視需要進一步被一個或 多個選自齒素、烷基或齒代烷基的取代基所取代； R1()為鹵素；R is a heteroaryl group, wherein the heteroaryl group is further substituted with one or more substituents selected from the group consisting of dentate, alkyl or dentate alkyl as desired; R1() is a halogen; R11選自氫原子、鹵素、氰基、烷基、-C(0)R2、 -C(0)〇R2 &gt; -C(〇)NR3R4 . -NR3C(0)R4 ' -NR3S(0)mR4 ' ~S(0)mR2 或-S(0)mNR3R4 ; 111 是 〇、1 或 2 ; 〇是0、卜2、3或4; R2至R4的定義如申請專利範圍第2項中所述。 η •如申請專利範圍第5項所述的通式（II)所示的化合物 或其可藥用的鹽，其中包括通式（VI )所示的化合物或 其可藥用的鹽·· 95344 9 201213319R11 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an alkyl group, -C(0)R2, -C(0)〇R2 &gt; -C(〇)NR3R4 . -NR3C(0)R4 ' -NR3S(0)mR4 ' ~S(0)mR2 or -S(0)mNR3R4 ; 111 is 〇, 1 or 2; 〇 is 0, Bu 2, 3 or 4; R2 to R4 are as defined in item 2 of the patent application. η. A compound of the formula (II) or a pharmaceutically acceptable salt thereof, as defined in claim 5, which comprises a compound of the formula (VI) or a pharmaceutically acceptable salt thereof. 9 201213319 (VI) -中· ％ B、R、R或n的定義如權中請專利範圍第5 項中所述。 .如申請專利範圍第5項所述的通式⑼所示化合物或(VI) - Medium · % B, R, R or n are as defined in clause 5 of the patent scope. a compound of the formula (9) as described in claim 5 or 其可藥用的鹽，其中包括通式加）所示的化合物或其 可藥用的鹽：A pharmaceutically acceptable salt thereof, which comprises a compound of the formula: or a pharmaceutically acceptable salt thereof: 其中：環B、R1、R1Q、R11或η的定義如權利要求5中所 述。 .如申睛專利範圍第5所述的通式（Π)所示化合物或其 可藥用的鹽’其中包括通式（VIII)所示的化合物或其可 藥用的鹽：Wherein: the definition of the ring B, R1, R1Q, R11 or η is as defined in claim 5. A compound of the formula (A) or a pharmaceutically acceptable salt thereof as described in the fifth aspect of the invention, which comprises a compound of the formula (VIII) or a pharmaceutically acceptable salt thereof: 申5青專利範圍第5項中所述。 如申請專利範圍第7項所述的化合物或其可藥用的 95344 201213319 鹽，其中環B為苯基。 如申請專利範圍第8項所述的化合物或其可藥用的 鹽’其中環B為The 5th patent scope of Shen 5 Qing is described in the fifth paragraph. The compound of claim 7 or a pharmaceutically acceptable 95344 201213319 salt thereof, wherein Ring B is a phenyl group. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein ring B is °^’1^°為_素，11為0，卜2,3或4。 11 ·如申請專利範圍第7或8項中任一項所述的化合物或其 可樂用的鹽，其中： Rl1選自氫原子、鹵素、氰基、烷基、-C(0)R2、 -C(0)NR3R4 , -C(〇)〇R2 , -S(〇)mR2 ； m疋〇、1或2。 12.如申請專利範圍第u項所述的化合物或其可藥用的 風其中R丨為-S(〇)mR2 ; m是1或2。 13·如申請專利範圍第1項所述的通式（I)所示的化合物或 其可藥用的鹽，其中環A為雜環基、芳基或雜芳基。 14·如申清專利範圍第13項所述的通式（I)所示的化合物 鲁或其可藥用的鹽’其中環A視需要被-個或多個選自齒 素、氰基、~C(〇)R2、-C(0)NR3R4、-C(0)0R2 或-S(0)nR2 的取代基所取代。 1 C ’如申請專利範圍第14項所述的通式（I)所示的化合物 或其可藥用的鹽，其中m是1或2。 ’如申請專利範圍第1項所述的通式（I)所示的化合物或 Η其可藥用的鹽，其中Li為一個鍵或_CH2_。 •如申請專利範圍第1項所述的通式（I)所示的化合物或 其可藥用的鹽，其中L2為-0-、-CH2-、-N(R7)-CH2-或 11 95344 201213319 -0-CH2-。 如申&amp;專利範圍第1項所述的通式（I)所示的化合物或 其·可藥用的鹽’其中Ri為烷基或雜芳基，其中該烷基 或雜^•基視需要進一步被一個或多個選自齒素、羥基、 烷基或齒代烷基的取代基所取代。 19.如申請專利範圍第1項所述的通式（I)所示的化合物或 其可藥用的鹽，其中Rl為°^’1^° is _ prime, 11 is 0, and 2, 3 or 4. The compound of any one of claims 7 or 8 or a cola salt thereof, wherein: Rl1 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an alkyl group, -C(0)R2, - C(0)NR3R4, -C(〇)〇R2, -S(〇)mR2; m疋〇, 1 or 2. 12. The compound of claim 5, or a pharmaceutically acceptable wind thereof, wherein R is -S(〇)mR2; m is 1 or 2. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, wherein the ring A is a heterocyclic group, an aryl group or a heteroaryl group. 14. The compound of the formula (I) as described in claim 13 of the patent application, or a pharmaceutically acceptable salt thereof, wherein the ring A is optionally selected from one or more selected from the group consisting of dentate and cyano, Substituted by ~C(〇)R2, -C(0)NR3R4, -C(0)0R2 or -S(0)nR2. 1 C 'A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as described in claim 14, wherein m is 1 or 2. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 wherein Li is a bond or _CH2_. The compound of the formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1, wherein L2 is -0-, -CH2-, -N(R7)-CH2- or 11 95344 201213319 -0-CH2-. A compound of the formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 of the invention, wherein Ri is an alkyl group or a heteroaryl group, wherein the alkyl group or the hetero group It is further required to be substituted by one or more substituents selected from the group consisting of dentate, hydroxyl, alkyl or dentate alkyl. 19. A compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is Rl°相同或不同地選自鹵素、烷基、環烷基或鹵代 烷基的取代基所取代；且Substituting R1 for the same or different substituents selected from halogen, alkyl, cycloalkyl or haloalkyl; η是 0、1、2、3 或 4。 2〇.如申請專利範圍第2項所述的通式（π)所示的化合物 或其可藥用的鹽，其中^^^或卜 2l.如申請專利範圍第3項所述的通式（in)所示的化合物 或其可藥用的鹽，其中ζ選自單鍵或一〇_。 22·如申請專利範圍第1至21項中任何一項所述的通式（I) 所示的化合物或其可藥用的鹽，其中該化合物為：η is 0, 1, 2, 3 or 4. 2. A compound represented by the formula (π) or a pharmaceutically acceptable salt thereof as described in claim 2, wherein the compound of the formula (3) (in) A compound or a pharmaceutically acceptable salt thereof, wherein the hydrazine is selected from the group consisting of a single bond or a hydrazine. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 21, wherein the compound is: 12 95344 20121331912 95344 201213319 FF 13 95344 20121331913 95344 201213319 201213319201213319 ο ο 15 95344 201213319ο ο 15 95344 201213319 16 95344 20121331916 95344 201213319 FF ΗΗ 17 95344 20121331917 95344 201213319 18 95344 201213319 23. —種製備申請專利範圍第丨項所述的通式（i)所示的化 合物或其可藥用鹽的方法，該方法包括： pg-q-. (IA) (IB) 將通式（ΙΑ)化合物與通式（IB)化合物反應，得到通 式（I)化合物； 其中PG為離去基團； 裒A &amp; B、環C、R1、Li和L2的定義如申請專利 • 範圍第1項中所述。 月寻矛J 24. 如申請專利範圍第23項所述的方法，其中 者磺醯基。 巧因 25. 人種製備如申請專利範圍第1所述的通式⑴所示的化 。物或其可藥用鹽的方法，該方法包括：18 95344 201213319 23. A method of preparing a compound of the formula (i) or a pharmaceutically acceptable salt thereof, according to the scope of the patent application, comprising: pg-q-. (IA) (IB) The compound of the formula (ΙΑ) is reacted with a compound of the formula (IB) to give a compound of the formula (I); wherein PG is a leaving group; 裒A &amp; B, ring C, R1, Li and L2 are as defined Patent • Scope is described in item 1. Seeking a spear J. 24. The method described in claim 23, wherein the sulfonyl group. Clever 25. The preparation of the human race is as shown in the general formula (1) of the first application of the patent application. Or a pharmaceutically acceptable salt thereof, the method comprising: 式⑴化 化合物與通細）化合物反應，得到通 R 二 1一 ^ 26 -種製備如卜#^專&amp;圍第1項中所述。 ，化=2專利範圍第1項所述的通式⑴所示的 m其义用㈣方法，該方法包括： 〇^&gt;PG (IF) (IE) 95344 19 201213319 將通式（IE)化合物與通式（IF)化合物反應，得到通 式（I)化合物； 其中PG為離去基團； 環A、環B、環c、R1、乙和b的定義如申請專利 範圍第1項中所述。 27. 如申請專利範圍第26項所述的方法，其中pg為鹵素或 者續酿基。 28. —種製備如申請專利範圍第丨項所述的通式（1)所示的 化合物或其可藥用鹽的方法，該方法包括：The compound of the formula (1) is reacted with a compound of the finely divided compound to obtain a compound of the formula R1, which is described in the above paragraph 1. The method of (4) represented by the formula (1) described in the first aspect of the patent range is as follows: 〇^&gt;PG (IF) (IE) 95344 19 201213319 The compound of the formula (IE) Reaction with a compound of the formula (IF) to give a compound of the formula (I); wherein PG is a leaving group; and ring A, ring B, ring c, R1, B and b are as defined in claim 1 Said. 27. The method of claim 26, wherein the pg is a halogen or a continuation base. A method for producing a compound of the formula (1) or a pharmaceutically acceptable salt thereof as described in the scope of the claims of the patent, the method comprising: 將通式（IH)化合物與通式（Ij)化合物反應，得到通 式（I)化合物； 其中Li為一個鍵；X為鹵素；環a、環b、環c、 R1和L2的定義如申請專利範圍第丨項中所述。 29· —種醫藥組成物，該醫藥組成物含有治療有效劑量的申 凊專利範圍第1至22中任何一項所述的通式（j)所示的 化合物或其可藥用的鹽及可藥用的載劑。 30. —種申請專利範圍第1至22項中任何一項所述的通式 (I)所示的化合物或其可藥用的鹽的用途，其係用於製 備GPR119激動劑。 31. —種申請專利範圍第29項所述的醫藥組成物的用途， 其係用於製備GPR119激動劑。 95344 20 201213319 32. —種申請專利範圍第i至22項中任何一項所述的通式 (I)所示的化合物或其可藥用的鹽的用途，其係用於製 備治療糖尿病和代謝綜合症的疾病的藥物。 33. —種申請專利範圍第29項所述的醫藥組成物的用途， 其係用於製備治療糖尿病和代謝綜合症的疾病的藥物。 34. 如申請專利範圍第1至22項中任何一項所述的通式（I) &gt; 所示的化合物或其可藥用的鹽，其作為GPR-119激動劑 的藥物。 ^ 35·如申請專利範圍第29項所述的醫藥組成物，其作為 GPR-119激動劑的藥物。 36.如申請專利範圍第1至22項中任何一項所述的通式（I) 所示的化合物或其可藥用的鹽，其作為治療糖尿病和代 謝综合症的疾病的藥物。 37·如申請專利範圍第29項所述的醫藥組成物，其作為治 療糖尿病和代謝綜合症的疾病的藥物。 鲁 8.如申睛專利範圍第1至22項中任何一項所述的通式（I) 所示的化合物或其可藥用的鹽，其作為調節胰島素的藥 物。 39.如申請專利範圍第29項所述的醫藥組成物，其作為調 節胰島素的藥物。 95344 21 201213319 四、指定代表圖： (一) 本案指定代表圖為：第（）圖。（本案無圖式) (二) 本代表圖之元件符號簡單說明：（無） 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式： (I)The compound of the formula (IH) is reacted with a compound of the formula (Ij) to give a compound of the formula (I): wherein Li is a bond; X is a halogen; and the definitions of ring a, ring b, ring c, R1 and L2 are as claimed The scope of the patent is described in the third paragraph. A pharmaceutical composition comprising a compound of the formula (j) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount thereof Medicinal carrier. The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, which is for the preparation of a GPR119 agonist. 31. Use of the pharmaceutical composition of claim 29, for the preparation of a GPR119 agonist. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, for the treatment of diabetes and metabolism Drugs for the disease of the syndrome. 33. Use of the pharmaceutical composition according to claim 29, which is for the preparation of a medicament for treating diseases of diabetes and metabolic syndrome. The compound of the formula (I) &gt; or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22, which is a drug of the GPR-119 agonist. The pharmaceutical composition according to claim 29, which is a drug of GPR-119 agonist. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, which is a medicament for treating diseases of diabetes and metabolic syndrome. 37. The pharmaceutical composition according to claim 29, which is a medicament for treating diseases of diabetes and metabolic syndrome. The compound of the formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22, which is an insulin-modulating drug. 39. The pharmaceutical composition according to claim 29, which is a medicament for regulating insulin. 95344 21 201213319 IV. Designated representative map: (1) The representative representative of the case is: (). (There is no picture in this case) (2) The symbol of the symbol of this representative figure is simple: (none) 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (I) 3 953443 95344
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