TW201102374A - Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment - Google Patents

Abstract

Substituted cyclopropyl compounds of the formula I: are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts and solvates are included as well. The compounds are useful as agonists of the g-protein coupled receptor GPR-119.

Description

201102374 六、發明說明： 【發明所屬之技術領域】 本發明係關於G蛋白偶合受體促效劑。詳言之，本發明 係針對GPR 119之促效劑，其適用於治療糖尿病（尤其2型 糖尿病）、肥胖症、代謝症候群及相關疾病及病狀。 【先前技術】 糖尿病為起源於多種病因因素之疾病。其特徵在於在空 腹狀態下或在口服葡萄糖耐量測試期間投與葡萄糖後血漿 葡甸糖含量升高(高血糖症）。存在兩種普遍公認之糖尿病 >式在1型糖尿病或騰島素依賴性糖尿病（IDDM)中，患 者4乎不產生或不產生胰島素（調控葡萄糖利用之激素）。 在2型糖尿病或非胰島素依賴性糖尿病（T2DM)中，體内仍 產生胰島素’且患者展示對胰島素在刺激主要的胰島素敏 感性組織（亦即肌肉、肝及脂肪組織）中之葡萄糖及脂質代 謝中之作料抗性。該等患者通常具有正常姨島素含量， 且可能具有高胰島素血症（升高之血漿姨島素含量），因為 其藉由分泌增加量之姨島素來補償姨島素之降低之效力。 肥胖症之特徵為相對於身體質量而言過度肥胖。臨床 上’肥胖症係由身體質量指數〔B胁體重（kg)/身高㈣2〕 界定，對應於麵值別。肥胖症及超重增加發展出諸如 高血壓、2型糖尿病、心臟病、中風、骨關節炎、睡眠呼 :暫^膽囊疾病及乳癌、***癌及結腸癌之病狀的風 險。較⑽重亦與所有原因之死亡率之增加相關。 更新之焦點在於受㈣糖依賴㈣島素分泌控制之基於 I41275.doc 201102374 胰島之胰島素分泌。就此而論，最近已鑑別出數種優先表 現於β細胞中且牽涉於葡萄糖依賴性胰島素分泌（GDIS)中 之孤兒G蛋白偶合受體（GPCR)。GPR119為高度表現於人 類（及齧齒動物）胰島中以及胰島素分泌細胞系中之細胞表 面Gs偶合GPCR。合成之GPR119促效劑僅在葡萄糖升高之 條件下增加胰島素自分離之靜態小鼠胰島之釋放，且改善 糖尿病性小鼠及膳食誘導之肥胖（DIO)C57/B6小鼠之葡萄 糖财量而不引起低血糖症。因此，GPR11 9促效劑具有充 當引起體重減輕之抗高血糖劑的潛能。 2005 年 1 月 27 日公開之 W02005/007647、2005 年 12 月 22 日公開之W02005/121 121及2006年6月29日公開之 W02006/067531係關於GPR 119促效劑化合物。 【發明内容】 本發明係關於一種化合物，其由下式表示：201102374 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a G protein coupled receptor agonist. In particular, the present invention is directed to an agonist of GPR 119 that is useful for treating diabetes (especially type 2 diabetes), obesity, metabolic syndrome, and related diseases and conditions. [Prior Art] Diabetes is a disease that originates from a variety of etiological factors. It is characterized by an increase in plasma glucose content (hyperglycemia) after administration of glucose in the laparoscopic state or during the oral glucose tolerance test. There are two commonly-recognized diabetes types. In type 1 diabetes or TB-dependent diabetes mellitus (IDDM), the patient does not produce or produce insulin (a hormone that regulates glucose utilization). In type 2 diabetes or non-insulin-dependent diabetes mellitus (T2DM), insulin is still produced in the body' and the patient demonstrates glucose and lipid metabolism in insulin-stimulated major insulin-sensitive tissues (ie muscle, liver and adipose tissue). In the middle of the feed resistance. These patients usually have normal imaginin levels and may have hyperinsulinemia (increased plasma muslin content) because they compensate for the reduced efficacy of gualin by secreting an increased amount of gualin. Obesity is characterized by obesity relative to body mass. Clinically, obesity is defined by the body mass index [B weight (kg) / height (4) 2], corresponding to the face value. Obesity and overweight increase the risk of developing conditions such as high blood pressure, type 2 diabetes, heart disease, stroke, osteoarthritis, sleep, temporary gallbladder disease, and breast, prostate, and colon cancer. The weight of (10) is also related to the increase in mortality for all causes. The focus of the update is on the insulin secretion of islets based on (4) glycosylation (IV) island secretion control based on I41275.doc 201102374. In this connection, several orphan G-protein coupled receptors (GPCRs) have recently been identified that are preferentially expressed in beta cells and are involved in glucose-dependent insulin secretion (GDIS). GPR119 is a cell surface Gs-coupled GPCR that is highly expressed in human (and rodent) islets and in insulin-secreting cell lines. The synthetic GPR119 agonist increases the release of insulin from isolated static mouse islets only under elevated glucose conditions and improves glucose flux in diabetic mice and diet-induced obese (DIO) C57/B6 mice. Does not cause hypoglycemia. Therefore, the GPR11 9 agonist has the potential to be an antihyperglycemic agent that causes weight loss. W02005/007647, published on January 27, 2005, WO2005/121121, published on December 22, 2005, and WO2006/067531, published on June 29, 2006, are related to GPR 119 agonist compounds. SUMMARY OF THE INVENTION The present invention is directed to a compound represented by the following formula:

或其醫藥學上可接受之鹽或溶劑合物，其中： 環A表示含有1個氮原子及視情況再含有1 -2個氮原子之6 員芳基或雜芳基； 環B表示含有1-2個氮原子之6員雜芳基環； 141275.doc 201102374 1及j獨立地表示選自〇、1及2之整數，以使得i+j為J或 2 ； R1表示選自由以下各基組成之群之成員：H、齒基、Ci 6烷基、鹵Cu烷基、（2(0)(^.6烷基、C(O)鹵cN6烷基、 CCC^NH-Cw 烷基、S(〇)c] 6 烷基、s〇2C“6 烷基、 S02NH2、SOAHCm 炫基、s〇2N(C,_6 烧基）2、CN 及視情況 經1-3個C!_6烧基、鹵基或鹵c〗_6烧基取代之HAR ; 且R2、R3及R4各自獨立地選自H、自基、Ci6烧基及函 C 1 _6烧基。 【實施方式】 除非另作說明，否則本文中使用以下定義之術語詳細描 述本發明。 「烷基」以及諸如烷氧基及其類似基團之具有字首「烷」 之其他基團意謂含有指示數目之碳原子的可為直鏈、^ 鏈或環狀或其組合之碳鏈。若未指定數目，則對直鏈烷基 而言’意欲為卜6個碳原子且對分支㈣基而t，意欲為^ 7個碳原子。烷基之實例包括曱基 '乙&、丙基、昱丙 基、丁基、第二丁基及第三丁基、戊基、己基、庚基;、辛 基、壬基及其類似基圏。環烷基為烷基之子集；若未指定 科數目，則意欲為3·7個碳原子，形成卜3個稍合之碳 心「環燒基」亦包括與芳基稍合之單環，其中連接點位 於非芳族部分上。環览基之實例包括環丙基 '環丁基、環 戍基、環己基、環庚基、四氫萘基、十氫萘基、二氫節基 及其類似基團。仏氧基^代时基可互換使用且係指 141275.doc 201102374 經由氧原子連接之經鹵基取代之烷基。鹵烷基及鹵烷氧基 包括單取代以及多取代烷基及烷氧基，至多全_取代烷基 及烷氧基。舉例而言，包括三氟甲基及三氟甲氧基。 「芳基」（Ar)意謂苯基或萘基，較佳為苯基。 除非另作說明，否則「雜芳基」（HAR)意謂含有5-6個原 子之單環芳環系統，其中至少一個原子為選自〇、S、 S(O)、S〇2及N之雜原子。實例包括（但不限於）咄咯基、異 °惡β圭基、異隹σ坐基、D比唾基、吼唆基 '。惡β坐基、^惡二唾 基、售二嗤基、噻唑基、咪唑基、***基、四唑基、吱嚼 基、二嗪基、噻吩基、嘧啶基、噠嗪基、吡嗪基及其類似 基團。雜芳基亦包括呈帶電形式之該等基團，例如吡啶 錯。 「_素」（鹵基）包括氟、氯、溴及碘。 本發明所關注之一態樣係關於一種化合物，其由下式表 示：Or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A represents a 6-membered aryl or heteroaryl group containing one nitrogen atom and optionally 1 to 2 nitrogen atoms; a 6-membered heteroaryl ring of 2 nitrogen atoms; 141275.doc 201102374 1 and j independently represent an integer selected from 〇, 1 and 2 such that i+j is J or 2; R1 represents a group selected from the following Members of the group: H, dentate, Ci 6 alkyl, halo C alkyl, (2(0)(^.6 alkyl, C(O) halo cN6 alkyl, CCC^NH-Cw alkyl, S(〇)c] 6 alkyl, s〇2C "6 alkyl, S02NH2, SOAHCm 炫, s〇2N (C, _6 alkyl) 2, CN and optionally 1-3 C!_6 alkyl , halo or halo _6 alkyl substituted by HAR; and R 2 , R 3 and R 4 are each independently selected from H, from a base, a Ci6 alkyl group and a C 1 -6 alkyl group. [Embodiment] Unless otherwise stated, Otherwise, the invention is described in detail herein using terms defined below. "Alkyl" and other groups having the initial "alkane" such as alkoxy and the like are meant to contain a number of carbon atoms which may be straight. A carbon chain of a chain, a chain or a ring or a combination thereof. If the number is not specified, it is intended to be 6 carbon atoms for the linear alkyl group and to the branch (tetra) group and t, which is intended to be 7 carbon atoms. Examples of the alkyl group include a mercapto group 'B& , propyl propyl, butyl, t-butyl and tert-butyl, pentyl, hexyl, heptyl; octyl, decyl and the like; cycloalkyl is a subset of alkyl; if not specified The number of families is intended to be 3.7 carbon atoms, forming a slightly carbon core. The "ring-burning group" also includes a single ring slightly fused to the aryl group, where the joint is located on the non-aromatic part. Examples of the base include cyclopropyl 'cyclobutyl, cyclodecyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, dihydrogenated and the like. Interchangeable use and refers to 141275.doc 201102374 Alkyl substituted by a halogen atom via an oxygen atom. Haloalkyl and haloalkoxy include monosubstituted as well as polysubstituted alkyl and alkoxy, up to fully substituted alkyl And alkoxy. For example, it includes trifluoromethyl and trifluoromethoxy. "Aryl" (Ar) means phenyl or naphthyl, preferably phenyl. Further, otherwise, "heteroaryl" (HAR) means a monocyclic aromatic ring system containing 5-6 atoms, at least one of which is selected from the group consisting of ruthenium, S, S(O), S〇2 and N. Examples of heteroatoms include, but are not limited to, fluorenyl, iso-β-methionyl, isoindole sigma, D-saltyl, fluorenyl'. oxa-β, dioxin, sold Anthracenyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxime, diazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like. Heteroaryl also includes These groups are in charged form, such as pyridine. "_" (halo) includes fluorine, chlorine, bromine and iodine. One aspect of the present invention is concerned with a compound which is represented by the following formula:

141275.doc 201102374 環B表示含有1_2個氮原子之6員雜芳基環； 、1及2之整數，以使得1+]為 i及j獨立地表示選自 2 ；141275.doc 201102374 Ring B represents a 6-membered heteroaryl ring containing 1_2 nitrogen atoms; an integer of 1 and 2 such that 1+] is i and j is independently selected from 2;

Rl表示選自由以下各基組成之群之成員：H、鹵基、A 6烷基、鹵Cm烷基、c(0)C〗-6烷基、c(0)鹵C〗.6烷基、 C(〇)NH~Cl·6 烷基、s(〇)Ci-6 烷基、so2c〗.6 烷基、 8〇2贿2、sc^NHCi·6貌基、S〇2N(Ci.6 烧基）2、CN及視情況 紅1-3個Ci·6烷基、鹵基或鹵c〗_6烷基取代之har ; 且R、R3及R4各自獨立地選、鹵基、C〗6烷基及鹵 C 1 -6燒基。 本發明所關注之一態樣係關於式j化合物或其醫藥學上 可接受之鹽或溶劑合物’其中環A係選自由以下各基組成 之群·芳基’其為苯基；及雜芳基，其選自由。比。定、n密咬 及吡嗪組成之群。 詳.έ之’本發明所關注之一態樣係關於式I化合物或其 ^藥學上可接受之鹽或溶劑合物，其中環Α係選自由苯基 及嘧啶組成之群。 甚至更詳言之’本發明所關注之一態樣係關於式I化合 物或其醫藥學上可接受之鹽或溶劑合物，其中環A為嘧啶R1 represents a member selected from the group consisting of H, halo, A 6 alkyl, halo Cm alkyl, c(0)C -6 alkyl, c(0) halogen C. 6. alkyl , C(〇)NH~Cl·6 alkyl, s(〇)Ci-6 alkyl, so2c〗.6 alkyl, 8〇2 bribe 2, sc^NHCi·6 appearance base, S〇2N (Ci. 6 calcined) 2, CN and optionally red 1-3 Ci·6 alkyl, halo or halogen c _6 alkyl substituted har; and R, R3 and R4 are each independently selected, halo, C〗 6 alkyl and halogen C 1 -6 alkyl. One aspect of the present invention relates to a compound of formula j or a pharmaceutically acceptable salt or solvate thereof wherein ring A is selected from the group consisting of the following groups: aryl is a phenyl group; An aryl group selected from the group consisting of. ratio. Set, n-bite and pyrazine group. DETAILED DESCRIPTION OF THE INVENTION One aspect of the present invention pertains to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein the guanidine is selected from the group consisting of phenyl and pyrimidine. Even more specifically, one aspect of the present invention is directed to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyrimidine.

•yfO 本發明所關注之另一態樣係關於式I化合物或其醫藥學 上可接受之鹽或溶劑合物，其中環B係選自由°比β定、喊咬 及吡嗪組成之群。 更詳S之’本發明所關注之另一態樣係關於式I化合物 141275.doc 201102374 或其醫藥學上可接受之鹽或溶劑合物，其中環B表示嘧 口定。 本發明所關注之另一態樣係關於式〗化合物或其醫藥學 上可接受之鹽，其中i及j表示0、丨或2,以使得丨與]之和為 1。 本發明所關注之另一態樣係關於式I化合物或其醫藥學 上可接受之鹽或溶劑合物，其中R1係選自由以下各基組成 之群：H、為F或仏之鹵基、Ci3烷基、鹵烷基、 c(o)nhc2.4烷基、s(0)Cl 3烷基、s〇2Cl 3烷基、s〇2NHCi 3烷基、CN及HAR，HAR為含有1個氮原子、視情況再含有 1-3個氮原子且視情況含有1個氧原子之5員雜芳環，該雜 芳基視情況經1個Cw烷基取代。• yfO Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is selected from the group consisting of β, β, and pyrazine. Further aspects of the present invention are directed to a compound of formula I 141275.doc 201102374 or a pharmaceutically acceptable salt or solvate thereof wherein ring B represents pyrimidine. Another aspect of the present invention is a compound of the formula or a pharmaceutically acceptable salt thereof, wherein i and j represent 0, 丨 or 2 such that the sum of 丨 and ] is 1. Another aspect of the present invention is directed to a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from the group consisting of H, F or fluorenyl, Ci3 alkyl, haloalkyl, c(o)nhc2.4 alkyl, s(0)Cl 3 alkyl, s〇2Cl 3 alkyl, s〇2NHCi 3 alkyl, CN and HAR, HAR contains 1 The nitrogen atom, optionally containing 1-3 nitrogen atoms and, as the case may be, a 5-membered heteroaryl ring of one oxygen atom, the heteroaryl group being optionally substituted with one Cw alkyl group.

本發明特別關注之一態樣係關於式I化合物或其醫藥學 上可接受之鹽或溶劑合物’其中Ri係選自由以下各基組成 之群：Η、為F或Br之鹵基、C丨-3烷基、CF3、C(0)NH-環丙 基、S(0)CH3、S02CH3、S02NH環丙基、CN及 HAR，HAR 係選自由噁二唑、***及四唑組成之群，該基團視情況經 曱基或環丙基取代。 甚至更詳言之，本發明所關注之一態樣係關於式〗化合 物或其醫藥學上可接受之鹽或溶劑合物，其中環A表示苯 環且R】表示選自由噁二唑、***及四唑組成之群之5員雜 芳環，該環視情況經甲基或環丙基取代。 另外’本發明所關注之一態樣係關於式I化合物或其醫 藥學上可接受之鹽或溶劑合物，其中環A表示吼啶環或嘧 141275.doc -9- 201102374 咬環m示CN、CF3或選自m三啥及四核成 之群之5員雜芳環，該環視情況經甲基或環丙基取代。 本發明所關注之另—態樣係關於式I化合物或其醫藥學 上可接受之鹽或溶料物，其中作㈣、選自^ci之齒 基 ' ch3及 cf3。 本發明所關注之另一態樣係關於式I化合物或其醫藥學 上可接叉之鹽或溶劑合物，其中R3&R4表示Η、選自F&C1 之鹵基、CH3及cf3。 本發明之另一尤其受關注之態樣係關於式〗化合物或其 邊藥學上可接受之鹽或溶劑合物，其中： 環A係選自由以下各基組成之群：芳基，其為苯基；及 雜芳基，其係選自由吡啶、嘧啶及吡嗪組成之群； 環B係選自由吡啶、嘧啶及吡嗪組成之群； i及j表示0、1或2，以使得i與j之和為2 ; R1係選自由以下各基組成之群：H、為F*Br之鹵基、鹵 c,-3 院基、c(o)nhc2_4烷基、s(0)Cl-3烷基、s〇2c】-3烷 基、SOsNHCu烷基、CN及HAR，HAR為含有1個氮原 子、視情況再含有1 - 3個氮原子及視情況含有1個氧原子之 5員雜芳環’該雜芳基視情況經1個Cl_3烷基取代； R2表示Η、選自F及C1之鹵基、CH3及CF3 ; 且R3及R4表示Η、選自F及Cl之鹵基、CH3及CF3。 本發明所關注之另一態樣係關於式I化合物或其醫藥學 上可接受之鹽或溶劑合物，其中環丙基環為順式環丙基異 構體。 141275.doc 201102374 下表中提供所關注之化合物之實例。 化合物名稱 外消旋順式氯-2·[4-(2·{2-[4-(甲基磺醯基)苯氧基]乙基}環丙基)哌 啶-1-基]嘧啶、5_氯-2-[4-((lS，2R)-2-{2_[4-(甲基續醯基)苯氧基]乙基} 環丙基)略啶-1-基]嘧啶及5-氯-2-[4-((lR，2S)-2-{2-[4-(曱基確醯基)苯 氧基]乙基}環丙基)哌啶-1-基]嘧啶 外消旋順式氣_2-{4_[2-(2-{[5-(甲基磺醯基户比啶·2·基]氧基}乙基） 環丙基]哌啶-l-基}嘧啶、順式-5-氣-2-{4-[(lS,2R)-2-(2-{[5-(曱基磺醯 基)°比咬-2-基]氧基}乙基)環丙基]哌咬-1-基}嘧啶、順式-5-氣-2-{4-[(lR,2S)-2-(2-{[5-(曱基磺醯基)°比啶-2-基]氧基}乙基)環丙基]哌咬-1-基}嘴啶 外消旋順式-5-氣-2-[4-(2-{2-[3-(甲基磺醯基)苯氧基]乙基}環丙基)哌 啶-1-基]嘧啶 外消旋順式-5-氯-2-[4-(2-{2-[3-(5-曱基-1，3,4-噁二唑-2-基)苯氧基]乙 基}環丙基)哌啶-1-基]嘧啶 外消旋順式_5_氯-2-[4-(2·{2-[3-(1Η-1，2,4-***-1-基)苯氧基]乙基}環 丙基)哌咬-1-基]嘧唆 外消旋順式-5-氣-2-[4_(2-{2-[3-(1，3,4-噁二唑_2_基)苯氧基]乙基}環丙 基)π底咬-1-基]ρ密咬 外消旋順式-4-(2-{2-[1-(5-氯嘧啶-2-基)哌啶-4-基]環丙基}乙氧^^7~ 環丙基·2-氟笨曱醯胺 外消旋順式-4-(2-{2_[1-(5-氯嘧啶_2_基)哌啶斗基]環丙基}乙氧基)_2· 氟笨甲晴 外消旋順式-5-氣-2·[4-(2-{2-[4-(環丙基續醯基)苯氧基]乙基} °底咬-1-基]。密咬 外消旋順式-5-氣-2-[4-(2-{2-[3-氟-4-(5-曱基-1，3,4-噁二唑 基]乙基}環丙基)哌啶-1 -基]嘧啶 ^外消旋順式-5-氯-2-[4-(2·{2-[4-(1,3,4-。惡二唑-2-基)苯氧基] 基)π辰咬-1 -基]嘴咬 外消旋順式-5-氯-2·[4-(2·{2-[4-(5-甲基-1,3,4-噁二唑-2-基)笨^]^ 基}環丙基)派啶-1-基1嘧啶 外消旋順式-5-氣-2-[4-(2-{2·[4·(1，2,4-嗔二唑-3-基)苯氧基 基)派咬·1-基]嘴咬 ~~~—~~~s 141275.doc 201102374 噁二嗤 基 >底啶-1-基]嘴啶 土/衣内 外消旋順式_5·虱部屮识4-異噁唑_4_基苯氧· 咬-1-基)嘴咬 夕卜概順式_5·乳-2-(4-{2-[2-(4-㈣峻-5-基苯氧基)乙基]環丙基} 口展 咬小基)喷咬 f 外如疋順式_5·氯-2·[4_(2_{2_[4_(1Η·吡嗤冬基)笨氡基]乙基}環丙基 派咬-1-基]嘧唆 ^^^^ί^ϊίΪ4·(1Η·吡唑-4-基)ϋ]乙基}環丙 夕卜消旋順式-5-亂邻识叫即-。比。坐小基)苯氧基]乙基 哌啶-1-基1嘧啶 J 順式-5-乳邻私帥··〗，2,4^嗤小基)笨氧基]乙基}環 丙基)娘·唆_ 1 -基]啼咕 式-5-氯-2-[4-(2-{2-[4-(4H-1，2,4-三唾斗基)笨氧基]乙基}環 丙基)派咬_ 1 ·基]ϋ密说 三嗤乙基}環- 丙基)哌啶-1-基]嘧啶 外^足順式-5-氟邻例叫肿⑶！哇小基)苯氧基]乙基}環 丙基)哌啶-1-基]嘧啶 外消旋順式-5-曱基-2-[4-(2-{2_[4-即-1，2,3-***-1_基)笨氧基]乙基} 環丙基)旅唆小基]嘧啶 外消旋順式_5•氣-2·[4-(2·{2-[4·(2Η-1，2,3!^·2-基)笨氧基]乙基}環 丙基)°底咬_1-基]痛沒 外消旋順式_5-氣-2-[4-(2·{2-[4-(1Η-1，2,3-***基)笨氧基]乙基}環 丙基)哌啶-1·基1嘧啶 外消旋順式-5-氯_2-[4-(2-{2-[4-(出·四唑小基)笨氧基]乙基}環丙基） 派咬-1-基1嘧吩 外消旋順式-5-氯-2-[4-(2-{2·[3-氟-4·(1Η-四唑-1-基)笨氧基]乙基}環丙 基)π辰嘴-1-基1痛峻 外消旋順式-5-氟-2·[4-(2-{2-[3-氟-4-(111-四唑-1-基)笨氧基]乙基}環丙 基)哌啶·1·基1嘧啶 141275.doc .12- 201102374 外消奴順式-2-[4-(2^2-[3-氟-4-(1Η-四唑-1 ·基)苯氧基]乙基}環丙基） °底咬-1-基]-5-甲基t»密咬 外消旋順式〇-氯-2-[4-(2·{2Χ2Η-四唑_2·基)苯氧基]乙基}環丙基 哌啶-1-基]嘧啶 凝順式-5-氯-2-[4-(2-{2-[4-(5-甲基-2Η-四唾-2-基)苯氧基]乙基}環 丙基)略咬-1-基】脅咬 外消_式·5_氣-2-[4-(2_{2_[4_(5_甲基.1Η_四唾小基)笨氧基 丙基)°底啶-1-基]嘧啶 外消旋順式-5-氯-2-[4-(2·{2-[3-氟-4-(5-甲基-U4-鳴二唾_2_基)i氧.. 基]乙基}環丙基)派咬_1_基]。密咬 外勒疋順式-5-氣-2-[4·(2-{2-[4_(甲基亞續酿基)苯氧基]乙基 哌啶-1-基1嘧啶 ) 對羊性順式氣嘧咬_2_基)0底啶_4_基]環丙基}乙氧基)·2· :基敏·4_甲腈、順式-6_(2.{(1S，2R)_2_{1(5氣錢_2舟底咬斗 :]環丙基}乙氧基)-2-曱基喂咬-4_曱腈、順式_6_(2_{(1R，2S) 基)哌啶-4-基]環丙基}乙氧基V2-甲基嘧啶·4-甲瞎 =，順式-2-甲基-6-(2_{2.[H5_曱基鱗_2_基)(>底各I基]環丙 嘧啶-4-曱腈 2 If式_6-(2_{2·[1-(5責密咬_2·基)°底咬_4_基]環丙基}乙氧基)嘧 式:(2·{2：^^ϊ-2-基)哌咬 / ί，順式-2-曱基·6·(2·{2·[1-(5_曱基倾_2_基)D展咬-4-基]環丙基} 乳基)敍-4-曱腈 '順式-2-曱基冬仏⑽观邻♦甲基嗜咬丨 辰咬-4_基]環丙基}乙氧基〉嘧咬+曱腈、順式1甲基·6·(2· $R，2S)部-(5·曱基魏_2_基)略咬_4_基]環丙基}乙氧基㈣。定_4·甲 -------- I41275.doc } -13 - 201102374 外消旋順式-6-(2-{2·[1-(5-氣吡啶-2-基)哌啶_4_基]環丙基}乙氧基)_2_ 曱基嘧啶-4-曱腈 外消旋順式_6-(2-{2-[1-(4,5·二甲基嘧啶_2_基)哌啶_4_基]環丙基}乙氧 基)-2-曱基嘧啶-4-甲腈 外消旋順式-6-(2-{2-[l-(5-氯-4-曱基吡啶-2-基)派啶-4-基]環丙基}乙 孔基)-2-曱基喷咬_4-甲腈 外消旋順式-6-(2-{2-[1-(5•氟-4-甲基嘧啶-2-基)娘啶斗基]環丙基}乙 氧基)-2-甲基嗜咬_4-甲腈 外消旋順式_2_曱基-6·[2-(2-{ 1-[5-(三氟甲基)吡啶-2-基]裱啶_4_基μ裒 丙基)乙氧基]鳴咬-4-甲腈 外消旋順式-5-氣-2-(4-{2-[2_(〇比唆_3_基氧基)乙基]環丙基卜辰咬小基） 嘧啶 外消旋順式-5-氣-2_(4-{2-[2-(响唉_4_基氧基)乙基]環丙基辰咬小基） 外消旋順式·5-(2-{2-[1·(5·氯喊咬_2_基)α底。定_4_基]環丙基}乙氧基)於 鹼腈 ' 外消旋順式_6·(2-{2-[1-(5-氯嘧啶_2_基)哌啶基]環丙基}乙氧基)_2_ 甲基嘧啶-4-甲腈 外消旋順式-4-(2-{2_[1-(5-氣嘧啶_2·基)娘啶_4·基]環丙基}乙氧基)_6· 曱基嘧啶-2-甲腈 外消旋順式-6-(2-{2-[1-(5-氟嘧啶_2_基)哌啶斗基]環丙基}乙氧基)_2_ 甲基嘧啶-4-甲腈 外消旋順式-5-(2_{2-[1-(5-氯嘧啶-：2-基)哌啶-4-基]環丙基}乙氧基户比 啶-2-甲腈 外消旋順式-5-氣-2-(4-{2-[2七比啶_4_基氧基)乙基]環丙基卜底咬_ ^基） 嘧啶 對掌性順式-5-氣-2_{4-[2-(2-{[5-(1从1，2,3-***-1·基)吼啶·2_基]氧基} 乙基)環丙基]哌咬-l-基}嘧啶、順式-5-氯-2-{4_(18,211)-[2-(2-{[5-(1//-1，2,3-三唆-1-基)吡啶_2·基]氧基}乙基)環丙基]D底啶小基)嘧啶、順式_ 5_ 氣·2-{4_(111，28)-[2-(2-{[5-(1//-1，2,3，三唾_1_基)吡啶_2_基]氧基}乙 基)環丙基]°底咬-1·基}哺咬 1 5-氣-2·[4-((1/?，25>2·{2-[3·氟-4-(5-甲基-1，3,4-喔二唑-2-基)苯氧基]乙 基}環丙基)0底咬-1-基]嘧啶及5_氯_2-[4-((ΐ^，2Λ)·2-{2-[3-氟·4-(5-甲基-丄3,4_噁二唑-：2-基)苯氧基]乙基丨環丙基)痕啶+基]喊啶 141275.doc • 14- 201102374 5-氯-2-[4-((15^)-2·{2-[4_(ιη-1，2,3-三嗤-l-基)笨氧基]乙基}環丙基） 0底咬-1-基]嘲咬及5_氣_2_[4·((1足嗅小基)苯氧 基]乙基}環丙基)〇底唆-1-基]嘴咬 > 氟-2-[4-((l/?，2S>2-{2-[4-(lH-l，2,3-三。坐-1-基)苯氧基]乙基}環丙基） 0底唆-1-基]嘧啶及5_氟_2·[4·(⑽2幻·^則木即]，2,3·三嗤小基)苯氧 基]乙基}環丙基)旅咬-1-基1喷咬 5_氯-2-[4-((1/?，2办2-{2_[4_(11^-四。坐_1_基)苯氧基]乙基}環丙基)派咬· 1-基Η啶及5-氯-2-[4-(⑽Μ)-2-{2-[4-(1Η-四唾-1-基)苯氧基]乙基} 環丙基)哌咬-1 ·基]嘧啶 >氣_2-[4_(( li?，25>2_ {2.[3备4_(! Η四唑小基)苯氧基]乙基}環丙基） 旅咬-1-基]喷啶及5-氣-2-[4-(⑽2i?)-2-{2-[3-氣-4-(1Η-四。坐-1-基)笨氧 基]乙基}環丙基)π辰咬_ 1 _某]0密喷 ^ 氟 L2-L4-((1 足 2lS)-2_{2-[3_ 氟 _4·(5-甲基 _1,3,4_ 噁二唑_2-基)苯氧基]乙 基}環丙基)娘咬-1-基]嘧啶及5-氟·2_[4_(( 1ι5,2；?)-2_ (2_[3·氟_4·(5·甲基· 1，3,4-。惡二唾·2-基)笨氧基]乙基μ衷丙基)哌啶小基ρ密啶 外消旋順式_2_[4-(2-{2-[3-氟_4-(5·曱基-ΐ，3,4-噁二唑-2·基)苯氧基]乙 基}環丙基)哌啶-1-基1-5-f基嘧啶 外消旋順式·2-[4-(2-{2-[3-氟-4-(5-甲基-1,3,4-噁二嗤-2-基)笨氧基]乙 基}環丙基)π底。定-1 -某1嘧咕 外消旋順式-5-氟-2-[4-(2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑·2-基)苯氧 基]乙基}環丙基)派咳·1_基]嘴啶 外消旋順式-5-氣·2·[4-(2_{2_[3_1-4_(5_甲基-I,3,4·噪二唑丨基)苯氧 基]乙基}環丙基)哌啶-1-基]_4_曱基嘧啶 外消旋順式-3,5·二氯-2-[4-(2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基)苯 氧基]乙基}ί衣丙基)娘σ定_1_基]υ比。定 外消旋順式-2-[4_(2_{2·[3_氟-4_(5·甲基_l53,4_噁二唑_2_基)苯氧基]乙 基}環丙基)旅咬-1-基1·5·(三氟甲基)吡啶鐳：r氟乙酸鹽 外消旋反式-5-氯-2-[4-(2-{2-[4-(甲基續醯基)苯氧基]乙基}環丙基)哌 咬-1-基]嘴咬 外消旋反式-5-氯-2-(4-{2-[2十比咬-4-基氧基)乙基]環丙基}哌啶-1-基） 4-(2-{(1/?，2幻_2-[ 1 -(5-氣嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)-N-環丙 基-2-獻笨曱酿胺 4-(2-{(l/?，2i?)-2-[ 1 -(5-氯嘧啶-2-基)派啶-4-基]環丙基}乙氧基)-2-氟苯 甲腈 141275.docA particular aspect of the invention is directed to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein Ri is selected from the group consisting of hydrazine, a halogen group of F or Br, C丨-3 alkyl, CF3, C(0)NH-cyclopropyl, S(0)CH3, S02CH3, S02NH cyclopropyl, CN and HAR, HAR is selected from the group consisting of oxadiazole, triazole and tetrazole. Group, which is optionally substituted with a thiol or cyclopropyl group. Even more particularly, one aspect of the present invention relates to a compound of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl ring and R] represents a selected from the group consisting of oxadiazole, three A 5-membered heteroaryl ring of the group consisting of azole and tetrazole, which ring is optionally substituted with methyl or cyclopropyl. Further, one aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents acridine ring or pyrimidine 141275. doc -9- 201102374 bite ring m shows CN , CF3 or a 5-membered heteroaryl ring selected from the group consisting of m triterpenes and tetranuclear groups, the ring being optionally substituted by methyl or cyclopropyl. A further aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt or solution thereof, wherein (iv) is selected from the group consisting of gemes 'ch3 and cf3 of ^ci. Another aspect of the present invention is directed to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein R3&R4 represents hydrazine, a halo group selected from F&C1, CH3 and cf3. Another aspect of the present invention is of particular interest to a compound of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is selected from the group consisting of aryl, which is benzene And a heteroaryl group selected from the group consisting of pyridine, pyrimidine and pyrazine; the ring B is selected from the group consisting of pyridine, pyrimidine and pyrazine; i and j represent 0, 1 or 2 such that i and The sum of j is 2; R1 is selected from the group consisting of H, a halogen group of F*Br, a halogen c, a -3, a c(o)nhc2_4 alkyl, s(0)Cl-3 Alkyl, s〇2c]-3 alkyl, SOsNHCu alkyl, CN and HAR, HAR is a 5-membered impurity containing one nitrogen atom, optionally containing 1-3 nitrogen atoms and optionally one oxygen atom The aromatic ring 'the heteroaryl group is optionally substituted with 1 Cl 3 alkyl group; R 2 represents an anthracene, a halogen group selected from F and C 1 , CH 3 and CF 3 ; and R 3 and R 4 represent a halogen group, a halogen group selected from F and Cl, CH3 and CF3. Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein the cyclopropyl ring is a cis-cyclopropyl isomer. 141275.doc 201102374 Examples of compounds of interest are provided in the table below. Compound name racemic cis-chloro-2·[4-(2·{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, 5-Chloro-2-[4-((lS,2R)-2-{2_[4-(methylthenyl)phenoxy]ethyl}cyclopropyl))-1-yl]pyrimidine and 5-Chloro-2-[4-((lR,2S)-2-{2-[4-(indolyl) phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine Racemic cis-gas 2-{4_[2-(2-{[5-(methylsulfonyl carbaryl)-yl)oxy}ethyl)cyclopropyl]piperidine-l- Pyrimidine, cis-5-gas-2-{4-[(lS,2R)-2-(2-{[5-(indolylsulfonyl)°)-bit-2-yl]oxy} Ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, cis-5-gas-2-{4-[(lR,2S)-2-(2-{[5-(nonylsulfonyl) ° 啶 pyridine-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl} acetonidine racemic cis-5-gas-2-[4-(2-{2-[ 3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis-5-chloro-2-[4-(2-{2-[ 3-(5-mercapto-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis-5-chloro -2-[4-(2·{2-[3-(1Η-1,2,4-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine Outside Cyclopentane-5-gas-2-[4_(2-{2-[3-(1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) π bottom bite -1-yl]ρ-biting racemic cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxylated^^ 7~ cyclopropyl·2-fluorobenzamide racemic cis-4-(2-{2_[1-(5-chloropyrimidin-2-yl)piperidinyl]cyclopropyl}ethoxy ))············································································ -1-yl]. Bite racemic cis-5-gas-2-[4-(2-{2-[3-fluoro-4-(5-mercapto-1,3,4-carbo) Azolyl]ethyl}cyclopropyl)piperidine-1-yl]pyrimidine^ racemic cis-5-chloro-2-[4-(2·{2-[4-(1,3,4- Oxadiazol-2-yl)phenoxy]yl)π辰咬-1 -yl] mouth biting racemic cis-5-chloro-2·[4-(2·{2-[4-( 5-methyl-1,3,4-oxadiazol-2-yl) phenyl]]yl}cyclopropyl)pyridin-1-yl 1 pyrimidine racemate cis-5- gas-2-[ 4-(2-{2·[4·(1,2,4-oxadiazol-3-yl)phenoxy)) bite 1-base] mouth bite~~~~~~~s 141275. Doc 201102374 oxadicarbyl group > decyl-1-yl] sulphonate / inside and outside the racemic cis- _5 · 虱 屮 4- 异 异 异 异 异 异 异 异 _ _ _ _ _ _ _ _ 4- - base) mouth bite _ _5 · milk-2-(4-{2-[2-(4-(tetra) quaternary-5-ylphenoxy)ethyl]cyclopropyl} mouth spread small base) Spray bite f as 疋 式 _5· 氯-2·[4_(2_{2_[4_(1Η·pyridylpyrylene) alum ]]ethyl}cyclopropyl ketone-1-yl]pyrimidine ^^^^ί^ϊίΪ4·(1Η·pyrazol-4-yl)ϋ]ethyl}cyclopropane oxime cis-5--chaotic neighbor is called-. ratio. Sitting on a small base) phenoxy]ethylpiperidin-1-yl 1 pyrimidine J cis-5-milk neighbor private · ·〗, 2,4 ^ 嗤 small base) stupid oxy] ethyl} cyclopropyl ) Niang·唆_1 -yl]啼咕-5-chloro-2-[4-(2-{2-[4-(4H-1,2,4-tris-sulphenyl)]oxy]B Base} cyclopropyl) pie bite _ 1 · base] ϋ 说 嗤 } } } } } } } } } } } } -5 -5 -5 -5 -5 -5 -5 -5 -5 ( ( ( ( ( ( ( ( ( ( ( ( ( ( Wow small base) phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis-5-mercapto-2-[4-(2-{2_[4- ie-1 , 2,3-triazole-1_yl) phenyloxy]ethyl}cyclopropyl) 唆 唆 ] ] 嘧啶 外 外 外 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [4·(2Η-1,2,3!^·2-yl) stupidoxy]ethyl}cyclopropyl)° bottom bite _1-base] pain no racemization _5-gas-2 -[4-(2·{2-[4-(1Η-1,2,3-triazolyl)phenyloxy]ethyl}cyclopropyl)piperidine-1·yl 1 pyrimidine racemic cis 5-5-Chloro-2-[4-(2-{2-[4-(out-tetrazole small)) phenyloxy]ethyl}cyclopropyl) Cis-5-chloro-2-[4-(2-{2·[3-fluoro-4·(1Η-tetrazol-1-yl)phenyloxy]ethyl}cyclopropyl) π 嘴 - 1-Base 1 Pain racemic cis-5-fluoro-2·[4-(2-{2-[3-Fluoro-4-(111-tetrazol-1-yl)phenyloxy]ethyl }cyclopropyl)piperidine·1·yl 1 pyrimidine 141275.doc .12- 201102374 Monosyl-2-(4-(2^2-[3-fluoro-4-(1Η-tetrazole-1) · phenoxy]ethyl}cyclopropyl) ° bottom bit-1-yl]-5-methyl t» close bite racemic cis-chloro-2-[4-(2·{2Χ2Η -tetrazol-2-yl)phenoxy]ethyl}cyclopropylpiperidin-1-yl]pyrimidine condensate-5-chloro-2- [4-(2-{2-[4-(5-Methyl-2Η-tetras-2-yl)phenoxy]ethyl}cyclopropyl)-bite-1-yl]式·5_气-2-[4-(2_{2_[4_(5_methyl.1Η_Tetrasinyl)) oxypropyl) °acridin-1-yl]pyrimidine racemic cis -5-chloro-2-[4-(2·{2-[3-fluoro-4-(5-methyl-U4- succinyl-2-yl)i-oxyl..yl]ethyl}cyclopropane Base) bite _1_ base].密外外疋 式-5-gas-2-[4·(2-{2-[4_(methyl succinyl)phenoxy]ethylpiperidin-1-yl 1 pyrimidine) Sexual cis-pyrazine _2_yl)0-decyl _4_yl]cyclopropyl}ethoxy)·2·: basal·4_carbonitrile, cis-6_(2.{(1S, 2R)_2_{1(5 gas money_2 boat bottom bite:]cyclopropyl}ethoxy)-2-mercapto feed bite-4_indene nitrile, cis_6_(2_{(1R,2S) Benzylpiperidin-4-yl]cyclopropyl}ethoxy V2-methylpyrimidine4-methylhydrazine=, cis-2-methyl-6-(2_{2.[H5_曱基鳞_ 2_基)(> bottom each I base] cyprodinil-4-indrene nitrile 2 If _6-(2_{2·[1-(5 密密 bit_2·基)° bottom bite_4_ Base] cyclopropyl}ethoxy)pyrimidine: (2·{2:^^ϊ-2-yl) piperidine / ί, cis-2-mercapto·6·(2·{2·[1 -(5_曱基倾_2_基)D展乙-4-基]Cyclopropyl} 乳基) 叙-4-曱 nitrile 'cis-2-mercaptopurine (10)咬丨辰 bit-4_基]cyclopropyl}ethoxyl>pyrimidine + decyl nitrile, cis 1 methyl·6·(2· $R,2S)--(5·曱基魏_2_ Base) slightly biting _4_yl]cyclopropyl}ethoxy (four). 定_4·甲-------- I41275.doc } -13 - 201102374 Racemic cis-6-(2- {2·[1-(5-Apipyridin-2-yl)piperidine-4-yl]cyclopropane Ethyl}ethoxy)_2_mercaptopyrimidine-4-indolecarbamate racemic cis-6-(2-{2-[1-(4,5·dimethylpyrimidin-2-yl)piperidine _4 _yl]cyclopropyl}ethoxy)-2-mercaptopyrimidine-4-carbonitrile racemic cis-6-(2-{2-[l-(5-chloro-4-mercaptopyridine- 2-yl)pyridin-4-yl]cyclopropyl}ethylheptyl)-2-mercaptopurine _4-carbonitrile racemic cis-6-(2-{2-[1-(5 • Fluoro-4-methylpyrimidin-2-yl)-n-propylidene]cyclopropyl}ethoxy)-2-methyl bite_4-carbonitrile racemic cis-2-_mercapto-6 [2-(2-{ 1-[5-(Trifluoromethyl)pyridin-2-yl]acridine_4_ylpyridinyl)ethoxy]hide-4-carbonitrile racemization Cis-5-gas-2-(4-{2-[2_(〇比唆_3_yloxy)ethyl]cyclopropylbhenyl)-pyrimidine racemic cis-5-gas -2_(4-{2-[2-(唉唉_4_yloxy)ethyl]cyclopropyl chenidine small base) racemic cis-type 5-(2-{2-[1·( 5. Chlorine shouts _2_base) α bottom. _4_yl] cyclopropyl} ethoxy) in the base nitrile 'racemic cis _6 · (2-{2-[1-(5 -chloropyrimidin-2-yl)piperidinyl]cyclopropyl}ethoxy)_2_methylpyrimidine-4-carbonitrile racemic cis-4-(2-{2_[1-(5-a pyrimidine) _2·基)Nionyl _4·yl]cyclopropyl}ethoxy)_6· fluorenyl Pyridine-2-carbonitrile racemic cis-6-(2-{2-[1-(5-fluoropyrimidin-2-yl)piperidinyl]cyclopropyl}ethoxy)_2_methylpyrimidine -4-carbonitrile racemic cis-5-(2_{2-[1-(5-chloropyrimidin-:2-yl)piperidin-4-yl]cyclopropyl}ethoxy oxime- 2-carbonitrile racemic cis-5-gas-2-(4-{2-[2-7-pyridyl-4-yloxy)ethyl]cyclopropylbendole _^-yl) pyrimidine Cis-5-gas-2_{4-[2-(2-{[5-(1 from 1,2,3-triazol-1·yl)acridin-2-yl]oxy} ethyl Cyclopropyl]piperidin-l-yl}pyrimidine, cis-5-chloro-2-{4_(18,211)-[2-(2-{[5-(1//-1,2,3- Triterpene-1-yl)pyridine-2·yl]oxy}ethyl)cyclopropyl]D-decyl small) pyrimidine, cis _ 5_ gas · 2-{4_(111,28)-[2- (2-{[5-(1//-1,2,3,Sansial_1-yl)pyridine-2-yl]oxy}ethyl)cyclopropyl]° bottom bite-1· base} Bite 1 5-Gas-2·[4-((1/?,25>2·{2-[3·Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl) Phenoxy]ethyl}cyclopropyl)0-bottom-1-yl]pyrimidine and 5-chloro-2-[4-((ΐ^,2Λ)·2-{2-[3-fluoro·4 -(5-methyl-indole 3,4-oxadiazole-:2-yl)phenoxy]ethylindole propyl)pyridinium +yl]pyroline 141275.doc • 14- 201102374 5-Chloro- 2-[4-(( 15^)-2·{2-[4_(ιη-1,2,3-Tris-l-yl)phenyloxy]ethyl}cyclopropyl) 0 bottom bit-1-yl] mime and 5 _ gas_2_[4·((1 foot odor small) phenoxy]ethyl}cyclopropyl) 〇 唆-1-yl] mouth bite> fluoro-2-[4-((l/? , 2S > 2-{2-[4-(lH-l, 2, 3-three. -1--1-yl)phenoxy]ethyl}cyclopropyl) 0-decyl-1-yl]pyrimidine and 5-fluoro-2-.[4·((10)2 幻·^则木即], 2,3· Triterpenoids) phenoxy]ethyl}cyclopropyl) brigade bite-1-yl 1 spray bite 5_chloro-2-[4-((1/?,2 office 2-{2_[4_(11 ^-四.Sit _1_yl)phenoxy]ethyl}cyclopropyl)-bite 1-yl acridine and 5-chloro-2-[4-((10)Μ)-2-{2-[4 -(1Η-tetras-l-yl)phenoxy]ethyl}cyclopropyl)piperidin-1 ·yl]pyrimidine> gas_2-[4_(( li?,25>2_ {2.[ 3 preparation 4_(! Ηtetrazole small) phenoxy]ethyl}cyclopropyl) brigade-1-yl]pyridinium and 5-gas-2-[4-((10)2i?)-2-{2 -[3- gas-4-(1Η-tetra. sit-1-yl) phenyloxy]ethyl}cyclopropyl)π辰咬_ 1 _某]0密喷^ Fluoride L2-L4-((1 Foot 2lS)-2_{2-[3_fluoro_4·(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) Pyrimidine and 5-fluoro·2_[4_((1ι5,2;?)-2_ (2_[3·fluoro_4·(5·methyl·1,3,4-. oxadihydro-2-yl)) Stupid oxy]ethyl propyl propyl) piperidine small ρ pyridine racemic cis _2_[4-(2-{2-[3-fluoro_4-(5· fluorenyl-hydrazine, 3 , 4-oxadiazol-2yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl1-5-f-pyrimidine racemic cis-type 2-[4 -(2-{2-[3-Fluoro-4-(5-methyl-1,3,4-oxadin-2-yl)phenyloxy]ethyl}cyclopropyl) π bottom. 1 - a certain pyrimidine cis-5-fluoro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazole) 2-yl)phenoxy]ethyl}cyclopropyl)pyrphate·1_yl] acetonidine racemate cis-5- gas·2·[4-(2_{2_[3_1-4_(5_ Methyl-I,3,4·nooxazolyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]_4_mercaptopyrimidine racemic cis-3,5·dichloro -2-[4-(2-{2-[3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl} isopropyl Niang 定定_1_基]υ比.定外消顺式-2-[4_(2_{2·[3_氟-4_(5·methyl_l53,4_oxadiazole_2_ Phenyloxy]ethyl}cyclopropyl) brigade-1-yl-1·5·(trifluoromethyl)pyridine radium: r-fluoroacetate racemic trans-5-chloro-2-[4 -(2-{2-[4-(methylthenyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl] mouth bite racemic trans-5-chloro-2-( 4-{2-[2 decyl-4-yloxy)ethyl]cyclopropyl}piperidin-1-yl) 4-(2-{(1/?, 2 illusion_2-[ 1 - (5-apyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-N-cyclopropyl-2-dedicylamine 4-(2-{(l/?, 2i?)-2-[ 1 -(5-chlorine 2-yl) sent 4-yl] cyclopropyl} ethoxy) -2-fluorobenzonitrile 141275.doc

[SI -15- 201102374 5-氣-2-[4-((1 足2Λ)·2·{2-[4·(1Η-1，2,4-***-1-基)苯氧基]乙基}環丙基） 哌咬-1-基1嘧啶 氯·2-[4-((1；?，2Λ)·2-{2-[3-氟斗(5-甲基-1，3,4·噁二唑 基)苯氧基]乙 基}壤丙基)π辰咬·1-基]嘴咬 5_ 氣-2-[4-((ΐπ，2/?)-2-{2·[4-(5-環丙基-1,3,4-噁二唑-2-基)-3-氟苯氧基] 乙基}環丙基)η底咬_1_基]嘴咬 外消旋反式-5-氯-2·(4-{2-[2-(吡啶-4-基氧基)乙基]環丙基}哌啶·ι_^~ 嘧啶 外消旋反式·4-(2-{2-[1-(5-氯嘧啶-2·基)哌啶-4-基]環丙基}乙氧基)-6_ 甲基嘧啶-2-甲腈 外消旋反式-6-(2-{2·[1-(5·氯嘧啶-2-基)哌啶_4_基]環丙基}乙氧基>2_ 曱基嘧啶-4-甲腈 外消旋反式-5-氣-2-{4-[(2-{[4-(甲基磺醯基)苯氧基]甲基}環丙基)曱 基]0底咬-1-基}略咬 5-氯-2-[4-((1/?，2办2-{2-[4-(甲基磺醯基)苯氧基]乙基}環丙基)旅咬小 基]嘴咬 5_氣-2-{4-[((1\25)-2·{[4-(曱基確醯基)苯氧基]曱基}環丙基)甲基]哌 变-l-基}喊咬 外消旋反式-4-[(2-{[1-(5_氣嘧咬·2_基)派啶_4_基]甲基}環丙基)甲氧 基]-2-氟苯曱腈 4-[((1足2i?)-2-{[l-(5·氣嘧啶-2-基)派啶·4_基]甲基}環丙基)曱氧基]_2_ 氟苯甲腈 外消旋反式-4-[(2-{[ι-(5·氣嘧啶-2_基)哌啶冬基]曱基μ裒丙基)甲氧 基]-Ν-環丙基-2-氟苯曱醯胺 4-[((1足2幻-2-{[1-(5-氱嘧啶-2-基)哌啶_4-基]甲基}環丙基)甲氧基]_Ν_ 環丙基-2-氟笨甲醯胺 4·[((15,25)-2·{[1_(5-氣嘧啶-2-基)略啶_4·基]曱基}環丙基)曱氧基]-Ν_ 環丙基-2-氟笨曱醯胺 5-氯-2-{4-[((1/?，2/?)-2-{[3-氟-4-(5-曱基-1,3,4-°惡二唾-2-基)苯氧基]曱 基}環丙基)甲基]哌咬-l-基}嘧啶 5-氣-2-{4-[((lS，25)-2-{[3-氟-4-(5-甲基·ΐ，3,4-°惡二唾-2-基)笨氧基]甲 基}環丙基)曱基]派啶-l-基}嘧啶 外消旋反式-5-氣-2-{4-[(2-{[4-(5-環丙基_ι，3,4·噪二唾-2-基)-3-氟笨氧 基]曱基}環丙基)甲基]哌啶-l-基}嘧啶 141275.doc _ 16· 201102374 4-[((LS，25>2_{[l-(5-氯嘀啶-2-基)哌啶-4-基]曱基}環丙基)曱氧基]苯 磺醯胺 . 外消旋反式-6-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]曱基}環丙基)曱氧 基]-2-甲基嘧啶-4-甲腈 外消旋反式-4-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]曱基}環丙基)曱氧 基]-6-甲基嘧啶-2-甲腈 外消旋反式-4-[((lS,2S)-2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]甲基}環丙 基)甲氧基]-3-氟苯曱腈 外消旋順式_5_氯-2-{4-[(2-{[4-(甲基磺醯基)苯氧基]曱基}環丙基)曱 基]。底咬-l-基}。密咬 外消旋順式-4-[(2-{[ 1-(5-氯嘧啶-2-基)哌啶-4-基]甲基}環丙基)曱氧 基]-N-環丙基-2-氟苯f醯胺 外消旋順式-4-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]曱基}環丙基)曱氧 基]-6-甲基。密11定-2-曱猜 外消旋順式-4-[(2-{[1-(5·氯嘧啶-2-基)哌啶-4-基]曱基}環丙基)曱氧 基笨曱猜 以及其醫藥學上可接受之鹽及溶劑合物。 所關注之本發明化合物之子集係關於式Ι-A化合物：[SI -15- 201102374 5-gas-2-[4-((1 foot 2Λ)·2·{2-[4·(1Η-1,2,4-triazol-1-yl)phenoxy]] Ethyl}cyclopropyl) piperidine-1-yl 1 pyrimidine chloride ·2-[4-((1;?,2Λ)·2-{2-[3-fluorocape (5-methyl-1,3 ,4·oxadiazolyl)phenoxy]ethyl}leaf propyl)π辰咬·1-base] mouth bite 5_ gas-2-[4-((ΐπ,2/?)-2-{2 ·[4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-3-fluorophenoxy]ethyl}cyclopropyl)η bottom bite _1_ base] mouth bite Racemic trans-5-chloro-2·(4-{2-[2-(pyridin-4-yloxy)ethyl]cyclopropyl}piperidine·ι_^~ pyrimidine racemic trans 4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-6-methylpyrimidine-2-carbonitrile racemic Formula-6-(2-{2·[1-(5-chloropyrimidin-2-yl)piperidine-4-yl]cyclopropyl}ethoxy>2_mercaptopyrimidine-4-carbonitrile Cyclo-trans-5-gas-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]methyl}cyclopropyl)indolyl]0 bottom bit-1-yl} Slightly bite 5-chloro-2-[4-((1/?,2) 2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) brigade base] Mouth bite 5_gas-2-{4-[((1\25)-2·{[4-(indolyl) phenoxy]indolyl}cyclopropyl)methyl]piper-l -base} Racemic trans-trans-4-[(2-{[1-(5-aestriazin-2-yl)pyridinyl-4-yl]methyl}cyclopropyl)methoxy]-2-fluoro Benzimidonitrile 4-[((1) 2i?)-2-{[l-(5·apyrimidin-2-yl)pyridinyl-4-yl]methyl}cyclopropyl)decyloxy]_2_ Fluorine Benzonitrile, racemic trans-4-[(2-{[ι-(5·apyrimidin-2-yl)piperidinyl]yl)pyranyl)methoxy]-indole-cyclopropane 4-fluorobenzophenone 4-[((1) 2 phanyl-2-{[1-(5-purpurin-2-yl)piperidin-4-yl]methyl}cyclopropyl) A Oxy]_Ν_cyclopropyl-2-fluorobenzamide 4·[(15,25)-2·{[1_(5-apyrimidin-2-yl)-l-yl)-yl] fluorenyl} Cyclopropyl)nonyloxy]-indole_cyclopropyl-2-fluorobenzamine 5-chloro-2-{4-[((1/?,2/?)-2-{[3-fluoro- 4-(5-mercapto-1,3,4-°oxadi-2-yl)phenoxy]indolyl}cyclopropyl)methyl]piperidin-l-yl}pyrimidine 5-gas-2 -{4-[((lS,25)-2-{[3-Fluoro-4-(5-methyl·indene, 3,4-° oxadi-2-yl)phenyloxy]methyl} Cyclopropyl)indolyl]pyridinyl-l-yl}pyrimidine racemic trans-5-gas-2-{4-[(2-{[4-(5-cyclopropyl_ι,3,4) ·Noise dis-2-yl)-3-fluorophenyloxy]fluorenyl}cyclopropyl)methyl]piperidine-l-yl}pyrimidine 141275.doc _ 16· 201102374 4-[((LS,25&g t; 2_{[l-(5-chloroacridin-2-yl)piperidin-4-yl]indolyl}cyclopropyl)decyloxy]benzenesulfonamide. Racemic trans-6-[ (2-{[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]indolyl}cyclopropyl)decyloxy]-2-methylpyrimidine-4-carbonitrile racemic 4-[(2-{[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]indolyl}cyclopropyl)decyloxy]-6-methylpyrimidin-2-yl Nitrile racemic trans-4-[((lS,2S)-2-{[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy ]-3-fluorobenzonitrile, racemic cis-5-chloro-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]indolyl}cyclopropyl)indole base]. Bottom bite-l-base}. Racemic racemic cis-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl) decyloxy]-N-cyclo Propyl-2-fluorobenzene f decylamine racemic cis-4-[(2-{[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]indolyl}cyclopropyl)曱oxy]-6-methyl.密11定-2-曱 guess racemic cis-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]indolyl}cyclopropyl)oxime A clumsy guess and its pharmaceutically acceptable salts and solvates. A subset of the compounds of the invention of interest relates to a compound of formula Ι-A:

(只4)2-3(only 4) 2-3

R1 (^2)2-3 或其醫藥學上可接受之鹽或溶劑合物，其中： 環A表示含有1個氮原子且視情況再含有1-2個氮原子之6 員芳基或雜芳基； 環B表示含有1-2個氮原子之6員雜芳基環； Ξ 1 141275.doc -17- 201102374 i及j獨立地表示選自0、1及2之整數，以使得i+j為1或 2 ； R1表示選自由以下各基組成之群之成員：H、鹵基、Cu 烷基、鹵C!-6烷基、烷基、C(0)鹵Cw烷基、 C(0)NH-Ci-6 烷基、8(0)(^.6 烷基、SOzCw 烷基、 S02NH2、S02NHC】-6烷基、s〇2N(C卜6烷基）2、CN及視情況 經1-3個（：卜6烷基、鹵基或鹵（：丨_6烷基取代之HAR ; 且R2、R3及R4各自獨立地選自Η、鹵基、C,-6烷基及鹵 Cu烷基。 本發明所關注之另一態樣係關於式Ι-A化合物，其係選 自由以下各物組成之群： 表l-a 外消旋順式-5-氣-2-[4-(2-{2-[4-(甲基磺醯基)苯氧基]乙基}環丙基)哌 啶-1-基]嘧啶、5-氯-2-[4-((lS，2R)-2-{2-[4-(曱基磺醯基)苯氧基]乙基} 環丙基)°底啶_1_基]嘴啶及5-氣-2-[4-((1民28)_2-{2-[4-(甲基磺醯基)苯氧 基]乙基}環丙基)哌啶-1 -基]嘧啶 外消旋順式-5-氯-2-{4-[2-(2·{[5-(甲基磺醯基户比啶-2-基]氧基}乙基)環 丙基]哌啶-l-基}嘧啶、5-氣-2-{4-[(1足25)-2-(2-{[5-(曱基績醯基)吡啶-2-基]氧基}乙基)環丙基]哌啶-l-基}嘧啶、5-氯-2-{4-[(lS,2R)-2-(2-{[5-(甲基磺醯基)吡啶·2_基]氧基}乙基)環丙基]哌啶小基}嘧啶 外消旋順式-5·氣_2-[4-(2_{2-[3-(曱基磺醯基)笨氧基]乙基}環丙基)哌 咬-1-基]0^咬 外消旋順式-5·氯-2-[4-(2-{2-[3-(5-甲基-1,3,4-噁二唑-2·基)苯氧基]乙 基}環丙基)哌啶-1-基]嘧啶 外消旋順式-5-氯-2-[4-(2-{2-[3-(出-1，2,4-***-1-基)苯氧基]乙基}環丙 基)°辰啶-1-基]嘧啶 「外消旋順式-5-氯·2-[4-(2-{2-[3-(1，3,4-。惡二唑-2-基)苯氧基]乙基}環丙 基)旅咬-1-基]嘴咬 141275.doc -18- 201102374 外消旋順式-4-(2-{2·!；!#·氯嘧啶_2_基)哌啶_4·基]環丙基}乙氧基)_队 環丙基-2-氟笨甲醯脸 外消旋順式ip-die-氣嘧啶_2_基)哌啶_4_基]環丙基}乙氧基)_2_ 氟苯甲腈 外消旋順式-5-氣-2-[4-(2-{2-[4-(環丙基磺醯基)苯氧基]乙基}環丙基) 哌啶-I-基]嘧啶 外消旋順式-5-氯-2·[4-(2-{2-[3-氟-4-(5-曱基-1，3,4-噁二唑-2-基)笨氧 外消旋順式·5_氯_2_[4·(2_{2_[4_(1，3,4·噁二唑_2_基)笨氧基]乙基}環丙 基)°底唆-1-基1痛咕 H乙基}環丙基)畈哈丄其·!崎设 将⑽冰麟氧肌 ϋ旋順式-5-氣部必㈣似‘療二坐_3·基)苯氧 基)哌啶小基]嘧唆 二私·基)苯細乙基 基 >底唆-1-基]♦定 噁唑-4-基)苯氧基]乙基 式_5_H(4-{2-[2_(4_異嗯嗤_4_基苯氧基)乙基]環丙基}旅咬-2)^^'5_1^2_(4-{2仰_異射_5_基苯氧基)乙基]環丙基}°底咬· 轉 1.細乙 1^^· 継氧基 忠思三嗤-4·基)苯氧 141275.doc S] -19- 201102374 外消旋順式·5_ 氟-2-[4-(2-{2-[4-(iH-i，2,3&m^a&]6*p^ 基)哌啶-1-基]嘧啶 外消旋順式_5-甲基-2-[4-(2-{2-[4-(111-1，2,3-三唾_1_基)苯氧基]乙基}環 丙基 >底啶-1-基]嘧啶 外消旋順式-5_氣_2_[4-(2- {2-[4_(2H-1,2,3-***_2·基)苯氧基]乙基}環丙 基)17辰咬-1 -基]喷唆 外消旋順式·5_氣-2-[4-(2-{2-[4_(111-1，2,3-***_5_基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶 外消旋順式-5-氣-2-[4-(2-{2-[4-(1Η-四嗤小基)苯氧基]乙基μ裒丙基)旅 咬-1-基]«密咬 外消旋順式-5-氣-2·[4·(2·{2_[3_氟·4_(1Η·四唾_丨_基)笨氧基]乙基)環丙 基户底咬-1-基]嘴咬 外消旋順式-5-氟-2-[4·(2·{2-[3备4_(1H-四唾小基)苯氧基]乙基}環丙 基)°底。定-1-基]嘴咬 外消旋順式·2-[4-(2_{2-[3-氣_4_(1H_四唾基)苯氧基]乙基}環丙基)〇底 咬-1-基]·5·甲基嘴咬 外消旋順式.5_氯_2-[4-(2-{2_1；4调_四唾_2•基)苯氧基]乙基}環丙基)哌 咬-1-基]喂咬 外消旋順式-5-氯-2-[4-(2_{2-[4-(5·曱基_2Η-四嗤_2_基)苯氧基;]乙基}環 丙基)a底咬-1-基1嘴啶 外消旋順式·5·氯-2-[4-(2-{2-[4_(5·甲基_1Η-四哇基)苯氧基]乙基}環 丙基)°底咬-1-基]唆咬_ 外消旋順式-5-氣·2-[4-(2-{2-[3·氟-4-(5-甲基-1，3,4-»惡二唾-2-基)苯氧 基]乙基}環丙基)娘咬-1-基]P密咬_______ 5-氯-2-[4-( 1 S，2R)-(2- {2-[4·(曱基亞磺醯基)笨氧基]乙基)環丙基)。底0定_ 基]嘴咬、5-氯甲基亞磺醯基)苯氧基]乙基} 環丙基)°底咬-1-某1嘧咭 6-(lS，2R)-(2-{2-[l-(5-氣喊咬-2-基)旅咬*4-基]環丙基}乙氧基)-2-甲基 ，咬·4_甲腈、氯嘧啶_2_基)。底啶冬基]環丙基}乙 氧基)-2-甲基啼哈_4-甲腈 外消旋順式·1-[4_(2_{2-[1-(5-氯嘧啶_2_基)哌啶-4-基]環丙基}乙氧基) 苯基]乙酮 外消旋順式·2·曱基·6·(2·{2-[1·(5-甲基吡嗪·2·基)哌啶·4_基]環丙基}乙 氧基)嘧啶-4-曱腈 141275.doc • 20· 201102374 2=式雖{2仰侧奴基)終4·綱_ 式-4_(2_{2·[1_(5_ 氯齡2·基)終4.基]環 咬-2·甲膀 2 T基 6 (lS，2R)-(2-{2-[l-(5-甲基魏 ^嘧啶-4’甲▼、2_甲基·6_(1民28)_(2_{2_[1_(5_甲基鳴咬_2_基>底各4· 基]環丙基}乙氧基)》密咬_4_甲腈 外献順式_2_曱基抑-制哗甲基錢』翁紋4基 氧基)漆咬_4_曱腈 & 外消旋順式-2,4-一曱基甲基哺咬_2基)。底咬斗 基}乙氧基)0¾咬____ ―外消旋順式-6-(2-{2-[1^7氯_4·曱基嘧^7基)〇辰咬斗基]環丙 基)_2_甲基哺咬_4·曱腈 外麟順式-6-(2-{2-[ 1-(5_氣0比咬_2_基)(1 辰咬_4_基]環丙基}乙氧基)_2_ 曱基嘧咬-4-曱腈 外雜順式·6_(2_{2-[1-(4,5·二甲基嘧淀_2.基)哌啶_4·基]環丙基）乙氧 基)-2-f基。密咬-4-曱猜 外消旋順式-6-(2-{2-[1-(5_氯外曱基吡咬_2_基)哌咬_冬基]環丙基}乙 基)-2-甲基。密咬-4-曱腈 外消旋順式-6-(2_{2-[ 1 -(5_氣_4_甲基嘧咬_2_基)哌咬冬基]環丙基}乙^~ 基)-2-f基嘧啶-4-曱腈 外消旋順式_2·曱基.6·[2-(2_{ΐ_[5-(三氟甲基户比啶_2·基]〇底咬冬基}^〜' 丙基)乙氧基]喷咬-4-甲腊 外消旋順式_5_氯·2_(4-{2·[2々比啶-3-基氧基)乙基]環丙基卜辰咬小基） 外消旋順式-5·氣-2-(4- {2-[2-(喊啶冬基氧基)乙基]環丙基}π底咬_1 ·基） 嘧啶 外消旋順式-5-(2_{2-[ 1 _(5·氯嘧啶_2Dn辰啶_4_基]環丙基）乙氧基)^~ 腈 、 外消旋順式-6_(2-{2-[ 1-(5-氯嘧啶_2_基)哌啶冬基]環丙基）乙氧基)_2_ 甲基嘧咬-4-曱腈 外消旋順式-4-(2-{2·[1-(5_氣嘧啶-2-基)娘啶·4_基]環丙基}乙氧基)_6_—~ 甲基嘧咬-2-甲腈 外消旋順式-6-(2-{2-[1-(5-氣嘧咬-2-基)哌咬_4_基]環丙基}乙氧基)-2^— 甲基嘧啶甲腈 I41275.doc 21 - 201102374 外消旋順式-5-(2-{2-[l-(5-氣嘧啶-2-基)哌啶-4·基]環丙基}乙氧基)0比 咬-2-甲腈________ 外消旋順式-5-氣-2-(4-{2-[2-(。比啶-4-基氧基)乙基]環丙基}哌啶-1-基） 嘴咬______ 5-氣-2-(15,211)-{4-[2-(2-{[5-(11'!-1，2,3-***-1-基)'1比啶-2-基]氧基}乙基) 環丙基]哌啶-l-基}嘧啶、5-氣-2-(111，28)-{4-[2-(2-{[5-(1沁1，2,3-***- 1-基)吡啶-2-基]氧基}乙基)環丙基]哌咬-i-基}嘧咬__ 5-氣-2-[4-((1 足25>2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基)苯氧基]乙 基}環丙基)哌啶-1-基]嘧啶及5·氣-2-[4-((1\2Λ)-2-{2-[3-氟-4-(5-曱基- 1，3,4-噁二唑-2-基)苯氧基]乙基}環丙基)派啶_1_基]嘧咬__ 外消旋順式氯-2-[4-(2-{2-[4-(1Η-1，2,3-***-1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶、5-氯4^-((^^)-1(244-(111-1,2,3-***-1-基)苯 氧基]乙基}環丙基>底啶-1 -基]嘧啶及5-氯-2-[4-(( 1足25>2- {2-[4-( 1H- i，2,3-三吐-1-基)苯氧基]乙基}環丙基)°辰°定-1-基]嘴咬_ 5_ 氟-2-[4_((1足25>2-{2-[4-(111-1，2,3-***-1-基)苯氧基]乙基}環丙基） 哌咬-1-基]嘧啶及 ***-1-基)苯氧 基]乙基}環丙基)哌交-1-基]嘧咬__ i^-2-[4-((ii?，2^)-2-{2-[4-(iH-四唑小基)苯氧基]丙基)哌咬小 基]°密咬及5_氯-四。坐-1-基)苯氧基]乙基)環丙 基)π辰咬-1-基]嘴咬R1 (^2)2-3 or a pharmaceutically acceptable salt or solvate thereof, wherein: ring A represents a 6-membered aryl or a heterocyclic group containing 1 nitrogen atom and optionally 1 to 2 nitrogen atoms. Aryl; Ring B represents a 6-membered heteroaryl ring containing 1-2 nitrogen atoms; Ξ 1 141275.doc -17- 201102374 i and j independently represent an integer selected from 0, 1 and 2 such that i+ j is 1 or 2; R1 represents a member selected from the group consisting of H, halo, Cu alkyl, halo C!-6 alkyl, alkyl, C(0) halo Cw alkyl, C ( 0) NH-Ci-6 alkyl, 8 (0) (^.6 alkyl, SOzCw alkyl, S02NH2, S02NHC)-6 alkyl, s〇2N (C 6 alkyl) 2, CN and optionally By 1-3 (: 6 alkyl, halo or halo (: 丨 6 alkyl substituted HAR; and R 2 , R 3 and R 4 are each independently selected from fluorene, halo, C, -6 alkyl and Halo Cualkyl. Another aspect of the present invention is directed to a compound of the formula Ι-A which is selected from the group consisting of: Table la Racemic cis-5-Ga-2-[4- (2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, 5-chloro-2-[4-((lS,2R) )-2-{2-[4-(indolylsulfonyl)phenoxy]B } cyclopropyl) ° 啶 _1 _1 _ _ 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 Ethyl}cyclopropyl)piperidine-1-yl]pyrimidine racemic cis-5-chloro-2-{4-[2-(2·{[5-(methylsulfonyl) 2-yl]oxy}ethyl)cyclopropyl]piperidine-l-yl}pyrimidine, 5-gas-2-{4-[(1 foot 25)-2-(2-{[5-(曱吡啶 )) pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-yl}pyrimidine, 5-chloro-2-{4-[(lS,2R)-2-(2 -{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine small group}pyrimidine racemic cis-5·gas_2-[4-( 2_{2-[3-(indolylsulfonyl)phenyloxy]ethyl}cyclopropyl)piperidin-1-yl]0^bita racemic cis-5-chloro-2-[4- (2-{2-[3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine Cyclo-5-chloro-2-[4-(2-{2-[3-(out-1,2,4-triazol-1-yl)phenoxy]ethyl}cyclopropyl)° Acetyl-1-yl]pyrimidine "racemic cis-5-chloro-2-[4-(2-{2-[3-(1,3,4-.oxadiazol-2-yl)benzene) Oxy]ethyl}cyclopropyl) travel bite-1-base] mouth bite 141275.doc -18- 201102374 racemic cis-4-(2-{2·!;!#·chloropyrimidine_2_ Piperidine_4 ·Based]cyclopropyl}ethoxy) _ ring cyclopropyl-2-fluorobenzidine face racemic cis-cis ip-die-a pyrimidine_2_yl) piperidine_4_yl]cyclopropyl }ethoxy)_2_ fluorobenzonitrile racemic cis-5-gas-2-[4-(2-{2-[4-(cyclopropylsulfonyl)phenoxy]ethyl} ring Propyl) piperidine-I-yl]pyrimidine racemic cis-5-chloro-2·[4-(2-{2-[3-fluoro-4-(5-mercapto-1,3,4) -oxadiazol-2-yl) oxo racemic cis- 5_chloro_2_[4·(2_{2_[4_(1,3,4·oxadiazol-2-yl)phenyloxy] Ethyl}cyclopropyl)° bottom 唆-1-yl 1 pain 咕H ethyl}cyclopropyl)畈哈丄其·!崎设(10) 冰麟氧肌肌ϋ式-5- 气部必(四) Like 'therapy two sitting _3 · yl) phenoxy) piperidine small group] pyrimidine bis-yl) phenyl fine ethyl group > base 唆-1-yl] ♦ oxazol-4-yl) benzene Oxy]ethyl form _5_H(4-{2-[2_(4_isoxanthene-4-ylphenoxy)ethyl]cyclopropyl} brigade bite-2)^^'5_1^2_(4 -{2 _ _ _ _ 5 _ phenoxy) ethyl] cyclopropyl} ° bottom bite · turn 1. fine B 1 ^ ^ · 継 忠 忠 嗤 嗤 嗤 · · · · · 141 141 141 141 141 .doc S] -19- 201102374 racemic cis- 5_ fluoro-2-[4-(2-{2-[4-(iH-i,2,3&m^a&]6*p^ Piperidin-1-yl]pyrimidine racemization _5-Methyl-2-[4-(2-{2-[4-(111-1,2,3-trisial-1-yl)phenoxy]ethyl}cyclopropyl> 1-yl]pyrimidine racemic cis-5-gas_2_[4-(2- {2-[4_(2H-1,2,3-triazol-2-yl)phenoxy]ethyl} Cyclopropyl) 17 Chenbit-1 -yl] sneeze racemic cis- 5_ gas-2-[4-(2-{2-[4_(111-1,2,3-triazole_5 _ yl) phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis-5-gas-2-[4-(2-{2-[4-(1Η-four嗤小基) phenoxy]ethyl 裒 propyl) brigade bite-1-yl] « close bite racemic cis-5-gas-2·[4·(2·{2_[3_fluor· 4_(1Η·四唾_丨_yl) stupidoxy]ethyl)cyclopropyl base biting-1-yl] mouth biting racemic cis-5-fluoro-2-[4·(2·{ 2-[3 Preparation 4_(1H-Tetrasyl) phenoxy]ethyl}cyclopropyl). Ding-1-yl] mouth biting racemic cis-type 2-[4-(2_{2-[3-gas_4_(1H_tetrasyl)phenoxy]ethyl}cyclopropyl) Biting-1-yl]·5·methyl-mouth bite racemic cis.5_Chloro-2-[4-(2-{2_1;4-modulate-tetras-_2-yl)phenoxy]ethyl }cyclopropyl)piperidin-1-yl]feed biting racemic cis-5-chloro-2-[4-(2_{2-[4-(5·曱基_2Η-tetrazole_2_) Phenoxy; ethyl}}}}}} Methyl-1Η-tetrawayl)phenoxy]ethyl}cyclopropyl)° bottom bit-1-yl] bite _ racemic cis-5- gas·2-[4-(2-{ 2-[3·Fluoro-4-(5-methyl-1,3,4-»oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) Ninjabita-1-yl]P-density Bite _______ 5-chloro-2-[4-( 1 S,2R)-(2- {2-[4.(indolylsulfinyl)phenyloxy]ethyl)cyclopropyl). Bottom 0 _ base] mouth bite, 5-chloromethylsulfinyl) phenoxy] ethyl} cyclopropyl) ° bottom bite 1- some pyrimidine 6-(lS, 2R)-(2 -{2-[l-(5-气叫咬二基)Break bite *4-yl]cyclopropyl}ethoxy)-2-methyl, bite·4_carbonitrile, chloropyrimidine_2 _base).底 冬 冬 ] 环 } } } } } } } } } } } } 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1-[4_(2_{2-[1-(5-chloropyrimidine_2 _yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]ethanone racemic cis- 2·indolyl·6·(2·{2-[1·(5-methyl) Pyrazin·2·yl) piperidine·4 —yl]cyclopropyl}ethoxy]pyrimidine-4-indolecarbonitrile 141275.doc • 20· 201102374 2=Formula {2Back side slave base) End 4· _ 式-4_(2_{2·[1_(5_ 氯龄二·基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基) (5-methyl-Wei-pyrimidine-4'-A, 2-methyl·6_(1min28)_(2_{2_[1_(5_methyl-biting_2_base> bottom 4· base ]cyclopropyl}ethoxy)"Bite bite _4_carbonitrile external cis _2_ 曱 抑 - 哗 哗 哗 哗 哗 翁 翁 翁 4 _ _ _ _ _ _ _ _ _ _ _ Racemic cis-2,4-mercaptomethyl chinyl _2 base). bottom hopper base} ethoxy) 03⁄4 bite ____ ― racemic cis-6-(2-{2- [1^7 氯_4·曱 嘧 ^ 7 7 7 ] ] ] ] ] ] ] ] ] ] ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -6 -6 -6 -6 -6 -6 -6 -6 1-(5_气0比咬_2_基)(1 辰咬_4_基]cyclopropyl}ethoxy)_2_ thiopyrimidine-4-indene nitrile cis-6·(2_{ 2-[1-(4,5·dimethyl Ethyl starch _2-yl) piperidin-4 ·-yl] cyclopropyl) ethoxy) -2-f group.密-4--4- guess racemic cis-6-(2-{2-[1-(5-chloro-purinylpyridin-2-yl) piperidine_winteryl]cyclopropyl}ethyl )-2-methyl.密-4--4-carbonitrile racemic cis-6-(2_{2-[ 1 -(5_气_4_methyl-pyrimidine_2_yl) piperidinyl]cyclopropyl}ethyl ~ yl)-2-f-pyrimidin-4-indene nitrile racemic cis _2. fluorenyl.6·[2-(2_{ΐ_[5-(trifluoromethylbenzidine-2-yl) Bottom bite winter base}^~' propyl) ethoxy] spray bite-4-carrageen racemate _5_chloro·2_(4-{2·[2々pyridin-3-yloxy Ethyl]cyclopropyl-b-butyl butyl group) racemic cis-5-gas-2-(4-{2-[2-(pyridinyloxy)ethyl]cyclopropyl} π bottom bite l · base) pyrimidine racemic cis-5-(2_{2-[ 1 _(5· chloropyrimidin-2-Dn succinyl-4-yl)cyclopropyl)ethoxy)^~ nitrile , racemic cis-6-(2-{2-[ 1-(5-chloropyrimidin-2-yl)piperidinyl]cyclopropyl)ethoxy)_2_methylpyrimidine-4-indrene Racemic cis-4-(2-{2·[1-(5-azaypyrimidin-2-yl)-nidinyl-4-yl]cyclopropyl}ethoxy)_6_-~ methylpyrimidine- 2-carbonitrile racemic cis-6-(2-{2-[1-(5-amphetidine-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2^ —Methylpyrimidinecarbonitrile I41275.doc 21 - 201102374 Racemic cis-5-(2-{2-[l-(5-apyrimidin-2-yl)piperidin-4yl]cyclopropyl} Ethoxy)0 than bite-2- ________ racemic cis-5-gas-2-(4-{2-[2-(.pyridin-4-yloxy)ethyl]cyclopropyl}piperidin-1-yl) mouth bite_ _____ 5-gas-2-(15,211)-{4-[2-(2-{[5-(11'!-1,2,3-triazol-1-yl)'1-pyridin-2-yl) ]oxy}ethyl)cyclopropyl]piperidine-l-yl}pyrimidine, 5-gas-2-(111,28)-{4-[2-(2-{[5-(1沁1, 2,3-triazole-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidone-i-yl}pyrimidine__ 5- gas-2-[4-((1 Foot 25> 2-{2-[3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidine-1 -yl]pyrimidine and 5·gas-2-[4-((1\2Λ)-2-{2-[3-fluoro-4-(5-fluorenyl-1,3,4-oxadiazole-2) -yl)phenoxy]ethyl}cyclopropyl)pyridine-1-yl]pyrimidine__ racemic cis-chloro-2-[4-(2-{2-[4-(1Η-1) , 2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, 5-chloro 4^-((^^)-1(244-(111 -1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl>pyridin-1 -yl]pyrimidine and 5-chloro-2-[4-((1 foot 25>) 2- {2-[4-( 1H- i,2,3-trioxa-1-yl)phenoxy]ethyl}cyclopropyl)°°°-1-yl] mouth bite_ 5_ fluorine- 2-[4_((1)25>2-{2-[4-(111-1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl) Benton-1-yl]pyrimidine and triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperazin-1-yl]pyrimidine __ i^-2-[4-((ii?, 2^)-2-{2-[4-(iH-tetrazole small)phenoxy]propyl)propylidene small base] ° bite and 5-chloro-tetra. Sodium-1-yl)phenoxy]ethyl)cyclopropyl)π辰咬-1-yl] mouth bite

I消旋順式：氟-244-(2-{2_[3_i^(5_ 甲基- 基]乙基}環丙基)哌淀-1-基1嘧咬___〜、一坐-2-基)本氧 ;卜消旋順式-5-氣-2-[4-(2-{2-[Γ^Γ(5-甲基其笑 基]乙基}環丙基)哌咬-1-某从甲基嘴咳 心一坐-2-基)本氧 141275.doc 22· 201102374 =旋順式办工氯邻必卯氟冬…甲基义认喔工吐^基偉 氧基]乙基}環丙基)哌啶_κ芊】 外消旋順式-州-(2-{2-[3-敦_4_(5_曱m4_喔二唾_2_基)苯氧基]乙 多環丙基曱基)吡啶鏽三氟乙酸鹽 外消旋順式_5_氯-2-{4-[(2_{[4-(甲基磺醯基)苯氧基]曱基}環丙基)曱 基]旅咬-1 -基丨嘴咬 外消旋順式-4-[(2- {[ 1 -(5-氣嘧咬_2_基)哌唆·4·基]曱基}環丙基)曱氧 基]-Ν-環丙基-2-氟苯甲醯胺 外消旋順式-4-[(2-{[1-〇氣嘧咬_2_基)哌咬基]甲基}環丙基)甲氧 基]-6-f基嘧咬-2·曱腈 外消紅順式-4-[(2_{[l-(5-氣嘧啶-2-基)派咬·4·基]甲基μ袤丙基)甲氣 基]-2-氤笨甲腈 & — --- 以及其醫藥學上可接受之鹽及溶劑合物。 效用 本發明化合物為GPR119受體之有效促效劑.本發明化 合物及其醫藥學上可接受之鹽為稱作GPR 119之受體之調 節劑，且因此適用於治療由GPR119配位體及促效劑調節 之疾病。下文概述許多該等疾病。 下列疾病及病狀之治療及預防包括於用於治療—或多種 該等疾病或病狀之藥物的製造中： (0 非胰島素依賴性糖尿病（2型糖尿病）； (2) 尚血糖症； (3) 代謝症候群； (4) 肥胖症； (5) 局部缺血及心肌梗塞’ (6) 神經病症，諸如阿兹海默氏病（alzheimer’s disease)、 精神***症及認知損傷； (5) 高膽固醇金症； 141275.doc -23- 201102374 (6) 高三酸甘油酯血症（富三酸甘油酯脂蛋白之含量升 高）； (7) 混合型或糖尿病性血脂異常； (8) 低HDL膽固醇； (9) 高LDL膽固醇； (10) 局脫輔基β -脂蛋白血症；及 (11) 動脈粥樣硬化。 更詳言之，可使用式I或la之化合物或其醫藥學上可接受 之鹽或溶劑合物治療下列疾病及病狀。使用該等化合物製 造用於治療或預防一或多種該等疾病或病狀之藥物： (1) 2型糖尿病且尤其高血糖症； (2) 代謝症候群； (3) 肥胖症；及 (4) 高膽固醇血症或血脂異常。 因為該等化合物為GPR119受體之促效劑，所以該等化 合物適用於降低糖尿病患者及具有葡萄糖耐量異常及/或 處於糖尿病前期狀況令之非糖尿病患者的葡萄糖、脂質及 胰島素抗性。該等化合物適用於改善通常發生在糖尿病患 =或糖尿病前期患者令之高騰島素血症，其係、藉由調節^ 常發生在該等患者中之血清葡萄糖含量的波動來改善。該 等化合物適用於治療或降低胰島素抗性。該等化合物適用 於治療或預防妊娠性糖尿病。 如本文中描述之化合物、組合物及藥物適用於降低 謝症候群相關之不利續發症之風險且適用於降低發展出動 141275.doc • 24 · 201102374 脈粥樣硬化之風險，延遲動脈粥樣硬化之發作及/或降低 動脈粥樣硬化之續發症之風險。動脈粥樣硬化之續發症包 括絞痛、跛行、心臟病發作、中風及其他病症。 藉由保持高血糖症在控制之下，該等化合物適用於延遲 或預防血管再狹窄及糖尿病性視網膜病。 本發明化合物適用於改善或恢復p細胞功能，因此其適 用於/α療1型糖尿病或適用於延遲或預防患有2型糖尿病之 患者對胰島素療法之需要。 該等化合物可適用於降低肥胖個體之食慾及體重且因此 可適用於降低與肥胖症相關之共發病（諸如高血壓、動脈 粥樣硬化、糖尿病及血脂異常）之風險。 藉由升高活體内活性GLP4之含量，該等化合物適用於 /口療諸如阿茲海默氏病、多發性硬化症及精神***症之神 經病症。 該等化合物通常適用於治療下列疾病及病狀：（1)2型糖 尿病（亦S為非姨島素依賴性糖尿病或T2DM);⑺高灰糖 ⑺葡萄糖耐量冑常；⑷姨島素抗性；⑺肥胖症；⑹ 脂質病症；（7)血脂異常；⑻高脂Α症；⑼高三酸甘油醋 =症；⑽高膽固醇血症；（11)低HDL含量；（12)高ldl含 量；（13)動脈粥樣硬化及其續發症；（14)血管再狹窄；（μ) 1部肥胖症；（16)視網膜病；（17)代謝症候群，· Ο”高血 壓；〇9)阿兹海默氏病；⑽精神***症；（21)多發性硬化 症及（22)胰島素抗性。 本發明之-態樣提供-㈣療及控制混合^或糖尿病性 141275.doc -25· 201102374 血脂異常、高膽固醇血症、動脈粥樣硬化、低hdl含量、 高LDL含量、高脂血症及/或高三酸甘油酯血症之方法，該 方法包含向需要該治療之患者投與治療有效量之式〗化合 物或其醫藥學上可接受之鹽或溶劑合物。化合物可單獨使 用或有利地可與以下物質一起投與：膽固醇生物合成抑制 劑’尤其HMG-CoA還原酶抑制劑，諸如洛伐他、;丁 (lovastatin)、辛伐他汀（simvastatin)、羅素他汀（r〇suvastatin) ’曰’伐他、/丁（pravastatin)、氟伐他、;丁（fluvastatin)、阿托伐 他汀（atorvastatin)、瑞伐他汀（rivastatin)、伊伐他汀 (itavastatin)或ZD-4522。化合物亦可有利地與其他降脂質 藥物組合使用’該等藥物諸如膽固醇吸收抑制劑（例如植 物固醇S曰（stanol ester)、諸如替奎安（tiqueside)之固醇糖普 (sterol glycoside)及諸如依澤替米貝（ezeUmibe)之氣雜環丁 嗣）、ACAT抑制劑（諸如阿伐麥布（avasimibe》、CETP抑制 劑（例如托西曲皮（torcetrapib))、於驗（niacin)、膽酸繁合 劑、微粒體三酸甘油酯轉運抑制劑抑制劑及膽酸再吸收抑 制劑。該等組合治療適用於治療或控制選自由高膽固醇血 症、動脈粥樣硬化、面脂血症、高三酸甘油g旨血症、金脂 異常、高LDL及低HDL組成之群之病狀。 本發明之另一態樣提供一種治療及控制肥胖症或代謝症 候群之方法’該方法包含向需要該治療之患者投與治療有 效量之具有式I之化合物或其醫藥學上可接受之鹽或溶劑 合物。化合物可單獨使用或有利地可與以下物質一起投 與：抗肥胖劑’尤其脂肪酶抑制劑，諸如奥利司他 141275.doc • 26 * 201102374 (orhstat);或單胺神經傳遞素吸收抑制劑，諸如曲美 (sibutramine)、芬特明（phentermine)及其類似物。化合物 亦可有利地與諸如利莫納班（rimonabant)及他拉納班 (taranabant)之CB-1反向促效劑或拮抗劑組合使用。 投藥及劑量範圍 可採用任何合適之投藥途徑向哺乳動物、尤其人類提供 有效劑量之本發明化合物。舉例而言，可採用經口、經直 腸、局部、非經腸、經眼、經肺、經鼻及其類似途徑。劑 型包括錠劑、片劑（troche)、分散液、懸浮液、溶液、膠 囊、乳膏、軟膏、氣霧劑及其類似劑型。式丨化合物或其 面藥學上可接受之鹽或溶劑合物較佳經口投與。 所採用之活性成份之有效劑量可視所採用之特定化合 物、投藥模式、所治療之病狀及所治療之病狀之嚴重程度 而改變。該劑量可由熟習此項技術者容易地確定。 當治療或控制糖尿病及/或高血糖症或高三酸甘油酯』 :或需要式I化合物之其他疾病時，當本發明化合物係c 每公斤動物體重約㈣克至約1〇〇毫克之日劑量投盥、棄 佳以單-日劑量或-天兩至六次分次劑量給Μ以持續湾 放形式給予時，通常獲得令人滿意的結果。對大多數大变 哺乳動物而言，總曰劑量為約1〇毫克至約1〇〇〇毫克。名 7〇 kg成年人類之情況下，總曰劑量通常將為約鴻 350毫克》對特別有效之化合物 ' 珉平人類之劑量可 ^至。可在該額内或甚至該範心 案以提供最佳治療反應。 剷里力 141275.doc •27- 201102374 口服投藥通常將使用鍵劑或膠囊進行。錢劑及膠囊中之 劑量之實例為 0·1 mg、0.25 mg、0.5 mg、1 mg、2 mg、5 mg、10 mg、25 mg、50 mg、100 mg、200 mg、350 mg、 5 00 mg、700 mg、750 mg、800 mg及 looo mg e 其他 口服 形式亦可具有相同或類似劑量β 醫藥組合物 本發明之另一態樣提供一種醫藥組合物，其包含式“匕 合物及醫藥學上可接受之載劑。本發明之醫藥組合物包含 作為活性成伤之式I化合物或醫藥學上可接受之鹽或溶劑 口物，以及醫藥學上可接受之載劑及視情況選用之其他治 療成份。術語「醫藥學上可接受之鹽」係指由醫藥學上可 接受之無毒驗或酸製備之鹽，該等驗或酸包括無機驗或無 機酸及有機鹼或有機酸。若投與前藥，則醫藥組合物亦可 包含前藥或其醫藥學上可接受之鹽。 組合物通常適合經口、經直腸、局部、非經腸（包括皮 下、肌肉内及靜脈内）、、經眼（眼用）、'經肺（經鼻或經賴吸 入)或經鼻投藥’但在任何給定狀況下，最合適之途徑將 視所治療之病狀之性質及嚴重程度及所選擇之敎活性成 ，而定。其可呈單位㈣方便地呈現且可採用製藥技術中 熟知之任何方法製備。 在實際使用中 〜 式1化合物或其醫藥學上可接受之鹽或 :劑合物可作為活性成份，根據習知醫藥混配技術，與 :載劑均句混合來組合。載劑可視例如經口或非經腸:包 括靜脈内)投藥所需之製劑形式，而採用多種形式。在製 141275.doc -28· 201102374 備口服劑型用組合物時，可採用任何常用醫藥介質，若製 備諸如懸浮液、酏劑及溶液之口服液體製劑時，可使用諸 如水、二元醇、油類、醇類、調味劑、防腐劑、著色劑及 其類似才勿；或若製備諸如散劑、⑨膠囊及軟滕囊及鍵劑之 口服固體製劑時’可使用諸如澱粉、糖、微晶纖維素、稀 釋劑、成粒劑、潤滑劑、黏合劑、崩解劑及其類似物之載 劑’其中固體口服製劑優於液體製劑。 鍵劑及膠囊因其投藥簡易性，而代表最有利的口服劑 型。因此，通常採用固體醫藥載劑。必要時，可由標準水 性或非水性技術包覆錠劑。該等組合物及製劑通^含L 少約0.1%活性化合物，組合物之其餘部分為載劑。該等組 合：中活性化合物之百分比當然可變化，且適宜介‘劑型 重量之約2%至約60%之間。適用於該等療法之組合物中活 性化合物用量應可將傳遞有效劑量。 或者，活性化合物可例如以液滴或噴霧形式經鼻内投 =劑、朦囊及其類似物通常亦含有黏合劑。合適黏合劑 之實例包括黃f膠、***膠、明膠及合成或半合成殺粉 =生物，諸如羥丙基甲基纖維素（HPMC);賦形劑，諸如 石枝-鈣；崩解劑’冑如玉米澱粉、馬鈐薯澱粉、海藻 酸；7滑劑，諸如硬脂酸鎂；且在一些情況下，甜味劑 諸如蔗糖、乳糖或糖精。當所採用之劑型為膠囊時，除上 述、’且伤外，其亦可含有諸如脂肪油之液體載劑。 可存在各種其他物質作為包衣或改變劑量單元之實體形 141275.doc -29- 201102374 式。舉例而言，可用蟲膠、糖或兩者包覆鍵劑。除含有活 性成份外，糖漿及舰劑通常亦含有作為甜味劑之斧糖、作 為防腐劑之對經基苯f酸甲酿或對經基苯甲酸丙醋、染料 及諸如櫻桃或橙調味劑之調味劑。 式1化合物或其醫藥學上可接受之鹽或溶劑合物亦可非 經腸投與。該等活性化合物之溶液或懸浮液可於合適地混 合有界面活性劑、緩衝劑及其類似物之水、生理食鹽水或 另一生物相容性媒射製備。亦可在於油中之甘油、液體 聚乙二醇及其混合針製備分散液。在普通儲存及使用條 件下，該等製劑亦可含有阻止微生物生長之防腐劑。 適於可注射使用之醫藥形式包括無以溶液及分散液及 臨時製備無菌可注射溶液及分散液之無菌散劑。製劑應在 無菌條件下製備且流動性應達到存在易於注射性之程度。 其在製造及料料τ應足_定且應防腐保細抵抗諸 如細菌及真菌之微生物的生長，可為溶劑或分散介 質’例如含有水、乙醇、多元醇（例如甘油、丙二醇及液 體聚乙二醇）、其合適混合物及合適油類。 組合療法 式I化合物可與其他亦可適用於治療或改善本文中描述 之疾病及病狀之藥物組合使用。該等其他藥物可以為此通 常使用之途徑及量，與式Ub合物或其醫藥學上可接受之 鹽或溶劑合物同時或相繼投與。在患有2型糖尿病、膜島 素抗性、肥胖症、代謝症候群、神經病症及伴隨該等疾病 之共發病之患者的治療中，通常投與-種以上藥物。通常 141275.doc 201102374 可向已服用一 本發明化合物 或多種用於該等病狀 之其他藥物之患者投與 當式I化合物與-或多種其他藥物同時使用時，含有該 等其他藥物及式I化合物之單位劑型醫藥組合物較佳。然 而’組合療法亦包括幻化合物及—或多種其他藥物以: 同的重疊時程投與之療法。亦涵蓋當與一或多種其他活性 成份組合使用時，本發明化合物及其他活性成份可以比各 自單獨使用時低之劑量使用。因此，本發明之醫藥組合物 包括除含有式I化合物外亦含有一或多種其他活性成份之 醫藥組合物。 可與式I化合物組合投與及分開投與或在同一醫藥組合 物中投與之其他活性成份之實例包括（但不限於）： (a) ΡΡΑΙΙγ促效劑及部分促效劑，包括格列酮類 (glitazones)與非格列酮類（non_glitaz〇nes)(例如曲格列酮 (troglitazone) ' 吡格列酮（pioglitazone)、恩格列酮 (englitazone)、MCC-555、羅格列酮（rosiglitazone)、巴格 列酮（balaglitazone)、萘格列酮（netoglitazone)、T-131、 LY-300512及 LY-818); (b) 雙胍類，諸如二曱雙胍（metformin)及苯乙雙胍 (phenformin)； (c) 蛋白質酪胺酸磷酸酶-IB(PTP-IB)抑制劑； (d) 二肽基肽酶lV(DPP-4)抑制劑，諸如西他列汀 (sitagliptin)、沙克列汀（saxagliptin)、德納列汀（denagliptin)、 SYR-3 22、阿格列汀（alogliptin)及維格列汀（vildagliptin); 141275.doc • 31 - 201102374 (e) 胰島素或胰島素模擬劑； (f) 崎酿腺類’諸如曱苯績丁腺（tolbutamide)、格列美 脲（glimepiride)、格列吡嗪（giipizide)及相關物質； (g) α-葡糖苦酶抑制劑（諸如阿卡波糖（acarb〇se)); (h) 改善患者脂質概況之藥劑，諸如（i)HMG-CoA還原酶 抑制劑（洛伐他汀、辛伐他汀、羅素他汀、普伐他汀、氟 伐他汀、阿托伐他汀、瑞伐他汀、伊伐他汀、ZD-4522及 其他士 他 >丁（statin)) ’（ii)膽酸鰲合劑（消膽胺（ch〇lestyramine) 、考來替潑（colestipol)及交聯右旋糖之二烷基胺基烷基衍 生物）’（iii)菸醇、菸酸或其鹽，（iv) PPARa促效劑，諸如 非諾貝酸（fenofibric acid)衍生物（吉非羅齊（gemfibrozil)、 氣貝丁酯（clofibrate)、非諾貝特（fenofibrate)及苯紮貝特 (bezafibrate)) ’（v)膽固醇吸收抑制劑，諸如依澤替米貝， (vi)醯基CoA :膽固醇醯基轉移酶（ACAT)抑制劑，諸如阿 伐麥布’（vii) CETP抑制劑，諸如托西曲皮，及（viii)酚系 抗氧化劑’諸如普羅布可（probucol); ⑴PPARa/γ雙重促效劑’諸如莫格他^(muragiitazar)、 特格他 ^(tesaglitazar)、法格列酮（fargiitazar)及 JT-501 ; (j) PPARS促效劑’諸如W097/28149中所揭示之PPAR5 促效劑； (k) 抗肥胖化合物’諸如芬氟拉明（fenfiurainine)、右芬 氟拉明（dexfenfluramine)、芬特明、蘇比拉明（subitramine)、 奥利司他、神經肽Y5抑制劑、MC4R促效劑、***鹼受體 l(CB-l)拮抗劑/反向促效劑及β3腎上腺素能受體促效劑； 141275.doc •32- 201102374 (l) 回腸膽酸轉運體抑制劑； (m) 意欲用於發炎性病狀之藥劑，諸如阿司匹林 (aspirin)、非類固醇消炎藥、糖皮質激素、柳氮磺胺吨啶 (azulfidine)及環加氧酶2選擇性抑制劑； (η)升糖素（glucagon)受體拮抗劑； (o) GLP-1 ； (p) GIP-1 ； (q) GLP-1類似物，諸如艾塞汀類（exendins)，例如艾塞 那肽（exenatide)(百泌達（Byetta))、艾塞那肽_LAR及利拉格 德（liraglutide); (r) 羥基固醇脫氫酶_ι(Η8ΓΜ)抑制劑。 以上組合包括本發明化合物與不僅一種其他活性化合物 而且兩種或兩種以上其他活性化合物之組合。非限制性實 例包括具有式I之化合物或其醫藥學上可接受之鹽或溶劑 合物與兩種或兩種以上選自雙胍類、確醯脲類、HMG_ CoA還原酶抑制劑、其他PPar促效劑、ρτρ_1Β抑制劑、 DPP-4抑制劑及抗肥胖化合物之活性化合物的組合。 本發明所關注之另一態樣為一種醫藥組合物，其包含式 !化合物或其f藥學上可接受之鹽或溶劑合物卩及醫藥學 上可接受之載劑。 本發明所關注之另-態樣係、關於—種治療需要該治療之 哺乳動物患者之高血糖症、糖尿病或胰島素抗性的方法， 該方法包含㈣患者投與可有效治療高血糖症、糖尿病或 胰島素抗性之量的式ί化合物或其醫藥學上可接受之鹽或 141275.doc -33- 201102374 溶劑合物。 更詳言之，本發明所關注之另一態樣係關於一種治療需 要該治療之哺乳動物患者之2型糖尿病的方法，該方法包 含向該患者投與可有效治療2型糖尿病之量的式丨化合物或 其醫藥學上可接受之鹽或溶劑合物。 本發明所關注之又一態樣係關於一種治療需要該治療之 哺乳動物患者之非胰島素依賴性糖尿病的方法，該方法包 含向該患者投與可有效治療非胰島素依賴性糖尿病之量的 式I化合物或其醫藥學上可接受之鹽或溶劑合物。 本發明所關注之又一態樣係關於一種治療需要該治療之 哺礼動物患者之肥胖症的方法，該方法包含向該患者投與 可有效治療肥胖症之量的式I化合物或其醫藥學上可接受 之鹽或溶劑合物。 本毛月所關，主之又一態樣係關於一種治療需要該治療之 哺乳動物患者之症候群X的方法，該方法包含向該患者投 與可有效治療症候群x之量的式〗化合物或其醫藥學上可接 受之鹽或溶劑合物。 本發明所關注之又一態樣係關於一種治療需要該治療之 哺乳動物患者之選自由血脂異f、高脂血症、高三酸甘油 酯血症、高膽固醇血症、mHDL及高LDL組成之群的脂質 病症的方法，該方法包含向該患者投與可有效治療該脂質 病症之量的式1化合物或其醫藥學上可接受之鹽或溶劑合 物。 本t月所關注之又一態樣係關於—種治療需要該治療之 141275.doc •34· 201102374 哺乳動物患者之動脈粥樣硬化的方法，該方法包含向該串 者投與可有效治療動脈粥樣硬化之量的式〗化合物或其醫 藥學上可接受之鹽或溶劑合物。 本發明所關注之又-態樣係關於_種治療需要該治療之 哺乳動物患者之選自由以下病狀組成之群的病狀的方法： (1)高盘糖症、（2)葡萄糖耐量異常、（3)胰島素抗性、肥 胖症、（5)脂質病症、（6)血脂異常、（7)高脂也症、高三 酸甘油酯血症、（9)高膽固醇血症、（1〇)低HDL含量、（ιι) 高LDL含量、（12)動脈粥樣硬化及其續發症' (13)血管再 狹窄、（14)胰腺炎、（15)腹部肥胖症、（16)神經退化性疾 病、（17)視網膜病、（18)腎病、（19)神經病、（2〇)症候群 X、（21)高血壓及其他以胰島素抗性為組成部分之病狀及 病症，該方法包含向該患者投與可有效治療該病狀之量的 式I化合物或其醫藥學上可接受之鹽或溶劑合物。 本發明所關注之又一態樣係關於一種延遲有需要之哺乳 動物患者的選自由以下病狀組成之群之病狀發作的方法： (1)高血糖症、（2)葡萄糖耐量異常、（3)胰島素抗性、（4)肥 胖症、（5)脂質病症、（6)血脂異常、（7)高脂血症' (8)高三 酸甘油酯血症、（9)高膽固醇血症、（1〇M&HDL含量、（u) 高LDL含量、（12)動脈粥樣硬化及其續發症、（13)血管再 狹乍、（14)胰腺炎、（1 5)腹部肥胖症、（1 6)神經退化性疾 病、（17)視網膜病、（18)腎病、（19)神經病、（2〇)症候群 X、（21)高血壓及其他以胰島素抗性為組成部分之病狀及 病症’該方法包含向該患者投與可有效延遲該病狀發作之 141275.doc -35· 201102374 量的式i化合物或其醫藥學上可接受之鹽或溶劑合物。 本發明所關注之又一態樣係關於一種降低有需要之哺乳 動物患者發展出選自由以下病狀組成之群的病狀之風險的 方法.（1)高血糖症、（2)葡萄糖耐量異常、（3)騰島素抗 性、（4)肥胖症、（5)脂質病症' (6)血脂異常、高脂也 症、（8)高三酸甘油酯血症、（9)高膽固醇血症、（1〇)低 含$、（ 11)高LDL含量、（12)動脈粥樣硬化及其續發症、 (13)血管再狹窄、（14)胰腺炎、（15)腹部肥胖症、（16)神經 退化性疾病、（17)視網膜病' (18)腎病、（19)神經病、（2〇) 症候群X、（21)高血壓及其他以胰島素抗性為組成部分之 病狀及病症，該方法包含向該患者投與可有效降低發展出 該病狀之風險之量的式I化合物或其醫藥學上可接為 _rm 或溶劑合物。 本發明所關注之又一態樣係關於一種治療需要該产療之 哺乳動物患者之選自由以下病狀組成之群的病狀的方法. (1)高血糖症、（2)葡萄糖耐量異常、（3)胰島素抗性、（句肥 胖症、（5)脂質病症' (6)血脂異常、（7)高脂血症、（8)高三 、（10)低 HDL含量、（u) 酸甘油酯血症、（9)高膽固醇血症 高LDL含量、（12)動脈粥樣硬化及其續發症、（丨3)血管再 狹窄、（14)胰腺炎、（15)腹部肥胖症、（16)神經退化性疾 病、（17)視網膜病、（18)腎病、（19)神經病、（2〇)症候群 X、（21)高血壓及其他以胰島素抗性為組成部分之病狀及 病症’該方法包含向該患者投與可有效治療該病狀之量的 式I化合物或其醫藥學上可接受之鹽或溶劑合物及選自& 141275.doc -36· 201102374 以下各物組成之群的化合物： (a) DP-IV抑制劑； (b) 選自由（i)PPAR促效劑及（Π)雙胍類組成之群的胰島 素致敏劑； (c) 胰島素及胰島素模擬劑； (d) 續酿脲類及其他騰島素促分泌素； Ο) α-葡糖苷酶抑制劑； (f) 升糖素受體拮抗劑； (g) GLP-1、GLP-1模擬劑及GLP-1受體促效劑； (h) GIP、GIP模擬劑及Gip受體促效劑； (1) PACAP、PACAP模擬劑及PACAp受體3促效劑； (j) 遥自由以下各物組成之群的降膽固醇劑： (1) HMG-CoA還原酶抑制劑，（Η)鰲合劑，（出）菸 醇、於酸及其鹽’（iv) ppARa促效劑，⑺ppARa~ 雙重促效劑’⑽膽固醇吸收抑制劑，（Wi)酿基c〇a : 膽固醇醯基轉移酶抑制劑，及（viii)抗氧化劑； (k) PPARi促效劑； (l) 抗肥胖化合物； (m) 回腸膽酸轉運體抑制劑； (η)除糖皮質激素以外之消炎劑；I racemic cis: fluoro-244-(2-{2_[3_i^(5_methyl-yl)ethyl}cyclopropyl)piperidin-1-yl 1 pyridyl ___~, one sitting -2- Oxygen; oxalate cis-5-gas-2-[4-(2-{2-[Γ^Γ(5-methyl acetonyl)ethyl}cyclopropyl) piperidine-1 - Someone from the methyl mouth coughing a sitting - 2 base) Oxygen 141275.doc 22· 201102374 = Rotary-type office chlorine chlorinated fluorinated winter ... methyl-based 喔 喔 吐 ^ 基 基 基 基 基 基 基}{cyclopropyl)piperidine _κ芊] racemic cis-state-(2-{2-[3-敦_4_(5_曱m4_喔disindol-2-yl)phenoxy] Ethylcyclopropylmercapto)pyridine pyridine trifluoroacetate racemic cis-5-chloro-2-{4-[(2_{[4-(methylsulfonyl)phenoxy]fluorenyl} Cyclopropyl) fluorenyl] brigade bite-1 - basal mouth bite racemic cis-4-[(2- {[ 1 -(5-aesthepyridin-2-yl)piperazin·4·yl] Mercapto}cyclopropyl)decyloxy]-indole-cyclopropyl-2-fluorobenzamide amine racemic cis-4-[(2-{[1-〇〇菌咬_2_基) Piperidine]methyl}cyclopropyl)methoxy]-6-fylpyrimidine-2·indole nitrile acetra--4-[(2_{[l-(5-a pyrimidine-2-) () base bite · 4 · base] methyl μ propyl propyl) methyl group] -2- 氤 carbonitrile & ---- and its pharmaceutically acceptable And solvates thereof. Utility The compound of the present invention is an effective agonist of the GPR119 receptor. The compound of the present invention and a pharmaceutically acceptable salt thereof are modulators of a receptor called GPR 119, and thus are suitable for treating a ligand derived from GPR119 The agent regulates the disease. A number of these diseases are outlined below. The treatment and prevention of the following diseases and conditions are included in the manufacture of drugs for the treatment of one or more of these diseases or conditions: (0 non-insulin dependent diabetes (type 2 diabetes); (2) still glycemic; 3) metabolic syndrome; (4) obesity; (5) ischemia and myocardial infarction' (6) neurological disorders such as Alzheimer's disease, schizophrenia and cognitive impairment; (5) high Cholesterolemia; 141275.doc -23- 201102374 (6) Triglycerideemia (increased content of triglyceride-rich lipoprotein); (7) Mixed or diabetic dyslipidemia; (8) Low HDL Cholesterol; (9) high LDL cholesterol; (10) apo-beta-lipoproteinemia; and (11) atherosclerosis. More specifically, a compound of formula I or la or its medicinal use may be used. Acceptable salts or solvates for the treatment of the following diseases and conditions. The use of such compounds to produce a medicament for the treatment or prevention of one or more of such diseases or conditions: (1) Type 2 diabetes and especially hyperglycemia; 2) metabolic syndrome; (3) obesity; and (4) hypercholesterolemia or Lipid abnormalities. Because these compounds are agonists of the GPR119 receptor, they are suitable for reducing glucose, lipid and insulin resistance in diabetic patients and non-diabetic patients with impaired glucose tolerance and/or pre-diabetes conditions. These compounds are useful for ameliorating hypertonic acidemia, which usually occurs in diabetic patients or pre-diabetic patients, which is improved by modulating fluctuations in serum glucose levels that often occur in such patients. The compounds are useful for treating or reducing insulin resistance.These compounds are useful for treating or preventing gestational diabetes. The compounds, compositions and medicaments as described herein are suitable for reducing the risk of adverse adverse events associated with Xie syndrome and are suitable for lowering Development 141275.doc • 24 · 201102374 Risk of atherosclerosis, delaying the onset of atherosclerosis and/or reducing the risk of atherosclerosis. The continuation of atherosclerosis includes colic, Minhang, heart attack, stroke and other conditions. By maintaining hyperglycemia in control These compounds are useful for delaying or preventing vascular restenosis and diabetic retinopathy. The compounds of the invention are useful for ameliorating or restoring p-cell function and are therefore suitable for use in /alpha therapy type 1 diabetes or for delaying or preventing type 2 The need for insulin therapy in patients with diabetes. These compounds are suitable for reducing the appetite and weight of obese individuals and are therefore suitable for reducing co-morbidities associated with obesity (such as hypertension, atherosclerosis, diabetes and dyslipidemia) Risks. By increasing the amount of active GLP4 in vivo, the compounds are suitable for use in/oral treatment of neurological disorders such as Alzheimer's disease, multiple sclerosis and schizophrenia. These compounds are generally indicated for the treatment of the following diseases and conditions: (1) type 2 diabetes (also S is non-choline-dependent diabetes or T2DM); (7) high-glucose (7) glucose tolerance; (4) 姨 素 resistance (7) obesity; (6) lipid disorders; (7) dyslipidemia; (8) hyperlipidemia; (9) high triglyceride = (10) hypercholesterolemia; (11) low HDL content; (12) high ldl content; 13) atherosclerosis and its continuation; (14) vascular restenosis; (μ) 1 obesity; (16) retinopathy; (17) metabolic syndrome, · Ο "hypertension; 〇 9) Az Herm's disease; (10) schizophrenia; (21) multiple sclerosis and (22) insulin resistance. The present invention provides - (d) treatment and control of mixed or diabetic 141275.doc -25· 201102374 blood lipids A method of abnormality, hypercholesterolemia, atherosclerosis, low hdl content, high LDL content, hyperlipidemia, and/or hypertriglyceridemia, the method comprising administering a therapeutically effective amount to a patient in need of such treatment A compound or a pharmaceutically acceptable salt or solvate thereof. The compound can be used alone Either or advantageously administered with: a cholesterol biosynthesis inhibitor', especially an HMG-CoA reductase inhibitor, such as lovastatin, lovastatin, simvastatin, rosuvastatin (r〇 Suvastatin) '曰', pravastatin, fluvastatin, fluvastatin, atorvastatin, rivastatin, itavastatin or ZD-4522. The compounds may also be advantageously used in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (eg, stanol esters, sterol glycoside such as tiqueside) and Such as ezetimibe (ezeUmibe), ACAT inhibitors (such as avasimibe (avasimibe), CETP inhibitors (such as torsetrapib), niacin, a bile acid complex, a microsomal triglyceride transport inhibitor, and a bile acid reuptake inhibitor. The combination therapy is suitable for treatment or control selected from the group consisting of hypercholesterolemia, atherosclerosis, facial lipemia, A condition of a group consisting of triglyceride g, arrhythmia, high LDL, and low HDL. Another aspect of the present invention provides a method of treating and controlling obesity or metabolic syndrome, which method comprises The patient to be treated is administered a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. The compound may be administered alone or advantageously together with an anti-obesity agent, especially a lipase. Inhibitors, such as orlistat 141275.doc • 26 * 201102374 (orhstat); or monoamine neurotransmitter absorption inhibitors, such as sibutramine, phentermine, and the like. The compounds may also be advantageously used in combination with CB-1 inverse agonists or antagonists such as rimonabant and taranabant. Administration and Dosage Range An effective dosage of a compound of the invention can be provided to a mammal, especially a human, by any suitable route of administration. For example, oral, transrectal, topical, parenteral, ocular, transpulmonary, nasal, and the like can be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The guanidine compound or a pharmaceutically acceptable salt or solvate thereof is preferably administered orally. The effective dose of the active ingredient employed will vary depending upon the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. This dosage can be readily determined by those skilled in the art. When treating or controlling diabetes and/or hyperglycemia or hypertriglyceride: or other diseases of the compound of formula I, when the compound of the invention is c, the daily dose of about (four) grams to about 1 milligram per kilogram of animal body weight Satisfactory results are usually obtained when a single-day dose or a two-to-six divided dose of bismuth is administered in the form of continuous bayot. For most large mammals, the total dose is from about 1 mg to about 1 mg. In the case of a 7 〇 kg adult class, the total sputum dose will usually be about 350 mg of "a particularly effective compound". The best therapeutic response can be provided within this amount or even in the heart of the case. Shovel force 141275.doc •27- 201102374 Oral administration will usually be done using a key or capsule. Examples of dosages in bulk and capsules are 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 350 mg, 5 00 Mg, 700 mg, 750 mg, 800 mg, and looo mg e Other oral forms may also have the same or similar doses of β Pharmaceutical Compositions Another aspect of the present invention provides a pharmaceutical composition comprising the formula "chelates and pharmaceuticals" A pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention comprises as an active compound of the formula I or a pharmaceutically acceptable salt or solvent, and a pharmaceutically acceptable carrier and optionally Other therapeutic ingredients. The term "pharmaceutically acceptable salts" means salts prepared by pharmaceutically acceptable non-toxic or acid preparations, including inorganic or inorganic acids and organic or organic acids. If a prodrug is administered, the pharmaceutical composition may also comprise a prodrug or a pharmaceutically acceptable salt thereof. The composition is generally suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), transocular (exophthalmic), 'trans-pulmonary (nasal or nasal inhalation) or nasal administration' However, in any given situation, the most appropriate route will depend on the nature and severity of the condition being treated and the activity selected. It can be conveniently presented in units of (iv) and can be prepared by any method well known in the art of pharmacy. In actual use, the compound of the formula 1 or a pharmaceutically acceptable salt or a compound thereof can be used as an active ingredient, and can be combined with a carrier in accordance with a conventional pharmaceutical compounding technique. The carrier can take a variety of forms, for example, in the form of a preparation required for administration, for example, orally or parenterally: including intravenously. When preparing a composition for oral dosage form, 141275.doc -28· 201102374, any conventional pharmaceutical medium can be used, and if an oral liquid preparation such as a suspension, an elixir and a solution is prepared, such as water, glycol, oil can be used. Classes, alcohols, flavoring agents, preservatives, coloring agents, and the like; or when preparing oral solid preparations such as powders, 9 capsules, and soft sacs and keying agents, such as starch, sugar, and microcrystalline fibers can be used. A carrier for a diluent, a diluent, a granulating agent, a lubricant, a binder, a disintegrant, and the like, wherein the solid oral preparation is superior to the liquid preparation. The key agents and capsules represent the most advantageous oral dosage form because of their ease of administration. Therefore, solid pharmaceutical carriers are usually employed. If necessary, the tablet can be coated by standard aqueous or non-aqueous techniques. The compositions and preparations contain about 0.1% less active compound, and the remainder of the composition is a carrier. The combination of these active compounds may of course vary and is suitably between about 2% and about 60% by weight of the dosage form. The amount of active compound used in the compositions suitable for such therapy will be such that an effective dose will be delivered. Alternatively, the active compound may be administered intranasally, for example, in the form of droplets or sprays, the sacs and the like, and usually also contain a binder. Examples of suitable binders include yellow f-gel, gum arabic, gelatin and synthetic or semi-synthetic flouricidal = biological, such as hydroxypropyl methylcellulose (HPMC); excipients such as stone-calcium; disintegrants' For example, corn starch, horse starch starch, alginic acid; 7 slip agents such as magnesium stearate; and in some cases, sweeteners such as sucrose, lactose or saccharin. When the dosage form employed is a capsule, it may contain, in addition to the above, and a wound, a liquid carrier such as a fatty oil. Various other substances may be present as a solid form for coating or changing the dosage unit 141275.doc -29- 201102374. For example, the shelling agent can be coated with shellac, sugar or both. In addition to the active ingredients, syrups and sachets usually contain axe as a sweetener, preservatives for the base benzene or propyl acetonate, dyes and flavors such as cherry or orange. Flavoring agent. The compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof may also be administered parenterally. Solutions or suspensions of such active compounds can be prepared in water, physiological saline or another biocompatible vehicle suitably mixed with a surfactant, a buffer, and the like. It is also possible to prepare a dispersion by glycerin, liquid polyethylene glycol and a mixed needle thereof in oil. Such preparations may also contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. The pharmaceutical forms suitable for injectable use include solutions and dispersions and sterile dispersions in the preparation of sterile injectable solutions and dispersions. The preparation should be prepared under sterile conditions and fluidity should be such that it is easy to inject. It should be prepared and the material τ should be sufficient and should be preserved against the growth of microorganisms such as bacteria and fungi. It can be a solvent or a dispersion medium, for example, containing water, ethanol, polyol (such as glycerin, propylene glycol and liquid polyethylene). Glycol), suitable mixtures thereof and suitable oils. Combination Therapy The compounds of formula I can be used in combination with other drugs which may also be suitable for the treatment or amelioration of the diseases and conditions described herein. These other drugs may be administered simultaneously or sequentially with the Ub compound or a pharmaceutically acceptable salt or solvate thereof for the route and amount which are usually used for this purpose. In the treatment of patients with type 2 diabetes, murine resistance, obesity, metabolic syndrome, neurological disorders, and co-morbidity associated with such diseases, more than one drug is usually administered. Typically 141275.doc 201102374 may be administered to a patient who has taken a compound of the invention or a plurality of other drugs for such conditions, when the compound of formula I is used in combination with - or a plurality of other drugs, containing the other drug and formula I A unit dosage form pharmaceutical composition of the compound is preferred. However, 'combination therapy also includes phantom compounds and- or a variety of other drugs to: the same overlapping time-course therapy. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients may be employed in lower dosages than when used alone. Accordingly, the pharmaceutical compositions of the present invention comprise a pharmaceutical composition which, in addition to a compound of formula I, also contains one or more additional active ingredients. Examples of other active ingredients which may be administered in combination with a compound of formula I and administered separately or in the same pharmaceutical composition include, but are not limited to: (a) ΡΡΑΙΙγ agonists and partial agonists, including Glutazones and non-glitaz〇nes (eg troglitazone 'pioglitazone, englitazone, MCC-555, rosiglitazone) , bagliglitazone, netoglitazone, T-131, LY-300512 and LY-818); (b) biguanides such as metformin and phenformin (c) Protein tyrosine phosphatase-IB (PTP-IB) inhibitor; (d) Dipeptidyl peptidase 1V (DPP-4) inhibitors, such as sitagliptin, saxagliptin (saxagliptin), denaglitin, SYR-3 22, alogliptin, and vildagliptin; 141275.doc • 31 - 201102374 (e) insulin or insulin mimetic; f) Saccharomyces gland 'tolbutamide, glimepiride, glipizide (giipizide) and related substances; (g) alpha-glucosidase inhibitors (such as acarbose); (h) agents that improve lipid profiles in patients, such as (i) HMG-CoA reductase Inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, revastatin, ivavastatin, ZD-4522 and other statins & statins) (ii) Cholic acid chelating agents (ch〇lestyramine, colestipol and crosslinked dextrose dialkylaminoalkyl derivatives)' (iii) nicotinic acid, nicotinic acid Or a salt thereof, (iv) a PPARa agonist such as a fenofibric acid derivative (gemfibrozil, clofibrate, fenofibrate, and benzal) (bezafibrate) '(v) Cholesterol absorption inhibitors, such as ezetimibe, (vi) thiol-based CoA: cholesterol thiotransferase (ACAT) inhibitors, such as avastamb' (vii) CETP Inhibitors, such as tolxine, and (viii) phenolic antioxidants such as probucol; (1) PPARa/gamma dual agonists' Mograta (muragiitazar), tesaglitazar, fargiitazar and JT-501; (j) PPARS agonist 'such as the PPAR5 agonist disclosed in W097/28149; k) Anti-obesity compounds such as fenfiurainine, dexfenfluramine, phentermine, supitramine, orlistat, neuropeptide Y5 inhibitor, MC4R agonist Agent, cannabinoid receptor l (CB-1) antagonist/reverse agonist and β3 adrenergic receptor agonist; 141275.doc •32- 201102374 (l) ileal cholic acid transporter inhibitor; m) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine and cyclooxygenase 2 selective inhibitors; (η) sucrose Glucagon receptor antagonist; (o) GLP-1; (p) GIP-1; (q) GLP-1 analogues, such as exendins, such as exenatide ( Byetta, exenatide _LAR and liraglutide; (r) hydroxysterol dehydrogenase _ι (Η8ΓΜ) inhibitor. Combinations of the above include the compounds of the invention in combination with not only one other active compound but also two or more other active compounds. Non-limiting examples include a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and two or more selected from the group consisting of biguanides, guanidines, HMG_CoA reductase inhibitors, other PPars. A combination of an agent, a ρτρ_1 Β inhibitor, a DPP-4 inhibitor, and an active compound of an anti-obesity compound. Another aspect of the present invention is a pharmaceutical composition comprising a compound of the formula or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. The present invention relates to a method for treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment, the method comprising (4) administering a patient to effectively treat hyperglycemia, diabetes Or an insulin-resistant compound of the formula ί or a pharmaceutically acceptable salt thereof or 141275.doc -33- 201102374 solvate. More particularly, another aspect of the present invention is directed to a method of treating type 2 diabetes in a mammalian patient in need of such treatment, the method comprising administering to the patient an amount effective to treat type 2 diabetes An anthraquinone compound or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention is directed to a method of treating non-insulin dependent diabetes in a mammalian subject in need thereof, the method comprising administering to the patient an amount of Formula I effective to treat non-insulin dependent diabetes A compound or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention is directed to a method of treating obesity in a patient in need of such treatment, the method comprising administering to the patient an amount of a compound of formula I or a pharmaceutically acceptable amount thereof effective to treat obesity An acceptable salt or solvate. A method of treating a symptom X of a mammalian patient in need of such treatment, the method comprising administering to the patient an amount of a compound or a compound thereof effective to treat the syndrome x A pharmaceutically acceptable salt or solvate. Another aspect of the present invention is directed to a mammalian patient in need of such treatment selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mHDL, and high LDL. A method of a lipid disorder of a population, the method comprising administering to the patient an amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, in an amount effective to treat the lipid disorder. Another aspect of this month's concern is the method of treating atherosclerosis in a mammalian patient, which involves administering the treatment to the vasculature. An amount of a compound of the formula or a pharmaceutically acceptable salt or solvate thereof. The method of interest in the present invention relates to a method for treating a condition of a mammalian patient in need of such treatment from a group consisting of: (1) hyperglycemia, (2) abnormal glucose tolerance , (3) insulin resistance, obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, hypertriglyceridemia, (9) hypercholesterolemia, (1〇) Low HDL content, (ι) high LDL content, (12) atherosclerosis and its recurrences' (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative Disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (2) syndrome X, (21) hypertension, and other conditions and disorders characterized by insulin resistance, the method comprising The patient is administered a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount effective to treat the condition. A further aspect of the present invention is directed to a method of delaying the onset of a condition in a mammalian patient in need thereof, selected from the group consisting of: (1) hyperglycemia, (2) abnormal glucose tolerance, 3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia (8) hypertriglyceridemia, (9) hypercholesterolemia, (1〇M&HDL content, (u) high LDL content, (12) atherosclerosis and its recurrence, (13) vasoconstriction, (14) pancreatitis, (1 5) abdominal obesity, (1) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (2〇) syndrome X, (21) hypertension, and other conditions characterized by insulin resistance and The present invention comprises administering to the patient a compound of formula i or a pharmaceutically acceptable salt or solvate thereof, which is effective to delay the onset of the condition 141275.doc -35.201102374. One aspect relates to a condition in which a mammalian patient in need is developed to develop a condition selected from the group consisting of the following conditions. Methods of risk. (1) hyperglycemia, (2) impaired glucose tolerance, (3) resistance to tamsin, (4) obesity, (5) lipid disorders' (6) dyslipidemia, hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (1) low inclusive, (11) high LDL content, (12) atherosclerosis and its continuation, (13) blood vessels Restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative diseases, (17) retinal disease (18) nephropathy, (19) neuropathy, (2〇) syndrome X, (21) Hypertension and other conditions and disorders characterized by insulin resistance, the method comprising administering to the patient an amount of a compound of formula I or a pharmaceutically acceptable amount thereof effective to reduce the risk of developing the condition Rm or a solvate. Another aspect of the present invention is directed to a method of treating a condition in a mammalian patient in need of such treatment, selected from the group consisting of: (1) hyperglycemia, 2) Abnormal glucose tolerance, (3) insulin resistance, (sentence obesity, (5) lipid disorder' (6) dyslipidemia, (7) hyperlipidemia, (8) high , (10) low HDL content, (u) acid glycerideemia, (9) hypercholesterolemia, high LDL content, (12) atherosclerosis and its continuation, (丨3) vascular restenosis, 14) Pancreatitis, (15) Abdominal obesity, (16) Neurodegenerative diseases, (17) Retinopathy, (18) Nephropathy, (19) Neuropathy, (2〇) Syndrome X, (21) Hypertension and others A condition and a condition comprising insulin resistance as part of the method comprising administering to the patient an amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable salt or solvate thereof, effective to treat the condition 141275.doc -36· 201102374 Compounds of the following composition: (a) DP-IV inhibitors; (b) Free (i) PPAR agonists and (Π) biguanides Sensitizer; (c) insulin and insulin mimetic; (d) continuation of urea and other gonadotropin; Ο) alpha-glucosidase inhibitor; (f) glycoside receptor antagonist; g) GLP-1, GLP-1 mimetic and GLP-1 receptor agonist; (h) GIP, GIP mimetic and Gip receptor agonist; (1) PACAP, PACAP mimetic and PACAp 3 agonists; (j) Free cholesterol-free cholesterol-lowering agents: (1) HMG-CoA reductase inhibitors, (Η) chelating agents, (extracting) niacin, acid and its salts (iv) ppARa agonist, (7) ppARa~ dual agonist' (10) cholesterol absorption inhibitor, (Wi) brewing base c〇a: cholesterol thiotransferase inhibitor, and (viii) antioxidant; (k) PPARi (l) an anti-obesity compound; (m) an ileal cholic acid transporter inhibitor; (η) an anti-inflammatory agent other than glucocorticoid;

II受體拮抗劑或腎素抑制劑， 〇皿g η又袖京或r京糸統之 •轉化酶抑制劑、血管收縮素 諸如卡托普利（captopril)、西 141275.doc •37· 201102374 拉普利（cilazapril)、依那普利（enalapril)、福辛普利 (fosinopril)、賴諾普利（iisinoprii)、喹那普利（qUinapril)、 雷米普利（ramapril)、佐芬普利（zofenopril)、坎地沙坦 (candesartan)、西來替晉（cilexetil)、依普羅沙坦（eprosartan) 、伊貝沙坦（irbesartan)、洛沙坦（losartan)、他索沙坦 (tasosartan)、替米沙坦（telmisartan)及織沙坦（valsartan); 該等化合物係以有效治療該病狀之量向患者投與。 本發明所關注之又一態樣係關於一種治療需要該治療之 哺乳動物患者之選自由高膽固醇血症、動脈粥樣硬化、低 HDL 3里、兩LDL含量、尚脂血症、高三酸甘油醋血症及 血脂異常組成之群之病狀的方法，該方法包含向該患者投 與可有效治療該病狀之量的式Z化合物或其醫藥學上可接 受之鹽或溶劑合物及HMG-CoA還原酶抑制劑。 更詳言之，本發明所關注之另一態樣係關於一種治療需 要該治療之哺乳動物患者之選自由高膽固醇血症、動脈粥 樣硬化、低HDL含量、高LDL含量、高脂血症、高三酸甘 油酯血症及血脂異常組成之群之病狀的方法，該方法包含 向該患者投與式I化合物或其醫藥學上可接受之鹽或溶劑 。物及壬士他>丁形式之HMG_c〇A還原酶抑制劑，該等化 合物係以有效治療該病狀之量投與。適用於此方面之士他 汀包括由洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿 托伐他汀、伊伐他汀、2〇_4522及瑞伐他汀組成之群。 本發明係關於-種降低發展出選自由高膽㈣血症、動 脈粥樣硬化、低HDL含量、高肌含量、高脂血症、高三 141275.doc -38- 201102374 酸甘油自旨血症及血脂異常及該等病狀之續發症組成之群的 病狀之風險的方法，其包含向需要該治療之哺乳動物患者 技與治療有效量之如技術方案丨之化合物及hmg_c〇a還原 酶抑制劑β 更詳言之，本發明所關注之另一態樣係關於一種延遲需 要該治療之人類患者的動脈粥樣硬化發作或降低其發展出 動脈粥樣硬化之風險的方法，該方法包含向該患者投與式 I化合物或其醫藥學上可接受之鹽或溶劑合物及呈士他汀 形式之HMG-CoA還原酶抑制劑，該等化合物係以有效治 療該病狀之量投與。適用於此方面之士他汀包括由洛伐他 >丁、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、伊伐 他汀、ZD-4522及瑞伐他汀組成之群。 更詳言之’本發明所關注之另一態樣係關於一種治療需 要該治療之人類患者的動脈粥樣硬化、延遲其動脈粥樣硬 化發作或降低其發展出動脈粥樣硬化之風險的方法，該方 法包含向該患者投與式I化合物或其醫藥學上可接受之鹽 或溶劑合物及膽固醇吸收抑制劑，該等化合物係以治療動 脈粥樣硬化、延遲動脈粥樣硬化發作或降低發展出動脈粥 樣硬化之風險的量投與。 甚至更詳言之’本發明所關注之另一態樣係關於一種治 療需要該治療之人類患者的動脈粥樣硬化、延遲其動脈粥 樣硬化發作或降低其發展出動脈粥樣硬化之風險的方法， 該方法包含向該患者投與式I化合物或其醫藥學上可接受 之鹽或溶劑合物及膽固醇吸收抑制劑，其中該膽固醇吸收 抑制劑為依澤替米貝，該等化合物係以治療動脈粥樣硬 141275.doc •39- 201102374 化、延遲動脈粥樣硬化發作或降低發展出動脈粥樣硬化之 風險的量投與。 本發明所關注之又一態樣係關於一種醫藥組合物，其包 含：（1)式I化合物或其醫藥學上可接受之鹽或溶劑合物， (2)選自由以下各物組成之群的化合物： (a) DP-IV抑制劑； (b) 選自由（i)PPAR促效劑及（ii)雙胍類組成之群的胰島 素致敏劑； (c) 胰島素及胰島素模擬劑； (d) 磺醯脲類及其他胰島素促分泌素； Ο) α-葡糖苷酶抑制劑； (〇升糖素受體拮抗劑； (g) GLP-1、GLP-1模擬劑及GLP-1受體促效劑； (h) GIP、GIP模擬劑及GIP受體促效劑； (i) PACAP、PACAP模擬劑及PACAP受體3促效劑； (j) 選自由以下各物組成之群的降膽固醇劑：⑴HMG-CoA還原轉抑制劑’（ϋ)鰲合劑，（⑴)於醇、於酸或其鹽， (iv) PPARa促效劑，（v) ppARa/γ雙重促效劑，（vi)膽固醇 吸收抑制劑，（vii)醯基CoA :膽固醇醯基轉移酶抑制劑， 及（viii)抗氧化劑； (k) PPAIU促效劑； (l) 抗肥胖化合物； (m) 回腸膽酸轉運體抑制劑； (η)除糖皮質激素以外之消炎劑； (〇)蛋白質酪胺酸磷酸酶-IB(PTP-IB)抑制劑；及 141275.doc -40· 201102374 壓劑’包括作用於血管收縮素或腎素系統之 肖如血f收、缩素轉化ϋ抑制劑、血管收縮素 劑或腎素抑制劑，諸如卡托普利、西拉普利、 依：普利、福辛普利、賴諾普利、喹那普利、雷米普利、 佐芬普利、坎地沙坦、西來替昔、依普羅沙坦、伊貝沙 土一洛"坦、他索沙坦、替米沙坦及纈沙坦；及 (3)醫藥學上可接受之載劑 本發月所關’主之另一態樣係關於式工化合物或其醫藥學 上可接又之鹽或溶劑合物之用途，其係用於製造用於治療 本文中描述之疾病或病狀的藥物。 可使用本文中描述之合成流程以及熟習此項技術之化學 家將容易觸到之數㈣代方法巾的任-種製備本發明之 化合物。合成流程或實例中可能使兩下列縮寫：II receptor antagonist or renin inhibitor, g g g η 袖 京 京 or r 京 之 • Invertase inhibitor, angiotensin such as captopril (captopril), West 141275.doc •37· 201102374 Cilazapril, enalapril, fosinopril, iisinoprii, qUinapril, ramapril, zofenp Zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tassosartan , telmisartan and valsartan; these compounds are administered to a patient in an amount effective to treat the condition. Another aspect of the present invention is directed to a mammalian patient in need of such treatment selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL 3, two LDL levels, hyperlipidemia, and high triglyceride A method of treating a condition of a group consisting of acetemia and dyslipidemia, the method comprising administering to the patient an amount of a compound of formula Z or a pharmaceutically acceptable salt or solvate thereof and HMG in an amount effective to treat the condition -CoA reductase inhibitor. More specifically, another aspect of the present invention is directed to a mammalian patient in need of such treatment selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia. A method of treating a condition of a group consisting of hypertriglyceridemia and dyslipidemia, the method comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvent thereof. And a gentleman's form of HMG_c〇A reductase inhibitor, which is administered in an amount effective to treat the condition. Statin which is suitable for use in this regard includes a group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, ivavastatin, 2〇_4522 and revastatin. The present invention relates to a reduction in the development of glycerol self-pyrexemia and its selection from hyperbilirubinemia, atherosclerosis, low HDL content, high muscle content, hyperlipidemia, high 141275.doc -38-201102374 A method of dyslipidemia and a risk of a condition of a group consisting of a continuation of the condition, comprising a compound and a therapeutically effective amount of a compound and hmg_c〇a reductase in a mammalian patient in need of such treatment. Inhibitor β More specifically, another aspect of the present invention is directed to a method of delaying the onset of atherosclerosis or reducing the risk of developing atherosclerosis in a human patient in need of such treatment, the method comprising The patient is administered a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and an HMG-CoA reductase inhibitor in the form of a statin, which are administered in an amount effective to treat the condition. Stistatin suitable for use in this regard includes a group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, ivavastatin, ZD-4522 and revastatin. More particularly, 'another aspect of the present invention is directed to a method of treating atherosclerosis in a human patient in need of such treatment, delaying the onset of atherosclerosis or reducing the risk of developing atherosclerosis. The method comprises administering to the patient a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a cholesterol absorption inhibitor, for treating atherosclerosis, delaying the onset of atherosclerosis or reducing The amount of risk of developing atherosclerosis is administered. Even more particularly, 'another aspect of the present invention is directed to treating atherosclerosis, delaying the onset of atherosclerosis, or reducing the risk of developing atherosclerosis in a human patient in need of such treatment. Method, the method comprising administering to the patient a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is ezetimibe, and the compounds are Treatment of atherosclerosis 141275.doc •39- 201102374 The dose of delayed atherosclerotic episodes or reduced risk of developing atherosclerosis. A further aspect of the present invention relates to a pharmaceutical composition comprising: (1) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (2) selected from the group consisting of: Compounds: (a) DP-IV inhibitors; (b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; (c) insulin and insulin mimics; Sulfonylureas and other insulin secretagogues; Ο) α-glucosidase inhibitors; (glucagon receptor antagonists; (g) GLP-1, GLP-1 mimics and GLP-1 receptors (h) GIP, GIP mimetic and GIP receptor agonist; (i) PACAP, PACAP mimetic and PACAP receptor 3 agonist; (j) Free from the group consisting of Cholesterol: (1) HMG-CoA reduction-transfer inhibitor '(ϋ) chelating agent, ((1)) in alcohol, acid or its salt, (iv) PPARa agonist, (v) ppARa/γ dual agonist, (vi Cholesterol absorption inhibitor, (vii) sulfhydryl-based CoA: cholesterol thiol transferase inhibitor, and (viii) antioxidant; (k) PPAIU agonist; (l) anti-obesity compound; (m) ileal cholic acid transporter Inhibitors; (η) anti-inflammatory agents other than glucocorticoids; (〇) protein tyrosine phosphatase-IB (PTP-IB) inhibitors; and 141275.doc -40·201102374 Pressure agents' include action on vasoconstriction a renin or a renin system, such as blood, a vasopressin inhibitor, an angiotensin agent, or a renin inhibitor, such as captopril, cilazapril, lycopene, fosinopril, Lienopril, quinapril, ramipril, zofenopril, candesartan, cilexetil, eprosartan, ybesha sulphate "tan,tasolartan,timi And medicinally acceptable carriers of this genus Use for the manufacture of a medicament for the treatment of a disease or condition as described herein. The synthetic procedure described herein and the chemist skilled in the art will readily be able to reach it. - Preparation of the compounds of the invention. The following abbreviations may be made in the synthetic scheme or example:

Ac為乙醯基[CH3C(〇H ; Ac"為乙酸酐；AcAc為乙醯 基丙酮化物（acetyl acet〇n〇ate) ; ^為芳基；ArX為芳基 鹵，9-：681<[為9-硼雙環[3.3.1]壬烷；811為苄基；30(：為第 二丁氧羰基；BuTMDOB為反2- 丁基-Ν,Ν,Ν',Ν'-四曱基-1，3,2-二氧硼咮_4,5-二甲醯胺，指定為R，R* s，s ; DBU為 二氮雜雙環十一烷；DBAD為偶氮二曱酸二第三丁酯； DIAD為偶氮二甲酸二異丙酯；DIBAL或εηβαΙ-Η為氫化二 異丁基鋁；DMA為二甲基乙醯胺；DMF為N，N-二甲基甲醯 胺；DMSO為二甲亞砜；EDAC(或EDC)為1-乙基_3-[3·(二 甲基胺基）丙基]-碳化二亞胺鹽酸鹽；Et3N為三乙胺；Et為 乙基；EtOAc為乙酸乙酯；EtOH為乙醇；HC1為鹽酸；Ac is an ethylene group [CH3C (〇H; Ac" is acetic anhydride; AcAc is acetyl acet〇n〇ate; ^ is an aryl group; ArX is an aryl halide, 9-: 681 < [ Is 9-borobicyclo[3.3.1]nonane; 811 is benzyl; 30 (: is a second butoxycarbonyl; BuTMDOB is trans-2-butyl-oxime, oxime, Ν', Ν'-tetradecyl- 1,3,2-dioxaboron _4,5-dimethylguanamine, designated as R, R* s, s; DBU is diazabicycloundecane; DBAD is arsenazo diacetate Butyl ester; DIAD is diisopropyl azodicarboxylate; DIBAL or εηβαΙ-Η is diisobutylaluminum hydride; DMA is dimethylacetamide; DMF is N,N-dimethylformamide; DMSO Is dimethyl sulfoxide; EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; Et3N is triethylamine; Et is B Base; EtOAc is ethyl acetate; EtOH is ethanol; HCl is hydrochloric acid;

Het-X 為雜環鹵化物（heterocyclic halide) ; HOBt 為 1-經基 [ 141275.doc •41 · 201102374 苯并***；HPLC為高效液相層析；iPrOAc為乙酸異丙 酯；LG為離去基；Μ為莫耳濃度；mmol為毫莫耳；Me為 曱基；MeOH為曱醇；MsCl為曱烷磺醯氯；N為當量濃 度；NaHMDS為雙（三曱基矽烷）胺基鈉；NaOAc為乙酸 鈉；NaOtBu為第三丁醇鈉；NMO為N-曱基嗎啉N-氧化 物；NMP為N-曱基吡咯啶酮；Pd(dba)2為參（二亞苄基丙 酮）二鈀；PdCl2(Ph3P)2為二氣雙（三苯基膦）鈀；PG表示未 指定之保護基；Ph為苯基；PhMe為曱苯；PPh3為三苯基 膦；PMB為對甲氧基苄基；RT為室溫；TBAF為四丁基氟 化銨；TBS為第三丁基二曱基矽烷基；tBu為第三丁基；Tf 為三氟曱磺酸鹽；TF A為三氟乙酸；THF為四氫呋喃； TLC為薄層層析；TMEDA為四甲基乙二胺；TMS為三甲基 矽烷基；TPAP為高釕酸四丙銨。 一般流程 流程中所示之經取代芳基及雜芳基偶合中間物可自市面 上購得或可由易得到之芳基、雜環或其他同源物經由許多 途徑製備。許多中間物可經由修飾預形成之雜芳基骨架或 經由重新環合成得到。 本發明之經取代烷基哌啶可由數種方法中之任一種製 備。下文詳述之特定實例可採用一些下列一般程序。許多 官能化哌啶可在市面上購得。若其不可自市面上購得，則 關於其製備之一種最適用合成途徑利用合適吡啶之還原。 在氫氣及5-10%鈀/木炭或類似氫化催化劑下在活化之吡啶 鑌酿基（pyridinium acyl)的乙酸還原或逐步還原中由氫化 物低壓還原，接著類似氫化將產生適當的哌啶。側鏈可以 141275.doc • 42· 201102374 其所要之最終構型存在，或可在產生哌啶環後由熟知方法 加工。（流程1) 流程1Het-X is a heterocyclic halide; HOBt is 1-mer radical [141275.doc •41 · 201102374 benzotriazole; HPLC is high performance liquid chromatography; iPrOAc is isopropyl acetate; LG is away De-based; Μ is molar concentration; mmol is millimolar; Me is thiol; MeOH is decyl alcohol; MsCl is decane sulfonium chloride; N is equivalent concentration; NaHMDS is bis(tridecyldecane) sodium NaOAc is sodium acetate; NaOtBu is sodium tributoxide; NMO is N-mercaptomorpholine N-oxide; NMP is N-decylpyrrolidone; Pd(dba)2 is ginseng (dibenzylideneacetone) Palladium; PdCl2(Ph3P)2 is di- gas bis(triphenylphosphine)palladium; PG represents unprotected protecting group; Ph is phenyl; PhMe is nonylbenzene; PPh3 is triphenylphosphine; PMB is para Oxybenzyl; RT is room temperature; TBAF is tetrabutylammonium fluoride; TBS is tert-butyldioxanylalkyl; tBu is tributyl; Tf is trifluorosulfonate; TF A is Trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; TMEDA is tetramethylethylenediamine; TMS is trimethyldecylalkyl; TPAP is tetrapropylammonium perrhenate. The substituted aryl and heteroaryl coupling intermediates shown in the general schemes are either commercially available or can be prepared from a wide variety of readily available aryl, heterocyclic or other homologs. Many intermediates can be obtained by modifying the preformed heteroaryl backbone or by recycling. The substituted alkyl piperidines of the invention can be prepared by any of several methods. Some of the following general procedures may be employed in the specific examples detailed below. Many functionalized piperidines are commercially available. If it is not commercially available, one of the most suitable synthetic routes for its preparation utilizes the reduction of a suitable pyridine. Reduction of the hydride by low pressure in the reduction or stepwise reduction of the activated pyridinium acyl under hydrogen and 5-10% palladium on charcoal or a similar hydrogenation catalyst, followed by similar hydrogenation will yield the appropriate piperidine. The side chain can be 141275.doc • 42· 201102374 The final configuration is desired, or can be processed by well-known methods after the piperidine ring is produced. (Process 1) Process 1

RR

ΝΝ

1) H2) Pd/C 2) RO(CO)X1) H2) Pd/C 2) RO(CO)X

CI(CO)OR 氫化物CI(CO)OR hydride

κκ

N^OR T oN^OR T o

Η2ι Pd/C R表禾低碳烷基，Rp及Rm表示環A上之對位取代及間位取代 本發明實例之連接鏈中之環丙基殘基可由數種方法中之 任一種引入。尤其方便之方法概述於以下流程2中。藉由 夕步方案使可容易獲得之經基甲基派π定轉化成乙炔使得在 琳德拉還原（Lindlar reduction)後隨即可得到指示之順式烯 烴。（關於方便之方案，例如參見Eymery等人，办价办 2000, 185-213.第 196頁）。經由威蒂格反應（wittig reacti〇n) 之霍，、内埃象斯改貝（Horner-Emmons modification)使相同 中間物同系化（homologation)使得容易地得到反式烯烴。 查雷特氏（Charette，s)Et2Zn/CH2I2環丙烷化得到外消旋非對 映異構富集環丙基類似物或對映異構富集環丙基類似物。 (Charette等人，州1998, /%，H943-H952 ;其他詳情 在 Charette 等人，川 2〇〇1，1216〇12167中）。在不 存在助劑對掌性路易斯酸（Lewisacid)之情況下，順式稀丙 系烯烴得到良好產率之所要之外消旋類似物。同時在不存 在助劑對掌性路易斯酸之情況下，自尺或8縮水甘油基環氧 化物開環獲得之對掌性醇得到合理比率之對掌性非對映異Η2ι Pd/C R and lower alkyl, Rp and Rm represent para-substitution and meta-substitution on ring A The cyclopropyl residue in the linker of the present invention may be introduced by any of several methods. A particularly convenient method is outlined in Scheme 2 below. The readily obtainable benzyl group is converted to acetylene by a smectic scheme such that the indicated cis olefin is obtained after Lindlar reduction. (For a convenient solution, see, for example, Eymery et al., Office 2000, 185-213. p. 196). The homo ligation of the same intermediate makes it easy to obtain a trans olefin via the Wittig reacti〇n, Horner-Emmons modification. The cyclopropanation of Charette, s Et2Zn/CH2I2 affords the racemic diastereomeric enriched cyclopropyl analog or enantiomerically enriched cyclopropyl analog. (Charette et al., State 1998, /%, H943-H952; other details in Charette et al., Chuan 2〇〇1, 1216〇12167). In the absence of an adjuvant to the palmitic Lewis acid, the cis-diazepine olefin gives the desired racemic analog in good yield. At the same time, in the absence of an adjuvant to the palmitic Lewis acid, the palmar alcohol obtained by ring-opening of the ruler or the 8-glycidyl epoxide gives a reasonable ratio of palmar diastereomeric

I41275.doc -43- 201102374 構環丙院化產物。 藉由添加助劑對掌性路易斯酸RR或SS反2- 丁基-N,N，N'，N'-四曱基-1，3,2-二氧硼咮-4,5-二曱醯胺 (BuTMDOB)，相同的環丙院化方案在稀丙系環丙烧化或 高烯丙系環丙烷化中產生極佳比率之所要對映異構體。所 描繪之對掌性高烯丙醇在雙非對映立體選擇方案中需要 「匹配」之二氧硼咪。 流程2I41275.doc -43- 201102374. By adding an adjuvant to the palmitic Lewis acid RR or SS trans-2-butyl-N,N,N',N'-tetradecyl-1,3,2-dioxaborin-4,5-diindole Indoleamine (BuTMDOB), the same cyclopropeneization scheme produces an excellent ratio of the desired enantiomer in dilute propylene propylene or high allylic cyclopropanation. The depicted palmar high allyl alcohol requires a "match" of dioxon in a dual diastereomeric selection scheme. Process 2

R'表示低碳烷基，R表示Η或PG2 = 1»02為保護基，較佳為苄基。 哌啶氮取代基之引入可由特別多之途徑實現。用於本文 141275.doc -44 - 201102374 中報導之實例之一些最通用的途徑描繪於流程3中。通常 可使用直接置換不穩定雜芳基lS或類似離去基來直接引入 氮取代基。芳基醚之隨後的官能化為類似直接的。三信偶 合（Mitsunobu coupling)、第一醇活化，接著雜芳基系統上 之置換或直接置換對從事合成之化學家而言皆為熟知的。 流程3R' represents a lower alkyl group, and R represents deuterium or PG2 = 1»02 is a protecting group, preferably a benzyl group. The introduction of a piperidine nitrogen substituent can be achieved in a particularly multitude of ways. Some of the most common approaches for the examples reported in this article 141275.doc -44 - 201102374 are depicted in Flow 3. Direct replacement of an unstable heteroaryl group 1S or a similar leaving group can be used to directly introduce a nitrogen substituent. Subsequent functionalization of the aryl ether is similarly straightforward. Mitsunobu coupling, first alcohol activation, followed by displacement or direct displacement on heteroaryl systems are well known to chemists engaged in the synthesis. Process 3

Het-LGHet-LG

(R4)3V^N Het-LG等於 表示6員或5員雜環；LG為可置換之鹵素或其他離去基=(R4)3V^N Het-LG is equal to 6 or 5 member heterocycle; LG is a replaceable halogen or other leaving group =

rT 藉由使用氮保護基（諸如BOC、FMOC、CBZ或其他容易 移除之PG)，可容易地顛倒引入芳基醚及哌啶N取代基之 順序。氮保護基之移除產生用於進一步加工之偶合搭配 物。 流程4rT The order of introduction of the aryl ether and piperidine N substituents can be easily reversed by using a nitrogen protecting group such as BOC, FMOC, CBZ or other readily removable PG. Removal of the nitrogen protecting group produces a coupling partner for further processing. Process 4

NaOiBu, NMP i及j在0-2之間變化 (R2)3NaOiBu, NMP i and j vary between 0-2 (R2)3

141275.doc -45- 201102374 用於哌啶N取代基之適度的最終加工之特別適用的合成 方法為如流程3b中概述及若干種文獻綜述中描述之布奇沃 德偶合（Buchwald coupling)。（例如參見6.8〇1111111111161*,11· Scholtzddv. Cilia/· 2004，3岑(5，1599-1626。） 流程3b 布奇沃德偶合141275.doc -45- 201102374 A particularly suitable synthetic method for modest final processing of piperidine N substituents is the Buchwald coupling as outlined in Scheme 3b and described in several literature reviews. (See, for example, 6.8〇1111111111161*, 11·Scholtzddv. Cilia/· 2004, 3岑 (5,1599-1626.) Process 3b Butchworth coupling

對一些取代模式而言，藉由重新環合成引入哌啶N取代 基更適宜。流程5中所示之熟知嘧啶合成為多種該等方法 之一個實例。 流程5For some substitution modes, it is more appropriate to introduce a piperidine N substituent by recyclization. The well-known pyrimidine synthesis shown in Scheme 5 is an example of one of many such methods. Process 5

R為Η或PGR is Η or PG

當Ν-芳基或Ν-雜芳基殘基經X基團（其中X = CM、Br、I 或OTf)取代時，有可能利用鐵或鈀有機金屬介導之偶合反 應使殘基進一步官能化。具有格外廣泛的適用性之方法為 流程6中概述之金屬介導之偶合。 141275.doc •46- 201102374 流程6When a fluorene-aryl or fluorene-heteroaryl residue is substituted with an X group (where X = CM, Br, I or OTf), it is possible to further functionalize the residue using an iron or palladium organometallic mediated coupling reaction. Chemical. A method with exceptionally broad applicability is the metal-mediated coupling outlined in Scheme 6. 141275.doc •46- 201102374 Process 6

Pd(OAc)2洳熱, Ph2P(CH2>5PPh2 (白 4)3 X = CI, Br, I, OTfPd(OAc)2洳, Ph2P(CH2>5PPh2 (white 4)3 X = CI, Br, I, OTf

(R4)3 KCN, TMEDA_(R4)3 KCN, TMEDA_

Fe(AcAc), MeMgXFe(AcAc), MeMgX

Pd (0), Bu3SnR3 或 i及j在0-2之間變化 Pd(0)_ ί^Β(ΟΗ)2, R為H或PG ^ 指定為「無水（dry)」或「無水（anhydrous)」之溶劑可為 商業無水溶劑或在惰性氣體中自適當乾燥劑中蒸餾之溶 劑。(.參 t Purification of Laboratory Chemicals D.D. Perrin，Elsevier Science。）環丙烧化反應係在嚴格空氣隔 絕下在蒸餾溶劑中進行。請注意A. B. Charette等人，X4CS 120, 46, 1 1943-1 1952,第1 1945頁中報導之放熱警告。 許多實例係以外消旋混合物形式製備且藉由對掌性固定 相層析分離。數種市售固定相適合該目的。通常使用商業 Chiralpak IA 4.6x250 mm, 5 μ管柱進行分析研究且通常使 用半製備型Chiralpak ΙΑ管柱（20x25 0 mm，5 μ)進行製備 型分離。通常使用庚烷醇混合物溶離對映異構體。 實例 製備實例1 製備外消旋順式-4-[2-(2-羥基乙基）環丙基]哌啶-1-甲酸第 141275.doc -47- 201102374 三丁酯，亦即（4-[(15,2i?)-2-(2-羥基乙基）環丙基】哌啶-1-曱 酸第三丁酯及4-[(lJ?，2<S)-2-(2-羥基乙基）環丙基]哌啶-1-甲 酸第三丁酯） 步驟1 :製備4-[(12Γ)-4-(苄基氧基）丁-1-稀-1-基】哌啶·ΐ_曱 酸第三丁酯Pd (0), Bu3SnR3 or i and j vary between 0 and 2 Pd(0)_ ί^Β(ΟΗ)2, R is H or PG ^ is designated as "dry" or "anhydrous" The solvent may be a commercial anhydrous solvent or a solvent which is distilled from a suitable drying agent in an inert gas. (. Ref. of Purification of Laboratory Chemicals D.D. Perrin, Elsevier Science.) The cyclization reaction was carried out in a distillation solvent under strict air separation. Please note the heat release warning reported in A. B. Charette et al., X4CS 120, 46, 1 1943-1 1952, pp. 1 1945. Many examples were prepared as racemic mixtures and separated by chromatographic stationary phase chromatography. Several commercially available stationary phases are suitable for this purpose. Commercial Chiralpak IA 4.6x250 mm, 5 μ column is commonly used for analytical studies and preparative separations are typically performed using semi-prepared Chiralpak® columns (20 x 25 0 mm, 5 μ). The enantiomers are typically dissolved using a heptanol mixture. EXAMPLES Preparation Example 1 Preparation of racemic cis-4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylic acid 141275.doc -47- 201102374 Tributyl ester, ie (4- [(15,2i?)-2-(2-hydroxyethyl)cyclopropyl] piperidine-1-decanoic acid tert-butyl ester and 4-[(lJ?,2<S)-2-(2- Hydroxyethyl)cyclopropyl]piperidine-1-carboxylic acid tert-butyl ester) Step 1: Preparation of 4-[(12Γ)-4-(benzyloxy)butan-1-yl-1-yl]piperidine ·ΐ_Certified third butyl citrate

將漠化（3 -卞基氧基丙基）三苯基鱗（2.88 g，5.86 mmol) 懸浮於15 mL THF中且冷卻至〇°C。逐滴添加雙（三曱基石夕 炫基）醯胺納（1 Μ(於THF中），5.63 mL，5.63 mmol)。混合 物變成深橙色。5分鐘後添加於3 mL THF中之4-曱醯基派 咬-1-曱酸第二丁酿（1 g，4.69 mmol)。顏色槐至微黃色。 在室溫下搜拌反應1.5小時’之後用飽和氯化錢水溶液中 止反應。用乙酸乙酯萃取水層兩次。合併有機層，用水及 鹽水洗滌’經硫酸鈉乾燥，過濾，濃縮且藉由穿過4〇公克 Biotage矽膠筒使用20°/。EtOAc/己烷純化，得到呈無色油 狀之產物。NMR積分指示z/E選擇率>20:1。LRMS計算 值：345.2 ;實測值：346.5 (M+1)。 步驟2 :外消旋4-{2-【2-(苄基氧基）乙基】環丙基}哌啶曱 酸第三丁醋’亦即（4_{(liS，2i?)_2_丨2·(苄基氧基）乙基]環丙 基}哌啶-1_曱酸第三丁酯及4-{(l/?，2S)-2-[2-(苄基氧基）乙 基】環丙基}哌啶-1-曱酸第三丁酯） 141275.doc • 48- 201102374The desertified (3-mercaptooxypropyl)triphenyl scale (2.88 g, 5.86 mmol) was suspended in 15 mL of THF and cooled to EtOAc. Bis(trimethylsulfanyl) guanamine (1 Torr (in THF), 5.63 mL, 5.63 mmol) was added dropwise. The mixture turns dark orange. After 5 minutes, it was added to 3 mL of THF in a solution of 2-mercapto-1-pyruic acid second butyl (1 g, 4.69 mmol). The color is slightly yellowish. The reaction was allowed to stand at room temperature for 1.5 hours' and then quenched with saturated aqueous solution of chlorinated acid. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine. dried over sodium sulfate, filtered, and concentrated and then passed through <RTIgt; Purification by EtOAc / EtOAc afforded EtOAc. The NMR integration indicated a z/E selectivity of > 20:1. LRMS calcd.: 345.2; found: 346.5 (M+1). Step 2: Racemic 4-{2-[2-(benzyloxy)ethyl]cyclopropyl}piperidinic acid terpene vinegar's (4_{(liS,2i?)_2_丨) 2·(Benzyloxy)ethyl]cyclopropyl}piperidine-1-decanoic acid tert-butyl ester and 4-{(l/?,2S)-2-[2-(benzyloxy)B Base] cyclopropyl} piperidine-1-decanoic acid tert-butyl ester) 141275.doc • 48- 201102374

Et2Zn, CICH2I cich2ch2ciEt2Zn, CICH2I cich2ch2ci

使一氯乙烧（5 mL)脫氣且用氬氣淨化三次，之後添加二 乙基鋅溶液（1 Μ(於己烷中），1.74 mL，1.74 mmol)。將溶 液冷卻至-20。(：。逐滴添加氯碘曱烷（613 mg，3.47 mmol)， 同時維持内部溫度在-15 °C以下。在-2(TC下攪拌1 〇分鐘 後’逐滴添加於脫氣二氯乙烧（1 mL)中之4-[(1Ζ)-4-(节基 氧基）丁-1-烯-1-基]哌啶-1-甲酸第三丁酯（來自該實例之步 驟1，200 mg，0.579 mmol)。在-20°C下攪拌反應1〇分鐘， 之後緩慢溫至室溫。1小時後，將反應混合物冷卻至_ 1 〇 C。緩慢引入飽和氣化敍水溶液與氫氧化錄水溶液（28 重量/重量％)之1:4混合物以使過量試劑中止反應。在室溫 下攪拌混合物3小時。分離水層且用二氯甲烧萃取兩次。 用鹽水洗蘇合併之有機層，經硫酸鋼乾燥，濃縮且藉由用 25% EtOAc/己烷溶離進行管柱層析而純化，得到呈無色油 狀之產物。LRMS計算值：359.25 ;實測值：360.5 (M+1)。 步驟3 :外消旋順式-4-[2·(2·羥基乙基）環丙棊】哌啶甲酸 第三丁酯，亦即（4-[(1·5,2Ι?)·2-(2-羥基乙基）環丙基]哌啶-；!· 甲酸第三丁酯及4-【（1及，2*5)-2-(2-羥基乙基）環丙基]哌啶小 甲酸第三丁酯）The chloroethene (5 mL) was degassed and purified with argon three times, then diethylzinc solution (1 EtOAc (hexane), 1.74 mL, 1.74 mmol). Cool the solution to -20. (: Add chloroiododecane (613 mg, 3.47 mmol) dropwise while maintaining the internal temperature below -15 °C. Add -2 to degassed dichloroethane after stirring at -2 (TC for 1 〇 minutes) 4-[(1Ζ)-4-(nodaloxy)but-1-en-1-yl]piperidine-1-carboxylic acid tert-butyl ester in (1 mL) (Step 1 from this example, 200 mg, 0.579 mmol). Stir the reaction at -20 ° C for 1 min, then slowly warm to room temperature. After 1 h, cool the reaction mixture to _ 1 〇 C. Slowly introduce saturated aqueous solution and hydroxide A 1:4 mixture of the aqueous solution (28 wt/wt%) was recorded to stop the reaction with excess reagent. The mixture was stirred at room temperature for 3 hours. The aqueous layer was separated and extracted twice with methylene chloride. The layers were dried over EtOAc EtOAc (EtOAc): EtOAc. Step 3: Racemic cis-4-[2·(2·hydroxyethyl)cyclopropene] piperidinecarboxylic acid tert-butyl ester, ie (4-[(1·5, 2Ι?)·2 -(2-hydroxyethyl)cyclopropyl] Piperidine - carboxylate and third ;!-4 - [(1 and 2 * 5) - 2- (2-hydroxyethyl) cyclopropyl] piperidine-carboxylic acid tert-butyl ester small)

EtOAc/乙醇EtOAc/ethanol

Pd(〇H)2l H2Pd(〇H)2l H2

將來自步驟2之外消旋順式-4-{2-[2-(苄基氧基）乙基]環 141275.doc -49- 201102374 丙基}°底定-1-曱酸第三丁 g旨（140 mg，0.39 mmol)溶解於5 mL乙酸乙酯及乙醇（ι:1)中。將溶液脫氣且用氮氣淨化3 次’之後添加氫氧化鈀（20%(於碳上），54.6 mg，〇.〇8 mmol)。將混合物脫氣且用氫氣淨化三次。在氫氣球下在 室溫下攪拌反應1小時且經小矽膠塞過濾以移除催化劑。 用丙酮充分洗滌該矽膠塞。濃縮溶離劑，得到粗產物，其 不經進一步純化即使用》LRMS計算值：269.2 ;實測值： 270.2 (M+1) 〇 製備實例2Will be from step 2, racemic cis-4-{2-[2-(benzyloxy)ethyl] ring 141275.doc -49- 201102374 propyl}° bottoming-1-butyric acid third g (140 mg, 0.39 mmol) was dissolved in 5 mL of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen 3 times&apos; after the addition of palladium hydroxide (20% (on carbon), 54.6 mg, 〇. 〇 8 mmol). The mixture was degassed and purged three times with hydrogen. The reaction was stirred at room temperature for 1 hour under a hydrogen balloon and filtered through a small seper plug to remove the catalyst. The silicone plug was thoroughly washed with acetone. The lysing agent was concentrated to give a crude product which was used without further purification. </RTI> <RTI ID=0.0></RTI> <RTIgt;

製備順式-4-[2-(2_|^基乙基）環丙基】|1底咬_1_曱酸第三丁西旨 步驟1 :製備4_丨(4R)-5-(苄基氧基）_4_羥基戊炔基】哌 啶-1-甲酸第三丁酯Preparation of cis-4-[2-(2_|^ylethyl)cyclopropyl]|1 bottom bite_1_decanoic acid third butyl group Step 1: Preparation of 4_丨(4R)-5-(benzylidene氧基oxy)_4_hydroxypentynyl] piperidine-1-carboxylic acid tert-butyl ester

將市售4-乙炔基哌啶_；[_曱酸第三丁酯溶解於4〇 ml THF 中且冷卻至-78。(：，形成白色漿液。在攪拌下逐滴添加經 滴定之 n-BuLi(2.2 Μ(於己烷中），23 9 m卜 52.6 mmol)。 在-78 C下攪拌澄清無色溶液5分鐘。逐滴添加R_(+)苄基縮 水甘油基環氧化物（8_63 g，52.6 mmol)於THF(20 ml)中之 溶液。隨後用注射器逐滴添加bf3醚合物（8,43 g，59 7 mmol)且在-78 C下攪拌溶液丄小時。添加飽和NH4C1水溶液 (100 ml)，將混合物溫至室溫，用水稀釋以溶解任何餘留 141275.doc -50· 201102374 固體，且用iPr〇Ac(3 χ 100 ml)萃取。合併有機部分， 77 ，用鹽 水洗滌，經MgS〇4乾燥，過濾且汽提。藉由用3〇% EtOAc :己院溶離進行Si〇2層析來純化粗產物。藉由〇 8 逆相管柱（具有0.1% TFA之12-100%水：乙腈，兩次操作） 層析將醇再純化。合併含產物溶離份，使體積缩咸約 5〇% ’藉由添加飽和NaHC〇3水溶液變成驗性，添力π水以 溶解一些白色固體，且用iPr〇Ac(3x100)萃取混合物。a 併有機部分，用鹽水洗滌，經MgS〇4乾燥，過渡且汽提。 步驟2 :製備4-丨(lZ，4R)-5-(苄基氧基）-4-羥基戊基】 哌啶-1-曱酸第三丁酯Commercially available 4-ethynylpiperidine _; [-tert-butyl citrate was dissolved in 4 mL of THF and cooled to -78. (:, a white slurry was formed. The titrated n-BuLi (2.2 Μ (in hexane), 23 9 m b 52.6 mmol) was added dropwise with stirring. The clear colorless solution was stirred at -78 C for 5 minutes. A solution of R_(+)benzyl glycidyl epoxide (8-63 g, 52.6 mmol) in THF (20 ml) was added dropwise, followed by dropwise addition of bf3 etherate (8,43 g, 59 7 mmol) with a syringe. The solution was stirred for a few hours at -78 C. A saturated aqueous NH4C1 solution (100 ml) was added and the mixture was warmed to room temperature and diluted with water to dissolve any remaining solid 141 275. doc - 50 · 201102374 solids with iPr 〇Ac ( 3 χ 100 ml), the organic fractions were combined, washed with brine, dried with EtOAc EtOAc EtOAc. Re-purification of the alcohol by chromatography on a 〇8 reverse phase column (12-100% water with 0.1% TFA: acetonitrile, two operations). Combine the product-containing fractions to reduce the volume by about 5% by weight. Adding a saturated aqueous solution of NaHC〇3 becomes an inertia, adding π water to dissolve some white solids, and extracting the mixture with iPr〇Ac (3x100). Part, washed with brine, dried over MgS〇4, transitioned and stripped. Step 2: Preparation of 4-indole (lZ,4R)-5-(benzyloxy)-4-hydroxypentyl]piperidin-1- Tert-butyl citrate

琳德拉還原Linda Restore

5% Pd CaCO, 以船¥化&quot;^ 啥4 將來自該實例之步驟1之醇（9.1 g，24.4 mmol)溶解於 EtOAc(100 ml)中且添加喹啉（0.48 ml，4_〇3 mmol)。添加 琳德拉催化劑（1.04 g)且將容器抽真空且用h2再填充三 次。在Hz氛圍下攪拌漿液40分鐘。SM完全耗盡。經碎藻 土過滤混合物且用EtOAc(4x50 ml)沖洗〇在真空中使5% Pd CaCO, in the form of a boat, &lt;^ 啥4 The alcohol from step 1 of this example (9.1 g, 24.4 mmol) was dissolved in EtOAc (100 ml) and quinoline (0.48 ml, 4_〇3) Mm). Linda catalyst (1.04 g) was added and the vessel was evacuated and refilled three times with h2. The slurry was stirred for 40 minutes in a Hz atmosphere. SM is completely exhausted. The mixture was filtered through celite and washed with EtOAc (4×50 mL) and evaporated.

EtOAc之體積縮減約80%。用***（1〇〇 ml)稀釋餘留溶液且 用？ Ν Ηςΐ(100 ml)洗滌。用***（2x50 ml)再萃取水性部 分，合併有1機物且用15 ml 2 N HC1洗滌。用飽和NaHC03 水溶液、鹽水洗滌有機部分，經MgS04乾燥，過濾且汽 提。藉由用30% EtOAc :己烷溶離進行Si〇2層析來純化所 r c-I ύ 141275.doc -51 - 201102374 得油狀物。 步驟3 :製備4-{(lR，2S)-2-[(2R)_3·(苄基氧基）_2_羥基丙基】 環丙基}哌啶甲酸第三丁酯The volume of EtOAc was reduced by about 80%. Diluted the remaining solution with diethyl ether (1 〇〇 ml) and used? Wash Ν (100 ml). The aqueous portion was re-extracted with diethyl ether (2 x 50 ml), combined with 1 and washed with 15 ml 2 N EtOAc. The organic portion was washed with aq. sat. NaH.sub.3, brine, dried over EtOAc, filtered and evaporated. The r c-I ύ 141275.doc -51 - 201102374 was purified by Si〇2 chromatography eluting with 30% EtOAc:hexane. Step 3: Preparation of 4-{(lR,2S)-2-[(2R)_3·(benzyloxy)_2-hydroxypropyl]cyclopropyl}piperidinecarboxylic acid tert-butyl ester

在A下自CaH2蒸餾經EtOH穩定之二氯曱烷且充以N2以 維持無氧溶劑。 使500 mi 3. N圓底燒瓶配備有頂部裝有三通旋塞之加料 漏斗及内部熱電偶。將裝置抽真空且用A回填4次。在乂 氛圍下向該脫氣容器中添加20mL DCM、***（5·06 g，以 重量計轉移）及Et2Zn溶液（8 43 g，68 2 mm〇1，於3〇⑹ DCM中）。將溶液冷卻至_2〇t：且逐滴添加ch山溶液6 $ g’ 136 mmol，於20 ml DCM*)。用内部溫度探針監測溫 度。改變添加速率以維持恆定的_2〇t之内部溫度。添加 完成約80%後，形成細沈澱物。攪拌混合物1〇分鐘。 添加市售（s，s)二氧硼味配位體（7.37 g，27 3 mm〇1)於 DCM(20 mL)中之溶液。攪拌混合物1〇分鐘。沈澱物溶 解，得到澄清溶液。添加來自該實例之步驟2之烯（8 53 g’ 22.7mmol)於DCM(2〇mL)中之溶液。將溶液溫至代且 攪拌24小時。溶液在攪拌24小時後仍澄清^ 24小時後藉由 141275.doc -52- 201102374 添加50 ml飽和NH4C1水溶液使反應中止。將混合物置於分 液漏斗中，添加250 ml DCM及200 ml 10% HC1(水溶液）， 震盪且分離各層。用DCM(2xl50 ml)再萃取水層，合併有 機層，轉移至莫頓燒瓶（Morton flask)中。添加2 N NaOH(3 00 ml)及50 ml 30% H202。劇烈攪拌兩相溶液12小 時。分離各層且用DCM(2xl50 ml)再萃取水相，合併有機 相’用 10% HC1(水溶液，250 ml)、]-N Na2S2O3(250 ml)、 飽和 NaHCO3(250 ml)、鹽水（250 ml)洗滌，經 MgS04乾 燥’過濾且汽提。藉由用3〇% EtOAc :己烷溶離進行Si〇2 層析來純化該物質。獲得呈具有少量非對映異構體及殘餘 SM之混合物形式的所要產物。藉由chiralpak IA固定相層 析來分離所要之非對映異構體。 步驟4 :製備順式-4-【2-(2-羥基乙基）環丙基】哌啶-1-甲酸第 三丁酯The EtOH-stabilized dichloromethane was distilled from CaH2 under A and charged with N2 to maintain an anaerobic solvent. A 500 mi 3. N round bottom flask was equipped with an addition funnel with a three-way cock on top and an internal thermocouple. The device was evacuated and backfilled 4 times with A. To the degassing vessel, 20 mL of DCM, diethyl ether (5·06 g, transferred by weight) and Et2Zn solution (8 43 g, 68 2 mm 〇1 in 3 〇 (6) DCM) were added to the degassing vessel. The solution was cooled to _2 〇t: and ch ch solution 6 $ g' 136 mmol was added dropwise to 20 ml DCM*). The temperature is monitored with an internal temperature probe. The rate of addition was varied to maintain a constant internal temperature of _2 〇t. After the addition was completed about 80%, a fine precipitate was formed. The mixture was stirred for 1 minute. A solution of a commercially available (s,s) diboron-flavored ligand (7.37 g, 27 3 mm 〇1) in DCM (20 mL) was added. The mixture was stirred for 1 minute. The precipitate was dissolved to give a clear solution. A solution of the olefin (8 53 g' 22.7 mmol) from step 2 of this example in DCM (2 mL) was added. The solution was warmed to the next and stirred for 24 hours. The solution was clarified after stirring for 24 hours. After 24 hours, the reaction was quenched by the addition of 50 ml of a saturated aqueous solution of NH4Cl in 141275.doc -52 - 201102374. The mixture was placed in a separatory funnel, 250 ml of DCM and 200 ml of 10% HCl (aq) were added, and the layers were shaken and separated. The aqueous layer was re-extracted with DCM (2×l 50 ml) and the organic layer was combined and transferred to a Morton flask. Add 2 N NaOH (3 00 ml) and 50 ml 30% H202. The two phase solution was stirred vigorously for 12 hours. The layers were separated and the aqueous phase was re-extracted with DCM (2×l 50 ml). The organic phase was combined with 10% HCl (aq., 250 ml), &lt;RTI ID=0.0&gt;&gt; Washed, dried by MgS04 'filtered and stripped. This material was purified by Si〇2 chromatography eluting with 3% EtOAc: hexane. The desired product is obtained in the form of a mixture of minor diastereomers and residual SM. The desired diastereomers were separated by chiralpak IA stationary phase stratification. Step 4: Preparation of cis-4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylic acid tert-butyl ester

1) H2Pd/C 2) Nal04 CH2CI2 / H20 3) NaBH4 EtOH1) H2Pd/C 2) Nal04 CH2CI2 / H20 3) NaBH4 EtOH

將來自該實例之步驟3之4-{(lR，2S)-2-[(2R)-3-(苄基氧 基）-2-羥基丙基]環丙基}旅。定·ι·曱酸第三丁酯（43 g，^ mmol)轉移至parr震盪器壓力管中55以具有〇 88 mg Aldrich氫氧化鈀（20重量％(於碳上），Degussa以〇1型）之 1:1 EtOAc/乙醇中。用parr震盪器在5〇 pSig氫氣下震盪混 合物。在30分鐘時HPLC檢查指示完全轉化。經石夕藻土過 141275.doc -53- 201102374 濾產物，用乙醇洗滌且在真空中縮減成油狀物。 將粗的去苄基化產物溶解於CH2Cl2(56 ml)中且在冰中冷4-{(lR,2S)-2-[(2R)-3-(benzyloxy)-2-hydroxypropyl]cyclopropyl} brigade from step 3 of this example. Ding ι· decyl citrate (43 g, ^ mmol) was transferred to a parr shaker pressure tube 55 to have 〇88 mg Aldrich palladium hydroxide (20% by weight (on carbon), Degussa 〇1 type) ) in 1:1 EtOAc/ethanol. The mixture was shaken under a 5 〇 pSig hydrogen using a parr shaker. HPLC examination indicated complete conversion at 30 minutes. The product was filtered, washed with ethanol and reduced to an oil in vacuo. The crude debenzylated product was dissolved in CH 2 Cl 2 (56 ml) and cooled in ice

緩慢逐滴添加。在(re下劇烈攪拌乳白色混合物。HPLC指 示在OC下在30分鐘時完全裂解。用鹽水及CH2Cl2稀釋反 應此合物。用CHsCl2萃取混合物三次，經MgS〇4乾燥且在 真空中縮減體積。 將粗醛再溶解於EtOH(56 ml)中，添加呈固體狀之硼氫 化鈉（0.422 g，11·2 mmol)且在室溫下攪拌混合物。還原在 3〇分鐘内完成。添加飽和NH4C1水溶液（7〇 ml)來中止反 應，且在真空中使混合物縮減成糊狀物。用水（35〇 ml)及 iPrOAc稀釋所得物。用iPr〇Ac萃取混合物3次，用鹽水洗 滌，經MgS〇4乾燥，過濾且在真空中縮減體積。藉由用 40%EtOAc :己烷溶離進行Si〇2層析來純化粗產物。 製備實例3 製備外消旋反式-4-[2-(2-羥基乙基）環丙基]哌啶曱酸第 三丁酯，亦即（4·[(1Λ，2/?)-2-(2-羥基乙基）環丙基】哌啶_直· 甲酸第二丁酯及4-[(lS，2&gt;S)-2-(2·羥基乙基）環丙基]旅啶·p 甲酸第三丁酯） 步驟1 : 4-[(1Ε)-3-甲氧基·3-側氧基丙烯4 —基】哌啶甲 酸第三丁酯Add slowly and drop by drop. The milky white mixture was vigorously stirred under re-HPLC. HPLC indicated complete cleavage at OC for 30 minutes. The reaction was diluted with brine and CH.sub.2Cl.sub.2, mixture was extracted three times with CHsCl.sub.2, dried over MgSO.sub.4 and reduced in vacuo. The crude aldehyde was redissolved in EtOH (56 ml), sodium borohydride (0.422 g, 11.2 mmol) was added as a solid and the mixture was stirred at room temperature. The reduction was completed in 3 min. 7 〇 ml) to stop the reaction, and the mixture was reduced to a paste in vacuo. The resultant was diluted with water (35 〇ml) and iPrOAc. The mixture was extracted 3 times with iPr 〇Ac, washed with brine, dried over MgS 〇4 Filtration and reduction in vacuo. The crude product was purified by chromatography eluting with 40% EtOAc: hexanes. </ RTI> </ RTI> Preparation Example 3 Preparation of racemic trans-4-[2-(2-hydroxyethyl) Tert-butyl]cyclopropyl]piperidinic acid tert-butyl ester, ie (4·[(1Λ,2/?)-2-(2-hydroxyethyl)cyclopropyl]piperidine-stra-carboxylic acid second Butyl ester and 4-[(lS,2&gt;S)-2-(2.hydroxyethyl)cyclopropyl]bendidine·p-tert-butyl formate) Step 1: 4-[(1Ε)-3-A oxygen 3-oxo-propenyl-4 - yl] piperidine-carboxylic acid tert-butyl ester

141275.doc •54- 201102374 將氯化鋰（1.013 g，j.23當量）懸浮於1〇〇 mL HPLC級乙 腈中。在室溫下緩慢添加（二乙氧基磷醯基）乙酸甲酯（433 g ’ 1·〇6當量）’接著添加DBU(3 M g，丨〇6當量）及於乙猜 (,mL)中之所私示之市售酸（414g，^當量）。在室溫下攪 拌混a物3小¥。在真空中移除過量溶劑。用水（1⑼mL) 稀釋&amp;餘物且用乙趟（5〇 mLx3)萃取。經硫酸鈉乾燥合併 之有機層，過濾且濃縮，得到呈淺黃色油狀之粗酯，其不 經進一步純化即用於下一步驟中。 步驟2 · 4-[(1五)-3-羥基丙稀基]哌啶i甲酸第三丁酯141275.doc •54- 201102374 Lithium chloride (1.013 g, j.23 equivalent) was suspended in 1 mL of HPLC grade acetonitrile. Methyl (diethoxyphosphonio)acetate (433 g '1·〇6 equivalent) was added slowly at room temperature followed by DBU (3 M g, 丨〇 6 equivalents) and B guess (, mL) Commercially available acid (414 g, ^ equivalent) sold by the company. Stir a mixture of 3 small ¥ at room temperature. Excess solvent was removed in vacuo. The &amp; residue was diluted with water (1 (9) mL) and extracted with acetonitrile (5 〇 mL x 3). The combined organic layers were dried with EtOAc EtOAc m. Step 2 · 4-[(1,5)-3-hydroxypropyl]piperidine icarboxylic acid tert-butyl ester

在氬氣氛圍下在-78°C下經20分鐘經由加料漏斗將於二 氯曱烷（42mL，2.2當量）中之丄MDiBA1_H緩慢添加至來自 該實例之步驟1之α，β-不飽和酯（514 g，丨當量）於無水 DCM(H)〇 mL)中之充分攪拌之溶液中。添加完成後將所得 溶液溫至〇 C且使其在該溫度下保持3 〇分鐘。將反應再冷 卻至-78°C且緩慢添加4 mL MeOH以使過量DiBANH中止反 應。在-78°C下進一步攪拌***液10分鐘，之後傾倒至15〇 mL飽和羅謝爾鹽（Rochelle salt)(酒石酸鉀鈉）水溶液中。在 室溫下劇烈攪拌混合物3小時直至其變澄清。分離有機 層’經硫酸納乾燥’過濾且在真空中濃縮。藉由管柱層析 使用丙酮/己烷（20°/〇，等度）進一步純化殘餘物，得到呈無 色油狀之所要產物。 步驟3 :心[(1五)-3-(苄基氧基）丙烯a —基]哌啶小甲酸第 141275.doc -55- 201102374 三丁酯The oxime MDiBA1_H in dichloromethane (42 mL, 2.2 eq.) was slowly added to the α,β-unsaturated ester from step 1 of this example via an addition funnel at -78 ° C for 20 min under argon. (514 g, 丨 equivalent) in a well stirred solution of anhydrous DCM (H) 〇 mL). After the addition was completed, the resulting solution was warmed to 〇 C and allowed to stand at this temperature for 3 Torr. The reaction was again cooled to -78 °C and 4 mL of MeOH was slowly added to quench the excess of Di. The cold solution was further stirred at -78 °C for 10 minutes and then poured into 15 mL of a saturated aqueous solution of Rochelle salt (sodium potassium tartrate). The mixture was vigorously stirred at room temperature for 3 hours until it became clear. The organic layer was separated and dried <RTI ID=0.0> The residue was further purified by column chromatography using EtOAc/hexanes (20° / EtOAc). Step 3: Heart [(1,5)-3-(benzyloxy)propene a-yl]piperidine-less formic acid 141275.doc -55- 201102374 Tributyl ester

將氫化鈉（60%(於礦物油中），2.73 g，l.i當量）懸浮於無 水DMF(180 mL)中且冷卻至(TC。緩慢添加於無水dmf(2〇 mL)中之來自該實例之步驟2之烯丙醇（15 g，1當量）。在氮 氣氣圍下在室溫下授拌混合物15分鐘。隨後逐滴添加节基 溴（8.13 mL，1.1當量）。在室溫下攪拌混合物2小時。用 300 mL水及200 mL EtOAc稀釋反應。分離水層且使用 EtOAc(50 mLx2)萃取兩次。經硫酸鈉乾燥合併之有機層， 濃縮且藉由用EtOAc/己烷（1 5% ’等度）溶離進行管柱層析 而純化’得到呈無色油狀之所要苄基醚。 步驟4 :外消旋反式-4-{2-[(苄基氧基）甲基]環丙基}哌啶 甲酸第三丁酯，亦即（4-{(ΐ5,2Λ)-2-丨（苄基氧基）甲基】環丙 基}哌啶-1-曱酸第三丁酯及4-{(1及，25)-2·[(苄基氧基）甲基】 環丙基}娘咬-1-甲酸第三丁酯）Sodium hydride (60% (in mineral oil), 2.73 g, li equivalent) was suspended in dry DMF (180 mL) and cooled to (TC) slowly added to anhydrous dmf (2 mL) from this example Step 2 of allyl alcohol (15 g, 1 eq.). Mix the mixture for 15 minutes at room temperature under nitrogen atmosphere. Then add the benzyl bromide (8.13 mL, 1.1 eq.) dropwise. The reaction was diluted with EtOAc / EtOAc (EtOAc) 'Isocratic' lyophilization by column chromatography to purify 'to give the desired benzyl ether as a colorless oil. Step 4: racemic trans-4-{2-[(benzyloxy)methyl]cyclopropane Tert-butyl piperidinecarboxylic acid, ie (4-{(ΐ5,2Λ)-2-丨(benzyloxy)methyl]cyclopropyl}piperidine-1-decanoic acid tert-butyl ester and 4-{(1 and,25)-2·[(benzyloxy)methyl]cyclopropyl}nivine bite-1-butylic acid tert-butyl ester)

將500 mL圓底燒瓶中之無水二氣乙烷（13〇 mL)脫氣且用 氬氣回填三次。在氬氣下經由注射器快速添加二乙基鋅（1 Μ(於DCM中），87 mL，5當量）。將溶液冷卻至·18。〇。經 由注射器以使内部溫度保持在_丨〇。〇以下之速率添加氣碘 甲烷（12.61 mL，10當量）。在·18〇c下攪拌反應混合物1〇分 鐘。觀察到白色沈澱物。緩慢添加於無水DCE(3() mL)中之 141275.doc •56- 201102374 來自該實例之步驟3之經苄基保護之烯丙醇（6 g，1當量）， 同時維持内部溫度在-5°C以下。在_18。(：下攪拌反應且由 LC-MS監測。反應通常在10-30分鐘内完成。完成後，趁 冷用100 mL飽和氯化銨水溶液及50 mL 28%氫氧化銨水溶 液中止反應。將混合物溫至室溫且劇烈攪拌直至兩相變得 澄清。分離有機相’經硫酸鈉乾燥，濃縮且藉由用EtOAc/ 己烧（15 % ’等度）溶離進行管柱層析而純化，得到呈無色 油狀之產物。 步驟5 :外消旋反式_4-[2-(羥基甲基）環丙基】哌啶甲酸 第三丁酯，亦即4-[(lS，2/〇-2-(羥基曱基）環丙基]哌啶甲 酸第三丁酯及4-[(li?，2S)-2-(羥基甲基）環丙基]哌啶-i-甲酸 第三丁酯Anhydrous dioxane (13 〇 mL) in a 500 mL round bottom flask was degassed and backfilled three times with argon. Diethylzinc (1 Torr (in DCM), 87 mL, 5 eq.) was quickly added via syringe under argon. The solution was cooled to ·18. Hey. The syringe is used to maintain the internal temperature at _丨〇. Gas iodine methane (12.61 mL, 10 eq.) was added at the following rate. The reaction mixture was stirred at -18 ° C for 1 Torr. A white precipitate was observed. Slowly added to anhydrous DCE (3 () mL) 141275.doc • 56- 201102374 benzyl protected allyl alcohol (6 g, 1 equivalent) from step 3 of this example while maintaining internal temperature at -5 Below °C. At _18. (The reaction was stirred and monitored by LC-MS. The reaction was usually completed in 10-30 minutes. After completion, the reaction was quenched with 100 mL of a saturated aqueous solution of ammonium chloride and 50 mL of a 28% aqueous solution of ammonium hydroxide. Stir to room temperature with vigorous stirring until the two phases became clear. The organic phase was separated and dried over sodium sulfate, concentrated and purified by column chromatography eluting with EtOAc / hexane (15% &lt;RTIgt; Oily product. Step 5: Racemic trans-4-butyryl 4-[2-(hydroxymethyl)cyclopropyl]piperidinecarboxylic acid, ie 4-[(lS,2/〇-2- (Hydroxymethyl)cyclopropyl]piperidinecarboxylic acid tert-butyl ester and 4-[(li?,2S)-2-(hydroxymethyl)cyclopropyl]piperidine-i-carboxylic acid tert-butyl ester

將來自該實例之步驟4之經苄基保護之羥基乙基環丙烷 (6 g，1當量）溶解於HPLC級EtOAc(75 mL)與乙醇（75 mL) 之混合物中。將溶液脫氣且用氮氣回填，之後添加 Pd(OH)2(20重量％(於碳上），2.34 g，0.2當量）。將反應容 器脫氣且用氫氣回填三次。在1 L氫氣球下劇烈攪拌反應 混合物且由LC-MS監測。通常在2小時内完成去保護。隨 後經矽膠塞（100 g)過濾混合物且用50% EtOAc/己烷（1 L) 充分洗滌。濃縮得到呈無色油狀之環丙醇。 步驟6 :反式外消旋4-(2-曱醯基環丙基）哌啶-1-甲酸第三丁 Γ 141275.doc •57- 201102374 酯，亦即4-[(l*S，2i?)-2-甲醯基環丙基]哌啶+曱酸第三丁 S旨及4-((11^,25)-2-曱酿基環丙基]旅咬_ι_曱酸第三丁醋The benzyl protected hydroxyethylcyclopropane (6 g, 1 eq.) from step 4 of this example was dissolved in a mixture of HPLC grade EtOAc (75 mL) and ethanol (75 mL). The solution was degassed and backfilled with nitrogen, then Pd(OH)2 (20% by weight (on carbon), 2.34 g, 0.2 eq.) was added. The reaction vessel was degassed and backfilled three times with hydrogen. The reaction mixture was stirred vigorously under a 1 L hydrogen balloon and was monitored by LC-MS. Deprotection is usually completed within 2 hours. The mixture was then filtered through a pad (100 g) and washed thoroughly with 50% EtOAc/hexanes (1 L). Concentration gave cyclopropanol as a colorless oil. Step 6: trans-racemic 4-(2-amidocyclopropyl)piperidine-1-carboxylic acid tert-butyl 141275.doc •57- 201102374 ester, ie 4-[(l*S,2i ?)-2-Methoxymethylcyclopropyl]piperidine + decanoic acid third butyl S and 4-((11^,25)-2-fluorenylcyclopropyl] brigade bit _ι_ citrate Tributyl vinegar

在室溫下在氮氣下將來自該實例之步驟5之經基乙基環 丙烷（9 g，1當量）、粉狀4 A活化分子篩（18 §)及义曱基嗎 琳氧化物（6.19 g，1.5當量）之混合物在無水dcm(200 中攪拌15分鐘。整份添加TPAP(1.24 g，（Μ當量反應放 熱且有時使用冰浴維持内部溫度為約室溫。在室溫下授摔 混合物1小時。用500 mL***稀釋反應且攪拌1〇分鐘。經 矽膠塞（200 g)過濾混合物，用50%丙酮/己烷（2 l)充分洗務 該矽膠塞。濃縮得到呈無色油狀之醛。 步驟7 :外消旋反式_4-(2-乙烯基環丙基）哌啶4-甲酸第三 丁酯’亦即4-((15,25)-2-乙稀基環丙基】略咬_1_甲酸第三丁 Sa及4-【（1及，2及)-2-乙稀基環丙基]略咬_ι_甲酸第三丁醋The ethylethylcyclopropane (9 g, 1 eq.) from the step 5 of this example, powdered 4 A activated molecular sieve (18 §) and hydrazine carbaryl oxide (6.19 g) at room temperature under nitrogen. , 1.5 equivalents of the mixture was stirred in anhydrous dcm (200 ° for 15 minutes. Add TPAP (1.24 g, Μ equivalent reaction exotherm and sometimes use an ice bath to maintain the internal temperature at about room temperature. The reaction was diluted with 500 mL of diethyl ether and stirred for 1 hr. The mixture was filtered through a pad (200 g), and the gelatin plug was washed thoroughly with 50% acetone/hexane (2 l) to give a colorless oil. Aldehyde. Step 7: Racemic trans-4-(2-vinylcyclopropyl)piperidine 4-carboxylic acid tert-butyl ester'. 4-((15,25)-2-Ethylcyclopropane Base] slightly bite _1_ formic acid third butyl Sa and 4-[(1 and, 2 and)-2-ethlylcyclopropyl] slightly bite _ι_carboxylic acid third vinegar

在氮氣下將碘化三笨基曱基鱗（1.92 g，1.2當量）懸浮於 無水THF(7 mL)中且冷卻至-78°C。緩慢添加n-BuLi(1.6 Μ ’ 2·84 mL，1.15當量）且攪拌混合物15分鐘。懸浮液變 成黃色。緩慢添加於無水THF(3 mL)中的來自該實例之步 驟6之搭（1 g ’ 1當量八將反應溫至室溫且攪拌3〇分鐘。添 加飽和氯化銨水溶液。用EtOAc萃取水層兩次。經硫酸鈉 14I275.doc -58- 201102374 乾燥合併之萃取物，濃縮且藉由用謝以己烷(i5%，等 度）溶離進行管柱層析而純化，得到呈無色油狀之所 烴。 ’ 步驟8 .外消旋反式-4·[2-(2-經基乙基）環丙基】錢]•子酸 第一丁知，亦即4-[(1及，2/?)-2-(2-羥基乙基）環丙基】哌啶]· 甲酸第三丁醋及4·[⑽叫2_(2_經基乙基）環丙基]派咬小 甲酸第三丁酯The triiodide iodide scale (1.92 g, 1.2 eq.) was suspended in anhydrous THF (7 mL) and cooled to -78. n-BuLi (1.6 Μ' 2·84 mL, 1.15 eq.) was slowly added and the mixture was stirred for 15 minutes. The suspension turned yellow. Slowly add to step 6 of this example in anhydrous THF (3 mL) (1 g '1 eq. s.. warm to room temperature and stir for 3 hrs. Add saturated aqueous ammonium chloride. Extract aqueous layer with EtOAc The extracts were dried over sodium sulphate 14I 275.doc - 58 - 201102374, concentrated and purified by column chromatography eluting with hexane (i 5%, isocratic) to give a colorless oil. Hydrocarbons. 'Step 8. Racemic trans-4·[2-(2-transethylethyl)cyclopropyl] Qian]•Sub-acid first known, ie 4-[(1 and, 2 /?)-2-(2-hydroxyethyl)cyclopropyl]piperidine]·carboxylic acid tert-butyl vinegar and 4·[(10) is called 2_(2_ylidylethyl)cyclopropyl] Tributyl ester

0 BH3Me；S, THF0 BH3Me;S, THF

NaOH, H2〇2 硼烧二甲基硫醚複合物（l.o μ(於THF中），0.7 mL，ο 5 當量）溶解於無水THF(2 mL)中且在〇°C下冷卻。緩慢添加 於無水THF(0.8 mL)中的來自該實例之步驟7之烯烴（35〇 mg ’ 1當量）。在室溫下授拌混合物2小時。極緩慢地添加 氫氧化鈉水溶液（5 Μ，1.5 mL) ^觀察到顯著的氣體逸 出。根據需要使用冰浴冷卻反應容器。緩慢添加過氧化氫 溶液（3 0°/。，1.3 9 mL) ^在室溫下攪拌混合物2小時。添加 水（3 mL)。用EtOAc萃取混合物三次。用鹽水洗滌合併之 有機層，經琉酸鈉乾燥’濃縮且藉由管柱層析使用EtOAc/ 己烷（40% ’等度）進行純化，得到呈無色油狀之所要之最 終產物。 製備實例4 製備外消旋反式-4-U2-(羥基甲基）環丙基】曱基}哌啶-1-曱 酸第三丁酯，亦即4-{[(1/?，2/〇-2-(羥基甲基）環丙基]曱基} 141275.doc -59- 201102374NaOH, H 2 〇 2 Boron-burned dimethyl sulfide complex (1.o μ (in THF), 0.7 mL, ο 5 eq) was dissolved in dry THF (2 mL) and cooled at EtOAc. The olefin from step 7 of this example (35 〇 mg '1 equivalent) was added slowly in anhydrous THF (0.8 mL). The mixture was stirred for 2 hours at room temperature. Very little aqueous sodium hydroxide solution (5 Μ, 1.5 mL) was added very slowly ^ significant gas evolution was observed. The reaction vessel was cooled using an ice bath as needed. Hydrogen peroxide solution (30 °/., 1.3 9 mL) was slowly added. The mixture was stirred at room temperature for 2 hours. Add water (3 mL). The mixture was extracted three times with EtOAc. The combined organics were washed with EtOAc (EtOAc m. Preparation Example 4 Preparation of racemic trans-4-U2-(hydroxymethyl)cyclopropyl]decyl}piperidine-1-decanoic acid tert-butyl ester, ie 4-{[(1/?, 2 /〇-2-(hydroxymethyl)cyclopropyl]fluorenyl} 141275.doc -59- 201102374

甲基}哌啶-1-甲酸第三丁酯Methyl}piperidine-1-carboxylic acid tert-butyl ester

ΛΛΛΛ

根據類似於如以上流程中指示之實例3步驟1 _ 5之製備的 途徑自4_(2_側氧基乙基）哌啶曱酸第三丁酯製備標題化 合物。 用對掌性固定相分離對映異構體 4-{[(18,28)-2-(經基甲基）環丙基]甲基}派咬_1-甲酸第三丁 酿及4-{[(lR，2R)-2-(輕基甲基）環丙基]甲基）略咬4甲酸第 三丁酯The title compound was prepared from 4-(2-hydroxyethyl)piperidinic acid tert-butyl ester according to a procedure similar to the procedure of Example 3 Steps 1 - 5 as indicated in the above. Separation of the enantiomer 4-{[(18,28)-2-(radiomethyl)cyclopropyl]methyl}-p-_1-carboxylic acid to the third palm and 4- {[(lR, 2R)-2-(Light-methyl)cyclopropyl]methyl) slightly bite 4 butyl terephthalate

藉由在 SFC條件（50mL/min，1〇〇 巴，i2%Me0H/C02)下 在35°C下用chiralpak IA 21.2x250 mm拆分外消旋反式-4- {[2-(羥基甲基）環丙基]甲基}哌啶曱酸第三丁酯獲得標 題對映異構體。滯留時間：較快對映異構體（4-{[(lS，2S)-2-(羥基甲基）環丙基]甲基}哌啶·1-甲酸第三丁酯）：Τ=2·89 141275.doc •60· 201102374 分鐘；較慢對映異構體（4-{[(lR，2R)-2-(羥基甲基）環丙基] 曱基}哌啶-1-甲酸第三丁酯）：τ=3.43分鐘。 製備實例5 製備外消旋順式_心{[2-(羥基甲基）環丙基]甲基}哌啶-1-甲 酸第三丁酯，亦即4-{[(15·，27?)-2-(羥基甲基）環丙基]甲基} 哌啶-1-甲酸第三丁酯及4-{[(1及，2*5)-2-(羥基甲基）環丙基】 甲基}哌啶-1-甲酸第三丁酯 步驟1 : 4-(3,3-二漠丙-2-稀-1-基）旅咬·ι_甲酸第三丁醋Resolution of racemic trans-4-{[2-(hydroxyl) by chiralpak IA 21.2x250 mm at 35 °C under SFC conditions (50 mL/min, 1 Torr, i2% Me0H/C02) The titled enantiomer is obtained as the titled butyl propyl]methyl}piperidinic acid tert-butyl ester. Residence time: faster enantiomer (4-{[(lS,2S)-2-(hydroxymethyl)cyclopropyl]methyl}piperidine·1-carboxylic acid tert-butyl ester): Τ=2 · 89 141275.doc •60· 201102374 min; slower enantiomer (4-{[(lR,2R)-2-(hydroxymethyl)cyclopropyl]indolyl}piperidine-1-carboxylic acid Tributyl ester): τ = 3.43 minutes. Preparation Example 5 Preparation of racemic cis-heart {[2-(hydroxymethyl)cyclopropyl]methyl}piperidine-1-carboxylic acid tert-butyl ester, ie 4-{[(15·,27? -2-(hydroxymethyl)cyclopropyl]methyl} piperidine-1-carboxylic acid tert-butyl ester and 4-{[(1 and, 2*5)-2-(hydroxymethyl)cyclopropyl 】 methyl} piperidine-1-carboxylic acid tert-butyl ester step 1: 4-(3,3-di-dipropyl-propyl-1-yl-1-yl) brigade bite ι_carboxylic acid third vinegar

OHCOHC

rr-n3, UDi4Rr-n3, UDi4

將四溴化碳（46.7 g，141 mmol)溶解於200 mL二氯甲烧 中。在冰水浴中冷卻溶液且經20分鐘經由加料漏斗引入於 200 mL二氯曱烷中之三苯基膦（73.9 g，282 mm〇1)。在〇t 下攪拌反應混合物10分鐘且經由加料漏斗添加4_(2•侧氧基 乙基）派咬-1·甲酸第三丁醋（16 g，7〇 4 mm〇1)M1〇〇 mL: 氯曱烷中之溶液。在0°C下攪拌溶液丨小時。添加水（25c mL)且用H)0 mL二氯曱烧萃取水層3次。用鹽水洗蘇合併 之有機層’經輕鈉乾燥，過渡且濃縮。向殘餘物中添加 3〇〇mL乙趟’且過滤所得懸料。用i5〇mL乙趟洗務固體 3次。濃縮合併之滤液且穿過㈣塞，用1()%丙_/己&amp;充 分洗蘇，得到黃色油狀物，其不經進—步純化即使用。 步驟Π(4_經基丁…·基)娘嚏小甲酸第三丁醋 (CH20)n1n-8uLjCarbon tetrabromide (46.7 g, 141 mmol) was dissolved in 200 mL of dichloromethane. The solution was cooled in an ice water bath and triphenylphosphine (73.9 g, 282 mm 〇1) was taken in 200 mL of dichloromethane. The reaction mixture was stirred at 〇t for 10 min and added 4_(2• ethoxyethyl)-spotted-1·carboxylic acid tert-butyl succinate (16 g, 7 〇 4 mm 〇1) M1 〇〇 mL via the addition funnel: a solution in chlorodecane. The solution was stirred at 0 ° C for a few hours. Water (25 c mL) was added and the aqueous layer was extracted 3 times with H) 0 mL dichloromethane. The organic layer combined with brine was dried by light sodium, and the mixture was concentrated. 3 mL of acetamidine was added to the residue and the resulting suspension was filtered. The solid was washed 3 times with i5 〇 mL acetonitrile. The combined filtrate was concentrated and passed through a (4) plug and washed with 1 (%) hexanes to afford a yellow oil which was used without further purification. Step Π(4_ via Keding...·base) Niangzi small formic acid third vinegar (CH20)n1n-8uLj

Br 141275.doc •61 · 201102374 ,3 - —漠丙-2 -稀-1-基）旅咬-Br 141275.doc •61 · 201102374 ,3 --- Desert C - 2 - Dil - 1 -) Bite -

將來自該實例之步驟丨之4_(3 1-曱酸第三丁酯（19.5 g，50.9 m 且冷卻至-78°C。緩慢添加n_Bu 拌1小時。添加飽和氯化銨水溶液，且用乙酸乙酯萃取水 層3次。用30%丙酮/己烷溶離進行管柱層析，得到呈無色 油狀之產物。 步驟3 : 4-【(2Z)-4-羥基丁 ^-烯^•基】哌啶甲酸第三丁酯From the step of this example, 4_(3-1-decanoic acid tert-butyl ester (19.5 g, 50.9 m and cooled to -78 ° C. Slowly add n_Bu for 1 hour. Add saturated aqueous ammonium chloride solution, and use acetic acid The aqueous layer was extracted three times with ethyl acetate. Chromatography was carried out with 30% acetone/hexanes to give the product as a colorless oil. Step 3: 4-[(2Z)-4-hydroxybutene-ene TP piperidinecarboxylic acid tert-butyl ester

將來自該實例之步驟2之4-(4-羥基丁 -2-炔-1 -基）派啶-；1 -曱酸第三丁酯（10.6 g’ 41.8 mmol)溶解於200 mL MeOH中 且添加 3，6-二硫雜·1，8'辛二醇（191 mg，1.05 mmol)，接著 添加琳德拉催化劑（5重量/重量％，4.45 g，2· 1 mmol) °將 反應容器脫氣且用氫氣回填3次，且在室溫下在氫氣球下 進一步攪拌1小時。經矽藻土過濾反應且在真空下濃縮， 得到呈無色油狀之粗產物，其直接用於下一步驟中。 步驟4-8 :製備外消旋順式-4-{[2-(羥基曱基）環丙基]甲基} 哌啶-1-甲酸第三丁酯，亦即4-{[(1心2及）-2-(羥基甲基）環丙 基】曱基}哌啶-1-甲酸第三丁酯及4-{[(1/?，2&lt;?〇-2-(羥基甲基） 環丙基】曱基}哌啶-1-甲酸第三丁酯 141275.doc • 62 - 2011023744-(4-Hydroxybut-2-yn-1-yl)pyridinyl-l-decanoic acid tert-butyl ester (10.6 g '41.8 mmol) from step 2 of this example was dissolved in 200 mL MeOH. Add 3,6-dithia-1,8'octanediol (191 mg, 1.05 mmol), then add Lindera catalyst (5 wt/wt%, 4.45 g, 2.1 mmol) ° The gas was backfilled 3 times with hydrogen and further stirred under a hydrogen balloon at room temperature for 1 hour. The reaction was filtered through EtOAc (EtOAc)EtOAc. Step 4-8: Preparation of racemic cis-4-([2-(hydroxyindenyl)cyclopropyl]methyl}piperidine-1-carboxylic acid tert-butyl ester, ie 4-{[(1 heart) 2 and) 2-(hydroxymethyl)cyclopropyl]decyl}piperidine-1-carboxylic acid tert-butyl ester and 4-{[(1/?,2&lt;?〇-2-(hydroxymethyl) Cyclopropyl]decyl}piperidine-1-carboxylic acid tert-butyl ester 141275.doc • 62 - 201102374

Et2Zn, CICH2I 備的程 丁酯製 根據類似於以上流程中指示之實例3步驟35之製備 序由4-[(2Z)-4-羥基丁 -2-烯-1-基]哌啶曱酸第三丁 備標題化合物。 實例6 製備外消旋順式-5-氯-2-[4-(2-{2-[4-(甲基磺醯基）苯氧基】 乙基}環丙基）哌啶-1-基】嘧啶，亦即5_氯_2_【4_((18,2” 2_ {2-[4-(甲基磺醯基）苯氧基]乙基}環丙基）哌啶·i基]嘧啶及 5-氣_2-[4-((lR，2S)-2-{2-[4-(甲基磺醯基）苯氧基】乙基}環丙 基）哌啶-1-基】嘧啶 步驟1 :製備2,5-二氯嘧啶The preparation of Et2Zn, CICH2I was carried out according to the procedure of Example 3, Step 35, as indicated in the above scheme, from 4-[(2Z)-4-hydroxybut-2-en-1-yl]piperidinic acid The third compound is the title compound. Example 6 Preparation of racemic cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1- Pyrimidine, ie 5_chloro_2_[4_((18,2" 2_ {2-[4-(methylsulfonyl)phenoxy)ethyl}cyclopropyl)piperidine·i] Pyrimidine and 5-gas_2-[4-((lR,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl Pyrimidine Step 1: Preparation of 2,5-dichloropyrimidine

將 2,4,5-二氣嘧啶（25 g，136 mmol)與鋅（26.7 g，409 mmol，顆粒狀）混合且添加THF〇〇〇 ml)。在室溫下攪拌漿 液，添加冰乙酸（11.7 m卜204 mmol)且在回流下加熱混合 物2小時。將混合物冷卻至室溫，用DCM(1〇〇 m][)稀釋且經 矽藻土過濾。隨後在真空中濃縮溶液。將粗物質溶解於 DCM(lOOml)中，以小份添加飽和NaHC〇3且震盪至水相之 pH值為8。隨後使用1 n NaOH(水溶液）調整PH值至1〇，震 盪且分離各層。經MgS〇4乾燥有機部分，過濾且在真空中 141275.doc -63· 201102374 移除揮發性物質.藉由用2%Et0Ac:己烷溶離進行si〇2層 析來純化該物質。 步驟2 :外消旋順式氯嘧啶_2_基）哌啶_4_基】環 丙基}乙醇 ΗΟ2,4,5-Di-pyrimidine (25 g, 136 mmol) was mixed with zinc (26.7 g, 409 mmol, granules) and THF (ml) was added. The slurry was stirred at room temperature, glacial acetic acid (11.7 m, 204 mmol) was then weighed and the The mixture was cooled to room temperature, diluted with DCM (1 EtOAc) and filtered over EtOAc. The solution was then concentrated in vacuo. The crude material was dissolved in DCM (100 ml), saturated NaHC?3 was added in small portions, and the pH was shaken to pH 8. The pH was then adjusted to 1 Torr using 1 n NaOH (aq.), shaken and the layers separated. The organic portion was dried over <RTI ID=0.0>M </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: Racemic cis-chloropyrimidin-2-yl)piperidine _4_yl]cyclopropyl}ethanol ΗΟ

i: TFA ii： Cs2C03 二氣嘧啶i: TFA ii: Cs2C03 di-pyrimidine

將來自實例2之步騾4之4-卜2-(2-羥基乙基）環丙基]哌啶· 1-曱酸第三丁酯（1.07 g，3.95 mmol)溶解於DCM(2〇 ml)中 且冷卻至o°c。逐滴添加過量TFA(20 mi)且在下攪拌溶 液3〇分鐘。HPLC-MS展示未餘留SM。在真空下移除揮發 性物質。藉由自DCM汽提兩次，接著在真空中乾燥進—步 移除殘餘TFA。將所得物質轉移至梨形燒瓶之dcm中且= 真空中移除揮發性物質。 將粗哌啶與來自該實例之步驟丨之二氯嘧啶（〇.59呂， 3.95 mm〇l)—起溶解於DMF(9 ml，〇44 m)中且添加碳趣 铯（7.08 g，21.7 _。卜5.5當量）。在室溫下授掉混合啦 6.0小時。將混合物傾入15〇⑹水中且用ίρΓ〇Α。瓜】 萃取。用鹽水洗務有機相，經ν_〇4乾燥，過滤且汽提。 藉由用4G% Et〇Ae:己烧溶離進行Si〇2管柱層析來純化米 物質。LRMS計算值：2811 ;實測值：282 2 (m+i)。 步称2b : 2-{(1S，2RM_u_(5_氯較_2·基）派咬*基]環这 基}乙醇 141275.doc -64 - 2011023744-B 2-(2-hydroxyethyl)cyclopropyl]piperidine 1-decanoic acid tert-butyl ester (1.07 g, 3.95 mmol) from Step 4 of Example 2 was dissolved in DCM (2 mL) ) and cooled to o ° c. Excess TFA (20 mi) was added dropwise and the solution was stirred for 3 min. HPLC-MS showed no remaining SM. Remove volatiles under vacuum. The residual TFA was removed by stripping twice from DCM followed by drying in vacuo. The resulting material was transferred to dcm in a pear shaped flask and = volatiles were removed in vacuo. The crude piperidine was dissolved in DMF (9 ml, 〇44 m) from the dichloropyrimidine (〇.59 ly, 3.95 mm 〇l) from the procedure of this example and carbon was added (7.08 g, 21.7). _. Bu 5.5 equivalent). The mixture was allowed to stand at room temperature for 6.0 hours. Pour the mixture into 15 〇 (6) water and use ίρΓ〇Α. Melon] Extraction. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated. The rice material was purified by Si〇2 column chromatography using 4G% Et〇Ae: hexane. Calculated for LRMS: 2811; found: 282 2 (m+i). Step 2b: 2-{(1S, 2RM_u_(5_氯比_2·基)) bite * base] ring base} ethanol 141275.doc -64 - 201102374

i: TFAi: TFA

ii: Cs2C03 二氣嘧啶Ii: Cs2C03 di-pyrimidine

將來自實例2之步驟4之4_[(1r，2S)_2_(2·羥基乙基）環丙 基]哌啶-1-甲酸第三丁酯（1 〇7 g，3.95随〇1)溶解於 DCM(20 ml)中且冷卻至〇乞。逐滴添加過量TFA(2〇如）且 在〇 C下攪拌溶液30分鐘。在真空下移除揮發性物質。藉 由自DCM汽提兩次，接著在真空中乾燥進一步移除殘餘 TFA。將所得物質轉移至梨形燒瓶之DCM中且在真空中移 除揮發性物質。 將粗哌啶與來自該實例之步驟丨之二氯嘧啶59 g， 3.95 mmol)—起溶解於DMF(9 〇44 M)中且添加碳酸 鉋（7.08 g，21_7 nmol，5.5當量在室溫下攪拌混合物 6.0小時。將混合物傾入150爪丨水中且用ipr〇Ac(3xi〇〇 μ) 萃取。用鹽水洗滌有機相，經NhSO4乾燥，過濾且汽提。 藉由用40% Et0Ac:己烷溶離進行Si〇2管柱層析而純化粗 物質。LRMS計算值：281.1 ;實測值：282 2 (M+1)。 步驟3 :外消旋順式_5·氯_2-[4_(2_{2_[4_(甲基磺醯基）苯氧 基】乙基}環丙基）哌啶-1-基】嘧啶，亦即5_氯·2_[4_((1S，2R)_ 2-{2-[4-(甲基續酿基）苯氧基】乙基}環丙基）哌啶4基】嘧啶 及5-氣-2-[4-((1R，2S)-2-{2-[4-(甲基磺醯基）苯氧基】乙基}環4_[(1r,2S)_2_(2.hydroxyethyl)cyclopropyl]piperidine-1-carboxylic acid tert-butyl ester (1 〇7 g, 3.95 with 〇1) from step 4 of Example 2 was dissolved in In DCM (20 ml) and cooled to 〇乞. Excess TFA (2 for example) was added dropwise and the solution was stirred at 〇 C for 30 minutes. The volatiles were removed under vacuum. The residual TFA was further removed by stripping twice from DCM followed by drying in vacuo. The resulting material was transferred to DCM in a pear-shaped flask and volatiles were removed in vacuo. The crude piperidine was dissolved in DMF (9 〇 44 M) from the dichloropyrimidine 59 g, 3.95 mmol) from the step of this example and added with carbonic acid planer (7.08 g, 21_7 nmol, 5.5 equivalents at room temperature). The mixture was stirred for 6.0 hours. The mixture was poured into 150-claw water and extracted with ipr 〇Ac (3 πμμ). The organic phase was washed with brine, dried over NhSO4, filtered and evaporated. The crude material was purified by EtOAc (EtOAc): EtOAc: EtOAc: EtOAc: {2_[4_(Methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, ie 5_chloro·2_[4_((1S,2R)_ 2-{ 2-[4-(methyl aryl)phenoxy]ethyl}cyclopropyl)piperidine-4-yl]pyrimidine and 5-gas-2-[4-((1R,2S)-2-{2 -[4-(methylsulfonyl)phenoxy]ethyl} ring

I 丙基）旅咬-1-基]喷咬I propyl) travel bite-1-base] spray bite

141275.doc •65- 201102374 將來自該實例之步驟2之外消旋2-{2-[ 1-(5-氯嘧啶-2-基） 哌啶_4_基]環丙基}乙醇（4〇 mg，0.142 mmol)、聚合物支撐 之三苯基膦（3 mmol/g，177 mg，0.532 mmol)及 4-(曱基磺 醯基）酚（29.3 mg，0.17 mmol)混合於3 mL二氯曱烷及 THF( 1:1)中。將混合物冷卻至〇°c且添加db AD。移除冷卻 浴且撥拌反應1小時。藉由過濾移除聚合物且用丙酮充分 洗蘇。濃縮濾液且藉由經24公克矽膠筒用15-30% EtOAc/ 己烧溶離進行管柱層析而純化，得到呈白色固體狀之產 物。LRMS計算值：435.1 ;實測值：436.6 (M+1)。 實例6a 製借外消旋順式-5-氣-2-{4-[2-(2-{【5-(甲基磺醯基比啶-2-基】氧基}乙基）環丙基]派咬-1-基}喷咬141275.doc •65- 201102374 Racemic 2-{2-[ 1-(5-chloropyrimidin-2-yl)piperidinyl-4-yl]cyclopropyl}ethanol from step 2 of this example (4 〇mg, 0.142 mmol), polymer supported triphenylphosphine (3 mmol/g, 177 mg, 0.532 mmol) and 4-(nonylsulfonyl)phenol (29.3 mg, 0.17 mmol) in 3 mL In chlorodecane and THF (1:1). The mixture was cooled to 〇 ° c and db AD was added. The cooling bath was removed and the reaction was stirred for 1 hour. The polymer was removed by filtration and fully washed with acetone. The filtrate was concentrated and purified by column chromatography eluting with EtOAc (EtOAc) Calculated for LRMS: 435.1; found: 436.6 (M+1). Example 6a Preparation of racemic cis-5-gas-2-{4-[2-(2-{[5-(methylsulfanylpyridin-2-yl)oxy}ethyl)cyclopropane Base]

將來自實例6步驟2之外消旋順式_2-{2-[1-(5-氯嘧啶-2-基）π底咬-4-基]環丙基}乙醇（338 mg，1，2 mmol)溶解於 DMF(0.7 ml ’ 0.38 M)中。添加NaH(600/〇(於油中），144 mg ’ 3.6 mm〇l)且在室溫下攪拌混合物1〇分鐘。添加2溴-5-(曱基績酿基）吡啶（340 mg’ 1.44 mmol)且在室溫下攪拌 混合物2.5小時。用75 ml水稀釋混合物且用ipr〇Ac(3x5〇 ml)萃取’添加鹽水以分開各層。合併有機相’用鹽水洗 蘇’經Na2S04乾燥，過濾且汽提。藉由用4〇0/〇 Et〇Ac :己 烧溶離進行Si〇2(40 g)層析來純化產物。 141275.doc -66 - 201102374 藉由RPHPLC進一步純化物質。溶離梯度1〇_1〇〇% :水： 乙腈+0.1% TFA。 LRMS計算值：436.13 ;實測值：436 93 (Μ+1；)。 實例6b 製備5-氯-2-{4-【(lR，2S)-2-(2-{[5-( f基磺醯基）吡啶-2-基】 氧基}乙基）環丙基】娘咬_1_基}嘧咬From the step 2 of Example 6, racemic cis-2-{2-[1-(5-chloropyrimidin-2-yl)π-dip-4-yl]cyclopropyl}ethanol (338 mg, 1, 2 mmol) was dissolved in DMF (0.7 ml '0.38 M). NaH (600/〇 (in oil), 144 mg ' 3.6 mm 〇l) was added and the mixture was stirred at room temperature for 1 hr. 2Br--5-(indenyl)pyridine (340 mg' 1.44 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with 75 ml of water and extracted with ipr 〇Ac (3 x 5 〇 ml) to add brine to separate the layers. The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated. The product was purified by chromatography on Si 〇 2 (40 g) using 4 〇 0 / 〇 Et 〇 Ac: hexanes. 141275.doc -66 - 201102374 Further purification of the material by RPHPLC. Dissolution gradient 1〇_1〇〇%: water: acetonitrile + 0.1% TFA. Found: 436.13; found: 436 93 (Μ +1;). Example 6b Preparation of 5-chloro-2-{4-[(lR,2S)-2-(2-{[5-(fylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl 】 Ninja bite _1_ base}

將來自實例6步驟2b之2-{(ls，2R)-2-[l-(5-氣嘧啶-2-基） 0底咬-4-基]環丙基}乙醇（338 mg，1.2 mmol)溶解於DMF (0·7 ml ’ 0.3 8 Μ)中。添加NaH(60%(於油中），144 mg， 3.6 mmol)且在室溫下攪拌混合物1〇分鐘。添加2_溴_5_(曱 基績酿基）吡咬（340 mg，1.44 mmol)且在室溫下授拌混合 物2.5小時。用75 ml水稀釋混合物且用ipr〇Ac(3x50 ml)萃 取’添加鹽水以分開各層。合併有機相，用鹽水洗滌，經 NaJO4乾燥，過濾且汽提。藉由用4〇% Et〇Ac :己烷溶離 進行Si〇2(40 g)層析來純化產物。 藉由RPHPLC進一步純化物質。溶離梯度ι〇_ι〇〇% :水： 乙腈 +0.1°/。TFA。 LRMS計算值：436.13 ;實測值：436.93 (M+1)。 可根據類似於以上實例6及6a中描述之一般程序製備表1 中報導之化合物。指定為對掌性之類似物係由自實例2步 驟4之順式-4-[2-(2-羥基乙基）環丙基]哌啶_1_曱酸第三丁醋 141275.doc •67· 201102374 製備之實例6步驟2之醇的單一對映異構體製備。不可自市 面上購得之酚係如下文實例56-81 c中所述製備。 表1 實例 化學名稱 化學結構 (M+l) 實例7 外消旋順式-5-氯-2-[4-(2-{2-[3-(曱基續醯基)笨 氧基]乙基}$哀丙基)°底淀-1-基]0^咬 J . 〇Λ}α Ue02S^/^{ Vy 436.16 實例8 外消旋順式-5-氯-2-[4-(2-{2-[3-(5-曱基-1,3,4-噁 二唑_2_基)苯氧基]乙基} 環丙基)α底咬-1-基]0^啶 440.63 實例9 外消旋順式-5-氯-2-[4-(2-{2-[3-(1沁1，2,4-***-1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶 γ^η&gt;· /=N 0^/ 425.2 實例10 外消旋順式-5-氣-2-[4-(2-{2-[3-(1,3,4-噁二唑-2-基)苯氧基]乙基}環丙基） π底咬-1-基]嘲咬 Γ°\ 424.61 實例11 外消旋順式-4-(2-{2-[1-(5-氣嘧啶-2-基)哌啶4-基]環丙基}乙氧基)-Ν-環 丙基-2-氟苯甲醯胺 459.16 實例12 外消旋順式-4-(2-{2-[1-(5-氣嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)-2-氟 苯曱腈 NC 401.58 實例13 外消旋順式-5-氣-2-[4-(2-{2-[4-(環丙基確酿基） 苯氧基]乙基}環丙基)哌 咬-1-基]0S啶 jCH&gt; y〇 462.67 141275.doc -68- 201102374 實例14 外消旋順式-5-氣-2-[4-(2-{2-[3-氟-4-(5-甲基-1，3,4-。惡二唑-2-基)苯氧 基]乙基}移丙基)娘°定-1_ 基]嘧啶 γ〇 458.63 實例15 外消旋順式-5-氣-2-[4-(2-{2-[4-(1，3,4-噁二《坐-2-基)苯氧基]乙基}環丙基） α底咬-1-基]嘴咬 N^〇 426.61 實例16 外消旋順式-5-氣-2-[4-(2-{2-[4-(5-曱基-1，3,4-噁 二唑-2-基)苯氧基]乙基} 環丙基)0底咬-1 -基]0^咬 jy。 y〇 440.62 實例17 外消旋順式-5-氣-2-[4-(2-{2-[4-(1，2,4-噁二唑-3-基)苯氧基]乙基}環丙基） °底咬-1-基]°密〇定 °\^N 426.63 實例18 外消旋順式-5-氣-2-[4-(2-{2-[4-(1，2,4-噁二唑-5-基)苯氧基]乙基}環丙基） 〇底咬-1-基]0^。定 426.61 實例19 外消旋順式-5-氯-2-[4-(2-{2-[4-(1,3-噁唑-4-基） 苯氧基]乙基}環丙基)哌 咬-1-基]0^咬 425.64 實例20 外消旋順式-5-氯-2-(4-{2-[2-(4-異噁唑-4-基笨 氧基)乙基]環丙基}哌啶· 1-基)嘧啶 jO&lt;；&gt; 425.15 141275.doc •69- 2011023742-{(ls,2R)-2-[l-(5-Apyrimidin-2-yl) 0-Butyl-4-yl]cyclopropyl}ethanol from Example 6 Step 2b (338 mg, 1.2 mmol ) Dissolved in DMF (0·7 ml '0.3 8 Μ). NaH (60% in oil, 144 mg, 3.6 mmol) was added and the mixture was stirred at room temperature for 1 min. 2_Bromo-5_(曱 绩 )) pyridine bit (340 mg, 1.44 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with 75 ml of water and extracted with ipr 〇Ac (3 x 50 ml) to add brine to separate the layers. The organic phases were combined, washed with brine, dried over Na.sub.4, filtered and evaporated. The product was purified by chromatography on Si〇2 (40 g) eluting with 4% EtOAc. The material was further purified by RPHPLC. Dissolution gradient ι〇_ι〇〇%: water: acetonitrile +0.1°/. TFA. Found: 436.13; found: 436.93 (M+1). The compounds reported in Table 1 can be prepared according to the general procedures similar to those described in Examples 6 and 6a above. The analog designated as palmar is from cis-4-[2-(2-hydroxyethyl)cyclopropyl]piperidine_1-decanoic acid third butyl vinegar of Example 2, step 4 141275.doc • 67· 201102374 Preparation Example 6 Preparation of the single enantiomer of the alcohol of Step 2. Phenols which are not commercially available are prepared as described in Examples 56-81c below. Table 1 Example Chemical Name Chemical Structure (M+l) Example 7 Racemic cis-5-chloro-2-[4-(2-{2-[3-(indolyl)indolyl]B }} 哀 propyl) ° bottom -1- base] 0 ^ bit J. 〇Λ} α Ue02S ^ / ^ { Vy 436.16 Example 8 racemic cis-5-chloro-2-[4-(2 -{2-[3-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)α-bottom-1-yl]0^pyridine 440.63 Example 9 Racemic cis-5-chloro-2-[4-(2-{2-[3-(1沁1,2,4-triazol-1-yl)phenoxy]ethyl} ring Propyl)piperidin-1-yl]pyrimidine γ^η&gt;· /=N 0^/ 425.2 Example 10 Racemic cis-5-gas-2-[4-(2-{2-[3-( 1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) π bottom bite-1-yl] 嘲 Γ ° ° 424.61 Example 11 Racemic cis-4- 2-{2-[1-(5-Azapirin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-indole-cyclopropyl-2-fluorobenzamide 459.16 Example 12 Racemic cis-4-(2-{2-[1-(5-apyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorobenzoanil NC 401.58 Example 13 Racemic cis-5-Ga-2-[4-(2-{2-[4-(cyclopropyl-decyl)phenoxy]ethyl}cyclopropyl)piperidine-1-基]0S pyridine jCH&gt; y〇462.67 141275.doc -68- 201102374 Example 14 Racemic cis-5-gas-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-.oxazolidine-2-) Benzyloxy]ethyl}transpropyl)Nanthine-1_yl]pyrimidine γ〇458.63 Example 15 Racemic cis-5-gas-2-[4-(2-{2-[4- (1,3,4-oxadi"Shen-2-yl)phenoxy]ethyl}cyclopropyl)α bottom bit-1-yl] mouth bit N^〇426.61 Example 16 Racemic cis-5 -Gas-2-[4-(2-{2-[4-(5-fluorenyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)0 bottom Bite -1 - base] 0 ^ bite jy. Y〇440.62 Example 17 Racemic cis-5-gas-2-[4-(2-{2-[4-(1,2,4-oxadiazol-3-yl)phenoxy]ethyl }cyclopropyl) ° bottom bite-1-yl] ° 〇定定°\^N 426.63 Example 18 Racemic cis-5-gas-2-[4-(2-{2-[4-(1 , 2,4-oxadiazol-5-yl)phenoxy]ethyl}cyclopropyl) guanidine-1-yl]0^. 426.61 Example 19 Racemic cis-5-chloro-2-[4-(2-{2-[4-(1,3-oxazol-4-yl)phenoxy]ethyl}cyclopropyl Piperidine-1-yl]0^Bite 425.64 Example 20 Racemic cis-5-chloro-2-(4-{2-[2-(4-isoxazole-4-ylphenyloxy)B ]]cyclopropyl}piperidine·1-yl)pyrimidine jO&lt;;&gt; 425.15 141275.doc •69- 201102374

141275.doc 70- 201102374 外消旋順式-5-氟-2-[4-實例（2-{2-[4-(111-1，2,3-***-27b 1-基)苯氧基]乙基}環丙 基)略淀-l-基]嘴咬 0'141275.doc 70- 201102374 Racemic cis-5-fluoro-2-[4-example (2-{2-[4-(111-1,2,3-triazol-27b 1-yl)phenoxy) Base]ethyl}cyclopropyl)semi-precipitate-l-base] mouth bite 0'

408.9 外消旋順式-5-曱基-2-[4-實例（2-{2-[4-(1Η-1，2,3-三唾-27c 1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶408.9 racemic cis-5-mercapto-2-[4-example (2-{2-[4-(1Η-1,2,3-tris-7-yl-1-yl)phenoxy]ethyl) }cyclopropyl)piperidin-1-yl]pyrimidine

,0C, 0C

405.2 實例28 外消旋順式-5-氣-2-[4-(2-{2-[4-(2仏1，2,3-***-2-基)苯氧基]乙基}環丙 基)D农咬-1-基]0^咬405.2 Example 28 Racemic cis-5-gas-2-[4-(2-{2-[4-(2仏1,2,3-triazol-2-yl)phenoxy]ethyl} Cyclopropyl) D-nung -1- base] 0 ^ bite

425.64 實例29 外消旋順式-5-氣-2-[4-(2-{2-[4-(111-1，2,3-***-5-基)苯氧基]乙基}環丙 基)π辰咬-1-基]α密咬425.64 Example 29 Racemic cis-5-gas-2-[4-(2-{2-[4-(111-1,2,3-triazol-5-yl)phenoxy]ethyl} Cyclopropyl) π chen-1-yl]

425.64 實例30 外消旋順式-5-氣-2-[4-(2-{2-[4·(1Η-四唑-1-基） 苯氧基]乙基}環丙基)哌 咬-1-基]嘧啶 0'425.64 Example 30 Racemic cis-5-gas-2-[4-(2-{2-[4.(1Η-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)pitrile -1-yl]pyrimidine 0'

426.6 外消旋順式-5-氣-2-[4-實例 （2-{2-[3-氟-4-(1 H-四0全- 30b 1-基)苯氧基]乙基}環丙 基)略咬-1 -基]。密咬426.6 racemic cis-5-gas-2-[4-example (2-{2-[3-fluoro-4-(1 H-tetrakis- 30b 1-yl)phenoxy]ethyl} Cyclopropyl) slightly bite -1 - group]. Bite

444.0 外消旋順式-5-氟-2-[4-實例 （2-{2-[3-氟-4-(1Η-四唆- 30d 1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶444.0 racemic cis-5-fluoro-2-[4-example (2-{2-[3-fluoro-4-(1Η-tetradecyl- 30d 1-yl)phenoxy]ethyl}cyclopropane Piperidin-1-yl]pyrimidine

428.1 141275.doc -71 - 201102374 實例 30e 外消旋順式-2-[4-(2-{2-[3-氟-4-(1Η-四唑-1-基） 苯氧基]乙基}環丙基)派 咬-1-基]-5-曱基嘲变 \ F 424.1 實例31 外消旋順式-5-氯-2-[4-(2-{2-[4-(2H-四唑-2-基） 苯氧基]乙基}環丙基)哌 咬-1-基]喊咬 N0 426.5 實例 31a 外消旋順式-5-氣-2-[4-(2-{2-[4-(5-曱基-2H-四 唑-2-基)苯氧基]乙基}環 丙基)π农咬-1-基]鳴咬 440.0 實例 31b 外消旋順式-5-氣-2-[4-(2-{2-[4-(5-曱基-1Η-四 唑-1-基)苯氧基]乙基}環 丙基)略咬-1 -基]0^咬 0。」. 440.0 實例32 外消旋順式-5-氣-2-[4_ (2-{2-[3-氟-4-(5-曱基-1，3,4-噁二唑-2-基)苯氧 基]乙基}環丙基)。辰°定小 基]嘴°定 Y〇 458.63 實例33 對掌性順式-5-氣-2-[4-(2-{2-[4-(曱基亞磺醯基） 苯氧基]乙基}環丙基)哌 啶·1-基]嘧啶 v- 〇Λ^α 0 o' 420.60 實例34 對掌性順式-6-(2-{2-[l-(5-氣o¾咬-2-基)π底咬-4-基]環丙基}乙氧基)-2-甲 基嘧啶-4-甲腈 0」 399.60 141275.doc -72- 201102374 實例35 外消旋順式-l-[4-(2-{2-[1-(5-氯嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)苯 基]乙酮 〇」 400.63 實例36 外消旋順式-2-曱基-6-(2-{2-[1-(5-曱基°比°秦-2-基） 。辰淀-4-基]壞丙基}乙乳 基)响咬-4-曱腈 \ 379.71 實例37 外消旋順式-6·(2-{2-[l-(5-¾σ密咬-2-基)α瓜咬-4-基]環丙基}乙氧基)嘧淀-4-曱腈 ν 0」 385.63 實例38 外消旋順式-4-(2-{2-[l-(5-氯嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)嘧咬-2-甲腈 Λ~\ ,Ν=\ 385.63 實例39 對掌性順式-2-甲基-6-(2-{2-[1-(5-曱基嘧啶-2-基） 哌啶-4-基]環丙基}乙氧 基)嘧啶-4-曱腈 0-^ n-A \ 379.71 實例40 外消旋順式-2-曱基-6-(2-{2-[1-(5-曱基嘧啶-2-基） 旅咬-4-基]壤丙基}乙氧 基)嘧啶-4-甲腈 \ 379.22 141275.doc -73· 201102374 實例41 外消旋順式-2,4-二甲基-6-(2-{2-[1-(5-甲基嘧啶-2_基)哌啶-4-基]環丙基} 乙氧基)嘧啶 Q」 368.67 實例42 外消旋順式-6-(2-{2-[l-(5-氣-4-甲基嘧啶-2-基） 哌啶-4-基]環丙基}乙氡 基)-2-甲基嘧啶-4-甲腈 七 Cl H=( Μ \ 413.17 實例43 外消旋順式-6-(2-{2-[l-(5-氯°比咬-2-基)派咬-4-基]環丙基}乙氧基)-2-甲 基嘧啶-4-曱腈 N=( Λΐ \ 398.58 實例44 外消旋順式-6-(2-{2-[l-(4,5-二曱基嘧啶-2-基)派 °定-4-基]壤丙基}乙氧 基)-2-曱基嘧啶斗甲腈 N=( \ 393.64 實例45 外 &gt;肖旋順式-6-(2-{2_[1 _ (5_氣-4-曱基°比咬-2-基） 哌啶斗基]環丙基}乙氧 基)-2·曱基嘧啶-4-曱腈 0」 Ν=( 412.11 實例46 外消旋順式-6-(2-{2-[l-(5-氟-4-曱基嘧啶-2-基） 略淀-4-基]環丙基}乙氣 基)-2-曱基σ密咬-4-甲腈 Ν—( 397.13 141275.doc -74- 201102374 實例47 外消旋順式-2-曱基-6-[2-(2-{1-[5-(三氟曱基户比 咬-2-基]略咬-4-基}壤丙 基)乙氧基]嘧啶-4-曱腈 0」 \ 432.65 實例48 外消旋順式-5-氯-2-(4-{2-[2-(他啶-3-基氧基)乙 基]環丙基}哌啶-1-基)嘧 啶 0—^ 359.60 實例49 外消旋順式-5-氯-2-(4-{2-[2-(痛啶-4-基氧基)乙 基]環丙基}哌啶-1-基)嘧 啶 N J 360.59 實例50 外消旋順式-5-(2-{2-[l-(5-氯嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)菸鹼 腈 Y^Cn、}ci 0」 384.57 實例51 外消旋順式-6-(2-{2-[卜 (5-氯1°¾咬-2-基)α底咬-4-基]環丙基}乙氧基)-2-曱 基嘧啶-4-曱腈 〇」 399.59 實例52 外消旋順式-4-(2-{2-[l-(5-氣嘧咬-2-基)派咬-4-基]環丙基}乙氧基)_6_甲 基嘧啶-2-曱腈 399.58 141275.doc 75- 201102374 實例53 外消旋順式-6-(2-{2-[l-(5-氟嘴咬-2-基)旅咬-4-基]環丙基}乙氧基)-2·甲 基嘧啶-4-曱腈 w=L \ 383.65 實例54 外消旋順式-5-(2-{2-[l-(5-氣嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)°比咬-2-甲腈 y 0、}ci 0」 0 f 384.10 實例55 外消旋順式-5 -氣-2-(4-{2-[2-(°比淀·4·基氧基)乙 基]環丙基}哌啶_1-基)嘧 啶 ύ 359.54 實例 55a 對掌性順式-5-氣-2-{4-[2-(2-{[5-(1Η-1，2,3-***-1-基)&gt;比啶-2-基]氧基}乙 基)環丙基]哌啶-1-基}嘧 啶 γ Ο、》。1 0」 0 426.14 用於表1中之實例之非商業酚起始物質之製備報導如 下。 製備實例56 製備3-(甲基磺醯基）酚428.1 141275.doc -71 - 201102374 Example 30e Racemic cis-2-[4-(2-{2-[3-fluoro-4-(1Η-tetrazol-1-yl)phenoxy]ethyl }cyclopropyl) 派-1-基]-5-曱基嘲变\ F 424.1 Example 31 Racemic cis-5-chloro-2-[4-(2-{2-[4-(2H -tetrazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl] shouting N0 426.5 Example 31a Racemic cis-5-Ga-2-[4-(2- {2-[4-(5-Mercapto-2H-tetrazol-2-yl)phenoxy]ethyl}cyclopropyl)π-negrin-1-yl]biting 440.0 Example 31b Racemic cis -5-Gas-2-[4-(2-{2-[4-(5-fluorenyl-1Η-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl) slightly bite-1 - Base]0^ bite 0. 440.0 Example 32 Racemic cis-5-Ga-2-[4_(2-{2-[3-Fluoro-4-(5-fluorenyl-1,3,4-oxadiazol-2-) Phenyloxy]ethyl}cyclopropyl).辰°定小基]嘴°定Y〇458.63 Example 33 For palm cis-5- gas-2-[4-(2-{2-[4-(indenylsulfinyl)phenoxy] Ethyl}cyclopropyl)piperidine·1-yl]pyrimidine v- 〇Λ^α 0 o' 420.60 Example 34 for palm cis-6-(2-{2-[l-(5-gas o3⁄4 bite) -2-yl)π bottom -4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-carbonitrile 0 399.60 141275.doc -72- 201102374 Example 35 Racemic cis- 1-[4-(2-{2-[1-(5-Chloropyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]ethanone oxime" 400.63 Example 36 Racemic cis-2-mercapto-6-(2-{2-[1-(5-fluorenyl ° °qin-2-yl). Chent-4-yl]-fragyl}ethyl lactyl ) 咬 曱-4-曱 nitrile \ 379.71 Example 37 Racemic cis-6-(2-{2-[l-(5-3⁄4σ密密-2-yl)α瓜咬-4-yl]cyclopropene Ethoxy}pyrimidine-4-indrene nitrile ν 0" 385.63 Example 38 racemic cis-4-(2-{2-[l-(5-chloropyrimidin-2-yl)piperidin-4 -yl]cyclopropyl}ethoxy)pyrimidine-2-carbonitrile Λ~\ ,Ν=\ 385.63 Example 39 for palm cis-2-methyl-6-(2-{2-[1- (5-Mercaprypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyrimidine-4-indolecarbonitrile 0-^nA \ 379.71 Example 40 Racemic 2-mercapto-6-(2-{2-[1-(5-fluorenylpyrimidin-2-yl)bend-4-yl]phosphinyl}ethoxy)pyrimidine-4-carbonitrile\ 379.22 141275.doc -73· 201102374 Example 41 Racemic cis-2,4-dimethyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidine-4 -yl]cyclopropyl}ethoxy]pyrimidine Q" 368.67 Example 42 Racemic cis-6-(2-{2-[l-(5-Ga-4-methylpyrimidin-2-yl)piperidin Pyridin-4-yl]cyclopropyl}ethenyl)-2-methylpyrimidine-4-carbonitrile-7 Cl H=( Μ \ 413.17 Example 43 Racemic cis-6-(2-{2-[ L-(5-chloro by butyl-2-yl) butyl-4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-indole N=( Λΐ \ 398.58 Example 44 Cyclo-6-(2-{2-[l-(4,5-diamidinopyrimidin-2-yl)pyr-4-yl]phosphinyl}ethoxy)-2-indenyl Pyrimidine piperazine N=( \ 393.64 Example 45 Outer > 肖 旋 cis-6-(2-{2_[1 _ (5_ 曱-4-曱 ° ° bit -2- base) piperidine ]cyclopropyl}ethoxy)-2·decylpyrimidine-4-indolecarbinal 0′ Ν=( 412.11 Example 46 Racemic cis-6-(2-{2-[l-(5-fluoro-) 4-decylpyrimidin-2-yl) succinyl-4-yl]cyclopropyl}ethenyl)-2-indenyl sigmine-4-carbonitrile oxime-(397.13 141275.doc -74- 20110 2374 Example 47 Racemic cis-2-mercapto-6-[2-(2-{1-[5-(trifluoromethyl phenyl)-biti-2-yl] slightly biti-4-yl} Ethyl]pyrimidin-4-indrenecarbazone 0" \ 432.65 Example 48 Racemic cis-5-chloro-2-(4-{2-[2-(tacyridin-3-yloxy) ]]cyclopropyl}piperidin-1-yl)pyrimidine 0—^ 359.60 Example 49 Racemic cis-5-chloro-2-(4-{2-[2-(indoct-4-yloxy) Ethyl]cyclopropyl}piperidin-1-yl)pyrimidine NJ 360.59 Example 50 Racemic cis-5-(2-{2-[l-(5-chloropyrimidin-2-yl)piperidine- 4-yl]cyclopropyl}ethoxy)nicotinonitrile Y^Cn,}ci 0" 384.57 Example 51 Racemic cis-6-(2-{2-[b (5-chloro 1°3⁄4 bite) -2-yl)α-bottom-4-yl]cyclopropyl}ethoxy)-2-mercaptopyrimidine-4-indolonitrile 〇 399.59 Example 52 Racemic cis-4-(2-{2 -[l-(5-aesthetidine-2-yl) ketone-4-yl]cyclopropyl}ethoxy)_6-methylpyrimidine-2-indolecarbonitrile 399.58 141275.doc 75- 201102374 Example 53 Racemic cis-6-(2-{2-[l-(5-fluoroindol-2-yl)bend-4-yl]cyclopropyl}ethoxy)-2.methylpyrimidine-4 -carbonitrile w=L \ 383.65 Example 54 Racemic cis-5-(2-{2-[l-(5-apyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy Base)° Specific bite-2-carbonitrile y 0,}ci 0" 0 f 384.10 Example 55 racemic cis-5-gas-2-(4-{2-[2-(°~~4·yloxy) Ethyl]cyclopropyl}piperidin-1-ylpyrimidinepyrimidine 359.54 Example 55a for palm cis-5-gas-2-{4-[2-(2-{[5-(1Η-1, 2,3-triazol-1-yl)&gt;pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine γ Ο, <<. 1 0” 0 426.14 The preparation of the non-commercial phenol starting materials used in the examples in Table 1 is reported below. Preparation Example 56 Preparation of 3-(methylsulfonyl)phenol

Me02S、^^(X7Me02S, ^^ (X7

Me02S HBr 將1-曱氧基-3-(甲基磺醯基）苯（300 mg，1.61 mmol)懸浮 於1.6 mL氫漠酸水溶液（48重量/重量％)及1.6 mL乙酸中。 在回流下加熱混合物24小時。再將反應冷卻至室溫且濃 141275.doc -76- 201102374 縮。藉由經40公克Biotage矽膠筒用40-70°/。乙酸乙酯/己烷 (梯度）溶離進行管柱層析來純化殘餘物，得到呈白色固體 狀之產物。LRMS計算值：172.0 ;實測值：173.2 (M+1)。 類似地製備下列酚： 製備實例57 製備3-(1,3,4-噁二唑_2_基）酚Me02S HBr 1-decyloxy-3-(methylsulfonyl)benzene (300 mg, 1.61 mmol) was suspended in 1.6 mL of aqueous hydrochloric acid (48 wt/%) and 1.6 mL of acetic acid. The mixture was heated under reflux for 24 hours. The reaction was then cooled to room temperature and concentrated 141275.doc -76 - 201102374. 40-70°/ with a 40g Biotage cartridge. The residue was purified by column chromatography eluting eluting elut elut elut Calculated for LRMS: 172.0; found: 173.2 (M+1). The following phenols were prepared similarly: Preparation Example 57 Preparation of 3-(1,3,4-oxadiazol-2-yl)phenol

根據類似於實例56之程序由市售2-(3-曱氧基苯基）-1，3,4-噁二唑合成目標酚。 製備實例58 製備4-(1,3-噁唑-4-基）酚The target phenol was synthesized from commercially available 2-(3-decyloxyphenyl)-1,3,4-oxadiazole according to procedures analogous to Example 56. Preparation Example 58 Preparation of 4-(1,3-oxazol-4-yl)phenol

根據類似於實例56之程序由市售4-(4-曱氧基苯基）-1,3 噁唑合成目標酚。 製備實例59 製備4-(1及-吡唑-5-基）酚The target phenol was synthesized from commercially available 4-(4-decyloxyphenyl)-1,3 oxazole according to a procedure analogous to Example 56. Preparation Example 59 Preparation of 4-(1--pyrazol-5-yl)phenol

根據類似於實例56之程序由市售5-(4-曱氧基苯基厂丨界 。比唑合成目標酚。 製備實例60 141275.doc -77· 201102374 製備4-(1孖-吡唑-1-基）酚The target phenol was synthesized according to a procedure similar to that of Example 56 from the commercially available 5-(4-decyloxyphenyl phthalate. The specific phenol was prepared. Preparation Example 60 141275.doc -77·201102374 Preparation of 4-(1孖-pyrazole- 1-yl)phenol

根據類似於實例56之程序由市售1-(4-曱氧基苯基）-1//-0比°坐合成目標盼。 製備實例61 製備3-(曱基磺醯基）酚 步驟1 : 2-{3-[(4-甲氧基苄基）氧基]苯基}-5-甲基-1，3,4-噁 二唾 ho2cThe commercially available 1-(4-decyloxyphenyl)-1//-0 ratio was synthesized according to a procedure similar to that of Example 56. PREPARATION EXAMPLE 61 Preparation of 3-(indolylsulfonyl)phenol Step 1: 2-{3-[(4-Methoxybenzyl)oxy]phenyl}-5-methyl-1,3,4- Evil two saliva ho2c

OPMBOPMB

HOBT, EDC 乙醯耕，DMF 伯吉斯試劑HOBT, EDC 醯 醯, DMF Burgess Reagent

OPMB 將3-[(4-曱氧基苄基）氧基]苯曱酸（9.26 g，35·9 mmol)、 乙酿肼（3.98 g，53·8 mmol)、HOBT(6.59 g，43 mmol)及 EDC(10.3 g，53.8 mmol)稱入 200 mL RB燒瓶中。添加 DMF(60 mL)。在室溫下劇烈攪拌混合物。固體在5分鐘内 溶解。LC-MS展示在30分鐘後酸完成耗盡。在真空下在 60°C下移除DMF。用100 mL EtOAc/水（1/1)處理殘餘物且 使之靜置隔夜。經由過濾收集固體且用EtOAc洗滌。將粗 V-乙醯基-3-[(4-甲氧基苄基）氧基]苯曱醯肼（8 g)懸浮於 100 mL THF 中且在伯吉斯試劑（Burgess' reagent)(12.8 g， 53.8 mmol)存在下在回流下加熱1小時。冷卻溶液且直接穿 過矽膠塞（300公克），用20%丙酮/己烷充分洗滌該矽膠 塞。濃縮溶離劑，得到呈白色固體狀之粗產物。 141275.doc -78- 201102374 步驟2 : 3-(5-甲基-1，3,4-噁二唑-2-基）酚OPMB 3-[(4-decyloxybenzyl)oxy]benzoic acid (9.26 g, 35·9 mmol), B. (3.98 g, 53.8 mmol), HOBT (6.59 g, 43 mmol) ) and EDC (10.3 g, 53.8 mmol) were weighed into a 200 mL RB flask. Add DMF (60 mL). The mixture was stirred vigorously at room temperature. The solid dissolved in 5 minutes. LC-MS showed that the acid was consumed after 30 minutes. The DMF was removed under vacuum at 60 °C. The residue was taken up in 100 mL EtOAc / water (1/1) and allowed to stand overnight. The solid was collected via filtration and washed with EtOAc. Crude V-acetamido-3-[(4-methoxybenzyl)oxy]phenylhydrazine (8 g) was suspended in 100 mL of THF and used in Burgess' reagent (12.8) Heating under reflux for 1 hour in the presence of g, 53.8 mmol). The solution was cooled and passed directly through a silicone plug (300 grams) and the gel plug was thoroughly washed with 20% acetone/hexane. The eluent was concentrated to give the crude material as a white solid. 141275.doc -78- 201102374 Step 2: 3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenol

用〇·5 mL TFA處理2-{3-[(4-甲氧基苄基）氧基]苯基卜5_ 甲基-1,3,4惡二峻（1〇〇 mg，〇 338 mmol)且在室溫下授拌 10分鐘。在真空下移除過量TFA且藉由使用24公克Bi〇tage 矽膠筒用2 0 - 5 0 %乙酸乙酯/己烷（梯度）溶離進行管柱層析來 純化殘餘物，得到呈白色固體狀之產物。LRMS計算值： 176.1 ;實測值：177 2 (M+1)。 製備實例62 製備3·氟-4-(5-甲基-l，3,4-噁二唑-2-基）酚Treatment of 2-{3-[(4-methoxybenzyl)oxy]phenyl b-5-methyl-1,3,4 dioxin (1 〇〇mg, 〇338 mmol) with mL·5 mL TFA And mix for 10 minutes at room temperature. The excess TFA was removed under vacuum and the residue was purified eluting with EtOAc EtOAc EtOAc The product. Calculated for LRMS: 176.1; found: 177 2 (M+1). Preparation Example 62 Preparation of 3·fluoro-4-(5-methyl-l,3,4-oxadiazol-2-yl)phenol

根據類似於實例61之方案由4-[(4-甲氧基苄基）氧基]笨曱 酸製備標題紛。 製備實例63 製備3-(1丑-1，2,4-三唾_1_基）紛 步驟1 : 1-[3-(苄基氧基）苯基卜***The title was prepared from 4-[(4-methoxybenzyl)oxy] alumic acid according to a procedure analogous to Example 61. PREPARATION EXAMPLE 63 Preparation of 3-(1 ugly-1,2,4-tris-sodium-1-yl) Step 1: 1-[3-(Benzyloxy)phenyl-triazole

OBn 三0坐，Cul 配位體，κ3ρ〇4OBn three zero sitting, Cul ligand, κ3ρ〇4

OBn 向了检封壓力皆中添加Cui(3i mg，0.16 mmol)、ι//_ 1’2’4 一 坐（245 mg ’ 3.55 mmol)、磷酸奸（1.37 g，6.45 mmol) ' 1-(苄基氧基）_3_蛾苯（1呂，3 22 mm〇i)及攪拌棒。 141275.doc •79- 201102374 使反應容器配備有橡膠隔片，抽真空且用氬氣回填，且重 複該順序。隨後在氬氣流下依次添加DMF(3 22麵。1)及 n，n，-二甲基乙二胺（28 mg，0·322 mm〇1)。用新的pTF_ 片捲曲密封反應管（警告：壓力可能增大；使用安全防護 罩）且浸於110°C之預加熱油浴中歷時24小時，同時磁力攪 拌。移除對反應混合物之加熱’使其達到周圍溫度，用乙 酸乙酯（2-3 mL)稀釋，經矽膠塞過濾且再用乙酸乙酯（1〇_ 20 mL)溶離。濃縮濾液且藉由矽膠層析（8〇公克矽 膠筒，40-60% EtOAc/己烷）純化所得殘餘物，得到呈白色 固體狀之所要產物。LRMS計算值：251.3 ;實測值：252.4 (M+1) 〇 步驟2 : 3-(1好-1,2,4-***-l_基）酚 /^Ν Λ=：ΝOBn added Cui (3i mg, 0.16 mmol), ι//_ 1'2'4 a sit (245 mg '3.55 mmol), and phosphate (1.37 g, 6.45 mmol) ' 1-( Benzyloxy)_3_ moth benzene (1 Lu, 3 22 mm〇i) and a stir bar. 141275.doc •79- 201102374 The reaction vessel was equipped with a rubber septum, evacuated and backfilled with argon, and the sequence repeated. Subsequently, DMF (3 22 face. 1) and n, n,-dimethylethylenediamine (28 mg, 0·322 mm〇1) were sequentially added under a stream of argon. The reaction tube was crimped with a new pTF_sheet (warning: pressure may increase; use a safety shield) and immersed in a preheated oil bath at 110 °C for 24 hours while magnetically stirring. The reaction mixture was removed and heated to ambient temperature, diluted with ethyl acetate (2-3 mL), filtered thru a plug and then eluted with ethyl acetate (1 _ _ 20 mL). The filtrate was concentrated and the residue was purified EtOAcjjjjjjjj LRMS calculated: 251.3; found: 252.4 (M+1) 〇 Step 2: 3-(1,1,2,4-triazol-l-yl)phenol /^Ν Λ=:Ν

Pd(0H)2, H2 /OH u ^ X7 將W3-(节基氧基）笨基]-1/m，2,4_***（25〇 mg，〇 995 mmol)溶解於5 mL甲醇中。將溶液脫氣且用氮氣回填。隨 後添加鈀/碳（10重量/重量％，106 mg，〇」mm〇i)。將反應 容器脫氣且用氫氣回填3次，且在室溫下在氫氣球下攪 拌。攪拌反應隔夜。隨後用5 mL丙酮稀釋且經矽膠塞（5 g) 過濾’用丙酮充分洗滌該矽膠塞。濃縮得到呈白色固體狀 之產物。LRMS計算值：161.1 ;實測值：162 2 (M+1)。 製備實例64 製備4_(環丙基磺醯基）酚 步驟1 : 1-(環丙基硫基）-4-甲氧基苯 141275.doc •80- 201102374Pd(0H)2, H2 /OH u ^ X7 Dissolve W3-(knotyloxy)phenyl]-1/m,2,4-triazole (25 〇mg, 〇995 mmol) in 5 mL of methanol . The solution was degassed and backfilled with nitrogen. Palladium/carbon (10 wt/wt%, 106 mg, 〇"mm〇i) was then added. The reaction vessel was degassed and backfilled 3 times with hydrogen and stirred under a balloon of hydrogen at room temperature. Stir the reaction overnight. It was then diluted with 5 mL of acetone and filtered through a plug (5 g) to thoroughly wash the gelatin plug with acetone. Concentration gave the product as a white solid. LRMS calcd.: 161.1; found: 162 2 (M+1). Preparation Example 64 Preparation of 4-(cyclopropylsulfonyl)phenol Step 1: 1-(Cyclopropylthio)-4-methoxybenzene 141275.doc •80- 201102374

HSHS

OMeOMe

C&gt;-Br Na OiBu, EtOHC&gt;-Br Na OiBu, EtOH

OMe 在〇 C下向第三丁醇鈉（317 mg，3 3 mmol)於15 mL EtOH中之溶液中緩板添加4_曱氧基苯硫驗（42〇 ，3 mmol)。添加完成後，在室溫下攪拌反應丨小時，之後冷卻 至〇c。緩慢添加溴環丙烷（417 mg，3 45 mm〇1)，且使混 合物回流1小時，冷卻且濃縮。添加水（1 mL)且用乙酸乙 面曰萃取混合物。乾燥有機相且藉由用2〇%乙酸乙酯/己烷溶 離進行管柱層析而純化，得到所要產物。 步驟2· 1-(壞丙基績醢基）·4_甲氧基苯OMe was added to a solution of sodium butoxide (317 mg, 3 3 mmol) in 15 mL of EtOH at 〇 C to add 4 曱 oxy thiophene (42 〇, 3 mmol). After the addition was completed, the reaction was stirred at room temperature for a few hours, and then cooled to 〇c. Bromocyclopropane (417 mg, 3 45 mm 〇1) was slowly added, and the mixture was refluxed for 1 hour, cooled and concentrated. Water (1 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried and purified by column chromatography eluting with EtOAc EtOAc EtOAc Step 2· 1-(bad propyl thiol)·4_methoxybenzene

久义》〇、Me 過硫酸氤@^ 將1-(環丙基硫基）_4-甲氧基苯（3〇〇 mg，i.66 mmol)溶解 於8 mL MeOH及水（1:1)中。添加過硫酸氫卸9 g，6 66 mmol)且授拌混合物隔夜。使用i N Hci溶解鹽且添加乙酸 乙酿以萃取產物。用1 N職先條有機萃取物三次且用鹽 欠洗條’經硫gt鈉乾燥，且在減壓下移除溶劑以獲得粗產 物，其不經進一步純化即使用。 步驟3 : 4-(環丙基磺醯基）酚久义》〇, Me persulfate 氤@^ Dissolve 1-(cyclopropylthio)_4-methoxybenzene (3〇〇mg, i.66 mmol) in 8 mL of MeOH and water (1:1) in. Add 9 g of hydrogen persulfate, 6 66 mmol) and mix the mixture overnight. The product was extracted by dissolving the salt using i N Hci and adding acetic acid. The organic extracts were taken three times with 1 N EtOAc and dried over EtOAc EtOAc. Step 3: 4-(cyclopropylsulfonyl)phenol

HBr, HOAcHBr, HOAc

該實例步驟2之Step 2 of the example

根據類似於實例56之程序藉由裂解來自 甲基醚製備標題酚。 製備實例65 141275.doc •81 · 201102374 製備4-(1，2,4-噁二唑-3-基）酚The title phenol was prepared by cleavage from methyl ether according to a procedure analogous to Example 56. Preparation Example 65 141275.doc •81 · 201102374 Preparation of 4-(1,2,4-oxadiazol-3-yl)phenol

原甲酸酯Orthoformate

將TV'，4-二羥基苯羰醯亞胺醯胺（1.28 g，8.4 mmol)懸浮 於20 mL Biotage微波反應管中之3 mL乙醇及3 mL原甲酸 三甲酯中。密封混合物且在150°C下微波加熱10分鐘。藉 由濃縮移除溶劑且藉由用20% DCM/己烧溶離進行管柱層 析來純化殘餘物，得到呈白色固體狀之所要產物。LRMS 計算值：162.0 ;實測值：163_2 (M+1)。 製備實例66 製備4-(1，2,4-噁二唑-5-基）酚 步驟1 : 7\^[(1五)-(二甲基胺基）亞曱基】-4-經基苯甲醯胺TV',4-dihydroxyphenylcarbonylimine decylamine (1.28 g, 8.4 mmol) was suspended in 3 mL of ethanol and 3 mL of trimethyl orthoformate in a 20 mL Biotage microwave reaction tube. The mixture was sealed and heated in a microwave at 150 °C for 10 minutes. The residue was purified by EtOAc (EtOAc) elute LRMS calculated: 162.0; found: 163_2 (M+1). PREPARATION EXAMPLE 66 Preparation of 4-(1,2,4-oxadiazol-5-yl)phenol Step 1: 7\^[(1,5)-(dimethylamino)indenyl]-4-thiol Benzylamine

在120°C下將4-羥基苯曱醯胺（5.58 g，40 mmol)於15 mL 二甲基甲醯胺二曱基縮醛中之溶液攪拌1 ·5小時，同時蒸 餾產物甲醇。冷卻後，收集固體且用***、DCM濕磨，得 到所要產物。 步驟2 : 4-(1，2,4-噁二唑-5-基）酚A solution of 4-hydroxybenzamine (5.58 g, 40 mmol) in 15 mL of dimethylformamide dinonyl acetal was stirred at 120 ° C for 1.5 hours while distilling the product methanol. After cooling, the solid was collected and triturated with diethyl ether and DCM to give the desired product. Step 2: 4-(1,2,4-oxadiazol-5-yl)phenol

向經胺鹽酸鹽（354 mg ’ 5· 1 mmol)於5 ν氫氧化鈉水溶液 (1 mL，5 mmol)、乙酸（10 mL)及二噁烷（85 mL)之混合物 141275.doc -82· 201102374 中之溶液中添加來自該實例步驟1之#-[(1Ε)-(二甲基胺基） 亞甲基]'4-經基苯甲醢胺（815 mg’ 4.24 mmol)»在9〇 下 攪拌反應3小時。冷卻至室溫後，在真空下移除溶劑且藉 由用80公克Bi〇tage矽膠筒用2〇_5〇%乙酸乙酯/己烷（梯度） 溶離進行管柱層析來純化殘餘物，得到呈白色固體狀之產 物。LRMS計算值：162.0 ;實測值：163.2 (M+1)。 製備實例67 製備4-異》惡唾_ _心基紛 步驟1 : 4-(4·甲氧基苯基）異噁唑a mixture of amine hydrochloride (354 mg '5.1 mmol) in 5 NaOH aqueous sodium hydroxide (1 mL, 5 mmol), acetic acid (10 mL) and dioxane (85 mL) 141. · Add #-[(1Ε)-(dimethylamino)methylene]'4-carbazinamide (815 mg' 4.24 mmol)» from step 9 of this example to the solution in 201102374 at 9 The reaction was stirred for 3 hours under the arm. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc The product was obtained as a white solid. Calculated for LRMS: 162.0; found: 163.2 (M+1). PREPARATION EXAMPLE 67 Preparation of 4-iso" 唾 _ _ _ heart base Step 1: 4-(4. methoxyphenyl) isoxazole

將甲氧基苯基）丙醛（2.5 g，μ mm〇1)與於乙醇（28 L)中之起胺鹽酸鹽（1.46 g，21 mm〇i) 一起在回流下加熱2 小時。在真空下移除乙醇且藉由經115公克Bi〇tage矽膠筒 用20-50% EtOAe/己烧溶離進行管柱層析來純化殘餘物， 得到淺色油狀物，其在靜置隔夜後固化。 步驟2 : 4-異°惡唾-4-基盼Methoxyphenyl)propanal (2.5 g, μ mm 〇1) was heated with refluxing amine salt (1.46 g, 21 mm 〇i) in ethanol (28 L) for 2 hours under reflux. The ethanol was removed under vacuum and the residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc Cured. Step 2: 4-iso-destinyl-4-pyrene

根據類似於實例56之程序藉由 甲基醚製備標題酚。 裂解來自該實例步驟1之 製備實例68 製備4-異噁唑-5-基酚 14I275.doc -83· 201102374The title phenol was prepared by methyl ether according to a procedure analogous to Example 56. The cleavage was carried out from the preparation example 68 of this example. Preparation of 4-isoxazole-5-ylphenol 14I275.doc -83· 201102374

OHOH

在100°c下將1-(4-羥基苯基）乙酮（5 3 &amp; mmol)在二 甲基甲酿胺二甲基㈣(6.56 g’ 55 _〇1)中加熱隔夜。： 液變成暗紅色。在高真空下移除揮發性溶劑。將粗(二T 基胺基）-1-(4-羥基苯基）丙-2-烯-1-酮溶解於乙醇中，接著 添加羥胺鹽酸鹽。在回流下加熱混合物3小時。在真空= 移除溶劑。藉由經120 g Biotage矽膠筒用1〇_4〇% EtfAe/ 己烷（梯度）及20%乙酸乙醋/己烷（等度）溶離進行管柱層析 來純化殘餘物兩次，得到呈白色固體狀之產物^ 算值：161.1 ;實測值：162.2 (M+1)。 製備實例69 -口比〇坐1-(4-Hydroxyphenyl)ethanone (5 3 &amp; mmol) was heated in dimethyl ketoamine dimethyl (tetra) (6.56 g' 55 _ 〇 1) overnight at 100 °C. : The liquid turns dark red. The volatile solvent was removed under high vacuum. The crude (di-T-amino)-1-(4-hydroxyphenyl)prop-2-en-1-one was dissolved in ethanol, followed by the addition of hydroxylamine hydrochloride. The mixture was heated under reflux for 3 hours. In vacuum = remove solvent. The residue was purified by column chromatography on a 120 g Biotage cartridge with 1 〇4 〇% EtfAe/hexane (gradient) and 20% ethyl acetate/hexane (isocratic). </ RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> Preparation Example 69 - mouth squat

製備4_(1开-咐^坐-4-基）紛 步驟1 : 4-(4-曱氧基苯基 將（4-曱氧基笨基）丙搭（1.5 g，842 mmol)溶解於乙醇（10 mL)中，接著添加肼（54〇 mg，16 8 mm〇1)。在n(rc下將 微波密封管中之淺黃色溶液加熱隔夜。形成大量白色結晶 固體。將反應混合物冷卻至〇°c。藉由過濾收集白色固體 且用5 mL冰冷乙醇洗滌，得到所要產物，將其在高真空泵 下進一步乾燥。 步驟2 : 4-(4·甲氧基苯基^比唑 141275.doc • 84 · 201102374Preparation 4_(1 咐-咐^ -4-yl) Step 1 : 4-(4-decyloxyphenyl) (4-methoxyphenyl) propylene (1.5 g, 842 mmol) dissolved in ethanol (10 mL), followed by the addition of hydrazine (54 〇 mg, 16 8 mm 〇 1). The light yellow solution in the microwave sealed tube was heated overnight at n (rc) to form a large amount of white crystalline solid. The reaction mixture was cooled to 〇. The white solid was collected by filtration and washed with 5 mL of ice-cold ethanol to give the desired product, which was further dried under a high vacuum pump. Step 2: 4-(4·Methoxyphenylpyrazole 141275.doc • 84 · 201102374

MeOMeO

HBr, HOAcHBr, HOAc

HOHO

根據類似於實例56之程序藉由裂解該實例步驟1之甲基 醚製備標題酚。 製備實例70 製備4_(4好-I，2,4·***_4_基）酚The title phenol was prepared by cleavage of the methyl ether of Example 1 in a procedure analogous to Example 56. Preparation Example 70 Preparation of 4_(4-I,2,4·triazole-4-yl)phenol

將4-胺基紛（1 g，9.16 mmol)及雙甲醯基肼（888 mg， 10.08 mmol)溶解於甲苯（30 mL)與DMF(3 mL)之混合物 中，接著添加pTSA( 1.92 g，10.08 mmol)。在回流下將混 ^ m m ^ yJx ° /r is.，&gt;昆节、初’刀、成 to /w ° 话、果 τ + 丄 層。藉由使用115公克Biotage矽膠筒用20-40%乙酸乙酯/己 烷（梯度）溶離進行管柱層析來直接純化深色DMF下層，得 到呈淺黃色固體狀之產物。LRMS計算值：161.1 ;實測 值：162.4 (M+1)。 製備實例71 製備4-(1开-1,2,3-***-1-基）酚及4-(2好-1，2,3-***-2-基）酚 步驟1 : 1-[4-(苄基氧基）苯基]-1好-1，2,3-***及2-[4-(苄基 氧基）苯基]-2丑-1，2,3-***4-Amino-(1 g, 9.16 mmol) and bis-methyl hydrazinium (888 mg, 10.08 mmol) were dissolved in a mixture of toluene (30 mL) and DMF (3 mL), then pTSA ( 1.92 g, 10.08 mmol). Under reflux, it will mix ^ m m ^ yJx ° /r is.,&gt; Kunming, first 'knife, into to /w ° words, fruit τ + 丄 layer. The dark DMF lower layer was directly purified by column chromatography using a EtOAc EtOAc EtOAc (EtOAc) elute LRMS calculated: 161.1; found: 162.4 (M+1). Preparation Example 71 Preparation of 4-(1 -1,2,3-triazol-1-yl)phenol and 4-(2-y-1,2,3-triazol-2-yl)phenol Step 1 : 1- [4-(Benzyloxy)phenyl]-1 good-1,2,3-triazole and 2-[4-(benzyloxy)phenyl]-2 ugly-1,2,3-three Azole

〇Bn 三°坐，Cul 配位體.NaiOBu〇Bn three° sitting, Cul ligand. NaiOBu

向可密封麼力管中添加Cul(614 mg，3 ·22 mmol)、1//- 141275.doc -85- 201102374 1，2,3-***（668 mg ’ 9.67 mmol)、第三丁醇鈉（1.085 g， 9.67 mmol)、1-(苄基氧基）_4_ 破苯（1 g，3 22 mmol)及搜拌 棒。使反應容器配備有橡膠隔片，抽真空且用氬氣回填， 且重複該順序。隨後在氬氣流下依次添加N，N'-二甲基乙Add Cul (614 mg, 3 · 22 mmol), 1//- 141275.doc -85- 201102374 1,2,3-triazole (668 mg ' 9.67 mmol), third butanol to the sealable tube Sodium (1.085 g, 9.67 mmol), 1-(benzyloxy)_4_ benzene (1 g, 3 22 mmol) and a stir bar. The reaction vessel was equipped with a rubber septum, evacuated and backfilled with argon, and the sequence was repeated. Subsequent addition of N,N'-dimethyl B under argon flow

二胺（853 mg，9.67 mmol)及 NMP(6_45 mL)。用新的PTFE 隔片捲曲密封反應管（警告：壓力可能增大；使用安全防 護罩）且浸於13〇°C之預加熱油浴中歷時3小時，且對溶液 磁力攪拌。移除對反應混合物之加熱，使其達到周圍溫 度’用乙酸乙酯（8 mL)、飽和氣化銨（8 mL)及28%氫氧化 銨水溶液（2 mL)稀釋。劇烈攪拌混合物30分鐘且經碎藻土 過濾。分離濾液。用乙酸乙酯進一步竿取水層。合併有機 層’用水、鹽水洗滌，經硫酸鈉乾燥，濃縮且藉由矽膠管 柱層析（11 5公克Biotage矽膠筒，10-20%乙酸乙酯/己燒， 隨後40-60%乙酸乙酯/己烷）純化所得殘餘物以分離兩種呈 白色固體狀之區位異構體。極性較強之溶離份為1 _[4&lt;节 基氧基）苯基]-1//-1，2,3-***。LRMS計算值：251.1 ;實測 值：252.5 (M+1)。極性較小之溶離份為2-[4-(苄基氧基）笨 基]-2//-1，2,3-***。1^]\^計算值：251.3;實測值：2524 (M+1)。 步驟2 : 4-(1孖·1，2,3·***-1-基）酚Diamine (853 mg, 9.67 mmol) and NMP (6-45 mL). The reaction tube was crimped with a new PTFE septum (warning: pressure may increase; use a safety shield) and immersed in a preheated oil bath at 13 °C for 3 hours with magnetic stirring of the solution. The reaction mixture was removed and allowed to warm to ambient temperature &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The mixture was stirred vigorously for 30 minutes and filtered through celite. The filtrate was separated. The aqueous layer was further taken up with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, dried and evaporated and th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th The resulting residue was purified by hexanes to isolate the two-positions as a white solid. The more polar soluble fraction is 1 _[4&lt;knotyloxy)phenyl]-1//-1,2,3-triazole. Calculated for LRMS: 251.1; found: 252.5 (M+1). The less polar soluble fraction is 2-[4-(benzyloxy)phenyl]-2//-1,2,3-triazole. 1^]\^ Calculated value: 251.3; measured value: 2524 (M+1). Step 2: 4-(1孖·1,2,3·Triazol-1-yl)phenol

j^Y〇Bn Pd(OH)2,H2 將卜[4-(f基氧基）苯基]-1//-1，2,3-三峻（200 mg , 〇 8 mmol)溶解於1.6 mL乙酸乙酯與乙醇之混合物（1:1)中。將 141275.doc -86 - 201102374 溶液脫氣且用氮氣淨化。添加氫氧化鈀（20重量/重量％(於 石反上），55·9 mg，〇·〇8 mmol)且使反應脫氣且用氫氣淨化 一人繼；在至溫下在氫氣球下氫化隔夜。藉由經石夕膠塞 過濾移除催化劑，用丙酮充分洗滌該矽膠塞。濃縮得到呈 白色固體狀之產物。LRMS計算值：161.1 ;實測值：162 2 (M+1) 〇 步驟2, ： 4-(2丑-i，2,3-***-2-基）酚j^Y〇Bn Pd(OH)2,H2 Dissolve [4-(f-oxy)phenyl]-1//-1,2,3-tris (200 mg, 〇8 mmol) in 1.6 A mixture of ethyl acetate and ethanol (1:1). The 141275.doc -86 - 201102374 solution was degassed and purged with nitrogen. Palladium hydroxide (20 wt/wt% (on stone), 55·9 mg, 〇·〇 8 mmol) was added and the reaction was degassed and purified with hydrogen for one person; hydrogenated under hydrogen balloon overnight at ambient temperature . The catalyst was removed by filtration through a plug of Celite, and the gel plug was thoroughly washed with acetone. Concentration gave the product as a white solid. LRMS calculated: 161.1; found: 162 2 (M+1) 〇 Step 2, : 4-(2 ugly-i,2,3-triazol-2-yl)phenol

M |TY〇Bn Pd(〇H)2,H2 f|^Y〇H 將2-[4-(节基氧基）笨基***（4〇〇 mg, 16 mmol)溶解於3·2 mL乙酸乙酯與乙醇之混合物（1:1)中。將 溶液脫氣且用氮氣淨化。添加氫氧化鈀（2〇重量/重量％(於 碳上），110 mg , 0.16 mmol)且將反應脫氣且用氫氣淨化三 次。繼續在室溫下在氫氣球下氫化1小時。藉由經矽膠塞 過濾移除催化劑，用丙酮充分洗滌該矽膠塞。濃縮得到呈 白色固體狀之產物。LRMS計算值：161.1 ;實測值：162.2 (M+1)。 製備實例71a 製備5-(1丑_1，2,3·三唾·1_基）_2_經基n比咬 步驟1 : 5-碘-2-(4，-甲氧基苄基氧基）吡啶M | TY 〇 Bn Pd(〇H) 2, H2 f|^Y〇H 2-[4-(nodaloxy) stilbene triazole (4 〇〇 mg, 16 mmol) was dissolved in 3·2 mL A mixture of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen. Palladium hydroxide (2 〇 wt/wt% (on carbon), 110 mg, 0.16 mmol) was added and the reaction was degassed and purified three times with hydrogen. Hydrogenation under hydrogen balloon was continued for 1 hour at room temperature. The catalyst was removed by filtration through a plug of rubber and the silicone plug was thoroughly washed with acetone. Concentration gave the product as a white solid. Found: 161.1; found: 162.2 (M + 1). Preparation Example 71a Preparation of 5-(1 ugly _1,2,3·trisinyl-1-yl)_2_transpyrynyl nibble Step 1: 5-iodo-2-(4,-methoxybenzyloxy Pyridine

OPMBOPMB

NaH, PMB-OH 在〇°C下將於15 mL DMF中之4-甲氧基苄基醇（6.51 g， 47.1 mol)添加至氫化鈉（ι·973 g，49.3 mmol)於DMF中之攪 141275.doc _87_ 201102374 掉懸專液中。1 0分鐘後，使用加料漏斗逐滴添加2_氟_5_峨 吡啶（10 g，44.8 mmol)於15 mL DMF中之溶液。反應緩慢 達到室溫’且使其攪拌1 8小時。再次冷卻均質黃色溶液且 用約50 ml水驟冷。隨後使懸浮液在乙酸乙酯（2〇〇 mL)與水 (150 mL)之間分溶。再次用乙酸乙酯萃取水層，且用水洗 務合併之有機層三次且用鹽水洗滌兩次。經硫酸鈉乾燥有 機層’過濾且蒸發。當蒸發接近完成時，沈澱出白色固 體。藉由添加己烷進行濕磨。過濾固體且在過濾器上乾 燥°對所得白色固體進行重複之部分蒸發、濕磨及過濾， 得到標題化合物。 NMR (CDC13): δ 8.35 (d, 1Η, J=2.3 Hz), δ 7.77 (dd, 1H, J=8.7, 1.3 Hz), δ 7.37 (d, 2H), δ 7.26 (s, CHC13), δ 6.90 (d, 2H), δ 6.61 (d, 1H, J=8.7 Hz), δ 5.26 (s, 2H), δ 3.81 (s 3H) 〇 步驟2 : 5-疊氮基-2-(4，-甲氧基苄基氧基）吼啶NaH, PMB-OH 4-methoxybenzyl alcohol (6.51 g, 47.1 mol) in 15 mL of DMF was added to sodium hydride (ι·973 g, 49.3 mmol) in DMF at 〇 °C 141275.doc _87_ 201102374 Drop the suspension. After 10 minutes, a solution of 2_fluoro_5_purine pyridine (10 g, 44.8 mmol) in 15 mL of DMF was added dropwise using an addition funnel. The reaction was allowed to reach room temperature and was allowed to stir for 18 hours. The homogeneous yellow solution was again cooled and quenched with about 50 ml of water. The suspension was then partitioned between ethyl acetate (2 mL) and water (150 mL). The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed three times with water and twice with brine. The organic layer was dried over sodium sulfate' filtered and evaporated. When the evaporation was nearly completed, a white solid precipitated. Wet milling was carried out by adding hexane. The solid was filtered and dried <RTI ID=0.0>: </RTI> <RTI ID=0.0> NMR (CDC13): δ 8.35 (d, 1 Η, J = 2.3 Hz), δ 7.77 (dd, 1H, J = 8.7, 1.3 Hz), δ 7.37 (d, 2H), δ 7.26 (s, CHC13), δ 6.90 (d, 2H), δ 6.61 (d, 1H, J=8.7 Hz), δ 5.26 (s, 2H), δ 3.81 (s 3H) 〇Step 2: 5-azido-2-(4,- Methoxybenzyloxy)acridine

將來自該實例步驟1之5-碘-2-(4，-甲氧基苄基氧基）。比啶 (682 mg，2.0 mmol)、疊氮化鈉（260 mg，4.00 mmol)、蛾 化銅（1)(3 8.1 mg ’ 0.200 mmol)及 L-抗壞血酸鈉鹽（19.81 mg ’ 0.100 mmol)添加至可密封之高壓容器中。將容器抽 真空且用氮氣淨化，隨後添加乙醇（2.75 ml)及水（1.25 ml)。隨後經由微升注射器添加n，N，-二曱基乙二胺（31.9 μΐ ’ 0.300 mmol)。密封頂部且將反應加熱至i〇〇°c。在反 141275.doc •88· 201102374 應前面置放安全防護罩作為作為保護措施^ 90分鐘後，將 反應冷卻至室溫。根據TLC判斷反應完成，因此使反應在 乙酸乙酯與水之間分溶。再次用乙酸乙酯萃取水層，且再 次用水洗務合併之有機物。經硫酸納乾燥有機層，過濾且 黑·發’得到粗產物。用Biotage 40 g Si02管柱用5-25%乙酸 乙酯/庚烧溶離進行管柱層析來純化物質，得到呈淺褐色 固體狀之標題化合物。 NMR (CDC13): δ 7.92 (d，1Η，J=3.0 Ηζ)，δ 7.38 (d，2Η)，δ 7.28 (dd, 1H, J=8.9, 3.0 Hz), δ 7.26 (s, CHC13), δ 6.90 (d, 2H), δ 6.78 (d, 1H, J=8.7 Hz), δ 5.27 (s, 2H), δ 3.81 (s 3H)。 步驟3 : 5-(1丑-1，2,3-***-1-基）_2-(4，_甲氧基苄基氧基）吡啶5-Iodo-2-(4,-methoxybenzyloxy) from step 1 of this example will be used. Bipyridine (682 mg, 2.0 mmol), sodium azide (260 mg, 4.00 mmol), copper moth (1) (3 8.1 mg '0.200 mmol) and sodium L-ascorbate (19.81 mg '0.100 mmol) In a high-pressure container that can be sealed. The vessel was evacuated and purged with nitrogen, followed by the addition of ethanol (2.75 ml) and water (1.25 ml). Then n,N,-didecylethylenediamine (31.9 μΐ '0.300 mmol) was added via a microliter syringe. The top is sealed and the reaction is heated to i〇〇°c. In the reverse 141275.doc •88· 201102374 The safety shield should be placed in front as a protective measure ^ After 90 minutes, the reaction is cooled to room temperature. The completion of the reaction was judged according to TLC, so that the reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the combined organics were washed again with water. The organic layer was dried over sodium sulfate, filtered and evaporated to give a crude material. The material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) NMR (CDC13): δ 7.92 (d, 1 Η, J = 3.0 Ηζ), δ 7.38 (d, 2 Η), δ 7.28 (dd, 1H, J = 8.9, 3.0 Hz), δ 7.26 (s, CHC13), δ 6.90 (d, 2H), δ 6.78 (d, 1H, J = 8.7 Hz), δ 5.27 (s, 2H), δ 3.81 (s 3H). Step 3: 5-(1 ugly-1,2,3-triazol-1-yl)_2-(4,-methoxybenzyloxy)pyridine

將來自該實例步驟2之5-疊氮基-2-(4'-曱氧基苄基氧基） 吡啶（55 mg，0.215 mmol)及乙酸乙烯酯（692 μΐ，7.51 mmol)在經火焰乾燥之高壓可密封容器中混合。將反應容 器抽真空且裝入氮氣’密封，且加熱至1 00〇c歷時丨5小 時。冷卻反應至室溫且TLC指示反應已完成。向反應中添 加少量二氯甲烷（恰好足以溶解冷卻後形成之固體）且將溶 液添加至Biotage 25 g Si02管柱上，用2〇_50%乙酸乙酯/庚 烷溶離’得到呈白色固體狀之標題化合物。 LRMS計算值：282.1 ;實測值：282.9 (M+1)。 141275.doc -89- 201102374 NMR (CDC13)： δ 8.50 (d, 1H, J=2.7 Hz), δ 7.97 (dd5 1H J=8.9, 2.7 Hz), δ 7.93 (d, 1H, J=0.9 Hz), δ 7.87 (d, 1H J=l.〇 Hz), δ 7.41 (d, 2H), δ 7.26 (s, CHC13), δ 6.93 (m 3H)，δ 5_37 (s，2H)，δ 3.82 (s 3H)。 步驟4:5-(1丑-1，2,3-***-1-基）-2-羥基吡啶5-Azido-2-(4'-decyloxybenzyloxy)pyridine (55 mg, 0.215 mmol) from step 2 of this example and vinyl acetate (692 μΐ, 7.51 mmol) were dried by flame. The high pressure sealable container is mixed. The reaction vessel was evacuated and filled with nitrogen to seal and heated to 100 〇c for 5 hours. The reaction was cooled to room temperature and TLC indicated the reaction was completed. A small amount of methylene chloride (just enough to dissolve the solid formed after cooling) was added to the reaction and the solution was added to a Biotage 25 g SiO 2 column and dissolved in 2 〇 50% ethyl acetate / heptane to give a white solid. The title compound. Calculated for LRMS: 282.1; found: 282.9 (M+1). 141275.doc -89- 201102374 NMR (CDC13): δ 8.50 (d, 1H, J=2.7 Hz), δ 7.97 (dd5 1H J=8.9, 2.7 Hz), δ 7.93 (d, 1H, J=0.9 Hz) , δ 7.87 (d, 1H J=l.〇Hz), δ 7.41 (d, 2H), δ 7.26 (s, CHC13), δ 6.93 (m 3H), δ 5_37 (s, 2H), δ 3.82 (s 3H). Step 4: 5-(1 ugly-1,2,3-triazol-1-yl)-2-hydroxypyridine

將來自該實例步驟3之5-(111-1，2,3-***-1-基）_2-(4，_曱氧 基苄基氧基）β比咬（890 mg，3.1 5 mmol)溶解於二氯曱烧（η ml)中。添加三氟乙酸（3.64 ml，47.3 mmol)且在室溫下搜 拌混合物。1 〇分鐘内，反應變成淡紫色。添加TF A後蒸發 反應混合物40分鐘，隨後於CH2C12/庚烷中重配且再次蒸 發。藉由用Biotage 40gSiO2管柱用於CH2C12中之0-1 5%甲 醇溶離進行管柱層析來純化殘餘物，得到白色固體。將白 色固體懸浮於丙酮中且經矽藻土過濾以自粗產物中移除二 氧化石夕。隨後蒸發濾液且在高真空下抽吸隔夜，得到呈與 丙酮之複合物之標題化合物。 LRMS計算值：162丨；實測值：162 9 (M+1)。 NMR (CD3OD)： δ 8.38 (d, 1H, J=l.l Hz), δ 8.03 (s, 1H), δ 8.02 (d, 1H, J=9 Hz), δ 7.87 (d, 1H, J=〇-9 Hz), δ 6.69 (d, 1H, J-10.5 Hz), δ 2.15 (丙酮）。 製備實例71b 製備 5-氣-2-(44(1/^25)-2-(245-(1 丑-1，2,3-***-1-基）吡 141275.doc 201102374 啶-2-基】氧基}乙基）環丙基】裱啶_1-基}嘧啶 步驟1 : 5-疊氮基-2-1»比咬 n35-(111-1,2,3-triazol-1-yl)_2-(4,- methoxybenzyloxy)β from step 3 of this example (890 mg, 3.1 5 mmol) Dissolved in dichlorohydrazine (η ml). Trifluoroacetic acid (3.64 ml, 47.3 mmol) was added and the mixture was taken at room temperature. Within 1 minute, the reaction turned into lavender. After addition of TF A, the reaction mixture was evaporated for 40 minutes, then re-suppleed in CH 2 C 12 /heptane and evaporated again. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc. The white solid was suspended in acetone and filtered through celite to remove the sulphur dioxide from the crude product. The filtrate was then evaporated and suctioned under high vacuum overnight to give the title compound as a complex with acetone. LRMS calculated: 162 丨; found: 162 9 (M+1). NMR (CD3OD): δ 8.38 (d, 1H, J=ll Hz), δ 8.03 (s, 1H), δ 8.02 (d, 1H, J=9 Hz), δ 7.87 (d, 1H, J=〇- 9 Hz), δ 6.69 (d, 1H, J-10.5 Hz), δ 2.15 (acetone). Preparation Example 71b Preparation of 5-gas-2-(44(1/^25)-2-(245-(1 ugly-1,2,3-triazol-1-yl)pyrene 141275.doc 201102374 pyridine-2-氧基 oxy}ethyl)cyclopropyl] acridine_1-yl}pyrimidine Step 1: 5-azido-2-1» than bite n3

NaN3, Cul, NMEDA 向經火焰乾燥之可密封反應容器中添加2-氟_5_碘吡咬 (1.12 g ’ 5 mmol)、疊氮化鈉（390 mg，. 6.00 mmol)、埃化 銅（1)(95 mg，0.500 mmol)及 L-抗壞血酸鈉鹽（49.5 mg， 0.250 mmol)。將容器抽真空且用氮氣淨化。向反應容器中 添加乙醇（7 mL)及水（3 ml) ’隨後抽真空且再用氮氣淨 化。經由微升注射器向容器中添加ν,ν·_二甲基乙二胺（8〇 μΐ ’ 0.750 mm〇i)。擰緊頂部且將反應加熱至i〇〇t：。在反 應w面置放安全防護罩作為作為保護措施。藉由TLC監測 反應，其指示45分鐘後起始物質耗盡。用水稀釋反應且用 乙酸乙酯萃取兩次。用水洗滌合併之有機物三次且用鹽水 洗滌-人。經硫酸鈉乾燥有機物，過濾且蒸發，得到63 〇 mg粗物質，該粗物質含有疊氮化物、起始物質及另一雜 貝。其不經純化即進行下一步驟。NMR (CDC13): § 7·95 (d，1Η)，7.45 (m，1Η)，7.26 (s, CDC13), 6·95 (dd, 1H)。 二唑-1-基）_2_氟吡啶 步驟 2 : 5·(1丑_i，2,3-NaN3, Cul, NMEDA Add 2-fluoro-5-iodopyridin (1.12 g '5 mmol), sodium azide (390 mg, 6.00 mmol), copper hydride to a flame-dried sealable reaction vessel ( 1) (95 mg, 0.500 mmol) and L-ascorbate sodium salt (49.5 mg, 0.250 mmol). The vessel was evacuated and purged with nitrogen. Ethanol (7 mL) and water (3 ml) were added to the reaction vessel, which was then vacuumed and then purified with nitrogen. ν,ν·_dimethylethylenediamine (8〇 μΐ '0.750 mm〇i) was added to the vessel via a microliter syringe. Tighten the top and heat the reaction to i〇〇t:. A safety shield is placed on the reaction w side as a protective measure. The reaction was monitored by TLC which indicated the starting material was consumed after 45 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organics were washed three times with water and washed with brine. The organics were dried over Na2SO4, filtered and evaporated to give &lt;RTIgt;&lt;/RTI&gt; It was carried on to the next step without purification. NMR (CDC13): § 7.95 (d, 1 Η), 7.45 (m, 1 Η), 7.26 (s, CDC13), 6.95 (dd, 1H). Diazol-1-yl)_2_fluoropyridine Step 2 : 5·(1 ugly _i, 2, 3-

將5-疊氮基-2-氟吼啶（262 mg，1.9 mmol)及乙酸乙烯酯 141275.doc -91 - 201102374 (4·〇 mL，43 mmol)在經火焰乾燥之高壓可密封容器中混 合。將反應容器抽真空且裝入氮氣，密封且加熱至丨〇〇〇C 歷時15小時。冷卻反應至室溫且TLC指示反應已完成❶向 反應中添加少量二氣甲烷（恰好足以溶解冷卻後形成之固 體）且用矽膠（Biotage 40S型管柱）用20·50%乙酸乙酯/庚烷 溶離直接層析溶液，得到呈白色固體狀之標題化合物。 LRMS s十算值：164.05 ;實測值：164.95 (Μ+1)。NMR (CDC13): δ 8.60 (d, 1H), 8.27 (m, 1H), 8.03 (d, 1H), 7.91 (d，1H)，7.26 (s, CDC13)，7.15 (dd，1H)。 製備實例72 製備4-(l丑-l，2,3-***_5_基）酚 步驟1 : 4-【4_(苄基氧基）苯基]-1丑-1，2,3-***Mix 5-azido-2-fluoroacridine (262 mg, 1.9 mmol) and vinyl acetate 141275.doc -91 - 201102374 (4·〇mL, 43 mmol) in a flame-dried high-pressure sealable container . The reaction vessel was evacuated and charged with nitrogen, sealed and heated to EtOAc over 15 s. The reaction was cooled to room temperature and TLC indicated that the reaction was completed. A small amount of methane methane (sufficiently enough to dissolve the solid formed after cooling) was added to the reaction, and a silica gel (Biotage 40S column) was used with 20.50% ethyl acetate/g The title compound was obtained as a white solid. LRMS s ten values: 164.05; measured value: 164.95 (Μ +1). NMR (CDC13): δ 8.60 (d, 1H), 8.27 (m, 1H), 8.03 (d, 1H), 7.91 (d, 1H), 7.26 (s, CDC13), 7.15 (dd, 1H). Preparation Example 72 Preparation of 4-(l-ugly-1,2,3-triazol-5-yl)phenol Step 1: 4-[4-(benzyloxy)phenyl]-1 ugly-1,2,3- Triazole

在氬氣下在壓力管中將三甲基矽烷基疊氮化物（4 i 5 mg ’ 3.6 mmol)添加至含有 CuI(22.9 mg，〇_12 mm〇1)及卜 (苄基氧基）-4-乙炔基苯（5 〇〇 mg，2.4 mmol)之DMF(4.3 mL)及MeOH(0.48 mL)溶液中（警告：壓力可能增大；使用 安全防護罩）。在lOOt：下攪拌反應混合物12小時》將混合 物冷卻至室溫且經短矽膠墊過濾且濃縮。藉由自DCM再結 晶來純化殘餘物。 步驟2 : 4-(1丑-1，2,3-***-5_基）酚 141275.doc -92- 201102374Trimethyl decyl azide (4 i 5 mg ' 3.6 mmol) was added to a pressure tube containing CuI (22.9 mg, 〇_12 mm〇1) and b (benzyloxy)- under argon. 4-Ethynylbenzene (5 〇〇mg, 2.4 mmol) in DMF (4.3 mL) and MeOH (0.48 mL) (Warning: pressure may increase; use safety shield). The reaction mixture was stirred at 100 °: for 12 hours. The mixture was cooled to room temperature and filtered over a pad of silica gel and concentrated. The residue was purified by recrystallization from DCM. Step 2: 4-(1 ugly-1,2,3-triazol-5-yl)phenol 141275.doc -92- 201102374

根據類似於實例71 + 0 a ,十_ , 驟2之程序錯由裂解來自該實例步 驟1之苄基醚來製備標題酚。 製備實例73 製備4-(1丑·四唑基）酚The title phenol was prepared by cleavage of the benzyl ether from step 1 of this example according to a procedure analogous to the procedure of </ RTI> </ RTI> <RTIgt; Preparation Example 73 Preparation of 4-(1 ugly tetrazolyl)phenol

一0Y\ —0 NaN〇2, NaN3f HOAcOne 0Y\—0 NaN〇2, NaN3f HOAc

N-NN-N

OH 將原甲酉夂一甲酉曰（9.34 g，88 _〇1)添加至裝有心經基苯 胺（3 g，27_5㈣1)之燒瓶中，接著添加亞《鈉（1.9 g， 27.5 mmol)及乙酸（5〇叫。加熱混合物至贼歷時剀、 時，自加熱浴令移出反應且轉移至錐形瓶（EHe_yei flask)中。用冰浴冷卻燒瓶至吖，隨後添加水（25 mL)及 HC1水溶液(6 M’ U mL)。向反應混合物中緩慢添加於水 中之疊氮㈣（2.234 ^34.4職。1)(呈3鄉液）。收集所 物且在真工下乾燥，得到所要產物。計算 值.162_1 ’ 貫測值· 163.2 1)。 製備實例73a 製備3-氟·4-(1好-四唑-l_基）紛OH Adds the original formazan-methyl hydrazide (9.34 g, 88 〇1) to a flask containing phenyl aniline (3 g, 27_5 (tetra) 1) followed by the addition of sub-sodium (1.9 g, 27.5 mmol) and acetic acid. (5 squeaking. When the mixture is heated to the thief for a while, the reaction is removed from the heating bath and transferred to a conical flask (EHe_yei flask). The flask is cooled to the crucible with an ice bath, followed by the addition of water (25 mL) and an aqueous solution of HCl. (6 M' U mL). Slowly add azide (4) (2.234 ^ 34.4 jobs.1) (in 3) to the reaction mixture. Collect the material and dry it under the actual work to obtain the desired product. Value .162_1 'Performance value · 163.2 1). Preparation Example 73a Preparation of 3-Fluoro-4-(1 good-tetrazole-l-yl)

N—N VNN-N VN

OH 根據類似於關於貫例73所述之程序由心胺基_3_氟酚製備 141275.doc •93· 201102374 標題化合物° 製備實例75 製備4-(2/^四唑-2-基）酚 步驟1 : 2-(4-硝基苯基）_2好·四唑OH was prepared from cardioamine-based _3_fluorophenol according to procedures similar to those described in Example 73. 141275.doc •93· 201102374 Title Compound ° Preparation Example 75 Preparation of 4-(2/^tetrazol-2-yl)phenol Step 1: 2-(4-Nitrophenyl)_2 good tetrazolium

將1H-四峻於乙腈中之溶液（〇.45 μ，19 mL，8.5 mmol) 與4-氟-石肖基苯（1 g ’ 7.09 mmol)混合於40 mL壓力管中，接 著添加碳酸鉀。將管密封且在11 〇°C下加熱隔夜（警告：壓 力可能增大；使用安全防護罩）。觀察到壓力增大。小心 地釋放壓力。濃縮反應至無水且用水稀釋。用DCM萃取水 性混合物4次。經硫酸鈉乾燥合併之有機層，過濾，濃縮 且藉由經40公克Biotage矽膠筒用5·20%乙酸乙酯/己烷（梯 度）溶離進行管柱層析來純化，得到呈白色固體狀之產 物。LRMS計算值：191.0 ;實測值：192.3 (Μ+1)。 步驟2 : 4-(2好-四唑-2_基）苯胺A solution of 1H-tetras in acetonitrile (〇.45 μ, 19 mL, 8.5 mmol) was mixed with 4-fluoro-succinylbenzene (1 g ' 7.09 mmol) in a 40 mL pressure tube, followed by the addition of potassium carbonate. Seal the tube and heat it overnight at 11 °C (warning: pressure may increase; use safety shield). An increase in pressure was observed. Carefully release the pressure. The reaction was concentrated to dryness and diluted with water. The aqueous mixture was extracted 4 times with DCM. The combined organic layers were dried with sodium sulfate, filtered, evaporated and purified eluting eluting eluting eluting eluting product. LRMS calculated: 191.0; found: 192.3 (Μ +1). Step 2: 4-(2--tetrazol-2-yl)aniline

將2-(4-石肖基苯基）-2Η-四坐（200 mg，1.05 mmol)懸浮於 乙醇（1 mL)中。添加乙酸乙酯（1 mL)以改良溶解性。將馨 液脫氣且用氮氣淨化3次，之後添加鈀/碳（1 〇重量/重量 %，223 mg，0.2 mmol)。將混合物脫氣且用氫氣淨化3夫 H1275.doc -94- 201102374 用丙酮稀釋反應且穿過矽膠 且在氫氣球下攪拌2小時。 基用丙酮充分洗滌該矽膠塞。濃縮濾出物以得到粗產 物，其如分離時原樣使用。 步驟3 : 4-(2丑-四唾_2_基）酚2-(4-Shidocylphenyl)-2Η-tetrazole (200 mg, 1.05 mmol) was suspended in ethanol (1 mL). Ethyl acetate (1 mL) was added to improve solubility. The sesame liquid was degassed and purged 3 times with nitrogen, after which palladium on carbon (1 〇 wt/wt %, 223 mg, 0.2 mmol) was added. The mixture was degassed and purified with hydrogen. 3H H1275.doc -94 - 201102374 The reaction was diluted with acetone and passed through a silica gel and stirred under a hydrogen balloon for 2 hours. The silicone plug was thoroughly washed with acetone. The filtrate was concentrated to give a crude product which was used as it was. Step 3: 4-(2 ugly-tetras-_2-yl)phenol

將粗4-(2仏四唑-2_基）苯胺（6〇 mg，〇 372 mm〇1)懸浮於 水（2 mL)及硫酸（0.2 mL)中，之後冷卻至0它。添加亞硝酸 鈉（26 mg，0.565 mmol)於水（2 mL)中之水溶液。在〇°c下 授拌混合物30分鐘。再添加水（1 mL)及硫酸（〇37 mL)且在 120°C下加熱混合物歷時丨小時。隨後冷卻反應且用乙酸乙 醋萃取3次。用鹽水洗務合併之有機層，經硫酸鈉乾燥， 過滤’濃縮且藉由用3 0%乙酸乙醋/己烧溶離進行製備型 TLC來純化’得到黃色固體狀之所要盼產物。lrms計算 值：162.1 ;實測值：163.2 (M+1)。 製備實例75a 製備4-(5-甲基-2丑-四唑-2-基）酚及4-(5-甲基·1丑_四0坐小 基）紛 步驟1 : 5-甲基·2-(4-硝基苯基）-2好-四唑及5-甲基^^^硝 基苯基）-1/Γ·四唑Crude 4-(2仏tetrazol-2-yl)aniline (6 〇 mg, 372 372 mm 〇 1) was suspended in water (2 mL) and sulfuric acid (0.2 mL), then cooled to 0. An aqueous solution of sodium nitrite (26 mg, 0.565 mmol) in water (2 mL) was added. The mixture was mixed for 30 minutes at 〇 °c. Water (1 mL) and sulfuric acid (〇37 mL) were further added and the mixture was heated at 120 ° C for an hour. The reaction was then cooled and extracted three times with ethyl acetate. The combined organic layer was washed with EtOAc (EtOAc m. Lrms calculated: 162.1; found: 163.2 (M+1). Preparation Example 75a Preparation of 4-(5-methyl-2 ugly-tetrazol-2-yl)phenol and 4-(5-methyl·1 ugly-four-positioned small base) Step 1: 5-methyl· 2-(4-Nitrophenyl)-2-tetrazolium and 5-methyl^^^nitrophenyl)-1/Γ·tetrazole

N〇2 NO； 141275.doc •95· 201102374 將 5-曱基-1//-四唑（715 mg，8‘5 mmol)溶解於 4〇 mL Biotage微波管中之DMF(7 mL)中。添加4-氟-硝基苯g ’ 7.09 mmol) ’接著添加碳酸鉀（i.i75 g，8_5 mmol)。將管 捲曲密封且在110。(：下加熱4小時（警告：壓力可能增大； 使用安全防護罩）。TLC指示起始物質完全耗盡。在真空下 移除大部分DMF。添加水（5 〇 mL)。形成大量棕色固體（1公 克）且藉由過渡故集。經由8〇公克Biotage石夕膠筒使用soys% 乙 酸乙酯 / 己烷經 管柱進 一步純 化固體 ，得到 5_ 甲基-2_ (4-硝基苯基四唑之純淨溶離份，[RMS計算值： 205.1 ;實測值：206.3 (M+1)。 過渡後用DCM萃取母液4次。經硫酸鈉乾燥合併之有機 相’過遽’漢縮且藉由經80公克Biotage梦膠筒使用30-75°/。乙酸乙酯/己烧進行管柱層析來純化，得到5_曱基-卜 (4-硝基苯基）-1//-四唑，[RMS計算值：205.1 ;實測值： 206.3 (M+1)。 步驟2 : 4-(5-甲基-2丑-四唑-2-基）苯胺及4-(5-曱基d好-四 唑-1-基）苯胺N〇2 NO; 141275.doc •95· 201102374 5-Mercapto-1//-tetrazole (715 mg, 8 '5 mmol) was dissolved in DMF (7 mL) in a 4 mL mL Biotage microwave tube. 4-Fluoro-nitrobenzene g ' 7.09 mmol) was added followed by potassium carbonate (i.i 75 g, 8-5 mmol). The tube is crimped and sealed at 110. (: heating for 4 hours (warning: pressure may increase; use safety shield). TLC indicates complete depletion of starting material. Most of DMF is removed under vacuum. Add water (5 〇 mL). Form a large amount of brown solid (1 gram) and further by a transitional collection. The solid was further purified via a column of 8 gram of Biotage, using a soys% ethyl acetate/hexane to give 5-methyl-2-(4-nitrophenyltetrazole). The pure dissolved fraction, [RMS calculated: 205.1; found: 206.3 (M + 1). After the transition, the mother liquor was extracted 4 times with DCM. The organic phase was dried over sodium sulfate and dried over 80. The Gram Biotage Dream Cartridge is purified by column chromatography using 30-75 ° / ethyl acetate / hexane to give 5 - mercapto-bu (4-nitrophenyl)-1 / / - tetrazole, [ RMS calculated: 205.1; found: 206.3 (M + 1). Step 2: 4-(5-methyl-2 ugly-tetrazol-2-yl)aniline and 4-(5-fluorenyl d-good-four Zin-1-yl)aniline

141275.doc •96· 201102374 將5曱基-2-(4-硝基苯基）-27/-四〇坐（200 mg，〇 gw mmol)懸浮於甲醇（15 mL)中。將溶液脫氣且用氮氣淨化3 次’之後添加鈀/碳（10重量/重量％，51 9 mg， mmol)。將混合物脫氣且用氫氣淨化3次且在氫氣球下攪拌 2小時。用丙酮稀釋反應且穿過矽膠塞，用丙酮充分洗滌 忒矽膠塞。濃縮濾出物，得到粗產物4_(5甲基_2丑-四唑 基）苯胺’其如分離時原樣使用。 在相同條件下合成4-(5-甲基-1好_四唑_丨·基）苯胺。 步驟3 · 4-(5-曱基-2丑·四唑-2-基）酚及4_(5_甲基-四唑_141275.doc •96· 201102374 5-Mercapto-2-(4-nitrophenyl)-27/-tetrazole (200 mg, 〇gw mmol) was suspended in methanol (15 mL). The solution was degassed and purged 3 times with nitrogen&apos; followed by the addition of palladium on carbon (10 wt/wt%, 51 9 mg, mmol). The mixture was degassed and purged 3 times with hydrogen and stirred under a hydrogen balloon for 2 hours. The reaction was diluted with acetone and passed through a silicone plug, and the silicone plug was thoroughly washed with acetone. The filtrate was concentrated to give the crude product 4-(5-methyl-2 ugly-tetrazolyl) phenylamine. 4-(5-Methyl-1?-tetrazol-indoleyl)aniline was synthesized under the same conditions. Step 3 · 4-(5-Mercapto-2 ugly tetrazol-2-yl)phenol and 4_(5-methyl-tetrazole_

1-基）酚1-yl)phenol

根據類似於實例75步驟3之程序合成標題化合物。 製備實例76 製備6 -經基-2-甲基喷咬甲猜 步驟1 : 4-氯-6·[(4-甲氧基f基）氧基】·2·甲基喷咬The title compound was synthesized according to a procedure similar to the procedure PREPARATION EXAMPLE 76 Preparation of 6-Pyridyl-2-methyl smear. Step 1: 4-Chloro-6·[(4-methoxyf-yl)oxy]·2·methyl lancet

將4-甲氧基$基醇（丨66 g ’ 12議。丨）溶解於叫Dissolve 4-methoxy-based alcohol (丨66 g ’ 12 丨.丨) in a called

[S 141275.doc -97- 201102374 中添加氣氧化鉀（2Ji g，36麵〇卜π%)且在室溫下授 拌ίο分鐘，接著冷卻至0它。將4,6-二氯_2_甲基嘧啶（215 g，13.2 mm〇i)溶解sDMF(4 mL)中且逐滴添加至溶液中。 控制内部溫度在2t以下。將反應溶液在（TC保持2小時， 隨後經1小時使其緩慢加熱至16。〇。用乙酸乙酯（5〇 稀 釋反應’用鹽水（50 mLx2)洗滌，經MgS〇4乾燥，過渡且 在真空中濃縮。藉由矽膠層析（用7.7%乙酸乙酯/己烷溶離） 純化粗混合物’得到呈無色油狀之標題化合物。lc_ms (M+1): 265.51，（M+23): 287_52。 步驟2 : 6-[(4-甲氧基f基）氧基】_2_甲基嘧啶_4_曱腈[S 141275.doc -97- 201102374 Add potassium oxychloride (2Ji g, 36 〇 π%) and allow it to be stirred at room temperature for 00 minutes, then cool to 0. 4,6-Dichloro-2-methylpyrimidine (215 g, 13.2 mm 〇i) was dissolved in sDMF (4 mL) and added dropwise to the solution. Control the internal temperature below 2t. The reaction solution was kept at (TC for 2 hours, then slowly heated to 16 hr over 1 hour. Ethyl acetate (5 〇 diluted reaction 'washed with brine (50 mL×2), dried over MgS 〇4, transition and The title compound was obtained as a colorless oil. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> Step 2: 6-[(4-Methoxyfyl)oxy]_2-methylpyrimidine_4_indolecarbonitrile

1) Pd (0C(0)CF3)21) Pd (0C(0)CF3)2

2) 鋅塵 3) 配位體 4) Zn(CN)20.56 當量2) Zinc dust 3) Ligand 4) Zn(CN) 20.56 equivalent

DMA 95 °C 將起始物質來自該實例步驟1之4-氣-6-[(4-曱氧基苄基） 氧基]-2 -甲基痛咬（3.7 g，14 mmol)、三氟乙酸纪（0_2 g， 0.6 mmol)、外消旋2-(二第三丁基膦基）-l，l-聯萘配位體 (0.49 g ’ 1.23 mmol)、鋅塵（0.17 g，2·65 mmol)及氰化鋅 (0·92 g，7.8 mmol)添加至燒瓶（1 〇〇 mL)中，且添加二甲基 乙醯胺（73 mL)。將燒瓶抽真空且用N2回填三次，且在室 溫下攪拌反應溶液30分鐘。隨後將反應加熱至95°C歷時30 分鐘且監測直至起始物質耗盡。冷卻反應至室溫，用乙酸 乙酯（100 mL)稀釋，用鹽水（50 mL&gt;&lt;2)洗滌，經MgS04乾 燥，過濾且在真空中濃縮。藉由矽膠層析（用7.7%乙酸乙 141275.doc •98· 201102374 酯/己烷溶離）純化粗的淺黃色油狀物，得到呈白色固體狀 之標題化合物。LC-MS (M+23): 278。 步驟3 : 6-羥基-2-甲基嘧啶-4-曱腈DMA 95 ° C The starting material was from 4-furo-6-[(4-decyloxybenzyl)oxy]-2-methyl pain bit (3.7 g, 14 mmol), trifluorobenzene from step 1 of this example. Acetic acid (0_2 g, 0.6 mmol), racemic 2-(di-t-butylphosphino)-l,l-binaphthyl ligand (0.49 g ' 1.23 mmol), zinc dust (0.17 g, 2·) 65 mmol) and zinc cyanide (0·92 g, 7.8 mmol) were added to the flask (1 mL) and dimethylacetamide (73 mL) was added. The flask was evacuated and backfilled three times with N2, and the reaction solution was stirred at room temperature for 30 minutes. The reaction was then heated to 95 °C for 30 minutes and monitored until the starting material was consumed. The reaction was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc)EtOAc. The crude title compound was obtained as a white solid. LC-MS (M+23): 278. Step 3: 6-Hydroxy-2-methylpyrimidine-4-indolecarbonitrile

將來自該實例步驟2之6-[(4-曱氧基苄基）氧基]-2-甲基嘴 0定-4-曱腈（2·8 g，11 mmol)溶解於DCM(9.1 mL)中且經由 注射器逐滴添加TFA( 1.8 mL)。使反應在室溫下進行丨〇分 鐘且在真空下在不加熱之情況下濃縮至近乎無水。將殘餘 物溶解於DCM(10 mL)中，且添加飽和NaHCCh溶液（水溶 液’ 5 mL)以將pH值調整至約7。隨後向溶液中添加乙酸（1 mL)以將PH值調整至約4且在真空中濃縮混合物至無水。 藉由使用梯度溶離（以30%乙酸乙酯/己烷起始，隨後變成 5%曱醇/DCM)進行矽膠層析來純化殘餘物，得到呈白色固 體狀之標題化合物。LC-MS (M+1): 136.16。 製備實例76a 製備6-氯-2-甲基嘧啶-4-甲腈 1) Pd〇-FA)2l 4.3mol% 2) 鋅塵 19mol% 3酒己位體8.8mol% 4) Zn(CN),6-[(4-decyloxybenzyl)oxy]-2-methyl-n-butyl-4-indenecarbonitrile (2·8 g, 11 mmol) from step 2 of this example was dissolved in DCM (9.1 mL) TFA (1.8 mL) was added dropwise via syringe. The reaction was allowed to proceed at room temperature for a minute and concentrated to near anhydrous under vacuum without heating. The residue was dissolved in DCM (10 mL) and a saturated NaHCCh solution (aq. Acetic acid (1 mL) was then added to the solution to adjust the pH to about 4 and the mixture was concentrated in vacuo to dryness. The residue was purified by EtOAc (EtOAc) elute LC-MS (M+1): 136.16. Preparation Example 76a Preparation of 6-chloro-2-methylpyrimidine-4-carbonitrile 1) Pd〇-FA) 2l 4.3 mol% 2) Zinc dust 19 mol% 3 wine octomer 8.8 mol% 4) Zn(CN),

將4,6-二氣-2-曱基密咬（10 g ’ 60 mmol)、三氣乙酸把 (11)(0.86 g，2.6 mmol)、鋅塵（65.3 g，11.4 mmol)、外消 141275.doc •99- 201102374 旋2-(二第二丁基膦基聯萘（2丨g，5 3 mm〇1)、氰化 鋅（3.95 g，33.7 mmol)及二甲基乙醯胺（316 ml)添加至5〇〇 mL經火焰乾燥之燒瓶中。將容器抽真空且用a回填3次。 在N2下在室溫下攪拌混合物3〇分鐘，隨後加熱至95°C。 2.5小時後’用EtOAc(300 mL)稀釋混合物且用水（3〇〇 mLx3)洗滌。合併有機部分，經MgS〇4乾燥，過濾且在真 空中移除揮發性物質。將殘餘物溶解於Et〇Ac(i〇〇 mL) 中，用水（50 ml)洗滌且分離各層。隨後用Et〇Ac(50 mL)萃 取水相’合併有機部分’經MgS04乾燥，過濾且在真空中 移除揮發性物質。藉由矽膠層析（用1 ·· 19乙酸乙酯：己烷溶 離）純化粗混合物，得到呈無色油狀之標題化合物。4 NMR (CD3OD): 8.235 (s，1H), 2.816 (s，3H)。 類似地製備下列酚前驅物： 製備實例77 製備4-羥基-6-甲基嘧啶-2-甲腈4,6-diox-2-indole (8 g '60 mmol), tri-acetic acid (11) (0.86 g, 2.6 mmol), zinc dust (65.3 g, 11.4 mmol), extinction 141275 .doc •99- 201102374 Cyclo 2-(di-tert-butylphosphine binaphthyl (2丨g, 5 3 mm〇1), zinc cyanide (3.95 g, 33.7 mmol) and dimethylacetamide (316 Ml) was added to a 5 mL mL flame-dried flask. The vessel was evacuated and backfilled 3 times with a. The mixture was stirred at room temperature for 3 minutes at N2, then heated to 95 ° C. After 2.5 hours' The mixture was diluted with EtOAc (300 mL) and washed with EtOAc (EtOAc &lt;RTI ID=0.0&gt; 〇mL), wash with water (50 ml) and separate the layers. Then extract the aqueous phase with 'Et〇Ac (50 mL) and combine the organic portion dried over MgS04, filter and remove volatiles in vacuo. The crude mixture was purified with EtOAc EtOAc (EtOAc: EtOAc) Ground The following phenol precursors were prepared: Preparation Example 77 Preparation of 4-hydroxy-6-methylpyrimidine-2-carbonitrile

根據類似於關於實例76描述之程序由2,4-二氯-6-曱基嘧 啶製備標題化合物。 LC-MS (M+1): 136.16。 製備實例78 製備6-羥基嘧啶-4-甲腈The title compound was prepared from 2,4-dichloro-6-decylpyrimidine according to a procedure similar to that described in Example 76. LC-MS (M+1): 136.16. Preparation Example 78 Preparation of 6-hydroxypyrimidine-4-carbonitrile

141275.doc •100· 201102374 根據類似於關於實例76描述之程序由4,6-二氣嘧啶製備 標題化合物。 LC-MS (M+1): 122.07。 製備實例79 製備4-羥基嘧啶-2-甲腈141275.doc • 100· 201102374 The title compound was prepared from 4,6-dioxapyrimidine according to procedures similar to those described for Example 76. LC-MS (M+1): 122.07. Preparation Example 79 Preparation of 4-Hydroxypyrimidine-2-carbonitrile

OH 根據類似於關於實例76描述之程序由2,4-二氯嘧啶製備 標題化合物。 LC-MS (M+1): 122.06。 製備實例80 製備5-羥基菸鹼腈 1) Pd(TFA)2 4.3mol% 2) 鋅塵 19moi〇/〇OH The title compound was prepared from 2,4-dichloropyrimidine according to procedures similar to those described for example 76. LC-MS (M+1): 122.06. Preparation Example 80 Preparation of 5-hydroxynicotinonitrile 1) Pd(TFA)2 4.3 mol% 2) Zinc dust 19 moi〇/〇

HOHO

DMAC (0.19M) 95CDMAC (0.19M) 95C

CN 3) 配位體 8.8mo!%e 4) Zn(CN)2 0.56 當量 根據類似於關於實例76步驟2描述之程序由5-氯吡啶-3-醇製備標題化合物。 LC-MS (M+1): 121.08。 製備實例81 製備5-羥基吡啶-2-甲腈 ν^τ〇η 根據類似於關於實例76步驟2描述之程序由6-氯吡啶-3-醇製備標題化合物。 LC-MS (M+1): 121.08。 141275.doc -101 - 201102374 製備實例81a 製備2-{2-[l-(5-氯-4-甲基嘧啶-2-基）哌啶-4-基】環丙基}乙醇 步驟1 :製備2,5-二氯-4-曱基嘧啶CN 3) Ligand 8.8 mo!%e 4) Zn(CN)2 0.56 eq. The title compound was obtained from 5-chloropyridin-3-ol. LC-MS (M+1): 121.08. PREPARATION EXAMPLE 81 Preparation of 5-hydroxypyridine-2-carbonitrile The title compound was prepared from 6-chloropyridin-3-ol. LC-MS (M+1): 121.08. 141275.doc -101 - 201102374 Preparation Example 81a Preparation of 2-{2-[l-(5-chloro-4-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol Step 1: Preparation 2,5-dichloro-4-mercaptopyrimidine

MgBrMe3M，1.2 當量 THF:NMP 10:1MgBrMe3M, 1.2 equivalents THF: NMP 10:1

在室溫下將2,4,5-三氯鳴唆（1.83 g，1 〇 mmol)溶解於 THF:NMP(10:1 ’ 1〇〇 mL)中且在Ns下添加乙醯基丙酮酸鐵 (111)(0.71 g，2.0 mmol)。經由注射器逐滴添；^MgBrMe(3 Μ，12 mmol)。將混合物冷卻至室溫，根據1^_]^!5確定進 展：典型結果展示產物：起始物質：5-氣-2,4-二甲基。密咬 副產物之比率為約2:2:1。用冰冷飽和氣化銨（，1 〇〇 mL)中 止反應，用乙酸乙酯（100 mL)萃取，用鹽水（1〇〇 mLx2)洗 務’經MgS〇4乾燥，過濾且在真空中濃縮。藉由矽膠層析 (5%乙酸乙酯/己烷）純化粗混合物，得到標題化合物。 LC-MS (M+1): 163.23。 步驟2 :外消旋順式-2-{2-[1-(5_氯_4_甲基嘧啶_2基）哌啶_ 基]環丙基}乙醇2,4,5-trichloropurine (1.83 g, 1 〇mmol) was dissolved in THF:NMP (10:1 '1〇〇mL) at room temperature and iron acetate pyruvate was added under Ns (111) (0.71 g, 2.0 mmol). Add dropwise via syringe; ^MgBrMe (3 Μ, 12 mmol). The mixture was cooled to room temperature and progress was determined according to 1^_]^!5: Typical results show the product: starting material: 5- gas-2,4-dimethyl. The ratio of the bite by-product is about 2:2:1. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The crude mixture was purified by EtOAc EtOAcEtOAcEtOAc LC-MS (M+1): 163.23. Step 2: Racemic cis-2-{2-[1-(5-chloro-4-methylpyrimidin-2-yl)piperidinyl]cyclopropyl}ethanol

1) TFA 2) Cs2C〇3i NMP, 70 °C1) TFA 2) Cs2C〇3i NMP, 70 °C

根據類似於實例6步驟2之程序由來自該實例步驟丨之2,5_ 二氣-4·曱基嘧啶及外消旋順式_4·[·2_(2_羥基乙基）環丙基] 娘咬-1-曱酸第三丁酯製備標題化合物。 141275.doc -102· 201102374 LC-MS (M+l)： 296.61 〇 製備實例81b 製備2-{2-[1-(4,5·二甲基嘧啶_2_基）哌啶_4_基】環丙基）乙醇 步驟1 ·製備2_氣_4,5_二甲基嘴咬According to the procedure similar to the procedure of Example 2, Step 2, 2,5-diox-4·mercaptopyrimidine and racemic cis_4·[·2_(2-hydroxyethyl)cyclopropyl] from the step of the example The title compound was prepared by the bite of 1-butyl phthalate. 141275.doc -102· 201102374 LC-MS (M+l): 296.61 〇Preparation Example 81b Preparation of 2-{2-[1-(4,5·dimethylpyrimidin-2-yl)piperidine-4-yl 】cyclopropyl)ethanol step 1 · preparation 2_ gas _4,5 dimethyl mouth bite

MgBrMe3M. 1.2 當量 THF:NMP10:1 Fe(acac)3, 0.2 當量 &lt;10 °C, N,_MgBrMe3M. 1.2 equivalents THF: NMP10:1 Fe(acac)3, 0.2 equivalents &lt;10 °C, N,_

除反應溫度外根據類似於實例42步驟1中描述之程序由 2,4-二氯-5-甲基嘧啶製備標題化合物。反應溫度維持在 10°C以下。 LC-MS (M+1): 143.22。 步驟2 :製備2-{2“[1-(4,5_二甲基嘧啶2基）哌啶_4_基】環丙 基}乙醇The title compound was prepared from 2,4-dichloro-5-methylpyrimidine according to a procedure similar to the procedure described in step 1 of Example 42 except for the reaction. The reaction temperature was maintained below 10 °C. LC-MS (M+1): 143.22. Step 2: Preparation of 2-{2"[1-(4,5-dimethylpyrimidinyl)piperidine-4-yl]cyclopropyl}ethanol

1) TFA 2) Cs2CO3,NMP,90°C1) TFA 2) Cs2CO3, NMP, 90 °C

除反應溫度及時間外根據類似於實例6步驟2中描述之程 序由2-氯_4’5_二甲基嘧啶及外消旋順式-4-[-2-(2-羥基乙 基）環丙基]哌啶-1·甲酸第三丁酯製備標題化合物。在9〇&lt;t 下加熱反應2小時。 LC-MS (M+1): 276.56。 製備實例81c 製備2-{2_[1-(5|4_甲基㈣小基)錢_4基]環丙基}乙醇 步驟1 :製備2-氯_5·氟_4_甲基嘧啶 141275.doc 201102374 ciExcept for the reaction temperature and time, according to the procedure similar to that described in Step 2 of Example 6, 2-chloro-4'5-dimethylpyrimidine and racemic cis-4-[2-(2-hydroxyethyl) The title compound was prepared from cyclopropyl]piperidine-1. The reaction was heated at 9 ° &lt; t for 2 hours. LC-MS (M+1): 276.56. PREPARATION EXAMPLE 81c Preparation of 2-{2_[1-(5|4-methyl(tetra))yl)]-yl]cyclopropyl}ethanol Step 1: Preparation of 2-chloro-5-fluoro-4-methylpyrimidine 141275 .doc 201102374 ci

FF

MgBrMe 3M，1.2 當量 THF:NMP 10:1 Fe(acac&gt;3,0.2 當量 &lt;10 °C, N?_ 除反應溫度及時間外根據類似於實例42步驟1中描述之 程序由2,4-二氯-5-曱基嘧啶獲得標題化合物。反應溫度維 持在10°C以下。 LC-MS (M+1): 147.22 〇 步驟2 : 2-{2-[1-(5-氟-4-甲基嘧啶_2_基）哌啶_4_基】環丙基} 乙醇MgBrMe 3M, 1.2 equivalents of THF: NMP 10:1 Fe (acac &gt; 3, 0.2 equivalents &lt; 10 ° C, N?_ except for the reaction temperature and time according to the procedure similar to that described in Step 1 of Example 42 by 2,4- The title compound was obtained as the dichloro-5-mercaptopyrimidine. The reaction temperature was maintained below 10 ° C. LC-MS (M+1): 147.22 〇 Step 2: 2-{2-[1-(5-fluoro-4- Methylpyrimidine_2-yl) piperidine_4_yl]cyclopropyl}ethanol

1) TFA 2) Cs2C03, NMP, 90 °C1) TFA 2) Cs2C03, NMP, 90 °C

除反應溫度外根據類似於步驟6步驟2之程序由2_氣_5_ 氟-4-甲基嘧啶及外消旋順式_4-[-2-(2-羥基乙基）環丙基；|哌 °疋-1 -曱酸第二丁 Sa製備標題化合物。在9〇。〇下加熱反應2 小時。In addition to the reaction temperature, according to the procedure similar to the step 2 of step 6, from 2-gas _5_fluoro-4-methylpyrimidine and racemic cis-4-[2-(2-hydroxyethyl)cyclopropyl; The title compound was prepared by piperazine-1 -decanoic acid sec. At 9 〇. Heat the reaction under the arm for 2 hours.

LC-MS (M+1): 280.22 〇 實例83 F及S 製備純對映異構體5-氯氟_4_(5_甲 基-1，3,4·鳴二峻-2-基）笨氧基】乙基}環丙基）略咬^基]喷啶 及 5-氯-2-(4-(㈨，2/〇-2-{2-【3_氣_4_(5_甲基_1，3,4_噪二唑_2_ 基）苯氧基]乙基}環丙基）娘咬-1-基】喷咬 141275.doc -104· 201102374LC-MS (M+1): 280.22 〇 Example 83 F and S Preparation of the pure enantiomer 5-chlorofluoro_4_(5-methyl-1,3,4. Oxyl]ethyl}cyclopropyl) succinate] pyridine and 5-chloro-2-(4-((9), 2/〇-2-{2-[3_气_4_(5_methyl) _1,3,4_noisemazole_2_yl)phenoxy]ethyl}cyclopropyl)niede-1-base] spray bite 141275.doc -104· 201102374

分析篩選：用 chiralpak ΙΑ 4.6x250 mm，5 μ在 40% 等度 乙醇/庚烷（0.75 mL/min)下成功拆分實例14之外消旋順式_ 5-氯 _2-[4-(2-{2-[3-氟-4-(5-甲基 _l，3,4-噁二唑 _2_基）苯氧 基]乙基}環丙基）哌啶-1 -基]嘧啶。滞留時間：較快對映異 構體：T= 12.4分鐘；較慢對映異構體：τ= 15.9分鐘。 將實例14之外消旋順式氯_2_[4·(2_{2_[3_氟_4_(5曱 基-1，3,4-噁一唑-2-基）苯氧基]乙基}環丙基）派啶_丨_基]嘧啶 (5 mg) &gt;谷解於2.5 mL乙醇中。使溶液經受用半製備型 chiralpak IA 管柱（20x250 mm，5 μ)在 40% 乙醇/庚烷以9 mL/min等度溶離下進行的HPLC分離。基線分離出對映異 構體。滯留時間：較快對映異構體：83 F，；36八 鐘；較慢對映異構體：83 S ’ Τ=44.37分鐘。鑑別溶離份 為順式-5-氯-2-[4-(2-{2-[3-氟-4-(5-甲基 _ι，3,4-。惡二唾 2Analytical screening: Example 14 was successfully resolved with chiralpak® 4.6×250 mm, 5 μ at 40% isocratic ethanol/heptane (0.75 mL/min). _ 5-Chloro-2-[4-( 2-{2-[3-Fluoro-4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl] Pyrimidine. Residence time: faster enantiomer: T = 12.4 min; slower enantiomer: τ = 15.9 min. Example 14 is a racemic cis-chloro-2_[4·(2_{2_[3_fluoro_4_(5-mercapto-1,3,4-oxaoxazol-2-yl)phenoxy]ethyl group }cyclopropyl)pyrazine_丨_yl]pyrimidine (5 mg) &gt; glutathione in 2.5 mL of ethanol. The solution was subjected to HPLC separation using a semi-prepared chiralpak IA column (20 x 250 mm, 5 μ) in 40% ethanol/heptane isocratic separation at 9 mL/min. The enantiomers were separated at baseline. Residence time: faster enantiomer: 83 F,; 36 octa; slower enantiomer: 83 S ′ Τ = 44.37 min. Identify the dissolving fraction as cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl _ι,3,4-. dioxin 2)

基）本氧基]乙基}環丙基）。底淀-1·基]。密唆之對映異構體。 實例83a F及S 製備純對映異構體5-氣-2-[4-((1*5,2/?)-2-{2-[4-(111-12 3 = 唑-1-基）苯氧基】乙基}環丙基）哌啶-1基]嘧啶及5_氣_2_【4 ((1及，2*5)-2-{2-[4-(111-1，2,3-***_1-基）苯氧基]乙基}環丙 基）旅咬-1-基]癌咬 141275.doc •】05· 201102374Base) oxy]ethyl}cyclopropyl). Deposition -1 base. Enantiomers of milano. Example 83a F and S Preparation of the pure enantiomer 5-gas-2-[4-((1*5,2/?)-2-{2-[4-(111-12 3 = azole-1- Phenoxy]ethyl}cyclopropyl)piperidin-1yl]pyrimidine and 5_gas_2_[4 ((1 and, 2*5)-2-{2-[4-(111-1 , 2,3-triazole-1-yl)phenoxy]ethyl}cyclopropyl) brigade-1-yl] cancer bite 141275.doc •]05· 201102374

0°0°

V 將來自實例27之外消旋順式_5_氯_2_[4 (2_{2_[4_(ih_ 1，2,3-二唑-1-基）苯氧基；]乙基）環丙基）略啶小基]喷啶（ι8 mg)溶解於2.5 mL乙醇中。使溶液經受用半製備裂 chiraipak IA 管柱（2〇x250 mm，5 μ)在 75% 乙醇 / 庚烷以 9 mL/min等度溶離下進行的Ηριχ分離。基線分離出對映異 構體。滯留時間：較快對映異構體：83a F，τ=ΐ7 〇5分 鐘；較慢對映異構體：83a S，Τ=22_18分鐘。V will be from the external race of the example 27 _5_chloro_2_[4 (2_{2_[4_(ih_ 1,2,3-oxadiazol-1-yl)phenoxy;] ethyl) cyclopropane Base) acridine small base] piperidine (ι 8 mg) was dissolved in 2.5 mL of ethanol. The solution was subjected to Ηριχ separation using a semi-prepared chiraipak IA column (2 〇 x 250 mm, 5 μ) in 75% ethanol/heptane at 9 mL/min isocratic. The enantiomers were separated at baseline. Residence time: faster enantiomer: 83a F, τ = ΐ 7 〇 5 minutes; slower enantiomer: 83a S, Τ = 22_18 minutes.

實例83b F及S 製備純對映異構體5-氟_2-【4_((1/?，25&gt;2-{2-[4-(1珏-1，2,3_ = 唑-1-基）苯氧基】乙基}環丙基）哌啶基】嘧啶及5_氟_2_[4_ ((1&amp;2/〇·2-{2-[4·(1Η_1，2,3-***]-基）苯氧基】乙基}環丙 基）哌啶-1-基】嘧啶Example 83b F and S Preparation of the pure enantiomer 5-fluoro_2-[4_((1/?,25&gt;2-{2-[4-(1珏-1,2,3_ = azole-1-) Phenyloxy]ethyl}cyclopropyl)piperidinyl]pyrimidine and 5-fluoro-2_[4_ ((1&amp;2/〇·2-{2-[4·(1Η_1,2,3-three) Azyl]-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine

Ο 將來自實例27b之外消旋順式_5_氟_2_[4-(2-{2-[4-(1ϋ. 1，2,3-三。坐-1-基）苯氧基]乙基丨環丙基）哌啶-丨·基]嘧啶（4〇 mg)溶解於5 mL甲醇中，添加1 mL DCM以改良溶解性。使 溶液經受用半製備型chiraipak IA管柱（20x250 mm，5 μ)在 75%乙醇/庚烷以9 mL/min等度溶離下進行的HPLC分離（進 141275.doc •106· 201102374 3 -^ )。基線分離出對映異構 構體：83b F，Τ=15·36分鐘； Τ=17.97 分鐘。 體。滯留時間：較快對映異 較慢對映異構體：83b s，Ο will be from the example 27b racemic cis_5_fluoro_2_[4-(2-{2-[4-(1ϋ. 1,2,3-tris.-1-yl)phenoxy] Ethyl fluorenylcyclopropyl)piperidine-hydrazinyl]pyrimidine (4 〇mg) was dissolved in 5 mL of methanol, and 1 mL of DCM was added to improve solubility. The solution was subjected to HPLC separation using a semi-prepared chiraipak IA column (20 x 250 mm, 5 μ) in 75% ethanol/heptane at 9 mL/min isocratic separation (in 141275.doc •106· 201102374 3 -^ ). The enantiomer was isolated at baseline: 83b F, Τ = 15.36 min; Τ = 17.97 min. body. Residence time: faster enantiomeric slower enantiomer: 83b s,

實例83c F及S 四唾-. 製備純對映異構體5_氯_2*((1及，叫2_沖_阳 基)苯氧基】乙基}環丙基)…_基】…5_二::_ ((1W2仰_(1H_㈣小基）苯氧基】乙基}環娘 啶-1-基】嘧啶Example 83c F and S tetras--. Preparation of the pure enantiomer 5-chloro-2*((1 and 2), phenoxy)ethyl}cyclopropyl). ...5_二::_ ((1W2 _ _(1H_(tetra))) phenoxy]ethyl}cyclonyl-1-yl]pyrimidine

將來自實例30之外消旋順式四 唑-1-基）苯氧基]乙基}環丙基）哌啶基]嘧啶（2〇 溶解 於2.5 mL曱醇中。使溶液經受用半製備型chiralpak IA管柱 (20x250 mm，5 μ)在50%乙醇/庚烷以9 mL/min等度溶離下 進行的HPLC分離。基線分離出對映異構體。滞留時間： 較快對映異構體.83c F ’ T=27.3分鐘；較慢對映異構 體：83c S，Τ=32·9分鐘。The racemic cis-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidinyl]pyrimidine from Example 30 was dissolved in 2.5 mL of decyl alcohol. The solution was subjected to semi-preparation. HPLC separation of a chiralpak IA column (20x250 mm, 5 μ) in 50% ethanol/heptane at 9 mL/min isocratic separation. The enantiomers were separated at baseline. Retention time: Faster enantiomeric Construct. 83c F 'T = 27.3 min; slower enantiomer: 83 c S, Τ = 32·9 min.

實例83d F及S 製備純對映異構體 5-氣-2-[4-((1/?，245)_2-{2-[3-氟-4-(111-四 唑-1-基）苯氧基】乙基}環丙基）哌啶-1-基]嘧啶及5_氯_2_[4_ ((lS，2i?)-2-{2-[3-氟-4-(1Η-四唑-1-基）苯氧基】乙基}環丙 基）B底咬-1-基]嘴咬 141275.doc •107· 201102374Example 83d F and S Preparation of the pure enantiomer 5-gas-2-[4-((1/?,245)_2-{2-[3-fluoro-4-(111-tetrazol-1-yl) Phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-[4_((lS,2i?)-2-{2-[3-fluoro-4-(1Η) -tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)B bottom bite-1-yl] mouth bite 141275.doc •107· 201102374

將來自實例30b之外消旋順式_5_氣_2-[4-(2-{2-[3-氟-4-(1H-四坐-1-基）本氧基]乙基}環丙基）略咬_ι_基]β密咬（45 mg)溶解於5 mL乙醇中。使溶液經受用半製備型chiraipak ΙΑ管柱（20x250 mm ’ 5 μ)在75%乙醇/庚烷以9 mL/min等度 溶離下進行的HPLC分離。基線分離出對映異構體。滯留 時間：較快對映異構體：83d F，T=21.9分鐘；較慢對映 異構體：83d S，Τ=26.2分鐘。The racemic cis-5_[2-(2-{2-[3-fluoro-4-(1H-tetra-l-yl)-yloxy]ethyl} from Example 30b Cyclopropyl) slightly bite_ι_基]β-bite (45 mg) was dissolved in 5 mL of ethanol. The solution was subjected to HPLC separation using a semi-prepared chiraipak(R) column (20 x 250 mm '5 μ) in 75%/min isocratic separation at 75% ethanol/heptane. The enantiomers were separated at baseline. Residence time: faster enantiomer: 83d F, T = 21.9 minutes; slower enantiomer: 83d S, Τ = 26.2 minutes.

實例83e F及S 製備純對映異構體5-氟-2-【4-((ΐπ，2·5)-2-{2-[3-氟-4-(5-甲 基_1，3,4-噁二唑-2-基）苯氧基]乙基}環丙基）哌啶基]嘧咬 及 5 -乳- 2-)^4-((15^21^)-2-(2-13-氟- 4-(5 -甲基-1，3,4-〇惡二唾 _2_ 基）苯氧基]乙基}環丙基）哌啶4 —基]嘧啶Example 83e F and S Preparation of the pure enantiomer 5-fluoro-2-[4-((ΐπ,2·5)-2-{2-[3-fluoro-4-(5-methyl_1, 3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidinyl]pyrimidine and 5-milk- 2-)^4-((15^21^)-2- (2-13-fluoro-4-(5-methyl-1,3,4-oxadioxa-2-yl)phenoxy]ethyl}cyclopropyl)piperidine-4-yl]pyrimidine

將來自實例86之外消旋順式-5-氟-2-[4-(2-{2-[3·氟-4-(5-甲基-1，3,4-°惡二β坐-2-基）笨氧基]乙基}環丙基）π底咬_丨_基]哺 啶（3 5 mg)溶解於3.5 mL乙醇中。使溶液經受用半製備型 chiralpak IA 管柱（20x250 mm，5 μ)在 50% 乙醇/庚燒以 9 mL/min等度溶離下進行的HPLC分離（進樣3次）。基線分離 14l275.doc -108 - 201102374 出對映異構體。滯留時間：較快對映異構體：83e F， T=20.68分鐘；較慢對映異構體：83e S，T=25.21分鐘。 實例84 製備外消旋順式-2-【4J2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基）苯氧基j乙基}環丙基）哌啶-1-基】-5-甲基嘧啶 步驟1 :外消旋順式-4-(2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基）苯氧基】乙基}環丙基）哌啶-1-甲酸第三丁酯Will be from Example 86 racemic cis-5-fluoro-2-[4-(2-{2-[3·fluoro-4-(5-methyl-1,3,4-° dioxin) -2-yl) phenyloxy]ethyl}cyclopropyl) π bottom biting 丨 基 基 哺 哺 哺 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 The solution was subjected to HPLC separation (injection 3 times) with a semi-prepared chiralpak IA column (20 x 250 mm, 5 μ) in 50% ethanol / heptane at 9 mL / min isocratic. Baseline separation 14l275.doc -108 - 201102374 Enantiomers. Retention time: faster enantiomer: 83e F, T = 20.68 min; slower enantiomer: 83 e S, T = 25.21 min. Example 84 Preparation of racemic cis-2-[4J2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxyjethyl }cyclopropyl)piperidin-1-yl]-5-methylpyrimidine Step 1: racemic cis-4-(2-{2-[3-fluoro-4-(5-methyl-1, 3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidine-1-carboxylic acid tert-butyl ester

根據類似於關於實例6步驟3所報導之程序的程序使用來 自實例1之外消旋4-[2-(2-羥基乙基）環丙基]派啶-1-甲酸第 二丁醋及3-氟-4-(5-曱基-1，3,4-°惡二σ坐_2_基）紛經由三信反 應（Mitsunobu reaction)合成標題化合物。 步驟2 :外消旋順式-5-甲基-2-[4-(2-{2-[3-氟-4-(5-甲基-1，3,4-°惡二&quot;坐-2-基）苯氧基]乙基}環丙基）派咬_1_基】喷咬The use of racemic 4-[2-(2-hydroxyethyl)cyclopropyl]pyridine-1-carboxylic acid second butyl vinegar and 3 from Example 1 was carried out according to procedures similar to those reported for the procedure described in Step 3 of Example 6. -Fluoro-4-(5-fluorenyl-1,3,4-° oxazepine _2-yl) The title compound was synthesized via a Mitsunobu reaction. Step 2: Racemic cis-5-methyl-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-° dioxin&quot; -2-yl)phenoxy]ethyl}cyclopropyl)

將來自該實例步驟1之外消旋順式_4_(2-{2-[3-氟-4-(5-甲 基-1，3,4-°惡一嗤-2-基）本氧基]乙基}環丙基）π底咬_ι_甲酸第 三丁酯（40 mg，0.09 mmol)溶解於05 mL二氯甲烷中。小 心地添加TFA(0.5 mL)。在室溫下攪拌混合物2〇分鐘，接 141275.doc •109- 201102374 著在真空中移除揮發性TF A與在真空中進一步乾燥2小 時。將殘餘物再溶解於1 mL NMP中。相繼添加2 -氯-5 -甲 基 °密°定（23 mg，0.18 mmol)及 DBU(0.135 mL，0.9 mmol)。 在90°C下加熱混合物1.5小時，之後再冷卻至室溫。隨後 用2 mL水及0.5 mL EtOAc稀釋反應。再用乙酸乙S旨進一步 萃取水相兩次。用水及鹽水洗滌合併之有機層，隨後濃縮 且經12公克Biotage矽膠筒用20%乙酸乙酯/己烷溶離進行 管柱層析而純化，得到呈白色固體狀之產物。LRMS計算 值：437.2 ;實測值：438.7 (M+1)。 根據類似於以上實例84中描述之一般程序製備表2中報 導之化合物。 表2 實例 化學名稱 化學結構 (M+1) 實例85 外消旋順式-2-[4-(2-{2-[3-^-4-(5-甲基-1,3,4-噁 二唑-2-基)苯氧基]乙基} 環丙基)旅咬-1 -基]σ密咬 γ〇 424.6 外消旋順式-5-氟·2-[4- V CN (2-{2-[3-氟-4-(5-曱基- 實例86 1，3,4-噁二唑-2-基)苯氧 442.6 基]乙基}壤丙基)σ农咬·1· 基]Β密咬 γ〇 外消旋順式-5-氯-2-[4- 分1 (2-{2-[3-氟-4-(5-曱基- 實例87 1,3,4-噁二唑-2-基)苯氧 472.2 基]乙基}壞丙基)娘咬-1- 基]-4-曱基嘧啶 Ny〇 141275.doc -110- 201102374 實例88 外消旋順式-3,5-二氯-2-[4-(2-{2-[3-氟-4-(5-曱基-I，3,4-噁二唑_2_基)苯氧 基]乙基}環丙基)哌咬-1-基]°比咬 ------- J γ〇 491.6 實例89 外消旋順式-2-[4-(2-{2-[3-氟-4-(5-曱基-1，3,4·°惡 二唑_2_基)苯氧基]乙基} 環丙基)哌啶-1-基]-5-(三 氟曱基)吡啶鑌三氟乙酸 越 -®_—__1 〇J γ〇 ----- —~~—~~~_ 491.7 實例90 製備外消旋反式-5-氯-244-(2-(244-(甲基磺醯基）苯氧烏 乙基}環丙基）《»辰咬-1-基】嘴咬 土】 步驟1:外消旋反式氣嘧咬_2_基）娘咬_4基I環From the step 1 of this example, the racemic cis___(2-{2-[3-fluoro-4-(5-methyl-1,3,4-°-oxan-2-yl)) oxygen Base]ethyl}cyclopropyl)π bottom bite_ι_carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) was dissolved in 0.05 mL of dichloromethane. Carefully add TFA (0.5 mL). The mixture was stirred at room temperature for 2 minutes, then 141275.doc • 109-201102374 was removed in vacuo to remove volatile TF A and further dried in vacuum for 2 hours. The residue was redissolved in 1 mL of NMP. 2-Chloro-5-methyl thiophane (23 mg, 0.18 mmol) and DBU (0.135 mL, 0.9 mmol) were added sequentially. The mixture was heated at 90 ° C for 1.5 hours and then cooled to room temperature. The reaction was then diluted with 2 mL water and 0.5 mL EtOAc. The aqueous phase was further extracted twice with acetic acid. The combined organic layers were washed with EtOAc EtOAc m. LRMS calculated: 437.2; found: 438.7 (M+1). The compounds reported in Table 2 were prepared according to a general procedure similar to that described in Example 84 above. Table 2 Example Chemical Name Chemical Structure (M+1) Example 85 Racemic cis-2-[4-(2-{2-[3-^-4-(5-methyl-1,3,4-) Oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) brigade bite-1 -yl]σ 密〇γ〇424.6 racemic cis-5-fluoro·2-[4- V CN ( 2-{2-[3-Fluoro-4-(5-fluorenyl-example 86 1,3,4-oxadiazol-2-yl)phenoxy 442.6-yl]ethyl}phosphinyl) 1·基基Β 咬 〇 〇 〇 〇-5-chloro-2-[4-min 1 (2-{2-[3-fluoro-4-(5-fluorenyl) - Example 87 1,3 , 4-oxadiazol-2-yl)phenoxy 472.2 yl]ethyl}-propyl propyl) Ninjabita-1-yl]-4-mercaptopyrimidine Ny〇141275.doc -110- 201102374 Example 88 Racemic Cis-3,5-dichloro-2-[4-(2-{2-[3-fluoro-4-(5-fluorenyl-I,3,4-oxadiazol-2-yl)phenoxy] Base]ethyl}cyclopropyl)piperidin-1-yl]° than bite------- J γ〇491.6 Example 89 Racemic cis-2-[4-(2-{2-[ 3-fluoro-4-(5-fluorenyl-1,3,4·°oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]-5-(three Fluorinyl)pyridiniumtrifluoroacetic acid--_____1 〇J γ〇------~~-~~~_ 491.7 Example 90 Preparation of racemic trans-5-chloro-244-(2 -(244-(methyl Acyl) phenoxy ethyl} cyclopropyl black) "» Chen bite-1-yl]] Soil mouth bite Step 1: Racemic trans gas pyrimidinyl bite _2_ yl) Mother bite _4 cycloalkyl group I

i： TFA ii： Cs2C03 二氣嘧啶 根據類似於實例6步驟2中所報導之一般程序由實例3 製備之外消旋反式_4-[2_(2·經基乙基）環丙基]〇底。定小: 第二丁醋製備標題化合物。 —文 醯基）笨氧 步驟2 :彳消旋反式_s•氯_2_μ·(2_{2_【4_(甲基續 基】乙基}環丙基）哌啶β1_基】嘧啶i: TFA ii: Cs2C03 di-pyrimidine. Preparation of racemic trans-_4-[2_(2·-ylethyl)cyclopropyl]oxime from Example 3 according to a general procedure similar to that reported in Step 2, Example 6. bottom. Small: The second vinegar was used to prepare the title compound. - 醯 )) 笨 步骤 Step 2 : 彳 反 反 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

根據類似於實例6步驟3中所報導之-般程序由實例9〇步 I41275.doc -111 - 201102374 驟1之產物製備標題化合物e LRMS計算值^ 435 i ;實測 值·· 436·3 (M+1)。 實例91 製備5-氯-2-[4-((lR，2R)_2_{2_【4-(曱基磺醯基）苯氧基】乙 基}環丙基）哌啶_1_基】嘧咬The title compound e LRMS was calculated according to the procedure similar to that reported in Step 3, Example 3, from the product of Example 9 Steps I41275.doc -111 - 201102374, and the calculated value of 435 i; measured value ·· 436·3 (M +1). Example 91 Preparation of 5-chloro-2-[4-((lR,2R)_2_{2_[4-(indolylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl]pyrimidine bite

Me02S 藉由用對草性固定相進行層析拆分獲得標題化合物。根 據類似於以上實例83之方法用製備型HpLC管柱分離以上 實例90中製備之外消旋5_氯_2_[4_(2_{2_[4 (甲基磺醯基）苯 乳基]乙基}拓丙基）派咬-1-基]D密U定。 實例92 製備外消旋反式-5-氯-2·(4-{2-[2-(»比啶-4-基氧基）乙基]環 丙基}哌啶_1_基）嘧啶Me02S The title compound was obtained by chromatography on a grassy stationary phase. The racemic 5-chloro-2-[4_(2_{2_[4 (methylsulfonyl)phenyl)]ethyl group was prepared in the above Example 90 by a preparative HpLC column according to the procedure of Example 83 above. }Terminyl) Pie bite-1-base]D dense U set. Example 92 Preparation of racemic trans-5-chloro-2·(4-{2-[2-(»pyridin-4-yloxy)ethyl]cyclopropyl}piperidinyl-1)pyrimidine

將氫化鈉（1 〇〇。/0 ’ 20 mg，0.85 mmol)稱入小瓶中，添加 DMF(無水’ 2丨mL),接著添加外消旋反式_2_{2_[卜（5_氯 街定2-基）d底咬_4_基]環丙基）乙醇（6〇 mg，〇21 mmol) ’ 且在室溫下攪拌混合物5分鐘。隨後添加氣化4_氟吡啶钂 在至下授拌1 〇分鐘。加熱混合物至5 0 °C歷時1 · 5小 時’冷卻至室溫’且用乙酸乙酯（5 mL)稀釋，用飽和 NH4C1水溶液（5 mL)中止反應，經MgS〇4乾燥，過濾且濃 141275.doc •112· 201102374 縮。藉由矽膠層析（30%乙酸乙酯/己烷）純化粗殘餘物，得 到呈白色固體狀之標題化合物。LC-MS (M+1): 359.54。 根據類似於以上描述之實例6步驟1及2中描述之一般程序 製備表3中報導之化合物。 表3 實例 化學名稱 化學結構 (M+l) 4-(2-{(li?,2^)-2-[l-(5-氯嘧啶-2-基)哌 實例93 咬-4·基]壤丙基}乙 F—^~ 459.6 氧基)~Ν-ί^丙基-2-氣 苯甲醯胺 4-(2-((1^,2i?)-2-[l- 實例94 (5-氯嘧啶-2-基)哌 °定-4-基]5哀丙基}乙 0」 401.6 氧基)-2-氟笨甲腈 NC 5-氣-2-[4-((1 尺 2i?)-2- {2-[4-(1Η-1,2,4-三 N 實例95 唑-1-基)苯氧基]乙 基}5哀丙基)旅咬-1- n0° 425.6 基]嘴咬 5-氣-2-[4-((li?,2i〇-2- {2-[3-氟-4-(5-甲基- 實例96 1,3,4-噁二唑-2-基)苯 氧基]乙基}環丙基） 458.6 0底唆-1-基]0f咬 丫 5-氣-2-[4-((l/?,2i?)-2- {2-[4-(5-環丙基- o—^ 242.9 (M+2)/2 實例97 1，3,4-噁二唑-2-基)- F_0 3-氤笨氧基]乙基}環 丙基)旅咬-1-基]。密咬 Ϊ 141275.doc -113 - 201102374 實例98 外消旋反式-5-氯-2-(4-{2·[2-(吼啶-4-基 氧基)乙基]環丙基} 0底咬-1-基)喊咬 rrcl Ν^ίι 359.54 實例99 外消旋反式-4-(2-{2-[1-(5-氯嘧啶_2_基)哌 咬-4·-基]壞丙基}乙 氧基)-6-甲基嘧咬-2-甲腈 Λ/ O ^Cl ο—/ Ν=( 399.58 實例100 外消旋反式-6-(2-{2-[1-(5-氣嘧啶_2_基)哌 啶冰基]環丙基}乙 氧基)-2-曱基嘧咬-4-甲腈 丄 Ν’Ν 399.56 實例ιοί 製備外消旋反式-5-氣-2-{4-[(2-{[4-(曱基磺醯基）苯氧基]曱 基}環丙基）甲基]哌啶-1-基}嘧啶Sodium hydride (1 〇〇./0 '20 mg, 0.85 mmol) was weighed into a vial, DMF (anhydrous '2 丨 mL) was added, followed by the addition of racemic trans _2_{2_[Bu (5_ chlorine street) 2-Based) d bottom _4_yl]cyclopropyl)ethanol (6 〇 mg, 〇 21 mmol) ' and the mixture was stirred at room temperature for 5 minutes. Then add gasified 4 fluoropyridinium and mix for 1 minute. The mixture was heated to 50 ° C for 1 · 5 hrs of 'cooled to room temperature' and diluted with ethyl acetate (5 mL). The reaction was quenched with saturated aqueous NH4CI (5 mL), dried over EtOAc EtOAc .doc •112· 201102374 Contraction. The crude residue was purified by EtOAc EtOAcjjjjj LC-MS (M+1): 359.54. The compounds reported in Table 3 were prepared according to the general procedure similar to that described in Example 6, Steps 1 and 2, described above. Table 3 Example Chemical Name Chemical Structure (M+l) 4-(2-{(li?,2^)-2-[l-(5-chloropyrimidin-2-yl)piperidin Example 93 Bite-4·yl] PF}B F-^~ 459.6 oxy)~Ν-ί^propyl-2-cetophenamide 4-(2-((1^,2i?)-2-[l- Instance 94 ( 5-chloropyrimidin-2-yl)piperazin-4-yl]5 ylide propyl}ethyl 0" 401.6 oxy)-2-fluorobenzonitrile NC 5- gas-2-[4-((1 ft) 2i?)-2- {2-[4-(1Η-1,2,4-TriN-case 95 oxazol-1-yl)phenoxy]ethyl}5 propyl propyl) brigade bite -1- n0° 425.6 base] mouth bite 5-gas-2-[4-((li?,2i〇-2- {2-[3-fluoro-4-(5-methyl-) 96, 1,3,4-oxo Oxazol-2-yl)phenoxy]ethyl}cyclopropyl) 458.6 0 base 唆-1-yl]0f gnashing 5-gas-2-[4-((l/?,2i?)-2- {2-[4-(5-cyclopropyl-o-^ 242.9 (M+2)/2 Example 97 1,3,4-oxadiazol-2-yl)-F_0 3-氤 氧基oxy]B }}cyclopropyl) brigade bite-1-yl]. 密ΪΪ 141275.doc -113 - 201102374 Example 98 racemic trans-5-chloro-2-(4-{2·[2-(acridine) -4-yloxy)ethyl]cyclopropyl} 0 bottom bite-1-yl) shout bite rrcl Ν^ίι 359.54 Example 99 racemic trans-4-(2-{2-[1-(5 -chloropyrimidine_2_yl) piperidine-4·- Base] bad propyl}ethoxy)-6-methylpyrimidine-2-carbonitrile oxime / O ^Cl ο-/ Ν=( 399.58 Example 100 racemic trans-6-(2-{2- [1-(5-Amphetyridyl-2-yl)piperidinyl]cyclopropyl}ethoxy)-2-mercaptopyrimidine-4-carbonitrile 丄Ν'Ν 399.56 Example ιοί Preparation of racemic 5-(4-[(2-{[4-(indolylsulfonyl)phenoxy]indolyl}cyclopropyl)methyl]piperidin-1-yl}pyrimidine

HOHO

i: TFA ii: Cs2C03 二氯嘧啶i: TFA ii: Cs2C03 dichloropyrimidine

Cl 0Cl 0

Me〇2S 根據類似於實例6步驟1至3中所報導之一般程序由實例4 之外消旋反式-4-{[2-(羥基曱基）環丙基]曱基}哌啶-1-曱酸 第三丁酯製備標題化合物。 實例102 141275.doc -114- 201102374 製備5-氯-2_[4-((li?，2i?)-2-{2-[4-(曱基磺醯基）苯氧基】乙 基}環丙基）旅咬-1-基】，咬Me〇2S was subjected to a general procedure similar to that reported in Steps 1 to 3 of Example 6 by Example 4 racemic trans-4-{[2-(hydroxyindenyl)cyclopropyl]indolyl}piperidine-1 - The title compound was prepared from tert-butyl phthalate. Example 102 141275.doc -114- 201102374 Preparation of 5-chloro-2_[4-((li?,2i?)-2-{2-[4-(indolylsulfonyl)phenoxy]ethyl} ring Propyl) brigade bite-1-base], bite

根據類似於實例6步驟1至3中所報導之一般程序由實例4 之4-{[(li?，2i?)-2-(經基甲基）環丙基]甲基}派咬小甲酸第三 丁酯製備標題化合物。 實例103 製備5-氯-2-{4-[⑽，叫2_{[4_(甲基橫酿基）苯氧基】甲基） 環丙基）甲基】哌啶-l-基}嘧咬4-{[(li?,2i?)-2-(ylmethyl)cyclopropyl]methyl} was used to bite the small formic acid according to the general procedure similar to that reported in Steps 1 to 3 of Example 6. The title compound was prepared from the third butyl ester. Example 103 Preparation of 5-chloro-2-{4-[(10), called 2_{[4_(methyl-bromo)phenoxy]methyl)cyclopropyl)methyl]piperidine-l-yl}pyrimidine

根據類似於實例6步驟⑴中所報導之—般程序由實例4 之4-{[(1仰)-2_(經基甲基）環丙基]甲基}娘咬小甲酸第三 丁酯製備標題化合物。 根據類似於以上實例1〇1、1〇2及1〇3中描述之—般程序 製備表4中報導之化合物。Prepared according to the general procedure similar to that reported in step (1) of Example 6 from 4-{[(1)-2-(ylmethyl)cyclopropyl]methyl} Title compound. The compounds reported in Table 4 were prepared according to a general procedure similar to that described in Examples 1, 〇 1, 1 〇 2 and 1-3 above.

141275.doc [ S -115- 201102374 實例105 4-[((1 足 2幻-2-{[l-(5-氯 嘧啶-2-基)哌啶-4-基] 曱基}環丙基)曱氧基]-2-氟笨曱猜 ^-0° NC 401.6 實例106 外消旋反式-4-[(2-{[l- (5-氯哺淀·2-基)喻淀· 4-基]甲基}環丙基)甲 氧基]-Ν-環丙基-2-氣 苯曱醯胺 一。_^令 459.2 實例107 4-[((li?,2i?)-2-{[l-(5-氯 嘴咬-2-基)派咬-4-基] 曱基}環丙基)曱氧基]-N-環丙基-2-氟笨甲醯 胺 459.6 實例108 4-[((1柳-2-{[1-(5·氯 嘴淀-2-基)旅咬-4-基] 曱基}環丙基)曱氧基]-Ν-環丙基-2-氟笨甲醯 胺 &lt;ί 0 459.6 實例109 5-氣-2-{4-[((li?，2i?)-2-{[3-氟-4-(5·甲基-1，3,4-噁二唑-2-基)苯 氧基]甲基}環丙基)甲 基]派咬·1-基}靖淀 N=\ Νγ° 458.6 實例110 5-氯-2-{4-[((1&amp;25)·2-{[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基)苯 氧基]曱基}環丙基)甲 基]哌啶-l-基}嘧啶 Λ^ΟΝΛ^&quot;α Ν=\ Νγ〇 458.6 實例111 外消旋反式-5-氯-2-{4-[(2-{[4-(5-環丙基-1,3,4-噁二唑-2-基)-3-氟苯氧基]曱基}環丙 基)曱基]派咬-1-基}嘧 啶 ϊ 484.6 141275.doc •116- 201102374 實例112 4-[((1&amp;25)-2-{[1-(5-氯 °密0基)派咬-4-基] 甲基}環丙基)曱氧基] 苯績醯胺 0 h2no2s 437.7 實例113 外消旋反式-6-[(2-{[l-(5-氡嘧啶-2-基)哌啶-4_基]曱基}環丙基)甲 氧基]_2_甲基嘧啶-4-甲腈 \ 399.67 實例114 外消旋反式-4-[P-{[l-(5 -氣c密咬-2-基)π底咬-4-基]曱基}環丙基)甲 氧基]-6-甲基嘧啶-2-甲腈 399.69 實例115 外消旋反式-4-[((lS,2S)-2-{[l-(5-氯 鳴唆-2-基)η底咬-4-基] 曱基}環丙基)甲氧基]-3_氟苯曱腈 NC 401.5 實例116 製備外消旋順式-5-氯-2-{4-[(2-{[4-(甲基磺醯基）苯氧基]曱 基}環丙基）甲基]哌啶-l-基}嘧啶141275.doc [S-115-201102374 Example 105 4-[((1 foot 2 phan-2-([l-(5-chloropyrimidin-2-yl)piperidin-4-yl) fluorenyl} cyclopropyl)曱 ] ] ] 氟 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 [ [ [ [ [ 4-yl]methyl}cyclopropyl)methoxy]-indole-cyclopropyl-2-phenylbenzamide I. _^ 459.2 Example 107 4-[((li?, 2i?)-2 -{[l-(5-Chlorodonk-2-yl) keto-4-yl] fluorenyl}cyclopropyl) decyloxy]-N-cyclopropyl-2-fluorobenzamide-59.6 Example 108 4-[((1 liu-2-{[1-(5·chlorophenate-2-yl)) 咬-4-yl] fluorenyl}cyclopropyl) decyloxy]-indole-cyclopropyl -2-fluorobenzamide&lt;ί 0 459.6 Example 109 5-Gas-2-{4-[((li?,2i?)-2-{[3-fluoro-4-(5·methyl-) 1,3,4-oxadiazol-2-yl)phenoxy]methyl}cyclopropyl)methyl]pyran·1-base} Jingdian N=\ Νγ° 458.6 Example 110 5-Chloro-2 -{4-[((1&amp;25)·2-{[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]indolyl} ring Propyl)methyl]piperidine-l-yl}pyrimidineΛ^ΟΝΛ^&quot;α Ν=\ Νγ〇458.6 Example 111 Racemic trans-5-chloro-2-{4-[(2-{[ 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-fluorobenzene曱 曱 } } 曱 曱 曱 曱 ϊ 4.6 4.6 4.6 484.6 141275.doc • 116- 201102374 Example 112 4-[((1&amp;25)-2-{[1-(5-氯°密0基)派乙-4-基] Methyl}cyclopropyl) decyloxy] Benzene decylamine 0 h2no2s 437.7 Example 113 Racemic trans-6-[(2-{[l-( 5-pyrimidin-2-yl)piperidine-4-yl]indolyl}cyclopropyl)methoxy]_2-methylpyrimidine-4-carbonitrile\399.67 Example 114 Racemic trans-4-[ P-{[l-(5-gas c-Bite-2-yl) π-bottom-4-yl]fluorenyl}cyclopropyl)methoxy]-6-methylpyrimidine-2-carbonitrile 399.69 Example 115 racemic trans-4-[((lS,2S)-2-{[l-(5-chloroxin-2-yl)) 底 -4--4-yl] fluorenyl}cyclopropyl) Oxy]-3_fluorobenzonitrile NC 401.5 Example 116 Preparation of racemic cis-5-chloro-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]anthracene Cyclopropyl)methyl]piperidine-l-yl}pyrimidine

S02Me DBAD，聚 Ph3P DCM/THFS02Me DBAD, Poly Ph3P DCM/THF

:TFA ii: Cs2C〇3 二氣嘧啶:TFA ii: Cs2C〇3 Di-pyrimidine

OHOH

MeQ2S 根據類似於實例6步驟1至3所報導之一般程序由實例5之 經保護外消旋順式-4-{[2-(羥基曱基）環丙基]甲基}哌啶-1- 141275.doc -117- 201102374 甲酸第三丁酯製備標題化合物。 根據以上實例116中描述之一般程序使用實例中其他地 方描述之酚製備表5中報導之化合物。 表5 實例 化學名稱 化學結構 (M+l) 實例117 外消旋順式-4-[(2-{[l-(5-氯鳴咬-2-基)派咬-4-基] 甲基}環丙基)甲氡基]-N-環丙基-2-氟笨甲醯胺 459.6 實例118 外消旋順式-4-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基] 甲基}環丙基)甲氧基]-6-曱基嘧啶-2-甲腈 399.59 實例119 外消旋順式-4-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基] 甲基}環丙基)曱氧基]-2-氟苯曱腈 NC 401.6 實例120 製備 5-氯-2-(4-((11^25)-2-(2-^5-(1 开-1,2,3-***-1-基）口比 啶-2-基]氧基}乙基）環丙基]哌啶-l-基}嘧啶MeQ2S was protected from the protected racemic cis-4-{[2-(hydroxyindenyl)cyclopropyl]methyl}piperidin-1- of Example 5 according to a procedure similar to that reported in Steps 1 to 3 of Example 6. 141275.doc -117- 201102374 Preparation of the title compound from tert-butyl formate. The compounds reported in Table 5 were prepared according to the general procedures described in Example 116 above using the phenols described elsewhere in the Examples. Table 5 Example Chemical Name Chemical Structure (M+l) Example 117 Racemic cis-4-[(2-{[l-(5-chloropterin-2-yl))-4-yl]methyl }cyclopropyl)carbamimidyl]-N-cyclopropyl-2-fluorobenzamide-59.6 Example 118 Racemic cis-4-[(2-{[l-(5-chloropyrimidin-2-) Benzylpiperidin-4-yl]methyl}cyclopropyl)methoxy]-6-mercaptopyrimidine-2-carbonitrile 399.59 Example 119 racemic cis-4-[(2-{[l- (5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)decyloxy]-2-fluorobenzonitrile NC 401.6 Example 120 Preparation of 5-chloro-2-(4-( (11^25)-2-(2-^5-(1 open-1,2,3-triazol-1-yl)-p-pyridin-2-yl]oxy}ethyl)cyclopropyl]per Pyridyl-l-yl}pyrimidine

Q 在0°C下用2-{(18,2尺)-2-[1-(5-氯嘧啶-2-基）哌啶-4-基]環 丙基}乙醇（3.9 g，13.84 mmol)於DMF(9 mL)中之溶液處理 NaH(720 mg，60 重量 ％，含有 432 mg NaH，17.99 mmol) 於DMF(9 mL)中之懸浮液。在0°C下攪拌混合物30分鐘。 141275.doc -118- 201102374 用2乱-5-(1/Μ，2,3-三唾q•基㈣邮柳g，15 22 於DMF(10 mL)中之溶液處理混合物。在旳下攪拌反應μ 分鐘，隨後使其溫至室溫且攪拌隔夜。用飽和而心水溶 液中止反應錢混合物在乙酸乙@旨與水之間分溶。再用水 洗務有㈣兩次，經硫⑽乾燥，過;慮且蒸發至殘餘物。 層析（Horizon 65丨二氧化矽筒；3〇%至45%乙酸乙酯/庚烷） 殘餘物。合併含所要產物之溶離份且蒸發至自色固體。此 外自層析溶離份中回收結晶固體。自Et〇H/庚烷再結晶自 層析分離之固體。將固體（4 g)懸浮於Et〇H(15〇 ml)中，隨 後加熱直至完全溶解，使其冷卻至室溫且添加庚烷（丨⑼ ml)。在室溫下使混合物陳化隔夜，冷卻至歷時5分鐘 且過濾，得到標題化合物。LCMS計算值：425 17 ;實測 值：426.09 (M+1)。巾 NMR (CDCl3): δ 8.48 (d, 1H)，8 2〇 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDC13), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2〇), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H)，0.61 (m，1H)，-0.08 (q，1H)。 實例121 製備 2-甲基-6-(2-((15,21^)-241-(5- f 基嘧啶 _2-基）哌啶 _4_ 基]環丙基}乙氧基）嘧啶-4-曱腈Q 2-{(18,2 ft)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g, 13.84 mmol) at 0 °C A solution of NaH (720 mg, 60% by weight, containing 432 mg NaH, 17.99 mmol) in DMF (9 mL) The mixture was stirred at 0 ° C for 30 minutes. 141275.doc -118- 201102374 The mixture was treated with 2 chaotic-5-(1/Μ,2,3-tris-qq-based (iv) lycopene g, 15 22 in DMF (10 mL). The reaction was allowed to react for 5 minutes, then allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous solution of the aqueous solution in ethyl acetate. The mixture was washed twice with water (4) and dried with sulfur (10). The residue was evaporated to a residue. Chromatography ( </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Further, the crystalline solid was recovered from the chromatographic fraction. The solid separated from the chromatogram was recrystallized from EtH/Heptane. The solid (4 g) was suspended in EtH (15 mL) and then heated until completely dissolved. The mixture was cooled to room temperature and was added EtOAc (EtOAc (EtOAc): EtOAc. (M+1). Towel NMR (CDCl3): δ 8.48 (d, 1H), 8 2〇(s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDC13), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m , 1H), 1.57 (S, H2〇), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), -0.08 ( q, 1H). Example 121 Preparation of 2-methyl-6-(2-((15,21^)-241-(5-f-pyrimidin-2-yl)piperidine-4-yl]cyclopropyl}B Oxy)pyrimidine-4-indolecarbonitrile

201102374 將 NaH(60%，1 8 mg，0.4 5 mmol，1.2 當量）置放於 1打蘭 (dram)小瓶中且添加DMF( 1.2 mL)。向聚液中逐滴添加2-{(lS,2R)-2-[l-(5-甲基嘧啶-2-基）哌啶-4-基]環丙基}乙醇 (100 mg，0.375 mmol)之溶液（0.5 mL)，且在室溫下攪拌 混合物10分鐘。冷卻溶液至-20°C，且逐滴添加6-氯-2-曱 基嘴咬-4-曱腈（115 mg，0.75 mmol)於 DMF(0.5 mL)中之溶 液。攪拌紅色混合物40分鐘。添加冰冷飽和NH4C1溶液（水 溶液，1 mL)，且用EtOAc( 1 00 mL)及水（50 mL)稀釋混合 物。將混合物轉移至分液漏斗中，震盪混合物且分離各 層。用水（20 mL)洗滌有機部分，經MgS04乾燥，過濾且在 真空中濃縮。藉由矽膠層析（1:7 EtOAc :己烷）純化紅色油 狀物，得到標題化合物。LC-MS :計算值：378.22 ;實測 值：379·03(Μ+1)。 使用環AMP(cAMP)均相時差式螢光（HTRF)檢定量測 GPR119信號轉導 將經容許鳥嘌呤核苷酸結合蛋白al5(Gal5)及鼠類 GPR119穩定轉染之中國倉鼠卵巢（CHO)細胞株維持在含有 FBS、盤尼西林（penicillin)-鏈黴素（streptomycin)、σ票吟黴 素（puromycin)及G418(遺傳黴素）之DMEM培養基中。或 者，用GPR119之人類SNP變體（S309L)穩定轉染人胚腎 (HEK)293 Flp-In 細胞（Invitrogen，Carlsbad, CA)且維持在 含有FBS、盤尼西林-鏈黴素及潮徽素（hygromycin)之 DME1V[培養基中。使用量測cAMP之商業均相時差式螢光 (HTRF)套組（CisBio, Bedford，MA)量測 GPR119 受體在經本 141275.doc -120- 201102374 發明化合物處理之上述受體轉染細胞中的促效劑活化。根 據製造商之說明在96孔半體積板（鼠類）或384孔板（人類）中 進行檢定。簡言之，將懸浮之細胞與劑量滴定之測試化合 物一起在室溫下培育60分鐘，細胞溶解且再與HTRF試劑 一起培育60分鐘。使用經調整以讀取時差式螢光之 Envision多標記讀取器（Perkin Elmer)來讀取板且自cAMP 校正曲線外推cAMP濃度。GPR119促效劑將展現細胞内 c AMP之濃度依賴性增加。根據正規化活性對化合物濃度 之所得曲線之S形四參數曲線擬合測定刺激半數最大反應 所需之測試化合物濃度（EC50)及與内部促效劑對照相比之 功效。 如下表中所說明，當在上述檢定中測試時，該狀況之實 例展示小於1 〇〇〇 nM之拐點（以EC5〇值表示）。 活性表示為：EC5。&lt; 10 nM #，10 nM &lt; EC5。&lt; 50 nM M，50 nM &lt; EC50 &lt; 200 nM #，200 nM &lt; EC50 刪#。 實例6 # 實例6a # 實例7 # 實例8 MM 實例9 m 實例10 MM 實例11 # 實例12 Μ 實例13 Μ 實例14 # 實例15 Μ 實例16 # 實例17 ### 實例18 #U 實例19 Μ 實例20 ### 實例21 U 實例22 ## 實例23 ### 實例24 ### 實例25 ## 實例26 ## 實例27 # 實例27b 141275.doc -121 - 201102374 實例27c ## 實例28 ### 實例29 #### 實例30 # 實例30b # 實例30d # 實例30e # 實例31 ## 實例3 la # 實例3 lb ## 實例32 # 實例33 # 實例34 # 實例35 實例36 實例37 # 實例38 m 實例39 # 實例40 # 實例41 m 實例42 # 實例43 # 實例44 ## 實例45 ## 實例46 # 實例47 # 實例48 mm 實例49 獅 實例50 ### 實例51 # 實例52 # 實例53 實例54 腳 實例55 ## 實例55a # 實例83 F # 實例83 S # 實例83aF ND 實例83aS # 實例83bF ### 實例83bS # 實例83cF # 實例83cS # 實例83dF ## 實例83dS # 實例83eF M# 實例83eS # 實例84 # 實例85 # 實例86 # 實例87 # 實例88 #### 實例89 # 實例90 m 實例91 ## 實例92 ### 實例93 # 實例94 ### 實例95 ## 實例96 ## 實例97 ## 實例98 ### 實例99 ## 實例100 m 實例101 m 實例102 mm 141275.doc -122- 201102374 實例103 ## 實例104 ### 實例105 #### 實例106 # 實例107 m 實例108 ## 實例109 _ 實例110 ## 實例111 ## 實例112 ### 實例113 M# 實例114 ### 實例115 ## 實例116 mu 實例117 m 實例118 Μ 實例119 mm 靜態分離小鼠胰島中葡萄糖依賴性胰島素分泌（GDIS)之評估 藉由膠原酶消化及不連續菲科爾梯度分離（discontinuous Ficoll gradient separation)(Lacy 及 Kostianovsky(Lacy 及 Kostianovsky，1967 Diabetes 16-35-39)之最初方法之修改） 自10-12週齡之C57BL/6小鼠之胰腺分離朗格漢斯 (Langerhans)胰島》實驗處理之前，在RPMI 1640培養基（11 mM葡萄糖’ 10% FCS)中將胰島培養隔夜。由對胰島在克 运布斯-林格氏碳酸虱鹽（Krebs-Ringers' bicarbonate)(KRB) 培養基中之60分鐘靜態培育測定本發明化合物對GDIS之 急性效應。KRB培養基除2 mg/mi牛血清白蛋白及2(G2)或 16(016)111河葡萄糖（？117.4)外亦含有143,5价+、5.8〖+、 2.5 Ca2+、1.2 Mg2+、124.1 cr、1.2 P043-、1.2 S042+、25 C032·及10 HEPES(pH 7.4)(#mM為單位）。用圓底96孔板 (每孔1個胰島，具有200 μΐ KRB培養基）進行靜態培育。將 化合物添加至KRB培養基中’隨後即刻開始6〇分鐘培育。 由來自ALPCO Diagnostics(Windham，NH)之超敏感大鼠胰 島素EIA套組量測培育缓衝液之等分試樣中之胰島素濃 141275.doc •123- 201102374 度。 令人驚訝的是本申請案之化合物可 效劑。 效作為GPR119促 醫藥調配物之實例 作為本發明化合物之口服組合物之一 mg任一貫例與足夠細之粉狀一 孔楓起調配以提供580 mg至 590 mg之總量來填充〇號硬明膠膠囊。 儘管已參考本發明之特定實施例描述且說明本發明，但 特定實施例，將50 在不脫離本發明之情況下，可對本發明作出多種改變、修 改及替代。舉例而言’可基於所治療之患者之反應施用替 代性有效劑量。同樣，藥理學反應可視所選擇之特定活性 化合物、調配物及投藥模式而變化。所有該等變化皆包括 在本發明内。 141275.doc 124-201102374 Place NaH (60%, 1 8 mg, 0.4 5 mmol, 1.2 eq.) in a 1 dram vial and add DMF (1.2 mL). 2-{(lS,2R)-2-[l-(5-Methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (100 mg, 0.375 mmol) was added dropwise to the liquid. (0.5 mL), and the mixture was stirred at room temperature for 10 minutes. The solution was cooled to -20 ° C, and a solution of 6-chloro-2-mercapto-4-acetonitrile (115 mg, 0.75 mmol) in DMF (0.5 mL) was added dropwise. The red mixture was stirred for 40 minutes. An ice-cold saturated NH4Cl solution (water solution, 1 mL) was added, and the mixture was diluted with EtOAc (100 mL) and water (50 mL). The mixture was transferred to a separatory funnel, the mixture was shaken and the layers were separated. The organic portion was washed with water (20 mL) dried EtOAc The red oil was purified by EtOAc (EtOAc:EtOAc) LC-MS calc.: 378.22; GPR119 signal transduction using cyclic AMP (cAMP) homogeneous time-lapse fluorescence (HTRF) assay. Chinese hamster ovary (CHO) stably transfected with guanine nucleotide binding protein al5 (Gal5) and murine GPR119. The cell line was maintained in DMEM medium containing FBS, penicillin-streptomycin, puromycin, and G418 (geneticin). Alternatively, human embryonic kidney (HEK) 293 Flp-In cells (Invitrogen, Carlsbad, CA) were stably transfected with GPR119 human SNP variant (S309L) and maintained in FBS, penicillin-streptomycin and hygromycin. ) in DME1V [in the medium. The GPR119 receptor was measured using the commercial homogeneous time difference fluorescence (HTRF) kit (CisBio, Bedford, MA) measuring cAMP in the above-described receptor-transfected cells treated with the inventive compound of 141275.doc-120-201102374 The agonist is activated. The assay was performed in 96-well half-volume plates (murines) or 384-well plates (humans) according to the manufacturer's instructions. Briefly, the suspended cells were incubated with the dose-titrated test compound for 60 minutes at room temperature, the cells were lysed and incubated with the HTRF reagent for 60 minutes. Plates were read using an Envision multi-label reader (Perkin Elmer) adjusted to read time difference fluorescence and the cAMP concentration was extrapolated from the cAMP calibration curve. The GPR119 agonist will exhibit a concentration-dependent increase in intracellular cAMP. The concentration of the test compound (EC50) required to stimulate the half maximal response and the efficacy compared to the internal agonist control were determined by a S-shaped four-parameter curve fit of the resulting curve of the normalized activity versus compound concentration. As illustrated in the table below, an example of this condition exhibits an inflection point (expressed as EC5 〇 value) of less than 1 〇〇〇 nM when tested in the above test. Activity is expressed as: EC5. &lt; 10 nM #, 10 nM &lt; EC5. &lt; 50 nM M, 50 nM &lt; EC50 &lt; 200 nM #,200 nM &lt; EC50 Delete #. Example 6 #Instance 6a #Instance 7 #Instance 8 MM Instance 9 m Instance 10 MM Instance 11 # Instance 12 实例 Instance 13 Μ Instance 14 # Instance 15 实例 Instance 16 # Instance 17 ### Instance 18 #U Instance 19 实例 Example 20 ### Instance 21 U Instance 22 ## Instance 23 ### Instance 24 ### Instance 25 ## Instance 26 ## Instance 27 # Instance 27b 141275.doc -121 - 201102374 Instance 27c ## Instance 28 ### Instance 29 #### Instance 30 # Instance 30b # Instance 30d # Instance 30e # Instance 31 ## Instance 3 la # Instance 3 lb ## Instance 32 # Instance 33 # Instance 34 # Instance 35 Instance 36 Instance 37 # Instance 38 m Instance 39 #Instance 40 #Instance 41 m Instance 42 # Instance 43 # Instance 44 ## Instance 45 ## Instance 46 # Instance 47 # Instance 48 mm Instance 49 Lion instance 50 ### Instance 51 # Instance 52 # Instance 53 Example 54 Feet Instance 55 ## Instance 55a # Instance 83 F # Instance 83 S # Instance 83aF ND Instance 83aS # Instance 83bF ### Instance 83bS # Instance 83cF # Instance 83cS # Instance 83dF ## Instance 83dS # Instance 83eF M# Instance 83eS # Instance 84 #Instance 85 # Instance 86 # Instance 87 # Instance 88 #### Instance 89 # Instance 90 m Instance 91 ## Instance 92 ### Instance 93 # Instance 94 ### Instance 95 ## Instance 96 ## Instance 97 ## Instance 98 ### Instance 99 ## Instance 100 m instance 101 m instance 102 mm 141275.doc -122- 201102374 instance 103 ## instance 104 ### instance 105 #### instance 106 # instance 107 m instance 108 ## instance 109 _ instance 110 ## instance 111 ## Example 112 ### Instance 113 M# Instance 114 ### Instance 115 ## Instance 116 mu Example 117 m Example 118 实例 Example 119 mm Static separation of glucose-dependent insulin secretion (GDIS) in mouse islets by collagenase Discontinuous Ficoll gradient separation (modification of the original method of Lacy and Kostianovsky (Lacy and Kostianovsky, 1967 Diabetes 16-35-39)) C57BL/6 mice from 10-12 weeks of age Islet cultures were overnight in RPMI 1640 medium (11 mM glucose '10% FCS) prior to experimental treatment of pancreas isolated Langerhans islets. The acute effects of the compounds of the invention on GDIS were determined by static incubation of islets in Krebs-Ringers' bicarbonate (KRB) medium for 60 minutes. KRB medium contains 143,5 valence +, 5.8 〖+, 2.5 Ca2+, 1.2 Mg2+, 124.1 cr, in addition to 2 mg/mi bovine serum albumin and 2 (G2) or 16 (016) 111 river glucose (?117.4). 1.2 P043-, 1.2 S042+, 25 C032· and 10 HEPES (pH 7.4) (# mM). Static incubation was performed using a round bottom 96-well plate (1 islet per well with 200 μΐ KRB medium). The compound was added to the KRB medium and then immediately started to grow for 6 minutes. Insulin concentrations in aliquots of incubation buffers were measured by the ultrasensitive rat insulin EIA kit from ALPCO Diagnostics (Windham, NH) 141275.doc • 123- 201102374 degrees. Surprisingly, the compound is an effective agent of the present application. Examples of GPR119 Promoting Pharmaceutical Formulations As one of the oral compositions of the compounds of the present invention, mg is consistently formulated with a finely powdered one-hole maple to provide a total amount of 580 mg to 590 mg to fill the size hard gelatin. capsule. While the invention has been described and illustrated with reference to the specific embodiments of the present invention, the invention may be modified, modified and substituted without departing from the invention. For example, an alternative effective dose can be administered based on the response of the patient being treated. Similarly, the pharmacological response will vary depending upon the particular active compound selected, the formulation, and the mode of administration. All such variations are included in the present invention. 141275.doc 124-

Claims (1)

201102374 七、申請專利範圍： 1. 一種化合物，其係由下式表示：201102374 VII. Patent application scope: 1. A compound, which is represented by the following formula: 或其醫藥學上可接受之鹽，其中： % A表不含有丨個氮原子且視情況再含有卜2個氮原子 之6員芳基或雜芳基； 環B表示含有1-2個氮原子之6員雜芳基環； 1及谓立地表示選自〇、之整數，以使得卜⑷或 2 ； R1表示選自由以下各基組成之群之成員：H、鹵基、 Cm烷基、齒Cl.6烷基、C(〇)Ci 6烷基、以⑺函匕^烷 基、c(〇)NH-Cl.6烧基、s(0)Ci 6院基、s〇2Cw炫基、 2 H2 s〇2NHC丨_6燒基、s〇2N(C丨·6烧基）2、CN及視情 況經1 =個CN6烷基、鹵基或鹵6烷基取代之HAR ; —且R、R3及R4各自獨立地選自H、自基、Ci6烧基及函 C 1 -6妓》基。 2.如請求項〗之化合物’或其醫藥學上可接受之鹽，立中 環A係選自由以下各基組成之群：芳基，其為苯基；及 雜芳基’其係選自由^ K及（嗪組成之群。 3·如明求項2之化合物，或其醫藥學上可接受之鹽，其中 141275.doc 201102374 4. 5. 6. 7. 8. 9. 10. 係選自由苯基及嘧啶組成之群。 ::青未項1之化合物’或其醫藥學上可接受之鹽，其中 展A為鳴咬環。 :請求項!之化合物’或其醫藥學上可接受之鹽，其中 係選自由吡啶、嘧啶及吡嗪組成之群。 月求項5之化合物，或其醫藥學上可接受之鹽，其中 環B表示哺咬。 如凊求項1之化合物，或其醫藥學上可接受之鹽，其中i 及J·表不0、1或2，以使得丨與j之和為2。 士叫求項1之化合物，或其醫藥學上可接受之鹽，其中 Rl係選自由以下各基組成之群：H、鹵基、 Cl·3烷基、鹵 Cl·3烷基、C(0)NHC2.4烷基、s(0)Ci-3 烷 基 S〇2C〗-3烧基、S02NHCK3院基、CN及 HAR，該 HAR 為含有1個氮原子、視情況再含有丨_3個氮原子及視情況 各有1個氧原子之5員雜芳環，該雜芳基視情況經丨個c i ·3 炫基_取代。 如請求項8之化合物’或其醫藥學上可接受之鹽，其中 R1係選自由以下各基組成之群：η、為F或以之鹵基、 Cw烷基、cf3、c(〇)NH_環丙基、s(〇)Ch3、s〇2CH3、 SO2NH環丙基、CN及HAR，該HAR係選自由噁二唑、三 °坐及四唑組成之群，該基團視情況經曱基或環丙基取 代。 如請求項1之化合物’或其醫藥學上可接受之鹽，其中 環A表示苯環且R1表示選自由„惡二吐、三β坐及四β坐組成 141275.doc 201102374 之群的5員雜芳環，該環視情況經甲基或環丙基取代。 Π.如請求項丨之化合物，或其醫藥學上可接受之趟，其 %八表示吡啶環或嘧啶環且Ri表示CN、 _ 3攻、自由°惡 7° 、***及四唑組成之群的5員雜芳環，該環視情況 、輕曱基或環丙基取代。 12·如請求項丨之化合物，或其醫藥學上可接受之鹽，其中 R2表示H、選自F及C1之鹵基、CH3或CF3。 、 13·如3請求項1之化合物，或其醫藥學上可接受之鹽，其中 R3及R4係選自由H、選自基、CH3及CF3組成之 群。 14. 如請求項丨之化合物，或其醫藥學上可接受之鹽，其中 该環丙基環為順式環丙基異構體。 15. 如請求項1之化合物，或其醫藥學上可接受之鹽，其 中： 環八係選自由以下各基組成之群：芳基’其為苯基； 及雜方基，其選自由吡啶、嘧啶及吡嗪組成之群； 裒B係選自由。比。定、°密°定及。比嗪組成之群； 1及J表示0、丨或2，以使得消】之和為2 ; Κ係選自由以下各基組成之群：ti、為F或Br之鹵基、 c】-3烷基、鹵c〗_3烷基、c(0)NHC2-4烷基、s(0)Ci 3烷 基 S〇2Cl-3燒基、院基、CN及 HAR，該 HAR 為3有1個氮原子、視情況再含有1 -3個氮原子及視情況 3有1個氧原子之5員雜芳環，該雜芳基視情況經1個C〗-3 烷基取代； 141275.doc 201102374 R表示Η、選自F及ci之鹵基、ch3及CF3 ; 且R3及R4表示Η、選自F及Cl之鹵基、CH3及CF3。 16.如明求項1之化合物，其係選自由以下各物組成之群： -化合物名稱 夕卜土奴，式氣-2-[4·(2_{2_[4_(甲基碌醯基〕苯氧基]乙基}環丙基} 、5n[4_((ls，2R&gt;2-{2-[4-(甲基雜基)苯氧基]乙 衣丙基)哌咬·1·基]嘧啶及5-氣(甲基磺醯 基)苯氧基]乙基}環丙基)旅唆-1-基]喷啶 ^消旋順式-5-氣·2-{4-[2-(2-{[5-(甲基磺醯基)吼啶-2·基]氧基}乙基） 環丙基]呱啶-l-基}嘧啶、順式-5-氣-2-{4-[(lS,2R)-2-(2-{[5-(甲基磺 醒基)D比咬·2·基]氧基}乙基)環丙基]旅咬_1·基㈣咬、順式_5_氣_2_ {4-[(lR，2S)-2-(2-{[5-(曱基磺醯基)°比啶-2-基]氧基}乙基)環丙基]哌 咳-1-基}嘴咬 外消旋順式-5-氣·2-[4-(2-{2-[3·(甲基磧酿基)笨氧基]乙基丨環丙基） 哌啶-1_基]嘧啶 外消旋順式-5-氣-2-[4-(2-{2-[3-(5-甲基-l，3,4-°惡二峻-2-基)苯氧基]乙 基}環丙基)°底咬-1 -基1 密咬 外消旋順式-5-氣-2-[4-(2-{2-[3-(1Η-1，2,4-三唾_ι_基)苯氧基]乙基}環 丙基)略咬-1-基]嘴啶 外消旋順式·5_氯-2-[4-(2-{2_[3-(1，3,4-鳴二唑_2_基)苯氧基]乙基}環 丙基)派咬小基]嘯咬 外消旋順式-4-(2-{2-[1-(5_氯嘧啶_2·基)派啶斗基]環丙基丨乙氧基)_ Ν-環丙基-2-氟笨曱醯胺 外消旋順式_4-(2-{2_[ 1 -(5·氯°密咬_2_基)依咬_4_基]環丙基}乙氧基)_ 外消旋順式-5-氣-2-[4-(2-{2-[4-(環丙基績醯基)苯氧基]乙基}環丙 基)π底咬-1-基]喷咬 Γί消旋順式-5-氣·2_[4-(2-{2·[3-氟-4-(5- 基]乙基}環丙基)嗓啶小基]嘧啶 外消旋順式-5-氣·2-[4-(2-{2-[4_-(1 丙基)哌啶-1-基1嘧啶 外/肖方疋順式-5-氯-2-[4-(2-{2-[4-(5-甲基-l，3,4-。惡二哇:_2_基)笨氧基]乙 基}環丙基)派唆-1-某&quot;μ密咬 外/肖旋順式-5-氣_2·[4-(2-{2-[4-(1，2,4-噁二唑_3·基)苯氣其〗乙基}環 丙基)0辰咬-1-基1喷咬 土 外4旋順式-5-氯-2-[4-(2-{2-[4-(1，2,4_噁二唑_5-基)笨氧基1乙基}環 丙基)〇辰咬-1-基^ '一 __— —--— _」 141275.doc 201102374 夕卜順式·5-氣-2-[4-(2-{2-[4-(l,3-噁唑-4-基)苯氧基]乙基}環丙基） 哌咬-1-基1峰喷 艾順式-5_氣_2-(4-{2-[2-(4-異嚼唾_4_基苯氧基)乙基]環丙基}娘 啶-1_基)嘧啶 順式-5-氯-2-(4_{2-[2-(4-異噁唑-5-基苯氧基)乙基]環丙基}哌 啶-1-基)嘧啶 疋順式氯_2_[4_(2_{2·[4_(1Η_吼嗤_3_基)苯氧基]乙基}環丙基） 哌啶-1-基]嘧啶 ^旋順式_5_氣吡唑_4_基)苯氧基]乙基}環丙基 σ辰0疋-1-基1确咬 式_5·氣_2_[4_(2_{2_[4_(1H4匕峻基)苯氧基]乙基}環丙基 0展咬-1-基]嘴咬 $ j旋顺式-5_氣:2_[4_(2_{2-[4_(111_1，24_三„坐小基)苯氧基]乙基}環 「丙基 &gt;底啶-1-基1嘧啶 旋順式，5·氣-州必叫叫⑸，2，‘***_4·基)苯氧基]乙基}環 丙基)哌啶-1-基]嘧啶 H旋順式_5-氣坐小基〉苯氧基]乙基}環 丙基)哌啶-1-基]嘧啶 H旋順式-5_氟-2-[4-(2-{2-[4-(ih-i,2,3·三嗤-1-基)苯氧基]乙基}環 丙基)哌啶-1-基1嘧啶 順式_5-曱基_2-[4-(2-{2_[4_即-1，2,3-三》坐-1-基)苯氧基]乙基} %丙基)派啶_ 1 -基]嘧啶 外肩故順式-5-氣-2-[4，(2-{2-[4-(況-1，2,3-***-2_基)笨氧基]乙基}環 丙基)哌啶-1-基]嘧啶 外辦疋順式-5-氣-州-叫州-邱义❽王唑巧-基)苯氧基]乙基}環 丙基)娘。定-1-基]嘴咬 外勒疋順式·5-氣-2-[4-(2_{2·[4_(1Η-四唾·n)苯氧基]乙基}環丙基） 哌啶-1-基1嘧啶 外/肖旋順式-5-氣-2-[4-(2-{2-[3-氟-4-(1Η-四唑-1-基)笨氧基]乙基}環 丙基)°底啶-1-基]嘧啶 外消誕順式-5-氟々[‘⑺心卜氣-吣出-凹唑]基)笨氧基]乙基》環 丙基)娘唆-1 ·基]嘴淀 外4從順式-2_〖4-(2-{2-[3-氟-4-(1Η-四唑-1-基)苯氧基]乙基}環丙基） 哌咬-1-基]-5-甲基嘧啶 外消旋順式-5-氣-2-[4-(2-{2-[4_(2H-四唑_2·基)苯氧基]乙基}環丙基） 0底咬-1-基]痛咬 外消旋順式-5-氣-2-[4-(2-{2-[4-(5-曱基_211-四唑-2-基)笨氧基]乙美} 環丙基)哌啶小基]嘧啶 外消旋順式_5·氯_2-[4-〇{2-[4-(5_甲基_出-四唑-1-基)苯氧基]乙基} 環丙基)哌啶-1-基]嘧啶 [SI 141275.doc 201102374 夕卜，旋順式-5-氯-2-[4-(2-{2-[3- 一基]乙基}環丙基)哌咬-丨-基]嘧啶 一坐-2-基)本氧 =^ΙΪΪΤ[4_(2·{2_[1_(5_ 氯做 _2_i)対_4：^系 基)本基]乙_ ά-6-(2Τ{2-[1-(5- f 乙氧基)嘧啶-4-甲腈 」么义 ί iU*式_6·(2_{2[1_(5_氣嘧啶_2_基)°底咬-4·基]環丙基）乙氧基)嘧 順式·Τ^·{2-[1_(5·氣做·2·基 Κ44·基] 咬-2-曱腈 對掌性順式-2-曱基-6-(2·{2-[1·(5-曱基嘧啶-2-基)哌啶 乙氧基)嘧啶-4-甲腈、順式-2-甲基-6-(2-{(lS，2R)-2-[l_(5-曱基喷咬_ 2-基)旅啶·4·基]環丙基}乙氧基)嘧啶_4_甲腈、順式_2_甲基_6_(2_ {(lR，2S)-2-[l-(5-曱基》密咬-2-基)派咬-4-基]環丙基}乙氧基)嘴。定_4_ 甲腈 外消旋順式-2-曱基-6-(2-{2-[1-(5_甲基嘧啶-2-基)派啶 乙氧基)嘧啶-4-甲腈 外消紅順式-2,4-二甲基-6-(2-{2-[l-(5-曱基嘴咬-2-基)。底咬-4-基]環丙 基}乙氧基)嘴咬 外消旋順式-6-(2-{2-[l-(5-氣-4-曱基嘧啶-2-基)哌啶-4-基]環丙基}匕… 氧基)-2-曱基嘧啶-4-甲腈 外消旋順式-6-(2-{2-[1·(5-氯吼啶-2-基)哌啶-4-基]環丙基}乙氧基;)_ 2-曱基嘧啶-4-曱腈 外消旋順式-6-(2-{2-[1-(4,5-二甲基嘧啶-2-基)哌啶-4-基]環丙基}乙 氧基)·2·甲基嘧啶-4-甲腈 外消旋順式-6-(2·{2-[1-(5·氣-4-甲基&quot;比啶-2-基)哌啶-4-基]環丙基}乙 氧基)·2-曱基嘧啶-4-甲腈 外消旋順式-6-(2-{2-[1-(5-氟-4-甲基嘧啶-2-基)哌啶-4-基]環丙基}乙 氧基)-2-甲基嘧啶·4-甲腈 外消旋順式-2-曱基-6-[2-(2-{ 1-[5-(三氟甲基)吡啶-2-基]哌啶-4-基} 環丙基)乙氧基]嘧啶-4-甲腈 外消旋順式-5-氯-2-(4-{2-[2-(&quot;比啶-3-基氧基)乙基]環丙基} »辰。定-1 - 基)D密咬 外消旋順式-5-氣-2-(4-{2-[2-(嘧咬-4-基氧基)乙基]環丙基}哌咬-1-基)响咬 141275.doc 201102374 外肩旋順式-5-(2-{2-[ 1 -(5-氯嘧啶-2-基)。底啶-4-基]環丙基}乙氧基)菸 鹼腈 ' ,- 外,旋順式-6-(2_{2-[l-(5-氯嘧啶_2_基)哌啶-4-基]環丙基}乙氧基)_ 嘧啶-4-甲腈 外肩旋順式-4-(2_{2·[1-(5-氯嘧啶冬基)派啶斗基]環丙基}乙氧基)_ 啶-2-曱腈 外消旋順式·6_(2_{2-[ 1-(5_氟嘧啶冬基)哌咬_4·基]環丙基}乙氧基)_ 啶-4-甲腈 外消旋順式-5-(2-{2-[ 1-(5-氯嘧啶-2-基)派啶-4-基]環丙基}乙氧基)吡 啶-2-曱腈 外/肖旋順式_5·乳-2·(4·{2-[2_(°比咬-4·-基氧基)乙基]環丙基]略咬-i_ 基)嗜啶 對莩性順式_5_氣***小基)吡啶：基]氧 基}乙基)環丙基]哌啶-l-基}嘧啶、順式-5-氣-2-{4-(lS，2R)-[2-(2-{[5-(敗·丨，2,3-***-1-基)吡啶_2_基]氧基}乙基)環丙基]哌咬]-基}嘧 咬、順式-5-氣-2-{4-(1民28)-[2-(2-{[5-(1//-1，2,3-***-1-基)吡咬_2· _基]氧基}乙基)環丙基]旅咬-l-基}嘧啶 5_ 氯·2-[4-((1 足 2S)-2-{2-[3-氟·4_(5·曱基-1，3,4-噁二唑-2·基)苯氧基]— 乙基}環丙基)哌啶-1 -基]嘧啶及5-氯-2-[4-(( 15；2J?)-2-{2-[3-氟-4-(5-曱 基-1，3,4-噁二唑-2-基)苯氧基]乙基}環丙基)哌务μ基1嘧啶 5_ 虱-2-[4-((1；5,2幻-2-{2-[4-(111-1，2,3-***-1-基)苯氧基]乙基}環丙 基)哌咬-1-基]嘧啶及5-氣·2·[4_((1足***小基） 苯氧基]乙基}環丙基)旅咬-1-基]嘧啶 氟·2-[4-((1足25&gt;2-{2-[4-(出-1，2,3-***-1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶及 5_ 氟 _2_[4_((15；2/?)-2-{2-[4-(111-1,2,3-***-1-基） 苯氧基]乙基}環丙基)哌咬-1-基]嘧啶 5_氯-2-[4-((li?，25&gt;2-{2-[4-(iH-四唑-1-基)苯氧基]乙基}環丙基)哌— 啶-1-基]嘧啶及5-氯·2·[4·((15；2π)-2-{2-[4-(1Η-四唑基)苯氧基]乙 基}環丙基)哌啶-1-基]嘧啶 5-氯-2-[4·((1足2S)-2-{2-[3-氟-4-(出-四唑-1-基)笨氧基]乙基}環丙基） 哌咬-1-基]嘧啶及5-氣-2-[4·((1及2i?)-2-{2-[3-氟-4-(1Η-四唑-1-基)笨 乳基]乙基}壞丙基)娘咬-1-基]癌咬 5·氟-2-[4-((l/?，2S&gt;2-{2-[3·氟-4·(5·曱基-I，3,4·噁二唑_2_ 基)苯氧基] 乙基}環丙基)哌啶-1·基]嘧啶及5-氟-2-[4-(( 1\2Λ)-2-{2-[3-氟-4-(5-曱 基-I，3,4-噁二唑·2·基)苯氧基]乙基}環丙基)哌啶小基]嘧啶 外消旋順式-2-[4-(2·{2-[3-氟-4-(5·甲基-I，3,4-喔二唑-2·基)苯氧基]乙 基}環丙基)哌啶-1-基1-5-甲基嘧啶 外消旋順式·2·[4-(2-{2-[3-氟斗(5·甲:ϊ-1，3,4-喔二唑-2-基)苯氧基]乙 基}環丙基)旅咬-1-基]哺咬 外消旋順式-5-氟-2·[4-(2-{2-[3-氟-4-(5-甲基-l，3,4-噁二唑-2-基)苯氧 基]乙基}環丙基)派咬-1-基]嘴咬 141275.doc 201102374 外 /紐順式-5-氣-2-[4-(2-{2-[3-氟-4-(5-曱基-1，3,4-嚼二唑-2-基)笨 i 基]乙基}環丙基)哌啶-1-基1-4-曱基嘧咬 外 4方疋順式 3,5-一氣-2-[4-(2-{2-[3-氟-4-(5-甲基-1,3,4-°惡二唾-2-基） 苯氧基]乙基}環丙基 外消旋順式-2-[4-(2-{2-[3-氟_4_(5·曱基―丨，3,4』惡二唑_2_基)苯氧基]乙 基}環丙基)哌啶-1 _基]-5-(三氟曱基户比啶鑌：r氟乙酸鹽 外肩旋反式-5-氣·2·[4-(2-{2-[4_(曱基續醯基)笨氧基]乙基μ裒丙基) 略咬-l-基]痛咬 外肩破汉式氣-2-(4-{2-[2十比啶斗基氧基)乙基]環丙基}α农咬+ — 基)嘧啶 4-(2-{(li?，2i?)-2-[l_(5·氣嘧咬j·基)哌啶斗基]環丙基}乙氧基)_Ν 丙基-2-氟苯曱酿胺 t(2-{(li?，2/?)-2-[l-(5-氯嘧咬_2_基)哌啶斗基]環丙基}乙氧基)_2_氣 苯甲腈 5-氯-244-((1/?，2办2-{2-[4-(111-1,2,4-三嗤-1-基)苯氧基]乙基}環丙 基)哌啶-1-基]嘧啶 5-氯-2-1_4·((1足 2/?)-2-{2-[3-氣-4-(5-甲基-1，3,4-°惡二唑-2-基)笨氧基 1 乙基}環丙基)哌啶-1-基1嘧啶 ；)-氣-2-L4-((l/i，：^)-2-{2-[4-(5-環丙基-1，3,4-噁二唑-2-基)-3-氟苯氧 基]乙基}環丙基&gt;·底咬-1-基1嘴咬 外消旋反式-5-氯-2-(4-{2-[2十比啶-4-基氧基)乙基]環丙基p底咬小 基)°密°定 外涓旋夂式-4-(2]2-[l-(5-氯嘧啶_2_基)哌啶冰基]環丙基）乙氧基)_ 6-曱基嘧啶-2-曱腈 外消旋反式-6-(2·{2-[1-(5-氯嘧啶-2-基)哌啶-4-基]環丙基}乙氧基)_ 2-甲基嘧啶-4-曱腈 外消旋反式-5-氣-2-{4-[(2-{[4-(甲基磺醯基)苯氧基]甲基μ裒丙基)甲 基]π底咬-1-基卜密咬 5 -氣-2· [4-(( 1 /?，2Λ)-2- { 2· [4_(曱基績醯基)苯氧基]乙基}環丙基)0底。定-1-基]嘲咬 5-氯-2-{4-[((以2习-2-{[4-(曱基磺鑪基)笨氧基]甲基}環丙基)甲基]哌 咬-1-基}嘴咬 外消旋反式-4-[(2·{[1-(5-氣嘧咬_2_基)哌啶-4-基]甲基}環丙基)曱氧 基]-2-氟笨甲腈 4-[((1/?，27?)-2_{[1-(5-氯嘧啶·2_基)哌啶斗基]甲基}環丙基)甲氧基]_2_ 氟苯甲腈 外消旋反式-4·[(2-{[1-(5-氣嘧啶-2-基)哌啶-4-基]甲基}環丙基)曱氧 基]-Ν-環丙基-2-氟苯甲醯胺 4-[((1/?，2Λ)-2-{[1-(5-氣嘧啶-2-基)《底啶-4-基]甲基}環丙基)曱氧基]-Ν-環丙基-2-氟苯甲醯胺 141275.doc 8 - 201102374 %丙基-2-氟苯甲醯胺 氯-2-{4-[((1 尺2/?)-2-{[3-銳-4-(5- f 基-1，3,4-嗔二冬2-基)苯氧基 J 甲 基}環丙基)，基]旅咬-1-基丨啼咬 1 氯-2-{4-[((1&amp;2分2-{(；3-氟-4-(5-甲基-i，3,4-喝二唾-2-基)苯氧基 J 甲 基}環丙基）f基]α底咬-1-基卜密咬 ^4¼ 反式-5-氯-2·{4-[(2-{[4-(5-環丙基-1，3,4-喔二唑-2-基)-3-氟苯 氧基J甲基}環丙基)甲基J派咬，1_基}痛唉 |Ti((10，2i)-2-UI-(5-氯嘧啶-2-基)哌啶_4_基]〒基)環丙基)甲氧基]苯 磺醯胺 外勒疋反式-6-L(2_{[l-(5-氯嘧啶_2_基)哌啶_4_基]甲基}環丙基)甲氧 基]_2_甲基嘴咬-4-甲赌 外4旋反式-4-[(2-{[l-(5-氣嘧啶-2-基)哌啶-4-基]甲基}環丙基)甲氧 基]-6-甲基嘴咬-2-甲腈 外/肖旋反式-4_[((lS，2S)_2-{[l-(5-氯嘴咬·2·基)派咬-4-基]甲基}環|5^—' 基)曱氧基]-3-氟苯甲腈 外肩方疋順式-5-氯-2-{4-[(2-{[4-(甲基磺醯基)苯氧基]曱基}環丙基)曱 基]哌咬-l-基}嘧啶 外消旋順式-4-[(2-{[1-(5-氯嘧啶-2-基)哌啶冰基]甲基}環丙基)曱氧 基]-Ν-環丙基-2-氟茉甲醯胺 外肩旋順式-4-[(2-{[ι_(5-氯嘧啶-2-基)哌啶-4-基]甲基}環丙基)甲氧〜 基]_6·甲基嘴咬-2-甲暗 外4汉順式-4-[(2· {[ 1-(5-氯嘧啶-2-基)哌啶_4_基]曱基}環丙基)甲氧 基]-2-氟苯甲腈 或其醫藥學上可接受之鹽。 17. —種式Ι-A化合物：Or a pharmaceutically acceptable salt thereof, wherein: % A represents a 6-membered aryl or heteroaryl group which does not contain a nitrogen atom and optionally contains 2 nitrogen atoms; Ring B represents 1-2 nitrogens a 6-membered heteroaryl ring of an atom; 1 and a standing position representing an integer selected from 〇, such that 卜(4) or 2; R1 represents a member selected from the group consisting of H, halo, Cm alkyl, Teeth Cl.6 alkyl, C(〇)Ci 6 alkyl, (7) functional alkyl, c(〇)NH-Cl.6 alkyl, s(0)Ci 6 phenyl, s〇2Cw 炫, 2 H2 s〇2NHC丨_6 alkyl, s〇2N (C丨·6 alkyl) 2, CN and, optionally, HAR substituted by 1 = CN6 alkyl, halo or halo 6 alkyl; R, R3 and R4 are each independently selected from the group consisting of H, self group, Ci6 alkyl group and C 1 -6 妓 group. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the group consisting of an aryl group which is a phenyl group; and a heteroaryl group which is selected from the group consisting of K and (a group of azines. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein 141275.doc 201102374 4. 5. 6. 7. 8. 9. 10. a group consisting of phenyl and pyrimidine. :: A compound of the formula 1 or a pharmaceutically acceptable salt thereof, wherein A is a bite ring. : Requested! Compounds' or pharmaceutically acceptable thereof a salt, wherein the compound is selected from the group consisting of pyridine, pyrimidine, and pyrazine. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring B represents a bite. a pharmaceutically acceptable salt, wherein i and J are not 0, 1 or 2 such that the sum of 丨 and j is 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rl is selected from the group consisting of H, halo, Cl.3 alkyl, haloCl.3 alkyl, C(0)NHC2.4 alkyl, s(0)Ci-3 alkyl S〇 2C〗 -3 alkyl, S02NHCK3, CN and HAR, the HAR is a 5-membered heteroaryl ring containing one nitrogen atom, optionally containing 丨3 nitrogen atoms and optionally one oxygen atom, respectively. The aryl group is optionally substituted by a ci 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Halogen group, Cw alkyl group, cf3, c(〇)NH_cyclopropyl group, s(〇)Ch3, s〇2CH3, SO2NH cyclopropyl group, CN and HAR, the HAR system is selected from oxadiazole, three° And a pharmaceutically acceptable salt of the compound of claim 1, wherein ring A represents a benzene ring and R1 represents a group selected from the group consisting of a tetrazole or a cyclopropyl group. „ 恶二吐,三β坐和四β坐 constitutes a group of 141275.doc 201102374 of the 5-membered heteroaryl ring, which is optionally substituted by methyl or cyclopropyl. 如. If requested, the compound or its medicine A five-membered heteroaryl ring of the group consisting of a group consisting of a pyridine ring or a pyrimidine ring and Ri representing a CN, a _ 3 attack, a free 7°, a triazole, and a tetrazole, </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 13. The compound of claim 1, wherein R3 and R4 are selected from the group consisting of H, selected from the group consisting of CH3 and CF3, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt thereof, wherein the cyclopropyl ring is a cis-cyclopropyl isomer. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the cyclic octane is selected from the group consisting of aryl 'which is a phenyl group; and a heterocyclic group selected from the group consisting of pyridine a group consisting of pyrimidine and pyrazine; 裒B is selected from the group consisting of. ratio. Set, ° density °. a group consisting of a pyrazine; 1 and J represent 0, 丨 or 2 such that the sum of the two is 2; the lanthanide is selected from the group consisting of ti, a halogen group of F or Br, c]-3 Alkyl, halogen c _3 alkyl, c(0)NHC2-4 alkyl, s(0)Ci 3 alkyl S〇2Cl-3 alkyl, yard, CN and HAR, the HAR is 3 and 1 a nitrogen atom, optionally containing from 1 to 3 nitrogen atoms, and optionally a 5-membered heteroaryl ring having one oxygen atom, optionally substituted by one C--3 alkyl group; 141275.doc 201102374 R represents fluorene, a halogen group selected from F and ci, ch3 and CF3; and R3 and R4 represent fluorene, a halogen group selected from F and Cl, and CH3 and CF3. 16. The compound according to claim 1, which is selected from the group consisting of: - the compound name Ubbutano, the formula gas-2-[4.(2_{2_[4_(methyl fluorenyl)] Phenoxy]ethyl}cyclopropyl}, 5n[4_((ls,2R&gt;2-{2-[4-(methylhetero)phenoxy)ethlyl)piperidone·1·yl Pyrimidine and 5-gas (methylsulfonyl)phenoxy]ethyl}cyclopropyl) 唆-1-yl]pyridinium ^despinidine-5-gas·2-{4-[2 -(2-{[5-(methylsulfonyl)acridin-2-yl]oxy}ethyl)cyclopropyl]acridine-l-yl}pyrimidine, cis-5-gas-2- {4-[(lS,2R)-2-(2-{[5-(methylsulfonyl)D) 2 yl)oxy}ethyl)cyclopropyl] brigade bite (4) bite, cis _5_gas_2_ {4-[(lR,2S)-2-(2-{[5-(indolylsulfonyl))pyridin-2-yl]oxy}ethyl Cyclopropyl]piperidin-1-yl} mouth bite racemic cis-5- gas·2-[4-(2-{2-[3·(methyl 碛)) phenyloxy] Cyanopropyl) piperidin-1_yl]pyrimidine racemic cis-5-gas-2-[4-(2-{2-[3-(5-methyl-l,3,4- °Ethyl dimer-2-yl)phenoxy]ethyl}cyclopropyl) ° bottom bite-1 -yl 1 bite racemic cis-5- gas-2-[4-(2-{2 -[3-(1Η-1,2,4-tris-sodium)phenoxy] } 环 ) ) ) ) -1- -1- -1- -1- -1- -1- 外 外 外 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 _ yl) phenoxy]ethyl}cyclopropyl) cleavage small base] whistling racemic cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)pyridine Bucket base] cyclopropyl hydrazine ethoxy) Ν 环-cyclopropyl-2-fluoro cumamine amine racemic cis _4-(2-{2_[ 1 -(5·氯°密咬_2 _ base) _4_yl]cyclopropyl}ethoxy)_ racemic cis-5-gas-2-[4-(2-{2-[4-(cyclopropyl) Phenoxy]ethyl}cyclopropyl) π bottom bit-1-yl] 喷 Γ ί Cyclos-5-gas·2_[4-(2-{2·[3-fluoro-4-( 5-yl]ethyl}cyclopropyl)acridine small group]pyrimidine racemic cis-5- gas·2-[4-(2-{2-[4_-(1 propyl) piperidine-1 -yl 1 pyrimidine / cholaryl cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-l,3,4-. oxazide:_2-yl) ) stupid oxy]ethyl}cyclopropyl)pyrazine-1-some&quot;μ密咬/肖旋顺式-5-气_2·[4-(2-{2-[4-(1 , 2,4-oxadiazole _3·yl) benzene gas 〗 〖Ethyl} cyclopropyl) 0 Chen bite-1-yl 1 spray biting soil 4 cis-cis-5-chloro-2-[4- (2-{2-[4-(1,2,4-oxadiazole-5-yl)phenyloxy 1ethyl}cyclopropyl)〇辰咬-1-基^ '一__— --- _" 141275.doc 201102374 卜卜顺·5-Gas-2-[4-(2-{2-[4-(l,3-oxazol-4-yl)phenoxy]ethyl }cyclopropyl) piperidine-1-yl 1 peak spray Ai Shun-5_ gas_2-(4-{2-[2-(4-iso-chesin-4-ylphenoxy)ethyl] Cyclopropyl}nidanyl-1_yl)pyrimidine cis-5-chloro-2-(4_{2-[2-(4-isoxazol-5-ylphenoxy)ethyl]cyclopropyl} Piperidin-1-yl)pyrimidine cis chloro-2_[4_(2_{2·[4_(1Η_吼嗤_3_yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl Pyrimidine 旋 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2_[4_(1H4匕匕基)phenoxy]ethyl}cyclopropyl 0-bend-1-yl] mouth bite $ j-spin--5_ gas: 2_[4_(2_{2-[4_( 111_1,24_三„Small base) phenoxy]ethyl}cyclo"propyl&gt; ethidin-1-yl 1 pyrimidine cis, 5 · gas - state must be called (5), 2, 'triazole _4·yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine H cis- _5-gas succinyl>phenoxy]ethyl}cyclopropyl)piperidine- 1-yl]pyrimidineH-cyclohex-5-fluoro-2-[4-(2-{2-[4-(ih-i,2,3·tris-1-yl)phenoxy]ethyl }cyclopropyl)piperidin-1-yl 1 pyrimidine Cis_5-fluorenyl_2-[4-(2-{2_[4_,-1,2,3-trisyl-1-yl)phenoxy]ethyl}%propyl)pyridine _ 1 -yl]pyrimidine external shoulder cis--5-gas-2-[4,(2-{2-[4-(condition-1,2,3-triazol-2-yl)phenyloxy] Ethyl}cyclopropyl)piperidin-1-yl]pyrimidine 外 式-5-gas-state-Chaozhou-Qiuyi ❽ oxazolyl-yl)phenoxy]ethyl}cyclopropyl) mother. Ding-1-yl] mouth bite 疋 · · 5- gas-2-[4-(2_{2·[4_(1Η-tetras-n)phenoxy]ethyl}cyclopropyl) piperidine Pyridin-1-yl 1 pyrimidine / cis-cis--5-gas-2-[4-(2-{2-[3-fluoro-4-(1Η-tetrazol-1-yl)]-oxy] Ethyl}cyclopropyl) °acridin-1-yl]pyrimidine exo- cis-5-fluoroanthracene ['(7)心气气-吣出-凹azole]-) phenyloxy]ethyl"cyclopropyl ))唆唆-1 ·基] mouth outside the 4 from cis-2_〖4-(2-{2-[3-fluoro-4-(1Η-tetrazol-1-yl)phenoxy]ethyl }cyclopropyl)piperidin-1-yl]-5-methylpyrimidine racemic cis-5-gas-2-[4-(2-{2-[4_(2H-tetrazol-2-yl) Phenoxy]ethyl}cyclopropyl) 0 bottom bit-1-yl] biting racemic cis-5-gas-2-[4-(2-{2-[4-(5-曱) Base _211-tetrazol-2-yl) phenyloxy] ethoxy] cyclopropyl) piperidinyl] pyrimidine racemic cis-5_chloro-2-[4-〇{2-[4- (5-methyl-exo-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine [SI 141275.doc 201102374 ,, 旋-5-chloro -2-[4-(2-{2-[3-yl]ethyl}cyclopropyl)piperidin-yl-yl]pyrimidine-s-yl-2-yl)Oxygen=^ΙΪΪΤ[4_(2· {2_[1_(5_ 氯做_2_i)対_4:^系基)本基]乙_ Ά-6-(2Τ{2-[1-(5- f ethoxy)pyrimidine-4-carbonitrile) 义义 ί iU* _6·(2_{2[1_(5_ apyrimidine_2_ Base) ° bottom bit-4·yl]cyclopropyl)ethoxy)pyrimidine·Τ^·{2-[1_(5·气做·2·基Κ44·基) bite-2-indene nitrile pair Palm cis-2-mercapto-6-(2·{2-[1·(5-decylpyrimidin-2-yl)piperidinyloxy)pyrimidine-4-carbonitrile, cis-2- Methyl-6-(2-{(lS,2R)-2-[l_(5-fluorenyl benzo-2-yl)) acyl-4-yl]cyclopropyl}ethoxy)pyrimidine_4_ Nitrile, cis- 2_methyl_6_(2_ {(lR,2S)-2-[l-(5-fluorenyl))-2-yl)-2-yl]cyclopropyl} Ethoxyl). _4_carbonitrile racemic cis-2-mercapto-6-(2-{2-[1-(5-methylpyrimidin-2-yl)pyridinyloxy) Pyrimidine-4-carbonitrile-o-red-cis-2,4-dimethyl-6-(2-{2-[l-(5-mercaptopurine-2-yl). Cyclopropyl}ethoxy) mouth biting racemic cis-6-(2-{2-[l-(5- oxa-4-mercaptopyrimidin-2-yl)piperidin-4-yl] Cyclopropyl}匕...oxy)-2-mercaptopyrimidine-4-carbonitrile racemic cis-6-(2-{2-[1·(5-chloroacridin-2-yl)piperidine 4-yl]cyclopropyl}ethoxy;) _ 2-mercaptopyrimidine-4-indene nitrile racemic cis-6-(2-{2-[1-(4,5-di Pyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)·2·methylpyrimidine-4-carbonitrile racemic cis-6-(2·{2-[1- (5·Ga-4-methyl&lt;bipyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)·2-mercaptopyrimidine-4-carbonitrile racemic cis- 6-(2-{2-[1-(5-fluoro-4-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine·4- Carbonitrile racemic cis-2-mercapto-6-[2-(2-{ 1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}cyclopropyl) Ethoxy]pyrimidine-4-carbonitrile racemic cis-5-chloro-2-(4-{2-[2-(&quot;pyridin-3-yloxy)ethyl]cyclopropyl} »辰. Ding-1 -yl)D-biting racemic cis-5-gas-2-(4-{2-[2-(pyridin-4-yloxy)ethyl]cyclopropyl}piperidine- 1-base) ringing 141275.doc 201102374 outer shoulder-spinning-5-(2-{2-[ 1 -(5-chloropyrimidin-2-yl). acridin-4-yl]cyclopropyl}B Oxy)nicotinonitrile ',-, Cyclo--6-(2_{2-[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy) _ Pyrimidine-4-carbonitrile external shoulder-rotating -4-(2_{2·[1-(5-chloropyrimidinyl)pyridinyl]cyclopropyl}ethoxy)_ pyridine-2-oxime Nitrile racemic cis- 6_(2_{2-[ 1-(5-fluoropyrimidinyl)piperidin-4-yl]cyclopropyl}ethoxy)-pyridine-4-carbonitrile racemization 5-(2-{2-[ 1-(5-chloropyrimidin-2-yl)pyridin-4-yl]cyclopropyl}ethoxy)pyridine-2-indoleonitrile / Cyclo-cis _5·乳-2·(4·{2-[2_(° ratio bit-4--yloxy)ethyl]cyclopropyl] slightly bite-i_ base) 啶 莩 莩 顺 cis _5_ Gas triazole small base) pyridine: yl) oxy} ethyl) cyclopropyl] piperidine-l-yl} pyrimidine, cis-5-gas-2-{4-(lS, 2R)-[2- (2-{[5-((?), 2,3-triazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin]-yl}pyridine, cis -5-气-2-{4-(1民28)-[2-(2-{[5-(1//-1,2,3- Oxazol-1-yl)pyridinium_2· _yl]oxy}ethyl)cyclopropyl] brigade-l-yl}pyrimidine 5_ chloro·2-[4-((1 foot 2S)-2-{ 2-[3-Fluoro-4_(5.indolyl-1,3,4-oxadiazol-2yl)phenoxy]-ethyl}cyclopropyl)piperidine-1 -yl]pyrimidine and 5 -Chloro-2-[4-(( 15; 2J?)-2-{2-[3-fluoro-4-(5-fluorenyl-1,3,4-oxadiazol-2-yl)phenoxy ]]ethyl}cyclopropyl)piperidinyl 1 pyrimidine 5_ 虱-2-[4-((1;5,2 幻-2-{2-[4-(111-1,2,3-three) Zin-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-gas·2·[4_((1) triazole small) phenoxy]ethyl} Cyclopropyl) brigade-1-yl]pyrimidine fluoride·2-[4-((1 foot 25&gt;2-{2-[4-(ex-1,2,3-triazol-1-yl)benzene) Oxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5_fluoro_2_[4_((15;2/?)-2-{2-[4-(111-1,2,3 -triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperazin-1-yl]pyrimidine 5-chloro-2-[4-((li?,25&gt;2-{2-[4 -(iH-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro·2·[4·((15;2π)-2- {2-[4-(1Η-tetrazolyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine 5-chloro-2-[4·((1)2S)-2- {2-[3-Fluoro-4-(out-tetrazol-1-yl)phenyloxy] }{cyclopropyl)piperidin-1-yl]pyrimidine and 5-gas-2-[4·((1 and 2i?)-2-{2-[3-fluoro-4-(1Η-tetrazole- 1-base) stupid base] ethyl} bad propyl) mother bite-1-yl] cancer bite 5 · fluoro-2-[4-((l/?, 2S&gt;2-{2-[3·Fluorine -4·(5·曱-I,3,4·oxadiazole_2_yl)phenoxy]ethyl}cyclopropyl)piperidine-1·yl]pyrimidine and 5-fluoro-2-[4 -(( 1\2Λ)-2-{2-[3-Fluoro-4-(5-fluorenyl-I,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl Piperidinyl]pyrimidine racemic cis-2-[4-(2·{2-[3-fluoro-4-(5·methyl-I,3,4-oxadiazole-2·yl) Phenoxy]ethyl}cyclopropyl)piperidin-1-yl1-5-methylpyrimidine racemic cis- 2·[4-(2-{2-[3-fluorocape (5· A: ϊ-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) brigade-1-yl]-biting racemic cis-5-fluoro-2· [4-(2-{2-[3-Fluoro-4-(5-methyl-l,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)-bite- 1-base] mouth bite 141275.doc 201102374 outer/newsup-5-gas-2-[4-(2-{2-[3-fluoro-4-(5-mercapto-1,3,4- Chewable diazol-2-yl) stupid i-yl]ethyl}cyclopropyl)piperidin-1-yl1-4-mercaptopyrimidine 4 疋 cis 3,5-one gas-2-[4- (2-{2-[3-fluoro-4-(5-methyl-1,3,4-) Oxadi-2-yl-2-phenoxy]ethyl}cyclopropyl racemic cis-2-[4-(2-{2-[3-fluoro_4_(5·曱-yl), 3 , 4"oxadiazole_2-yl)phenoxy]ethyl}cyclopropyl)piperidine-1 _yl]-5-(trifluoromethyl carbylpyridinium: r fluoroacetate outer shoulder spin式-5-气·2·[4-(2-{2-[4_(曱 醯 )))]]]]]]]]]] Benzene-2-(4-{2-[2:10-pyridinyloxy)ethyl]cyclopropyl}α-negative +-yl)pyrimidine 4-(2-{(li?,2i?)- 2-[l_(5·Azoxypyridinyl)piperidinyl]cyclopropyl}ethoxy)-Νpropyl-2-fluorobenzoquinone-t-(2-{(li?,2/? )-2-[l-(5-chloropyrimidin-2-yl)piperidinyl]cyclopropyl}ethoxy)_2_gasbenzonitrile 5-chloro-244-((1/?,2 2-{2-[4-(111-1,2,4-trimethyl-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine 5-chloro-2- 1_4·((1 foot 2/?)-2-{2-[3- gas-4-(5-methyl-1,3,4-°oxadiazol-2-yl) phenyloxy 1 ethyl }cyclopropyl)piperidin-1-yl 1 pyrimidine ;)-gas-2-L4-((l/i, :^)-2-{2-[4-(5-cyclopropyl-1,3 , 4-oxadiazol-2-yl)-3-fluorophenoxy]ethyl}cyclopropyl&gt;·Bottom bite-1-yl 1 mouth bite racemic trans-5-chloro -2-(4-{2-[2 decapyridin-4-yloxy)ethyl]cyclopropyl p bottom bite small base) ° 密 ° 定 涓 -4- -4- -4-(2]2- [l-(5-chloropyrimidin-2-yl)piperidinyl]cyclopropyl)ethoxy)-6-mercaptopyrimidine-2-indene nitrile racemic trans-6-(2·{2 -[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-indolene racemic trans-5- gas- 2-{4-[(2-{[4-(methylsulfonyl)phenoxy]methyl]pyridylpropyl)methyl]π bottom bite-1-kibium bite 5-gas-2· [4-(( 1 /?, 2Λ)-2- { 2·[4_(曱基醯醯))phenoxy]ethyl}cyclopropyl)0 base. Ding-1-yl] mocking 5-chloro-2-{4-[((2)-2-{[4-(fluorenylsulfonyl)phenyloxy]methyl}cyclopropyl)methyl Piperidine-1-yl} mouth bite racemic trans-4-[(2·{[1-(5-amphetidine-2-yl)piperidin-4-yl]methyl}cyclopropyl曱oxy]-2-fluorobenzonitrile 4-[((1/?,27?)-2_{[1-(5-chloropyrimidin-2-yl)piperidinyl]methyl}cyclopropane Methoxy]_2_ fluorobenzonitrile racemic trans-4·[(2-{[1-(5-apyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl曱oxy]-indole-cyclopropyl-2-fluorobenzamide 4-[((1/?,2Λ)-2-{[1-(5-apyrimidin-2-yl)" 4-yl]methyl}cyclopropyl)decyloxy]-indole-cyclopropyl-2-fluorobenzamide 141275.doc 8 - 201102374 % propyl-2-fluorobenzamide HCl-2 -{4-[((1 ft 2/?)-2-{[3- sharp-4-(5-f-group-1,3,4-indolyl-2-yl)phenoxy-J-methyl} Cyclopropyl),yl]Break bite-1-ylation bite 1 chloro-2-{4-[((1&amp;2 points 2-{(; 3-fluoro-4-(5-methyl-i, 3,4-di-di-sial-2-yl)phenoxy-J-methyl}cyclopropyl)f-based]α-biting--1-yl-branched ^41⁄4 trans-5-chloro-2·{4- [(2-{[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-fluorophenoxymethyl]methyl}cyclopropyl)methyl J ,1_基}, 唉 唉|Ti((10,2i)-2-UI-(5-chloropyrimidin-2-yl)piperidine-4-yl]indolyl)cyclopropyl)methoxy]benzenesulfonate Indoleamine oxime trans-6-L (2_{[l-(5-chloropyrimidin-2-yl)piperidine-4-yl]methyl}cyclopropyl)methoxy]_2_methyl mouth Bite -4- gamma 4 rot trans-4-[(2-{[l-(5-apyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy] -6-methyl mouth bite-2-carbonitrile outer / spirulina trans--4_[((lS,2S)_2-{[l-(5-chloro-nose bit 2· base) pie -4- base ]methyl}cyclo]5^-'yl) oxime]-3-fluorobenzonitrile outer shoulder square cis-5-chloro-2-{4-[(2-{[4-(methyl) Sulfhydryl)phenoxy]indolyl}cyclopropyl)indolyl]piperidin-l-yl}pyrimidine racemic cis-4-[(2-{[1-(5-chloropyrimidin-2-) Benzylpyridinyl]methyl}cyclopropyl)decyloxy]-indole-cyclopropyl-2-fluoromosilamide external shoulder-spinning -4-[(2-{[ι_(5- Chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy~yl]_6·methyl-mouth bite-2-methyl dark outer 4 Hanshun-4-[(2· { [1-(5-Chloropyrimidin-2-yl)piperidine-4-yl]indolyl}cyclopropyl)methoxy]-2-fluorobenzonitrile or a pharmaceutically acceptable salt thereof. 17. —Formula Ι-A compound: (卩4)2-3 或其醫藥學上可接受之鹽，其中： 141275.doc 201102374 環A表示含有1個氮原子且視情況再含有1_2個氮原子 之6員芳基或雜芳基； 環B表示含有1_2個氮原子之6員雜芳基環； i及j獨立地表示選自0、1及2之整數，以使得i+j為1或 2 ； R1表示選自由以下各基組成之群之成員：H、鹵基、 Cu烷基、ilCu烷基' (:(0)(^.6烷基、 基、C^CONH-Cm 烷基、SiCOC^烷基、s〇2Ci_6烷基、 S02NH2、SC^NHCw烧基、SC^NiCu燒基)2、CN及視情 況經1 -3個C!·6跋基、鹵基或鹵Ci·6烧基取代之HAR ; 且R2、R3及R4各自獨立地選自H、鹵基、Cl_6烷基及鹵 Cu烷基。 18.如請求項17之化合物，其係選自由以下各物組成之群： 表l-a 外消旋順式-5-氣·2·[4-(2-{2-[4-(甲基磺醯基)苯氧基]乙基}環丙基） 旅咬-1-基]嘧啶、5-氣-2-[4-((lS，2R)-2-{2-[4-(甲基磺醯基)苯氧基] 乙基}環丙基)》底咬-1-基]嘧啶及5-氣-2-[4_((lR，2S)-2-{2-[4-(甲基磺 醯基)笨氧基]乙基}環丙基)哌啶-1-基]嘧啶 外消旋順式-5-氣-2-{4-[2-(2-{[5-(曱基磺醯基)°比啶-2-基]氧基}乙基） 環丙基]哌啶-l-基}嘧啶、5-氯-2-{4-[(LR，25)-2-(2-{[5-(曱基續醯基） «比咬-2-基]氧基}乙基)環丙基]哌啶_丨_基}嘧啶、5n{4_[(ls，2R)-2-(2-{[5-(曱基磺酿基)吼啶_2基1氧基丨乙基)環丙基]哌啶小基）嘧啶 外消旋順式-5-氯·2-[4-(2-{2-[3·(曱基磺醯基)苯氧基]乙基}環丙基） 0底咬-1-基]喷0定 外消旋順式-5-氣·2·[4·(2-{2_[3_(5-甲基-ΐ，3,4-噁二唑_2_基)苯氧基] 乙基}環丙基)哌咬小基1嘴咬 外消旋順式-5-氯-2-[4·(2-{2·[3-(1Η-1,2,4·***-1-基)苯氧基]乙基}環 丙基)π底咬·1·基]嗜咬 外消旋順式-5-氣-2-[4合{2-[3_(1，3,4-噁二唑-2-基)苯氧基]乙基}環 丙基)。底咬-1-基]鳴唆 141275.doc •10· 201102374 外消旋順式-4·(2-{2-[1·(5-氣嘧咬-2-基)。底咬-4-基]環丙基}乙氧基)， N-每丙基-2·氣笨甲酿胺 外，，順式斗(2-{2-[1-(5-氣嘧啶_2·基)哌啶斗基]環丙基}乙氧基)_ 2-氟苯曱腈 外消旋順式-5-氯-2-[4-(2-{2-[4-(環丙基磺醯基)苯氧基]乙基}環丙 基)°底淀-1-基]&quot;密咬 外消旋順式-5-乳-2-[4-(2-{2-[3-氟-4-(5-曱基-1,3,4-°惡二〇坐.2·基)笨氧 基]乙基}環丙基)派咬-1-基卜密咬 外消旋順式-5-氯·2-[4-(2-{2-[4-(1，3,4-喔二唑-2-基)苯氧基]乙基}環 丙基)°底咬-1-基]嘴咬 外’/肖方疋順式-5-氯·2-[4-(2_{2·[4·(5-曱基-1，3,4-噁二唑-2-基)笨氧基] 乙基}環丙基)旅嗓-1-基]喊咬 外消旋順式_5_氣-2·[4-(2-{2-[4-(1,2,4·噁二唑_3_基)苯氧基]乙基}環 丙基)派淀-1-基]嘴口定 外消方疋順式_5-氣-2-[4_(2-{2-[4-(1，2,4-噁二唑-5-基)苯氧基]乙基}環 丙基)略咬-1-基]嘴淀 外'/肖旋順式_5_氣-2-[4-(2-{2-[4-(1，3_°惡唾_4_基)笨氧基]乙基}環丙基） 旅咬-l-基]ρ密咬 外消旋順式-5-氣-：ζ-(4-{24；ζ_(4-異°恶嗤-4·基笨氧基)乙基]環丙基}0辰 咬-1-基)嘴咬 外消旋〗嗅式-5-氯丨:呉。恶《•坐·5·基苯氧基)乙基]環丙基} 0底 0定-1-基)癌咬 外消鉍順式-5-氣-2-[4-(2_{2·[4-(1Η-&quot;比唑-3-基)苯氧基]乙基}環丙基） 派咬-1-基]癌咬 外消旋順式_5-氣-2·[4-(2-{2-[4_(1Η-°比唑_4·基)苯氧基]乙基}環丙基） °辰啶-1-基]σ密咬 外消旋順式_5_氯-2-[4-(2-{2·[4-(1Η-吡唾-1-基)笨氧基]乙基)環丙基） 派咬-l-基]嘧啶 外消旋順式-5-|t-：z-(_4-(；z-{；z-L4-(iH-l，2,4-三唾-1·基)笨氧基]乙基}環 丙基底咬小基]嘴咬 外消旋順式-5·氣1，2,4-三唾-4-基)苯氧基]乙基}環 丙基)°底咬-1-基]嘴咬 外消旋順式-5-氯-2-[4-(2-{2-[4-(lH-l，2,3-^m^[&amp;][ik 丙基)〇底咬-1-基]喷咬 外消旋順式-5-氟-2-[4-(2-{2-[4-(1Η-1，2,3-***-1-基)苯氧基1乙基}環 丙基)0底咬-1-基]。密咬 !消旋順式-5_甲基-2-[4-(2-{2·[4·(1Η-ΐ，2,3-三唾·卜基)苯氧基]乙基） 壤丙基)派咬·1·基1嘴嗔 式-=-2-[4-(2_{2-[4-(211-1，2,3-三唾-2.基)笨氧基]乙基}環 丙基)娘咬-1-基]喷咬(卩4) 2-3 or a pharmaceutically acceptable salt thereof, wherein: 141275.doc 201102374 Ring A represents a 6-membered aryl or heteroaryl group containing one nitrogen atom and optionally 1 to 2 nitrogen atoms; Ring B represents a 6-membered heteroaryl ring containing 1_2 nitrogen atoms; i and j independently represent an integer selected from 0, 1 and 2 such that i+j is 1 or 2; R1 represents a component selected from the following groups Members of the group: H, halo, Cu alkyl, ilCu alkyl ' (: (0) (^.6 alkyl, yl, C^CONH-Cm alkyl, SiCOC^alkyl, s〇2Ci_6 alkyl , S02NH2, SC^NHCw base, SC^NiCu base) 2, CN and HAR substituted by 1-3 C!·6 fluorenyl, halo or halogen Ci·6 alkyl groups; and R2, R3 And R4 are each independently selected from the group consisting of H, halo, Cl-6, and haloalkyl. 18. The compound of claim 17, which is selected from the group consisting of: Table la Racemic cis-5 - gas · 2 · [4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) brigade-1-yl]pyrimidine, 5-gas-2- [4-((lS,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)" bottom bit-1-yl]pyrimidine and 5-gas- 2-[4_((lR,2S)-2-{2-[4-( Sulfosyl)phenyloxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis-5-gas-2-{4-[2-(2-{[5-(曱 醯 sulfoxime) ° pyridine-2-yl]oxy}ethyl) cyclopropyl] piperidine-l-yl}pyrimidine, 5-chloro-2-{4-[(LR,25)-2 -(2-{[5-(曱基醯)) «Bist-2-yl]oxy}ethyl)cyclopropyl]piperidine-丨-yl}pyrimidine, 5n{4_[(ls,2R )-2-(2-{[5-(indolylsulfonic acid) acridine-2-yl 1oxyindoleethyl)cyclopropyl]piperidine small)pyrimidine racemic cis-5-chloro· 2-[4-(2-{2-[3·(Mercaptosulfonyl)phenoxy]ethyl}cyclopropyl) 0-Bottom--1-yl] oxime-substituted racemic cis-5 - gas · 2 · [4 · (2-{2_[3_(5-methyl-indole, 3,4-oxadiazol-2-yl)phenoxy] ethyl} cyclopropyl) piperidinyl 1 mouth bite racemic cis-5-chloro-2-[4·(2-{2·[3-(1Η-1,2,4·triazol-1-yl)phenoxy]ethyl} Cyclopropyl) π bottom bite · 1 · base] biting racemic cis-5-gas-2-[4 in {2-[3_(1,3,4-oxadiazol-2-yl)benzene Oxy]ethyl}cyclopropyl). Bottom bite-1-yl] Ming 唆 141275.doc •10· 201102374 Racemic cis--4·(2-{2-[1·(5-Acetone-2-yl). Bottom bite -4- (cyclopropyl}ethoxy), N-perpropyl-2. Cyclopropyl]cyclopropyl}ethoxy)_2-fluorobenzonitrile, racemic cis-5-chloro-2-[4-(2-{2-[4-(cyclopropylsulfonyl) Phenoxy]ethyl}cyclopropyl)°Date-1-yl]&quot;Bite of racemic cis-5-mil-2-[4-(2-{2-[3-fluoro- 4-(5-mercapto-1,3,4-° dioxin sit.2·yl) stupidoxy]ethyl}cyclopropyl)-bite-1-kib-Bite-bito-racea- 5-Chloro-[4-(2-{2-[4-(1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)° bottom bite-1- Base] mouth bite outside '/ 肖方疋 cis-5-chloro·2-[4-(2_{2·[4·(5-mercapto-1,3,4-oxadiazol-2-yl)) Stupid oxy] ethyl}cyclopropyl) 嗓-1-yl] shout biting racemic _5_气-2·[4-(2-{2-[4-(1,2,4 · Oxadiazole _3_ yl) phenoxy] ethyl} cyclopropyl) derivative -1- group] mouth mouth to eliminate the external 疋 疋 _5-qi-2-[4_(2-{2 -[4-(1,2,4-oxadiazol-5-yl)phenoxy]ethyl}cyclopropyl)-biti-1-yl] Cis _5_ gas-2-[4-(2-{2-[4-(1,3_° 唾 _ _4_yl)) oxy]ethyl}cyclopropyl) brigade-l-based ρ密咬外消顺-5-气-:ζ-(4-{24;ζ_(4-iso-oxo-4·yloxy)ethyl]cyclopropyl}0-bit bite- 1-base) mouth bite racer olfactory-5-chloropurine: 呉. Evil "• sit · 5 · phenoxy) ethyl] cyclopropyl} 0 base 0 -1- base) cancer bite 铋 式 -5 -5 - -2- [4- (2_{2 · [4-(1Η-&quot;Bizozol-3-yl)phenoxy]ethyl}cyclopropyl) ketone-1-yl]carcinoma biting racemic cis-5-gas-2·[4- (2-{2-[4_(1Η-°Bizozolyl-4)phenoxy]ethyl}cyclopropyl) ° 啶 -1--1-yl] σ 密 外 外 _5_ 氯-2-[4-(2-{2·[4-(1Η-pyrazin-1-yl)phenyloxy]ethyl)cyclopropyl)-bite-l-yl]pyrimidine racemic cis- 5-|t-:z-(_4-(;z-{;z-L4-(iH-l,2,4-tris-l-l)yloxy]ethyl}cyclopropyl bottom bite Mouth bite racemic cis-5-gas 1,2,4-tris-4-yl)phenoxy]ethyl}cyclopropyl) bottom bite-1-yl] mouth bite racemic 5- 5-Chloro-2-[4-(2-{2-[4-(lH-l,2,3-^m^[&amp;][ik propyl)) Biting racemic cis-5-fluoro-2-[4-(2-{2-[4-(1Η-1,2,3-triazol-1-yl)phenoxy 1ethyl}cyclopropane Base) 0 bottom bite-1-yl]. Bite bite! Racemic cis-5-methyl-2-[4-(2-{2·[4·(1Η-ΐ, 2,3-three saliva·基基)phenoxy]ethyl) propyl) pie bite ·1·base 1 mouth --=[4-(2_{2-[4-(211-1,2,3-three Saliva-2. base) Stupid oxy]ethyl}cyclopropyl) Ninja bite-1-yl] spray bite 141275.doc 201102374 外ί!疋J1貝式·5-氣-2-[4-(2-{2_14_(111_1，2,3-三°坐'5-基)苯氧基]乙基}每' 丙基)娘°定小基]嘧唆 外4旋順式氣-2-14-(2·{2-[4-(1Η-四嗤-1-基)笨氧基]乙基μ裒丙基） 口底啶-1-基]嘧啶 7 外消旋順式〇-虱-2叶4-〇{；2-13-氟_4·( 1Η-四唑_ 1 _基)苯氧基]乙基}環 丙基)β底咬-1-基]嘴咬 、 外/肖旋順式*5-氣-2-[4-〇{2-[3-氣_4·(1Η-四唾-ι_基)苯氧基]乙基μ袞 丙基)旅咬-1 ·基]嘴峻 外4奴順式-2·14-(2-{2-13·氟_4·(1Η-四嗤·1_基)笨氧基]乙基μ裒丙基） 娘咬·1·基]·5-曱基痛咬 外肩旋^式·5·氣-2-[4-(2·{2-[4-(2Η-四唑-2-基)苯氧基]乙基μ裒丙基） 旅啶-1-基]嘧啶 J Ϊ^Λ5Λ114_(2_{2_[4-(5·甲基-2H_ 四哇-2_ 基)苯氧基]乙基 &gt; 環丙基)哌啶-1-基1嘧啶 f 甲基视四°坐_1_基)苯氧基]乙基} 基]乙基}壞丙基)痕咬-1-基]。密咬 tfli1 s，2R&gt;(2-{2_[4_(甲基亞續醯基〉笨氧基]乙基}環丙基&gt; 哌 氣嘧咬·2_基)〇底°定_4_基]環丙基}乙氧基)-2-甲 腈、6-(1R，2S&gt;(2-{2_[1-(5i密咬-2-基)〇底唆-4-基]環丙 基}乙氧基)-2-甲基嘧啶-4-甲腈 順式·Η4·(2_{2-[1·(5-氣嘧啶-2_i)哌啶斗基]環丙基}乙氧. 暴)本基]乙_ 氯嘧咬啶 _4·基]環·^ χρ 心 丁 4^ 0 n? tf , ' ----- β : 1S，2R)_(2-《2_[1_(5_甲基嘧咬_2_基)哌啶-4·基]環丙基}乙 仰·[1·(5·糊於綱 _%6_(2_{241_(5_ 甲基做·2·基)°祕4·基]環丙基} 141275.doc -12- 201102374 f f ^順式-6_(2]2-[i-(5-氣吡啶-2-基)哌咬-4_基]環丙基}乙氧基)-甲基嘧啶-4-甲腈 2 疋峨式_6-(2-{2-[1-(4,5-二-甲基嘲咬-2-基)略咬-4-基 氧基)-2-甲基略咬_4-甲暗 外讲古今 ill，_L· , ,Τ—--- --- 貝式心糾叫办氣斗甲基吡咬_2·基)哌咬_4·基]環丙基}乙 乳巷·)-2-甲基〇密咬_4_审陡 々1 '^v :---•々月 ‘ ^疋川負式_6·(2_{2-[ι·(5·氟_4_甲基癌咬_2_基)0底咬_4.基]環丙墓}乙 乳基)-2-甲基嘴咬_4_甲睹 ^ 式·2·曱基·6_[2-(2-{ 1-[5·(三氟甲基)吡啶-2-基]哌啶斗基} 氧基]嘧啶斗甲謄 式-5_亂-2_(4_{2-[2-(°比咬_3·基氧基)乙基]環丙基}〇底咬-1· 式〇-氣：(4-{2-[2十密啶-4-基氧基)乙基]環丙基}哌唆小_ 1 =^式-：)-(2-{2-[1-(5-氣嘧咬_2·基)哌咬冬基]環丙基}乙氧基） 於驗勝 巧^順式-6-(2-{2-[1_(5_氯嘧唆：基)哌咬_4_基]環丙基}乙氧基)_ 2-曱基嘧啶-4-甲腈 :卜f繁順式··4-(2-{2·[ι-(5-氣喷咬-2-基户底咬_4_基]環丙基}乙氧基}-6-曱基嘧啶-2-甲蹐 $ 順式冬糾2々-…氟嘴咬心基)旅咬斗基]環丙基}乙氧1)· 2-曱基嘧啶-4-甲腈 外消知順式氯嘧啶各基)哌啶斗基]環丙基}乙氧基） 吡咬-2-甲腈 外消旋順式-5-氯-2-(4-{2-[2-(。比啶-4-基氧基)乙基]環丙基}旅咬-1-基)嘴啶 基)環丙基]哌咬小基}嘧啶、5j_2_(1R，2SH4-[2-(2_{[5-(iH_l，2,3-三峻· 1-基)吡啶-2-基1氧基丨乙基)環丙基]哌咬_ 1_基}嘧啶 5_ 氯_2-[4_(( 1足25&gt;2_ (2_[3_ 氟冬(5_ 曱基_ 1，3,4-噁二唑·2·基)苯氧基] 乙基}環丙基)。底啶小基]嘧啶及5_氯-2-[4-((1«5,2/?)-2-{2-[3-1-4-(5-甲基-1,3,4-噁二唑-2-基)笨氣基1乙基}環丙基)哌啶-1-基]嘧啶 外消旋順式·5·氯-2-[4-(2·{2_[4_(1Η-1，2,3·***-1-基)笨氧基]乙基}環 丙基)哌啶-1-基]嘧啶、5-氯-2-[4-((以2及)-2-{2-[4-(1Η-1,2,3-三。坐-1-基)笨氧基]乙基}環丙基)娘啶-1·基]嘧啶及5-氯-2-[4-((1足2·5)-2-{2-[4-(1Η-1,2,3-***-1-基)笨氧基1乙基}環丙基)哌啶-1-基]嘧啶 5_氟-2-[4-((1尺2办2-{2-[4-(1沁1，2,3-***-1-基)苯氧基]乙基}環丙 基)农啶-1-基]嘧啶及 5-氟-2-[4-((1&amp;2Λ)-2-{2-[4_(1Η-1，2,3-三。坐 _1_ 基)笨氧基]乙基}環丙基)派啶-1-基]嘧啶141275.doc 201102374 外 疋!疋J1 贝式·5-Gas-2-[4-(2-{2_14_(111_1,2,3-Tri-Sit'5-yl)phenoxy]ethyl} per' Propyl) Niang °ding small base] pyrimidine outside 4-cyclocis-gas-2-14-(2·{2-[4-(1Η-tetradec-1-yl)phenyloxy]ethyl )) 口 啶 -1-yl]pyrimidine 7 racemic cis 〇-虱-2 leaf 4-〇{;2-1 1-trifluoro_4·(1Η-tetrazole_1 _yl)phenoxy] Ethyl}cyclopropyl)β bottom biting-1-yl] mouth biting, outer/xising cis*5-gas-2-[4-〇{2-[3-gas_4·(1Η-four saliva -ι_基)phenoxy]ethyl 衮 propyl) brigade bite - · base] mouth stern 4 slave shun -2 · 14-(2-{2-13 · fluoro _4 · (1 Η -四嗤·1_基) Stupid oxy]ethyl 裒 propyl) Ninja bite · 1 · base] · 5 - 曱 base pain bite shoulder rotation ^ type · 5 · gas -2- [4- (2 · {2-[4-(2Η-Tetrazol-2-yl)phenoxy]ethyl 裒 propyl) 旅 -1--1-yl]pyrimidine J Ϊ^Λ5Λ114_(2_{2_[4-(5·A -2-2H_四哇-2_yl)phenoxy]ethyl&gt; cyclopropyl)piperidin-1-yl 1 pyrimidine f methyl 四 ° _ _ _1 _1 _1 _1 _1 _1 _1 _1 _1 Ethyl}low propyl) dentate-1-yl]. Bite tfli1 s, 2R&gt;(2-{2_[4_(methyl succinyl)] oxy]ethyl}cyclopropyl> Piperazine bite 2_ base) 〇 bottom _4_ ]]cyclopropyl}ethoxy)-2-carbonitrile, 6-(1R,2S&gt;(2-{2_[1-(5i)-2-yl)pyridin-4-yl]cyclopropane }}ethoxy)-2-methylpyrimidine-4-carbonitrile cis·Η4·(2_{2-[1·(5-apyrimidine-2_i)piperidinyl]cyclopropyl}ethoxy.暴)本基]B_ 氯氯咬_4·基]环·^ χρ心丁4^ 0 n? tf , ' ----- β : 1S,2R)_(2-《2_[1_( 5_Methylpyrimidine_2_yl)piperidin-4·yl]cyclopropyl}Ethyl][1·(5·糊于纲_%6_(2_{241_(5_ 莫做·2·基°°4·基]cyclopropyl} 141275.doc -12- 201102374 ff ^cis-6-(2]2-[i-(5-apyridin-2-yl)piperidin-4_yl] ring Propyl}ethoxy)-methylpyrimidine-4-carbonitrile 2 疋峨6-(2-{2-[1-(4,5-di-methyl-trim-2-yl) slightly bite -4-yloxy)-2-methyl bite _4--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ·基)Pipolin _4·基]Cyclopropyl}Ethyl lactone·)-2-Methyl 〇 ____ 々 々 1 '^v :---•々月' ^疋川负式_6 ·(2_{2-[ι·(5·Fluoro_4_methylcarcinoma bite_2_base)0 bottom bite_4. base] ring propyl tomb} ethyl lactyl)-2-methyl mouth bite _4 _甲睹^ 式·2·曱基·6_[2-(2-{ 1-[5·(trifluoromethyl)pyridin-2-yl]piperidinyl}oxy]pyrimidine 5_乱-2_(4_{2-[2-(°Bite_3·yloxy)ethyl]cyclopropyl} 〇 bottom bite-1· 〇-gas: (4-{2-[2 Decidin-4-yloxy)ethyl]cyclopropyl}piperidine small _ 1 =^---)-(2-{2-[1-(5-aesthepyridin-2-yl)piperidin Bite winter base] cyclopropyl} ethoxy) in the test wins ^ ^ cis--6-(2-{2-[1_(5_ chloropyridinium: yl) piperidine _4_yl] cyclopropyl} Ethoxy) _ 2-mercaptopyrimidine-4-carbonitrile: b f complex cis type · 4-(2-{2·[ι-(5-gas squirting -2- base bottom bite _4_ Base] cyclopropyl}ethoxy}-6-mercaptopyrimidine-2-carbenium $ cis-style winter correction 2々-...fluorine mouth bite base) brigade bite base]cyclopropyl}ethoxy 1)· 2-Mercaptopyrimidine-4-carbonitrile, cis chloropyrimidine, piperidinyl]cyclopropyl}ethoxy), pyridine-2-carbonitrile, racemic cis-5-chloro- 2-(4-{2-[2-(. Bipyridin-4-yloxy)ethyl]cyclopropyl}Break-l-yl) propylidene)cyclopropyl]piperidinyl}pyrimidine, 5j_2_(1R,2SH4-[2-(2_{ [5-(iH_l,2,3-Trisyl-1-yl)pyridin-2-yl 1oxyindoleethyl)cyclopropyl]piperidin _ 1_yl}pyrimidine 5_ chloro-2-[4_(( 1 foot 25 &gt; 2_ (2_[3_fluorodong (5_ fluorenyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl). acridine small group] pyrimidine and 5 _Chloro-2-[4-((1«5,2/?)-2-{2-[3-1-4-(5-methyl-1,3,4-oxadiazol-2-yl) Stupid base 1 ethyl}cyclopropyl)piperidin-1-yl]pyrimidine racemic cis·5·chloro-2-[4-(2·{2_[4_(1Η-1,2,3) Triazol-1-yl) phenyloxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, 5-chloro-2-[4-((2)-2-{2-[ 4-(1Η-1,2,3-tris.-1-yl)phenyloxy]ethyl}cyclopropyl)nidanyl-1·yl]pyrimidine and 5-chloro-2-[4-(( 1 foot 2·5)-2-{2-[4-(1Η-1,2,3-triazol-1-yl)phenyloxy 1ethyl}cyclopropyl)piperidin-1-yl]pyrimidine 5-fluoro-2-[4-((1 ft 2 2-{2-[4-(1沁1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl) Acridine-1-yl]pyrimidine and 5-fluoro-2-[4-((1&amp;2Λ)-2-{2-[4_(1Η-1,2,3-three. sit_1_yl) oxy Ethyl]ethyl propyl)pyridin-1-yl]pyrimidine 141275.doc .13- 201102374 5_氯-2-[4-((1/?，2办2-{2-[4-( 1H-四唾-1 -基)苯氧基]乙基}環丙基)哌 啶-1-基 Η 啶及 5-氣-2-[4·((1&amp;2Λ)-2-{2-[4-(1Η-四唑-1-基)苯氧基]乙 基}環丙基)Β底咬-1-基]，咬 5_氯_2-[4_((1足2办2-{2-[3-氟-4-即-四唑-1-基)笨氧基]乙基}環丙 基户底咬-1-基]嘧啶及 5_ 氣-2-[4-((1\2/?)-2-{2-[3-氟-4·(1Η-四唑-1-基） 苯氧基]乙基}環丙基)《辰咬-1-基]嘴咬 5-氟-2-[4·((1 足 25&gt;2-{2-13-氟-4-(5-曱基-1,3,4-&quot;惡二唑-2-基)苯氧基] 乙基}環丙基)娘咬· 1 -基]嘧啶及5 -氣_2_ [4_(( 1幻及)·2_ {2- [3 -氟-4-(5 -曱基-1，3,4_σ惡一°坐-2-基)苯氧基]乙基}環丙基 &gt;辰咬_1_某]喊咬 外消旋順式-2-[4-(2-{2-[3-氟-4-(5-曱基-1,3,4-噁二唑-2-基)苯氧基] 乙基}環丙基)旅咬·1·基]·5-曱基Ρ密σ定 外消旋順式-2-[4-(2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基)笨氧基] 乙基}環丙基)哌咬-1-基]嘧啶 外消旋順式-5-氟-2-L4-(2-{2-[3-氟-4-(5-甲基-1，3,4-噁二唑-2-基)苯氧 基]乙基}環丙基)娘啶-1-基]嘧啶 外消旋順式-5-氣-2-[4·(2·{2·[3·氟-4·(5-曱基-1，3,4-噁二唑-2_基)苯氧 基]乙基}環丙基)Π辰咬-1-基]_4·甲基σ密咬 外消旋 W負式·；3，ί)-二氣-2-|_4-(2- {2- [3 -1-4-(5-曱基 1,3，4- °惡二嗤-2-基） 笨氧基1乙基}環丙基)哌咬-1-基1吡啶 外消旋順式-2-[4·(2-{2·[3-民-4-(5-曱基-1,3,4-°惡二峻-2-基)苯氧基] 乙基}環丙基)°底咬-1-基]-5-(三氟甲基&gt; 比淀銪=氟乙酸鹽 外消旋順式-5-氣-2-{4-[(2-{[4-(f基磺醯基)苯氧基]甲基}環丙基)甲 基&gt;辰啶-l-基}嘧啶 外消旋順式-4-[(2-{[l-(5-氣嘧咬-2-基)哌啶-4-基]甲基}環丙基)甲氧 基]-N-環丙基-2-氟苯甲醯胺 外消旋順式-4-[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]甲基}環丙基)曱氧 基]-6-甲基嘧啶-2-甲腈 外消旋順式-4_[(2-{[l-(5-氯嘧啶-2-基)哌啶-4-基]甲基}環丙基)甲氧 基]_2-氟苯曱腈 ------ -- ' ' 1 — -_ ...___ 或其醫藥學上可接受之鹽。 19_ 一種化合物’其係選自由以下各物組成之群： 141275.doc -14- 201102374 0_) 〇~1 0 % \ 5-氣-2-{4-[(17?，25^)-2-(2-{[5-(曱基續臨 基)吡啶-2-基]氧基}乙基)環丙基]哌啶-1-基}嘧啶 2-甲基-6-(2-{(1*9,2；?)-2-[1-(5-甲基嘧啶- 2-基)喻&gt;淀-4-基]環丙基}乙乳基)°¾淀-4-曱腈 v&quot;.…〇Λ^α /=( J Μ P a N Η 0 5-氣-2-[4-((17?,2S)-2-{2-[4-(l/M，2,3-三 唑-1 -基)苯氧基]乙基}環丙基)略啶-1 -基]p密咬 5-氯-2-{4-[(1 足 25)-2-(2-{[5-(1/ί-1,2,3-三 °坐-1-基)。比咬-2-基]氧基}乙基)¾丙基] 派淀小基}°密咬 或其醫藥學上可接受之鹽。 20. —種醫藥組合物，其包含如請求項1之化合物或其醫藥 學上可接受之鹽以及醫藥學上可接受之載劑。 21. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，為需要此治療之哺乳動物患者 治療高血糖症、糖尿病或胰島素抗性。 22. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，為需要此治療之哺乳動物患者 治療2型糖尿病。 23. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 141275.doc -15- 201102374 治療之哺乳動物患者 途，其係用於製造藥物，為需要此 治療非胰島素依賴性糖尿病。 24. 25. 26. 27. 28. 或其醫藥學上可接受之鹽的用 為需要此治療之哺乳動物患者 一種如請求項1之化合物 途’其係用於製造藥物， 治療肥胖症。 、種如凊求項1之化合物或其醫藥學上可接受之鹽的用 途/、係用於製造藥物’為需要此治療之哺乳動物患者 治療症候群X。 種如4求項1之化合物或其醫藥學上可接受之鹽的用 途’其係用於製造藥物，為需要此治療之哺乳動物患者 …療選自由血脂異常、高脂血症' 高三酸甘油酯血症、 高膽固醇血症、低HDL及高LDL組成之群的脂質病症。 一種如請求項丨之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，為需要此治療之哺乳動物患者 治療動脈粥樣硬化。 一種如請求項1之化合物或其醫藥學上可接受之鹽的用 途’其係用於製造藥物’為需要此治療之哺乳動物患者 治療選自由以下病狀組成之群的病狀：（1)高血糖症、 (2)葡萄糖耐量異常、（3)騰島素抗性、（句肥胖症、（5)脂 質病症、（6)血脂異常' (7)高脂血症' (8)高三酸甘油酯 血症、（9)高膽固醇血症、（1〇)低HDL含量、（11)高Ldl 含量、（12)動脈粥樣硬化及其續發症、（13)血管再狹 窄、（14)胰腺炎、（15)腹部肥胖症、（16)神經退化性疾 病、（17)視網膜病、（18)腎病、（19)神經病、（20)症候群 141275.doc .16- 201102374 X、（21)高血壓及其他以胰島素抗性為組成部分之病狀及 病症。 種如Μ求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，為有需要之哺乳動物患者延遲 選自由以下病狀組成之群的病狀發作：（1)高血糖症、 (2)葡萄糖耐量異常、（3)胰島素抗性、（4)肥胖症、（5)脂 貝病症（6)血脂異常、（7)高脂血症、（8)高三酸甘油酯 血症、（9)兩膽固醇血症、（1〇)低HDL含量、（11)高Ldl 3量、（12)動脈粥樣硬化及其續發症、（丨3)血管再狹 乍（14)胰腺炎、（15)腹部肥胖症、（16)神經退化性疾 病、（17)視網膜病、（18)腎病、（19)神經病、（2〇)症候群 X、（21)高血壓及其他以胰島素抗性為組成部分之病狀及 病症。 3〇· —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，為有需要之哺乳動物患者降低 發展出選自由以下病狀組成之群的病狀之風險：〇)高血 糖症、（2)葡萄糖耐量異常、（3)胰島素抗性、（4)肥胖 症、（5)脂質病症、（6)血脂異常、高脂血症、高三 酸甘油酯血症、（9)高膽固醇血症、（1〇)低HDL含量、 (11)高LDL含量、（12)動脈粥樣硬化及其續發症、（13)血 管再狹窄、（14)胰腺炎、（15)腹部肥胖症' 〇6)神經退化 性疾病、（17)視網膜病、（18)腎病、（19)神經病、（2〇)症 候群X、（21)高血壓及其他以胰島素抗性為組成部分之病 狀及病症。 r 141275.doc _ 17_ 201102374 31. 一種如請求項1之化合物或盆醫 / 、請樂予上可接受之鹽的用 途’其係用於製造藥物，供鱼遠6 供興選自由以下各物組成之群 的化合物組合： (a) DP-IV抑制劑； (b) 選自由（i)PPAR促效劑及n(r』 叹双d及（u)雙胍類組成之群的胰島 素致敏劑； (c) 胰島素及胰島素模擬劑； (d) 磺醯脲類及其他胰島素促分泌素； (e) α-葡糖苷酶抑制劑； (0升糖素受體拮抗劑； (g) GLP-1、GLP-1模擬劑&amp;GLIM受體促效劑； (h) GIP、GIP模擬劑及GIP受體促效劑； (1) PACAP、PACAP模擬劑及pACAp受體3促效劑； (j) 選自由以下各物組成之群的降膽固醇劑： (i) HMG-CoA還原酶抑制劑，（丨丨）鰲合劑，（丨丨丨）於 醇、於酸及其鹽’（iv) PPARo^效劑，（ν) ρρΑΚα/γ 雙重促效劑’（vi)膽固醇吸收抑制劑，（vii)醯基 CoA :膽固醇酿基轉移酶抑制劑，及（vHi)抗氧化 劑； (k) PPARS促效劑； (l) 抗肥胖化合物； (m) 回腸膽酸轉運體抑制劑； (η)除糖皮質激素以外之消炎劑； (〇)蛋白質酪胺酸磷酸酶-1Β(ΡΤΡ_1Β)抑制劑；及 141275.doc • 18- 201102374 (p)抗高血壓劑’包括作用於血管收縮素或腎素系統 之抗南血壓劑’諸如血管收縮素轉化酶抑制劑、血管收 縮素II受體拮抗劑或腎素抑制劑，諸如卡托普利 (captopril)、西拉普利（Ciiazapril)、依那普利（enalapH1) ' 福辛普利（fosinopril)、賴諾普利（lisin〇pril)、喹那普利 (quinapril) _ 米普利（ramapril)、佐芬普利（zofenopril)、 坎地沙坦（candesartan)、西來替昔（cilexetil)、依普羅沙 坦（eprosartan)、伊貝沙坦（irbesartan)、洛沙坦（1〇sartan)、 他索沙坦（tasosartan)、替米沙坦（telmisartan)及纈沙坦 (valsartan)； 為需要該治療之哺乳動物患者治療選自由以下病狀組 成之群的病狀：（1)高血糖症、（2)葡萄糖耐量異常、（3) 胰島素抗性、（4)肥胖症、脂質病症、（6)也脂異常、 (7)向脂血症、（8)高三酸甘油酯血症、（9)高膽固醇血 症' (10)低HDL含量、（11)高]^^含量、（12)動脈粥樣硬 化及其續發症、（13)血管再狹窄、（14)胰腺炎、（15)腹部 肥胖症、（16)神經退化性疾病、（17)視網膜病、（18)腎 病、（19)神經病、（20)症候群X、（21}高血壓及其他以騰 島素抗性為組成部分之病狀及病症。 32. 一種如請求項1之化合物或其醫藥學上可接受之鹽的用 途’其係用於製造藥物，供與HMG-CoA還原酶抑制劑組 合，為需要該治療之哺乳動物患者治療選自由高膽固醇 血症、動脈粥樣硬化、低HDL含量、高LDL含量、高脂 血症、高三酸甘油酯血症及血脂異常組成之群的病狀。 141275.doc 19 201102374 33. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，供與呈士他汀（statin)形式之 HMG-CoA還原酶抑制劑組合，為需要該治療之哺乳動物 患者治療選自由高膽固醇血症、動脈粥樣硬化、低HDL 含量、高LDL含量、高脂血症、高三酸甘油酷血症及血 脂異常組成之群的病狀。 3 4.如請求項3 1之用途，其中該士他汀係選自由洛伐他汀 (lovastatin)、辛伐他汀（simvastatin)、普伐他丁（pravastatin)、 氟伐他、;丁（fluvastatin)、阿托伐他汀（atorvastatin)、伊伐 他 丁（itavastatin)、ZD-4522 及瑞伐他、;丁（rivastatin)組成 之群。 3 5. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，供與HMG-CoA還原酶抑制劑組 合，降低發展出選自由高膽固醇血症、動脈粥樣硬化、 低HDL含量、高LDL含量、高脂血症、高三酸甘油自旨血 症及血脂異常及該等病狀之續發症組成之群的病狀之風 險。 3 6. —種如請求項1之化合物或其醫藥學上可接受之鹽的用 途，其係用於製造藥物，供與呈士他汀形式之HMG-CoA 還原酶抑制劑組合，為需要該治療之人類患者延遲動脈 粥樣硬化發作或降低發展出動脈粥樣硬化之風險。 3 7.如請求項34之用途，其中該士他汀係選自由洛伐他汀、 辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、伊伐他 汀、ZD-4522及瑞伐他汀組成之群。 141275.doc -20- 201102374 38. —種如請求項丨之化合物或其醫藥學上可接受之鹽的用 途’其係用於製造藥物’供與膽固醇吸收抑制劑組合， 為需要該洽療之人類患者治療動脈粥樣硬化、延遲其動 脈粥樣硬化發作或降低其發展出動脈粥樣硬化之風險。 、，月求項3 8之用途，其中該膽固醇吸收抑制劑為依澤替 米貝（ezetimibe)。 40· —種醫藥舨合物，其包含： (1) 如請求項1之化合物或其醫藥學上可接受之鹽； (2) 選自由以下各物組成之群的化合物： (a) DP-IV抑制劑； (b) 選自由⑴ppar促效劑及（Η)雙胍類組成之群的 姨島素致敏劑； 0)胰島素及胰島素模擬劑； (d)磺醯脲類及其他胰島素促分泌素； Ο) α-葡糖苷酶抑制劑； (0升糖素受體拮抗劑； (g) GLP-1、GLP-1模擬劑及见卩」受體促效劑； (h) GIP、GIP模擬劑及GIP受體促效劑； (i) PACAP、PACAP模擬劑及PACAP受體3促效 劑； (j) 選自由以下各物組成之群的降膽固醇劑：⑴ HMG-CoA還原酶抑制劑，（ii)鰲合劑，（出）菸醇、菸酸或 其鹽，（iv) PPARa促效劑，⑺pPARa/Y雙重促效劑， (vi)膽固醇吸收抑制劑，（vii)醯基c〇A :膽固醇醯基轉移 r 141275.doc Λ1 201102374 酶抑制劑，及（viii)抗氧化劑； (k) PPAR5促效劑； (l) 抗肥胖化合物； (m) 回腸膽酸轉運體抑制劑； (η)除糖皮質激素以外之消炎劑； (〇)蛋白質酪胺酸磷酸酶-IB(PTP-IB)抑制劑；及 (P)抗高血壓劑，包括作用於血管收縮素或腎素系 統之抗高血壓劑，諸如血管收縮素轉化酶抑制劑、血管 收縮素II文體拮抗劑或腎素抑制劑，諸如卡托並利 拉普利、依那普利、福辛普利、賴諾普利、喹那普西 雷来普利、佐芬普利、坎地沙坦、西來替音、依二:、 :::貝沙坦、洛沙坦、他索沙坦1米沙坦及：: (3)醫藥學上可接受之載劑 141275.doc 22· 201102374 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：141275.doc .13- 201102374 5_Chloro-2-[4-((1/?,2) 2-{2-[4-( 1H-tetras-l-yl)phenoxy]ethyl} ring Propyl)piperidin-1-ylindole and 5-gas-2-[4·((1&amp;2Λ)-2-{2-[4-(1Η-tetrazol-1-yl)phenoxy] Ethyl}cyclopropyl) Β bottom bite-1-yl], bite 5_chloro_2-[4_((1 foot 2 to 2-{2-[3-fluoro-4- ie-tetrazole-1- Alkyl]ethyl}cyclopropyl-based ketone-1-yl]pyrimidine and 5-formaldehyde-2-[4-((1\2/?)-2-{2-[3-fluoro-4 ·(1Η-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl) "Chenbite-1-yl" mouth bite 5-fluoro-2-[4·((1 foot 25&gt;2-{ 2-13-fluoro-4-(5-fluorenyl-1,3,4-&quot;oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)nipine bite 1 -yl]pyrimidine and 5 - gas_2_ [4_((1幻和)·2_ {2- [3 -Fluoro-4-(5-mercapto-1,3,4_σ 一一° sit-2-yl)phenoxy]B }}cyclopropyl> 辰 bit _1_ some] shout biting racemic cis-2-[4-(2-{2-[3-fluoro-4-(5-mercapto-1,3, 4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl) brigade bit ·1·yl]·5-mercaptopurine σ deterministic racemic cis-2-[4-(2 -{2-[3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyloxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine Racemic cis-5-fluoro-2-L4-(2-{2-[ 3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)nidanyl-1-ylpyrimidine racemic cis -5-Gas-2-[4·(2·{2·[3·Fluoro-4·(5-mercapto-1,3,4-oxadiazol-2-yl)phenoxy]ethyl} Cyclopropyl)Π辰咬-1-yl]_4·Methyl σ-Bite Racer W Negative ·3, ί)-Digas-2-|_4-(2- {2- [3 -1 4-(5-fluorenyl 1,3,4-°oxadiazin-2-yl) phenyloxy 1 ethyl}cyclopropyl)piperidin-1-yl 1 pyridine racemic cis-2- [4·(2-{2·[3-Min-4-(5-fluorenyl-1,3,4-°cadio-2-yl)phenoxy]ethyl}cyclopropyl) Bite-1-yl]-5-(trifluoromethyl) 比 铕 = fluoroacetate racemic cis-5-gas-2-{4-[(2-{[4-(f-sulfonate) Mercapto)phenoxy]methyl}cyclopropyl)methyl&gt; henidine-l-yl}pyrimidine racemic cis-4-[(2-{[l-(5-a pyridine)-2 -yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-N-cyclopropyl-2-fluorobenzamide A racemic cis-4-[(2-{[l -(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)decyloxy]-6-methylpyrimidine-2-carbonitrile racemic cis-4_[(2 -{[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]_2-fluorobenzonitrile- -- ' ' 1 — -_ ...___ or a pharmaceutically acceptable salt thereof. 19_ A compound' is selected from the group consisting of: 141275.doc -14- 201102374 0_) 〇~1 0 % \ 5-气-2-{4-[(17?,25^)-2- (2-{[5-(indolyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine 2-methyl-6-(2-{( 1*9,2;?)-2-[1-(5-Methylpyrimidin-2-yl)Yu>Precipitated 4-yl]cyclopropyl}ethylidyl)°3⁄4 v&quot;....〇Λ^α /=( J Μ P a N Η 0 5-气-2-[4-((17?,2S)-2-{2-[4-(l/M,2, 3-triazol-1 -yl)phenoxy]ethyl}cyclopropyl)l-l-yl-1 -yl]p-biti 5-chloro-2-{4-[(1)25-2-(2) -{[5-(1/ί-1,2,3-三°坐-1-yl). Bite-2-yl]oxy}ethyl)3⁄4 propyl] Derivatized small base}°Bite Or a pharmaceutically acceptable salt thereof. 20. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hyperglycemia, diabetes or insulin resistance in a mammalian subject in need of such treatment. 1 Use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of type 2 diabetes in a mammalian patient in need of such treatment. 23. A compound of claim 1 or a pharmaceutically acceptable compound thereof The accepted salt is administered to a mammalian patient treated with 141275.doc -15-201102374, which is used in the manufacture of a drug for the treatment of non-insulin dependent diabetes. 24. 25. 26. 27. 28. or its medicine An acceptable salt for use in a mammalian patient in need of such treatment is a compound of claim 1 which is used in the manufacture of a medicament for the treatment of obesity. A compound such as a compound of claim 1 or a pharmaceutically acceptable compound thereof Use of the salt accepted / for the manufacture of a drug 'is a therapeutic syndrome X for a mammalian patient in need of such treatment. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof' is used in the manufacture The drug, which is a mammalian patient in need of such treatment, is treated with a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL. A use of a compound of claimant or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of atherosclerosis in a mammalian subject in need of such treatment. A compound of claim 1 or a medicament thereof Use of a scientifically acceptable salt 'is used in the manufacture of a medicament' for treating a mammalian patient in need of such treatment for a condition selected from the group consisting of: (1) hyperglycemia, (2) abnormal glucose tolerance (3) Tennessin resistance, (sentence obesity, (5) lipid disorder, (6) dyslipidemia (7) hyperlipidemia (8) hypertriglyceridemia, (9) high cholesterol Blood, (1) low HDL, (11) high Ldl, (12) atherosclerosis and its continuation, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity , (16) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome 141275.doc .16- 201102374 X, (21) hypertension and other insulin resistance The symptoms and conditions of the component. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for delaying the onset of a condition selected from the group consisting of: (1) ) Hyperglycemia, (2) Abnormal glucose tolerance, (3) Insulin resistance, (4) Obesity, (5) Absinoid disease (6) Dyslipidemia, (7) Hyperlipidemia, (8) Triglyceride Glycerolemia, (9) hypercholesterolemia, (1) low HDL content, (11) high Ldl 3 amount, (12) atherosclerosis and its continuation, (丨3) vascular re-narrowness (14) Pancreatitis, (15) Abdominal obesity, (16) Neurodegenerative diseases, (17) Retinopathy, (18) Nephropathy, (19) Neuropathy, (2〇) Syndrome X, (21) Hypertension and Other conditions and conditions that are characterized by insulin resistance. 3. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the reduction of the development of a disease selected from the group consisting of the following conditions for a mammalian patient in need thereof Risks: 〇) hyperglycemia, (2) impaired glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, hyperlipidemia, high triglycerides Esteremia, (9) hypercholesterolemia, (1) low HDL, (11) high LDL, (12) atherosclerosis and its continuation, (13) vascular restenosis, (14) Pancreatitis, (15) Abdominal obesity '〇6) Neurodegenerative diseases, (17) Retinopathy, (18) Nephropathy, (19) Neuropathy, (2〇) Syndrome X, (21) Hypertension and other insulin Resistance is a component of the condition and condition. r 141275.doc _ 17_ 201102374 31. A compound of claim 1 or a pelvic doctor/, please use a salt acceptable for the use of 'these' for the manufacture of a drug, for the fish to be selected from the following a combination of compounds consisting of: (a) a DP-IV inhibitor; (b) an insulin sensitizer selected from the group consisting of (i) PPAR agonists and n(r) singly d and (u) biguanides (c) insulin and insulin mimics; (d) sulfonylureas and other insulin secretagogues; (e) alpha-glucosidase inhibitors; (glucagon receptor antagonists; (g) GLP- 1. GLP-1 mimetic &amp; GLIM receptor agonist; (h) GIP, GIP mimetic and GIP receptor agonist; (1) PACAP, PACAP mimetic and pACAp receptor 3 agonist; j) Choose a cholesterol-lowering agent from the group consisting of: (i) HMG-CoA reductase inhibitor, (丨丨) chelating agent, (丨丨丨) in alcohol, in acid and its salt '(iv) PPARo, (ν) ρρΑΚα/γ dual agonist'(vi) cholesterol absorption inhibitor, (vii) sulfhydryl-based CoA: cholesterol basal transferase inhibitor, and (vHi) antioxidant (k) PPARS agonist; (l) anti-obesity compounds; (m) ileal cholic acid transporter inhibitors; (η) anti-inflammatory agents other than glucocorticoids; (〇) protein tyrosine phosphatase-1Β (ΡΤΡ_1Β) Inhibitors; and 141275.doc • 18- 201102374 (p) Antihypertensive agents 'including anti-Southern blood pressure agents acting on angiotensin or renin system, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonist or renin inhibitor, such as captopril, Ciiazapril, enalapH1 'fosinopril, lisinopril 〇pril), quinapril _ mamapri (ramapril), zofenopril, candesartan, cilexetil, eprosartan Irbesartan, losartan (1 sartan), tasosartan, telmisartan, and valsartan; treatment options for mammals in need of such treatment Symptoms of a group consisting of the following conditions: (1) hyperglycemia, (2) Glucose tolerance abnormality, (3) insulin resistance, (4) obesity, lipid disease, (6) abnormal lipid, (7) lipemia, (8) hypertriglyceridemia, (9) high Cholesterolemia (10) low HDL content, (11) high]^^ content, (12) atherosclerosis and its continuation, (13) vascular restenosis, (14) pancreatitis, (15) abdomen Obesity, (16) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X, (21) hypertension, and other components that are resistant to tensin Symptoms and conditions. 32. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with an HMG-CoA reductase inhibitor for the treatment of a mammalian patient in need of such treatment Symptoms of a group consisting of hypercholesterolemia, atherosclerosis, low HDL content, high LDL content, hyperlipidemia, hypertriglyceridemia, and dyslipidemia. 141275.doc 19 201102374 33. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibition with HMG-CoA reductase in the form of statin Combination of agents for treating a mammalian patient in need of such treatment from a group consisting of hypercholesterolemia, atherosclerosis, low HDL content, high LDL content, hyperlipidemia, hypertriglyceridemia, and dyslipidemia Symptoms. 3. The use of claim 3, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, fluvastatin, A group of atorvastatin, itavastatin, ZD-4522, and rivastatin; rivastatin. 3. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with an HMG-CoA reductase inhibitor, which is reduced in development from hypercholesterolemia Risk of atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, dyslipidemia, and the continuum of these conditions. 3. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a Herstatin form of an HMG-CoA reductase inhibitor, in need of such treatment Human patients delay the onset of atherosclerosis or reduce the risk of developing atherosclerosis. 3. 7. The use of claim 34, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, ivavastatin, ZD-4522 and revastatin. Group. 141275.doc -20- 201102374 38. The use of a compound of the claim or a pharmaceutically acceptable salt thereof for the manufacture of a drug for use in combination with a cholesterol absorption inhibitor, in need of such treatment Human patients treat atherosclerosis, delay their onset of atherosclerosis or reduce their risk of developing atherosclerosis. The use of the monthly solution 38, wherein the cholesterol absorption inhibitor is ezetimibe. 40. A pharmaceutical composition comprising: (1) a compound according to claim 1 or a pharmaceutically acceptable salt thereof; (2) a compound selected from the group consisting of: (a) DP- IV inhibitors; (b) Free (1) ppar agonist and (Η) bismuth-based group of sensitizers; 0) insulin and insulin mimics; (d) sulfonylureas and other insulin-promoting ;) α-glucosidase inhibitor; (0 glucosamine receptor antagonist; (g) GLP-1, GLP-1 mimetic and see 受体 receptor agonist; (h) GIP, GIP Mimetic and GIP receptor agonist; (i) PACAP, PACAP mimetic and PACAP receptor 3 agonist; (j) Free cholesterol lowering agents selected from the following groups: (1) HMG-CoA reductase inhibition Agent, (ii) chelating agent, (out) nicotinol, nicotinic acid or its salt, (iv) PPARa agonist, (7) pPARa/Y dual agonist, (vi) cholesterol absorption inhibitor, (vii) thiol c 〇A: cholesterol thiol transfer r 141275.doc Λ1 201102374 enzyme inhibitor, and (viii) antioxidant; (k) PPAR5 agonist; (l) anti-obesity compound; (m) ileal cholic acid Transport inhibitors; (η) anti-inflammatory agents other than glucocorticoids; (〇) protein tyrosine phosphatase-IB (PTP-IB) inhibitors; and (P) antihypertensive agents, including vasoconstriction An anti-hypertensive agent of the rennin or renin system, such as an angiotensin-converting enzyme inhibitor, an angiotensin II morphosome antagonist or a renin inhibitor, such as captopril, enalapril, fosinopril Lili, lisinopril, quinapril, zoproxil, zofenopril, candesartan, cilostatin, y:2, ::: besartan, losartan, hesolartan 1 mirsartan and:: (3) pharmaceutically acceptable carrier 141275.doc 22· 201102374 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The components of the representative figure Brief description of the symbol: 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 141275.doc141275.doc